UN ITE D STATES ENVIRONMENTAL PR OTEC TION AGENCY

WASHINGTON, D. C. 20460

MEMORANDUM

Date: January 21,2015 OFFICE OF CHEMICAL SA FETY

AND POL LUTION PREVENTION

SUBJECT : Paclobutr azo l: Fina l H um an Health Risk Assessment for Registration R ev iew

.

PC Cod e: 12560 I

Decision No.: 49' 

### 3053

Petition N o.: NA

Risk Assessment Type: Si ng le ChemicaVAggregate

TX R N o.: NA

MRIDNo.: NA DP Barcode: D41 5247 Registration N o. : I 00-1 0 1 4 Regulatory Ac tion : Registration R eview

Case N o

. : 7002

CAS No.: 76738

- 62

- 0

40 CFR: NA

FROM : Shei l a Pip e r
, Risk Assessor

# ~**~** Ill ' 

## ci./_

. . . 

## I /

Monica Hawkins, Ph.D., M. P .H., E nvironmental Health

### i nti s

### r(9f'J;C/lV't'11W**~** Nancy McCarroll, Ph.D.

,

### ene~c**st/Tox icologist**  

# 1/a'1 {i

P

. Yvonne Barnes, Chem i st**ik'~~~** 

### ... Risk Assessment Branch V I

THROUGH: Donn a Davis, Br anch Chief

Risk Assessment Branch VI

H ea l th Effects Division

TO: Khue Nguyen, Chemical Review M anage r Neil Anderson, Branch Chief

Risk Management and Im p l ementation Br anch I

Pesticide Re-eva luati on Di vision (7508 P )

The He a l t h Effects D i visio n ( HED) ofthe Offi ce ofPest icid e Pr ograms (OPP) is c har g ed with

estimati ng the ri sk t o human health f rom exposu r e to pesticides

. As part of Registration Re view,

the Pestic i de Re-evaluation Divi s ion ( PRD ) of OPP has requested that HED eva l uate th e ha zar d

and exposure da ta and conduct dietary

, occupational, residential, and aggregate exposure
assessments, as n eeded, to est im ate the risk to human health that will r esu lt from the registered

uses of paclobutr azo l.

HED has e val ua ted the toxicity and exposure d atabases for the active in gredie nt

, paclobutrazol

,

a nd has conducted a human heal th risk assessment in sup port o f Re g i st r a tion R ev iew.

P age 1 of 77Paclobutrazol Human H ea lth Ri s k Assess m ent DP No. 415 2 47

A s ummary of the findin gs and an assessment of human health risk resultin g fr om the currently registered uses of paclobutrazol are provid ed in thi s document. The H E D team members

co ntributing t o this risk assess men t i ncl ude S h eila Piper ( risk assessmen t ), Mon i ca Hawkins (occupational and residentia l assessme n t), Nancy M cC arroll (h azard as sessment), and P. Yvonne

Barnes (ch emi stry and di etary assess men t). Faruque Khan ofthe Environmental Fate and Effec ts
Division (EFED) p e rf o rm e d the drinking wate r assessment.

Pag e 2 of 77Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 3 of 77 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 As sessment

................................ ..................... 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

................................ .......... 1 3

4.2.1 Dermal Absorption

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

4.3 Toxicity E ffects

................................ ................................ ................................ ............. 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 Dat abase

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

4. 4.2 Evidence of Neurotoxicity

................................ ................................ ............................ 1 5

4. 4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

........... 1 5

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 Rec ommendation 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

................................ ................................ .. 2 0

5. 3 Water Residue Profile

................................ ................................ ................................ .. 2 1

5.4.1 Description of Residue Data Used in Dietary Assessment

................................ .... 2 2

5.4.2 Percent Crop Treated Used in Dietary Assessment

................................ .............. 2 2

5.4.3 Acute Dietary Risk Assessment

................................ ................................ ............... 2 2

5.4.4 Chronic Dietary Risk Assessment

................................ ................................ ........... 22

5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ............. 2 3

5.4.6 Dietary Sum mary Table

................................ ................................ ........................... 2 3

6.0 Residential Exposure/Risk Estimates

................................ ................................ ............. 2 4Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 4 of 77 6.1 Residential Handler Exposure /Risk Estimate

................................ ........................... 2 4

6. 2 Residential Po st

- Application Exposure /Risk Estimate

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

6. 3 Residential Risk Estimates for Use in Aggregate Assessment

................................ .. 2 5

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

- Application Dermal 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

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

A .4. Executive Summaries

................................ ................................ ................................ ... 58 A.5. Absorption, Distribution, Metabolism and Elimination (ADME)...

.................. 78Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 5 of 77 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 (inc luding 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.

