Cyromazine Human Health Risk Assessment DP No. 0414914 

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

MEMORANDUM 

Date: February 27,2014 

OFFICE OF 

CHEMICAL SAFETY AND 

POLLUTION PREVENTION 

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

PC Code: 121301 

Decision No.: 482882 

Petition No.: NA 

Risk Assessment Type: Human Health Risk 

Assessment 

DP Barcode: 04 14914 

Registration No.: None 

Regulatory Action: Registration Review 

Case No.: 7439 

TXRNo.: NA CASNo.: 66215-27-8 

MRI D No.: None 40 CFR: 180.414 

FROM: Ivan Nieves, ORE, Risk Assessor~-. Thu

Abdallah 

rston G. 

Khasaw

Morton, 

inah, 

Chemist 

Ph.D., To

~~ 

xicologist 

Risk Assessment Branch 4 

Health Effects Division (7509P) 

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

Susan V. Hummel, Branch Senior Scientis 

Risk Assessment Branch 4, HED (7509P) 

And , ~~c/~ Chr

Char

istine 

les Smit

Olinge

h, RARC 

r, RARC 

Des

Designated 

ignated Reviewer 

Rev ewe~ 

C~ 

t> ~ 

Risk Assessment Review Committee (RARC)/HED 

TO: James Parker 

Risk Management and Implementation Branch 1 

Pesticide Re-Evaluation Division (PRD) (7508P) 

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

Registration Review of the herbicide cyromazine. 

Page 1 of 58 
Cyromazine Human Health Risk Assessment DP No. D414914 

Table of Contents 

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

2.0 HED Recommendations ................................................................. .... .... .... ........................... 6 

2.1 Data Deficiencies ............................ ... .... .... .... .... .... .... .... .................................... ............... 6 

2.2 Tolerance Considerations ...................................................... .... ........ .. .. .... .... .................... 6 

2.2.1 Enforcement Analytical Method ............................ ................................ .... ......... .... ... 6 

3.0 International Harmonization ................................................................................................. 7 

4.0 Recommended Tolerances ............................................................................... .... ................. 7 

4.1 Label Recommendations .................................. .... ............ .... ............................................. 8 

5.0 Introduction ................................... ................................................................................... .... . 8 

5.1 Identity ............. ... ................................................................ .... .... .... .... .... ........ .................. 8 

5.2 Physical/Chemical Characteristics ...................................... .... .... .... .... .............................. 9 

5.3 Pesticide Use Pattern .................... .... ....... ............ .... .......................................................... 9 

5.4 Anticipated Exposure Pathways .......................... ............ .... .... .... .... ................................ 1 0 

5. 5 Consideration of Environmental Justice ......................................................................... 11 

6.0 Hazard Characterization and Dose-Response Assessment.. ....................................... ........ 11 

6.1 Toxicology Studies Available for Analysis ................................................................... .11 

6.2 Absorption, Distribution, Metabolism, & Elimination (ADME) ....................... ............. 12 

6.2.1 Dermal Absorption ................................................................................................... 13 

6.3 Toxicological Effects ............................ .... .... .... .... .......................................................... 13 

6.4 Safety factor for Infants and Children (FQPA Safety Factor) ........................................ 13 

6.4.1 Completeness ofthe Toxicology Database ............... ......................................... ..... . 14 

6.4.2 Evidence ofNeurotoxicity ..................... .... .... ... ..... ....................... ............. .... ..... ..... 14 

6.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal .......... 14 

6.4.4 Residual Uncertainty in the Exposure Database .............................. _. .... .... ............. .. 14 

6.5 Toxicity Endpoint and Point ofDeparture Selections .. ............ ....................................... 14 

6.5 .1 Dose-Response Assessment.. .... .... ............ .... .... ....................................................... 14 

6.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment.. ....... 15 

6.5.3 Cancer Classification and Risk Assessment Recommendation ............................... 15 

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

Assessment. ............................................................................................................................ 16 

6.6 Endocrine Disruption ............................................................................................ · ........... 17 

7.0 Dietary Exposure and Risk Assessment ............................................................................. 18 

7.1 Metabolite/Degradate Residue Profile ................................................ .. ......... ................. 18 

7 .1.1 S urnmary of Plant and Animal Metabolism Studies ................................................ 18 

7 .1.2 Summary of Environmental Degradation .................................................. ..... .... .... . 18 

7.1.3 Comparison of Metabolic Pathways ........................................................................ 19 

7 .1.4 Residues of Concern Summary and Rationale ........................................................ .19 

7.2 Food Residue Profile ....................................................................................................... 19 

7.3 Water Residue Profile .............................................................................. ........ .... ..... .... .. 22 

Page 2 of 58 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 3 of 58

7.4 Dietary Risk Assessment.................................................................................................23

7.4.1 Description of Residue Data Used in Dietary Assessment......................................23

7.4.2 Percent Crop Treated Used in Dietary Assessment .................................................23

7.4.3 Acute Dietary Risk Assessment...............................................................................23

7.4.4 Chronic Dietary Risk Assessment ...........................................................................23

7.4.5 Cancer Dietary Risk Assessment.............................................................................23

7.4.6 Summary Table........................................................................................................23

8.0 Residential (Non-Occupational) Exposure/Risk Characterization .....................................24

8.1 Residential Bystander Postapplication Inhalation Exposure...........................................24

8.2 Spray Drift.......................................................................................................................25

8.2.1 Children (1<2 yrs old) Hand-to-Mouth Risk Estimates From Lawn Deposition 

Adjacent to Applications........................................................................................................26

9.0 Aggregate Exposure/Risk Characterization........................................................................27

10.0 Cumulative Exposure/Risk Characterization......................................................................27

11.0 Occupational Exposure/Risk Characterization ...................................................................27

11.1 Short-/Intermediate- Handler Risk..................................................................................27

11.1.1 Bulb Onion Seed Treatment Occupational Handlers (Trigard OMC; EPA Reg. No. 

100-790).................................................................................................................................34

11.2 Short-/Intermediate-/Long-Term/Cancer (if needed) Post-Application Risk .................36

11.2.1 Dermal Postapplication Risk....................................................................................36

11.2.2 Inhalation Postapplication Risk ...............................................................................36

12.0 References...........................................................................................................................38

Appendix A. Toxicology Profile and Executive Summaries........................................................39

Appendix B. Physical/Chemical Properties..................................................................................54

Appendix C. Review of Human Research ....................................................................................58
Cyromazine Human Health Risk Assessment DP No. D414914

Page 4 of 58

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 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

Decreases in body weight and food consumption are the common features of cyromazine toxicity 

following subchronic or chronic oral exposures as seen in dogs, rats, mice, and rabbits. Other 

effects reported were organ weight (relative) changes and changes to some hematological 

parameters that were biologically insignificant and non adverse. There are no indicators in the 

hazard database for cyromazine to suggest a concern for immunotoxicity. 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. An acute neurotoxicity (ACN) study in rats demonstrated reduced motor 

activity as the main effect with no treatment related effects on mortality, brain weight or gross 

and histologic pathology or neuropathology up to the limit dose tested. 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 tested. There is no 

evidence of developmental toxicity following in utero exposures or that offspring are more 

susceptible following postnatal exposure. In the two-generation reproduction study in rats no 

reproductive effects were observed. Cyromazine was not carcinogenic in mice or rats following 

long-term dietary administration and is classified as a “Group E- Evidence of Noncarcinogenicity

for humans”. The available mutagenicity data suggest that cyromazine does not have genotoxic 

activity. Cyromazine is 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 (Category IV).

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. No developmental effects attributable to a single dose were seen following in utero

exposures to rats and rabbits; therefore, a dose and endpoint were not selected for acute oral 

exposure for the female 13 plus subpopulation. For the general population, the reduced motor 

activity seen at 250 mg/kg (LOAEL) in the acute neurotoxicity study was used to establish the 

point of departure (POD) for acute dietary exposure risk assessment. A 3X UF was applied to the 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 5 of 58

acute dietary POD for extrapolating from a LOAEL to NOAEL. The default 10X UF factor was 

reduced to 3X based on the ADME (absorption, distribution, metabolism and excretion) findings 

in rats. An endpoint of toxicity from the 2-generation study was selected as the POD for the 

chronic dietary assessment. The LOAEL of 150 mg/kg/day in this study was based on decreased 

body weight and decreased food efficiency with a NOAEL of 50 mg/kg/day. No dermal or 

systemic toxicity was observed following repeated dermal application at the limit dose tested to 

rabbits. A POD for the dermal scenario was therefore, not selected. A POD for short- and 

intermediate-term inhalation scenario was selected from a 28-day inhalation rat study based on 

the clinical signs of toxicity seen at the LOAEL. A NOAEL was not established in this 

inhalation rat study. A 3X uncertainty factor was applied for the extrapolation from a LOAEL in 

the inhalation study to NOAEL. The default 10X uncertainty factor was reduced to 3x because 

the effects seen were not severe at the LOAEL and were reversible upon exposure cessation. The 

MOE for assessing risk via occupational inhalation exposure is 100 which includes 10x for interspecies extrapolation, 3x-for intra-species variation based on human equivalent calculations 

(HEC), and 3x for the use a LOAEL (UFL) as the POD. There are no residential uses for 

cyromazine; however incidental oral exposure from spray drift is likely. To assess this incidental 

oral exposure resulting from spray drifts, a point of departure of 50 mg/kg/day derived from the 

2-gen study was used. 

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 along with the recommended tolerances for 

indirect residues of cyromazine from application of manure which has been treated with 

cyromazine to crop fields. Conservative acute and chronic dietary and drinking water risk 

assessments for cyromazine conclude that dietary and drinking water exposure estimates are 

below 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. All occupational handler scenarios risk estimates resulted below HED’s level of 

concern (LOC) at its lowest mitigation level (i.e., baseline) and therefore, not of concern to the 

Agency (i.e., MOEs ≥ 100 for short-and intermediate-term exposure durations).

For seed treatment (Trigard OMC; EPA Reg. No. 100-790) handler exposure, MOEs did not 

exceed HED's level of concern (i.e., MOEs ≥ 100) at baseline attire, except for the 

loader/applicator scenario that presented an MOE of 99. 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 and seed treaters and secondary handlers (i.e., planters). 

Handler exposure resulting from application of pesticides outdoors is likely to result in higher 

exposure than post-application exposure. It is expected that these handler inhalation exposure 

estimates would be protective of most occupational post-application inhalation exposure 

scenarios.
Cyromazine Human Health Risk Assessment DP No. D414914

Page 6 of 58

There are no currently registered or proposed residential uses of cyromazine. However, a spray 

drift assessment was conducted based on the potential for dermal and incidental oral exposure to 

occur as a result of drift from cyromazine being applied via aerial and groundboom equipment. 

Dermal risk estimates were not quantified since no dermal endpoint was identified. However,

incidental oral risk estimates were calculated since an incidental oral point of departure was 

selected (NOAEL of 50 mg/kg/day). Children’s (1<2 year old) incidental oral risk estimates 

from indirect exposure to cyromazine related to spray drift did not exceed HED’s level of 

concern (i.e., MOEs ≥ 100) at the edge of the field for both groundboom and aerial applications. 

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 C, 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 in this 

assessment 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.

2.0 HED Recommendations

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

discussed in Section 2.2.

2.1 Data Deficiencies

None.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate methods are available in Pesticide Analytical Manual (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 Human Health Risk Assessment DP No. D414914

Page 7 of 58

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

HED concluded that the data were acceptable and no additional cyromazine multiresidue method 

(MRM) recovery data were required.

3.0 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).

The current tolerance expression, which includes only cyromazine, is not in harmony with the

residue expression in Canada, which includes melamine (see Table B.2. in appendix B). 

However, data demonstrate that melamine is a minor residue from the use of cyromazine. Thus, 

HED recommends increasing established U.S. tolerances to numerically 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 (Table 4.0.2). 

4.0 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 (Table 4.0.1 below).

Table 4.0.1. Cyromazine Revised US Tolerances

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
Cyromazine Human Health Risk Assessment DP No. D414914

Page 8 of 58

Table 4.0.1. Cyromazine Revised US Tolerances

Commodity Existing US Tolerance (ppm) Revised US Tolerance

Mango 0.3 0.51

Milk 0.05 0.11

Mushroom 1.0 8.02

Onion, bulb, subgroup 3-07A 0.2 0.32

Pepper 1.0 3.02

Poultry, meat 0.05 0.11

Poultry, meat byproducts 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 level only. Tolerance expression is not harmonized.

