### MEMORANDUM

March 13, 2014 

### OFFICE OF CHEMICAL SAFETY AND POLLUTION PREVENTION

SUBJECT: Piperalin: Summary of Hazard and Science Policy Council (HASPOC) Meeting of January 30, 2014: Recommendations on a Registrant Submitted Waiver Request on Immunotoxicity Study for Registration Review.

PC Code: 097003 Decision No.: N/A Petition No.: N/A Risk Assessment Type: N/ A TXR No.: 0056881 MRID No.: N/A



### FROM: Marquea King, Toxicologist Kelly O'Rourke, ORE Risk Assessment Branch IV Health Effects Division (7509P) DP Barcode: D402337 Registration No.: N/A Regulatory Action: N/A Case No.: N/A CASNo.: N/A 40CFR: N/A



### THROUGH: Kristin Rury, Executive Secretary

## ~ Jess Rowland, Co-Chair 

# qLg

Anna Lowit, Co-Chair 

# 7 j/ HASPOC 

# l.7f

Health Effects Division (7509P)



### TO: Jose Gayoso, CRM Risk Management and Implementation Branch II Pesticide Re-Evaluation Division (7508P)

MEETING ATTENDEES:

HASPOC Members: Anna Lowit, Elissa Reaves, JeffDawson, Jeff Evans, Jess Rowland, John Kough, Jonathan Leshin, Kristin Rury, Monique Perron, P.V. Shah, Ray Kent, Uma Habiba

Presenters:

Other Attendees: Marquea King, Kelly O'Rourke

Charles Smith, Christine Olinger, Christopher Schlosser, Jennifer Tyler, Myron Ottley, Tom Bloem, William Irwin

Page 1 of5Page 2 of 5 I. PURPOSE OF MEETING

In 2009, the Risk Assessment Branch IV (RAB IV) of the Health E ffects Division (HED) prepared a Registration Review scoping documen t evaluating the adequacy of the piperalin toxicity and exposure databases. An immunotoxicity study was requi red for piperalin as part of Registration Review, and in 2010, the Agency issu ed a Data Call-In (DCI) for this study. In 2010, 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 . In 2012, the registrant submitted a waiver request for the immunotoxi city study as required in the 2007 Part 158 toxicology data requirements. Th e registrant indicated that th e minor use/low volume exemption request should be considered in combination with the scientific rationale for the waiver of the immunotoxicity (MRID No. 48825501).

The HASPOC, during an August 30, 2012 meeting gr anted waivers for th e following studies: a subchronic inhalation toxicity study, a rabbit developmental t oxicity study, a two-generation reproduction toxicity study, and acute and subchroni c neurotoxicity studies. At that time, OPP was conducting an independent retrospective anal ysis of more than 120 immunotoxicity studies submitted to Agency and final findings of OPP’s retr ospective analysis were not available, and in the interim, HED recommended that immunotoxicity studies c ontinue to be required during registration and Registration Review. Thus HASPOC did not grant a waiver for the immunotoxicity study at that time; however, sinc e then OPP has completed its retrospective analysis and is now considering a waiver for the immunotoxicity study for piperalin.

II. SUMMARY OF PREVIOUS RI SK ASSESSMENT & USE PROFILE

Piperalin (3-[(2 RS )-2-methylpiperidino]propyl 3,4-dichlor obenzoate) is a fungicide active ingredient formulated into a si ngle registered liquid end-use pr oduct, Pipron L.C. (Registration Number 67690-1. It is applied as a foliar sp ray, most commonly usi ng a high-volume, highpressure sprayer. It is only registered for use in commercial greenhouses and similarly enclosed structures with nonporous coverings on ornamental plants, including roses. There are no food uses for piperalin and since the uses are limite d to greenhouses, residues in drinking water are not anticipated. The label does not specify an application interval or maximum number of applications per crop; therefor e, the exposure duration is assu med to range from short- to intermediate-term for both the dermal and inhalati on routes. The current label requires gloves for occupational handlers.

