UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: January 21,2015 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Paclobutrazol: Final Human Health Risk Assessment for Registration Review. 

PC Code: 12560 I 

Decision No.: 49' 3053 

Petition No.: NA 

Risk Assessment Type: Single 

ChemicaVAggregate 

TXR No.: NA 

MRIDNo.: NA 

DP Barcode: D41 5247 

Registration No.: I 00-1 014 

Regulatory Action: Registration Review 

Case No.: 7002 

CAS No.: 76738-62-0 

40 CFR: NA 

FROM: Sheila Piper, Risk Assessor ~ ~ Ill ' ci./_ .. . I/ 

Monica Hawkins, Ph.D., M.P.H., Environmental Health i ntis r(9f'J;C/lV't'11W ~ Nancy McCarroll, Ph.D., ene~c st/Tox icologist 1/a'1 {i 

P. Yvonne Barnes, Chemist ik'~~~ ... Risk Assessment Branch VI 

THROUGH: Donna Davis, Branch Chief 

Risk Assessment Branch VI 

Health Effects Division 

TO: Khue Nguyen, Chemical Review Manager 

Neil Anderson, Branch Chief 

Risk Management and Implementation Branch I 

Pesticide Re-evaluation Division (7508P) 

The Health Effects Division (HED) ofthe Office ofPesticide 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, paclobutrazol, 

and has conducted a human health risk assessment in support of Registration Review. 

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Paclobutrazol Human Health Risk Assessment DP No. 415247 

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 Sheila Piper (risk assessment), Monica Hawkins 

(occupational and residential assessment), Nancy McCarroll (hazard assessment), and P. Yvonne 

Barnes (chemistry and dietary assessment). Faruque Khan ofthe Environmental Fate and Effects 

Division (EFED) performed the drinking water assessment. 

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1.0 Executive Summary ........................................................................................................... 5

2.0 HED Recommendations .................................................................................................... 7

2.1 Data Deficiencies ............................................................................................................ 8

2.2 Tolerance Considerations.............................................................................................. 9

2.2.1 Enforcement Analytical Method ............................................................................... 9

2.2.2 Recommended Tolerances......................................................................................... 9

2.2.3 Revisions to Petitioned-For Tolerances.................................................................... 9

2.2.4 International Harmonization..................................................................................... 9

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

2.3.1 Recommendations from Residue Reviews................................................................ 9

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

2.3.3 Recommendations from Residential Assessment..................................................... 9

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

3.1 Chemical Identity ........................................................................................................... 9

3.2 Physical/Chemical Characteristics ............................................................................. 10

3.3 Pesticide Use Pattern.................................................................................................... 11

3.4 Anticipated Exposure Pathways................................................................................. 12

3.5 Consideration of Environmental Justice.................................................................... 12

4.0 Hazard Characterization and Dose-Response Assessment.......................................... 13

4.1 Summary of Toxicological Effects.............................................................................. 13

4.2 Absorption, Distribution, Metabolism and Elimination .......................................... 13

4.2.1 Dermal Absorption....................................................................................................... 13

4.3 Toxicity Effects............................................................................................................. 14

4.3.1 Toxicology Profile......................................................................................................... 14

4.4 Safety Factor for Infants and Children (FQPA Safety Factor) ............................... 14

4.4.1 Completeness of the Toxicology Database ................................................................. 15

4.4.2 Evidence of Neurotoxicity............................................................................................ 15

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal ........... 15

4.4.4 Residual Uncertainty in the Exposure Database ...................................................... 15

4.5 Toxicity Endpoint and Point of Departure Selections............................................... 16

4.5.1 Dose-Response Assessment.......................................................................................... 16

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment.......... 17

4.5.3 Cancer Classification and Risk Assessment Recommendations ............................. 17

4.5.4 Points of Departure and Toxicity Endpoints............................................................. 18

4.6 Endocrine Disruption .................................................................................................. 19

5.0 Dietary Exposure and Risk Assessment......................................................................... 20

5.1 Food Residue Profile .................................................................................................... 20

5.2 Summary of Environmental Degradation.................................................................. 20

5.3 Water Residue Profile.................................................................................................. 21

5.4.1 Description of Residue Data Used in Dietary Assessment.................................... 22

5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 22

5.4.3 Acute Dietary Risk Assessment............................................................................... 22

5.4.4 Chronic Dietary Risk Assessment........................................................................... 22

5.4.5 Cancer Dietary Risk Assessment............................................................................. 23

5.4.6 Dietary Summary Table........................................................................................... 23

6.0 Residential Exposure/Risk Estimates............................................................................. 24
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6.1 Residential Handler Exposure/Risk Estimate ........................................................... 24

6.2 Residential Post-Application Exposure/Risk Estimate............................................. 24

6.3 Residential Risk Estimates for Use in Aggregate Assessment.................................. 25

6.4 Spray Drift.................................................................................................................... 26

6.5 Residential Bystander Post-Application Inhalation Exposure ................................ 27

7.0 Aggregate Exposure/Risk Characterization.................................................................. 27

7.1 Acute Aggregate Risk................................................................................................... 27

7.2 Short-and Intermediate-Term Aggregate Risk ......................................................... 27

7.3 Chronic Aggregate Risk .............................................................................................. 28

7.4 Cancer Aggregate Risk ................................................................................................ 28

8.0 Cumulative Exposure/Risk Characterization ............................................................... 28

9.0 Occupational Exposure and Risk Estimates.................................................................. 29

9.1 Occupational Handler Exposure/Risk Estimates...................................................... 29

9.2 Occupational Post-Application Exposure/Risk Estimate ......................................... 40

9.2.1 Occupational Post-Application Inhalation Exposure/Risk Estimates................. 40

9.2.2 Occupational Post-ApplicationDermal Exposure/Risk Estimates....................... 40

10.0 References......................................................................................................................... 44

Appendix A. Toxicology Profile and Executive Summaries .................................................. 45

A.1 Toxicology Data Requirements................................................................................... 45

A.2 Toxicity Profiles............................................................................................................ 47

 A.3. Hazard Identification and Endpoint Selections ........................................................ 55

 A.4. Executive Summaries................................................................................................... 58

 A.5. Absorption, Distribution, Metabolism and Elimination (ADME).....................78
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1.0 Executive Summary

Paclobutrazol is a plant growth regulator. Syngenta Crop Protection has registered labels for 

paclobutrazol with formulations including liquids, wettable powders, and granulars. It is 

currently registered for use as a foliar spray for turf (including parks, athletic fields, 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 registered food uses for 

paclobutrazol.

Paclobutrazol is one of several active ingredients that has triazole metabolites. The triazole 

metabolites produce a different toxic response than the parent compound; therefore separate risk 

assessments are performed for the parent compound and its triazole metabolites. In 2013, HED 

updated the aggregate human health risk assessments for 1,2,4-triazole and the conjugated 

triazole metabolites (D414952, T. Morton, 10/24/13), which addresses risks from triazole 

metabolites produced form all registered triazole producing active ingredients.

The toxicology database for paclobutrazol is complete, no additional data are required. In the 

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 included: 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 rat pre-natal developmental toxicity studies were available. In both studies, there was 

increased evidence of quantitative susceptibility, in the form of delayed ossification of the 7th

cervical vertebrae and an increased incidence of extra rib (14th rib). These effects were 

significantly altered for both fetuses and litters at a dose that was not maternally toxic. There 

was, however, no evidence (quantitative or qualitative) of increased susceptibility following in 

utero 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 paclobutrazol since currently 

registered use patterns are all non-food uses. While there are potential exposures to infants and 

children from turf use patterns of paclobutrazol, there are adequate pre-and/or post natal toxicity 

studies that demonstrate no residual uncertainties to infants and children for pre-and/or post natal 

susceptibilities. The points of departure (PoDs) used for assessing risks to infants and children 

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

concern. There is also no clear evidence of neurotoxicity in the database, and the negative 

findings from the acute neurotoxicity study support this conclusion. 

Although carcinogenicity studies are not required for non-food use chemicals, carcinogenicity 

mouse and rat studies are available in the database. However, the Agency was unable to

determine the potential carcinogenicity of paclobutrazol because the maximum tolerated dose 
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(MTD) was not achieved in the 2-year carcinogenicity/ chronic study in rats and the 

carcinogenicity/chronic study in mice. It is noted that paclobutrazol was not mutagenic in a 

comprehensive battery of acceptable/guideline genetic toxicology assays.

Residential post-application exposure is expected to be short-term in duration only. Since there 

is not intermediate-term residential exposure, an intermediate-term aggregate risk assessment is 

not appropriate. Paclobutrazol is not registered for homeowner use on residential lawns. A 

residential handler assessment was not conducted as part of the risk assessment. A residential 

post-application assessment was performed as use of paclobutrazol in parks and golf courses is 

expected to result in residential post-application exposure. Based on the turf use pattern in parks, 

the target population for incidental oral was identified as young (1-2 year old) children, because 

of hand-to-mouth activities. Quantification of incidental oral ingestion risks was performed 

using the 2-generation reproduction study. The offspring NOAEL was 23.2 mg/kg/day and the 

LOAEL from this study was 116.9 mg/kg/day. A target MOE of 100 is considered adequate for 

all exposure scenarios (10x for interspecies extrapolation, 10x for intraspecies variability).

The dermal (short-term) and inhalation risk for females 13-49 years old from paclobutrazol were 

estimated using a developmental oral toxicity study in rats. The NOAEL of 10 mg/kg/day was 

based on increases in partial ossification of the 7th cervical vertebra and increases in an extra rib 

(14) at the LOAEL of 40 mg/kg/day. A target MOE of 100 is considered adequate for all 

exposure scenarios (10x for interspecies extrapolation, 10x for intraspecies variability).

Paclobutrazol is a highly to moderately mobile chemical 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 using the highest application 

rates. The highest estimated drinking water concentrations were from groundwater. Since 

EFED completed their drinking water assessment prior to the Residue of Concern 

Knowledgebase Sub-committee (ROCKS) determination of the drinking water residues of 

concern; HED notes that EFED took a total residue approach which overestimates residues. 

However, since no dietary risks of concern were identified, a revised drinking water assessment, 

which included only the recommended residues of concern, was not conducted. 

No exposure to food is expected. The acute drinking water risk estimates are below HED’s level 

of concern (<100% of the acute population adjusted dose (aPAD) for the general U.S. population 

(17% of the aPAD) and all population subgroups. The most highly exposed population subgroup 

was all infants (<1 years old) with an estimated risk equivalent to 54% of the aPAD at the 95th

percentile of exposure. The resulting drinking water chronic exposure estimates were less than 

HED’s level of concern (<100% cPAD) for the general U.S. population (12% of the cPAD) and 

all population subgroups; the most highly exposed population subgroup was all infants (<1 years 

old) with an estimated risk of 31% of the cPAD.

Paclobutrazol is currently not registered for homeowner use on residential lawns. Therefore, a 

residential handler exposure assessment was not conducted. Paclobutrazol is applied 

commercially to parks and golf courses; therefore residential post-application exposure was 

assessed. Dermal post-application risks were assessed for adults, and children 11 to 16 years old. 
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All adult and older children golfing dermal risk estimates for both liquid and granular 

formulations are greater than HED’s level of concern (MOEs ≥ 100). All adults on treated turf 

dermal risk estimates for both liquid and granular formulations MOEs range from 170 to 1,100. 

All children 1 – 2 years old oral non-dietary ingestion risk from hand-to-mouth activity on 

treated turf estimates for both liquid and granular formulations MOEs range from 210 to 

1,400,000. 

A quantitative spray drift assessment for paclobutrazol is not required because the maximum 

application rate to a crop/target site multiplied by the adjustment factor for drift of 0.26 is less 

than the maximum direct spray residential turf application rate (0.75 lb ai/A)1for the 

paclobutrazol products. The turf post-application MOEs are protective for any potential 

exposures related to spray drift for paclobutrazol. 

An acute and chronic aggregate assessments are equivalent to the corresponding dietary risk 

estimates, which are not of concern. HED has conducted short-term aggregate assessments that 

includes residential post-application exposure and average dietary (water only) exposures. 

Short/intermediate-term aggregate MOEs for adults (including females 13-49 years old) is 140

and children (1 to < 2 years old) is 780. Intermediate-term aggregate exposure is not expected; 

therefore an intermediate-term aggregate assessment was not conducted.

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 the occupational handler scenarios are greater than HED’s LOC (MOEs ≥100) with the 

exception of mixing/loading/applying liquids via a backpack sprayer. The MOEs range from 29 

to 19,000,000. The backpack sprayer equipment scenario is still not greater than HED’s LOC 

(MOEs < 100) even with the use of personal protective equipment PPE of a double layer and 

gloves (MOE = 58).

Occupational handler exposures to the existing seed treatment uses of paclobutrazol may occur 

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

commercial seed treatment facilities) and secondary handlers (i.e., those who plant paclobutrazol 

treated seeds). The short- and intermediate-term risk estimates for all primary and secondary 

handler scenarios MOEs range from 16,000 to 13,000,000.

Occupational post-application exposures to the existing uses of paclobutrazol may occur via the 

dermal route. The results indicate that occupational post-application risks MOEs range from 

110 to 2,800 on day zero after application for all post-application activities that were assessed.

2.0 HED Recommendations

2.1 Data Deficiencies

There are no data deficiencies relating to toxicology, residue chemistry, residential or 

occupational exposure associated with this registration review for paclobutrazol. 

 

1 0.59 lb ai/A x 0.26 ≤ 0.75 lb ai/A
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2.2 Tolerance Considerations

Paclobutrazol has no food use registration; therefore, there are no tolerances established and a 

discussion of tolerances and enforcement methods is not pertinent to this risk assessment.

2.3 Label Recommendations

None.

3.0 Introduction

The most recent human health risk assessment for paclobutrazol was conducted 2013 (D394230, 

S. Piper, C. Smith, M. Hawkins, and N. McCarroll, 9/11/13). The document was revised to 

incorporate data from the acceptable/guideline acute neurotoxicity study and to account for the 

data waivers granted for the subchronic inhalation, the subchronic neurotoxicity, and the 

immunotoxicity studies by the Hazard and Science Policy Council on March 13, 2014 (TXR # 

0056914). As a result of the meeting, the 10X database uncertainty factor was removed. In 

addition, the dermal absorption factor was updated to be consistent with current HED policy. 

The Toxicity Science Advisory Council (ToxSAC), held on October 02, 2014 approved these 

refinements.

Paclobutrazol (αR,βR)-rel-β-[(4-chlorophenyl)methyl]-α-(1,1-dimethylethyl)-1H-1,2,4-triazole1-ethanol is a plant growth regulator that is currently registered for application to turf grass and a 

number of ornamentals (trees, shrubs, bulbs). It is also registered for use as a seed treatment for

broccoli, cabbage, cauliflower, cucurbits, peppers, and tomatoes. There are currently no 

registered food uses for paclobutrazol. 

Paclobutrazol is one of several active ingredients that has triazole metabolites. The triazole 

metabolites produce a different toxic response than the parent compound; therefore separate risk 

assessments are performed for the parent compound and its triazole metabolites. In 2013, HED 

updated the aggregate human health risk assessments for 1,2,4-triazole and the conjugated 

triazole metabolites (D414952, T. Morton, 10/24/13), which addresses risks from triazole 

metabolites produced form all registered triazole producing active ingredients. The assessment 

include the contributions from all the registered uses of paclobutrazol. The findings of the 1,2,4-

triazole and the conjugated triazole metabolites assessment were that risk estimates for all 

exposure scenarios were below HED’s level of concern.
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3.1 Chemical Identity

Table 3.1. Paclobutrazol Nomenclature

Chemical Structure

Common Name Paclobutrazol

IUPAC name (2RS,3RS)-1-(4-chlorophenyl)-4,4-dimethyl-2-(1H-1,2,4-triazol-1-yl)pentan-3-

ol

CAS Name (αR,βR)-rel-β-[(4-chlorophenyl)methyl]-α-(1,1-dimethylethyl)-1H-1,2,4-

triazole-1-ethanol

CAS Registry 

Number 76738-62-0

Chemical Class Triazole plant growth regulator

3.2 Physical/Chemical Characteristics

Paclobutrazol’s vapor pressure (1.28 x 10-9mm Hg @ 25.0°C) and Henry's Law Constant (8.09 x 

10-10 atm m3/mol) indicate that the compound is relatively non-volatile under field conditions. 

The log Kow 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, paclobutrazol 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. 

