### Pa clob u trazol Hum an Health R isk Assessment D P No. D 39 4 230

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D.C. 20460

MEMORANDUM

Date: Septembe r 1 1, 2013 OFFICE OF CH EMICAL SAFETY

AND POLLUTION PRE VEN TION



### SUBJECT: Paclobutr azol: Preliminary Human Health Risk Assessment for Registra t ion

Review

PC C ode: 125601

Decision No.: 455061

Petition No.:

Risk Assessment Type: Sing le

Chemi cal/ Agg r ega t e
TXRNo.:

MRID No.: 45310801,45336601,45214201 DP Barcode: D 394230 Registration No.: Regulatory Action : Registration Re view

Case No.: 7002

CAS No.: 76738-62-0



### 40 CFR:

FROM: Monica Hawkins, Ph.D., M.P.H., Environmental

# H~~**h Sf.ie~f**  t

# ~/ ( 

## j)

Nancy M cCa rroll

, Ph.D.

, Gencll. ti c is :roxicol ogjst

# ~~**~** 

# llteu**.J~** Sheila Piper, Sen ior Chemist**uC!.JJo~:{j.-6--** 

# . Risk Assessment Bran c h VI

and

Charles Smit h

, Ch i ef

Risk Assessment**Branc...._._~** 

### Hea lth Effects Division (7509P) /7



### THROUGH: FeleciaFort

, C hi ef

--. 

# d&**t1--f** Ri sk Assessment Br anch V I

H ealth Effects Division

TO: K.h u e Ng u yen Risk Man age m ent and Impl eme ntation Branch I

Pesticide Re-evaluat i on Division (750 8P )

Page I of 58

### Paclobutrazol Human Health Risk Assessment DP No. D394230

The Health Effects Division (HED) of the Office of Pestic i de Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. As part of Registration Review)

the Pesticide Re-evaluation Division (PRD) of OPP has requested that HED evaluate the hazard

and exposure data and conduct dietary, occupational, residential, and aggregate exposure
assessments, as needed

, to estimate the risk to human health that will result from the registered

uses of paclobutrazol.

HED has evaluated the toxicity and exposure databases for the active ingredient, paclobutra z ol,

and has conducted a human health risk assessment in support of Registration Review. Based on this assessment, HED has determined that there are potential risk estimates of concern for the currently registered uses of paclobutrazol.

A summary of the findings and an assessment of human health risk resulting from the currently registered uses of paclobutrazol are provided in this document. The HED team members contributing to this risk assessment include Charles Smith (risk assessment), Monica Hawkins (occupational and residential assessment), Nancy McCaroll (hazard assessment), and Sheila Piper (chemistry assessment). Faruque Khan of the Environmental Fate and Effects Division (EFED) performed the drinking water assessment for paclobutrazol.

Page 2 of 58

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 3 of 58 1.0 Executive Summary

................................ ................................ ................................ ................... 5

2.0 Ingredient Profile

................................ ................................ ................................ ....................... 8

2.1 Struct ure and Nomenclature

................................ ................................ ................................ ... 8

2.2 Physical/Chemical Characteristics

................................ ................................ ......................... 8

2.3 Summary of Existing Uses

................................ ................................ ................................ ..... 9

2.4 Anticipated Exposure Pathways

................................ ................................ ........................... 10

2.5 Consideration of Environmental Justice

................................ ................................ .............. 10

3.0 Hazard Characterization and Dose

- Response Assessment

................................ ...................... 10

3.1 Toxicology Studies Available for Analysis

................................ ................................ ......... 10

3.2 Absorption, Distribution, Metabolism and Elimination (ADME)

................................ ....... 11

3.3 Toxicological Profile

................................ ................................ ................................ ............ 12

3.4 Consideration of Toxicity to Children

................................ ................................ ................. 12

3.4.1 Completeness of the Toxicology Database

................................ ................................ ... 12

3.4.2 Evidence of Neurotoxicity

................................ ................................ ............................ 13

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

............... 13

3.4.4 Residual Uncertainty in the Exposure Database

................................ ........................... 14

3.5 Toxicity Endpoint and Point of Departure Selections

................................ .......................... 14

3.5.1 Dose

- Response Assessment

................................ ................................ .......................... 14

3.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

............... 15

3.5.3 Cancer Classification and Risk Assessment Recommendations

................................ .. 15

3.6 Endocrine Disruption

................................ ................................ ................................ ........... 17

4.0 Dietary Exposure and Risk Assessment

................................ ................................ .................. 17

4.1 Summary of Environmental Degradation

................................ ................................ ............ 17

4.2 Food Residue Profile

................................ ................................ ................................ ............ 18

4.3 Water Residue Profile

................................ ................................ ................................ .......... 18

4.4 Dietary Risk Assessment

................................ ................................ ................................ ...... 19

4.4. 1 Acute Dietary Risk Assessment

................................ ................................ .................... 19

4.4.2 Chronic Dietary Risk Assessment

................................ ................................ ................ 19

4.4.3 Cancer Dietary Risk Assessment

................................ ................................ .................. 19

4.4.4 Dietary Risk Assessment Summary Table

................................ ................................ .... 20

5.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ .......... 20

5.1 Residential Handler Exposure and Risk

................................ ................................ ............... 20

5.2 Residential Postapplication Exposure and Risk

................................ ................................ ... 21

5.3 Combined Residential Risk Estimates

................................ ................................ ................. 24

6.0 Aggregate Exposure/Risk Characterization

................................ ................................ ............. 26

6.1 Acute Aggregate Risk

................................ ................................ ................................ .......... 26

6.2 Short

- and Intermediate

- Term Aggregate Risk

................................ ................................ .... 26

6.3 Chronic Aggregate Risk

................................ ................................ ................................ ....... 27

6.4 Cancer Aggregate Risk

................................ ................................ ................................ ......... 27

6.5 Updated Aggregate Assessment of Free Triazole & its Conjugates

................................ .... 27

7.0 Cumulative Exposure/Risk Characterization

................................ ................................ ........... 29

8.0 Occupational Exposure/Risk Characterization

................................ ................................ ........ 29

8.1 Short

- /Intermediate

- Term Handler Risk

................................ ................................ .............. 29

8.1.1 Short

- /Intermediate

- Term Handler Risk for Turf, Ornamental, and Tree Uses

........... 29

8.1.2 Short

- /Intermediate

- Term Handler Risk for Seed Treatments

................................ ...... 33

8.2 Occupational Post

- Application Exposure and Risk

................................ ............................. 37

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 4 of 58 9.0 References

................................ ................................ ................................ ................................ 39 Appendix A: Paclob utrazol Toxicity Profiles

................................ ................................ ..................... 40 Appendix B: Review of Human Research

................................ ................................ .......................... 57 Appendix C: Physical and Chemical Properties

................................ ................................ ................. 58

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 5 of 58 1.0 Executive Summary

As part of Registration Review, t he Pesticide Re

- evaluation Division ( P RD) of the Office of Pesticide Programs ( OPP ) has requested that the Health Effects Divisio n ( HED ) evaluate the hazard and exposure data and conduct dietary (drinking water only)

, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will

result from the registered uses of paclobutrazol

. A summary of the findings and an assessment of human health risk resulting from the currently registered uses of paclobutrazol are provided in

this document.

Use Profile : Paclobutrazol (α R ,β R )

- rel

- β

- [(4

- chlorophenyl)methyl]

- α

- (1,1

- dimeth ylethyl)

- 1 H

1,2,4

- triazole

- 1

- ethanol is a triazole plant growth regulator

. There are a number of currently registered labels for paclobutrazol with formulations including liquids, wettable powders, and granulars. It is currently registered for use as a f oliar spray for turf (including parks, athletic fields, residential lawns, and golf courses); a foliar spray for ornamentals in greenhouses and nurseries; as a tree injection; as a tree root drench; and as a seed treatment

. There are currently

no registere d food uses for paclobutrazol.

Hazard Assessment : The studies available for consideration of paclobutrazol toxicity provide a comprehensive database; however, t here are three outstanding studies according to revised 40 CFR Part 158 Toxicology Data Requirement

. These studies include an acute neurotoxicity (ACN) study, a subchronic neurotoxicity (SCN) study, and an immunotoxicity study ( D. Smegal, TXR0056149, 01/03/12 )

. The registrants have recently submitted the final ACN study report to the Agency . The Agency plans to review and incorporate the ACN into the revised Registration

Review risk assessment. In addition, as specified in the 2012 HASPOC memo, the Agency will

reevaluate the need for an SCN based on the results of the ACN. Consistent with current Agency policies, the need for an immunotoxicity study will also be reevaluated at that time.

In subchronic feeding studies in rats and dogs, the target organ was the liver, based on increased organ weights and alterations in clinical chemistry parameters associated with liver function. In agreement with the subchronic findings, the liver was the target organ following chronic exposure via the diet in dogs, rats, and mice. Adverse effects consisted of: increased liver weights, steatosis, and/or alterations in clinical chemistry parameters associated with liver

function.

A 21

- day dermal study in rabbits showed a dose

- related increase in the degree of hyperkeratosis, acanthosis, and inflammatory changes of the superficial dermis at higher doses. These effects are, however, local and no systemic effects were seen in the study.

Two pre

- natal developmental toxicity studies were available. In one study, there was evidence for increased qualitative susceptibility where d evelopmental effects, in the form of delayed ossification and cleft palates, were seen at a maternally toxic dose

. In another study, there was evidence for quantitative susceptibility; developmental effects characterized as renal dilation, hydrouretar minor skeletal defects were seen in the absence of maternal toxicity. There was no evidence (quantitative or qualitat ive) of increased susceptibility was seen following in utero

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 6 of 58 exposures to rabbit or following pre

- and/or post natal exposure in rats for two generations in the reproduction study.

Food Quality Protection Act (FQPA) considerations do not apply to paclobu trazol as the currently registered use patterns are all non

- food uses. However, a cute and subchronic neurotoxicity studies are required since p aclobutrazol is a member of the triazole chemical class which in general appear to be neurotoxic and there is no t sufficient data that evaluated the neurotoxic potential of paclobutrazol. Consequently, the default 10X database uncertainty factor (UF DB 

### ) has been retained for the lack of these studies. The Agency will reconsider this database uncertainty factor after the review of the recently submitted ACN study is completed

.

Following chronic dietary administration to mice, rats and dogs, the liver was the target organ for paclobutrazol

- induced toxicity. Liver toxicity manifested as alteration in hepatic enzymes, changes in liver weights and histopathological lesions in all three species.

Carcinogenicity studies are not required for non

- food use chemicals. Carcinogenicity studies in

mice and rats are available ; however, t he Agency was unable to determine the pote ntial carcinogenicity of paclobutrazol because the maximum tolerated dose (MTD) was not achieved

in the 2

- year carcinogenicity/chronic study in rats and the carcinogenicity/chronic study in mice. The carcinogenic potential of paclobutrazol will be re

- evaluated if the use pattern changes (i.e., food uses are proposed).

Food Residue Profile : There are no proposed or currently registered food uses for paclobutrazol

.

Drinking Water Profile : Paclobutrazol is a highly to moderately mobile c hemical that is expected to be fairly persistent in the environment. Based on the environmental fate parameters, there is the potential for paclobutrazol to reach drinking water resources. The Environmental Fate and Effects Division (EFED) performed Tier 1 surface water and groundwater modeling

. The results of this modeling were incorporated into the paclobutrazol dietary assessment.

Dietary Exposure and Risk: Although there are no registered food uses for paclobutrazol, dietary exposure is possible via drinking water. An acute dietary (drinking water only) exposure

assessment was not performed as n o appropriate endpoints were identified from the available pacl obutrazol toxicity studies for the acute dietary scenario

. A chronic dietary (drinking water only ) exposure assessment was performed that directly incorporated potential drinking water

residues

. The chronic dietary risk estimates are below HED’s level of concern for all population subgroups, including those comprised of infants and children.

Residential Exposure : R esidential handler exposures to the existing uses of paclobutrazol may

occur to adults via the dermal and inhalation route. All residential handler dermal exposure scenarios do not exceed HED’s level of concern (MOEs ≥ 1000) except for mixing/loading/applying with a belly grinder (MOE = 790).

Residential postapplication exposures to the existing uses of paclobutrazol may occur via the dermal and oral (non

- dietary ingestion) route. Dermal post

- application risks were assessed for

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 7 of 58 adults and children 1 < 2 years old while oral post

- application ri sks were assessed for children 1 < 2 years old. All adult and children mowing and golfing dermal risk estimates for both liquid and granular formulations do not exceed HED’s level of concern (MOEs ≥ 1000). All adult and children playing on treated turf dermal risk estimates for both liquid and granular formulations exceed HED’s level of concern (MOEs ≥ 1000). All children 1 < 2 years old oral non

- dietary ingestion risk estimates for both liquid and granular formulations do not exceed HED’s level of concern (MOEs ≥ 1000).

Aggregate Risk : An acute aggregate assessment was not performed as no appropriate endpoints were identified from the available paclobutrazol toxicity studies for the acute dietary (drinking water only) scenario. The chronic aggregate risk estimates are equivalent to the corresponding dietary risk estimates, which are not of concern

. The short

- and intermediate

- term toxicological endpoints for paclobutrazol are the same. As a result, for r esidential exposure scenarios, only

short

- term exposures were assessed. Chronic dietary exposure is considered to be a background exposure level to which the adult and children short

- term residential exposures are added. All of

the adult and children 1 < 2 years old chronic dietary + dermal aggregate risk estimates exceed HED’s level of concern (MOEs ≤ 1000) while a ll of the children 1 < 2 years old chronic dietary

+ hand

- to

- mouth aggregate risk estimates do not exceed HED’s level of concern (MOEs ≥ 1000).

Occupational Exposure/Risk: Occupational handler exposures to the existing turf, ornamental,

and tree uses of paclobutrazol may occur via the dermal and inhalation route. The short

- and

intermediate

- term risk estimates for most occupational handle r scenarios do not exceed HED’s

level of concern (MOEs > 1000) at some level of personal protective equipment (PPE)

. However, there are some handheld equipment scenarios that exceed HED’s level of concern (MOEs < 1000) even with the use of PPE

.

Occupatio nal handler exposures to the existing seed uses of paclobutrazol may occur via the

dermal and inhalation route for both primary handler s (i.e., those who treat the seed in

commercial seed treatment facilities) and secondary handler s (i.e., those who p lant paclobutrazol

treated seeds )

. The short

- and intermediate

- term risk estimates for all primary and secondary

handler scenarios do not exceed HED’s level of concern (MOEs > 1000) at some level of personal protective equipment (PPE)

.

Occupational postapplic ation exposures to the existing uses of paclobutrazol may occur via the

dermal route

. The short

- and intermediate

- term risk estimates for all occupational postapplication activities do not exceed HED’s level of concern (MOEs > 10 00) except for hand set irrigation in nurseries. The restricted entry interval (REI) listed on the existing paclobutrazol

labels is based on the acute toxicity of the technical material. Paclobutrazol is classified as Toxicity Category II for acute derma l toxicity and Toxicity Category III for eye and skin

irritation. In accordance with the Worker Protection Standard (WPS), acute T oxicity Category

II I and I I chemicals require a 24

- or 12

- hour REI , respectively

. Based on the acute dermal toxicity, t he 1 2

- hour REI that appears on the current paclobutrazol labels may not be adequate and should be revisited. Special consideration should also be given to use of hand set irrigation

in nurseries.

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 8 of 58 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 studies (listed in Appendix B ) have been determined to require a r eview of their ethical conduct and a ll

of the studies utilized in this assessment have received the appropriate review.

2 .0 Ingredient Profile

Paclobutrazol is a triazole plant growth regulator with a number of currently registered products.

2 .1 Structure and Nomenclature

Table 2 .1 : Flumethrin Nomenclature

Chemical Structure

Common Name Paclobutrazol

IUPAC name (2 RS, 3 RS )

- 1

- (4

- chlorophenyl)

- 4,4

- dimethyl

- 2

- (1 H

- 1,2,4

- triazol

- 1

- yl)pentan

- 3

- ol

CAS Name (α R ,β R )

- rel

- β

- [(4

- chlorophenyl)methyl]

- α

- (1,1

- dimethylethyl)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol
CAS Registry Number 76738

- 62

- 0

Chemical Class Triazole plant growth regulator



### 2 .2 Physical/Chemical Characteristics

The physical and chemical properties, as well as a summary of relevant environmental fate parameters are detailed in Appendix C.

Paclobutrazol’s vapor pressure ( 1.28 x 10 - 9 

### mm Hg @ 25.0°C ) and Henry's Law Constant (8.09 x

10 - 10 

### atm m 3 

### /mol) indicate that the compound is relatively non

- volatile under field conditions. The log K

ow 

### of 3.2 indicates the potential for this chemical to bioaccumulate in aquatic organisms. Paclobutrazol has a low solubility (25.9 mg/L) in water ; however, p aclobutrazol is a highly to moderately mobile chemical that is expected to be fairly persistent in the environment.

Based on the use pattern and environmental fate parameters, there is the potential for paclobutrazol to reach water resources.

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 9 of 58 2 .3 Summary of Existing Uses

There are a number of currently registered labels for paclobutrazol including liquid, wettable powder, and granular formulation s. It is currently registered for use as a foliar spray for turf (including parks, athletic fields, residential lawns, and golf courses); a foliar spray for ornamentals in greenhouses and nurseries; as a tr ee injection; as a tree root drench; and as a seed

treatment. Table 2 .3 provides more detail related to the currently registered uses of paclobutrazol.

