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I. INTRODUCTION

This document is the Environmental Protection Agency's (EPA or the Agency) Interim Registration

Review Decision for cyromazine (Case 7439), which is being issued pursuant to 40 CFR sections 155.56

and 155.58. A registration review decision is the Agency's determination of whether a pesticide

meets, or does not meet, the standard for registration in the Federal Insecticide, Fungicide, and

Rodenticide Act (FIFRA). The Agency may issue, when it determines it to be appropriate, an

Interim Registration Review Decision before completing a registration review. Among other

things, the Interim Registration Review Decision may require new risk mitigation measures,

impose interim risk mitigation measures, identify data or information required to complete the

review, and include schedules for submitting the required data, conducting the new risk

assessment and completing the registration review. For further information on cyromazine, 

additional documents can be found in EPA's public docket (EPA-HQ-OPP-2006-0108) at

www.regulations.gov. 

FIFRA, as amended by the Food Quality Protection Act (FQPA) of 1996, mandated the 

continuous review of existing pesticides. All pesticides distributed or sold in the United States 

generally must be registered by the EPA based on scientific data showing that they will not cause 

unreasonable risks to human health or to the environment when used as directed on product 

labeling. The registration review program is intended to make sure that, as the ability to assess and 

reduce risk evolves and as policies and practices change, all registered pesticides continue to meet 

the statutory standard of no unreasonable adverse effects. Changes in science, public policy, and 

pesticide use practices will occur over time. Through the registration review program, the Agency 

periodically re-evaluates pesticides to make sure that as these changes occur, products in the 

marketplace can continue to be used safely. Information on this program is provided at 

www.epa.gove/oppsrrd1/registration review/. 

In 2006, the Agency implemented the registration review program pursuant to FIFRA section

3(g) and will review each registered pesticide every 15 years to determine whether it continues to

meet the FIFRA standard for registration.

Cyromazine is an insect growth regulating triazine insecticide which exerts its effects by inhibiting 

chitin synthesis. Cyromazine is currently registered for use on several crops, ornamentals and 

livestock commodities (including livestock premises) for control of a variety of fly pests, maggots, 

fly larvae, and leaf miners. Cyromazine is formulated as a wettable powder, soluble concentrate and 

granular. It is also registered for use as a feed through for horses and chickens to control fly pests in 

their manure and as a seed treatment for bulb onions for the onion maggots. There are no 

cyromazine products registered for residential use. Cyromazine was first registered as a pesticide in 

1993, and therefore was not subject to reregistration. The following timeline highlights significant 

cyromazine registration review documents and actions that can be found in the public docket under 

EPA-HQ-OPP-2006-0108, which can be accessed through http://www.regulations.gov/.

• March 28, 2007 - The Agency published the Cyromazine Summary Document, dated March 23,

2007 in docket number EPA-HQ-OPP-2006-0108 for a 60-day public comment period. 

The Summary Document included the Agency’s Preliminary Work Plan for Cyromazine, in 

addition to the cyromazine Ecological Risk Assessment Problem Formulation, dated February 20, 
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2007, and the Registration Review Scoping Document for Human Health Assessment, dated March 

21, 2007. The Agency received six comments during the public comment period, which 

were addressed in the Final Work Plan.

• September 7, 2007 - Cyromazine Final Work Plan for Registration Review dated August 21,

2007 posted to the docket. The Cyromazine Final Work Plan confirmed that the Agency 

would conduct a comprehensive human health and ecological risk assessment during the 

Registration Review process, in addition to providing responses to the six comments that 

were received during the public comment period for the Cyromazine Summary Document.

• September 17, 2008 -EPAissued the Generic Data Call-In (DCI) for cyromazine. Data 

requirements included: UV/visible absorption (GLN 830.7050); oyster acute toxicity

(GLN 850.1025); mysid chronic toxicity (GLN 850.1350); and inhalation toxicity (GLN

870.3465).

• March 7, 2013 - The Agency published the Preliminary Ecological Risk Assessment for the 

Registration Review of Cyromazine, dated January 24, 2013 and the Human Health Risk

Assessment for Registration Review, dated January 31, 2013 for a 60-day public comment period.

• May 6, 2013 – One comment was submitted by Syngenta which contained information 

regarding the ecological fate and effects of cyromazine. Syngenta also submitted an acute 

neurotoxicity study (ACN study). 

• July 23, 2014 - The Agency published the Cyromazine Proposed Interim Registration 

Review Decision for a 60-day public comment period, in addition the Environmental Fate 

and Effects Division's Response to Public Comments on the Registration Review Preliminary Risk 

Assessment for Cyromazine, dated March 26, 2014 and the Cyromazine: Human Health Risk 

Assessment for Registration Review, dated February 17, 2014 in the public docket, EPA-HQOPP-2006-0108, which can be accessed through http://www.regulations.gov/

• December 2014 – The Agency is now publishing the Cyromazine Interim 

 Registration Review Decision on regulations.gov under docket number EPA-HQ-

 OPP-2006-0108.

Public Comments

One comment was submitted to the Agency by the Center for Biological Diversity during the 60-day 

public comment period for the Cyromazine Proposed Interim Registration Review Decision. The 

Center for Biological Diversity’s comment addressed the Agency’s responsibilities under the 

Endangered Species Act (ESA). The Center for Biological Diversity’s comment is summarized 

below along with the Agency’s response. The Center for Biological Diversity’s comment in its 

entirety is located in the docket, EPA-HQ-OPP-2006-0108 accessible at www.regulations.gov. 

