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OFFICE OF CHEMICAL SAFETY

AND POLLUTION PREVENTION

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460

May 3, 2016

PC Code: 128993

MEMORANDUM DP Barcodes: 432534

SUBJECT: Cyproconazole: Response to Comments on the EFED Problem Formulation for 

Registration Review

FROM: Elyssa Arnold, Risk Assessment Process Leader

Environmental Risk Branch 2

Environmental Fate and Effects Division (7507P)

THROUGH: Donna Judkins, Biologist

Brian Anderson, Branch Chief

Environmental Risk Branch 2

Environmental Fate and Effects Division (7507P)

TO: Miguel Zavala, Chemical Review Manager

Tracy Perry, Team Leader

Kelly Sherman, Branch Chief

Risk Management Implementation Branch 3

Pesticide Re-evaluation Division (7508P)

The Environmental Fate and Effects Division (EFED) reviewed comments from the technical registrant, 

Syngenta, and from the Physician’s Committee for Responsible Medicine (PCRM) on the “EFED and 

AD Registration Review Problem Formulation for Cyproconazole” (DP429082, Docket ID EPA-HQOPP-2015-0462). The purpose of this memorandum is to respond to these comments. The comments are 

briefly paraphrased below and followed by a response from EFED.

Comments from Syngenta 

1. Conclusions from Previous Risk Assessments: EPA conclusion of acute and chronic LOC 

exceedances for small birds eating short grass is very conservative. The low caloric and nutritive 

value of short grass makes it unlikely for small birds to rely on it as their sole dietary source. The 

unlikely occurrence of small birds feeding exclusively on short grass is specifically highlighted in 

the US EPA T-REX v1.5.1 Manual Section 4.1.

Estimates of acute and chronic exposure for avian species associated with the use of cyproconazole 

can be refined. For example, US EPA (2012) previously used a foliar dissipation half-life (DT50) of 

11.9 days in a Memorandum entitled (“Analysis of Cyproconazole Avian Risk Assessment for 

Proposed Turf Use” [PC Code 128993; DP Barcode 403335; Date October 25, 2012). Syngenta 

conceptually agrees with the aforementioned approach for refining the foliar DT50 value of 
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cyproconazole and believes that the available weight-of-evidence supports use of a DT50 value of 

11.9 days in future cyproconazole ecological risk assessments for terrestrial animals.

EFED Response: The cited section of the Problem Formulation reiterates conclusions presented in 

previous assessments. A new assessment will be conducted for Registration Review. Refinements 

identified in the cited 2012 memo will be used unless new information suggests that they are no 

longer applicable.

2. Chronic Daphnid Endpoint: Syngenta believes that the endpoint for MRID No. 43187701

(NOAEC=0.29 ppm) should be used for risk assessment rather than the endpoint for MRID No. 

47036201 (NOAEC=0.019 ppm). Syngenta is aware of three Daphnia chronic studies (MRID No. 

43187701 and MRID No. 47036201; as well as Jenkins et al. 1989, which can be provided to the 

EPA upon request). The NOAEC for MRID No. 47036201 of 0.019 mg ai/L is >15-fold lower than 

the endpoint for MRID No. 43187701 and >3-fold lower than the endpoint for Jenkins et al. (1989). 

Calculations from the US ECOSAR modeling tool provide additional evidence that the endpoint 

reported in MRID No. 43187701 more accurately represents the threshold of biological effect.

EFED Response: EFED’s policy is to use the lowest endpoint from studies classified as acceptable 

or supplemental/quantitative for each taxon. 

3. Chronic Mysid ACR Calculation: As previously commented, Syngenta believes that the collective 

weight of evidence provides strong support for use of data from MRID No. 43187701 in ecological 

risk assessments of cyproconazole. Therefore, the ACR for mysid shrimp should be calculated using 

the NOAEC from that study.

EFED Response: The EFED Problem Formulation recommends that a chronic mysid toxicity study 

be requested as part of Registration Review to remove the uncertainty inherent in the use of an ACR.

4. Avian Reproduction MRID: Syngenta wants to bring a typo to the attention of the Agency 

concerning data evaluation for MRID No. 47340801 to avoid potential confusion in the future. In the 

Memorandum entitled “Transmittal of the Data Evaluation Record for MRID 43287701” dated 

January 23, 2014; PC Code: 128993; DP Barcode: 47739, the MRID No. is incorrectly stated. As 

noted in the Memorandum, this specific DER pertains to the Frey et al. (2007) study, which is MRID 

No. 47340801. The full DER report has the correct MRID listed and the error appears limited to only 

the Memorandum transmittal.

EFED Response: EFED acknowledges that the MRID is incorrect in the referenced DER transmittal 

memo.

