Cyromazine Human Health Risk Assessment DP No. 04 14 914

UN ITE D STATES E NVIRONMEN TAL PROTECTION AGENCY

WASHINGTON, D .C. 20460



### MEMORANDUM

Date: February 27,2014 OFF I CE OF
C H EM I CAL S AFE TY AND
POLLUTION PREVENTION



### SUBJECT : Cyromaz i ne: Human He a l th Risk Assessment for Registration R ev ie w

.

PC Code: 121301

Decis i on No.: 482882

Petit i on No.: NA

Risk Assessment Type: Human Health Risk

Assessment DP Barcode: 04 1 4914 Registration No.: None Regu lat ory Actio n : Registration Review

Case No.: 7439

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

MR I D No.: None 40 CFR: 180.414



### FROM : Ivan Nieves, ORE, Risk

# Assessor~-. Thu r ston G. Morton, Chemist

### ~~ Abdallah Khasaw i nah, Ph

. D.

, To xico l ogist

Risk Assessment Branch 4

Health Effects Division (7509P)



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

Susa n V. Hummel, Branch Senior Scientis

Risk Assessme n t Branch 4, H E D (7509P)

And

,

### ~~c/~ Chr i stine Olinge r
, RARC Designated**Rev ewe~**  t>**~** Char l es Smit h

, RARC D es i gnated Reviewer

### C~ Risk Assessment Review Committee (RARC)/HED



### TO: James Parker

Risk Management and Implementation Branch 1

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

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

R egistration Review of the herbicide cyromazine.

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

Table of Contents

1.0 Exec utiv e Summary

........................... .. . .. .. .. .. .. .. .. .. .. .. ...... .... ........... ....... .. . ..... . .. .. ... .. .. .. .. .. .. .. .. 4

2

. 0 HED Recommendations

. . .. .. .. . .. .............................. . ...... . ... .... ... .. .. .. .. .. .. .. .. .. .. . .................. . ..... 6

2.1 Data Defic i enc ies

...................... .. .. .. . .. .. .. .. .. .. .. .. .. .. .. . ... .. .. . .................... .. . ... . ..... ... .. .. .. .. .. .. ... 6

2.2 Tolerance Considera ti ons

........ . ... . ........................ . ........ .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. .. ... . ................ 6

2.2.1 Enfo rc e ment Analyt i cal Method

.. .. .. .. .. .. .. .. . ....... .. .. .. .......................... . ... . ... . .... . ... . ... . .. 6

3.0 In ternational Harmon i zation

..................................................................................... . ........... 7

4.0 Recommended Tolerances

........................................................... . ....... . ... .. . ... .. .. .. . ................ 7

4.1 Labe l Recommendat ion s

................................ .. .. .. . .. .. .. .. ... . ... ............................ . ................ 8

5.0 In troduct i on

................................. .. .. . ....... . .. .......... .......... .............................................. .. .. .. .. . 8

5.1 Identity

. . .. ... .. . . .. . .. ...... . .. . .................................................... .. .. .. .. .. .. .. . ... .. .. .. . ... .. .. .. .. ............ 8

5

. 2 Physical/Chemical Characteristics

.................... ......... .... . .. .. .. .. .. .. . ... . ... . ... ..... ..................... 9

5.3 Pe sticide Use Pattern

............... . .. .. . ... . ... . .. .. ... .. . .. .. .. .. ........ . .......................... ............... .. ...... 9

5.4 Anticipated Exposure Pathways

........................ .. . ....... . ... . ... . ... . ... . ... . ....... . ....... . ............... 1 0

5. 5 Consideration of Environmen t al Justice

............................................................... . ......... 11

6

. 0 Hazard Characterization and Do s e-Re s ponse Assessment..

. .............. .. .................... .. .. . .... . 11

6.1 Toxicology S tudies Avai l able for Analysis

................................................................... .11

6.2 Absorption, Di s tribu t ion, Metabolism

, & Elimina tion (ADME)

....... ...... .. ...... .. .. .. .. ....... 12

6.2.1 Dermal Absorption

.. . .. . ...... .. .. . .............. .. ... .... .......................................................... . 13

6.3 Toxicological Effects

.......................... .. .. .. .. .. .. .. .. .. .. . .. .. ........ . ..... ............... .. ....... .......... ... 13

6.4 Safety factor for Infants and Ch il dren (FQPA Safety Factor)

........................................ 13

6.4.1 Completeness ofthe Toxi cology Database

.. ..... ...... .. .. .. .............. ... .. . ............ . .. .. ... .. . 14

6.4.2 E vide nce ofNeurotoxicity

..... ... ........ ... .. . ... .. .. ... . .. .. . .................. .. .. .......... ... .. .. .. ... . .. .. 14

6.4.3 E vi dence of Sensitivity/Susceptibility in th e Developing or Young Animal

.. . ....... 14

6.4.4 Residual Uncerta inty in the Exposure Database

. ........ . .. .............. .. .. _. .. .. .. .. .. .. .. .. .. ... .. 14

6.5 Toxicity Endpoint and Point ofDeparture Selections

.. .. . .. . .... .. ...... . ........... . .... . .. . .. .... ...... 14

6.5 .1 Dose-Response Assessment..

. . .. .. .. .. . .. .... . .. .. .. . ... ... ..................................... ......... ...... 14

6.5.2 Recommendation fo r Comb i ning Route s of Expo sures for Risk Assessment..

....... 15

6.5.3 Cancer Classificat i on and Risk Assessment Recommendation

............................... 15

6

. 5.4 Summa r y of Points of Departure and Toxicity Endpoints Used in H uman R i sk

Assessment.

........................................................................................................ . ................... 16

6.6 Endocrine Disruption

............................................. . .............................................. ·

........... 17

7.0 Dietary Exposure and Risk Assessment

....... ........ ....... . ...... . .... . ............... . ...... .................... 18

7

. 1 Metabolite/Degradate Residue Profile

.................... .. .. .. .. .. .. .............. .. .. .. .. .. ... .. . ........ . .. ... 18

7

. 1.1 S urnmary of P l ant and Anima l Metabolism Studies

..................... .. ......................... 18

7 .1.2 Summary of Environmental De g r adation

........................................ . .... . .. .. .. ... .. .. .. .. . 18

7.1.3 Comparison of Metabo li c Pathway s

................................................. . ................... . .. 19

7 .1.4 Residues of Concern Summary and Rationale

........................................................ .19

7.2 Food Residue Profile

. ...................................................................................................... 19

7.3 Water Residue Profile

........................... .. .............................................. ... . .. .. ... .. .. ... .. . ... .. 22

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

Page 3 of 58 7.4 Dietary Risk Assessment

................................ ................................ ................................ . 23

7.4. 1 Description of Residue Data Used in Dietary Assessment

................................ ...... 23

7.4.2 Percent Crop Treated Used in Dietary Assessment

................................ ................. 23

7.4.3 Acute Dietary Risk Assessment

................................ ................................ ............... 23

7.4.4 Chronic Dietary Risk Assessment

................................ ................................ ........... 23

7.4.5 Cancer Dietary Risk Assessment

................................ ................................ ............. 23

7.4.6 Summary Table

................................ ................................ ................................ ........ 23

8.0 Residential (Non

- Occupational) Exposure/Risk Characterization

................................ ..... 24

8.1 Residential Bystander Postapplication Inhalation Exposure

................................ ........... 24

8.2 Spray Drift

................................ ................................ ................................ ....................... 25

8.2.1 Children (1<2 yrs old) Hand

- to

- Mouth Risk Estimates From Lawn Deposition Adjacent to Applications

................................ ................................ ................................ ........ 26

9.0 Aggregate Exposure/Risk Characterization

................................ ................................ ........ 27

10.0 Cumulative Exposure/Risk Characterization

................................ ................................ ...... 27

11.0 Occupational Exposure/Risk Characterization

................................ ................................ ... 27

11.1 Short

- /Intermediate

- Handler Risk

................................ ................................ .................. 27

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

100

- 790)

................................ ................................ ................................ ................................ . 34

11.2 Short

- /Intermediate

- /Long

- Term/Cancer (if needed) Post

- Application Risk

................. 36

11.2.1 Dermal Postapplication Risk

................................ ................................ .................... 36

11.2.2 Inhalation Postapplication Risk

................................ ................................ ............... 36

12.0 References

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

................................ ........................ 39 Appendix B. Physical/Chemical Properties

................................ ................................ .................. 54 Appendix C. Review of Human Research

................................ ................................ .................... 58Cyromazine Human Health Risk Assessment DP No. D414914

Page 4 of 58 1.0 Executive Summary

This assessment provides information to support the registration review for the use of cyromazine. This document addresses the exposures and risk estimates associated with currently registered uses. It provides a reassessment of tolerances (pesticide residue limits in food) to

determine if they meet the safety standard established by the Food Quality Protection Act (FQPA) of 1996.

Use Profile Cyromazine (N

- cyclop ropyl

- 1,3,5

- triazine

- 2,4,6

- triamine) is an insecticide/larvicide. Tolerances are established (40 CFR §180.414) for residues of cyromazine in or on a variety of commodities ranging from 0.05 ppm (livestock commodities) to 10.0 ppm (brassica vegetables). Cyromazine works as an insect growth regulator. It exerts its toxic action by affecting the nervous system of the immature stages (larvae) of certain insects. C yromazine is applied to food crops with aircraft and ground application e quipment. It is applied to non

- food, landscape and greenhouse ornamentals using hand held spray equipment. There are no current or proposed residential uses of cyromazine.

Hazard Identification

Decrease s in body weight and food consumption are the common features of cyromazine toxicity following subchronic or chronic oral exposures as seen in dog s , rat s
, mice , and rabbit s

. Other effects reported were organ weight (relative) changes and changes to some hematological parameters that were biologic ally insignificant and non adverse. There are no indicators in the hazard database for cyromazine to suggest a concern for immunotoxicity. No dermal or systemic toxicity was seen at the highest dose tested (>2000 mg/kg/day) in two 21

- day dermal toxicity

st udies in rabbits. An acute neurotoxicity (ACN) study in rats demonstrated reduced motor activity as the main effect with no treatment related effects on mortality, brain weight or gross and histologic pathology or neuropathology up to the limit dose teste d

. In a 28

- day inhalation study in rats, cyromazine produced clinical signs of toxicity (hunched posture, piloerection, and reduced spontaneous activity) consistent with dyspnea at all concentrations tested. There is no

evidence of developmental toxicity following in utero exposures or that offspring are more susceptible following postnatal exposure . In the two

- generation reproduction study in rats no reproductive effects were observed. Cyromazine was not carcinogenic in mice or rats following long

- term dietary administration and is classified as a “ Group E

- Evidence of Noncarcinogenicity

for humans ”

. The available mutagenicity data suggest that cyromazine does not have genotoxic activity. Cyromazine is Toxicity Category III for acute oral, dermal and i nhalation toxicity. Cyromazine is not an eye irritant or a dermal sensitizer but is a mild skin irritant (Category IV)

.

Dose Response Assessment Based on the current use pattern for cyromazine, t oxicological points of departure (PODs) were selected for dietary/drinking water and short

- and intermediate

- term occupational exposure

scenarios. No developmental effects attributable to a single dose were seen following in utero exposures to rats and ra bbits; therefore, a dose and endpoint were not selected for acute oral exposure for the female 13 plus subpopulation. For the general population, the reduced motor activity seen at 250 mg/kg (LOAEL) in the acute neurotoxicity study was used to establish t he point of departure (POD) for acute dietary exposure risk assessment. A 3X UF was applied to theCyromazine Human Health Risk Assessment DP No. D414914

Page 5 of 58 acute dietary POD for extrapolating from a LOAEL to NOAEL. The default 10X UF factor was reduced to 3X based on the ADME (absorption, distribution, metabolis m and excretion) findings

in rats. An endpoint of toxicity from the 2

- generation study was selected as the POD for the chronic dietary assessment

. The LOAEL of 150 mg/kg/day in this study was based on decreased body weight and decreased food efficiency wi th a NOAEL of 50 mg/kg/day

. No dermal or systemic toxicity was observed following repeated dermal application at the limit dose tested to

rabbits. A POD for the dermal scenario was therefore

, not selected. A POD for short

- and

intermediate

- term inhalati on scenario was selected from a 28

- day inhalation rat study based on the clinical signs of toxicity seen at the LOAEL

. A NOAEL was not established in this inhalation rat study. A 3X uncertainty factor was applied for the extrapolation from a LOAEL in

the inhalation study to NOAEL. The default 10X uncertainty factor was reduced to 3x because the effects seen were not severe at the LOAEL and were reversible upon exposure cessation. The MOE for assessing risk via occupational inhalation exposure is 100 which includes 10x for inter

species extrapolation, 3x

- for intra

- species variation based on human equivalent calculations (HEC), and 3x for the use a LOAEL (UF L ) as the POD. There are no residential uses for cyromazine; however incidental oral exposure from spr ay drift is likely. To assess this incidental oral exposure resulting from spray drifts

, a point of departure of 50 mg/kg/day derived from the

2

- gen study was used.

Exposure/Risk Assessment and Risk Characterization

Risk assessments were conducted for dietary (food and water) and occupational exposure pathways based on registered uses of cyromazine along with the recommended tolerances for indirect residues of cyromazine from application of manure which has been treated with cyromazine to crop fields

. Conservative acute and chronic dietary and drinking water risk assessments for cyromazine conclude that dietary and drinking water exposure estimates are below HED’s level of concern for the general population and all population subgroups

.

Occupational exposures and risks were estimated for short and intermediate

- ter m timeframes at baseline attire. All occupational handler scenarios risk estimates resulted below HED’s level of concern (LOC) at its lowest mitigation level (i.e., baseline) and therefore

, not of concern to the Agency (i.e., MOEs ≥ 100 for short

- and intermediate

- term exposure durations).

For seed treatment (Trigard OMC; EPA Reg. No. 100

- 790) handler exposure, MOEs did not
exceed HED's level of concern (i.e. , MOEs ≥ 100 ) at baseline attire, except for the loader/applicator scenario that presented an MOE of 9 9. Risk estimates from planting treated seeds with cyromazine resulted in MOEs that do not exceed HED's level of concern with

baseline attire.

Although a quantitative occupational post

- a pplication inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for agricultural occupational/commercial handlers and seed treaters and secondary handlers (i.e., planters)

. Handler exposure resulting from appli cation of pesticides outdoors is likely to result in higher exposure than post

- application exposure. I t is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure

scenarios.Cyromazine Human Health Risk Assessment DP No. D414914

Page 6 of 58 There are no currently registered or proposed residential uses of cyromazine. However, a spray

drift assessment was conducted based on the potential for dermal and incidental oral exposure to
occur as a result of drift from cyromazine being applied via aerial and groundboom equipment.

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

incidental oral risk estimates were calculated since an incidental oral point of departure was selected (NOAEL of 50 mg/kg/da y). Children’s (1<2 year old) incidental oral risk estimates from indirect exposure to cyromazine related to spray drift did not exceed HED’s level of

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

.

Use of Human Studies
This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, listed in Appendix C , have been determined to require a review of their eth ical conduct. Some of these studies are also subject to review by the Human Studies Review Board. All of the studies used in this

assessment have received the appropriate review.

Tolerance Recommendation

Tolerances for inadvertent residues are required for crops grown in soil to which livestock manure containing cyromazine has been applied. A tolerance of 0.6 0 ppm should be established

.

2.0 HED Recommendations

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

discussed in Section 2.2.

2.1 Data Deficiencies

None.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

Adequate methods are available in Pesticide Analytical Manual ( PAM ) , Vol. II for enforcement of the established tolerances for cyromazine in/on pl ant commodities. The working method “Determination of Cyromazine in Bean (snap)” Revision O, was derived from Ciba

- Geigy

Ana l ytical Method No. AG0621, “Analytical Method for the Determination of Cyromazine and

its Metabolite M e lamine residues in Crops by Gas Chromatography with a Nitrogen/Phosphorous detector in the Nitrogen Spec i fic Mode. (January 12, 1995).” Minor modifications were made to improve the performance of the method. T he limit of quantitation for cyromazine is 0.05 ppm in most plant commod ities.

Adequate methods are available in PAM , Vol. II for enforcement of the established tolerances for cyromazine in/on meat, milk, poultry, and eggs.Cyromazine Human Health Risk Assessment DP No. D414914

Page 7 of 58 Cyromazine

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

HED conc luded that the data were acceptable and no additional cyromazine multiresidue method ( MRM ) recovery data were required.

3.0 International Harmonization

There are Codex and Canadian and Mexican tolerances /Maximum Residue Limits (MRLs) for cyromazine. The tolerance expression for cyromazine has been reviewed and updated as necessary based on HED’s Interim Guidance on Tolerance Expressions (S. Knizner, 5/27/09).

