MEMORANDUM 

November29, 2012 

TXR #: 005644 7 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

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

of August 30, 2012: Recommendations on a Registrant Submitted Waiver 

Request on Toxicity Data Required for Registration Review. 

PC Code: 097003 DP Barcode: N/A 

Decision No.: N/A Registration No.: N/A 

Petition No.: N/A Regulatory Action: N/A 

Risk Assessment Type: N/A Case No.: N/A 

TXR No.: 0056447 · CAS No.: N/A 

MRID No.: N/A 40 CFR: N/A 

FROM: Juli eVanAlstine,MPH l- ~ ~IV'- \.~ Executive Secretary 

Hazard and Science Policy Council (HASPOC) 

Health Effects Division (HED; 7509P) 

THROUGH: Jess Rowland, Co-Chair je~ao~USj l Anna Lowit, Ph.D, Co-Chair 9vt ' 

HASPOC '

11 

HED (7509P) / 

TO: Marquea D. King, Ph.D., Toxicologist 

Kelly O'Rourke, ORE 

And 

Elissa Reaves, Branch Chief 

Risk Assessment Branch IV (RABIV) 

HED (7509P) 

Jose Gayoso 

Risk Management and Implementation Branch II 

Pesticide Re-Evaluation Division (7508P) 

MEETING ATTENDEES: 

HASPOC Members: Anna Lowit, Elissa Reaves, Elizabeth Mendez, Jeff Evans, Jess Rowland, 

John Kough, Jonathan Chen, Michael Metzger, P.V. Shah, Ray Kent 

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Presenters: Marquea King, Kelly O'Rourke 

Other Attendees: Scott Miller, Ed Scollon, Christine Olinger, Jose Gayoso, Kristin Rury, Julie 

Van Alstine 

I. PURPOSE OF MEETING 

At the time of initial registration, the toxicology data base for piperalin was complete for a nonfood use chemical. However, in accordance with the 2007 revised toxicology data requirements, 

a prenatal rabbit developmental toxicity study, a rat reproduction study, a neurotoxicity battery 

and an immunotoxicity study are now required for non-food use chemicals. In 2009, the Risk 

Assessment Branch IV (RABIV) of the Health Effects Division (HED) prepared a scoping 

document for an upcoming Registration Review of piperalin which identified that a 28-day 

inhalation toxicity study was required in addition to the studies listed above. In 201 0, the 

Agency issued a Data Call-In (DCI) for these studies. The Registrant submitted the following 

responses to the DC I: 1) a waiver based on low volume/minor use provision in 2010 and 2) a 

waiver based on scientific rationale in 2012 (MRID No. 48825501). The 2012 waiver request 

included a DEREK SAR analysis, and while the Agency supports the use of such tools, the 

HASPOC did not put emphasis on the DEREK SAR analysis in its weight of the evidence 

(WOE) approach. On August 30, 2012, HED's Hazard and Science Policy Council (HASPOC) 

met to discuss the Registrant's waiver requests for the studies listed above. 

II. SUMMARY OF PREVIOUS RISK ASSESSMENT & USE PROFILE 

Piperalin (3-[(2RS)-2-methylpiperidino]propyl 3,4-dichlorobenzoate) is the active ingredient in a 

single EPA registered end-use product, Pipron L.C. (Registration Number 67690-1 ). Pipron L.C. 

contains 84.4% piperalin and is formulated as a liquid/soluble concentrate. It is applied as a 

foliar spray, most commonly using a high-volume, high-pressure sprayer. It is only registered 

for use in commercial greenhouses and similar enclosed structures with nonporous coverings on 

ornamental plants, including uses on roses. It is the only EPA-registered fungicide that can 

eradicate or cure powdery mildew fungal infections on ornamental plants and fresh-cut flowers. 

There are no food uses for piperalin and since the uses are limited to greenhouses, residues in 

drinking water are not anticipated. The label does not specify an application interval or 

maximum number of applications per crop; therefore, the exposure duration is assumed to range 

from short- to intermediate-term for both the dermal and inhalation routes. 

