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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY 

WASHINGTON, D.C. 20460 

 OFFICE OF PREVENTION, PESTICIDE 

 AND TOXIC SUBSTANCES 

MEMORANDUM 

August, 20 2009 

SUBJECT: Cyromazine Human Health Risk Assessment for Proposed New Use of 

Cyromazine on Succulent Beans 

PC Code: 121301 DP Barcode: D358720, D359607 

Decision No.: 402535 Registration No.: 100-654 

Petition No.: PP8E7470 Regulatory Action: Section 3 Registration 

Risk Assessment Type: Single Chemical Aggregate Case No.: NA 

TXR No.: NA CAS No.: 66215-27-8 

MRID No.: NA 40 CFR: 180.414

FROM: Becky Daiss, Biologist 

Jerry Stokes, Chemist 

Risk Assessment Branch 4 

Health Effects Division (7509P) 

THROUGH: Susan V. Hummel, Branch Senior Scientist 

Risk Assessment Branch 4, HED (7509P) 

TO: Susan Stanton, Risk Manager 

 MUIRB 

 Registration Division (7505P) 

 This document provides Health Effects Division’s (HED’s) risk assessment of proposed 

new uses of cyromazine on succulent beans. Supporting documents are listed below. 

Residue Chemistry Assessment – J. Stokes, D359605, 7/14/09 

Dietary and Drinking Water Exposure Assessment – B. Daiss, D359606 8/x/2009 

Drinking Water Exposure Assessment – J. Wolf, D358724, 7/6/09 

Occupational Exposure Assessment – J. Arthur, D285851, 1/30/2003
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TABLE OF CONTENTS 

 pg. 

1.0 EXECUTIVE SUMMARY .................................................................................................4 

2.0 INGREDIENT PROFILE ....................................................................................................6 

2.1 Registered Products .............................................................................................................6 

2.2 Registered and Proposed New Uses ....................................................................................7 

2.3 Structure, Nomenclature and Physical/Chemical Properties ...............................................7 

3.0 HAZARD CHARACTERIZATION/ASSESSMENT ........................................................8 

3.1 Hazard Characterization .....................................................................................................8 

3.2 FQPA Hazard Considerations .............................................................................................9 

3.2.1 Developmental Toxicity ........................................................................................9 

3.2.2 Reproductive Toxicity ..........................................................................................11 

3.2.3 Pre-and/or Postnatal Toxicity ................................................................................11 

 3.2.4 Immunotoxicity......................................................................................................12 

 3.2.5 FQPA Factor ..........................................................................................................12 

3.3 Toxicity Endpoint Selection ..............................................................................................12

3.3.1 Acute Reference Dose ...........................................................................................12 

3.3.2 Chronic Reference Dose – All Populations ...........................................................12 

3.3.3 Incidental Oral Exposure .......................................................................................13 

3.3.4 Dermal Exposure ...................................................................................................13 

3.3.5 Inhalation Exposure ...............................................................................................14 

3.3.6 Classification of Carcinogenic Potential................................................................14 

3.4 Margins of Exposure..........................................................................................................14 

3.5 Recommendation for Aggregate Exposure........................................................................15 

3.6 Summary of Endpoints Selected for Risk Assessment......................................................15 

3.7 Endocrine Disruption.........................................................................................................16 

4.0 DIETARY AND DRINKING WATER EXPOSURE ASSESSMENT ............................16 

4.1 Residue Chemistry Profile .................................................................................................16 

4.1.1 Metabolism in Primary Crops................................................................................16 

4.1.2 Residue Analytical Method ...................................................................................17 

4.1.3 Residues in Crops, Livestock, and Processed Commodities .................................17 

4.2 Drinking Water Profile ......................................................................................................18 

4.2.1 Environmental Fate and Transport ........................................................................18 

4.2.2 Estimated Drinking Water Concentrations ............................................................18 

4.3 Dietary and Drinking Water Exposure and Risk ...............................................................19 

4.3.1 Acute Dietary and Drinking Water Analysis.........................................................19 

4.3.2 Chronic Dietary and Drinking Water Analysis......................................................19 

5.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT ...............................................20 
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6.0 OCCUPATIONAL EXPOSURE AND RISK ...................................................................20 

6.1 Exposure Scenarios............................................................................................................20 

6.1.1 Handler Exposure Scenarios..................................................................................20 

6.1.2 Post Application Exposure Scenarios....................................................................21 

6.2 Occupational Exposure Data and Assumptions.................................................................21 

6.2.1 Exposure Data........................................................................................................21 

 6.2.2 Exposure Assumptions...........................................................................................21 

6.3 Occupational Exposure and Risk Estimates .....................................................................22 

 

7.0 CUMULATIVE RISK.......................................................................................................22 

8.0 DATA NEEDS...................................................................................................................23 

APPENDICES 

1.0 GUIDELINE TOXICOLOGY DATA SUMMARY .........................................................24 

 1.1 Guideline Data Requirements................................................................................24 

 1.2 Toxicity Profiles ....................................................................................................25 

2.0 STUDIES REVIEWED FOR ETHICAL CONDUCT ......................................................28 

3.0 ADDITIONAL TOXICITY STUDIES .............................................................................29 

4.0 REFERENCES FOR TOXICITY STUDIES ....................................................................31 

 
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1.0 EXECUTIVE SUMMARY

This assessment provides information to support an amended Section 3 registration for 

the use of cyromazine on succulent beans. This document addresses the exposures and risks 

associated with currently registered uses and the proposed new uses of cyromazine. It provides a 

reassessment of tolerances (pesticide residue limits in food) to ensure that they meet the safety 

standard established by the Food Quality Protection Act (FQPA) of 1996. 

Use Profile 

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

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

cyromazine is an insecticide/larvicide. Tolerances are established (40 CFR §180.414) for 

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

commodities) to 10.0 ppm (brassica vegetables). Cyromazine works as an insect growth 

regulator. It exerts its toxic action by affecting the nervous system of the immature stages 

(larvae) of certain insects. Cyromazine is applied to food crops with aircraft and ground 

application equipment. It is applied to non-food, landscape and greenhouse ornamentals using 

hand held spray equipment. There are no current or proposed residential uses of cyromazine. 

 

Proposed New Uses

 Interregional Research Project No. 4 (IR4) has submitted a proposal for the use of 

cyromazine as an insecticide in/on bean, succulent for the control of leafminer. Syngenta has 

submitted the label Trigard® 75WP Insecticide (EPA Reg. No. 100-654) for this use. This 

product contains 75% by weight of the active ingredient cyromazine. An application rate of 

0.125 lb ai/A is proposed with a seasonal maximum of 0.75 lb ai/A for 6 applications. Ground or 

aerial application equipment is permitted. 

Hazard Identification 

The toxicology database for cyromazine is adequate for evaluating and characterizing 

toxicity and selecting endpoints for purposes of this risk assessment. 

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

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

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

cyromazine based on a chronic dog study. Decrease in body weight and food consumption are 

also common effects of cyromazine as observed in chronic dog, rat, mouse, and rabbit studies. 

No dermal or systemic toxicity was seen at the highest dose tested in two 21 day dermal toxicity 

studies in rabbits. No neurotoxicity studies with cyromazine are available. However, the 

cyromazine chemical class (triazine) does not generally target the central or peripheral nervous 

system and available data show no evidence of neurotoxic potential for cyromazine. There is no 

evidence that cyromazine is teratogenic or that offspring are more susceptible than adults based 
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on developmental toxicity studies in rats and rabbits. In the two-generation reproduction study 

in rats no reproductive effects were observed. The FQPA SF was reduced to 1X because there 

are no residual uncertainties with regard to pre- and/or postnatal toxicity. Cyromazine was 

shown not to be carcinogenic in mice or rats following long-term dietary administration and is 

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

cyromazine does not have genotoxic activity. 

 A neurotoxicity battery (870.6200 a and b) and an immunotoxicity study (870.7800) are 

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

Dose Response Assessment

Toxicological points of departure (PODs) were selected for dietary/drinking water and 

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

exposure of cyromazine observed in oral toxicity studies. Therefore, a POD for acute dietary 

exposure was not selected. An RfD from a chronic feeding study in dogs was selected as the 

POD for chronic dietary exposure. No dermal or systemic toxicity was seen following repeated 

dermal application at the highest dose tested for 21 days to rabbits. Therefore a POD for dermal 

exposure was not selected. A POD for short-term inhalation was selected from a developmental 

toxicity study in rabbits. An intermediate-term inhalation exposure POD was selected from the 

chronic feeding study in dogs. An uncertainty factor of 100x was applied to PODs for all 

exposure routes (10x for interspecies extrapolation, 10x for intraspecies variation). 

Exposure/Risk Assessment and Risk Characterization

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

pathways based on registered uses and requests for new uses of cyromazine on succulent bean 

commodities. Screening level 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. Worker exposures were 

assessed for handler and post-application activities. Occupational exposure and risk estimates 

indicate that worker handler and post-application exposures are not of concern at the maximum 

allowable application rates for the proposed new uses. 

Use of Human Studies 

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

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

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

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

received the appropriate review. 

Environmental Justice 
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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. 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. 

Tolerance Recommendation 

There are no residue chemistry issues that would preclude establishing a tolerance and 

granting a registration for the requested use of cyromazine or establishment of the following 

tolerances for residues of cyromazine: 

Bean, succulent ........................................................ 2.0 ppm 

2.0 INGREDIENT PROFILE 

2.1 Registered Products 

There are currently 15 active cyromazine registrations according to the OPPIN data base. 

Reg # Name % ai Company Name 

100-632 Cyromazine Technical 97 

100-654 Trigard 75w 75 

100-656 Armor Insect Growth Regulator 5 

100-667 Citation Insecticide 75 

100-790 Trigard Omc 75 

Syngenta Crop Protection, Inc. 

1007-93 Serene Fly Control Pellets 2.12 Pfizer Inc 

70585-1 Larvadex 1% Premix 1 

70585-2 Larvadex 2sl 2 

70585-6 Novartis Cyromazine Technical Spec Ground 97 

70585-7 Neporex 2sg 2 

70585-I Neporex 2 

Novartis Animal Health Us, Inc. 