The current tolerance expression, which includes only cyromazine, is not in harmony with the residue expression in Canada, which includes melamine (see Table B.2. in appendix B). However, data demonstrate that melamine is a minor residue from the use of cyromazine. Thus, HED recommends increasing established U.S. tolerances to numerically harmo nize with Codex, Canadian, and Mexican tolerances in cases where higher international tolerances have been established by these entities. Accordingly, established tolerances for the commodities established at 40 CFR §180.414 subsection (a) should be revis ed as follows to harmonize with

Codex and Canadian tolerances (Table 4.0.2 ).

4.0 Recommended Tolerances

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

of 0. 60 ppm for all crops that are grown in soil amend ed with c y romazine treated fertilizer and that do not have current tolerances established based on direct application of cyromazine. These

tolerances would be established at 40 CFR §180.414 subsection (d) should be revised as follows. Change existing sub section d to d(1). Add subsection d(2).

(d)(2) Indirect or inadvertent residues. Tolerances are established for indirect or inadvertent residues of the insecticide cyromazine, including its metabolites and degradates, in or on the

commodities in the tab le in this paragraph when present therein as a result of the application of fertilizer containing cyromazine to growing crops that do not have a higher tolerance in paragraph (a)(1) of this section. Compliance with the tolerance levels specified in this p aragraph is to be determined by measuring only cyromazine, N

- cyclopropyl

- 1,3,5

- triazine

- 2,4,6

- triamine, in or on the commodity (Table 4.0.1 below)

.

Table 4.0 .1. Cyromazine Revised US Tolerances Commodity Existing US Tolerance (ppm) Revised US Tolerance Cattle, kidney 0.2 0.3 1

Egg 0.25 0.3 1

Goat, kidney 0.2 0.3 1

Goat, meat 0.05 0.3 1

Goat, meat byproducts, except kidney 0.05 0.3 1

Hog, kidney 0.2 0.3 1

Hog, meat 0.05 0.3 1

Hog, meat byproducts, except kidney 0.05 0.3 1

Horse, kidney 0.2 0.3 1

Horse, meat 0.05 0.3 1

Horse, meat byproducts, except kidney 0.05 0.3 1Cyromazine Human Health Risk Assessment DP No. D414914

Page 8 of 58 Table 4.0 .1. Cyromazine Revised US Tolerances Commodity Existing US Tolerance (ppm) Revised US Tolerance Mango 0.3 0.5 1

Milk 0.05 0.1 1

Mushroom 1.0 8.0 2

Onion, bulb, subgroup 3

- 07A 0.2 0.3 2

Pepper 1.0 3.0 2

Poultry, meat 0.05 0.1 1

Poultry, meat byproducts 0.05 0.2 1

Sheep, kidney 0.2 0.3 1

Sheep, meat 0.05 0.3 1

Sheep, meat byproducts, except kidney 0.05 0.3 1

Tomato 0.5 1.0 2

Vegetable, brassica, leafy, group 5, except broccoli 10.0 35.0 2

Vegetable, leafy, except brassica, group 4 7.0 10.0 2

Vegetable, cucurbit, group 9 1.0 2.0 1

1 Increased to harmonize with Codex MRL

2 Increased to harmonize with Canadian MRL level only. Tolerance expression is not harmonized.

Table. 4.0.2 Tolerance Summary for Cyromazine

Inadvertent Tolerances ppm Vegetable, r oot and t uber , group 1 0. 60 Vegetable, Leaves of r oot and t uber , group 2 0. 60 Onion, bulb, subgroup 3

- 07A 0. 60 Vegetable, Legume, group 6 0.60 Vegetable, Legume, foliage of, group 7 0. 60 Vegetable , fruiting, group 8

- 10 0. 60 Strawberry 0. 60 Grain, cereal, group 15 0. 60
Grain, cereal, forage, fodder and straw, group 16 0. 60

Herbs and spices, group 19 0. 60

Oilseed

, group 20 0. 60

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

5.0 In troduction

5.1 Identity

Structure and nome nclature are reported in Table 5

. 1

.

Table 5 .1

. Cyromazine Nomenclature.

Chemical structureCyromazine Human Health Risk Assessment DP No. D414914

Page 9 of 58 Table 5 .1

. Cyromazine Nomenclature.

Common name Cyromazine (ISO approved)

Company experimental name CGA

- 72662

IUPAC name N

- cyclopropyl

- 1,3,5

- triazine

- 2,4,6

- triamine

CAS name N

- cyclopropyl

- 1,3,5

- triazine

- 2,4,6

- triamine

CAS # 66215

- 27

- 8

End

- use product/EP Trigard®75WP

5.2 Physical/Chemical Characteristics

The physicochemical properties of cyromazine are reported in Appendix B

.

5.3 Pesticide Use Pattern

Cyromazine is an insecti cide intended for the control of leafminer by foliar application to a variety of vegetables (such as leafy vegetables, cucurbit, lima bean, and tomato) and is intended for fly control in livestock premises. Maximum application rates for existing an d proposed uses are provided in Table 5.3

. Maximum rates are based on a review of active and proposed labels.

Table 5.3 . Summary of Cyromazine End

- Use Products.

Product Name (EPA Reg. No.) Product

Formulation Use Site Method of Application Application Rate

Trigard ®

(100

- 654) Water

- Soluble

Packets (Wettable Powder) (75% ai) Abyssinian and seakale cabbage, bulb

vegetables, cucurbits, certain varieties of dried beans, hanover salad, leafy vegetables including brassica, succulent beans, peppers, tomatoes, and turnip greens and control of Colorado potato beetle and leafminer in

potatoes. Foliar spray with ground equipment

and/or aircraft 2.66 oz (one

packet)/A

0.125 lb ai/A

L abel Instructions: Do not apply product through any type of irrigation system. Do not use in greenhouses. PHI = 7 days. RE I =

12 hours

Citation ®

Insecticide (100

- 667) Wettable Powder

in Water

- Soluble Packet (75% ai) For control of selected insects, including

Dipterous leafminers, and fungus gnats in landscape ornamentals; container grown ornamentals; greenhouse, lath and shadehouse grown ornamental bedding plants, and ornamental crops; and interiorscapes; and shore fl ies, only in greenhouse ornamental crops and interiorscapes. Foliar Spray with

handheld equipment 0.125 lb ai/A

0.00125 lb ai/gal

Label Instructions: Do not make more than a total of 6 applications to one crop. Make no more than 3 applications at 7 day intervals. Apply 2.66 oz of product in 100 gallons of water as a spray or drench to all surfaces where insect pests may bree d.

REI = 12 hours Trigard ® OMC Wettable Powder Onion maggot control in bulb onions Seed Treatment 0.05 lb ai/lb seedCyromazine Human Health Risk Assessment DP No. D414914

Page 10 of 58 Table 5.3 . Summary of Cyromazine End

- Use Products.

Product Name (EPA Reg. No.) Product

Formulation Use Site Method of Application Application Rate

(100

- 790) (75% ai)
Label Instructions: Do not use on agricultural establishments in hopper

- box, planter

- box, slurry

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

Solitude TM IGR (1007

- 93) Granules (2.12%

ai) For fly control in and around horses, horse

barns, horse stables and paddocks, horse race

tracks. This product which, when mixed into a horse's ration will control certain fly species that develop in the horse ma nure. Feed

- through into

horses' ration 300 mg (1

scoop)/horse/day

0.00066 lb ai/horse/day

Label Instructions: Feed the recommended dosage to each horse separately. To be fed top

- dressed on grain or mixed with horse's

total ration.

Larvadex ® 1%

Premix (70585

- 1) Granules

(1% ai) For fly control in and around 1) caged or

slatted flooring layer chicken operations 2) Breeder Chicken Operations Feed

- through

blended into poultry ration 1 lb prod/ton feed

0.01 lb ai/ton of

feed Flyzine TM 1%

Premix (75066

- 1)

Label Instructions: Treated feed must not be fed to layers and breeders for a minimum of 3 days before slaughter for food. During winter months or periods of low fly pressure, discontinue use for at least 4 consecutive months per year. Do not feed treated feed to broiler poultry. Use is limited to chicken layer and breeder operations only; not to be fed to any other pou ltry species. Do not apply more than 3 tons of manure/acre/year. Do not feed treated manure to animals.

Armor ® Insect

Growth Regulator (100

- 656) Liquid

(5% ai) Mushroom compost to stop development of

sciard fly larvae Coarse drenching spray with low

pressure 43 oz prod/1,000

sq ft

or 0.14 lb ai/1,000 sq

ft Cyromazine

5% (42750

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

12 hours

Larvadex ® 2SL (70585

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

handheld equipment 8.6x10
- 5 lb ai/sq ft

(Dilution rate:

6.5 fl oz of 0.1% product/gal/100 sq ft; 0.17 lbs ai/gallon) Label Instructions: Dilute Larvadex 2SL with water to make a 0.1 % spray. Apply 1 gallon of finished spray per 100 sq ft. Apply once every 21 days. Do not apply directly to poultry or poultry feed. Do not feed treated manure to animals. Allow 24 hours between last application and slaughter. Do not use in conjunction with Larvadex 1% Premix; Do not apply more than 4 tons of treated manure/acre/year. Do not apply treated ma nure to small grain crops to be harvested or grazed.

Neporex ® 2SG (70585

- 7) Soluble Granule

(2% ai) For Housefly, Lesser Housefly, Stable Fly

and Soldier Fly Control in Cattle Operations, Hog Operations, Poultry Operations Including Layer and Breeder Chickens, and

Horse Barns Where Horses are not Intended for Slaughter or Food Dry Scattering 0.02 lb ai/200 ft 2

Spraying 0.02 lb ai/200 ft 2

or 4.36 bs ai/A

or 0.02 lb ai/gal Label Instructions: Apply only on fly breeding sites; not to fly resting sites (walls, ceilings, etc.). Use dry scattering only in case of wet or liquid manure. Do not apply more than once every 21 days. Do not administer via feed or drinking water or contaminate feed troughs or water troughs. Do not apply directly to livestock o r livestock feed. Do not feed manure treated with product to animals. Allow 1 Day between last application and slaughter. Do not use in conjunction with Larvadex 1% Premix i n chickens. Manure treated with product may be used as soil fertilizer, do not apply more than 4 tons of manure/Acre/year. Do not apply treated manure to small grain crops that will be harvested or grazed.

5.4 A nticipated Exposure PathwaysCyromazine Human Health Risk Assessment DP No. D414914

Page 11 of 58 The Pesticide Re

- Evaluation Division has requested an assessment of human health risk to support the registration review of cyromazine. For domestic uses, humans may be exposed to cyromazine in food and drinking water, since cyromazine may be applied dire ctly to growing crops and application may result in cyromazine reaching surface and ground water sources of drinking water. In an occupational setting, applicators may be exposed while handling the pesticide prior to application, as well as during applica tion. There is a potential for post

application exposure for workers re

- entering treated fields and incidental oral exposure from application spray drift. There are no residential uses of cyromazine ; t herefore, there is no exposure in residential settings

. However, potential risk estimates from spray drift to children (1<2 years old) were evaluated to account for off

- target movement of cyromazine from applications via groundboom and aerial equipment.

5.5 Consideration of Environmental Justice

Potential area s 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 Popul ations," ( 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

- est ablished procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the National Health and Nutrition Survey/What We Eat in America (NHANES/WWEIA) and are used in pesticide risk assessments for all registered food uses of a p esticide. These data are analyzed and categorized by subgroups based on age and ethnic group. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when

conditions or circumstances war rant. 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

considerat ions are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

6.0 Hazard Characterization and Dose

- Response Assessment

6.1 Toxicology Studies Available for Analysis

The studies available for consideration of cyromazine toxicity provide a complete database for selecting endpoints and points of departure for risk assessment. As part of the revised 40 CFR Toxicology Data Requirements , an immunotoxicity study is necessary for registered uses;

however t he HED Hazard and Science Policy Council (HASPOC) concluded using a weight

- of

evidence approach that this study is not required at this time ( TXR 0 056806 ). Based on the findings in the ACN study and the total weight of evidence, HASPOC waived the requirement for the subchronic neurotoxicity study (TXR 0056682). The available studies are:Cyromazine Human Health Risk Assessment DP No. D414914

Page 12 of 58  Acute: Oral, dermal, inhalation, eye irritation, dermal irritation, and skin sensitization

 Subchronic: 90

- day oral toxicity (rat, dog) , 21

- day dermal toxicity (rabbit), 21

- day inhalation toxicity (rat)

 Developmental toxicity: developmental toxicity (rat and rabbit)

 Reproduction: 2

- generation reproduction (rat)

 Chronic: combined oral chronic toxicity/carcinogenicity (rat), carcinogeni city (mouse), chronic oral toxicity (6

- month dog)

 Neurotoxicity: Acute neurotoxicity (rat)

 Other: mutagenicity battery, metabolism, dermal penetration

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

The disposit i on and metabolism of 14 C

- cyroma zine was investigated in male and female rats at a low oral dose (3 mg/kg), a low intravenous dose (3 mg/kg), repeated low oral doses (3 mg/kg) and a high dose (300 mg/kg). Comparison of oral and i.v. disposition data demonstrated that cyromazine was well absorbed after oral administration. Excretion was also rapid at the low dose, with the majority of radioactivity eliminated in the urine by 24 hours. At the high dose, however, there was an apparent delay in elimination of cyromazine derived radioactivity, suggesting saturation of the metabolism sites

.

Fecal elimination of 14 C

- cyromazine derived radioactivity was equivalent between dose groups and sexes, with the exception that in the high dose males, a greater percentage of radioactivity was apparently el iminated by this route. The origin of fecal radioactivity from administration of

14 Cy ro mazine was apparently biliary in nature, as an equivalent percentage of 14 C

- cyromazine

derived radioactivity was eliminated by both orally dosed and intravenously dosed rats,
Residual 14C

- cyromazine derived radioactivity was minimal in all dose groups, with non

detectable levels in all tissues examined except liver, red blood calls, and carcass. Urinary and

fecal metabolites of 14 C

- cyromazine were isolated and identified by TLC, HPLC, and GC/MS. The major compounds identified were the N

- dealkylated product melamine, hydroxy

cyromazine, and un

- metabolized cyromazine

.

The disposit i on and metabolism of 14 C

- cyromazine was investigated in male and female rats at a

low oral d ose (3 mg/kg), a low intravenous dose (3 mg/kg), repeated low oral doses (3 mg/kg) and a high dose (300 mg/kg). Comparison of oral and i.v. disposition data demonstrated that cyromazine was well absorbed after oral administration. The time of peak effect i n an ACN study was estimated to be 2 to 4 hours post

- dosing based on the rapid absorption f rom the gastrointestinal tract following oral gavage. Excretion was rapid at the low dose (3 mg/kg), but an apparent delay in excretion occurred at the high dose (30 0 mg/kg) suggesting saturation of the

metabolism sites

. Urinary excretion accounted for 50%

- 60% of the administered radioactivity at the 3 mg/kg dose, while it was 25% of the administered dose at the 300 mg/kg dose d uring the

first 16 hours following o ral dosing

. Renal excretion was the primary route of elimination. Fecal elimination was equivalent among dose groups except the high dose males, where a greater percentage was eliminated by this route. The origin of fecal radioactivity was via biliary

el imination. There was no evidence of preferential distribution or bioaccumulation of cyromazine in the body tissues. Urinary and fecal metabolites of 14 C

- cyromazine were isolatedCyromazine Human Health Risk Assessment DP No. D414914

Page 13 of 58 and identified by TLC, HPLC, and GC/MS. The major compounds identified were the N

dealkylated product melamine, hydroxy

- cyromazine, and un

- metabolized cyromazine

.

6.2.1 Dermal Absorption

A dermal absorption factor of 13% was derived for cyromazine from two dermal absorption studies using 14 C labeled cyromazine in rats. The amount absorbed was determined by the total radioactivity in blood, urine, feces, and carcass after 10 hours of exposure. Cyromazine is

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

decreased as dose i ncreased indicating saturation of absorption with increasing dose. The absorption into the skin is followed by a slower release into the body. The main route of

excretion of the absorbed cyromazine is in the urine.

6.3 Toxicological Effects

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

doses. Decrease s in body weight and food consumption are the common features of cyromazine toxicity following subchronic or chronic oral exposures as seen in dog s , rat s
, mice , an d rabbit s

. Other effects reported were organ weight (relative) changes and changes to some hematological parameters that were biologically insignificant and non adverse. No dermal or systemic toxicity was seen at the highest dose tested (>2000 mg/kg/day) in two 21

- day dermal toxicity studies in

rabbits. In a 28

- day inhalation study in rats, cyromazine produced clinical signs of toxicity (hunched posture, piloerection, and reduced spontaneous activity) consistent with dyspnea at all

concentrations tested. There is no evidence of developmental toxicity following in utero

exposures or that offspring are more susceptible following postnatal exposure . In the two

generation reproduction study in rats no reproductive effects were observed.

