Cyromazine Hwnan Health Risk Assessment DP No. 038.7940 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.c ·. 20460. 

MEMORANDUM 

Date: January 31,2013 

,OFFICE. OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

SUBJECT: Cyromazine: Human Health Risk Assessment for Registration Review of 

Cyromazine. 

PC Code: 121301 

Decision No.: 437241 

Petition No.: NA 

DP Barcode:· 0387940 

Registration No.: None 

Regulatory. Action: Registration Review 

Risk Assessment Type: Human Health Risk Case No.: .: 7439 

Assessment 

TXR No.: NA ·· CAS No.: 66215-27-8 

MRID No.: None 40 CFR: 180.414 

FROM: 

Rebecca Daiss, Biologist · · . · 

Ivan Nieves, Biologist --fJ~ ' , ---./1 In~ Abdallah Khasawimili, Toxico gist / / l...-~ 

Risk Assessment Branch 4 

Health Effects Division (7509P) 

THROUGH: 

Susan 

Elissa 

Risk Assessment 

Reaves, 

V. H~et 

Ph.D., 

Branch 

Branch 

Branch 

4, 

Sen

HED 

Chief 

.ior 

(7509P) 

Sci{!n~ist 

· " 

· . 

~ 

~ 

A .

l~ 

. A ~ ... V ~ ~ 

TO: Kelly Ballard . 

Risk Management and Implementation Branch 1 

Pesticide Re-Evaluation Divisiop. (l>Rp~ (7508P) 

This document provides the Health Effects Division (fffiD) human health assessment for the . 

Registration Review of the herbicide cyromazine. · · 

Page 1 of56 
Cyromazine Human Health Risk Assessment DP No. 0387940 

1.0 Executive Summary ........................................................................................................... 4 

2.0 HED Recommendations .................................................................................................... 8 

2.1 Data Deficiencies ............................................................................................................ 8 

2.2 Tolerance Considerations .............................................................................................. 8 

2.2.1 Enforcement Analytical Method .................................................... ........................... 8 

2.2.2 International Harmonization ..................................................................................... 8 

2.2.3 Recommended Tolerances ......................................................................................... 9 

2.3 Label Recommendations .............................................................................................. 10 

2.3.1 Recommendations from Residue Reviews .............................................................. 10 

2.3.2 Recommendations from Occupational Assessment.. ............................................. 1 0 

2.3.3 Recommendations from Residential Assessment ................................................... 10 

3.0 Introduction ............... ................... ·.· .................................................................................... 1 0 

3.1 Chemical Identity ....................................................................................................... .. 10 

3.2 Physic~l/ChemicaJ Characteristics ........................................................................... .. 11 

3.3 Pesticide Use Pattern .................................................................................................... 11 

3.4 Anticipated Exposure Pathways ............................................. .................................... 14 

3.5 Consideration of Environmental Justice .................................................................... 14 

4.0 Hazard Characterization and Dose-Response Assessment .......................................... 14 

4.1 Toxicology Studies Available for Analysis ................................................................. 14 

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME) ............................. 15 

4.2.1 Dermal Absorption ................................................................................................... 15 

4.3 Toxicological Effects .................................................................... ................................ 15 

4.4 Safety factor for Infants and Children (FQPA Safety Factor) ................................ 16 

4.4.1 Completeness of the Toxicology Database .............................................................. 16 

4.4.2 Evidence of Neurotoxicity ........................................................................................ 16 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal.. ...... 17 

4.4.4 Residual Uncertainty in the Exposure Database ................................................... 17 

4.5 Toxicity Endpoint and Point of Departure Selections .............................................. 17 

4.5.1 Dose-Response Assessment ..................... ................................................................. 17 

4.5.2 Recommendation for Combining Routes .of Exposures for Risk Assessment.. ... 18 

4.5.3 Cancer Cl~ssification and Risk Assessment Recommendation ................. ........... 18 

4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment ..................... .......................................................................................................... 19 

4.6 Endocrine Disruption ................................................................................ ................... 20 

5.1 Metabolite/Degradate Residue Profile .................................................... ................... 21 

5.1.1 Summary of Plant and Animal Metabolism Studies ............................................. 21 

5.1.2 Summary of Environmental Degradation .............................................................. 21 

5.1.3 Comparison of Metabolic Pathways ....................................................................... 22 

5.1.4 Residues of Concern Summary and Rationale ...................................................... 22 

5.2 Food Residue Profile .................................................................................................... 22 

5.3 Water Residue Profile .................................................................................................. 25 

5.4 Dietary Risk Assessment .............................................................................................. 26 

5.4.1 Description of Residue Data Used in Dietary Assessment .................................... 26 

5.4.2 Percent Crop Treated Used in Dietary Assessment .............................................. 27 

5.4.3 Acute Dietary Risk Assessment ............................................................................... 27 

5.4.4 Chronic Dietary Risk Assessment ........................................................................... 28 

Page 2 of 56 
Cyromazine Human Health Risk Assessment DP No. D387940

Page 3 of 56

5.4.5 Cancer Dietary Risk Assessment............................................................................. 28

5.4.6 Summary Table......................................................................................................... 28

6.0 Residential (Non-Occupational) Exposure/Risk Characterization ............................. 28

6.1 Residential Handler Exposure .................................................................................... 28

6.2 Post-Application Exposure .......................................................................................... 29

6.3 Combined Exposure..................................................................................................... 29

6.4 Residential Bystander Postapplication Inhalation Exposure................................... 29

6.5 Spray Drift.................................................................................................................... 29

7.0 Aggregate Exposure/Risk Characterization.................................................................. 30

7.1 Acute Aggregate Risk................................................................................................... 30

7.2 Short-Term Aggregate Risk ........................................................................................ 30

7.3 Intermediate-Term Aggregate Risk ........................................................................... 30

7.4 Chronic Aggregate Risk .............................................................................................. 30

7.5 Cancer Aggregate Risk ................................................................................................ 31

8.0 Cumulative Exposure/Risk Characterization ............................................................... 31

9.0 Occupational Exposure/Risk Characterization ............................................................ 31

9.1 Short-/Intermediate- Handler Risk ............................................................................ 31

9.2 Short-/Intermediate-/Long-Term/Cancer (if needed) Post-Application Risk ........ 45

9.2.1 Dermal Postapplication Risk ................................................................................... 45

9.2.2 Inhalation Postapplication Risk .............................................................................. 45

10.0 References......................................................................................................................... 46

Appendix A. Toxicology Profile and Executive Summaries .................................................. 47

A.2 Toxicity Profiles............................................................................................................ 48

A.3 Hazard Identification and Endpoint Selection .......................................................... 51

Appendix B. Physical/Chemical Properties............................................................................. 55

Appendix C. Review of Human Research................................................................................ 56
Cyromazine Human Health Risk Assessment DP No. D387940

Page 4 of 56

1.0 Executive Summary

This assessment provides information to support the registration review for the use of 

cyromazine. This document addresses the exposures and risk estimates associated with currently 

registered uses. It provides a reassessment of tolerances (pesticide residue limits in food) to 

determine if they meet the safety standard established by the Food Quality Protection Act 

(FQPA) of 1996. 

Use Profile

Cyromazine (N-cyclopropyl-1,3,5-triazine-2,4,6-triamine) is a member of the triazine class of 

chemicals. While most of the chemicals of this class of chemicals are herbicides, cyromazine is 

an insecticide/larvicide. Tolerances are established (40 CFR §180.414) for residues of 

cyromazine in or on a variety of commodities ranging from 0.05 ppm (livestock commodities) to 

10.0 ppm (brassica vegetables). Cyromazine works as an insect growth regulator. It exerts its 

toxic action by affecting the nervous system of the immature stages (larvae) of certain insects. 

Cyromazine is applied to food crops with aircraft and ground application equipment. It is 

applied to non-food, landscape and greenhouse ornamentals using hand held spray equipment. 

There are no current or proposed residential uses of cyromazine.

Hazard Identification

The studies available for consideration of cyromazine toxicity provide a comprehensive 

database; however, there are three outstanding studies according to the revised 40 CFR Part 158 

Toxicology Data Requirement. These studies include an acute neurotoxicity study, a subchronic 

neurotoxicity study, and an immunotoxicity study. (The registrant has notified the Agency of the 

conduct of an ACN study to be completed and submitted by Spring 2013).

Cyromazine is categorized as Toxicity Category III for acute oral, dermal and inhalation toxicity. 

Cyromazine is not an eye irritant or a dermal sensitizer but is a mild skin irritant. The liver and 

hematological parameters are the most commonly observed effects in both subchronic and 

chronic studies in the dog and subchronic study in the rat. Decreases in body weight and food 

consumption are also common effects of cyromazine as observed in oral chronic dog, rat, mouse, 

and developmental rabbit studies. Cyromazine is not absorbed via the dermal route since no 

dermal or systemic toxicity was seen at the highest dose tested (>2000 mg/kg/day) in two 21-day 

dermal toxicity studies in rabbits. In a 28-day inhalation study in rats, cyromazine produced 

clinical signs of toxicity (hunched posture, piloerection, and reduced spontaneous activity) 

consistent with dyspnea at all concentrations. There is no evidence of developmental toxicity 

following in utero exposures or that offspring are more susceptible than adults based on 

developmental toxicity studies in rats and rabbits. In the two-generation reproduction study in 

rats no reproductive effects were observed. Cyromazine was shown not to be carcinogenic in 

mice or rats following long-term dietary administration and is classified as a “not likely” human 

carcinogen. The available mutagenicity data suggest that cyromazine does not have genotoxic 

activity. 
Cyromazine Human Health Risk Assessment DP No. D387940

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The acute and subchronic neurotoxicity studies are required in revised 40 CFR Part 158 

Toxicology Data Requirements because they provide important scientific information on 

potential nervous system effects from pesticide exposure. These studies can provide data on a 

wide range of functional tests for evaluating neurotoxicity including sensory effects, 

neuromuscular effects, learning and memory and histopathology of the nervous system. The 

Agency acknowledges that there are no clear signs of neurotoxicity following acute, subchronic 

or chronic dosing in multiple species in the cyromazine database. However, the Agency also 

notes that the existing guideline studies are inadequate in their assessment of behavioral effects 

and do not use optimal methods to evaluate the potential toxicity to the nervous tissue structure 

and function. Because there is not sufficient information to remove the requirements for these 

studies, the HASPOC concluded that the acute and subchronic neurotoxicity studies are required 

in accordance with revised 40 CFR Part 158 Toxicology Data Requirements. Consequently, a

10X database uncertainty factor (UFDB) has been retained for the lack of these neurotoxicity 

studies. This 10X database uncertainty factor will be reconsidered upon receipt and evaluation of 

the neurotoxicity study(s) by the Agency.

The outstanding acute and subchronic studies were recently considered in a weight-of-evidence 

(WOE) approach by the Hazard and Science Policy Council (HASPOC) (January 3, 2012

TXR 0056148). Cyromazine contains a symmetrical triazine substructure like atrazine, 

propazine and simazine. However, atrazine, propazine and simazine are halotriazines (see the 

structures below); cyromazine is not a halotriazine. Atrazine, propazine and simazine disrupt the 

hypothalamic-pituitary-gonadal (HPG) axis which results in neuroendocrine-related effects in 

experimental toxicology studies. No such neuroendocrine effects have been observed for 

cyromazine. For cyromazine, the liver and hematological system is the primary target organs. 

The chronic point of departure (POD) is based on decreased food consumption and body weight 

in rats. There is no basis at this time to believe that cyromazine has a mechanism of toxicity like 

the other triazines. Because cyromazine has a different toxicological profile from other 

triazines, it is not appropriate to infer or bridge information about the potential neurotoxic 

potential from atrazine, propazine, or simazine. 

 

Cyromazine Atrazine Propazine Simazine

Dose Response Assessment

Based on the current use pattern for cyromazine, toxicological points of departure (PODs) were 

selected for dietary/drinking water and short- and intermediate-term occupational exposure 

scenarios. There were no toxicological effects attributable to a single exposure of cyromazine 
Cyromazine Human Health Risk Assessment DP No. D387940

Page 6 of 56

observed in oral toxicity studies and an acute neurotoxicity (ACN) study is currently not 

available. Therefore, a Point of Departure (POD) for the acute (general population) dietary 

assessment was not selected. An endpoint of concern from the chronic/carcinogenicity rat study 

was selected as the POD for the chronic dietary assessment. No dermal or systemic toxicity was 

observed following repeated dermal application at the highest dose tested for 21 days to rabbits. 

A POD for the dermal scenario was therefore not selected. A POD for short- and intermediateterm inhalation scenario was selected from a 28-day inhalation rat study. A NOAEL was not 

established in this inhalation rat study. 

The FQPA Safety Factor is retained in the form of a database uncertainty factor (UFDB) due to 

the lack of the acute and subchronic neurotoxicity studies. Thus, the total uncertainty factor of 

1000x (10x for inter-species extrapolation, 10x-for intra-species variation, and 10x for the data 

gaps) was applied to the POD for deriving the chronic Reference Dose (cRfd). This 10X 

database uncertainty factor will be reconsidered upon receipt and evaluation of the neurotoxicity 

study(s) by the Agency. Quantification of dermal risk is not required since no dermal or systemic

toxicity was seen following repeated dermal applications at twice the Limit Dose and there were 

no concerns for developmental or reproductive toxicity. A Margin of Exposure of 3000 is 

required for assessing risk via inhalation exposure from occupational use; there are no current or 

proposed residential uses. The MOE of 3000 includes: 10x for inter-species extrapolation, 10xfor intra-species variation, 10x for the data gaps and 3x for the use a LOAEL (UFL) as the POD. 

The 3000x UF is in accordance with the recommendation by the Agency’s RfC/RfD Technical 

Panel (EPA/630/P-02/002F December, 2002 Final Report).

OPP is conducting an independent retrospective analysis of more than 120 immunotoxicity 

studies submitted to Agency. Preliminary findings of OPP’s retrospective analysis suggest that 

immunotoxicity studies have not yet provided lower PODs than are selected from other guideline 

experimental toxicology studies and thus, so far, immunotoxicity studies would not have 

impacted the Agency’s risk assessments. The OPP retrospective analysis is anticipated to be 

completed in the summer of 2012. There are no indicators in the hazard database for cyromazine 

to suggest a concern for immunotoxicity, consequently a 10x UFDB would not be retained solely 

due to an outstanding immunotoxicity study. HED believes preliminary results of the 

retrospective analyses support this approach of not retaining the UFDB for cyromazine.

Exposure/Risk Assessment and Risk Characterization

Risk assessments were conducted for dietary (food and water) and occupational exposure 

pathways based on registered uses of cyromazine. Slightly refined chronic dietary and drinking 

water risk assessments for cyromazine conclude that dietary and drinking water exposure 

estimates are above HED’s level of concern for the general population and all population 

subgroups. 

Occupational exposures and risks were estimated for short and intermediate-term timeframes at 

baseline attire and at some level of mitigation (i.e., PF 5 respirator). Most scenarios did not 

exceed HED’s level of concern (LOC) with baseline attire (i.e., single layer of clothing and no 

respirator)(i.e., MOEs ≥ 3,000 for short-and intermediate-term exposure durations), except for 

the mixer/loader/applicator mechanically pressurized handgun sprayer scenario for fly control in 
Cyromazine Human Health Risk Assessment DP No. D387940

Page 7 of 56

mushrooms, and fly larvae control in cattle, hog, and poultry operations. Both scenarios at 

baseline (no respirators) had MOEs of 2,400 and 720, respectively; when a PF 5 respirator was 

added, the MOEs increased to 12,000 and 3,600 and were therefore identified as not of concern.