71176-1 Cyfly Technical 98 

71176-2 Cyfly 1% Premix 1 Blue Ridge Pharmaceuticals Inc 

75066-1 Flyzine 1% Premix 1 Novil, Inc. 
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Reg # Name % ai Company Name 

75066-2 Flyzine Technical 96.8 

2.2 Registered and Proposed New Uses 

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

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

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

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

larvicide. The current application proposes use on succulent bean as an insecticide. The 

proposed label for this use, Trigard® 75WP Insecticide (EPA Reg. No. 100-654), contains 75% 

ai by weight. An application rate of 0.125 lb ai/A is proposed with a seasonal maximum of 0.75 

lb ai/A for 6 applications. Ground or aerial application equipment is permitted. No adjuvant 

was added to the spray mixtures. Maximum application rates for existing and proposed uses are 

provided in Table 2. Maximum rates are based on a review of active and proposed labels. 

Table 2. Maximum Application Rates for Cyromazine Existing and Proposed New Uses

Application Site Max % AI Max Single AR Reg No.

leafy vegetables, bulb vegetables, cucurbit vegetables, tomato, onion, 

mushroom, lima bean, pepper, mango, potato, succulent bean. 75 0.125 lb/ai A 100-654 

2.3 Structure, Nomenclature, and Physical/Chemical Properties 

 The nomenclature and physicochemical properties of cyromazine are provided in Tables 

3 and 4. 

Table 3. Cyromazine Nomenclature 

Chemical structure 

Common name Cyromazine (ISO approved) 

Company experimental name CGA-72662 

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

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

CAS # 66215-27-8 

End-use product/EP Trigard®75WP 

Table 4. Physicochemical Properties of Cyromazine 

Parameter Value Reference
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Table 4. Physicochemical Properties of Cyromazine 

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 

Methonal, 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 

3.0 HAZARD CHARACTERIZATION/ASSESSMENT

3.1 Hazard Characterization 

The toxicology database for cyromazine is adequate for evaluating and characterizing 

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

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. 

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

toxicity for cyromazine based on a chronic dog study. Pronounced treatment-related effects on 

hematological parameters were manifest in animals as decreases in hematocrit and hemoglobin 

levels at mid and high dose levels. Slight increases were also noted in relative brain, heart, and 

liver weights of the high dose males and females and the ovary weights of the high dose females. 

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

observed in observed in chronic dog, rat, mouse, and rabbit studies. No systemic toxicity was 

seen following repeated dermal application at 2000 mg/kg/day, the highest dose tested (HDT) for 

21 days to rabbits in two dermal toxicity studies. An inhalation study is not available. 

The available oral perinatal and prenatal data demonstrated no indication of increased 

sensitivity of rats or rabbits to in utero exposure to cyromazine. Acceptable developmental 

toxicity studies in the rat and rabbit and a two-generation reproduction study in the rat are 

available. In the prenatal developmental toxicity study in rats, the NOAEL (300 mg/kg/day) for 
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developmental effects was higher than the Maternal NOAEL (100 mg/kg/day). In the 

developmental toxicity study in rabbits, no evidence of developmental toxicity was noted. The 

NOAEL for developmental toxicity was > 60 mg/kg/day (HDT); a LOAEL was not established. 

In the two-generation reproduction study in rats, no reproductive effects were observed. In this 

study the reproductive toxicity NOAEL is > 150 mg/kg/day (HDT). No reproductive toxicity 

LOAEL was obtained. 

In a metabolism study in rats, cyromazine was well absorbed after oral administration. 

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

administered dose recovered in the urine and feces at 24 hours. There was no evidence of 

preferential distribution or bioaccumulation of cyromazine. 

Cyromazine was shown not to be carcinogenic in mice or rats following long-term 

dietary administration is classified as a “not likely” human carcinogen. The available 

mutagenicity data suggest that cyromazine does not have genotoxic activity. 

Based on the results of the available toxicity studies, there is no evidence for 

neurotoxicity or immunotoxicity. However, in accordance with the revised 40 CFR Part 158 

Toxicology Data Requirements, a Neurotoxicity Battery (870.6200a and b) and an 

Immunotoxicity study (870.7800) are required (Appendix A and B). 

The complete toxicity profile for cyromazine is provided in Appendix 1.2, Tables 2 and 

3. 

3.2 FQPA Hazard Considerations

The toxicity database for cyromazine is sufficient for a full hazard evaluation and is 

considered adequate to evaluate risks to infants and children. Acceptable developmental toxicity 

studies in the rat and rabbit and acceptable multi- and single generation reproduction studies in 

the rat have been submitted. 

3.2.1 Developmental Toxicity 

3.2.1.1 Rat Developmental Study 

Study 1 

In a developmental toxicity study in COBS® CD® rats (25/group) (MRID 00002748) 

technical was administered by gavage in aqueous 1.0% carboxymethylcellulose at a dose volume 

of 10 ml/kg on gestation days 6-19. Dose levels were 0, 100, 300, or 600 mg/kg/day. Animals 

were observed daily for mortality and clinical signs of toxicity. Individual maternal body 

weights were recorded on gestation days 0, 6, 9, 12, 16 and 20. No data were provided for food 

consumption. All dams were sacrificed on gestation day 20 and the uterus was weighed prior to 

removal of fetuses. At 300 and 600 mg/kg/day dose levels, animals showed red nasal discharge 
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and increase in matting and staining of the anogenital haircoat. At the lowest dose rats showed 

clear oral discharge on 2 separate days. The mid dose group showed a slight reduction in overall 

maternal body weight gain (0-20 days), whereas the high dose group showed a reduction in both 

overall maternal body weight gain and body weight gain during the dosing periods (days 6-19). 

All of the dams survived. There were no statistically significant differences in mean numbers of 

viable fetuses, late or early resorptions, postimplantation loss, total implantations, corpora lutea 

or fetal sex distribution in any treatment group compared to control. At the highest dose, a 

significant increase in skeletal variations (unossified stemebrae) was observed in fetuses. For 

maternal toxicity, the NOAEL was 100 mg/kg/day, and the LOAEL was 300 mg/kg/day based 

on increased incidences of clinical observations (red or clear nasal discharge) and decreased 

body weight gain. For developmental toxicity, the NOAEL was 300 mg/kg/day, and the LOAEL 

was 600 mg/kg/day, based on increased incidence of minor skeletal variations. 

 Study 2

In a prenatal developmental toxicity study (MRID 00150471) in New Zealand white 

rabbits (16/group artificially inseminated females), 95.2% cyromazine was administered by 

gavage at doses of 0, 5, 10, 30, or 60 mg/kg/day on GD 7-19. The test substance was delivered 

in 0.5% aqueous carboxymethylcellulose at a dose volume of 1 ml/kg. All animals were 

observed daily for moribundity and mortality and clinical signs of toxicity. Females which 

aborted during the experimental period were sacrificed and necropsied on that day. A gross 

necropsy was performed on the females that died during the course of the study. Maternal body 

weights were recorded on gestation days 0, 7, 10, 14, 20, 24, and 29. Mean gravid uterine 

weights were determined for each female at the scheduled cesarean section. Individual food 

consumption was recorded dally from days 0 though 29 of gestation. On gestation day 29, all 

surviving females were sacrificed by an intravenous injection of T-61 euthanasia solution and 

the uterus was weighed prior to removal of fetuses. There were no treatment related deaths. A 

low pregnancy rate (7 litters with viable fetuses/45 fetuses) in the 10 mg/kg group limited 

information from this group. At 5 and 10 mg/kg/day doses, cyromazine did not produce toxic 

symptoms or any significant changes in food consumption, body weight, and reproductive status 

in pregnant rats. Three dams with resorprtions were found at the 30 mg/kg level and one each in 

the vehicle, 0 and 5 mg/kg groups. The number of corpora lutea was similar between the treated 

and control groups except for the 10 mg/kg group which had a slightly higher number of corpora 

lutea. However, these maternal toxicities were not considered treatment related. No compound 

related changes in pre-implantation loss were observed. However, the incidences of 

postimplantation loss was slightly increased in the two high dosage levels. Significant decreases 

in the number of female fetuses/dam were noted in the lower doses of 5, 10, and 30 mg/kg, but 

not in the higher dose of 60 mg/kg group. No significant changes were observed in fetal weights 

at any dose level. Slight decreases in fetal weight were noted in the mid doses of 10 and 30 

mg/kg groups, but apparently resulted from a larger litter size associated with these two dosage 

levels. The only treatment related effects observed in pregnant rabbits were decreased body 

weight gain and food consumption at 30 and 60 mg/kg/day. For maternal toxicity, the NOAEL 

was 10 mg/kg/day and the LOAEL was 30 mg/kg/day, based on decreased body weight gain and 

food consumption. For developmental toxicity, the NOAEL was 60 mg/kg/day (HDT); a 
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LOAEL was not established. 

 3.2.2 Reproductive Toxicity 

In a two-generation reproduction study (MRID 00103197) in Sprague-Dawley 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. 

There was a significant decrease in parental mean body weights in the F0 and F1 

generation at 1000 and 3000 ppm. The corresponding decrease in food consumption of F0 and 

F1 generations at 1000 ppm (slightly decreased) and 3000 ppm group (moderately decreased) 

provided a clear indication of a response to the treatment. 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. The pup weights in the high dose group averaged 10 to 20 

% less than that of the control group from birth to weaning. The parental systemic toxicity 

NOAEL was 1000 ppm (50 mg/kg/day), and the parental systemic toxicity LOAEL was 3000 

ppm (150 mg/kg/day) based on decreased body weights that were associated with decreased food 

efficiency. The offspring developmental toxicity NOAEL was 1000 ppm (50 mg/kg/day) and the 

offspring systemic/developmental toxicity LOAEL was 3000 ppm (150 mg/kg/day), based on 

decreased body weights at birth and through weaning. The reproductive toxicity NOAEL is 3000 

ppm (150 mg/kg/day - HDT). The reproductive toxicity LOAEL was not achieved. 

3.2.4 Pre-and/or Postnatal Toxicity

The database is considered adequate for selection of study endpoints and determination 

of a dose/response to characterize the potential prenatal or postnatal toxicity of cyromazine to 

infants and children. No increase in susceptibility was seen in developmental toxicity studies in 

rat and rabbit or reproductive toxicity studies in the rat. Toxicity to offspring was observed at 

dose levels the same or greater than those causing maternal or parental toxicity. Based on the 

results of developmental and reproductive toxicity studies, there is not a concern for increased 

qualitative and/or quantitative susceptibility following in utero exposure to cyromazine. 