Table 2.3: Paclobutrazol Use Patterns and Formulations

Formulation Use Sites Maximum Application Rate Application

Equipment REI Notes

Soluble

Concentrate Turf 0.75 lb ai/A Ground and

handheld 24 hrs or 12

hrs depending

on label Although p aclobutrazol turf

products do not appear to be specifically marketed towards residential handler use (i.e., homeowners); residential handler

use was assumed to be protective of any such use

Granul ar Turf 0.5 lb ai/A Ground and

handheld 12 hrs Although paclobutrazol turf products do not appear to be specifically marketed towards residential handler use (i.e., homeowners); residential handler

use was assumed to be protective of any such use

Soluble

Concentrate Tree Injection

(Soil injection at base of tree) 0.352 lb ai/tree Soil injection equipment N/A

Emulsifiable

Concentrate Pre

- plant

plugs/liners 0.0000051 lb ai/gal Plug/liner soak N/A

Emulsifiable

Concentrate Bulbs 0.00255 lb ai/gal Bulb soak N/A Application rate represents highest application rate for a bulb (freesia)

Emulsifiable

Concentrate Ornamental

Plants in

Greenhouses

and Nurseries 0.59 lb ai/A Ground and

handheld 12 hours Application rate represents highest application rate for an ornamental (chrysanthemums)

Soluble

Concentrate Tree Injection

(8 inch tree) 0.0099 lb ai/tree Pressurized injection system

N/A Application rates on labels are presented for multiple diameter trees; two application rates were selected to be representative of

those on the labels Tree Injection (35 inch tree) 0.07 lb ai/tree Pressurized injection system

Soluble

Concentrate Cucurbit Seed 0.00027 lb ai/lb seed

Commercial seed treatment equipment N/A On

- farm seed treatment is prohibited Tomato Seed 0.00414 lb ai/lb seed Pepper Seed 0.00247 lb ai/lb seed

Broccoli Seed 0.000661 lb ai/lb seed

Cauliflower

Seed 0.000635 lb ai/lb seed

Cabbage Seed 0.000639 lb ai/lb seed

Wettable

Powder Tree Injection

(6

- 16 inches in diameter) 0.000059 lb ai/tree Pressurized injection system

N/A Application rates on labels are presented for multiple diameter trees; two application rates were

selected to be representative of

those on the labels Tree Injection (>16 inches in diameter) 0.00024 lb ai/tree Pressurized injection system

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 10 of 58 2 .4 Anticipated Exposure Pathways

Humans are not expected to be exposed to paclobutrazol via food as the existing uses of paclobutrazol are all considered to be non

- food uses

. Drinking water exposure is expected based on the existing use pattern and environmental fate parameters of paclobutrazol . The existing

uses will also potentially result in residential handler and post

- application exposures

. A dditionally, there is a potential for occupational handler and post

- application exposure s

.

2 .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 populatio n 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 compi led by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) 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 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 postapplication are evaluated. Further considerations are currently in development as OPP has com mitted 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.

3.0 Hazard Characterization and Dose

- Response Assessment

3.1 Toxicology Studies Available for Analysis

The studies available for consideration of paclobutrazol toxicity provide a comprehensive database; however, t here are three outstanding studies according to revised 40 CFR Part 158

Toxic ology Data Requirement

. These studies include an acute neurotoxicity study, a subchronic neurotoxicity study, and an immunotoxicity study ( D. Smegal, TXR0056149, 01/03/12 )

. The registrants have recently submitted the final ACN study report to the Agency. The Agency plans to review and incorporate the ACN into the revised Registration Review risk assessment. In addition, as specified in the 2012 HASPOC memo, the Agency wil l reevaluate the need for an

SCN based on the results of the ACN. Consistent with current Agency policies, the need for an immunotoxicity study will also be reevaluated at that time. Data requirements for the non

- food uses of paclobutrazol are listed in Table A.1 in Appendix A. The data from the following studies were used to evaluate the hazard potential of paclobutrazol (see Appendix A: Tables A.2 and

A.3 ) :

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 11 of 58 Acute lethality studies (oral, dermal, inhalation, primary eye and dermal irritation,

and derm al sensitization) Subchronic oral toxicity studies [rat (with supplemental data) and dog) Developmental (2 rat and 2 rabbit) and reproductive toxicity (rat) studies (with supplemental data) Dermal toxicity (21

- day dermal toxicity in rabbits)

Chronic oral toxicity studies (rat and dog) Carcinogenicity studies [rat [chronic combined, with supplemental data) and
mouse] Metabolism studies (rat and dog) Mutagenicity battery Paclobutrazol hazard was last reviewed by HED’s RfD/Peer Review Committee in 1994 (Memo, G. Ghali, 6/21/94). New data have been submitted since that review was completed. 

### The registrant submitted a number of pieces of supplemental data (MRID 47338506) re lated to the 2

- generation reproduction study. These data include the following: individual pup clinical observational signs; historical control data for these observations; and data for achieved dietary levels based on nominal dietary concentrations, food consumption, and body weight. Additional data for achieved dietary levels were also received for the 90

- day feeding study in rats and for the 2

- year chronic feeding study in rats (MRID 47078901). These supplemental data have recently been reviewed (TXR. No.0056158). The risk assessment team has incorporated these data into th is risk assessment and reevaluated the points of departure and toxicity endpoints for the occupational and residential scenarios using current policies on selecting endpoints and unc ertainty factors.



### 3.2 Absorption, Distribution, Metabolism and Elimination (ADME)

Rats and dogs readily absorb low and high oral doses of paclobutrazol and excretion is rapid (70

to 80% of paclobutrazol is excreted within 72 hours). The major route of e xcretion is the urine but it is still present in the liver, kidneys, and gastrointestinal tract mostly as the parent compound after 72 hours. Paclobutrazol is included in the triazole alanine group of triazole derivatives. However, findings from a rat metabolism study indicate that the diol and carboxylic acid analogues of paclobutrazol are the major metabolites and that no triazole alanine was found.

3 .2.1 Dermal Absorption

A dermal penetration study in rats (MRID 41048202) was available for paclobutrazol in which male rats were dermally exposed on an area of 10 cm 2 

### /rat. The highest percentage of the absorbed dose and the remaining dose on the washed application site for exposures of 10 and 24 hours were: 0.011 mg/rat: total absorbed dose ( after 10 hours) = 15.1%; total absorbed dose (after 24 hours) = 24.5%. For risk assessment purposes, HED is using the conservative assumption that the dermal absorption of paclobutrazol is 24.5%.

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 12 of 58 3.3 Toxicological Profile

In subchronic feeding studies i n rats and dogs, the target organ was the liver, based on increased organ weights and alterations in clinical chemistry parameters associated with liver function. In agreement with the subchronic findings, the liver was the target organ following chronic exposure via the diet in dogs, rats, and mice. Adverse effects consisted of: increased liver weights, steatosis, and/or alterations in clinical chemistry parameters associated with liver

function.

A 21

- day dermal study in rabbits showed a dose

- related increase in the degree of hyperkeratosis, acanthosis, and inflammatory changes of the superficial dermis at higher doses. These effects are, however, local and no systemic effects were seen in the study.

Two pre

- natal developmental toxicity studies were available. In one study, there was evidence for increased qualitative susceptibility where developmental effects, in the form of delayed ossification and cleft palates, were seen at a maternally toxic dose. In another study, there was evidence for quantit ative susceptibility; developmental effects characterized as renal dilation, hydrouretar minor skeletal defects were seen in the absence of maternal toxicity. There was no evidence (quantitative or qualitative) of increased susceptibility was seen followin g in utero exposures to rabbit or following pre

- and/or post natal exposure in rats for two generations in the reproduction study.

Paclobutrazol has low toxicity in the rat, rabbit, and guinea pig via the oral (category III) route of exposure. It is mod erately toxic via the dermal route (category II) in rats and rabbits and via the inhalation route (category II) in rats. It is moderately irritating to the skin and the eye and is negative for dermal sensitization.

3. 4 Consideration of Toxicity to Children

Food Quality Protection Act (FQPA) considerations do not apply to paclobutrazol as the currently registered use patterns are all non

- food uses

. However, there are potential exposures to

infants and children from the residential uses of paclobutrazol. There are adequate pre

- and/or post natal toxicity studies that demonstrated no residual uncertainties to infants and children for pre and/or post natal susceptibility. The PODs used for assessing risks to infants and children

from dermal and inhalation exposures are based on the most sensitive developmental effects of

concern.

3

. 4 .1 Completeness of the Toxicology Database

The toxicology data base is not complete for this non

- food use chemical. T here are three outstanding toxicological stud ies for paclobutrazol according to revised 40 CFR Part 158 Toxicology Data Requirements. These studies include an acute neurotoxicity study, a subchronic neurotoxicity study , and an immunotoxicity study. The registrants have recently

submitted the final ACN study report to the Agency. The Agency plans to review and incorporate the ACN into the revised Registration Review risk assessment. In addition, as specified in the 2012 HASPOC memo, the Agency will reevaluate the need for an SCN based on

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 13 of 58 the result s of the ACN. Consistent with current Agency policies, the need for an immunotoxicity study will also be reevaluated at that time.

A n oral NOAEL is used for assessing inhalation risk for short and intermediate term exposure scenarios from occupational and residential uses. A repeated exposure inhalation study is not required at this time since the Margins of Exposure (MOEs) for all th e occupational and

residential inhalation exposure scenarios are greater than HED’s Level of Concern of 1000 which includes the conventional 100 (10X for inter

- species extrapolation and 10X for intra

species variation) and a 10X for data gaps

.

3 .4.2 Evide nce of Neurotoxicity

As discussed in Section 3 .4.1, neither an acute nor a subchronic neurotoxicity study has been conducted for paclobutrazol.

Paclobutrazol is a member of the triazole chemical class. Based on an initial review of the experimental to xicology databases for triazole pesticides, at least seven triazoles resulted in evidence of neurotoxicity and have points of departure (PODs) based on acute

, subchronic , or developmental neurotoxicity studies. Neurotoxic effects include reduced fore

- limb grip strength, hyperactivity, clinical signs (piloerection, diarrhea, tip toe gait, hunched posture), and changes in motor activity. Because the triazoles as a chemical class appear to be neurotoxic, and there is not

sufficient information to remove the requirements for these studies, the HASPOC concluded that the acute and subchronic neurotoxicity studies are required for paclobutrazol in accordance with revised 40 CFR Part 158 Toxicology Data Requirements ( D. Smegal, TXR0056149 , 01/03/12 )

. The registrants have recently submitted the final ACN study report to the Agency. The Agency plans to review and incorporate the ACN into the revised Registration Review risk assessment. In addition, as specified in the 2012 HASPOC memo, the Agency will reev aluate the need for an

SCN based on the results of the ACN. Consistent with current Agency policies, the need for an immunotoxicity study will also be reevaluated at that time.

3 .4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

No evidence of increased quantitative or qualitative susceptibility was observed in developmental toxicity studies in rabbits or in a two

- generation reproduction toxicity study in rats. However, increased quantitative susceptibility was seen in tw o developmental toxicity

studies in rats. Developmental effects, in the form of delayed ossification and cleft palates, were seen at a maternally toxic dose in rats in one study while renal dilation, hydroureter and minor

skeletal defects were seen in a s econd rat developmental study at doses lower than the highest dose tested, which was not toxic to the dams.

The concern is low for the increased susceptibility seen in the rats since: 1) clear NOAELs and LOAELs were established for the developmental eff ects seen in two studies conducted in this species, 2) there was no evidence of increased susceptibility in two studies with rabbits; 3) there was no evidence of increased susceptibility in the offspring following exposures for two generations in the repro duction study, and 4) the developmental endpoints are used for assessing risk from dermal and inhalation exposures. Thus, there are no residual uncertainties for pre

- and or post natal susceptibility.

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 14 of 58 3 .4.4 Residual Uncertainty in the Exposure Database

T here are no residual uncertainties with regard to dietary (drinking water only) and residential

exposure. C onservative, upper

- bound assumptions were used to determine exposure through drinking water and residential sources, such that these exposures have not been underestimated.

3.5 Toxicity Endpoint and Point of Departure Selections

3 .5.1 Dose

- Response Assessment

The details for selecting toxicity endpoints and points of departure (PODs) are presented in Appendix A2. Based on the existing use pattern for paclobutrazol , the expected exposure profile

will be for dietary (drinking water only), dermal , inhalation, and incidental oral exposures.

Acute Dietary : No appropriate endpoints were identified from the available paclobutrazol toxicity studies for the acute dietary (drinking water only) scenario

.

Chronic Dietary : Quantification of chronic dietary (drinking water only) risks was performed using the 2

- year chronic/carcinogenicity feeding study in rats with a NOAEL of 10.8 mg/kg/day

based on increased liver weights (both sexes), hypertrophy, and steatosis (both sexes) and decreased triglycerides (females) (LOAEL = 54.2 mg/kg/day)

. An Uncertainty Factor (UF) of 1000 was applied to account for interspecies extrapolation (10X), intraspe cies variability (10X), and the database uncertainty factor for lack of a neurotoxicity battery. The chronic reference dose ( cRfD) was calculated to be 0.01 mg/kg/day

.

Short

- term Dermal : Quantification of dermal risks was performed using a developmental rat study with a NOAEL of 10 mg/kg/day based on renal dilation, hydroureter and minor skeletal

defects or variations (LOAEL = 40 mg/kg/day)

. Since an oral dose was selected, a dermal absorption factor of 24.5% should be used in estima ting dermal risks (see Section 3 .2.1). A n MOE of 1000 is required which includes interspecies extrapolation (10X), intraspecies variability (10X), and the database uncertainty factor for lack of a neurotoxicity battery.

Short

- term Inhalation : Quantification of inhalation risks was performed using a developmental rat study with a NOAEL of 10 mg/kg/day based on renal dilation, hydroureter and minor skeletal defects or variations (LOAEL = 40 mg/kg/day)

. Since an oral dose was selected absorption via inhalation is presumed to be equivalent to oral absorption. A n MOE of 1000 is required which

includes for interspecies extrapolation (10X), intraspecies variability (10X), and the database uncertainty factor for lack of a neurotoxicity battery.

Short

- term Incidental Oral : Quantification of incidental oral ingestion risks was performed using

a 90

- day oral rat study with a NOAEL of 18.8 mg/kg/day based on elevated liver weights, and changes in clinical chemistry parameters associated with the liver (LOAEL = 93 mg/kg/day)

. A n MOE of 1000 is required which includes interspecies extrapolation (10X), intraspecies variability (10X), and the database uncertainty factor for lack of a neurotoxicity battery.

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 15 of 58 3 .5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

W hen there are potential occupational and residential exposures to a pesticide, the risk assessment must address exposures from three major sources: oral, dermal and inhalation exposures, and determine whether the individual exposures can be combined if the y have the same toxicological effects. For paclobutrazol

, dermal and inhalation exposures can be combined

since developmental toxicity from an oral study was selected for the dermal and inhalation

routes.

3 .5.3 Cancer Classification and Risk Assessment Recommendations

There are no currently registered food uses for paclobutrazol. Carcinogenicity studies are not required for non

- food use chemicals. Carcinogenicity studies in mice and rats are available for paclobutrazol and these studies were reviewed i n 1994 by the RfD Peer Committee (TXR 0011081). At that time the Agency was unable to determine the potential carcinogenicity of paclobutrazol because the maximum tolerated dose (MTD) was not achieved in the 2

- year carcinogenicity/chronic study in rats a nd the carcinogenicity/chronic study in mice. The carcinogenic potential will be re

- evaluated if the use pattern changes (i.e., food uses are proposed).

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 16 of 58 3 .5.4 Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

Table 3 .5 .4 a : Summary of Toxicological Doses and Endpoints for Paclobutrazol for Use in Dietary and

Non

- Occupational Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty

Factors Level of Concern for

Risk Assessment Study and Toxicological Eff ects

Acute Dietary No appropriate endpoints were identified from the available paclobutrazol toxicity studies for the acute dietary (drinking water only) scenario

.

Chronic Dietary NOAEL = 10.8 mg/kg/day UF A =10x

UF H =10x

UF D B =10x 10.8mg/kg/day NOAEL

1000 (UF)

cRfD = 0.11 mg/kg/day Chronic (2

- Year Rat) Feeding Toxicity MRID

40734301 LOAEL = 54.2 mg/kg/day 2 , based on increased liver weights (both sexes), hypertrophy, and steatosis (both sexes) and decreased triglycerides (females)

Incidental Oral

Short

- and Intermediate

Term NOAEL =

18.8 mg/kg/day UF A =10x

UF H =10x

UF D B =10x Residential LOC = 1000 90

- Day Oral Toxicity Study in Rats

MRID 00132689 LOAEL = 93 mg/kg/day, based on elevated liver weights and changes in clinical chemistry parameters associated with the liver

Dermal

Short

- and Intermediate

Term Oral NOAEL = 10

mg/kg/day

(Dermal Absorption rate = 24.5%) UF A =10x

UF H =10x

UF D B =10x Residential LOC = 1000 Developmental (Rat) Toxicity Study

MRID 00143158 LOAEL = 40 mg/kg/day, based on renal dilation, hydroureter

, and minor skeletal defects

or variations

Inhalation Short

- and

Intermediate

- Term Oral NOAEL = 10 mg/kg/day UF A =10x

UF H =10x

UF D B =10x Residential LOC = 1000 Developmental (Rat) Toxicity Study

MRID 00143158 LOAEL for this study is 40 mg/kg/day, based on renal dilation, hydroureter

, and minor

skeletal defects or variations Cancer (oral, dermal, inhalation) Not required for non

- food use pesticides

. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF D B = database uncertainty factor . MOE = margin of exposure. LOC = level of concern. N/A = not applicable.