Most seed treatment (Trigard OMC; EPA Reg. No. 100-790) handler exposures resulted in 

MOEs that do not exceed HED's level of concern (i.e., MOEs ≥ 3,000) at baseline attire, except 

for the loader/applicator and “multiple activities” scenarios that presented MOEs of 97, and 

2,600, respectively. The “multiple activities” scenario presented no risk of concern with 

additional Protective Personal Equipment (PPE) (i.e., PF 5 respirator; MOE = 13,000). 

However, the loader/applicator scenario, even at the highest level of PPE (i.e., PF 10 respirator) 

did not reach the level of concern of 3,000 (MOE = 970). For characterization purposes, note 

that this chemical has 1) a low vapor pressure (1.3 x 10-9 mm Hg); 2) acute inhalation toxicity 

category of III; and a 10x database uncertainty factor (UF) for the lack of neurotoxicity battery 

and immunotoxicity studies. This 10X database uncertainty factor will be reconsidered upon 

receipt and evaluation of the neurotoxicity study(s) by the Agency.

Risk estimates from planting treated seeds with cyromazine resulted in MOEs that do not exceed 

HED's level of concern with baseline attire.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for agricultural 

occupational/commercial handlers. Handler exposure resulting from application of pesticides 

outdoors is likely to result in higher exposure than post-application exposure. Therefore, it is 

expected that these handler inhalation exposure estimates would be protective of most 

occupational post-application inhalation exposure scenarios.

A post-application inhalation exposure assessment is not required as exposure is expected to be 

negligible. Seed treatment assessments provide quantitative inhalation exposure assessments for 

seed treaters and secondary handlers (i.e. planters). It is expected that these exposure estimates 

would be protective of most postapplication inhalation exposure scenarios.

Use of Human Studies

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies, listed in Appendix 2.0, 

have been determined to require a review of their ethical conduct. Some of these studies are also 

subject to review by the Human Studies Review Board. All of the studies used have received the 

appropriate review.

Tolerance Recommendation

Tolerances for inadvertent residues are required for crops grown in soil to which livestock manure 

containing cyromazine has been applied. A tolerance of 0.60 ppm should be established for 

crops grown in soil amended with cyromazine treated fertilizer based on data from 1) a confined 

rotational crop study on crops grown in soil amended with chicken manure containing 
Cyromazine Human Health Risk Assessment DP No. D387940

Page 8 of 56

cyromazine, and 2) a study on residues in poultry manure resulting from feed through and topical 

applications of cyromazine. 

2.0 HED Recommendations

Deficiencies are outlined in Section 2.1 below. The specific tolerance recommendations are 

discussed in Section 2.2, and label modifications are discussed in Section 2.3.

2.1 Data Deficiencies

Acute and subchronic neurotoxicity studies (GLN 870.6200a and b). (The registrant has notified 

the Agency of the conduct of an ACN study to be completed and submitted by Spring 2013)

An immunotoxicity study (GLN 870.7800).

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate methods are available in PAM, Vol. II for enforcement of the established tolerances 

for cyromazine in/on plant commodities. The working method “Determination of Cyromazine in 

Bean (snap)” Revision O, was derived from Ciba-Geigy Analytical Method No. AG0621, 

“Analytical Method for the Determination of Cyromazine and its Metabolite Melamine residues 

in Crops by Gas Chromatography with a Nitrogen/Phosphorous detector in the Nitrogen Specific 

Mode. (January 12, 1995).” Minor modifications were made to improve the performance of the 

method. The limit of quantitation for cyromazine is 0.05 ppm in most plant commodities.

Adequate methods are available in PAM, Vol. II for enforcement of the established tolerances 

for cyromazine in/on meat, milk, poultry, and eggs. 

Cyromazine, per se, was recovered when analyzed through Protocol III (present Protocol D). 

HED concluded that the data were acceptable and no additional cyromazine MRM recovery data 

were required.

2.2.2 International Harmonization

There are Codex and Canadian and Mexican tolerances/Maximum Residue Limits (MRLs) for 

cyromazine. The tolerance expression for cyromazine has been reviewed and updated as 

necessary based on HED’s Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09).

HED recommends increasing established U.S. tolerances to harmonize with Codex, Canadian, 

and Mexican tolerances in cases where higher international tolerances have been established by 

these entities. Accordingly, established tolerances for the commodities established at 40 CFR 

§180.414 subsection (a) should be revised as follows to harmonize with Codex and Canadian 

tolerances. 
Cyromazine Human Health Risk Assessment DP No. D387940

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Commodity Existing US Tolerance (ppm) Revised US Tolerance

Cattle, kidney 0.2 0.31

Egg 0.25 0.31

Goat, kidney 0.2 0.31

Goat, meat 0.05 0.31

Goat, meat byproducts, except kidney 0.05 0.31

Hog, kidney 0.2 0.31

Hog, meat 0.05 0.31

Hog, meat byproducts, except kidney 0.05 0.31

Horse, kidney 0.2 0.31

Horse, meat 0.05 0.31

Horse, meat byproducts, except kidney 0.05 0.31

Mango 0.3 0.51

Milk 0.05 0.11

Mushroom 1.0 8.02

Onion, bulb 0.2 0.32

Pepper 1.0 3.02

Poultry, meat (from chicken layer hens 

and chicken breeder hens only)

0.05 0.11

Poultry, meat byproducts (from 

chicken layer hens and chicken breeder 

hens only)

0.05 0.21

Sheep, kidney 0.2 0.31

Sheep, meat 0.05 0.31

Sheep, meat byproducts, except kidney 0.05 0.31

Tomato 0.5 1.02

Vegetable, brassica, leafy, group 5, 

except broccoli

10.0 35.02

Vegetable, leafy, except brassica, 

group 4

7.0 10.02

Vegetable, cucurbit, group 9 1.0 2.01

1

Increased to harmonize with Codex MRL

2

Increased to harmonize with Canadian MRL

2.2.3 Recommended Tolerances

HED recommends the registrant petition for establishment of a tolerance for inadvertent residues

of 0.60 ppm for all crops that are grown in soil amended with cyromazine treated fertilizer and 

that do not have current tolerances established based on direct application of cyromazine. These

tolerances would be established at 40 CFR §180.414 subsection (d) should be revised as follows. 

Change existing subsection d to d(1). Add subsection d(2). 

(d)(2) Indirect or inadvertent residues. Tolerances are established for indirect or inadvertent 

residues of the insecticide cyromazine, including its metabolites and degradates, in or on the 

commodities in the table in this paragraph when present therein as a result of the application of 

fertilizer containing cyromazine to growing crops that do not have a higher tolerance in 

paragraph (a)(1) of this section. Compliance with the tolerance levels specified in this paragraph 

is to be determined by measuring only cyromazine, N -cyclopropyl-1,3,5-triazine-2,4,6-triamine, 

in or on the commodity.
Cyromazine Human Health Risk Assessment DP No. D387940

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Table 2.2.3. Tolerance Summary for Cyromazine ppm

Vegetable, Root and Tuber (except potato) 0.60

Leaves of Root and Tuber Vegetables 0.60

Vegetable, Bulb (except leek and green onion) 0.60

Soybean 0.60

Vegetable Fruit (except Pepper 0.60

Strawberry 0.60

Cereal Grain CG 15 (except small grain) 0.60

Forage, fodder CG 16 (except small grain) 0.60

Herbs and Spices (CG 19) 0.60

Oil Seeds (CG 20) 0.60

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

The registrant has submitted adequate use directions for the registered end use products.

2.3.2 Recommendations from Occupational Assessment

The mixer/loader/applicator mechanically pressurized handgun sprayer scenario for fly control in 

mushrooms, and fly larvae control in cattle, hog, and poultry operations had MOEs below 3000. 

Both scenarios at baseline (no respirators) had MOEs of 2,400 and 720, respectively; when a PF 

5 respirator was added, the MOEs increased to 12,000 and 3,600 and were therefore identified as 

not of concern.

The loader/applicator and “multiple activities” scenarios presented MOEs of 97, and 2,600, 

respectively. The “multiple activities” scenario presented no risk of concern with additional 

Protective Personal Equipment (PPE) (i.e., PF 5 respirator; MOE = 13,000). However, the 

loader/applicator scenario, even at the highest level of PPE (i.e., PF 10 respirator) did not reach 

the level of concern of 3,000 (MOE = 970). For characterization purposes, note that this 

chemical has 1) a low vapor pressure (1.3 x 10-9 mm Hg); 2) acute inhalation toxicity category of 

III; and a 10x database uncertainty factor (UF) for the lack of neurotoxicity battery and 

immunotoxicity studies.

2.3.3 Recommendations from Residential Assessment

Cyromazine is not registered for residential uses.

3.0 Introduction

3.1 Chemical Identity

Structure and nomenclature are reported in Table 3.1
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TABLE 3.1 Cyromazine Nomenclature.

Chemical structure

Common name Cyromazine (ISO approved)

Company experimental name CGA-72662

IUPAC name N-cyclopropyl-1,3,5-triazine-2,4,6-triamine

CAS name N-cyclopropyl-1,3,5-triazine-2,4,6-triamine

CAS # 66215-27-8

End-use product/EP Trigard®75WP

3.2 Physical/Chemical Characteristics

The physicochemical properties of cyromazine are reported in Appendix B. 

3.3 Pesticide Use Pattern

Cyromazine is an insecticide intended for the control of leafminer by foliar application to a 

variety of vegetables (such as leafy vegetables, cucurbit, lima bean, and tomato) and is intended 

for fly control in livestock premises. Cyromazine belongs to the triazine class of pesticides. 

Cyromazine is the only compound in this class that is used as an insecticide and larvicide. 

Maximum application rates for existing and proposed uses are provided in Table 2. Maximum 

rates are based on a review of active and proposed labels. 
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Table 2. Summary of Cyromazine End-Use Products.

Reg No Formulation

Max 

Application 

Rate

Target Use Sites

Max. No. 

Applic. 

per Season

Max No 

Applic/

Season

PHI

100-654 75% WP 0.125 lb ai/A

Beans, dried, succulent

Brassica (Head and 

Stem) Vegetables

Bulb Vegetables

Cucurbit Vegetables

Leafy Vegetables

Peppers

Potatoes

6

0.75 lb 

ai/A 7 day PHI

Label Directions: Apply 2.66 oz. (one packet) of Trigard Insecticide /A as a foliar spray when leafminers first 

appear. Apply with aircraft in a minimum of 5 gals. of water/A, or apply with ground application

Equipment in a minimum of 10 gals. of water/A, using sufficient carrier to achieve adequate coverage. Repeat 

application, as needed, at 7-day Intervals to maintain control. Do not make more than 6 applications to one crop of 

beans. Do not make the last application Within 7 days of harvest. (7-day PHI). The following plant back intervals 

must be observed when planting rotational crops after an application of Trigard Insecticide: All crops on the Trigard 

insecticide label – 0 days; Sweet corn, radishes, and cotton – 30 days; any other crop – 300 days.

100-656

5% L 6.29 lb ai/A Compost for mushroom 

spawn

NS NS NA

Label Directions: Apply Armor when preparing the mushroom substrate using a coarse drenching spray with low 

pressure to minimize the formation of mists. Apply in sufficient water for uniform distribution to the compost at 

label prescribed rates that result in a concentration of 5 parts per million (ppm) of active ingredient. Thoroughly 

incorporate with a spawning machine or similar equipment.

100-667 75% WP 0.125 lb ai/A Ornamental NS NS NA

Label Directions: For control of Dipterous leafminers (Liriomyza spp.), apply 2.66 oz.lA in a minimum of 100 gals. 

of water as a foliar spray to the point of runoff when stippling first appears. Repeat applications at 7 -day intervals 

or as necessary to maintain control. Do not make more than a total of 6 applications to one crop. For control of 

fungus gnats (Bradysia spp.) and shore flies (Scatel/a spp.), apply 2.66 oz. of Citation in 100 gals. of water as a 

spray or drench to all surfaces where insect pests may breed. This includes the potting media surfaces, bench tops, 

undersides of benches, and the areas under benches that may be contaminated with potting media or algae. Repeat 

application on a 7 to 14-day schedule to minimize reinfestation. Citation will not control adult ·stages of the insect 

pests. For control of adults, insecticides labeled for adult insect control should be used.

100-790 75% WP 4.95 lb ai/lb 

seed Onion seed treatment NS NS 60 day PHI

Label Directions: Apply Trigard OMC to seed at the rate of 6.6 lbs. of product per 100 lbs. of seed (4.95 lbs. active 

ingredient per 100 lbs. of seed). Do not apply concurrent applications at planting time of insecticide products which 

have activity against onion maggot. Note: Do not harvest bulb vegetables grown from seed treated with Trigard 

OMC within 60 days of planting. The following plant back intervals must be observed when planting rotational 

crops after an application of Trigard Insecticide: Leafy vegetables (except leafy Brassica), lima beans, peppers, 

cucurbits, tomatoes, Chinese cabbage, Chinese mustard, onions, and potatoes – 0 days; Sweet corn, radishes, and 

cotton – 30 days; any other crop – 300 days.

1007-93 2.12% P/T 0.000028 

lb/animal Feed through NS NS NA

Label Directions: Begin feeding in the spring before flies begin to appear and continue feeding throughout the 

summer and into the fall until cold weather inhibits fly development. Daily Dosage: Using 1/2 oz. scoop supplied 

with the product, mix one (1) scoop of SolitudeTM IGR in the horse's ration every day. Alternate Day Dosage: Using 

1/2 oz. scoop supplied with the product, mix two (2).scoops of SolitudeTM lOR in the horse's ration every other day.

42750-222 5% 6.29 lb ai/A Compost for mushroom 

spawn

NS NS NS

Label Directions: Apply Cyromazine 5% FL when preparing the mushroom substrate using a coarse drenching spray 

with low pressure to minimize the formation of mists. Apply in sufficient water for uniform distribution to the

compost according to the rates in the following table. These rates result in a concentration of 5 parts per
Cyromazine Human Health Risk Assessment DP No. D387940

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Table 2. Summary of Cyromazine End-Use Products.

Reg No Formulation

Max 

Application 

Rate

Target Use Sites

Max. No. 

Applic. 

per Season

Max No 

Applic/

Season

PHI

million (ppm) of active ingredient. Thoroughly incorporate with a spawning machine or Similar equipment.

70585-1 1% G 0.000005 

lb/lb Poultry Feed NS NS

3 day 

preslaughter 

interval

Label Directions: If required based on label prescribed monitoring, feed Larvadex 1 % Premix continuously as 

directed for 4 to 6 weeks. Usually, this is enough time for Larvadex 1 % Premix to thoroughly cover the droppings 

and break the fly population cycle in the poultry house. After a minimum of 4 to 6 weeks of Larvadex 1% Premix 

feeding, carefully examine the manure pits. If little or no activity is observed in the manure, discontinue Larvadex 1 

% Premix and continue the sanitary and management program. Continue monitoring the manure pits. If maggots 

become active again, repeat the procedure. Use bait, sprays, or fogs as needed during and between Larvadex 1 % 

Premix feeding periods to control any adult flies. During winter months or during periods of low fly pressure, 

discontinue Larvadex 1 % Premix use for at least 4 consecutive months per year. Consult with local extension 

service poultry entomologists or your State Agricultural Experiment station for additional localized fly control 

suggestions. Do not feed Larvadex 1 % Premix treated feed to broiler poultry. Larvadex 1 % Premix use in poultry 

is limited to use as a feed-through in chicken layer and breeder operations only and may not be fed to any other 

poultry species. To avoid illegal residues, Larvadex 1 % Premix treated feed must be removed at least 3 days (72 

hrs.) before slaughter. Manure from chickens fed Larvadex 1 % Premix may be used as a soil fertilizer supplement. 