A developmental neurotoxicity study is not required. Based on available data there is no 

evidence of neurotoxic potential for cyromazine. Neurotoxicity was not observed in the prenatal 

developmental toxicity studies in either rats or rabbits. Additionally, the cyromazine chemical 

class (triazine) does not generally target the central or peripheral nervous system. 
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3.2.5 Immunotoxicity 

There are no indications in the available studies that organs associated with immune 

function, such as the thymus and spleen, are affected by cyromazine. An immunotoxicity study 

is required, however, under 40 CFR Part 158 as a part of the new data requirements for 

registration of a pesticide (food and non-food uses). 

 3.2.6 FQPA Factor 

 Since there are adequate developmental studies in rats and rabbits and an adequate multigeneration study in rats, and no residual uncertainties that indicate the need for a factor, the 

FQPA factor has been reduced to 1X. 

3.3 Toxicity Endpoint Selection

3.3.1 Acute Reference Dose (aRfD) – All Populations 

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

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

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

and an acute aggregate exposure assessment is not required.

3.3.2 Chronic Reference Dose (cRfD) - All Populations 

Selected Study: Combined chronic/carcinogenicity in the rat; MRID 00103202 

 In a 24-month chronic toxicity/oncogenicity study in rats, 60 Charles River SpragueDawley rats sex/dose were administered 0, 30, 300 and 3000 ppm of cyromazine. An additional 

10 animals per sex in the control and 3000 ppm groups were designated for interim sacrifice at 

one year. The study design allocated groups of 60 rats per sex to dose levels of 0, 30, 300 nd 

3000 ppm (0, 1.5, 15, 150 mg/kg/day) of cyromazine (95.5%). An additional 10 animals per sex 

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

statistical evaluation of mortality provided by the registrant indicated no significant incremental 

charges with increasing doses of cyromazine in male or female rats (41% survival in HDT vs. 

42% survival in controls). Survival in males and females were excellent in all groups after 24 

months. There were no statistically significant differences between the control and treated 

groups in benign tumors (adenomas and fibroadenomas), malignant tumors (adenocarcinomas) 

or combined benign and malignant tumors (adenomas and/or fibroadenomas and/or 

adenocarcinomas); there were no statistical trends and no dose response. Hence, there was no 

evidence of carcinogenicity at the dose levels tested in this study. Female rats had decreased 

body weight gain at doses of 300 and 3000 ppm, as did males at doses of 3000 ppm. Body 

weight gains were reduced by 22% in the high-dose males and 33% in females, and in the middose females body weight gain was reduced by about 10% from week 49 until termination. Food 

consumption was also decreased at these dose levels; however food efficiency was unchanged 
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from control. The systemic toxicity LOAEL is 300 ppm (15 mg/kg/day) based on decreased 

body weight. The systemic toxicity NOAEL is 30 ppm. (1.5 mg/kg/day). There is no evidence of 

carcinogenicity. 

Dose and Endpoint for Establishing a POD: NOAEL = 1.5 mg/kg/day day based on food 

consumption and body weight decreases at 15 mg/kg/day (LOAEL). 

Uncertainty Factor (UF): 100x (10x for interspecies variation and 10x for intraspecies 

variation) 

Chronic RfD = 1.5 mg/kg (NOAEL) = 0.015 mg/kg 

 100 (UF)

[Note: The chronic RfD has been revised been revised from previous risk assessments based on 

reevaluation of the existing data.] 

3.3.3 Incidental Oral Exposure (Short and Intermediate Term) 

Cyromazine has not been registered for residential uses; therefore, selection of a toxicity 

endpoint is not necessary for this exposure scenario at this time. 

3.3.5 Dermal Exposure 

Selected Study: 21-day dermal toxicity in the rabbit; MRID No. 44060901 & 44060902. 

In a 21 day dermal toxicity study (MRID# 44060902), New Zealand White Rabbits (5-7 

males/dose; 5 females/dose) were exposed to either 0, 50, 200, or 2000 mg/kg/day Cyromazine 

Technical (94.6% a.i). No treatment related systemic toxicity was noted. The Systemic Toxicity 

NOAEL is equal to or greater than 2000 mg/kg/day and the Systemic Toxicity LOAEL is greater 

than 2000 mg/kg/day. No dermal irritation was noted. The Dermal Toxicity NOAEL = 2000 

mg/kg/day and the Dermal Toxicity LOAEL is greater than 2000 mg/kg/day. In a second 21-day 

dermal toxicity study (MRID# 44060902), HAR:PF/CF (NZW) BR Albino Rabbits (5/sex/dose) 

were exposed to either 0, or 2010 mg/kg/day cyromazine technical (96% a.i.). No treatment 

related systemic toxicity was noted. The systemic toxicity NOAEL is equal to or greater than 

2010 mg/kg/day and the systemic toxicity LOAEL is greater than 2010 mg/kg/day. Dermal 

irritation was slightly increased over control. 

Dose and Endpoint for Risk Assessment: No hazard was identified via the dermal route 

of exposure and therefore quantification of risk via this route of exposure is not required. 

3.3.6 Inhalation Exposure 
Page 14 of 36 

3.3.6.1 Inhalation Exposure (Short-Term)

Selected Study: Developmental toxicity in the rat; MRID 00150471. See Section 3.2.1 

 Dose and Endpoint for Establishing a POD: Maternal Toxicity NOAEL = 10 mg/kg/day 

on based on decreased body weight gain and food consumption at 30 mg/kg/day. 

Uncertainty Factor (UF): 100 – 10x for interspecies extrapolation and 10x for 

intraspecies variation. 

Comments about Study/Endpoint: Since an oral POD was selected for inhalation risk 

assessment, an inhalation absorption factor of 100% is assumed. 

3.3.6.2 Inhalation Exposure (Intermediate-Term) 

Selected Study: Combined chronic/carcinogenicity in the rat; MRID 00103202. See 

Section 3.3.2. 

Dose and Endpoint for Establishing a POD: NOAEL = 1.5 mg/kg/day day based on food 

consumption and body weight decreases at 15 mg/kg/day (LOAEL). 

Uncertainty Factor (UF): 100 – 10x for interspecies extrapolation and 10x for 

intraspecies variation. 

Comments about Study/Endpoint: Since an oral POD was selected for inhalation risk 

assessment, an inhalation absorption factor of 100% is assumed. 

[Note: The POD for intermediate-term inhalation exposure been revised from previous risk 

assessments based on reevaluation of the existing data.] 

3.3.7 Classification of Carcinogenic Potential 

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

evidence of carcinogenicity in the mouse and rat cancer studies (HED CPRC, TXR No. 011384, 

1/6/95). The available data suggest that cyromazine does not have genotoxic activity. Three 

acceptable studies on cyromazine were submitted to OPP. All three mutagenicity studies were 

negative. 

3.4 Margins of Exposure 

A summary of target Levels of Concern for risk assessment is provided in Table 5. 

Table 5. Target Levels of Concern/Margin of Exposure for Cyromazine 
Page 15 of 36 

Route/Duration Short-Term 

(1-30 Days) 

Intermediate-Term 

(1 - 6 Months) 

Long-Term 

(> 6 Months) 

Occupational (Worker) Exposure 

Dermal NA NA NA 

Inhalation 100 100 100 

Residential (Non-Dietary) Exposure 

Oral N/A N/A N/A 

Dermal NA N/A N/A 

Inhalation N/A N/A N/A 

3.5 Recommendation for Aggregate Exposure Risk Assessments

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

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

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

and non-food oral exposures is not required. 

 

3.6 Summary of Endpoints Selected for Risk Assessment

Toxicological doses/endpoints selected for the cyromazine risk assessment are provided 

in Tables 6 and 7. 

Table 6. Summary of Toxicological Doses and Endpoints for Cyromazine for Use in Dietary Human Health Risk Assessments 

Exposure/Scenario Point of 

Departure 

Uncertainty/FQPA 

Safety Factors 

RfD, PAD, LOC 

for Risk 

Assessment 

Study and Toxicological Effects 

Chronic Dietary 

(All Populations) 

NOAEL= 

1.5 

mg/kg/day 

UFA= 10x 

UFH=10x 

FQPA SF= 1x 

Chronic RfD = 

0.015 

mg/kg/day 

cPAD = 0.015 

mg/kg/day 

Combined Chronic/Carcinogenicity Toxicity in 

Rats. 

LOAEL = 15 mg/kg/day based on food 

consumption and body weight decreases at 15 

mg/kg/day (LOAEL). 

Cancer (all routes) Not likely human carcinogen 

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

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

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

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

among members of the human population (intraspecies). 

SF = FQPA Safety Factor. 

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

RfD = reference dose. 

MOE = margin of exposure. 

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

Table 7. Summary of Toxicological Doses and Endpoints for Cyromazine for Use in Occupational Human Health Risk 

Assessments 
Page 16 of 36 

Exposure/ 

Scenario 

Point of 

Departure 

Uncertainty 

Factors 

Level of Concern 

for Risk 

Assessment 

Study and Toxicological Effects 

Inhalation Short-Term 

(1-30 days) 

NOAEL= 

10mg/kg/day 

UFA= 10x 

UFH=10x 

Occupational 

LOC for MOE = 

100 

Developmental Toxicity study in rabbits. 

LOAEL = 30 mg/kg/day based on decreases in 

body weight gain and food consumption. 

Inhalation 

Intermediate/Long-Term 

(1-6 mo/ > 6 mos) 

NOAEL = 

1.5 

mg/kg/day 

UFA= 10x 

UFH=10x 

Occupational 

LOC for MOE = 

100 

Combined Chronic/Carcinogenicity Toxicity in 

Rats. 

LOAEL = 15 mg/kg/day based on food 

consumption and body weight decreases at 15 

mg/kg/day (LOAEL). 

Cancer (all routes) Not likely human carcinogen 

3.7 Endocrine Disruption

EPA is required under the FFDCA, as amended by FQPA, to develop a screening 

program to determine whether certain substances (including all pesticide active and other 

ingredients) “may have an effect in humans that is similar to an effect produced by a 

naturally occurring estrogen, or other such endocrine effects as the Administrator may 

designate.” Following recommendations of its Endocrine Disruptor and Testing Advisory 

Committee (EDSTAC), EPA determined that there was a scientific basis for including, as 

part of the program, the androgen and thyroid hormone systems, in addition to the estrogen 

hormone system. EPA also adopted EDSTAC’s recommendation that the Program include 

evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA 

and, to the extent that effects in wildlife may help determine whether a substance may have 

an effect in humans, FFDCA authority to require the wildlife evaluations. As the science 

develops and resources allow, screening of additional hormone systems may be added to the 

Endocrine Disruptor Screening Program (EDSP). 