### Table 3 .5 .4b : Summary of Toxicological Doses and Endpoints for Paclobutrazol for Use in Dietary and

Non

- Occupational Human Health Risk Assessments

Exposure/

Scenario Point of Departure Uncertainty

Factors Level of Concern for Risk

Assessment Study and Toxicological Effects

Dermal

Short

- and

Intermediate

- Term Oral NOAEL = 10 mg/kg/day

(Dermal Absorption rate = 24.5%) UF A =10x

UF H =10x

UF D B =10x Occupational LOC = 1000 Developmental (Rat) Toxicity Study

MRID 00143158 LOAEL = 40 mg/kg/day, based on renal dilation, hydroureter

, and minor skeletal

defects or variations

Inhalation Short

- and

Intermediate

- Term Oral NOAEL = 10 mg/kg/day UF A =10x

UF H =10x

UF D B =10x Occupational LOC = 1000 Developmental (Rat) Toxicity Study

MRID 00143158 LOAEL for this study is 40 mg/kg/day,

based on renal dilation, hydroureter

, and

minor skeletal defects or variations Cancer (oral, dermal, inhalation) Not required for non

- food use pesticides.

NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF D B = database uncertainty factor . MOE = margin of exposure. LOC = level of co ncern. N/A = not applicable.

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 17 of 58 3. 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, neurotoxici ty, 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 maturat ion, 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 registration review

, EPA will review these data and select the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), paclobutrazol is subject to the endocr ine screening part of the Endocrine Disr uptor 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

pro duced 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 t o 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

es tablish a dose

- response relationship between the do se 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. In November of 2010, issued test orders/data call

- ins for the second group of 134 chemicals, which contains 5 1 pesticide active ingredients

. Paclobutrazol is among the group of 51 pesti cide active ingredients

on the second list to be screened under the EDSP. Accordingly, as part of registration review,

EPA will issue future EDSP orders/data call

- ins, requiring the submission of EDSP screening assays for paclobutrazo l

. For further information on the status of the EDSP, the policies and procedures, the list of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please visit our website: http://www.epa. gov/endo/

.

4 .0 Dietary Exposure and Risk Assessment

4 .1 Summary of Environmental Degradation
Tier I Drinking Water Assessment for the Registration Review of Paclobutrazol, D395022, F. Khan,

01/05/12



### Available data suggest that p aclobutrazol is stable to hydrolysis and photolysis. Under aerobic conditions, paclobutrazol appears to be generally quite persistent in acidic soils, with half

- lives greater than 300 days. However in soils with neutral or higher pH, estimated half

- lives were as

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 18 of 58 short as 25 days . In anaerobic aquatic metabolism studies, paclobutrazol variably partitioned to the sediment and degraded with a half

- life of more than one year in flood loam and silt loam soils. Since, the extrapolated half

- lives were beyond the duration of experiment, paclobutrazol was considered stable in the anaerobic aquatic system. Paclobutrazol residues were persistent

and mobile in terrestr ial field dissipation studies. P aclobutrazol residues ranged from 450

- 950 days for orchard soils (CA

, WV , and FL) and 175

- 2 52 days in agricultural soils (MS, NC, and IL) . Two major environmental degradates, ketone analog of parent (CGA 149907, ≤ 40.0%) and

1H

- 1,2,4

- triazol

- 3

- ol (NOA457654, ≤ 25.1%) were identified in the environmental fate and terrestrial field dissipation stu dies.

4

. 2 Food Residue Profile

There are no curr ently registered food uses for paclobutrazol

.

4

. 3 Water Residue Profile

T here are no monitoring data currently available for paclobutrazol or its residues of concern in drinking water

. E stimated drinking water concentrations (EDWCs) were generated using computer modeling methods. T he screening model FIRST (FQPA Index Reservoir Screening Tool, version 1. 1 , 0 1 /01/0 7 ) was used to calculate the surface water EDWCs. Estimated groundwater EDW Cs were calculated using the screening model SCI

- GROW (Screening Concentrations in Ground Water, version 2.3, 07/29/ 03).

The surface water and groundwater modeling w ere conducted with the highest application rate scenario which is 6.1 lbs/A for nursery production of container

- grown ornamentals through soil drench method. This rate was normalized with the lowest fraction (0.59) of paclobutrazol retained in the soil column leaching study which resulted in an effective modeled drinking water application rate of 2.5 lbs/A. The maximum surface and ground water EDWCs for use in the

human health risk assessment for paclobutrazol are shown in Table 4 .3.

Table 4 .3: Maximum Estimated Surface Water and Groundwater Concentrations for

Paclobutrazol

Drinking Water Source Model Use rate (lbs ai/A/season) Acute (μg/L) Chronic

(μg/L)

Parent only

Surface water FIRST

2.50 1 133.5 43.5 2

Groundwater SCI

- GROW 20.0 20.0

1 Maximum rate of 6.1 lbs/A was normalized with the lowest fraction (0.59) of paclobutrazol retained in the soil column leaching study.

2 Bolded value was used for the chronic dietary assessment.

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 19 of 58 4

. 4 Dietary Risk Assessment

Although there are no registered food uses for paclobutrazol, dietary exposure is possible via drinking water. In accordance with typical HED dietary exposure assessments which incorporate potential residues in drinking water, the modeled drinking water residues were incorpora ted into

DEEM

- FCID in the categories “water, direct, all sources” and “water, indirect, all sources.”

4

. 4 .1 Acute Dietary Risk Assessment An acute dietary (drinking water only) exposure assessment was not performed as n o appropriate endpoints were iden tified from the available paclobutrazol toxicity studies for the acute dietary

scenario

.

4

. 4 .2 Chronic Dietary Risk Assessment

A chronic dietary (drinking water only) exposure assessment was performed that directly incorporated potential drinking water residues

. The estimated exposure (drinking water only) to the highest population subgroup (all infants < 1 year old ) resulted in an estimated risk equivalent

to 27% of the chronic referen ce dose (cRfD). The estimated exposure (drinking water only) to the general U.S. population resulted in an estimated risk equivalent to 8% of the chronic reference dose (cRfD).

4.4 .3 Cancer Dietary Risk Assessment

There are no currently registered food uses for paclobutrazol. Carcinogenicity studies are not required for non

- food use chemicals. Carcinogenicity studies in mice and rats are available for paclobutrazol and these studies were reviewed i n 1994 by the RfD Peer Committee (TXR 0011081). At that time th e Agency was unable to determine the potential carcinogenicity of paclobutrazol because the maximum tolerated dose (MTD) was not achieved in the 2

- year carcinogenicity/chronic study in rats and the carcinogenicity/chronic study in mice. The carcinogenic p otential and the need for a cancer dietary assessment will be re

- evaluated if the use pattern changes (i.e., food uses are proposed).

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 20 of 58 4.4

. 4 Dietary Risk Assessment Summary Table

Table 4.4 .4: Summary of Dietary ( Drinking Water Only) Exposure and Risk Es timates for Paclobutrazol

Population Subgroup Chronic Dietary

Dietary Exposure (mg/kg/day) % cPAD

General U.S. Population 0.000917 8

All Infants (< 1 year old) 0.003006 27

Children 1

- 2 years old 0.001362 12

Children 3

- 5 years old 0.001275 12

Children 6

- 12 years old 0.000879 8

Youth 13

- 19 years old 0.000663 6

Adults 20

- 49 years old 0.000856 8

Adults 50+ years old 0.000901 8

Females 13

- 49 years old 0.000853 8



### 5.0 Residential (Non

- Occupational) Exposure/Risk Characterization

Paclobutrazol is currently registered for use as a foliar spray for turf (including parks, athletic fields, residential lawns, and golf courses). Although, paclobutrazol products do not appear to be specifically marketed towards residential handler use (i .e., homeowners); a residential handler assessment was performed to be protective of any such use. A residential postapplication assessment was also performed as use of paclobutrazol in parks, residential lawns, and golf courses is expected to result in r esidential postapplication exposure. In assessing these exposures, the Health Effects Division’s 2012 Standard Operating Procedures for Residential Pesticide Exposure Assessment: Lawns/Turf was used. Some of the data included in the

Lawns/Turf SOP are p roprietary and thus are subject to the data protection provisions of the Federal Insecticide, Fungicide, and Rodenticide Act ( FIFRA ).

5 .1 Residential Handler Exposure and Risk

Residential handler exposures may occur via the dermal and inhalation route s while a homeowner is using paclobutrazol to treat a residential lawn. As a result, a dermal and

inhalation residential handler exposure assessment was performed for paclobutrazol

. The duration of handler exposure relevant to the proposed use pattern is s hort

- term

. Dermal and

inhalation handler risks were assessed only for adults. Based on the existing use pattern, HED expects the following residential pesticide handler s cenarios :

1) mixing/loading/applying liquids with a backpack sprayer; 2) mixing/loading/a pplying liquids with a manually pressurized sprayer; 3) mixing/loading/applying liquids with a hose

- end sprayer;

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 21 of 5 8 4) loading/applying granulars via a push

- type spreader; and 5) loading/applying granulars via a belly grinder.

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 the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Outdoor Residential Exposure Task Fo rce (ORETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., ORETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting reside ntial handler exposure that are used in this assessment, known as “unit exposures”, are outlined in 2012

Lawns/Turf SOP.

All residential h andler dermal exposure scenarios do not exceed HED’s level of concern (MOEs
≥ 100 0 ) except for the belly grinder scen ario (MOE = 790) . Handler exposure and risk estimates

are summarized in Table 5 .1. 1

.

Table 5 .1.1: Residential Handler Exposure and Risk Estimates for Paclobutrazol

Scenario Application

Rate a (lb ai/A) Area

Treated Daily b
(acres/day) Dermal

Unit Exposure b
(mg/lb ai) Inhalation

Unit Exposure b
(mg/lb ai) Dermal

Dose c (mg/kg/day) Dermal

MOE d Inhalation

Dose e (mg/kg/day) Inhalation

MOE f Total

Dermal +

Inhalation

MOE

Mixer/Loader/Applicator (Liquids)

- Manually

Pressurized Handwand Application

Turf 0.75 0.023 g 63 0.018 0.0033 3000 0.0000039 2600000 3000

Mixer/Loader/Applicator (Liquids)

- Hose End Sprayer Application 0.5 13.4 0.022 0.024 2500 0.000048 1200000 2500

Mixer/ Loader/Applicator (Liquids)

- Backpack Sprayer Application 0.023 g 130 0.14 0.0069 1500 0.00003 330000 1400

Mixer/Loader/Applicator (Granules)

- Push Type Spreader Application 0.5 0.5 0.81 0.0026 0.00062 16000 0.0000081 1200000 16000

Mixer/ Loader/Applicator (Granules)

- Belly Grinder Application 0.023 g 360 0.039 0.013 790 0.0000056 1800000 790

a. Application rates = maximum application rates from labels.

b. Data taken from 2012 Lawns/Turf SOP

. c. Dermal Dose = exposure (mg/lb ai) x App Rate x Area Treated x %Abs (24.5% dermal ) / Body weight (80 kg). d. Dermal MOE = NOAEL ( 10 mg/kg/day)/Dermal Dose

.

e. Inhalation Dose = Unit exposure (mg/lb ai) x App Rate x Area Treated x %Abs (100% inhalation ) / Body weight (80 kg).

f

. Inhalation MOE = NOAEL (10 mg/kg/day ) / Inhalation Dose (mg/kg/day) g. 0.023 acres is equivalent to 1,000 ft 2

.



### 5 .2 Residential Postapplication Exposure and Risk

Residential postapplication exposures may occur via the dermal and oral routes after a residential lawn is treated with paclobutrazol. Residential postapplication exposures may also occur via the dermal route after a golf course is treated with paclobutrazol. As a result, a dermal residential postappl ication exposure assessment was performed for paclobutrazol

. Based on the existing use pattern, HED expects the following residential postapplication s cenarios :

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 22 of 58 1) dermal postapplication exposure for adults playing on treated turf; 2) dermal and oral postappli cation exposure for children 1<2 years olds playing on treated turf; 3) dermal postapplication exposure for adults and children 11 < 16 years old mowing 

### treated turf; and 4) dermal postapplication exposure for adults, children 11 < 16 years old, and children 6 < 11

years old 

### playing golf on treated turf.

The lifestages (i.e., 

### adults, children 1<2 years old, children 11 < 16 years old, and children 6 < 11 years old) selected for each postapplication scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs. These lifestages are not the only lifestages that could be potentially exposed for these postapplication scenarios; however, the assessment of these lifestages is health protective for the exposures and risks for any other poten tially exposed lifestages.



### Dermal and oral exposures during postapplication activities were estimated using exposure algorithms and other standard assumptions (e.g., transfer coefficients, exposure time, fraction of pesticide on hands, hand

- to

- mouth events) taken from the 2012 Lawns/Turf SOP. A TTR study was also used to assess the liquid formulation scenarios ( Turf Enhancer® 2SC Plant Growth Regulator Transferable Turf Residue Study

– MRID No.: 45214201). Data were collected at

three sites in the T TR study including New York, California, and North Carolina. Data from the California site was used in this assessment as it resulted in the highest predicted Day 0 residues.

5 .2. 1 Dermal Postapplication Exposure

All adult and children mowing and golf d ermal risk estimates for both liquid and granular

formulations do not exceed HED’s level of concern (MOEs ≥ 1000). All adult and children playing on treated turf dermal risk estimates for both liquid and granular formulations exceed

HED’s leve l of concern (MOEs ≥ 1000). A summary of the adult and children short

- term dermal exposure and risk estimates is shown in Table 5 .2. 1

.

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 23 of 58 Table 5 .2.1: Short

- Term Dermal Residential Post

- application Exposure and Risk

Estimates for Paclobutrazol

Lifestage Post

- application Exposure Scenario Application Rate a
(lb ai/A) TTR

(ug/cm2) Dermal Dose b

(mg/kg/day) Dermal

MOEs c
Liquid Formulation s

Adult

Dermal Physical Activities on Turf

0.75 0.077 d 0.064 160 Mowing 0.0013 7700 Golfing 0.005 2000

Child 11 < 16 years old Mowing 0.0015 6700 Golfing 0.0058 1700 Child 6 < 11 years old Golfing 0.0069 1500 Child 1 < 2 year old Physical Activities on Turf 0.12 82

Granular Formulation s

Adult

Dermal Physical Activities on Turf

0.5 0.011 e 0.010 970 Mowing 0.00019 53000 Golfing 0.00073 14000

Child 11 < 16 years old Mowing 0.00022 46000 Golfing 0.00084 12000 Child 6 < 11 years old Golfing 0.00099 10000 Child 1 < 2 year old Physical Activities on Turf 0.019 520

a. Application rates = maximum application rates from labels.

b. Dermal Dose (mg/kg/day) = TTR (μg/cm 2 ) x 0.001 (mg/μg) x short

- term TC (cm 2 /hr) x ET (hr/day) x DAF (40%) BW (kg)

c. Dermal MOE = NOAEL (10 mg/kg/day) / Dermal Dose (mg/kg/day) d. Representative of California TTR data taken from MRID No.: 45214201 ; the site that resulted in the highest TTR values. e. Turf Transferable Residues (TTR) = Application Rate x 0.2 % x 11.2



### 5 .2. 2 Oral Postapplication Exposure

All children oral non

- dietary ingestion risk estimates for both liquid and granular formulations do not exceed HED’s level of concern (MOEs ≥ 1000). A summary of the children short

- term
oral non

- dietary ingestion exposure and risk estimates is shown in Table 5 .2. 2.

Table 5 .2. 2 : Short

- Term Oral Non

- dietary Ingestion Residential Post

- application

Exposure and Risk Estimates for Paclobutrazol

Lifestage Post

- application Exposure Scenario Application Rate a
(lb ai/A) TTR

(ug/cm2) Oral Dose b, c, d

(mg/kg/day) Oral

MOEs e
Liquids

Child 1 < 2 year old Oral Hand

- to

- Mouth

0.75 0.077 f 0.01 0 1800 Object

- to

- Mouth 0.00032 59000 Soil Ingestion 0.000025 770000

Granulars

Child 1 < 2 year old Oral Hand

- to

- Mouth

0.5 0.011 g 0.00074 25000 Object

- to

- Mouth 0.00023 82000 Soil Ingestion 0.000016 1200000 Episodic Granular Ingestion N/A h

a. Application rates = maximum application rates from labels.

b. Hand

- to

- Mouth Dose (mg/kg/day) = E = [HR * ( F M * SA H ) * (ET * N_Replen) * (1

- (1

- SE ) (Freq_Replen/N

- Replen) )] c. Object

- to

- Mouth Dose (mg/kg/day) = E = [OR* CF1 * SAM O * (ET * N_Replen) * (1

- (1

- SE O ) (Freq_Replen/N_Replen) )]

d. Soil Ingestion Dose (mg/kg/day) = E = SRt * SIgR * CF1

e. Oral MOE = NOAEL (1 8.8 mg/kg/day) / Oral Dose (mg/kg/day) f. Representative of California TTR data taken from MRID No.: 45214201 ; the site that resulted in the highest TTR values. h. Turf Transferable Residues (TTR) = Application Rate x 0.2 % x 11.2 g. No endpoints identified from the ava ilable developments toxicity studies (rat and rabbit) appropriate for an acute dietary assessment for paclobutrazol and thus no assessment is required for episodic granular ingestion.

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 24 of 58 5 .2. 3 Inhalation Postapplication Exposure

Based on the Agency's current practices, a quantitative residential postapplication inhalation exposure assessment was not performed for paclobutrazol at this time primarily because paclobutrazol’s vapor pressure ( 1.28 x 10 - 9 

### mm Hg @ 25.0°C ) and Henry's La w Constant (8.09 x

10 - 10 

### atm m 3 

### /mol) indicate that the compound is relatively non

- volatile under field conditions. However, volatilization of pesticides may be a potential source of postapplication inhalation exposure to individuals nearby pesticide appli cations. 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 Marc h 2, 2010 ( http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html ). The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorpor ate postapplication inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative postapplication inhalation exposure assessment

for paclobutrazol.