Do not apply more than 3 tons of manure per acre per year. Do not apply to small grain crops that will be harvested 

or grazed or illegal residues may result. Do not feed manure from chickens fed Larvadex 1 % Premix to animals.

70585-2 2% L 4.36 lb ai/A Poultry Manure NS NS

1 day 

preslaughter 

interval

Label Directions: First, monitor adult flies in and near the poultry house. When the population reaches a level to 

cause concern, use registered adulticide baits, sprays or fogs to reduce fly numbers and breeding potential. Then, 

examine manure and other fly breeding areas for maggot activity. If maggots are active, treat breeding sites with 

Larvadex 2SL. Mixing Application Dilute Larvadex 2SL with water to make a 0.1 % spray (see following Dilution 

Chart). Apply 1 gallon of finished spray per 100 sq. ft. of area over surface of manure, manure storage areas, spilled 

feed and other sites where maggots are active. Do not apply Larvadex 2SL more frequently than once every 21 days. 

Registered baits, sprays or fogs should be used to reduce adult flies present at the onset of

larvicide program and best management practices followed

70585-7 2% DF 4.36 lb ai/A Manure NS NS

1 day 

preslaughter 

interval

Label Directions: Neporex 2SG is a water-soluble granule suitable for dry scattering or spraying. The application 

rate is 0.02 lb cyromazine per 200 sq. ft., independent of the method of application. Apply NEPOREX 2SG only on 

fly breeding sites. It is not intended for application to fly resting sites (walls, ceilings, etc.), as it has no effect on 

adult flies. Prevent contamination of feed troughs and water troughs.

75066-1 1% G .000005 lb / 

lb Poultry Feed NS NS

3 day 

preslaughter 

interval

Label Directions: If maggots are active, start FlyzineTM 1 % Premix in the ration. Feed FlyzineTM 1 % Premix 

continuously as directed for four (4) to six (6) weeks. Usually, this is enough time for FlyzineTM 1 % Premix to 

thoroughly cover the droppings and break the fly population cycle in the poultry house. After a minimum of four (4) 

to six (6) weeks of FlyzineTM 1 % Premix feeding, carefully examine the manure pits. If little or no activity is 

observed in the manure, discontinue the use of FlyzineTM 1% Premix and continue the sanitary and management 

program. Continue monitoring the manure pits. If maggots become active again, repeat the procedure. Use bait, 

sprays, or fogs as needed during and between FlyzineTM 1 % Premix feeding periods to control any adult flies. 

During the winter months or during periods of low fly pressure, discontinue FlyzineTM 1% Premix use for at least 

four (4) consecutive months per year.
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3.4 Anticipated Exposure Pathways

The Pesticide Re-Evaluation Division has requested an assessment of human health risk to 

support the registration review of cyromazine. For domestic uses, humans may be exposed to 

cyromazine in food and drinking water, since cyromazine may be applied directly to growing 

crops and application may result in cyromazine reaching surface and ground water sources of 

drinking water. In an occupational setting, applicators may be exposed while handling the 

pesticide prior to application, as well as during application. There is a potential for postapplication exposure for workers re-entering treated fields. There are no residential uses of 

cyromazine. Therefore, there is no exposure in residential settings.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this 

human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions 

to Address Environmental Justice in Minority Populations and Low-Income Populations," 

(http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf. As a part of every pesticide risk 

assessment, OPP considers a large variety of consumer subgroups according to well-established 

procedures. In line with OPP policy, HED estimates risks to population subgroups from 

pesticide exposures that are based on patterns of that subgroup’s food and water consumption, 

and activities in and around the home that involve pesticide use in a residential setting. 

Extensive data on food consumption patterns are compiled by the USDA under the Continuing 

Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all 

registered food uses of a pesticide. These data are analyzed and categorized by subgroups based 

on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to 

assess dietary exposure to smaller, specialized subgroups and exposure assessments are 

performed when conditions or circumstances warrant. Whenever appropriate, non-dietary 

exposures based on home use of pesticide products and associated risks for adult applicators and 

for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. 

Further considerations are currently in development as OPP has committed resources and 

expertise to the development of specialized software and models that consider exposure to 

bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific 

subgroups.

4.0 Hazard Characterization and Dose-Response Assessment

4.1 Toxicology Studies Available for Analysis

The studies available for consideration of cyromazine toxicity provide a comprehensive 

database; however, there are three outstanding studies according to revised 40 CFR Part 158 

Toxicology Data Requirement. These studies include an acute neurotoxicity study, a subchronic 

neurotoxicity study, and an immunotoxicity study. (The registrant has notified the Agency of the 

conduct of an ACN study to be completed and submitted by Spring 2013)
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Acute- Oral rat, dermal rat, inhalation rat, eye irritation rabbit, dermal irritation rabbit, and skin 

sensitization guinea pig.

Subchronic- Oral 90-day rat and oral 90-day dog;

Chronic- Oral rat and dog;

Reproductive/developmental- Oral developmental rabbit and rat, 2-generation reproductive rat

Other- Oral rat and mouse cancer studies, 21-day dermal rabbit toxicity, 28-day rat inhalation, 

metabolism, mutagenicity screens.

4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)

Cyromazine was well absorbed after oral administration to rats. Excretion was rapid at the lower 

dose (3 mg/kg), but an apparent delay in excretion occurred at the high dose (300 mg/kg). Renal 

excretion was the primary route of elimination. Excretion was rapid with 54-82% of the 

administered dose recovered in the urine and feces at 24 hours. Fecal elimination was equivalent 

among dose groups except the high dose males, where a greater percentage was eliminated by 

this route. The origin of fecal radioactivity was via biliary elimination. There was no evidence 

of preferential distribution or bioaccumulation of cyromazine in the body tissues. Urinary and 

fecal metabolites of 14C-cyromazine were isolated and identified by TLC, HPLC, and GC/MS. 

The major compounds identified were the N-dealkylated product melamine, hydroxycyromazine, and un-metabolized cyromazine identified. 

Dermal absorption at 10 hrs = 13 %. Cyromazine is absorbed into the skin in an inverse dose 

related manner. The absorption into the skin is followed by a slower release into the body. The 

main route of excretion is in the urine. There is no evidence that the compound is sequestered in 

the skin.

4.2.1 Dermal Absorption

No dermal or systemic toxicity was seen following repeated dermal applications to rabbits at 

2000 mg/kg/day. In addition, there are no concerns for developmental or reproductive toxicity. 

Therefore, quantification of dermal risk is not required.

4.3 Toxicological Effects

The liver and bone marrow (hematological system) are the primary targets for oral toxicity of 

cyromazine seen in a chronic dog study. Pronounced treatment-related effects on hematological 

parameters were manifest in animals as decreases in hematocrit and hemoglobin levels at mid 

and high dose levels. Slight increases were also noted in relative brain, heart, and liver weights 

of the high dose males and females and the ovary weights of the high dose females. Decrease in 

body weight and food consumption are also common effects of cyromazine as observed in 

chronic dog, rat, mouse, and rabbit studies. No systemic toxicity was seen in rabbits following 

repeated dermal application at 2000 mg/kg/day for 21 days. A subchronic (28 day) inhalation 

study in rats is available where a NOAEL was not established. Clinical signs of toxicity such as 

hunched posture, piloerection, and reduced spontaneous activity were observed which is 

consistent with the dyspnea also observed at all concentrations. 
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The available oral perinatal, prenatal and postnatal data demonstrated no indication of increased 

sensitivity of rats or rabbits to in utero exposure to cyromazine. No quantitative or qualitative 

susceptibility was observed in any study. In the prenatal developmental rat toxicity study, the 

NOAEL (300 mg/kg/day) for developmental effects was higher than the maternal NOAEL (100 

mg/kg/day). In the developmental toxicity study in rabbits, no evidence of developmental 

toxicity was noted since the NOAEL was greater than the highest dose tested (> 60 mg/kg/day). 

In the two-generation reproduction rat study, no reproductive effects were observed up to the 

highest dose tested (NOAEL was > 150 mg/kg/day (HDT)). 

Cyromazine was not carcinogenic in mice or rats following long-term dietary administration and 

was classified as a “not likely” human carcinogen. The available mutagenicity data suggest that 

cyromazine does not have genotoxic activity. 

Cyromazine is categorized as Toxicity Category III for acute oral, dermal and inhalation toxicity. 

Cyromazine is neither an eye irritant nor a dermal sensitizer; however, it is mild skin irritant. 

4.4 Safety factor for Infants and Children (FQPA Safety Factor)

Although there are no residual uncertainties or concerns for pre- and/or post-natal toxicity, HED 

recommends the FQPA SF of 10x be retained as a database uncertainty factor based on the 

following: 

- The toxicological data base is incomplete. A neurotoxicity battery (acute and 

subchronic) and an immunotoxicity study are lacking. (The registrant has notified the

Agency of the conduct of an ACN study to be completed and submitted by Spring 2013)

4.4.1 Completeness of the Toxicology Database

The toxicology database for cyromazine is partially adequate for evaluating and characterizing 

cyromazine toxicity and selecting endpoints for purposes of this risk assessment. A 

neurotoxicity battery of acute and subchronic duration is lacking. An immunotoxicity test is also 

not available. (The registrant has notified the Agency of the conduct of an ACN study to be 

completed and submitted by Spring 2013)

(see Appendixes for Toxicity Profile tables). 

4.4.2 Evidence of Neurotoxicity

The outstanding acute and subchronic studies were recently considered in a weight-of-evidence 

(WOE) approach by the Hazard and Science Policy Council (HASPOC) (January 3, 2012

TXR 0056148). Cyromazine contains a symmetrical triazine substructure like atrazine, 

propazine and simazine. However, atrazine, propazine and simazine are halotriazines (see the 

structures below); cyromazine is not a halotriazine. Atrazine, propazine and simazine disrupt the 

hypothalamic-pituitary-gonadal (HPG) axis which results in neuroendocrine-related effects in 

experimental toxicology studies. No such neuroendocrine effects have been observed for 

cyromazine. For cyromazine, the liver and hematological system is the primary target organs. 
Cyromazine Human Health Risk Assessment DP No. D387940

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The chronic point of departure (POD) is based on decreased food consumption and body weight 

in rats. There is no basis at this time to believe that cyromazine has a mechanism of toxicity like 

the other triazines. Because cyromazine has a different toxicological profile from other 

triazines, it is not appropriate to infer or bridge information about the potential neurotoxic 

potential from atrazine, propazine, or simazine. 

 

Cyromazine Atrazine Propazine Simazine

The acute and subchronic neurotoxicity studies are required in revised 40 CFR Part 158 

Toxicology Data Requirements because they provide important scientific information on 

potential nervous system effects from pesticide exposure. These studies can provide data on a 

wide range of functional tests for evaluating neurotoxicity including sensory effects, 

neuromuscular effects, learning and memory and histopathology of the nervous system. The 

Agency acknowledges that there are no clear signs of neurotoxicity following acute, subchronic 

or chronic dosing in multiple species in the cyromazine database. However, the Agency also 

notes that the existing guideline studies are inadequate in their assessment of behavioral effects 

and do not use optimal methods to evaluate the potential toxicity to the nervous tissue structure 

and function. Because there is not sufficient information to remove the requirements for these 

studies, the HASPOC concluded that the acute and subchronic neurotoxicity studies are required 

in accordance with revised 40 CFR Part 158 Toxicology Data Requirements. Consequently, the 

10X database uncertainty factor (UFDB) has been retained for the lack of these neurotoxicity 

studies. This 10X database uncertainty factor will be reconsidered upon receipt and evaluation 

of the neurotoxicity study(s) by the Agency.

 

4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

There is no evidence of increases susceptibility following in utero exposures to rats and rabbits 

or following pre-and post-natal exposure to rats.

4.4.4 Residual Uncertainty in the Exposure Database

The chronic dietary exposure analysis used tolerances and was refined with the use of percent 

crop treated data for some commodities. The dietary assessment is not a highly refined 

assessment. Therefore, dietary exposure to cyromazine will not be underestimated.

4.5 Toxicity Endpoint and Point of Departure Selections

4.5.1 Dose-Response Assessment
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Based on the current use pattern for cyromazine, toxicological points of departure (PODs) were 

selected for dietary/drinking water and short- and intermediate-term occupational exposure 

scenarios. There were no toxicological effects attributable to a single exposure of cyromazine 

observed in the available oral toxicity studies. Therefore, a POD for the acute (general 

population) dietary assessment was not selected. This may be revised upon the receipt of the 

ACN study currently being conducted by the registrant . A chronic/carcinogenicity rat study was 

selected as the POD for the chronic dietary assessment. No dermal or systemic toxicity was 

observed following repeated dermal application at the highest dose tested for 21 days to rabbits.

Additionally, there were no concerns for developmental or reproductive toxicity; therefore a 

POD for the dermal scenario was not selected. A POD for short- and intermediate-term 

inhalation scenario was selected from a 28-day inhalation rat study. 

Chronic Dietary: UF= 1000x- 10x for inter-species extrapolation, 10x for intra-species variation 

and 10x database UF for the lack of neurotoxicity battery. This 10X database uncertainty factor 

will be reconsidered upon receipt and evaluation of the neurotoxicity study(s) by the Agency.

Inhalation Occupational: MOE = 3000 – 10x for interspecies extrapolation, 10x for intraspecies 

variation, 3x for the use of a LOAEL (UFL) and 10x for data gaps (UFDB) for the lack of 

neurotoxicity battery. This 10X database uncertainty factor will be reconsidered upon receipt 

and evaluation of the neurotoxicity stud(y) by the Agency. The 3000x UF is in accordance with 

the recommendation by the Agency’s RfC/RfD Technical Panel (EPA/630/P-02/002F December, 

2002, Final Report). 

OPP is conducting an independent retrospective analysis of more than 120 immunotoxicity 

studies submitted to Agency. There are no indicators in the hazard database for cyromazine to 

suggest a concern for immunotoxicity, consequently a 10x UFDB is not retained solely due to an 

outstanding immunotoxicity study. The preliminary results of the retrospective analyses support 

this approach of not retaining a database uncertainty factor for the lack of an immunotoxicity 

study.

4.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential residential exposures to the pesticide, aggregate risk assessment must 

consider exposures from three major sources: oral, dermal and inhalation exposures. Since there 

are no residential incidental oral exposures to cyromazine, aggregate exposure from food and 

non-food oral exposures is not required.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Cyromazine is classified as a “Not Likely Human Carcinogen” based on the lack of evidence of 

carcinogenicity in the mouse and rat cancer studies (HED CPRC, TXR No. 011384, 1/6/95). 

Cyromazine was not mutagenic in three mutagenicity studies submitted to OPP
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4.5.4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk 

Assessment

A summary of toxicological endpoints for use in human health risk assessment is presented 

below:

Table 4.5.4.1 Summary of Toxicological Doses and Endpoints for Cyromazine for Use in Dietary 

Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty

/FQPA Safety 

Factors

RfD, PAD, LOC 

for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

(general 

population)

A dose and an endpoint for acute dietary exposure were not identified for cyromazine.

Chronic 

Dietary 

(All 

Populations)

NOAEL= 1.5 

mg/kg/day

UFA = 10x

UFH = 10x

UFDB = 10x

Chronic RfD = 

0.0015

mg/kg/day

cPAD = 0.0015 

mg/kg/day

Combined Chronic/Carcinogenicity 

Toxicity in Rats, MRID 00103202

LOAEL = 15 mg/kg/day based on 

food consumption and body weight 

decreases at 15 mg/kg/day (LOAEL).

Cancer 

(all routes)

Not likely human carcinogen

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to 

mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. 

NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. 

UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity 

among members of the human population (intraspecies). UFdb= incomplete database.

SF = FQPA Safety Factor. 

PAD = population adjusted dose (a = acute, c = chronic). 

