Thidiazuron Human Health Risk Assessment DP No. 0424978 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, O.C. 20460 

MEMORANDUM 

Date: June 9, 2015 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Thidiazuron: Human Health Combined Scoping Document and Draft Risk 

Assessment for Registration Review. D424978. 

PC Code: 12030 I 

Decision No.: 498947 

Petition No.: NA 

Risk Assessment Type: Single Chemical 

Aggregate 

TXR No.: NA 

MRID No.: NA 

DP Barcode: 0424978 

Registration No.: NA 

Regulatory Action: Registration Review 

Case No.: 4092 

CAS No.: 51707-55-2 

40 CFR: § 180.412 

FROM: Ronnie J. Bever Jr., PhD, DABT; Risk Asse~or/ j · ~ ;. 

ldeliz Negr6n-Encarnaci6n, PhD, Chemist !()~ 

Alexandra Gavelek, Biologist .; I ,,CJ~ L 0_ Ct 

Risk Assessment Branches V and VII (RAB V N II) 

Health Effects Division (I IED; 7509P) 

THROUGH: Michael S. Metzger, Chief, RAB VNII r. I ;J /} ). /Id 

HED (7509P) f( tlft-~ ' 

TO: Khue Nguyen/Thomas Moriarty, Risk Manager 

Risk Management and Implementation Branch J 

Pesticide Re-evaluation Division 

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Thidiazuron Human Health Risk Assessment DP No. D424978 

Table of Contents 

1.0 Executive Sum1nary ............................... ...................... .................. ...................................... 4 

2.0 HED Recom1nendations ................................. ...................................................................... 6 

2.1 Data Deficiencies/Conditions of Registration and Re-Registration ................................. 6 

2.2 Tolerance Considerations ....................................... .......................................................... 7 

2.2.1 Enforcement Analytical Method ............................................................................... 7 

2.2.2 Recommended Tolerances ........................................................................................ 7 

2.2.3 International Harmonization ..................................................................................... 9 

2.3 Label Recommendations .................................................................................................. 9 

2.3 .1 Recommendations from Residue Reviews ............................................................... 9 

2.3.2 Recommendations from Occupational Assessment. ................................................. 9 

3.0 Introduction .......................................................................................................................... 9 

3.1 Chen1ical Identity .......................... ............. ........ .............................................................. 9 

3 .2 Physical/Chemical Characteristics ................................................................................. I 0 

3.3 Pesticide Use Pattern ...................................................................................................... 10 

3.4 Anticipated Exposure Pathways ..................................................................................... l 0 

3 .5 Consideration of Environmental Justice ........................................................................ 10 

4.0 Hazard Characterization and Dose-Response Assessment.. .............................................. 1 l 

4.1 Toxicology Studies Available for Analysis ................................................................... 11 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) ................................... l l 

4.2.1 D.ennal Absorption ................ ........ .......................................................................... 12 

4.3 Toxicological Effects ..................................................................................................... 12 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ................................ ....... 13 

4.4.1 Completeness of the Toxicology Database ............................................................. 13 

4.4.2 Evidence of Neurotoxicity ........................ .............................................................. 14 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ......... 14 

4.4.4 Residual Uncertainty in the Exposure Database ..................................................... 14 

4.5 Toxicity Endpoint and Point of Departure Selections ....................................................... 14 

4.5.1 Dose-Response Assessment .................................................................................... 14 

4.5.2 Reconunendation for Combining Routes of Exposures for Risk Assessment. ....... l 6 

4.5.3 Cancer Classification and Risk Assessment Recommendation .. ............................ 16 

4.5.4 Summary of Points of Departure and Toxicity Endpoints ...................................... 16 

4.6 Endocrine Disruption ..................................................................................................... 17 

5.0 Dietary Exposure and Risk Assessment ............................................................................ 18 

5.1 Residues of Concern Summary and Rationale ........................................................ 18 

5.2 food Residue Profile .. .................................................................................................... 19 

5.3 Water Residue Profile .................................................................................................... 20 

5.4 Dietary Risk Assessment ................................................................................................ 20 

5.4. l Description o[ Residue Data Used in Dietary Assessment.. ................................... 20 

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5.4.2 Percent Crop Treated Used in Dietary Assessment ................................................ 20

5.4.3 Acute Dietary Risk Assessment.............................................................................. 20

5.4.4 Chronic Dietary Risk Assessment .......................................................................... 20

5.4.5 Cancer Dietary Risk Assessment............................................................................ 20

5.4.6 Summary Table....................................................................................................... 20

6.0 Residential (Non-Occupational) Exposure/Risk Characterization .................................... 21

6.1 Residential Bystander Post-application Inhalation Exposure ........................................ 21

6.2 Spray Drift...................................................................................................................... 21

7.0 Aggregate Exposure/Risk Characterization....................................................................... 23

7.1 Acute Aggregate Risk .................................................................................................... 23

7.2 Short-Term Aggregate Risk ........................................................................................... 24

7.3 Intermediate- and Long-Term Aggregate Risk .............................................................. 24

7.4 Long-Term Aggregate Risk ........................................................................................... 24

7.5 Cancer Aggregate Risk................................................................................................... 24

8.0 Cumulative Exposure/Risk Characterization..................................................................... 24

9.0 Occupational Exposure/Risk Characterization ....................................................................... 24

9.1 Short-/Intermediate-Term Handler Risk............................................................................. 24

9.2 Short-/Intermediate-Term Post-Application Risk .......................................................... 26

9.2.1 Dermal Post-Application Risk ....................................................................................... 26

9.2.2 Inhalation Post-Application Risk ................................................................................... 26

10.0 Incident Report............................................................................................................... 27

11.0 References.......................................................................................................................... 29

Appendix A. Toxicology Profile and Executive Summaries....................................................... 31

A.1 Toxicology Data Requirements...................................................................................... 31

A.2 Toxicity Profiles............................................................................................................. 32

A.3 Hazard Identification and Endpoint Selection ............................................................... 36

A.4 Executive Summaries..................................................................................................... 38

Appendix B. International Residue Limits Table ........................................................................ 53

Appendix C. Metabolites............................................................................................................. 54

Appendix D. Physical/Chemical Properties................................................................................. 54

Appendix E. Review of Human Research ................................................................................... 55
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1.0 Executive Summary

As part of Registration Review, the Pesticide Re-evaluation Division (PRD) of the Office of 

Pesticide Program (OPP) has requested that the Health Effects Division (HED) evaluate the 

hazard and exposure database and conduct dietary, and occupational and residential exposure 

assessments, as needed, to estimate the risk to human health that will result from the currently 

registered uses of thidiazuron. This memorandum serves both as HED’s Draft Registration 

Review risk assessment of the currently registered uses of thidiazuron and obviates the need for a 

separate scoping document. 

Thidiazuron (N-phenyl-N′-1,2,3-thiadiazol-5-ylurea) is a phenylurea herbicide used for the 

defoliation of cotton. In cotton, thidiazuron defoliates green leaves and immature fruiting 

structures. Thidiazuron can be applied by ground or air to late season cotton. The registered 

formulations include wettable powders (WP) in water-soluble bags (WSB), soluble concentrates 

(SC), emulsifiable concentrates (EC), and liquids. 

The chronic toxicity studies in rats and mice show that thidiazuron caused decreased body 

weights, body weight gains, and/or food consumption; adverse effects on the kidney and male 

reproductive system were also noted. Similar effects were also noted in the subchronic rat study. 

In the subchronic mouse study, only marginal effects were noted at the mid-dose, whereas all 

mice died at the high dose. Anemia and marked hemosiderosis in liver and spleen were apparent 

in the chronic dog study. 

The data from the developmental toxicity studies in rat suggested a quantitative susceptibility to 

fetuses. The only finding was a similar decrease in body weight in both dams and fetuses; 

however, the marginal effect in the fetus is a concern. There was no increased quantitative or 

qualitative susceptibility observed for rabbit fetuses, and the point of departure in the rabbit 

developmental study is protective for all effects noted in the rat developmental and 

reproduction studies. In the rabbit developmental study, maternal effects included abortions and 

decreased food consumption and body weight gain. Similarly, body weights were decreased in 

the fetuses; more runts and delayed skeletal ossification were observed, in addition to the 

abortions. Reproductive toxicity was conservatively set based on a delay of 3 days in vaginal 

opening; no adverse effects were noted on parental or offspring toxicity.

Dermal toxicity was not observed at the limit dose in a 28-day dermal study in rats. Dermal 

absorption is extremely limited to 1% or less. No definitive evidence of neurotoxicity was

reported in any of the submitted studies. Carcinogenicity studies in both rats and mice produced

no treatment-related increase in tumor incidence. The standard battery of genotoxicity tests was

negative. 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 nor a skin irritant.

Based on the toxicity, duration of exposure, and uses of thidiazuron, the following toxicity 

endpoints were selected: 
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Acute dietary (all populations): Not required.

Chronic dietary (all populations): chronic PAD (cPAD) = 0.0393 mg/kg/day derived 

from a NOAEL of 3.93 mg/kg/day in a chronic dog 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.

Incidental oral exposures (short- and intermediate-term): NOAEL = 25 mg/kg/day 

in a developmental study in rabbit. LOAEL = 125 mg/kg/day based on abortions.

Dermal (short- and intermediate-term): No point of departure was determined, as a 

hazard was not identified.

Inhalation (short- and intermediate-term): NOAEL = 25 mg/kg/day in a 

developmental study in rabbit. LOAEL = 125 mg/kg/day based on abortions.

For the occupational and residential risk assessments, the level of concern (LOC) is for MOEs 

less than 100. The FQPA safety factor has been reduced to 1X since the database is complete, 

concern for quantitative susceptibility is low due to the marginal endpoints of fetal toxicity (7% 

decrease in fetal body weight; 6% in dams) and 3-day delay in vaginal opening, points of 

departure are protective in the fetus and offspring, and exposure estimates are not likely to 

underestimate risk.

The residue chemistry database for thidiazuron is incomplete but adequate to support registration 

review. Tolerances are established in the 40 CFR 180.403 for residues of thidiazuron in/on 

cotton and livestock commodities. The tolerance expression needs to be modified according to 

the residue of concern definition, and the interim guidance for writing tolerance expressions. 

Adequate enforcement methods for plant and livestock commodities are available; however, 

radio-validation data for the tolerance enforcement method in livestock commodities was not 

submitted and is still required. Based on the results of storage stability studies, the residue data 

for thidiazuron was reevaluated. A tolerance of 0.5 ppm is recommended for cotton un-delinted 

seed, 1.5 ppm for cotton hulls, and 30 ppm for cotton gin byproducts. A reevaluation of the 

secondary residues of thidiazuron on livestock commodities show that the current tolerance 

levels are adequate. There are no Canadian, Mexican or Codex maximum residue limits (MRLs)

established or proposed for residues of thidiazuron. Therefore, there are no issues regarding 

international harmonization with established U.S. tolerances.

A revised dietary assessment was conducted. An acute dietary assessment was not performed, 

because a toxicological endpoint was not identified. The chronic dietary exposure and risk 

assessment were highly conservative, using tolerance levels residues and 100% of crop treated 

assumptions. The chronic dietary (food and water) estimated risks were all well below HED’s 

level of concern (< 100% of the cPAD) for the U.S. population and all population subgroups. 

The highest exposure and risk estimates were for children 1 to 2 years old which occupied 9.3% 

of the cPAD for thidiazuron. 

There are no residential uses of thidiazuron. A spray drift assessment was completed. The spray 

drift risk estimates are based on an estimated deposited residue concentration, as a result of the 

screening level agricultural application scenarios. Children’s (1 to < 2 year old) incidental oral 
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risk estimates from indirect exposure to thidiazuron, related to spray drift, result in no buffers for 

any application scenario, including ground boom or aerial applications. Risk estimates from 

ground boom and aerial applications are not of concern at the field edge for all situations 

considered. 

HED conducted occupational handler exposure and risk assessments for all registered uses. 

Short- and intermediate-term MOEs for handlers were not of concern to HED, because they 

exceeded the target MOE of 100. Inhalation MOEs for the occupational handler assessment 

range from 30,000 to 1,500,000. As quantitation of dermal risk assessment is not required; a

quantitative occupational post-application risk assessment was not performed since only dermal 

exposures are expected, and no dermal hazard was identified for thidiazuron. 

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide to determine their exposure. Appendix E provides additional 

information on the review of human research used to complete the risk assessment. There is no 

regulatory barrier to continued reliance on these studies, and all applicable requirements of 

EPA’s Rule for the Protection of Human Subjects of Research (40 CFR Part 26) have been 

satisfied.

2.0 HED Recommendations

HED did not identify any risks of concern related to current uses of thidiazuron.

The data needs are specified in section 2.1, and tolerance recommendations in section 2.2. 

Phenylurea and 4-hydroxy-thidiazuron reference standards are not available at the EPA National 

Pesticide Standards Repository. These standards need to be sent by the registrant. Please, refer 

to section 5.1.4 for instructions. 