The available oral perinatal, prenatal and postnatal data demonstrated no indication of increased sensitivity of rats or rabbits to in utero exposure to cyromazine. No quantitative or qualitative susceptibility was observed in any study. In the prenatal developmental rat t oxicity study, the NOAEL (300 mg/kg/day) for developmental effects (increased incidence of minor skeletal variations) was higher than the m aternal NOAEL (100 mg/kg/day). In the developmental toxicity study in rabbits, no evidence of developmental toxicity was noted since the NOAEL was greater than the highest dose tested (> 60 mg/kg/day) . In the two

- generation reproduction rat study, no reproductive effects were observed up to the highest dose tested ( NOAEL wa s > 150 mg/kg/day (H DT)).

Cyromazine was not carcinogenic in mice or rats following long

- term dietary administration and

was classified “ Group E

- Evidence of Noncarcinogenicity for humans ” . The available mutagenicity data suggest that cyromazine does not have genotoxic activity.

Cyromazine is categorized as Toxicity Category III for acute oral, dermal and inhalation toxicity. Cyromazine is neither an eye irritant nor a dermal sensitizer; however, it is mild skin irritant. (see Appendi c es for Toxicity Profile tables).

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

Page 14 of 58 There are no residual uncertainties or concerns for pre

- and/or post

- natal toxicity; HED recommends the FQPA SF of 10x be reduced to 1x

.

6.4.1 Completeness of the Toxicology Database

T he toxicology databas e for cyromazine is complete for evaluating and characterizing cyromazine toxicity and selecting endpoints for purposes of this risk assessment. The selected toxicity endpoints and points of departure for risk assessment are based on the most sensitive an d

relevant data.

6.4.2 Evidence of Neurotoxicity

There is no evidence of neurotoxicity in the cyromazine database including acute, subchronic or chronic dosing in multiple species . In the acute neurotoxicity study conducted in rats, reduced motor activity was seen with no treatment related effects on mortality, brain weight or gross and histological pathology or neuropathology up to the limit dose. Based on the findings in the ACN study an d the total weight of evidence, HASPOC waived the requirement for the subchronic neurotoxicity study (TXR 0056682). The HED HIARC concluded in 2002 that there is not a concern for developmental neurotoxicity resulting from exposure to cyromazine ( TXR NO.

0050774 ).

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

There is no evidence of susceptibility following in utero and/or postnatal exposure in the developmental toxicity studies in rats or rabbits, and in the 2

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

effects (increased incidence of minor skeletal variations) was higher than the m aternal NOAEL (100 mg/kg/day).

6.4.4 Residual Uncertainty in the Exposure Database

The acute and chronic dietary exposure analys e s used tolerances and 100 percent crop treated. The dietary assessment is no t a highly refined assessment. Therefore, dietary exposure to cyromazine will not be underestimated.

6.5 Toxicity Endpoint and Point of Departure Selections

6.5.1 Dose

- Response Assessment

The toxicity endpoints and points of departure are presented in Table 6 .5.4 below , and the details for selecting toxicity endpoints and points of departure for various exposure scenarios are presented in Appendix A

.

The most sensitive and protective endpoints from the toxicity database were selected to establish points of de parture for the risk assessment. No developmental effects attributable to a singleCyromazine Human Health Risk Assessment DP No. D414914

Page 15 of 58 dose were seen following in utero exposures to rats or rabbits; therefore, a dose and endpoint were not selected for acute oral exposure for the female 13

- 49 subpopulatio n

. For the general population, the reduced motor activity (↓44%) seen at 250 mg/kg (LOAEL) in the acute neurotoxicity study was used to establish the point of departure (POD) for acute dietary exposure. A 3X UF was applied to the acute dietary POD for ex trapolating from a LOAEL to

NOAEL. The default 10X LOAEL to NOAEL UF factor was reduced to 3X based on the ADME (absorption, distribution, metabolism and excretion) findings in rats. As discussed in section 4.2 ADME data (MRID 41442101) suggests that 250 mg/kg/day is a dose that saturated the animals metabolic capabilities in the ACN study. It is therefore believed that at doses below saturation, the chemical would be cleared from the body and would not produce the effects observed in the ACN study.

A dose of 150 mg/kg/day in chronic exposure studies resulted in minimal effects (body weight decrements). An endpoint from the 2

- generation study was selected as the POD of 50 mg/kg/day

for the chronic dietary assessment

. The LOAEL of 150 mg/kg/day in this study was based on decreased body weight and decreased food efficiency

. The combined chronic/carcinogenicity study was co

- critical with the selected 2

- genration reproduction study where the LOAEL of 150 mg/kg/day was also based on decreased body weight and decreased body weight gain and lower food consumption.

No dermal or systemic toxicity was observed following repeated dermal application at the highest dose tested to rabbits. A POD for the dermal scenario was therefore not selected. A

POD for short

- and intermediate

- term inhalation scenario was selected from a 28

- day inhalation

rat study based on the LOAEL

. The LOAEL in this inhalation study was 0.055 mg/L/day based on impairment of the general condition with the symptoms of piloerection, dyspnea, h unched posture, and reduced spontaneous activity. A NOAEL was not established in this inhalation rat study. A 3X uncertainty factor was applied for the use of a LOAEL. The default 10X uncertainty factor was reduced to 3x because the effects seen were slig ht in degree and not severe at the LOAEL and were reversible upon exposure cessation. A human equivalent concentration was derived and the interspecies variation uncertainty factor was reduced to 3x.

There are no residential uses for cyromazine; however i ncidental oral exposure from spray drift is likely. To assess this incidental oral exposure resulting from spray drift a point of departure of 50 mg/kg/day derived from the 2

- gen eration study (co

- critical with the chronic/carcinogenicity study) cited abov e was used.

6.5.2 Recommendation for Combining Routes of Exposures for Risk Assessment

When there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. There are no common endpoints to combine routes of exposure.

6.5.3 Cancer Class ification and Risk Assessment Recommendation

Cyromazine is classified as a “ Group E

- Evidence of Noncarcinogenicity for humans ” based on the lack of evidence of carcinogenicity in the mouse and rat c ancer studies (HED CPRC

, TXRCyromazine Human Health Risk Assessment DP No. D414914

Page 16 of 58 No. 0 011384 , 1/6/95 ). C yromazine was not mutagenic in three mutagenicity studies submitted to

OPP

.

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

Assessment

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

be low:

Table 6.5.4. Summary of Toxicological Doses and Endpoints for Cyromazine for Use in Dietary, Non

Occupational and Occupational Human Health Risk Assessments 09

- 27

- 2013

Exposure/

Scenario Point of

Departure Uncertainty

/FQPA Safety

Factors RfD, PAD,

LOC for Risk

Assessment Study and Toxicological Effects

Acute Dietary

females 13+ No developmental effects attributable to a single dose were seen following in utero

exposures to rats and rabbits

Acute Dietary (general population) LOAEL =

250 mg/kg UF A = 10x

UF H = 10x

UF L = 3x aRfD = 0.83

mg/kg

aPAD = 0.83 mg/kg ACN Study in rats, MRID

49109701 LOAEL = 250 mg/kg BW based on decreased motor activity (mean cumulative ambulatory LMA counts (↓ 44%) in males at the time of peak effect on Day 0, and decreased food consumption (p < .01, ↓17.4%) on Day 1.

Chronic Dietary (All Populations) NOAEL=

50 mg/kg/day UF A = 10x

UF H = 10x cRfD = 0.5

mg/kg/day

cPAD = 0.5 mg/kg/day 2 Generation Reproductive Study

(MRID 00103197 ) co

- critical with

Chronic Carcinogenicity Study (MRID 00103202, 00115735 ) in

the rat

LOAEL = 150 mg/kg/day for decreased body weight and decreased food efficiency.

Incidental Oral

Short

- Term (1

- 30 Days) NOAEL=

50 mg/kg/day UF A = 10x

UF H = 10x LOC for MOE

= 100 2 Generation Reproductive Study

(MRID 00103197 ) co

- critical with Chronic Carcinogenicity Study (MRID 00103202, 00115735 ) in

the rat

LOAEL = 150 mg/kg/day for decreased body weight and decreased food efficiency.

Dermal

Short/intermediate

term No hazard was identifie d via the dermal route of exposure and therefore

quantification of risk via this route of exposure is not required. No systemic toxicity

occurred in two 21

- dermal rabbit toxicity studies at the highest doses tested of 2000 mg/kg/day.Cyromazine Human Health Risk Assessment DP No. D414914

Page 17 of 58 Table 6.5.4. Summary of Toxicological Doses and Endpoints for Cyromazine for Use in Dietary, Non

Occupational and Occupational Human Health Risk Assessments 09

- 27

- 2013

Exposure/

Scenario Point of

Departure Uncertainty

/FQPA Safety

Factors RfD, PAD,

LOC for Risk

Assessment Study and Toxicological Effects

Inhalation Short

- to
Intermediate Term (1

- day

– 6 months) LOAEL=

0.055 mg/L Equivalent

to HEC of

0.04012 mg/L*

HED for applicators

2.28 mg/kg/day;

For

handlers:

4.59 mg/kg/day;

for the

hand

- held

sprayers: 7.98 mg/kg/day UF A = 3x**

UF H =10x

UF L = 3x Occupational

LOC for MOE

= 100 28

- day Inhalation Toxicity study in

rats MRID 47940804

LOAEL = 0.055 mg/L based on impairment of the general condition with the symptoms of piloerection, dyspnea, hunched posture, and reduced spontaneous activity. This was the lowest

concentration tested.

Cancer (all routes) Cancer classification (Group E

- Evidence of Noncarcinogenicity for humans ) (HED

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

. Point of Departure (POD) = A data point or an estimated point that is derived from observed dose

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures.

NOAEL = no o bserved 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)

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

text. SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic).

RfD = reference dose. MOE = margin of exposure; the maxim um allowed by the Agency.

LOC = level of concern. N/A = not applicable. *mg/L conversion to Human Equivalent Dose (HED) mg/kg/day, see Appendix.

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

6.6 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and

chronic toxicity, including assessments of carcinogenicity, neurotoxicity, developmental, reproductive, and general or systemic toxicity. These studies include endpoints which may be susceptible to endocrine influence, including effects on endocrine target organ histopathology, organ weights, estrus cyclicity, sexual maturation, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, development al and reproductive effects in different taxonomic groups. As part of its reregistration decision for cyromazine , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing

hazard database. Ho wever, as required by FFDCA section 408(p), cyromazine is subject to the endocrine screening part of the Endocrine Disruptor Screening Program (EDSP).Cyromazine Human Health Risk Assessment DP No. D414914

Page 18 of 58 EPA has developed the EDSP to determine whether certain substances (including pesticide

active and oth er ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily required determinations. Tier 1 consists of a battery of 11 screening assays to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening an d are found to have the potential to interact with E, A, or T hormonal systems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to i dentify any adverse endocrine

- related effects caused by the substance, and

establish a dose

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

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

October 2009 and February 2010, EPA issued test orders/data call

- ins for the first group of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. A second list of chemicals identified for EDSP screening was published on June 14, 2013 1 an d includes some pesticides scheduled for registration review and chemicals found in water

. Neither of these lists should be construed as a list of known or likely endocrine disruptors.

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

issue test orders/data call

- ins in the near future. For further information on the status of the EDSP, the policies and procedures, the lists of chemicals, future lists, the test guidelines and the Tier 1 screening battery, please v isit our website 2

.

7.0 Dietary Exposure and Risk Assessment

7.1 Metabolite/Degradate Residue Profile

7.1.1 Summary of Plant and Animal Metabolism Studies

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

residue of concern is the parent compound cyromazine as determined by the HED Metabolism Committee on 11/4/97. The metabolism of cyromazine in plants is adequately understood and additional plant metabolism data are not required

.

Data concerning the metabolism of cyromaz ine in lactating goats and laying hens have been previously submitted. The livestock metabolism data for cyromazine have been presented to the HED Metabolism Assessment Review Committee (MARC, meeting date: 11/4/97). The MARC

determined that the residue o f concern in livestock commodities is the parent compound, cyromazine (Memo, 4/15/98 J.B. Stokes, D245214).

7.1.2 Summary of Environmental Degradation

1 See http://www.regulations.gov/#!documentDetail;D=EPA

- HQ

- OPPT

- 2009

- 0477

- 0074 for the final second list of

chemicals.

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

Page 19 of 58 Based on previously submitted data, cyromazine is stable to hydrolysis and photolysis, and is persistent in a erobic 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. The K ads values are not equal to K d , because the slope (1/n) in the adsorption isotherm was less than 1 (0.77 to 0.85). The logarithms ( 1.6 to 2.3 ) of the Koc values are generally less than 2, which falls into the “Mobile” category as described by t he 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.

7.1.3 Comparison of Metabolic Pathways

The major plant and poultry metabolism residues are cyromazine and melamine. The major ruminant metabolism residues are cyromazine, melamine, and 1

- methylc yromazine. The major rat metabolism residues were cyromazine, melamine, and hydroxy cyromazine.

7.1.4 Residues of Concern Summary and Rationale

A summary of the metabolites and degradates to be included in the risk assessment and tolerance expressio n are presented below in Table 7.1.4

. The residue of concern is the parent compound cyromazine as determined by the HED Metabolism Assessment Review Committee (MARC) (D245214, 11/4/97 )

. The MARC determined that the residue of concern in livestock

commodities i s the parent compound, cyromazine (D245214

, J.B. Stokes

, 4/15/98).

Table 7.1.4 : Summary of MARC Decisions for Cyromazine

Matrix Residues of Concern

For Risk Assessment For Tolerance Expression

Plants

Parent Only Parent Only Livestock Rotational Crops Drinking Water Note: EPA’s final rule on cyromazine; pesticide tolerance (Volume 65, 87) (May 4, 2000) removed melamine, a metabolite of cyromazine from the tolerance expression because melamine did not contribute a significant amount to the cyromazine residue

.

7.2 Food Residue Profile

Crop Field Trials

HED’s evaluation of available crop field trial and livestock feeding studies submitted in support of registered uses of cyromazine indicates that available residue data are adequate to support existing tolerances for cyromazine on plant and animal commodities. Crop field trial data are

available for onion (green and dry bulb), broccoli, cabbage, mustard greens, tomato, lettuce (head and leaf), celery, spinach, cantaloupe, cu cumber, honey dew melon, mushroom, pepper (bell, chili, tabasco), corn (sweet K+CWHR, forage, fodder), radish (root, tops), mangoes,Cyromazine Human Health Risk Assessment DP No. D414914

Page 20 of 58 cottonseed, and bean (succulent). An adequate number of crop field trials conducted in appropriate ly representative locati ons are available for cyromazine for the currently registered crop applications and use patterns (application rate and PHI).

Processed Food and Feed

The available processing data on tomatoes are adequate to support existing registered uses of cyromazin e. Processing trials were conducted in accordance with commercial procedures. The only significant concentrations found in processed commodities were in dry pom ace ( average, 2.4X) and paste (2.2X).

The processing study on potatoes shows concentration of combined residues of cyromazine in potato granules/flakes (avg 2.6X) and potato chips (avg 1.9X). The alfalfa processing studies

indicate average lX concentration of cyromazine residues in the proces sed commodities

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

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

cottonseed oils or soapstock even at the 5x rate

. Meat, Milk, Poultry, and Eggs

Novartis submitted studies on cyromazine residues in poultry excreta from a poultry feed product and a product applied topically to poultry excreta. In the feed

- through study

, residues of cyromazine were 3.6

- 5.8 ppm on St udy Days 1

- 21 (before plateau) and 7.2

- 8.0 ppm on Study Days 28

- 42 (after plateau); corresponding residues of melamine (as cyromazine equivalents)

were 0.23

- 0.35 ppm and 0.46

- 0.48 ppm. Residues of cyromazine and melamine in excreta declined steadily after the final application, reaching <LOQ (0.05 ppm) by Depuration Days 3 and 2, respectivel y. In the topical application to excreta study residues of cyromazine and melamine (as cyromazine equivalents) in excreta occurred in a cyclical pattern, with the high est residues occurring immediately after each application and then declining. From Study Day 0 through Study Day 21 after the first application, residues of cyromazine and melamine declined from 49 to 3.0 ppm and from 0.53 to 0.18 ppm, respectively. Afte r the second application on Study Day 21, residues of cyromazine and melamine increased to 39 ppm and 0.62 ppm, respectively, and then declined to 20 ppm and 0.51 ppm five days later. The second spray application did not result in residue buildup as compa red to single treatment data.