Comment Submitted by the Center for Biological Diversity in EPA-HQ-OPP-2006-0108-0045.
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Comment: The Center for Biological Diversity’s (CBD) comments focus on the EPA’s independent duty under the 

Endangered Species Act (ESA) to consult with the U.S. Fish and Wildlife Service and the National Marine 

Fisheries Service (the Services) on the registration review of cyromazine. 

Response: EPA has reviewed the comments from for cyromazine and plans to address many of the 

concerns raised by CBD as part of the implementation plan for assessing the risks of pesticides to 

listed species based on the recommendations of the April 2013 National Academy of Sciences 

(NAS) report. EPA will address concerns specific to cyromazine in connection with the 

development of its registration review decision for cyromazine. 

In November 2013, the EPA, along with the U.S. Fish & Wildlife Service (USFWS), the National 

Marine Fisheries Service (NMFS) (collectively, the Services), and the U.S. Department of Agriculture 

(USDA) released a summary of their joint Interim Approaches for assessing risks to listed species 

from pesticides. The Interim Approaches were developed jointly by the agencies in response to the 

National Academy of Sciences’ (NAS) recommendations and reflect a common approach to risk 

assessment shared by the agencies as a way of addressing scientific differences between the EPA and 

the Services. The NAS report outlines recommendations on specific scientific and technical issues 

related to the development of pesticide risk assessments that EPA and the Services must conduct in 

connection with their obligations under the Endangered Species Act (ESA) and FIFRA. 

The joint Interim Approaches were released prior to a stakeholder workshop held on November 15, 

2013. In addition, the EPA presented the joint Interim Approaches at the December 2013 Pesticide 

Program Dialogue Committee (PPDC) and State-FIFRA Issues Research and Evaluation Group 

(SFIREG) meetings, and held a stakeholder workshop in April 2014, allowing additional 

opportunities for stakeholders to comment on the Interim Approaches. As part of a phased, 

iterative process for developing the Interim Approaches, the agencies will also consider public 

comments on the Interim Approaches in connection with the development of upcoming 

Registration Review decisions. The details of the joint Interim Approaches are contained in the 

white paper “Interim Approaches for National-Level Pesticide Endangered Species Act Assessments 

Based on the Recommendations of the National Academy of Sciences April 2013 Report,” dated 

November 1, 2013.

Given that the agencies are continuing to develop and work toward implementation of the Interim 

Approaches to assess the potential risks of pesticides to listed species and their designated critical 

habitat, the ecological risk assessment supporting this Interim Registration Review Decision for 

cyromazine does not contain a complete ESA analysis that includes effects determinations for 

specific listed species or designated critical habitat. Although EPA has not yet completed effects 

determinations for specific species or habitats, for this preliminary assessment EPA conducted a 

screening-level assessment for all taxa of non-target wildlife and plants that assumes for the sake of 

the assessment that listed species and designated critical habitats may be present in the vicinity of the 

application of cyromazine. This screening level assessment will allow EPA to focus its future 

evaluations on the types of species where the potential for effects exists once the scientific methods 

being developed by the agencies have been fully vetted. While the agencies continue to develop a 

common method for ESA analysis, the regulatory section of the Interim Registration Review 

Decision document will describe the level of ESA analysis completed for this particular registration 

review case. Once the agencies have fully developed and implemented the scientific methods 
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necessary to complete risk assessments for endangered and threatened (listed) species and their 

designated critical habitats, these methods will be applied to subsequent analyses for cyromazine as 

part of completing this registration review.

II. SCIENTIFIC ASSESSMENT

A. Human Health Risk Assessment 

Since the publication of the Cyromazine Preliminary Risk Assessment an ACN study has been

submitted by Syngenta. Submission of the ACN data, and other updates led to several changes 

in the human health risk assessment including the following.

• Establishing an acute dietary endpoint

• Revision of the chronic dietary endpoint

• Revision of the safety factors for dietary risk assessment

• Revision of safety factors for occupational risk assessment

• Establishing an incidental oral endpoint (for use in bystander assessment)

• Estimates of bystander risk (via spray drift)

• Revision of occupational risk estimates based upon updated inputs

A summary of the Agency's human health risk assessment is presented below. For detailed 

discussions of all aspects of the human health risk assessment, see the Cyromazine: Human Health

Risk Assessment for Registration Review, dated Feb. 27, 2014 available in the public docket under EPAHQ-OPP-2006-0108, which can be accessed at www.regulations.gov.

 1. Human Health Risk Summary

Dietary Exposure

Revisions to the dietary analysis were incorporated into the revised screening-level human health 

analysis. Exposure to cyromazine, through food and drinking water, to the highest exposed

population subgroup, (children 1-2 years) was estimated to be 18% of the acute population

adjusted dose (aPAD) and 8.2% of the chronic population adjusted dose (cPAD) which is less

than the level of concern (LOC) of 100% of the PAD. For the general population, dietary

exposure to cyromazine (food + drinking water) is estimated to be 7.5% of the aPAD, 3.8% of

the cPAD.

