UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

DATE: 12 March 2014 

OFFICE OF CHEMICAL SAFETY 

AND POLLUTION PREVENTION 

SUBJECT: Piperalin: Qualitative Preliminary Risk Assessment for Registration Review 

PC Code: 097003 

Decision No.: 473716 

DP Barcode: 408105 

Registration No.: N/A 

Petition No.: Not Applicable (N/ A) 

Risk Assessment Type: Qualitative 

TXRNo.:N/A 

Regulatory Action: Registration Review 

Case No.: NIA 

MRID No.: N/A 

CAS No.: 3478-94-2 

40 CFR: N/A I 

FROM: Kelly O'Rourke, Risk Assessor {.) j,{.: wli..-.._ Marquea D. King, Ph.D., ~o~i.cologi , · !/:~~ RAB IV, Health Effects Div1s1on (7509P) · ~ 

THROUGH: Elissa Reaves, Ph.D., Branch Chief f&.._;_~~----· RAB IV, Health Effects Division (7509P) 

TO: Jose Gayoso, Chemical Review Manager 

Kevin Costello, Branch Chief 

RMIB2, Pesticide Re-Evaluation Division (7508P) 

Attached is the Health Effect Division's (RED's) qualitative human health risk assessment for 

piperalin to support registration review. A screening level occupational assessment did not 

identify potential risks of concern via dermal or inhalation routes of exposure; the margins of 

exposure for dermal and inhalation routes exceeded the Agency's level of concern. A dietary 

risk assessment is not required because piperalin has no registered food uses. A drinking water 

exposure assessment is not required based on label specifications that limit use to commercial 

greenhouses. Based on the registered uses, there are no residential exposures for piperalin; 

therefore, a residential exposure assessment is not applicable. 

Page 1 of6 
Introduction 

Piperalin is registered as a fungicide to control powdery mildew on ornamental plants grown in 

commercial greenhouses. Currently, there is only one active registered product: Pipron (EPA 

Reg. #67690-1 ). It is a liquid/soluble concentrate formulation which contains 84.4% piperalin. 

The label specifies application rates of 0.25 to 0.5 pounds active ingredient per 100 gallons of 

water. Applications are made by high volume ground spray methods to the foliage of 

ornamentals; the intervals and maximum number of applications are not specified on the label. 

All handlers must wear chemical-resistant gloves and the restricted entry interval (REI) is 12 

hours. 

Hazard Identification and Dose Response Assessment 

The toxicology data base is limited but sufficient for this non-food use chemical. Acute toxicity 

studies are available and range from toxicity category III or IV. A subchronic dermal toxicity 

study in rabbits resulted in no dermal or systemic toxicity up to 450 mg/kg/day, the highest dose 

tested (HDT). In a pre-natal developmental rat study, the maternal no observed effect level 

(NOEL) was 20 mg/kg/day and the LOEL was 100 mg/kg/day, based on excessive salivation and 

decreases in body weight and food consumption. For developmental toxicity., the NOEL was 

100 mg/kg/day and the lowest observed effect level (LOEL) was 500 mg/kg/day based on 

decreased fetal body weight. 

The California Department of Pesticide Regulations (CDPR) reported the results of a chronic 

toxicity study in rats, a chronic toxicity study in dogs and a reproduction study in rats. Although 

these studies were judged to be unacceptable by that Agency, no adverse effects were seen when 

piperalin was administered in the diet at doses of 0, 500, 1 000 or 2000 ppm to male and female 

rats and dogs. In the reproduction study, when administered up to 1000 ppm, no adverse effects 

were seen in the Fo and F t generations. There was no evidence for mutagenicity (California EPA, 

2003). 

The Hazard and Science Policy Council (HASPOC) recently considered the limited use pattern 

and toxicity database to determine if additional toxicity studies were required for piperalin. 

Based on the weight of the evidence, the HASPOC determined that additional toxicity studies 

were not warranted and granted waivers for the subchronic inhalation, rabbit developmental, 

two-generation reproduction, acute and subchronic neurotoxicity and immunotoxicity studies. 

The HASPOC based their decision on the following considerations: chronic toxicity and 

carcinogenicity studies are not required since there are no current or proposed food uses. Based 

on the non-food use, there are no dietary exposure and thus no potential for hazard via the oral 

route. The rabbit developmental toxicity study is not required since there was no evidence for 

developmental toxicity study in rats. The reproduction study is not required since the use pattern 

does not indicate the potential for significant human exposure in terms of frequency, magnitude 

or duration of exposure. The immunotoxicity study is not required since the Agency's 

retrospective analysis, 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 points of departure (PODs) and toxicity endpoints of 

concern used for human health risk assessments (TXR Nos. 0056447 and 0056881). 

Page 2 of6 
Page 3 of 6

Updated incident data indicate that the risk posed to human health by piperalin is minimal (one 

case reported, with a symptom of itchy skin) and there does not appear to be a concern at this 

time that would warrant further investigation (email communication from S. Recore).

Dietary Exposures

There are no food uses for piperalin, so exposure from consumption of food is not assessed. 