Based on changes using Table 1 Feedstuffs (June 2008), dietary burdens have been estimated for beef, dairy, chicken, and swine. Novartis (formerly Ciba , now Syngenta) submitted a three

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

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

detectable residues of cyromazine and melamine in tissues at a feeding level of 10 ppm in the diet were observed. The worst case theoretical dietary burden contribution from cotton products fed to beef and dairy cattle is less than 0.05 ppm. This is some 200 fold less than the 10 ppm diet

in the aforem entioned feeding study. Based on these calculations, there will be no detectable transfer of incurred cyromazine equivalent residues in any consumed beef or dairy commodities, from cattle fed treated cotton products. Cotton meal is also the only cotton co mmodity fed to swine and is equally expected to result in no detectable residues in any commonly consumed hog food products.Cyromazine Human Health Risk Assessment DP No. D414914

Page 21 of 58 Field Accumulation in Rotational Crops

Data from rotational crop field accumulation study were also used to derive inadvertent tolerances for use of cyromazine treated manure as fertilizer on agricultural fields. In the rotational crop study, v arious indicator crops were grown to maturity in the greenhouse in soil that had been amended with the equivalent of 5 tons per acre of ch icken manure treated with

C 14 cyromazine at a rate of 0.05 lb. a.i. per acre and aged for 30 days. The 0

- 3 inch soil layer of aluminum pails contained approximately 0.05 ppm C 14 cyromazine. There was little evidence of leaching during the course of the stud y. Soil from the 0

- 3 inch layers contained 72% cyromazine 30 days after treatment and 65% cyromazine 121 days after treatment. Analyses of crops at various stages of growth indicate that only spring wheat straw (0.08 ppm) and hulls (0.06 ppm)

had measurab le uptake greater than 0.05 ppm. Immature sugar beet tops (0.008 ppm) and spring wheat stalk (0.016 ppm)

, contained measurable uptake of total radioactivity < 0.05 ppm. Lettuce and other crop fractions (sugar beets, spring wheat) contained detectable amo unts of radioactivity at a level too low for reliable quantitation.

Six trials were conducted in AZ (2), CA, (2), FL, and TX areas where rotational cotton, alfalfa, and sudangrass were planted back 30 days following primary crop of head lettuce. Maximum residues of cyromazine in RACs from cotton, alfalfa and sudangrass planted 30 days after the last application of cyromazine to lettuce were as follows: cottonseed, <0.05; alfalfa forage, 0.32; alfalfa hay, 0.51; alfalfa seed, <0.05; sudangrass forage, 0.17 ; and sudangrass hay; 0.10.

Various crops (lettuce, sugar beet, wheat, carrot, and soybean) were grown to maturity in soil in which tomatoes had been grown. The tomatoes had been treated with six applications of C

14 cyromazine at 0.25 lb ai/A. At the t ime of the first crop planting (lettuce), cyromazine soil residues were 0.064 ppm (0

- 3 in). Samples of lettuce, carrot tops and roots, sugar beet roots and tops, soybean stalks, pods, and seeds, and wheat grain, stalks, and hulls each had < 0.01 ppm

cyrom azine equivalent residues. The foregoing plant metabolism and soil uptake studies are sufficient to reflect the metabolic behavior of cyromazine in plants in general. Therefore, the

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

Based on submitted studies on cyromazine residues in poultry excreta from a poultry feed product and a product applied topically to poultry excreta as described above, a tolerance of 0. 6 ppm on crops grown in soil amended with fertilizer treated with cyromazine was derived as

follows

.

The highest level of cyromazine found in the greenhouse rotational crop study was 0.08 ppm in spring wheat straw. The application rate for the rotational crop study was 0.05 lb a.i. per acre (based on a 4 ton per acre application of cyromazine treated fertilizer). A conservatively estimated residue of 40 ppm cyromazine is assumed based on results of a magnitude of the residue study in excreta topically tre ated with a 0.17 lb ai/gal soluble concentrate (SL). Residues from that study ranged from 49 ppm at day 0 to 20 ppm at day 26 with 40 ppm at day 24. Assuming 40 ppm cyromazine in treated manure, the calculated maximum label application rate of cyromazin e at 4 tons treated manure per acre is 0. 33 lb a.i. per acre.Cyromazine Human Health Risk Assessment DP No. D414914

Page 22 of 58 40 mg ai/kg manure x 4 tons manure/A x 2000 lb/ton x 1 kg/2.2 lb = 0.1 5 kg ai/A

0.1 5 kg ai/A x 2.2 lb/kg = 0. 33 lb ai/A

The calculated rate of 0. 33 lb ai/A is 7 X the 0.05 lb a.i. per acre ra te used in the green house rotational crop study which resulted in a maximum residue level of 0.08 ppm in spring wheat straw. Adjusting the maximum residue level found in the greenhouse study in accordance with the maximum application rate derived from th e magnitude of the residue study results in a

conservative tolerance level of 0. 6 0 ppm.

7.3 Water Residue Profile

Currently, cyromazine may be directly applied to various crops (including celery, bulb onion, pepper, lettuce, cucurbits, dried and succulent be ans, tomatoes, potatoes, mushrooms, leafy brassica)

, applied using a feed

- through system in chicken productions, or directly applied to manure generated by hogs and horses. Drinking water residues were provided by the

Environmental Fate and Effects Divis ion Table 7 .3.1 (EFED; D398026, T. Dowen, 2/10/12).

Because PRZM

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

DWA and the PRZM

- GW model is being used in FQPA drinking water assessments to estimate pesticide concentrations i n ground water sourced drinking water, PRZM

- GW modeling for cyromazine was conducted to update the DWA to adhere to current Agency policy. The estimated concentrations in drinking water (EDWC) of cyromazine are not expected to exceed

111 μg/L for a daily peak concentration in ground water (acute) and 86 μg/L for the average breakthrough concentration in ground water (chronic) (Table 7 .3.2 ). Cyromazine is expected to breakthrough into ground water between 3 to 7 years.

PRZM

- GW modeling was conducted us ing PRZM

- GW (version 1.0). Application rate, number, and interval are representative of the current maximum label rate for beans. The first pesticide application date was May 1 for all the PRZM

- GW scenarios. The ground water modeling was conducted using a different hydrolysis half

- life (stable) and aerobic soil metabolism half

- life (450 days) than used in the DWA (DP 398026, 2/10/12). As per input parameter guidance, the upper 90 th percent confidence limit ( CL ) of mean aerobic soil metabolism half

- life (147.3 days)

was used because there are three aerobic soil metabolism half

- lives for cyromazine. A hydrolysis half

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

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

. Application rate (lb a.i./A) / Number of applications per

season / Application interval (days)/ Number of seasons per year Peak Concentration (μg/L) Annual Average Concentration (μg/L )

Surface Water (FIRST)

0.125/6/7/1 47.1 15.8

Ground Water (SCI

- GROW)

0.125/6/7/1 1.1 1.1Cyromazine Human Health Risk Assessment DP No. D414914

Page 23 of 58 Table 7 .3 .2. Estimated Drinking Water Concentrations of Cyromazine in Ground Water Source Drinking

Water.

Scenario Peak Chronic Breakthrough Time μg/L Days

WI Corn 90.6 71.3 2581

NC Cotton 38.3 30.4 1089

FL Citrus 111 86.1 1104

MD Corn 94.2 77.8 1089

7.4 Dietary Risk Assessment

7.4.1 Description of Residue Data Used in Dietary Assessment

Tolerance level residues and 100 percent crop treated assumptions were used. DEEM default and empirical processing factors were used to modify the tolerance values. The acute analysis incorporated the peak EDWC of 75.5 ug/L while the chronic analysis incorporated the chronic

EDWC for cy romazine.

7.4.2 Percent Crop Treated Used in Dietary Assessment

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

7.4.3 Acute Dietary Risk Assessment

A conservative acute dietary exposure analysis was performed for the general U.S. population and various population subgroups. Acute dietary risk estimates are not of concern for general population or other population subgroups. The subgroup with the hig hest risk estimate was

children 1

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

7.5%.

7.4.4 Chronic Dietary Risk Assessment

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

and vari ous population subgroups. Chronic dietary risk estimates are not of concern for general population or other population subgroups. The subgroup with the highest risk estimate was

children 1

- 2 years old with a cPAD of 8 .2 %. The cPAD for the general U.S. p opulation was

3. 8 %.

7.4.5 Cancer Dietary Risk Assessment

Cyromazine is classified as a “ Group E

- Evidence of Noncarcinogenicity for humans ” based on the lack of evidence of carcinogenicity in the mouse and rat c ancer studies (HED CPRC

, TXR

No. 0 011384 , 1/6/95 )

. Therefore, a cancer dietary risk assessment was not performed.

7.4.6 Summary TableCyromazine Human Health Risk Assessment DP No. D414914

Page 24 of 58 A dietary assessment was conducted for the registered uses of cyromazine. The dietary risk estimates

are below HED’s level of concern; see Table 7 .4. 6 .1 and 7 .4.6.2

.

Table 7 .4.6.1: Summary of Acute Dietary (Food and Water) Exposure and Risk for Cyromazine

Population Subgroup aPAD (mg/kg/day) Acute Exposure (mg/kg/day) % aPAD General U.S. Population

0.83 0.063037 7.6 All Infants (< 1 year old) 0.054077 6.5

Children 1

- 2 years old 0.148758 18

Children 3

- 5 years old 0.102108 12

Children 6

- 12 years old 0.061079 7.4

Youth 13

- 19 years old 0.041088 5.0

Adults 20

- 49 years old 0.057766 7.0

Adults 50

- 99 years old 0.067807 8.2

Females 13

- 49 years old 0.059258 7.1

Table 7 .4.6.2: Summary of Chronic Dietary (Food and Water) Exposure and Risk for Cyromazine.

Population Subgroup cPAD (mg/kg/day) Chronic Exposure (mg/kg/day) % cPAD General U.S. Population

0.50 0.041309 8.3 All Infants (< 1 year old) 0.032854 6.6

Children 1

- 2 years old 0.021037 4.2

Children 3

- 5 years old 0.013667 2.7

Children 6

- 12 years old 0.017346 3.5

Youth 13

- 19 years old 0.018921 3.8

Adults 20

- 49 years old 0.017374 3.5

Adults 50

- 99 years old 0.041309 8.3

Females 13

- 49 years old 0.032854 6.6

8.0 Residential (Non

- Occupational) Exposure/Risk Characterization

The re are no currently registered residential uses of cyromazine

.

8.1 Residential Bystander Postapplication Inhalation Exposure

Based on the Agency's current practices, a quantitative post

- application inhalation exposure assessment was not performed for cyromazine at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV), and low vapor pressure (3.3 x 10 - 9 mm Hg @ 25 o C )

. However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticide s from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 3 . The Agency is in the process of evaluating the SAP report and may, as appropriate, deve lop policies and procedures to identify the need for and, subsequently, the way to incorporate post

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

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

Page 25 of 58 policies or procedures are developed, the Agency may revisit the need for a quan titative post

application inhalation exposure assessment for cyromazine.

8.2 Spray Drift

Off

- target movement of pesticides can occur via many types of pathways and it is governed by a variety of factors. Sprays that are released and do not deposit in the ap plication area end up off

target and can lead to exposures to those it may directly contact. They can also deposit on surfaces where contact with residues can eventually lead to indirect exposures ( e.g. , children playing on lawns where residues have deposi ted next to treated fields). The potential risk estimates from these residues can be calculated using drift modeling onto 50 feet wide lawns coupled with methods employed for residential risk assessments for turf products. The approach to be used for quan titatively incorporating spray drift into risk assessment is based on a premise of compliant applications which, by definition, should not result in direct exposures to individuals because of existing label language and other regulatory requirements intend ed to prevent them. 4 Direct exposures would include inhalation of the spray plume or being sprayed directly. Rather, the exposures addressed here are thought to occur indirectly through contact with impacted areas, such as residential lawns, when compliant applications are conducted. Given this premise, exposures for children (1 to 2 years old) and adults who have contact with turf where residues are assumed to have deposited via spray drift thus resulting in an indirect exposure are the focus of this analysis analogous to how exposures to turf products are

considered in risk assessment.

In order to evaluate the drift potential and associated risks, an approach based on drift modeling coupled with techniques used to evaluate residential uses of pesticides was utilized. E ssentially, a residential turf assessment based on exposure to deposited residues has been completed to address drift from the agricultural applications of cyromazine

. In the spray drift scenario, the deposited residue value was determined based on the am ount of spray drift that may occur at varying distances from the edge of the treated field using the AgDrift ( v2.1.1) model and the Residential Exposure Assessment Standard Operating Procedures Addenda 1: Consideration of Spray Drift Policy

. Once the depos ited residue values were determined, the remainder of the spray drift assessment was based on the algorithms and input values specified in the recently revised (2012) Standard Operating Procedures For Residential Risk Assessment (SOPs)

.

A screening appro ach was developed based on the use of the AgDrift model in situations where specific label guidance that defines application parameters is not available. 5 AgDrift is appropriate for use only when applications are made by aircraft, airblast orchard sprayers , and groundboom sprayers. When AgDrift was developed, a series of screening values (i.e., the Tier 1 option) were incorporated into the model and represent each equipment type and use under varied conditions. The screening options specifically recommend ed in this methodology were selected because they are plausible and represent a reasonable upper bound level of drift for common application methods in agriculture. These screening options are consistent with how spray drift is considered in a number of e cological risk assessments and in the process used to develop drinking water concentrations used for risk assessment. In all cases, each scenario is to

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

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

Page 26 of 58 be evaluated unless it is not plausible based on the anticipated use pattern (e.g., herbicides are

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

8.2.1 Children (1<2 yrs old) Hand

- to

- Mouth Risk Estimates From Lawn Deposition Adjacent to Applications

The spray drift risk estimates are based o n an estimated deposited residue concentration as a result of the screening level agricultural application scenarios. Cyromazine is used on Brassica (cole) leafy vegetables group 5 ( i.e., abyssinian cabbage; bok choy; broccoli; Brussels sprouts)

and turni p greens; and can be applied via groundboom, and aerial equipment. The recommended drift scenario screening level options are listed below:

 Groundboom applications are based on the AgDrift option for high boom height and using very fine to fine spray ty pe using the 90th percentile results.

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

.

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

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

selected from a 2 Generation Reproductive Study (MRID 00103197 ) co

- critical with a Chronic Carcinogenicity Study (MRID 00103202, 00115735 ) in the rat . The NOAEL identified was 50 mg/kg/day.

The total applicable Level of Concern is 100 so MOEs < 100 would be of concern. Children’s (1<2 year old) incidental oral risk estimates from indirect exposure to cyromazine related to spray drift did not excee d HED’s level of concern (i.e., MOEs ≥ 100 ) at the edge of the field for

both groundboom and aerial applications Results for the drift scenarios of the highest application rate assessed are presented in Table 8.2 .1 below

.

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

Equipment Spray Type/ Nozzle Configuration App.Rate (lb ai/A) TTR t (ug/cm 2 ) At Edge

HtM MOE

Aerial Fine to Medium
0.125 0.014 100,000

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

Page 27 of 58 9.0 Aggregate Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate pesticide exposures and risks from dietary (food and water) and residential (dermal, inhalation, and/or incidental oral) sources. When aggregating exposures and risks from these sources, HED con siders the route and duration of exposure as well as the toxicological effects for each route. Aggregate risk assessments evaluate the combined risk from dietary exposure (food and water) and any non

- occupational (residential) uses. There are currently n o registered residential uses associated with cyromazine; therefore, a residential/non

- occupational exposure assessment is not required. As a result, the cyromazine aggregate risk assessment includes only dietary exposure (food and water). The

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

level of concern (see Sections 5 .4. 3 and 5 .4. 4)

.

Cyromazine was not carcinogenic in mice or rats following long

- term dietary administration and

was classified as a “ Group E

- Evidence of Noncarcinogenicity for humans ”

. Therefore, a cancer aggregate risk assessment is not required.

10.0 Cumulative Exposure/Risk Characterization

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

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

to cyromazine and any other substances and cyromazine does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, th erefore,

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 c hemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pest icides/cumulative/.

11.0 Occupational Exposure/Risk Characterization

Occupational exposure to cyromazine working with Trigard ( EPA Reg. No. 100

- 654 ) and Neporex 2SG (EPA Reg. No. 70585

- 7) have been previously assessed ( D284994, August 27, 2002; D285851, January 30, 2003). More recently, a registration review scoping document for human health assessments (D 337096 , March 21, 2007) and a h uman h ealth r isk a ssessment for a

p ropos ed new use on s ucculent beans ( D358720, D359607, August 20, 2009) indicated that occupational exposure and risk estimates were not of concern at the maximum single application

rates for the assessed products

. However, due to a revision of the standard input values recommended for use in predicting handler exposure such as “unit expos ures” and body weights ; every registered use associated with cyromazine was re

- assessed for the purposes of this action.