When additional appropriate screening and/or testing protocols being considered under 

the Agency’s EDSP have been developed, cyromazine may be subjected to further screening 

and/or testing to better characterize effects related to endocrine disruption. 

4.0 DIETARY AND DRINKING WATER EXPOSURE ASSESSMENT

4.1 Residue Chemistry Profile 

 4.1.1 Metabolism in Primary Crops and Livestock 

 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 Assessment Review Committee (MARC) (D245214, J. Stokes, 11/4/97). The 

metabolism of cyromazine in plants is adequately understood and additional plant metabolism 

data are not required for this proposed use on bean, succulent. Data concerning the metabolism 

of cyromazine in lactating goats and laying hens have been previously submitted. The MARC 
Page 17 of 36 

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

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

 4.1.2 Residue Analytical Methods 

 4.1.2.1 Enforcement Methods 

Methods AG-408 (HPLC,/UV) and AG-417A (GLC/NPD) are the tolerance enforcement 

methods for cyromazine as published in the Pesticide Analytical Manual (PAM), Vol. II. These 

methods combined and with minor modifications comprise Method AG-621. The residue data 

submitted in support of this petition were generated using Methods AG-408 and AG-621. 

Method AG-621 has been adequately validated for use for the determination of residues of 

cyromazine in/on bulb vegetables, leafy Brassica vegetables, and turnip greens. Method AG-408 

is adequate for enforcement of the proposed tolerance for residues of cyromazine. Adequate 

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

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

 4.1.2.2 Multiresidue Methods 

 The registrant submitted recovery data through 5 GC columns using electron capture and 

nitrogen/phosphorus detectors. Flame photometric detectors were not used as the compounds 

contained neither phosphorus nor sulfur. When analyzed through Protocol D, cyromazine per se

was recovered when the 2% DEGS column was used. These data were forwarded to FDA. No 

additional cyromazine MRM recovery data were required. FDA does not report the capability to 

detect cyromazine per se in its monitoring program, nor does USDA FSIS. 

 

 4.1.3 Residues in Crops, Livestock and Processed Commodities 

The Interregional Research Project No. 4 (IR-4) has submitted field trial data for 

cyromazine on bean, succulent. Eight trials were conducted on snapbean (edible-podded) during 

the 2002 growing season. Three field trials were conducted in NAFTA growing regions 1 (NY, 

1), 2 (GA, 3), 5 (WI, 2), and 11(WA, 2). At each test location, six foliar broadcast applications 

of a 75% wettable powder (WP) formulation of cyromazine (Trigard ® 75 WP) were made, with 

6- to 8-day retreatment intervals, at a rate of 0.125 lb ai/A/application for a total rate of 

approximately 0.75 lb ai/A Applications were made using ground equipment or backpack in 20-

51 gal/A spray volumes without an adjuvant. Samples of mature bean were harvested 6 to 7 

days after the last application. Samples of bean were analyzed for residues of cyromazine using 

an GC with a nitrogen/phosporous detector (No. AG-621). This method is adequate for data 

collection based on acceptable method verification and concurrent method recoveries. The 

lower level of method validation (LLMV) was 0.10 ppm for cyromazine. Based on recoveries of 

samples fortified at the LLMV, the estimated limit of detection (LOD) and the limit of 

quantitation (LOQ) were calculated as 0.05 ppm and 0.15 ppm, repetitively. Samples were 

stored frozen up to 140 days prior to analysis; adequate storage stability data are available to 

support sample storage conditions and durations. Cyromazine residues ranged from 0.4955 to 
Page 18 of 36 

1.4108 ppm in/on bean harvested 6 to7 days after foliar treatment with the 75% WP at a total 

rate of 0.75 lb ai/A. 

 No additional livestock studies were submitted for the proposed use in/on bean, 

succulent. There are no livestock commodities associated with the proposed use on bean, 

succulent. However, revised dietary burdens have been estimated for beef, dairy, chicken, and 

swine based on changes using Table 1 Feedstuffs (June 2008). 

 Processing data were not provided in this petition. No processing data are needed for the 

proposed use as in any processed succulent bean commodity would not be expected to exceed 

the crop tolerance. 

4.2 Drinking Water Profile 

 4.2.1 Environmental Fate and Transport 

 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. Based on 

Koc values, cyromazine falls into the “Mobile” category as described by the Environmental Fate 

and Effects Division (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. Melamine was identified as the 

primary cyromazine degradate. In aerobic metabolism studies the melamine levels ranged 

between 33 and 60 percent of the parent (as applied radioactivity). The persistence (T1⁄2), 

adsorption (Kd), and dissipation rate of melamine have not been specified, but in terrestrial field 

studies, melamine is shown to be more persistent and mobile than the parent, and may 

accumulate in soil with repeated uses. Melamine is not a residue of toxicological concern for 

dietary or drinking water exposure (D245214, MARC, 11/4/97). Two other degradates were also 

noted, but not identified. 

4.2.2 Estimated Drinking Water Concentrations 

Drinking water residues were incorporated directly into the chronic dietary analysis 

(“water, direct, all sources” and “water, indirect, all sources”) and were provided by EFED 

(D358724, J Wolf, 7/6/09). EFED generated the surface water and ground water estimates using 

the Tier 1 surface water FQPA Index Reservoir Screening Tool (FIRST) and Screening 

Concentration in Ground Water (SCIGROW; Tier 1) models, respectively. EFED provided 

estimates for the proposed use of cyromazine on succulent beans using the Tier 1 FIRST applied 

as 6 applications at (0.125 lb ai/ac) rates, and a seasonal rate of 0.75 lb ai/acre. The 

concentrations have been adjusted with the Percent Crop Area (PCA) of 0.87 for a national 

assessment. Surface water EDWCs for cyromazine used in the exposure assessment, are 
Page 19 of 36 

provided in Table x. Acute and chronic exposure concentrations of cyromazine in ground water 

are estimated using SCI-GROW which considers the additional fate information (Koc = 99.6 

mL/goc and mean ASM half-life of 104 days). 

 

Table 8. EDWCs for use in screening the Cyromazine Health Risk Assessment 

Drinking Water Source Peak (μg/L) Annual Mean (μg/L)

Surface Water 47.1 15.8 

Ground Water 1.1 1.1 

4.3 Dietary and Drinking Water Exposure and Risk 

 A screening-level chronic dietary and drinking water exposure and risk assessment was 

conducted using the Dietary Exposure Evaluation Model with the Food Commodity Intake 

Database (DEEM-FCIDTM). Dietary risk assessment incorporates both exposure and toxicity of 

a given pesticide. For acute and chronic dietary assessments, the risk is expressed as a 

percentage of a maximum acceptable dose (i.e., the dose which HED has concluded will result in 

no unreasonable adverse health effects). This dose is referred to as the population adjusted dose 

(PAD). The PAD is equivalent to the reference dose (RfD) divided by the additional Safety 

Factor, if applied. For acute and non-cancer chronic exposures, HED is concerned when 

estimated dietary risk exceeds 100% of the PAD. 

 4.3.1 Acute Dietary and Drinking Water Analysis 

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

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

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

and an acute aggregate exposure assessment is not required.

 4.3.2 Chronic Dietary and Drinking Water Analysis 

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

population and various population subgroups. Tolerance level residues and 100 crop treated 

assumptions were used. DEEM default and empirical processing factors were used to modify the 

tolerance values. The chronic analysis incorporated the 10 year average surface drinking water 

estimate from application of cyromazine to succulent bean crop. 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 85%. The cPAD for the general 

U.S. population was 50%. 

Table 9: Summary of Chronic Dietary Exposure and Risk for Cyromazine

Chronic Population Subgroup cPAD (mg/kg/day) Exposure (mg/kg/day) % cPAD 

General U.S. Population 0.0073 50 

All Infants (< 1 year old)

0.015 

0.0060 40 
Page 20 of 36 

Table 9: Summary of Chronic Dietary Exposure and Risk for Cyromazine

Chronic Population Subgroup cPAD (mg/kg/day) Exposure (mg/kg/day) % cPAD 

Children 1-2 years old 0.0127 85 

Children 3-5 years old 0.0114 76 

Children 6-12 years old 0.0081 54 

Youth 13-19 years old 0.0060 40 

Adults 20-49 years old 0.0066 44 

Adults 50+ years old 0.0073 49 

Females 13-49 years old 0.0065 43 

5.0 AGGREGATE EXPOSURE AND RISK ASSESSMENT 

 In accordance with the FQPA, when there are potential residential exposures to a 

pesticide, aggregate risk assessment must consider exposures from three major routes: oral, 

dermal, and inhalation. There are three sources for these types of exposures: food, drinking 

water, and residential uses. In an aggregate assessment, exposures from relevant sources are 

added together and compared to quantitative estimates of hazard (e.g., a NOAEL or PAD), or the 

risks themselves can be aggregated. When aggregating exposures and risks from various 

sources, HED considers both the route and duration of exposure. The proposed/registered 

cyromazine uses are not expected to result in residential exposure. Therefore, the acute and 

chronic exposure estimates provided in the Dietary Exposure Section represent aggregate 

exposure. 

6.0 OCCUPATIONAL EXPOSURE AND RISK

6.1 Exposure Scenarios

 Occupational handler and post-application exposure scenarios were evaluated for the risk 

assessment of the proposed new uses on succulent bean crops. There is a potential for short- and 

intermediate-term occupational exposure to cyromazine during mixing, loading, application, and 

post-application activities. Long-term exposure is not expected for the proposed use patterns. A 

POD for dermal exposure was not selected for cyromazine because no hazard was identified via 

the dermal route (i.e., no systemic toxicity was observed at the limit dose of 2,000 mg/kg/day). 

Therefore, the occupational risk assessment was based on inhalation exposure only. The 

formulation of cyromazine evaluated in this assessment is a wettable powder, packaged in watersoluble packets (Trigard® 75% ai). 

6.1.1 Handler Exposure Scenarios 

 The term “handler” applies to individuals who mix, load, and apply the pesticide product. 

Formulation-specific unit exposure data for wettable powder products was used for this 

assessment. The following handler exposure scenarios were assessed for proposed new 

cyromazine uses. 
Page 21 of 36 

 1) Mixing/Loading wettable powder packaged in water-soluble packets for aerial 

application. 

 2) Mixing/Loading wettable powder packaged in water-soluble packets for 

groundboom application. 

 3) Applying sprays with fixed-wing aircraft. 