Paclobutrazo l 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 metabolit es. 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 d oses. 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 7 th

cervical vertebrae and an increased incidence of extra rib ( 14 th 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 ad equate 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 in halation 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 c arcin ogenicity studies are not requir ed for non

- food use chemicals

, c arcinogenicity

m ouse and rat studies are available in the database

. However, the Agency was unable to determine the potential carcinogenicity of paclobutrazol because the maximum tolerated dosePaclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 6 of 77 (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 a ggregate 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 performe d 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

o f hand

- to

- mouth activities. Quantification of incidental oral ingestion risks was performed using t he 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 consi dered 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 7 th 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 (10 x 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 f or 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

rate s. The highest estimated drinking water concentrations were f rom 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 over estimates 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.

N o exposure to food is expected. The acute drinking water r isk estimate s 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 . T he most high ly exposed population subgroup

wa s all infants (<1 years old) with an estimated risk equivalent to 54% of the aPAD at the 95 th percentile of exposure. The resulting drinking water chronic exposure estimates were less than
HED’s level of concern (<100% cPAD) for the ge neral U.S. population (12% of the cPAD) and all p opulation 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

. P aclobutrazol 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

.Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 7 of 77 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 ra nge 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) 1 for the paclobutrazo l products. The turf post

- application MOEs are protective for any potential exposures related to spray drift for paclobutrazol.

An acute and chronic aggregate assessment s are equivalent to the corresponding dietary risk estimates, which are not of conc ern

. HED has conducted short

- term aggregate assessment s that includes residential post

- application exposure and average dietary (water only) e xposures. Short /intermediate

- term aggregate MOEs for adults ( including females 13

- 49 y ea rs old ) is 14 0 and children (1 to < 2 years old) is 7 80

. 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 paclo butrazol 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 spra yer. 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

- applicatio n 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/APaclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 8 of 77 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 In troduction

Th e 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 meet ing, 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 0 2, 2014 approved these

refinements.

Paclobutrazol (α

R ,β R )

- rel

- β

- [(4

- chlorophenyl)methyl]

- α

- (1,1

- dimethylethyl)

- 1 H

- 1,2,4

- triazole

1

- 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 re gistered 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 al l the registered uses of paclobutrazol . The findings of t he 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.Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 9 of 77 3 .1 Chemical Identity

Table 3.1. Paclobutrazol Nomenclature

Chemical Structure

Common Name Paclobutrazol

IUPAC name (2 RS, 3 RS )

- 1

- (4

- chlorophenyl)

- 4,4

- dimethyl

- 2

- (1 H

- 1,2,4

- triazol

- 1

- yl)pentan

- 3

-

ol

CAS Name (α R ,β R )

- rel

- β

- [(4

- chlorophenyl)methyl]

- α

- (1,1

- dimethylethyl)

- 1 H

- 1,2,4

- triazole

- 1

- ethanol CAS Registry

Number 76738

- 62

- 0

Chemical Class Triazole plant growth regulator

3 .2 Physical/Chemical Characteristics

Paclobutrazol’s vapor pressure ( 1.28 x 10

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

10

- 10 atm m 3 /mol) indicate that the compound is relatively non

- volatile under field conditions. The log K ow of 3.2 indicates the potential for this chemical to bioaccumulate in aquatic organisms. Paclobutrazol has a low solubility (25.9 mg/L) in water; however, p acl obutrazol 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 M 3 mol

- 1Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 10 of 77 (8.09 x 10

- 12 atm M 3 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), orna mentals 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 trea tment for cucurbit, pepper,

t omato, broccoli, cauliflower, an d 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

seedPaclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 11 of 77 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 post

application settings. In an occupational setting, handlers may be exposed while handling the pesticide prior to application, as wel l as during application. There is also a potential for post

application 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 Lo w

- 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 acco rding 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 involv e 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 E at 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

fo r 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.Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 12 of 77 4.0 Hazard Characterization and Dose

- Response Assess ment

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 in halation 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 eval uate 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 asses sment 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 a nd 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 performedPaclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 13 of 77 using both low

- and high

- dose, single and repeated dosing protocols. Bile

- c annulation 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 paclo butrazol 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. Pac lobutrazol 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

an d 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 hour s on an area of 10 cm 2 /rat. At the time this study was reviewed, t he 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 incl uded 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 p olicy 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 followi ng 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, HE D 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 l iver 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 acu te exposure, paclobutrazol exhibited only minimal signs indicative of neurotoxicity in rats.Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 14 of 77 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 a t 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 7 th 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 compa rable 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

m g/kg/day in the 2 nd 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. Paclobu trazol 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 lo w 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 an d 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 the re 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, afte r a thorough review of the database, there are potential exposures to infants and children from the turf use pattern f

or paclobutrazol were uncovered . There are adequate pre

- and/or pos t

- 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 exposu res 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 a n 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).Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 15 of 77 4.4.2 Evidence of Neurotoxicity

As discussed in Section 4

. 4 .1, an acceptable/guideline acute neuroto xicity 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 neur opathology 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/Susce ptibility 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 7 th vertebra and an increased incidence of extra rib (14) in two developmental toxicity studies in rats at non

- toxic doses in the dams.
However, t here was no evidence of qualitative or quantitative susceptibility in rabbits or in the

rat two

- generation reproduction toxicity study.