Table. 4.0.2 Tolerance Summary for Cyromazine

Inadvertent Tolerances ppm

Vegetable, root and tuber, group 1 0.60

Vegetable, Leaves of root and tuber, group 2 0.60

Onion, bulb, subgroup 3-07A 0.60

Vegetable, Legume, group 6 0.60

Vegetable, Legume, foliage of, group 7 0.60

Vegetable, fruiting, group 8-10 0.60

Strawberry 0.60

Grain, cereal, group 15 0.60

Grain, cereal, forage, fodder and straw, group 16 0.60

Herbs and spices, group 19 0.60

Oilseed, group 20 0.60

4.1 Label Recommendations

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

5.0 Introduction

5.1 Identity

Structure and nomenclature are reported in Table 5.1.

Table 5.1. Cyromazine Nomenclature.

Chemical structure
Cyromazine Human Health Risk Assessment DP No. D414914

Page 9 of 58

Table 5.1. Cyromazine Nomenclature.

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

5.2 Physical/Chemical Characteristics

The physicochemical properties of cyromazine are reported in Appendix B. 

5.3 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. Maximum application rates for existing and proposed uses 

are provided in Table 5.3. Maximum rates are based on a review of active and proposed labels. 

Table 5.3. Summary of Cyromazine End-Use Products.

Product Name

(EPA Reg. 

No.)

Product 

Formulation Use Site Method of Application Application Rate

Trigard®

(100-654)

Water-Soluble 

Packets

(Wettable 

Powder)

(75% ai)

Abyssinian and seakale cabbage, bulb 

vegetables, cucurbits, certain varieties of 

dried beans, hanover salad, leafy vegetables 

including brassica, succulent beans, peppers, 

tomatoes, and turnip greens and control of 

Colorado potato beetle and leafminer in 

potatoes.

Foliar spray with 

ground equipment 

and/or aircraft

2.66 oz (one 

packet)/A

0.125 lb ai/A 

Label Instructions: Do not apply product through any type of irrigation system. Do not use in greenhouses. PHI = 7 days. REI = 

12 hours

Citation®

Insecticide

(100-667)

Wettable Powder 

in Water-Soluble 

Packet (75% ai)

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.

Foliar Spray with 

handheld 

equipment

0.125 lb ai/A

0.00125 lb ai/gal

Label Instructions: Do not make more than a total of 6 applications to one crop. Make no more than 3 applications at 7 day 

intervals. Apply 2.66 oz of product in 100 gallons of water as a spray or drench to all surfaces where insect pests may breed. 

REI = 12 hours

Trigard® OMC Wettable Powder Onion maggot control in bulb onions Seed Treatment 0.05 lb ai/lb seed
Cyromazine Human Health Risk Assessment DP No. D414914

Page 10 of 58

Table 5.3. Summary of Cyromazine End-Use Products.

Product Name

(EPA Reg. 

No.)

Product 

Formulation Use Site Method of Application Application Rate

(100-790) (75% ai)

Label Instructions: Do not use on agricultural establishments in hopper-box, planter-box, slurry-box, or other seed treatment 

applications at or immediately before planting. Only for use by licensed commercial seed treatment companies.

SolitudeTM IGR

(1007-93)

Granules (2.12% 

ai)

For fly control in and around horses, horse 

barns, horse stables and paddocks, horse race 

tracks. This product which, when mixed into 

a horse's ration will control certain fly 

species that develop in the horse manure.

Feed-through into 

horses' ration

300 mg (1 

scoop)/horse/day

0.00066 lb 

ai/horse/day

Label Instructions: Feed the recommended dosage to each horse separately. To be fed top-dressed on grain or mixed with horse's 

total ration.

Larvadex®1% 

Premix

(70585-1) Granules 

(1% ai)

For fly control in and around 1) caged or 

slatted flooring layer chicken operations 2) 

Breeder Chicken Operations

Feed-through 

blended into 

poultry ration

1 lb prod/ton feed

0.01 lb ai/ton of 

feed

FlyzineTM 1% 

Premix 

(75066-1)

Label Instructions: Treated feed must not be fed to layers and breeders for a minimum of 3 days before slaughter for food. 

During winter months or periods of low fly pressure, discontinue use for at least 4 consecutive months per year. Do not feed

treated feed to broiler poultry. Use is limited to chicken layer and breeder operations only; not to be fed to any other poultry 

species. Do not apply more than 3 tons of manure/acre/year. Do not feed treated manure to animals.

Armor® Insect 

Growth 

Regulator

(100-656) Liquid

(5% ai)

Mushroom compost to stop development of 

sciard fly larvae

Coarse drenching 

spray with lowpressure

43 oz prod/1,000 

sq ft

or

0.14 lb ai/1,000 sq 

ft

Cyromazine 

5%

(42750-222)

Label Instructions: Apply when preparing the mushroom substrate. Do not apply through any type of irrigation system. REI = 

12 hours

Larvadex®2SL

(70585-2) Liquid (2% ai) For fly control in and around chicken layer and breeder operations

Spray with 

handheld 

equipment

8.6x10-5lb ai/sq ft

(Dilution rate:

6.5 fl oz of 0.1% 

product/gal/100 sq 

ft; 0.17 lbs 

ai/gallon)

Label Instructions: Dilute Larvadex 2SL with water to make a 0.1 % spray. Apply 1 gallon of finished spray per 100 sq ft. 

Apply once every 21 days. Do not apply directly to poultry or poultry feed. Do not feed treated manure to animals. Allow 24 

hours between last application and slaughter. Do not use in conjunction with Larvadex 1% Premix; Do not apply more than 4 

tons of treated manure/acre/year. Do not apply treated manure to small grain crops to be harvested or grazed.

Neporex®2SG

(70585-7)

Soluble Granule 

(2% ai)

For Housefly, Lesser Housefly, Stable Fly 

and Soldier Fly Control in Cattle Operations, 

Hog Operations, Poultry Operations 

Including Layer and Breeder Chickens, and 

Horse Barns Where Horses are not Intended 

for Slaughter or Food

Dry Scattering 0.02 lb ai/200 ft2

Spraying

0.02 lb ai/200 ft2

or

4.36 bs ai/A

or 

0.02 lb ai/gal

Label Instructions: Apply only on fly breeding sites; not to fly resting sites (walls, ceilings, etc.). Use dry scattering only in case 

of wet or liquid manure. Do not apply more than once every 21 days. Do not administer via feed or drinking water or 

contaminate feed troughs or water troughs. Do not apply directly to livestock or livestock feed. Do not feed manure treated with 

product to animals. Allow 1 Day between last application and slaughter. Do not use in conjunction with Larvadex 1% Premix in 

chickens. Manure treated with product may be used as soil fertilizer, do not apply more than 4 tons of manure/Acre/year. Do not 

apply treated manure to small grain crops that will be harvested or grazed.

5.4 Anticipated Exposure Pathways
Cyromazine Human Health Risk Assessment DP No. D414914

Page 11 of 58

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 and incidental oral exposure from 

application spray drift. There are no residential uses of cyromazine; therefore, there is no 

exposure in residential settings. However, potential risk estimates from spray drift to children 

(1<2 years old) were evaluated to account for off-target movement of cyromazine from 

applications via groundboom and aerial equipment.

5.5 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 National Health and 

Nutrition Survey/What We Eat in America (NHANES/WWEIA) 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 and ethnic group. 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.

6.0 Hazard Characterization and Dose-Response Assessment

6.1 Toxicology Studies Available for Analysis

The studies available for consideration of cyromazine toxicity provide a complete database for 

selecting endpoints and points of departure for risk assessment. As part of the revised 40 CFR 

Toxicology Data Requirements, an immunotoxicity study is necessary for registered uses; 

however the HED Hazard and Science Policy Council (HASPOC) concluded using a weight-ofevidence approach that this study is not required at this time (TXR 0056806). Based on the 

findings in the ACN study and the total weight of evidence, HASPOC waived the requirement 

for the subchronic neurotoxicity study (TXR 0056682). The available studies are: 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 12 of 58

 Acute: Oral, dermal, inhalation, eye irritation, dermal irritation, and skin sensitization

 Subchronic: 90-day oral toxicity (rat, dog), 21-day dermal toxicity (rabbit), 21-day 

inhalation toxicity (rat)

 Developmental toxicity: developmental toxicity (rat and rabbit)

 Reproduction: 2-generation reproduction (rat)

 Chronic: combined oral chronic toxicity/carcinogenicity (rat), carcinogenicity (mouse), 

chronic oral toxicity (6-month dog)

 Neurotoxicity: Acute neurotoxicity (rat)

 Other: mutagenicity battery, metabolism, dermal penetration

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

The disposition and metabolism of 14C-cyromazine was investigated in male and female rats at a 

low oral dose (3 mg/kg), a low intravenous dose (3 mg/kg), repeated low oral doses (3 mg/kg) 

and a high dose (300 mg/kg). Comparison of oral and i.v. disposition data demonstrated that 

cyromazine was well absorbed after oral administration. Excretion was also rapid at the low 

dose, with the majority of radioactivity eliminated in the urine by 24 hours. At the high dose, 

however, there was an apparent delay in elimination of cyromazine derived radioactivity,

suggesting saturation of the metabolism sites.

Fecal elimination of 14C-cyromazine derived radioactivity was equivalent between dose groups 

and sexes, with the exception that in the high dose males, a greater percentage of radioactivity 

was apparently eliminated by this route. The origin of fecal radioactivity from administration of 

14Cyromazine was apparently biliary in nature, as an equivalent percentage of 14C-cyromazine 

derived radioactivity was eliminated by both orally dosed and intravenously dosed rats,

Residual 14C-cyromazine derived radioactivity was minimal in all dose groups, with nondetectable levels in all tissues examined except liver, red blood calls, and carcass. 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.

The disposition and metabolism of 14C-cyromazine was investigated in male and female rats at a 

low oral dose (3 mg/kg), a low intravenous dose (3 mg/kg), repeated low oral doses (3 mg/kg) 

and a high dose (300 mg/kg). Comparison of oral and i.v. disposition data demonstrated that 

cyromazine was well absorbed after oral administration. The time of peak effect in an ACN 

study was estimated to be 2 to 4 hours post-dosing based on the rapid absorption from the 

gastrointestinal tract following oral gavage. Excretion was rapid at the low dose (3 mg/kg), but 

an apparent delay in excretion occurred at the high dose (300 mg/kg) suggesting saturation of the 

metabolism sites. Urinary excretion accounted for 50% - 60% of the administered radioactivity 

at the 3 mg/kg dose, while it was 25% of the administered dose at the 300 mg/kg dose during the 

first 16 hours following oral dosing. Renal excretion was the primary route of elimination. 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 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 13 of 58

and identified by TLC, HPLC, and GC/MS. The major compounds identified were the Ndealkylated product melamine, hydroxy-cyromazine, and un-metabolized cyromazine.

6.2.1 Dermal Absorption

A dermal absorption factor of 13% was derived for cyromazine from two dermal absorption 

studies using 14C labeled cyromazine in rats. The amount absorbed was determined by the total 

radioactivity in blood, urine, feces, and carcass after 10 hours of exposure. Cyromazine is

absorbed via the skin in an inverse dose related manner. Total radioactivity absorbed generally 

decreased as dose increased indicating saturation of absorption with increasing dose. The 

absorption into the skin is followed by a slower release into the body. The main route of 

excretion of the absorbed cyromazine is in the urine.

6.3 Toxicological Effects

No specific toxicity was associated with cyromazine, with LOAELs occurring at relatively high 

doses. Decreases in body weight and food consumption are the common features of cyromazine 

toxicity following subchronic or chronic oral exposures as seen in dogs, rats, mice, and rabbits. 

Other effects reported were organ weight (relative) changes and changes to some hematological 

parameters that were biologically insignificant and non adverse. 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 tested. There is no evidence of developmental toxicity following in utero

exposures or that offspring are more susceptible following postnatal exposure. In the twogeneration reproduction study in rats no reproductive effects were observed. 

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 (increased incidence of minor skeletal 

variations) 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 “Group E- Evidence of Noncarcinogenicity for humans”. 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. 

(see Appendices for Toxicity Profile tables). 

6.4 Safety factor for Infants and Children (FQPA Safety Factor)
Cyromazine Human Health Risk Assessment DP No. D414914

Page 14 of 58

There are no residual uncertainties or concerns for pre- and/or post-natal toxicity; HED 

recommends the FQPA SF of 10x be reduced to 1x.

6.4.1 Completeness of the Toxicology Database

The toxicology database for cyromazine is complete for evaluating and characterizing 

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

toxicity endpoints and points of departure for risk assessment are based on the most sensitive and 

relevant data. 