2.1 Data Deficiencies/Conditions of Registration and Re-Registration

The toxicity and ORE exposure databases are considered complete. Although HED would 

typically require dislodgeable foliar residue (DFR) studies based on the existing use pattern, no 

studies are required, because no quantitation of dermal risk is required for thidiazuron.

The residue chemistry database for thidiazuron is incomplete but adequate to support registration 

review. Radio-validation data for the tolerance enforcement method (TU-002-A06-01) in 

livestock commodities was not submitted and is required. This data is necessary because the 

livestock metabolism study was performed following a different extraction procedure than that 

used in the analytical method for livestock. 
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2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Plants: Analytical methods are available for enforcing tolerances in plant commodities. The 

Pesticide Analytical Manual, Volume II lists Methods I and A. Method I is no longer 

recommended for enforcement on plant commodities. Method A is a reverse-phase HPLC with 

UV detection, which determines parent thidiazuron, and is recommended for tolerance 

enforcement. Additionally, a method that determines parent thidiazuron in cotton un-delinted 

seed and gin trash by HPLC with UV detection is available for enforcement (AW-94R-08). 

Livestock: Method TU-002-A06-01 is available for the determination of residues of thidiazuron, 

4-hydroxy-thiadiazuron, and phenylurea in bovine kidney, muscle, liver, fat, and milk. Briefly, 

thidiazuron, 4-hydroxy-thiadiazuron and phenylurea residues are extracted from bovine tissues 

and milk with acetonitrile, and from fat with a mixture of hexane and acetonitrile. After 

extraction, a mixture of isotopically labeled internal standards is added to the extract. The 

extracts are filtered, diluted or further separated, and concentrated. The samples are analyzed via 

liquid chromatography/mass spectroscopy/mass spectroscopy (LC-MS/MS) with electrospray 

ionization. Primary and confirmatory transition ions were monitored for each analyte. The 

validated limit of quantitation (LOQ) for each analyte is 0.05 ppm in bovine tissues and 0.01 

ppm in bovine milk.

 

2.2.2 Recommended Tolerances

Tolerances are established in the 40 CFR 180.403 for residues of thidiazuron in/on cotton and 

livestock commodities. Based on the evaluation of the residue data received the following 

changes to the tolerance levels are recommended:

Table 2.2.1. Tolerance Summary for Thidiazuron.

Commodity Established Tolerance 

(ppm)

HED-Recommended 

Tolerance (ppm)

Comments 

(correct commodity definition)

Cotton, undelinted seed 0.3 0.5

Cotton, hulls None 1.5

Cotton, gin byproducts 24.0 30 OECD rounding procedures

The tolerance expression needs to be modified according to the interim guidance for writing 

tolerance expressions, and the residues of concern need to be modified according to the 

recommendations of the 2005 RED and the Metabolism Assessment Review Committee 

(MARC). The residues of concern to be included are parent thidiazuron for plants and parent 

thidiazuron, 4-hydroxy thidiazuron, and phenylurea for livestock commodities. Consequently, 

two sections are needed in the CFR, one for tolerances for cotton commodities and the other for 

livestock commodities as described below.
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(a) General. (1) Tolerances are established for residues of the defoliant thidiazuron, including its 

metabolites and degradates, in or on the commodities in the table in this paragraph. Compliance 

with the tolerance levels specified in this paragraph is to be determined by measuring only 

thidiazuron, N-phenyl-N-1,2,3-thiadiazol-5-ylurea, in or on the commodity.

Commodity Parts per million

Cotton, gin byproducts 30

Cotton, undelinted seed 0.5

Cotton, hulls 1.5

(a) General. (2) Tolerances are established for residues of the defoliant thidiazuron, including its 

metabolites and degradates, in or on the commodities in the table in this paragraph. Compliance 

with the tolerance levels specified in this paragraph is to be determined by measuring thidiazuron 

(N-phenyl-N-1,2,3-thiadiazol-5-ylurea), 4-hydroxy thidiazuron (N-(4-Hydroxyphenyl)-N’-1,2,3-

thiadiazol-5-ylurea), and phenylurea in or on the commodity.

Commodity Parts per million

Cattle, fat 0.4

Cattle, meat 0.4

Cattle, meat byproducts 0.4

Goat, fat 0.4

Goat, meat 0.4

Goat, meat byproducts 0.4

Hog, fat 0.4

Hog, meat 0.4

Hog, meat byproducts 0.4

Horse, fat 0.4

Horse, meat 0.4

Horse, meat byproducts 0.4

Milk 0.05

Sheep, fat 0.4

Sheep, meat 0.4

Sheep, meat byproducts 0.4
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2.2.3 International Harmonization

No Canadian, Mexican or Codex maximum residue limits (MRLs) are established or proposed 

for residues of thidiazuron. Therefore, there are no issues regarding international harmonization 

with the established U.S. tolerances. The International Residue Limits (IRL) table is included in 

Appendix B.

2.3 Label Recommendations

There are no label recommendations at this time. 

2.3.1 Recommendations from Residue Reviews

None.

2.3.2 Recommendations from Occupational Assessment

No revisions to the labels are required.

3.0 Introduction

Thidiazuron is a phenylurea herbicide used for the defoliation of cotton. In cotton, thidiazuron 

defoliates green leaves and immature fruiting structures. 

3.1 Chemical Identity

The structure and chemical identity for thidiazuron are shown in Table 3.1. The structures for 

metabolites discussed in this risk assessment are shown in Appendix C.

TABLE 3.1. Thidiazuron Nomenclature.

Compound Chemical Structure

Common Name Thidiazuron

Trade and other Names DROPP, FreeFall, Ginstar, Leafless

IUPAC Name 1-phenyl-3-(1,2,3-thidiazol-5-yl)urea

CAS Name N-phenyl-N-1,2,3-thidiazol-5-ylurea

CAS Registry Number 51707-55-2

End-Use Product (EP) Not applicable
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3.2 Physical/Chemical Characteristics

Thidiazuron is readily soluble in water and is not volatile. It has a low octanol/water partition 

coefficient; therefore, it is not likely to bioaccumulate. The physical and chemical properties are 

detailed in Appendix D.

3.3 Pesticide Use Pattern

Thidiazuron can be applied by ground or air to late season cotton. The registered formulations 

include wettable powders (WP) in water-soluble bags (WSB), soluble concentrates (SC), 

emulsifiable concentrates (EC), and liquids. The maximum single application rate is 0.2 lb 

ai/acre, and the maximum seasonal application rate is 0.3 lb ai/A per year. Rotational crop 

restrictions are included in the label. Plant back intervals (PBI) are similar or longer than those 

required based on rotational studies, i.e. 2 weeks for small grain crops and 1 month for root and 

leafy vegetable. There are no residential uses of thidiazuron. 

3.4 Anticipated Exposure Pathways

Thidiazuron is used as a defoliant on cotton. Exposure to thidiazuron may occur from ingestion 

of residues on foods and in drinking water and via the dermal and inhalation routes for adults 

using thidiazuron products in occupational settings. In addition, both adults and children may be 

exposed orally and/or dermally due to spray drift. There is a potential for post-application dermal 

exposure for workers re-entering treated fields. 

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups, according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and/or the CDC under the National Health and 

Nutrition Examination Survey/What We Eat in America (NHANES/WWEIA) and are used in 

pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and 

categorized by subgroups based on age, season of the year, ethnic group, and region of the 

country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups,

and exposure assessments are performed when conditions or circumstances warrant. Whenever 

appropriate, non-dietary exposures are evaluated based on home use of pesticide products and 

associated risks for adult applicators and for toddlers, youths, and adults entering or playing on 

treated areas post-application. Further considerations are currently in development as OPP has 
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committed resources and expertise to the development of specialized software and models that 

consider exposure to bystanders and farm workers, as well as lifestyle and traditional dietary 

patterns among specific subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The toxicology database for thidiazuron provides a robust characterization of the hazard potential 

of this pesticide. The toxicology studies for thidiazuron are summarized in Table A.1 in 

Appendix A.1. There are studies available for toxicity endpoint selection, which include: 

Subchronic oral toxicity studies in rats and mice

Chronic oral toxicity studies in rats, mice, and dogs 

Carcinogenicity studies in rats and mice 

Mutagenicity battery 

Developmental studies in rats and rabbits 

Reproduction study in rats 

Dermal toxicity study in rats

Metabolism study in rats

Hazard and Science Policy Council (HASPOC) determined that immunotoxicity (Habiba, 2013, 

TXR# 0056795), 90-day inhalation, acute neurotoxicity, and subchronic neurotoxicity studies

(Habiba, 2015, TXR# 0057116) were not needed for the risk assessment of thidiazuron. The 

studies available for consideration of thidiazuron toxicity provide a comprehensive database, 

with routes of administration that are consistent with potential exposure scenarios. 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

In the metabolism study, thidiazuron was administered in dimethyl sulfoxide at a single oral 

gavage dose (10 or 1000 mg/kg). Additionally, thidiazuron was administered by gavage in daily 

doses at 10 mg/kg for 14 days followed by a single oral dose of 14C-thidiazuron at 10 mg/kg. 

Absorption (considered the sum of residues in the urine, cage wash, and carcass) occurred 

predominantly within 24 hours at 10 mg/kg (single or repeated dosing) and within 48 hours at 

1000 mg/kg. Absorption was 61-68% of the administered dose (AD) after a single 10 mg/kg 

dose, slightly higher after repeated 10 mg/kg doses (74-76% AD), but only 41-48% AD after 

1000 mg/kg. After a single 10 mg/kg dose, urinary excretion accounted for 59-74% AD, and 

fecal excretion accounted for 26-31% AD (single and repeated). Compared to the low dose, after 

a single 1000 mg/kg dose, urinary excretion decreased to 40-47% AD, and fecal excretion 

increased to 56-60% AD. Approximately 0.1% AD or less was found in the expired air. At 120 

hours post-dose, <2% AD remained in the body, and the highest concentration was found in the 

thyroid. Concentrations were also sometimes higher than in whole blood in the female kidney 

and in male and female adrenal glands. A negligible amount of the parent was isolated in the 
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excreta. The primary metabolites were 4-hydroxy thidiazuron and 3 different conjugates of 

4-hydroxy thidiazuron.

4.2.1 Dermal Absorption

A dermal absorption study is available for thidiazuron, which identified a dermal absorption 

factor of ≤1%. Quantification of dermal risk is not required, as discussed in Section 4.5.1 (DoseResponse Assessment).

4.3 Toxicological Effects

The mode of action for thidiazuron in animals is unknown. Both subchronic and chronic toxicity

studies in rats show that thidiazuron causes decreased body weights, body weight gains, and/or

food consumption; adverse effects on the kidney and seminal vesicles are also noted. Findings in 

the kidney included glomerular mineralization, bilateral hyperplasia of the pelvic epithelium, 

mineralized concretions of the renal pelvis, focal mononuclear cell inflammation, renal collecting

duct hyperplasia, papillary mineralization, focal mineralization of the inner medulla, 

suburothelial congestion, bilateral pelvic dilatation, chronic progressive nephropathy, urothelial

mineralization, and increased relative weight. Seminal vesicles are described as small or 

atrophied with decreased secretions. The prostate gland was also small in the subchronic rat 

study. In the mouse, only marginal effects were noted at the mid-dose in the subchronic study, 

whereas all mice died at the high dose. In the chronic mouse study, as with the rat, decreased 

body weights, body weight gains, and food consumption were observed, in conjunction with 

nephrotoxicity. Additionally, epididymis toxicity was observed as indicated by dilated tubules,

interstitial mononuclear cell infiltrate, unilateral and bilateral oligospermia, and spermatic 

granuloma. Anemia and marked hemosiderosis in liver and spleen was apparent in the chronic 

dog study. 

The data from the developmental toxicity studies in rat suggested a quantitative susceptibility to 

fetuses. The only finding was a similar decrease in body weight in both dams (↓6%) and fetuses

(↓7%); however, the marginal effect in fetuses is of concern. There was no increased 

quantitative or qualitative susceptibility observed for rabbit fetuses, and the point of departure 

in the rabbit developmental study is protective for all effects noted in the rat developmental and 

reproduction studies. In the rabbit developmental study, maternal effects included abortions. 

Similarly, body weights were decreased in the fetuses; more runts and delayed skeletal 

ossification were observed, in addition to the abortions. Reproductive toxicity was 

conservatively set based on a delay of 3 days in vaginal opening; no adverse effects were noted 

on parental or offspring toxicity. No adverse effect was noted on parents or reproduction 

parameters.

Dermal toxicity was not observed at the limit dose in a 28-day dermal study in rats. Dermal 

absorption is extremely limited, as detailed above. No definitive evidence of neurotoxicity was

reported in any of the submitted studies. Acute and subchronic neurotoxicity studies, as well as an 

inhalation toxicity study, were not submitted, but the requirement for these studies was waived
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by HAPSOC (Habiba, 2015, TXR# 0057116). Carcinogenicity studies in both rats and mice

produced no treatment-related increase in tumor incidence. The standard battery of genotoxicity

tests was negative.

