UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON
, D

. C. 20460

MEMORANDUM

DATE: 12 March 2014 OFFICE OF CHEMICAL SAFETY AND POLLUT I ON 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 App lic ab le (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, Ri sk Assessor {.) 

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. -. . _ Marquea D. King, Ph.D.,

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### !/:~~ RAB IV, Health Effec t s Div1s1on (7509P) ·**~**

THROUGH : Elissa Reaves, Ph.D., Branch Chief

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, Health Effects Di vision (7509P)

TO: Jose Gayoso
, Chemical Review Manager Kevin Costello, Branch Chief RMIB2, Pesticide Re-Evaluation Division (7508P)

Attached is the Hea lth 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 u ses. A drinking water exposure assessment is not required based on l abe l 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 i s a liquid/sol uble concentrate formulation which contains 84.4% piperalin. The label specifies application rates of 0.25 to 0.5 pounds active in gredie nt per 100 gallons of
water. Applications are made b y high volume ground s pray methods to the foliage of ornamentals; the intervals and maximum number of applications are not spec i fied on th e labe l. All hand le r s must wear chemical-resistant g lo ves and t he restric ted entry interval (REI) i s 12 hours.



### Hazard Identification and Dose Response Assessment

The toxicology data base is lim ited but sufficient for this non

- food use chemical. Acute toxicity studi e s are available and range from tox icity 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 th e LOEL was 100 mg/kg/day

, ba sed on exce ssive sa liva t ion and decreases in body weight and food consumption. For developmental toxicity

. , th e NOEL was 1 00 mg/kg/day and the lowes t 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 reproduct ion s tudy 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 u p to 1000 ppm, no adverse effects

were seen in th e 

### Fo and F t generations. There was no evidence for mutagenicity (California EPA, 2003).

The Hazard and Science Policy Council (HASPOC) recently considered the lim ited use pattern and toxicity database to determine if additional tox icity studies were required for piperalin. Based on t he weight of the evidence, the HASPOC determined that additional toxic ity stu dies

were not warranted and gran t ed 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 us es. Based

on the non-food use, there are no d ietary exposure and thus no potential for hazard via the oral
route. The rabbit developmental toxicity study is not req ui red since there was no evidence for developmental toxici ty study in ra ts

. The reproduction study is not required since the use pattern does not indicate the potential for significant human exposure in terms of f requency, magnitude

or duration of exposure. The immunotoxicity st udy is not required since th e Agency's retrospective analysis, which included 171 studies conducted on 15 5 c hemical s 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 toxici ty endpoints of

concern used for human health risk assessments (TXR Nos. 0056447 and 0056881).
Page 2 of6Page 3 of 6

U pdated 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, s o 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 reg istered 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 no t 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

m argins of e xposure (MOEs) that are not of concern . Dermal MOEs ranged from 670 to 15,000 ( level of concern is generally an MOE of ≤ 100, refl ective 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, t he 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

- ap plication 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 inhal ation 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

- applica tion 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 as sessment 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 s ubject 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 simi lar 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 1 1 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, o r 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 t he 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 f or 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, t he 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 do cument 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 d ietary risk assessment is not required because piperalin has no registered food uses and drinking water exposure is not anticipated based o n 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 D 368328 . August 25, 2009.

Dang, W. 1994. Occupational and Residential Exposure Assessment and Recommendations for the Reregistration Eligibility Document for Piperal in. 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

. T XR 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