11.1 Short

- /Intermediate

- Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide applicat ion process. HED believes that there are distinct job functions or tasks related toCyromazine Human Health Risk Assessment DP No. D414914

Page 28 of 58 applications and exposures can vary depending on the specifics of each task. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can potentially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment developed for occupational handlers is based on the following scenarios based on their different product formulations :

Wettable Powder Formulations Trigard (75% ai) :

• Mixing/l oading w ettable p owder packaged in w ater

- s oluble p ackets for a erial a pplication (engineering controls);

• mixing/l oading w ettable p owder packaged in w ater

- s oluble p ackets for g roundboom

a pplication (engineering controls);

• applying sprays with fixed

- wing aircraft (engineering controls);

• applying sprays with open cab groundboom s prayer ; and

• flagging sprays for a erial o perati ons.

Citation (75% ai) :

• M ix ing /load ing /appl ying wettable powder packaged in water

- soluble packets with a backpack sprayer, a manually

- pressurized handwand and a mechanically pressurized handgun sprayer.

Liquid Formulations Armor (5% ai)

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

• Mixing/loading l iquids ; and

• mixer/loader/applicator with a backpack sprayer, a manually

- pressurized handwand and a mechanically pressurized handgun sprayer.

Granular Formulations

Solitude IGR (2 .12 %) :

• Mixing/loading g ranules for feed

- through fly control.

Larvadex and Flyzine 1% Premix :

• Mixing/loading g ra nules for feed

- through fly control

.

Neporex 2SG (2%) :

• Loading/a pplying granules with a b elly g rinder ;

• applying granules by h and ; and

• mixer/loader/applicator with a backpack sprayer, a manually

- pressurized handwand and a mechanically pressurized handgun sprayer.

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

Page 29 of 58 A series of assumptions and exposure factors served as the basis for completing the occupational handler risk assessments. Each assumption and factor is detailed below on an individual basis.

Application Rate : Application rates were based on the registered labels (see Table 5

. 3 ).

Unit Exposures: It is the policy of HED to use the best available data to assess handler exposure. Sources of generic handler data, used as surrogate data in th e absence of chemical

- specific data, include PHED 1.1, the AHETF database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), an d subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessment, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Sur rogate Reference Table 6 ”, which, along with additional information on HED policy on use of surrogate data, including descriptions of the various sources, can be found at the Agency website 7

.

Area Treated or Amount Handled : Applicable assumptions for dai ly areas treated and amounts handled were taken from the HED’s ExpoSAC Policy #9: “Standard Values for Daily Acres Treated in Agriculture”, which was revised on July 5, 2000. Some daily areas treated and

amounts handled were defined for each handler scena rio by assuming an amount that can be reasonably treated by an individual in a single day. Area treated and amounts handled assumed

are as follows:

Wettable Powder Formulations

• 350 acres/day for mixing/loading and applying wettable powder packaged in wat er

soluble packets for aerial application

.

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

- soluble packets for groundboom application

.

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

• 40 gallons/ day for mixing/loading/applying with a backpack sprayer and a manually

pressurized handwand

.

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

- pressurized handgun

sprayer.

Liquid Formulations

• 1 A /day for mixing/loading liquids

.

• 43,560 sq ft/day for mixing/loading/applying with a backpack sprayer, a manually

pressurized handwand, and a mechanically pressurized handgun sprayer.

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

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

.

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

- pressurized handwand and a mechanically pressurized handgun sprayer to mushroom compost wharves [p ersonal

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

. Granular Formulations

6 Available: http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf

7 Available: http://www.epa.gov/pesticides/science/handler

- exposure

- data.htmlCyromazine Human Health Risk Assessment DP No. D414914

Page 30 of 58 • 1,000 horse s /day for mixing/loading granules for feed

- through fly control

.

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

• 1 000 sq ft

/day for applying granules by hand;

• 40 gal/day for mixing/loading/applying with a backpack sprayer and a manually

pressurized handwand; and

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

sprayer.

Exposure Duration : HED classifies exposures from 1 to 30 day s as short

- term and exposures 30 days to six months as intermediate

- term. Exposure duration is determined by many things, including the exposed population, the use site, the pest pressure triggering the use of the pesticide, and the cultural practices sur rounding that use site. For most agricultural uses, it is reasonable to believe that occupational handlers will not apply the same chemical every day for

more than a one

- month time frame; however, there may be a large agribusiness and/or commercial applic ators who may apply a product over a period of weeks (e.g., completing multiple applications for multiple clients within a region).

Based on use patterns, short

- and intermediate

- term exposures were expected but since no dermal endpoint was identified and the inhalation endpoint selected is the same for short

- and

intermediate

- term exposure, risk estimate quantification is inclusive of both durations. Chronic exposures (i.e., greater than 6 months) are not expected.

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

baseline attire defined as a single layer of clothing consisting of a long sleeved shirt, long pants, shoes plus socks, no protective gloves, and no respirator . Current registered labels recommend

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

Summary of Occupational Handler Non

- Cancer Exposure and Risk Estimates

Table 11.1. presents the exposure/risks for short a nd i ntermediate

- term inhalation exposures at

baseline and with engineering controls (for aerial equipment). All of the risk estimates are below HED’s level of concern (LOC) at the lowest mitigation level (i.e., baseline) and, therefore, are

not of concern to the Agency (i.e. , MOEs ≥ 100 for short

- and intermediate

- term exposure
durations )

.Cyromazine Human Health Risk Assessment DP No. D414914

Page 31 of 58 Table 11.1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Cyromazine

. All estimates are at various levels of mitigation ( baseline, respirators, and water

- soluble packages ).

Exposure Scenario Crop or Target Inhalation

Unit Exposure 1
(μ g/lb ai) Maximum

Application

Rate 2 Amount

Treated Daily 3 Inhalation Route of

Exposure

Mitigation

Level Dose 4
(mg/kg/day) MOE 5

(LOC = 100)

Mixer/Load er

Mixing/Loading Wettable Powder packaged in

Water

- Soluble Packets for Aerial Application Brassica (cole) leafy vegetables group 5 (including: abyssinian cabbage; bok choy; broccoli; broccoli, Chinese; broccoli raab ; Brussels sprouts; cabbage; cabbage, Chinese; cabbage Chinese mustard; cabbage, seakale; cauliflower; cavalo broccolo; collards; Hanover salad; kale, common; kohlrabi; mustard, wild; mustard, Chinese; mustard greens; mustard spinach; and rape greens) and turnip greens 0. 24 (Eng.

Control s ) 0.125

(lbs ai/A) 350

(A/day) 0.00013 61,000 e

Mixing/Loading Wettable Powder packaged in

Water

- Soluble Packets for Groundboom Application 80 (A/day) 0.000030 270,000 e

Mixing/Loading Liquids Sciard fly control in mushrooms 0. 219 (Baseline) 0.00014

(lbs ai/sq ft) 576,000 a

(sq ft) 0.00022 21,000 f

For fly control in and around chicken layer and breeder operations only 3.75 (lb ai/A) 1

(A) 0.0000103 450,000 f

Mixing/Loading Granules Feedt hrough application for f ly c ontrol in and around horses, horse barns, horse stables and paddocks, horse race tracks 1. 7 (Baseline) 0.00066

(lb ai/horse) 1,000

(horses/day) b 0.000014 570,000 e

Feedthrough application for the control of fly larvae in poultry manure. 0.010 (lb ai/ton feed) 100

(tons feed/day) c 0.000021 370,000 e

Applicator

Applying Sprays with

Fixed

- wing Aircraft Brassica (cole) leafy vegetables group 5 (including: abyssinian cabbage; bok choy; broccoli; broccoli, Chinese; broccoli raab; Brussels sprouts; cabbage; cabbage, Chinese; cabbage Chinese mustard; cabbage, seakale; cauliflower; cavalo broccolo; collards; Hanover salad; kale, common; kohlrabi; mustard, wild; mustard, Chinese; mustar d greens; mustard spinach; and rape greens) and turnip greens 0.0049 (Eng.

Control s )

0.125

(lbs ai/A) 350

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

Applying Sprays with Open Cab Groundboom Sprayer 0. 34 (Baseline) 80 (A/day) 0.000043 54,000 gCyromazine Human Health Risk Assessment DP No. D414914

Page 32 of 58 Table 11.1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Cyromazine

. All estimates are at various levels of mitigation ( baseline, respirators, and water

- soluble packages ).

Exposure Scenario Crop or Target Inhalation

Unit Exposure 1
(μ g/lb ai) Maximum

Application

Rate 2 Amount

Treated Daily 3 Inhalation Route of

Exposure

Mitigation

Level Dose 4
(mg/kg/day) MOE 5

(LOC = 100) Loading/Applying Granules, Belly Grinder Control of fly larvae in cattle, hog, and poultry operations 62 (Baseline) 4.36

(lb ai/A) 1

(A/day) 0.0034 2,400 e

Applicator, Granules by Hand (No Respirator) 470 (Baseline) 0.02 lb ai /200

ft 2 1,000 sq. ft. 0.00059 1 4,000 e

Flagger

Flagging (Sprays) for Aerial Operations Brassica (cole) leafy vegetables group 5 (including: abyssinian cabbage; bok choy; broccoli; broccoli, Chinese; broccoli raab; Brussels sprouts; cabbage; cabbage, Chinese; cabbage Chinese mustard; cabbage, s eakale; cauliflower; cavalo broccolo; collards; Hanover salad; kale, common; kohlrabi; mustard, wild; mustard, Chinese; mustard greens; mustard spinach; and rape greens) and turnip greens 0. 35 (Baseline) 0.125

(lbs ai/A) 350

(A/day) 0.00019 42,000 e

Mixer/Loader/Applicator
Manually

- pressurized

Handwand For control of selected insects, including d ipterous

leafminers, and fungus gnats in landscape ornamentals; container grown ornamentals; greenhouse, lath and shadehouse grown ornamental bedding plants, and ornamental crops; and interiorscapes; and shore flies, only in greenhouse ornamental crops and interiorscapes 30 (Baseline) 0.00125

( lb ai/gal )

Wettable

Powder

Formulation 40

(gal/day) 0.000019 420,000 e

Backpack Sprayer 140 (Baseline) 40 (gal/day) 0.000088 53 ,000 f

Mechanically

- pressurized Handgun Sprayer 120 (Baseline) 1,000 (gal/day) 0.0019 4,200 e

Manually

- pressurized

Handwand Sciard fly control in mushrooms 30 (Baseline) 1.4x10 - 4

(lb ai/sq. ft.) Liquid

Formulation 43,560 sq. ft.

(1 acre)/day d 0.0023 3,500 e

Mechanically pressurized Handgun Sprayer 120 (Baseline) 0.00 92 870 e

Backpack Sprayer / Manually

pressurized Handwand fly control in and around chicken layer and breeder operations 30 (Baseline) 8.6x10 - 5

(lb ai/sq ft) Liquid

Formulation 43,560 sq. ft.

(1 acre)/day 0.0014 5,700 e

Mechanically pressurized Handgun Sprayer 79 (Baseline) 0.0037 2,200 eCyromazine Human Health Risk Assessment DP No. D414914

Page 33 of 58 Table 11.1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Cyromazine

. All estimates are at various levels of mitigation ( baseline, respirators, and water

- soluble packages ).

Exposure Scenario Crop or Target Inhalation

Unit Exposure 1
(μ g/lb ai) Maximum

Application

Rate 2 Amount

Treated Daily 3 Inhalation Route of

Exposure

Mitigation

Level Dose 4
(mg/kg/day) MOE 5

(LOC = 100) Backpack Sprayer / Manually

pressurized Handwand Control of fly larvae in cattle, hog, and poultry operations 30 (Baseline) 0.020

(lb ai/gal) Dry Flowable

Formulation 40

(gal/day) 0.00030 27 ,000 e

Mechanically pressurized Handgun Sprayer 79 (Baseline) 1,000 (gal/day) 0.020 400 e

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

2. Based on registered label.

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

.

a. F rom personal communications with the American Mushroom Institute (I. Nieves, 11/10/2011). The vast majority of cyromazine is applied as the compost is being produced on the wharf. These compost wharves vary in size from a basketball court (4,700 sq ft) to several football fields (1 football field is 57,6 00 sq ft). 576,000 square feet (i.e., 10 football fields) was assessed as a high

- end assumption.

b. Lacking specific data regarding how many horses a single worker may treat per day, a high

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

c. Lacking specific data regarding how many tons of chicken fee d a single worker may handle per day, a high

- end assumption of 100 tons was assessed; assuming 20 tons of feed per load truck x 5 trucks for large operations.

d. From personal communications with the American Mushroom Institute, an employee can apply the pest icide in the mushroom room when the casing layer is added. One employee would treat a room of 8,000 sq ft once per crop. HED does not have information with respect to the number of rooms an employee mig ht treat in one day, therefore, the standard HED ass umption of 1 acre (43,560 sq ft) was assessed. This is equivalent to 5

– 6 rooms of 8000 square feet treated per day).

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

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

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

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

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

Page 34 of 58 11.1.1 Bulb Onion Seed Treatment Occupational Handler s (Trigard OMC; EPA Reg. No.

100

- 790)

Based upon the seed treatment use, occupational handler exposure is expected for individuals involved in commercial seed treatment and planting

. The registered label specifies that this use

is permitted only to licensed commercial seed treatment companies. Therefore, on

- farm

treatment was not assessed. Moreover, according to ExpoSAC policy 15.1: Standard Operating Procedures (SOPs) for a mount of c ommercial s eed t reated p er d ay , HED assumes tha t
commercial seed treatment risk assessment is protective of on

- farm seed treatment involving

small

- scale commercial equipment.

Commercial seed treatment equipment is designed to apply accurately measured quantities of pesticides to a given weight or qu antity of seed. For bulb onions , potential occupational exposure scenarios from the use of cyromazine as a commercial seed treatment include:

 Loading/applying a wettable powder formulation;

 Bagging treated seed;

 Sewing bags;

 “ Multiple activities ” ; and

 P lanting treated seed.

Typically for large

- scale commercial seed treatments, handlers perform only those specific individual tasks listed above; however, it is assumed that handlers also may perform multiple activities throughout the day. As a result a “m ultiple activities” scenario (i.e., where one handler performs all seed treatment tasks such as loading/applying, sewing, bagging, cleaning, calibration, repair, forklift driver, etc.) is included.

It is the policy of HED to use the best available data to assess handler exposure. U nit exposure data from PHED and HED ExpoSAC Policy 14: SOP for Seed Treatment were used in this assessment. Unit exposure data for mixing/loading wettable powder formulations from PHED was used as a surrogate for the loader/a pplicator liquid formulation seed treatment scenarios,

since no seed

- treatment

- specific unit exposure values are available for wettable powder

formulations.

For purposes of performing commercial seed treatment assessments, HED used ExpoSAC Policy 15.1 to estimate amount of seeds treated per day. The amount assessed for bulb onions was 3,000 seeds treated per d ay.

Commercial Seed Treatment Exposure and Ris k Estimates

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

concern (i.e., MOEs ≥ 100) at baseline attire (i.e., single layer of clothing and no respirator) and therefore not of concern to the Agency, except for the loader/applicator scenario which resulted

in an MOE of 99.

The seed treatment loader/applicator MOE of 99 is based on highly conservative assumptions. The amount of seed treated is assumed to be 3,000 seeds per day. However, according to theCyromazine Human Health Risk Assessment DP No. D414914

Page 35 of 58 USDA NASS s urvey for 2012, the amount planted for onions was approximately 155,000 acres. Assuming that each acre is planted with 2 to 150 pounds of seed per acre (depending on variety), this would indicate that the US is treating a maximum possible value of 77,500 pounds of seed per year (J. Becker, Acres Planted per Day and Seeding Rates of Crops Grown in the United States, 03/24/2011).

In the US, there are at least six facilities treating green onion seeds, and at least nine facilities treating bulb onion seeds (E. Kennedy, AHETF Report Number AH 189, Small Seeded Vegetable Use and Usage Report, 11/22/2010). To be conservative, if we assume that only six facilities are treating 100% of the onion market, then each facility would treat an average of ~13,000 pounds of seed annually. If each facility treated 3,000 pounds of seed per day, then it would only take an average of four days of operation to treat the entire annual US supply of

onion seeds.

Furthermore, seed treatments vary by region and all small seeded vegetable seeds are custom treated based on individual customer requests (E. Kennedy, AHETF Report Number AH 189, Small Seeded Vegetable Use and Usage Report, 11/22/2010).

Table 11 .1.1.1 presents a summary of the short

- and intermediate

- term occupational handler risk

estimate s for commercial seed treatment.

