### Page 1 of 36 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 Divi sion’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

### Page 2 of 36 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 CHARACTERIZ ATION/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......................................................................................................1 2 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 .................................................................................................1 6 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

### Page 3 of 36 6.0 OCCUPATIONAL EX POSURE 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 TOXICO LOGY 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

### Page 4 of 36 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 chemi cals 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 ingr edient 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

### Page 5 of 36 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 fo llowing 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 chr onic 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 a nd 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-applicati on 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 Re view Board. All of the studies used have received the appropriate review.

Environmental Justice

### Page 6 of 36 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.

### Page 7 of 36 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 Cy romazine 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

### Page 8 of 36 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 pK a1 value = 5.3 @ 20 C pk a2 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 toxi city study in rats, the NOAEL (300 mg/kg/day) for

### Page 9 of 36 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 Neurot oxicity 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 a queous 1.0% carboxymethylcellulose at a dose volume of 10 ml/kg on gestation days 6-19. Dose le vels 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 gesta tion 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

### Page 10 of 36 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 co mpared to control. At the highest dose, a significant increase in skeletal variations (unossi fied 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 toxic ity, 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 s acrificed 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 signi ficant 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 toxi city, the NOAEL was 60 mg/kg/day (HDT); a

### Page 11 of 36 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 wa s 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 we ight, 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 pa rental systemic toxicity LOAEL was 3000 ppm (150 mg/kg/day) based on decreased body weight s that were associated with decreased food efficiency. The offspring developmental toxi city 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 w eaning. 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.

### Page 12 of 36 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 a ffected 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 deve lopmental 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. Bodyweight 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

### Page 13 of 36 from control. The systemic toxicity LOA EL 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 re vised 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 syst emic 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 cyro mazine 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 LOA EL 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 inhalati on 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 exposur es 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 Cyro mazine 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 dos e-response data and used to mark the beginning of extrapolation to determine risk associat ed with lower environmentally relevant human exposures.

NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = 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 UF A = 10x

UF H =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 UF A = 10x

UF H =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 re quire 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 Brassi ca 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 photometri c detectors were not used as the compounds contained neither phosphorus nor sulfur. When an alyzed 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 (T 1⁄2 

### > 60 days). This was confirmed in the field studies, where dissipation half-lives are as long as 250 days. Freundlich adsorption coefficients (K ads 

### ) for the mineral soils are less than 5 mL/g, and for the organic soil the K ads 

### 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 10 4 

### 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 (T 1⁄2 

### ), adsorption (K d 

### ), 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 di rectly into the chronic dietary analysis (“water, direct, all sources” and “water, indi rect, 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/g

oc 

### and mean ASM half-life of 104 days).

Table 8. EDWCs for use in screening th e Cyromazine Health Risk Assessment Drinking Water Source Peak ( μ g/L) Annual Mean ( μ g/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 dri nking water exposure and risk assessment was conducted using the Dietary Exposure Evaluation Model with the Food Commodity Intake Database (DEEM-FCIDTM). Dietary risk assessmen t 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 deve lopmental 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 empiri cal 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: Summar y of Chronic Dietar y Ex p osure and Risk for C y romazine

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

General U.S. Po p ulation 0.0073 50

All Infants ( < 1 y ear old ) 0.015

0.0060 40

### Page 20 of 36 Table 9: Summar y of Chronic Dietar y Ex p osure and Risk for C y romazine

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

Children 1-2 y ears ol d 0.0127 85

Children 3-5 y ears ol d 0.0114 76

Children 6-12 y ears ol d 0.0081 54

Youth 13-19 y ears ol d 0.0060 40

Adults 20-49 y ears ol d 0.0066 44

Adults 50+ y ears ol d 0.0073 49

Females 13-49 y ears ol d 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. Theformulation 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-applicationexposures 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 fo r 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 Ri sk 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 w ithout a respirator. There is low conf idence in values used for M/L wettable powder in water-soluble packets, high confidence in the valu es 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 a i/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 ha ndled) x Application Rate (lb ai/A) x Acre s Treated (A/day)] / Body Weight (70 kg used because endpoint effects were not considered gender-specific)

5 MOE = NOAEL/ Daily Inhalation Dose. Short-term Inhala tion 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 th e 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 Or al Toxi city .......................................................

870.1200 Acute De rmal Toxi city ..................................................

870.1300 Acute Inha lation Toxi city .............................................. 870.2400 Primary Eye Irrita tion .................................................... 870.2500 Primary De rmal Irrita tion ..............................................

870.2600 Dermal Sensitiza tion...................................................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subc hronic (rode nt) ...............................................

870.3150 Oral Subc hronic (nonr odent) .........................................

870.3200 21-Da y Dermal ..............................................................

870.3250 90-Da y Dermal .............................................................. 870.3465 90-Day Inhalatio n .......................................................... yes

yes

yes

no

no yes

yes

yes

no

no

870.3700a Developmental Toxicity (r odent)................................... 870.3700b Developmental T oxicity (nonr odent).............................

870.3800 Re productio n ................................................................. yes

yes

yes yes

yes

yes

870.4100a Chronic Toxi city (rode nt) ..............................................

870.4100b Chronic Toxic ity (nonrode nt) ........................................ 870.4200a Oncogeni city (ra t) .......................................................... 870.4200b Oncogenic ity (mous e)....................................................

870.4300 Chronic/ Oncogeni city.................................................... yes a

yes

yes a

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity—Gen e Mutation - b acterial ..................... 870.5300 Mutagenicity—Gen e Mutation - mammalian ................ 870.5375 Mutagenicity—Structural Chromosomal Aberrations ... 870.5900 Mutagenicity—Oth er Genotoxic Effects ....................... yes

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen) ..................................... 870.6100b 90-Day Neurot oxicity (h en)...........................................

