MEMORANDUM 

DATE: June 26th, 2014 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Paclobutrazol: Summary of Hazard and Science Policy Council (HASPOC) 

Meeting of January 23,2014: Recommendations on the Need for a Subchronic 

Neurotoxicity Study, a Subchronic Inhalation Study, and an Immunotoxicity 

Study for Paclobutrazol 

PC Code: 125601 

Decision No.: N/A 

Petition No.: N/A 

Risk Assessment Type: N/ A 

TXR No.: 0056914 

MRID No.: N/A 

DP Barcode: N/A 

Registration No.: N/ A 

Regulatory Action: N/ A 

Case No.: N/A 

CAS No.: 76738-62-0 

40 CFR: §870. 7800 

FROM: Jonathan 

Antimicrobial 

Executive 

Leshin, 

Secretary, 

Division 

Ph.D. 

HASPOC 

(751 OP) 

~ 

~ 

THROUGH: Jeff Dawson, Co-Chair 

Anna Lowit, Ph.D, Co~Chai 

HASPOC 

Health Effects Division (7509P) 

TO: Yvonne Barnes, Risk Assessor 

Nancy McCarroll, Toxicologist 

Monica Hawkins, Environmental Health Scientist 

Donna Davis, Chief 

Registration Action Branch VI 

Health Effects Div.ision (7509P) 

Khue Nguyen, Chemical Review Manager 

PRDRMIB 1 

MEETING ATTENDEES: 

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Other Attendees: Yung Yang, Kelly Lowe, Monica Hawkins, Linnea Hansen, Margarita 

Collantes, Donna Davis, Billy Smith, William Donovan, Anwar Dunbar, Christina Swartz 

 

I. PURPOSE OF MEETING: 

In accordance with the revised 2007 40 CFR Part 158 Toxicology Data Requirements, acute and 

subchronic neurotoxicity studies, subchronic inhalation studies, and an immunotoxicity study are 

required for food and non-food use pesticides. Previously, the HED Hazard and Science Policy 

Council (HASPOC) reviewed the paclobutrazol toxicity database and concluded that acute and 

subchronic neurotoxicity studies were required (TXR# 0056149). Since that time, the registrant 

has submitted an acute neurotoxicity study (MRID 49211902), which has been classified as 

Acceptable/Guideline. Accordingly, the paclobutrazol risk assessment team requested that 

HASPOC to re-consider the need for a subchronic neurotoxicity study (870.6200). 

At the time of the first HASPOC meeting, the need for a 28-day inhalation study and an 

immunotoxicity study was also not addressed (TXR# 0056149). Accordingly, the paclobutrazol 

risk assessment team further requested that HASPOC conduct a review to specifically consider 

the need for a 28-day inhalation study and an immunotoxicity study (870.7800). 

II. SUMMARY OF USE PROFILE, EXPOSURE, & HAZARD CONSIDERATIONS: 

a. Use Profile

Paclobutrazol is a plant growth regulator currently registered for use on turf, outdoor 

ornamentals, greenhouse ornamentals, as a bulb soak, and as a seed treatment (on cucurbit, 

pepper, and tomato seeds). All of the registered applications are classified as non-food uses. 

b. Toxicity Profile: 

In subchronic feeding studies in rats and dogs, the target organ was the liver, based on increased 

organ weights and alterations in clinical chemistry parameters associated with liver function. In 

agreement with the subchronic findings, the liver was the target organ following chronic 

exposure via the diet in dogs, rats, and mice. Adverse effects consisted of: increased liver 

weights, steatosis, and/or alterations in clinical chemistry parameters associated with liver 

function. 

A 21-day dermal study in rabbits showed a dose-related increase in the degree of hyperkeratosis, 

acanthosis, and inflammatory changes of the superficial dermis at higher doses. These effects 

are, however, local and no systemic effects were seen in the study. Two pre-natal rat 

developmental toxicity studies were available. In one study, there was evidence for increased 

qualitative susceptibility where developmental effects, manifested as delayed ossification and 

cleft palates, were seen at a maternally toxic dose. In the second rat study, there was evidence 

for quantitative susceptibility; developmental effects characterized as renal dilation, hydroureter, 

and minor skeletal defects, which were seen in the absence of maternal toxicity. There was, 

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

exposures to rabbits or following pre-and/or post natal exposure in rats for two generations in the 
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reproduction study. Food Quality Protection Act (FQPA) considerations do not apply to 

paclobutrazol as the currently registered use patterns are all non-food uses. While, there are 

potential exposures to infants and children from the residential uses of paclobutrazol, there are 

no residual uncertainties to infants and children for pre and/or post natal susceptibility based on 

1) there are clear No Observable Adverse Effect Levels (NOAELs) established for the 

developing organism and 2) the PODs used for assessing risks to infants and children from 

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

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

findings from the acute neurotoxicity supports this conclusion. 