Table 11 .1.1.1. Occupational Handler Exposures and Risks for Treating Onion Seeds

Type Exposure scenario Application

Rate 1

(lb ai/lb seed) Amount

Treated/ Day 2

(lbs seed/day) Unit

Exposure 3,4
(mg/lb ai) Daily Dose 5

(mg/kg/day) Short/Int

Term

Inhalation

MOE 6,7

(LOC = 100)

Commercial Loader/Applicator (baseline)

0.050 3,000 0.043 0.081 99

Loader/Applicator ( PF5 Respirator ) 0.0086 0.0160 290

Sewer (baseline) 0.00023 0.00043 11,000
Bagger (baseline) 0.00016 0.00030 15,000 Multiple Activities (baseline) 0.0016 0.0030 1,500

1. Application Rates = maximum application rate based on Trigard OMC label (EPA Reg. No. 100

- 790)

. 2. Assumption for pounds of small vegetable seeds treated per day from Policy #15.1 was used for all vegetable seeds on label wh ich included: bulb vegetables.

3. Unit Exposures from HED Science Advisory Council for Exposure Policy #14 ; Bas eline Inhalation: No r espirator. PF5 Respirator: HED assumes an 80% protection factor is provided by a NIOSH

- approved quarter

- face, cup

- style respirator (it is similar to the paint masks painters often wear).

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

5. Daily Dose (mg/kg/day) = daily unit exposure (mg/ lb ai) x application rate (lb ai/lb seed) x amount treated or planted (lb seed/day) x absorption factor (100 %) / body weight (80 kg adult);

6. Short

- and Intermedia te

- term Inhalation MOE = HE D based on 16.7 L/min breathing rate (4.59 mg/kg/day) / inhalation daily dose (mg/ kg/ day).

Level of concern = 100.

7. Loader/Applicator scenarios Short

- and Intermediate

- term Inhalation MOE = HE D based on 29 L/min breathing rate (7.98 mg/kg/day) / inhalation daily dose (mg/ kg/ day). Level of concern = 100

Seed Planting (Secondary Handler Exposure) Planting treated seed consists of the grower purchasing bags of treated seed, placing the seed in the hopper, and applying seed to fields. This is considered a secondary handler exposure

scenario.Cyromazine Human Health Risk Assessment DP No. D414914

Page 36 of 58 Risk from planting treated seeds with cyromazine resulted in MOEs that do not exceed HED's

level of concern when ba seline attire is worn. Table 11 .1.1.2 presents the short

- and

intermediate

- term risk estimate s for planters.

Table 11 .1.1.2. Short

- and Intermediate

- Term Occupational Handler Exposures and Risks for Planting

Onion Seeds

Type Exposure

scenario Application

Rate 1

(lb ai/lb seed) Amount

Treated /

D ay 2
(lbs seed/day) Unit

Exposure 3
(mg/lb ai) Daily Dose 4

(mg/kg/day) Inhalation

MOE 5

(LOC = 100) Mitigation Level : Baseline

Planters Seed

Planter 0.050 320 0.0034 0.00067 6,800

1. Application Rates = maximum application rate based on Trigard OMC label (EPA Reg. No. 100

- 790) ; 2. HED default for lb of seed treated per day from HED Science Advisory Council for Exposure Policy # 15;

3. Unit Exposures from HED Science Advisory Council for Exposure Policy #14 ; Bas eline Inhalation: No respirator;

4. Daily Dose (mg/kg/day) = daily unit exposure (mg/ lb ai) x application rate (lb ai/lb seed) x amount treated or planted (lb seed/day) x absorption factor (100 %) / body weight (80 kg adult);

5. Short

- and Intermediate

- term Inhalation MOE = HEC based on 16.7 L/min breathing rate (4.59 mg/kg/day) / inhalation daily dose (mg/ kg/ day). Level of concern = 100.

11.2 Short

- /Intermediate

- /Long

- Term/Cancer (if needed) Post

- Application Risk

HED uses the term post

- application to describe exposures that occur when ind ividuals are present in an environment that has been previously treated with a pesticide (also referred to as re

entry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related t o crop production, such as scouting for pests or harvesting. Post

- application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application,

and the c hemical’s degradation properties. In addition, the timing of pesticide applications, relative to harvest activities, can greatly reduce the potential for post

- application exposure.

11.2.1 Dermal Postapplication Risk

No hazard was identified via the dermal rout e of exposure and therefore quantification of risk via this route of exposure is not required.

11.2.2 Inhalation Postapplication Risk

Inhalation Post

- Application Risk Based on the Agency's current practices, a quantitative occupational post

- application inhala tion

exposure assessment was not performed for cyromazine at this time primarily because of the acute inhalation toxicity (Toxicity Category III), and the low vapor pressure (1.3 x 10 - 9 mm Hg)

. However, there are multiple potential sources of post

- applica tion inhalation exposure to individuals performing post

- application activities in previously treated fields. These potential sources include volatilization of pesticides and re

- suspension of dusts and/or particulates that contain pesticides. The Agency s ought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009. The Agency received the SAP’s final report on March 2, 2010 (htt p://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html). The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposureCyromazine Human Health Risk Assessment DP No. D414914

Page 37 of 58 data generated by the Agricultural Reentry Task Force and may, as appropriat e, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational

post

- application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may r evisit the need for a quantitative occupational

post

- application inhalation exposure assessment for cyromazine.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was p erformed for agricultural occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

- application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post

- application inhalation exposure scenarios.

Furthermore, with respect to the greenhouse uses of cyromazine, the Worker Protection Standard for Agricultural Pesticides contains requirements fo r protecting workers from inhalation exposures during and after greenhouse applications through the use of ventilation requirements. [40 CFR 170.110, (3) (Restrictions associated with pesticide applications)].

Bulb onion Seed Treatment Inhalation Post

- App lication Exposure/Risk

A post

- application inhalation exposure assessment is not required as exposure is expected to be negligible. Seed treatment assessments provide quantitative inhalation exposure assessments for seed treaters and secondary handlers (i.e.

, planters). It is expected that these exposure estimates would be protective of most post

- application inhalation exposure scenarios.

Restricted Entry Interval (REI) The REI of 12 hours specified on the registered labels ( 42750

- 222, 100

- 667, 100

- 654, and 100

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

Bulb Onion Seed Treatment Restricted Entry Interval (REI)

The Worker Protection Standard (WPS) allows workers to enter treated areas without restriction if there will be no worker contact with the treated seeds in the soil or planting media. For purposes of seed treatment (once the seeds are planted), workers can enter during the restricted entry interval ( REI )

, provided they do not contact the soil/media subsurface that contains the

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

Page 38 of 58 12.0 References

J erry Stokes, 4/15/98

, D245214 , Cyromazine. Conclusions of the Metabolism Assessment Review Committee at Meeting of 11/04/97.

R

. Daiss & T. Morton

, 1 / 31 /201 3 , D 398364

, Cyromazine. Reregistration Review of Cyromazine on a Variety of Commodities. Summary of Analytical Chemistry and Residue Data.

T. Morton, 10/30/2013, D414945, Cyromazine

– Acute Chronic Dietary and Drinking Water Exposure and Risk Assessment for Registration Review.

Ivan Nieves

, 1 2 / 03 /2013, D 398369

, Cyromazine : Occupational and Residential Exposure and Risk Assessment for Registration Review.

Tiffany Dowen, James Het rick, & Rosanna Louie

- Juzwiak, 2/10/2012, D398026, Drinking Water Assessment for All Currently Registered Uses of Cyromazine.

Uma Habiba, October 29, 2013, T XR 0056806

. Cyromazine: Summary of Hazard and Science Policy Council (HASPOC) Meetings: Recommendations on the need for an immunotoxicity study.

Kristin Rury

, June 26, 2013 , TXR 0056682

, Cyromazine : Summary of Hazard and Science Policy Council ( HASPOC ) Meeting of: Recommendat ions on data requirements for a subchronic neurotoxicity study for cyromazine

.

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

Page 39 of 58 A ppendix A

. Toxicology Profile and Executive Summaries

A.1. Cyromazine Toxicology Data Requirements : The toxicology data requirements (40 CFR 158.340) for food use are presented in Table A. 1 .1 . Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Table A. 1. 1. Cyromazine Guideline Data Requirements

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

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

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

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

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

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

................................ ...................... yes

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

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

................................ ......... 870.3200 21

- Day Dermal

................................ .............................. 870.3250 90

- Day Dermal

................................ .............................. 870.3465 21/ 90

- Day Inhalation

................................ ..................... yes

yes

yes

no

yes yes

yes

yes

- yes

870.3700a Developmental Toxicity (rodent)

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

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

................................ ................................ . yes

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

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

................................ ........ 870.4200a Carcinogenicity (rat)

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

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

................................ ............... yes *

yes

yes *

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

..................... 870.5300 Mutagenicity

— Gene Mutation

- mammalian

................ 870.5375 Mutagenicity

— Structural Chromosomal Aberrations

... 870.5900 Mutagenicity

— Other Genotoxic Effects

....................... yes

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen)

................................ ..... 870.6100b 90

- Day Neurotoxicity (hen)

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

....................... 870.6200b 90

- Day Neuro. Screening Battery (rat)

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

................................ .............................. no

no

yes

yes **

no -

- yes

-

no

870.7485 General Metabolism

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

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

................................ ............................. yes

yes

yes *** yes

yes

-

* Guideline 870.4300 satisfies guideline 870.4100a and 870.4200a.

** 90

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

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

Page 40 of 58 A.2 Toxicity Profile s

Table A.2.1. Acute Toxicity of Cyromazine.

GLN Study Type MRID #(s) Results Toxicity Category

81

- 1 Acute Oral 00082836 LD50 = > 3387 mg/kg III

81

- 2 Acute Dermal 00082839 LD50 = > 3100 g/kg III

81

- 3 Acute Inhalation 43799901 LC50 > 0.744 mg/L IV

81

- 4 Primary Eye Irritation

- rabbits 00082841 No irritation. IV

81

- 5 Primary Skin Irritation

- rabbits 00082842 Mild irritant. IV

81

- 6 Dermal Sensitization 00082843 Non

- sensitizing N/A

Table A.2. 2 Subchronic, Chronic and Other Toxicity Profile of Cyromazine

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3150 Subchronic

Dietary

– Rat 00135433 (1979)

Acceptable/Guideline 0, 30, 300, 1000 and 3000 ppm (0, 3, 30, 100, and 300 mg/kg/day) NOAEL = 1000 ppm (100 mg/kg/day)

LOAEL = 3000 ppm (300 mg/kg/day) based on decreased body weight (↓12%) in females.

There were no effects on males

870.3150 Subchronic

Dietary Dog 00135432 (1979)

Acceptable/Guideline 0, 30, 300, 1000 or 3000 ppm (0, 0.75, 7.5, 25 and 75 mg/kg/day) NOAEL = 3000 ppm (75 mg/kg/day, HDT).

LOAEL not observed. Reported relative organ weight changes and hematological parameters are within biological variation and not significant.

870.3200 21

- Day Dermal

-

Rabbit 44060901 (1992)

Acceptable/Guideline

0, 50, 200 & 2000 mg/kg/day Systemic Toxicity

NOAEL = 2000 mg/kg/day

LOAEL > 2 000 mg/kg/day Dermal Toxicity

No dermal irritation was noted

870.3200 21

- Day Dermal

-

Rabbit 44060902 (1984)

Acceptable/Guideline

0 & 2010 mg/kg/day Systemic Toxicity

NOAEL = 2000 mg/kg/day

LOAEL > 2 000 mg/kg/day Dermal Toxicity

No dermal irritation was noted

870.3465 21

- Day Inhalation

- Rat 47940804 (1988)

Acceptable/Guideline Nominal 0.055, 0.210, or 0.710 mg/L NOAEL not established

LOAEL = 0.055 mg/L/day based on impairment of the general condition with the symptoms of piloerection, dyspnea, hunched posture, and reduced spontaneous activity.

870.3700a Gavage

Developmental Toxicity

- Rat 00027488 (1979)

Acceptable/Guideline 0, 100, 300 and 600 mg/kg/day Maternal NOAEL = 100 mg/kg/day

Maternal LOAEL = 300 mg/kg/day, based on clinical signs (red or clear nasal discharge at 1.5 hours after dosing) and slight reduction in body weight gain (days 0

- 20). Developmental NOAEL = 300 mg/kg/day Developmental LOAEL = 600 mg/kg/day (HDT), based on increased incidence of minor

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

Page 41 of 58 Table A.2. 2 Subchronic, Chronic and Other Toxicity Profile of Cyromazine

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.3700b Gavage

Developmental Toxicity

- Rabbit 00150471 (1985)

Acceptable/Guideline

0, 10, 30, and 60 mg/kg/day Maternal NOAEL = 6 0 mg/kg/day, HDT

Maternal LOAEL not observed.

Developmental NOAEL ≥ 6 0 mg/kg/day (HDT) Developmental LOAEL not established

870.3800 Reproductive

Toxicity 00103197 (1981)

Acceptable/Guideline

0, 30, 1000 and 3000 ppm (0, 1.5, 50, and 150 mg/kg/day based on

default conversion factor 1ppm =0.05 mg/kg)

Based on actual compound consumption 1000 ppm = 70 mg/kg/day F

0 ♂
54.6 mg/kg/day F 1 ♂
84.5 mg/kg/day F 0 ♀ 70.5 mg/kg/day F 1 ♀ Parental NOAEL = 1000 ppm (50 mg/kg/day).

Parental LOAEL = 3000 ppm (150 mg/kg/day) based on decreased body weights (↓27%) that were associated with decreased food efficiency. Reproductive NOAEL ≥ 3000 ppm (150 mg/kg/day). Reproductive LOAEL not established Offspring NOAEL = 1000 ppm (50 mg/kg/day). Offspring LOAEL = 3000 ppm ( 150 mg/kg/day), based on decreased body weights at birth and through weaning (↓8

- 22%)

.

870.4100b 6

- month Toxicity

Dietary

- Dog 00103193 (1982)

Acceptable/Guideline 0, 30, 300 or 3000 ppm (0, 0.75, 7.5 and 75 mg/kg/day) NOAEL = 3000 ppm (75 mg/kg/day).

LOAEL > 3000 ppm (75 mg/kg/day) Reported relative organ weight changes and hematological parameters within biological variation and not significant.

870.4300 Combine Chronic/

Carcinogenicity

Rat 00103202, 00115735

(1982) Acceptable/Guideline 0, 30, 300 and 3000 ppm (0, 1.5, 15, and 150 mg/kg/day) NOAEL = 300 ppm (15 mg/kg/day).

LOAEL = 3000 ppm (150 mg/kg/day) based on decreased body weight (↓20% for males and ↓29% for females), body weight gains (↓23% for males and ↓33% for females) accompa nied with lower food consumption (10

- 15%), compared to controls.

There is no evidence of carcinogenicity

.

870.4200 Carcinogenicity

Mouse 00115736 (1982)

Acceptable/Guideline 0, 50, 1000, and 3000 ppm (0, 7.5, 150, and 450 mg/kg/day) NOAEL (♂)= 1000 ppm (150 mg/kg/day). LOAEL (♂)= 3 000 ppm (450 mg/kg/day) based on decreased body weight (↓9.6% in males, ↓6% in females) at 104 weeks. NOAEL (♀)= 3000 ppm (450 mg/kg/day, HDT). LOAEL (♀)> 3000 ppm (HDT) There is no evidence of carcinogenicity

.

870.5100 Bacterial Reverse

Gene Mutation Test (Ames Assay)

TXR No. 0002687 0089923 (1978)

limited/Guideline 25, 75, 255, 675 and 2025 μg/0.1 mL plate in DMSO, ± S

- 9. Negative results for point mutations in TA1537, TA1537, TA98, and TA100 with and

without activation. This study was limited due to the use of low

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

Page 42 of 58 Table A.2. 2 Subchronic, Chronic and Other Toxicity Profile of Cyromazine

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.5300 In Vitro

Cytogenetic Assay Measuring

Chromosomal

Aberration Frequencies in

Chinese Hamster Ovary (CHO)

Cells

TXR No. 0002664 00103199 (1980)

Minimum acceptable/Guideline

Lavardex tech. 98.9%

pure 2000, 4000, and 8000 mg/kg in 20 mL/kg 0.7%

CMC solution Negative mutagen

Mutagenic.

- Dominant lethal test species:

Mouse

TXR No. 0002687 00103198 (1981)

limited/Guideline 226 and 678 mg/kg in

PEG400 vehicle (0.2 mL/log of body weight) Negative mutagen. This study was limited since the mating period

was too short.