RfD = reference dose. 
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Table 4.5.4.2 Summary of Toxicological Doses and Endpoints for Cyromazine for Use in Occupational 

Human Health Risk Assessments

Exposure/

Scenario

Point of 

Departure

Uncertainty 

Factors

Level of 

Concern for 

Risk 

Assessment

Study and Toxicological Effects

Dermal 

Short/intermediateterm

No hazard was identified via the dermal route of exposure and therefore quantification 

of risk via this route of exposure is not required. No systemic toxicity occurred in two 

21-dermal rabbit toxicity studies at the highest doses tested of 2000 mg/kg/day.

Inhalation Shortto Intermediate 

Term 

(1-day – 6 months) 

LOAEL= 

14.36 

mg/kg/day*

UFA = 10x

UFH =10x

UFDB = 10x

UFL = 3x

Occupational 

LOC for MOE 

= 3000

28-day Inhalation Toxicity study in 

rats. MRID 47940804

LOAEL = 0.055 mg/L (equivalent 

to 14.36 mg/kg/day oral dose) 

based on impairment of the general 

condition with the symptoms of 

piloerection, dyspnea, hunched 

posture, and reduced spontaneous 

activity. This was the lowest 

concentration tested.

Cancer (all routes) Not likely human carcinogen

Point of Departure (POD) = A data point or an estimated point that is derived from observed dose-response data and used to 

mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. 

NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. 

UF = uncertainty factor. UFA = extrapolation from animal to human (interspecies). UFH = potential variation in sensitivity 

among members of the human population (intraspecies). UFdb=incomplete database.

SF = FQPA Safety Factor. 

PAD = population adjusted dose (a = acute, c = chronic). 

RfD = reference dose. 

*mg/L conversion to mg/kg/day see A.3.6. page 41

MOE = margin of exposure; the maximum allowed by the Agency. 

LOC = level of concern. N/A = not applicable.

4.6 Endocrine Disruption

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 reregistration decision, 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 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 
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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. Cyromazine is 

not among the group of 58 pesticide active ingredients on the initial list to be screened under the 

EDSP. Accordingly, as part of registration review, EPA will issue future EDSP orders/data callins, requiring the submission of EDSP screening assays for cyromazine. For further information 

on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the 

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

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

5.0 Dietary Exposure and Risk Assessment 

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

The metabolism of cyromazine has been studied in celery, head lettuce, and tomatoes. The 

residue of concern is the parent compound cyromazine as determined by the HED Metabolism 

Committee on 11/4/97. The metabolism of cyromazine in plants is adequately understood and 

additional plant metabolism data are not required. 

Data concerning the metabolism of cyromazine in lactating goats and laying hens have been 

previously submitted. The livestock metabolism data for cyromazine have been presented to the 

HED Metabolism Assessment Review Committee (MARC, meeting date: 11/4/97). The MARC 

determined that the residue of concern in livestock commodities is the parent compound, 

cyromazine (Memo, 4/15/98 J.B. Stokes, D245214).

5.1.2 Summary of Environmental Degradation

Based on previously submitted data, cyromazine is stable to hydrolysis and photolysis, and is 

persistent in aerobic soil (T1⁄2 > 60 days). This was confirmed in the field studies, where 

dissipation half-lives are as long as 250 days. Freundlich adsorption coefficients (Kads) for the 

mineral soils are less than 5 mL/g, and for the organic soil the Kads value was 17 mL/g. The Kads

values are not equal to Kd, because the slope (1/n) in the adsorption isotherm was less than 1 

(0.77 to 0.85). The logarithms (1.6 to 2.3) of the Koc values are generally less than 2, which falls 

into the “Mobile” category as described by the EFED Standardized Soil Mobility Classification 

Guidance (Bradbury, 2006). Cyromazine is also highly soluble (1.16 x 104 mg/L). These 
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characteristics would suggest that cyromazine has the potential to leach through soils, especially 

sand, fine sands, and loamy sands, or to be transported in solution in runoff water. 

5.1.3 Comparison of Metabolic Pathways

The major plant and poultry metabolism residues are cyromazine and melamine. The major 

ruminant metabolism residues are cyromazine, melamine, and 1-methylcyromazine. The major 

rat metabolism residues were cyromazine, melamine, and hydroxy cyromazine. 

5.1.4 Residues of Concern Summary and Rationale

A summary of the metabolites and degradates to be included in the risk assessment and tolerance 

expression are presented below in Table 5.4.1. The residue of concern is the parent compound 

cyromazine as determined by the HED Metabolism Assessment Review Committee (MARC) 

(D245214, 11/4/97). The MARC determined that the residue of concern in livestock 

commodities is the parent compound, cyromazine (D245214, J.B. Stokes, 4/15/98).

Table 5.4.1: Summary of MARC Decisions for Cyromazine

Matrix Residues of Concern 

For Risk Assessment For Tolerance Expression

Plants

Parent Only Parent Only Livestock

Rotational Crops 

Drinking Water

Note: EPA’s final rule on cyromazine; pesticide tolerance (Volume 65, 87) (May 4, 2000) 

removed melamine, a metabolite of cyromazine from the tolerance expression because melamine 

did not contribute a significant amount to the cyromazine residue.

5.2 Food Residue Profile

Crop Field Trials

HED’s evaluation of available crop field trial and livestock feeding studies submitted in support 

of registered uses of cyromazine indicates that available residue data are adequate to support 

existing tolerances for cyromazine on plant and animal commodities. Crop field trial data are 

available for onion (green and dry bulb), broccoli, cabbage, mustard greens, tomato, lettuce 

(head and leaf), celery, spinach, cantaloupe, cucumber, honey dew melon, mushroom, pepper 

(bell, chili, tabasco), corn (sweet K+CWHR, forage, fodder), radish (root, tops), mangoes, 

cottonseed, and bean (succulent). An adequate number of crop field trials conducted in 

appropriately representative locations are available for cyromazine for the currently registered 

crop applications and use patterns (application rate and PHI). 
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Processed Food and Feed

The available processing data on tomatoes are adequate to support existing registered uses of 

cyromazine. Processing trials were conducted in accordance with commercial procedures. The 

only significant concentrations found in processed commodities were in dry pomace (average, 2.4X) 

and paste (2.2X). 

The processing study on potatoes shows concentration of combined residues of cyromazine in 

potato granules/flakes (avg 2.6X) and potato chips (avg 1.9X). The alfalfa processing studies 

indicate average lX concentration of cyromazine residues in the processed commodities. The data 

from the cotton processing studies show that cyromazine combined residues concentrate on 

cottonseed hulls (avg. 1.5X) and in cottonseed meal (avg. 1.lX). No residues were found in 

cottonseed oils or soapstock even at the 5x rate. 

Meat, Milk, Poultry, and Eggs

Inadvertent tolerances need to be established for use of cyromazine treated manure as fertilizer 

on agricultural fields based on data submitted by Novartis Animal Health, U.S. Novartis

submitted studies on cyromazine residues in poultry excreta from a poultry feed product and a 

product applied topically to poultry excreta. In the feed-through study, residues of cyromazine 

were 3.6-5.8 ppm on Study Days 1-21 (before plateau) and 7.2-8.0 ppm on Study Days 28-42 

(after plateau); corresponding residues of melamine (as cyromazine equivalents) were 0.23-0.35 

ppm and 0.46-0.48 ppm. Residues of cyromazine and melamine in excreta declined steadily 

after the final application, reaching <LOQ (0.05 ppm) by Depuration Days 3 and 2, respectively. 

In the topical application to excreta study residues of cyromazine and melamine (as cyromazine 

equivalents) in excreta occurred in a cyclical pattern, with the highest residues occurring 

immediately after each application and then declining. From Study Day 0 through Study Day 21 

after the first application, residues of cyromazine and melamine declined from 49 to 3.0 ppm and 

from 0.53 to 0.18 ppm, respectively. After the second application on Study Day 21, residues of 

cyromazine and melamine increased to 39 ppm and 0.62 ppm, respectively, and then declined to 

20 ppm and 0.51 ppm five days later. The second spray application did not result in residue 

buildup as compared to single treatment data. 

Based on changes using Table 1 Feedstuffs (June 2008), dietary burdens have been estimated for 

beef, dairy, chicken, and swine. Novartis (formerly Ciba, now Syngenta) submitted a three-level 

dairy cattle feeding study that has been evaluated by the Agency for PP#’s 6F3329, 6F3333 and 

2H5640. A maximum combined residue of cyromazine and melamine of 0.09 ppm and no 

detectable residues of cyromazine and melamine in tissues at a feeding level of 10 ppm in the 

diet were observed. The worst case theoretical dietary burden contribution from cotton products 

fed to beef and dairy cattle is less than 0.05 ppm. This is some 200 fold less than the 10 ppm diet 

in the aforementioned feeding study. Based on these calculations, there will be no detectable 

transfer of incurred cyromazine equivalent residues in any consumed beef or dairy commodities, 

from cattle fed treated cotton products. Cotton meal is also the only cotton commodity fed to 

swine and is equally expected to result in no detectable residues in any commonly consumed hog 

food products.
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Field Accumulation in Rotational Crops

Data from rotational crop field accumulation study were also used to derive inadvertent 

tolerances for use of cyromazine treated manure as fertilizer on agricultural fields. In the 

rotational crop study, various indicator crops were grown to maturity in the greenhouse in soil 

that had been amended with the equivalent of 5 tons per acre of chicken manure treated with 

C

14cyromazine at a rate of 0.05 lb. a.i. per acre and aged for 30 days. The 0-3 inch soil layer of 

aluminum pails contained approximately 0.05 ppm C14cyromazine. There was little evidence of 

leaching during the course of the study. Soil from the 0-3 inch layers contained 72% cyromazine 

30 days after treatment and 65% cyromazine 121 days after treatment. Analyses of crops at 

various stages of growth indicate that only spring wheat straw (0.08 ppm) and hulls (0.06 ppm) 

had measurable uptake greater than 0.05 ppm. Immature sugar beet tops (0.008 ppm) and spring 

wheat stalk (0.016 ppm), contained measurable uptake of total radioactivity < 0.05 ppm. Lettuce 

and other crop fractions (sugar beets, spring wheat) contained detectable amounts of 

radioactivity at a level too low for reliable quantitation. 

Six trials were conducted in AZ (2), CA, (2), FL, and TX areas where rotational cotton, alfalfa, 

and sudangrass were planted back 30 days following primary crop of head lettuce. Maximum 

residues of cyromazine in RACs from cotton, alfalfa and sudangrass planted 30 days after the 

last application of cyromazine to lettuce were as follows: cottonseed, <0.05; alfalfa forage, 0.32; 

alfalfa hay, 0.51; alfalfa seed, <0.05; sudangrass forage, 0.17; and sudangrass hay; 0.10. 

Various crops (lettuce, sugar beet, wheat, carrot, and soybean) were grown to maturity in soil in 

which tomatoes had been grown. The tomatoes had been treated with six applications of C 

14cyromazine at 0.25 lb ai/A. At the time of the first crop planting (lettuce), cyromazine soil 

residues were 0.064 ppm (0-3 in). Samples of lettuce, carrot tops and roots, sugar beet roots and 

tops, soybean stalks, pods, and seeds, and wheat grain, stalks, and hulls each had < 0.01 ppm 

cyromazine equivalent residues. The foregoing plant metabolism and soil uptake studies are 

sufficient to reflect the metabolic behavior of cyromazine in plants in general. Therefore, the 

nature of the residue in rotational crops is adequately understood. The residue of concern in 

rotational crop is the parent cyromazine. 

Based on submitted studies on cyromazine residues in poultry excreta from a poultry feed 

product and a product applied topically to poultry excreta as described above, a tolerance of 0.6

ppm on crops grown in soil amended with fertilizer treated with cyromazine was derived as 

follows.

The highest level of cyromazine found in the greenhouse rotational crop study was 0.08 ppm in 

spring wheat straw. The application rate for the rotational crop study was 0.05 lb a.i. per acre 

(based on a 4 ton per acre application of cyromazine treated fertilizer). A conservatively 

estimated residue of 40 ppm cyromazine is assumed based on results of a magnitude of the 

residue study in excreta topically treated with a 0.17 lb ai/gal soluble concentrate (SL). 

Residues from that study ranged from 49 ppm at day 0 to 20 ppm at day 26 with 40 ppm at day 

24. Assuming 40 ppm cyromazine in treated manure, the calculated maximum label application 

rate of cyromazine at 4 tons treated manure per acre is 0.33 lb a.i. per acre. 
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40 mg ai/kg manure x 4 tons manure/A x 2000 lb/ton x 1 kg/2.2 lb = 0.15 kg ai/A 

0.15 kg ai/A x 2.2 lb/kg = 0.33 lb ai/A

The calculated rate of 0.33 lb ai/A is 7X the 0.05 lb a.i. per acre rate used in the green house 

rotational crop study which resulted in a maximum residue level of 0.08 ppm in spring wheat 

straw. Adjusting the maximum residue level found in the greenhouse study in accordance with 

the maximum application rate derived from the magnitude of the residue study results in a 

conservative tolerance level of 0.60 ppm.

5.3 Water Residue Profile

Currently, cyromazine may be directly applied to various crops (including celery, bulb onion, 

pepper, lettuce, cucurbits, dried and succulent beans, tomatoes, potatoes, mushrooms, leafy 

brassica), applied using a feed-through system in chicken productions, or directly applied to 

manure generated by hogs and horses. Based on additional information included in a refinement 

performed by the Agency which incorporated suggestions by Novartis (2007 DP338467), an 

updated drinking water assessment (DWA) was performed for the manure applications (labels 

70585-2, and 70585-7). The highest drinking water numbers resulted from direct application to 

succulent beans (refer to Table 5.3) and were previously estimated in the July 6, 2009 drinking 

water assessment (DWA, DP 358724); for full details on this assessment, refer to Appendix B. 

Estimated Drinking Water Concentrations (EDWCs) Surface water concentrations were modeled 

using FIRST and groundwater concentrations were modeled using SCI-GROW; refer to 

http://www.epa.gov/pesticides/science/models_pg.htm#aquatic for additional information on 

these aquatic models. 

Table 5.3. Estimated drinking water concentrations (EDWCs) for Cyromazine on Succulent Beans (2006, DP 

317886).

Application rate (lb a.i./A)/

Number of applications per 

season/

Application interval (days)/

Number of seasons per year

Peak Concentration (μg/L) Annual Average Concentration 

(μg/L )

Surface Water (FIRST) 

0.125/6/7/1 47.1 15.8

Ground Water (SCI-GROW)

0.125/6/7/1 1.1 1.1

* Applied as 6 applications at (0.125 lb ai/ac) rates, and a seasonal rate of 0.75 lb ai/acre. The concentrations have been adjusted 

with the Percent Crop Area (PCA) of 0.87 for a national assessment.
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5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

A conservative chronic dietary exposure analysis was performed. Tolerance level residues and 

available average percent crop treated assumptions were used. DEEM default and empirical 

processing factors were used to modify the tolerance values. The chronic analysis incorporated 

the 10 year average surface drinking water estimate from application of cyromazine to succulent 

beans. As noted in the Executive Summary, although chronic dietary risk estimates significantly 

exceed OPP’s level of concern, HED did not attempt further refinement of the dietary exposure 

analysis because data that could be used to refine exposure estimates for the commodities that 

account for the highest contributions to dietary exposure (e.g., field trial data for inadvertent 

tolerances) are not available. [Note: an inadvertent tolerance of 0.6 ppm is being established for 

all crops that are grown in soil amended with cyromazine treated manure and that do not have 

current tolerances established based on direct application of cyromazine (D398364, T. Morton & 

B. Daiss, 1/31/13)] Field trial and Pesticide Data Program data are available for a number of 

commodities. Crop field trial data are available for onion (green and dry bulb), broccoli, 

cabbage, mustard greens, tomato, lettuce (head and leaf), celery, spinach, cantaloupe, cucumber, 

honey dew melon, mushroom, pepper (bell, chili, tabasco), corn (sweet K+CWHR, forage, 

fodder), radish (root, tops), mangoes, cottonseed, and bean (succulent). 
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5.4.2 Percent Crop Treated Used in Dietary Assessment

February 16, 2011

Screening Level Estimates of Agricultural Uses of Cyromazine (121301)

Sorted Alphabetically

Percent Crop Treated

Crop Lbs. A.I. Avg. Max.