6.4.2 Evidence of Neurotoxicity

There is no evidence of neurotoxicity in the cyromazine database including acute, subchronic or 

chronic dosing in multiple species. In the acute neurotoxicity study conducted in rats, reduced 

motor activity was seen with no treatment related effects on mortality, brain weight or gross and 

histological pathology or neuropathology up to the limit dose. Based on the findings in the ACN 

study and the total weight of evidence, HASPOC waived the requirement for the subchronic 

neurotoxicity study (TXR 0056682). The HED HIARC concluded in 2002 that there is not a 

concern for developmental neurotoxicity resulting from exposure to cyromazine (TXR NO. 

0050774).

 

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

There is no evidence of susceptibility following in utero and/or postnatal exposure in the 

developmental toxicity studies in rats or rabbits, and in the 2-generation rat reproduction study. 

In the prenatal developmental rat toxicity study, the NOAEL (300 mg/kg/day) for developmental 

effects (increased incidence of minor skeletal variations) was higher than the maternal NOAEL 

(100 mg/kg/day). 

6.4.4 Residual Uncertainty in the Exposure Database

The acute and chronic dietary exposure analyses used tolerances and 100 percent crop treated. 

The dietary assessment is not a highly refined assessment. Therefore, dietary exposure to 

cyromazine will not be underestimated.

6.5 Toxicity Endpoint and Point of Departure Selections

6.5.1 Dose-Response Assessment

The toxicity endpoints and points of departure are presented in Table 6.5.4 below, and the details 

for selecting toxicity endpoints and points of departure for various exposure scenarios are 

presented in Appendix A.

The most sensitive and protective endpoints from the toxicity database were selected to establish 

points of departure for the risk assessment. No developmental effects attributable to a single 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 15 of 58

dose were seen following in utero exposures to rats or rabbits; therefore, a dose and endpoint 

were not selected for acute oral exposure for the female 13 - 49 subpopulation. For the general 

population, the reduced motor activity (↓44%) seen at 250 mg/kg (LOAEL) in the acute 

neurotoxicity study was used to establish the point of departure (POD) for acute dietary 

exposure. A 3X UF was applied to the acute dietary POD for extrapolating from a LOAEL to 

NOAEL. The default 10X LOAEL to NOAEL UF factor was reduced to 3X based on the ADME 

(absorption, distribution, metabolism and excretion) findings in rats. As discussed in section 4.2 

ADME data (MRID 41442101) suggests that 250 mg/kg/day is a dose that saturated the animals 

metabolic capabilities in the ACN study. It is therefore believed that at doses below saturation, 

the chemical would be cleared from the body and would not produce the effects observed in the 

ACN study. 

A dose of 150 mg/kg/day in chronic exposure studies resulted in minimal effects (body weight 

decrements). An endpoint from the 2-generation study was selected as the POD of 50 mg/kg/day 

for the chronic dietary assessment. The LOAEL of 150 mg/kg/day in this study was based on

decreased body weight and decreased food efficiency. The combined chronic/carcinogenicity 

study was co-critical with the selected 2-genration reproduction study where the LOAEL of 150 

mg/kg/day was also based on decreased body weight and decreased body weight gain and lower 

food consumption.

No dermal or systemic toxicity was observed following repeated dermal application at the 

highest dose tested to rabbits. A POD for the dermal scenario was therefore not selected. A 

POD for short- and intermediate-term inhalation scenario was selected from a 28-day inhalation 

rat study based on the LOAEL. The LOAEL in this inhalation study was 0.055 mg/L/day based 

on impairment of the general condition with the symptoms of piloerection, dyspnea, hunched 

posture, and reduced spontaneous activity. A NOAEL was not established in this inhalation rat 

study. A 3X uncertainty factor was applied for the use of a LOAEL. The default 10X 

uncertainty factor was reduced to 3x because the effects seen were slight in degree and not 

severe at the LOAEL and were reversible upon exposure cessation. A human equivalent 

concentration was derived and the interspecies variation uncertainty factor was reduced to 3x.

There are no residential uses for cyromazine; however incidental oral exposure from spray drift 

is likely. To assess this incidental oral exposure resulting from spray drift a point of departure of 

50 mg/kg/day derived from the 2-generation study (co-critical with the chronic/carcinogenicity 

study) cited above was used.

6.5.2 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. There are 

no common endpoints to combine routes of exposure.

6.5.3 Cancer Classification and Risk Assessment Recommendation

Cyromazine is classified as a “Group E- Evidence of Noncarcinogenicity for humans” based on 

the lack of evidence of carcinogenicity in the mouse and rat cancer studies (HED CPRC, TXR 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 16 of 58

No. 0011384, 1/6/95). Cyromazine was not mutagenic in three mutagenicity studies submitted to 

OPP.

6.5.4 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 6.5.4. Summary of Toxicological Doses and Endpoints for Cyromazine for Use in Dietary, NonOccupational and Occupational Human Health Risk Assessments 09-27-2013

Exposure/

Scenario

Point of 

Departure

Uncertainty

/FQPA 

Safety 

Factors

RfD, PAD, 

LOC for Risk 

Assessment

Study and Toxicological Effects

Acute Dietary

females 13+

No developmental effects attributable to a single dose were seen following in utero

exposures to rats and rabbits

Acute Dietary

(general population)

LOAEL = 

250 mg/kg

UFA = 10x

UFH = 10x

UFL = 3x

aRfD = 0.83 

mg/kg

aPAD = 0.83 

mg/kg

ACN Study in rats, MRID 

49109701

LOAEL = 250 mg/kg BW based 

on decreased motor activity (mean 

cumulative ambulatory LMA 

counts (↓ 44%) in males at the time 

of peak effect on Day 0, and 

decreased food consumption (p < 

.01, ↓17.4%) on Day 1.

Chronic Dietary 

(All Populations)

NOAEL= 

50 

mg/kg/day

UFA = 10x

UFH = 10x

cRfD = 0.5

mg/kg/day

cPAD = 0.5 

mg/kg/day

2 Generation Reproductive Study

(MRID 00103197 ) co-critical with 

Chronic Carcinogenicity Study 

(MRID 00103202, 00115735 ) in 

the rat

LOAEL = 150 mg/kg/day for 

decreased body weight and 

decreased food efficiency.

Incidental Oral

Short-Term

(1 - 30 Days)

NOAEL= 

50 

mg/kg/day

UFA = 10x

UFH = 10x

LOC for MOE 

= 100

2 Generation Reproductive Study

(MRID 00103197 ) co-critical with 

Chronic Carcinogenicity Study 

(MRID 00103202, 00115735 ) in 

the rat

LOAEL = 150 mg/kg/day for 

decreased body weight and 

decreased food efficiency.

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.
Cyromazine Human Health Risk Assessment DP No. D414914

Page 17 of 58

Table 6.5.4. Summary of Toxicological Doses and Endpoints for Cyromazine for Use in Dietary, NonOccupational and Occupational Human Health Risk Assessments 09-27-2013

Exposure/

Scenario

Point of 

Departure

Uncertainty

/FQPA 

Safety 

Factors

RfD, PAD, 

LOC for Risk 

Assessment

Study and Toxicological Effects

Inhalation Short- to 

Intermediate Term 

(1-day – 6 months) 

LOAEL= 

0.055 mg/L

Equivalent 

to HEC of 

0.04012

mg/L*

HED for 

applicators

2.28 

mg/kg/day;

For 

handlers: 

4.59 

mg/kg/day; 

for the 

hand-held 

sprayers: 

7.98 

mg/kg/day

UFA = 3x**

UFH =10x

UFL = 3x

Occupational 

LOC for MOE 

= 100

28-day Inhalation Toxicity study in 

rats MRID 47940804

LOAEL = 0.055 mg/L 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)

Cancer classification (Group E- Evidence of Noncarcinogenicity for humans) (HED 

CPRC, TXR No. 0011384, 1/6/95); Risk Assessment not required.

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). UFL = extrapolation from LOAEL to NOAEL: this was reduced to 3x based on the reasons explained in the 

text.

SF = FQPA Safety Factor.

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

RfD = reference dose.

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

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

*mg/L conversion to Human Equivalent Dose (HED) mg/kg/day, see Appendix.

** the UFA was reduced to 3x based on the conversion of the animal concentration to human equivalent concentration (HEC). 

6.6 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 for cyromazine, EPA reviewed these data 

and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing 

hazard database. However, as required by FFDCA section 408(p), cyromazine is subject to the 

endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).
Cyromazine Human Health Risk Assessment DP No. D414914

Page 18 of 58

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

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

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

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

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

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

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

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

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

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

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

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between

October 2009 and February 2010, EPA issued test orders/data call-ins for the first group of 67

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

of chemicals identified for EDSP screening was published on June 14, 20131and includes some

pesticides scheduled for registration review and chemicals found in water. Neither of these lists

should be construed as a list of known or likely endocrine disruptors.

Cyromazine is on List 2. List 2 represents the next set of chemicals for which EPA intends to 

issue test orders/data call-ins in the near future. For further information on the status of the

EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the

Tier 1 screening battery, please visit our website2.

7.0 Dietary Exposure and Risk Assessment 

7.1 Metabolite/Degradate Residue Profile

7.1.1 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).

7.1.2 Summary of Environmental Degradation

 

1

See http://www.regulations.gov/#!documentDetail;D=EPA-HQ-OPPT-2009-0477-0074 for the final second list of

chemicals.

2

 http://www.epa.gov/endo/
Cyromazine Human Health Risk Assessment DP No. D414914

Page 19 of 58

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 

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. 

7.1.3 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. 

7.1.4 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 7.1.4. 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 7.1.4: 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.

7.2 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, 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 20 of 58

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). 

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

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.
Cyromazine Human Health Risk Assessment DP No. D414914

Page 21 of 58

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. 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 22 of 58

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.

7.3 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. Drinking water residues were provided by the 

Environmental Fate and Effects Division Table 7.3.1 (EFED; D398026, T. Dowen, 2/10/12). 

Because PRZM-GW was not available as a screening level model at the time of the cyromazine 

DWA and the PRZM-GW model is being used in FQPA drinking water assessments to estimate 

pesticide concentrations in ground water sourced drinking water, PRZM-GW modeling for 

cyromazine was conducted to update the DWA to adhere to current Agency policy. The 

estimated concentrations in drinking water (EDWC) of cyromazine are not expected to exceed 

111 μg/L for a daily peak concentration in ground water (acute) and 86 μg/L for the average 

breakthrough concentration in ground water (chronic) (Table 7.3.2). Cyromazine is expected to 

breakthrough into ground water between 3 to 7 years. 

PRZM-GW modeling was conducted using PRZM-GW (version 1.0). Application rate, number, 

and interval are representative of the current maximum label rate for beans. The first pesticide 

application date was May 1 for all the PRZM-GW scenarios. The ground water modeling was 

conducted using a different hydrolysis half-life (stable) and aerobic soil metabolism half-life 

(450 days) than used in the DWA (DP 398026, 2/10/12). As per input parameter guidance, the 

upper 90th percent confidence limit (CL) of mean aerobic soil metabolism half-life (147.3 days) 

was used because there are three aerobic soil metabolism half-lives for cyromazine. A 

hydrolysis half-life of 400 days was estimated from abiotic hydrolysis data. 

Table 7.3.1. Previous Estimated Drinking Water Concentrations of Cyromazine in Drinking Water.

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
Cyromazine Human Health Risk Assessment DP No. D414914

Page 23 of 58

Table 7.3.2. Estimated Drinking Water Concentrations of Cyromazine in Ground Water Source Drinking 

Water.

Scenario Peak Chronic Breakthrough Time

μg/L Days

WI Corn 90.6 71.3 2581

NC Cotton 38.3 30.4 1089

FL Citrus 111 86.1 1104

MD Corn 94.2 77.8 1089

7.4 Dietary Risk Assessment

7.4.1 Description of Residue Data Used in Dietary Assessment

Tolerance level residues and 100 percent crop treated assumptions were used. DEEM default 

and empirical processing factors were used to modify the tolerance values. The acute analysis 

incorporated the peak EDWC of 75.5 ug/L while the chronic analysis incorporated the chronic 

EDWC for cyromazine. 

7.4.2 Percent Crop Treated Used in Dietary Assessment

Percent crop treated information was not used in the acute and chronic dietary exposure analyses.

7.4.3 Acute Dietary Risk Assessment

A conservative acute dietary exposure analysis was performed for the general U.S. population 

and various population subgroups. Acute dietary risk estimates are not of concern for general 

population or other population subgroups. The subgroup with the highest risk estimate was 

children 1-2 years old with a aPAD of 18%. The aPAD for the general U.S. population was 

7.5%.