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

exposure. It is moderately toxic via the dermal route (category II) in rats and rabbits and via the 

inhalation route (category II) in rats. It is moderately irritating to the skin and the eye and is 

negative for dermal sensitization. 

c. Risk Assessment Consideration 

Two occupational exposure assessments were completed in 2007 to support new non-food uses 

of paclobutrazol as a seed treatment and a bulb soak. The scoping document was completed in 

March 2007, prior to the requirement for conducting neurotoxicity, subchronic inhalation and 

immunotoxicity studies, and thus these studies are outstanding. A risk assessment to support the 

registration review of paclobutrazol is due to be released in June 2014 and will evaluate all 

registered uses including residential turf use, and potential for drinking water exposure from the 

turf use. With the exception of the recently received acute neurotoxicity study, no additional 

toxicity studies have been submitted since the peer review committee reports were released. 

III. STUDY WAIVER REQUESTS 

a. Subchronic Neurotoxicity Study 

In the earlier HASPOC report, HED acknowledged that there were no clear signs of 

neurotoxicity following acute, subchronic or chronic dosing in multiple species in the 

paclobutrazol database. The findings from the recently submitted Acceptable/Guideline acute 

neurotoxicity study (MRID 49211902) support this conclusion. In this study, the only 

toxicological endpoint to set the NOAEL at 30 mg/kg/day was transient alterations (i.e., 

decreased rearing and decreased subsession distances in female rats) at the Lowest Observable 

Adverse Effect Level (LOAEL) of 150 mg/kg. There were no treatment-related adverse effects 

on clinical signs, brain weight, gross pathology or neuropathology. Similarly, Functional 

Observational Battery (FOB) testing was largely negative. Based on these considerations, the 

acute neurotoxicity study in rats, with a NOAEL of 30 mg/kg was selected for the acute dietary 

PoD. Other factors that influenced this decision included the appropriate exposure duration of 

concern (effects were seen within 3-4 hours of dosing) and the response in the most sensitive 

species. In contrast, the prenatal developmental toxicity study in rats (MRID 00143158) with a 

developmental NOAEL of 10 mg/kg/day was not selected for the acute PoD because an 

appropriate endpoint attributable to a single dose was not found in this study. Developmental 

effects consisted of hydroureter and minor skeletal defects or variations at the LOAEL of 40 

mg/kg/day. 
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The HASPOC concludes, based on a weight of the evidence (WOE) approach, that a 

subchronic neurotoxicity study for paclobutrazol is not required at this time. This approach 

considered all of the available hazard and exposure information for paclobutrazol, including: 1) 

there are no clear signs of neurotoxicity following acute, subchronic or chronic dosing in 

multiple species in the paclobutrazol database; 2) the liver is the target tissue and a subchronic 

neurotoxicity study is not expected to provide a more sensitive endpoint than existing studies; 

and 3) the findings from an acute neurotoxicity study showing no adverse effects on clinical 

signs, brain weight, gross pathology or neuropathology and a negative FOB supports the earlier 

findings. 

b. Inhalation Study 

Previously, the Office of Pesticide Programs (OPP) used a set of criteria to determine whether an 

inhalation study could be waived. These criteria considered the scientific information available 

for the chemical, including: 1) the degree of irritation and corrosivity; 2) volatility; 3) aerosol 

particle size; and 4) Acute Toxicity Category and extrapolated MOEs (e.g., MOEs 10 times 

higher than the target). In 2009, OPP developed an issue paper on risk assessment approaches 

for semi-volatile pesticides. As part of that issue paper, an analytical comparison was conducted 

of oral and inhalation experimental toxicology studies. In general, this analysis showed that the 

degree to which oral PODs were protective of potential inhalation toxicity varied. In many cases 

the oral POD was protective, but in some cases the inhalation PODs were significantly more 

protective. Currently, OPP uses a weight of the evidence (WOE) approach that builds upon 

OPP’s experience using the criteria listed above and conclusions from the 2009 SAP. As 

approaches for route-to-route extrapolation continue to evolve and improve, OPP may 

incorporate additional considerations into the WOE analysis. 

Inhalation exposure can be to vapors, droplets, and/or particles/dusts. The form of inhalation 

exposure is determined by a number of factors including physical-chemical properties, use 

pattern, and exposure scenarios. OPP’s interim WOE approach considers: 

1. Physical-chemical properties: Paclobutrazol (MW = 293.79 g/mol) has a low vapor 

pressure of 1.28 x 10-9 mm Hg at 25 C and a Henry’s law constant of 8.09 x 10-10 atm 

m3

/mol., which indicates that this chemical is relatively non-volatile under field 

conditions. These parameters are key considerations with respect to the volatilization after 

sprays have settled. The low vapor pressure and/or Henry’s law constant, however, does 

not preclude exposure to aerosolized droplets or particles/dusts. 

 

2. Use pattern & exposure scenarios: Any application scenario that leads to inhalation 

exposure to droplets needs to be considered in the WOE analysis for an inhalation 

toxicology study waiver request. In the case of paclobutrazol, mixing/loading/applying 

liquids with a manually pressurized handwand for drench tree treatments (35 inch tree) 

results in the highest inhalation exposure (MOE = 1,700).

