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 R ev iew. PC Code: 097003 DP Barcode: N/A Dec isio n No.: N/A Registration No.: N/A Petition No.: N / A Regulatory Action: N/ A Risk Assessment Typ e: N/ A Case No.: N / A TXR No.: 0056447 · CAS No.: N/A MRID No. : N / A 40 CFR: N/A FROM:

# Juli**eVanAlst ine,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 '1 1 HED (7509P) / TO: Marquea D. King, Ph.D., Toxicolo gis t Kelly O ' Rourke, ORE

And Elissa Reaves , Branch Chief Risk Assessment Branch IV (RABIV) HED (7509 P) J ose Gayoso Risk Management and Imp lementation Branch II P esticide Re-Evaluation Division (7508P) MEETING ATTENDEES: HASPOC Members : Anna Lowit, Elissa Reaves, Elizabeth Mendez , Jeff Evans , Jess Rowland , J ohn Kough, Jonathan Chen, Michael Metzger, P.V. Shah, Ray Kent Page 1 of7Presenters: Marquea King, Kelly O'Rourke Other Attendees: Scott Miller, Ed Scollon, Chri stine Olinger, Jo se Gayoso, Kristin Rury, Julie Van Alstine I. PURPOSE OF MEETING At the time of initial registration, the toxicology data base for piperalin was comp lete for a nonfood use chemical. However, in accordance with the 2007 revised toxico logy data requirements, a prenatal rabbit develo p mental toxicity study, a rat reproducti on study, a neurotoxicity battery and an immunotoxicity study are now requi red for non-food use che micals. In 2009, the Risk Assessment Branch IV (RABIV) of the Hea lth E ffects Division (HED) prepared a scoping document for an upcoming Registration Review of piperalin which identified that a 28-day inhalation tox ic ity study was requ ired in addition to the studies listed above. In 201 0, the Agency issued a Data Call-In (DCI) for th ese studies
. The Registrant submitted the following responses to the D CI: 1) a wai ve r based on lo w volume/mino r use prov i sio n in 2010 and 2) a waiver based on scientific ra tionale in 2012 (MRID No. 48825501). The 2012 waiver requ est included a DEREK SAR an alysis, and whil e the Agency supports the use of such t oo l s, the HASPOC d id not put emph asis on the DEREK SAR analysis in its weight of t he evidence (WOE) approach. On August 30, 2012, HED' s H azard and Scien ce Policy Council (HASPOC) met to discuss the Registrant 's waiver reques ts for the s tudies lis ted above. II
. SUMMARY OF PREVIO US RI SK ASSESSMENT & USE PROFILE Piperalin (3

- [ (2RS)-2-methylpiperidino]propy l 3 ,4

- dichlorobenzoate) is the active ingredient in a sing le EPA reg i stered end-use product, Pipron L.C
. (Reg i stration Number 67690

- 1 ). Pipron L.C
. contains 84.4% piperalin and is formula ted as a liquid / soluble conc entrate. It i s appl ie d as a foliar sp ray , most commo n ly using a high-vo lume , high

-pressure sprayer. It is only registered for use in commercial greenhouses and similar enclosed st ru ctures with nonporous coverings on o rnamen tal plants, incl udin g u ses 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 p ip era lin and s ince the uses are limited to greenho u ses, residues in drinking water are not anticipated. The labe l does not spec ify an app li cation in terval or maximum number of applications per crop; therefore, the expo s ure duration is assumed to range from sho rt
- to intermediate- term for both the dermal and inhalation routes . P iperali n has a low acute tox ici ty profile by oral , d ermal, and inhalation routes of exposure (Category III or IV). It is no t a sk in sensiti zer but was origi n all y cl assified as a Tox icity Category I for skin irri tation in New Zeal and rabbits (similar effects we re found in the 21-day dermal toxicity study of edema, erythema, and ep i dermal dehydration). Sub sequ ently, its Tox i city Category for skin irritation was reclassified to Toxicity Category II a n d then to Toxici ty Category II I. T h ere are no subchronic and chronic oral toxicity or inhalation studies avai l ab le for piperalin. In a subchroni c dermal rabbit toxicity study no systemic tox icity was observed at 450 mg/kg/day, the hi ghest dose tes ted (HDT)
. A rat developmental toxici t y study showed no evi dence of prenatal developmental toxicity or fetal suscep tibility at maternall y toxic doses. Avail ab le mutagenicity test s indicate that piperalin is not mutagenic. Toxicity p oints of departure (PODs) were not se le cted for the 1994 risk assessment. The HED asses sment for the Page 2 of7RED concluded that a quantitati ve exposure assessment was not required for p ipera lin s ince the toxico l ogy criteria were not triggered (i.e., the acute dermal tox icity is classified as Toxicity Category IV, the acute inhalation toxicity is classified as Tox icity Category I II , and n o systemic toxicity was o b served in the dermal tox icity study at the HDT). A quantitati ve occupational exposure assessment has not been conducted for piperalin. The Agency determined in August 1994 that a quantitative assessment of occupational handler and post-app li cation exposure would not be performed since the tox ico logical endpoints do not meet the triggers for the exposure, b ut would be mit i gated by using appropriate label precautions for inhal ation and dermal protection for applicators and mixers/loaders (D368328). As part of Reg i strati on Review, an updated occupa t ional risk assessment will be completed. Preliminary dermal margins of exposure (MOEs) for handlers range from 1,800 to 1 5,000 w ith baseline attire (i .e . , no additional PPE) and preliminary inhalati on MOEs r ange from 2,700 to 270,000 without a respirator. The current labe l requ ires g loves for handlers. For post
- app li cation exposure scenarios, prelimina ry 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 l abel does no t indicate an app li cation interval or maximum number of applications; t herefore, the exposure duration is assumed to range from s h ort- to intermediate

