### 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 Leshin, Ph.D.**~** Executive Secretary, HASPOC

### ~ Antimicrobial Division (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:

Page 1 of7Page 2 of 7 Other Attendees: Yung Yang, Kelly Lowe, M onica Hawkins, Linnea Hansen, Margarita Collantes, Donna Davis, Billy Smith, Willia m 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 pa clobutrazol toxicity database and concluded that acute and subchronic neurotoxicity studies were required (TXR# 0056149). Si nce that time, the registrant has submitted an acute neurotoxicity study (M RID 49211902), which has been classified as Acceptable/Guideline. Accordingly, the paclob utrazol 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, th e need for a 28-day inhalation study and an immunotoxicity study was also not addressed (TXR# 0056149). Accordi ngly, the paclobutrazol
risk assessment team further re quested that HASPOC conduct a revi ew to specifically consider the need for a 28-day inhalation study and an immunotoxicity study (870.7800).

II. SUMMARY OF USE PROFILE, EX POSURE, & 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 register ed applications are clas sified as non-food uses.

b. Toxicity Profile:

In subchronic feeding studies in rats and dogs, th e target organ was the liver, based on increased organ weights and alterations in c linical chemistry parameters asso ciated 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 clinic al chemistry parameters associated with liver
function.

A 21-day dermal study in rabbits showed a dose-rela ted increase in the degree of hyperkeratosis, acanthosis, and inflammatory changes of the superfi cial 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 e ffects, manifested as delayed ossification and cleft palates, were seen at a maternally toxic dose. In the second rat study, there was evidence for quantitative susceptib ility; developmental effects characte rized as renal dilation, hydroureter, and minor skeletal defects, which were seen in the absence of maternal toxicity. There was, however, no evidence (quantitat ive or qualitative) of increased susceptibility following in utero exposures to rabbits or following pr e-and/or post natal exposure in rats for two generations in thePage 3 of 7 reproduction study. Food Quality Protection Act (FQPA) considerations do not apply to paclobutrazol as the currently registered use pa tterns are all non-food uses. While, there are potential exposures to infants a nd children from the residential uses of paclobutrazol, there are
no residual uncertainties to infant s and children for pre and/or pos t 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 th e most sensitive developmental effects of
concern. There is also no clear evidence of ne urotoxicity in the data base, and the negative findings from the acute neurotox icity supports this conclusion.

Paclobutrazol has low toxicity in th e rat, rabbit, and guinea pig via the oral (categor y 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 mode rately irritating to the skin and the eye and is negative for dermal sensitization.

c. Risk Assessment Consideration

Two occupational exposure assessm ents were completed in 2007 to support new non-food uses of paclobutrazol as a seed treatment and a bul b soak. The scoping document was completed in March 2007, prior to the requirement for conduc ting 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 resident ial 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 acknowledg ed 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 Accep table/Guideline acute neurotoxicity study (MRID 49211902) support this conclusion. In this study, the only toxicological endpoint to se t the NOAEL at 30 mg/kg/day wa s 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. Th ere were no treatment-related adverse effects on clinical signs, brain weight , gross pathology or neuropath ology. Similarly, Functional Observational Battery (FOB) testing was largel y 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 deci sion included the appropria te exposure duration of concern (effects were seen within 3-4 hours of dosing) and the response in the most sensitive species. In contrast, the pren atal developmental toxicity st udy in rats (MRID 00143158) with a developmental NOAEL of 10 mg/kg/day was not selected for the acute PoD because an appropriate endpoint attr ibutable to a single dose was not found in this study. Developmental effects consisted of hydroureter and minor skelet al defects or variations at the LOAEL of 40 mg/kg/day.Page 4 of 7 The HASPOC concludes, based on a weight of the evidence (WOE) approach, that a subchronic neurotoxicity study for paclo butrazol 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 ne urotoxicity following acute, su bchronic 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 neurotoxic ity study showing no adverse effects on clinical signs, brain weight, gross pat hology or neuropathology and a ne gative FOB supports the earlier findings.

b. Inhalation Study

Previously, the Office of Pesticid e Programs (OPP) used a set of cr iteria to determine whether an inhalation study could be waived. These criteria c onsidered 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 Categor y and extrapolated MO Es (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 poten tial 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 a bove and conclusions from the 2009 SAP. As approaches for route-to-route extrapolation continue to evolve and improve, OPP may incorporate additional consideratio ns into the WOE analysis.