Table 3.2. Paclobutrazol Physical and Chemical Properties

Parameter Value

Molecular Weight 293.8 g/mol

Water solubility (20°C) 25.9 mg/L

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 M3 mol-1
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(8.09 x 10-12 atm M3 mol-1)

Octanol/water partition coefficient (25°C) log Kow = 3.18

3.3 Pesticide Use Pattern

There are a number of existing uses for paclobutrazol with formulations including liquids, 

wettable powders, and granulars. Paclobutrazol is currently registered for use as a foliar spray 

for turf (including parks, athletic fields, and golf courses), ornamentals in greenhouses and 

nurseries, as a drench treatment, as a bulb soak treatment, as a tree injection treatment, as a soil 

injection, as a pre-plant plug/liners treatment, and as a seed treatment for cucurbit, pepper, 

tomato, broccoli, cauliflower, and cabbage seeds. Table 3.3 provides more detail related to the 

currently registered uses of paclobutrazol.

Table 3.3. 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

Granular Turf 0.5 lb ai/A Ground and 

handheld 12 hrs

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
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Table 3.3. Paclobutrazol Use Patterns and Formulations

Formulation Use Sites Maximum 

Application Rate

Application 

Equipment REI Notes

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

3.4 Anticipated Exposure Pathways

Exposure is not expected to occur through food because there are no registered agricultural uses 

of paclobutrazol. Residential handler exposure is not expected since paclobutrazol is currently 

not registered for homeowner use on residential lawns. There are residential post-application 

uses of paclobutrazol, so exposure to paclobutrazol is likely to occur in residential postapplication settings. In an occupational setting, handlers may be exposed while handling the 

pesticide prior to application, as well as during application. There is also a potential for postapplication exposure for workers re-entering treated sites. 

3.5 Consideration of Environmental Justice

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

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

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

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

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

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

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

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

Extensive data on food consumption patterns are compiled by the U.S. Department of 

Agriculture under the National Health and Nutrition Examination Survey, What We Eat in 

America, (NHANES/WWEIA). These food consumption patterns 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 children, youths, and adults entering or playing on treated areas 

post-application are evaluated. Exposure risk estimates were not of concern. Further 

considerations are currently in development, as OPP has committed resources and expertise to 

the development of specialized software and models that consider exposure to bystanders and 

farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.
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4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The most recent risk assessment for paclobutrazol (D3944230, 9/11/2013) was conducted prior 

to the review of an acceptable/guideline acute neurotoxicity study, previously identified as a data 

gap; this study has been incorporated into the risk assessment. In addition, based on the weight 

of the evidence (WOE) approach used by HASPOC at the meeting, which was held February 27, 

2014, it was recommended that the subchronic neurotoxicity, the subchronic inhalation and the 

immunotoxicity studies can each be granted data waivers (Leshin , 2014, TXR # 0056914). 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): 

 Acute lethality studies (oral, dermal, inhalation, primary eye and dermal irritation, 

and dermal sensitization)

 Acute neurotoxicity study (rat)

 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 previously reviewed by HED’s RfD/Peer Review Committee in 1994 

(Memo, G. Ghali, 06/21/1994). New data have been submitted since that review was completed. 

The registrant submitted a number of pieces of supplemental data (MRID 47338506) related 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) as well as the acute neurotoxicity study (ToxSAC; 

October 2, 2014). The risk assessment team has incorporated these data into this risk assessment and 

reevaluated the points of departure and toxicity endpoints for the acute and chronic dietary and the 

occupational and residential scenarios using current policies on selecting endpoints and uncertainty 

factors.

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

The absorption, distribution, metabolism and excretion (ADME) of paclobutrazol was 

extensively characterized in a series of studies in rats and dogs. These studies were performed 
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using both low- and high-dose, single and repeated dosing protocols. Bile-cannulation was 

included as part of one of the studies. Estimation of absorption from the gastro-intestinal (GI) 

tract were based upon data from pharmaco/toxicokinetic and excretion experiments.

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 excretion is the urine 

but it is still present in the liver, kidneys, and gastrointestinal tract mostly as the parent 

compound after 72 hours. Paclobutrazol also does not bioaccumulate. It 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. Details of these studies are found in Appendix 5.

4.2.1 Dermal Absorption

A dermal penetration study in rats (MRID 41048202) was available for paclobutrazol in which 

male rats were dermally exposed for 10 or 24 hours on an area of 10 cm2 /rat. At the time this 

study was reviewed, the absorbed dose was calculated as the sum of the residues from the urine, 

feces, cage wash, and carcass (excluding the skin at the application site). The potentially 

absorbable dose included the residues in the skin at the application site. Previously, the most 

conservative value for total absorbable (sum of the absorbed dose and potentially absorbable 

dose) was used, which was 24.5% following a 24-hour exposure period. Currently, the policy is 

to use 8-hours exposure and to assume that residues found in the skin are potentially absorbable, 

unless data are provided to demonstrate otherwise. This policy reflects an 8-hour work day, and 

ongoing exposure is expected to cease at the end of the workday. Likewise, the Agency’s 

position is to be protective; this is reflected in the assumption that residues found in the skin will 

eventually be absorbed, unless there are specific data which contradicts this assumption. 

Therefore, values following the 10-hour exposure period were used and the total absorbable dose 

was calculated to be 18.7%. The percentage of the dose absorbed and remaining on the washed 

application site (potentially absorbable) at 10 hours was 15.1% and 3.6% respectively, and 24.5 

% and 2.7% (24 hours), respectively. Since absorption rates were not measured beyond 24 

hours, the percent absorbed plus the percent potentially absorbed (18.7%) for 10 hours was 

calculated. For risk assessment purposes, HED is using the conservative assumption that the

dermal absorption factor (DAF) of paclobutrazol is 18.7% (See Appendix A.3.4).

4.3 Toxicological Effects

4.3.1 Toxicology Profile

In subchronic feeding studies in rats and dogs, the target organ was consistently 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. Following acute exposure, paclobutrazol exhibited only minimal signs indicative of 

neurotoxicity in rats. 
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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 rat pre-natal developmental toxicity studies were available. In both studies, there was 

increased evidence of quantitative susceptibility in the form of delayed ossification of the 7th

cervical vertebra and an increased incidence of extra rib (14); these effects were significantly 

altered for both fetuses and litters. The finding of developmental defects and/or variations was 

seen in both studies at comparable doses, was dose-related, significantly altered and outside of 

the historical control ranges. These events occurred in the absence of maternal toxicity (maternal 

NOAELs of ≥100 mg/kg/day vs. developmental NOAELs of 10 mg/kg/day in one study and <40 

mg/kg/day in the 2nd study). There was, however, no evidence of susceptibility (quantitative or 

qualitative) following in utero exposures to rabbits or following pre-and/or post-natal exposure 

in rats for two generations in the reproduction study. Paclobutrazol was not mutagenic,

immunotoxic, or neurotoxic. Although there is no evidence in the database that paclobutrazol is

carcinogenic, chronic/carcinogenicity studies in rats and mice are insufficient to draw a 

definitive conclusion.

Paclobutrazol has low toxicity in the rat, rabbit, and guinea pig via the oral (category III) route of 

exposure, the dermal route (category III) in rats and rabbits, and via the inhalation route 

(category III to IV) in rats. It is slightly to mildly irritating to the skin and the eye and is 

negative for dermal sensitization. 

4.4 Safety Factor for Infants and Children (FQPA Safety Factor)/ Lifestage Sensitivity

Food Quality Protection Act (FQPA) considerations do not apply to paclobutrazol as there are no 

current registered food/feed uses; therefore, paclobutrazol is not subject to the Food Quality 

Protection Act (1996). Accordingly, for the purposes of the forthcoming paclobutrazol risk 

assessment for Registration Review, an FQPA assessment is not included. However, after a 

thorough review of the database, there are potential exposures to infants and children from the 

turf use pattern for paclobutrazol were uncovered. There are adequate pre-and/or post-natal 

toxicity studies that show quantitative pre-natal susceptibility with clear NOAELs and LOAELs 

in the two rat developmental studies. Because of the concern for the developmental lifestage, the 

point of departure (PoD) used for assessing the incidental risks to infants and children from oral, 

dermal or inhalation exposures is based on offspring effects in these studies. Thus protecting the 

most sensitive lifestage in humans. 

4.4.1 Completeness of the Toxicology Database

The toxicology database is complete for this non-food use chemical. The registrant has 

submitted an acceptable/guideline acute neurotoxicity study, which has been incorporated into 

this risk assessment. In addition, based on the weight of the evidence (WOE) approach used by 

HASPOC at the meeting, which was held March 13, 2014, it was recommended that the 

subchronic neurotoxicity, the subchronic inhalation and the immunotoxicity studies can each be 

granted data waivers (Leshin, 2014, TXR # 0056914). 
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4.4.2 Evidence of Neurotoxicity

As discussed in Section 4.4.1, an acceptable/guideline acute neurotoxicity study (ACN, MRID 

49211902) has been conducted for paclobutrazol. Based on the weight of the evidence from this 

study and other studies in the database, there is no evidence of neurotoxicity for paclobutrazol. 

The findings of no treatment-related adverse effects on clinical signs, brain weight, gross 

pathology or neuropathology and the negative Functional Observation Battery (FOB) in the ACN 

study support this conclusion. For these reasons, the HASPOC concluded that a subchronic 

neurotoxicity study is not required at this time. 

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

Quantitative evidence of susceptibility was observed in the rat developmental toxicity studies. 

The evidence consisted of delayed ossification of the 7th vertebra and an increased incidence of 

extra rib (14) in two developmental toxicity studies in rats at non-toxic doses in the dams. 

However, there was no evidence of qualitative or quantitative susceptibility in rabbits or in the 

rat two-generation reproduction toxicity study. 

Although there is convincing evidence of increased susceptibility, the concern is low because: 1) 

the response was seen in one species (rat); 2) clear NOAELs and LOAELs were established for 

the developmental effects seen in the two rat studies conducted in this species, 3) there was no

evidence of increased susceptibility in two developmental studies with rabbits; 4) there was no 

evidence of increased susceptibility in the offspring following exposures for two generations in 

the rat reproduction study; 5) the developmental endpoints are used as the PoD for assessing risk 

from oral, dermal and inhalation exposures; and 6) the database is complete. Thus, there are no 

residual uncertainties for pre-and/or post-natal susceptibility.

4.4.4 Residual Uncertainty in the Exposure Database

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

exposure. Conservative, upper-bound assumptions were used to determine exposure through 

drinking water and residential sources, such that these exposures have not been underestimated.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 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 exposure to paclobutrazol 

is expected to be via the oral, dermal, and inhalation routes. 

Acute Dietary (General Population): Quantification of acute dietary (drinking water only) risks 

was performed using the acute neurotoxicity study in rats (MRID 49211902) with a NOAEL of 

30 mg/kg, based on transient alterations in motor activity (i.e., decreased rearing counts (2 ♀) 

and decreased subsession distances) in females 3 to 4 hours after dosing at the LOAEL of 150 
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mg/kg. An Uncertainty Factor (UF) of 100 was applied to account for interspecies extrapolation 

(10X) and intraspecies variability (10X). The acute reference dose (aRfD) for the general 

population was calculated to be 0.3 mg/kg/day.

Acute Dietary (Females 13-49): The most sensitive point of departure was 10 mg/kg/day from 

the developmental rat study (MRID 00143158), based on increased incidences of partial 

ossification of the 7th vertebra and 14th rib in fetuses at the LOAEL of 40 mg/kg/day. Both 

effects were dose-related, statistically significant, outside of the historical control ranges 

provided by the investigator, and reproducible at comparable doses (also seen MRID 00132693),

which occurred in the absence of maternal toxicity. The study was specifically selected for this 

exposure scenario because increases in 14th rib may be the result of a single exposure. An 

Uncertainty Factor (UF) of 100 was applied to account for interspecies extrapolation (10X) and 

intraspecies variability (10X). The acute reference dose (aRfD) for females 13-49 was calculated 

to be 0.1 mg/kg/day. The selection of this study and the PoD is protective of the pregnant female 

and the developing fetus.

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 in the females at the LOAEL of 54.2 mg/kg/day. An Uncertainty Factor 

(UF) of 100 was applied to account for interspecies extrapolation (10X) and intraspecies 

variability (10X). The chronic reference dose (cRfD) was calculated to be 0.11 mg/kg/day.

Short- and Intermediate-Term Incidental Oral (Young children, 1-2 years old): Based on the turf 

use pattern in parks. The target population for incidental oral (short and intermediate term) was 

identified as young (1-2 year old) children, because of hand-to-mouth activities. Quantification

of incidental oral ingestion risks was performed using the 2-generation reproduction study, based 

on a revisit of the data and in consideration of supplemental data on achieved doses provided by 

the registrant (TXR No. 0056158). The offspring NOAEL for this study is 23.2 mg/kg/day. The 

LOAEL is 116.9 mg/kg/day, based on increased incidence of chromodacryorrhea, thickened 

eyelids and dental malocclusion; increased liver weights; mottling or accentuation of the lobular 

structure of the liver along with liver enlargement, pallor and discoloration in the male and 

female pups of both generations. This study was selected to protect the infants and small 

children. An MOE of 100 is required which includes interspecies extrapolation (10X) and

intraspecies variability (10X). 

Short-and Intermediate-term Dermal (Young children, 1-2 years old): A dermal assessment is not 

necessary because in a 3-week dermal toxicity test (MRID 00132688), paclobutrazol was not 

systemically toxic up to the limit dose. Additionally, there was no evidence suggesting that the 

young offspring was more susceptible than their parents to the toxic action of paclobutrazol. 

Short-and Intermediate-term Dermal (Females 13-49): A 3-week dermal toxicity test was 

available for paclobutrazol (MRID 00132688); however, with the exception of local irritation, no 

systemic effects were recorded up to the limit dose. Consequently, quantification of the dermal 

risks was performed using the rat developmental study (MRID 00143158) with a developmental 

NOAEL of 10 mg/kg/day, based on increases in partial ossification of the 7th cervical vertebra 
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and increases in an extra rib (14) at the LOAEL of 40 mg/kg/day. Both effects were doserelated, statistically significant, outside of the historical control ranges provided by the 

investigator, and reproducible at comparable doses (MRID 00132693). The dermal absorption 

rate of 18.7% (MRID 41048202) was applied to the NOAEL (See Section 4.2.1). An MOE of 

100 is required which includes interspecies extrapolation (10X) and intraspecies variability 

(10X). The selection of rat developmental study provides protection to the potentially pregnant 

worker and the developing fetuses but is equally protective for the general population. 

Short- and Intermediate-term Inhalation (Young children, 1-2 years old): Based on the current 

use patterns, there is no exposure to young children via the inhalation route.

Short- and Intermediate-term Inhalation (Females 13-49): No inhalation study was available to 

establish this endpoint. Therefore, quantification of the inhalation risks was performed using the 

rat developmental study (MRID 00143158) with a developmental NOAEL of 10 mg/kg/day, 

based on increases in partial ossification of the 7th cervical vertebra and increases in an extra rib 

(14) at the LOAEL of 40 mg/kg/day. Both effects were dose-related, statistically significant, 

outside of the historical control ranges provided by the investigator, and reproducible at 

comparable doses (MRID 00132693). An inhalation absorption rate of 100% was applied to the 

NOAEL and an MOE of 100 is required which includes interspecies extrapolation (10X) and 

intraspecies variability (10X). The selection of rat developmental study provides protection to 

the potentially pregnant worker and the developing fetuses but is equally protective for the 

general population.

4.5.2 Recommendation for Combining Routes of Exposure for Risk Assessment

When 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 they have the 

same toxicological effects. For paclobutrazol, oral studies with the same toxicological effects

were used to develop the risk assessment for oral, dermal, and inhalation exposures; accordingly, 

exposures can combined, if appropriate for all three routes of exposure.

4.5.3 Cancer Classification and Risk Assessment Recommendations

There are no currently registered food uses for paclobutrazol and carcinogenicity studies are not 

required for non-food use chemicals. Carcinogenicity studies in mice and rats are, however, 

available for paclobutrazol and these studies were reviewed in 1994 by the RfD Peer Committee 

(TXR 0011081). At that time, the Agency determine that there was no evidence in the database 

of carcinogenicity in the database. However, the maximum tolerated dose (MTD) was not 

achieved in the 2-year carcinogenicity/chronic study in rats and the carcinogenicity/chronic study 

in mice. Therefore, the carcinogenic potential of paclobutrazol will be re-evaluated if the use 

pattern changes (i.e., food uses are proposed). It is noted that paclobutrazol was not mutagenic 

in a comprehensive battery of acceptable/guideline genetic toxicology assays.
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4.5.4 Points of Departure and Toxicity Endpoints Used in Human Risk Assessment

Table 4.5.4.1. Summary of Toxicological Points of Departure and Endpoints Used for Dietary 

Exposure to Paclobutrazol

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern for 

Risk Assessment Study and Toxicological Effects

Acute Dietary

General Population

NOAEL = 30 

mg/kg UFA=10x

UFH=10x

30 mg/kg NOAEL 

 100 (UF)

aRfD = 0.3 mg/kg

Acute Neurotoxicity Study (Rats)

MRID 49211902

LOAEL = 150 mg/kg, based on transient 

alterations in motor activity (decreased rearing 

and decreased subsession distances in females 

3-4 hours after dosing)

Acute Dietary

Females 13-49

NOAEL = 10

mg/kg/day

UFA=10x

UFH=10x

10 mg/kg/day NOAEL 

 100 (UF)

aRfD = 0.1 mg/kg 

Developmental Toxicity in Rats

MRID 00143158)

Developmental LOAEL = 40 mg/kg/day, based 

on partial ossification of the 7th vertebra and an 

increased incidence of 14th rib on a fetal and 

litter basis at a dose that was not maternally 

toxic.