Although there is convincing e vidence of increased susceptibility , t he 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. C onservative, 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 (P o Ds) are presented in Appendix A2. Based on the existing use patter n 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 150Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 16 of 77 mg/kg. An Uncertainty Factor (UF) of 100 was applied to account for interspecies extrapolation (10X) and intraspecies variability (10X ). The acute reference dose ( a RfD) for the general population was calculated to be 0. 3 mg/kg/day

.

Acute Dietary (Fe males 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 7 th vertebra and 14 th rib in fetuses at the LOAEL of 40 mg/kg/day. Both

eff ects 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. T he study was spe cifically selected for this exposure scenario because increases in 14 th 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 acut e reference dose ( a RfD) for females 13

- 49 was calculated

to be 0. 1 mg/kg/day . T he 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 female s at the LOAE L 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

- T erm In cidental 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 t he 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) . T he offspri ng 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 a long 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. A n MOE of 100 is required which includes interspecies extrapolation (10X) and

intra species 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, q uantification 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 7 th cervical vertebraPaclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 17 of 77 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 histori cal control ranges provided by the investigator, and reproducible at comparable doses (MRID 00132693)

. The dermal absorption

rate of 18.7% (MR I D 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

- t erm Inhalation (Young children, 1

- 2 years old ): Based on the current
use patterns, t here is no exposure to young children via the inhalation route.

Short

- and Intermediate

- t erm Inhalation (Females 13

- 49) : No inhalation study was available to establish this endpoint. Therefore, q uantification 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 ossif ication of the 7 th 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

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

NOAEL and a n MOE of 100 is required which includes interspecies extrapolation (10X) and intraspecies variability (10X). The selection of rat developmental study provid es 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 residen tial 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 pacl obutrazol , 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 Classific ation and Risk Assessment Recommendations

There are no currently registered food uses for paclobutrazol and c arcinogenicity 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 i n 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.Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 1 8 of 77 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 UF A =10x

UF H =10x 30 mg/kg NOAEL

100 (UF)

a RfD = 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 UF A =10x

UF H =10x 10 mg/kg/day NOAEL

100 (UF)

a RfD = 0. 1 mg/kg Developmental Toxicity in Rats MRID 00143158) Developmental LOAEL = 40 mg/kg/day, based on partial ossification of the 7 th vertebra and an

increased incidence of 14 th 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 UF A =10x

UF H =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. UF A = extrapolation from animal to human (interspecies). UF H = 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 Intermediate

Term (Young children 1

- 2

- years old) NOAEL = 23.2 mg/kg/day UF A =10x

UF H =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

struc ture of the liver along with liver enlargement; pallor and discoloration in male and female pups of both generations.

Dermal

Short

- and Intermediate

Term (Young Children 1

- 2 years old) No dermal risk assessment because in a 3

- week dermal toxicity test (MR ID 00132688), paclobutrazol was not systemically toxic up to the limit dose.Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 19 of 77 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 Intermediate

Term (Young Children 1

- 2 years old) There is no exposure to young children via the inhalation route

.

Dermal

Short

- and Intermediate

Term (Females 13

- 49) Oral NOAEL = 10 mg/kg/day

(Dermal Absorption R ate =
18.7 % ; (MRID 41048202) UF A =10x

UF H =10x Residential /Occupational

LOC = 100 Developmental Toxicity in Rats MRID 00143158) Developmental LOAEL = 40 mg/kg/day, based on partial ossification of the 7 th vertebra and an

increased incidence of 14 th rib on a fetal and litter basis at a dose that was not maternally

toxic.

Inhalation

Short

- and Intermediate

Term (Females 13

- 49) Oral NOAEL = 10 mg/kg/day

Inhalation Rate =

100% UF A =10 x

UF H =10x Residential /Occupational

LOC = 100 Developmental Toxicity in Rats MRID 00143158) Developmental LOAEL = 40 mg/kg/day, based on partial ossification of the 7 th vertebra and an

increased incidence of 14 th 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. UF A = extrapolation from animal to human (interspecies). UF H = 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, neurotoxici ty, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturati on, 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.

EP A 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 a s 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 estroge n, 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

.Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 20 of 77 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). F or 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 t otal radioactive residues (TRR) were all below 1 ppb and no food tolerances are required.