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 nor a skin irritant.

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)

HED recommends that the 10X FQPA Safety Factor (for the protection of infants and children) 

be reduced to 1X. An FQPA Safety Factor of 1X is appropriate for the following reasons:

 

 The toxicological database for thidiazuron is complete under the new 40 CFR Part 158 

data requirements for conventional pesticides.

 There is evidence of increased susceptibility/sensitivity in rats to prenatal exposure to 

thidiazuron. However, the concern is low based on clear no observed adverse effect 

(NOAEL) levels for the findings that are greater than the chosen points of departure. 

 There was no conclusive evidence of neurotoxicity or neuropathology in the available 

studies. The acute and subchronic neurotoxicity study requirements have been waived.

 The exposure assessment will not underestimate children’s exposure to thidiazuron. 

Further details may be found in the following sections.

4.4.1 Completeness of the Toxicology Database

The database of toxicology studies for thidiazuron is complete and considered adequate for risk 

assessment (see Appendix A.1). Developmental toxicity studies in rats and rabbits and a 

reproductive toxicity study in rats are available. Waivers were granted by HED’s HASPOC for 

the acute and subchronic neurotoxicity studies (Habiba, 2015, TXR# 0057116) and 

immunotoxicity study (Habiba, 2013, TXR# 0056795). 

4.4.2 Evidence of Neurotoxicity

There is no conclusive evidence of neurotoxicity or neuropathology in the available studies. In a 

mouse carcinogenicity study (MRID 46346001), tremors were observed at 280/330 mg/kg/day 

(M/F) in 3/120 animals in the presence of numerous other indications of systemic toxicity. 

Additionally in the combined chronic toxicity and carcinogenicity study (MRID 46345201), 

decreased motor activity was observed as a clinical sign in the 76 mg/kg/day male rats (22/59) 

compared to controls (6/59); however, only 13% of these animals survived 24 months. No other 

evidence of neurotoxicity was found in the database. Therefore, the tremors and motor activity 

findings were considered unlikely to be frank neurotoxic effects, but were more likely the result 
Thidiazuron Human Health Risk Assessment DP No. D424978

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of the general systemic toxicity of the pesticide. Without any evidence of neurotoxicity in the 

toxicity database, there is not a concern for developmental neurotoxicity.

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is evidence of increased susceptibility following in utero exposure to thidiazuron in the 

rabbit developmental toxicity study. However, there is low concern because clear NOAELs 

were defined for these effects, and the chosen points of departure for risk assessment for each 

exposure scenario are protective for these effects.

4.4.4 Residual Uncertainty in the Exposure Database

There are no residual uncertainties in the exposure database. The dietary exposure estimates 

were based on tolerance-level residues and 100% of crop treated assumption. Upper-bound 

drinking water estimates based on modeling were used which are conservative assumptions (see 

Section 5.4). HED is confident that the dietary risk is not underestimated. Additionally, HED 

does not believe that non-occupational exposure and risk estimates are underestimated. The 

assumptions are detailed in Section 6.0.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment

There have been no changes since the last risk assessment to the dose-response assessment, 

endpoint selection, or cancer classification, except for revisions to the executive summaries of 

the rat developmental and reproduction studies. The studies selected for risk assessment for each 

exposure scenario represent the lowest points of departure in the database and as such are 

protective for any other effects observed for the exposure scenario. The detailed description of 

the toxicity studies used for selecting toxicity endpoints and points of departure for various 

exposure scenarios are presented in Appendix A.4.

Acute Dietary Endpoint (All Populations): A dose and endpoint were not selected for this 

population group, because there were no effects observed in the available toxicology studies that 

could be attributed to a single exposure (dose).

Chronic Dietary Endpoint (All Populations): The chronic dietary endpoint was from a dog 

chronic toxicity study. The chronic PAD (cPAD) of 0.0393 mg/kg/day is based on a NOAEL of 

3.93 mg/kg/day with a 100-fold uncertainty factor (10X interspecies and 10X intraspecies) 

applied and an FQPA SF of 1. At the study LOAEL of 11.1 mg/kg, increased incidence of 

anemia, changes in hematological parameters, and marked hemosiderosis in liver and spleen

were observed. 

Short- and Intermediate-Term Incidental Oral: The dose and endpoint selected for short- and 

intermediate-term incidental oral exposure was from a rabbit developmental study. The maternal 
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NOAEL of 25 mg/kg/day and maternal LOAEL of 125 mg/kg/day were chosen based on based 

on 5 abortions occurring at GD 27-29. This endpoint is the most sensitive effect identified for 

the short and intermediate term exposure and is protective for offspring effects seen in the 

reproduction study (NOAEL = 35.4 mg/kg/day). The standard 100X UF was applied to account 

for interspecies extrapolation and intraspecies variation. A margin of exposure (MOE) of 100 is 

considered adequate for incidental oral risk assessment level of concern. 

Short- and Intermediate-Term Dermal Endpoints: In a 28-day dermal toxicity study in rats, no 

adverse local or systemic effects were observed at the limit dose. Additionally, the dermal 

absorption factor is only 1%. Correcting the NOAELs from the developmental and reproduction 

studies for 1% dermal absorption results in PODs well above the limit dose. Therefore, no 

toxicity is expected to result from dermal exposure to thidiazuron, and a quantitative dermal risk 

assessment is not required.

Short- and Intermediate-Term Inhalation Endpoints: HASPOC waived the requirement for 

subchronic inhalation study after a weight of evidence analysis considering the physicalchemical properties of the compound, use pattern and exposure scenarios, margins of exposure,

and inhalation toxicity in structural analogs. The absorption through the inhalation route was 

assumed to be similar to the oral route. The dose and endpoint selected for short- and 

intermediate-term inhalation exposure was from a rabbit developmental study. The maternal 

NOAEL of 25 mg/kg/day and maternal LOAEL of 125 mg/kg/day were chosen based on based 

on 5 abortions occurring at GD 27-29. The standard 100X UF was applied to account for 

interspecies extrapolation and intraspecies variation. A margin of exposure (MOE) of 100 is 

considered adequate for the inhalation risk assessment level of concern.

Carcinogenicity: Both rat and mouse carcinogenicity studies did not show treatment related 

increase in tumor incidences, and assays from the mutagenicity battery were negative. 

Therefore, a quantitative cancer risk assessment is not required. 

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

As indicated by 1996 FQPA, when there are potential residential exposures to the pesticide, 

aggregate risk assessment must consider exposures from three major routes: oral, dermal, and 

inhalation. There are no residential uses for thidiazuron; therefore, combining routes of 

exposures for risk assessment is unnecessary.

4.5.3 Cancer Classification and Risk Assessment Recommendation

There is no evidence of carcinogenicity in acceptable rat and mouse carcinogenicity studies, and 

assays from the mutagenicity battery were negative. 

4.5.4 Summary of Points of Departure and Toxicity Endpoints 
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Table 4.5.4.1. Summary of Toxicological Doses and Endpoints for Thidiazuron for Use in Human Health 

Risk Assessments

Exposure/ 

Scenario

Point of 

Departure

Uncertainty/

FQPA Safety 

Factors

RfD, PAD, 

Level of

Concern for 

Risk 

Assessment Study and Toxicological Effects

Acute Dietary 

(All 

Populations)

No toxic effects were identified likely to be a result of a single exposure.

Chronic 

Dietary (All 

Populations)

NOAEL= 

3.93 

mg/kg/day

UFA=10x

UFH=10x

FQPA SF=1x

Chronic RfD 

= cPAD = 

0.0393

mg/kg/day 

00159344, Chronic toxicity in dog

LOAEL = 11.1 mg/kg/day based on 

increased incidence of anemia, changes 

in hematological parameters and marked 

hemosiderosis in liver and spleen

Incidental 

Oral ShortTerm (1-30 

days)

Incidental 

Oral 

IntermediateTerm (1-6 

months)

NOAEL= 

25 

mg/kg/day

UFA=10x

UFH=10x

FQPA SF=1x

Residential 

LOC for 

MOE = 100

46121507, Developmental toxicity in 

rabbit

LOAEL = 125 mg/kg/day based on 

abortions

Dermal ShortTerm (1-30 

days)

Dermal 

IntermediateTerm (1-6 

months)

Not needed; no dermal hazard identified. No dermal toxicity was observed at the limit dose in 

the 28-day dermal toxicity study. Very low (<1%) dermal absorption results in calculated PoDs 

above the limit dose. 

Inhalation 

Short-Term 

(1-30 days)

Inhalation 

IntermediateTerm (1-6 

months)

NOAEL= 

25 

mg/kg/day

UFA=10x

UFH=10x

FQPA SF=1x

Occupational

LOC for 

MOE = 100

46121507, Developmental toxicity in 

rabbit

LOAEL = 125 mg/kg/day based on 

abortions

Cancer (oral, 

dermal, 

inhalation)

Classification: No increase in tumorigenesis or genotoxicity was observed. 

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and 

used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human 

exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = 
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uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in 

sensitivity among members of the human population (intraspecies). UFL = use of a LOAEL to extrapolate a 

NOAEL. UFS = use of a short-term study for long-term risk assessment. UFDB = to account for the absence of key 

data (i.e., lack of a critical study). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c 

= chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

4.6 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental,

reproductive, and general or systemic toxicity. These studies include endpoints which may be

susceptible to endocrine influence, including effects on endocrine target organ histopathology,

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss,

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and

chronic studies that assess growth, developmental and reproductive effects in different

taxonomic groups. As part of its preliminary re-registration decision for thidiazuron, EPA 

reviewed these data and selected the most sensitive endpoints for relevant risk assessment 

scenarios from the existing hazard database. However, as required by FFDCA section 408(p), 

thidiazuron is subject to the endocrine screening part of the Endocrine Disruptor Screening 

Program (EDSP). 

EPA has developed the EDSP to determine whether certain substances (including pesticide 

active and other ingredients) may have an effect in humans or wildlife similar to an effect 

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator 

may designate.” The EDSP employs a two-tiered approach to making the statutorily required

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal

systems. Chemicals that go through Tier 1 screening and are found to have the potential to

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2

testing is designed to identify any adverse endocrine-related effects caused by the substance, and

establish a dose-response relationship between the dose and the E, A, or T effect.

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 

2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, 

which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals 

identified for EDSP screening was published on June 14, 20131and includes some pesticides 

scheduled for registration review and chemicals found in water. Neither of these lists should be 

construed as a list of known or likely endocrine disruptors.

 

1

See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of chemicals.
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For further information on the status of the EDSP, the policies and procedures, the lists of 

chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our 

website2.

5.0 Dietary Exposure and Risk Assessment

5.1 Residues of Concern Summary and Rationale

Residue Chemistry Memo, D425934, I. Negrón-Encarnación, 05/07/2015

The qualitative nature of the residue in cotton and livestock commodities is adequately 

understood. The parent compound thidiazuron is the residue of concern in cotton. Thidiazuron, 

and its metabolites, 4-hydroxythidiazuron and phenylurea, are the residues of concern for 

livestock commodities. Estimated drinking water concentrations (EDWCs) that include 

thidiazuron, its two photodegradates (photo-thidiazuron, 1-cyano-3-phenylurea), and 

thidiazolurea were provided by EFED. Photothidiazuron, 1-cyano-3-phenylurea, and 

thidiazolurea are not expected to be more toxic than parent thidiazuron (I. Negron-Encarnacion, 

D425935, 05/13/2015).

Table 5.1. Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance 

Expression1,2

Matrix Residues included in Risk 

Assessment

Residues included in 

Tolerance Expression

Plants Primary Crop Thidiazuron Thidiazuron Rotational Crop

Livestock

Ruminant Thidiazuron,

4-hydroxythidiazuron, 

Phenylurea

Thidiazuron,

4-hydroxythidiazuron, 

Phenylurea Poultry

Drinking Water

Thidiazuron, Photothidiazuron, 1-cyano-3-

phenylurea, Thidiazolurea

Not Applicable

1 2005 Registration Eligibility Decision. The residues of concern for plant and livestock commodities were determined by the 

HED Metabolism Committee (9/29/95, F. Fort). 

2 Thidiazolurea was included as a residue of concern in the most recent drinking water assessment (I. Maher, D427241, 

05/13/2015). The risk assessment team has characterized the relative toxicity of the environmental degradates of thidiazuron 

with respect to parent thidiazuron. . 