7.4.4 Chronic Dietary Risk Assessment

A conservative chronic dietary exposure analysis was performed for the general U.S. population 

and various population subgroups. Chronic dietary risk estimates are not 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 8.2%. The cPAD for the general U.S. population was 

3.8%.

7.4.5 Cancer Dietary Risk Assessment

Cyromazine is classified as a “Group E- Evidence of Noncarcinogenicity for humans” based on 

the lack of evidence of carcinogenicity in the mouse and rat cancer studies (HED CPRC, TXR 

No. 0011384, 1/6/95). Therefore, a cancer dietary risk assessment was not performed.

7.4.6 Summary Table
Cyromazine Human Health Risk Assessment DP No. D414914

Page 24 of 58

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

are below HED’s level of concern; see Table 7.4.6.1 and 7.4.6.2. 

Table 7.4.6.1: Summary of Acute Dietary (Food and Water) Exposure and Risk for Cyromazine

Population Subgroup aPAD (mg/kg/day) Acute

Exposure (mg/kg/day) % aPAD

General U.S. Population

0.83

0.063037 7.6

All Infants (< 1 year old) 0.054077 6.5

Children 1-2 years old 0.148758 18

Children 3-5 years old 0.102108 12

Children 6-12 years old 0.061079 7.4

Youth 13-19 years old 0.041088 5.0

Adults 20-49 years old 0.057766 7.0

Adults 50-99 years old 0.067807 8.2

Females 13-49 years old 0.059258 7.1

Table 7.4.6.2: Summary of Chronic Dietary (Food and Water) Exposure and Risk for Cyromazine.

Population Subgroup cPAD (mg/kg/day) Chronic

Exposure (mg/kg/day) % cPAD

General U.S. Population

0.50

0.041309 8.3

All Infants (< 1 year old) 0.032854 6.6

Children 1-2 years old 0.021037 4.2

Children 3-5 years old 0.013667 2.7

Children 6-12 years old 0.017346 3.5

Youth 13-19 years old 0.018921 3.8

Adults 20-49 years old 0.017374 3.5

Adults 50-99 years old 0.041309 8.3

Females 13-49 years old 0.032854 6.6

8.0 Residential (Non-Occupational) Exposure/Risk Characterization

There are no currently registered residential uses of cyromazine. 

8.1 Residential Bystander Postapplication Inhalation Exposure

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

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

inhalation toxicity (Toxicity Category IV), and low vapor pressure (3.3 x 10-9 mm Hg @ 25 oC). 

However, volatilization of pesticides may be a source of post-application inhalation exposure to 

individuals nearby pesticide applications. 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, 20103. The Agency is in the process of evaluating the SAP report and may, as 

appropriate, develop policies and procedures to identify the need for and, subsequently, the way 

to incorporate post-application inhalation exposure into the Agency's risk assessments. If new 

 

3 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html
Cyromazine Human Health Risk Assessment DP No. D414914

Page 25 of 58

policies or procedures are developed, the Agency may revisit the need for a quantitative postapplication inhalation exposure assessment for cyromazine.

8.2 Spray Drift

Off-target movement of pesticides can occur via many types of pathways and it is governed by a 

variety of factors. Sprays that are released and do not deposit in the application area end up offtarget and can lead to exposures to those it may directly contact. They can also deposit on 

surfaces where contact with residues can eventually lead to indirect exposures (e.g., children 

playing on lawns where residues have deposited next to treated fields). The potential risk 

estimates from these residues can be calculated using drift modeling onto 50 feet wide lawns 

coupled with methods employed for residential risk assessments for turf products. The approach 

to be used for quantitatively incorporating spray drift into risk assessment is based on a premise 

of compliant applications which, by definition, should not result in direct exposures to 

individuals because of existing label language and other regulatory requirements intended to 

prevent them.4 Direct exposures would include inhalation of the spray plume or being sprayed 

directly. Rather, the exposures addressed here are thought to occur indirectly through contact 

with impacted areas, such as residential lawns, when compliant applications are conducted. 

Given this premise, exposures for children (1 to 2 years old) and adults who have contact with 

turf where residues are assumed to have deposited via spray drift thus resulting in an indirect 

exposure are the focus of this analysis analogous to how exposures to turf products are 

considered in risk assessment. 

In order to evaluate the drift potential and associated risks, an approach based on drift modeling 

coupled with techniques used to evaluate residential uses of pesticides was utilized. Essentially, 

a residential turf assessment based on exposure to deposited residues has been completed to 

address drift from the agricultural applications of cyromazine. In the spray drift scenario, the 

deposited residue value was determined based on the amount of spray drift that may occur at 

varying distances from the edge of the treated field using the AgDrift (v2.1.1) model and the 

Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of 

Spray Drift Policy. Once the deposited residue values were determined, the remainder of the 

spray drift assessment was based on the algorithms and input values specified in the recently 

revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs). 

A screening approach was developed based on the use of the AgDrift model in situations where 

specific label guidance that defines application parameters is not available.5 AgDrift is 

appropriate for use only when applications are made by aircraft, airblast orchard sprayers, and 

groundboom sprayers. When AgDrift was developed, a series of screening values (i.e., the Tier 

1 option) were incorporated into the model and represent each equipment type and use under 

varied conditions. The screening options specifically recommended in this methodology were 

selected because they are plausible and represent a reasonable upper bound level of drift for 

common application methods in agriculture. These screening options are consistent with how 

spray drift is considered in a number of ecological risk assessments and in the process used to 

develop drinking water concentrations used for risk assessment. In all cases, each scenario is to 

 

4 This approach is consistent with the requirements of the EPA’s Worker Protection Standard.

5

http://www.agdrift.com/ 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 26 of 58

be evaluated unless it is not plausible based on the anticipated use pattern (e.g., herbicides are 

not typically applied to tree canopies) or specific label prohibitions (e.g., aerial applications are 

not allowed). 

8.2.1 Children (1<2 yrs old) Hand-to-Mouth Risk Estimates From Lawn Deposition 

Adjacent to Applications

The spray drift risk estimates are based on an estimated deposited residue concentration as a 

result of the screening level agricultural application scenarios. Cyromazine is used on Brassica 

(cole) leafy vegetables group 5 (i.e., abyssinian cabbage; bok choy; broccoli; Brussels sprouts) 

and turnip greens; and can be applied via groundboom, and aerial equipment. The recommended 

drift scenario screening level options are listed below: 

 Groundboom applications are based on the AgDrift option for high boom height and 

using very fine to fine spray type using the 90th percentile results. 

 Aerial applications are based on the use of AgDrift Tier 1 aerial option for a fine to 

medium spray type.

Dermal risk estimates were not quantified since no dermal endpoint was identified. However,

incidental oral risk estimates were calculated since an incidental oral point of departure was 

selected from a 2 Generation Reproductive Study (MRID 00103197) co-critical with a Chronic 

Carcinogenicity Study (MRID 00103202, 00115735) in the rat. The NOAEL identified was 50 

mg/kg/day. 

The total applicable Level of Concern is 100 so MOEs < 100 would be of concern. Children’s 

(1<2 year old) incidental oral risk estimates from indirect exposure to cyromazine related to 

spray drift did not exceed HED’s level of concern (i.e., MOEs ≥ 100) at the edge of the field for 

both groundboom and aerial applications Results for the drift scenarios of the highest 

application rate assessed are presented in Table 8.2.1 below. 

Table 8.2.1. Children (1<2 years old) Risk Estimates (MOEs) Related to Indirect Exposure to Spray Drift for Cyromazine for the 

Incidental Oral Route of Exposure

Equipment Spray Type/ Nozzle Configuration App.Rate (lb 

ai/A) TTRt (ug/cm2

)

At Edge 

HtM MOE 

Aerial Fine to Medium

0.125 0.014

 100,000 

Groundboom High Boom Very fine to Fine 140,000 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 27 of 58

9.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks 

from dietary (food and water) and residential (dermal, inhalation, and/or incidental oral) sources. 

When aggregating exposures and risks from these sources, HED considers the route and duration 

of exposure as well as the toxicological effects for each route. Aggregate risk assessments 

evaluate the combined risk from dietary exposure (food and water) and any non-occupational 

(residential) uses. There are currently no registered residential uses associated with cyromazine;

therefore, a residential/non-occupational exposure assessment is not required. As a result, the 

cyromazine aggregate risk assessment includes only dietary exposure (food and water). The 

acute and chronic dietary exposure estimates from food and drinking water do not exceed HED’s 

level of concern (see Sections 5.4.3 and 5.4.4).

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

was classified as a “Group E- Evidence of Noncarcinogenicity for humans”. Therefore, a cancer 

aggregate risk assessment is not required.

 

10.0 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/.

11.0 Occupational Exposure/Risk Characterization

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 action.

11.1 Short-/Intermediate- Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide 

application process. HED believes that there are distinct job functions or tasks related to 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 28 of 58

applications and exposures can vary depending on the specifics of each task. Job requirements 

(amount of chemical used in each application), the kinds of equipment used, the target being 

treated, and the level of protection used by a handler can cause exposure levels to differ in a 

manner specific to each application event. 

Based on the anticipated use patterns and current labeling, types of equipment and techniques 

that can potentially be used, occupational handler exposure is expected from the proposed uses. 

The quantitative exposure/risk assessment developed for occupational handlers is based on the 

following scenarios based on their different product formulations: 

Wettable Powder Formulations

Trigard (75% ai):

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

(engineering controls);

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

application (engineering controls);

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

• applying sprays with open cab groundboom sprayer; and

• flagging sprays for aerial operations.

Citation (75% ai):

• Mixing/loading/applying wettable powder packaged in water-soluble packets with a 

backpack sprayer, a manually-pressurized handwand and a mechanically pressurized 

handgun sprayer.

Liquid Formulations

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

• Mixing/loading liquids; and 

• mixer/loader/applicator with a backpack sprayer, a manually-pressurized handwand and a 

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; and 

• mixer/loader/applicator with a backpack sprayer, a manually-pressurized handwand and a 

mechanically pressurized handgun sprayer.

Occupational Handler Exposure Data and Assumptions
Cyromazine Human Health Risk Assessment DP No. D414914

Page 29 of 58

A series of assumptions and exposure factors served as the basis for completing the occupational 

handler risk assessments. Each assumption and factor is detailed below on an individual basis.

Application Rate: Application rates were based on the registered labels (see Table 5.3). 

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 chemical-specific data, 

include PHED 1.1, the 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 Table6”, which, along with additional information on HED policy 

on use of surrogate data, including descriptions of the various sources, can be found at the 

Agency website7. 

Area Treated or Amount Handled: 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

• 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.

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

• 40 gallons/day for mixing/loading/applying with a backpack sprayer and a manuallypressurized handwand.

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

sprayer. 

Liquid Formulations

• 1 A/day for mixing/loading liquids.

• 43,560 sq ft/day for mixing/loading/applying with a backpack sprayer, a manuallypressurized handwand, and a mechanically pressurized handgun sprayer.

• 576,000 sq ft/day for mixing/loading liquids to mushroom compost wharves [personal 

communications with the American Mushroom Institute (I. Nieves, 11/10/2011)].

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

a mechanically pressurized handgun sprayer to mushroom compost wharves [personal 

communications with the American Mushroom Institute (I. Nieves, 11/10/2011)]. 

Granular Formulations

 

6 Available: http://www.epa.gov/opp00001/science/handler-exposure-table.pdf

7 Available: http://www.epa.gov/pesticides/science/handler-exposure-data.html
Cyromazine Human Health Risk Assessment DP No. D414914

Page 30 of 58

• 1,000 horses/day for mixing/loading granules for feed-through fly control. 

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

• 1000 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.

Exposure Duration: HED classifies exposures from 1 to 30 days as short-term and exposures 30 

days to six months as intermediate-term. Exposure duration is determined by many things, 

including the exposed population, the use site, the pest pressure triggering the use of the 

pesticide, and the cultural practices surrounding that use site. For most agricultural uses, it is 

reasonable to believe that occupational handlers will not apply the same chemical every day for 

more than a one-month time frame; however, there may be a large agribusiness and/or 

commercial applicators who may apply a product over a period of weeks (e.g., completing 

multiple applications for multiple clients within a region).

Based on use patterns, short-and intermediate- term exposures were expected but since no dermal 

endpoint was identified and the inhalation endpoint selected is the same for short- and 

intermediate-term exposure, risk estimate quantification is inclusive of both durations. Chronic 

exposures (i.e., greater than 6 months) are not expected.

Mitigation/Personal Protective Equipment: Estimates of inhalation exposure were calculated for 

baseline attire defined as a single layer of clothing consisting of a long sleeved shirt, long pants, 

shoes plus socks, no protective gloves, and no respirator. Current registered labels recommend 

handlers to wear long sleeved shirt, long pants, shoes plus socks, and protective gloves.