870.6200a Acute

Neurotoxicity

- Rats 49109701 (2013)

250, 1000, or 2000 mg/kg

bw NOAEL not established

LOAEL = 250 mg/kg BW, the lowest dose

tested based on the decreased motor activity (mean cumulative ambulatory LMA counts ↓44%) in males at the time of peak effect on Day 0, and decreased food consumption (p<.01, ↓17.4%) on Day 1

870.6200b Subchronic

Neurotoxicity

- Rats Waived (HASPOC TXR 0056682)

870.7485 Metabolism

- Rat 41442101 (1989) Acceptable/Guideline

3 and 300 mg/kg Cyromazine was well absorbed after oral administration. Excretion was rapid (When?) at the lower dose (3 mg/kg), but an apparent delay in excretion occurred at the high dose (300 mg/kg). Fecal elimination was equivalent among dose groups except the high dose males, where a greater percentage was eliminated by this route. The origin of fecal radioactivity was via biliary elimination. Residual radioactivity in tissues was minimal in all dose groups. Urinary and fecal metabolites of 14 C

cyromazine were is olated and identified by TLC, HPLC, and GC/MS. The major compounds identified were the N

- dealkylated product melamine, hydroxycyromazine, and

un

- metabolized cyromazine identified.Cyromazine Human Health Risk Assessment DP No. D414914

Page 43 of 58 Table A.2. 2 Subchronic, Chronic and Other Toxicity Profile of Cyromazine

Guideline

No. Study Type MRID No. (year)/

Classification /Doses Results

870.7600 Dermal

Penetration

- Rat 40168601 (1987)

Acceptable/Guideline

0.10, 1.00, and 10 mg/rat Male rats received dermal application of a

“simulated” 75W formulation of 14 C

Cyromazine in aqueous solution. Absorption at 10 hrs at 0.1, 1.0, and 10 mg/rat was 12.6%, 7.8% and 11%, respectively. The main route of

excretion of the absorbed radioactivity was the urine. There is no evidence that the compound is sequestered in the skin. Amounts remaining in/on the skin at termination ranged from 4.5% (10 mg dose/2 h exposure) to 24% (0.1 mg dose/24 hour exposure). Most of the unabsorbed radioactivity was found in the skin washes from

each dose/duration.

870.7600 Dermal

Penetration

- Rat 00149656 (1985)

Acceptable/Guideline 0.1, 1.0, and 100 mg/rat to

a 10 cm 2 area on the upper back portion of the rats A formulation of “simulated” 75W formulation

of 14 C

- Cyromazine in aqueous solution was administered to 36 male Harlan Sprague

Dawley albino rats (3 rats per dose group per time period). Total radioactivity absorbed generally increased with increasing expo sure time but decreased with increasing dose indicating saturation of penetration with increasing dose. Absorption at 10 hours was 10%, 11.4% and 7% at 0.01 mg/cm 2 , 0.1 mg/cm 2 and 10 mg/cm 2 , respectively

870.7800 Immunotoxicity Waived (HASPOC TXR 00 56806 )

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD)

– All Population s

An endpoint attributable to a single dose was not identified.

A.3.2 Acute Reference Dose (aRfD)

– All Population s

Study Selected: Acute neurotoxicity study

- rat

MRID No: 49109701

Executive Su mmary: In an acute neurotoxicity study (MRID 49109701), groups of non

- fasted,

6

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

a.i ., batch # 666428) in 0.5% carboxymethylcellulose (CMC) in sterile water at doses of 250, 1000, or 2000 mg/kg bw and observed for 14 days. Neurobehavioral assessment (functional observational battery and motor activity testing) was performed in 10 animals /sex/group prior to the initiation of dosing (study day

- 6), at the time of peak effect (approximately 3 hours post

dosing, the time of peak effect was considered to be 2 to 4 hours post

- dosing based on theCyromazine Human Health Risk Assessment DP No. D414914

Page 44 of 58 toxicokinetic finding that cyromazine is rapidly absorbed from the gastrointestinal tract of the rat following oral gavage (MRID 41442101)) on study day 0, and on study days 7 and 14. At study termination, 5

- 7 animals/sex/group were euthanized and perfused in situ in a 4.0% paraformaldehyde/0.1M phosph ate

- buffered solution for neuropathological examination. Of the perfused animals, 5 were subjected to histopathological evaluation of brain and peripheral nervous system tissues. The central and peripheral nervous system tissues were dissected and

preser ved. Fixed brain weight and brain dimensions (length, excluding olfactory bulbs, and width) were recorded. The prepared tissues from the control and high

- dose group rats were examined microscopically.

There were no treatment related effects on mortality , clinical signs, brain weight or gross and histological pathology or neuropathology. Cyromazine

- related clinical signs (red material around the nose in males and females on days 3

- 8 and day 15) were limited to the 2000 mg/kg rats. Statistically signific ant (p<0.05

- p<0.1) lower body weight gains compared to the controls were observed in the 1000 and 2000 mg/kg rats of both sexes during the first day of treatment. Body weight loss was more pronounced in the males and resulted in lower body weight gains fo r days 0

- 7 and days 0

- 15 at the 2000 mg/kg dose. Lower body weights were also observed in the 2000 mg/kg male rats (

- 10.5% compared to controls on Day 3. Body weight losses were accompanied with lower food consumption during the first days after treatmen t.

Home cage observations, handling observations and sensory observations were not affected by the test substance administration. In the open field observations, statistically significantly higher (p<0.05) mean numbers of rears (10.1) were noted for the 2000 mg/kg females compared to the control group (5.0) on study day 7. However, this was within the range of the lab historical control data (8.1

- 10.3) and was not considered test substance

- related. A test substance

- related, statistically significantly lower (p<0.01) mean hindlimb footsplay was noted for the 2000 mg/kg males (39.5 mm) compared to the control group (63.3 mm) at the time of peak effect (approximately 3 hours following dose administration) on study day 0. A treatment

- related statistically significantly lower (p<0.01) mean body temperature was noted for the 2000 mg/kg males (36.2°C), as compared to the control group (37.2°C), at the time of peak effect on study day 0.

Cyromazine treatment resulted in decreases in the mean cumulative tota l LMA counts in males at 1000 mg/kg (↓25.1%, p<0.05) and 2000 mg/kg (↓24.3%, p<0.05) at the time of peak effect on study day 0. Mean cumulative ambulatory LMA counts were decreased at 250 mg/kg (↓44.3%), 1000 mg/kg (↓48.8%) and 2000 mg/kg (↓52.3%) at the time of peak effect on Day 0. These effects on the motor activity are considered adverse effects resulting from the single oral dosing of cyromazine. The flat dose response can be explained from a reported metabolism study (MRID 41442101). In this metab olism study, cyromazine was tested at a low dose of 3 and a high dose of 300 mg/kg bw. At the high dose, saturation of excretion was seen which may help explain the flat dose response for the decrease in cumulative LMA since the lowest dose tested in

the ACN was 250 mg/kg BW. At 250 mg/kg BW, the clearance mechanism(s) may be as overwhelmed as at the higher doses tested of 1000 and 2000 mg/kg BW, resulting in a flat dose response curve. Total and ambulatory LMA counts were also decreased in females (p<0.05

- p<0.01) for the 250, 1000, and 2000 mg/kg by 18

- 56% as compared to the control group, during the first LMA subinterval (0

- 10 minutes) at the time of peak effect on study day 0. TheseCyromazine Human Health Risk Assessment DP No. D414914

Page 45 of 58 decreases resulted in decreases in the mean cumulative total (p<0.05) by 28% at the 2000 mg/kg dose and ambulatory (p<0.05) LMA counts at 1000 and 2000 mg/kg. Statistically significantly lower mean cumulative total and/or ambulatory LMA counts were noted for females in the 250, 1000, and 2000 mg/kg groups on study day 7 and in the 1000 and 2000 mg/kg groups on study day 14. These changes were not considered to be test substance related, since these changes did

not occur in a dose

- related manner and/or the mean values in the control group exceeded the

maximum mean values in the lab historical control data. Furthermore, the lower cumulative values noted in these groups were due to greater habituation of test substance

- treated females, as activity in the treated groups was similar to the control group during the first 10

- minute

subinterval.

Based on the decreased motor activity (mean cumulative ambulatory LMA counts ↓44%) in males at the time of peak effect on Day 0, and decreased food consumption (p< .01, ↓17.4%) on Day 1, the LOAEL is 250 mg/kg BW, the lowest dose tested. The NOAEL was

not established.

EPA statisticians have found that that statistical analysis performed and presented in the study submission was not optimal in terms of fully incor porating important features of the study design. As a result, EPA statisticians have redone the analysis of cumulative locomotor activity: total LMA and ambulatory LMA using a more appropriate statistical approach. The results, nevertheless, are similar to those reached by the registrant, similarly indicating that the low dose was significant (TXR 0056676 )

.

T his neurotoxicity study is classified as acceptable/guideline and satisfies the guideline requirement for an acute neurotoxicity study in rats (870. 6200; OECD 424).

Dose for Risk Assessment : LOAEL = 250 mg/kg Uncertainty Factor: 300x (10x interspecies extrapolation, 10x intraspecies variability, 3x for LOAEL to NOAEL)

Comments about Study/Endpoint/Uncertainty Factor : The effects produced in this study are due to a single dose. The effects seen at the LOAEL are decreased motor activity (mean cumulative ambulatory LMA counts ↓44% ) in males at the time of peak effect on Day 0, and decreased food consumption (p< 0 .01, ↓17.4%) on Day 1. An uncertainty factor of 3X, instead of 10X, was applied for use of a LOAEL as a point of departure because the available ADME data (MRID 41442101) sugges ts that 250 mg/kg/day is a dose that saturated the animals metabolic capabilities in the ACN study. A t doses below saturation, the chemical would be cleared from the body and would not produce the effects observed in the ACN study. This endpoint isCyromazine Human Health Risk Assessment DP No. D414914

Page 46 of 58 consi dered appropriate for all populations because the effects were observed following a single dose, and the route of administration (oral) is appropriate for dietary considerations.

A.3.3 Chronic Reference Dose (cRfD )

Study Selected : 2

- gen reproduction study

MRID No. : 0010319 7 co

- critical with the Chronic/Carcinogenicity Study in rats MRID 00103202, 00115735

Executive Summary ( 2

- gen reproduction study ) : In a two

- generation reproduction study (MRID No. 00103197) in Sprague

- Dawley rats COBS ® CD ® rats ( 15 males and 30 females/group), 95.3% cyromazine was administered at dietary levels of 30, 1000, or 3000 ppm (1.5, 50, or 150 mg/kg/day).

The F 0 rats were mated once to produce the F 1 litters. F 1 rats were randomly selected to mate to produce the F 2 lit ters. 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

- relate d effects were observed in general appearance, behavioral changes, parturition and length of gestation in the

animals.

Parental mean body weights in the F 0 generation males and females were decreased at 1000 ppm (↓9

- 12%) and 3000 ppm (↓20

- 21%) compared to the control. Body weight gains were depressed at the 1000 ppm in the males (↓16%) and females (↓20%) compared to controls. Body weight gains were more depressed at the 3000 ppm in the males (↓25%) and females (↓38%) compared

to co ntrols. In the F 1 generation parental animals, body weights were significantly reduced (p<0.01) in the 3000 ppm males and females (↓17%

- 20%). Food consumption was decreased (↓10

- 15%) in males and females of both generations at the 3000 ppm dose

. Food c onsumption at the 1000 ppm was decreased slightly at the 1000 ppm (↓6

- 8%). No effect was noted on pup survival rates in all groups and generations. Fertility rates were unaffected by treatment. No

differences in mean litter size were noted. The differe nce between the group mean pup weights at birth and on postnatal days 7, 14, and 21 for the high dose and control groups in each generation was consistently statistically significant (p < 0.05 or p < 0.01). The pup weights in the high dose (3000 ppm) group av eraged 8 to 2 2 % less than that of the control group from birth to weaning (Table 6)

. Pup body weights at the 1000 ppm were comparable to controls.

The parental systemic toxicity NOAEL in this study is 100 0 ppm ( 50 mg/kg/day using the

default conversion of 1 ppm = 0.05 mg/kg, or 70, 54.6, 84.5, 70.5 mg/kg/day for F 0 males, F 1 males, F 0 females, F 1 females, respectively using actual food consumption data and actual test material dietary concentrations) , based on decreased body weights (↓15

- 22%) in males and

females that were associated with decreased food consumption (↓10

- 15%) at the LOAEL of

3 000 ppm ( 1 50 mg/kg/day). The decreased body weight seen at the 1000 ppm was less than 10% and is not considered biologically significant to be adverse. The body we ight effects in theCyromazine Human Health Risk Assessment DP No. D414914

Page 47 of 58 F 1 generation at 1000 ppm were not remarkable either. The offspring systemic / developmental toxicity NOAEL was 1000 ppm (50 mg/kg/day using the default conversion of 1 ppm = 0.05 mg/kg, or 54.6, 70.5 mg/kg/day for F 1 males and F 1 femal es, respectively using actual food consumption data and actual dietary concentrations ) and the offspring systemic/developmental toxicity LOAEL was 3000 ppm (150 mg/kg/day), based on decreased body weights at birth and through weaning ((↓8

- 22%) . The reprodu ctive toxicity NOAEL is ≥ 3000 ppm (150 mg/kg/day

- HDT). The reproductive toxicity LOAEL was not achieved.

Th is reproduction toxicity study in the rat is classified Acceptable/Guideline. This study was conducted prior to the new OPPTS guidelines; however, it satisfies the guideline requirement for

a two

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

.

Executive Summary ( Chronic/Carcinogenicity study ) : In a combined chr onic/carcinogenicity study (MRID 00115735 ) Cyromazine (95.5% purity

- Larvadex technical) was administered to

60 Sprague

- Dawley rats / sex/dose in the diet at dose levels of 0, 30, 300 , or 3000 ppm (equivalent to 0, 1.5, 15, 150 mg/kg/day ) for 24 months

. An additional 10 animals per sex in the control and 3000 ppm groups were designated for interim sacrifice at one year.

There were no significant difference s between the contr ol and treated animals in appearance clinical signs, survival, hematology, biochemistry and urinalysis. F requently observed in all groups were palpable masses, corn e al opacity, red area around eye

, and red material in eye,

decu b ital ulcer and hair loss. Some treated animals wore noted to have excessive salivation,

cha nges in eye size, emaciation and distention.

Statistically significantly lower body weights (↓2 0 % for males and ↓2 9 % for females ) , body weight gains (↓2 3 % for males and ↓ 33 % for females ) , compared to controls were noted for the high dose rats . Food consu mption was decreased about 15% in both sexes at the high dose; however food efficiency was unchanged from control . Statistically significantly lower body weights and body weight gains were reported for mid

- dose females at some intervals and

occasional low er food consumption in males and females. The high dose interim sacrifice groups of both sexes immediately and continually through the four weeks withdrawal period had mean food consumption equal to or greater than those control animals sacrificed at 12 m onth interim during the withdrawal period.

Clinical and macroscopic pathology was comparable among control and treated groups. The mean organ weight decreases found only at 3000 ppm in liver, kidney, testes, heart and brain

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

A pilot investigation of T 3 , T 4 and testosterone at 18 months an d 24 months in 5 males each of the control and high dose rats yielded similar results.

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

interim sacrifice. At the 24

- month sacrifice, cystic hyperplasia was found in 0/55, 1/59, 5/56, and 4/59 rats in the 0, 30, 300, and 3000 ppm groups, respectively.Cyromazine Human Health Risk Assessment DP No. D414914

Page 48 of 58 Female rats showed a number of different neoplasms of the ma mmary glands. There was no increase in the incidence of benign tumors of the mammary gland due to cyromazine treatment. Although the number of animals with the malignant tumors in the mammary gland was slightly greater in the highest dose group (150 mg/kg/ day) as compared to the control females, this difference was not statistically significant and there was an absence of dose response. Neither the adenomas nor the fibroadenomas nor the combination of adenomas, fibroadenomas and

adenocarcinaomas showed a si gnificant trend (p< 0 .01) and pair

- wise comparison (p< 0.05 ). Moreover the incidence of mammary tumors in treated rats did not exceed the historical control data, and the tumors were not considered treatment related ( H ED CPRC, Jan. 6, 1995, TXR No. 0011384).

Based on statistical analysis, there was a slight increased incidence of renal interstitial cell tumors in high dose males (6/57 or 11%) compared to controls (1/60 or 2%), however, these lesions were within the historical control range and the lesions we re not considered treatment

related.

The systemic toxicity LOAEL is revised to 3000 ppm (150 mg/kg/day) based on decreased body weight (↓20% for males and ↓29% for females), body weight gains (↓23% for males and ↓33% for females) accompanied with lower fo od consumption (10

- 15%) , compared to

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

Th is combined chronic/carcinogenicity study in the rat is classified Acceptable/Guideline. This study was conducted prior to the new OPPTS guidelines; however, it satisfies the guideline requirement for a combined chronic/carcinogenicity study in the rat (OPPTS 870. 4300 ; OECD

453

.

Dose/Endpoint for establishing cRfD: NOAEL = 50 mg/kg/day based on decreased body weights in adults that were associated with decreased food efficiency at 150 mg/kg/day (LOAEL) seen in the generation study and the combined chronic/carcinogenicity study in rats.