- term for both the dermal and inhalation routes. III. SUMMARY OF WA IVER REQUEST Exponent, on behalf of SePRO (the registrant), submitted a toxicity wai ver 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 mil dew. The registrant indicated that t he 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 fo ll owing rationale for waiving the subchronic inhalation study (MRID 4882550 1) : 1. "The existing data on piperalin and QSAR analysis indicate that the conduct of a 28

- or 90-day repeated dose inhalation study would n ot fu lfill any data need that would be reasonably predicted to impact the existing risk assessment." 2. "The ri sk assessment perfo rmed by SePRO [
.. .]demonstrates a conservative approach based upon the available product-spec ific data that result in acceptable MOE's
. '' 3
. "[SePRO's risk] assessment indicates that a repeated dose inhalati on study i s not warranted based on piperalin's very low potential for human tox icity as demonstrated by its history of safe use, experimenta l testing, SAR and QSAR analysis, and most importantly, an established risk assessment that provides a conservati ve MOE." 4
. "[
. .. ] Piperal in has experimentally demons t rated low toxicity via acute inhalation, and although technicall y an EPA Tox icity Inhalation Category III substance, piperalin could arguably be considered to be long to EPA T oxic ity 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 4882550 1): 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 th e exis t ing risk assessment or MOE." 3. "Based on the available toxico logi cal 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 re sources necessary) to conduct a developmental toxicity study in rabbits is not justified because the existing ris k 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
. Addition al 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 fo r waiv ing the two-gene ration reproductive toxicity study (MRID 48825501): 1. " The availa ble t oxicity 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 relati ve binding affinity ofpiperalin to the estrogen receptor (ERBA) indicates that piperalin has no binding affinity to the estrogen recep tor . "

Page 4 of73. "The results ofOECD Too lbox QSAR modeling for the reproductive study indicate that the existing risk assessmen t and resulting MOEs would not be significantly altered if the reproductive tox icity 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. Thi s 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 screenin g batte ry (MRID 48825501): I
. ''Based on results observed in the acute toxicity and rat developmental toxicity studies, EPA has determined that a Neuroto xicity Screening Battery is appropriate for piperalin; however the effec ts 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 toxic ity 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 th at is incapab le of vomiting
. The symptoms of excessive salivation were noted after th e 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 likewi se attributable to the general toxicity of piperalin." 4
. "Effects potentially interpre ted as neurotoxic were only observed in studies where the dose approached or surpassed the maximum tolerated dose. Therefore any NOEL derived from the reques ted neurotoxicity study wou ld be attrib utable 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 no t alter the current MOEs." Page 5 of7The HASPOC concurred with the Registrant's rational for granting a waiver for the neurotoxicity battery. 5 . I mmunotoxicity Study (GLN 870.7800) Exponent provided the fo ll owing 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 (patho logy 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 availab le 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 NOAE L 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 analys i s 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 experimenta l 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 analys i s is end of2012. 

### In the interim, HED recommends that irnrnunotoxicity studies continue to be required for registration and registration review chemica l s.

Page 6 of7IV. HA S P OC RECOMMENDATIONS The HASPOC , based on the current us e pattern, h as g ranted waivers for the fo llowing studies with piperalin: • a subchronic inhalation tox i c ity study; • a rabbit developmental toxicity st ud y; • a two
- ge ne ration rep r oduction toxicity study; and • acute and subchronic neuro toxicity studies. The HASPOC did not grant a waiver for the immunotoxicity study which is required at this time. The 2 012 waiver requ est included a D EREK SAR analy sis , and while t h e Agency s upports the u se of such tools , t h e HASPOC did not put emphasis on the D ERE K SAR analysis in its weight of the ev idence app roach.

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