Piperalin has a low acute toxicity profile by oral, dermal, and inhalation routes of exposure 

(Category III or IV). It is not a skin sensitizer but was originally classified as a Toxicity 

Category I for skin irritation in New Zealand rabbits (similar effects were found in the 21-day 

dermal toxicity study of edema, erythema, and epidermal dehydration). Subsequently, its 

Toxicity Category for skin irritation was reclassified to Toxicity Category II and then to Toxicity 

Category III. There are no subchronic and chronic oral toxicity or inhalation studies available 

for piperalin. In a subchronic dermal rabbit toxicity study no systemic toxicity was observed at 

450 mg/kg/day, the highest dose tested (HDT). A rat developmental toxicity study showed no 

evidence of prenatal developmental toxicity or fetal susceptibility at maternally toxic doses. 

Available mutagenicity tests indicate that piperalin is not mutagenic. Toxicity points of 

departure (PODs) were not selected for the 1994 risk assessment. The HED assessment for the 

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RED concluded that a quantitative exposure assessment was not required for piperalin since the 

toxicology criteria were not triggered (i.e., the acute dermal toxicity is classified as Toxicity 

Category IV, the acute inhalation toxicity is classified as Toxicity Category III, and no systemic 

toxicity was observed in the dermal toxicity study at the HDT). 

A quantitative occupational exposure assessment has not been conducted for piperalin. The 

Agency determined in August 1994 that a quantitative assessment of occupational handler and 

post-application exposure would not be performed since the toxicological endpoints do not meet 

the triggers for the exposure, but would be mitigated by using appropriate label precautions for 

inhalation and dermal protection for applicators and mixers/loaders (D368328). As part of 

Registration Review, an updated occupational risk assessment will be completed. Preliminary 

dermal margins of exposure (MOEs) for handlers range from 1,800 to 15,000 with baseline attire 

(i.e., no additional PPE) and preliminary inhalation MOEs range from 2,700 to 270,000 without 

a respirator. The current label requires gloves for handlers. For post-application exposure 

scenarios, preliminary dermal MOEs range from 670 to 14,000 on the day of application using 

the current label restricted-entry interval (REI) of 12 hours. Note that the current label does not 

indicate an application interval or maximum number of applications; therefore, the exposure 

duration is assumed to range from short- to intermediate-term for both the dermal and inhalation 

routes. 

III. SUMMARY OF WAIVER REQUEST 

Exponent, on behalf of SePRO (the registrant), submitted a toxicity waiver request based on the 

limited use pattern of piperalin in indoor greenhouse on ornamental flowers (fresh cut roses 

make up nearly 70-80% of the use) to control powdery mildew. The registrant indicated that the 

minor use/low volume exemption request should be considered in combination with this waiver 

request to support the continued registration containing piperalin. 

1. Subchronic Inhalation Toxicity Study (GLN 870.3465) 

Exponent provided the following rationale for waiving the subchronic inhalation study (MRID 

48825501): 

1. "The existing data on piperalin and QSAR analysis indicate that the conduct of a 28-

or 90-day repeated dose inhalation study would not fulfill any data need that would be 

reasonably predicted to impact the existing risk assessment." 

2. "The risk assessment performed by SePRO [ .. . ]demonstrates a conservative 

approach based upon the available product-specific data that result in acceptable 

MOE's.'' 

3. "[SePRO's risk] assessment indicates that a repeated dose inhalation study is not 

warranted based on piperalin's very low potential for human toxicity as demonstrated 

by its history of safe use, experimental testing, SAR and QSAR analysis, and most 

importantly, an established risk assessment that provides a conservative MOE." 

4. "[ ... ] Piperalin has experimentally demonstrated low toxicity via acute inhalation, 

and although technically an EPA Toxicity Inhalation Category III substance, piperalin 

could arguably be considered to belong to EPA Toxicity Category IV, designated 

non-hazardous." 

Page 3 of7 
The HASPOC concurred with the Registrant's rationale for granting a waiver for a 

subchronic inhalation toxicity study. Furthermore, hazard and exposure data also 

provided additional support for the waiver, with the use of an oral Point of Departure 

(POD) resulting in MOEs that range from 2,700 to 270,000 for potential inhalation 

exposure resulting from occupational uses (no residential uses). 