Summary of Occupational Handler Non-Cancer Exposure and Risk Estimates

Table 11.1. presents the exposure/risks for short and intermediate-term inhalation exposures at 

baseline and with engineering controls (for aerial equipment). All of the risk estimates are below 

HED’s level of concern (LOC) at the lowest mitigation level (i.e., baseline) and, therefore, are 

not of concern to the Agency (i.e., MOEs ≥ 100 for short-and intermediate-term exposure 

durations).
Cyromazine Human Health Risk Assessment DP No. D414914

Page 31 of 58

Table 11.1. 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

(μg/lb ai)

Maximum 

Application 

Rate 2

Amount 

Treated 

Daily 3

Inhalation Route of 

Exposure

Mitigation 

Level

Dose 4

(mg/kg/day)

MOE 5

(LOC = 

100)

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

0.24

(Eng. 

Controls)

0.125

(lbs ai/A)

350

(A/day) 0.00013 61,000e

Mixing/Loading Wettable 

Powder packaged in 

Water-Soluble Packets for 

Groundboom Application

80

(A/day) 0.000030 270,000e

Mixing/Loading Liquids

Sciard fly control in mushrooms 0.219

(Baseline)

0.00014

(lbs ai/sq ft)

576,000a

(sq ft) 0.00022 21,000f

For fly control in and around chicken layer and 

breeder operations only

3.75

(lb ai/A)

1

(A) 0.0000103 450,000f

Mixing/Loading Granules

Feedthrough application for fly control in and 

around horses, horse barns, horse stables and 

paddocks, horse race tracks 1.7

(Baseline)

0.00066

(lb ai/horse)

1,000

(horses/day)b 0.000014 570,000e

Feedthrough application for the control of fly larvae 

in poultry manure.

0.010

(lb ai/ton 

feed)

100

(tons 

feed/day)c

0.000021 370,000e

Applicator

Applying Sprays with 

Fixed-wing Aircraft

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

0.0049

(Eng. 

Controls)

0.125

(lbs ai/A)

350

(A/day) 0.0000027 3,000,000e

Applying Sprays with 

Open Cab Groundboom 

Sprayer

0.34

(Baseline)

80

(A/day) 0.000043 54,000g
Cyromazine Human Health Risk Assessment DP No. D414914

Page 32 of 58

Table 11.1. 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

(μg/lb ai)

Maximum 

Application 

Rate 2

Amount 

Treated 

Daily 3

Inhalation Route of 

Exposure

Mitigation 

Level

Dose 4

(mg/kg/day)

MOE 5

(LOC = 

100)

Loading/Applying 

Granules, Belly Grinder Control of fly larvae in cattle, hog, and poultry 

operations

62

(Baseline)

4.36

(lb ai/A)

1

(A/day) 0.0034 2,400e

Applicator, Granules by 

Hand (No Respirator)

470

(Baseline)

0.02 lb ai/200 

ft2 1,000 sq. ft. 0.00059 14,000e

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 rape greens) and turnip greens

0.35

(Baseline)

0.125

(lbs ai/A)

350

(A/day) 0.00019 42,000e

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

30

(Baseline) 0.00125

(lb ai/gal)

Wettable 

Powder 

Formulation

40

(gal/day) 0.000019 420,000e

Backpack Sprayer 140

(Baseline)

40

(gal/day) 0.000088 53,000f

Mechanically-pressurized 

Handgun Sprayer 

120

(Baseline)

1,000

(gal/day) 0.0019 4,200e

Manually-pressurized 

Handwand Sciard fly control in mushrooms

30

(Baseline)

1.4x10-4

(lb ai/sq. ft.)

Liquid 

Formulation

43,560 sq. ft.

(1 acre)/dayd

0.0023 3,500e

Mechanically pressurized 

Handgun Sprayer

120

(Baseline) 0.0092 870e

Backpack 

Sprayer/Manuallypressurized Handwand fly control in and around chicken layer and breeder 

operations

30

(Baseline)

8.6x10-5

(lb ai/sq ft)

Liquid 

Formulation

43,560 sq. ft.

(1 acre)/day

0.0014 5,700e

Mechanically pressurized 

Handgun Sprayer

79

(Baseline) 0.0037 2,200e
Cyromazine Human Health Risk Assessment DP No. D414914

Page 33 of 58

Table 11.1. 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

(μg/lb ai)

Maximum 

Application 

Rate 2

Amount 

Treated 

Daily 3

Inhalation Route of 

Exposure

Mitigation 

Level

Dose 4

(mg/kg/day)

MOE 5

(LOC = 

100)

Backpack 

Sprayer/Manuallypressurized Handwand Control of fly larvae in cattle, hog, and poultry 

operations

30

(Baseline)

0.020

(lb ai/gal)

Dry Flowable 

Formulation

40

(gal/day) 0.00030 27,000e

Mechanically pressurized 

Handgun Sprayer

79

(Baseline)

1,000

(gal/day) 0.020 400e

1. PHED/ORETF (level of mitigation: Baseline and Eng. Controls)

2. Based on registered label.

3. Exposure Science Advisory Council Policy #9.1 and other assumptions based on specific product and scenario.

a. 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.

b. 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.

c. 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.

d. 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 does not have information 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). 

4. Inhalation Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/acre or gal) x Amount Treated (A/day) /BW (kg)

5. Inhalation MOE = Inhalation Human Equivalent Dose (HED) based on Activity Level (mg/kg/day)/ Inhalation Dose (mg/kg/day)

e. HED = 7.98 From HEC (29 L/min)

f. HED = 4.59 From HEC (16.7 L/min)

g. HED = 2.28 From HEC (8.3 L/min)
Cyromazine Human Health Risk Assessment DP No. D414914

Page 34 of 58

11.1.1 Bulb Onion Seed Treatment Occupational Handlers (Trigard OMC; EPA Reg. No. 

100-790)

Based upon the 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, on-farm 

treatment was not assessed. Moreover, according to ExpoSAC policy 15.1: Standard Operating 

Procedures (SOPs) for amount of commercial seed treated per day, HED assumes that 

commercial seed treatment risk assessment is protective of on-farm seed treatment involving 

small-scale commercial equipment. 

Commercial seed treatment equipment is designed to apply accurately measured quantities of 

pesticides to a given weight or quantity of seed. For bulb onions, potential occupational 

exposure scenarios from the use of cyromazine as a commercial seed treatment include:

 Loading/applying a wettable powder formulation;

 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. 

It is the policy of HED to use the best available data to assess handler exposure. Unit exposure 

data from PHED and HED ExpoSAC Policy 14: SOP 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 liquid formulation seed treatment scenarios, 

since no seed-treatment-specific unit exposure values are available for wettable powder 

formulations. 

For purposes of performing commercial seed treatment assessments, HED used ExpoSAC Policy 

15.1 to estimate amount of seeds treated per day. The amount assessed for bulb onions was 

3,000 seeds treated per day. 

Commercial Seed Treatment Exposure and Risk Estimates

Seed treatment handler exposure scenarios resulted in MOEs not exceeding HED's level of 

concern (i.e., MOEs ≥ 100) at baseline attire (i.e., single layer of clothing and no respirator) and 

therefore not of concern to the Agency, except for the loader/applicator scenario which resulted 

in an MOE of 99.

The seed treatment loader/applicator MOE of 99 is based on highly conservative assumptions.

The amount of seed treated is assumed to be 3,000 seeds per day. However, according to the 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 35 of 58

USDA NASS survey for 2012, the amount planted for onions was approximately 155,000 acres.

Assuming that each acre is planted with 2 to 150 pounds of seed per acre (depending on variety), 

this would indicate that the US is treating a maximum possible value of 77,500 pounds of seed 

per year (J. Becker, Acres Planted per Day and Seeding Rates of Crops Grown in the United 

States, 03/24/2011).

In the US, there are at least six facilities treating green onion seeds, and at least nine facilities 

treating bulb onion seeds (E. Kennedy, AHETF Report Number AH 189, Small Seeded 

Vegetable Use and Usage Report, 11/22/2010). To be conservative, if we assume that only six 

facilities are treating 100% of the onion market, then each facility would treat an average of 

~13,000 pounds of seed annually. If each facility treated 3,000 pounds of seed per day, then it 

would only take an average of four days of operation to treat the entire annual US supply of 

onion seeds.

Furthermore, seed treatments vary by region and all small seeded vegetable seeds are custom 

treated based on individual customer requests (E. Kennedy, AHETF Report Number AH 189, 

Small Seeded Vegetable Use and Usage Report, 11/22/2010).

Table 11.1.1.1 presents a summary of the short- and intermediate- term occupational handler risk

estimates for commercial seed treatment. 

Table 11.1.1.1. 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 

Exposure3,4

(mg/lb ai)

Daily Dose5

(mg/kg/day)

Short/IntTerm 

Inhalation 

MOE6,7

(LOC = 100)

Commercial

Loader/Applicator (baseline)

0.050 3,000

0.043 0.081 99

Loader/Applicator (PF5 Respirator) 0.0086 0.0160 290

Sewer (baseline) 0.00023 0.00043 11,000

Bagger (baseline) 0.00016 0.00030 15,000

Multiple Activities (baseline) 0.0016 0.0030 1,500

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 #15.1 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. PF5 Respirator: HED 

assumes an 80% protection factor is provided by a NIOSH-approved quarter-face, cup-style respirator (it is similar to the paint masks painters 

often wear).

4. Unit Exposure values for the Loader/Applicator scenarios are from PHED (Mixing/Loading Wettable Powders). 

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 = HED based on 16.7 L/min breathing rate (4.59 mg/kg/day) / inhalation daily dose (mg/kg/day). 

Level of concern = 100.

7. Loader/Applicator scenarios Short- and Intermediate- term Inhalation MOE = HED based on 29 L/min breathing rate (7.98 mg/kg/day) / 

inhalation daily dose (mg/kg/day). Level of concern = 100

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.
Cyromazine Human Health Risk Assessment DP No. D414914

Page 36 of 58

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 11.1.1.2 presents the short- and 

intermediate-term risk estimates for planters. 

Table 11.1.1.2. 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 Dose4

(mg/kg/day)

Inhalation

MOE5

(LOC = 

Mitigation Level 100) : Baseline

Planters Seed 

Planter 0.050 320 0.0034 0.00067 6,800

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. 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);

5. Short- and Intermediate- term Inhalation MOE = HEC based on 16.7 L/min breathing rate (4.59 mg/kg/day) / inhalation daily dose 

(mg/kg/day). Level of concern = 100.

11.2 Short-/Intermediate-/Long-Term/Cancer (if needed) Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are 

present in an environment that has been previously treated with a pesticide (also referred to as reentry exposure). Such exposures may occur when workers enter previously treated areas to 

perform job functions, including activities related to crop production, such as scouting for pests 

or harvesting. Post-application exposure levels vary over time and depend on such things as the 

type of activity, the nature of the crop or target that was treated, the type of pesticide application, 

and the chemical’s degradation properties. In addition, the timing of pesticide applications, 

relative to harvest activities, can greatly reduce the potential for post-application exposure.

11.2.1 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. 

11.2.2 Inhalation Postapplication Risk

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 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 37 of 58

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, with respect to the greenhouse uses of cyromazine, 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)].

Bulb onion Seed Treatment Inhalation Post-Application Exposure/Risk

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.

Restricted Entry Interval (REI)

The REI of 12 hours specified on the registered labels (42750-222, 100-667, 100-654, and 100-

656) is based on the acute toxicity of the cyromazine technical material, and is considered to be 

appropriate.

Bulb Onion Seed Treatment Restricted Entry Interval (REI)

The Worker Protection Standard (WPS) allows workers to enter treated areas without restriction

if there will be no worker contact with the treated seeds in the soil or planting media. For 

purposes of seed treatment (once the seeds are planted), workers can enter during the restricted 

entry interval (REI), provided they do not contact the soil/media subsurface that contains the 

treated seeds. 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 38 of 58

12.0 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.

T. Morton, 10/30/2013, D414945, Cyromazine – Acute Chronic Dietary and Drinking Water 

Exposure and Risk Assessment for Registration Review. 

Ivan Nieves, 12/03/2013, 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.

Uma Habiba, October 29, 2013, TXR 0056806. Cyromazine: Summary of Hazard and Science 

Policy Council (HASPOC) Meetings: Recommendations on the need for an immunotoxicity 

study.

Kristin Rury, June 26, 2013, TXR 0056682, Cyromazine: Summary of Hazard and Science 

Policy Council (HASPOC) Meeting of: Recommendations on data requirements for a 

subchronic neurotoxicity study for cyromazine.