Chronic Dietary

All Populations

NOAEL = 

10.8 mg/kg/day

UFA=10x

UFH=10x

10.8 mg/kg/day NOAEL 

 100 (UF)

cRfD = 0.11 mg/kg/day 

Chronic (2-Year Rat) Feeding Toxicity MRID 

40734301

LOAEL = 54.2 mg/kg/day , based on increased 

liver weights (both sexes), hypertrophy, and 

steatosis (both sexes) and decreased 

triglycerides (females)

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. UFA = 

extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human 

population (intraspecies). aRfD = acute reference dose. cRfD = chronic acute reference dose. Note: A FQPA factor was not 

applied because the currently registered use patterns are all non-food uses. 

Table 4.5.4.2. Summary of Toxicological Points of Departure and Endpoints Used for Non-Dietary

Exposures to Paclobutrazol

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern for 

Risk Assessment Study and Toxicological Effects

Incidental Oral

Short- and IntermediateTerm (Young children 1-

2- years old)

NOAEL = 23.2 

mg/kg/day

UFA=10x

UFH=10x Residential LOC = 100

Reproductive Toxicity in Rats

MRID 40734303/47338506

Offspring LOAEL = 116.9 mg/kg/day, based 

on the increased incidence of 

chromodacryorrhea, thickened eyelids and 

dental malocclusion; increased liver weights; 

mottling or accentuation of the lobular 

structure of the liver along with liver 

enlargement; pallor and discoloration in male 

and female pups of both generations.

Dermal

Short- and IntermediateTerm (Young Children 1-

2 years old)

No dermal risk assessment because in a 3-week dermal toxicity test (MRID 00132688), paclobutrazol was 

not systemically toxic up to the limit dose.
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Table 4.5.4.2. Summary of Toxicological Points of Departure and Endpoints Used for Non-Dietary

Exposures to Paclobutrazol

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of Concern for 

Risk Assessment Study and Toxicological Effects

Inhalation

Short- and IntermediateTerm (Young Children 1-

2 years old)

There is no exposure to young children via the inhalation route.

Dermal

Short- and IntermediateTerm (Females 13-49)

Oral NOAEL = 10

mg/kg/day

(Dermal 

Absorption Rate = 

18.7%; (MRID 

41048202)

UFA=10x

UFH=10x Residential/Occupational

LOC = 100

Developmental Toxicity in Rats

MRID 00143158)

Developmental LOAEL = 40 mg/kg/day, based 

on partial ossification of the 7th vertebra and an 

increased incidence of 14th rib on a fetal and 

litter basis at a dose that was not maternally 

toxic.

Inhalation 

Short- and IntermediateTerm (Females 13-49)

Oral NOAEL = 10 

mg/kg/day

Inhalation Rate = 

100%

UFA=10x

UFH=10x Residential/Occupational

LOC = 100

Developmental Toxicity in Rats

MRID 00143158)

Developmental LOAEL = 40 mg/kg/day, based 

on partial ossification of the 7th vertebra and an 

increased incidence of 14th rib on a fetal and 

litter basis at a dose that was not maternally 

toxic.

NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UFA = 

extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity among members of the human 

population (intraspecies). MOE = margin of exposure. LOC = level of concern. 

4.6 Endocrine Disruption

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

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

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

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

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

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

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

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

taxonomic groups. 

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

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

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

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

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

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

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

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

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

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

establish a dose-response relationship between the dose and the E, A, or T effect. 
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At this time paclobutrazol is not subject to the endocrine screening part of the Endocrine 

Disruptor Screening Program (EDSP) as required by FFDCA section 408(p). For more 

information on the status of the EDSP, the policies and procedures, the list of 67 chemicals 

selected for Tier 1 testing, future lists, the test guidelines and the Tier 1 screening battery, please 

visit our website: http://www.epa.gov/endo/.

5.0 Dietary Exposure and Risk Assessment

5.1 Food Residue Profile

There are no currently registered food uses for paclobutrazol. However, the registrant has 

registration of seed treatment uses for broccoli, cabbage, cauliflower, cucurbit, pepper and 

tomato for the active ingredient paclobutrazol to be classified as non-food uses. Based on the 

metabolism studies (D366305; D402767), the seed treatment use of paclobutrazol can be 

classified as non-food since total radioactive residues (TRR) were all below 1 ppb and no food 

tolerances are required.

5.2 Summary of Environmental Degradation

Available data suggest that paclobutrazol 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 

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 terrestrial field dissipation studies. Paclobutrazol residues ranged from 450-950 

days for orchard soils (CA, WV, and FL) and 175-252 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 studies.

5.3 Water Residue Profile

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

Environmental Fate and Effects Division (EFED) and were generated using computer modeling 

methods. The screening model FIRST (FQPA Index Reservoir Screening Tool, version 1.1, 

01/01/07) was used to calculate the surface water EDWCs. Estimated groundwater EDWCs 

were calculated using the screening models SCI-GROW (Screening Concentrations in Ground 

Water, version 2.3, 07/29/03) and PRZM-GW (Pesticide Root Zone Model for Groundwater, 

version 1.0, August 31, 2012). The models and the descriptions are available at the EPA internet 

site: http://www.epa.gov/oppefed1/models/water/. The surface water and groundwater modeling 

were 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 
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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 ground water EDWCs were used in the human health risk assessment for 

paclobutrazol. See Table 5.3.

Two major environmental degradates, CGA 149907 (maximum of 40.4%) and NOA 457654 

(maximum of 25.1%) were identified in the environmental fate and terrestrial field dissipation 

studies, and were included into the drinking water exposure assessment. However, the Residues 

of Concern Knowledgebase Sub-committees (ROCKS) had determined the residues of concern 

in drinking water are the parent compound and its ketone analog CGA 149907. Since EFED 

completed their drinking water assessment prior to the ROCKS determination of the drinking

water residues of concern; HED notes that EFED took a total residue approach which 

overestimates residues. However, since no dietary risks of concern were identified, a revised 

drinking water assessment, which included only the recommended residues of concern, was not 

conducted.

Table 5.3. Estimated Maximum Drinking Water Environmental Concentrations (EDWCs) for 

Paclobutrazol 

Drinking 

Water Source 

(model)

Use

(modeled rate)

Application 

Method

Acute

(μg/L)

Chronic

(μg/L)

Average 

Simulation 

Breakthrough 

Time (days)

Total Residue (Paclobutrazol plus CGA 149907 and NOA 457654)

Surface Water

(FIRST)

Nursery:

(1app. X 2.50 lbs 

ai/acre)

Drench 255.3 166.2

Ground Water

(SCIGROW)

Nursery:

(1app. X 2.50 lbs 

ai/acre)

Drench 25.0 25.0

Groundwater

(PRZM-GW)

Nursery:

(1app. X 2.50 lbs 

ai/acre)

Drench 945.0 622.0 868

High solubility (760000 mg/L) and very low Kd (0.16 L/kg) of NOA457654 are the drivers of high concentrations for total 

toxic residue 

Bolded values are recommended for human health concerns

5.4 Dietary Risk Assessment

5.4.1. Description of Residue Data Used in Dietary Assessment

An updated acute and chronic dietary (drinking water only) exposure and risk assessments were 

conducting using the Dietary Exposure Evaluation Model software with the Food Commodity 

Intake Database (DEEM-FCID) Version 3.16. This software uses 2003-2008 food consumption 

data from the U.S. Department of Agriculture’s (USDA’s) National Health and Nutrition 

Examination Survey, What We Eat in America, (NHANES/WWEIA). The drinking water 
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estimates provided by EFED are modeled estimates, and were generated using the most 

conservative model available for the existing uses. The unrefined acute and chronic approach to 

dietary risk exposure analysis will not underestimate risk to the general U.S. population or any 

population subgroup.

5.4.2 Percent Crop Treated Used in Dietary Assessment

Percent crop treated refinements were not used in this assessment. 

5.4.3 Acute Dietary Risk Assessment

An unrefined acute dietary analysis for paclobutrazol was conducted that directly incorporated 

potential drinking water residues. The resulting acute drinking water risk estimates are below 

HED’s level of concern (<100% acute population adjusted dose (aPAD)) at the 95th percentile of 

the exposure distribution for the general U.S. population 17% aPAD, and all population 

subgroups. The most highly-exposed population subgroup was all infants <1 year old which 

utilized 54% of the aPAD at the 95th percentile of exposure. The detailed results for the general 

population and all population subgroups are shown below in Table 5.4.6.

5.4.4 Chronic Dietary Risk Assessment

The unrefined chronic dietary (drinking water only) risk estimate utilizes 12% of the chronic 

population-adjusted dose (cPAD) for the U.S. population. The estimated risk for the most highly 

exposed population subgroup all infants <1 year is 31% of the cPAD. Thus, chronic dietary 

exposure to paclobutrazol for all population subgroups is not of concern. The detailed results for 

the general population and all population subgroups are shown below in Table 5.4.6.

5.4.5 Cancer Dietary Risk Assessment

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

non-food use pesticides under the 40 CFR Part 158 Toxicology Data Requirements. However, 

carcinogenicity studies were reviewed 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 and in mice. The carcinogenic potential of paclobutrazol and the need for a cancer dietary

assessment will be re-evaluated if the use pattern changes (i.e., food uses are proposed). Since 

the Agency has not classified the carcinogenic potential of paclobutrazol a cancer aggregate risk 

assessment was not conducted at this time.

5.4.6 Dietary Summary Table

The acute and chronic dietary exposure and risks for paclobutrazol are summarized below.
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Table 5.4.6. Summary of Dietary (Drinking Water Only) Exposure and Risk for 

Paclobutrazol 

Population Subgroup

aPAD 

(mg/kg

/day)

Acute Results

95th Percentile Chronic Results Cancer Results

Exposure 

(mg/kg/day)

% 

aPAD

Exposure 

(mg/kg/day)

% 

aPAD

Exposure 

(mg/kg/day)

% 

aPAD

General U.S. 

Population

0.3

0.051528 17 0.013024 12

Not Applicable

All Infants (<1 year 

old) 0.161395 54 0.033582 31

Children 1-2 years old 0.079458 27 0.018788 17

Children 3-5 years old 0.064474 22 0.015829 14

Children 6-12 years 

old 0.049263 16 0.011416 10

Youth 13-19 years old 0.042913 14 0.009498 9

Adults 20-49 years old 0.050707 17 0.012994 12

Adults 50-99 years old 0.045169 15 0.012846 12

Females 13-49 years 

old 0.1 0.051429 51 0.012947 12

1 Values for the population with the highest risk are bolded. 

6.0 Residential Exposure and Risk Estimates

Paclobutrazol is currently registered for use as a foliar spray for turf (including parks, athletic 

fields, and golf courses). Paclobutrazol is currently not registered for homeowner use on 

residential lawns. Therefore, a residential handler exposure assessment was not conducted. A 

residential post-application assessment was performed as use of paclobutrazol in parks and golf 

courses is expected to result in residential post-application exposure. In assessing these 

exposures, HED’s 2012 Residential SOPs2for Residential Pesticide Exposure Assessment: 

Lawns/Turf was used. 

6.1 Residential Post-application Exposure/Risk Estimates

There is the potential for post-application exposure for individuals exposed as a result of being in 

an environment that has been previously treated with paclobutrazol. The quantitative 

exposure/risk assessment for residential post-application exposures is based on the following 

scenarios:

 Physical activities on turf: adults (dermal) and children 1 < 2 years old (incidental oral)

 Golfing: adults (dermal), children 11 < 16 years old (dermal)

 

2 Available: http://www.epa.gov/pesticides/science/residential-exposure-sop.html
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Residential post-application exposure is expected to be short-term in duration. 

The incidental oral scenarios (i.e., hand-to-mouth and object-to-mouth) should be considered 

inter-related and it is likely that they occur interspersed amongst each other across time. 

However, combining these scenarios would be overly-conservative because of the conservative 

nature of each individual assessment. Therefore, the post-application exposure scenarios that 

represents the highest exposure for children 1 to < 2 years old is the hand-to-mouth scenario. 

This scenario should be considered a protective estimate of children’s exposure to pesticides 

used outdoors. A summary of the adult and children short-term dermal exposure and risk 

estimates is shown in Table 6.1.1. All adult and children golfing dermal risk estimates for both 

liquid and granular formulations are greater than the LOC (MOEs ≥ 100). All adults on treated 

turf dermal risk estimates for both liquid and granular formulations are greater than the LOC 

(MOEs ≥ 100). 

Table 6.1.1. Residential Post-application Non-cancer 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 Formulations

Adult Dermal 

Physical Activities on 

Turf

0.75 0.080 d,

0.058 170

Golfing 0.0046 2,200

Child 11 < 16 years 

old Dermal Golfing 0.75 0.080 d 0.0046 2,200

Granular Formulations

Adult

Dermal 

Physical Activities on 

Turf

0.5 0.01e

0.01 1,100

Golfing

0.0006 16,000

Child 11 < 16 years 

old 0.0006 16,000

a. Application rates = maximum application rates from labels.

b. Dose (mg/kg/day) equations provided in Appendix A. 

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.

A summary of the children short-term oral non-dietary ingestion exposure and risk estimates is 

shown in Table 6.1.2. All children oral non-dietary ingestion risk estimates for both liquid and 

granular formulations do not exceed HED’s level of concern (MOEs ≥ 100).
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Table 6.1.2. 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

(mg/kg/day)

Oral 

MOEs c

Liquids

Child 1 < 2 year old Oral 

Hand-to-Mouth

0.75 0.080 d

0.011 2,100

Object-to-Mouth 0.00033 70,000

Soil Ingestion 0.000025 910,000

Granulars

Child 1 < 2 year old Oral 

Hand-to-Mouth

0.5 0.01e

0.0008 31,000

Object-to-Mouth 0.00005 500,000

Soil Ingestion 0.000017 1,400,000

Episodic Granular 

Ingestion

(1.4% ai)

0.05 210

a. Application rates = maximum application rates from labels.

b. Dose (mg/kg/day) equations provided in Appendix A.

c. Oral MOE = NOAEL (23.2 mg/kg/day) / Oral 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.

6.2 Residential Risk Estimates for Use in Aggregate Assessment

Table 6.2 reflects the residential risk estimates that are recommended for use in the aggregate 

assessment for paclobutrazol.

 The recommended residential exposure for use in the adult short-term aggregate 

assessment reflects dermal exposure from post-application exposure from physical 

activities on turf.

 The recommended residential exposure for use in the children 1 to <2 years old shortterm aggregate assessment reflects hand-to-mouth exposures from post-application 

exposure to turf applications.

Table 6.2. Recommendation for the Residential Exposures for the Paclobutrazol Aggregate 

Assessment

Lifestage Exposure 

Scenario

Dose (mg/kg/day)1 MOE2

Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Adult

Turf

(Liquids)

0.058 N/A N/A 0.058 170 N/A N/A 170

Child 1 to

<2 yrs old

Hand-toMouth

(Liquids)

N/A N/A 0.011 0.011 N/A N/A 2,100 2,100

1 Dose = the highest dose for each applicable lifestage of all residential scenarios assessed. Total = dermal + inhalation + incidental oral 

(where applicable).

2 MOE = the MOEs associated with the highest residential doses. Total = 1 ÷ (1/Dermal MOE) + (1/Inhalation MOE) + (1/Incidental 

Oral MOE), where applicable.
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6.3 Spray Drift

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

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

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

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

estimates from these residues can be calculated using drift modeling coupled with methods 

employed for residential risk assessments for turf products.

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

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

to individuals because of existing label language and other regulatory requirements intended to 

prevent them.3 Direct exposures would include inhalation of the spray plume or being sprayed 

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

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

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

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

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

considered in risk assessment. 

Several paclobutrazol products have existing labels for use on turf, thus it was considered 

whether the risk assessment for that use may be considered protective of any type of exposure 

that would be associated with spray drift. The currently registered maximum single application 

rate of paclobutrazol for foliar sprays on ornamentals in nurseries is 0.59 lb ai/A which is less 

than the direct turf application rate of 0.75 lbs ai/A, therefore the registered residential uses on 

turf result in exposure greater than potential exposure from spray drift; and no new spray drift 

residential assessment needs to be completed. The turf post-application MOEs are protective for 

any potential exposures related to spray drift for paclobutrazol. 