5 .3 Combined Residential Risk Estimates

HED combines risk values resulting from separate exposure pathways when it is likely they can occur simultaneously based on the use pattern

, the behavior associated with the exposed population , and the hazard associated with the points of departure

. HED reviewed all residential sources of exposure to determine which residential exposure scenarios would be appropriate to combine with dietary exposure for an aggregate risk assessment

.

HED did not combine exposure resul ting from adult handler and postapplication exposure resulting from treated lawns and /or golf ing because of the conservative assumptions and inputs within each estimated exposure scenario. HED believes that combing exposures resulting from handler and pos tapplication activities would result in an overestimate of adult exposure. Therefore, HED selected the most conservative adult residential scenario, dermal postapplication exposure (MOE = 160 ) as the contributing source of residential exposure to be combi ned with the dietary exposure for the aggregate assessment.

The children’s oral exposure is based on postapplication hand

- to

- mouth exposures only. To include exposure from object

- to

- mouth and soil ingestion in addition to hand

- to

- mouth could

result in a very conservative estimation of exposure

, as it would overestimate the potential f or oral exposure. Furthermore, although there is the potential for co

- occurrence of dermal and oral exposure, the toxicological effects from the dermal and oral routes of ex posure are different. As a result, a combined residential exposure assessment is not possible for children. Therefore, two independent children’s aggregate assessments are required (postapplication dermal combined with dietary exposure and postapplicatio n oral combined with dietary exposure) to ensure no unacceptable risk will result to children when combining residential and dietary exposure for purposes of estimating an aggregate risk

.

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 25 of 58 Table 5 .3 summarizes the residential exposure scenarios that are to be used for estimating

aggregate exposure.

Table 5 .3. Combined Residential Exposure and Risk Estimates for Paclobutrazol

Use Site Handler

Dermal a Handler

Inhalation a Post

- application

Dermal MOE b Hand

- to

- Mouth

MOE c

Dose MOE Dose MOE Dose MOE Dose MOE

Adults

– Turf (Granulars) 0.013 790 0.0000056 1800000 0.010 970 N / A

Adults

– Turf (Liquids) 0.0069 1500 0.00003 330000 0.064 160 N / A

Children 1 < 2 Years Old

- Turf (Granulars) N / A N / A 0.019 520 0.00 0 74 25000

Children 1 < 2 Years Old

- Turf (Liquids) N / A N / A 0.12 82 0.0 10 1800

a. See Table 5 .1. 1 : Residential Handler Dermal Exposure and Risk ( granulars represents belly grinder and liquids represents backpack sprayer )

b. See Table 5 .2. 1 Dermal Po stapplication Exposure and Risk

c. See Table 5 .2. 2 Hand

- To

- Mouth Exposure and Risk



### 5 .4 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 off

targe t 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). Th e potential risk estimates from these residues can be calculated using drift modeling coupled with methods employed for residential risk assessments for turf products.

The approach to be used for quantitatively incorporating spray drift into risk assessme nt 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 prevent them. 1 

### Direct exposures would include in halation 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, exp osures 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.

Paclobutrazol is not registered on use sites that are likely to result in spray drift outside of the currently registered turf uses

. Since p ostapplication exposure from the direct turf application s is already assessed for paclobutrazol ( see above in Section 5.2 ), quantitative assessment of spray drift is not required for paclobutrazol at this time.

1 This approach is consistent with the requirements of the EPA’s Worker Protection Standard which,
when included on all labels, precludes direct exposure pathways.

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 26 of 58 6.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposur es and risks from three major sources: food, drinking water, and residential exposures. In an aggregate assessment, exposures from relevant sources are added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks th emselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure.

6 .1 Acute Aggregate Risk

An acute dietary (drinking water only) exposure assessment was not performed as n o appropriate endpoints were identified from the available paclobutrazol toxicity studies for the acute dietary

scenario

.

6.2 Short

- and Intermediate

- Term Aggregate Risk

The short

- and intermediate

- term toxicological endpoints for paclobutrazol are the s ame for each route of exposure. Therefore, for residential exposure scenarios, only short

- term exposures were assessed, and are considered to be protective of intermediate

- term exposure and risk.

T here are six aggregate risk scenarios that are of interest to HED: 1) adult dermal postapplication expo sure to granular formulations ; 2 ) adult dermal postapplication expo sure to liquid formulations; 3 ) children’s postapplication dermal exposure to granular formulatio ns; 4 )

children’s postapplication dermal exposure to liquid formulations; 5 ) children’s hand

- to

- mouth

exposure to granular formulations; and 6) children’s hand

- to

- mouth exposure to liquid

formulations

. Exposure from these six scenarios is aggregated with c hronic dietary exposure (drinking water only) which is considered to be background exposure.

For the adult short

- and intermediate

- term aggregate risk assessment, chronic dietary exposure is added directly to the adult dermal postapplication exposure est imate s . The chronic dietary exposure estimate for the general U.S. population was used to determine the aggregate risk

estimate.

For the children’s short

- and intermediate

- term aggregate risk assessments, chronic dietary exposure is added directly to the children’s postapplication dermal and oral exposure estimates. As the toxic effects are different for these two routes of exposure, separate calculations were performed. H and to mouth and dermal exposures for children 1 < 2 years old were separately

com bined with the chronic dietary exposure for children 1 < 2 years old

.

All of the adult and children 1 < 2 years old chronic dietary + dermal aggregate risk estimates exceed HED’s level of concern (MOEs ≤ 1000). All of the children 1 < 2 years old chronic dietary + hand

- to

- mouth aggregate risk estimates do not exceed HED’s level of concern (MOEs ≥ 1000). The results of the adult and children’s aggregate risk determinations are presented in

Table 6 .2.

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 27 of 58 Table 6 .2: Short

- and Intermedia te

- Term Aggregate Risk Calculations

Lifestage Residential

Scenario NOAEL

(mg/kg/day) LOC 1 Chronic Dietary Dose for Drinking Water Only (mg/kg/day) Residential

Postapplication

Dermal Exposure 2
(mg/kg/day) Residential

Postapplication

Hand

- to

- Mouth Exposure 3
(mg/kg/day) Total

Exposure 4
(mg/kg/day) Aggregate

MOE (food, water, and residential) 5

Adult Male Dermal Turf

Granular

10

1000 0.000917 0.01 N/A 0.0109 920

Dermal Turf

Liquid 0.064 N/A 0.0649 150

Children 1 < 2 yrs old Dermal Turf

Granular

0.001362 0.019 N/A 0.0204 490

Dermal Turf

Liquid 0.12 N/A 0.1214 82

Children 1 < 2 yrs old HtM Turf

Granular 18.8 N/A 0.00074 0.0021 9000

HtM Turf

Liquid N/A 0.010 0.01136 1700

1 The level of concern is 100 0 which account s for interspecies extrapolation (10x)

, intraspecies variation (10x) and additional

database uncertainty factor (10x)

. 2 Residential Exposure = Dermal exposur e from treated turf (see Table 5 .2. 1 ).

3 Residential Exposure = Hand

- to

- mouth exposure from treated turf (se e Table 5 .2. 2 ).

4 Total Exposure = Chronic Food & Water Exposure + Residential Exposure

5 Exposure]



### 6 .3 Chronic Aggregate Risk

T he chronic aggregate risk assessment is equivalent to the chronic dietary ris k assessment (discus sed in Section 4 .4.4) as there are no residential scenarios that result in long

- term

exposure. All of the chronic dietary risk estimates do not exceed HED’s level of concern.

6 .4 Cancer Aggregate Risk

Paclobutrazol currently has no registered food uses and carcinogenicity studies are not required

for non

- food use pesticides under the 40 CFR Part 158 Toxicology Data Requirements. The Agency has not classified the carcinogenic potential of paclobutrazol and thus a cancer aggregate
risk assessment was not conducted at this time

.

6.5 Updated Aggregate Assessment of Free Triazole & its Conjugates

Paclobutrazol is a member of the class of compounds known as the triazoles (a.k.a. triazole

derivative fungicid es, T

- D fungicides, conazoles). In 2006, HED issued aggregate human health risk assessments for T and the conjugated triazole metabolites (D322215, M. Doherty, et al

., 2/7/06). Those assessments addressed a back

- log of triazole use requests that had been held by the Agency pending resolution of various toxicological and exposure concerns for the common triazole metabolites. The findings of that assessment were that risk estimates for all exposure

scenarios were below HED’s level of concern. Since that t ime, a number of requests for new

uses of triazole

- derivative fungicides have been submitted to the Agency. As a result of these requests, new dietary exposure estimates have been made for T and combined residues of TA, TAA, and TP, and new aggregate expo sure and risk estimates are necessary (T. Morton,

D 397592, 01/26/2012) . Neither the toxicological information nor the non

- dietary exposure estimates detailed in the 2006 memorandum have changed; thus, the only alterations to the

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 28 of 58 previous aggregate exposur e and risk estimates are due to changes in the dietary exposure estimates. For complete hazard characterization and non

- dietary exposure assessments for the common triazole metabolites, see the 2006 risk assessment.

The revised aggregate estimates are su mmarized below for short

- and intermediate

- term scenarios for T (Tables 6.5a and 6.5b, respectively). The conjugated triazole metabolites are formed in plants by the conjugation of 1,2,4

- T to serine. The TA may then be further

metabolized to form TAA and /or TP. Because of the nature of this process, HED has assumed that it occurs within the plant itself and not on leaf surfaces. Therefore, the residues are not available for dermal, hand

- to

- mouth, or object

- to

- mouth exposures and HED has not conducted a residential exposure assessment for the triazole conjugates. Residues of TA, TAA, and TP may occur in soil. 1,2,4

- Triazole is more toxic than TA/TAA/TP and exposures to these via soil ingestion are unlikely to exceed those of 1,2,4

- T. The assessment for soil ingestion of 1,2,4

- T shows that risk estimates are below HED’s level of concern; therefore, risk estimates for soil ingestion of the conjugates will also be below HED’s level of concern.

Table 6.5a. Short

- term Aggregate Exposure and Risk Estimates for 1,2,4

- Triazole

Population Subgroup Exposure Estimate, mg/kg/day 1

Aggregate

MOE 2 Dietary Dermal

(M/L/A) Dermal

(Post

Applic.) Hand

- to

Mouth Object

- to

Mouth Soil

Ingestion Aggregate U.S. Population (total) 0.001 409 0.00183 0.0051 N/A N/A N/A 0.008 339 3 6 00 All infants (< 1 year) 0.00 1923 N/A 0.0086 0.0041 0.0010 0.000019 0.015 642 1900

Children 1

- 2 yrs 0.003723 N/A 0.0086 0.0041 0.0010 0.000019 0.017442 1 7 00

Children 3

- 5 yrs 0.002 994 N/A 0.0086 0.0041 0.0010 0.000019 0.016713 1 8 00

Children 6

- 12 yrs 0.001 891 N/A 0.0086 N/A N/A N/A 0.010491 2900

Youth 13

- 19 yrs 0.001 266 0.00183 0.0051 N/A N/A N/A 0.008196 3 7 00

Adults 20

- 49 yrs 0.00 1162 0.00183 0.0051 N/A N/A N/A 0.008092 3 7 00 Adults 50+ yrs 0.00 1097 0.00183 0.0051 N/A N/A N/A 0.008027 3 7 00

Females 13

- 49 yrs 0.00 1167 0.00183 0.0051 N/A N/A N/A 0.008097 3 7 00

1 Exposure estimates for dermal, hand

- to

- mouth, object

- to

- mouth, and soil ingestion are from J. Arthur, DP 322240, 12/9/05.

2 Aggregate MOE = NOAEL (30 mg/kg/day) ÷ Aggregate Exposure Estimate (mg/kg/day). Level of Concern = 1000.



### Table 6.5b. Intermediate

- term Aggregate Exposure and Ri sk Estimates for 1,2,4

- Triazole

Population Subgroup Exposure Estimate, mg/kg/day Aggregate MOE 2 Dietary Soil Ingestion 1 Aggregate U.S. Population (total) 0.001 409 N/A 0.001 409 1 1 000 All infants (< 1 year) 0.00 1923 0.000019 0.001942 7 7 00

Children 1

- 2 yrs 0.003723 0.000019 0.003742 40 00

Children 3

- 5 yrs 0.002 994 0.000019 0.003013 5 000

Children 6

- 12 yrs 0.001 891 N/A 0.001 891 79 00

Youth 13

- 19 yrs 0.001 266 N/A 0.001 266 12 000

Adults 20

- 49 yrs 0.00 1162 N/A 0.001 162 1 3 000 Adults 50+ yrs 0.00 1097 N/A 0.00 1097 1 4 000

Females 13

- 49 yrs 0.00 1167 N/A 0.00 1167 1 3 000

1 Soil ingestion estimates are from J. Arthur, DP 322240, 12/9/05

2 Aggregate MOE = NOAEL (15 mg/kg/day) ÷ Aggregate Exposure Estimate (mg/kg/day). Level of Concern = 3000.

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 29 of 58 7.0 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 n ot made a common mechanism of toxicity finding as

to paclobutrazol and any other substances. For the purposes of this assessment , therefore, EPA

has not assumed that paclobutrazol has a common mechanism of toxicity with other substances.

For information r egarding 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

determina tions and procedures for cumulating effects from substances found to have a common

mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/

.

8.0 Occupational Exposure/Risk Characterization

Paclobutrazol is currently registered for use as a foliar spray for turf (including parks, athletic fields, residential lawns, and golf courses); a foliar spray for ornamentals in greenhouses and nurseries; as a tree injection; as a tree root drench; and as a seed treatment. Based on the existing use pattern for paclobutrazol , there is potential for both occupational handler and occupational

post

- application exposure to occur.

8 .1 Short

- and Intermediate

- Term Handler Risk

8 .1.1 Short

- and Intermediate

- Term Handler Risk for Turf, Ornamental, and Tree Uses

Paclobutrazol is currently registered for use as a foliar spray for turf (including parks, athletic fields, residential lawns, and golf courses); a foliar spray for ornamentals in greenho uses and nurseries; and as a tree injection; as a tree root drench (see Table 2 .3 )

. Based on the existing use pattern, HED expects the following occupational pesticide handler s cenarios :

5) m ixing/ l oading l iquids for ground a pplications; 6) m ixing/ l oading l iqu ids for tree injections ; 7) m ixing/ l oading liquid s for dips ; 8) mixing/loading wettable powders for tree injections ; 9) mixing/loading granulars for ground a pplications ; 10) a pplying s prays via g roundboom e quipment ; 11) applying granulars via tractor drawn spreader ; 12) mixing/loading/applying liquids with a backpack sprayer ; 13) mixing/loading/applying liquids with a manually pressurized sprayer; 14) mixing/loading/applying liquids with a mechanically pressurized sprayer; and 15) loading/applying granulars via a push

- type spreader.

It is the policy of HED to use the best available data to assess handler exposure. Sources of generic occupational handler data, used as surrogate data in the absence of chemical

- specific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant

- submitted occupational exposure

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 30 of 58 studies. Some of these data are proprietary (e.g., AHETF data) an d subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting occupational handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf), which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler

- exposure

data.html

.

Handler exposure is expected to be short

- or intermediate

- term in duration based on information provided on the propose d labels. In addition, the short

- and intermediate

- term toxicological endpoints are the same for the respective routes of exposure ; therefore, the estimates of risk for

short

- term duration exposures are protective of those for intermediate

- term duration s

. Long

- term exposures are not expected ; therefore, a long

- term assessment was not conducted.

Table 8 .1.1 presents the estimated dermal and inhalation risk estimate s from the paclobutrazol turf, ornamental, and tree uses for occupational handlers. The s hort

- and intermediate

- term risk estimates for most occupational handler scenarios do not exceed HED’s level of concern (MOEs > 1000) at some level of personal protective equipment (PPE) . However, there are some handheld equipment scenarios that exceed HE D’s level of concern (MOEs < 1000) even with the

use of PPE

.