1 Beans, Green <500 <1 <2.5

2 Cantaloupes <500 <1 <2.5

3 Celery 3,000 45 60

4 Chicory* <500 N/C N/C

5 Lettuce 5,000 10 25

6 Onions <500 <2.5 <2.5

7 Peppers <500 <2.5 5

8 Spinach 2,000 20 35

9 Tomatoes 2,000 5 25

10 Watermelons <500 <1 <2.5

All numbers rounded.

<500 Less than 500 pounds of active ingredient

<2.5 Less than 2.5 percent of crop treated

<1 Less than 1 percent of crop treated

N/C Only Lbs. A.I. available

* Based on CA DPR data only (valid because 95% or more of U.S. acres grown are 

in California)

SLUA data sources include: 

USDA-NASS (United States Department of Agriculture's National Agricultural Statistics 

Service) 

Private Pesticide Market Research

California DPR (Department of Pesticide Regulation)

These results reflect amalgamated data developed by the Agency and are releasable to the public.

5.4.3 Acute Dietary Risk Assessment

There were no toxicological effects attributable to a single exposure (dose) of cyromazine 

observed in oral toxicity studies including the developmental toxicity studies in rats or rabbits. 

Therefore, a dose and an endpoint for acute dietary exposure were not identified for cyromazine 

and an acute exposure assessment was not conducted.
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5.4.4 Chronic Dietary Risk Assessment

Chronic dietary risk estimates are of concern for general population or other population 

subgroups. The subgroup with the highest risk estimate was children 1-2 years old with a %

cPAD of 930%. The % cPAD for the general U.S. population was 420%.

Although chronic dietary risk estimates significantly exceed OPP’s level of concern, HED did 

not attempt further refinement of the dietary exposure analysis (e.g., use of anticipated residues 

rather than tolerances) because data that could be used to refine exposure estimates for the 

commodities that account for the highest contributions to dietary exposure are not available.

5.4.5 Cancer Dietary Risk Assessment

Cyromazine is classified as a “Not Likely Human Carcinogen” based on the lack of evidence of 

carcinogenicity in the mouse and rat cancer studies (HED CPRC, TXR No. 011384, 1/6/95). 

Therefore, a cancer dietary risk assessment was not performed.

5.4.6 Summary Table

A dietary assessment was conducted for the registered uses of cyromazine. The dietary risk estimates 

are above HED’s level of concern; see Table 5.4.6. Table 5.4.6 includes the dietary risk estimates 

using tolerances (both recommended tolerances in addition to highest field trial residues for some 

commodities) and with the tolerance for inadvertent residues. 

Table 5.4.6. Summary of Chronic Dietary Exposure and Risk for Cyromazine.

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) % cPAD

General U.S. Population

0.0015

0.006223 420

All Infants (< 1 year old) 0.008391 560

Children 1-2 years old 0.013987 930

Children 3-5 years old 0.011413 760

Children 6-12 years old 0.007749 520

Youth 13-19 years old 0.004756 320

Adults 20-49 years old 0.005329 360

Adults 50-99 years old 0.005944 400

Females 13-49 years old 0.005138 340

Although chronic dietary risk estimates significantly exceed OPP’s level of concern, HED did 

not attempt further refinement of the dietary exposure analysis because data that could be used to 

refine exposure estimates for the commodities that account for the highest contributions to 

dietary exposure (e.g., field trial data for tolerances for inadvertent residues) are not available. 

6.0 Residential (Non-Occupational) Exposure/Risk Characterization

The registered cyromazine uses are not expected to result in residential exposure. 

6.1 Residential Handler Exposure

The registered cyromazine uses are not expected to result in residential exposure. 
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6.2 Post-Application Exposure

The registered cyromazine uses are not expected to result in residential exposure.

6.3 Combined Exposure

The registered cyromazine uses are not expected to result in residential exposure, therefore, 

chronic aggregate exposures include food plus drinking water exposures only. 

6.4 Residential Bystander Postapplication Inhalation Exposure

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

exposure assessment was not performed for cyromazine at this time primarily because of the 

acute inhalation toxicity (Toxicity Category III), and the low vapor pressure (1.3 x 10-9 mm Hg). 

However, there are multiple potential sources of post-application inhalation exposure to 

individuals performing post-application activities in previously treated fields. These potential 

sources include volatilization of pesticides and re-suspension of dusts and/or particulates that 

contain pesticides. The Agency sought expert advice and input on issues related to volatilization 

of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory 

Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for cyromazine.

6.5 Spray Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. 

This is particularly the case with aerial application, but, to a lesser extent, could also be a 

potential source of exposure from the ground application method employed for [chemical]. The 

Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State 

Lead Agencies for pesticide regulation and other parties to develop the best spray drift 

management practices (see the Agency’s Spray Drift website for more information at 

http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the 

Agency is now requiring interim mitigation measures for aerial applications that must be placed 

on product labels/labeling. The Agency has completed its evaluation of the new database 

submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is 

developing a policy on how to appropriately apply the data and the AgDRIFT computer model to 

its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. 

After the policy is in place, the Agency may impose further refinements in spray drift 

management practices to reduce off-target drift with specific products with significant risks 

associated with drift.
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Although a quantitative residential postapplication inhalation exposure assessment was not 

performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation 

exposure assessment was performed for flaggers. This exposure scenario is representative of a 

worse case inhalation (drift) exposure and may be considered protective of most outdoor 

agricultural and commercial postapplication inhalation exposure scenarios.

7.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and 

risks from three major sources: food, drinking water, and residential exposures (dermal and 

residential). In an aggregate assessment, exposures from relevant sources are added together and 

compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the risks themselves 

can be aggregated. When aggregating exposures and risks from various sources, HED considers 

both the route and duration of exposure.

7.1 Acute Aggregate Risk

Current practice is to include only food and water in the acute aggregate assessment. There were 

no toxicological effects attributable to a single exposure (dose) of cyromazine observed in oral 

toxicity studies including the developmental toxicity studies (rats or rabbits). Therefore, a dose 

and an endpoint for acute dietary exposure were not identified for cyromazine and an acute 

aggregate exposure assessment is not required. Refer to section 5.4.3 for the acute dietary 

assessment.

7.2 Short-Term Aggregate Risk

There are no current or proposed residential uses of cyromazine. Therefore, the acute and 

chronic exposure estimates provided in the dietary and drinking water exposure section represent 

aggregate exposure. 

7.3 Intermediate-Term Aggregate Risk

There are no current or proposed residential uses of cyromazine. Therefore, the acute and 

chronic exposure estimates provided in the dietary and drinking water exposure section represent 

aggregate exposure.

7.4 Chronic Aggregate Risk

There are no current or proposed residential uses of cyromazine. Therefore, the acute and 

chronic exposure estimates provided in the dietary and drinking water exposure section represent 

aggregate exposure.
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7.5 Cancer Aggregate Risk

Cyromazine was not carcinogenic in mice or rats following long-term dietary administration and 

was classified as a “not likely” human carcinogen. Therefore, a cancer aggregate risk assessment 

is not required.

 

8.0 Cumulative Exposure/Risk Characterization

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/.

9.0 Occupational Exposure/Risk Characterization

9.1 Short-/Intermediate- Handler Risk

Occupational exposure to cyromazine working with Trigard (EPA Reg. No. 100-654) and 

Neporex 2SG (EPA Reg. No. 70585-7) have been previously assessed (D284994, August 27, 

2002; D285851, January 30, 2003). More recently, a registration review scoping document for 

human health assessments (D337096, March 21, 2007) and a human health risk assessment for a 

proposed new use on succulent beans (D358720, D359607, August 20, 2009) indicated that 

occupational exposure and risk estimates were not of concern at the maximum single application 

rates for the assessed products. However, due to a revision of the standard input values 

recommended for use in predicting handler exposure such as “unit exposures” and body weights, 

every registered use associated with cyromazine was re-assessed for the purposes of this 

document. 

Based on use patterns and current labeling occupational handler exposure the following scenarios 

are expected:

Wettable Powder Formulations

Trigard (75% ai):

• Mixing/loading wettable powder packaged in water-soluble packets for aerial application;

• mixing/loading wettable powder packaged in water-soluble packets for groundboom 

application;

• applying sprays with fixed-wing aircraft (engineering controls);

• applying sprays with open cab groundboom sprayer; and

• flagging sprays for aerial operations.
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Citation (75% ai):

• Mixer/loader/applicator, manually-pressurized handwand;

• mixer/loader/applicator, backpack sprayer; and

• mixer/loader/applicator, mechanically-pressurized handgun sprayer.

Liquid Formulations

Armor (5% ai), Larvadex 2SL (2%) and Cyromazine 5%:

• Mixing/loading liquids;

• mixer/loader/applicator with manually-pressurized handwand; and

• mixer/loader/applicator with mechanically pressurized handgun sprayer.

Granular Formulations

Solitude IGR (2.12%):

• Mixing/loading granules for feed through fly control.

Larvadex and Flyzine 1% Premix:

• Mixing/loading granules for feed through fly control.

Neporex 2SG (2%):

• Loading/applying granules with a belly grinder;

• applying granules by hand;

• mixer/loader/applicator with backpack sprayer;

• mixer/loader/applicator with manually-pressurized handwand; and

• mixer/loader/applicator with mechanically-pressurized handgun sprayer.

Data and Assumptions for Handler Exposure Scenarios

The assumptions and factors used for the exposure calculations include:

• Application rates were based on the registered labels (see Table 4). 

• Unit Exposures: It is the policy of HED to use the best available data to assess handler 

exposure. Sources of generic handler data, used as surrogate data in the absence of chemicalspecific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the 

Agricultural Handler Exposure Task Force (AHETF) database, the Outdoor Residential 

Exposure Task Force (ORETF) database, or other registrant-submitted occupational exposure 

studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data 

protection provisions of FIFRA. The standard values recommended for use in predicting 

handler exposure that are used in this assessment, known as “unit exposures”, are outlined in 

the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” 

(http://www.epa.gov/opp00001/science/handler-exposure-table.pdf), which, along with 

additional information on HED policy on use of surrogate data, including descriptions of the 

various sources, can be found at http://www.epa.gov/pesticides/science/handler-exposuredata.html.

• The baseline clothing level was used as a starting point to calculate handler exposures, even 

though the proposed label recommends the use of baseline clothing plus water-proof gloves. 
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Depending upon the need for additional protection, additional PPE is added to obtain an 

MOE higher than the LOC. The baseline clothing level for occupational exposure scenarios 

generally represents an individual wearing long pants, a long-sleeved shirt, shoes, socks, no 

chemical-resistant gloves, and no respirator. As reflected in the calculations included herein, 

PPE may involve the addition of chemical-resistant gloves or a respirator, which none of the 

registered labels currently requires. 

• Daily Area Treated: Applicable assumptions for daily areas treated and amounts handled 

were taken from the HED’s ExpoSAC Policy #9: “Standard Values for Daily Acres Treated 

in Agriculture”, which was revised on July 5, 2000. Some daily areas treated and amounts 

handled were defined for each handler scenario by assuming an amount that can be 

reasonably treated by an individual in a single day. Area treated and amounts handled 

assumed are as follows:

Wettable Powder Formulations

Trigard (75% ai):

• 350 acres/day for mixing/loading and applying wettable powder packaged in watersoluble packets for aerial application;

• 80 acres/day for mixing/loading and applying wettable powder packaged in water-soluble 

packets for groundboom application; and 

• 350 acres/day for flagging (sprays) for aerial operations.

Citation (75% ai):

• 40 gallons/day for mixing/loading/applying with a manually-pressurized handwand;

• 40 gallons/day for mixing/loading/applying with a Backpack Sprayer; and 

• 1,000 gallons/day for mixing/loading/applying with a mechanically-pressurized handgun 

sprayer.

Liquid Formulations

Armor (5% ai), and Cyromazine 5%:

• 576,000 sq ft/day for mixing/loading liquids (from personal communications with the 

American Mushroom Institute (I. Nieves, 11/10/2011) the vast majority of cyromazine is 

applied as the compost is being produced on the wharf. These compost wharves vary in 

size from a basketball court (4,700 sq ft) to several football fields (1 football field is 

57,600 sq ft). 576,000 square feet (i.e., 10 football fields) was assessed as a high-end 

assumption.);

• 43,560 sq ft/day for mixing/loading/applying with a manually-pressurized handwand and 

a mechanically pressurized handgun sprayer (from personal communications with the 

American Mushroom Institute an employee can apply the pesticide in the mushroom 

room when the casing layer is added. One employee would treat a room of 8,000 sq ft 

once per crop. HED is not specific with respect to the number of rooms an employee 

might treat in one day, therefore the standard HED assumption of 1 acre (43,560 sq ft) 

was assessed. This is equivalent to 5 – 6 rooms of 8000 square feet treated per day); and 

Larvadex 2SL (2%) (1 Acre or 43,560 sq ft was assessed based upon HED standard 

assumptions):
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• 43,560 sq ft/day for mixing/loading liquids

• 43,560 sq ft/day for for mixing/loading/applying with a manually-pressurized handwand; 

and 

• 43,560 sq ft/day for for mixing/loading/applying with a mechanically pressurized 

handgun sprayer.

Granular Formulations

Solitude IGR (2.12%):

• 1,000 horse/day for mixing/loading granules for feed through fly control (lacking specific 

data regarding how many horses a single worker may treat per day, a high-end 

assumption of 1,000 horses was assessed; 100 horses per venue x 10 venues/day).

Larvadex 1% Premix and Flyzine 1% Premix:

• 100 tons feed/day for mixing/loading granules (lacking specific data regarding how many 

tons of chicken feed a single worker may handle per day, a high-end assumption of 100

tons was assessed; assuming 20 tons of feed per load truck x 5 trucks for large 

operations)

Neporex 2SG (2%):

• 1 acre/day for loading/applying granules with a belly grinder;

• 1,000 sq ft/day for applying granules by hand; 

• 40 gal/day for mixing/loading/applying with a backpack sprayer and a manuallypressurized handwand; and

• 1,000 gal/day for mixing/loading/applying with a mechanically pressurized handgun 

sprayer.

• Body Weight: In order to estimate risk, toxicological points of departure (POD) are 

compared with exposure estimates. These PODs are typically normalized by body weight 

(e.g., mg/kg). Therefore, to make an appropriate comparison to estimate risk, exposure 

estimates must also be normalized by body weight. Over the last 14 years, OPP has used the 

mean values for body weight as presented in the 1997 Exposure Factors Handbook in 

assessing occupational and residential risk. The body weight values in the 1997 handbook 

are based on an analysis of data from the National Center for Health Statistics (NCHS, 1987). 

In October of 2011, EPA published a revised edition of the handbook (EPA, 2011) which 

provides the most up-to-date data on exposure factors, including body weight. The body 

weight values in the 2011 handbook are based on an analysis of 1999-2006 data from the 

National Health and Nutrition Examination Survey (http://www.cdc.gov/nchs/nhanes.htm). 

The average (male and female combined) body weight of 80 kg was used for this 

assessment.

