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 

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I. PURPOSE OF MEETING

In 2009, the Risk Assessment Branch IV (RABIV) of the Health Effects Division (HED) 

prepared a Registration Review scoping document evaluating the adequacy of the piperalin 

toxicity and exposure databases. An immunotoxicity study was required for piperalin as part of 

Registration Review, and in 2010, the Agency issued 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 immunotoxicity study as required in the 2007 Part 158 

toxicology data requirements. The registrant indicated that the 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 granted waivers for the following studies: a 

subchronic inhalation toxicity study, a rabbit developmental toxicity study, a two-generation 

reproduction toxicity study, and acute and subchronic neurotoxicity studies. At that time, OPP 

was conducting an independent retrospective analysis of more than 120 immunotoxicity studies 

submitted to Agency and final findings of OPP’s retrospective analysis were not available, and in 

the interim, HED recommended that immunotoxicity studies continue to be required during 

registration and Registration Review. Thus HASPOC did not grant a waiver for the 

immunotoxicity study at that time; however, since then OPP has completed its retrospective 

analysis and is now considering a waiver for the immunotoxicity study for piperalin. 

II. SUMMARY OF PREVIOUS RISK ASSESSMENT & USE PROFILE

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

ingredient formulated into a single registered liquid end-use product, Pipron L.C. (Registration 

Number 67690-1. It is applied as a foliar spray, most commonly using 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 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. The current label requires gloves for 

occupational handlers. 

Piperalin has low acute toxicity via the oral, dermal, and inhalation 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 developmental toxicity or fetal susceptibility at 

maternally toxic doses. Available mutagenicity tests indicate that piperalin is not mutagenic. 

Chronic oral toxicity and carcinogenicity studies are not required for piperalin because there are 

no current or proposed food uses. Dietary risk assessment not required because piperalin has no 

registered food uses. A drinking water exposure assessment is not required based on label 

restrictions that limit uses to confined enclosures. Based on the registered uses and label 
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restrictions limiting the application area, there are no residential exposures for piperalin. 

Occupational exposure was mitigated by using appropriate label precautions for inhalation and 

dermal protection for applicators and mixers/loaders. However, as noted in the scoping 

document, an updated occupational risk assessment will be completed during Registration 

Review (B. Daiss, D368328, 08/25/2009). Preliminary 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 from 2,700 to 270,000 without a respirator. For postapplication 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. 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 study (MRID No. 40509301). For inhalation, the MOEs 

were estimated using the NOAEL of 20 mg/kg/day from the rat developmental study, based on 

maternal effects observed at the LOAEL of 100 mg/kg/day (MRID No. 40584901) . 

III. SUMMARY OF WAIVER REQUEST 

a. Registrant’s Rationale

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

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 

immunotoxicity 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 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 alter the toxicological endpoints used in the 

risk assessment.” 

4. “Based on the available toxicological database, the oral NOAEL of 20 mg/kg bw/day 

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

effects.” 
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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 same class. These pesticides can provide 

important information with respect to potential immunotoxic effects. Specifically, if 

other similar pesticides show immunotoxicity 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 are no immunotoxicity studies available for 

chemicals structurally related to piperalin 

IV. STUDY WAIVER REQUESTS

The HASPOC recommends that a waiver be granted for an immunotoxicity study for piperalin, 

based on the following considerations: 

 Based on the non-food use, there are no dietary exposure and thus no potential for 

hazard via the oral route. Additionally, the oral developmental toxicity study in rats 

did not show any concern for potential immunotoxicity. 

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

 The Agency’s “Retrospective Analysis of the Immunotoxicity Studies” which 

included 171 studies conducted on 155 chemicals covering a wide variety of pesticide 

products and chemical classes showed that the 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.
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V. HASPOC CONCLUSIONS: 

The HASPOC, based on all of the available hazard and exposure information for piperalin, 

concluded that an immunotoxicity study is not required at this time.