Inhalation exposure can be to vapor s, droplets, and/or particles/ dusts. The form of inhalation exposure is determined by a number of factor s including physical-chem ical 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

m 3 /mol., which indicates that this chemi cal is relatively non-volatile under field conditions. These parameters are key considera tions with respect to the volatilization after sprays have settled. The lo w vapor pressure and/or Henr y’s law constant, however, does not preclude exposure to aerosoli zed 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 paclobutrazo l, mixing/loading/applying liquids with a manually pressurized handwand fo r drench tree treatments (35 inch tree) results in the highest inha lation exposure (MOE = 1,700).

3. Margins of Exposure (MOEs): The MOE estimates for inhalation scenarios were calculated using a developmental rat study w ith a NOAEL of 10 mg/kg/day based on renalPage 5 of 7 dilation, hydroureter and minor skeletal defects or vari ations at the LOAEL of 40 mg/kg/day. Since an oral dose was selected, absorption via i nhalation is presumed to be equivalent to oral absorption. This oral toxicity study shoul d be considered in the WOE analysis for an inhalation toxicology study wa iver 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 approa ch is appropriate for most pesticides, but not all. Using this inter im 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) fr om paclobutrazol inha lation scenarios are greater than 1000; the reside ntial 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 occ upational or the resi dential uses because conservative exposure assumptions we re used to derive the MOE.

4. Specific Toxicological Considerations: Paclobutrazol is moderate ly toxic in an acute inhalation study (Toxicity Category II); LD 50 is 770 mg/m 3

, which is approximately 145 mg/kg

.

The HASPOC concludes, based on a WOE appr oach, 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, in cluding: 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 re sidential inhalation MOEs were >1,000.

c. Immunotoxicity Study

Indicators for Potential Immunotoxicity

There are no signs of immunotoxicity following s ubchronic 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) NonePage 6 of 7 Toxicity Profile (Target Organs) Liver in both subchronic and chroni c studies in dogs, rats and mice.
Adverse effects consiste d of increased liver weights, steatosis,
and/or alterations in cl inical chemistry parameters associated with
liver function.

Evidence for Immunotoxicity from S AR Chemicals – Retrospective Analysis

Several of the azole-type pesticid es, which in general are structur ally 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 f our test substances caused suppression of the anti-sheep red blood cells (SRBC) IgM response; however, none of the NOAELs/LOAELs established for this endpoint aff ected the PODs or toxicity endpoints of concern for the respective human health risk assessments. Conseque ntly, immunotoxicity was not the most sensitive endpoint in the da tabases for any of these pesticides.

The HASPOC concludes, based on a WOE appr oach, that an immunotoxicity study for paclobutrazol is not required at this time. This approach consider ed all of the available hazard and exposure information for paclobutra zol, including: 1) the findings from the toxicology database, which reveal no clear evid ence of treatment-relate d 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 simila r 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 th at data waivers can be granted for the subchronic inhalation study, the subchronic neurot oxicity 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 (UF DB ) for the lack of this study. Thus , the Agency’s LOC in the HASPOC’s WOE evaluation for inhalation exposure risk as sessment is a MOE of 1,000 which includes the 10X inter-species ex trapolation, 10X intra-species variation, and the 10X WOE UF DB . The use of an oral point of departur e resulted in MOEs higher th an the WOE LOC of 1,000. This
indicates that the lack of an inhalation study does not reduce th e 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.Page 7 of 7 USEPA (2013). A Retrospective Analysis of the Immunotoxicity Study (O CSPP Test Guideline No. 870.7800). Internal Memo from Jess Rowlan d, Associate Director , OCSPP\OPP\HED to Jack Housenger, Director, OCSPP\ OPP\HED, dated February 2013.