.

Uncertainty Factor (UF): An UF of 100 was applied to a ccount for inter (10 x)

- and intra

- (10 x) species variation.

Comments about Study/Endpoint: This endpoint is appropriate for the population of concern (general population ), duration (long term), and route of exposure (oral)

. This endpoint is protective of adverse effects observed at higher doses in other studies. The observation of a similar effect in chronic/carcinogenicity in rat s strengthens our confidence in this endpoint.

A.3.4 Incidental Oral Exposure (Short

- and Intermediate

- Term)Cyromazine Human Health Risk Assessment DP No. D414914

Page 49 of 58 There are no residential uses for cyromazine; however incidental oral exposure from spray drift is likely.

Study Selected : 2

- Generation Reprodu ctive Study in rats co

- critical with the Chronic/Carcinogenicity Study in rats

MRID No. : 00103197, 00103202, 00115735

Executive Summary : See A.3.3 above

Dose and Endpoint for Risk Assessment : 50 mg/kg/day , based on decreased body weight and decreased food efficiency in the 2

- generation reproductive toxicity study at a LOAEL of 150 mg/kg/day and the LOAEL of 150 mg/kg/day for decreased body weight in the chronic/carcinogenicity study in rats.

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

- and intra

- (10 x) species variation.

Comments about Study/Endpoint: The 2

- generation reproductive toxicity study and chronic toxicity/carcinogenicity studies are appropriate for this endpoint because it examines the toxicity to the population of concern. The route of exposure (in the feed) is appropriate for this exposure scenario and this endpoint is protective of effects observed at higher doses. The body weight changes in the chronic rat study were taken from the interim sacrifice data and occurred at 19 weeks in females and 51 weeks in males. This provides an appropriate duration for the incidental oral endpoint.

A.3.5 Dermal Exposure (Short

- , Intermediate

- and Long

- Term )

No hazard was identified via the dermal route of exposure and therefore quantification of risk via this route of exposure is not required. No systemic toxicity occurred in two 21

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

A.3.6 I nhalation Exposure (Short

- and Intermediate

- Term)

Selected Study : 28

- day inhalation toxicity stud y.

MRID No : 47940804

.

Executive Summary : In this subchronic inhalation toxicity study (28

- Day), c yromazine (95%

a.i ) was administered to 60 Albino Rats {(Tif: RAIF (SPF), hybrids of RII/1 x RII/2 strain}

5 /sex/concentration by dynamic nose only exposure

, for 4 hours per day, 7 days/week for a total of 28 days. Nominal concentrations were 55, 210, or 710 mg/m 3 ( 0, 0.055, 0.210, or 0.710 mg/L) with analytical concentrations of 58 ± 10, 206 ± 13, and 706 ± 19 mg/m 3

. Additionally, one satellite control group (5 males and 5 females) and one satellite high dose ( 0.710 mg/L) group (5Cyromazine Human Health Risk Assessment DP No. D414914

Page 50 of 58 males and 5 females) were allowed to survive for 3 additional weeks then sacrificed to observe

recovery.

No clinical symptoms or signs of systemic toxicity were observed in the control animals. The test

article

- exposed animals of all exposure groups showed an impairment of the general condition

with the symptoms of piloerection, dyspnea, hunched posture, and reduced spontaneous activity. The time of first occurrence, the duration, and the degree of clinical signs were concentration

dependent. No mortality was encountered in any group.

Body weights i n males of all treatment groups were slightly (but not significantly) decreased when compared with the controls. This decrease was independent of the aerosol concentration. No exposure

- related changes were observed in food consumption.

Hematology investig ation revealed slightly higher values of red blood cell parameters (erythrocyte count, hemoglobin, packed cell volume) in the males of the high exposure group (710 mg/m 3 ) at the end of the treatment period. At the end of the recovery period, the values

ret urned back to normal. Blood chemistry data revealed no evidence of treatment

- induced significant changes to the parameters measured.

Pituitary glands weight of the test article

- exposed males was dose

- dependently lower compared

to controls after 4 weeks, h owever; in the satellite groups that were sacrificed at week 8, both weights were similar. Also, no corroborating microscopic effects on the pituitary were observed. Therefore, this effect was not considered adverse. The liver of the females of the mid (0.210 mg/L) and high (0.710 mg/L) dose groups showed a significantly higher weight than that of the controls. However, in the recovered satellite animals of the 0.710 mg/L group, liver weights returned back to normal. Also, no corroborating microscopic ef fects in the liver were observed. Therefore, this effect was not considered adverse. Gross examination revealed no changes which could be attributed to test article toxicity. Microscopic examination revealed 3 females from the 0.710 mg/L group and one fe male from the 0.055 mg/L group with small foci of lymphocytic infiltration in the adrenal cortex. This change was absent in control female rats and was not dose dependent. Therefore, it was not considered adverse.

The LOAEL is 0.055 mg/L/day based on i mpairment of the general condition with the symptoms of piloerection, dyspnea, hunched posture, and reduced spontaneous activity.

The NOAEL wa s not observed.

Dose and Endpoint for Establishing a POD : The point of departure is the LOAEL of 0.055 mg/L /day based on impairment of the general condition with the symptoms of piloerection, dyspnea, hunched posture, and reduced spontaneous activity. The NOAEL was not observed. A human equivalent concentration (HEC) was derived according to RfC methodology for

occ upational exposures described below in Table A.3.6.1

Comments about Study/Endpoint/Uncertainty Factor : Since the study selected is a route specific study, the inhalation study is the most appropriate for assessing the inhalation exposure

of the short and intermediate duration

. The default 10x uncertainty factor for the use of deriving

a POD from the LOAEL was reduced to 3x because the effects seen at the LOAEL were notCyromazine Human Health Risk Assessment DP No. D414914

Page 51 of 58 severe (i.e., only slight dyspnea). The severity of the clinical signs at this lowest concentration was slight and the observed clinical signs appeared mostly after 7 days of exposure. Piloerection

increase to moderate after 23 days of exposure at this lowest concentration. In contrast, the clinical signs at the mid and high exposure group s were more severe and appeared within 1

- 3 days after exposure. Following cessation of exposure during recovery, all the clinical signs in the high exposure group disappeared except for decreasing slight dyspnea and hunched posture. Although there were n o recovery groups in the mid and low exposure groups, it would also be expected that clinical signs would have resolved as in the high dose group, especially since the clinical signs were much less severe than in the high dose group. There were also no

bi ologically significant changes in the hematological parameters at the lowest concentration tested of 0.055 mg/L, unlike the mid

- and high

- dose groups. All these data in a weight of evidence consideration suggests a steep dose

- response curve, suggesting th e low concentration is

near a true no effect level. In addition, the study used a milled powder for the exposure while exposures following the current usage pattern will be a liquid.

Uncertainty Factor (UF ): 1 00 which includes 10x for int ra species variat ion

, 3x for int e rspecies extrapolation (reduced to 3x for converting the concentration to human equivalent concentration

- See appendix below) , 3x for extrapolation of LOAEL to NOAEL

. MOE = 1 0 0 for short

- and

intermediate

- term duration.

Table A.3.6.1. RFC Methodology to Derive the HEC

RDDR Worksheet: Occupational

Blue: inputs

Green: outputs

(1) DURATION ADJUSTMENT

(a) Daily Exposures: Enter inhalation exposure duration from animal toxicity study in cell A9 and expected human exposure duration in cell B9

Animal Inhalation Study Human Expected Exposure

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

4 8 0.5

(b) Weekly Exposures: Enter weekly regimen (days/week) from animal toxicity study in cell A14 and expected human weekly regimen in cell B14

Animal Inhalation Study Human Expected Exposure

Animal Weekly Exposure (days/week) Human Weekly Exposure (days/week) Weekly Duration Adjustment

7 5 1.4

Animal Inhalation Study POD (mg/L; NOAEL,

LOAEL, or BMDL) Duration

- Adjusted Animal Study POD (mg/L)

0.055 0.0385

(2) ESTIMATE THE HUMAN EQUIVALENT CONCENTRATION

(a) Enter the RDDR estimated value from the "RDDR.exe" output corresponding to portal of entry [respiratory tract (extrathoracic, tracheobronchial, or pulmonary)] or systemic effectsCyromazine Human Health Risk Assessment DP No. D414914

Page 52 of 58 Adjusted animal POD (mg/L) RDDR (from RDDR.exe output)* HEC (mg/L)

0.0385 1.042 0.04012

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

.

Note: Stop here if air monitoring data is readily available. MOE can be calculated by directly comparing an HEC (mg/L) to inhalation exposure concentration estimate (mg/L)

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

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

Exposure

Scenario Ventilation

rates (L/min) Relative Activity

Factor (AF) 1 Human

Specific

Convers

ion

Factor (CF,L/h r*kg BW) 2 Absorption ratio

(A) 3 Hum

an Daily

Dura

tion HED (mg/kg

BW/day) 4

Applicators [pilots, tractor

drivers (groundboom, airblast)] 8.3 0.6 11.8 1.0 8 2.283

Handlers (mixers/loaders,

lawncare operators) 16.7 1.2 11.8 1.0 8 4.594

Handheld spray applications (backpack, handguns) 29 2.1 11.8 1.0 8 7.978

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

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

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

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

Regional deposited dose ratios (RDDR)

MMAD = 1.61 Sigma g = 1.00

Body Extrathoracic Tracheobronchial Pulmonar y SPECIES weight(g) VE(ml) SA(cm^2) dep SA(cm^2) dep SA(m^2) dep

-------------------------------------------------------------------------------- rat 236 171.5 15.000 0.417 22.500 0.088 0.340 0.160

human 70000 13800.0 200.000 0.247 3200.000 0.065 54.000 0.303

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

Page 53 of 58 RDDR 0.280 2.392 1.042

Thoracic Total RT Extrarespiratory SA(m^2) dep SA(m^2) dep BW(g) dep

-------------------------------------- ------------------------------------------ rat 0.342 0.248 0.344 0.666 236 0.666

human 54.320 0.125 54.340 0.616 70000 0.616

--------------------------------------------------- ----------------------------- RATIO 0.006 1.984 0.006 1.081 0.003 1.081

RDDR 1.330 2.124 3.985

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

Page 54 of 58 Appendix B

. Physical/Chemical Properties

Table B. 1

. Physicochemical Properties of Cyromazine (EPA Reg. No. 100

- 632 PAI ).

Parameter Value Reference

Melting point/range 224

- 225 C MRID 40594903

pH 8.0 @ 25 C MRID 40594903

Density 1.35 g/mL @ 20 C MRID 40594903

Water solubility @ 20 C 1.16 g/ 100mL MRID 40594903

Solvent solubility( g/mL @25

C) Hexane, not soluble

Cyclohexane, not soluble

Methanol , 1.49 Toluene, not soluble Acetone, 0.16

2

- Propanol, 0.13 Methylene chloride, 0.01 Octanol, 0.18 MRID 40594903

Vapor pressure 3.3 x 10 - 9 mm Hg @ 25 C MRID 40594903

Dissociation constant 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

Table B.2. Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 Codex 3

40 CFR 180.414:

Plants/Livestock : cyromazine, N

- cyclopropyl

- 1,3,5

- triazine

- 2,4,6

- triamine N

- cyclopropyl

- 1,3,5

- triazine

2,4,6

- triamine, including the metabolite 1,3,5

- triazine

2,4,6

- triamine Plants and animal

commodities: cyromazine.

Commodity Tolerance (ppm) /Maximum Residue Limit (mg/kg)

US Canada Mexico 2 Codex 3

Bean, dry, except cowpea 3.0 3 beans (dry)
Bean, lima 1.0 1 Lima bean (young pods and/or immature beans)
Bean, succulent 2.0

Broccoli 1.0 1 Cabbage, Abyssinian 10.0 Cabbage, seakale 10.0
Cattle, fat 0.05
Cattle, kidney 0.2 0.3 edible offal (mammalian)
Cattle, meat 0.05 0.3 meat (from

mammals other than marine mammals)Cyromazine Human Health Risk Assessment DP No. D414914

Page 55 of 58 Table B.2. Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 Codex 3

Cattle, meat byproducts, except kidney 0.05 0.3 edible offal (mammalian) Egg 0.25 0.3

Garlic 0.2 Garlic, great

- headed, bulb 0.2
Goat, fat 0.05 Goat, kidney 0.2 0.3 edible offal (mammalian)
Goat, meat 0.05 0.3 meat (from

mammals other than marine mammals) Goat, meat byproducts, except kidney 0.05 0.3 edible offal (mammalian)
Hanover salad, leaves 10.0 Hog, fat 0.05 Hog, kidney 0.2 0.3 edible offal (mammalian) Hog, meat 0.05 0.3 meat (from

mammals other than marine mammals) Hog, meat byproducts, except kidney 0.05 0.3 edible offal (mammalian)
Horse, fat 0.05 Horse, kidney 0.2 0.3 edible offal (mammalian)
Horse, meat 0.05 0.3 meat (from

mammals other than marine mammals) Horse, meat byproducts, except kidney 0.05 0.3 edible offal (mammalian)

Leek 3.0 Mango 1 0.3 0.5

Milk 0.05 0.01

Mushroom 1.0 8.0 7
Onion, bulb 0.2 0.3 dry bulb onions 0.1 Onion, green 3.0 3.0 3 spring onion Onion, potato 3.0
Onion, tree 3.0
Onion, welsh 3.0 Pepper 1.0 3.0 1 F ruiting vegetables other

than cucurbits (except mushrooms

and sweet corn (corn

- on the cob) 10 peppers chili,

dried

Potato 0.8 0.8 Poultry, fat (from chicken layer hens and chicken breeder hens only) 0.05Cyromazine Human Health Risk Assessment DP No. D414914

Page 56 of 58 Table B.2. Summary of US and International Tolerances and Maximum Residue Limits Residue Definition :
US Canada Mexico 2 Codex 3

Poultry, meat (from chicken layer hens and chicken breeder hens only) 0.05 0.1 poultry meat

Poultry, meat byproducts (from chicken layer hens and

chicken breeder hens only) 0.05 0.2 poultry edible

offal of

Rakkyo, bulb 0.2
Shallot, bulb 0.2
Shallot, fresh leaves 3.0 Sheep, fat 0.05 Sheep, kidney 0.2 0.3 edible offal (mammalian) Sheep, meat 0.05 0.3 meat (from

mammals other than marine mammals) Sheep, meat byproducts, except kidney 0.05 0.3 edible offal (mammalian)

Tomato 0.5 1.0 1 F ruiting vegetables other

than cucurbits (except mushrooms

and sweet corn (corn

- on the cob) Turnip, greens 10.0 Vegetable, brassica, leafy, group 5, except broccoli 10.0 35 Bok choy Chinese cabbages, broccoli raab, collards, kale, mustard greens, mustard spinach, rape greens 10 mustard greens

Vegetable, leafy, except brassica, group 4 7.0 10 amaranth, arugula, cardoon, celery, celtuce, C hinese celery, corn salad, dandelion leaves, dock, edible leaved chrysanthemum, endives, fresh chervil leaves, fresh Florence fennel leaves and stalks, fresh parsley leaves, garden cress, garden purslane

, g arland chrysanthemum, head lettuce, leaf lettuce, New Zealand spinach, orach leaves, radicchio, rhubarb, spinach, S wiss chard, upland cress, vine spinach, winter purslane 4 celery, head lettuce, leaf lettuce

Vegetable, cucurbit, group 9 1.0 1.0 cucumbers , melons 2 cucumber, squash

summer 0.5 melons, except

watermelon MRLs with NO US equivalent Artichoke, globe 3

Completed: M. Negussie; 01/19/2012

1 There are no U.S. registrations on mango as of May 4, 2000

.Cyromazine Human Health Risk Assessment DP No. D414914

Page 57 of 58 2 Mexico adopts US tolerances and/or Codex MRLs for its export purposes.

3 * = absent at the limit of quantitation; Po = postharvest treatment, such as treatment of stored grains. PoP = processed postharvest treated commodity, such as processing of treated stored wheat. (fa t) = to be measured on the fat portion of the sample. MRLs indicated as proposed have not been finalized by the CCPR and the CAC.Cyromazine Human Health Risk Assessment DP No. D414914

Page 58 of 58 Appendix C

. Review of Human Research

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies were determined to require a review of their ethical conduct, have received that review and have been determined to be

ethical.

The PHED Task Force, 1995. The Pesticide Handlers Exposure Database, Version 1.1. Task Force members Health Canada, U.S. Environmental Protection Agency, and the National Agricultural Chemicals Association, released February, 1995.

The Agricultural Handler Exposure Task Force (AHETF), 2011. The Occupat ional Handler Unit Exposure Surrogate Reference Table. U.S. Environmental Protection Agency. Released June 21, 2011.