 

2

http://www.epa.gov/endo/
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5.2 Food Residue Profile

Residue Chemistry Memo, D425934, I. Negrón-Encarnación, 05/07/2015

Dietary Assessment Memo, D425935, I. Negrón-Encarnación, 05/13/2015

Crop field trial and processing studies are available to support the registration for the use of 

thidiazuron on cotton. The residue data were reevaluated to consider the results of storage 

stability studies. Storage stability data indicates that residues of thidiazuron in/on cotton 

undelinted seed, meal and hulls should be adjusted for loss during storage. Tolerances for 

thidiazuron in/on cotton undelinted seed and cotton hulls are recommended at 0.5 ppm and 1.5 

ppm, respectively. The tolerance for cotton undelinted seed covers potential residues in cotton 

meal. Residues of thidiazuron in cotton gin byproducts are stable; therefore, the established 

tolerance (24.0 ppm) is adequate; however, a tolerance of 30 ppm is recommended following 

OECD rounding procedures. The field rotational crop study showed that residues of thidiazuron 

are not expected in rotated crops following the recommended PBI specified on the label. Storage 

stability data indicates that residues of 4-hydroxy-thidiazuron are not stable in muscle, kidney 

and fat but stable in milk, and residues of thidiazuron and phenyl urea in milk are stable in 

muscle, kidney, fat and milk. Tolerances are established in 40 CFR 180.403 for residues of 

thidiazuron in ruminant commodities: 0.4 ppm for meat, meat byproducts, fat, and 0.05 for milk. 

The dietary burden was reassessed to consider updated residue data and the current guidance. 

Residues in livestock commodities were estimated using the results of the livestock metabolism 

study. HED concludes that the tolerances established for ruminant commodities are adequate. 

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by EFED in the 

following memorandum: “Thidiazuron: Drinking Water Exposure Assessment Memorandum for 

Preliminary Risk Assessment in Support of Thidiazuron Registration Review.” (I. Maher, 

D427241, 05/13/2015) and incorporated directly into this dietary assessment. Potential drinking 

water concentrations for the chronic assessments were estimated using two EFED Tier 1 

screening-level models: SWCC, Version 1.106 and SCI-GROW, Version 1.07. The highest 

water concentration value obtained, 0.0215 ppm for the FL citrus scenario modeled by PRZMGW, was incorporated in the chronic dietary assessment.

Table 5.3. Estimated Drinking Water Concentrations (EDWCs) for Thidiazuron, its Photodegradates (I and 

II) and Thidiazolurea ResiduesA

Drinking water source 

(model)

Use

(modeled rate)

1-in-10 year acute 

(μg/L)

1-in-10 year 

chronic (μg/L)

30- year average 

(μg/L)

Surface water 

(SWCC)

Cotton (MS)

(0.31 lb ai/A) aerial 3.8 0.66 0.46

Ground water

(PRZM-GW)

Cotton (as FL citrus)

(0.31 lb ai/A) aerial

Max. Daily 

Conc(μg/L)

Post-breakthrough 

mean (μg/L)

Entire Simulation 

Mean (μg/L)

21.7 21.5 10.6

A Based on the total annual rate of 0.31 lbs ai/A/yr (2 apps, 5-d interval, 0. 21b a.i./A and 0.1 a.i/A, respectively). 

Surface water corrected for national maximum cotton PCA of 0.21. 
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5.4 Dietary Risk Assessment

Dietary Assessment Memo, D425935, I. Negrón-Encarnación, 05/13/2015

5.4.1 Description of Residue Data Used in Dietary Assessment

The chronic dietary exposure assessment for thidiazuron on food crops used tolerance level 

residues and DEEM default processing factors.

5.4.2 Percent Crop Treated Used in Dietary Assessment

100% of the crop was assumed to be treated.

5.4.3 Acute Dietary Risk Assessment

No acute endpoint was selected for thidiazuron; therefore, a quantitative acute dietary assessment 

was not needed. 

5.4.4 Chronic Dietary Risk Assessment

An unrefined dietary exposure assessment was performed for thidiazuron. The assumptions of 

this dietary exposure assessment were tolerance level residues and 100% crop treated. The 

dietary exposure analysis in this assessment for thidiazuron result in dietary risk for food and 

water estimates that are below the Agency’s level of concern for chronic dietary exposure

(<100% of the cPAD). The highest exposure and risk estimates were for children 1 to 2 years 

old. The chronic exposure for children 1 to 2 years old was 0.003647 mg/kg/day, which utilizes 

9.3% of the cPAD for thidiazuron (see Table 5.4.6.). 

5.4.5 Cancer Dietary Risk Assessment

Thidiazuron is not classified by CARC. However, no increase in tumorigenesis or genotoxicity 

was observed; therefore, a dietary cancer exposure and risk analysis was not conducted.

5.4.6 Summary Table

Table 5.4.6. Summary of Dietary Exposure and Risk for Thidiazuron Food 

and Drinking Water

Population Subgroup Chronic Dietary

Dietary Exposure (mg/kg/day) % cPAD

General U.S. Population 0.001248 3.2

All Infants (< 1 year old) 0.001967 5.0

Children 1-2 years old 0.003647 9.3

Children 3-5 years old 0.002628 6.7

Children 6-12 years old 0.001710 4.4

Youth 13-19 years old 0.001069 2.7

Adults 20-49 years old 0.001064 2.7

Adults 50-99 years old 0.000970 2.5
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Table 5.4.6. Summary of Dietary Exposure and Risk for Thidiazuron Food 

and Drinking Water

Population Subgroup Chronic Dietary

Dietary Exposure (mg/kg/day) % cPAD

Females 13-49 years old 0.000983 2.5

*The subpopulation(s) with the highest risk estimates.

The chronic assessment is unrefined, tolerance level residues and 100% of crop treated 

assumptions were incorporated in the dietary assessment. Therefore, this dietary assessment 

represents a high end estimate of potential dietary risks. HED is confident that the dietary risk is 

not underestimated.

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no registered residential (non-occupational) uses of thidiazuron; therefore, a residential

exposure and risk assessment is not required.

6.1 Residential Bystander Post-Application Inhalation Exposure

Volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. The agency sought expert advice and input on issues 

related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act 

Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on 

March 2, 2010 (http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The 

agency has evaluated the SAP report and has developed a Volatilization Screening Tool and a 

subsequent Volatilization Screening Analysis 

(http://www.regulations.gov/#!docketDetail;D=EPA-HQ-OPP-2014-0219). The Agency is 

currently not assessing volatility for non-fumigants; however, the Agency will utilized this 

analysis in the future to determine if data (i.e., flux studies and route-specific inhalation 

toxicological studies) or further analysis is required for thidiazuron.

6.2 Spray Drift

Off-target movement of pesticides can occur via many types of pathways, and it is governed by a 

variety of factors. Sprays that are released and do not deposit in the application area end up offtarget and can lead to exposures to those it may directly contact. They can also deposit on 

surfaces where contact with residues can eventually lead to indirect exposures (e.g., children 

playing on lawns where residues have deposited next to treated fields). The potential risk 

estimates from these residues can be calculated using drift modeling onto 50-feet wide lawns 

coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessment is based 

on a premise of compliant applications which, by definition, should not result in direct exposures 

to individuals because of existing label language and other regulatory requirements intended to 
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prevent them.3 Direct exposures would include inhalation of the spray plume or being sprayed 

directly. Rather, the exposures addressed here are thought to occur indirectly through contact 

with impacted areas, such as residential lawns, when compliant applications are conducted. 

Given this premise, exposures for children (1 to 2 years old) and adults who have contact with 

turf where residues are assumed to have deposited via spray drift, thus resulting in an indirect 

exposure, are the focus of this analysis analogous to how exposures to turf products are 

considered in risk assessment. 

In order to evaluate the drift potential and associated risks, an approach based on drift modeling 

coupled with techniques used to evaluate residential uses of pesticides was utilized. Essentially, a 

residential turf assessment based on exposure to deposited residues has been completed to 

address drift from the agricultural applications of thidiazuron. In the spray drift scenario, the 

deposited residue value was determined based on the amount of spray drift that may occur at 

varying distances from the edge of the treated field using the AgDrift (v2.1.1) model and the 

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of 

Spray Drift Policy. Once the deposited residue values were determined, the remainder of the 

spray drift assessment was based on the algorithms and input values specified in the recently 

revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs). 

A screening approach was developed based on the use of the AgDrift model in situations where 

specific label guidance that defines application parameters is not available.4,5 AgDrift is 

appropriate for use only when applications are made by aircraft, airblast orchard sprayers, and 

groundboom sprayers. When AgDrift was developed, a series of screening values (i.e., the Tier 

1 option) were incorporated into the model and represent each equipment type and use under 

varied conditions. The screening options specifically recommended in this methodology were 

selected because they are plausible and represent a reasonable upper bound level of drift for 

common application methods in agriculture. These screening options are consistent with how 

spray drift is considered in a number of ecological risk assessments and in the process used to 

develop drinking water concentrations used for risk assessment. In all cases, each scenario is to 

be evaluated, unless it is not plausible based on the anticipated use pattern (e.g., herbicides are 

not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are 

not allowed). Section 6.2.1 provides the screening level drift-related risk estimates. 

 

3 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.

4http://www.agdrift.com/ 

5 Note that for many cases the scenarios outlined in the screening approach represent actual use practice so risk assessors should 

be aware and characterize these appropriately.
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6.2.1 Risk Estimates From Lawn Deposition Adjacent to Applications

The spray drift risk estimates are based on an estimated deposited residue concentration, as a 

result of the screening level agricultural application scenarios. Thidiazuron is used on cotton and 

can be applied via groundboom and aerial equipment. The spray drift assessment was completed 

assuming the highest registered application rate of 0.2 lb ai/A. The recommended drift scenario 

screening level options are listed below: 

 Groundboom applications are based on the AgDrift option for high boom height and 

using very fine to fine spray type using the 90th percentile results. 

 Aerial applications are based on the use of AgDrift Tier 1 aerial option for a fine to 

medium spray type and a series of other parameters which will be described in more 

detail below (e.g., wind vector assumed to be 10 mph in a downwind direction for entire 

application/drift event).6

Only incidental oral risk estimates are shown since quantitation of dermal risk to thidiazuron is 

not required. The applicable Level of Concern is 100, so MOEs < 100 would be of concern. 

Exposures were considered for 50 feet wide lawns where the nearest side of the property was 

directly adjoining the treated field (at field edge). Results are presented in Table 6.4.1; no risk 

estimates of concern were identified at field edge. 

Table 6.2.1 Children (1<2 years old) Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for 

Thidiazuron for the Oral Route of Exposure

Crop/Rate Group Spray Type/ Nozzle 

Configuration

Appl. Rate 

(lb ai/A) TTR (μg/cm2

) At Edge

Cotton

Groundboom High Boom Very fine to Fine

0.2 0.022

44,000

Aerial Fine to Medium 32,000

7.0 Aggregate Exposure/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 (see Section 5).

7.1 Acute Aggregate Risk

There are no acute aggregate risks for thidiazuron, as a hazard was not identified that could result 

from a single exposure.

 

6 AgDrift allows for consideration of even finer spray patterns characterized as very fine to fine. However, this 

spray pattern was not selected as the common screening basis since it is used less commonly for most agriculture.
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7.2 Short-Term Aggregate Risk

There are no short-term aggregate risks for thidiazuron, as there are no residential uses.

7.3 Intermediate- and Long-Term Aggregate Risk

There are no intermediate- or long-term aggregate risks for thidiazuron, as there are no 

residential uses.

7.4 Chronic Aggregate Risk

Since there are no residential uses, the chronic aggregate risk is equal to the aggregate risk from 

dietary sources, food plus drinking water, summarized in Section 5.4. There are no chronic 

aggregate risks of concern for thidiazuron. 

7.5 Cancer Aggregate Risk

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

incidences. Thus, a cancer dietary risk assessment was not performed.

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a 

common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as 

to thidiazuron and any other substances. For information regarding EPA’s efforts to determine 

which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of 

such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs 

concerning common mechanism determinations and procedures for cumulating effects from 

substances found to have a common mechanism on EPA’s website at 

http://www.epa.gov/pesticides/cumulative/.

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

incidences. Thus, a cancer dietary exposure assessment was not performed.

9.0 Occupational Exposure/Risk Characterization

An occupational exposure and risk assessment was completed to include all registered uses of 

thidiazuron.

9.1 Short-/Intermediate-Term Handler Risk

HED uses the term “handlers” to describe those individuals who are involved in the pesticide 

application process. HED has determined that there are potential exposures to handlers during 
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application of thidiazuron. Scenarios assessed include mixing/loading liquids and water soluble 

packets (WSPs) formulations for groundboom and aerial applications, applying sprays via 

groundboom and aerial equipment, and flagging. 

It is the policy of HED to use the best available data to assess handler exposure. Sources of 

generic handler data, used as surrogate data in the absence of chemical-specific data, include 

PHED 1.1, the AHETF database, the Outdoor Residential Exposure Task Force (ORETF) 

database, or other registrant-submitted occupational exposure studies. Some of these data are 

proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The 

standard values recommended for use in predicting handler exposure that are used in this 

assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit 

Exposure Surrogate Reference Table7”, which, along with additional information on HED policy 

on use of surrogate data, including descriptions of the various sources, can be found at the 

Agency website8. 

Respirators are not required on the labels. The occupational handler exposure and risk estimates 

indicate that short- and intermediate-term MOEs are not of concern to HED (i.e., MOEs > 100). 