Residential and Aggregate Exposure

Cyromazine products are not registered for residential use. However, the Agency considered 

potential residential exposure that may result from off-target movement of cyromazine, also referred 

to as a "bystander exposure assessment". The Agency estimated potential bystander risk (dietary, 

hand-to-mouth exposure) by using spray drift modeling coupled with methods used for residential 
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turf assessments. The Agency identified no risks of concern to bystanders from either aerial or 

ground application scenarios, (MOEs were estimated at 100,000 and 140,000 respectively) where 

margins of exposure (MOEs) were greater than the LOC of 100. The Agency did not aggregate 

bystander exposure with dietary exposures, therefore, aggregate risk is considered equal to acute 

dietary (food + drinking water) which does not represent a risk of concern

Cumulative

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common 

mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to 

cyromazine and any other substances and cyromazine does not appear to produce a toxic metabolite 

produced by other substances. For the purposes of this tolerance action, therefore, EPA has not 

assumed that cyromazine has a common mechanism of toxicity with other substances. For 

information regarding EPA’s efforts to determine which chemicals have a common mechanism of 

toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released 

by EPA’s Office of Pesticide Programs concerning common mechanism determinations and 

procedures for cumulating effects from substances found to have a common mechanism on EPA’s 

website at http://www.epa.gov/pesticides/cumulative/ .

Occupational Exposure

Occupational risks from cyromazine were revised with updated inputs and revised uncertainty

factors. Estimates of risk for handlers (i.e., those who mix/load or apply pesticides) were assessed

and determined not to be a risk concern (MOEs > 99). Post-application risks to workers (i.e.,

those who work in an area previously treated with a pesticide) were not quantitatively assessed

because (i) the low vapor pressure of cyromazine would preclude significant inhalation exposure;

and, (ii) restricted entry intervals (REI) established under the worker protection standard (WPS)

adequately addresses the low dermal toxicity of cyromazine.

Human Health Incidents

At the time of the Cyromazine Scoping document development in 2007, the Agency searched for 

incidents associated with cyromazine in its Human Health Incident Data System; the National 

Institute for Occupational Safety and Health Sentinel Event Notification System for Occupational 

Risks (NIOSH SENSOR) pesticides program (1998 thru 2003); and, the Poison Control Center 

Data (1993 thru 2005). One incident was recorded in the Poison Control Database, which reported 

an individual had experienced an occupational exposure that resulted in mild (unknown) symptoms

because the individual did not visit a HCF. No recommendations are being made based on the 

limited availability of information and because there were no reports located in the Incident 

Data System

Food Tolerances

The Agency has determined that current tolerances for residues of cyromazine in or on certain

commodities established under 40 CFR §180.414(a) should be revised in order to harmonize with

Codex maximum residue limit (MRL) and Canadian MRLs. The Agency has also determined that
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tolerances for cyromazine in/on certain crops should be established for indirect or inadvertent 

residues of cyromazine from the application of cyromazine to manure which is then applied as a

soil amendment to fields. For harmonization of cyromazine tolerances with Codex and Canada

MRLs,see Table 4.0.1 Cyromazine Revised US Tolerances, and for tolerances for indirect and inadvertent 

cyromazine residues see Table 4.0.2, Tolerance Summary for Cyromazine found in Cyromazine: Human Health

Risk Assessment for Registration Review, dated Feb. 27, 2014. The Agency will pursue harmonizing

tolerances and establishing tolerances for indirect or inadvertent residues during registration

review.

B. Ecological Risk Assessment

Following the issuance of the cyromazine preliminary risk assessment, the Agency received 

comments and information from the technical registrant regarding the ecological fate and effects

of cyromazine. The Agency addressed and/or incorporated Syngenta's comments and 

information in its ecological analysis of cyromazine in its document, Environmental Fate and Effects 

Division's Response to Public Comments on the Registration Review Preliminary Risk Assessment for Cyromazine, dated

March 26, 2014 which can be found in the public docket: (EPA-HQ-OPP-2006-0108) that can 

be accessed on http://www.regulations.gov/.

In the registration review for cyromazine, the Agency identified no risks of concern for aquatic 

animals, and found that risks to plants are uncertain. Potential risks to birds were identified from 

cyromazine use on potatoes, its use as manure treatment (which is then applied to soil as an 

amendment), and its use as an onion seed treatment. Potential risks to mammals were associated 

with cyromazine use as a manure treatment, and its use as an onion seed treatment. Potential risks 

could not be excluded for terrestrial invertebrates from the agricultural uses of cyromazine. A 

summary of these findings and risk estimates is presented below.

The Agency also completed a screening-level threatened and endangered (listed) species assessment 

for cyromazine and identified potential effects to several taxa (birds, mammals, reptiles, amphibians, 

terrestrial invertebrates, terrestrial and semi-aquatic plants). The Agency is currently working with 

its federal counterparts and other stakeholders to implement an interim approach for assessing 

potential risk to listed species and their designated critical habitats. Once, the scientific methods 

necessary to complete risk assessments for listed species and their designated critical habitats are 

finalized, the Agency will complete its listed species assessment for cyromazine. As such, only 

screening-level risks to listed species will be enumerated here. Risk to listed species will not be 

characterized herein.

1. Ecological Exposure and Risk Summary

Cyromazine is stable to both hydrolysis and photolysis and displays a low vapor pressure. 

Laboratory half-life information indicates that in aerobic soil cyromazine half-life ranged from 107 -

142 days, which was confirmed with field dissipation data where cyromazine half-life ranged from

93-240 days. Cyromazine is highly water-soluble and considered mobile, but also persistent.

Additional details associated with the characterization of the ecological risk can be found in the 

“Risk Characterization” Section (II.B.3) of this document (on page 10).
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Birds

Based upon comments received on the preliminary risk assessment, EPA revised several of the 

inputs to its terrestrial risk assessment. The revised analysis identified no acute or chronic LOC 

exceedances for avian species from the agricultural uses of cyromazine (RQs < 0.01), with the 

exception of cyromazine use on potatoes. Slight LOC exceedances from the potato use were 

identified for small birds (20g) consuming short grass where the acute RQ= 0.1 (which is below the 

non-listed LOC of 0.5 but not below the listed LOC of0.1) and the chronic RQ=1.39, which 

exceeds the LOC of 1. Birds also serve as a surrogate for terrestrial phase amphibians and reptiles. 