 4) Applying sprays with a groundboom sprayer 

 5) Flagging sprays for aerial operations. 

6.1.2 Post-Application Exposure Scenarios 

 The proposed new use on cyromazine involves foliar applications. Therefore, there is a 

potential for postapplication exposure to scouts, harvesters and other field workers. However, 

because no appropriate dermal endpoints were identified for this exposure potential and 

postapplication inhalation exposure is expected to be negligible, an occupational postapplication 

risk assessment was not conducted. 

6.2 Occupational Exposure Data and Assumptions

6.2.1 Exposure Data

Maximum application rates for all of the exposure scenarios assessed are based on 

information provided in the cyromazine labels for the proposed new uses. The maximum 

application rate for wettable powder formulations is 0.125 lb ai per acre. Data from the 

Pesticide Handlers Exposure Database (PHED) was used to assess handler and post-application 

exposures in the absence of chemical-specific data. The transfer coefficients used in the postapplication exposure assessment are from an interim transfer coefficient guidance document 

developed by HED’s Science Advisory Council for Exposure using proprietary data from the 

Agricultural Re-entry Task Force (ARTF) data base (SOP #3.1) 

6.2.2 Exposure Assumptions 

 The following standard exposure assumptions were used in estimating risks to handlers 

from exposure to cyromazine for the proposed new uses on onion and cucurbits. 

• Average body weight of an adult handler is 70 kg. 

• Exposure duration is short-term and intermediate-term for all workers assessed. 

• Maximum application rates as determined by label review were used for all types and 

methods of application. 

• SOP daily volumes handled and/or area treated used for the scenarios assessed are: 

- 80 acres treated per day for groundboom mixing, loading and applying 

- 350 acres treated per day for aerial mixing, loading and applying 

6.3 Occupational Exposure and Risk Estimates 
Page 22 of 36 

 

 A target LOC or MOE of 100 is considered adequate for inhalation exposure. All worker 

exposures are assessed as short-and intermediate-term based on label prescribed uses and 

expected exposure durations. Exposure and risk estimates indicate MOEs are not of concern 

(MOEs > 100) at the maximum use rate for occupational handler activities for the proposed new 

uses. A summary of occupational handler exposure and risk calculations, assumptions, and 

results is provided in Table 14. 

Table 4. Inhalation Exposure and Risk Assessment for Occupational Handlers

Exposure Scenario PHED Unit 

Exposure 1

(mg/lb ai)

Application 

Rate 2

(lb ai/A)

Area 

Treated 3

(A/day)

Daily 

Dose 4

(mg/kg/day)

Short- Term 

Inhalation 

MOE 5

IntermedTerm 

Inhalation 

MOE 5

1. Mixing/Loading Wettable 

Powder packaged in Water-Soluble 

Packets for Aerial Application 

0.00024 0.125 350 0.00015 67,000 50,000

2. Mixing/Loading Wettable 

Powder packaged in Water-Soluble 

Packets for Groundboom 

Application 

0.00024 0.125 80 0.000034 290,000 44,000

3. Applying Sprays with Fixedwing Aircraft (enclosed cockpit) 0.000068 0.125 350 0.000043 240,000 36,000

4. Applying Sprays with a 

Groundboom Sprayer (open cab) 0.00074 0.125 80 0.00011 95,000 14,000

5. Flagging (Sprays) for Aerial 

Operations 0.00035 0.125 350 0.00022 46,000 6,800

1

Unit Exposure values are based on exposure without a respirator. There is low confidence in values used for M/L wettable 

powder in water-soluble packets, high confidence in the values for groundboom application and flagging for aerial operations, 

and medium confidence in values used for aerial application with an enclosed-cockpit aircraft. 2

 Maximum application rate of 0.125 lb ai/acre was used as a screening value. 3

Standard values for acres treated in a day were used. 

4

 Daily Dose = [Unit Exposure (mg/lb ai handled) x Application Rate (lb ai/A) x Acres Treated (A/day)] / Body Weight (70 kg 

used because endpoint effects were not considered gender-specific) 5

 MOE = NOAEL/ Daily Inhalation Dose. Short-term Inhalation NOAEL = 10 mg/kg/day. Intermediate-term Inhalation 

NOAEL = 1.5 mg/kg/day. 

7.0 CUMULATIVE RISK

Section 408(b)(2)(D)(v) of FFDCA requires that, when considering whether to establish, 

modify, or revoke a tolerance, the Agency consider “available information” concerning the 

cumulative effects of a particular pesticide's residues and “other substances that have a common 

mechanism of toxicity.” 

 EPA does not have, at this time, available data to determine whether cyromazine has a 

common mechanism of toxicity with other substances. 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 
Page 23 of 36 

which have tolerances in the U. S. For the purposes of this tolerance reassessment 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 OPP 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/fedrgstr/EPA_PEST/2002/January/Day_16/. 

8.0 DATA NEEDS

 - Immunotoxicity Study (GLN 870.7800) 

 - Acute Neurotoxicity Study (GLN 870. 6200a) 

 - Subchronic Neurotoxicity Study (GLN 870.6200b) 
Page 24 of 36 

APPENDICES 

1.0 TOXICOLOGY DATA SUMMARY 

1.1 Guideline Data Requirements 

Table 1. Guideline Data Requirements 

Technical

Test

Required Satisfied

870.1100 Acute Oral Toxicity ....................................................... 

870.1200 Acute Dermal Toxicity .................................................. 

870.1300 Acute Inhalation Toxicity .............................................. 

870.2400 Primary Eye Irritation .................................................... 

870.2500 Primary Dermal Irritation .............................................. 

870.2600 Dermal Sensitization...................................................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.3100 Oral Subchronic (rodent) ............................................... 

870.3150 Oral Subchronic (nonrodent) ......................................... 

870.3200 21-Day Dermal .............................................................. 

870.3250 90-Day Dermal .............................................................. 

870.3465 90-Day Inhalation .......................................................... 

yes 

yes 

yes 

no 

no 

yes 

yes 

yes 

no 

no 

870.3700a Developmental Toxicity (rodent)................................... 

870.3700b Developmental Toxicity (nonrodent)............................. 

870.3800 Reproduction ................................................................. 

yes 

yes 

yes 

yes 

yes 

yes 

870.4100a Chronic Toxicity (rodent) .............................................. 

870.4100b Chronic Toxicity (nonrodent) ........................................ 

870.4200a Oncogenicity (rat) .......................................................... 

870.4200b Oncogenicity (mouse).................................................... 

870.4300 Chronic/Oncogenicity.................................................... 

yesa 

yes 

yesa

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.5100 Mutagenicity—Gene Mutation - bacterial ..................... 

870.5300 Mutagenicity—Gene Mutation - mammalian ................ 

870.5375 Mutagenicity—Structural Chromosomal Aberrations ... 

870.5900 Mutagenicity—Other Genotoxic Effects ....................... 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

yes 

870.6100a Acute Delayed Neurotox. (hen) ..................................... 

870.6100b 90-Day Neurotoxicity (hen)........................................... 

870.6200a Acute Neurotox. Screening Battery (rat)........................ 

870.6200b 90-Day Neuro. Screening Battery (rat).......................... 

870.6300 Develop. Neuro.............................................................. 

no 

no 

yes 

yes 

no 

- 

- 

no

no 

no 

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

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

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

yes 

no 

yes 

yes 

yes 

no 

a Guideline 870.4300 satisfies guideline 870.4100a and 870.4200a. 
Page 25 of 36 

1.2 Toxicity Profiles 

Table 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 2. Toxicology profile for Cyromazine 

Study Type / 

Guideline No. 

MRID (Year) / 

Classification / Doses Results 

Subchronic oral - Dog 

 

870.3100 (82-1) 

00135432 (1979) 

Acceptable/Guideline 

0, 30, 300, 1000 or 3000 

ppm (0, 0.75, 7.5, 25 and 75 

mg/kg/day) 

The systemic toxicity LOAEL is 1000 ppm (25 mg/kg/day) based on 

alteration in liver weight in males. 

The systemic toxicity NOAEL is 300 ppm (7.5 mg/kg/day). 

Subchronic oral - Rat 

870.3100 (82-1) 

00135433 (1979) 

Acceptable/Guideline 

0, 30, 100 and 300 ppm (0, 

3, 10, and 30 mg/kg/day) 

The systemic toxicity LOAEL is 300 ppm (30 mg/kg/day), based on 

alteration in the liver weight changes in males. 

The systemic toxicity NOAEL is 30 ppm (3 mg/kg/day). 

21-day dermal toxicity 

-Rabbit 

870.3200 (82-2) 

44060901 (1992) 

Acceptable/Guideline 

0, 50, 200 & 2000 

mg/kg/day 

No treatment related systemic toxicity was noted. The systemic toxicity 

NOAEL > 2000 mg/kg/day and the systemic toxicity LOAEL > 2000 

mg/kg/day. 

No dermal irritation was noted. The dermal toxicity NOAEL > 2000 

mg/kg/day and the dermal toxicity LOAEL > 2000 mg/kg/day. 

21-day dermal toxicity 

-Rabbit 

870.3200 (82-2) 

44060902 (1984) 

Acceptable/Guideline 

0 & 2010 mg/kg/day 

No treatment related systemic toxicity was noted. The systemic toxicity 

NOAEL > 2010 mg/kg/day and the systemic toxicity LOAEL > 2010 

mg/kg/day. 

No dermal irritation was noted. The dermal toxicity NOAEL > 2010 

mg/kg/day and the dermal toxicity LOAEL > 2010 mg/kg/day. 

Chronic oral 

(6-months) - Dog 

870.4100 (83-1) 

00103193 (1982) 

Acceptable/Guideline 

0, 30, 300 or 3000 ppm (0, 

0.75, 7.5 and 75 mg/kg/day) 

The systemic toxicity LOAEL is 3000 ppm (75 mg/kg/day) based on 

alteration in hematological parameters (hemoglobin, and hematocrit). 

The systemic toxicity NOAEL is 300 ppm (7.5 mg/kg/day). 

Combine Chronic/ 

Carcinogenicity- Rat 

870.4300 (83-5) 

 00103202 (1982) 

Acceptable/Guideline 

0, 30, 300 and 3000 ppm (0, 

1.5, 15, and 150 mg/kg/day) 

The systemic toxicity LOAEL is 300 ppm (15 mg/kg/day) based on 

decreased body weight. The systemic toxicity NOAEL is 30 ppm. (1.5 

mg/kg/day). There is no evidence of carcinogenicity. 