Inhalation MOEs for the occupational handler assessment range from 30,000 to 1,500,000. 

Table 9.1.1. Occupational Handler Short- and Intermediate-Term Non-Cancer Exposure and Risk Estimates for Thidiazuron. 

Exposure Scenario Crop or 

Target

Inhalation Unit 

Exposure (μg/lb ai)1

Maximum 

Application 

Rate2

Area Treated or 

Amount Handled 

Daily3

Inhalation

Mitigation Level Dose (mg/kg/day)4 MOE5

Mixer/Loader

L/SC/EC - Aerial 

applications

Cotton

No Respirator: 0.219

0.2

1200 0.000762 33,000

L/SC/EC - Groundboom 

applications 200 0.000127 200,000

WSP – Aerial Application

Eng. Control: 0.24

1200 0.000835 30,000

WSP – Groundboom 

applications 200 0.000139 180,000

Applicator

Spray - Aerial applications

Cotton

Eng. Control: 0.0049

0.2

1200 0.0000171 1,500,000

Spray – Groundboom 

applications

No Respirator: 0.34 200 0.000197 130.000

Flagger

Spray - Flagger Cotton No Respirator: 0.35 0.2 350 0.000355 70,000

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2014); Level of mitigation: Baseline, PPE, 

Eng. Controls.

2 Based on registered labels.

3 Exposure Science Advisory Council Policy #9.1.

4 Inhalation Dose = Inhalation Unit Exposure (μg/lb ai) × Conversion Factor (0.001 mg/μg) × Application Rate (lb ai/acre or gal) × Area Treated 

or Amount Handled (A or gal/day) ÷ BW (kg).

5 Inhalation MOE = Inhalation NOAEL (25 mg/kg/day) ÷ Inhalation Dose (mg/kg/day).

 

7 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf

8 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
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9.2 Short-/Intermediate-Term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical’s degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure.

9.2.1 Dermal Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). HED has determined that there are potential exposures to persons entering 

treated sites (e.g., harvesters) after application of thidiazuron is complete. 

Since quantitation of dermal risk is not required for thidiazuron, a quantitative occupational 

dermal post-application risk assessment is not required.

Restricted Entry Interval

The REI specified on the labels is based on the acute toxicity of thidiazuron. Thidiazuron is 

classified as Toxicity Category IV via the dermal route, Toxicity Category IV for skin irritation, 

and Toxicity Category IV for eye irritation. It is not a skin sensitizer. Under 40 CFR 156.208 

(c) (2) (iii), active ingredient’s classified as Acute III or IV for acute dermal, eye irritation and 

primary skin irritation are assigned a 12-hour REI. Therefore, the [156 subpart K] Worker 

Protection Statement interim REI of 12 hours is adequate to protect agricultural workers from 

post-application exposures to thidiazuron. 

9.2.2 Inhalation Post-Application Risk

There are multiple potential sources of post-application inhalation exposure to individuals 

performing post-application activities in previously treated fields. These potential sources 

include volatilization of pesticides and resuspension of dusts and/or particulates that contain 

pesticides. The agency sought expert advice and input on issues related to volatilization of 

pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel 

(SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The agency has 

evaluated the SAP report and has developed a Volatilization Screening Tool and a subsequent 

Volatilization Screening Analysis (http://www.regulations.gov/#!docketDetail;D=EPA-HQOPP-2014-0219). 
Thidiazuron Human Health Risk Assessment DP No. D424978

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In addition, the Agency is continuing to evaluate the available post-application inhalation 

exposure data generated by the Agricultural Reentry Task Force. Given these two efforts, the 

Agency will continue to identify the need for and, subsequently, the way to incorporate 

occupational post-application inhalation exposure into the agency's risk assessments.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for occupational/commercial 

handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in 

higher exposure than post-application exposure. Therefore, it is expected that these handler 

inhalation exposure estimates would be protective of most occupational post-application 

inhalation exposure scenarios. Handler inhalation risks are not of concern (see Section 9.1).

10.0 Incident Report 

One component of the Agency’s registration review program is consideration of human 

observational information including incident data, medical case reports, general medical 

information, and epidemiology studies. In conjunction with a human health risk assessment 

based on other data sources, such human incident and other human data can assist the Agency in 

better defining and characterizing the risk of pesticides/pesticide products. 

Based on the low frequency and severity of incident cases reported for thidiazuron in both IDS 

and CDC/NIOSH SENSOR-Pesticides, there does not appear to be a concern at this time with 

respect to incident cases that would warrant further investigation. The Agency will continue to 

monitor the incident information and will re-evaluate these conclusions as needed.

HED has prepared a thidiazuron incident report review (Recore and Evans, 2015, D425469). The 

review considers a variety of types and sources of human observational information including 

human incident data, medical data/case report information, and epidemiological information in 

an effort to inform the re-evaluation of thidiazuron in this phase of registration review. The 

human incident databases that were reviewed are: the OPP Incident Data System (IDS) and 

CDC/NIOSH’s Sentinel Event Notification System for Occupational Risks (SENSOR).

OPP’s IDS includes reports of alleged human health incidents from various sources, including 

mandatory Federal Insecticide, Fungicide and Rodenticide Act (FIFRA) Section 6(a)(2) reports 

from registrants, other federal and state health and environmental agencies, and individual 

consumers. Overall, there are few incidents involving thidiazuron reported to IDS. Incidents in 

the IDS system include:

 For the Main IDS, from January 1, 2010 to December 30, 2014, there were no incidents 

reported involving thidiazuron. 

 In Aggregate IDS, from January 1, 2010 to December 30, 2014, 1 incident of minor 

severity was reported involving thidiazuron. 
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The SENSOR-Pesticides database covers 12 states from 1998-2011, although reporting varies 

from state to state. Cases of pesticide-related illnesses are ascertained from a variety of sources, 

including: reports from local Poison Control Centers, state Department of Labor workers’ 

compensation claims when reported by physicians, reports from State Departments of 

Agriculture, and physician reports to state Departments of Health. A query of SENSORPesticides 1998-2010 identifies sixteen cases involving thidiazuron (PC Code 120301), one of 

which involved a single active ingredient. This case occurred in Texas in 1998 and was low in 

severity. The case is described in SENSOR as follows, “Complainant heard an aerial application 

occurring nearby. She went outside and saw an aerial applicator spraying a cotton field.” 

In addition to the incident/poisoning data and medical case reports, epidemiological research can 

be an important source for human observational data and can potentially assist in identifying, 

characterizing, and (ideally) quantifying linkages between human exposures and resulting health 

effects. For thidiazuron, epidemiological data is not available from the AHS.

In summary, based on the low frequency and severity of cases involving thidiazuron reported in

both IDS and SENSOR-Pesticides, there does not appear to be a concern at this time that would 

warrant further investigation. The Agency will continue to monitor the incident information and 

if a concern is triggered, additional analysis will be included in the risk assessment.
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11.0 References

Assaad, A. and Bonner, M. 03/19/2003. TXR# 0051694. THIDIAZURON - Second Report of 

the Hazard Identification Assessment Review Committee.

Cheng, L. 04/04/97. Thidiazuron. Case 2600. Phase V Review of Soybeans, Tomatoes, Goats, 

and Poultry Metabolism Studies. CBRS17851. DP Barcode: None.

Donovan, W. H. 04/22/2005. Thidiazuron. HED Chemistry Chapter of the Reregistration 

Eligibility Decision (RED). Summary of Analytical Chemistry and Residue Data. Case No. 

2600. 

Drew, D. 3/30/05. D312569. Thidiazuron: HED Chapter of the Reregistration Eligibility 

Decision (RED) Document.

Habiba, U. 09/25/13. TXR# 0056795. Forchlorfenuron and Phenyl Urea Herbicides: Summary 

of Hazard and Science Policy Council (HASPOC) Meeting of September 12, 2013: 

Recommendations on the Data Requirement for an Immunotoxicity Study for Forchlorfenuron 

and for the Phenyl Urea Herbicides as a Class.

Habiba, U. 04/14/15. TXR# 0057116. Thidiazuron: Summary of Hazard and Science Policy 

Council (HASPOC) Meeting of January 22, 2015: Recommendations on the Need for a 

Subchronic Inhalation Toxicity Study and Neurotoxicity (Acute and Subchronic) Studies

King, K. 12/16/14. D422745. Thidiazuron. Acute and Chronic Aggregate Dietary (Food and 

Drinking Water) Exposure and Risk Assessments for the Proposed Uses on Highbush Blueberry 

and Fescue Grass as well as registration review for all registered crops and updating crop group 

and sub-groups for Thidiazuron. 

Knizner, S. 05/27/09. Interim Guidance on Tolerance Expressions.

Lin, J. 06/25/14. Thidiazuron: Drinking Water Exposure Assessment for IR-4 Petition on 

Fescue, Oilseeds, Fruits, and Vegetables.

Loranger, R. 05/27/98. Thidiazuron. Conclusions of the 5/14/98 Meeting of the Metabloism 

Assessment Review Committee. 

Maher, I. 05/13/15. D427241. Thidiazuron: Drinking Water Exposure Assessment 

Memorandum for Preliminary Risk Assessment in Support of Thidiazuron Registration Review.

Recore, S. and Evans, E. 02/05/15. D425469. Thidiazuron: Tier 1 Review of Human Incidents

Savoia, P. 12/18/2014. Thidiazuron. Section 3 Registration for Grass Grown for Seed; Request 

for an Amended Use on Blueberry; Crop Group Conversions; Group 3 to Group 3-07, Group 8 to 
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Group 8-10, Group 10 to Group 10-10, Group 11 to Group 11-10; and Crop Subgroup 

Conversions: Caneberry to Subgroup 13-07A, Blueberry to Subgroup 13-07B, Grape to 

Subgroup 13-07F Except Fuzzy Kiwifruit, Strawberry to Subgroup 13-07G Except Cranberry, 

Cranberry to Subgroup 13-07H, Canola Seed to Subgroup 20A, Sunflower Seed to Subgroup 

20B Except Safflower, and Cotton Undelinted Seed to Subgroup 20C. Summary of Analytical 

Chemistry and Residue Data. 

Soderberg, D. 04/12/12. Thidiazuron: Submission of a Study of Residues on Safflower in 

Response to a RED Data Gap Requirement.

Tadayan, S. 10/30/14. Thidiazuron: Occupational and Residential Exposure and Risk 

Assessment for Registration Review and to Support the Registration of Proposed Uses on High 

Bush Blueberry and Fine Fescue Grasses.
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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.500) for food-use for thidiazuron are in Table 1. Use of the new guideline numbers 

does not imply that the new (1998) guideline protocols were used.

Study

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation..............................................

870.2600 Dermal Sensitization .....................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (non-rodent) .......................................

870.3200 28-Day Dermal..............................................................

870.3250 90-Day Dermal..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

yes

yes

yes a

yes

-

yes b

870.3700a Developmental Toxicity (rodent) ..................................

870.3700b Developmental Toxicity (non-rodent)...........................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent)..............................................

870.4100b Chronic Toxicity (non-rodent) ......................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse) ...................................................

yes

no

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Bacterial reverse mutation assay ....................

870.5300 Mutagenicity—In vitro mammalian cell gene mutation test.......

870.5375 Mutagenicity—In vitro mammalian chromosome aberration test

870.5385 Mutagenicity—Mammalian bone marrow chromosomal aberration test

870.5395 Mutagenicity—Mammalian erythrocyte micronucleus test........

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes c

870.6100a Acute Delayed Neurotoxicity (hen)...............................

870.6100b 90-Day Neurotoxicity (hen) ..........................................

870.6200a Acute Neurotoxicity Screening Battery (rat).................

870.6200b 90-Day Neurotoxicity Screening Battery (rat) ..............

870.6300 Developmental Neurotoxicity .......................................

no

no

yes

yes

no

-

-

yes b

yes b

-

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration........................................................