6.4 Residential Bystander Post-Application Inhalation Exposure

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

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

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

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

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

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

subsequent Volatilization Screening Analysis 

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

Review, the agency will utilize this analysis to determine if data (i.e., flux studies, route-specific 

inhalation toxicological studies) or further analysis is required for paclobutrazol.

 

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

when included on all labels, precludes direct exposure pathways.
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7.0 Aggregate Exposure/Risk Characterization

HED must consider and aggregate (add) pesticide exposures and risks from three major sources: 

food, drinking water, and residential exposures. In an aggregate assessment, exposures from 

relevant sources are added together and compared to quantitative estimates of hazard (e.g., a 

NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and 

risks from various sources, HED considers both the route and duration of exposure.

7.1 Acute Aggregate Risk

Acute aggregate risks is by definition acute exposures to food and water only. Since there are no 

food exposures, this assessment would address exposure from drinking water only. As a result, 

the acute aggregate risk assessment is equivalent to the acute dietary risk assessment discussed in 

Section 5.4.6 above. There are no acute aggregate risks of concern.

7.2 Short- -Term Aggregate Risk

There is a potential for short-term exposure to paclobutrazol. To estimate short-term aggregate 

risk, HED combined average dietary (water only) exposures (as a measure of average 

background dietary exposure) with short-term residential exposures. 

The most conservative residential exposure scenario was chosen for the adult population which 

reflects dermal exposure from post-application exposure to turf (refer to Table 6.2). The 

residential exposure for use in the children 1 to <2 years old aggregate assessment reflects handto-mouth exposures from post-application high contact lawn activity exposure from turf 

applications.

Short-term aggregate margins of exposure for adults (including females 13-49 years old) and 

children (1 to < 2 years old) are above the LOC of 100 and do not exceed HED’s level of 

concern (MOEs ≥ 100). Short-term aggregate risk estimates are shown below in Table 7.2. 

Table 7.2. Short-Term Aggregate Risk Calculations

Short -Term Scenario

Population NOAEL 

mg/kg/day

LOC1 Maximum

Allowable 

Exposure 

mg/kg/day2

Average 

Food and 

Water 

Exposure 

mg/kg/day3

Residential 

Postapplication 

Dermal 

Exposure 

mg/kg/day4

Total 

Exposure 

mg/kg/day5

Aggregate 

MOE (food, 

water, and 

residential)6
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Child 1-2 yrs 

old 23.2 100 0.232 0.018788 0.011 0.030 780

Adults 

(females 13-

49 yrs old)

10 100 0.1 0.012947 0.058 0.071 140

1 An UF of 100x was applied to account for interspecies extrapolation (10x) and intraspecies variation 

(10x) and no additional uncertainty factors/safety factors are required.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC [23.2 mg/kg/day/100] child 1-2 yrs; [10

mg/kg/day/100] females 13-49 yrs. See Table 4.5.4.1

3 Average food and water exposure from chronic dietary exposure for child 1-2 yrs old and females 13-49 

yrs old. See Table 5.4.6 

4Residential Exposure = Dermal exposure from treated turf (see Tables 6.1.1 and 6.1.2). 

5 Total Exposure = Avg Food & Water Exposure + Residential Exposure

6 Aggregate MOE = [NOAEL/ (Avg Food & Water Exposure + Residential Exposure)]

7.3 Intermediate-Term Aggregate Risk

Residential post-application exposure is expected to be short-term in duration only. Since there 

is not intermediate-term residential exposure, an intermediate-term aggregate risk assessment is 

not appropriate.

7.4 Chronic Aggregate Risk

The chronic aggregate risk assessment is equivalent to the chronic dietary risk assessment

(discussed in Section 5.4.6) 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. 

7.5 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.

8.0 Cumulative Exposure/Risk Characterization

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

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

to 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 regarding EPA’s efforts to determine which chemicals have a common 

mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy 

statements released by EPA’s Office of Pesticide Programs concerning common mechanism 

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

mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.
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9.0 Occupational Exposure and Risk Estimates

9.1 Occupational Handler Exposure/Risk Estimates

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

application process. HED believes that there are distinct job functions or tasks related to 

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler dermal and inhalation exposure is expected 

from the existing uses. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios:

 Mixing/loading liquids for groundboom applications;

 Mixing/loading liquids for tree injection;

 Mixing/loading liquids for soil injection;

 Mixing/loading wettable powders for tree injections;

 Loading granules for open cab solid broadcast spreader applications;

 Mixing/loading liquid concentrations via dip (bulb soak)/liner soaks;

 Applying sprays for open cab groundboom equipment;

 Applying granules for open cab solid broadcast spreader;

 Loading/applying granules for belly grinder applications;

 Loading/applying granules for push type spreader applications;

 Mixing/loading/applying liquids for backpack sprayer applications;

 Mixing/loading/applying liquids for manually pressurized handwand applications; and

 Mixing/loading/applying liquids for mechanically pressurized handgun sprayer 

applications.

HED received written information from several paclobutrazol registrants that for occupational 

applicators, about 50 trees per day are treated for tree injection applications and soil injection 

applications. The data ranged from 10 trees per day to 70 trees per day. HED selected 50 trees 

per day for tree and soil injection applications because it was the most typical number from the 

available information.

Estimates of dermal and inhalation exposure were calculated for various levels of personal 

protective equipment (PPE). Results are presented for “baseline,” defined as a single layer of 

clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and 

no respirator, as well as baseline with various levels of PPE as necessary (e.g., gloves, respirator, 

etc). The paclobutrazol product labels direct mixers, loaders, applicators and other handlers to 
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wear long-sleeved shirt and long pants, chemical-resistant gloves, and shoes plus socks. In 

addition, some of the labels also state that chemical-resistant aprons should also be used. 

The short- and intermediate-term risk estimates for occupational handlers are included in Table 

9.1.1. The short- and intermediate-term risk estimates for the occupational handler scenarios are 

greater than HED’s LOC (MOEs ≥100) with the exception of mixing/loading/applying liquids 

via a backpack sprayer. The backpack sprayer equipment scenario is still not greater than HED’s 

LOC (MOEs < 100) even with the use of PPE of a double layer and gloves (MOE = 58).
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Table 9.1.1. Occupational Handler Exposures and Risks for Paclobutrazol Turf, Ornamental, and Tree Uses

Activity Use Site

PPE-G Dermal 

Unit Exposure 

(mg/lb ai)a

Baseline 

Inhalation Unit 

Exposure 

(mg/lb ai)a

Application 

Rate b

Area 

Treated 

Daily c

PPE-G Baseline Inhalation

Total MOE (PPE-G + 

Baseline Inhalation) Dermal 

Dose

(mg/kg/day)d

MOEf Dose (mg/kg/day)e MOEg

Mixer/Loader

Mixing/Loading Liquids

Groundboom 

Applications on 

Ornamentals in 

Nurseries

0.0376 0.000219

0.59 lb ai/A 40 A 0.0024 4,200 0.000075 130,000 4,000

Groundboom 

Applications on 

Golf Courses

0.75 lb ai/A 40 A 0.0031 3,300 0.000095 110,000 3,200

Tree Injection (8 

diameter Inch 

Trees)

0.0099 lb 

ai/tree 50 trees 0.00005 200,000 0.0000016 6,400,000 190,000

Tree Injection (35 

diameter Inch 

Trees)

0.07 lb 

ai/tree 50 trees 0.00036 28,000 0.000011 900,000 27,000

Tree Soil Injection 0.352 lb 

ai/tree 50 trees 0.0018 5,600 0.000056 180,000 5,400

Dips for 

Plug/Liner Soaks

0.000051 lb 

ai/gal 100 gals 0.00000052 19,000,000 1.60E-08 620,000,000 19,000,000

0.000051 lb 

ai/gal

1000 

gals 0.0000052 1,900,000 1.60E-07 62,000,000 1,900,000

Dips for Bulb 

Soaks (Freesia)

0.00255 lb 

ai/gal 100 gals 0.000026 380,000 8.1E-07 12,000,000 370,000

0.00255 lb 

ai/gal

1000 

gals 0.00026 38,000 0.0000081 1,200,000 37,000

Mixing/Loading Wettable 

Powders

Tree Injection (6-

16 inches in 

diameter)

0.17 0.043 0.000059 lb 

ai/tree 50 trees 0.0000014 7,400,000 0.0000018 5,400,000 3,100,000
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Table 9.1.1. Occupational Handler Exposures and Risks for Paclobutrazol Turf, Ornamental, and Tree Uses

Activity Use Site

PPE-G Dermal 

Unit Exposure 

(mg/lb ai)a

Baseline 

Inhalation Unit 

Exposure 

(mg/lb ai)a

Application 

Rate b

Area 

Treated 

Daily c

PPE-G Baseline Inhalation

Total MOE (PPE-G + 

Baseline Inhalation) Dermal 

Dose

(mg/kg/day)d

MOEf Dose (mg/kg/day)e MOEg

Tree Injection 

(>16 inches in 

diameter)

0.00024 lb 

ai/tree 50 trees 0.0000055 1,800,000 0.0000075 1,300,000 770,000

Loading Granulars

Tractor Drawn 

Spreader 

Applications on 

Golf Courses

0.0069 0.0017 0.5 lb ai/A 40 A 0.00037 27,000 0.00049 20,000 12,000

Applicator

Applying Liquid Sprays 

via Groundboom

Golf Courses

0.0161 0.00034

0.75 lb ai/A 40 A 0.0013 7,600 0.00015 68,000 6,900

Ornamentals in 

Nurseries 0.59 lb ai/A 40 A 0.001 9,700 0.00012 86,000 8,700

Applying Granulars via 

Tractor Drawn Spreader Golf Courses 0.0072 0.0012 0.5 lb ai/A 40 A 0.00039 26,000 0.00035 29,000 14,000

Mixer/Loader/Applicator

Mixing/Loading/Applying 

Liquids via Backpack 

Sprayer

Turf

8.26 0.00258

0.75 lb ai/A 5 A 0.084 120 0.00014 71,000 120

Golf Course 0.75 lb ai/A 5 A 0.084 120 0.00014 71,000 120

Drench Tree 

Treatments (8 inch 

Tree)

0.07 lb 

ai/tree 50 trees 0.078 130 0.00013 76,000 130

Drench Tree 

Treatments (35 

inch Tree)

0.31 lb 

ai/tree 50 trees 0.35 29 0.00058 17,000 29

Drench Tree 

Treatments

(35 inch Tree)

4.12

(PPE G-DL)

0.00258 0.31 lb 

ai/tree 50 trees 0.17 58 0.00058 17,000 58

(PPE G-DL + baseline 

Inhalation)

Foliar Sprays on 

Ornamentals in 

Nurseries and 

Greenhouses

11200 140 0.00423 lb 

ai/gallon

40 

gallons 0.00515 1,900 0.000343 29,000 1,800
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Table 9.1.1. Occupational Handler Exposures and Risks for Paclobutrazol Turf, Ornamental, and Tree Uses

Activity Use Site

PPE-G Dermal 

Unit Exposure 

(mg/lb ai)a

Baseline 

Inhalation Unit 

Exposure 

(mg/lb ai)a

Application 

Rate b

Area 

Treated 

Daily c

PPE-G Baseline Inhalation

Total MOE (PPE-G + 

Baseline Inhalation) Dermal 

Dose

(mg/kg/day)d

MOEf Dose (mg/kg/day)e MOEg

Mixing/Loading/Applying 

Liquids via Manually 

Pressurized Handwand

Foliar Sprays on 

Ornamentals in 

Nurseries and 

Greenhouses

0.43 30

0.00423 lb 

ai/gallon

40 

gallons 0.000197 51,000 0.0000736 140,000 37,000

Drench Tree 

Treatments (8 inch 

Tree)

0.07 lb 

ai/tree 50 trees 0.0041 2,500 0.0015 6,600 1,800

Drench Tree 

Treatments (35 

inch Tree)

0.31 lb 

ai/tree 50 trees 0.018 550 0.0067 1,500 400

Loading/Applying 

Granulars via Push-type

Spreader

Turf

0.24 0.01

0.5 lb ai/A 5 A 0.0016 6,100 0.00036 28,000 5,000

Golf Course 0.5 lb ai/A 5 A 0.0016 6,100 0.00036 28,000 5,000

Mixing`/Loading/Applying 

Liquids via Mechanically 

Pressurized Handwand

Turf 0.88 0.0019 0.75 lb ai/A 5 A 0.0089 1,100 0.0001 97,000 1,100

Golf Course 0.75 lb ai/A 5 A 0.0089 1,100 0.0001 97,000 1,100

Foliar Sprays on 

Ornamentals in 

Nurseries

390 3.9 0.00423 lb 

ai/gallon

1,000 

gallons 0.00447 2,200 0.000239 42,000 2,100

Foliar Sprays on 

Ornamentals in 

Greenhouses

2,500 120 0.00423 lb 

ai/gallon

1,000 

gallons 0.0287 350 0.00736 1,400 280

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. Exposure Science Advisory Council Policy #9.1.

d. Dermal Dose (mg/kg/day) = Dermal Unit exposure (mg/lb ai) × Conversion Factor (0.001 mg/μg) x Application Rate x Area Treated or Amount Handled x % Dermal 

Absorption Factor (18.7%) /Body weight (69 kg). 

e. Inhalation Dose (mg/kg/day) = Inhalation Unit Exposure (mg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate x Area Treated x %Absorption (100% inhalation ) / 

Body weight (69 kg). 

f. Dermal MOE = Dermal NOAEL (10 mg/kg/day) / Dermal Dose (mg/kg/day). LOC = 100. 

g. Inhalation MOE = Inhalation NOAEL (10 mg/kg/day) / Inhalation Dose (mg/kg/day). LOC = 100
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Short-/Intermediate-Term Handler Risk for Seed Treatments

Paclobutrazol is currently registered for commercial seed treatment use on tomato, pepper, and 

cucurbit, broccoli, cauliflower, and cabbage seeds. The paclobutrazol labels do not permit onfarm seed treatment. Based on the existing seed treatment use pattern, there is a 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 exposure is 

expected to be short- or intermediate-term in duration based on the information provided on the 

existing labels. 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 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” scenario (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 onfarm seed treatment as the 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 seed. Summaries of the risk estimates for 

primary and secondary handlers are included in Tables 9.1.2 and 9.1.3. The short- and 

intermediate-term risk estimates for all primary and secondary handler scenarios are greater than 

HED’s LOC (MOEs ≥100).
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Table 9.1.2 Summary of Short- and Intermediate-Term Handler Exposures and Risks for Paclobutrazol Seed Treatment

Seed Type

Max 

Application 

Ratea

Unit Exposureb

(mg/lb ai)

Amount of 

Seed Treatedc

Absorbed Dose

(mg/kg/day)d MOEe

lb ai/lb seed Dermal Inhal. lb seed/day Dermal Inhal. Dermal Inhal.

LOADER/APPLICATOR (single layer, gloves)

Cucurbit

(Cucumber) 0.000229

0.00023 0.00034 3,000

0.000043 0.000003 230,000 3,000,000

Cucurbit

(Cantaloupe) 0.00027 0.000050 0.000004 200,000 2,500,000

Cucurbit

(Pumpkin) 0.000107 0.000020 0.000002 500,000 6,300,000

Cucurbit

(Squash) 0.000172 0.000032 0.000003 310,000 3,900,000

Cucurbit

(Watermelon) 0.000157 0.000029 0.000002 340,000 4,300,000

Pepper 0.00247 0.000462 0.000037 22,000 270,000

Tomato 0.00414 0.000774 0.000061 13,000 160,000

Broccoli 0.000661 0.000124 0.000010 81,000 1,000,000

Cauliflower 0.000635 0.000119 0.000009 84,000 1,100,000

Cabbage 0.000639 0.000119 0.000009 84,000 1,100,000

SEWER (single layer, no gloves)

Cucurbit

(Cucumber) 0.000229

0.0062 0.00023 3,000

0.000012 0.000002 870,000 4,400,000

Cucurbit

(Cantaloupe) 0.00027 0.000014 0.000003 730,000 3,700,000

Cucurbit

(Pumpkin) 0.000107 0.000005 0.000001 1,900,000 9,300,000

Cucurbit

(Squash) 0.000172 0.000009 0.000002 1,200,000 5,800,000

Cucurbit 0.000157 0.000008 0.000002 1,300,000 6,400,000
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Table 9.1.2 Summary of Short- and Intermediate-Term Handler Exposures and Risks for Paclobutrazol Seed Treatment

Seed Type

Max 

Application 

Ratea

Unit Exposureb

(mg/lb ai)

Amount of 

Seed Treatedc

Absorbed Dose

(mg/kg/day)d MOEe

lb ai/lb seed Dermal Inhal. lb seed/day Dermal Inhal. Dermal Inhal.