RQs for terrestrial-phase amphibians and reptiles were calculated using the Terrestrial Herpetofaunal 

Exposure Residue Program Simulation (f-HERPS), and exceedances were identified for amphibians 

from cyromazine use on potatoes where an acute RQ for small (2g) amphibian/reptiles was 

estimated to be 0.14, and chronic RQs were estimated at 1.07 and 1.39 (See Appendix C for a table 

of LOCs). In order to mitigate remaining potential risks from use on potatoes, the application 

interval will be increased from 7 days to 17 days. The increased application interval will reduce 

EECs and therefore reduce estimated exceedances at or below the chronic LOC. 

Syngenta commented, and the Agency agreed, that based on typical grower practices, an appropriate 

representative onion seed rate is 2 – 4 lbs seed/acre and therefore, EPA used 4 lbs seed/acre in 

evaluating potential exposure from the onion seed treatment use. Avian RQs from the onion seed 

use were estimated using (i) the median lethal dose (LD50) per square foot method, where estimated 

risk to avian species was below LOCs (RQs < 0.01); and, (ii) the dietary-based method, where both 

acute and chronic LOC exceedances were identified (acute RQs ranged from 1.45 – 10.19, and the 

chronic RQ = 660). These exceedances are further characterized below in Section 3.

Finally, the Agency also identified potential acute risk to birds from exposure to food sources 

contaminated with cyromazine from application of cyromazine on manure that is then used as a soil 

amendment. Acute risks ranged based upon whether the application is assumed to be of wet 

manure or dry manure (i.e., where the amount of soil amendment per acre is measured on a weightbasis of excreted material). RQ estimates for “wet” application ranged from below the LOCs to 

slightly above the listed species LOC (acute RQs = <0.001 – 0.11). RQ estimates of “dry” 

applications ranged from below the LOCs to above the LOCs (acute RQs = 0.01 – 1.14). 

Characterization of the conservative assumptions and uncertainties in the soil amendment analysis 

and exceedances is provided below in Section 3.

Mammals

Acute risk estimates for mammals from the onion seed treatment use were revised to reflect the 

more appropriate seeding rate (i.e., 4 lbs/acre). RQs were estimated using two methods; (i) an LD50 

per square foot method, where RQs were below LOCs (RQs < 0.01); and, (ii) a dietary-based 

method, where both acute and chronic RQs exceeded LOCs, (acute RQs ranged from 2.08 – 4.55, 

and the chronic RQ = 49.5). However, as discussed below in Section 3, the Agency believes risks 

from the onion seed use may be limited to small and medium mammals and may also be both 

temporally and spatially limited. Acute RQs from the manure treatment use (dry application) ranged 
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from < LOC – 0.81, and as noted above, characterization of the conservative assumptions and 

uncertainties in the soil amendment analysis is provided below in Section 3. 

Terrestrial Invertebrates

With respect to terrestrial invertebrates, the Agency only has acute oral data with adult bees. Given

the mode of action for cyromazine, which targets the larval stage of development, the data on hand 

do not provide sufficient information to estimate potential risk. Information available in the open 

literature or conducted under OECD guidelines, indicate effects to other terrestrial invertebrate

species (such as beetle, bumblebee, and fruit fly) at levels that are above the single maximum 

application rate but that are roughly equivalent to concentrations that may be present in the 

environment following several applications. Based upon the mode of action for cyromazine, the 

ability for cyromazine to persist in the environment, and lack of appropriate effects and exposure 

data (i.e., data identified under the Agency's new risk assessment framework for bees), the Agency 

cannot preclude potential risk to terrestrial invertebrates at this time. Therefore, language will be 

added to certain cyromazine labels to inform users of potential risks to pollinators, and additional 

pollinator data will be required (see Section IV. Interim Registration Review Decision).

Plants

The Agency also has limited data on cyromazine effects to plants. While some phytotoxicity was 

observed for some terrestrial plant species (dicot - soybean, and monocot -maize) at concentrations 

at or below the labeled application rate, information available from the open literature did not 

provide a consistent indication that cyromazine causes adverse effects to terrestrial plants.

With respect to aquatic plants, based upon the information from the one aquatic non-vascular study 

(with green algae), estimated RQs are below LOCs (RQs < 0.01). The Agency does not anticipate 

that data with other non-vascular plants would lead to dissimilar conclusions. Data on vascular 

aquatic plants were not available, but again based upon the level at which effects were observed in 

the one non-vascular plant study and estimated environmental concentrations (EECs) from the uses 

of cyromazine, risk to aquatic vascular plants is not expected. Therefore, despite the limited data, 

effects to either terrestrial or aquatic plants are considered unlikely.

Fish and Aquatic Invertebrates

For many of the aquatic species examined, definitive acute endpoints were not reported in the

effects data, and therefore, RQs were not calculated. However, based upon a comparison 

between lowest reported acute effect and EECs, acute risks to aquatic species are not expected. 

Chronic RQs however, were estimated and found to be below LOCs. The Agency has also 

determined that its conclusion of low potential risk is applicable to sediment dwelling aquatic 

organisms as well.