5. Avian Reproduction Endpoint: Syngenta believes that the cyproconazole NOAEC for mallard 

duck is 16.4 mg/kg-diet, as reported in the original study report (MRID No. 47340801). This 

conclusion is based on biological relevance and is further supported by MCnest modeling. The 

cyproconazole problem formulation describes the chronic avian LOAEC based on live 

embryos/viable embryos (LE/VE) as 10.9 mg/kg-diet due to a 2.4% reduction. While EPA’s 

subsequent statistical analysis in the data evaluation record (US EPA 2014) concluded that this effect 

was significant, Syngenta believes that it is not biologically relevant, rather it is due to a statistical 

manifestation rather than dose dependent effect associated with exposure to cyproconazole. In 

addition, Syngenta notes that such a small effect would not culminate in a population-level effect as 

demonstrated by MCnest model simulations.
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EFED Response: EFED continues to believe that the conclusions presented in the DER for MRID 

47340801 are valid. EFED expects to continue to use the MCnest model for assessment of risks to 

birds during Registration Review for cyproconazole and will carefully evaluate the results from the 

modeling.

6. Endangered Species Assessment: Simple deterministic screening level assessments, which are 

highly conservative by design, can facilitate rapid initial screening/exclusion criteria for a pesticide 

active ingredients’ potential to adversely affect listed (threatened or endangered species) and nonlisted species. If a pesticide exposure results in a risk quotient (RQ) below a predefined level of 

concern (LOC), which are additionally conservative with respect to endangered (listed) species 

assessments (e.g. 5x to 10x lower than already conservative non-listed LOCs), then the potential 

risks are considered de minimis and unlikely to jeopardize the existence of a listed species. If, 

however, an RQ is generated that exceeds the highly conservative LOC, additional higher-tier 

scientific information must be incorporated in order to refine the risk assessment and more 

accurately and realistically reflect potential exposures and effects, and reducing potential type I 

errors (falsely rejecting the null hypothesis of de minimus risk). This information includes 

community-level effects data, environmental fate and exposure data, monitoring data, geospatial 

location and proximity data, species biology data, and a variety of refined modelling and assessment 

analysis, and other pertinent species-specific and pesticide-specific data. 

EFED Response: EFED’s methodology for assessing risk to listed species is under development, as 

described in Section 8.4 of the Problem Formulation.

7. Pollinator Studies: Syngenta notes that exposure of terrestrial invertebrates to pesticides alone does 

not equate to impact and highlights that ecological risk assessment should both consider and 

compare exposure and hazard (i.e. effects) profiles in order to evaluate potential risk.

EFED Response: EFED concurs that consideration of both exposure and hazard profiles is 

necessary for assessment of risk.

Comments from the Physician’s Committee for Responsible Medicine

1. Acute Passerine Toxicity Testing: Acute toxicity testing with a passerine species is a data gap for 

seven conazole chemicals including cyproconazole. As such, PCRM is requesting that the Agency 

consider selecting representative conazoles with which to generate test data, thereby reducing the 

number of overall tests conducted. Additionally, PCRM recommends that the OECD Test Guideline 

223, Avian Acute Oral Toxicity Test be used as the protocol instead of the EPA Guideline 850.2100 

in an effort to potentially reduce the number of animals tested. 

EFED Response: EFED appreciates the comment from PCRM. PCRM’s comment was considered 

by EFED’s Terrestrial Technical Team (TTT). In regard to PCRM’s comment about selecting 

representative chemical(s)/data to bridge to untested chemicals, EFED considers such an approach 

when it is appropriate. Based on the limited dataset for the conazoles, results for acute oral toxicity 

testing with the bobwhite quail vary widely despite similar chemical structures (acute LD50s range 

from 150 to 2,825 mg/kg). Therefore, selection of appropriate chemical(s) to represent the 

conazoles group as surrogates is difficult and the test is unlikely to capture the broad range of results 

possible for the conazoles group. Additionally, the known challenges in conducting acute oral 

testing with passerines (i.e., regurgitation), increase the uncertainty in results and decrease the 
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confidence in successfully implementing a bridging approach to use data from one chemical to 

another. As such, EFED does not recommend using this approach to generate acute oral toxicity data 

with passerines. With regard to the use of OECD TG 223 as the test protocol, current EFED 

guidance states that species other than bobwhite quail may be used if low background mortality in 

the laboratory is demonstrated (such that the assumed incidence of random mortality does not depart 

from the test animal TG 223 background mortality used to validate the protocol for other birds) and 

regurgitation during the study is not observed (see guidance document for complete description of 

terms and criteria) [1].

 [1] Guidance for Classifying Studies Conducted Using the OECD Test Guideline 223 (TG223) (Acute Avian Oral Sequential 

Dose Study). Memorandum from D. Brady, November 9, 2011. Available at: https://www.epa.gov/pesticide-science-andassessing-pesticide-risks/guidance-classifying-studies-conducted-using-oecd [accessed April 25, 2016].