CarcinogenicityMouse 

870.4200 (83-2) 

00115736 (1982) 

Acceptable/Guideline 

0, 50, 1000, and 3000 ppm 

(0, 7.5, 150, and 450 

mg/kg/day) 

The systemic toxicity LOAEL is 1000 ppm (150 mg/kg/day) based on 

decreased body weight. The systemic toxicity NOAEL is 50 ppm. (7.5 

mg/kg/day). There is no evidence of carcinogenicity. 
Page 26 of 36 

Table 2. Toxicology profile for Cyromazine 

Study Type / 

Guideline No. 

MRID (Year) / 

Classification / Doses Results 

Cancer Classification: 

The HED CPRC TXR 

No. 011384 

Jan. 6, 1995 The HED CPRC re-evaluated the weight-of-evidence on Cyromazine 

with particular reference to its carcinogenic potential. The HED CPRC 

concluded that cyromazine should be re-classified as Group E, based on 

a submission of data from a re-examination of the tissues from the 

mouse and rat studies. Cyromazine is classified as a “Not Likely Human 

Carcinogen” based on the lack of evidence of carcinogenicity in the 

mouse and rat cancer studies. 

Developmental 

toxicity -Rabbit 

870.3700 (83-3b) 

00150471 (1985) 

Acceptable/Guideline 

0, 10, 30, and 60 mg/kg/day 

The maternal toxicity LOAEL is 30 mg/kg/day, based on reduced body 

weight gain and food consumption, and the maternal toxicity NOAEL is 

10 mg/kg/day. The developmental toxicity LOAEL was not established 

and the developmental toxicity NOAEL = 60 mg/kg/day (HDT). 

Developmental 

toxicity- Rat 

870.3700 (83-3a) 

00027488 (1979) 

Acceptable/Guideline 

0, 100, 300 and 600 

mg/kg/day 

The maternal toxicity LOAEL is 300 mg/kg/day, based on clinical signs 

(red or clear nasal discharge) and decreased body weights. The 

maternal toxicity NOAEL = 100 mg/kg/day. 

The developmental toxicity LOAEL is 600 mg/kg/day (HDT), based on 

increased incidence of minor skeletal variations. The developmental 

toxicity NOAEL is 300 mg/kg/day. 

Two generation 

reproduction- Rat 

870.3800 (83-4) 

00103197 (1981) 

Acceptable/Guideline 

0, 30, 1000 and 3000 ppm 

(0, 1.5, 50, and 150 

mg/kg/day) 

The parental systemic toxicity LOAEL is 3000 ppm (150 mg/kg/day) 

based on decreased body weights that were associated with decreased 

food efficiency. 

The parental systemic toxicity NOAEL is 1000 ppm (50 mg/kg/day). 

The offspring systemic/developmental toxicity LOAEL is 3000 ppm 

(150 mg/kg/day), based on decreased body weights at birth and through 

weaning. The systemic/developmental toxicity NOAEL is 1000 ppm 

(50 mg/kg/day). 

No effects were noted on reproductive parameters and no reproductive 

toxicity LOAEL was determined. The reproductive toxicity NOAEL is 

3000 ppm (150 mg/kg/day). 

Metabolism- Rat 

870.7485 (85-1) 

41442101 (1989) 

Acceptable/Guideline 

3 and 300 mg/kg 

Cyromazine was well absorbed after oral administration. Excretion was 

rapid at the lower dose (3 mg/kg), but an apparent delay in excretion 

occurred at the high dose (300 mg/kg). Fecal elimination was 

equivalent among dose groups except the high dose males, where a 

greater percentage was eliminated by this route. The origin of fecal 

radioactivity was via biliary elimination. Residual radioactivity in 

tissues was minimal in all dose groups. Urinary and fecal metabolites of 

14C_cyromazine were isolated and identified by TLC, HPLC, and 

GC/MS. The major compounds identified were the N-dealkylated 

product melamine, hydroxycyromazine, and unmetabolized cyromazine 

identified. 
Page 27 of 36 

Table 2. Toxicology profile for Cyromazine 

Study Type / 

Guideline No. 

MRID (Year) / 

Classification / Doses Results 

Dermal Absorption - 

Rat 

870.7600 (85-3) 

40168601 (1987) 

Acceptable/Guideline 

0.10, 1.00, and 10 mg/rat 

Absorption at 10 hrs = 13 %. Cyromazine apparently rapidly absorbed 

into the skin in an inverse dose related manner. The absorption into the 

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

excretion is apparently by the urine. There is no evidence that the 

compound is sequestered in the skin. 

Mean absorption based on blood, urinary/fecal excretion, and carcass, 

ranged from 0.6 to 7% for animals sacrificed at the end of the exposure 

periods. For animals exposed for 10 and 24 hours and followed for 48 

hours post-exposure, mean absorption ranged from 8 to 14.5%. Total 

radioactivity absorbed generally decreased as dose increased indicating 

saturation of absorption with increasing dose. Amounts remaining in/on 

the skin at termination ranged from 4.5% (10 mg dose/2 h exposure) to 

24% ( 0.1 mg dose/24 hour exposure). The majority of the absorbed 

radioactivity was found in the urine and carcass. Most of the 

unabsorbed radioactivity was found in the skin washes from each 

dose/duration. 

Dermal Absorption - 

Rat 

870.7600 (85-3) 

Accession No: 257488 

(1987) 

Acceptable/Guideline 

0.10, 1.00, and 100 mg/rat 

Absorption at 10 hrs = 10%. 

Mean total recoveries of applied radioactivity from all dose groups 

ranged from 85 to 101%. Mean absorption based on blood, urinary/fecal 

excretion, and carcass, ranged from 2% to 11%. Total radioactivity 

absorbed generally increased with increasing exposure time but 

decreased with increasing dose indicating saturation of penetration with 

increasing dose. The majority of the absorbed radioactivity was found 

in the urine and carcass. Most of the unabsorbed radioactivity was 

found in the skin washes from each dose/duration (35-90%). However, 

based on measurements of skin absorption, a significant amount of 

radioactive dose was also found in the skin itself (9-40%). Mean 

absorption with inclusion of radioactivity in dissolved skin ranged from 

10 to 45%. The ratio of the amount of radioactive dose in the skin wash 

to the radioactivity in the skin itself decreased with time indicating 

penetration into the subsurface of the skin with time after treatment. 

Mutagenicity 

Gene mutation in 

Hamster (Chinese) - 

(84-4.) 

Mutagenic- Nucleus 

Anomaly) 

MRID: 00103199 (1980) 

Minimum 

acceptable/Guideline 

Lavardex tech. 98.9% pure 

2000, 4000, and 8000 mg/kg 

in 20 mL/kg 0.7% CMC 

solution 

Negative mutagen. 

 Mutagenic - Point 

Mutation Salmonella 

typhimurium (84-4) 

MRID: 0089923 (1978) 

limited/Guideline 

25, 75, 255, 675 and 2025 

g/0.1 mL plate in DMSO, 

+ - S-9. 

Negative results for point mutations in TA1537, TA1537, TA98, and 

TA100 with and without activation. 

84-2b. Mutagenic. - 

Dominant lethal test 

species: Mouse 

 (84-2b) 

MRID:00103198 (1981) 

limited/Guideline 

226 and 678 mg/kg in 

PEG400 vehicle (0.2 mL/log 

of body weight) 

Negative mutagen. 
Page 28 of 36 

2.0 Studies Reviewed for Ethical Conduct 

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. 

Agricultural Re-entry Task Force (ARTF) data base (SOP #3.1) 
Page 29 of 36 

3.0 ADDITIONAL TOXICOLOGY STUDIES 

6-Month Oral Toxicity in Dogs MRID 00103193 

In this study, groups of male and female beagle dogs (3/sex/dose at 30 and 300 ppm and 

4/sex/dose at 3000 ppm and control) were fed diets containing cyromazine at 0, 30, 300 or 3000 

ppm (0, 0.75, 7.5 or 75 mg/kg/day, respectively) for 6 months. All dogs were housed 

individually in controlled environments and observed twice daily for mortality and moribundity 

and once daily for appearances, behavior, appetite, elimination, and signs of toxicity. Food 

consumption was recorded twice weekly. Hematology, clinical chemistry, and urinalysis were 

performed on all dogs at week 0, 4, 8, 13, 17, 21 and 26; and for recovery animals at week 30. 

Ophthalmologic examinations were performed on all dogs prior to treatment and during week 12 

and 26. Selected surviving animals were sacrificed for gross and microscopic pathology. No 

treatment-related effects were observed in survival, clinical signs, food consumption, body 

weights, ophthalmologic parameters and gross and microscopic pathology. Mean body weight 

and body weight gain values were minimally decreased in males at the highest dose, and in 

females at all dose levels. Mean food consumption values of the high dose animals were also 

slightly decreased. These changes were slight, hence may not be treatment related. Pronounced 

treatment-related effects on hematological parameters, were manifested in males and females as 

decreases in hematocrit, and hemoglobin (males) levels at 3000 ppm. Decreased mean 

cholesterol and serum glutamic oxaloacetic transaminase values were noted at high dose (3000 

ppm) during the treatment time period, however, the values reached normal during the recovery 

period. Slight increases were noted for the relative brain, heart, and liver weights of the high 

dose (3000 ppm) males and females and the ovary weights of the high dose females. The 

NOAEL was 300 ppm (7.5 mg/kg/day) and the LOAEL was 3000 ppm (75 mg/kg/day) based on 

alterations in hematological parameters (hematocrit and hemoglobin). 

Carcinogenicity Study in Mice MRID No. 00115736/43068901/43068902 

In a 24-month chronic toxicity/oncogenicity study in mice (MRIDs 00115736 / 43068901 

/ 4306890220), 60 Charles River CD-i mice per sex/dose levels were administered 0, 50, 1000 

and 3000 ppm of Cyromazine. An additional 8 animals/sex/dose were designated for interim 

sacrifice at one year. Female mice showed various mammary tumors which the PRC analyzed in 

accordance with the NTP guidance (McConnell et al. 1986), both alone and combined. Female 

mice had a significant increasing trend in mammary gland adenocarcinomas (p<0.005). The 

female mice also had a significant difference in the pair-wise comparison of the controls with the 

3000 ppm dose group for mammary gland adenocarcinomas (p<0.05). This statistical analysis of 

tumor rates was based upon the Exact trend test and the Fisher’s Exact test for pair-wise 

comparisons since there were small occurrences of tumors and no significant statistical evidence 

of differential mortality with increasing doses of Cyromazine. Based on the re-evaluation, the 

RED CPRC (Jan. 6, 1995; TXRNo. 011384) concluded that there were no statistically significant 

increase in tumors in the treated groups; there were no statistical trends and no dose response. 