2. Ecological Incidents

At the time of the cyromazine ecological problem formulation document development in 2007, the 

Agency searched its Ecological Incident Information System (EIIS), the Avian Incident 
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Monitoring System (AIMS), and the EPA Incident Data System (IDS) for cyromazine related 

adverse ecological incident information. One incident was recorded in the IDS database, dated 

2002, which involved the cyromazine product Trigard is classified as a minor incident and involved

wildlife.

3. Risk Characterization

Risks to Birds and Mammals from Onion Seed Use

The Agency considers its risk estimates for the onion seed use conservative for several reasons. 

While both the LD50 per ft2 and the dietary-based exposure assessment assume that the treated seed 

is readily available to the bird or mammal, cultural practice for planting bulb onion is to drill seed, 

i.e., incorporate the seed into the soil, thereby reducing availability and potential exposure to birds 

and mammals. In addition, the dietary-based approach reflects the risk that a bird/mammal would 

receive from eating an entire day's diet of just cyromazine-treated onion seed. However, natural 

competition for food typically would reduce the amount of onion seed that an organism would be 

able to access. 

The Agency also performed two additional analyses to further characterize risk estimates to birds

andmammals from cyromazine-treated onion seed. In one analysis, the Agency estimated the 

number of cyromazine-treated seeds an organism would need to eat in order to reach LOCs

(tables 1 and 2). In a second analysis the Agency estimated the number of square feet that a

bird/mammal would need to glean in order to reach the non-listed LOC. That is, given the

number of onion seeds planted per square foot in onion bulb production, the Agency estimated

the number of square feet of cropland a bird or mammal would need to glean of cyromazinetreated seed in order to reach the LOC. (tables 3 and 4).

Table 1. Number of Cyromazine-Treated Onion Seeds Needed to be Consumed to Reach

Acute non-Listed LOC - Birds

Mammal Size Acute non-listed LOC (0.5)

Small 55 - 71

Med. 348 - 452

Large 4,911 - 6388

Taken from Table 27 of the Preliminary Risk Assessment for the Registration Review of Cyromazine dated January 24, 2013 and Table 15

of the Environmental Fate and Effects Divisions Response to Public Comments on the Registration Review Preliminary Risk Assessment for Cyromazine 

dated March 26, 2014.

Table 2. Number of Cyromazine-Treated Onion Seeds Needed to be Consumed to Reach nonListed Acute LOC - Mammals

Mammal Size Acute non-listed LOC (0.5)

Small 77- 100

Med. 281 - 365

Large 3,468 - 4510

Taken from Table 27 of the Preliminary Risk Assessment for the Registration Review of Cyromazine dared January 24, 2013 and

Table 15 of the Environmental Fate and Effects Division’s Response to Public Comments on the Registration Review Preliminary Risk

Assessment for Cyromazine dated March 26, 2014.
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Table 3. Number of Square Feet Needed to be Gleaned to Reach LOCs - Birds

Bird Size Acute non-listed LOC (0.5)

Small 6

Med. 38

Large

. . . 

532 - 546

Taken from Table 15 of the Environmental Fate and Effects Division’s Response to Public Comments on the Registration Review Preliminary Risk 

Assessment for Cyromazine dated March 26, 2014.

Table 3. Number of Square Feet Needed to be Gleaned to Reach LOCs - Mammals

Bird Size Acute non-listed LOC (0.5)

Small 16

Med. 30

Large

. . .

385-376

Taken from Table 15 of the Environmental Fate and Effects Division’s Response to Public Comments on the Registration Review 

Preliminary Risk Assessment for Cyromazine dated March 26, 2014.

The alternative analyses suggest that risk estimates for larger organisms may be less likely than for 

small organisms. That is, given variables such as seed incorporation and resource competition, the 

likelihood of a small bird consuming 55 - 71 seeds in a day, or gleaning the seeds in a 6 ft2 area (or

equivalent) seems greater than a large bird consuming greater than 3000 seeds or gleaning all the 

onion seed from an onion bulb production area greater than 500 ft2 in a single day. Considering 

these different lines of information, the Agency reasons that risks may exist, but may be acute in 

nature, and limited to small birds or mammals.

Risks to Birds and Mammals from Manure Use

The use of manure to treat an agricultural field is dictated mainly by the nitrogen needs for the crop 

to be grown in that field, and the type of manure that is being applied. Therefore, actual practices 

for soil amendment can vary significantly, making it difficult to accurately estimate potential risk.

When estimating risk from this use, the Agency employed conservative assumptions including (i) 

risk was estimated based upon potential exposure associated with cyromazine-treated manure that is 

applied wet (i.e., lower cyromazine exposure), and cyromazine-treated manure that is applied dry 

(i.e., higher cyromazine exposure); (ii) risk was estimated assuming no incorporation; (iii) risk was 

explored from both the dermal and dietary routes of exposure; and, (iv) risk was estimated by 

assuming the organism eats all treated material in a square foot, including all contaminated plant 

material and contaminated soil. Therefore, based upon the low exceedances and conservative 

assumptions built into the estimate, the Agency believes that the overall risk from the soil

amendment use of cyromazine-treated manure is low.

C. Endangered Species Assessment

In November 2013, the EPA, along with the U.S. Fish & Wildlife Service (USFWS), the National 

Marine Fisheries Service (NMFS) (collectively, the Services), and the U.S. Department of Agriculture 

(USDA) released a summary of their joint Interim Approaches for assessing risks to listed species 

from pesticides. The Interim Approaches were developed jointly by the agencies in response to the 
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National Academy of Sciences’ (NAS) recommendations and reflect a common approach to risk 

assessment shared by the agencies as a way of addressing scientific differences between the EPA and 

the Services. The NAS report outlines recommendations on specific scientific and technical issues 

related to the development of pesticide risk assessments that EPA and the Services must conduct in 

connection with their obligations under the Endangered Species Act (ESA) and FIFRA.