(Watermelon)

Pepper 0.00247 0.000125 0.000025 80,000 400,000

Tomato 0.00414 0.000209 0.000041 48,000 240,000

Broccoli 0.000661 0.000033 0.000007 300,000 1,500,000

Cauliflower 0.000635 0.000032 0.000006 310,000 1,600,000

Cabbage 0.000639 0.000032 0.000006 310,000 1,600,000

BAGGER (single layer, no gloves)

Cucurbit

(Cucumber) 0.000229

0.0091 0.00016 3,000

0.000017 0.000002 590,000 6,300,000

Cucurbit

(Cantaloupe) 0.00027 0.000020 0.000002 500,000 5,300,000

Cucurbit

(Pumpkin) 0.000107 0.000008 0.000001 1,300,000 13,000,000

Cucurbit

(Squash) 0.000172 0.000013 0.000001 790,000 8,400,000

Cucurbit

(Watermelon) 0.000157 0.000012 0.000001 860,000 9,200,000

Pepper 0.00247 0.000183 0.000017 55,000 580,000

Tomato 0.00414 0.000306 0.000029 33,000 350,000

Broccoli 0.000661 0.000049 0.000005 200,000 2,200,000

Cauliflower 0.000635 0.000047 0.000004 210,000 2,300,000

Cabbage 0.000639 0.000047 0.000004 210,000 2,200,000

MULTIPLE ACTIVITIES (combination of loader/applicator with gloves and no coveralls, sewer without gloves, stacker 

without gloves)

Cucurbit

(Cucumber) 0.000229 0.042 0.0016 3,000 0.000078 0.000016 130,000 630,000

Cucurbit 0.00027 0.000092 0.000019 110,000 530,000
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Table 9.1.2 Summary of Short- and Intermediate-Term Handler Exposures and Risks for Paclobutrazol Seed Treatment

Seed Type

Max 

Application 

Ratea

Unit Exposureb

(mg/lb ai)

Amount of 

Seed Treatedc

Absorbed Dose

(mg/kg/day)d MOEe

lb ai/lb seed Dermal Inhal. lb seed/day Dermal Inhal. Dermal Inhal.

(Cantaloupe)

Cucurbit

(Pumpkin) 0.000107 0.000037 0.000007 270,000 1,300,000

Cucurbit

(Squash) 0.000172 0.000059 0.000012 170,000 840,000

Cucurbit

(Watermelon) 0.000157 0.000054 0.000011 190,000 920,000

Pepper 0.00247 0.000843 0.000172 12,000 58,000

Tomato 0.00414 0.001414 0.000288 7,100 35,000

Broccoli 0.000661 0.000226 0.000046 44,000 220,000

Cauliflower 0.000635 0.000217 0.000044 46,000 230,000

Cabbage 0.000639 0.000218 0.000044 46,000 220,000

a Application Rates based on existing labels for paclobutrazol.

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

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

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 (18.7%) / body weight (69 kg 

adult). Dermal MOE = NOAEL (10.0 mg/kg/day for short- and intermediate-term exposure) / Dermal Dose (mg/kg/day). Level of concern = 100.

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 (69 

kg adult). Inhalation MOE = NOAEL (10.0 mg/kg/day for short- and intermediate-term exposure) / Inhalation Dose (mg/kg/day). Level of concern = 100.
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Table 9.2.3. Summary of Secondary Handler (Planter) Exposures and Risks for Paclobutrazol (Single Layer, 

Gloves during Loading Only)

Seed Type

Max

Application 

Rate a

(lb ai/lb 

seed)

Dermal Unit 

Exposureb

(mg/lb ai)

Inhalation 

Unit 

Exposureb

(mg/lb ai) 

Amount 

of Seed 

Planted 

Per 

Dayc

(lb seed/day)

Absorbed 

Dermal 

Dosed

(mg/kg/day)

Absorbed 

Inhalation 

Dosed

(mg/kg/day)

Dermal 

MOEe

Baseline 

Inhalation 

MOEe

Cucurbit Seed 

(Cucumber) 0.000229 0.25 0.0034 3,000 0.00046547 0.0000339 21,000 300,000

Cucurbit Seed 

(Cantaloupe) 0.00027 0.25 0.0034 3,000 0.00054880 0.0000399 18,000 250,000

Cucurbit Seed 

(Pumpkin) 0.000107 0.25 0.0034 3,000 0.00021749 0.0000158 46,000 630,000

Cucurbit Seed 

(Squash) 0.000172 0.25 0.0034 3,000 0.00034961 0.0000254 29,000 390,000

Cucurbit Seed 

(Watermelon) 0.000157 0.25 0.0034 3,000 0.00031912 0.0000232 31,000 430,000

Pepper 0.00247 0.25 0.0034 3,000 0.00502054 0.0003651 2,000 27,000

Tomato 0.00414 0.25 0.0034 3,000 0.00841500 0.0006120 1,200 16,000

Broccoli 0.000661 0.25 0.0034 3,000 0.00134355 0.0000977 7,400 100,000

Cauliflower 0.000635 0.25 0.0034 3,000 0.00129071 0.0000939 7,700 110,000

Cabbage 0.000639 0.25 0.0034 3,000 0.001298837 0.0000945 7,700 110,000

a Application Rates based on existing labels for paclobutrazol.

b Unit Exposures from HED Exposure Science Advisory Council Policy 14: Standard Operating Procedures for Seed Treatment.

c HED default for lb seed planted per day from HED Exposure Science Advisory Council Interim Policy 15 and the BEAD memo “Acres Planted Per Day and Seeding Rates of 

Crops Grown in the United States” (J. Becker, March 2011).
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d Daily Absorbed Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x application rate (lb ai/lb seed) x amount treated (lb seed/day) x absorption factor (18.7% for dermal, 100% 

for inhalation) / body weight (69 kg adult). Level of concern = 100.

e MOE = NOAEL (dermal and inhalation = 10.0 mg/kg/day for short- and intermediate-term exposure) /Absorbed Dose (mg/kg/day). Level of concern = 100.
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9.2 Occupational Post-application Exposure/Risk Estimates

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

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

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

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

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

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

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

9.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates

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. 

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

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

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

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

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

inhalation exposure scenarios.

The Worker Protection Standard for Agricultural Pesticides contains requirements for protecting 

workers from inhalation exposures during and after greenhouse applications through the use of 

ventilation requirements. [40 CFR 170.110, (3) (Restrictions associated with pesticide 

applications)].

A post-application inhalation exposure assessment is not required as exposure is expected to be 

negligible. Seed treatment assessments provide quantitative inhalation exposure assessments for 

seed treaters and secondary handlers (i.e., planters). It is expected that these exposure estimates 

would be protective of any potential low-level post-application inhalation exposure that could 

result from these types of applications.

9.2.2 Occupational Post-application Dermal Exposure/Risk Estimates

Occupational Post-application Dermal Exposure Data and Assumptions

A series of assumptions and exposure factors served as the basis for completing the occupational 

post-application risk assessments. Each assumption and factor is detailed below on an individual 

basis. HED classifies exposures from 1 to 30 days as short-term and exposures 30 days to six 

months as intermediate-term. For paclobutrazol, based on the currently registered use, short- and 

intermediate-term exposures are expected. The short- and intermediate-term PODs are the same; 

therefore, short-term risk estimates are protective of longer-term exposures.
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Table 9.2.2.1. provides a summary of the transfer coefficients and activities associated with turf

and ornamentals in greenhouse and nurseries.

Table 9.2.2.1. Post-application Activities and Dermal Transfer Coefficients.

Crops Crop Height Foliage

Density

Transfer Coefficients 

(cm2/hr) Activities

Turf Low Full 2,500

Golf course 

maintenance, greens 

only

Turf Low Full 3,700 Maintenance

Ornamentals in 

Nurseries

Low Min 230 Grafting, Propagating, 

Transplanting

Low Full 230

Hand harvesting, Hand 

pruning, Scouting, 

Hand Weeding , 

Transplanting, 

Pinching, 

Tying/Training

High Min 230 Hand harvesting, Hand 

pruning, Transplanting

High Full 230

Hand harvesting, Hand 

pruning, Scouting, 

Container Moving, 

Hand weeding, 

Transplanting, Pinching

Low/High Full 1900 Hand set irrigation

Ornamentals in 

Greenhouses

Low Min

230

Grafting, Propagating, 

Transplanting

Low Full Hand harvesting, Hand 

pruning, Scouting, 

Hand weeding, 

Transplanting, 

Pinching, 

Tying/Training

High Min Hand harvesting, Hand 

pruning, Transplanting

High Full Hand harvesting, Hand 

pruning, Scouting, 

Container Moving, 

Hand weeding, 

Transplanting, Pinching
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A summary of the estimated occupational post-application risks are provided in Table 9.2.2.2. 

The short- and intermediate-term risk estimates for golf course maintenance activities are greater 

than HED’s LOC (MOEs ≥ 100) using predicted Day 0 residue values from the TTR study. The 

short- and intermediate-term risk estimates for ornamentals in greenhouses and nurseries are 

greater than HED’s LOC (MOEs ≥ 100) using predicted Day 0 residue values from either the 

Chrysanthemum or Poinsettia DFR data for all activities. 

Table 9.2.2.2. Occupational Post-application Non-Cancer Exposure and Risk Estimates

for Paclobutrazol.

Crop/Site Activities Transfer Coefficient 

(cm2/hr) DFR/TTR1 Dermal Dose (mg/kg/day)2 MOE3

Short- and Intermediate-term

Turf4

Golf course 

maintenance, 

greens only

2,500 0.080 0.004 2,300

Turf4 Maintenance 3,700 0.080 0.006 1,600

Ornamentals in 

Nurseries using 

Chrysanthemum 

DFR Data5

Hand harvesting, 

Hand pruning, 

Scouting, 

Container 

moving, Hand 

Weeding, 

Transplanting, 

Grafting, 

Propagating, 

Pinching, 

Tying/Training

230 0.73 0.004 2,800

Hand set 

irrigation 1,900 0.73 0.030 330

Ornamentals in 

Greenhouse using 

Chrysanthemum 

DFR Data5

Hand harvesting, 

Hand pruning, 

Scouting, 

Container 

moving, Hand 

Weeding, 

Transplanting, 

Grafting, 

Propagating, 

Pinching,

Tying/Training

230 0.73 0.004 2,800
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Table 9.2.2.2. Occupational Post-application Non-Cancer Exposure and Risk Estimates

for Paclobutrazol.

Crop/Site Activities Transfer Coefficient 

(cm2/hr) DFR/TTR1 Dermal Dose (mg/kg/day)2 MOE3

Short- and Intermediate-term

Ornamentals in 

Nurseries using 

Poinsettia DFR 

Data6

Hand harvesting, 

Hand pruning, 

Scouting, 

Container 

moving, Hand 

Weeding, 

Transplanting, 

Grafting, 

Propagating, 

Pinching, 

Tying/Training

230 2.20 0.011 910

Hand set 

irrigation 1,900 2.20 0.091 110

Ornamentals in 

Greenhouse using 

Poinsettia DFR 

Data6

Hand harvesting, 

Hand pruning, 

Scouting, 

Container 

moving, Hand 

Weeding, 

Transplanting, 

Grafting, 

Propagating, 

Pinching, 

Tying/Training

230 2.20 0.011 910

1 (See MRID 45214201, MRID 45310801, MRID 45336601).

2 Daily Dermal Dose = [DFR or TTR (μg/cm2) × Transfer Coefficient × 0.001 mg/μg × 8 hrs/day × dermal 

absorption (18.7 %)]  BW (69 kg).

3 MOE = POD (mg/kg/day) / Daily Dermal Dose. Daily Dermal Dose = [DFR/TTR (μg/cm2) × TC × 0.001 mg/μg 

× 8 hrs/day × dermal absorption factor (18.7 %)]  BW (69 kg).

4 TTR data represents CA which was the test site with the highest residues (MRID 45214201).

5 Chrysanthemum DFR data represents use in a greenhouse in Oregon (MRID 45310801).

6 Poinsettia DFR data represents use in a shade house in Florida (MRID 45336601).

Restricted Entry Interval

Paclobutrazol is classified as Toxicity Category III via the dermal route and or skin irritation 

potential based on studies submitted in 2012. It is not a skin sensitizer. Short- and intermediateterm post-application risk estimates were not a concern on day 0 (12 hours following application) 

for all post-application activities. Under 40 CFR 156.208 (c) (2) (iii), ai’s classified as Acute 

Toxicity Category III chemicals require a 12- REI. The occupational post-application 

assessment, dermal risk estimates do not exceed HED’s level of concern (MOEs >100). Based 

on the acute dermal toxicity, the 12-hour REI that appears on the current paclobutrazol labels is 

supported by the acute toxicity data.
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Review of Human Research

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

intentionally exposed to a pesticide or other chemical. These data, which include studies from 

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

database; the ARTF database; ExpoSAC Policy 14 (SOPs for Seed Treatment); the Residential 

SOPs (Lawns/Turf); a chemical-specific turf transferable residue study (MRID 45214201), and a 

chemical-specific dislodgeable foliar residue study (MRID 45310801 and 45336601) are (1) 

subject to ethics review pursuant to 40 CFR 26, (2) have received that review, and (3) are 

compliant with applicable ethics requirements. For certain studies, the ethics review may have 

included review by the Human Studies Review Board. Descriptions of data sources, as well as 

guidance on their use, can be found at the Agency website4. 

Review of Incident Report

Paclobutrazol incidents were analyzed in 2007 (M. Hawkins and H. Allender, 02/27/2007, 

D335541). There were 2 incidents identified in IDS from 1999 to 2007; there were no incidents 

identified in Poison Control Center Data from 1993 to 2005; and there were no incidents 

identified in NIOSH SENSOR data from 1998 to 2003. An updated incident analyses of the 

Main and Aggregate Incident Data System (IDS) from January 1, 2010 to January 20, 2015, and 

the National Institute of Occupational Safety and Health Sentinel Event Notification System for 

Occupational Risks (NIOSH SENSOR-Pesticides) from 1998 to 2011 are consistent with the 

previous analyses (S. Recore, via email dated 1/20/2015).

10.0 References

Hawkins, M., McCarroll, N., Piper. S., and Smith, C. (2013). Paclobutrazol. Preliminary Human 

Health Risk Assessment for Registration Review. DP Number: D394230, dated September 11, 

2013.

Khan, F. (2014). Revised Tier 1 Drinking Water Assessment for the Registration Review of 

Paclobutrazol on Turf (commercial, ornamental and golf courses), Ornamental and Shade Trees, 

and Seed Treatment of Tomato, Pepper and Cucurbit. DP Number: D418301, dated March 13, 

2014.

Barnes, Y. (2014). Paclobutrazol. Acute and Chronic Dietary (Drinking Water Only) Exposure 

and Risk Assessment. DP Number: D419143, dated 1/21/2015.

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

meeting of December 8, 2011: Recommendations on the need for immunotoxicity and acute and 

subchronic neurotoxicity studies for paclobutrazol, TXR 0056149.

 

4 http://www.epa.gov/pesticides/science/handler-exposure-data.html and 

http://www.epa.gov/pesticides/science/post-app-exposure-data.html
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Smith, C. (2012). Paclobutrazol: Non-food Use for Seed Treatment on Broccoli. DP Number: 

D402767, dated September 13, 2012.

Morton, T. (2013). Common Triazole Metabolites: Updated Aggregate Human Health Risk 

Assessment to Address The New Section 3 Registrations For Use of Propiconazole on Rapeseed 

Crop Subgroup 20A; Use of Difenoconazole on Rapeseed Crop Subgroup 20A; and Use of 

Tebuconazole on Imported Oranges. DP Number: D414952, dated October 24, 2013.
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Appendix A. Toxicology Profile and Executive Summaries

A.1 Toxicology Data Available for Paclobutrazol

A.1 Toxicology Data Requirements

The requirements (40 CFR 158.340) for food vs. non-food for Paclobutrazol are in Table A.1 below. 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

yes

yes

yes

yes

no

yes

yes

noa

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).........................................

yes

yes

yes

yes

yes

yes

yes

no

yes

yesb

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

no

---

---

yes

noa

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 noa
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Non-Guideline: Comparative dermal absorption, in vitro (rat 

 and human skin)

No no

a Data waivers granted by HASPOC March 13, 2014 (TXR 0056914).

b Only the chronic portion of the Chronic/Carcinogenicity (rat) study is acceptable. 