The dosing was considered to be adequate for assessing the carcinogenic potential of 

Cyromazine in the male mice; however, in females only marginally adequate doses were used. 
Page 30 of 36 

Higher doses could probably have been used successfully because of the lack of toxicity and 

enhanced survival in females. 

 Dermal Absorption Rat MRID No. 40168601 

 In a dermal absorption study (MMD 40168601), male rats received dermal application of 

a “simulated” 75W formulation of 14C-Cyromazine in aqueous solution at doses of 0.10, 1.0 and 

10 mg/rat. Four animals per dose were exposed for durations of 2, 4, 10 and 24 hours. A second 

set of rats (4 per dose) also received dermal doses of 0.10, 1.0 and 10 mg/rat for 10 and 24 

exposure periods followed by a 48 hour “depletion period”. Mean recoveries of applied 

radioactivity from all dose groups ranged from 77 to 120%. Table 1 summarizes mean percent 

absorption at each time period for rats terminated immediately after exposure and percent 

absorption for animals followed for 48 hours post-exposure. Mean absorption based on blood, 

urinary/fecal excretion, and carcass, ranged from 0.6 to 7% for animals sacrificed at the end of 

the exposure periods. For animals exposed for 10 and 24 hours and followed for 48 hours postexposure, mean absorption ranged from 8 to 14.5%. Total radioactivity absorbed generally 

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

remaining im’on the skin at termination ranged from 4.5% (10 mg dose/2 h exposure) to 24% 

(0.1 mg dose/24 hour exposure). The majority of the absorbed radioactivity was found in the 

urine and carcass. Most of the unabsorbed radioactivity was found in the skin washes from each 

dose/duration. Dermal Absorption Factor: 13 % based on a measurement at 10 hrs 

 Mutagenicity 

 MRID No.00103199 Chinese hamster nucleus anomaly test (Feb.06, 1980). In this CibaGeigy, study no. 79-1347 (TXR No. 002664), the chemical tested was Lavardex Technical 

98.9% pure. The test material concentration: 2000, 4000, and 8000 mgfkg in 20 mI/kg 0.7% 

CMC solution. The results were negative. This is the only acceptable (minimally) study. 

 MRID No. 00089923 Salmonella point mutation assay. In this (Acession No. 098384; 

TXR No. 002687), the chemical tested was Lavardex Technical. The test material concentration 

was 25, 75, 255, 675 and 2025 jag/0. I ml plate in DM50. Negative results were obtained for 

point mutations in TA1 535, TA1537, TA98, TAIOO with or without activation. This study was 

limited due to the use of inappropriately low concentrations of test substance. 

 MRID No. 00103198 Mouse dominant lethal test (March 17, 1981). . In this Ciba- Geigy, 

study no. 790033 (TXR No. 002687), the chemical tested was Lavardex Technical 98.9% pure. 

In this study was limited since the mating period was too short.
Page 31 of 36 

4.0 TOXICOLOGY STUDY REFERENCES 

Subchronic Oral Toxicity: 90-Day Study 

MRID Citation Reference 

27485 Ciba-Geigy Corporation (1980) (Data on 90-Day Subacute Toxicity Study with CGA72662 in Albino Rats). (Unpublished study re- ceived Mar 6, 1980 under 100-EX-65; 

CDL:099272-A) 

103192 Pence, L.; Twigg, C.; Weatherholtz, W. (1979) Final Report: Acute Oral Dose Range in 

Dogs: (CGA-72662 Technical): Project No. 483-179. (Unpublished study received Jun 

10, 1982 under 100-631; prepared by Hazleton Laboratories America, Inc., submitted 

by Ciba-Geigy Corp., Greensboro, NC; CDL:070919-A) 

103193 Marshall, P.; Voelker, R.; Dawkins, K. (1980) Subchronic Toxicity Study in Dogs: 

CGA-72662 Technical: Final rept: Project No. 483-180. (Unpublished study received 

Jun 10, 1982 under 100-631; prepared by Hazleton Laboratories America, Inc., 

submitted by Ciba-Geigy Corp., Greensboro, NC; CDL:070919-B) 

103200 Jessup, D.; Brewer, L. (1980) 4-Week Range-finding Study in Mice (Extended to 7 

Weeks): ?CGA-72662 Technical|. (Unpublished study received Jun 10, 1982 under 

100-631; prepared by Inter- national Research and Development Corp., submitted by 

Ciba-Geigy Corp., Greensboro, NC; CDL:070921-C) 

115734 Ciba-Geigy Corp. (1982) Addendum to Section C on the Chronic Toxic- ity and 

Oncogenicity of Larvadex ...: Summary of the Toxicology Studies. (Compilation; 

unpublished study received Oct 20, 1982 under 100-631; CDL:071193-A) 

135432 Jessup, D.; Geil, R.; Mehring, J.; et al. (1979) 90-Day Subacute Oral Toxicity Study 

with CGA-72662 in Purebred Beagle Dogs: 382-048. (Unpublished study received Jul 

10, 1979 under 100- EX-65; prepared by International Research and Development 

Corp., submitted by Ciba-Geigy Corp., Greensboro, NC; CDL: 098385-A) 

135433 Goldenthal, E.; Jessup, D.; Geil, R.; et al. (1979) 90-Day Subacute Toxicity Study with 

CGA-72662 in Albino Rats: 382-052. (Un- published study received Jul 10, 1979 under 

100-EX-65; prepared by International Research and Development Corp., submitted by 

Ciba-Geigy Corp., Greensboro, NC; CDL:098385-B) 

21-day dermal-rabbit/rat 

MRID Citation Reference 

44060901 Kuhn, J. (1982) 21-Day Dermal Toxicity Study in Rabbits: Cyromazine Technical: Lab 

Project Number: 3805-85. Unpublished study prepared by Stillmeadow, Inc. 88 p. 

44060902 Tai, C. (1984) 21-Day Dermal Toxicity Study in Rabbits: Cyromazine Technical: Lab 

Project Number: 842009: 152-84. Unpublished study prepared by Ciba-Geigy Corp. 

140 p. 
Page 32 of 36 

Chronic Toxicity 

MRID Citation Reference 

103193 Marshall, P.; Voelker, R.; Dawkins, K. (1980) Subchronic Toxicity Study in Dogs: 

CGA-72662 Technical: Final rept: Project No. 483-180. (Unpublished study received 

Jun 10, 1982 under 100-631; prepared by Hazleton Laboratories America, Inc., 

submitted by Ciba-Geigy Corp., Greensboro, NC; CDL:070919-B) 

103202 Blair, M.; Kruger, S.; Nair, K. (1981) 2-year Chronic and Oncogenicity Study with 

CGA-72662 Technical in Albino Rats (12-month Interim): 382-081. (Unpublished 

study received Jun 10, 1982 under 100-631; prepared by International Research and 

Development Corp., submitted by Ciba-Geigy Corp., Greensboro, NC; CDL:070923-A) 

115734 Ciba-Geigy Corp. (1982) Addendum to Section C on the Chronic Toxic- ity and 

Oncogenicity of Larvadex ...: Summary of the Toxicology Studies. (Compilation; 

unpublished study received Oct 20, 1982 under 100-631; CDL:071193-A) 

115735 Blair, M.; Vander Meer, D.; Marroquin, F.; et al. (1982) 2-year Chronic and 

Oncogenicity Study with CGA-72662 Technical in Albino Rats: 382-081. (Unpublished 

study received Oct 20, 1982 under 100-631; prepared by International Research and 

Develop- ment Corp., submitted by Ciba-Geigy Corp., Greensboro, NC; CDL:071186-

A; 071187; 071188; 071189) 

43069003 Luempert, L. (1993) Statistical Analysis of Survival and Tumor Data: Two-Year 

Chronic and Oncogenicity Study with CGA-72662 Technical in Sprague-Dawley Rats: 

Supplement. Unpublished study prepared by Ciba-Geigy Corp. 14 p. 

Oncogenicity 

MRID Citation Reference 

103201 Blair, M.; Kruger, S.; Marroquin, F. (1981) Oncogenicity Study with CGA-72662 in 

Albino Mice (12-month Interim): 382-082. (Unpublished study received Jun 10, 1982 

under 100-631; prepared by International Research and Development Corp., submitted 

by Ciba-Geigy Corp., Greensboro, NC; CDL:070922-A) 

103202 Blair, M.; Kruger, S.; Nair, K. (1981) 2-year Chronic and Oncogenicity Study with 

CGA-72662 Technical in Albino Rats (12-month Interim): 382-081. (Unpublished 

study received Jun 10, 1982 under 100-631; prepared by International Research and 

Development Corp., submitted by Ciba-Geigy Corp., Greensboro, NC; CDL:070923-A) 

115735 Blair, M.; Vander Meer, D.; Marroquin, F.; et al. (1982) 2-year Chronic and 

Oncogenicity Study with CGA-72662 Technical in Albino Rats: 382-081. (Unpublished 

study received Oct 20, 1982 under 100-631; prepared by International Research and 

Develop- ment Corp., submitted by Ciba-Geigy Corp., Greensboro, NC; CDL:071186-

A; 071187; 071188; 071189) 

115736 Blair, M.; VanderMeer, D.; Marroquin, F.; et al. (1982) Onco- genicity Study with 
Page 33 of 36 

CGA-72662 in Albino Mice: 382-082. (Unpub- lished study received Oct 20, 1982 

under 100-631; prepared by International Research and Development Corp., submitted 

by Ciba-Geigy Corp., Greensboro, NC; CDL:071189-A; 071190; 071191; 071192) 

130731 Ciba-Geigy Corp. (1979) ?Chemistry of Melamine|. (Compilation; un- published study 

received Aug 24, 1983 under 100-631; CDL: 251065-J) 

145363 Ciba-Geigy Corp. (1984) Response Document to EPA's August 8, 1984 Letter 

Requesting Additional Information on Cyromazine: [Teratogenicity and Oncogenicity 

in Laboratory Animals]. Unpublished compilation. 409 p. 

43068901 Hardisty, J. (1993) Reevaluation of the Significance of Neoplasms of the Mammary 

Gland in Female Rats and Mice: Lab Project Number: 382-081: 382-082. Unpublished 

study prepared by Experimental Pathology Labs., Inc. 121 p. 