870.7800 Immunotoxicity .............................................................

yes

yes

yes

yes

yes

yes d

a Test was not submitted but is not required at this time because the toxicological data requirements for the 90-day feeding 

study in non-rodents are satisfied by the 1-year feeding study in dogs.

b Requirement waived by HASPOC (TXR # 0057116, 2015).

c Although not submitted, there are mutagenicity studies that evaluate both somatic and germinal cells, and are considered 

sufficient to satisfy CFR requirements.

d Requirement waived by HASPOC (TXR # 0056795, 9/25/2013).
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A.2 Toxicity Profiles

Table A.2.1 Acute Toxicity Profile - Thidiazuron

Guideline No. Study Type MRID(s) 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 Acute eye irritation - Rabbit 42099601 Irritation clearing 

within 48 hours

IV

870.2500 Acute dermal irritation - Rabbit 42099602 No dermal effects IV

870.2600 Skin sensitization - Guinea Pig 46121504 Not a skin 

sensitizer

NA

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Thidiazuron

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.3050 28-Day oral 

toxicity (rat)

46121509 (2001) 

-see under 46121506

Acceptable, guideline

♂♀: 0, 900, 1800, 3600

ppm

♂♀: 0, 67, 135, 254 

mg/kg/day

NOAEL = 67 mg/kg/day

LOAEL = 135 mg/kg/day based on ↓ serum 

glucose and urinary pH, small seminal vesicles 

and prostate gland, prominent liver lobulation, 

and focal/multifocal basophilic tubules in the 

kidneys

870.3100 90-Day oral 

toxicity (rat)

46121506 (2001)

Acceptable, guideline

♂♀: 0, 200, 600, 1800, 

5400, 16,200 ppm

♂: 0, 11.2, 34.5, 102, 294, 

NC mg/kg/day

♀: 0, 14.0, 42.1, 123, 325, 

NC mg/kg/day

NC = highest dose not 

calculated

NOAEL = 34.5 mg/kg/day

LOAEL = 102 mg/kg/day based on ↓ body 

weights, body weight gains, and food 

consumption; ↓ epididymides and prostate 

gland weight; ↑ ALP; ↑ urea; microscopic 

findings in: adrenal gland, kidney, liver, and 

spleen (♂♀); prostate gland, seminal vesicle, 

mammary gland, and thymus (♂); bone and 

marrow of the sternum and ovary (♀); small 

prostate and small seminal vesicles

At the high dose, all animals were either found 

dead or were sacrificed moribund by Day 10.

870.3100 90-Day oral 

toxicity (mouse)

46121505 (2001)

Acceptable, guideline

♂♀: 0, 500, 1000, 2000, 

4000 ppm

♂: 0, 85.2, 170.9, 351.4 

mg/kg/day

♀: 0, 99.8, 202.6, 383.9 

mg/kg/day

NOAEL = 85.2 mg/kg/day

LOAEL = 170.9 mg/kg/day based on ↓ 

cholesterol (♂); ↑ incidences of centrilobular 

hepatocellular hypertrophy (♂) and diffuse 

acinar hypertrophy in salivary glands (♀)

At the high dose, all mice died or were 

sacrificed moribund on Days 6-9. 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Thidiazuron

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.3150 90-Day oral 

toxicity (dog)

Not submitted Chronic dog study satisfies this data 

requirement

870.3200 28-Day dermal 

toxicity (rat)

46261501 (2004)

Acceptable, guideline

♂♀: 0, 100, 300, 1000 

mg/kg/day

NOAEL = 1000 mg/kg/day

LOAEL was not determined

870.3465 90-Day inhalation 

toxicity (species)

Not submitted Study requirement waived by HASPOC

870.3700a Prenatal 

developmental 

(rat)

00077127 (1981)

Acceptable, guideline

0, 25, 50, 100, 300

mg/kg/day

Maternal NOAEL = 300 mg/kg/day

LOAEL was not observed 

Developmental NOAEL = 100 mg/kg/day

LOAEL = 300 mg/kg/day based on decreased 

fetal body weight

870.3700b Prenatal 

developmental 

(rabbit)

46121507 (2003)

Acceptable, guideline

0, 5, 25, 125 mg/kg/day

46252001 – historical 

control data

46241001 – range-finding 

developmental toxicity 

study

Maternal NOAEL = 25 mg/kg/day

LOAEL = 125 mg/kg/day based on 5 abortions

(GD 27-29)

Developmental NOAEL = 25 mg/kg/day

LOAEL = 125 mg/kg/day based on 5 abortions

(GD 27-29), ↓ fetal body weights (↓12-13%); ↑ 

number of runts and delayed skeletal 

ossification

870.3800 Reproduction and 

fertility effects

(rat)

46209601 (2003)

Acceptable, guideline

♂♀: 0, 100, 400, 1200 

ppm 

♂: 0, 8.8, 35.4, 108.5 

mg/kg/day

♀: 0, 9.9, 39.8, 121.1 

mg/kg/day

Parental/Systemic NOAEL = 108.5 mg/kg/day

LOAEL was not observed

Reproductive NOAEL = 108.5 mg/kg/day

LOAEL was not observed

Offspring NOAEL = 35.4 mg/kg/day

LOAEL = 108.5 mg/kg/day based on delayed 

vaginal opening

870.4100a Chronic toxicity

(rat)

Not submitted. See 

870.4300.

-

870.4100b Chronic toxicity 

(dog)

00159344 (1985)

Acceptable, guideline

♂♀: 0, 100, 300, 1000 

ppm 

♂: 0, 3.93, 11.8, 38.3 

mg/kg/day

♀: 0, 4.01, 11.1, 36 

mg/kg/day

NOAEL = 3.93 mg/kg/day

LOAEL = 11.1 mg/kg/day based on increased 

incidence of anemia, changes in hematological 

parameters, and marked hemosiderosis in liver 

and spleen

Additionally at the high dose, findings such as 

increased spleen and lymph node weight, 

localized infiltration of lymphocytes in the 

mucosa of the gallbladder, early or progressive 

involution in the thymus, and interfollicular cell 

increase in the thyroid were noted.
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Thidiazuron

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.4200a Carcinogenicity

(rat)

Not submitted. See 

870.4300.

-

870.4200b Carcinogenicity

(mouse)

46346001 (2004)

Acceptable, guideline

♂♀: 0, 200, 650, 2000 

ppm 

♂: 0, 26.5, 86.7, 279.9 

mg/kg/day

♀: 0, 33.4, 107.8, 329.7 

mg/kg/day

NOAEL = 86.7 mg/kg/day

LOAEL = 279.9 mg/kg/day based on:

decreased body weight, body weight gain, and 

food consumption, decrease in renal 

corticoepithelial vacuolation (♂);

↑ epididymis toxicity (indicated by ↑ interstitial 

mononuclear cell infiltrate, unilateral and 

bilateral oligospermia, spermatic granuloma 

(♂)); ↑ clinical signs of toxicity (♀)

no evidence of carcinogenicity

870.4300 Combined 

Chronic Toxicity/ 

Carcinogenicity

(rat)

46345201 (2004)

Acceptable, guideline

♂♀: 0, 200, 900, 1800 

ppm 

♂: 0, 8.0, 36.4, 75.6 

mg/kg/day

♀: 0, 11.3, 51.4, 105 

mg/kg/day

NOAEL = 8 mg/kg/day

LOAEL = 36.4 mg/kg/day based on ↓ body 

weight and body weight gain (♂),

↑ bilateral seminal vesicle atrophy and 

nephrotoxicity (♂♀)

no evidence of carcinogenicity

870.4300 Combined 

Chronic Toxicity/ 

Carcinogenicity

(rat)

00159346 (1986)

Acceptable, non-guideline

♂♀: 0, 70, 200, 600 ppm 

♂: 0, 3.7, 10.6, 31.7 

mg/kg/day

♀: 0, 4.6, 13, 40.1 

mg/kg/day

NOAEL = 31.7 mg/kg/day

LOAEL was not determined

no evidence of carcinogenicity

870.5100 Genotoxicity

Ames bacterial 

gene mutation 

assay

46121508 (2001)

Acceptable, guideline

±S9, Trial 2: 0, 1.5, 5, 15, 

50, 150, 500, 1500 

μg/plate

No evidence of mutagenic activity was seen at 

any dose level tested in the presence or absence 

of S-9 mix in either mutation test.

870.5300 Genotoxicity

In vitro 

mammalian cell 

gene mutation in 

the HGPRT locus 

in Chinese 

Hamster V79 cells

41761102 (1990)

Acceptable, guideline

±S9: 15, 30, 100, 250

μg/plate

Not mutagenic. Test chemical did not cause 

mutations at the HGPRT locus in V79 cells.

870.5375 Genotoxicity

In vitro 

mammalian 

chromosome 

aberration assay 

46121510 (2001)

Acceptable, guideline

±S9: 0, 9.4, 18.75, 37.5, 

75, 150, 200, 250 μg/mL

Not mutagenic. There was no evidence of 

chromosome aberration induction above 

background in the presence or absence of S9 at 

either time point. 
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Thidiazuron

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.5385 Genotoxicity

Mammalian bone 

marrow 

chromosomal 

aberration test

070129 (1981)

Acceptable, guideline

2.4, 24, 120 mg/mL

Not mutagenic. No increase in micronucleated 

cells was observed.

870.5395 Genotoxicity

In vivo

chromosome 

aberration (mouse 

micronucleus) 

assay

Not submitted -

870.5550 Genotoxicity

Unscheduled 

DNA synthesis 

assay in primary 

rat hepatocytes

41761103 (1990)

Acceptable, guideline

0.25, 0.75, 2.5, 7.5, 25 

μg/mL

Not mutagenic. There were no indications of 

UDS activity.

870.6200a Acute 

neurotoxicity 

screening battery

Not submitted Study requirement waived by HASPOC

870.6200b Subchronic 

neurotoxicity 

screening battery

Not submitted Study requirement waived by HASPOC
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Table A.2.2 Subchronic, Chronic and Other Toxicity Profile - Thidiazuron

Guideline 

No. Study Type

MRID No. (year)/ 

Classification /Doses Results

870.7485 Metabolism and 

pharmacokinetics

(rat)

42529001 (1992)

Acceptable, guideline

(1) Single oral gavage

dose (10 or 1000 mg/kg)

(2) 14-day repeated oral

doses at 10 mg/kg (not 

radiolabeled) followed by 

a 10 mg/kg radiolabeled 

dose

Absorption occurred predominantly within 24 

hours at 10 mg/kg (single or repeated dosing) 

and within 48 hours at 1000 mg/kg. 

Absorption was 61-68% of the administered 

dose (AD) after a single 10 mg/kg dose, 74-

76% AD after repeated 10 mg/kg doses, and 

only 41-48% AD after 1000 mg/kg. 

After a single 10 mg/kg dose, urinary excretion 

accounted for 59-66% AD, and fecal excretion 

accounted for 29-31% AD. After repeated 10 

mg/kg dosing, urinary excretion accounted for 

72-74% AD, and fecal excretion accounted for 

26-28% AD. After a single 1000 mg/kg dose, 

urinary excretion accounted for 40-47% AD, 

and fecal excretion accounted for 56-60%. 

Approximately 0.1% AD or less was found in 

the expired air. 

At 120 hours post-dose, only <2% AD 

remained in the body, and the highest 

concentrations was found in the thyroid, whole 

blood, kidney, and adrenal glands. 

Negligible amounts of the parent was isolated 

in the excreta. The primary metabolites were 

4-hydroxy thidiazuron and 3 different 

conjugates of 4-hydroxy thidiazuron.

870.7600 Dermal 

penetration (rat)

46261502 (2004)

Acceptable, guideline

0.004, 0.04, 5.0 mg/cm2

Dermal absorption based on the amount in the 

systemic compartment (excreta & tissues) 

corresponding to the total amount of test 

chemical directly absorbed was similar after 

24-hour and 8-hour exposures with termination 

at 120 hours post-application (0.20% and 

0.22% for high dose, 0.75% and 1.25% for 

middle dose, and 1.18% and 1.17% for low 

dose). 

870.7800 Immunotoxicity 

(rat)

Not submitted Study requirement waived by HASPOC

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) – All Populations

Study Selected: None. No endpoint could be considered due to a single exposure.
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A.3.2 Chronic Reference Dose (cRfD)

Study Selected: Chronic toxicity study in dogs

MRID No.: 00159344

Executive Summary: See Appendix A.4, Guideline OPPTS 870.4200b

Dose and Endpoint for Risk Assessment: NOAEL = 3.93 mg/kg/day; LOAEL = 11.1

mg/kg/day based on increased incidence of anemia, changes in hematological parameters and 

marked hemosiderosis in liver and spleen

Comments about Study/Endpoint/Uncertainty Factors: The selected endpoints are the lowest 

values for this exposure scenario and are the most protective. A 100-fold uncertainty factor (10X 

interspecies and 10X intraspecies) was applied. Thus, a cRfD of 0.0393 mg/kg/day was 

calculated. The FQPA SF is 1X; therefore, the cPAD is also 0.0393 mg/kg/day. 

A.3.3 Incidental Oral Exposure (Short- and Intermediate-Term)

Study Selected: Prenatal developmental study in rabbits 

MRID No.: 46121507

Executive Summary: See Appendix A.4, Guideline OPPTS 870.3700b

Dose and Endpoint for Risk Assessment: Maternal NOAEL = 25 mg/kg/day; LOAEL = 125 

mg/kg/day based on abortions

Comments about Study/Endpoint/Uncertainty Factors: The selected endpoints are the lowest 

values for this exposure scenario and are the most protective. A 100-fold uncertainty factor (10X 

interspecies and 10X intraspecies) was applied. The FQPA SF is 1X. The residential level of 

concern for MOE = 100; an occupational LOC is not appropriate for this exposure scenario.

A.3.4 Dermal Exposure (Short-, Intermediate-, and Long-Term)

Dermal risk assessment was not required. No dermal or systemic toxicity was seen following 

repeated dermal applications at the limit dose (1000 mg/kg/day) in rats. Dermal absorption 

factor was only 1%. 