5

. 2 Summary of Environmental Degradation

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

- lives greater than 300 da ys. 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 a nd silt loam soils. Since, the extrapolated half

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

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

- 950 days for orchard soils (CA

, WV , and FL) and 175

- 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 (NOA45 7654, ≤ 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. T he screening model FIRST (FQPA Index Reservoir Screening Too l, version 1. 1

, 0 1 /01/0 7 ) was used to calculate the surface water EDWCs. Estimated groundwater EDWCs were calculated using the screening model s SCI

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

- GW (Pesticide Root Zone Mod el 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 groundwat er modeling

w ere conducted with the highest application rate scenario which is 6.1 lbs/A for nursery production of container

- grown ornamentals through soil drench method. This rate wasPaclobutrazol Human Health Risk Assessment DP No. 415247

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Page 21 of 77 normalized with the lowest fraction (0.59) of paclobutrazol retained i n 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 use d 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 Concer n Knowledgebase Sub

- committees (ROCKS) had determined the residues of concern in drinking water are the parent compound and its ketone analog C GA 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 co ncern, 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 K d (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

Exam ination Survey, What We Eat in America, (NHANES/WWEIA). The drinking waterPaclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 22 of 77 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 D ietary Risk Assessment

An unrefined acute dietary analysis for paclobutrazol was conducted that directly incorporated potential drinking water residue s. The resulting acute drinking water risk estimates are below HED’s level of concern (<100% acute population adjusted dose (aPAD)) at the 95 th 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 a PAD 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 ut ilizes 1 2 % 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 populatio n subgroups is not of concern. The detailed results for the general population and all population subgroups are shown below in T able 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,

c arcinogenicity studies were reviewed by the RfD Peer Committee (TXR 0011081). At that time the Agency was unable to de termine 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

. T he 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 S ummary Table

The acute and chronic dietary exposure and risks for paclobut r azol are summarized below.Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 23 of 77 Table 5.4.6 . Summary of Dietary (Drinking Water Only) Exposure and Risk for

Paclobutrazol

Population Subgroup aPAD (mg/kg /day) Acute Results

95 th 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 hom eowner use on residential lawns. Therefore, a residential handler exposure ass essment 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 SOPs 2 for 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 h as 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.htmlPaclobutrazol Human Health Risk Assessment DP No. 415247

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Page 24 of 77 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, c ombining these scenarios would be overly

- conservative becaus e of the conservative nature of each individual assessment. Therefore, the post

- application exposure scenarios that
represent s the highest exposure for children 1 to < 2 years old is the hand

- to

- mouth scenario. This scenario should be considered a protec tive 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 Ris k Estimates for

Paclobutrazol

Lifestage Post

- application Exposure

Scenario Application

Rate a (lb ai/A) TTR

(ug/cm 2 ) 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 Derma l Golfing 0.75 0.080 d 0.0046 2,200

Granular Formulations

Adult

Dermal Physical Activities on

Turf

0.5 0.01 e 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)

.Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 25 of 77 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/cm 2 ) 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 0.01 e 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 2 10

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 fro m physical

activities on turf

.

 The recommended residential exposure for use in the children 1 to <2 years old short

term 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 MOE 2

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

- to

Mouth
(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 + i ncidental 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.Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 26 of 77 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 off

target 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 indi rect 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 fo r 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 impact ed 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 tu rf post

- appli cation 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 200 9, 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 f urther analysis is required for paclobutrazol

.

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

when in cluded on all labels, precludes direct exposure pathways.Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 27 of 77 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 aggre gating exposures and risks from various sources, HED considers both the route and duration of exposure.

7 .1 Acute Aggregate Risk

A cute aggregate risks is by definition acute exposures to food and water only. Since there are no food exposures, this asses sment would address exposure from drinking water only. As a result, the acute aggregate risk assessment is equivalent to the acute dietary risk assess ment 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 exp osures. 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 ol d aggregate assessment reflects hand

to

- 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 LOC 1 Maximum

Allowable Exposure mg/kg/day 2 Average

Food and

Water Exposure mg/kg/day 3 Residential

Post

application

Dermal Exposure mg/kg/day 4 Total

Exposure mg/kg/day 5 Aggregate

MOE (food, water, and residential) 6Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 28 of 77 Child 1

- 2 yrs

old 23.2 100 0.232 0.018788 0.011 0.030 7 80

Adults (females 13

- 49 yrs old) 10 100 0.1 0.012947 0.0 58 0.0 71 14 0

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

4 Residential Exposure = Dermal e xposure from treated turf (s ee T able s 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 exp os ure, an intermediate

- term aggregate risk assessment is not appropriate.

7

. 4 Chronic Aggregate Risk

T he 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

Paclo butrazol 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 t hus 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://ww w.epa.gov/pesticides/cumulative/

.Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 29 of 77 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 t ask. 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 assessme nt developed for occupational handlers is based on the following scenarios:

 Mixing/loading liquids for groundboo m applications ;

 Mixing/loading liquids for tree injection ;

 Mixing/loading liquids for soil injection ;

 Mixing/loading wettable powders for tree injections ;

 L oading 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 spreade r ;

 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 wa s the most typical number from the

available info rmation

.