The joint Interim Approaches were released prior to a stakeholder workshop held on

November 15, 2013. In addition, the EPA presented the joint Interim Approaches at the December 

2013 Pesticide Program Dialogue Committee (PPDC) and State-FIFRA Issues Research and 

Evaluation Group (SFIREG) meetings, and held a stakeholder workshop in April 2014, allowing 

additional opportunities for stakeholders to comment on the Interim Approaches. As part of a 

phased, iterative process for developing the Interim Approaches, the agencies will also consider 

public comments on the Interim Approaches in connection with the development of upcoming 

Registration Review decisions. The details of the joint Interim Approaches are contained in the 

white paper "Interim Approaches for National-Level Pesticide Endangered Species Act

Assessments Based on the Recommendations of the National Academy of Sciences April 2013 

Report,” dated November 1, 2013.

Given that the agencies are continuing to develop and work toward implementation of the 

Interim Approaches to assess the potential risks of pesticides to listed species and their designated 

critical habitat, the ecological risk assessment supporting this Interim Registration Review Decision

for cyromazine does not contain a complete ESA analysis that includes effects determinations for

specific listed species or designated critical habitat. Although EPA has not yet completed effects

determinations for specific species or habitats, for this preliminary assessment EPA conducted a

screening-level assessment for all taxa of non-target wildlife and plants that assumes for the sake

of the assessment that listed species and designated critical habitats may be present in the vicinity

of the application of cyromazine. This screening-level assessment will allow EPA to focus its

future evaluations on the types of species where the potential for effects exists once the scientific

methods being developed by the agencies have been fully vetted. While the agencies continue to

develop a common method for ESA analysis, the regulatory section of the Interim Registration 

Review Decision document will describe the level of ESA analysis completed for this particular

registration review case. Once the agencies have fully developed and implemented the scientific

methods necessary to complete risk assessments for endangered and threatened (listed) species

and their designated critical habitats, these methods will be applied to subsequent analyses for

cyromazine as part of completing this registration review.

D. Endocrine Disrupter Screening Program

As required by FIFRA and the Federal Food Drug and Cosmetic Act (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 that 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
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assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and

reproductive effects in different taxonomic groups. As part of its most recent registration

decision for cyromazine, EPA reviewed these 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), cyromazine is subject to the endocrine screening part of the Endocrine 

Disrupter Screening Program (EDSP).

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

other active 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 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 disrupters.

Cyromazine is on list two. List two represents the next set of chemicals for which EPA intends to 

issue test orders/DCI in the near future. In the interim, EPA is making no human health or

environmental safety findings associated with the EDSP screening of cyromazine. Before 

completing this registration review, the Agency will make an EDSP FFDCA section 408(p) 

determination for cyromazine. 

III. USE AND USAGE/BENEFITS

Because the estimated risks to birds and mammals from the onion seed treatment use is high, the 

Agency investigated the potential benefits from that use. The Agency referred to printed sources, 

and solicited information from individuals with USDA who have specific knowledge in onion bulb 

production. Onion bulb acreage does not represent a significant area in the United States, totaling 

approximately 125,000 acres, where California, (approximately 18,000 acres) Idaho- Eastern Oregon 

(approximately 20,000 acres) and Washington (approximately 24,000 acres) represent the leading 

states in onion production. Cyromazine is reportedly used to combat the larvae of the onion 

maggot, Delia antiqua (Meigen), which is the primary insect pest in bulb production. Foliar

applications are reportedly not effective at controlling the adult onion maggot, as it is a very active 

fly, therefore, soil or seed treatments are reportedly needed to control these soil-inhabiting pests. 
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Cyromazine has been used by itself, as well as in conjunction with other compounds. Cyromazine 

use in onion bulb production has reportedly declined over time and currently it is not considered the 

first choice for protection from onion seed maggot. Currently, other compounds (neonicotinoids) 

are the preferred treatment for onion seed maggot. However, since the onion seed maggot has 

demonstrated development of resistance to insecticides, such as organophosphates and carbamates, 

entomologists believe the continued availability of cyromazine is valuable for resistance management 

in bulb onion production where maggots are pests. (See Characterization of Cyromazine Use as a Seed 

Treatment for Commercial Bulb Onions; dated April 7, 2014, available in the public docket under EPAHQ-OPP-2006-0108, which can be accessed at www.reglations.gov).

IV. INTERIM REGISTRATION REVIEW DECISION 

A. Tolerance Amendments

The Agency will pursue changes to the cyromazine tolerances to harmonize with CODEX and 

Canadian MRLs and to establish tolerances for indirect and inadvertent residues of cyromazine 

during registration review. For the harmonization of the cyromazine tolerances (which will be 

harmonized with Codex and Canada MRLs), see Table 4.0.1 Cyromazine Revised US Tolerances,

and for tolerances for indirect and inadvertent cyromazine residues, see Table 4.0.2, Tolerance 

Summary for Cyromazine found in Cyromazine: Human Health Risk Assessment for Registration Review, dated 

Feb. 27, 2014.