A.3.5 Inhalation Exposure (Short- and Intermediate-Term)

Study Selected: Prenatal developmental study in rabbits 

MRID No.: 46121507

Executive Summary: See Appendix A.4, Guideline OPPTS 870.3700b

Dose and Endpoint for Risk Assessment: Maternal NOAEL = 25 mg/kg/day; LOAEL = 125 

mg/kg/day based on abortions

Comments about Study/Endpoint/Uncertainty Factors: The selected endpoints are the lowest 

values for this exposure scenario and are the most protective. A 100-fold uncertainty factor (10X 

interspecies and 10X intraspecies) was applied. The FQPA SF is 1X. The occupational level of 

concern for MOE = 100; a residential LOC is not appropriate for this exposure scenario (no 

residential uses, only considers spray drift).
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A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90-Day Oral Toxicity - Rat

MRID 46121506: In a subchronic oral toxicity study (MRID 46121506), thidiazuron (99.5% 

a.i., Batch # 107623-03) was administered to 10 Wistar (RJ:WI[IOPS HAN]) rats/sex/dose in

the diet at dose levels of 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) for 90 days.

No treatment-related effects were observed at 200 or 600 ppm, or on ophthalmology or

hematology at any dose.

At >=1800 ppm in the males, decreased body weights, overall (Days 1-90) body weight gains,

and food consumption were observed. Increased serum alkaline phosphatase was noted.

Decreases were noted in absolute epididymides weight and absolute and relative (to body)

prostate gland weight, and small prostate gland and small seminal vesicles were observed. The

following alterations in microscopic pathology were noted: (i) slight to mild diminished

secretion of the prostate gland; (ii) slight to mild diffuse hypertrophy of the zona glomerulosa

of the adrenal gland; (iii) slight to mild vacuolation/mineralization glomerulopathy of the

kidney; (iv) slight to mild bilateral hyperplasia of the pelvic epithelium of the kidney; (v) slight

to mild mineralized concretions of the renal pelvis; (vi) slight focal mononuclear cell

inflammation of the kidney; (vii) slight to mild centrilobular hepatocellular hypertrophy; (viii)

slight to mild hyperplasia of germinal centers in the spleen; (ix) slight to marked diminished

secretion of the seminal vesicle; (x) slight to moderate diffuse atrophy of the mammary gland;

and (xi) slight to mild germinal centers in the medulla of the thymus.

At >=1800 ppm in the females, the following alterations in microscopic pathology were noted:

(i) slight to mild diffuse hypertrophy of the zona glomerulosa of the adrenal gland; (ii) slight to

mild vacuolation/mineralization glomerulopathy of the kidney; (iii) slight centrilobular

hepatocellular hypertrophy; (iv) slight to moderate adipose infiltration of the bone and marrow

of the sternum; (v) slight to mild hypertrophy of the interstitial gland of the ovary; and (vi)

slight to moderate hyperplasia of germinal centers in the spleen.

At >=1800 ppm, increased urea was observed in both sexes.

At 5400 ppm in the males, the following increases in relative organ weights were observed: (i)

adrenal gland; (ii) kidney; (iii) liver; and (iv) spleen. Relative testes weight was decreased.

Additionally, the following alterations in microscopic pathology were observed: (i) slight focal

mononuclear cell inflammation of the epididymis; (ii) slight focal mineralization of the inner

medulla of the kidney; (iii) slight to mild adipose infiltration of the bone and marrow of the

sternum; (iv) slight focal foamy alveolar macrophages; (v) slight focal hemorrhage of the lung;
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(vi) slight to mild germinal centers of the mesenteric and inguinal lymph nodes; and (vii) slight

unilateral atrophy of the seminiferous epithelium of the testes.

At 5400 ppm in the females, decreased body weights, overall (Days 1-90) body weight gains,

and food consumption were observed. Increased serum alkaline phosphatase and phosphorus

were noted. Decreases were noted in absolute and relative adrenal gland and uterus weights.

Increases in relative kidney and liver weights were observed, and decreased absolute

mesenteric lymph node weight was noted. Small uterus was observed. The following

alterations in microscopic pathology were observed: (i) slight to mild atrophy of the zona

reticularis of the adrenal gland; (ii) slight brown pigment in the zona reticularis of the adrenal

gland; (iii) no cyclical activity of the uterus; (iv) slight to marked diffuse atrophy of the

uterus; (v) slight to marked diffuse atrophy of the vagina; (vi) reduced numbers of recent

corpora lutea in the ovary; (vii) slight to mild diffuse atrophy of the mammary gland; (viii)

slight germinal centers of the mesenteric and inguinal lymph nodes; and (ix) slight to mild

atrophy of the trabecular bone.

At 5400 ppm in both sexes, rats exhibited piloerection, appeared thin, and excreted few feces.

Increased cholesterol and potassium were observed, and urine volume was increased.

At 16,200 ppm, males were observed to have hunched posture, and all animals demonstrated

deficits in righting, grasping, corneal, pupillary, head shaking, and auditory startle reflexes.

All animals in this dose group were either found dead or were sacrificed moribund by Day 10.

The LOAEL is 1800 ppm (equivalent to 102/123 mg/kg/day [M/F]), based on decreased

body weights, overall (Days 1-90) body weight gains, and food consumption, increased

serum alkaline phosphatase, decreased absolute epididymides and absolute and relative (to

body) prostate gland weight, small prostate and small seminal vesicles, and microscopic

findings in the prostate gland, seminal vesicle, mammary gland, and thymus of the males,

microscopic findings in the bone and marrow of the sternum and ovary of the females, and

increased urea and microscopic findings in the adrenal gland, kidney, liver, and spleen of

both sexes. The NOAEL is 600 ppm (equivalent to 34.5/42.1 mg/kg/day [M/F]).

This study is classified as acceptable/guideline and satisfies the guideline requirements (OPPTS 

870.3100a; OECD 408) for a subchronic oral toxicity study in the rat.

870.3100 90-Day Oral Toxicity - Mouse

MRID 46121505: In a subchronic oral toxicity study (MRID 46121505), Thidiazuron (99.5% 

a.i., Batch/Lot #: 107623-03) was administered to 10 C57BL/6JICO mice/sex/dose in the diet at

doses 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]) for up to 90 days.

Urinalysis, hematology, neurological evaluations, and ophthalmoscopic examinations were not

performed. There were no treatment-related macroscopic findings.
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All mice in the 4000 ppm group died or were sacrificed moribund on Days 6-9. In this group,

animals exhibited the following clinical signs of toxicity prior to their death or sacrifice: (i)

reduced motor activity, prostration, piloerection, dyspnea, cold to touch, thin appearance, and

hunched posture in both sexes; (ii) staggering step in males; and (iii) no feces in females.

Body weights were decreased by 28- 29% (p<=0.001) in the two males and three females still

alive on Day 8. Food consumption was decreased by 53-62% (p<=0.001) in both sexes for

Days 1-8.

At 2000 ppm, hunched posture was observed in two males and one female on Day 15, and

reduced motor activity was noted in one female on Days 28-29. Body weights were decreased

by 4-7% (p<=0.05) throughout treatment in the males, except Days 57 and 90, and throughout

treatment by 6-17% in the females. Overall (Days 1-90) body weight gains at this dose were

decreased in the males (decr. 19%; not significant) and females (decr. 40%; p<=0.001).

Weekly food consumption was decreased throughout treatment in the females (decr. 7-23%),

resulting in decreased average food consumption for the overall (Days 1-90) study (decr. 12%;

p<=0.01). Additionally in the 2000 ppm males, alkaline phosphatase was increased by 14%

(p<=0.05), and albumin was decreased by 9% (p<=0.05). At 2000 ppm in both sexes, terminal

body weights were decreased by 5-9% (p<=0.05), and relative (to body) liver weights were

increased by 10-16% (p<=0.01). Slight centrilobular hepatocellular hypertrophy was observed

in the 2000 ppm females (2/10 treated vs 0/10 controls).

At >=1000 ppm in the males, cholesterol was dose-dependently decreased by 16-34%

(p<=0.05) and absolute, relative (to body), and relative (to brain) kidney weights were

decreased by 9-15% (p<=0.01). The organ weight changes in the kidney were considered

equivocal because there were no macroscopic or microscopic findings in the kidney.

Additionally, slight centrilobular hepatocellular hypertrophy was observed in the >=1000 ppm

males (1-9/10 treated vs 0/10 controls). Increased incidences of slight diffuse acinar

hypertrophy were observed in the submaxillary salivary glands of the >=1000 ppm females (4-

8/10 treated vs 1/10 controls).

At 500 ppm, no treatment-related effects were found.

The LOAEL is 1000 ppm (equivalent to 170.9/202.6 mg/kg/day in M/F) based on decreased

cholesterol in the males and on increased incidences of centrilobular hepatocellular

hypertrophy in the males and diffuse acinar hypertrophy in the salivary glands in the

females. The NOAEL is 500 ppm (equivalent to 85.2/99.8 mg/kg/day in M/F).

This study is classified acceptable/guideline and satisfies the guideline requirement (OPPTS

870.3100; OECD 408) for a 90-day oral toxicity study in the mouse.
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870.3150 90-Day Oral Toxicity – Dog (no study submitted)

870.3200 21/28-Day Dermal Toxicity – Rat

MRID 46261501: In a 28-day dermal toxicity study (MRID 46261501), Thidiazuron (>99.9%

a.i., Batch #: 107623-03) was moistened with tap water and applied by semi-occlusive dressing

to the shaved intact skin of 10 HsdCpb:WU rats/sex/dose at dose levels of 0, 100, 300, or 1000

mg/kg bw/day (limit dose), 6 hours/day for 5 days/week (males and females received 20 and

21 applications, respectively) during a 29-day period.

No compound-related effects were observed in mortality, clinical signs, dermal effects, body

weight, body weight gain, food or water consumption, hematology, clinical chemistry,

ophthalmology, absolute or relative organ weights, gross or histologic pathology.

The LOAEL was not observed. The NOAEL was 1000 mg/kg/day (HDT) (limit dose).

This study is classified as acceptable/guideline and satisfies the Guideline requirement

(OPPTS 870.3200; OECD 410) for a 28-day dermal toxicity study in rats. A LOAEL was not

observed; however, the compound was tested at the limit dose.

870.3465 28-Day Inhalation – Rat (no study submitted)

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity Study – Rat

MRID 00077127: 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.

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.

No dams died during the course of the study. No clinical observations of toxicity were noted.

Although 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 minor (6%; 

Table 1).
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The maternal LOAEL was not observed. The maternal NOAEL is 300 mg/kg/day.

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 by 7% (Table

1). Although the magnitude of effect was similar in dams and fetuses, currently EPA considers a 

7% decrease in fetal body weights to be adverse, while a 6% decrease in maternal body weights 

is not considered adverse. There were no treatment-related 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 (OCSPP 870.3700a) and satisfies the requirements

for a developmental study in the rat.

COMMENTS: This is a revised Executive Summary only. The LOAEL statement for maternal 

toxicity was updated to reflect current EPA polices concerning body weight gain and body 

weight. 

870.3700b Prenatal Developmental Toxicity Study – Rabbit

MRID 46121507: 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) 
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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. 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 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). Body weight gain (both correct and uncorrected for gravid uterine weight) was 

decreased, but no statistical effect was noted on body weight. 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. As decreased food consumption did not 

adversely impact body weight, the effect was not considered adverse.

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. 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. 
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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.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effects – Rat

MRID 46209601: 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 0/0, 8.8/9.9, 35.4/39.8, and 108.5/121.1 mg/kg/day [M/F]). The P and F1 parents 

were dosed for 10 weeks before they were mated to produce the F1 and F2 litters. The F1 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 F2 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 

pre-mating (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). Only minor 

decreases of 5-7% (not statistically significant) in body weights were noted at Weeks 17 and 19 

in the P and F1 generations, respectively.

In the F1 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 was not observed. The NOAEL is 1200 ppm (equivalent 

to 108.5/121.1 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, organ weights, or gross 

pathology.

At 1200 ppm, body weight gains were decreased by 7-10% (p≤0.05) in the F1 pups during PND 

1-21 and during PND 1-28, and in the F2 pups during PND 1-28 in the males, and during PND 

1-21 and PND 1-28 in the females. No statistical differences were noted on body weights in 

either generation from Day 1 up to 28.
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No effects of treatment were observed at 100 or 400 ppm. 

The LOAEL for offspring toxicity was not observed. The NOAEL is 1200 ppm (equivalent 

to 108.5/121.1 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.

At 1200 ppm, the day to vaginal opening was increased (p≤0.01) by 3 days (from 34.3 to 37.3 

days). This effect was conservatively considered adverse.

The LOAEL for reproductive performance is 1200 ppm (equivalent to 108.5/121.1 

mg/kg/day [M/F]) based on delay in vaginal opening. The NOAEL is 400 ppm (equivalent

to 35.4/39.8 mg/kg/day [M/F]).