870.6200a Acute Neurotox. Sc reening Batte ry (rat)........................ 870.6200b 90-Day Neuro. Scr eening Battery (rat)..........................

870.6300 Devel op. Neuro.............................................................. no

no

yes

yes

no -

-

no

no

no

870.7485 Genera l Metabo lism.......................................................

870.7600 Dermal Penetra tion ........................................................

870.7800 Imm unotoxic ity.............................................................. 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 N o irritation. IV 81-5 Primary Skin Irritation - rabbits 00082842 Mild irritant. IV

81-6 Dermal Sensitization 00082843 N on-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 skelet al 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, urin ary/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 d ecreased 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 sacrif iced 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 L OAEL 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 14 

### C-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 ofthe 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 w ith 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 Ra nge-finding Study in Mice (Extended to 7 Weeks): ?CGA-72662 Technical|. (Unpublis hed study received Jun 10, 1982 under 100-631; prepared by Inter- national Resear ch and Development Corp., submitted by Ciba-Geigy Corp., Greensboro, NC; CDL:070921-C)

115734 Ciba-Geigy Corp. (1982) Addendum to S ection 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 In ternational 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- pub lished study received Jul 10, 1979 under 100-EX-65; prepared by International R esearch 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 St udy 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 St udy 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; prep ared by International Research and Development Corp., submitted by Ciba-Gei gy Corp., Greensboro, NC; CDL:070923-A)

115734 Ciba-Geigy Corp. (1982) Addendum to S ection 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 Techni cal in Albino Rats: 382-081. (Unpublished study received Oct 20, 1982 under 100-631; prep ared 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 C GA-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; prep ared by International Research and Development Corp., submitted by Ciba-Gei gy 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 Techni cal in Albino Rats: 382-081. (Unpublished study received Oct 20, 1982 under 100-631; prep ared 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 Me lamine|. (Compilation; un- published study received Aug 24, 1983 under 100-631; CDL: 251065-J)

145363 Ciba-Geigy Corp. (1984) Response Do cument to EPA's August 8, 1984 Letter Requesting Additional Information on Cyrom azine: [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 St udy 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: 1117C6J S: 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 C GA-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) Tera tology 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. (Unpublishe d study received Jun 10, 1982 under 100-631; prepared by Inter- national Resear ch 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. (U npub- 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 36103196 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 Ju ly 11, 1984 Meeting with EPA. Unpublished study. 139 p.

145363 Ciba-Geigy Corp. (1984) Response Do cument to EPA's August 8, 1984 Letter Requesting Additional Information on Cyrom azine: [Teratogenicity and Oncogenicity in Laboratory Animals]. Unpublished compilation. 409 p.

149514 Rodwell, D. (1985) Letter sent to W. Ca mpbell 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. Ca mpbell 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 (Seg ment 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 Po stnatal Study in Albino Rab- bits with Cyromazine Technical: Final Report: Pr oject 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 Postnata l 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 Re production Study with CGA-72662 in Albino Rats: 382-086. (Unpublis hed study received Jun 10, 1982 under 100-631; pre- pared by International Resear ch 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 pr epared by Ciba-Geigy Corp. 20 p.

Interaction with Gonadal DNA

MRID Citation Reference

89923 Arni, P.; Muller, D. (1978) Salmonella/M ammalian-microsome Muta- genicity Test: Experiment No. 78/2572. (Unpublished study re- ceived Jul 10, 1979 under 100-EX-65; prepared by Ciba-Geigy, Ltd., Switzer land, 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 Ce lls): 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. (Unpublis hed 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) Metabo lism of Topically Applied (delta)-14C-CGA72662 in Chicken Manure: Report No. A BR-79024. (Unpublished study received Jun 10, 1982 under 100-631; sub- mitted by Ci ba-Geigy Corp., Greensboro, NC; CDL:070915-T)

103184 Simoneaux, B.; Cassidy, J. (1979) Metabo lism 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-G eigy 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 Ci ba-Geigy Corp., Greensboro, NC; CDL:070924-A)

103204 Simoneaux, B.; Cassidy, J. (1978) Metabo lism and Balance Study of (delta)-Carbon 14- CGA-72662 in the Rat: ABR-78072. (Unpublis hed study received Jun 10, 1982 under 100-631; submitted by Ciba- Geigy Co rp., Greensboro, NC; CDL:070925-A)

130727 Simoneaux, B.; Cassidy, J. (1978) Metabo lism and Balance Study of ?delta|-14C-CGA72662 in the Rat: Report No. ABR-78072. (U npub- 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) Metabo lism and Balance Study of ?delta|14C-CGA72662 in a Mature Sheep: Report No. A BR-80055. (Unpublished study received Aug 24, 1983 under 100-631; sub- mitted by Ci ba-Geigy Corp., Greensboro, NC; CDL:251065-G)

135434 Ciba-Geigy Corp. (1979) Poultry and Pou ltry/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 Id entification of ?Carbon 14|-Cyromazine and Metabolites in Rats: Lab Project Nos. ABR- 89108; HLA 6117-160; ASM-134. Unpublished study prepared by Ciba-Geigy Corp. and Hazleton Laboratories America, Inc. 168 p.

Dermal penetration

MRID Citation Reference

149656 Murphy, T.; Simoneaux, B. (1985) Adva nced 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. Unpublishe d study prepared by Ciba-Geigy Corp. 71 p.