A POD for dermal exposure was not selected for cyromazine because no hazard was identified 

via the dermal route (i.e., no systemic toxicity was observed at the limit dose of 2,000 

mg/kg/day). Therefore, the occupational risk assessment was based on inhalation exposure only. 

Daily inhalation handler exposures are estimated for each applicable handler task with the 

application rate, amount handled or area treated in a day, and the applicable inhalation unit 

exposure using the following formulas:
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Daily Exposure = Unit Exposure x Application Rate x Daily Area Treated

Where: 

Daily Exposure = Amount (mg/day) inhaled that is available for inhalation 

absorption;

Unit Exposure = Unit exposure value (mg/lb ai) derived from Sept 26, 2011

handler

exposure data;

Application Rate = Normalized application rate based on a logical unit 

treatment;

Daily Area Treated = Normalized application area based on a logical unit 

treatment;

The daily inhalation dose is calculated by normalizing the daily exposure by body weight and 

adjusting.

Average Daily Dose = Daily Exposure / Body Weight

Where:

Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given 

scenario; toxicity

by the inhalation route is considered to be equivalent to the 

estimated toxicity by 

the oral route of exposure (i.e., no inhalation absorption factor);

Daily Exposure = Amount inhaled that is available for inhalation absorption;

Body Weight = Body weight determined to represent the population of interest.

Exposure and Risk Estimates

Table 9.1.1 presents the exposure/risks for short and intermediate-term inhalation exposures at 

baseline and with additional PPE as needed (i.e., a PF 5 respirator). With a PF 5 respirator the 

Agency assumes an 80% protection factor is provided by a NIOSH-approved quarter-face, cupstyle respirator (it is similar to the paint masks painters often wear). This 80% PF respirator only 

provides dust/mist filtering capability and is not assessed when the active ingredient has a vapor 

pressure in the range that organic vapors are a concern. 

Mostly all scenarios were below HED’s level of concern (LOC) at baseline and therefore not of 

concern (i.e., MOEs ≥ 3,000 for short-and intermediate-term exposure durations), except for the 

mixer/loader/applicator mechanically pressurized handgun sprayer scenario for fly control in 

mushrooms; and fly larvae control in cattle, hog, and poultry operations. Both scenarios at 

baseline (no respirators) had MOEs of 2,400 and 720, respectively; when a PF 5 respirator was 

added, the MOEs increased to 12,000 and 3,600 and were therefore identified as not of concern.
Cyromazine Human Health Risk Assessment DP No. D387940

Page 36 of 56
Cyromazine Human Health Risk Assessment DP No. D387940

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Table 9.1.1. Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Cyromazine.

All estimates are at various levels of mitigation (baseline, respirators, and water-soluble packages).

Exposure Scenario Crop or Target

Inhalation Unit 

Exposure 1

(mg/lb ai) Maximum

Application Rate 

2

Amount Treated 

Daily 3

Inhalation

Mitigation 

Level

Dose 4

(mg/kg/day)

MOE 5

(LOC = 

3,000)

Mixer/Loader

Mixing/Loading Wettable 

Powder packaged in 

Water-Soluble Packets for 

Aerial Application

Brassica (cole) leafy vegetables 

group 5 (including: abyssinian 

cabbage; bok choy; broccoli; 

broccoli, Chinese; broccoli 

raab; Brussels sprouts; 

cabbage; cabbage, Chinese; 

cabbage Chinese mustard; 

cabbage, seakale; cauliflower; 

cavalo broccolo; collards; 

Hanover salad; kale, common; 

kohlrabi; mustard, wild; 

mustard, Chinese; mustard 

greens; mustard spinach; and 

rape greens) and turnip greens

0.00024

(Eng. Control)

0.125

(lbs ai/A)

350

(A/day) 0.00013 109,000

Mixing/Loading Wettable 

Powder packaged in 

Water-Soluble Packets for 

Groundboom Application

80

(A/day) 0.000030 480,000

Mixing/Loading Liquids

Sciard fly control in 

mushrooms

0.000219

0.00014

(lbs ai/sq ft)

576,000

(sq ft) 0.00022 65,000

For fly control in and around 

chicken layer and breeder 

operations only

3.75

(lb ai/A)

1

(A) 0.000010 1,400,000

Mixing/Loading Granules

Feed-Through Fly Control in 

and around horses, horse barns, 

horse stables and paddocks, 

horse race tracks 0.0017

0.00066

(lb ai/horse)

1,000

(horses/day) 0.000014 1,020,000

For fly control in and around 1) 

caged or slatted flooring layer 

chicken operations 2) Breeder 

Chicken Operations

0.010

(lb ai/ton feed)

100

(tons feed/day) 0.000021 670,000

Applicator

Applying Sprays with Brassica (cole) leafy vegetables 0.000068 0.125 350 0.000037 380,000
Cyromazine Human Health Risk Assessment DP No. D387940

Page 38 of 56

Table 9.1.1. Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Cyromazine.

All estimates are at various levels of mitigation (baseline, respirators, and water-soluble packages).

Exposure Scenario Crop or Target

Inhalation Unit 

Exposure 1

(mg/lb ai) Maximum

Application Rate 

2

Amount Treated 

Daily 3

Inhalation

Mitigation 

Level

Dose 4

(mg/kg/day)

MOE 5

(LOC = 

3,000)

Fixed-wing Aircraft group 5 (including: abyssinian 

cabbage; bok choy; broccoli; 

broccoli, Chinese; broccoli 

raab; Brussels sprouts; 

cabbage; cabbage, Chinese; 

cabbage Chinese mustard; 

cabbage, seakale; cauliflower; 

cavalo broccolo; collards; 

Hanover salad; kale, common; 

kohlrabi; mustard, wild; 

mustard, Chinese; mustard 

greens; mustard spinach; and 

rape greens) and turnip greens

(Eng. Control) (lbs ai/A) (A/day)

Applying Sprays with 

Open Cab Groundboom 

Sprayer

0.00034 80

(A/day) 0.000043 340,000

Loading/Applying 

Granules, Belly Grinder Control of fly larvae in cattle, 

hog, and poultry operations

0.062 4.36

(lb ai/A)

1

(A) 0.0034 4,200

Applicator, Granules by 

Hand (No Respirator) 0.47 0.00010(lb ai/sq ft)

1,000

(sq ft) 0.00059 24,000

Flagger

Flagging (Sprays) for 

Aerial Operations

Brassica (cole) leafy vegetables 

group 5 (including: abyssinian 

cabbage; bok choy; broccoli; 

broccoli, Chinese; broccoli 

raab; Brussels sprouts; 

cabbage; cabbage, Chinese; 

cabbage Chinese mustard; 

cabbage, seakale; cauliflower; 

cavalo broccolo; collards; 

Hanover salad; kale, common; 

kohlrabi; mustard, wild; 

mustard, Chinese; mustard 

greens; mustard spinach; and 

0.00035 0.125

(lbs ai/A)

350

(A/day) 0.00019 75,000
Cyromazine Human Health Risk Assessment DP No. D387940

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Table 9.1.1. Short-/Intermediate-Term Occupational Exposure and Risk Estimates for Cyromazine.

All estimates are at various levels of mitigation (baseline, respirators, and water-soluble packages).

Exposure Scenario Crop or Target

Inhalation Unit 

Exposure 1

(mg/lb ai) Maximum

Application Rate 

2

Amount Treated 

Daily 3

Inhalation

Mitigation 

Level

Dose 4

(mg/kg/day)

MOE 5

(LOC = 

3,000)

rape greens) and turnip greens

Mixer/Loader/Applicator

Manually-pressurized 

Handwand

For control of selected insects, 

including Dipterous leafminers, 

and fungus gnats in landscape 

ornamentals; container grown 

ornamentals; greenhouse, lath 

and shadehouse grown 

ornamental bedding plants, and 

ornamental crops; and 

interiorscapes; and shore flies, 

only in greenhouse ornamental 

crops and interiorscapes.

0.030

0.125

(lbs ai/A)

40

(gal/day) 0.000019 760,000

Backpack Sprayer 0.14 40

(gal/day) 0.000088 160,000

Mechanically-pressurized 

Handgun Sprayer 0.0039 1,000(gal/day) 0.000061 230,000

Mechanically-pressurized 

Handgun Sprayer 

(General Broadcast/Foliar 

Applications -

Greenhouses)

0.12 1,000

(gal/day) 0.0019 7,600

Manually-pressurized 

Handwand Sciard fly control in 

mushrooms

0.030 6.10

(lb ai/A)

1

(A)

0.0023 6,300

Mechanically pressurized 

Handgun Sprayer

0.079

PF 5 = 0.0158

0.0060

PF 5 = 0.0012

2,400

PF 5 = 12,000

Manually-pressurized 

Handwand fly control in and around 

chicken layer and breeder 

operations

0.030 3.75

(lb ai/A)

1

(A)

0.0014 10,100

Mechanically pressurized 

Handgun Sprayer 0.079 0.0037 3,900

Backpack Sprayer

Control of fly larvae in cattle, 

hog, and poultry operations

0.030 0.020

(lb ai/gal)

40

(gal/day) Manually-pressurized 0.00030 48,000

Handwand

Mechanically pressurized 

Handgun Sprayer

0.079

PF 5 =0.0158

1,000

(gal/day)

0.020

PF 5 = 0.0040

724

PF 5 = 3,600

1. PHED/ORETF (level of mitigation: Baseline, PPE, Eng. Controls = water-soluble packages, PF 5 = 80% protection factor provided by a NIOSH-approved quarter-face, cup-style respirator (it is 

similar to the paint masks painters often wear).)

2. Based on registered label.

3. Exposure Science Advisory Council Policy #9.1 and other assumptions based on specific product and scenario (described in section 4.1).

4. Inhalation Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/acre or gal) x Amount Treated (A/day) /BW (kg)
Cyromazine Human Health Risk Assessment DP No. D387940

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5. Inhalation MOE = Inhalation NOAEL (mg/kg/day)/ Inhalation Dose (mg/kg/day)
Cyromazine Human Health Risk Assessment DP No. D387940

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Based upon the proposed seed treatment use, occupational handler exposure is expected for 

individuals involved in commercial seed treatment and planting. The registered label specifies 

that this use is permitted only to licensed commercial seed treatment companies. Therefore, onfarm treatment was not assessed.

Post-application exposure to agricultural workers is possible if they perform tasks that involve 

the soil subsurface following planting of treated seeds.

Commercial seed treatment equipment is designed to apply accurately measured quantities of 

pesticides to a given weight or quantity of seed. For all crops, potential occupational exposure 

scenarios from use of cyromazine as a commercial seed treatment include:

Mixing, loading, applying wettable powder formulations;

Bagging treated seed;

Sewing bags; 

Multiple activities; and

Planting treated seed.

Typically for large-scale commercial seed treatments, handlers perform only those specific 

individual tasks listed above; however, it is assumed that handlers also may perform multiple 

activities throughout the day. As a result a “multiple activities” scenario (i.e., where one handler 

performs all seed treatment tasks such as loading/applying, sewing, bagging, cleaning, 

calibration, repair, forklift driver, etc.) is included. 

Chemical-specific data for assessing exposure from the proposed uses of cyromazine were not 

submitted to the Agency in support of this Section 3 application. Unit exposure data from PHED 

and HED ExpoSAC Policy 14: Standard Operating Procedures (SOPs) for Seed Treatment were 

used in this assessment. Unit exposure data for mixing/loading wettable powder formulations 

from PHED was used as a surrogate for the loader/applicator seed treatment scenarios, since no 

seed-treatment-specific unit exposure values are available for wettable powder formulations. 

Table 9.1.2 provides a summary of the unit exposure values used to assess commercial seed 

treaters and planters. 

Table 9.1.2. Unit Exposure Values Used for Assessing Commercial Seed Treaters and 

Planters.

 Scenario Inhalation (mg/lb ai) PPE Level

Loader/Applicator10.0434 Baseline, no respirator

Loader/Applicator 0.0087 Baseline + PF 5 Respirator3

Loader/Applicator 0.0043 Baseline + PF 10 Respirator4

Sewer20.00023 Baseline, no respirator

Bagger20.00016 Baseline, no respirator

Multiple Activities20.0016 Baseline, no respirator

Multiple Activities 0.0003 Baseline + PF 5 Respirator3

1. Based on unit exposure for mixing/loading wettable powder formulations from PHED.

2. Based on unit exposures from HED Policy #14.

3. PF 5: 80% protection factor is provided by a NIOSH-approved quarter-face, cup-style respirator; 

4. PF 10: 90% protection factor is provided by a NIOSH-approved half-face cartridge or canister respirator or a powered airpurifying respirator (PAPR). This 90% PF respirator can be fitted with a dust/mist filter only or with an organic-vapor-removing 

filter with a dust/mist filter. 
Cyromazine Human Health Risk Assessment DP No. D387940

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For purposes of performing commercial seed treatment assessments, HED used ExpoSAC Policy 

15 to estimate amount of seeds treated per day and seeds planted per day. The amount assessed 

was 5,500 seeds treated per day assumed for bulb onion seeds.

Daily Exposure

Daily handler exposures are estimated for each applicable handler task with the application rate, 

the amount of seed treated/planted in a day, and the applicable unit exposure using the following 

formula:

Daily Exposure (mg ai/day) = Unit Exposure (μg ai/lb ai handled) * Application Rate 

(lbs ai/lb seed) * Daily Amount Handled (lbs seed/day) * 

Conversion Factor (mg/1,000 μg)

Where: 

Daily Exposure = Amount (mg ai/day) inhaled that is available for inhalation

absorption;

Unit Exposure = Unit exposure value (μg ai/day);

Application Rate = Normalized application rate based on a logical unit 

treatment, such as 

lb ai/lb seed; and,

Daily Amount Handled = Amount seed treated/planted per day (lb seed/day).

Daily Dose

Daily dose (inhalation) was calculated by normalizing the daily inhalation exposure value by 

body weight and accounting for inhalation absorption: 

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x {Absorption Factor 

(%/100)}

 Body Weight (kg)

Where:

Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given 

scenario (mg

 pesticide active ingredient/kg body weight/day);

Daily Exposure = Amount (mg ai/day) inhaled that is available for inhalation 

absorption;

Absorption Factor = A measure of the amount of chemical that crosses a biological 

boundary such as

the lungs; and

Body Weight = Body weight determined to represent the population of interest in a 

risk 

assessment.
Cyromazine Human Health Risk Assessment DP No. D387940

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Margin of Exposure (MOE)

The daily inhalation doses received by occupational handlers were compared to the appropriate 

points of departure (i.e., NOAEL) to assess the inhalation risks to occupational handlers. 

MOE = _____NOAEL (mg/kg/day)____

 Average Daily Dose (mg/kg/day)

Where:

MOE = Margin of exposure value used by HED to represent risk or how 

close a 

chemical exposure is to being a concern (unitless);

ADD = Average daily dose (ADD) is absorbed dose received from 

exposure to pesticide; 

NOAEL = Dose level in a toxicity study, where no observed adverse effects 

occurred in the 

study.

Commercial Seed Treatment Exposure and Risk Estimates

Most seed treatment (Trigard OMC; EPA Reg. No. 100-790) handler exposures resulted in 

MOEs that do not exceed HED's level of concern (i.e., MOEs ≥ 3,000) at baseline attire (i.e., 

single layer of clothing and no respirator), except for the loader/applicator and “multiple 

activities” scenarios that presented MOEs of 97, and 2,600, respectively. The “multiple 

activities” scenario presented no risk of concern with additional Protective Personal Equipment 

(PPE) (i.e., PF 5 respirator; MOE = 13,000). However, the loader/applicator scenario, even at 

the highest level of PPE (i.e., PF 10 respirator) did not reach the level of concern of 3,000 (MOE 

= 970). For characterization purposes, note that this chemical has 1) a low vapor pressure (1.3 x 

10-9 mm Hg); 2) acute inhalation toxicity category of III; and a 10x database uncertainty factor

(UF) for the lack of neurotoxicity battery and immunotoxicity studies.