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 31 of 58 Table 8 .1.1. Occupational Handler Exposures and Risks for Paclobutrazol Turf, Ornamental, and Tree Uses

Activity Use Site PPE

- G

Dermal

Unit Exposure (mg/lb ai) a PPE

- DL

Dermal

Unit Exposure (mg/lb ai) a Baseline

Inhalation

Unit Exposure (mg/lb ai) a Application

Rate b Area

Treated Daily c PPE

- G PPE

- G, DL Baseline Inhalation Total MOE ( PPE

- G +

Baseline

Inhalation ) Total MOE

( PPE G

- DL

+ Baseline

Inhalation ) Dermal

Dose (mg/kg/day) d MOE f Dermal

Dose (mg/kg/day) d MOE f Dose (mg/kg/day) e MOE g

Mixing/Loading Liquids Groundboom Applications on

Ornamentals in

Nurseries

0.0376 0.0291 0.000219 0.59 lb ai/A 40 A 0.0027 3,700 0.0021 4,800 0.000065 150,000 3,600 4,600

Groundboom Applications on Golf

Courses 0.75 lb ai/A 40 A 0.0035 2,900 0.0027 3,700 0.000082 120,000 2,800 3,600

Tree Injection (8 diameter Inch Trees) 0.0099 lb

ai/tree 50 trees 0.000057 180,000 0.000044 230,000 0.0000014 7,400,000 170,000 220,000

Tree Injection (35 diameter Inch Trees) 0.07 lb ai/tree 50 trees 0.0004 25,000 0.00031 32,000 0.0000096 1,000,000 24,000 31,000

Tree Soil Injection 0.352 lb

ai/tree 50 trees 0.002 4,900 0.0016 6,400 0.000048 210,000 4,800 6,200

Dips for Plug/Liner

Soaks 0.000051 lb ai/gal 100 gals 0.00000059 17,000,000 0.00000045 22,000,000 1.40E

- 08 720,000,000 17,000,000 21,000,000

0.000051 lb ai/gal 1000 gal s 0.0000059 1,700,000 0.0000045 2,200,000 1.40E

- 07 72,000,000 1,700,000 2,100,000

Dips for Bulb Soaks (Freesia) 0.00255 lb ai/gal 100 gals 0.000029 340,000 0.000023 440,000 0.0000007 14,000,000 330,000 430,000

0.00255 lb ai/gal 1000 gals 0.00029 34,000 0.00023 44,000 0.000007 1,400,000 33,000 43,000

Mixing/Loading Wettable

Powders Tree Injection (6

- 16 inches in diameter)
0.17 0.13 0.043 0.000059 lb

ai/tree 50 trees 0.0000015 6,500,000 0.0000012 8,500,000 0.0000016 6,300,000 3,200,000 3,600,000

Tree Injection (>16 inches in diameter) 0.00024 lb

ai/tree 50 trees 0.0000062 1,600,000 0.0000048 2,100,000 0.0000065 1,600,000 790,000 890,000

Loading Granulars Tractor Drawn Spreader Applications on Golf

Courses 0.0069 0.0034 0.0017 0.5 lb ai/A 40 A 0.00042 24,000 0.00021 48,000 0.00043 24,000 12,000 16,000

Applying Liquid Sprays

via Grounboom Golf Courses

0.0161 0.0126 0.00034 0.75 lb ai/A 40 A 0.0015 6,800 0.0012 8,600 0.00013 78,000 6,200 7,800

Ornamentals in

Nurseries 0.59 lb ai/A 40 A 0.0012 8,600 0.00091 11,000 0.0001 100,000 7,900 9,900

App l ying Granulars via Tractor Drawn Spreader Golf Courses 0.0072 0.0042 0.0012 0.5 lb ai/A 40 A 0.00044 23,000 0.00026 39,000 0.0003 33,000 13,000 18,000

### Paclobutrazol Human Health Risk Assessment DP No. D 394230

Page 32 of 58 Table 8 .1.1. Occupational Handler Exposures and Risks for Paclobutrazol Turf, Ornamental, and Tree Uses

Activity Use Site PPE

- G

Dermal

Unit Exposure (mg/lb ai) a PPE

- DL

Dermal

Unit Exposure (mg/lb ai) a Baseline

Inhalation

Unit Exposure (mg/lb ai) a Application

Rate b Area

Treated Daily c PPE

- G PPE

- G, DL Baseline Inhalation Total MOE ( PPE

- G +

Baseline

Inhalation ) Total MOE

( PPE G

- DL

+ Baseline

Inhalation ) Dermal

Dose (mg/kg/day) d MOE f Dermal

Dose (mg/kg/day) d MOE f Dose (mg/kg/day) e MOE g

Mixing/Loading/Applying Liquids via Backpack Sprayer Turf

8.26 4.12 0.00258 0.75 lb ai/A 5 A 0.095 110 0.047 210 0.00012 83,000 110 210

Golf Cou rse 0.75 lb ai/A 5 A 0.095 110 0.047 210 0.00012 83,000 110 210

Drench Tree Treatments (8 inch Tree) 0.07 lb ai/tree 50 trees 0.089 110 0.044 230 0.00011 89,000 110 230

Drench Tree Treatments (35 inch Tree) 0.31 lb ai/tree 50 trees 0.39 26 0.2 51 0.0005 20,000 25 51

Foliar Sprays on

Ornamentals in

Nurseries and

Greenhouses 11.2 6.23 0.14 0.59 lb ai/A 5 A 0.1 99 0.056 180 0.0052 1,900 94 160

Mixing/Loading/ Applying Liquids via Manually

Pressurized Handwand Foliar Sprays on

Ornamentals in

Nurseries and

Greenhouses

0.43 0.365 0.03 0.59 lb ai/A 5 A 0.0039 2,600 0.0033 3,000 0.0011 9,000 2,000 2,300

Drench Tree Treatments (8 inch Tree) 0.07 lb ai/tree 50 trees 0.0046 2,200 0.0039 2,600 0.0013 7,600 1,700 1,900

Drench Tree Treatments (35 inch Tree) 0.31 lb ai/tree 50 trees 0.02 490 0.017 580 0.0058 1,700 380 430

Mixing/Loading/Applying Liquids via Mechanically

Pressurized Handwand Turf 0.88 0.45 0.0019 0.75 lb ai/A 5 A 0.01 990 0.0052 1,900 0.000089 110,000 980 1,900

Golf Course 0.75 lb ai/A 5 A 0.01 990 0.0052 1,900 0.000089 110,000 980 1,900 Foliar Sprays on

Ornamentals in

Nurseries 0.39 0.29 0.0039 0.59 lb ai/A 25 A 0.018 570 0.013 760 0.00072 14,000 550 720

Foliar Sprays on

Ornamentals in

Greenhouses 2.5 1.6 0.12 0.59 lb ai/A 25 A 0.11 89 0.072 140 0.022 450 74 110

Loading/Applying

Granulars via Pu sh

- type Spreader Turf

0.24 0.13 0.01 0.5 lb ai/A 5 A 0.0018 5,400 0.001 10,000 0.00031 32,000 4,700 7,600

Golf Course 0.5 lb ai/A 5 A 0.0018 5,400 0.001 10,000 0.00031 32,000 4,700 7,600

a

. Unit Exposures taken from Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf)

b. Application rates = maximum application rates from labels.

c. Amount handled per day values are HED estimates of acres treated or gallons applied per day based on Exposure SAC SOP #9 “St andard Values for Daily Acres Treated in Agriculture,” industry sources, and HED estimat es. d. Dermal Dose (mg/kg/day) = Dermal Unit exposure (mg/lb ai) x App Rate x Area Treated x %Absorption ( 24.5 % dermal) / Body weight ( 80 kg).

e. Inhalation Dose (mg/kg/day) = Inhalation Unit exposure (mg/lb ai) x App Rate x Area Treated x %Absorp tion (100% inhalation ) / Body weight ( 80 kg).

f

. Dermal MOE = NOAEL ( 10 mg/kg/day) / Dermal Dose (mg/kg/day)

g. Inhalation MOE = NOAEL ( 10 mg/kg/day) / Inhalation Dose (mg/kg/day)

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 33 of 58 8 .1. 2 Short

- and Intermediate

- Term Handler Risk for Seed Treatments

Paclobutrazol is currently registered for commercial seed treatment use on tomato, pepper,
cucurbit , broccoli, cauliflower, and cabbage seeds (see Table 2.3)

. The paclobutrazol labels do

not permit on

- farm seed treatment. Based on the existing seed treatment use pattern, t here is potential for exposure to paclobutrazol to primary handlers (i.e., activities related to treating the seed) and secondary handlers (i.e., planting treated seed). Primary and secondary handler

expo sure is expected to be short

- or intermediate

- term in duration based on information provided on the proposed label. The short

- and intermediate

- term toxicological endpoints are the same for the respective routes of exposure; therefore, the estimates of ri sk for short

- term duration exposures are protective of those for intermediate

- term durations.

Primary Handler (Treating Seed )

Potential primary occupational handler exposure scenarios from the use of paclobutrazol as a commercial seed treatment include: Mixing, loading, applying liquid formulations; Bagging treated seed; Sewing bags; and Multiple activities.

Typically, for large

- scale commercial seed treatments, workers perform only those specific individual tasks listed above; however, it is assumed that workers also may perform multiple activities throughout the day. As a result a “multiple activities” scen ario (i.e. where one worker performs all seed treatment tasks such as loading/applying, sewing, bagging, cleaning, calibration, repair, forklift driver, etc.) was addressed. No assessment was performed for on

farm seed treatment as t he paclobutrazol labels do not permit on

- farm seed treatment.

Secondary Handler (Planting Treated Seed)

Potential secondary occupational handler exposure scenarios from the use of paclobutrazol as a commercial seed treatment include planting treated se ed.

It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data for seed treatment are incorporated in HED ExpoSAC Policy 14: SOPs for

Seed Treatment. The amount of active ingredient handled depends on the application rate (lb ai/lb seed or lb ai/seed), the pounds of seed treated in a day, and the pounds of seed that can be planted in a day, all of which vary depending upon the seed type. Values for the amount of seed treated and planted per day wer e obtained from a Biological and Economic Analysis Division memo entitled, “

Acres Planted per Day and Seeding Rates of Crops Grown in the United States” (J. Becker and S. Ratnayake; 3/24/11).

Summaries of the risk estimates for primary and secondary h andl ers are included in Tables

8 .1. 2a and 8 .1.2 b , respectively

. The short

- and intermediate

- term risk estimates for all primary and secondary handler scenarios do not exceed HED’s level of concern (MOEs > 1 0 00) at some level of personal protective equipment ( PPE)

.

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 34 of 58 Table 8 .1.2a : Summary of Short

- and Intermediate

- Term Occupational Handler Exposure and Risk Estimates for Paclobutrazol

Seed Treatment Uses

Seed Type lbs seed

treated/day

a Application

Rate b

(lb ai/lb seed) Amount

Handled per day (lb ai/day) Baseline

Dermal Unit Exposure c (mg/lb ai) Baseline

Inhalation Unit Exposure c (ug/lb ai) PPE

- G

Dermal

Unit Exposure c (mg/lb ai) Baseline

Dermal

MOE d PPE

- G

Dermal

MOE d Baseline

Inhalation

MOE e Total

Baseline

MOE Total MOE

(Baseline

Inhalation + Gloves)

Loader/Applicator

Cucurbit (Cucumber) 5512 0.000229 1.3

No Data 0.34 0.023 N/A 110000 1900000 N/A 100000

Cucurbit (Cantaloupe) 5512 0.00027 1.5 N/A 95000 1600000 N/A 90000

Cucurbit (Pumpkin) 5512 0.000107 0.6 N/A 240000 4000000 N/A 230000

Cucurbit (Squash) 5512 0.000172 0.9 N/A 150000 2500000 N/A 140000

Cucurbit (Watermelon) 5512 0.000157 0.9 N/A 160000 2700000 N/A 150000

Pepper 5512 0.00247 13.6 N/A 10000 170000 N/A 9400

Tomato 5512 0.00414 22.8 N/A 6200 100000 N/A 5800

Broccoli 5512 0.000661 3.65 N/A 39000 650000 N/A 37000

Cauliflower 5512 0.000635 3.5 N/A 41000 670000 N/A 39000

Cabbage 5512 0.000639 3.52 N/A 40000 670000 N/A 38000

Sewer

Cucurbit (Cucumber) 5512 0.000229 1.3

0.0062 0.23 No Data 420000 N/A 2800000 360000 N/A

Cucurbit (Cantaloupe) 5512 0.00027 1.5 350000 N/A 2300000 300000 N/A

Cucurbit (Pumpkin) 5512 0.000107 0.6 890000 N/A 5900000 770000 N/A

Cucurbit (Squash) 5512 0.000172 0.9 560000 N/A 3700000 490000 N/A

Cucurbit (Watermelon) 5512 0.000157 0.9 610000 N/A 4000000 530000 N/A

Pepper 5512 0.00247 13.6 39000 N/A 260000 34000 N/A

Tomato 5512 0.00414 22.8 23000 N/A 150000 20000 N/A

Broccoli 5512 0.000661 3.65 140000 N/A 950000 120000 N/A

Cauliflower 5512 0.000635 3.5 150000 N/A 990000 130000 N/A

Cabbage 5512 0.000639 3.52 150000 N/A 990000 130000 N/A

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 35 of 58 Table 8.1.2a : Summary of Short

- and Intermediate

- Term Occupational Handler Exposure and Risk Estimates for Paclobutrazol

Seed Treatment Uses

Seed Type lbs seed

treated/day a Application

Rate b

(lb ai/lb seed) Amount

Handled per day (lb ai/day) Ba seline

Dermal Unit Exposure c (mg/lb ai) Baseline

Inhalation Unit Exposure c (ug/lb ai) PPE

- G

Dermal

Unit Exposure c (mg/lb ai) Baseline

Dermal

MOE d PPE

- G

Dermal

MOE d Baseline

Inhalation

MOE e Total

Baseline

MOE Total MOE

(Baseline

Inhalation + Gloves)

Bagger

Cucurbit (Cucumber) 5512 0.000229 1.3

0.0091 0.16 No Data 280000 N/A 4000000 260000 N/A

Cucurbit (Cantaloupe) 5512 0.00027 1.5 240000 N/A 3400000 220000 N/A

Cucurbit (Pumpkin) 5512 0.000107 0.6 610000 N/A 8500000 570000 N/A

Cucurbit (Squash) 5512 0.000172 0.9 380000 N/A 5300000 350000 N/A

Cucurbit (Watermelon) 5512 0.000157 0.9 410000 N/A 5800000 380000 N/A

Pepper 5512 0.00247 13.6 26000 N/A 370000 24000 N/A

Tomato 5512 0.00414 22.8 16000 N/A 220000 15000 N/A

Broccoli 5512 0.000661 3.65 98000 N/A 1400000 91000 N/A

Cauliflower 5512 0.000635 3.5 100000 N/A 1400000 93000 N/A Cabbage 5512 0.000639 3.52 100000 N/A 1400000 93000 N/A Multiple Activi ti es
Cucurbit (Cucumber) 5512 0.000229 1.3

No Data 1.6 0.042 N/A 62000 400000 N/A 54000

Cucurbit (Cantaloupe) 5512 0.00027 1.5 N/A 52000 340000 N/A 45000

Cucurbit (Pumpkin) 5512 0.000107 0.6 N/A 130000 850000 N/A 110000

Cucurbit (Squash) 5512 0.000172 0.9 N/A 82000 530000 N/A 71000

Cucurbit (Watermelon) 5512 0.000157 0.9 N/A 90000 580000 N/A 78000

Pepper 5512 0.00247 13.6 N/A 5700 37000 N/A 4900

Tomato 5512 0.00414 22.8 N/A 3400 22000 N/A 2900

Broccoli 5512 0.000661 3.65 N/A 21000 140000 N/A 18000

Cauliflower 5512 0.000635 3.5 N/A 22000 140000 N/A 19000 Cabbage 5512 0.000639 3.52 N/A 22000 140000 N/A 19000

a HED default for lb seed treated per day from HED Exposure Science Advisory Council Policy 15.

b Application Rates based on existing labels for paclobutrazol

.

c Unit Exposures from HED Exposure Science Advisory Council Policy 14.

d Dermal Dose (mg/kg/day) = dermal unit exposure (mg/ lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x absorption factor (24.5%) / body weight ( 8 0 kg adult). Dermal MOE = NOAEL (10.0 mg/kg/day for short

- and intermediate

- term expo sure ) / Dermal Dose (mg/kg/day). Level of concern = 100 0

.

e Inhalation Dose (mg/kg/day) = inhalation unit exposure (mg/ lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x absorption factor (100%) / body weight ( 8 0 kg adult). Inha lation MOE = NOAEL ( 10 .0 mg/kg/day for short

- and intermediate

- term exposure ) / Inhalation Dose (mg/kg/day). Level of concern = 100 0

.

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 36 of 58 Table 8 .1.2 b : Summary of Secondary Handler (Planter) Exposures and Risks for Paclobutrazol

Crop Application

Rate a (lb ai/lb seed) Seeds/lb b seeds planted/acre b lbs

seed/acre Amount

Handled per day c (lb ai/day) PPE

- G Dermal

Unit Exposure (mg/lb ai) d Baseline

Inhalation Unit Exposure (ug/lb ai) d PPE

- G

Dermal

MOE e Baseline

Inhalation

MOE f Total MOE

(Baseline

Inhalation + Gloves)

Cucurbit Seed (Cucumber) 0.000229 12000 139392 11.6 0.21 0.25 3.4 61000 1100000 58000

Cucurbit Seed (Cantaloupe) 0.00027 16000 38848 2.4 0.052 0.25 3.4 250000 4500000 240000

Pepper 0.00247 50000 69696 1.4 0.2 8 0.25 3.4 47000 850000 45000

Cucurbit Seed (Pumpkin) 0.000107 1600 7260 4.5 0.03 9 0.25 3.4 340000 6100000 320000

Cucurbit Seed (Squash) 0.000172 1920 15374 8.0 0.11 0.25 3.4 120000 2100000 110000

Cucurbit Seed (Watermelon) 0.000157 4800 43560 9.1 0.11 0.25 3.4 110000 2100000 100000

Tomato 0.00414 120000 130680 1.1 0.36 0.25 3.4 36000 650000 34000

Broccoli 0.000661 80000 210845 2.6 0.1394 0.25 3.4 94000 1700000 89000

Cauliflower 0.000635 80000 23232 0.3 0.0148 0.25 3.4 890000 16000000 840000

Cabbage 0.000639 45000 98010 2.2 0.1113 0.25 3.4 120000 2100000 110000

a Application Rates based on existing labels for paclobutrazol. b Taken from a Biological and Economic Analysis Division memo entitled, “ Acres Planted per Day and Seeding Rates of Crops Grown in the United States” ( J. Becker and S. Ratnayake; 3/24/11). c Amount Handled per Day = Application Rate (lb ai/seed) * lbs seed/acre * 80 acres.

d Unit Exposures from HED Exposure Science Advisory Council Policy 14. No data is available for baseline dermal exposure (i.e., no gloves).

e Dermal Dose (mg/k g/day) = dermal unit exposure (mg/ lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x absorption factor (24.5%) / body weight ( 8 0 kg adult). Dermal MOE = NOAEL (10.0 mg/kg/day for short

- and intermediate

- term exposure ) / Dermal Do se (mg/kg/day). Level of concern = 100 0

. f Inhalation Dose (mg/kg/day) = inhalation unit exposure (mg/ lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x absorption factor (100%) / body weight ( 8 0 kg adult). Inhalation MOE = NOAE L ( 10 .0 mg/kg/day for short

- and intermediate

- term exposure ) / Inhalation Dose (mg/kg/day). Level of concern = 100 0

.