Piperalin has low acute toxicity via the oral, dermal, and inhalati on routes of exposure (Category III or IV). It is not a skin sensitizer, In a subchronic dermal rabbit toxicity study, no systemic toxicity was observed up to 450 mg /kg/day, the highest dose tested (HDT). A rat developmental toxicity study showed no evidence of prenatal deve lopmental toxicity or fetal susceptibility at maternally toxic doses. Available mutagenicity te sts indicate that piperalin is not mutagenic. Chronic oral toxicity and carcinoge nicity studies are not required for piperalin because there are no current or proposed food uses. Dietary risk assessment not requ ired because piperalin has no registered food uses. A drinking water exposur e assessment is not re quired based on label restrictions that limit uses to confined encl osures. Based on the registered uses and labelPage 3 of 5 restrictions limiting the applic ation area, there are no reside ntial exposures for piperalin. Occupational exposure was mitigated by using appr opriate label precautio ns for inhalation and dermal protection for applicators and mixers/lo aders. However, as noted in the scoping document, an updated occupational risk assessment will be completed during Registration Review (B. Daiss, D368328, 08/25/2009). Prelimin ary dermal margins of exposure (MOEs) for occupational handlers range from 1,800 to 15,000 with baseline attire (i.e ., no additional PPE) and preliminary inhalation MOEs range from2,700 to 270,000 without a respirator. For postapplication exposure scenarios, preliminary de rmal MOEs range from 670 to 14,000 on the day of application using the current label restricted-entry interval (REI) of 12 hours. The point of departure (PODs) used to estimate the dermal MOEs were based on the NOAEL (and HDT) of 450 mg/kg/day from the dermal toxicity st udy (MRID No. 40509301). For inhalation, the MOEs were estimated using the NOAEL of 20 mg/kg/day from the ra t developmental study, based on maternal effects observed at the LOAEL of 100 mg/kg/day (MRI D No. 40584901) .

III. SUMMARY OF WAIVER REQUEST

a. Registrant’s Rationale

The Registrant provided the following scientific rationale for waiving th e immunotoxicity study:

1. “The available toxicity data for piperalin indicate that piperalin is highly unlikely to affect immune organs or related hema tological parameters (pathology in acute toxicity tests, maternal gross internal obs ervations in the rat developmental toxicity study, fetal visceral examinations in the ra t developmental toxicity study, hematology in the dermal repeated dose study in rabbi ts, 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 mu ltifocal 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 immunotoxicit y study] review reveals that guideline immunotoxicity studies that have been c onducted thus far for a wide variety of compounds (over 75 different compounds) elic it general toxicity effects at lower thresholds than immunotoxicological 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 alte r the toxicological e ndpoints used in the risk assessment.” 4. “Based on the available toxicological data base, the oral NOAEL of 20 mg/kg bw/day used in the risk assessment of piperali n is therefore protec tive for immunological effects.”Page 4 of 5 b. Indicators for Potential Immunotoxicity:

Indicators for Potential Immunotoxicity 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

Toxicity Profile (Target Organs) none

c. Evidence for Immunotoxicity from SAR Chemicals: In considering the need for an immunotoxicity study, the agency will evaluate other pesticides which share the same mode of action (MOA) and/or are in the sa me class. These pesticides can provide important information with respect to poten tial immunotoxic effects. Specifically, if other similar pesticides show immunotoxic ity studies to be more sensitive, an immunotoxicity study may be required, depending on the exposure profile. Piperalin is an unclassified fungicide. According to HED’s Integrated Structure, Toxicology, Endpoints and Properties (ISTEP) data base, there ar e no immunotoxicity studies available for chemicals structurally related to piperalin

IV. STUDY WAIVER REQUESTS

The HASPOC recommends that a waiver be gr anted for an immunotoxicity study for piperalin, based on the following considerations:

 Based on the non-food use, there are no di etary exposure and thus no potential for hazard via the oral route. Additionally, the or al developmental toxicity study in rats did not show any concern fo r potential immunotoxicity.

 No dermal or systemic toxicity was seen in the dermal toxicity study within rabbits; s

 The Agency’s “Retrospective Analys is of the Immunotoxicity Studies” which included 171 studies conducted on 155 chemical s covering a wide variety of pesticide products and chemical classes showed that t he NOAELs established in the immunotoxicity studies did not impact the PODs and toxicity endpoints of concern used for human health risk assessments. Consequently, immunotoxicity was not the most sensitive endpoint in the toxicity data base of pesticide chemicals.Page 5 of 5 V. HASPOC CONCLUSIONS :

The HASPOC, based on all of the available ha zard and exposure information for piperalin, concluded that an immunotoxicity st udy is not required at this time.