B. Risk Mitigation Measures and Rationale

1. Risk Management for Onion Seed Use

As discussed in this document, the Agency believes that the potential risk to small birds and 

mammals from the onion seed use of cyromazine exists but that the use of cyromazine on onion 

seed represents certain benefits. To address potential ecological risks from cyromazine, certain 

changes to cyromazine labels will be made. This conclusion is based upon (i) the lack of adverse

ecological incident information associated with cyromazine; (ii) the alternative analyses that suggest 

that potential risk may be acute, and relevant to small birds and mammals; (iii) risk may be spatially 

and temporally limited; and (iv) availability of cyromazine as a component of onion bulb production 

as a means of countering pesticide resistance by the onion maggot larvae. The following statement 

must be added to cyromazine labels (i.e., cyromazine labels registered for use on onion seed).

“Treated seeds exposed on soil surface may be hazardous to wildlife; cover or collect treated 

seeds that are spilled during loading and in areas such as row ends.”

2. Risk Management for Terrestrial Invertebrates and Pollinators

As noted above, based upon available information, the Agency cannot preclude potential risks to

bees or other terrestrial invertebrates. Conversely, without pollinator data, the Agency cannot 

assess potential exposure or hazard from cyromazine and develop appropriate risk mitigation 

measures. Therefore, the Agency intends to require pollinator data (listed below), consistent with 

the Agency’s new pollinator risk assessment framework, to better assess potential risks to bees. 
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 Acute oral toxicity to adult honey bees (Non-guideline, OECD TG 213)

 Acute oral toxicity to larval honey bees (Non-guideline, OECD TG 237)

 Chronic oral toxicity to larval honey bees (Non-guideline)

 Honey bee toxicity of residues on foliage (Guideline 850.3030)

 Field trial of residues in pollen and nectar (Non-guideline)

 Semi-field testing for pollinator (Non-guideline, OECD Guidance 75)

 Field testing for pollinators (Guideline 850.3040)

While data are being generated and reviewed, changes will be made to cyromazine labels to inform 

users of potential risks to developing bees. The new language to be added to cyromazine labels is 

considered advisory, and so the “Protection of Pollinators” box will added to relevant labels (i.e., 

cyromazine products labeled for direct application to an agricultural crop), and the cyromazine bee 

language will be placed in the “Pollinator Protection” box along with other advisory language for 

pollinators. The Agency believes that in the absence of pollinator data to inform a chemical-specific 

pollinator risk assessment and mitigation measures, providing information to inform the pesticide 

user of the potential effects of a product is appropriate. (See Appendix B. Cyromazine Label Table,

for additional label description).

 

In the “Protection of Pollinators” box, the following language will be added.

“Cyromazine acts as a growth regulator, affecting the molting process of target pests, and 

therefore, may have an effect on bee larvae, but not on adult bees. Exposure to adult bees, 

either through overspray or contact with residues may lead to effects to bee larvae.”

3. Risk Management for Potato Use

Based on revised inputs to the ecological risk analysis (e.g., revised toxicity endpoint and terrestrial 

half-life information), LOC exceedances for mammals from cyromazine use on potatoes was 

removed. However, the revised ecological risk analysis estimated chronic avian LOC exceedances 

(RQ = 1.39). To address this, the application interval for cyromazine use on potato will be increased 

from 7 days to 17 days. The remaining chronic LOC exceedance (chronic RQ = 1.39) to birds will 

result in RQs that are below the Agency’s LOC with the increased application interval. (See the 

Preliminary Ecological Risk Assessment for the Registration Review of Cyromazine dated January 24, 2013, 

pages 3 and 61.)

4. Risk Management for Reduction of Spray Drift

In addition, all cyromazine products labeled for direct application to an agricultural crop must be 

changed to specify use of foliar application technology (to all agricultural uses of cyromazine) that

will deliver medium-coarse or larger spray droplets as defined in the American Society of

Agricultural and Biological Engineers standard ANSI /ASAE S572.1. 

 C. Interim Registration Review Decision
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In accordance with 40 CFR Sections 155.56 and 155.58, the Agency is issuing this Interim 

Registration Review Decision for cyromazine. Except for the EDSP and ESA components in this 

case, the Agency has made the following Interim Registration Review Decision: (1) cyromazine does 

not represent human health risks of concern; (2) cyromazine represents limited potential ecological 

risks; (3) considering the characterization of the ecological risks and the benefits of cyromazine, that 

these ecological risks are acceptable; (4) the Agency intends to change the affected registrations and 

their labeling to address these ecological risks (see Appendix B: Cyromazine Label Table); and, (5) 

the Agency intends to issue a Data Call-In to require additional pollinator data, which will be used to 

assess the effects of cyromazine on pollinators (see Appendix A Summary of Registration Review 

Mitigation and Data Requirements for Cyromazine).

In this interim registration review decision, EPA is making no human health or environmental safety 

findings associated with the EDSP screening of cyromazine, nor is it making a complete endangered 

species finding. The Agency's final registration review decision for cyromazine will depend upon 

the result of an ESA Section 7 consultation with the Services, and an EDSP FFDCA section 408(p) 

determination.

V. NEXT STEPS AND TIMELINE

A. Implementation of Mitigation Measures and Issuance of Required Data

Amended label(s) that include the risk mitigation measures required in this interim decision 

document must be submitted to the Agency for approval within 60 days following issuance of this

Interim Registration Review Decision in final form. A summary of the required mitigation measures 

and data requirements are described in Appendix A, and anticipated changes to labels are described 

in Appendix B.