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, sh oes 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 toPaclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 30 of 77 wear long

- slee ved 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 hand lers are inclu ded 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).Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 31 of 77 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 MOE f Dose (mg/kg/day) e MOE g

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 3,100,000Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 32 of 77 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 MOE f Dose (mg/kg/day) e MOE g

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 1,800Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 33 of 77 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 MOE f Dose (mg/kg/day) e MOE g

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 Tre ated or Amount Handled x % Dermal Absorption Factor (18.7%) /Body weight (69 kg).

e. Inhalation Dose (mg/kg/day) = Inhalation U nit 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 = 100Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 34 of 77 Short

- /Intermediate

- Term Handler Risk for Seed Treatments

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

cucurbi t, broccoli, cauliflower, and cabbage se eds . The paclobutrazol labels do not permit on

farm seed treatment. Based on the existing seed treatment use pattern, t here 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 label s

. The short

- and interme diate

- 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 p rimary occupational handler exposure scenarios from the use of paclobutrazol as a commercial seed treatment include:

 Mixing, loading, applying liquid formulations;

 Bagging treated seed;

 Sewing bags; and

 Multiple activities.

Typically, for large

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

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

- farm seed treatment.

Secondary Handler (Planting Treated Seed)

Potential secondary occupational handler exposure scenarios from the use of paclobutrazol as a commercial seed treatment include planting treated se ed. Summaries of the risk estimates for primary and secondary h andlers 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)

.Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 35 of 77 Table 9 .1.2 Summary of Short

- and Intermediate

- Term Handler Exposures and Risks for Paclobutrazol Seed Treatment

Seed Type Max

Application

Rate a Unit Exposure b

(mg/lb ai) Amount of

Seed Treated c Absorbed Dose

(mg/kg/day) d MOE e

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

LOADER/APPLICATOR (single layer, gloves)

Cu curbit (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 6,400,000Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 36 of 77 Table 9 .1.2 Summary of Short

- and Intermediate

- Term Handler Exposures and Risks for Paclobutrazol Seed Treatment

Seed Type Max

Application

Rate a Unit Exposure b

(mg/lb ai) Amount of

Seed Treated c Absorbed Dose

(mg/kg/day) d MOE e

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 110,000 530,000Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 37 of 77 Table 9 .1.2 Summary of Short

- and Intermediate

- Term Handler Exposures and Risks for Paclobutrazol Seed Treatment

Seed Type Max

Application

Rate a Unit Exposure b

(mg/lb ai) Amount of

Seed Treated c Absorbed Dose

(mg/kg/day) d MOE e

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 s eed/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.Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 38 of 77 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

Exposure b (mg/lb ai) Inhalation

Unit Exposure b (mg/lb ai) Amount

of Seed

Planted

Per Day c

(lb seed/day) Absorbed

Dermal

Dose d (mg/kg/day) Absorbed

Inhalation

Dose d (mg/kg/day) Dermal

MOE e Baseline

Inhalation

MOE e

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 m emo “Acres Planted Per Day and Seeding Rates of Crops Grown in the United States” (J. Becker, March 2011).Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 39 of 77 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 a dult). Level of concern = 100.

e MOE = NOAEL ( dermal and inhalation = 10.0 mg/kg/day for short

- and intermedi ate

- term exposure) /Absorbed Dose (mg/kg/day). Level of concern = 100.Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 40 of 77 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 re

entry 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 t ime 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 ex posure 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 expo sure. 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

w ould 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 a nd 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, sh ort

- term risk estimates are protective of longer

- term exposures.Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 41 of 77 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

(cm 2 /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, PinchingPaclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 42 of 77 A summary of the estimated occupational post

- application r isks are provided in Table 9 .2.2.2.

The short

- and intermediate

- term risk estimates for golf course maint enance activities are greater
than HED’s LOC (MOEs ≥ 100) using predicted Day 0 residue values from the TTR study. The

short

- and in termediate

- term risk estimates for ornamentals in greenhou ses 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 (cm 2 /hr) DFR/TTR 1 Dermal Dose

(mg/kg/day) 2 MOE 3

Short

- and Intermediate

- term

Turf 4 Golf course

maintenance, greens only 2,500 0.080 0.004 2,300

Turf 4 Maintenance 3,700 0.080 0.006 1,600

Ornamentals in Nurseries using Chrysanthemum

DFR Data 5 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 Data 5 Hand harvesting,

Hand pruning, Scouting,

Container moving, Hand Weeding, Transplanting, Grafting, Propagating, Pinching, Tying/Training 230 0.73 0.004 2,800Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 43 of 77 Table 9 .2.2.2. Occupational Post

- application Non

- Cancer Exposure and Risk Estimates

for Paclobutrazol

.
Crop/Site Activities Transfer Coefficient (cm 2 /hr) DFR/TTR 1 Dermal Dose

(mg/kg/day) 2 MOE 3

Short

- and Intermediate

- term

Ornamentals in Nurseries using

Poinsettia DFR

Data 6 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

Data 6 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/cm 2 ) × 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/cm 2 ) × 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 4 5310801).