This study is classified as acceptable, guideline and satisfies the guideline requirements 

(OCSPP 870.3800; OECD 416) for a two-generation reproduction study in the rat.

COMMENTS: This is a revised Executive Summary only. The LOAEL statement for maternal 

and offspring toxicity was updated to reflect current EPA polices concerning body weight gain 

and body weight. The effect on vaginal opening was added.

A.4.4 Chronic Toxicity/Carcinogenicity

870.4300a Chronic Toxicity/Carcinogenicity Study – Rat

MRID 46345201: 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 
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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 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 
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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.

870.4100b Chronic Toxicity Study – Dog

MRID 00159344: 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 doserelated 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) compoundrelated changes in clinical chemistry parameters (alkaline phosphatase, total serum protein and 
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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.

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 highdose females with severe anemia had increased Kupffer cells, hemosiderin in the spleen,

increased splenic hematopoiesis, and iron-negative 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 (high-dose, 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].

A.4.5 Carcinogenicity

870.4300a Chronic Toxicity/Carcinogenicity Study – Rat, MRID 46345201 (See 

Section A.4.4)

870.4200b Carcinogenicity Study – Mouse 

MRID 46346001: 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.
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At 2000 ppm at the interim sacrifice (n=10), increased incidence of slight renal cortical 

basophilic tubules was observed in the females.

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.
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A.4.6 Mutagenicity

870.5100 Bacterial Reverse Gene Mutation Assay

MRID 46121508: In two independent reverse gene mutation assays in bacteria (MRID 

46121508), Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 and 

Escherichia coli strain WP2 uvrA/pKM101 (CM891) were exposed to Thidiazuron (98.7% 

purity, Batch/Lot #: CH 107623-02) in dimethylsulfoxide (DMSO) at concentrations of 0, 5, 15, 

50, 150, 500, 1500, or 5000 μg/plate (±S9, Trial 1), and 0, 1.5, 5, 15, 50, 150, 500, or 1500 

:g/plate (±S9, Trial 2). The standard plate incorporation method was performed in Trial 1 and a 

pre-incubation step was added in Trial 2. Standard strain-specific mutagens served as positive 

controls.

Thidiazuron was tested at up to the limit dose (5000 μg/plate) in Trial 1, and up to cytotoxic

concentrations (1500 μg/plate) in Trial 2. Cytotoxicity (indicated by an incomplete background 

lawn) was observed in all strains at >=1500 μg/plate in Trial 1 (plate incorporation test), and in 

all strains at >=500 μg/plate in Trial 2 (pre-incubation test). No treatment-related increases in the 

number of revertants/plate were observed in any bacterial strain at any dose level of Thidiazuron 

in the presence or absence of S9-activation, compared to solvent controls. The positive controls 

induced the appropriate responses. There was no evidence of induced mutant colonies over 

background under the conditions of these tests.

The study is classified as acceptable, guideline and satisfies the guideline requirement (OPPTS 

870.5100; OECD 471) for in vitro mutagenicity (bacterial reverse gene mutation) data.

870.5375 In Vitro Chromosomal Aberration Assay in Human Peripheral Blood 

Lymphocytes 

MRID 46121510: In independently performed mammalian cell cytogenetic (chromosome

aberration) assays (MRID 46121510), lymphocyte cultures prepared from human peripheral 

blood were exposed to Thidiazuron (98.7% a.i., Batch/Lot #: CH107623-02) in dimethyl 

sulfoxide for 4 hours at concentrations of 0, 9.4, 18.75, 37.5, 75, 150, 200, or 250 μg/mL both in 

the presence and absence of S9-activation, and for 20 hours at concentrations of 0, 4.7, 9.4, 

18.75, 37.5, 75, 150, or 200 μg/mL in the absence of S9-activation. Cells were harvested at 20 

hours after initiation of treatment.

Thidiazuron was tested up to cytotoxic concentrations (mitotic suppression; 53-60% at 150 

μg/mL [±S9] at 4 hours of exposure and 51% at 37.5 μg/mL [-S9] at 20 hours of exposure). No 

significant increases in aberration frequency were observed at up to 150 μg/mL (±S9) after 4 

hours of exposure or at up to 37.5 μg/mL (-S9) after 20 hours of exposure. The positive controls 

induced the appropriate response. There was no evidence of chromosome aberration induced 

over background in the presence or absence of S9-activation at either time point.

This study is classified as acceptable, guideline and satisfies the guideline requirement (OPPTS 

870.5375, OECD 473) for in vitro cytogenetic mutagenicity (chromosome aberration) data.
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A.4.7 Neurotoxicity (no study submitted)

A.4.8 Metabolism

870.7485 Metabolism – Rat

MRID 42529001: In a metabolism study (MRID 42529001), groups of male and female 

Sprague-Dawley CD rats were dosed with 14C-thidiazuron [(14C-aniline) thidiazuron or (14Cthiadizaole) thidiazuron (purity: >97% a.i.; batch No: 1695-3 and 1695-4)] at a single oral 

gavage dose (10 or 1000 mg/kg) or 14-day repeated oral doses of thidiazuron at 10 mg/kg 

followed by a single oral dose of 14C-thidiazuron at 10 mg/kg. An intravenous dose group was 

not included in this study.

The results of the pilot study showed that less than 0.2% of administered radioactivity was 

eliminated as 14CO2 from administration of either (14C-aniline) thidiazuron or (14C-thiadizaole) 

thidiazuron. In addition, the study showed no significant differences in the percentages 

eliminated through urine or feces from administration of the two radiolabeled forms.

Absorption of thidiazuron was rapid but incomplete at both doses, and appeared decreased at the 

high dose relative to the low dose. Elimination of thidiazuron was relatively rapid at the single 

low oral dose level. The major route of elimination was shown to be via urine. The single low, 

single high, and multiple low oral dose studies indicate that the total radioactivity recovered 

within 5 days after dosing in the urine and feces were 91-104% of administered dose. At the low 

dose, the radioactivity recovered in the urine and feces was 60-66% and 29-31% of the dose over 

a 5-day period, respectively. At the repeated low oral dose, the radioactivity recovered in the 

urine and feces was 73-75% and 26-28% of the dose over a 5-day period, respectively. At the 

high dose, the radioactivity recovered in the urine and feces was 41-47% and 56-60% of the dose 

over a 5-day period, respectively. Administration of a single high dose resulted in a decreased 

percentage of thidiazuron derived radioactivity eliminated in urine (approximately 20%), with 

concomitant rise in fecal elimination. This alteration is likely due to reduced absorption of test 

material at the high dose.

Terminal tissue distribution data showed that highest concentrations of thidiazuron derived 

radioactivity at sacrifice were found in the liver, kidneys, thyroid, whole blood and adrenals at 

both low and high doses. Repeated oral dosing did not significantly affect distribution of 

thidiazuron derived radioactivity.

Identification of urinary and fecal metabolites by TLC and HPLC indicated the presence of one 

oxidative metabolite in urine (4-hydroxy thidiazuron, metabolite J) and the presence of sulfate 

and glucuronide conjugates of 4-hydroxy thidiazuron (metabolites A/B, D, and F). However, 

insufficient evidence was presented to justify the presence of more than one sulfate and one 

glucuronide conjugate of 4-hydroxy thidiazuron in urine. This deficiency does not render the 

study inadequate, as the other possible oxidative metabolite(s) as candidates for conjugation 

represent a minor percentage of metabolized thidiazuron.
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In urine, the significant metabolites found at low dose were metabolite F (males, 36-38% of 

dose; females, 14-21%), metabolite J (males, 11%; females, 18-19%), metabolite A/B ( males, 

4%; females, 3- 6%), and metabolite D (males, 5-8%; females, 7-9%). Significant urinary 

metabolites in rats from the repeated low dose group were metabolites F (24-41%), metabolite J 

(12-25%), metabolite A/B (3-4%), and metabolite D (7-9%). Percentages of each of metabolites 

F and J rose slightly in both sexes of rats from repeated low dose administration, indicating a 

possible mild induction of metabolism. At high dose, the percentage of metabolite F in males and 

females (2% of dose) was smaller than that of metabolite J (7- 11%).

In feces, the major metabolites identified were 4-hydroxy thidiazuron (14-16%) at the low and 

repeated low dose, and unmetabolized thidiazuron (37-44%) at the high dose.

This study is classified as acceptable, guideline and satisfies the guideline data requirement for 

a metabolism study (85-1) in rats.

870.7600 Dermal Absorption – Rat 

MRID 46261502: In a dermal penetration study (MRID 46261502) Thidiazuron (99.9 %a.i.,

batch # OR 1844 (SEL/1098), [phenyl-U14C]-thidiazuron) was administered to 5 male Sprague

Dawley CD rats/dose to a 12 cm

2

area of the back in a formulation and water dilution thereof at

dose levels of 5.0, 0.04 and 0.004 mg/cm2. Exposure durations and percent of dose absorbed are

presented in the table below.

Dose Level

Mean Percentage of Dose Absorbed

1 hour 4 hours 8 hours 24 hours 24 hours* 72 hours* 120 hours*

5.0 mg/cm2 0.114 0.147 0.141 0.204 0.137 0.178 0.220

0.04 mg/cm2 0.214 0.406 0.388 0.754 0.634 0.660 1.252

0.004 mg/cm2 0.455 0.534 0.721 1.179 0.635 0.910 1.170

* washed at 8 hours

The mean total recoveries were in the range 88% and 99.54% dose for all groups. The amount

in the stratum corneum was 0.73%, 10.68% and 8.14% at 24 hours for the high, middle and low

dose groups respectively after a 24-hours exposure and 0.41%, 3.24% and 5.37% at 120 hours

following 8-hours exposure for the high, middle and low dose groups respectively. However,

the results showed that the majority of the radioactive material in the stratum corneum was lost

by desquamation and upward renewal of the stratum corneum with time.

This study in the rat is acceptable, guideline and satisfies the guideline requirement for a

dermal penetration study (870.7600) in rats.

A.4.9 Immunotoxicity (no study submitted)
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Appendix B. International Residue Limits Table

Table B. Summary of US and International Tolerances and Maximum Residue Limits for 

Thidiazuron (120301)

Residue Definition:

US Canada Mexico2 Codex

40 CFR 180.403:

thidiazuron (N-phenyl-N-1,2,3-

thiadiazol-5-ylurea) and its aniline 

containing metabolites

None None

Commodity1 Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex

Cattle, fat 0.4

Cattle, meat 0.4

Cattle, meat byproducts 0.4

Cotton, gin byproducts 24.0

Cotton, undelinted seed 0.3

Goat, fat 0.4

Goat, meat 0.4

Goat, meat byproducts 0.4

Hog, fat 0.4

Hog, meat 0.4

Hog, meat byproducts 0.4

Horse, fat 0.4

Horse, meat 0.4

Horse, meat byproducts 0.4

Milk 0.05

Sheep, fat 0.4

Sheep, meat 0.4

Sheep, meat byproducts 0.4

Completed: M. Negussie; 12/31/2014

1

Includes only commodities of interest for this action. Tolerance values should be the HED recommendations and 

not those proposed by the applicant.

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.
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Appendix C. Metabolites

TABLE C. Nomenclature for the Metabolites of Thidiazuron.

Compound Chemical Structure

Common Name 4-Hydroxy Thidiazuron

IUPAC Name 1-(4-hydrophenyl)-3-(1,2,3-thidizol-5-yl)urea

CAS Name N-(4-hydroxyphenyl-N-1,2,3-thidiazol-5-yl)urea

CAS Registry Number Not applicable

Compound Chemical Structure

Common Name Phenylurea

IUPAC Name 1-phenylurea

CAS Name N-phenylurea

CAS Registry Number 64-10-8

Appendix D. Physical/Chemical Properties

Table D. Physicochemical Properties of the Technical Grade Compound (Thidiazuron).

Parameter Value Reference

Melting point/range 217 °C D311632; T. Jimerson; 

pH (20 °C) 5.21 1/27/05

Density (20 °C) 0.324 gm/cc

Water solubility (25 °C, pH 7.0) 31.0 mg/L

Solvent solubility

(temperature not specified)

Very soluble in dimethylsulfoxide, 

dimethylformanide, acetone, 

cyclohexanone, and isophrone. Slightly 

soluble in aliphatic and aromatic 

hydrocarbons and water

Vapour pressure (20 °C) 3.5 x 10-9 mPa

Dissociation constant, pKa (25 °C) 8.86

Octanol/water partition coefficient, KO/W

(25 °C, pH 7.3)

50.0

UV/visible absorption spectrum λ max = 238 nm; ε = 985M-1cm-1
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Appendix E. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

PHED 1.1; the AHETF database; and the Outdoor Residential Exposure Task Force (ORETF) 

database; are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that review, 

and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review 

may have included review by the Human Studies Review Board. Descriptions of data sources, 

as well as guidance on their use, can be found at http://www.epa.gov/pesticides/science/handlerexposure-data.html and http://www.epa.gov/pesticides/science/post-app-exposure-data.html.