Based on the use pattern, dietary exposure from food and drinking water is unlikely to occur. 

Therefore, no dietary assessments are needed. 

Occupational and Residential Exposures 

Based on the registered uses, there are no residential exposures for piperalin; therefore, a 

residential exposure assessment is not applicable.

Although exposure may occur during occupational handling and post-application activities, a 

quantitative risk assessment was not conducted since screening level assessments in support of 

the HASPOC determination indicated no risk via dermal and inhalation routes of exposure. The

conservative use of a dermal point of departure (POD) of 450 mg/kg/day (no lowest observed 

adverse effect level [LOAEL] established) from the dermal toxicity study resulted in dermal 

margins of exposure (MOEs) that are not of concern. Dermal MOEs ranged from 670 to 15,000

(level of concern is generally an MOE of ≤ 100, reflective of uncertainty factors for interspecies 

extrapolation [10x] and intraspecies variability [10x]). For inhalation, an oral POD of 20 

mg/kg/day from the rat developmental study resulted in MOEs that ranged from 2,700 to 

270,000 and are not of concern.

Furthermore, the current label requires all handlers to wear chemical-resistant gloves and 

specifies a restricted entry interval of 12 hours; which is considered to be adequately protective.

Volatilization

Based on the Agency's current practices, a quantitative post-application inhalation exposure 

assessment was not performed for piperalin at this time primarily because of the low acute 

inhalation toxicity (Toxicity Category III) and low vapor pressure (< 1.0 x 10-7 mmHg). 

Although a quantitative post-application inhalation exposure assessment was not performed, a 

screening-level inhalation exposure assessment was performed for handlers. This exposure 

scenario is representative of a worse case inhalation exposure and should be considered 

protective of most post-application inhalation exposure scenarios.

Spray Drift

The registered use for piperalin is limited to ornamentals in greenhouses; this use pattern is not 

likely to result in spray drift.
Page 4 of 6

Endocrine Disruptor Screening Program

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse

outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental,

reproductive, and general or systemic toxicity. These studies include endpoints which may be

susceptible to endocrine influence, including effects on endocrine target organ histopathology,

organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss,

and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and

chronic studies that assess growth, developmental and reproductive effects in different

taxonomic groups. As part of its preliminary risk assessment for registration review of piperalin, 

EPA reviewed the available data and selected the most sensitive endpoints for relevant risk 

assessment scenarios from the existing hazard database. However, as required by FFDCA 

section 408(p), piperalin is subject to the endocrine screening part of the Endocrine Disruptor 

Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide

active and other ingredients) may have an effect in humans or wildlife similar to an effect

produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator

may designate.” The EDSP employs a two-tiered approach to making the statutorily required

determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a

chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal

systems. Chemicals that go through Tier 1 screening and are found to have the potential to

interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA

will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2

testing is designed to identify any adverse endocrine-related effects caused by the substance, and

establish a dose-response relationship between the dose and the E, A, or T effect. Under FFDCA 

section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and 

February 2010, EPA issued test orders/data call-ins for the first group of 67 chemicals, which 

contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals 

identified for EDSP screening was published on June 14, 2013

(http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074) and 

includes some pesticides scheduled for registration review and chemicals found in water. Neither 

of these lists should be construed as a list of known or likely endocrine disruptors. For further 

information on the status of the EDSP, the policies and procedures, the lists of chemicals, future 

lists, the test guidelines and the Tier 1 screening battery, please visit our website

(http://www.epa.gov/endo/).

Data Requirements

None. The studies required as part of the 2009 HED scoping document have been waived (TXR 

Nos. 0056447 and 0056881).
Page 5 of 6

Conclusions

A quantitative risk assessment was not conducted since a screening-level exposure assessment 

did not identify potential risks via dermal or inhalation routes resulting from occupational 

exposure scenarios. The conservative dermal and inhalation MOEs are not of concern. A

dietary risk assessment is not required because piperalin has no registered food uses and 

drinking water exposure is not anticipated based on label specifications that limit use to

commercial greenhouses. Based on the registered uses, there are no residential exposures for 

piperalin; therefore, a residential exposure assessment is not applicable.
Page 6 of 6

References

California EPA. 2003. Summary of Toxicology Data Piperalin. California Environmental 

Protection Agency, Department of Pesticide Regulation, Medical Toxicology Branch. Chemical 

Code # 000488, Tolerance # 50024. June 10, 2003. 

Daiss, R. 2009. Piperalin (PC code 097003). Revised Human Health Risk Scoping Document in 

Support of Registration Review. DP Barcode D368328. August 25, 2009.

Dang, W. 1994. Occupational and Residential Exposure Assessment and Recommendations for 

the Reregistration Eligibility Document for Piperalin. DP Barcode D220596. August 10, 1994.

Hawkins, M. 2009. Updated Review of Piperalin Incident Reports. June 18, 2009.

Recore, S. 2014. Piperalin. Email communication of updated incident analyses. February 12, 

2014.

Rury, K. 2014. 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. TXR No. 0056881

Van Alstine, J. 2012. 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. TXR No. 0056447