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

Restricted Entry Interval

Paclobutrazol is classified as Toxicity Category II I via the der mal route and or skin irritation potential based on studies submitted in 2012 . It is not a skin sensitizer. Short

- and intermediate

term post

- application risk estimates were not a concern on day 0 (12 hours foll owing application) for all post

- application activities. Under 40 CFR 156.208 (c) (2) (iii), ai’s classifi ed as Acute Toxicity Category I II 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

.Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 44 of 77 R eview 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 R eview Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency website 4

.

Review of Incident Report

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

D 335541 ). There were 2 i ncidents 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 A ggregate 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 Registra tion Review. DP Number: D394230, dated S eptember 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.htmlPaclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 45 of 77 Smith, C. (2012). Paclobutrazol: Non

- food Use for Seed Treatment on Brocco li. 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 Registration s For Use of Propiconazole on Rapeseed Crop Subgroup 20A; Use of Dif enoconazole on Rapeseed Crop Subgroup 20A; and Use of Tebuconazole on Imported Oranges . DP Number: D414952, dated October 24, 2013.Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 46 of 77 A ppendix 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

no a

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

yes b

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

no a

no

no

870.7485 General Metabolism (rat)

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

, in vivo (male rat)

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

yes yes

yes

870.7800 Immunotoxicity (rat and mouse)........................... yes no aPaclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 47 of 77 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) LD 50 = 1954 mg/kg (M) 1336 mg/kg (F) III

870.1100 Acute Oral (97% ai)

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

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

870.1100 Acute Oral (97% ai)

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

870.1200 Acute Dermal (97% ai)

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

870.1200 Acute Dermal (97% ai)

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

870.1300 Acute Inhalation (97% ai)

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

359

- 766 mg/m 3 (F) 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. III a

870.2500 Primary Skin Irritation

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

72 hours III

870.2500 Primary Skin Irritation

( 97% ai) Alderley Park Albino Rat 00117479 (1982) 3/5 M showed erythema; 2/5 (F) showed desquamation and scabbing. Effects did not persist in either sex. III

870.2600 Dermal Sensitization (Guinea

pig) Dunkin Hartley Albino 00117479 (1982) Not a skin sensitized

a Reclassified in 1995, based on additional data provided by the registrant (HED Document 011460). \Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 48 of 77 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

- N

demethylase activity and alanine transaminase levels in

females.

870.3150

6

- Week oral toxicity in dogs 00132690 (1983) Unacceptable 0, 15, 75, or 225 mg/kg/day (M & F). NOAEL = 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 2 nd 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 7 th cervical bone at 40, 100 and 250 mg/kg/day and in b ilateral 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).Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 49 of 77 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 N OAEL = 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 7 th vertebra and with significant and

dos e

- 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. L ow 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 (F 0 M); 0, 5.1, 25.9 and 126.2 (F 0 F); 0, 4.7, 23.2 and 116.9 (F 1 M); and 0, 5.1, 24.8 and 124.1 mg/kg /day (F 1 F)] a Parental systemic NOAEL = 23.2 mg/kg /day LOAEL = 116.9 mg/kg/day, based on the increases in liver weights and fatty changes and thickening of the urinary bladder walls in females

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

LOAEL = N/A

Offspri ng NOAEL =23.2 mg/kg /day b

LOAEL= 116.9 mg/kg/day, based on the increased incidence of chromodacryorrhea, thickened eyelids and dental malocclusion, increased liver weights, 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.Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 50 of 77 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

40762 501 (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 steato sis of the liver in males, decreased triglycerides and cholesterol (males) and increased absolute & relative liver weights (M & F).

Borderline increase in Leydig cell tumors in high dose males with a significant (p<0.05) pairwise comparison

and a 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 LD 50 via ip injection.

870.5450

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

gavage Acceptable/guideline Negative for dominant lethal mutations.

870.5550

In vivo unscheduled DNA synthesis (UDS, rat hepatocytes) 40734304 (1986) 0, 40, 200 or 400 mg/kg Acceptable Negative, no induction of UDSPaclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 51 of 77 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, 3 0, 150 or 5 00 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 sub session 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 (r at) 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

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

g astrointestinal absorption of the dose.