B. Data Requirements

In order to assess potential risks to pollinators, the Agency will issue a DCI for data gaps 

identified in the cyromazine pollinator database as described in the “Risk Management for 

Terrestrial Invertebrates and Pollinators” section above (IV.B.2). 

C. Final Registration Review Decision

EPA will make a final registration review decision for cyromazine after ESA Section 7 consultation 

with the Services and an EDSP FFDCA section 408(p) determination has been made. 
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Appendix A: Summary of Registration Review Mitigation and Data Requirements for Cyromazine

Registration Review Case # 7439: PC Code: 121301

Chemical Names: Cyromazine

Chemical Type: Insect Growth Regulator

Chemical Family: Triazine

Mode of Action: Chitin Inhibitor

Cyromazine Mitigation

Affected 

Population(s)

Source of 

Exposure

Route of Exposure Duration of

Exposure

Risk(s) of Concern Action(s) 

Taken

Mitigation

Birds (small) Foliar 

application 

to potato

dietary Acute/chronic Acute RQ = 0.1 / 

1.39

Increase 

interval 

between 

applications

&

Droplet Size 

Restriction

Increase Application 

Interval:

Require a minimum of 17 

days between cyromazine 

applications to potatoes. 

Drop Size Restriction:

Require medium coarse or 

larger spray droplet size for 

foliar applications.

Birds and 

mammals

Onion 

seed 

treatment

dietary Acute/chronic Birds acute RQ = 

1.45 – 10.19

Birds chronic RQ 

= 660

Mammals acute = 

2.08 – 4.55 

Mammals chronic 

= 49.5 

Label language See Appendix B. Label Table

Bees and other 

insect pollinators

Foliar 

application 

to 

agricultural 

sites

dietary Acute N/A Label language See Appendix B. Label Table

Cyromazine Data Requirements

Number Data Requirement Guideline Number

1. Acute oral toxicity to adult honey bees Non-guideline, OECD TG 213
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2. Acute oral toxicity to larval honey bees Non-guideline, OECD TG 237

3. Chronic oral toxicity to larval honey bees Non-guideline

4. Honey bee toxicity of residues on foliage Guideline Number 850.3030

5. Field trail of residues in pollen and nectar Non-guideline

6. Semi-field testing for pollinator Non-guideline, OECD Guidance 75

7. Field testing for pollinators Guideline 850.3040

Appendix B: Cyromazine Label Table

Summary of Labeling Changes for Cyromazine

Description Amended Labeling Language for Cyromazine Use Products Placement on Label

End Use Products

Medium coarse or larger spray 

droplet size requirements for all 

foliar applications

“When making foliar applications of this product (aerial or ground), use spray 

nozzles that will deliver medium course or larger spray droplets as defined in 

the American Society Agricultural and Biological Engineers (ASABE) standard 

ANSI/ASAE S572.1(March 2009).”

Mixing and Application Instructions

Change to the current label 

language

The current minimum 7 day application interval, must be changed to indicate a 

minimum 17 day application interval.

Directions for Use

New label language, (for 

cyromazine labels which are 

intended for use to treat onion 

seed

“Treated seeds exposed on soil surface may be hazardous to wildlife; cover or 

collect treated seeds that are spilled during loading and in areas such as row 

ends.”

Directions for Use

New label language Addition of the “Protection of Pollinators” box to products that are labeled for

direct application to agricultural crops.

Placed on the label after between the 

Environmental Hazards section and 

the Directions for Use section.

New label language “Cyromazine acts as a growth regulator, affecting the molting process of target 

pests, and therefore, may have an effect on bee larvae, but not adult bees. 

Exposure to adult bees, either through overspray or contact with residues may 

lead to effects to bee larvae.”

Inside the “Protection of 

Pollinators” box (see below)
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 PROTECTION OF POLLINATORS

“Cyromazine acts as a growth regulator, affecting the 

molting process of target pests, and therefore, may have an 

effect on bee larvae, but not on adult bees. Exposure to 

adult bees, either through overspray or contact with 

residues may lead to effects to bee larvae.”

Bees and other insect pollinators will forage on plants when they flower, shed pollen, or produce 

nectar.

Bees and other insect pollinators can be exposed to this pesticide from:

o Direct contact during foliar applications, or contact with residues on plant surfaces after 

foliar applications

o Ingestion of residues in nectar and pollen when the pesticide is applied as a seed 

treatment, soil, tree injection, as well as foliar applications.

When Using This Product, Applicators Should Take Steps To:

o Minimize exposure of this product to bees and other insect pollinators when they are 

foraging on pollinator attractive plants around the application site.

o Minimize drift of this product on to beehives or to off-site pollinator attractive habitat. 

Drift of this product onto beehives or off-site to pollinator attractive habitat can result in 

bee kills.

Information on protecting bees and other insect pollinators may be found at the Pesticide 

Environmental Stewardship website at:

http://pesticidestewardship.org/PollinatorProtection/Pages/default.aspx. 

Pesticide incidents (for example, bee kills) should immediately be reported to the state/tribal lead 

agency. For contact information for your state, go to: www.aapco.org/officials.html. Pesticide 

incidents should also be reported to the National Pesticide Information Center at: 

www.npic.orst.edu or directly to EPA at: beekill@epa.gov 
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Appendix C: Levels of Concern (LOC) for Ecological Risk Assessment

Taxa Non-Listed Species LOC Listed Species LOC

Acute Chronic

Birds and Wild Mammals 0.5 1 0.1

Aquatic Animals 0.5 1 0.05

Plants 1 1 1

Terrestrial Invertebrates 0.4 1 0.05 (interim)