43068902 Hardisty, J. (1993) Mouse Oncogenicity Study with Cyromazine: Pathology Quality 

Assessment and Pathology Working Group Peer Review of Female Mammary Glands: 

Lab Project Number: 382-082. Unpublished study prepared by Experimental Pathology 

Labs., Inc. 102 p. 

43068903 Hardisty, J. (1993) Rat Oncogenicity Study with Cyromazine Pathology Quality 

Assessment and Pathology Working Group Peer Review of Female Mammary Glands: 

Lab Project Number: 382-081. Unpublished study prepared by Experimental Pathology 

Labs., Inc. 103 p. 

43069001 Campbell, W.; Stevens, J. (1991) A Supplement to CGA-72662 Oncogenicity Study in 

Albino Mice: Lab Project ID: 1117C6JS: 004313: R205LJS0409WRC. Unpublished 

study prepared by Ciba-Geigy Corporation. 33 p. 

43069003 Luempert, L. (1993) Statistical Analysis of Survival and Tumor Data: Two-Year 

Chronic and Oncogenicity Study with CGA-72662 Technical in Sprague-Dawley Rats: 

Supplement. Unpublished study prepared by Ciba-Geigy Corp. 14 p. 

Teratogenicity -- 2 Species 

MRID Citation Reference 

27488 Tasker, E.J.; Rodwell, D.E. (1979) Teratology Study in Rats: IRDC No. 382-070. 

(Unpublished study received Mar 6, 1980 under 100- EX-65; prepared by International 

Research and Development Corp., submitted by Ciba-Geigy Corp., Greensboro, N.C.; 

CDL:099272-D) 

103194 Rodwell, D.; Dangler, T.; Blair, M.; et al. (1979) Pilot Teratology Study in Rats: 

?CGA-72662 Technical|: 382-069. (Unpublished study received Jun 10, 1982 under 

100-631; prepared by Inter- national Research and Development Corp., submitted by 

Ciba- Geigy Corp., Greensboro, NC; CDL:070920-A) 

103195 Rodwell, D.; Ziemke, K.; Campbell, G.; et al. (1979) Pilot Teratol- ogy Study in 

Rabbits: ?CGA-72662 Technical|: 382-071. (Unpub- lished study received Jun 10, 1982 

under 100-631; prepared by International Research and Development Corp., submitted 

by Ciba-Geigy Corp., Greensboro, NC; CDL:070920-B) 
Page 34 of 36 

103196 Blair, M.; McMeekin, S.; Allen, S.; et al. (1981) Teratology Study in Rabbits: ?CGA72662 Technical|: 382-072/072a. (Unpublished study received Jun 10, 1982 under 100-

631; prepared by Inter- national Research and Development Corp., submitted by CibaGeigy Corp., Greensboro, NC; CDL:070920-C) 

143517 Ciba-Geigy Corp. (1984) Peer Review Document on the Cyromazine Rab- bit 

Teratology Study and Follow-up to the July 11, 1984 Meeting with EPA. Unpublished 

study. 139 p. 

145363 Ciba-Geigy Corp. (1984) Response Document to EPA's August 8, 1984 Letter 

Requesting Additional Information on Cyromazine: [Teratogenicity and Oncogenicity 

in Laboratory Animals]. Unpublished compilation. 409 p. 

149514 Rodwell, D. (1985) Letter sent to W. Campbell dated Jan 28, 1985: [Two teratology 

studies on New Zealand white rabbits]. Prepared by WIL Research Laboratories, Inc. 5 

p. 

149515 Rodwell, D. (1985) Letter sent to W. Campbell dated Feb 14, 1985: Teratology study 

on albino rabbits with cyromazine technical. Prepared by WIL Research Laboratories, 

Inc. 4 p. 

150471 Hagen, C. (1985) A Teratology Study (Segment II) in Albino Rabbits with Cyromazine 

Technical: Final Report: Project No. WIL-82001. Unpublished study prepared by WIL 

Research Laboratories, Inc. 299 p. 

158626 Koehler, S. (1986) A Teratology and Postnatal Study in Albino Rab- bits with 

Cyromazine Technical: Final Report: Project No. WIL- 82008. Unpublished study 

prepared by WIL Research Laboratories, Inc. 320 p. 

158627 Aldridge, D. (1985) Teratology Study in Rabbits: Cyromazine: 382- 104. Unpublished 

study prepared by International Research and Development Corp. 103 p. 

40728601 Nemec, M. (1986) Teratology and Postnatal Study in Albino Rabbits with Cyromazine 

Technical: Supplemental to: Study No. 82008. Unpublished study prepared by WIL 

Research Laboratories, Inc. 14 p. 

2-generation repro.-rat 

MRID Citation Reference 

103197 Blair, M.; Slezak, S.; Allen, S.; et al. (1981) Two-generation Reproduction Study with 

CGA-72662 in Albino Rats: 382-086. (Unpublished study received Jun 10, 1982 under 

100-631; pre- pared by International Research and Development Corp., submitted by 

Ciba-Geigy Corp., Greensboro, NC; CDL:070920-D; 070921) 

Dietary: Combined Chronic Toxicity/Oncogenicity Studies 

MRID Citation Reference 

43069002 Stevens, J. (1993) A Supplement to the 2-Year Chronic and Oncogenicity Study with 
Page 35 of 36 

CGA-72662 in Albino Rats. Unpublished study prepared by Ciba-Geigy Corp. 20 p. 

Interaction with Gonadal DNA 

MRID Citation Reference 

89923 Arni, P.; Muller, D. (1978) Salmonella/Mammalian-microsome Muta- genicity Test: 

Experiment No. 78/2572. (Unpublished study re- ceived Jul 10, 1979 under 100-EX-65; 

prepared by Ciba-Geigy, Ltd., Switzerland, submitted by Ciba-Geigy Corp., 

Greensboro, N.C.; CDL:098384-J) 

103198 Hool, G. (1981) Dominant Lethal Study--CGA 72 662: Mouse (Test for Cytotoxic or 

Mutagenic Effects on Male Germinal Cells): Project No. 790033. (Unpublished study 

received Jun 10, 1982 under 100-631; prepared by Ciba-Geigy, Ltd., Switz., submitted 

by Ciba-Geigy Corp., Greensboro, NC; CDL:070921-A) 

103199 Hool, G.; Langauer, M. (1980) Nucleus Anomaly Test in Somatic Interphase Nuclei: 

CGA 72 662--Chinese Hamster (Test for muta- genic Effects on Bone Marrow Cells): 

No. of Experiment: 79- 1347. (Unpublished study received Jun 10, 1982 under 100-

631; prepared by Ciba-Geigy, Ltd., Switz., submitted by Ciba-Geigy Corp., 

Greensboro, NC; CDL:070921-B) 

General metabolism 

MRID Citation Reference 

103183 Simoneaux, B.; Cassidy, J. (1979) Metabolism of Topically Applied (delta)-14C-CGA72662 in Chicken Manure: Report No. ABR-79024. (Unpublished study received Jun 

10, 1982 under 100-631; sub- mitted by Ciba-Geigy Corp., Greensboro, NC; 

CDL:070915-T) 

103184 Simoneaux, B.; Cassidy, J. (1979) Metabolism of Topically Applied (delta)-14C-CGA72662 in Beef Manure: Report No. ABR-79045. (Unpublished study received Jun 10, 

1982 under 100-631; sub- mitted by Ciba-Geigy Corp., Greensboro, NC; CDL:070915-

U) 

103203 Ross, J. (1982) Cyromazine--Poultry: Residues Observed and Metabo- lism Including 

Analytical Methods Used: Report No. ABR-82015. (Unpublished study received Jun 

10, 1982 under 100-631; sub- mitted by Ciba-Geigy Corp., Greensboro, NC; 

CDL:070924-A) 

103204 Simoneaux, B.; Cassidy, J. (1978) Metabolism and Balance Study of (delta)-Carbon 14-

CGA-72662 in the Rat: ABR-78072. (Unpublished study received Jun 10, 1982 under 

100-631; submitted by Ciba- Geigy Corp., Greensboro, NC; CDL:070925-A) 

130727 Simoneaux, B.; Cassidy, J. (1978) Metabolism and Balance Study of ?delta|-14C-CGA72662 in the Rat: Report No. ABR-78072. (Unpub- lished study received Aug 24, 1983 

under 100-631; submitted by Ciba-Geigy Corp., Greensboro, NC; CDL:251065-C) 
Page 36 of 36 

130728 Clayton, F. (1983) Residues of Cyromazine and Metabolites in Tis- sues and Milk of 

Dairy Cows Receiving Cyromazine in Their Diet: Report No. ABR-83040. 

(Unpublished study received Aug 24, 1983 under 100-631; submitted by Ciba-Geigy 

Corp., Greensboro, NC; CDL:251065-D) 

130729 Simoneaux, B.; Cassidy, J. (1981) Metabolism and Balance Study of ?delta|14C-CGA72662 in a Mature Sheep: Report No. ABR-80055. (Unpublished study received Aug 

24, 1983 under 100-631; sub- mitted by Ciba-Geigy Corp., Greensboro, NC; 

CDL:251065-G) 

135434 Ciba-Geigy Corp. (1979) Poultry and Poultry/Livestock Manure: ?Res- idue Studies: 

CGA-72662|. (Compilation; unpublished study re- ceived Jul 10, 1979 under 100-EX65; CDL:098386-A; 098387; 098388) 

147382 Ballantine, L. (1984) Cyromazine [on] Celery and Lettuce: Residues Observed and 

Metabolism Data Including Analytical Methods: Re- port No. ABR-84076. 

Unpublished study prepared by Ciba-Geigy Corp. 20 p. 

41442101 Capps, T. (1990) Characterization and Identification of ?Carbon 14|-Cyromazine and 

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Unpublished study prepared by Ciba-Geigy Corp. and Hazleton Laboratories America, 

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Dermal penetration 

MRID Citation Reference 

149656 Murphy, T.; Simoneaux, B. (1985) Advanced Product Chemistry: Percutaneous 

Absorption of Cyromazine in Rats: Report No. ABR- 85022. Unpublished study 

prepared by Ciba-Geigy Corp. 40 p. 

 

40168601 Murphy, T. (1987) Dermal Absorption of Cyromazine in Rats (Special Metabolism 

Study): Lab./Study No. ABR-86069. Unpublished study prepared by Ciba-Geigy Corp. 

71 p.