870.7485

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

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

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

0.012

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

870.7485

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

- 80% of the 250

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

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

870.7485

General Metabolism (rat) 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 basi s for doses selection.Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 52 of 77 Table A.2.2: Toxicity Profile of Paclobutrazol Technical

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

Classification/Doses Results

870.7485

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

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

870.7485

General Metabolism (rat) 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 2 nd phase were 6.69 and 9.26 days, respe ctively.

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

cm 2 /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.Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 53 of 77 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 ac ute 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 spec ies. 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 pa rtial ossification of the 7 th vertebra and 14 th 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 d oses (also seen MRID 00132693), which occurred in the absence of maternal toxicity. The study was specifically selected for this exposure scenario because increases in 14 th rib may be the result of a singlePaclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 54 of 77 exposure. An Uncertainty Factor (UF) of 100 was applied to account for interspecies extrapolation (10X) and intraspecies variability (10X). The acute reference dose (a RfD) for females 13

- 49 was calculated to be 0.1 mg/kg/day. T he selection of this study and the PoD is protective of the pregnant femal e 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 (U F) 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. 40734303/473 3 8506

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 t he 2

- generation reproduct ion study, based on a revisit of the data and in consideration of supplemental data on achieved doses provided by the registrant (TXRPaclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 55 of 77 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 inci dence 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

genera tions. 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 In termediate

- 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 occupationa l 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

sens itive point of departure was 10 mg/kg/day from the developmental rat study (MRID 00143158), based on increased incidences of partial ossification of the 7 th vertebra and 14 th rib in fetuses at the LOAEL of 40 mg/kg/day. Both effects were dose

- related, sta tistically 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 14 th 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 var iability (10X). T he 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 exposur e 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/dayPaclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 56 of 77 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 i s 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 ar ea of 10 cm 2 /rat. At the time this study was reviewed,

t he 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 r esidues 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 t o 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 workda y. 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 followi ng 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/grou p 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

- N

demethylase activity was seen in the females. These effects were noted to a lesser extent in the females given diets containing 250 ppm. Without concomitant his tological 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 i n females, serumPaclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 57 of 77 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 toxicit y 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 tes t 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 w as 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 applica tion 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

fo r 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 hyperkerato sis, 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 w eeks 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), paclobutr azol (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 thei r 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 foodPaclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 58 of 77 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 revi sited 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).

Developmenta l 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 7 th cervical vertebra, which is classified as a minor defect an d 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 7 th vertebra was significant (p<0.01) at ≥100 mg/kg while

the incidence of this effect bilat erally 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 group s. 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 fetus es with bilateral extra ribs (14 th ) 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 cont rol 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 i ncrease in fetuses with the incidence of bilateral partial

ossification of the 7 th 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 (OP PTS 870.3700; §83

-Paclobutrazol Human Health Risk Assessment DP No. 415247

_________________________________________________________________________________

Page 5 9 of 77 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 ta bles 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 7 th 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 14 th 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)Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 60 of 77 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 gest ation 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.

Developmenta l 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 conc lusions 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 variat ions 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 7 th cervica l 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 7 th 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 wa s 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 a bove 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

ear lier 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 7 th vertebra, the response was lim ited to the high

dose.

The incidence of fetuses with bilateral extra ribs (14 th ) 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 ef fects 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 renalPaclobutrazol Human Health Risk Assessment DP No. 415247

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Page 61 of 77 dilation were noted at 40 and 100 mg/kg/day but the number of litters affected was not sign ificant. 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 i n 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 a nd litters with unilateral partial ossification of the 7 th 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 8 70.3700; §83

- 3[a]) and satisfies the requirement for a developmental toxicity study in the rat.

R EFERENCES

Woo, DC and Hoar, RM. (1972). “Apparent hydronephrosis” as a normal aspect of renal development in late gestation of rats: The effect of methyl sal icylate. 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.Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 62 of 77 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/k g/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 7 th 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 14 th 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%Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 63 of 77 Observation Dose of Paclobutrazol (mg/k g/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 4073430 3, 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 con trol 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 F 0 parental animals were given test diets for 12 weeks before they were mated, and

the F 1 parental animals were not mated until 11 weeks after they were selected from the F 1A litters. Selection of parents for the F 1 generation was made when the pups were 36 days of age, and the mated

animals in the stud y 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:Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 64 of 77 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

F 0 Parents: Male

Female 4.8 24.4 121.2

5.1 25.9 126.2

F 1 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 wi thin the historical control range. At 1250 ppm, increased liver weights were observed in females in both generations (23% absolute, 26% relative F 0 ; 7 % absolute,

14% relative F 1 ) and fatty change in the liver was observed in F 0 females (23/30 versus 0/30 for the controls). Increased liver weights, mottling or accentuation of the lobular structure, liver enlargement and pallor and discoloration were observed in male and female pups from both generations. In addition to the changes in
the liver, dental mal occlusion was observed in both generations (parental animals and pups; incidence in the parental animals was within the historical control range) and thickening of the urinary bladder wall was

observed in 1 F 0 and in 3 F 1 high dose females. The reproducti ve/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 stat istical 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 reduc ed 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 observationa l signs observed in the parental animals are presented in Table 1:Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 65 of 77 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 genera lly 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

inciden ce 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 chrom odacryorrhea 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

nu mber 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 contr ol for these observations. Likewise, the incidence of dental malocclusions was only increased in all generations of pups in the high

dose groups.