Table 9.1.3 presents summaries of the short- and intermediate- term occupational handler risk

estimates for commercial seed treatment. 
Cyromazine Human Health Risk Assessment DP No. D387940

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Table 9.1.3. Short- and Intermediate-Term Occupational Handler Exposures and Risks for Treating Onion Seeds

Type Exposure scenario

Application 

Rate1

(lb ai/lb 

seed)

Amount 

Treated/

Day2

(lbs 

seed/day)

Unit 

Exposure3

(mg/lb ai)

Daily Dose5

(mg/kg/day)

Short/IntTerm 

Inhalation

MOE6

(LOC = 3,000)

Mitigation 

Level4

Mitigation 

Level4

Commercial

Loader/applicator

0.050 5,500

0.0434

PF 5 = 0.0087

PF 10 = 0.0087

0.1477

PF 5 = 0.0295

PF 10 = 0.0148

97

PF 5 = 480

PF 10 = 970

Sewer 0.00023 0.0008 18,000

Bagger 0.00016 0.0005 26,000

Multiple Activities 0.0016

PF 5 = 0.0003

0.0054

PF 5 = 0.0011

2,600

PF 5 = 13,000

1. Application Rates = maximum application rate based on Trigard OMC label (EPA Reg. No. 100-790);

2. Assumption for pounds of small vegetable seeds treated per day from Policy #15 was used for all vegetable seeds on label which 

included: bulb vegetables; 

3. Unit Exposures from HED Science Advisory Council for Exposure Policy #14; Baseline Inhalation: No respirator;

4. PF 5: 80% protection factor is provided by a NIOSH-approved quarter-face, cup-style respirator; 

5. Daily Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x application rate (lb ai/lb seed) x amount treated or planted (lb seed/day) x 

absorption factor (100 %) / body weight (80 kg adult);

6. Short- and Intermediate- term Inhalation MOE = NOAEL (14.33 mg/kg/day for short-term exposure) / inhalation daily dose (mg/kg/-

day). Level of concern = 3,000.

Seed Planting (Secondary Handler Exposure) 

Planting treated seed consists of the grower purchasing bags of treated seed, placing the seed in 

the hopper, and applying seed to fields. This is considered a secondary handler exposure 

scenario.

Risk from planting treated seeds with cyromazine resulted in MOEs that do not exceed HED's 

level of concern when baseline attire is worn. Table 9.1.4 presents the short- and intermediateterm risk estimates for planters. 

Table 9.1.4. Short- and Intermediate-Term Occupational Handler Exposures and Risks for Planting 

Onion Seeds

Type Exposure 

scenario

Application 

Rate1

(lb ai/lb 

seed)

Amount 

Treated/

Day2

(lbs seed/day)

Unit 

Exposure3

(mg/lb ai)

Daily Dose5

(mg/kg/day)

Short/IntTerm 

Inhalation

MOE6

(LOC = 

3,000)

Mitigation 

Level4

Mitigation 

Level4

Planters Seed 

Planter 0.050 320 0.0034 0.00067 21,000

1. Application Rates = maximum application rate based on Trigard OMC label (EPA Reg. No. 100-790);

2. HED default for lb of seed treated per day from HED Science Advisory Council for Exposure Policy # 15;

3. Unit Exposures from HED Science Advisory Council for Exposure Policy #14; Baseline Inhalation: No respirator;

4. PF 5: 80% protection factor is provided by a NIOSH-approved quarter-face, cup-style respirator; 

5. Daily Dose (mg/kg/day) = daily unit exposure (mg/lb ai) x application rate (lb ai/lb seed) x amount treated or planted (lb seed/day) x 

absorption factor (100 %) / body weight (80 kg adult);

6. Short- and Intermediate- term Inhalation MOE = NOAEL (14.33 mg/kg/day for short-term exposure) / inhalation daily dose (mg/kg/-

day). Level of concern = 3,000.
Cyromazine Human Health Risk Assessment DP No. D387940

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9.2 Short-/Intermediate-/Long-Term/Cancer (if needed) Post-Application Risk

9.2.1 Dermal Postapplication Risk

No hazard was identified via the dermal route of exposure and therefore quantification of risk via 

this route of exposure is not required. 

9.2.2 Inhalation Postapplication Risk

Dermal Post-Application Risk

There are no concerns regarding exposure through the dermal route for post-application workers 

conducting post-application activities since no toxicological endpoint was selected. 

Inhalation Post-Application Risk

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

exposure assessment was not performed for cyromazine at this time primarily because of the 

acute inhalation toxicity (Toxicity Category III), and the low vapor pressure (1.3 x 10-9 mm Hg). 

However, there are multiple potential sources of post-application inhalation exposure to 

individuals performing post-application activities in previously treated fields. These potential 

sources include volatilization of pesticides and re-suspension of dusts and/or particulates that 

contain pesticides. The Agency sought expert advice and input on issues related to volatilization 

of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory 

Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 

(http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the 

process of evaluating the SAP report as well as available post-application inhalation exposure 

data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies 

and procedures, to identify the need for and, subsequently, the way to incorporate occupational 

post-application inhalation exposure into the Agency's risk assessments. If new policies or 

procedures are put into place, the Agency may revisit the need for a quantitative occupational 

post-application inhalation exposure assessment for cyromazine.

Although a quantitative occupational post-application inhalation exposure assessment was not 

performed, an inhalation exposure assessment was performed for agricultural 

occupational/commercial handlers. Handler exposure resulting from application of pesticides 

outdoors is likely to result in higher exposure than post-application exposure. Therefore, it is 

expected that these handler inhalation exposure estimates would be protective of most 

occupational post-application inhalation exposure scenarios.

Furthermore, the Worker Protection Standard for Agricultural Pesticides contains requirements 

for protecting workers from inhalation exposures during and after greenhouse applications 

through the use of ventilation requirements. [40 CFR 170.110, (3) (Restrictions associated with 

pesticide applications)].
Cyromazine Human Health Risk Assessment DP No. D387940

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Bulb Onion Seed Treatment Occupational Post-application Exposure and Risk (Trigard 

OMC; EPA Reg. No. 100-790)

A post-application inhalation exposure assessment is not required as exposure is expected to be 

negligible. Seed treatment assessments provide quantitative inhalation exposure assessments for 

seed treaters and secondary handlers (i.e.planters). It is expected that these exposure estimates 

would be protective of most post-application inhalation exposure scenarios.

Occupational dermal post-application risks to agricultural workers following the planting of 

treated seeds were not assessed, since a dermal endpoint was not selected for cyromazine. 

10.0 References

Jerry Stokes, 4/15/98, D245214, Cyromazine. Conclusions of the Metabolism Assessment 

Review Committee at Meeting of 11/04/97.

R. Daiss & T. Morton, 1/31/2013, D398364, Cyromazine. Reregistration Review of Cyromazine 

on a Variety of Commodities. Summary of Analytical Chemistry and Residue Data.

R. Daiss & T. Morton, 1/30/2013, D398366, Cyromazine – Chronic Dietary and Drinking Water 

Exposure and Risk Assessment for Registration Review. 

Ivan Nieves, 1/31/2013, D398369, Cyromazine: Occupational and Residential Exposure and

Risk Assessment for Registration Review..

Tiffany Dowen, James Hetrick, & Rosanna Louie-Juzwiak, 2/10/2012, D398026, Drinking 

Water Assessment for All Currently Registered Uses of Cyromazine.

Deborah Smegal, 1/3/2012, TXR0056148, Cyromazine: Summary of Hazard and Science Policy 

Council (HASPOC) Meeting of December 8, 2011: Recommendations on data requirements for 

immunotoxicity and acute and subchronic neurotoxicity studies for cyromazine.

Steve Dapson & Esther Rinde, 1/6/95, Carcinogenicity Peer Review of Cyromazine.
Cyromazine Human Health Risk Assessment DP No. D387940

Page 47 of 56

Appendix A. Toxicology Profile and Executive Summaries

Table A.1. Cyromazine Toxicology Data Requirements

Table 1. Guideline Data Requirements

Test

Technical

Required Satisfied

870.1100 Acute Oral Toxicity.......................................................

870.1200 Acute Dermal Toxicity ..................................................

870.1300 Acute Inhalation Toxicity..............................................

870.2400 Primary Eye Irritation....................................................

870.2500 Primary Dermal Irritation ..............................................

870.2600 Dermal Sensitization......................................................

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)...............................................

870.3150 Oral Subchronic (nonrodent) .........................................

870.3200 21-Day Dermal ..............................................................

870.3250 90-Day Dermal ..............................................................

870.3465 90-Day Inhalation..........................................................

yes

yes

yes

no

no

yes

yes

yes

no

no

870.3700a Developmental Toxicity (rodent)...................................

870.3700b Developmental Toxicity (nonrodent).............................

870.3800 Reproduction .................................................................

yes

yes

yes

yes

yes

yes

870.4100a Chronic Toxicity (rodent) ..............................................

870.4100b Chronic Toxicity (nonrodent)........................................

870.4200a Oncogenicity (rat)..........................................................

870.4200b Oncogenicity (mouse)....................................................

870.4300 Chronic/Oncogenicity....................................................

yesa

yes

yesa

yes

yes

yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gene Mutation - bacterial.....................

870.5300 Mutagenicity—Gene Mutation - mammalian................

870.5375 Mutagenicity—Structural Chromosomal Aberrations...

870.5900 Mutagenicity—Other Genotoxic Effects.......................

yes

yes

yes

yes

yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen) .....................................

870.6100b 90-Day Neurotoxicity (hen)...........................................

870.6200a Acute Neurotox. Screening Battery (rat) .......................

870.6200b 90-Day Neuro. Screening Battery (rat)..........................

870.6300 Develop. Neuro..............................................................

no

no

yes

yes

no

-

-

no

no

no

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration ........................................................

870.7800 Immunotoxicity .............................................................

yes

no

yes

yes

yes

no

a Guideline 870.4300 satisfies guideline 870.4100a and 870.4200a.
Cyromazine Human Health Risk Assessment DP No. D387940

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A.2 Toxicity Profiles

Table A.2.1. Acute Toxicity of Cyromazine.

GLN Study Type MRID #(s) Results Toxicity Category

81-1 Acute Oral 00082836 LD50 = > 3387 mg/kg III

81-2 Acute Dermal 00082839 LD50 = > 3100 g/kg III

81-3 Acute Inhalation 43799901 LC50 > 0.744 mg/L IV

81-4 Primary Eye Irritation - rabbits 00082841 No irritation. IV

81-5 Primary Skin Irritation - rabbits 00082842 Mild irritant. IV

81-6 Dermal Sensitization 00082843 Non-sensitizing N/A

Table A.2.2. Toxicology profile for Cyromazine

Study Type /

Guideline No.

MRID (Year) /

Classification / Doses Results

Subchronic oral - Dog 

870.3100 (82-1) 

00135432 (1979)

Acceptable/Guideline 

0, 30, 300, 1000 or 3000 

ppm (0, 0.75, 7.5, 25 and 75 

mg/kg/day)

The systemic toxicity LOAEL is 1000 ppm (25 mg/kg/day) based on 

alteration in liver weight in males. 

The systemic toxicity NOAEL is 300 ppm (7.5 mg/kg/day).

Subchronic oral - Rat

870.3100 (82-1)

00135433 (1979)

Acceptable/Guideline

0, 30, 100 and 300 ppm (0, 

3, 10, and 30 mg/kg/day)

The systemic toxicity LOAEL is 300 ppm (30 mg/kg/day), based on 

alteration in the liver weight changes in males.

The systemic toxicity NOAEL is 30 ppm (3 mg/kg/day).

28-day Inhalation -

Rat 

870.3465 

47940804 (1988)

Acceptable/Guideline

Nominal 55, 210, or 710 

mg/m3

The LOAEL is 0.055 mg/L/day based on impairment of the general 

condition with the symptoms of piloerection, dyspnea, hunched posture, 

and reduced spontaneous activity. 

The NOAEL was not observed.

21-day dermal toxicity 

-Rabbit

870.3200 (82-2)

44060901 (1992)

Acceptable/Guideline

0, 50, 200 & 2000 

mg/kg/day 

No treatment related systemic toxicity was noted. The systemic toxicity 

NOAEL > 2000 mg/kg/day and the systemic toxicity LOAEL > 2000 

mg/kg/day. 

No dermal irritation was noted. The dermal toxicity NOAEL > 2000 

mg/kg/day and the dermal toxicity LOAEL > 2000 mg/kg/day. 

21-day dermal toxicity 

-Rabbit

870.3200 (82-2)

44060902 (1984)

Acceptable/Guideline

0 & 2010 mg/kg/day 

No treatment related systemic toxicity was noted. The systemic toxicity 

NOAEL > 2010 mg/kg/day and the systemic toxicity LOAEL > 2010 

mg/kg/day. 

No dermal irritation was noted. The dermal toxicity NOAEL > 2010 

mg/kg/day and the dermal toxicity LOAEL > 2010 mg/kg/day. 

Chronic oral 

(6-months) - Dog 

870.4100 (83-1) 

00103193 (1982)

Acceptable/Guideline 

0, 30, 300 or 3000 ppm (0, 

0.75, 7.5 and 75 mg/kg/day)

The systemic toxicity LOAEL is 3000 ppm (75 mg/kg/day) based on 

alteration in hematological parameters (hemoglobin, and hematocrit). 

The systemic toxicity NOAEL is 300 ppm (7.5 mg/kg/day).

Combine Chronic/ 

Carcinogenicity- Rat

870.4300 (83-5)

00103202 (1982)

Acceptable/Guideline

0, 30, 300 and 3000 ppm (0, 

1.5, 15, and 150 mg/kg/day)

The systemic toxicity LOAEL is 300 ppm (15 mg/kg/day) based on 

decreased body weight. The systemic toxicity NOAEL is 30 ppm. (1.5 

mg/kg/day). There is no evidence of carcinogenicity.

CarcinogenicityMouse

870.4200 (83-2) 

00115736 (1982)

Acceptable/Guideline

0, 50, 1000, and 3000 ppm 

(0, 7.5, 150, and 450 

mg/kg/day)

The systemic toxicity LOAEL is 1000 ppm (150 mg/kg/day) based on

decreased body weight. The systemic toxicity NOAEL is 50 ppm. (7.5 

mg/kg/day). There is no evidence of carcinogenicity.
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Table A.2.2. Toxicology profile for Cyromazine

Study Type /

Guideline No.

MRID (Year) /

Classification / Doses Results

Cancer Classification:

The HED CPRC TXR 

No. 011384

Jan. 6, 1995 The HED CPRC re-evaluated the weight-of-evidence on Cyromazine 

with particular reference to its carcinogenic potential. The HED CPRC 

concluded that cyromazine should be re-classified as Group E, based on 

a submission of data from a re-examination of the tissues from the 

mouse and rat studies. Cyromazine is classified as a “Not Likely Human 

Carcinogen” based on the lack of evidence of carcinogenicity in the 

mouse and rat cancer studies.

Developmental 

toxicity -Rabbit

870.3700 (83-3b)

00150471 (1985)

Acceptable/Guideline

0, 10, 30, and 60 mg/kg/day 

The maternal toxicity LOAEL is 30 mg/kg/day, based on reduced body 

weight gain and food consumption, and the maternal toxicity NOAEL is 

10 mg/kg/day. The developmental toxicity LOAEL was not established 

and the developmental toxicity NOAEL = 60 mg/kg/day (HDT).