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) LD50 = 1954 mg/kg (M)

 1336 mg/kg (F)

III

870.1100 Acute Oral (97% ai)

Alderley Park Mouse

00117478 (1982) LD50 = 490 mg/kg (M)

 1219 mg/kg (F)

 

 II

870.1100 Acute Oral (97% ai)

Dunkin Hartley Albino Guinea pig

00117478 (1982) LD50 = 542 mg/kg (M)

 >400 and <640 mg/kg (F) III

870.1100 Acute Oral (97% ai)

NZW Rabbit

00117478 (1982) LD50 = 835 mg/kg (M)

 937 mg/kg (F)

III

870.1200 Acute Dermal (97% ai) 

Alderley Park Rat

00117478 (1982) LD50 = >1000 mg/kg 

 (M F) II

870.1200 Acute Dermal (97% ai) 

NZW Rabbit 00117478 (1982)

 

LD50 = >1000 mg/kg

 (M F) II

870.1300 Acute Inhalation (97% ai)

50% ai 

Alderley Park Rat

00117482 (1982) LC50 = >766 mg/m3 (M)

359-766 mg/m3 (F)

III

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. 

IIIa

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 sensitized

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

\
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The Toxicity Profile Table is presented below in Table A.2.2

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-Ndemethylase 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 = 15 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 2nd week of application. Degree increased with 

increasing dose. Hyperkeratosis, acanthosis and 

inflammatory changes of superficial dermis. 

No systemic toxicity seen at any dose.

870.3465 

28-Day inhalation toxicity

(rat)

Data waiver granted by HASPOC March 13, 2014 (TXR 0056914)

870.3700a

Prenatal developmental 

toxicity in rodents

(Wistar rats, derived from 

Alderley Park strain)

00132693 (1983)

Acceptable/guideline

0, 40, 100, or 250 

mg/kg/day from days 6 

through 15 of gestation

Oral gavage; solvent = 

corn oil. 

Maternal NOAEL = 100 mg/kg /day 

LOAEL =250 mg/kg /day, based on mortality, 

significantly decreased body weight gain and food 

efficiency, and gross liver effects (pallor and 

enlargement).

Developmental NOAEL was not established. LOAEL 

= 40 mg/kg/day (lowest dose tested), based on 

significant and dose-related increases in fetuses with 

bilateral partial ossification of the 7th cervical bone at 

40, 100 and 250 mg/kg/day and in bilateral significant 

increases in the number of fetuses with an extra rib 

(15). Increases in the number of litters affected with 

these defects were also seen but not analyzed 

statistically. Cleft palate was also seen in 3 fetuses from 

2 litters at 250 mg/kg/day.

870.3700a

Prenatal developmental 

toxicity in rodents

00143158 (1984)

Acceptable/guideline

Maternal NOAEL =>100 mg/kg /day (HDT).
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Table A.2.2: Toxicity Profile of Paclobutrazol Technical

Guideline No./

Study Type

MRID No. (year)/ 

Classification/Doses Results

(Wistar rats, derived from 

Alderley Park strain)

0, 2.5, 10, 40, or 100 

mg/kg/day from days 7 

through 16 of gestation.

Oral gavage; solvent = 

corn oil.

Developmental NOAEL = 10 mg/kg /day LOAEL = 

40 mg/kg/day, based on significant and dose-related 

increases in fetuses and litters with unilateral partial 

ossification of the 7th vertebra and with significant and 

dose-related bilateral increases in fetuses and litters 

with extra rib (14). (See TXR No. 0056512) 

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.

Oral gavage; solvent = 

corn oil.

Maternal NOAEL =75 mg/kg /day 

LOAEL = 125 mg/kg/day, based on decreased body 

weight gain during dosing. Low fertility; only low and 

mid-dose groups had > minimum number of litters at 

sacrifice.

Developmental NOAEL = None observed

870.3700b

Prenatal developmental 

toxicity in nonrodents

(NZW rabbit)

40734302 (1986)

Acceptable/guideline

0, 25, 75, or 125 

mg/kg/day from days 7 

through 19 of gestation.

Maternal NOAEL = 75 mg/kg /day 

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 (F0 M); 0, 5.1, 

25.9 and 126.2 (F0 F); 0, 

4.7, 23.2 and 116.9 (F1

M); and 0, 5.1, 24.8 and 

124.1 mg/kg /day (F1 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 /dayb

LOAEL= 116.9 mg/kg/day, based on the increased 

incidence of chromodacryorrhea, thickened eyelids and 

dental malocclusion, increased liver weights, mottling 

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), and 

increased absolute and relative liver weights (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. 
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Table A.2.2: Toxicity Profile of Paclobutrazol Technical

Guideline No./

Study Type

MRID No. (year)/ 

Classification/Doses Results

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.

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 steatosis 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 significant (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 LD50 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
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Table A.2.2: Toxicity Profile of Paclobutrazol Technical

Guideline No./

Study Type

MRID No. (year)/ 

Classification/Doses Results

870.6200a

Acute neurotoxicity 

screening battery (rat)

49211902 (2013)

0, 30, 150 or 500 mg/kg

10/sex/dose; solvent = 

0.5% CMC

Acceptable/guideline

NOAEL = 30 mg/kg

LOAEL = 150 mg/kg, based on transient alterations in motor activity 

(i.e., decreased rearing counts and 

decreased subsession distances) in females 3-4 hours after dosing

in motor rearing counts and decreased subsession distances in 

females 3-4 hours postdosing. activity in motor activity (decrease

rearing counts and decreased subsession distances) in females 3-4 

hours after dosing. The NOAEL was 30 mg/kg bw.

870.6200b

90 Day neurotoxicity 

screening battery (rat)

Data waiver granted by HASPOC March 13, 2014 (TXR 0056914)

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 

accounted 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 

gastrointestinal 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 were 

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)

EPA Accession No. 

254865

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 doses selection. 
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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 14c 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. 

870.7485

General Metabolism 

(rat)

00143164 (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 2nd 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. Two male and 2 female rats received a 

single dose of 250 mg/kg paclobutrazol and were 

allowed a 24-hour recovery period. The bile duct of 

these rats was cannulated and the rats were given a 

second dose of 250 mg/kg paclobutrazol, and samples 

of the bile, urine and feces were collected over a 4-day 

interval and measured. The highest percentage of 

radioactivity was general recovered after 48 hours in 

bile (46%, ♂ and 24% ♀), urine (12%, ♂ and♀), and 

feces (0.9%, ♂ and 0.3% ♀).

870.7485

General Metabolism 

(dog)

00143163 (1984)

Acceptable/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 

plasma) 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 

cm2/rat

Acceptable/guideline

The % dose absorbed and remaining on the washed 

application site (potentially absorbable) at 10 hours was 

15.1% and 3.6% respectively. (10 hours) and 24.5 % 

and 2.7% (24 hours), respectively. Since absorption 

rates were not measured beyond 24 hours, the percent 

absorbed + the percent potentially absorbed = 18.7% 

for 10 hours.
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Table A.2.2: Toxicity Profile of Paclobutrazol Technical

Guideline No./

Study Type

MRID No. (year)/ 

Classification/Doses Results

870.7800

Immunotoxicity Data waiver granted by HASPOC March 13, 2014 (TXR 0056914)

a Based on new supplemental data on achieved doses (TXR no. 0056158).

b Based on new supplemental data on individual and historical control pup data submitted by the registrant in MRID 

47338506 (TXR no. 0056158).

Appendix A.3. Hazard Identification and Endpoint Selection

A.3 .1 Acute Reference Dose (aRfD) –General Population

Study Selected: Acute Neurotoxicity in rats 870.6200a [§81-8]

MRID No. 49211902

Dose and Endpoint for Risk Assessment: NOAEL = 30 mg/kg 

Comments about Study/Endpoint/Uncertainty Factors: For the acute dietary risk assessment, 

the acute neurotoxicity study in rats, with a NOAEL of 30 mg/kg, was selected because it was 

the appropriate exposure duration of concern (effects were seen within 3-4 hours of dosing) and 

it occurred in the most sensitive species. An Uncertainty Factor (UF) of 100 was applied to 

account for both the interspecies extrapolation (10X) and intraspecies variability (10X). On this 

basis, the aRfD was calculated to be 0.30 mg/kg.

Acute RfD

(general population) = 30 mg/kg (NOAEL) = 0.30 mg/kg

 100 (UF)

A.3.2. Acute Reference Dose (aRfD) –Females 13-49

Study Selected: Prenatal developmental study in rats 870.3700a [§83-3]

MRID No. 00143158

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

Comments about Study/Endpoint/Uncertainty Factors: The most sensitive point of departure 

was 10 mg/kg/day from the developmental rat study (MRID 00143158), based on increased 

incidences of partial ossification of the 7th vertebra and 14th rib in fetuses at the LOAEL of 40 

mg/kg/day. Both effects were dose-related, statistically significant, outside of the historical control 

ranges provided by the investigator, and reproducible at comparable doses (also seen MRID 

00132693), which occurred in the absence of maternal toxicity. The study was specifically 

selected for this exposure scenario because increases in 14th rib may be the result of a single 
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exposure. An Uncertainty Factor (UF) of 100 was applied to account for interspecies extrapolation 

(10X) and intraspecies variability (10X). The acute reference dose (aRfD) for females 13-49 was 

calculated to be 0.1 mg/kg/day. The selection of this study and the PoD is protective of the 

pregnant female and the developing fetus.

Acute RfD

(general population) = 10 mg/kg (NOAEL) = 0.10 mg/kg

 100 (UF)

A.3.3. Chronic Reference 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 chronic 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 

100 was applied to account for both the interspecies extrapolation (10X) and intraspecies 

variability (10X). On this basis, the cRfD was calculated to be 0.11 mg/kg/day.

Chronic RfD = 10.8 mg/kg/day (NOAEL) = 0.11 mg/kg/day

 100 (UF)

A.3. 4 Incidental Oral Exposure (Young children, 1-2 years old): Short- (1-30 days) and 

Intermediate-term (1-6 months)69

Study Selected: Reproductive Toxicity (Rats) 870.3800 [§83-3]

MRID No. 40734303/47338506

Dose and Endpoint for Risk Assessment: Offspring NOAEL = 23.2 mg/kg/day 

Comments about Study/Endpoint/Uncertainty Factors: Based on the turf use pattern in parks. 

The target population for incidental oral (short and intermediate term) was identified as young (1-

2 year old) children, because of hand-to-mouth activities. Quantification of incidental oral 

ingestion risks was performed using the 2-generation reproduction study, based on a revisit of the 

data and in consideration of supplemental data on achieved doses provided by the registrant (TXR 
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No. 0056158). The offspring NOAEL for this study is 23.2 mg/kg/day. The LOAEL is 116.9 

mg/kg/day, based on increased incidence of chromodacryorrhea, thickened eyelids and dental 

malocclusion; increased liver weights; mottling or accentuation of the lobular structure of the liver 

along with liver enlargement, pallor and discoloration in the male and female pups of both 

generations. This study was selected to protect the infants and small children. An MOE of 100 

is required which includes interspecies extrapolation (10X) and intraspecies variability (10X). 

A.3.5. Dermal Exposure (Females 13-49): Short- (1-30 days) and Intermediate-term (1-6 

months) Occupational

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 occupational 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 the pregnant female and the developing fetus, the most 

sensitive point of departure was 10 mg/kg/day from the developmental rat study (MRID 

00143158), based on increased incidences of partial ossification of the 7th vertebra and 14th rib in 

fetuses at the LOAEL of 40 mg/kg/day. Both effects were dose-related, statistically significant, 

outside of the historical control ranges provided by the investigator, and reproducible at 

comparable doses (also seen MRID 00132693), which occurred in the absence of maternal toxicity. 

The study was specifically selected for this exposure scenario because increases in 14th rib may be 

the result of a single exposure. The dermal absorption factor (DAF) of 18.7 is applied to the 

NOAEL See A.3.7). An MOE of 100 which accounts for interspecies extrapolation (10X) and 

intraspecies variability (10X). The selection of this study and the PoD is protective of the pregnant 

female and the developing fetus.

A.3.6. Inhalation Exposure (Young children, 1-2 years old): Short- (1-30 days) and 

Intermediate-term (1-6 months)

There is no exposure of young children to paclobutrazol via the inhalation route.

A.3.5. Inhalation Exposure (Females 13-49): Short- (1-30 days) and Intermediate-term (1-6 

months) Occupational

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 
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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 presumed to be equivalent to oral 

absorption. An MOE of 100 is required which includes the interspecies extrapolation (10X) and 

intraspecies variability (10X.

A.3.7 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 cm2 /rat. At the time this study was reviewed, 

the absorbed dose was calculated as the sum of the residues from the urine, feces, cage wash, and carcass 

(excluding the skin at the application site). The potentially absorbable dose included the residues in the 

skin at the application site. Previously, the most conservative value for total absorbable (sum of the 

absorbed dose and potentially absorbable dose) was used, which was 24.5% following a 24-hour exposure 

period. Currently, the policy is to use 8-hours exposure and to assume that residues found in the skin are 

potentially absorbable, unless data are provided to demonstrate otherwise. This policy reflects an 8-hour 

work day, and ongoing exposure is expected to cease at the end of the workday. Likewise, the Agency’s 

position is to be conservative to insure public safety, and this is reflected in the assumption that residues 

found in the skin will be absorbed, unless there are data which contradicts this assumption. Therefore, 

values following the 10-hour exposure period were used and the total absorbable dose was calculated to be 

18.5%The percentage of the dose absorbed and remaining on the washed application site 

(potentially absorbable) at 10 hours was 15.1% and 3.6% respectively, and 24.5 % and 2.7% (24 

hours), respectively. Since absorption rates were not measured beyond 24 hours, the percent 

absorbed plus the percent potentially absorbed (18.7%) for 10 hours was calculated. For risk 

assessment purposes, HED is using the conservative assumption that the dermal absorption 

factor (DAF) of 18.7% for paclobutrazol. 

A.4 Executive 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 Wistar rats/sex/group 

received diets containing 0, 50, 250, or 1250 ppm paclobutrazol (91.9%) for 90 days. The actual 

doses were 0, 3.7/4.4, 18.8/21.6 or 93.0/106.5 mg/kg/day (M/F). 

No deaths or clinical signs of toxicity were seen. Body weight was unaffected by treatment. 

However, at 1250 ppm, increased liver weights (16%) and a 2-fold increase in aminopyrene-Ndemethylase activity was seen in the females. These effects were noted to a lesser extent in the 

females given diets containing 250 ppm. Without concomitant histological changes, however, 

the effects at the mid dose are unlikely to be toxicologically significant. 

Accordingly, the NOAEL is 250 ppm [18.8/21.6 mg/kg/day (M/F)] and the LOAEL is 1250 

ppm [93.0/106.5 mg/kg/day (M/F)], based on elevated liver weights in females, serum 
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cholesterol in females, hepatic aminopyrene-N- demethylase activity in both sexes and 

alanine transaminase levels in males. 

The study is classified as Acceptable guideline and satisfies the guideline requirements of a 90-

day oral toxicity study (OPPTS 870.3100; OECD 408). 

COMMENT: This is an updated Executive Summary. The original Executive Summary was 

revised to include the actual dose levels on a mg/kg/day basis and provides table correcting the 

previous one and making it consistent with the risk assessment of March 2012. 

870.3200 21/28-Day Dermal 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 intact. 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 

bodyweight. 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 

warm tap water and blotted dry. This procedure was followed once each day 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 only 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 

irritation increased with dose. Histologically, treated skin exhibited hyperkeratosis, acanthosis, 

and inflammatory changes of the superficial dermis. The NOAEL 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. 

The study is classified as Acceptable/guideline

A.4.2 Prenatal Developmental Toxicity

870.3700a Prenatal Developmental Toxicity- Rat (#1)

In a prenatal developmental toxicity study (MRID 00132693), paclobutrazol (92.4%) suspended 

in corn oil was administered to pregnant Wistar derived Alderley Park strain rats (24/dose) via 

gavage at concentrations of 0, 40, 100, or 250 mg/kg/day on gestation days (GD) 6 through 15. 

All dams were sacrificed on GD 21 and their uterine contents examined. 

Maternal effects: The highest dose tested (250 mg/kg/day) caused mortality (5/24 animals) as 

well as significant decreases in body weight gain, decreased food consumption and food 
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utilization. Staining of the genital and ventral areas and grossly observable liver effects (pallor 

and enlargement) were also noted at the high dose. Toxic effects at 100 mg/kg/day were 

decreased food consumption and food utilization. Based on a revisit of the data, the decreased 

food consumption and food efficiency reported at 100 mg/kg/day are not considered 

toxicologically relevant because neither observation was significant and no adverse effects 

were reported on body weight. 

Accordingly, the revisited maternal NOAEL is 100 mg/kg/day and the LOAEL is 250 

mg/kg/day, based on mortality, significantly decreased body weight gain and food 

efficiency during dosing, and gross liver effects (pallor, accentuated lobulation, and 

enlargement). 