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 37 of 58 8. 2 Occupat ional Post

- Application Exposure and Risk

8 .2.1 Postapplicati o n Inhalation Exposure

Based on the Agency's current practices, a quantitative postapplication inhalation exposure assessment was not performed for paclobutrazol at this time primarily because paclobutrazol’s vapor pressure ( 1.28 x 10 - 9 

### mm Hg @ 25.0°C ) and Henry's Law Constant (8.09 x 10 - 10 

### atm

m 3 

### /mol) indicate that the compound is relatively non

- volatile under field conditions. However, 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 e xpert 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 is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop poli cies and procedures, to identify the need for and, subsequently, the way to incorporate occupational

post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational

post

- application inhalation exposure assessment for paclobutrazol.

8 .2.2 Postapplication Dermal Exposure

Based on the existing paclobutrazol use pattern (see Table 2 .3), HED expects the occupational postapplication to occ ur in two ways : contact with treated turf on golf courses and contact with treated ornamentals in greenhouses and nurseries. Dermal exposures during postapplication activities were estimated using 1) standard default values for dermal transfer coefficients from the Science Advisory Council for Exposure Policy Number 3.2: Agricultural Transfer Coefficients, June 3, 201 1, 2) a TTR study ( discussed above in Section 5 .2 )

, and 3) two

chemical

- specific dislodgeable foliar residue ( DFR) studies ( Bonzi® on Chrysanthemums: Dislodgeable Foliar Residue Study

– MRID No.: 45310801 and Bonzi® on Poinsettias: Dislodgeable Foliar Residue Study

– MRID No.: 45336601 ) submitted in support of the existing paclobutrazol uses. HED used both of the DFR studies to anal yze postapplication exposures to paclobutrazol resulting from contact with treated ornamentals in greenhouses and nurseries.

A summary of the postapplication exposure and risk estimates resulting from use of paclobutrazol is provided in Table 8 .2.2

. The short

- and intermediate

- term risk estimates for golf

course maintenance activities do not exceed HED’s level of concern (MOEs > 10 00) using predicted Day 0 residue values form the TTR study. The short

- and intermediate

- term risk

estimates for ornament als in greenhouses and nurseries do not exceed HED’s level of concern (MOEs > 10 00) using predicted Day 0 residue values from either the Chrysanthemum or

Poinsettia DFR data for all activities except for hand set irrigation. Hand set irrigation would not be performed in greenhouses and thus this issue only applies to nursery situations.

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 38 of 58 Table 8 .2.2: Summary of Short

- and Intermediate

- term Occupational Post

- Application Risks for

Paclobutrazol

Crop/Site Activities Transfer

Coefficient (cm 2 /hr) Application

Rate (lb ai/A) Predicted

Day 0 TTR

or DFR (ug/cm 2 ) Day 0 Dermal

Dose (mg/kg/day) d Day 0

MOE e Day X at

which MOE

>= LOC

Turf a golf course

maintenance 3,700 0.75 0. 0 77 0.0 07 150 0 N/A

Ornamentals in

Greenhouse and Nurseries using Chrysanthemum

DFR Data b transplanting,

irrigation, hand harvesting, container moving, hand weeding, pinching, tying/ training, propagating, hand pruning 230 0.59 0.68 0.0041 2,500 N/A

I rrigation (hand set) f 1900 0.59 0.68 0.034 300 40

Ornamentals in

Greenhouse and Nurseries using Poinsettia DFR

Data c transplanting,

irrigation , hand harvesting, container moving, hand weeding, pinching, tying/ training, propagating, hand pruning 230 0.59 0.47 0.0 027 3800 N/A

I rrigation (hand set) f 1900 0.59 0.47 0. 022 460 6

a

. TTR data represents CA which was the test site with the highest residues.

b

. Chrysanthemum DFR data represents use in a greenhouse in Oregon. c. Poinsettia DFR data represents use in a shadehouse in Florida

d . Dermal Dose = [DFR or TTR (ug/cm 2 ) x Tc (cm 2 /hr) x 0.001 mg/ug x 8 hrs/day x DAF ( 24.5 %)] body weight ( 80 kg)

e

. Dermal MOE = NOAEL ( 10 mg/kg/day)/ Dermal Dose (mg/kg/day). f. Hand set irrigation only applies to nursery settings.



### Restricted Entry Interval

The r estricted entry interval (REI) listed on the existing paclobutrazol labels is based on the acute toxicity of the technical material. Paclobutrazol is classified as Toxicity Category II for

acute dermal toxicity and Toxicity Category III for eye and skin irritation . It is not a dermal

sensitizer ( Category IV )

. In accordance with the Worker Protection Standard (WPS), acute

T oxicity Category II I and I I chemicals require a 24

- or 12

- hour REI , respectively

. Furthermore,

based on the occu pational postapplication assessment, most postapplication dermal risk estimates

do not exceed HED’s level of concern (MOEs > 10 00). Based on the acute dermal toxicity, t he

12

- hour REI that appears on the current paclobutrazol labels may not be adequate an d should be

revisited

. Special consideration should also be given to use of hand set irrigation in nurseries.

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 39 of 58 9.0 References

Becker , J. and S. Ratnayake. (2011 ). Acres Planted per Day and Seeding Rates of Crops Grown

in the United States

.

Doherty, M., et al . (2006). 1,2,4

- Triazole, Triazole Alanine, Triazole Acetic Acid: Human Health Aggregate Risk Assessment in Support of Reregistration and Registration Actions for

Triazole

- derivative Fungicide Compounds. DP Number: D322215, dated February 7 , 20 06

.

Hurley , P

. (1994). Toxicology Endpoint Selection Document, dated 04/11/1994, TXR No.

013485.

Ghali, G. (1994). RfD/Peer Review Report of Paclobutrazol dated June 23, 1994, TXR No.

011081.

Morton, T. (2012). Common Triazole Metabolites: Updated Aggregate Human Health Risk

Assessment to Address The Amended Propiconazole Section 3 Registration to Add Uses on Snap beans, succulent shelled beans, dry beans, tomato (post

- harvest, citrus (post

- harvest), and

stone f ruit (post

- harvest); The Amended Difenoconazole Section 3 Registration to Add Use on Potato; and the Flutriafol Section 3 Registration to Add Use on Field Corn and the Section 18

Use on Cotton. DP Number: D 397592 , dated January 26, 2012.

Reaves , E. and C . Smith. (2007). Paclobutrazol: Registration Review Scoping Document for

Hum an Health Assessments. PC Code: 125601; DP Number: D 335538, dated March 13, 2007.

Smegal, D. (2012). Paclobutrazol: Summary of Hazard and Science Policy (HASPOC) Meeting

o f December 8, 2111: Recommendations on data requirements for immunotoxicity and acute and subchronic neurotoxicity studies for paclobutrazol dated January 3, 2012, TXR No.

0056149.

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 40 of 58 Appendix A: Paclobutrazol Toxicity Profiles

A.1 Toxicology Data Requirements

The toxicological data requirements (40 CFR 158.340) for non

- food uses for paclobutrazol are listed in Table A.1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A.1 Test Required for Nonfood Use Pesticides 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 (rat)

................................ ...................... 870.3150 Oral Subchronic (dog)

................................ .................... 870.3200 21/28

- Day Dermal (rat)

................................ .................. 870.3250 90

- Day Dermal

................................ ............................... 870.3465 28

- Day Inhalation

................................ ........................... yes

no

n o

yes
CR yes

no

yes

yes

--- 870.3700a Developmental Toxicity (rat)

................................ ......... 870.3700b Developmental Toxicity (rabbit)

................................ .... 870.3800 Reproduction (rat)

................................ ........................... yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rat)

................................ ..................... 870.4100b Chronic Toxicity (dog)

................................ ................... 870.4200a Carcinogenicity (rat)

................................ ....................... 870.4200b Carcinogenicity (mouse)

................................ ................. 870.4300 Chronic/Carcinogenicity (rat)

................................ ......... C R

yes
CR

CR

CR yes

yes

no

no

no

870.5100 Mutagenicity

— Gene Mutation

- bacterial

...................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................. 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

.... 870.5395 Mutagenicity

— Mammalian Erythrocyte Micronucleus

. 870.5450 Mutagenicity

— Rodent dominant lethal assay 870.5500 Mutagenicity

— Bacterial DNA Damage or Repair Test 870.5550 Mutagenicity

— Unscheduled DNA Synthesis

................. yes

yes

yes

yes

no

no

no yes

yes

yes

yes

yes

yes

yes

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 (rat)

................................ . no

no

yes

yes
CR no

no

no 1

no

no

870.7485 General Metabolism (rat)

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

, in vivo (male rat)

............................ yes

yes yes

yes 870.7800 Immunotoxicity (rat and mouse)........................... yes no

1 The ACN study has recently been submitted to the Agency and is under review.

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 41 of 58 Appendix A.2. Toxicity Profiles

A.2 Toxicity Profiles

The toxicological data for the acute toxicity studies with paclobutrazol are listed on Table

A.2.1

.

Table A2.1: Acute Toxicity of Paclobutrazol Technical Grade

Guideline No/Study Type MRIDs Results Toxicity Category

870.1100 Acute Oral (97% ai)

Alderley Park Rat 00117478 (1983) LD 50 = 1954 mg/kg (M) 1336 mg/kg (F) III

870.1100 Acute Oral (97% ai)

Alderley Park Mouse 00117478 (1982) LD 50 = 490 mg/kg (M) 1219 mg/kg (F) II

870.1100 Acute Oral (97% ai) Dunkin Hartley Albino Guinea pig 00117478 (1982) LD 50 = 542 mg/kg (M) >400 and <640 mg/kg (F) III

870.1100 Acute Oral (97% ai)

NZW Rabbit 00117478 (1982) LD 50 = 835 mg/kg (M) 937 mg/kg (F) III

870.1200 Acute Dermal (97% ai)

Alderley Park Rat 00117478 (1982) LD 50 = >1000 mg/kg (M F) II

870.1200 Acute Dermal (97% ai)

NZW Rabbit 00117478 (1982) LD 50 = >1000 mg/kg (M F) II

870.1300 Acute Inhalation (97% ai)

50% ai Alderley Park Rat 00117482 (1982) LC 50 = >766 mg/m 3 (M)

359

- 766 mg/m 3 (F) II

870. 2400 Primary Eye Irritation ( 97% ai)

NZW Rabbit 00117479 (1982) 5/6 rabbits with unwashed eyes had slight corneal opacity, which cleared within 7 days; 3/6 rabbits with washed eyes had slight redness of the conjunctiva, with some chemosis and discharge, which was not apparent by 3 days. III a

870.2500 Primary Skin Irritation

(97% ai) NZW Rabbit 00117479 (1982) Mild irritation that persisted for

72 hours III

870.2500 Primary Skin Irritation

( 97% ai) Alderley Park

Albino Rat 00117479 (1982) 3/5 M showed erythema; 2/5 (F) showed desquamation and scabbing. Effects did not persist in either sex. III

870.2600 Dermal Sensitization (Guinea

pig) Dunkin Hartley Albino 00117479 (1982) Not a skin sensitize r

a Reclassified in 1995, based on additional data provided by the registrant (HED Document 011460).

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 42 of 58 Table A.2.2: Toxicity Profile of Paclobutrazol Technical

Guideline No./ Study Type MRID No. (year)/

Classification/Doses Results

870.3100

90

- Day oral toxicity rodents (rat) 00132689 (1983)/ 47338506 (2007) Acceptable/guideline 0, 50, 250 or 1250 ppm [equivalent to 0, 3.7, 18.8 or 93.0 mg/kg/day (M)

0, 4.4, 21.6 or 106.5 mg/kg/day (F)] a

. NOAEL =18.8 mg/kg/day for both sexes LOAEL = 93.0 mg/kg/day, based on elevated liver weights, serum cholesterol, hepatic aminopyrene

- N

demethylase activity and alanine transaminase levels in

females.

870.3150

6

- Week oral toxicity in dogs 00132690 (1983) Unacceptable 0, 15, 75, or 225 mg/kg/day (M & F). NOAEL = 1 5 mg/kg/day (LDT) LOAEL = 75 mg/kg/day, based on increased liver weights and serum alkaline phosphatase levels. Only 1

M and 1 F tested at each level.

870.3200

21/28

- Day dermal toxicity (rabbit) 00132688 (1980) Acceptable/guideline
0, 10, 100, or 1000 mg/kg/day, 6 hrs/day for 5 d/week during a 21

- day period. NOAEL =10 mg/kg/day (intact skin) LOAEL = 100 mg/kg/day, based on irritation at all

doses with abraded skin and at 100 and 1000 mg/kg/day with intact skin. Irritation began to appear during 2 nd week of application. Degree increased with increasing dose. Hyperkeratosis, acanthosis and inflammatory changes of superficial dermis.

870.3700a Prenatal developmental toxicity in rodents (Wistar rats, derived from Alderly Park strain) 00132693 ( 1 983 ) Acceptable /guideline 0, 40, 100, or 250 mg/kg/day from days 6 through 15 of gestation. Maternal NOAEL = 40 mg/kg /day (LDT). LOAEL =100 mg/kg /day, based on decreased body weight gain and food utilization efficiency during dosing. Mortality (5/24) and grossly observable liver pallor and enlargement at 250 mg/kg/day (HDT)

Developmental NOAEL = 40 mg/kg /day. LOAEL

=close to 4 0 but set at 100 mg/kg/day, based on delayed ossification and partial ossification of odontal bone at 100 and 250 mg/kg/day. Delayed ossification statistically significant for fetuses at 40 mg/kg/day but not for litters. Partial ossification of occipital bone at 250 mg/kg/day. Cleft palate in 3 fetuses from 2 litters at 250 mg/kg/day.

870.3700a Prenatal developmental toxicity in rodents (Wistar rats, derived from Alderly Park strain) 00143158 ( 1984 ) Acceptable /guideline
0, 2.5, 10, 40, or 100 mg/kg/day from days 7 through 16 of gestation. Maternal NOAEL = >100 mg/kg /day (HDT).

Developmental NOAEL = 10 mg/kg /day. LOAEL = 40 mg/kg/day, based on renal dilation, hydroureter and

minor skeletal defects or variations.

870.3700b Prenatal developmental toxicity in nonrodents (NZW rabbit) 00132692 (1983) Unacceptable
0, 25, 75, or 125 mg/kg/day from days 6 through 18 of gestation. Maternal NOAEL =75 mg/kg /day LOAEL = 125 mg/kg/day, based on decreased body weight gain during dosing. L ow fertility; onl y low and

mid

- dose groups had > minimum number of litters

at sacrifice.

Developmental NOAEL = None observed

870.3700b 40734302 (1986) Maternal NOAEL = 75 mg/kg /day

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 43 of 58 Table A.2.2: Toxicity Profile of Paclobutrazol Technical

Guideline No./ Study Type MRID No. (year)/

Classification/Doses Results

Prenatal developmental toxicity in nonrodents (NZW rabbit) Acceptable /guideline 0, 25, 75, or 125 mg/kg/day from days 7 through 19 of gestation. LOAEL = 125 mg/kg/day, based on decreased body weights and food consumption during dosing. Developmental NOAEL = 75 mg/kg/day

LOAEL = 125 mg/kg/day, based on the increased

incidence of extra ribs in pups.

870.3800 Reproduction and fertility

effects (rat) 40734303 (1987)/ 47338506 (2007) Acceptable/guideline 0, 50, 250 and 1250 ppm in the diet [ equivalent to 0, 4.8, 24.4, and 121.2 mg/kg/day (F 0 M); 0, 5.1, 25.9 and 126.2 (F 0 F); 0, 4.7, 23.2 and 116.9 (F 1 M); and 0, 5.1, 24.8 and 124.1 mg/kg /day (F 1 F)] a Parental systemic NOAEL = 23.2 mg/kg /day LOAEL = 116.9 mg/kg/day, based on the increases in liver weights and fatty changes and thickening of the urinary bladder walls in females

Reproductive NOAEL = 116.9 mg/kg/day (HDT)

LOAEL = N/A

Offspring NOAEL =23.2 mg/kg /day b

LOAEL= 116.9 mg/kg/day, based on the increased incidence of chromodacryorrhea, thickened eyelids and dental malocclusion, increased liver weights, mottl ing or accentuation of the lobular structure of the liver, along with liver enlargement, pallor and discoloration.

870.4100a Chronic toxicity (rat) 40734301 (1986)/ 47078901 (2007) Acceptable/guideline 0, 50, 250 or 1250 ppm
[ equivalent to 0, 2.2, 10.8, 54.2 mg/kg/day (M) & 0, 2.8, 14.0, 72.1 mg/kg/day (F) for 2 years] a NOAEL = 10.8 mg/kg/day

LOAEL. = 54.2 mg/kg/day based on an increase in hypertrophy/steatosis of the liver (both sexes), decreased triglycerides (females) and increased liver weig hts (both sexes). Possible borderline increase in uterine stromal polyps in high and mid

- dose females.