Steve Dapson & Esther Rinde, 1/6/95, Carcinogenicity Peer Review of Cyromazine.
Cyromazine Human Health Risk Assessment DP No. D414914

Page 39 of 58

Appendix A. Toxicology Profile and Executive Summaries

A.1. Cyromazine Toxicology Data Requirements: The toxicology data requirements (40 CFR 158.340) 

for food use are presented in Table A.1.1. Use of the new guideline numbers does not imply that the new (1998) 

guideline protocols were used.

Table A.1.1. Cyromazine Guideline Data Requirements

Study

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 21/90-Day Inhalation.....................................................

yes

yes

yes

no

yes

yes

yes

yes

-

yes

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 Carcinogenicity (rat)......................................................

870.4200b Carcinogenicity (mouse)................................................

870.4300 Chronic/ Carcinogenicity...............................................

yes*

yes

yes*

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

-

-

yes

-

no

870.7485 General Metabolism ......................................................

870.7600 Dermal Penetration ........................................................

870.7800 Immunotoxicity .............................................................

yes

yes

yes

***

yes

yes

-

* Guideline 870.4300 satisfies guideline 870.4100a and 870.4200a.

** 90-Day Neuro. Screening Battery (rat) was waived (HASPOC TXR 0056682)

*** Immunotoxicity was waived (HASPOC TXR 0056806 )
Cyromazine Human Health Risk Assessment DP No. D414914

Page 40 of 58

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 Subchronic, Chronic and Other Toxicity Profile of Cyromazine

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.3150 Subchronic 

Dietary – Rat

00135433 (1979)

Acceptable/Guideline

0, 30, 300, 1000 and 3000 

ppm (0, 3, 30, 100, and 

300 mg/kg/day)

NOAEL = 1000 ppm (100 mg/kg/day)

LOAEL = 3000 ppm (300 mg/kg/day) based 

on decreased body weight (↓12%) in females. 

There were no effects on males

870.3150 Subchronic 

Dietary Dog

00135432 (1979)

Acceptable/Guideline 

0, 30, 300, 1000 or 3000 

ppm (0, 0.75, 7.5, 25 and 

75 mg/kg/day)

NOAEL = 3000 ppm (75 mg/kg/day, HDT).

LOAEL not observed. Reported relative organ 

weight changes and hematological parameters 

are within biological variation and not 

significant.

870.3200 21-Day Dermal -

Rabbit

44060901 (1992)

Acceptable/Guideline

0, 50, 200 & 2000 

mg/kg/day

Systemic Toxicity 

NOAEL = 2000 mg/kg/day

LOAEL > 2000 mg/kg/day

Dermal Toxicity

No dermal irritation was noted 

870.3200 21-Day Dermal -

Rabbit

44060902 (1984)

Acceptable/Guideline

0 & 2010 mg/kg/day 

Systemic Toxicity 

NOAEL = 2000 mg/kg/day

LOAEL > 2000 mg/kg/day

Dermal Toxicity

No dermal irritation was noted

870.3465 21-Day Inhalation 

- Rat

47940804 (1988)

Acceptable/Guideline

Nominal 0.055, 0.210, or 

0.710 mg/L

NOAEL not established

LOAEL = 0.055 mg/L/day based on 

impairment of the general condition with the 

symptoms of piloerection, dyspnea, hunched 

posture, and reduced spontaneous activity.

870.3700a

Gavage 

Developmental 

Toxicity - Rat

00027488 (1979)

Acceptable/Guideline 

0, 100, 300 and 600 

mg/kg/day 

Maternal NOAEL = 100 mg/kg/day

Maternal LOAEL = 300 mg/kg/day, based on 

clinical signs (red or clear nasal discharge at 

1.5 hours after dosing) and slight reduction in 

body weight gain (days 0-20). 

Developmental NOAEL = 300 mg/kg/day

Developmental LOAEL = 600 mg/kg/day 

(HDT), based on increased incidence of minor 

skeletal variations.
Cyromazine Human Health Risk Assessment DP No. D414914

Page 41 of 58

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile of Cyromazine

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.3700b

Gavage 

Developmental 

Toxicity - Rabbit

00150471 (1985)

Acceptable/Guideline

0, 10, 30, and 60 

mg/kg/day 

Maternal NOAEL = 60 mg/kg/day, HDT

Maternal LOAEL not observed.

Developmental NOAEL ≥ 60 mg/kg/day 

(HDT)

Developmental LOAEL not established

870.3800

Reproductive 

Toxicity 

00103197 (1981)

Acceptable/Guideline

0, 30, 1000 and 3000 ppm 

(0, 1.5, 50, and 150 

mg/kg/day based on 

default conversion factor 

1ppm =0.05 mg/kg)

Based on actual 

compound consumption 

1000 ppm =

70 mg/kg/day F0 ♂

54.6 mg/kg/day F1 ♂

84.5 mg/kg/day F0 ♀

70.5 mg/kg/day F1 ♀

Parental NOAEL = 1000 ppm (50 

mg/kg/day).

Parental LOAEL = 3000 ppm (150 

mg/kg/day) based on decreased body weights 

(↓27%) that were associated with decreased 

food efficiency.

Reproductive NOAEL ≥ 3000 ppm (150 

mg/kg/day).

Reproductive LOAEL not established

Offspring NOAEL = 1000 ppm (50 

mg/kg/day).

Offspring LOAEL = 3000 ppm (150 

mg/kg/day), based on decreased body weights 

at birth and through weaning (↓8-22%).

870.4100b

6-month Toxicity 

Dietary- Dog

00103193 (1982)

Acceptable/Guideline 

0, 30, 300 or 3000 ppm 

(0, 0.75, 7.5 and 75 

mg/kg/day)

NOAEL = 3000 ppm (75 mg/kg/day).

LOAEL > 3000 ppm (75 mg/kg/day) Reported 

relative organ weight changes and 

hematological parameters within biological 

variation and not significant.

870.4300

Combine Chronic/ 

CarcinogenicityRat

00103202, 00115735 

(1982)

Acceptable/Guideline

0, 30, 300 and 3000 ppm 

(0, 1.5, 15, and 150 

mg/kg/day)

NOAEL = 300 ppm (15 mg/kg/day).

LOAEL = 3000 ppm (150 mg/kg/day) based 

on decreased body weight (↓20% for males and 

↓29% for females), body weight gains (↓23% 

for males and ↓33% for females) accompanied 

with lower food consumption (10-15%), 

compared to controls.

There is no evidence of carcinogenicity.

870.4200 CarcinogenicityMouse

00115736 (1982)

Acceptable/Guideline

0, 50, 1000, and 3000 

ppm (0, 7.5, 150, and 450 

mg/kg/day)

NOAEL (♂)= 1000 ppm (150 mg/kg/day).

LOAEL (♂)= 3000 ppm (450 mg/kg/day) 

based on decreased body weight (↓9.6% in 

males, ↓6% in females) at 104 weeks.

NOAEL (♀)= 3000 ppm (450 mg/kg/day, 

HDT). 

LOAEL (♀)> 3000 ppm (HDT)

There is no evidence of carcinogenicity. 

870.5100

Bacterial Reverse 

Gene Mutation 

Test (Ames 

Assay)

TXR No. 0002687

0089923 (1978)

limited/Guideline 

25, 75, 255, 675 and 2025 

μg/0.1 mL plate in 

DMSO, ± S-9.

Negative results for point mutations in 

TA1537, TA1537, TA98, and TA100 with and 

without activation.

This study was limited due to the use of low 

concentrations of test substance.
Cyromazine Human Health Risk Assessment DP No. D414914

Page 42 of 58

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile of Cyromazine

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.5300

In Vitro

Cytogenetic Assay 

Measuring 

Chromosomal

Aberration 

Frequencies in 

Chinese Hamster 

Ovary (CHO) 

Cells

TXR No. 0002664

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. -

Dominant lethal 

test species: 

Mouse

TXR No. 0002687

00103198 (1981)

limited/Guideline 

226 and 678 mg/kg in 

PEG400 vehicle (0.2 

mL/log of body weight)

Negative mutagen.

This study was limited since the mating period 

was too short.

870.6200a Acute 

Neurotoxicity -

Rats

49109701 (2013)

250, 1000, or 2000 mg/kg 

bw

NOAEL not established

LOAEL = 250 mg/kg BW, the lowest dose 

tested based on the decreased motor activity 

(mean cumulative ambulatory LMA counts 

↓44%) in males at the time of peak effect on 

Day 0, and decreased food consumption (p<.01, 

↓17.4%) on Day 1

870.6200b Subchronic 

Neurotoxicity -

Rats

Waived (HASPOC TXR 0056682)

870.7485 Metabolism - Rat

41442101 (1989)

Acceptable/Guideline

3 and 300 mg/kg

Cyromazine was well absorbed after oral 

administration. Excretion was rapid (When?) 

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 14Ccyromazine 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.
Cyromazine Human Health Risk Assessment DP No. D414914

Page 43 of 58

Table A.2.2 Subchronic, Chronic and Other Toxicity Profile of Cyromazine

Guideline 

No. Study Type MRID No. (year)/ Classification /Doses Results

870.7600 Dermal 

Penetration - Rat

40168601 (1987)

Acceptable/Guideline

0.10, 1.00, and 10 mg/rat

Male rats received dermal application of a 

“simulated” 75W formulation of 14CCyromazine in aqueous solution. Absorption at 

10 hrs at 0.1, 1.0, and 10 mg/rat was 12.6%, 

7.8% and 11%, respectively. The main route of 

excretion of the absorbed radioactivity was the 

urine. There is no evidence that the compound 

is sequestered in the skin. 

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). Most of the unabsorbed 

radioactivity was found in the skin washes from 

each dose/duration.

870.7600 Dermal 

Penetration - Rat

00149656 (1985)

Acceptable/Guideline

0.1, 1.0, and 100 mg/rat to 

a 10 cm2area on the upper 

back portion of the rats

A formulation of “simulated” 75W formulation 

of 14C-Cyromazine in aqueous solution was 

administered to 36 male Harlan SpragueDawley albino rats (3 rats per dose group per 

time period). Total radioactivity absorbed 

generally increased with increasing exposure 

time but decreased with increasing dose 

indicating saturation of penetration with 

increasing dose. Absorption at 10 hours was 

10%, 11.4% and 7% at 0.01 mg/cm2, 0.1 

mg/cm2 and 10 mg/cm2, respectively

870.7800 Immunotoxicity Waived (HASPOC TXR 0056806 )

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD) – All Populations

An endpoint attributable to a single dose was not identified.

A.3.2 Acute Reference Dose (aRfD) – All Populations

Study Selected: Acute neurotoxicity study-rat 

MRID No: 49109701

Executive Summary: In an acute neurotoxicity study (MRID 49109701), groups of non-fasted, 

6- weeks old Crl:CD(SD) rats (10/sex/dose) were given a single oral dose of cyromazine (95.8% 

a.i., batch # 666428) in 0.5% carboxymethylcellulose (CMC) in sterile water at doses of 250, 

1000, or 2000 mg/kg bw and observed for 14 days. Neurobehavioral assessment (functional 

observational battery and motor activity testing) was performed in 10 animals/sex/group prior to 

the initiation of dosing (study day -6), at the time of peak effect (approximately 3 hours postdosing, the time of peak effect was considered to be 2 to 4 hours post-dosing based on the 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 44 of 58

toxicokinetic finding that cyromazine is rapidly absorbed from the gastrointestinal tract of the rat 

following oral gavage (MRID 41442101)) on study day 0, and on study days 7 and 14. At study 

termination, 5-7 animals/sex/group were euthanized and perfused in situ in a 4.0% 

paraformaldehyde/0.1M phosphate-buffered solution for neuropathological examination. Of the 

perfused animals, 5 were subjected to histopathological evaluation of brain and peripheral 

nervous system tissues. The central and peripheral nervous system tissues were dissected and 

preserved. Fixed brain weight and brain dimensions (length, excluding olfactory bulbs, and 

width) were recorded. The prepared tissues from the control and high-dose group rats were 

examined microscopically.

There were no treatment related effects on mortality, clinical signs, brain weight or gross and 

histological pathology or neuropathology. Cyromazine-related clinical signs (red material 

around the nose in males and females on days 3-8 and day 15) were limited to the 2000 mg/kg 

rats. Statistically significant (p<0.05-p<0.1) lower body weight gains compared to the controls 

were observed in the 1000 and 2000 mg/kg rats of both sexes during the first day of treatment. 