Developmental effects: In the previous DER, a NOEL was not established. Therefore, the data 

were revisited and the following conclusions were reached:

As summarized in Table 1, the incidence of total skeletal defects and/or variations in the fetuses 

was dose-related and significant (p<0.01) at 40, 100 and 250 mg/kg/day. The major contributors 

to the increased incidence of defects and variations were partial ossification of the transverse 

process of the 7th cervical vertebra, which is classified as a minor defect and extra rib (14), which 

is considered a variant. As further shown in Table 1, the dose-related increase in the incidence 

of unilateral partial ossification of the 7th vertebra was significant (p<0.01) at ≥100 mg/kg while 

the incidence of this effect bilaterally was dose-related and significantly (p<0.01) increased at 

≥40 mg/kg. These increases, which were all outside of the historical control ranges, generally 

resulted from the occurrence of multiple fetuses in the affected litters of all treatment groups. 

However, the combined number and frequency of litters affected was not appreciably higher than 

control at any dose (e.g., 79% at 250 mg/kg/day vs. 54% for controls); the litter data were not 

evaluated statistically. 

Similarly, the incidence of fetuses with bilateral extra ribs (14th) was dose-related and 

significantly increased at all doses, with the majority or 100% of the treated litters demonstrating 

this effect in multiple fetuses per litter. These values were also outside of the historical control 

range. Nevertheless, the frequency of unilateral extra rib (14) was lower or comparable to 

control for all treatment groups. It is of note that these findings were reproduced in a subsequent 

study (MRID 00143158). 

The only external/visceral defect of note was cleft palate, which was only observed at a low 

frequency (3 fetuses from 2 litters) at a maternally toxic dose (250 mg/kg/day). 

The developmental NOAEL was not established. The LOAEL is 40 mg/kg/day, based on a 

significant and dose-related increase in fetuses with the incidence of bilateral partial 

ossification of the 7th cervical bone and in bilateral significant increases in the number of 

fetuses with an extra rib (14). These incidence rates were outside of the historical control 

ranges. Increases in the number of litters affected with these defects were also seen but not 

analyzed statistically. Cleft palate was reported in 3 fetuses from 2 litters at 250 mg/kg/day.

This developmental toxicity study is classified acceptable/guideline (OPPTS 870.3700; §83-
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3[a]) and satisfies the guideline requirement for a developmental toxicity study in the rat.

COMMENTS: This is a revised Executive Summary, which provides a discussion of changes 

made to the original DER (revised NOAEL/LOAEL) and data tables to support the conclusions. 

Table 1. Summary of the incidence of fetuses/litters with most frequently observed skeletal 

defects or variations following exposure to paclobutrazol in the rat developmental study 

(MRID 00132693).

Observation

Dose of Paclobutrazol (mg/kg/day)

0 40 100 250

Total Skeletal Defects/Variations

No. Fetuses Examined 204 198 190 153

No. Fetuses Showing 

Effect

84 110 117 111

% Fetuses Affected 41% 56% ** 61% ** 73 **

No. Litters 24 24 24 19

Partial Ossification of 7th Cervical Vertebra

Unilateral Fetal Historical control Range: 2.5-13%

No. Fetuses Showing 

Effect/% Fetuses Affected 12/6% 20/10% 33**/17% 29**/19%

Bilateral Fetal Historical Control Range : 0.6 -3.4%

No. Fetuses Showing 

Effect/% Affected

1/0.5% 12**/6% 16**/ 8% 18**/12%

Combined No. Litters 

Affected/% Affected

13/54% 10/42% 14/58% 15/79%

Increased Incidence of 14th Rib

Unilateral Extra Rib 

(14)

Fetal Historical Control Range: 8 – 16%

No. Fetuses Showing 

Effect/% Affected

32/16% 18/9% 34/18% 21/14%

No. Litters Affected/% 

Affected

14/58% 17/71% 20/83% 16/84%

Bilateral Extra Rib (14) Fetal Historical Control Range: 8 – 14%

No. Fetuses Showing 

Effect/% Affected

22/11% 36*/18% 101**/53% 104**/68%

No. Litters Affected/% 

Affected

12/50 14/58% 24/100% 19/100%

Note: Two-thirds of the fetuses were examined for skeletal defects

*Significantly altered p<0.05

**Significantly altered p<0.01

870.3700a Prenatal Developmental Toxicity- Rat (#2)
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In a prenatal developmental toxicity study (MRID 00143158), paclobutrazol (92.4%) suspended 

in corn oil was administered to pregnant Wistar derived Alderley Park strain rats (24/dose) via 

gavage at concentrations of 0, 2.5, 10, 40, or 100 mg/kg/day on gestation days (GD) 7 through 

16. All dams were sacrificed on GD 21 and their uterine contents examined. 

Maternal effects: There were no treatment-related effects on the dams at any dose. 

Consequently, the maternal NOAEL is > 100 mg/kg/day. 

Developmental effects: In the previous DER, the NOEL was listed as 10 mg/kg/day and the 

LOEL was 40 mg/kg/day, based on dose-related fetal effects (renal dilatation, hydroureter, and 

minor skeletal defects or variations. The data were revisited and the following conclusions were 

reached:

The numbers of corpora lutea, implantations, and live fetuses were comparable among the 

groups, and fetal body weights were comparable among the groups. 

As summarized in Table 1, the incidence of total skeletal defects and/or variations in the fetuses 

was dose-related and significantly increased at 40 (p<0.05) and 100 mg/kg/day (p<0.01). The 

major contributors to the increased incidence of defects and variations were partial ossification 

of the transverse process of the 7th cervical vertebra, which is classified as a minor defect and an 

extra rib, which is considered a variant. As further shown in Table 1, the increased incidence of 

fetuses with unilateral partial ossification of the 7th vertebra was dose-related and significantly 

increased at 10 mg/kg/day (p<0.05) and at ≥40 mg/kg (p<0.01) while the incidence of this effect 

bilaterally was only significant (p<0.05) at 100 mg/kg. Although the incidence of this effect 

was significant for affected fetuses, no significant increase was seen in the number of litter 

affected. Since the number of affected litters is considered the critical a indicator of 

developmental toxicity, the findings at 10 mg/kg/day are insufficient to conclude developmental 

toxicity. It is also of note that the above values were outside of the historical control ranges. The 

significant increases generally result from the occurrence of multiple fetuses in the affected 

litters of all treatment groups. These data are in good agreement with similar findings in an 

earlier rat developmental study performed by the same laboratory on paclobutrazol (MRID 

00132693). With the exception of a significant increase (p<0.05) in the number of fetuses 

showing bilateral partial ossification of the 7th vertebra, the response was limited to the high 

dose. 

The incidence of fetuses with bilateral extra ribs (14th) and the percentage of litters showing this 

effect were dose-related and significantly increased at 40 and 100 mg/kg/day paclobutrazol. As 

previously observed for skeletal effects in this and the earlier studies, the majority or 100% of 

the treated litters demonstrated these effects in multiple fetuses per litter. These values were also 

outside of the historical control ranges. Nevertheless, the frequency of unilateral extra rib (14) 

was unaffected by treatment. 

Table 2 summarized the incidence data for external and/or visceral defects. As shown, the 

incidence of fetuses with external and/or visceral defects was significantly (p<0.01) increased at 

40 and 100 mg/kg/day. The most frequently observed effects were slight to moderate renal 

dilation, increased hydroureter and unilateral kinked ureter. Significant increases in slight renal 
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dilation were noted at 40 and 100 mg/kg/day but the number of litters affected was not 

significant. Significant hydroureter was seen in 3% of the fetuses of the high dose group in 4 of 

24 litters. However, information from the open literature (Woo and Hoar, 1972; NTP-CERHR, 

2004) indicates that hydroureter is more appropriately classified as a variation and not as a defect 

or a malformation. Likewise, the significant increase in unilateral kinked ureter at 40 and 100 

mg/kg/day may be resolved at weaning since Woo and Hoar (1972) also observed that the rate of 

development of the renal system in normal rats occurs very late and may not be completed until 

several weeks after birth. 

Based on a revisit of the data, the developmental NOAEL is 10 mg/kg/day. The LOAEL is 

40 mg/kg/day, based on the significant and dose-related increases in fetuses and litters with 

unilateral partial ossification of the 7th cervical vertebra and significant and dose-related 

bilateral increases in fetuses and litters with an extra rib (14). 

This developmental toxicity study is classified acceptable/guideline (OPPTS 870.3700; §83-

3[a]) and satisfies the requirement for a developmental toxicity study in the rat.

REFERENCES

Woo, DC and Hoar, RM. (1972). “Apparent hydronephrosis” as a normal aspect of renal 

development in late gestation of rats: The effect of methyl salicylate. Teratology 6: 191-196.

NTP-CERHR, 2004. National Toxicology Program-Center for evaluation of Risks to Human 

Reproduction. NTP-CERHR Monograph on the potential human reproductive and 

developmental effects of ethylene glycol. NIH Publication No. 04-4481. U.S. Department of 

Health and Human Services. 

COMMENTS: This is a revised Executive Summary. The original review NOEL (10 

mg/kg/day) was based on dose-related fetal effects (renal dilatation, hydroureter, and minor 

skeletal defects or variations) at the LOEL of 40 mg/kg/day. Based on a reassessment of the data, 

the NOAEL and LOAEL have been revised to reflect new information and to make it consistent 

with the risk assessment of October 2014. Additionally, data tables have been added to provide 

support for these conclusions.
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Table 1. Summary of the incidence of fetuses/litters with skeletal defects or variations following 

exposure to paclobutrazol in the rat developmental study (MRID 00143158).

Observation

Dose of Paclobutrazol (mg/kg/day)

0 2.5 10 40 100

Total Skeletal Defects/Variations

No. Fetuses 

Examined

176 213 199 200 202

No. Fetuses 

Showing Effect

61 80 75 89 106

% Fetuses 

Affected

35% 38% 38% 44%* 52.5%**

No. Litters 22 24 24 24 24

Partial Ossification of 7th Cervical Vertebra

Unilateral Fetal Historical Control Range 2.5-13%

No. Fetuses 

Showing 

Effect/% Affected

7/4% 16/7.5% 18*/ 9% 35**/17% 40**/20%

No. Litters 

Affected/% 

Affected

6/27% 10/42% 11/46% 15*/62.5% 20**/83%

Bilateral Fetal Historical Control Range 0.63-3.4%

No. Fetuses 

Showing 

Effect/% Fetuses 

Affected

3/2% 4/2% 1/0.5% 7/3% 14*/7%

No. Litters 

Affected

3/14% 3/12.5% 1/4% 5/21% 7/29%

Increased Incidence of 14th Rib

Bilateral Extra 

Rib (14)

Fetal Historical Control Range 9.7-14.2

No. Fetuses 

Showing 

Effect/% Affected

24/14% 31/15% 25/13% 57**/29% 86**/43%
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Observation

Dose of Paclobutrazol (mg/kg/day)

0 2.5 10 40 100

Total Skeletal Defects/Variations

No. Litters 

Affected/% 

Affected

11/50% 12/50% 9/37.5% 19**/79% 23**/96%

Note: Two-thirds of the fetuses were examined for skeletal defects

*Significantly altered p<0.05

**Significantly altered p<0.01

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 (0, 2.5, 12.5 or 62.5 mg/kg/day) in the diet. Each generation began with 17 males and 34 females 

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 from the same test group until sperm plugs were observed in 

vaginal smears. The F0 parental animals were given test diets for 12 weeks before they were mated, and 

the F1 parental animals were not mated until 11 weeks after they were selected from the F1A litters. 

Selection of parents for the F1 generation was made when the pups were 36 days of age, and the mated 

animals in the study were between 16 and 20 weeks of age at mating. 

Supplemental information (MRID 47338506) was provided by the registrant on individual pup data and 

achieved doses of paclobutrazol. Based on an evaluation of these data, the overall doses administered were

as follows:
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Overall Average Dose Received (mg/kg/day) of Paclobutrazol During the Pre-mating Period in the 2-

Generation Reproduction Study (MRID 40734303)a

Generation/Sex

Dietary Concentrations of Paclobutrazol (mg/kg/day)

50 ppm 250 ppm 1250 ppm

F0 Parents: Male

 Female

4.8 24.4 121.2

5.1 25.9 126.2

F1 Parents: Male

 Female

4.7 23.2 116.9

5.1 24.8 124.1

a Data were extracted from the Study Report, p. 10, MRID 47338506, Supplemental data 

In the previous DER 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, increased 

liver weights were observed in females in both generations (23% absolute, 26% relative F0; 7% absolute, 

14% relative F1) and fatty change in the liver was observed in F0 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 F0 and in 3 F1 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, dental 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). 

From a revisit of the data, the following was seen:

Parental animals: There were no treatment-related deaths in the parental animals, and body 

weights were not adversely affected in either sex/generation. The maternal body weights were 

also not adversely affected (< 10% reduction) during gestation or lactation, although statistical 

significance was sometimes attained. Although there was a slight increase in the incidence of 

chromodacryorrhea, thickened eyelids, and twisted snout in the F1 adult animals, the incidence at 

250 ppm was within the historical control incidence and not considered adverse. There were no 

adverse effects on mating, fertility, or gestation interval in either generation. There were no 

treatment-related effects on litter size, pup body weights, or pup survival, although pup survival 

(F1A litters) was reduced compared to the control at 250 ppm and 1250 ppm. However, the 

survival rate was within the historical control, and survival was not reduced in the F1B litters or 

in the F2 generation. 

Based on a revisit of the parental data, the following observational signs observed in the parental 

animals are presented in Table 1:
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Table 1. Observational Signs Observed in the Parental Animals

Parameter/dose 0 ppm 50 ppm 250 ppm 1250 ppm

F0 generation (males/females)

Chromodacryorrhea

Thickened eyelid

Twisted snout

0/1

0/1

0/1

0/1

0/1

0/0

0/2

0/2

0/0

1/1

0/1

1/0

F1 generation (males/females)

Chromodacryorrhea

Thickened eyelid

Twisted snout

0/0

0/2

0/0

0/0

0/0

0/0

2/3

2/2

1/1

3/7

1/8

0/1

n= 15/30

Based on these data, the parental NOAEL for the two-generation reproduction study should 

be 250 ppm (equivalent to 23.2 mg/kg/day) because the response noted at 250 ppm (an 

increased incidence of chromodacryorrhea and thickened eyelids observed in both 

generations) was generally within the provided historical control ranges, and, therefore, is 

not considered a treatment-related effect. Consequently, the parental LOAEL he should be 

1250 ppm (equivalent to 116.9 mg/kg/day; the highest dose tested), based on an increased 

incidence of chromodacryorrhea and thickened eyelids in F1 females and increases in liver 

weight and fatty changes in the liver and thickening of the urinary bladder wall in the 

females. 

Reproductive effects: Since there were no consistent effects on reproductive performance, the 

reproductive NOAEL is 1250 ppm (equivalent to 116.9 mg/kg/day); an LOAEL was not 

established.

Offspring: Table 2 presents the incidence of chromodacryorrhea in the offspring. As shown, the 

number of pups affected with chromodacryorrhea and the number of litters affected is generally 

within the historical control for all generations at 250 ppm. Only the pups and litters of the 1250-

ppm group show increases beyond the historic control for these observations. Similarly, the 

number of pups affected with thickened eye lids and the number of litters affected is generally 

within the historical control for all generations at 250 ppm (Table 3). Only the pups and litters of 

the high dose group show increases beyond the historic control for these observations. Likewise, 

the incidence of dental malocclusions was only increased in all generations of pups in the highdose groups. 

The offspring NOAEL is 250 ppm (equivalent to 23.2 mg/kg/day), and the LOAEL is 1250 

ppm (equivalent to 116.9 mg/kg/day), based on the increased incidence of dental 

malocclusions, chromodacryorrhea, thickened eyelids, increased liver weights, mottling or 

accentuation of the lobular structure of the liver, along with liver enlargement, pallor and 

discoloration in the male and female pups of both generations.

This study is classified acceptable/guideline (OPPTS 870.3800; §83-4) and satisfies the 

guideline requirement for a two-generation reproductive study in the rat.

COMMENTS: This is a revised Executive Summary. The original review considered the 

findings at 250 ppm as the basis for an adverse effect (LOAEL) for the entire study (reproductive 

and systemic). Based on a reassessment of the data, the NOAEL and LOAEL have been revised 
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to reflect the new information and to make it consistent with the risk assessment of October 

2014. Additionally, separate NOAELs/LOAELs for offspring and reproductive toxicity have 

been identified, and data tables have been added to provide support for these conclusions.

Table 2. Summary of the incidence of pups with chromodacryorrhea following exposure to paclobutrazol 

in the rat developmental study (MRID 40734303).