3. Margins of Exposure (MOEs): The MOE estimates for inhalation scenarios were 

calculated using a developmental rat study with a NOAEL of 10 mg/kg/day based on renal 
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dilation, hydroureter and minor skeletal defects or variations at the LOAEL of 40 

mg/kg/day. Since an oral dose was selected, absorption via inhalation is presumed to be 

equivalent to oral absorption. This oral toxicity study should be considered in the WOE 

analysis for an inhalation toxicology study waiver request. In the past, OPP has used 

MOEs of approximately 10 times higher than the LOC as a benchmark for granting waiver 

requests. The 2009 analysis suggests this approach is appropriate for most pesticides, but 

not all. Using this interim WOE approach, MOEs from 10-100 times greater than the 

LOC will be considered in combination with other factors discussed here. 

Occupational exposure estimates (MOEs) from paclobutrazol inhalation scenarios are 

greater than 1000; the residential inhalation MOEs are in excess of 330,000. Therefore, 

the Agency is confident that the lack of an inhalation study does not underestimate risk 

from the inhalation route for either the occupational or the residential uses because 

conservative exposure assumptions were used to derive the MOE. 

4. Specific Toxicological Considerations: Paclobutrazol is moderately toxic in an acute 

inhalation study (Toxicity Category II); LD50 is 770 mg/m3

, which is approximately 145 

mg/kg. 

The HASPOC concludes, based on a WOE approach, that a subchronic inhalation study 

for paclobutrazol is not required at this time. This approach considered all of the available 

hazard and exposure information for paclobutrazol, including: 1) moderate acute toxic in rats via 

the inhalation route (Toxicity Category II), 2) the physical/chemical properties and low volatility 

(1.28 x 10-9 mm Hg at 25 C), and 3) all occupational and residential inhalation MOEs were 

>1,000. 

c. Immunotoxicity Study 

Indicators for Potential Immunotoxicity 

There are no signs of immunotoxicity following subchronic or chronic dosing in multiple species 

in the paclobutrazol guideline database. 

Parameter Findings 

Hematology Indicators 

(WBC changes) None 

Clinical Chemistry 

Indicators 

(A/G Ratio) 

None 

Organ Weight Indicators 

(Spleen, Thymus) None 

Histopathology Indicators 

(Spleen, Thymus, 

Lymph nodes) 

None 
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Toxicity Profile 

(Target Organs) 

Liver in both subchronic and chronic studies in dogs, rats and mice. 

Adverse effects consisted of increased liver weights, steatosis, 

and/or alterations in clinical chemistry parameters associated with 

liver function. 

Evidence for Immunotoxicity from SAR Chemicals – Retrospective Analysis

Several of the azole-type pesticides, which in general are structurally similar to paclobutrazol 

(i.e., two conazole fungicides, Difenoconazole and Triflumizole; an imidazole fungicide, 

Fenamidone; and a pyrazole herbicide, Pyraflufen-ethyl), were included in the retrospective 

analysis of the immunotoxicity study (USEPA, 2013). All four test substances caused 

suppression of the anti-sheep red blood cells (SRBC) IgM response; however, none of the 

NOAELs/LOAELs established for this endpoint affected the PODs or toxicity endpoints of 

concern for the respective human health risk assessments. Consequently, immunotoxicity was 

not the most sensitive endpoint in the databases for any of these pesticides. 

The HASPOC concludes, based on a WOE approach, that an immunotoxicity study for 

paclobutrazol is not required at this time. This approach considered all of the available 

hazard and exposure information for paclobutrazol, including: 1) the findings from the 

toxicology database, which reveal no clear evidence of treatment-related effects on the immune 

system suggesting that the immune system is not the primary target organ (the primary target 

organ is the liver) and 2) in structurally similar chemicals such as difenoconazole, triflumizole, 

fenamidone and pyraflufen-ethyl, immunotoxicity was not the most sensitive endpoint. 

IV. HASPOC CONCLUSIONS 

Based on a WOE approach, HASPOC recommends that data waivers can be granted for the 

subchronic inhalation study, the subchronic neurotoxicity and the immunotoxicity studies for 

paclobutrazol at this time. 

In determining the need for a subchronic inhalation study, EPA’s WOE decision process 

included both hazard and exposure considerations as well as incorporation of a 10X database 

uncertainty factor (UFDB) for the lack of this study. Thus, the Agency’s LOC in the HASPOC’s 

WOE evaluation for inhalation exposure risk assessment is a MOE of 1,000 which includes the 

10X inter-species extrapolation, 10X intra-species variation, and the 10X WOE UFDB. The use 

of an oral point of departure resulted in MOEs higher than the WOE LOC of 1,000. This 

indicates that the lack of an inhalation study does not reduce the overall confidence in the risk 

assessment or result in an uncertainty (i.e., that study will not provide a POD sufficiently low to 

result in a risk of concern). 

V. REFERENCES 

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. 
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USEPA (2013). A Retrospective Analysis of the Immunotoxicity Study (OCSPP Test Guideline 

No. 870.7800). Internal Memo from Jess Rowland, Associate Director, OCSPP\OPP\HED to 

Jack Housenger, Director, OCSPP\OPP\HED, dated February 2013.