2. Developmental Toxicity Study in Rabbits (GLN 870.3700b) 

Exponent provided the following rationale for waiving the rabbit developmental study (MRID 

48825501): 

1. "The available developmental toxicity study in rats does not indicate an effect on 

offspring or endpoints of fertility." 

2. "OECD Toolbox QSAR modeling and experimental data demonstrate that the rat is 

more susceptible to developmental toxicity endpoints than the rabbit, suggesting that 

conduct of an additional developmental toxicity study in the rabbit as requested by 

the DCI would not alter the existing risk assessment or MOE." 

3. "Based on the available toxicological database, the oral NOAEL of20 mg/kg bw/day 

used in the risk assessment of piperalin is protective for developmental toxicity 

effects." 

4. "The number of animals sacrificed (and other resources necessary) to conduct a 

developmental toxicity study in rabbits is not justified because the existing risk 

assessment and MOEs are protective and the results of the requested study would not 

provide any additional data necessary to assess occupational risk." 

The HASPOC concurred with the Registrant's rationale for not conducting a 

developmental toxicity study in rabbits. Additional support for granting a waiver for this 

study include: 1) the lack of concern for developmental toxicity in rats; 2) the lack of 

systemic toxicity via the dermal route at one half of the Limit Dose which indicates that 

rabbits are not more sensitive than rats, and therefore it is less likely that piperalin will 

cause developmental toxicity in rabbits; and 3) a developmental toxicity study will not yield 

a lower POD for risk assessment. 

3. Reproduction and Fertility Effects (GLN 870.3800) 

Exponent provided the following rationale for waiving the two-generation reproductive toxicity 

study (MRID 48825501): 

1. "The available toxicity data do not indicate an effect on offspring or endpoints of 

fertility for piperalin and SAR and QSAR modeling do not suggest that piperalin has 

the potential to be toxic to the reproductive system or affect fertility endpoints." 

2. "[The] OECD Toolbox analysis to assess the relative binding affinity ofpiperalin to 

the estrogen receptor (ERBA) indicates that piperalin has no binding affinity to the 

estrogen receptor." 

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3. "The results ofOECD Toolbox QSAR modeling for the reproductive study indicate 

that the existing risk assessment and resulting MOEs would not be significantly 

altered if the reproductive toxicity study were conducted." 

4. "OECD Toolbox QSAR modeling predicted a LOEL for reproductive toxicity of 34 

mg/kg bw/day based on structurally similar compounds with a protein binding 

mechanism of action. This suggests that the data currently available on piperalin are 

adequate to support an effective risk assessment." 

The HASPOC concurred with the Registrant's rationale for granting a waiver to the twogeneration reproduction study. Furthermore hazard and exposure information also 

provided additional support for the waiver, including: 1) the use of piperalin is limited to 

greenhouses under occupational setting and therefore exposure is limited to adults 

(potential pregnant workers); and 2) the available pre-natal developmental toxicity study 

in rats does not show developmental toxicity, and thus any concern for potential risk to the 

developing fetuses has been evaluated. 

4. Neurotoxicity Battery (GLN 870.6200) 

Exponent provided the following rationale for waiving the neurotoxicity screening battery 

(MRID 48825501): 

I. ''Based on results observed in the acute toxicity and rat developmental toxicity 

studies, EPA has determined that a Neurotoxicity Screening Battery is appropriate for 

piperalin; however the effects observed in these studies are more accurately 

characterized as non-specific general toxicity as opposed to neurotoxicity." 

2. "The purported neurotoxic effects observed at 500 mg/kg in the same study were not 

reproducible (leg weakness, hypoactivity) in the rat developmental toxicity study at 

the same dose and route of administration. Additionally, the 500 mg/kg bw/day dose 

level is at or above the maximum tolerated dose [ ... ]." 