Body weight loss was more pronounced in the males and resulted in lower body weight gains for 

days 0-7 and days 0-15 at the 2000 mg/kg dose. Lower body weights were also observed in the 

2000 mg/kg male rats (-10.5% compared to controls on Day 3. Body weight losses were 

accompanied with lower food consumption during the first days after treatment.

Home cage observations, handling observations and sensory observations were not affected by 

the test substance administration. In the open field observations, statistically significantly higher 

(p<0.05) mean numbers of rears (10.1) were noted for the 2000 mg/kg females compared to the 

control group (5.0) on study day 7. However, this was within the range of the lab historical 

control data (8.1 - 10.3) and was not considered test substance-related. A test substance-related, 

statistically significantly lower (p<0.01) mean hindlimb footsplay was noted for the 2000 mg/kg 

males (39.5 mm) compared to the control group (63.3 mm) at the time of peak effect 

(approximately 3 hours following dose administration) on study day 0. A treatment-related 

statistically significantly lower (p<0.01) mean body temperature was noted for the 2000 mg/kg 

males (36.2°C), as compared to the control group (37.2°C), at the time of peak effect on study 

day 0. 

Cyromazine treatment resulted in decreases in the mean cumulative total LMA counts in males at 

1000 mg/kg (↓25.1%, p<0.05) and 2000 mg/kg (↓24.3%, p<0.05) at the time of peak effect on 

study day 0. Mean cumulative ambulatory LMA counts were decreased at 250 mg/kg (↓44.3%), 

1000 mg/kg (↓48.8%) and 2000 mg/kg (↓52.3%) at the time of peak effect on Day 0. These 

effects on the motor activity are considered adverse effects resulting from the single oral dosing 

of cyromazine. The flat dose response can be explained from a reported metabolism study 

(MRID 41442101). In this metabolism study, cyromazine was tested at a low dose of 3 and a 

high dose of 300 mg/kg bw. At the high dose, saturation of excretion was seen which may help 

explain the flat dose response for the decrease in cumulative LMA since the lowest dose tested in 

the ACN was 250 mg/kg BW. At 250 mg/kg BW, the clearance mechanism(s) may be as 

overwhelmed as at the higher doses tested of 1000 and 2000 mg/kg BW, resulting in a flat dose 

response curve. Total and ambulatory LMA counts were also decreased in females (p<0.05 -

p<0.01) for the 250, 1000, and 2000 mg/kg by 18-56% as compared to the control group, during 

the first LMA subinterval (0-10 minutes) at the time of peak effect on study day 0. These 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 45 of 58

decreases resulted in decreases in the mean cumulative total (p<0.05) by 28% at the 2000 mg/kg 

dose and ambulatory (p<0.05) LMA counts at 1000 and 2000 mg/kg. Statistically significantly 

lower mean cumulative total and/or ambulatory LMA counts were noted for females in the 250, 

1000, and 2000 mg/kg groups on study day 7 and in the 1000 and 2000 mg/kg groups on study 

day 14. These changes were not considered to be test substance related, since these changes did 

not occur in a dose-related manner and/or the mean values in the control group exceeded the 

maximum mean values in the lab historical control data. Furthermore, the lower cumulative 

values noted in these groups were due to greater habituation of test substance-treated females, as 

activity in the treated groups was similar to the control group during the first 10-minute

subinterval.

Based on the decreased motor activity (mean cumulative ambulatory LMA counts ↓44%) 

in males at the time of peak effect on Day 0, and decreased food consumption (p<.01, 

↓17.4%) on Day 1, the LOAEL is 250 mg/kg BW, the lowest dose tested. The NOAEL was 

not established. 

EPA statisticians have found that that statistical analysis performed and presented in the 

study submission was not optimal in terms of fully incorporating important features of the 

study design. As a result, EPA statisticians have redone the analysis of cumulative 

locomotor activity: total LMA and ambulatory LMA using a more appropriate statistical 

approach. The results, nevertheless, are similar to those reached by the registrant, 

similarly indicating that the low dose was significant (TXR 0056676).

This neurotoxicity study is classified as acceptable/guideline and satisfies the guideline 

requirement for an acute neurotoxicity study in rats (870.6200; OECD 424).

Dose for Risk Assessment: LOAEL = 250 mg/kg

Uncertainty Factor: 300x (10x interspecies extrapolation, 10x intraspecies variability, 3x for 

LOAEL to NOAEL)

 

 

 

 

 

 

 

 

Comments about Study/Endpoint/Uncertainty Factor: The effects produced in this study are 

due to a single dose. The effects seen at the LOAEL are decreased motor activity (mean 

cumulative ambulatory LMA counts ↓44%) in males at the time of peak effect on Day 0, and 

decreased food consumption (p<0.01, ↓17.4%) on Day 1. An uncertainty factor of 3X, instead of 

10X, was applied for use of a LOAEL as a point of departure because the available ADME data 

(MRID 41442101) suggests that 250 mg/kg/day is a dose that saturated the animals metabolic 

capabilities in the ACN study. At doses below saturation, the chemical would be cleared from 

the body and would not produce the effects observed in the ACN study. This endpoint is 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 46 of 58

considered appropriate for all populations because the effects were observed following a single 

dose, and the route of administration (oral) is appropriate for dietary considerations.

A.3.3 Chronic Reference Dose (cRfD)

Study Selected: 2-gen reproduction study

MRID No.: 00103197 co-critical with the Chronic/Carcinogenicity Study in rats MRID 

00103202, 00115735

Executive Summary (2-gen reproduction study): In a two-generation reproduction study 

(MRID No. 00103197) in Sprague-Dawley rats COBS®CD®rats (15 males and 30 

females/group), 95.3% cyromazine was administered at dietary levels of 30, 1000, or 3000 ppm 

(1.5, 50, or 150 mg/kg/day). 

The F0 rats were mated once to produce the F1 litters. F1 rats were randomly selected to mate to 

produce the F2 litters. Animals were observed for toxicity, behavioral changes, mortality, clinical 

signs, body weight, food consumption, pregnancy rate, litter size and weight, pup weight, gross 

pathology, organ weights, and histopathology. No significant treatment-related effects were 

observed in general appearance, behavioral changes, parturition and length of gestation in the 

animals. 

Parental mean body weights in the F0 generation males and females were decreased at 1000 ppm 

(↓9-12%) and 3000 ppm (↓20-21%) compared to the control. Body weight gains were depressed 

at the 1000 ppm in the males (↓16%) and females (↓20%) compared to controls. Body weight 

gains were more depressed at the 3000 ppm in the males (↓25%) and females (↓38%) compared 

to controls. In the F1 generation parental animals, body weights were significantly reduced 

(p<0.01) in the 3000 ppm males and females (↓17% -20%). Food consumption was decreased 

(↓10-15%) in males and females of both generations at the 3000 ppm dose. Food consumption at 

the 1000 ppm was decreased slightly at the 1000 ppm (↓6-8%). No effect was noted on pup 

survival rates in all groups and generations. Fertility rates were unaffected by treatment. No 

differences in mean litter size were noted. The difference between the group mean pup weights 

at birth and on postnatal days 7, 14, and 21 for the high dose and control groups in each 

generation was consistently statistically significant (p<0.05 or p<0.01). The pup weights in the 

high dose (3000 ppm) group averaged 8 to 22 % less than that of the control group from birth to 

weaning (Table 6). Pup body weights at the 1000 ppm were comparable to controls.

The parental systemic toxicity NOAEL in this study is 1000 ppm (50 mg/kg/day using the 

default conversion of 1 ppm = 0.05 mg/kg, or 70, 54.6, 84.5, 70.5 mg/kg/day for F0 males, F1

males, F0 females, F1 females, respectively using actual food consumption data and actual test 

material dietary concentrations), based on decreased body weights (↓15-22%) in males and 

females that were associated with decreased food consumption (↓10-15%) at the LOAEL of

3000 ppm (150 mg/kg/day). The decreased body weight seen at the 1000 ppm was less than 

10% and is not considered biologically significant to be adverse. The body weight effects in the 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 47 of 58

F1 generation at 1000 ppm were not remarkable either. The offspring systemic / developmental 

toxicity NOAEL was 1000 ppm (50 mg/kg/day using the default conversion of 1 ppm = 0.05 

mg/kg, or 54.6, 70.5 mg/kg/day for F1 males and F1 females, respectively using actual food 

consumption data and actual dietary concentrations) and the offspring systemic/developmental 

toxicity LOAEL was 3000 ppm (150 mg/kg/day), based on decreased body weights at birth and 

through weaning ((↓8-22%). The reproductive toxicity NOAEL is ≥ 3000 ppm (150 mg/kg/day -

HDT). The reproductive toxicity LOAEL was not achieved.

This reproduction toxicity study in the rat is classified Acceptable/Guideline. This study was 

conducted prior to the new OPPTS guidelines; however, it satisfies the guideline requirement for 

a two-generation reproduction study (OPPTS 870.3800; OECD 416) in the rat.

Executive Summary (Chronic/Carcinogenicity study): In a combined chronic/carcinogenicity 

study (MRID 00115735) Cyromazine (95.5% purity - Larvadex technical) was administered to 

60 Sprague-Dawley rats /sex/dose in the diet at dose levels of 0, 30, 300, or 3000 ppm 

(equivalent to 0, 1.5, 15, 150 mg/kg/day) for 24 months. An additional 10 animals per sex in the 

control and 3000 ppm groups were designated for interim sacrifice at one year.

There were no significant differences between the control and treated animals in appearance 

clinical signs, survival, hematology, biochemistry and urinalysis. Frequently observed in all 

groups were palpable masses, corneal opacity, red area around eye, and red material in eye, 

decubital ulcer and hair loss. Some treated animals wore noted to have excessive salivation, 

changes in eye size, emaciation and distention.

Statistically significantly lower body weights (↓20% for males and ↓29% for females), body 

weight gains (↓23% for males and ↓33% for females), compared to controls were noted for the 

high dose rats . Food consumption was decreased about 15% in both sexes at the high dose; 

however food efficiency was unchanged from control. Statistically significantly lower body 

weights and body weight gains were reported for mid-dose females at some intervals and 

occasional lower food consumption in males and females. The high dose interim sacrifice 

groups of both sexes immediately and continually through the four weeks withdrawal period had 

mean food consumption equal to or greater than those control animals sacrificed at 12 month 

interim during the withdrawal period. 

Clinical and macroscopic pathology was comparable among control and treated groups. The 

mean organ weight decreases found only at 3000 ppm in liver, kidney, testes, heart and brain 

were associated with animal body weight loss and not compound related.

A pilot investigation of T3, T4 and testosterone at 18 months and 24 months in 5 males each of 

the control and high dose rats yielded similar results.

Cystic hyperplasia of the mammary gland was observed only in 1/9 control female rat at the 

interim sacrifice. At the 24-month sacrifice, cystic hyperplasia was found in 0/55, 1/59, 5/56, and 

4/59 rats in the 0, 30, 300, and 3000 ppm groups, respectively.
Cyromazine Human Health Risk Assessment DP No. D414914

Page 48 of 58

Female rats showed a number of different neoplasms of the mammary glands. There was no 

increase in the incidence of benign tumors of the mammary gland due to cyromazine treatment. 

Although the number of animals with the malignant tumors in the mammary gland was slightly 

greater in the highest dose group (150 mg/kg/day) as compared to the control females, this 

difference was not statistically significant and there was an absence of dose response. Neither the 

adenomas nor the fibroadenomas nor the combination of adenomas, fibroadenomas and 

adenocarcinaomas showed a significant trend (p<0.01) and pair-wise comparison (p<0.05). 

Moreover the incidence of mammary tumors in treated rats did not exceed the historical control 

data, and the tumors were not considered treatment related (HED CPRC, Jan. 6, 1995, TXR No. 

0011384).

Based on statistical analysis, there was a slight increased incidence of renal interstitial cell 

tumors in high dose males (6/57 or 11%) compared to controls (1/60 or 2%), however, these 

lesions were within the historical control range and the lesions were not considered treatment 

related.

The systemic toxicity LOAEL is revised to 3000 ppm (150 mg/kg/day) based on decreased 

body weight (↓20% for males and ↓29% for females), body weight gains (↓23% for males 

and ↓33% for females) accompanied with lower food consumption (10-15%), compared to 

controls and the systemic toxicity NOAEL is 300 ppm (15 mg/kg/day).

This combined chronic/carcinogenicity study in the rat is classified Acceptable/Guideline. This 

study was conducted prior to the new OPPTS guidelines; however, it satisfies the guideline 

requirement for a combined chronic/carcinogenicity study in the rat (OPPTS 870.4300; OECD 

453.