Developmental 

toxicity- Rat

870.3700 (83-3a) 

00027488 (1979)

Acceptable/Guideline

0, 100, 300 and 600 

mg/kg/day 

The maternal toxicity LOAEL is 300 mg/kg/day, based on clinical signs 

(red or clear nasal discharge) and decreased body weights. The 

maternal toxicity NOAEL = 100 mg/kg/day.

The developmental toxicity LOAEL is 600 mg/kg/day (HDT), based on 

increased incidence of minor skeletal variations. The developmental 

toxicity NOAEL is 300 mg/kg/day.

Two generation 

reproduction- Rat

870.3800 (83-4)

00103197 (1981)

Acceptable/Guideline

0, 30, 1000 and 3000 ppm 

(0, 1.5, 50, and 150 

mg/kg/day)

The parental systemic toxicity LOAEL is 3000 ppm (150 mg/kg/day) 

based on decreased body weights that were associated with decreased 

food efficiency.

The parental systemic toxicity NOAEL is 1000 ppm (50 mg/kg/day).

The offspring systemic/developmental toxicity LOAEL is 3000 ppm 

(150 mg/kg/day), based on decreased body weights at birth and through 

weaning. The systemic/developmental toxicity NOAEL is 1000 ppm 

(50 mg/kg/day).

No effects were noted on reproductive parameters and no reproductive 

toxicity LOAEL was determined. The reproductive toxicity NOAEL is 

Metabolism- Rat

870.7485 (85-1)

41442101 (1989)

Acceptable/Guideline

3 and 300 mg/kg

Cyromazine was well absorbed after oral administration. Excretion was 

rapid at the lower dose (3 mg/kg), but an apparent delay in excretion 

occurred at the high dose (300 mg/kg). Fecal elimination was 

equivalent among dose groups except the high dose males, where a 

greater percentage was eliminated by this route. The origin of fecal 

radioactivity was via biliary elimination. Residual radioactivity in 

tissues was minimal in all dose groups. Urinary and fecal metabolites of 

14C_cyromazine were isolated and identified by TLC, HPLC, and 

GC/MS. The major compounds identified were the N-dealkylated 

product melamine, hydroxycyromazine, and un-metabolized cyromazine 

identified.
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Table A.2.2. Toxicology profile for Cyromazine

Study Type /

Guideline No.

MRID (Year) /

Classification / Doses Results

Dermal Absorption -

Rat

870.7600 (85-3)

40168601 (1987)

Acceptable/Guideline

0.10, 1.00, and 10 mg/rat

Absorption at 10 hrs = 13 %. Cyromazine apparently rapidly absorbed 

into the skin in an inverse dose related manner. The absorption into the 

skin is followed by a slower release into the body. The main route of 

excretion is apparently by the urine. There is no evidence that the 

compound is sequestered in the skin. 

Mean absorption based on blood, urinary/fecal excretion, and carcass, 

ranged from 0.6 to 7% for animals sacrificed at the end of the exposure 

periods. For animals exposed for 10 and 24 hours and followed for 48 

hours post-exposure, mean absorption ranged from 8 to 14.5%. Total 

radioactivity absorbed generally decreased as dose increased indicating 

saturation of absorption with increasing dose. Amounts remaining in/on 

the skin at termination ranged from 4.5% (10 mg dose/2 h exposure) to 

24% ( 0.1 mg dose/24 hour exposure). The majority of the absorbed 

radioactivity was found in the urine and carcass. Most of the 

unabsorbed radioactivity was found in the skin washes from each 

dose/duration.

Dermal Absorption -

Rat

870.7600 (85-3)

Accession No: 257488 

(1987)

Acceptable/Guideline

0.10, 1.00, and 100 mg/rat

Absorption at 10 hrs = 10%. 

Mean total recoveries of applied radioactivity from all dose groups 

ranged from 85 to 101%. Mean absorption based on blood, urinary/fecal 

excretion, and carcass, ranged from 2% to 11%. Total radioactivity 

absorbed generally increased with increasing exposure time but 

decreased with increasing dose indicating saturation of penetration with 

increasing dose. The majority of the absorbed radioactivity was found 

in the urine and carcass. Most of the unabsorbed radioactivity was 

found in the skin washes from each dose/duration (35-90%). However, 

based on measurements of skin absorption, a significant amount of 

radioactive dose was also found in the skin itself (9-40%). Mean 

absorption with inclusion of radioactivity in dissolved skin ranged from 

10 to 45%. The ratio of the amount of radioactive dose in the skin wash 

to the radioactivity in the skin itself decreased with time indicating 

penetration into the subsurface of the skin with time after treatment.

Mutagenicity

Gene mutation in 

Hamster (Chinese) - 

(84-4.) 

Mutagenic- Nucleus 

Anomaly)

MRID: 00103199 (1980)

Minimum 

acceptable/Guideline

Lavardex tech. 98.9% pure

2000, 4000, and 8000 mg/kg 

in 20 mL/kg 0.7% CMC 

solution

Negative mutagen.

Mutagenic - Point 

Mutation Salmonella 

typhimurium (84-4)

MRID: 0089923 (1978)

limited/Guideline 

25, 75, 255, 675 and 2025 

plate in DMSO, 

+ - S-9.

Negative results for point mutations in TA1537, TA1537, TA98, and 

TA100 with and without activation.

84-2b. Mutagenic. -

Dominant lethal test 

species: Mouse

(84-2b)

MRID:00103198 (1981)

limited/Guideline 

226 and 678 mg/kg in 

PEG400 vehicle (0.2 

mL/log of body weight)

Negative mutagen.
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A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) – All Populations

There were no toxicological effects attributable to a single exposure (dose) of cyromazine 

observed in the available oral toxicity studies including the developmental toxicity studies in rats 

or rabbits. An acute neurotoxicity study that could provide an endpoint for assessing acute 

dietary exposure is not available. Therefore, a dose and an endpoint for acute dietary exposure is

not identified for cyromazine and an acute aggregate exposure assessment is not required.

A.3.2 Chronic Reference Dose (cRfD) `

Selected Study: Combined chronic/carcinogenicity in the rat; MRID 00103202

In a 24-month chronic toxicity/oncogenicity study in rats, 60 Charles River Sprague-Dawley rats 

sex/dose were administered 0, 30, 300 and 3000 ppm of cyromazine. An additional 10 animals 

per sex in the control and 3000 ppm groups were designated for interim sacrifice at one year. 

The study design allocated groups of 60 rats per sex to dose levels of 0, 30, 300 or 3000 ppm (0, 

1.5, 15, 150 mg/kg/day) of cyromazine (95.5%). An additional 10 animals per sex in the control 

and 3000 ppm groups were designated for interim sacrifice at one year. The statistical evaluation 

of mortality provided by the registrant indicated no significant incremental charges with 

increasing doses of cyromazine in male or female rats (41% survival in HDT vs. 42% survival in 

controls). Survival in males and females were excellent in all groups after 24 months. There 

were no statistically significant differences between the control and treated groups in benign 

tumors (adenomas and fibroadenomas), malignant tumors (adenocarcinomas) or combined 

benign and malignant tumors (adenomas and/or fibroadenomas and/or adenocarcinomas); there 

were no statistical trends and no dose response. Hence, there was no evidence of carcinogenicity 

at the dose levels tested in this study. Female rats had decreased body weight gain at doses of 

300 and 3000 ppm, as did males at doses of 3000 ppm. Body weight gains were reduced by 22% 

in the high-dose males and 33% in females, and in the mid-dose females body weight gain was 

reduced by about 10% from week 49 until termination. Food consumption was also decreased at 

these dose levels; however food efficiency was unchanged from control. The systemic toxicity 

LOAEL is 300 ppm (15 mg/kg/day) based on decreased body weight. The systemic toxicity 

NOAEL is 30 ppm (1.5 mg/kg/day). There was no evidence of carcinogenicity.

Dose and Endpoint for Establishing a POD: NOAEL = 1.5 mg/kg/day day based on food 

consumption and body weight decreases at 15 mg/kg/day (LOAEL).

Uncertainty Factor (UF): 1000x (10x for interspecies variation and 10x for intraspecies 

variation and 10x database UF)

Chronic RfD = 1.5 mg/kg (NOAEL) = 0.0015 mg/kg

 1000 (UF)

[Note: The chronic RfD has been revised from previous risk assessments based on reevaluation 

of the existing data.]
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A.3.3 Incidental Oral Exposure (Short- and Intermediate-Term)

Cyromazine has not been registered for residential uses; therefore, selection of a toxicity 

endpoint is not necessary for this exposure scenario at this time.

A.3.4 Dermal Exposure (Short-, Intermediate- and Long-Term)

No hazard was identified via the dermal route of exposure and therefore quantification of risk via 

this route of exposure is not required. No systemic toxicity occurred in two 21-dermal rabbit 

toxicity studies at the highest doses tested of 2000 mg/kg/day.

A.3.6 Inhalation Exposure (Short- and Intermediate- Term) 

Inhalation Exposure (Short-Term)

Selected Study: 28-day inhalation toxicity study; MRID 47940804. In this subchronic inhalation 

toxicity study (28-Day), cyromazine (95% a.i) was administered to 60 Albino Rats {(Tif: RAIF 

(SPF), hybrids of RII/1 x RII/2strain} 5/sex/concentration by dynamic nose only exposure, for 4 

hours per day, 7 days/week for a total of 28 days. Nominal concentrations were 55, 210, or 710 

mg/m3 (0, 0.055, 0.210, or 0.710 mg/L) with analytical concentrations of 58±10, 206±13, and 

706±19 mg/m3. Additionally, one satellite control group (5 males and 5 females) and one 

satellite high dose (0.710 mg/L) group (5 males and 5 females) were allowed to survive for 3 

additional weeks then sacrificed to observe recovery. 

No clinical symptoms or signs of systemic toxicity were observed in the control animals. The test 

article-exposed animals of all exposure groups showed an impairment of the general condition 

with the symptoms of piloerection, dyspnea, hunched posture, and reduced spontaneous activity. 

The time of first occurrence, the duration, and the degree of clinical signs were concentrationdependent. No mortality was encountered in any group.

Body weights in males of all treatment groups were slightly (but not significantly) decreased 

when compared with the controls. This decrease was independent of the aerosol concentration. 

No exposure-related changes were observed in food consumption.

Hematology investigation revealed slightly higher values of red blood cell parameters 

(erythrocyte count, hemoglobin, packed cell volume) in the males of the high exposure group 

(710 mg/m3) at the end of the treatment period. At the end of the recovery period, the values 

returned back to normal. Blood chemistry data revealed no evidence of treatment-induced 

significant changes to the parameters measured.

Pituitary glands weight of the test article-exposed males was dose-dependently lower compared 

to controls after 4 weeks, however; in the satellite groups that were sacrificed at week 8, both 

weights were similar. Also, no corroborating microscopic effects on the pituitary were observed. 

Therefore, this effect was not considered adverse. The liver of the females of the mid (0.210 
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mg/L) and high (0.710 mg/L) dose groups showed a significantly higher weight than that of the 

controls. However, in the recovered satellite animals of the 0.710 mg/L group, liver weights 

returned back to normal. Also, no corroborating microscopic effects in the liver were observed. 

Therefore, this effect was not considered adverse. Gross examination revealed no changes which 

could be attributed to test article toxicity. Microscopic examination revealed 3 females from the 

0.710 mg/L group and one female from the 0.055 mg/L group with small foci of lymphocytic 

infiltration in the adrenal cortex. This change was absent in control female rats and was not dose 

dependent. Therefore, it was not considered adverse. 

The LOAEL is 0.055 mg/L/day based on impairment of the general condition with 

the symptoms of piloerection, dyspnea, hunched posture, and reduced spontaneous activity. 

The NOAEL was not observed.

Dose and Endpoint for Establishing a POD: The point of departure is the LOAEL of 

0.055 mg/L/day based on impairment of the general condition with the symptoms of 

piloerection, dyspnea, hunched posture, and reduced spontaneous activity. The NOAEL was not 

observed. This study is appropriate for use since it is route specific and the duration coincides 

with the short- (1-30 days) and intermediate- (1-6 mos) term scenarios. The study also provided 

a recovery group of animals which showed that adverse effects did reverse within 3 weeks.

The inhalation LOAEL of 0.055 mg/L/day is equivalent to 14.36 mg/kg/day oral dose using the 

following formula:

 mg/kg/day = mg/L x A x CF x D x AF (0.055 x 1 x 43.5 x 6 x 1 = 14.36)

where 

A is absorption factor. Default value of was used.

CF is a conversion factor in L/hr/kg to account for respiratory volume and body weight for a 

given species and strain. For the rat strain used in this study it is 43.5

D is duration of daily exposure in hours. A 6 hour daily exposure was used.

AF is activity factor. The animal default factor of 1 was used.

Uncertainty Factor (UF): 3000 – 10x for interspecies extrapolation, 10x for intraspecies 

variation, 3x for extrapolation of the study LOAEL to NOAEL, and 10x data base UF for the 

lack of neurotoxicity battery and immunotoxicity studies. The Agency’s RfD/RfC Technical 

Panel limits the total UF applied for any particular chemical to be 3000 (EPA/630/P-002F). , 

Clinical signs observed (piloerection, dyspnea, hunched posture, and reduced spontaneous 

activity) at the lowest concentration tested were not as severe as at the mid- and highest 

concentrations. The severity of the clinical signs at this lowest dose was slight and the observed 

clinical signs appeared mostly after 7 days of exposure. Piloerection increased to moderate after 

23 days of exposure at this lowest concentration. In contrast, the clinical signs at the mid and 

high exposure groups were more severe and appeared within 1--3 days after exposure. 

Following cessation of exposure during recovery, all the clinical signs in the high exposure 

group disappeared except for decreasing slight dyspnea and hunched posture. Although there 
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were no recovery groups in the mid and low exposure groups, it would also be expected that 

clinical signs would have resolved as in the high dose group, especially since the clinical signs 

were much less severe than in the high dose group. There were also no biologically significant 

changes in the hematological parameters at the lowest concentration tested of 0.055 mg/L, unlike 

the mid- and high-dose groups. All these data in a weight of evidence consideration suggests a 

steep dose-response curve, suggesting the low concentration is near a true no effect level. 

MOE: 3000 for short- and intermediate-term duration.

Comments about Study/Endpoint: Since the study selected is a route specific study, the 

inhalation study is the most appropriate for assessing the inhalation exposure of the short and 

intermediate duration.
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Appendix B. Physical/Chemical Properties

Table C1. Physicochemical Properties of Cyromazine (EPA Reg. No. 100-632 PAI).

Parameter Value Reference

Melting point/range 224-225 C MRID 40594903

pH 8.0 @ 25 C MRID 40594903

Density 1.35 g/mL @ 20 C MRID 40594903

Water solubility @ 20 C 1.16 g/ 100mL MRID 40594903

Solvent solubility(g/mL @25

C)

Hexane, not soluble

Cyclohexane, not soluble

Methanol, 1.49

Toluene, not soluble

Acetone, 0.16

2-Propanol, 0.13

Methylene chloride, 0.01

Octanol, 0.18

MRID 40594903

Vapor pressure 3.3 x 10-9 mm Hg @ 25 C MRID 40594903

Dissociation constant pKa1 value = 5.3 @ 20 C

pka2 value = 1.7 @ 20 C

MRID 40594903

Octanol/water partition 

coefficient

Log p = - 0.16 @ 25 ± 1 C MRID 40594903

UV/visible absorption 

spectrum

208 nm MRID 40594903
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Appendix C. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were 

intentionally exposed to a pesticide or other chemical. These studies were determined to require 

a review of their ethical conduct, have received that review and have been determined to be 

ethical.

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force 

members Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemicals 

Association, released February, 1995.

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupational Handler Unit Exposure 

Surrogate Reference Table. U.S. Environmental Protection Agency. Released June 21, 2011.