3. "In the rat developmental toxicity study, the potential neurotoxic effect of excessive 

salivation [ ... ] could easily be attributed to nausea and stomach discomfort as 

opposed to a neurological effect of piperalin, especially considering that the dose 

route was gavage and that the effect occurred on the initial days of dosing in a species 

that is incapable of vomiting. The symptoms of excessive salivation were noted after 

the first few doses (GD6-8) of piperalin, within 5 minutes of dosing [and] [ ... ] 

typically resolved within 15 minutes of dosing. On GD 16-20 no symptoms of 

excessive salivation were recorded in any animal at any dose level. The non-specific 

finding of soiled fur, which is commonly associated with general toxicity, was only 

observed at the high dose level (500 mg/kg bw/day) and is likewise attributable to the 

general toxicity of piperalin." 

4. "Effects potentially interpreted as neurotoxic were only observed in studies where the 

dose approached or surpassed the maximum tolerated dose. Therefore any NOEL 

derived from the requested neurotoxicity study would be attributable to general 

toxicity and only present at a test concentration greater than the 20 mg/kg bw/day 

currently utilized in the risk assessment." 

5. "The sacrifice of animals to effectively re-determine the acute toxicity of piperalin, is 

not justified and would not alter the current MOEs." 

Page 5 of7 
The HASPOC concurred with the Registrant's rational for granting a waiver for the 

neurotoxicity battery. 

5. Immunotoxicity Study (GLN 870.7800) 

Exponent provided the following rationale for waiving the irnrnunotoxicity study (MRID 

48825501): 

1. "The available toxicity data for piperalin indicate that piperalin is highly unlikely to 

affect immune organs or related hematological parameters (pathology in acute 

toxicity tests, maternal gross internal observations in the rat developmental toxicity 

study, fetal visceral examinations in the rat developmental toxicity study, hematology 

in the dermal repeated dose study in rabbits, organ weights and gross pathology in the 

dermal repeated dose study in rabbits and histopathology in the dermal repeated dose 

study in rabbits)." 

2. "The only potentially immune-related effect observed in the available toxicological 

database for piperalin is a finding of multifocal thymic hemorrhages in the acute 

inhalation study in rats at dose levels which resulted in death (5.040 mg/L), an effect 

attributed to gross toxicity. No other effects to the immune system or immune 

parameters were noted in any other studies at acute oral dose levels up to 2500 mg/kg, 

oral repeated dose levels up to 500 mg/kg bw/day or dermal repeated dose levels up 

to 400 mg/kg bw/day." 

3. "The [Crop Life America immunotoxicity study] review reveals that guideline 

irnrnunotoxicity studies that have been conducted thus far for a wide variety of 

compounds (over 75 different compounds) elicit general toxicity effects at lower 

thresholds than irnrnunotoxicological effects. This demonstrates that risk assessment 

based on endpoints of general toxicity is protective and the conduct of a specific 

immunotoxicity study is very unlikely to alter the toxicological endpoints used in the 

risk assessment." 

4. "Based on the available toxicological database, the oral NOAEL of20 mg/kg bw/day 

used in the risk assessment of piperalin is therefore protective for immunological 

effects." 

The HASPOC does not concur with the Registrant's request for a waiver of this study. 

OPP is conducting an independent retrospective analysis of more than 120 immunotoxicity 

studies submitted to Agency. Preliminary findings of OPP' s retrospective analysis suggest that 

the submitted immunotoxicity studies have not yet resulted in PODs that are lower than the 

PODs selected from other available guideline experimental toxicology studies. As a result, the 

currently available immunotoxicity studies have not impacted the Agency's risk assessments. 

OPP's anticipated completion date of the retrospective analysis is end of2012. In the interim, 

HED recommends that irnrnunotoxicity studies continue to be required for registration and 

registration review chemicals. 

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IV. HASPOC RECOMMENDATIONS 

The HASPOC, based on the current use pattern, has granted waivers for the following studies 

with piperalin: 

• a subchronic inhalation toxicity study; 

• a rabbit developmental toxicity study; 

• a two-generation reproduction toxicity study; and 

• acute and subchronic neurotoxicity studies. 

The HASPOC did not grant a waiver for the immunotoxicity study which is required at this time. 

The 2012 waiver request included a DEREK SAR analysis, and while the Agency supports the 

use of such tools, the HASPOC did not put emphasis on the DEREK SAR analysis in its weight 

of the evidence approach. 

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