T he offspring NOAEL is 250 ppm (equivalent to 23.2 mg/kg/day), and the LOAEL is 1250 ppm (equivalent to 11 6.9 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 revisedPaclobutrazol Human Health Risk Assessment DP No. 415247

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Page 66 of 77 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. Su mmary 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

F 1A

0 303 5 2 25 4 16

50 320

- - 27

- -

250 279 10 4 28 5 18

1250 305 37 12 28 16 57

F 1B

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

F 2

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).Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 67 of 77 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

F 1A

0 303 4 1 25 4 16

50 320

- - 27

- -

250 279 8 6 28 4 14

1250 305 38 12 28 17 61

F 1B

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

F 2

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 addedPaclobutrazol Human Health Risk Assessment DP No. 415247

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Page 68 of 77 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 ma les 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 obs erved 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 classificati on 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 sufficientl y 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 inc rease 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 becau se 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 E xecutive Summary that includes the actual dose levels (on a mg/kg/day basis) attained in the study.Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 69 of 77 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 s erum alkaline phosphatase and triglyceride levels, the enlarged hepatic cells, increased liver weights, and increased hepatic aminopyrine N

- demethy

- lase activity indicate that the two highest doses (75 and 300 mg/kg/day) have definite effects. 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

S ee MRID 40734301

870.4200b Carcinogenicity

– Mouse

In a combined chronic feed ing/oncogenicity study (MRID 40 762501) 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 incr ease 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

absolu te and relative liver weights, respectively for females) the LOEL is 750 ppm (112.5Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 70 of 77 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 add ition, 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 conside red 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 requi res 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 +/

- S9Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 71 of 77 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%, respective ly of the

LD 50 when delivered via intrapertioneal injection.

Guideline 870.5450 Rodent Dominant Lethal Test (Mouse) MRID 00143155 Classification: Acceptable/guideline Paclobutrazol was negative for the induction of dominant lethal mutations in the sperm atocytes 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

- te st, 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) an d 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 thanPaclobutrazol Human Health Risk Assessment DP No. 415247

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Page 72 of 77 controls) and bins 1

- 3 (60

- 83% less than contro ls), 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 distan ces during bins 1

- 2 (14

- 31% and 31

- 58% less than controls for mid

- and high

dose, 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 sub session 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), treatment

related statistically significant decreases in m ean 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 nor mal 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 landi ng foot splay. In this study, the lowest

- observed

- adverse

- effect level (LOAEL) for paclobutrazol in Han

Wistar rats was 150 mg/kg bw, based on transient alterations in motor activity ( i.e., decreased rearing counts and decreased subsession distances) in f emales 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 Subch ronic 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

14 C on the triazole ring for 4 days. Single rats/sex were subjected to autoradiography 24 hours after dosing an d 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

.Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 73 of 77 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 e xpired 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 14 c label after a single oral dose of 250 mg/kg is limited to the gastrointestinal contents and to a les ser extent to the liver and kidneys.

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 hour s ( 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 conta ined 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 b y 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 propo rtion 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.Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 74 of 77 870.74 85 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 we re 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 ex tracted 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 d etectable 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 [ 14 C]

- triazole labeled paclobutrazol, prepared in sterile deionized water. Approximately 24 hours before exposure, test sites were shaved and undamaged skin was wash ed 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 cm 2 (total defined skin application area = ~10

cm 2 . A Queen Anne pla stic 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 cm 2 test 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 f or 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 exposu res are shown in Table 1, and were as follows:Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 75 of 77 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 cm 2 /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, t he 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 e xposure 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, t he 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 th e 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).Paclobutrazol Human Health Risk Assessment DP No. 415247

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Page 76 of 77 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 experimen ts.

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 co ntent 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% o f 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 blo od levels at 1 hour (T max ) after dosing ranged from 4.1

- 4.4 ppm in plasma (C max ) 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 (T 1/2 ) 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 a nd 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 0 0143160) 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 paclobutrazo l does not bioaccumulate is supported by database and illustrated by the points of departure (PoDs) selected for the risk assessment. Regardless of the duration ofPaclobutrazol Human Health Risk Assessment DP No. 415247

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Page 77 of 77 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 a nd 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 c annulated 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 ly recovered

after 48 hours in bile

.