Dose No. of 

pups

No. of 

pups 

affected

% pups 

affected

No. of 

litters

No. of 

litters 

affected

% litters 

affected

F1A

0 303 5 2 25 4 16

50 320 - - 27 - -

250 279 10 4 28 5 18

1250 305 37 12 28 16 57

F1B

0 237 2 1 24 1 4

50 262 1 0.4 26 1 4

250 223 6 3 27 4 15

1250 250 7 3 26 5 19

F2

0 282 - - 27 - -

50 295 4 1 27 2 7

250 334 10 3 30 7 23

1250 266 13 5 27 8 30

Historical control = 1-22 pups affected; 0-6 litters affected (MRID 47338506).
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Table 3. Summary of the incidence of pups with thicken eye lids following exposure to 

paclobutrazol in the rat developmental study (MRID 40734303).

Dose No. of

pups

No. of 

pups 

affected

% pups 

affected

No. of 

litters

No. of 

litters 

affected

% litters 

affected

F1A

0 303 4 1 25 4 16

50 320 - - 27 - -

250 279 8 6 28 4 14

1250 305 38 12 28 17 61

F1B

0 237 2 1 24 1 4

50 262 1 0.4 26 1 0.4

250 223 6 3 27 4 15

1250 250 12 5 26 8 31

F2

0 282 - - 27 - -

50 295 - - 27 - -

250 334 5 1.5 27 4 13

1250 266 17 6 30 8 30

Historical control = 1-8 pups affected; 0-4 litters affected (MRID 47338506).

A.4.4 Chronic Toxicity

870.4100a Chronic Toxicity – Rat 

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

Crl:CD(SD)BR rats (50/sex/dose group) were fed 0, 50, 250 or 1250 ppm technical 

Paclobutrazol (92.4% pure) in the diet (males 0, 2.2, 10.8, or 54.2 mg/kg/day; females 0, 2.8, 

14.0, or 72,1 mg/kg/day) for 2 years. An additional ten animals/sex/group were placed in the 

control and high dose groups as microbiological sentinels. Another 10 animals/sex were added 
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that were sacrificed at 52 weeks. Based on new information provided by the registrant (MRID 

47078901) actual achieved doses were as follows:

Dose

Dietary Concentrations of Paclobutrazol (mg/kg/day)

50 ppm 250 ppm 1250 ppm

Male 2.2 10.8 54.2

Female 2.8 14.0 72.1

For more details see TXR 0056158. 

There were no treatment-related effects on mortality or any clinical signs of toxicity in either sex. 

Body weight was not adversely affected in males, but females at the high dose showed a 

progressive decrease in body weight, which was not statistically significant (↓10% by week 20; 

↓15% by week 52, and ↓16% by week 104).

Results show that at 1250 ppm, 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). 

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<0.0l for the low dose, mid-dose and high dose groups, respectively), 

and a positive trend was observed with increasing dose (p<0.05). 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. Although these chronic effects are considered to be sufficient to 

establish a NOAEL and an LOAEL for chronic toxicity, they are not considered adequately 

severe to assure that the animals were tested at a sufficiently high dose for an acceptable 

oncogenicity study.

The LOAEL is 1250 ppm (54.2 /72.1 mg/kg/day) based upon an increase in 

hypertrophy/steatosis of the liver (both sexes), increased absolute and relative liver weights 

(both sexes) and possible borderline increase in uterine stromal polyps (females). The 

NOAEL for chronic effects is 250 ppm (10.8/14.0 mg/kg/day).

This study is classified as Acceptable/guideline as a chronic feeding study. The adequacy of the 

oncogenicity phase of testing is questionable because the low dose levels evaluated may not be 

sufficient to assess the relevance of the increased incidence of uterine stromal polyps. If the use 

pattern for the chemical changes a repeat carcinogenicity study may be warranted.

COMMENTS: This is a revised Executive Summary that includes the actual dose levels (on a 

mg/kg/day basis) attained in the study.
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Based on new information provided by the registrant (MRID 47078901) actual achieved doses were as 

follows:

Dose

Dietary Concentrations of Paclobutrazol (mg/kg/day)

50 ppm 250 ppm 1250 ppm

Male 2.2 10.8 54.2

Female 2.8 14.0 72.1

For more details see TXR 0056158. 

This supplemental DER provides an updated Executive Summary correcting the previous one 

and making it consistent with the risk assessment of October 2014.

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 serum 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. However, 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

See MRID 40734301

870.4200b Carcinogenicity – Mouse

In a combined chronic feeding/oncogenicity study (MRID 40762501) in Crl: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. Nine 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 increase 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 

absolute and relative liver weights, respectively for females) the LOEL is 750 ppm (112.5 
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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 addition, 

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 considered 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 (see 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 requires 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
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In Vivo 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 Micronucleus 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 the 

LD50 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 870.550 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 –

In an acute neurotoxicity study (MRID 49211902), four groups of unfasted 7-week-old 

RccHanTM: WIST(SPF) rats (ten/sex/dose) were given single oral doses of paclobutrazol (99.6% 

a.i; Batch no. 680195) in 0.5% (w/v) aqueous carboxymethylcellulose at doses of 0, 30, 150, or 

500 mg/kg bw. Dosing was on day 1, and the animals were observed for 14 days, until 

termination on day 16. Neurobehavioral assessments [functional observational battery (FOB) 

and motor activity testing] were performed on all animals pre-test, on day 1 (3-4 hours after 

dosing), and on days 8 and 15. At study termination, five animals per sex per dose were 

perfused in situ for collection of tissues, and fixed brain weights were also recorded. The tissues 

from all of the perfused control and high-dose animals were subjected to histopathological 

evaluation of brain and peripheral nervous system tissues. 

No deaths or other clinical signs of toxicity or were observed at any dose. Effects on food 

consumption and body weight gain were seen in high-dose animals of both sexes. Relative to 

controls, high-dose males had transiently decreased mean body weight gain (-84%; p<0.05) and 

a correlated slight decrease in food consumption (-16%) over days 1-2. High-dose females had 

decreased food consumption over days 1-2 and 2-3 (24-30% less than controls), with a 

corresponding decrease in body weight gain over days 2-3 (-74%). Treatment-related effects on 

motor activity were seen on day 1 in mid- and high-dose females. Relative to controls, mid- and 

high-dose females had significantly decreased rearing counts for bins 1-2 (53-67% less than 
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controls) and bins 1-3 (60-83% less than controls), respectively, which in both cases were of 

sufficient magnitude to result in decreased total rearing counts for the session overall (mid-dose: 

-54%, p<0.05; high-dose: -78%, p<0.01). Mid- and high-dose females also had decreased mean 

subsession distances during bins 1-2 (14-31% and 31-58% less than controls for mid- and highdose, respectively; not significant at the mid dose during bin 1), but total distance for the overall 

session was only decreased in high-dose females (-32%; p<0.05). Decreased subsession center 

time was seen during bin 2 in high-dose females (-78%; p<0.01), only, without a corresponding 

effect on total center time for the session overall. On day 1 (3-4 hours after dosing), treatmentrelated statistically significant decreases in mean body temperature were seen in high-dose males 

(37.3 vs. 37.8 °C for controls; p<0.05) and high-dose females (37.0 vs. 38.0 °C for controls; 

p<0.05); this effect is of equivocal biological significance as these body temperatures are still 

within the normal range. There were no treatment-related effects on mortality, clinical signs, 

brain weight, gross pathology, or neuropathology. FOB testing revealed no treatment-related 

effects on home cage, handling, or open field parameters, grip strength, or landing foot splay. In 

this study, the lowest-observed-adverse-effect level (LOAEL) for paclobutrazol in HanWistar rats was 150 mg/kg bw, based on transient alterations in motor activity (i.e.,

decreased rearing counts and decreased subsession distances) in females 3-4 hours after 

dosing. The NOAEL was 30 mg/kg bw.

This acute neurotoxicity study is classified as Acceptable/Guideline and satisfies the guideline 

requirement for an acute neurotoxicity study in rats [OCSPP 870.6200a; OECD 424]. 

870.6200 Subchronic Neurotoxicity Screening Battery – Data waiver granted by 

HASPOC March 13, 2014 (TXR 0056914)

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 received a single oral 

gavage dose of 10 mg/kg of paclobutrazol (99%) or 10 mg/kg paclobutrazol radiolabeled with 

14C 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 and 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 concentrations in tissues 3 or 

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. 
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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. Similarly, the disposition of the 14c 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 days. 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 study (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 samples 

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 intervals for 4 days. Animals were 

sacrificed and samples of the bile, urine and feces were collected over a 4-day interval and 

measured. The highest percentage of radioactivity was general recovered after 48 hours in bile 

(46%, ♂ and 24% ♀), urine (12%, ♂ and♀), and feces (0.9%, ♂ and 0.3% ♀). 

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.

The study is Acceptable. 
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870.7485 Metabolism – Dog

In a metabolism study (MRID 00143163) 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, 

96, 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 

observed. 

The study was classified as Acceptable/guideline

A.4.9 Dermal penetration 

870.7600 Dermal penetration – Rat

In a dermal penetration study (MRID 41048202), groups of five adult male Alpk:APfsd rats

received dermal applications of 0, 0.011, 0.025, 0.125, 1.23 or 12.49 mg/rat [14C]-triazole labeled 

paclobutrazol, prepared in sterile deionized water. Approximately 24 hours before exposure, 

test sites were shaved and undamaged skin was washed with acetone and fitted with two 22.5 x 3 

mm nitrile rubber “O” rings that were held in place using cyano-acrylate glue. The internal 

surface area of skin within each “O” ring was ~5 cm2(total defined skin application area = ~10 

cm2. A Queen Anne plastic collar was secured around the neck of each rat and rats were 

individually housed in metabolism cages for an overnight acclimatization. Each animal was 

doses with 25 μl of the appropriate dosing solution spread over the ~5 cm2test site within each 

“O” ring. Application sites were dried, and protected. At 10 hours after dosing, “O” rings were 

detached and the “O” rings and application sites were rinsed. Samples of washes were collected 

from the skin, “O” rings, and gauze and analyzed for radioactivity. In addition to following the 

same procedures at 24 hours, carcasses, urine, feces and cage wash were measured for 

radioactivity. 

The percent of dose absorbed and remaining on the washed application site for the 10- and 24-

hour exposures are shown in Table 1, and were as follows: 
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Table 1. Absorbed Dose Remaining on the Intact Skin of Male Rats 10 or 24 Hours after 

Receiving Paclobutrazol Dermally over a Total Area of 10 cm2/Rat

Dose

(mg/rat)

Absorbed (%) Potentially Absorbable 

(%)

Total Absorbable (%)

10 hours 24 hours 10 hours 24 hours 10 hours 24 hours

12.48 1.12 2.8 2.6 2.4 3.7 5.2

1.23 3.3 3.2 1.6 0.8 4.9 4.0

0.125 11.6 10.4 0.8 1.6 12.4 12.0

0.025 16.0 20.8 2.4 2.4 18.4 23.2

0.011 15.1 24.5 3.6 2.7 18.7 27.2

 

At the time this study was reviewed, the absorbed dose was calculated as the sum of the residues from 

the urine, feces, cage wash, and carcass (excluding the skin at the application site). The potentially 

absorbable dose included the residues in the skin at the application site. Previously, the most conservative 

value for total absorbable (sum of the absorbed dose and potentially absorbable dose) was used, which was 

24.5% following a 24-hour exposure period. Currently, the policy is to use 8-hours exposure and to assume 

that residues found in the skin are potentially absorbable, unless data are provided to demonstrate otherwise. 

This policy reflects an 8-hour work day, and ongoing exposure is expected to cease at the end of the 

workday. Likewise, the Agency’s position is to be conservative to insure public safety, and this is reflected 

in the assumption that residues found in the skin will be absorbed, unless there are data which contradicts 

this assumption. Therefore, values following the 10-hour exposure period were used and the total 

absorbable dose was calculated to be 18.5%The percentage of the dose absorbed and remaining on the 

washed application site (potentially absorbable) at 10 hours was 15.1% and 3.6% respectively, and 

24.5 % and 2.7% (24 hours), respectively. Since absorption rates were not measured beyond 24 

hours, the percent absorbed plus the percent potentially absorbed (18.7%) for 10 hours was 

calculated. For risk assessment purposes, HED is using the conservative assumption that the

dermal absorption factor (DAF) of 18.7% for paclobutrazol. 

COMMENTS:

This supplemental DER provides an updated Executive Summary correcting the previous one and 

making it consistent with the risk assessment of March 2014. The original DER is attached.

 

This study is classified Acceptable/Guideline, and it satisfies the guideline requirement 

(870.7600) for a dermal penetration study.

870.7800 Immunotoxicity – Rat 

Data waiver granted by HASPOC March 13, 2014 (TXR #0056914).
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A.5 Absorption, Distribution, Metabolism, and Elimination (ADME) 

The absorption, distribution, metabolism and excretion (ADME) of paclobutrazol was 

extensively characterized in a series of studies in rats and dogs. These studies were performed 

using both low- and high-dose, single and repeated dosing protocols. Bile-cannulation was 

included as part of one of the studies. Estimation of absorption from the gastro-intestinal (GI) 

tract were based upon data from pharmaco/toxicokinetic and excretion experiments.

In two guideline studies, rats readily absorbed low (5 mg/kg) and high (250 mg/kg) doses of 

paclobutrazol and excretion was rapid (70-80% within 72 hours). For the 5 mg/kg dosing 

(MRID 00143161), approximately 55% of paclobutrazol was recovered in the urine of both sexes 

in addition to 32 or 24% that was recovered in the feces of male or female rats, respectively. 

Seven days after dosing, livers contained 0.017 to 0.028 μg equivalents/g of tissue for males and 

females and the gastrointestinal tract content was 0.012-0.025 μg equivalents/g, respectively. 

Radioactivity was not detected in other tissues. 

For the 250 mg/kg dosing (MRID 00143162), approximately 33% F/43%M of the dose was 

recovered in the urine after 72 hours and approximately, 30% or 40% of the dose was recovered 

in the feces of male or female rats, respectively. Seven days after dosing, the respective amount 

of test material found in the liver was 0.848 and 0.444 μg equivalents/g of tissue for males and 

females. 

Excretion was more rapid in dogs administered a single gavage dose of 5 mg/kg (MRID 

00143163). Approximately 80 to 85% of the doses were excreted within the first 24 hours; 50% 

of the dose was recovered in the urine of both sexes and 35-40% was recovered in the feces. 

Peak blood levels at 1 hour (Tmax) after dosing ranged from 4.1-4.4 ppm in plasma (Cmax) for 

both sexes and declined to baseline 24-48 hours after treatment. There were no detectable levels 

in any tissues.

In a guideline bioaccumulation study (MRID 00143164), male rats received daily oral 

administrations of radiolabeled 5 mg/kg paclobutrazol for 28 or 49 days. Concentrations of 

radiolabel plateaued in the liver and kidneys after 28 days. From 28 to 49 days, maximum levels 

were 2.22-4.76 ppm in the liver and 1-2.7 ppm in the kidney. Blood levels rose throughout the 

49-day period (maximum = 0.158 ppm); levels in fat were below the level of detection. 

Elimination from the livers and kidney occurred in a biphasic manner: half-lives (T1/2) for phase 

1 (α-phase) were 1.36 and 1.56 days for liver and kidney, respectively. Half times for phase 2 

(β-phase) were 6.69 and 9.26 days, respectively. After dosing was stopped, tissue levels 

declined below detectable levels after 28 days. Three days after dosing was halted, 15 and 8% of 

radioactivity was recovered from liver and kidney samples. By day 7, only 2% of the dose 

remained in the liver or kidney. It was concluded, therefore, that paclobutrazol does not 

bioaccumulate. In another guideline bioaccumulation study (MRID 00143160) lasting 48 hours, 

disposition of the single oral doses of radiolabeled 250 mg/kg paclobutrazol to rats was limited 

and generally confined to the gastrointestinal tract and to a lesser extent in the liver and kidneys. 

The finding that paclobutrazol does not bioaccumulate is supported by database and illustrated 

by the points of departure (PoDs) selected for the risk assessment. Regardless of the duration of 
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the study from acute to repeated exposures, the LOAELS range from 40 mg/kg (acute dietary, 

females 13-49) to 117 mg/kg/day (incidental oral, young children, 1-2 years old).

Paclobutrazol is included in the triazole alanine group of triazole derivatives. However, major 

metabolites found in another metabolism study (MRID 00143165) were the diol and carboxylic 

acid analogues of paclobutrazol; triazole alanine was not found. As part of this study, 2 male 

and 2 female rats received a single dose of 250 mg/kg paclobutrazol and were allowed a 24-hour 

recovery period. The bile duct of these rats was cannulated and the rats were given a second 

dose of 250 mg/kg paclobutrazol, and samples of the bile, urine and feces were collected over a 

4-day interval and measured. The highest percentage of radioactivity was generally recovered 

after 48 hours in bile.