870.4100b Chronic toxicity (dog) 00132691/00143166 (1986) Acceptable/guideline
0, 15, 75 or 300 mg/kg/day) for 1 year. NOAEL =15 mg/kg/day

LOAEL = 75 mg/kg/day, based on elevated serum alkaline phosphatase and triglycerides levels, enlarged hepatic cells, increased liver weights, and increased hepatic aminopyrine N

- demethylase activity.

870.4200a Carcinogenicity (rat) See 870.4100a

40762501 (1986)

Unacceptable Maximum tolerated dose (MTD) was not achieved and possible positive response for uterine stromal polyps.

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Page 44 of 58 Table A.2.2: Toxicity Profile of Paclobutrazol Technical

Guideline No./ Study Type MRID No. (year)/

Classification/Doses Results

870.4200b Carcinogenicity (mouse) 40762501 (1986) Acceptable/guideline (Chronic phase) 0, 25, 125, or 750 ppm (equivalent to 0, 3.75, 18.75 or 112.5mg/kg /day

for 104 weeks.

Unacceptable (Carcinogenicity phase) NOAEL =125 ppm (18.85 mg/kg/day both sexes). LOAEL = 750 ppm (112.5 mg/kg/day both sexes), based on increased severity of steato sis of the liver in males, decreased triglycerides and cholesterol (males) and increased absolute & relative liver weights (M & F).

Borderline increase in Leydig cell tumors in high dose males with a significant (p<0.05) pairwise comparison and a signifi cant (p<0.05) trend.

However, the high dose is considered inadequate because of the minimal toxicity at this level

. 870.5100

Bacterial reverse mutation (Ames Assay) 00017480 (1982)

1.6

- 5000 μg/plate +/

- S9 Acceptable/guideline Negative up to 5,000 μg/plate.

870.5300

In vitro mammalian cell gene mutation (mouse lymphoma cells) 00132695 (1983)

1.0

- 100 μg/mL

– S9; 60

- 140 μg/mL +S9

Acceptable/guideline Negative up to cytotoxic doses.

870. 5375

In vivo chromosome aberration (rat bone marrow) 00143156 (1984) 0, 30, 150 or 300 mg/kg/ oral gavage Acceptable/guideline Negative; no clastogenic effects at any dose tested.

870. 5395 Mammalian erythrocyte micronucleus assay (mouse) 00132694 (1983) 0, 87.5 or 140 mg/kg /ip Acceptable/guideline Negative up to 50 or 80% of the LD 50 via ip injection.

870.5450

Rodent dominant lethal test (mouse) 00143155 (1983) 0, 25, 1000 or 300 mg/kg/day X 5 days/oral

gavage Acceptable/guideline Negative for dominant lethal mutations.

870.5550

In vivo unscheduled DNA synthesis (UDS, rat hepatocytes) 40734304 (1986) 0, 40, 200 or 400 mg/kg Acceptable Negative, no induction of UDS

870.6200a Acute neurotoxicity screening battery (rat) Not available

870.6200b 90 Day neurotoxicity screening battery (rat) Not available

870.7485

General Metabolism (rat) 00132696 (1983) Nonguideline M&F: 10 mg/kg single gavage dose During the 4 days following administration, 39.18 and

52.6 % of the dose was recovered in the urine of male and female rats, respectively. Fecal recoveries were

53.49% in the males and 37% in females. Approximately 60% of the administered dose was

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Page 45 of 58 Table A.2.2: Toxicity Profile of Paclobutrazol Technical

Guideline No./ Study Type MRID No. (year)/

Classification/Doses Results

accoun ted for in feces and urine of males and females during the first 24 hours of dosing. Residue concentrations in tissues 3 or 4 days after dosing did not indicate accumulation, and urinary excretion along with slow fecal excretion indicated a significant

g astrointestinal absorption of the dose.

870.7485

General Metabolism 

### (rat) 00143161 (10/1983) Acceptable/guideline 5 mg/kg (single oral gavage) 70

- 80% of the 5 mg/kg dose was excreted during 72 hours after dosing. Approximately 55% of the dose

was recovered in the urine of both sexes, and 32% or 24% was recovered in the feces of males and females, respectively. 7 days after dosing, liver tissue contained 0.017 to 0.028 ppm; gastrointestinal tract contained

0.012

- 0.025 ppm. No other tissue levels w ere detectable.

870.7485

General Metabolism 

### (rat) 00143162 (2/1984) Acceptable/guideline 250 mg/kg 70

- 80% of the 250

- mg/kg dose was excreted during first 72 hours after dosing. Approximately 40% of the

dose was excreted in urine from males and 30% from females. Approximately 30% and 40% of the dose was recovered in the feces of males and females, respectively after 72 hours. Gastrointestinal contents had 0.303 (♂) and 1.461 ppm (♀); liver samples contained from 0.444 to 0.848 ppm.

870.7485

General Metabolism 

### (rat) 00143160 (5/1984) Acceptable/guideline 5 and 250 mg/kg (dose selection study for MRID

00143160 A single dose of 250 mg/kg increased the liver weight, and the 5 mg/kg dose had no effect. These results were

used as the basis for do ses selection.

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Page 46 of 58 Table A.2.2: Toxicity Profile of Paclobutrazol Technical

Guideline No./ Study Type MRID No. (year)/

Classification/Doses Results

870.7485

General Metabolism (Bioaccumulation in rat) 00143160 (5/1984) Acceptable/guideline 250 mg/kg (single oral gavage) Autoradiographs indicated that the liver, kidneys, and gastrointestinal tract contained the administered

radiolabel. Similarly, the disposition of the 14 c label after a single oral dose of 250 mg/kg is limited to the gastrointestinal contents and to a les ser extent to the liver and kidneys.

870.7485

General Metabolism 

### (rat) EPA Accession No.

254865 (5/1984) Acceptable/guideline 5 mg/kg (oral gavage) Concentrations of radiolabel plateaued in livers and kidneys after 28 days consecutive daily 5 mg/kg doses.

Maximum levels: 2.22

- 2.55 ppm in liver and approx. 1 ppm in kidney. Blood levels rose throughout the 49

- day dosing period (max. level = 0.158 ppm). Levels in fat were below the limit of detection (0.081 ppm) at most observations, and ranged from 0.046

- 0.148 ppm at other observations. Elimination of radioactivity from the livers and kidneys occurred in a biphasic manner. Half times for the first phase were 1.36 & 1.56 days for liver & kidney, respectively. Times for the 2 nd phase

were 6.69 and 9.26 days, respectively.

870.7485

General Metabolism 

### (rat) 00143165 (5/1984) Acceptable/guideline 5 or 250 mg/kg (single oral gavage) A single oral gavage dose (5 or 250 mg/kg) paclobutrazol was absorbed almost completely by male

and female rats. Triazole and halogenated phenyl moieties not affected in rat. Pentanol moiety oxidized to a diol or carboxylic acid & excreted in free or conjugated forms. Males excreted more of carboxylic acid metabolites than females but proportion of acid

metabolites excreted by females increased as dose decreased. Approx. 75% of dose was recovered in bile during first 48 hours after dosing in males, and 50% is recovered from females during first 72 hours.

870.7485

General Metabolism 

### (dog) 00143163 (1984) Accept able/guideline 5 mg/kg ( single oral gavage) 80

- 85% of 5 mg/kg dose extracted during first 24 hours after dosing. Approx. 50% of dose recovered in urine of both sexes, & 35

- 40% recovered in feces. Peak blood levels at 1 hour after dosing (4.1

- 4.4 ppm in

p lasma) declined to pre

- dose levels 24

- 48 hours after

treatment. No detectable levels in tissue & no sex

differences were observed.

870.7600 Dermal penetration (Rat) 41048202

0.011 mg/kg on an area 10

cm 2 /rat

Acceptable/guideline The highest % dose absorbed and remaining on the washed application site was 15.1% (10 hours) and 24.5% (24 hours), respectively.

870.7800 Immunotoxicity Not available

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Page 47 of 58 Appendix A.3

. Hazard Identification and Endpoint Selection

A.3 .1 Acute Reference Dose (aRfD)

– Females age 13

- 49/ General Population: None

As shown in Table A. 4, no appropriate endpoint attributable to a single dose was found in the available database, including the four developmental studies (2 in rats and 2 in rabbits).

A.3.2. Chronic Refer ence Dose (cRfD)

Study Selected: Two

- year chronic/carcinogenicity feeding study in rats 870.4300a [§83

- 5]

MRID No. 40734301

Dose and Endpoint for Risk Assessment : NOAEL = 10.8 mg/kg/day

Comments About Study/Endpoint/Uncertainty Factors: For the ch ronic dietary risk assessment, the 2

- year chronic/carcinogenicity feeding study in rats, with a NOAEL of 10.8 mg/kg/day, was selected because it was near the lowest NOAEL in the most sensitive species and more appropriately covers the exposure duration of concern. An Uncertainty Factor (UF) of 1000 was applied to account for both the interspecies extrapolation (10X) and intraspecies variability (10X) and the lack of data for neurotoxicity (acute and subchronic) and immunotoxicity (10X). On this basis, the cRfD was calculated to be 0.01 mg/kg/day.

Chronic RfD = 10.8 mg/kg/day (NOAEL) = 0.01 mg/kg/day 1000 (UF)

A.3. 3 Incidental Oral Exposure: Short

- (1

- 30 days) and Intermediate

- term (1

- 6 months) Study Selected: 90

- day oral toxicity in rats 870.3100 [§82

- 1]

MRID No. 00132689

Dose and Endpoint for Risk Assessment: NOAEL = 18.8 mg/kg/day

Comments About Study/Endpoint/Uncertainty Factors: The 90

- day subchronic oral toxicity

test in rats was se lected for these scenarios because the endpoint of concern is appropriate for the population (infants and children) and the duration of the study covers the period of concern (short and intermediate term) for these exposures. The NOAEL for this study is 1 8.8 mg/kg/day; the LOAEL is 93.0 mg/kg/day, based on elevated liver weights and changes in clinical chemistry parameters associated with the liver. A n MOE of 1000 is required which includes the interspecies extrapolation (10X) and intraspecies variability (10X) and the lack of data for neurotoxicity (acute and subchronic) and immunotoxicity (10X).

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Page 48 of 58 A.3.4. Dermal Exposure: Short

- (1

- 30 days) and Intermediate

- term (1

- 6 months)

Study Selected: Prenatal developmental study in rats 870.3700a [§83

- 3]

MRID No. 00143158

Dose and Endpoint for Risk Assessment: NOAEL = 10 mg/kg/day

Comments About Study/Endpoint/Uncertainty Factors: The original study considered for these exposure scenarios was the 21

- day dermal study in rabbits with a NOAEL of 10 mg/kg/day. However, the LOAEL (100 mg/kg/day) was based solely on irritation, which is not considered an appropriate endpoint for occupat ional or residential exposure. The Agency prefers to mitigate irritation through product labeling and the use of gloves and/or other protective clothing, which minimizes dermal contact. To safeguard against residential exposure via turf, the developmenta l study in rats (MRID 00143158) was selected to protect children playing on the lawn. The NOAEL for this study is 10 mg/kg/day; the LOAEL is 40 mg/kg/day, based on renal dilation, hydroureter and minor skeletal defects or variations. If the dermal absorp tion factor [25.4% for the 24

- hour exposure, from the data in a dermal penetration study (MRID 41048202)], were applied, the derived dermal equivalent dose (DED) would be 40.8 mg/kg/day. This dose would be protective of the potential pregnant population (f emales 13

- 49) as well as irritation seen following dermal application. An MOE of 1000 is required which includes the interspecies extrapolation (10X) and intraspecies variability (10X) and the lack of data for neurotoxicity (acute and subchronic) and immu notoxicity (10X).

A.3.5. Inhalation Exposure: Short

- (1

- 30 days) and Intermediate

- term (1

- 6 months)

Study Selected: Prenatal developmental study in rats 870.3700a [§83

- 3]

MRID No. 00143158

Dose and Endpoint for Risk Assessment: NOAEL = 10 mg/kg/d ay

Comments About Study/Endpoint/Uncertainty Factors: Since a repeated dose inhalation study was not available, an oral NOAEL was selected for this risk assessment. See Section A.3. 4

. Since an oral dose was selected absorption via inhalation is presume d to be equivalent to oral absorption. An MOE of 1000 is required which includes the interspecies extrapolation (10X) and intraspecies variability (10X) and the lack of data for neurotoxicity (acute and subchronic) and immunotoxicity (10X).

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Page 49 of 58 A.4 Executi ve Summaries

A.4.1 Subchronic Toxicity

870.3100 90

- Day Oral Toxicity

- Rat

In a 90

- day feeding study (MRID 00132689/47338506), groups of 20 male and female Wistar rats received diets containing 0, 50, 250, 1250 ppm paclobutrazol (91.9%) for 90 days.

At 1250 ppm

, increased liver weights and doubled the aminopyrene

- N

- demethylase activity was seen in the females. These effects were noted to a lesser extent in the females given diets containing 250 ppm, but without concomitant histological changes, the e ffects at the mid dose are unlikely to be toxicologically significant. Therefore, the NOEL for rats given paclobutrazol in the diet for 90 days is 250 ppm, and the lowest effect level (LEL) is 1250 ppm.

Based on additional data provided by the registrant (MRID 47338506, HED Document 011460), the actual doses used in the study were 0, 3.7, 18.8 or 93.0 mg/kg/day (M) and 0, 4.4, 21.6 or 106.5 mg/kg/day (F). Accordingly, the NOAEL is 18.8 mg/kg/day (both se xes) and the LOAEL is 93.0 mg/kg/day, based on elevated liver weights, serum cholesterol, hepatic aminopyrene

- N

demethylase activity and alanine transaminase levels in females.

The study is classified as Acceptable guideline.

870.3200 21/28

- Day Der mal Toxicity

- Rabbit

In a 21

- day dermal toxicity study (MRID 00132688), groups of 10 male and 10 female New Zealand white rabbits were treated with paclobutrazol at rates of 0, 10, 100, or 1000 mg per kg for 21 days. Twenty

- four hours prior to the first application of the test substance

, hair was clipped from the mid dorsal region of each rabbit. About 10% of each animal’s surface area was clipped ; clipped treatment sites were abraded. The treatment sites on the remaining animals in each group were left i ntact. Hair clipping was repeated as needed during the 21

- day treatment period, and abrasion was done on a weekly basis during the test. The test substance was suspended in 1% aqueous carboxymethyl cellulose and applied to the prepared skin sites bodyweig ht. After each application the treated areas were covered with an occlusive dressing for

6 hours. At the end of that time the bandages were removed, and each test site was washed with

war m tap water and blotted dry. This procedure was followed once each d ay 5 days each week for 3 consecutive weeks. During the study the animals were observed daily for the appearance of toxic signs, mortality, and behavioral changes.

All dose levels (10, 100, or 1000 mg/kg/day) caused irritation of the abraded skin of test animals

but o nly the 100 and 1000 mg/kg/day doses irritated the intact skin sites of test animals. The irritation began to appear during the second week of dermal applications, and the degree of

irritatio n increased with dose. Histologically, treated skin exhibited hyperkeratosis, acanthosis, and inflammatory changes of the superficial dermis. The NO A EL for intact skin with respect to these effects is 10 mg/kg/day, and the LOAEL is 100 mg/kg/day. The 1000 mg/kg/day dose (highest dose tested) caused severe irritation after two weeks of application to the skin of rabbits.

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 50 of 58 The study is classified as Acceptable/guideline

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity

- Rat

In a developmental toxicity study (MRID 00132693), Paclobutrazol was tested in Wistar derived Alderley Park rats at the following dose levels: 0, 40, 100 or 250 mg/kg/day on days 6

- 15 of gestation. The NO A EL for maternal toxicity is 40 mg/kg/day and the L O E A L is 100 mg/kg/day.

The effects were decrease i n body weight gain (100 mg/kg/day and above), pallor and enlargement of the liver, decreased food consumption and food utilization, staining of the genital and ventral areas and mortality (250 mg/kg/day). The NO A EL for developmental toxicity is 40 mg/kg/da y (LDT) and the L O E A L is 100 mg/kg/day based on a dose

- related increase in the incidence of delayed ossification at various sites and partial ossification of the odontal bone in

the mid

- and high dose groups and partial ossification of the occipital bone i n the high dose group. The L OA E L is very close to 40 mg/kg/day because the increased incidence of delayed ossification was statistically significant for fetuses but not for litters. Cleft palate was also observed at dose levels that were maternally toxic.

The study is reclassified as Acceptable/guideline

870.3700b Prenatal Developmental Toxicity

- Rabbit

In a developmental toxicity study (MRID 407343020), Paclobutrazol was tested in New Zealand White rabbits at the following dose levels: 0, 25, 75 or 125 mg/kg/day. The maternal toxicity NOEL is 75 mg/kg/day and the maternal LEL is. 125 mg/kg/day based on decreases in body weights and body weight gain and food consumption during dosing. The developmental toxicity NOEL is 75 mg/kg/day and the LEL is 125 mg/ kg/day based on the increased incidence of extra ribs in pups.

The study is reclassified as Acceptable/Guideline

A.5.3 Reproduction and Fertility Toxicity

870.3800 Reproduction and Fertility Effects

– Rat In a multigenerational reproduction study (MRIDs 40734303, 47338506)

, paclobutrazol (technical, 92.4%) was tested in Alpk:AP (Wistar derived) rats at the following dose levels: 0, 50, 250 and 1250 ppm (o, 2.5, 12.5 or 62.5 mg/kg/day) in the diet. Each generation began with

17 males and 34 fema les for each control and high does group and 15 males and 30 females for

each low and mid

- dose group. One male was mated with 2 females for m the same test group

until sperm plugs were observed in vaginal smears. The F 0 

### parental animals were given test diets for 12 weeks before they were mated, and the F 1 

### parental animals were not mated until 11 weeks after they were selected from the F 1A 

### litters. Selection of parents for the F 1 

### generation was made when the pups were 36 days of age, and the mated animal s in the study were between 16 and 20 weeks of age at mating.