Dose/Endpoint for establishing cRfD: NOAEL = 50 mg/kg/day based on decreased body 

weights in adults that were associated with decreased food efficiency at 150 mg/kg/day 

(LOAEL) seen in the generation study and the combined chronic/carcinogenicity study in rats..

Uncertainty Factor (UF): An UF of 100 was applied to account for inter (10 x)-and intra-(10 x) 

species variation.

 

 

 

 

 

 

 

 

Comments about Study/Endpoint: This endpoint is appropriate for the population of concern 

(general population), duration (long term), and route of exposure (oral). This endpoint is 

protective of adverse effects observed at higher doses in other studies. The observation of a 

similar effect in chronic/carcinogenicity in rats strengthens our confidence in this endpoint.

A.3.4 Incidental Oral Exposure (Short- and Intermediate-Term)
Cyromazine Human Health Risk Assessment DP No. D414914

Page 49 of 58

There are no residential uses for cyromazine; however incidental oral exposure from spray drift 

is likely.

Study Selected: 2-Generation Reproductive Study in rats co-critical with the 

Chronic/Carcinogenicity Study in rats

MRID No.: 00103197, 00103202, 00115735

Executive Summary: See A.3.3 above

Dose and Endpoint for Risk Assessment: 50 mg/kg/day, based on decreased body weight and 

decreased food efficiency in the 2-generation reproductive toxicity study at a LOAEL of 150 

mg/kg/day and the LOAEL of 150 mg/kg/day for decreased body weight in the 

chronic/carcinogenicity study in rats. 

Uncertainty Factor (UF): An UF of 100 was applied to account for inter (10 x)-and intra-(10 x) 

species variation.

Comments about Study/Endpoint: The 2-generation reproductive toxicity study and chronic 

toxicity/carcinogenicity studies are appropriate for this endpoint because it examines the toxicity 

to the population of concern. The route of exposure (in the feed) is appropriate for this exposure 

scenario and this endpoint is protective of effects observed at higher doses. The body weight 

changes in the chronic rat study were taken from the interim sacrifice data and occurred at 19 

weeks in females and 51 weeks in males. This provides an appropriate duration for the 

incidental oral endpoint.

A.3.5 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) 

Selected Study: 28-day inhalation toxicity study.

MRID No: 47940804. 

Executive Summary: 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 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 50 of 58

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 

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. A 

human equivalent concentration (HEC) was derived according to RfC methodology for 

occupational exposures described below in Table A.3.6.1

Comments about Study/Endpoint/Uncertainty Factor: 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. The default 10x uncertainty factor for the use of deriving 

a POD from the LOAEL was reduced to 3x because the effects seen at the LOAEL were not 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 51 of 58

severe (i.e., only slight dyspnea). The severity of the clinical signs at this lowest concentration

was slight and the observed clinical signs appeared mostly after 7 days of exposure. Piloerection 

increase 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 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. In addition, the study used a milled powder for the exposure while 

exposures following the current usage pattern will be a liquid.

Uncertainty Factor (UF): 100 which includes 10x for intraspecies variation, 3x for interspecies 

extrapolation (reduced to 3x for converting the concentration to human equivalent concentration 

- See appendix below), 3x for extrapolation of LOAEL to NOAEL. MOE = 100 for short- and 

intermediate-term duration.

Table A.3.6.1. RFC Methodology to Derive the HEC

RDDR Worksheet: Occupational

Blue: inputs

Green: outputs

(1) DURATION ADJUSTMENT

(a) Daily Exposures: Enter inhalation exposure duration from animal toxicity study in cell A9 and expected 

human exposure duration in cell B9

Animal Inhalation Study Human Expected Exposure

Daily Duration (hours) Daily Exposure (hr) Daily Duration 

Adjustment

4 8 0.5

(b) Weekly Exposures: Enter weekly regimen (days/week) from animal toxicity study in cell A14 and 

expected human weekly regimen in cell B14

Animal Inhalation Study Human Expected Exposure

Animal Weekly Exposure (days/week) Human Weekly Exposure 

(days/week)

Weekly Duration 

Adjustment

7 5 1.4

Animal Inhalation Study POD (mg/L; NOAEL, 

LOAEL, or BMDL) Duration-Adjusted Animal Study POD (mg/L)

0.055 0.0385

(2) ESTIMATE THE HUMAN EQUIVALENT CONCENTRATION

(a) Enter the RDDR estimated value from the "RDDR.exe" output corresponding to portal of entry 

[respiratory tract (extrathoracic, tracheobronchial, or pulmonary)] or systemic effects
Cyromazine Human Health Risk Assessment DP No. D414914

Page 52 of 58

Adjusted animal POD (mg/L) RDDR (from 

RDDR.exe output)* HEC (mg/L)

0.0385 1.042 0.04012

* the RDDR of 1.042 corresponds to effects in the pulmoanry region based on Dyspnea effects seen in the rat 

inhalation study.

Note: Stop here if air monitoring data is readily available. MOE can be calculated by directly comparing an HEC 

(mg/L) to inhalation exposure concentration estimate (mg/L)

(3) ESTIMATE THE HUMAN EQUIVALENT DOSE (mg/kg bw/day)

(a) Estimate the corresponding HED associated with different occupational settings

Exposure 

Scenario

Ventilation 

rates 

(L/min)

Relative Activity 

Factor (AF)1

HumanSpecific 

Convers

ion 

Factor 

(CF,L/h

r*kg 

BW)2

Absorption ratio 

(A)3

Hum

an 

Daily 

Dura

tion

HED (mg/kg 

BW/day)4

Applicators 

[pilots, tractor 

drivers 

(groundboom, 

airblast)]

8.3 0.6 11.8 1.0 8 2.283

Handlers 

(mixers/loaders, 

lawncare 

operators)

16.7 1.2 11.8 1.0 8 4.594

Handheld spray 

applications 

(backpack, 

handguns)

29 2.1 11.8 1.0 8 7.978

1 AF is the ratio of the exposure specific scenario Ve and the default value of 13.8 L/min

2 CF is the default ventilation rate of 13.8 L/min converted to hours and normalized to a body weight of 70 kg

3 A is the absorption ratio as compared to the oral route (assumed to be unity)

4 HED = HEC(mg/L) x CF(L/hr/kg bw) x D (hr) x AF X A

 Regional deposited dose ratios (RDDR)

MMAD = 1.61

Sigma g = 1.00

 Body Extrathoracic Tracheobronchial Pulmonary

SPECIES weight(g) VE(ml) SA(cm^2) dep SA(cm^2) dep SA(m^2) dep

--------------------------------------------------------------------------------

 rat 236 171.5 15.000 0.417 22.500 0.088 0.340 0.160

 human 70000 13800.0 200.000 0.247 3200.000 0.065 54.000 0.303

--------------------------------------------------------------------------------

RATIO 0.003 0.012 0.075 1.688 0.007 1.354 0.006 0.528
Cyromazine Human Health Risk Assessment DP No. D414914

Page 53 of 58

RDDR 0.280 2.392 1.042

 Thoracic Total RT Extrarespiratory

 SA(m^2) dep SA(m^2) dep BW(g) dep

--------------------------------------------------------------------------------

 rat 0.342 0.248 0.344 0.666 236 0.666

 human 54.320 0.125 54.340 0.616 70000 0.616

--------------------------------------------------------------------------------

RATIO 0.006 1.984 0.006 1.081 0.003 1.081

RDDR 1.330 2.124 3.985

 V. 2.3
Cyromazine Human Health Risk Assessment DP No. D414914

Page 54 of 58

Appendix B. Physical/Chemical Properties

Table B.1. 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

Table B.2. Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

40 CFR 180.414:

Plants/Livestock: cyromazine, N -

cyclopropyl-1,3,5-triazine-2,4,6-

triamine

N-cyclopropyl-1,3,5-triazine2,4,6-triamine, including

the metabolite 1,3,5-triazine2,4,6-triamine

Plants and animal 

commodities: 

cyromazine.

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico2 Codex3

Bean, dry, except cowpea 3.0 3 beans (dry)

Bean, lima 1.0 1 Lima bean (young 

pods and/or 

immature beans)

Bean, succulent 2.0

Broccoli 1.0 1 

Cabbage, Abyssinian 10.0

Cabbage, seakale 10.0

Cattle, fat 0.05

Cattle, kidney 0.2 0.3 edible offal 

(mammalian)

Cattle, meat 0.05 0.3 meat (from 

mammals other than 

marine mammals) 
Cyromazine Human Health Risk Assessment DP No. D414914

Page 55 of 58

Table B.2. Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

Cattle, meat byproducts, 

except kidney

0.05 0.3 edible offal 

(mammalian)

Egg 0.25 0.3

Garlic 0.2

Garlic, great-headed, bulb 0.2

Goat, fat 0.05

Goat, kidney 0.2 0.3 edible offal 

(mammalian)

Goat, meat 0.05 0.3 meat (from 

mammals other than 

marine mammals) 

Goat, meat byproducts, 

except kidney

0.05 0.3 edible offal 

(mammalian)

Hanover salad, leaves 10.0

Hog, fat 0.05

Hog, kidney 0.2 0.3 edible offal 

(mammalian)

Hog, meat 0.05 0.3 meat (from 

mammals other than 

marine mammals) 

Hog, meat byproducts, 

except kidney

0.05 0.3 edible offal 

(mammalian)

Horse, fat 0.05

Horse, kidney 0.2 0.3 edible offal 

(mammalian)

Horse, meat 0.05 0.3 meat (from 

mammals other than 

marine mammals) 

Horse, meat byproducts, 

except kidney

0.05 0.3 edible offal 

(mammalian)

Leek 3.0

Mango10.3 0.5

Milk 0.05 0.01

Mushroom 1.0 8.0 7

Onion, bulb 0.2 0.3 dry bulb onions 0.1

Onion, green 3.0 3.0 3 spring onion

Onion, potato 3.0

Onion, tree 3.0

Onion, welsh 3.0

Pepper 1.0 3.0 1 Fruiting 

vegetables other 

than cucurbits

(except mushrooms 

and sweet corn 

(corn-on the cob)

10 peppers chili, 

dried

Potato 0.8 0.8

Poultry, fat (from chicken 

layer hens and chicken 

breeder hens only)

0.05
Cyromazine Human Health Risk Assessment DP No. D414914

Page 56 of 58

Table B.2. Summary of US and International Tolerances and Maximum Residue Limits 

Residue Definition:

US Canada Mexico2 Codex3

Poultry, meat (from chicken 

layer hens and chicken 

breeder hens only)

0.05 0.1 poultry meat

Poultry, meat byproducts 

(from chicken layer hens and 

chicken breeder hens only)

0.05 0.2 poultry edible 

offal of

Rakkyo, bulb 0.2

Shallot, bulb 0.2

Shallot, fresh leaves 3.0

Sheep, fat 0.05

Sheep, kidney 0.2 0.3 edible offal 

(mammalian)

Sheep, meat 0.05 0.3 meat (from 

mammals other than 

marine mammals) 

Sheep, meat byproducts, 

except kidney

0.05 0.3 edible offal 

(mammalian)

Tomato 0.5 1.0 1 Fruiting 

vegetables other 

than cucurbits

(except mushrooms 

and sweet corn 

(corn-on the cob)

Turnip, greens 10.0

Vegetable, brassica, leafy, 

group 5, except broccoli

10.0 35 Bok choy Chinese cabbages, 

broccoli raab, collards, kale, mustard 

greens, mustard spinach, rape greens

10 mustard greens

Vegetable, leafy, except 

brassica, group 4

7.0 10 amaranth, arugula, cardoon, 

celery, celtuce, Chinese celery, corn 

salad, dandelion leaves, dock, edible 

leaved chrysanthemum, endives, 

fresh chervil leaves, fresh Florence 

fennel leaves and stalks, fresh parsley 

leaves, garden cress, garden purslane 

, garland chrysanthemum, head 

lettuce, leaf lettuce, New Zealand 

spinach, orach leaves, radicchio,

rhubarb, spinach, Swiss chard, 

upland cress, vine spinach, winter 

purslane

4 celery, head 

lettuce, leaf lettuce

Vegetable, cucurbit, group 9 1.0 1.0 cucumbers, melons 2 cucumber, squash 

summer

0.5 melons, except 

watermelon

MRLs with NO US equivalent

Artichoke, globe 3

Completed: M. Negussie; 01/19/2012

1There are no U.S. registrations on mango as of May 4, 2000.
Cyromazine Human Health Risk Assessment DP No. D414914

Page 57 of 58

2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = 

processed postharvest treated commodity, such as processing of treated stored wheat. (fat) = to be measured on the 

fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.
Cyromazine Human Health Risk Assessment DP No. D414914

Page 58 of 58

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.