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 51 of 58 At 250 ppm and above, an increased incidence of chromodacryorrhea and thickened
eyelids was observed in both generations. This was observed in both the prenatal animals and in the pups. In the parental animals, the incidences were within the historical control range. At 1250 ppm, increase I liver weights were observed in females in both generations (23% absolute, 26% relative F 0 

### ; 7 % absolute, 14% relative F 1 

### ) and fatty change in

the live r was observed in F 0 

### females (23/30 versus 0/30 for the controls). Increased liver weights, mottling or accentuation of the lobular structure, liver enlargement and pallor and discoloration were observed in male and female pups from both generations. In addition to the changes in the liver, dental malocclusion was observed in both generations (parental animals and pups, incidence in the parental animals was within the historical control range) and thickening of the urinary bladder wall was observed in 1 F 0 

### and in 3 F 1 

### high dose females. The reproductive/systemic LOEL is 250 ppm (12.5 mg/kg/day) based on increased liver weights and on fatty change in the liver of parental females; and on an increased incidence of chromodacryorrhea and thickened eyelids, de ntal malocclusion, increased liver mottling or accentuation of the lobular structure, liver enlargement and pallor and discoloration in male and female pups. The reproductive/systemic NOEL is 50 ppm (2.5 mg/kg/day). This study is classified Acceptable/G uideline, and it satisfies the guideline requirement (870.7600) for a dermal penetration study.

Based on new information provided by the registrant (MRID 47338506) and HED’s analysis of individual data and historical control data on chromodacryorrhea and thickened eyelids, and dental malocclusion and twisted snouts and data on achieved doses for this study, the following changes have been made: NOELs and LOELs have been changed to NOAELs and LOAELs The parental NOAEL for the two

- generation reproduction study should be 250 ppm (equivalent to 23.2 mg/kg/day), and the LOAEL should be 1250 ppm (equivalent to 116.9 mg/kg/day; the highest dose tested), based on increases in liver weight and fatty changes and thickening of the urinary bladder wall in the femal es. The reproductive NOAEL is 1250 ppm (equivalent to 116.9 mg/kg/day).

T he offspring NOAEL and LOAEL should be 250 ppm (equivalent to 23.2 mg/kg/day), and the LOAEL should be 1250 ppm (equivalent to 116.9 mg/kg/day), based on the increased

incidence of dental malocclusions, chromodacryorrhea and thickened eyelids; increased liver weights, mottling or accentuation of the lobular structure of the liver, along with liver enlargement, pallor and discoloration.

For more details see TXR 0056158

A.4.4 Chron ic Toxicity

870.4100a Chronic Toxicity

– Rat

In a combined chronic feeding/oncogenicity study (MRIDs 40734301, 47078901) Sprague

Dawley Crl:CD(SD)BR rats. Fifty animals/dose/sex were fed 0, 50, 250 or 1250 ppm technical Paclobutrazol (92.4% pure) in th e diet (0, 2.5, 12.5 or 62.5 mg/kg/day) for 2 years. An additional

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 52 of 58 ten animals/sex were placed in the control and high dose groups as microbiological sentinels.

A nother 10 animals/sex were added that were sacrificed at 52 weeks.

At 62.5 mg/kg/day, there was an increase in hypertrophy/steatosis of the liver (both sexes) and increased liver weights (14 and 13% in males and 9 and 24% in females for absolute and relative liver weights over control values, respectively). The LOEL is 1250 ppm (62.5 mg/kg/day) b ased upon an increase in hypertrophy/steatosis of the liver (both sexes). The NOEL for chronic effects is 250 ppm (12.5 mg/kg/day).

There appeared to be a borderline increase in uterine stromal polyps in the high dose and possibly mid

— dose females (0/50, 4/50, 5/50 and 7/50 for the control, low dose, mid

— dose and high dose groups, respectively). Pairwise comparisons were statistically significant at all dose levels (p<0.05, p<0.0l and p<0.Ol for the low dose, mid

- dose and high dose groups, respectively), a nd a positive trend was observed with increasing dose (p<0.O5). Although the authors stated that this was due to the 0 frequency in the controls, which is unusual, it is considered to be a possible positive response. However, the study is considered to be inadequate for classification of the chemical for carcinogenicity for the following reason: although the

chronic effects are considered to be sufficient to establish a NOEL and an LEL for chronic toxicity, they are not considered to be severe enough to ind icate that the animals were tested at a sufficiently high dose level for an adequate oncogenicity study.

This study is classified as Core Minimum as a chronic feeding study and Core Supplementary as oncogenicity study. It does not satisfy the regulatory requirement for an oncogenicity study. Due to the low dose levels tested and to the possible positive response for uterine stromal polyps, a repeat study will be needed if the use pattern for the chemical requires it.

870.4100b Chronic Toxicity

– Dog

In a one

- year chronic toxicity study (MRID 00132691/00143166), groups of four groups of six male and female beagles received daily doses of paclobutrazol (92.4%) at 0, 15, 75 and 300 mg/kg/day for 1 year. Doses were administered in capsules.

Elevated s erum alkaline phosphatase and triglyceride levels, the enlarged hepatic cells, increased liver weights, and increased hepatic aminopyrine N

- demethy

- lase activity indicate that the two highest doses (75 and 300 mg/kg/day) have definite effects. H owever, no toxicologically significant effects were observed at the .15 mg/kg/day dose level. The NOEL is 15 mg/kg/day, and the LEL is 75 mg/kg/day in beagle dogs.

This study is classified as Core Minimum.

A.4.5 Carcinogenicity

870.4200a Carcinogenicity

- Rat

S ee MRID 40734301

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Page 53 of 58 870.4200b Carcinogenicity

– Mouse

In a combined chronic feeding/oncogenicity study (MRID 402762501) in C r l:CD

- l (ICR)BR

albino mice. Fifty

- one animals/sex/group were fed 0, 25, 125 or 750 ppm technical Paclobutrazol (92.4% pure) in the diet for 2 years (0, 3.75, 18.75 or 112.5 mg/kg/day). Two control groups of 51 animals/sex were utilized. N ine additional animals/sex in the first control and high dose groups were kept as microbiological sentinels.

At 112.5 mg/kg/day, there was an inc rease in the severity of steatosis of the liver (males). There were also minor increases in relative and absolute liver weights (21% greater than controls for both absolute and relative, liver weights in sales and 18 and 19% greater than controls for

absol ute and relative liver weights, respectively for females) the LOEL is 750 ppm (112.5 mg/kg/day) based on increases in severity of steatosis of the liver in males. The NOEL for chronic effects is 125 ppm (18.85 mg/kg/day).

There appeared to be a borderline increase in Leydig cell tumors in high dose males (2/53, 0/50, 2/51, 1/52 and 5/52 for the control 1, control 2, low, mid

- and high

- dose groups, respectively). A pairwise comparison was statistically significant at the highest dose level (p<0.05)*. In ad dition, a positive trend was observed with increasing dose (pcO.O5). Although the authors stated that this was not considered to be biologically significant because the control values were low, it is considered to be a possible positive response. However, the study is considered to be inadequate for classification of the chemical for carcinogenicity for the following reason: although the

chronic effects are considered to be sufficient to establish a NOEL and an LEL for chronic toxicity, they are not consid ered to be severe enough to indicate that the animals were tested at a sufficiently high dose level for an adequate carcinogenicity study.

This study is classified as core Minimum as a chronic feeding study and Core Supplementary as oncogenicity study (se e discussion). It does not satisfy the regulatory requirement for an oncogenicity study. Due to the low dose levels tested and to the possible positive response for Leydig cell tumors, a repeat study will be needed if the use pattern for the chemical requ ires it.

A.4.6 Mutagenicity

Gene Mutation

Guideline 870.5100 Bacterial reverse mutations (Ames assay)

MRID 00017480 Classification: Acceptable/guideline Paclobutrazol was negative for the induction of reverse gene mutations in Salmonella typhimurium TA1535, TA1537, TA1538, TA98, and TA100 at concentrations of 0, 1.6, 8.0, 40, 200, 500, 1000, 2500 or 5000 μg/plate +/

- S9 activation. Cytotoxicity and compound precipitation was reported at 5000 μg/plate. Guideline 870.5300 In vitro mammalian cell gene mutation (mouse lymphoma L5178Y cells)

MRID 00132695 Classification: Acceptable/guideline Paclobutrazol was negative for the induction of forward gene mutations in mouse lymphoma L5178Y cells at the TK locus at concentrations 0, 0.1, 12.0, 10.3, and 102. 5 μg/mL +/

- S9. Severe cytotoxicity (≤6% cell survival) was seen at 102.5 μg/mL +/

- S9

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 54 of 58 In V ivo Chromosomal Aberrations

Guideline 870.53.75 In vivo bone marrow chromosome aberration (Rat)

MRID 00143156 Classification: Acceptable/guideline Paclobutrazol was negative for the induction of

chromosome aberrations in the bone marrow of Alderly Park male and female rats at doses of 0, 30, 150, or 300 mg/kg/day, once daily for 5 consecutive days via oral gavage.

Guideline 870.5300 Mouse Micronuc leus Assay

MRID 00132694 Classification: Acceptable/guideline Paclobutrazol was negative for the induction of micronucleated polychromatic erythrocytes in the bone marrow of mice at 0, 87.5 or 140 mg/kg. The doses represent 50 and 80%, respectively of th e
LD 50 when delivered via intrapertioneal injection.

Guideline 870.5450 Rodent Dominant Lethal Test (Mouse) MRID 00143155 Classification: Acceptable/guideline Paclobutrazol was negative for the induction of dominant lethal mutations in the spermatocytes of

CD

- 1 mice administered 0, 30, 150 or 300 mg/kg/day, once daily for 5 consecutive days via oral gavage.



### Other In Vivo Studies

Guideline 870.5 50 In vivo Unscheduled DNA Synthesis assay ( UDS, rat hepatocytes )

MRID 00017480

Classification: Acceptable/guideline Paclobutrazol was negative for the induction of UDS in hepatocytes harvested from Alderly Park rats treated with 0, 40, or 400 mg/kg of the test

material.



### A.4.7 Neurotoxicity

870.6200 Acute Neurotoxicity Screening Battery

– data gap

870.6200 Subchronic Neurotoxicity Screening Battery

– data gap

870.6300 Developmental Neurotoxicity Study

– not required at this time

A.4.8 Metabolism

870.7485 Metabolism

– Rat

In a metabolism study (MRID 00132696), male and female Wistar rats re ceived a single oral gavage dose of 10 mg/kg of paclobutrazol (99%) or 10 mg/kg paclobutrazol radiolabeled with

14 

### C on the triazole ring for 4 days. Single rats/sex were subjected to autoradiography 24 hours after dosing and 3 rats per sex were sacrificed 72 hours after dosing and autoradiography, Urine, feces, cage washings and tissues (adipose tissue, gonads, kidneys, and liver were analyzed.

During the 4 days following administration, 39.18 and 52.6 % of the dose was recovered in the

urine of male a nd female rats, respectively. Fecal recoveries were 53.49% in the males and 37% in females. Approximately 60% of the administered dose was accounted for in feces and urine of males and females during the first 24 hours of dosing. Residue concentration s in tissues 3 or

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 55 of 58 4 days after dosing did not indicate accumulation, and urinary excretion along with slow fecal excretion indicated a significant gastrointestinal absorption of the dose.

The study is Acceptable/guideline.

In a metabolism study (MRID 00143160), 1 male and 1 female rat received a single oral gavage dose of 250 mg/kg of paclobutrazol (99%) mixed with radiolabeled paclobutrazol (specific activity = 1.68 GBq/mM 32.16 μCi/mg) for 48 hours. Urine, feces and expired air samples were collected for analysis at 24 and 48 hours. Animals were sacrificed at 48 hours and subjected to autoradiography.

Autoradiographs indicated that the liver, kidneys, and gastrointestinal tract contained the

administered radiolabel . Sim ilarly, the disposition of the 14 

### c label after a single oral dose of 250 mg/kg is limited to the gastrointestinal contents and to a lesser extent to the liver and kidneys.

The study is Acceptable

In a metabolism study (MRID 00143161), 4 male and 4 female Wistar rats received a single oral gavage dose of 5 mg/kg of paclobutrazol (99%) or 5 mg/kg paclobutrazol radiolabeled (specific activity = 32.16 μCi/mg) for 7 days. Urine and feces samples were collected for analysis at 24 hour intervals for 7 day s. Animals were sacrificed at 7 days post

- treatment and organ samples

were taken.

Most of the 5 mg/kg dose was excreted within 72 hours ( 70

- 80%). Approximately 55% of the dose was recovered in the urine of both sexes, and 32% or 24% was recovered in the feces of males and females, respectively. 7 days after dosing, liver tissue contained 0.017 to 0.028 ppm; gastrointestinal tract contained 0.012

- 0.025 ppm. No other tissue levels were detectable.

The study is Acceptable/guideline.

In a metabolism s tudy (MRID 00143165), male and female rats received a single oral gavage dose of 5 or 250 mg/kg of radiolabeled paclobutrazol (specific activity = 1.68 GBq/mM 32.16 μCi/mg) for 3 days. The animals were placed in metabolism cages and urine and feces sample s were collected for analysis at 24

- hour intervals for 3 days. A second series of animals (2 males and 2 females) were cannulated and given 250 mg/kg paclobutrazol by oral gavage. Urine, bile and feces samples were collected for analysis at 24

- hour inte rvals for 4 days. Animals were sacrificed at the end of the treatment time subjected to autoradiography.

A single oral gavage dose (5 or 250 mg/kg) paclobutrazol was absorbed almost completely by

male and female rats. Triazole and halogenated phenyl moieties not affected in rat. Pentanol moiety oxidized to a diol or carboxylic acid & excreted in free or conjugated forms. Males excreted more of carboxylic acid metabolites than females but proportion of acid metabolites excreted by females increased as dose decreased. Approx. 75% of dose was recovered in bile during first 48 hours after dosing in males, and 50% is recovered from females during first 72

hours.

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 56 of 58 The study is Acceptable.

870.7485 Metabolism

– Dog

In a metabolism study (MRID 0014316 3) in dogs, three male and three female beagle dogs were given single oral doses of 5mg//kg radiolabeled (specific activity = 32.16 μCi/mg) and unlabeled paclobutrazol. Blood samples were drawn prior to dosing, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24,48, 72,

9 6, 120, 144, and 168 hours after treatment. Urine and feces samples were collected for analysis at 24 hour intervals for 7 days. Animals were sacrificed at 7 days pot

- treatment and organ samples were taken.

Paclobutrazol was rapidly absorbed in the dog after a single oral dose of 5 mg/kg is administered. Peak plasma and blood levels were observed 1.5 hours after dosing. During the 24 hours following dosing, approximately 80

- 85% of 5 mg/kg dose extracted during first 24 hours after dosing. Approx. 50% of dose recovered in urine of both sexes, & 35

- 40% recovered in feces. Peak blood levels at 1 hour after dosing (4.1

- 4.4 ppm in plasma) declined to pre

- dose

levels 24

- 48 hours after treatment. No detectable levels in tissue & no sex differences were

obs erved.

The study was classified as Acceptable/guideline

A.4.9 Dermal penetration

870.7600 Dermal penetration

– Rat

In an in vivo percutaneous absorption study (MRID 41048202), groups of five male rats (5/dose/exposure period) were dosed dermally on an area of 10 cm 2 

### per rat with 0.011, 0.025, 0.125, 1.23, or 12.49 mg/rat paclobutrazol for 10 or 24 hours. The percentage of dose absorbed and remaining on the washed application site, for exposures of 10 and 24 hours are as follows:

Dose mg/rat 

### Tota l Absorbed (%) Application Site

10 hrs 24 hrs 10 hrs 24 hrs

12.49 1.12 2.78 2.57 2.4

1.23 3.3 3.2 1.6 0.8

0.125 11.6 10.4 0.8 1.6

0.025 16.0 20.8 2.4 2.4

0.011 15.1 24.5 3.6 2.7

This study is classified Acceptable/Guideline, and it satisfies the guideline requirement (870.7600) for a dermal penetration study.

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 57 of 58 Appendix B: 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. T hese studies, which comprise the Pesticide Handlers Exposure Database (PHED), the Outdoor Residential Exposure Task Force (ORETF) Database, the Agricultural Handler Exposure Task Force (AHETF), Agricultural Reentry Task Force (ARTF), and a number of studie s utilized in the 2012 Lawn/Turf SOP have been determined to require a review of their ethical conduct, have received that review, and have been determined to be ethically conducted.

### Paclobutrazol Human Health Risk Assessment DP No. 394230

Page 58 of 58 Appendix C: Physical and Chemical Properties

Appendix Table C.1 : Paclobutrazol Physical and Chemical Properties

Parameter Value

Molecular Weight 293.8 g/mol

Water solubility (20°C) 25.9 mg/L (water)

Solvent solubility (20°C) 2.8 g /L (n

- Octanol) 79.8 g/L (methanol) 5.22 g/L (xylene)
Vapor pressure (20°C) 1.28 x 10 - 9 mmHg

Henry’s Law Constant (25°C) 8.2 x 10 - 7 Pa M 3 mol - 1

(8.09 x 10

- 12 atm M 3 mol - 1 )
Octanol/water partition coefficient (25°C) log Kow = 3.18