Cyromazine Hwnan Health Risk Assessment DP No. 038

. 7940

UNITED STATES ENV I RONMENTAL PROTECTION AGENCY

WASHINGTON

, D

. c

·

. 20460

.



### MEMORANDUM

Date: January 31,2013 , OFF I CE

. OF
CHEMICAL SAFETY AND
POLLUTION PREVENTION

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

.

PC Code: 121301

Decision No.: 437241

Petition No .: N A DP Barcode: · 0387940 Registration No .: None Regulatory

. Action: Registration Review

Case No.: .: 7439 Risk Assessment T ype: Human Health Risk

Assessment

TXR No .: NA ·· CAS 

### No.: 66215-27-8

MRID No.: None 40 CFR: 180.414



### FROM:

Rebecca Daiss, Biologist · ·

. · Ivan Nieves, Biologist

### --fJ~ 

# '

, ---./1

### In~ Abdallah Khasaw i mili

, To xico gist / /**l...-~** Risk Assessme nt Branc h 4

Health Effects Division (7 509P)



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

## ~**l~ ~**  Susan V.

### H~et Branch Sen

. ior

### Sci{!n~ist ·

. 

# A

. . A

### ~ ... 

# V**~** Risk Assessment Branch 4, HED (7509P)**~**



### TO : Kelly Ballard

. Risk Management and Implementation Branch 1

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

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

. Registration Review of the herbicide cyromazine. · ·

Page 1 of56Cyromazine Human Health Risk Assessment DP N o. 0387940

1.0 Exe cutive Summary

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


### 2.0 H ED Recommendations

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

2.1 Data Deficiencies

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

2.2 Tolerance Considerations

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

2.2.1 E nforcement Analytical Method

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

2.2.2 International Harmonization

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

2.2.3 Recommended T olerances

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

2.3 Label Recommendations

. . ... .. .. . ............ . .. ........... .. ........................................ ................ 10

2.3. 1 Recommendations from Residue Reviews

............................................... .............. . 10

2.3.2 Recommendations from Occupational Assessment..

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

2.3.3 Recommendations from Resident ia l Assessment

................................................... 10

3.0 Introduction

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

. ·

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

3. 1 Che m ica l Identity

....................... . ............................................................ . ...... ............ .. 10

3.2**Physic~l/ChemicaJ** Characteristics

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

3.3 Pesti cide Use Pattern

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

3.4 Anti cipated Exposure Pathways

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

3 .5 Considera tion of Environmental Justice

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

4.0 Hazard Ch aracterization and Dose-Response Assessme nt

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

4.1 Toxico logy Studies Available for Analysis

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

4.2 Absorption, Distribution, Metabolism, & E limination (ADME)

............................. 1 5

4.2.1 Dermal A bsorption

. .................................................................................................. 1 5

4.3 T o xic ological Effects

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

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

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

4.4

. 1 Co mpleteness of the Toxicology Database

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

4.4.2 Ev id ence of Ne urotoxicity

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

4.4.3 Ev idence of Sensitivity/Susceptibility in the Developing or Young Animal..

...... 17

4.4.4 Residual Uncertainty in the Exposure Database

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

4.5 Toxicity Endpoint and Point of Departure Selections

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

4.5 .1 Dose-Response Assessment

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

4.5.2 Recommendation for Combining Routes

. of E xposures f or Risk Assessment..

... 18

4.5.3 Ca ncer**Cl~s sification**  and Risk Assessment Recommendation

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

4.5 .4 S ummary of Points of Departure and Toxicity Endp oints Us ed in Human Risk

Assessment

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

4.6 Endocrine Disruption

..... . .... . .. ... . ... . ......................................................... .. .. . ................ 20

5.1 Metabolite/Degradate Residue Profile

.......... .. .. ............... .. .. .. ....... .. .. . ... .. .. ........... ...... 21

5

. 1.1 S ummary of Plant and Animal Metabolism St udi es

................................. ............ 21

5.1.2 S ummary of E nvironmental Degradation

......................................................... .. ... 21

5.1.3 C omparison of Metabolic Pathways

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

5.1.4 Residues of Concern Summary and Rationale

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

5.2 Food Residue Profile

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

5.3 Water Residue Profile

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

5.4 Di etary Risk Assessment

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

5.4.1 Description of Residue Data Us ed in Dietary Assessment

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

5.4.2 Percent Crop Treated Used in Dietary Assessment

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

5.4.3 A cut e Dietary Risk Assessment

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

5 .4.4 Chronic Dietary Risk Assessment

..... ................... . .................... .............................. 28

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

Page 3 of 56 5.4.5 Cancer Dietary Risk Assessment

................................ ................................ ............. 28

5.4.6 Summary Table

................................ ................................ ................................ ......... 28

6.0 Resident ial (Non

- Occupational) Exposure/Risk Characterization

............................. 28

6.1 Residential Handler Exposure

................................ ................................ .................... 28

6.2 Post

- Application Exposure

................................ ................................ .......................... 29

6.3 Combined Exposure

................................ ................................ ................................ ..... 29

6.4 Reside ntial Bystander Postapplication Inhalation Exposure

................................ ... 29

6.5 Spray Drift

................................ ................................ ................................ .................... 29

7.0 Aggregate Exposure/Risk Characterization

................................ ................................ .. 30

7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 30

7.2 Short

- Term Aggregate Risk

................................ ................................ ........................ 30

7.3 Intermediate

- Term Aggregate Risk

................................ ................................ ........... 30

7.4 Chronic Aggregate Risk

................................ ................................ .............................. 30

7.5 Ca ncer Aggregate Risk

................................ ................................ ................................ 31

8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 31

9.0 Occupational Exposure/Risk Characterization

................................ ............................ 31

9.1 Short

- /Intermediate

- Handler Risk

................................ ................................ ............ 31

9.2 Short

- /Intermediate

- /Long

- Term/Cancer (if needed) Post

- Application Ris k

........ 45

9.2.1 Dermal Postapplication Risk

................................ ................................ ................... 45

9.2.2 Inhalation Postapplication Risk

................................ ................................ .............. 45

10.0 References

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

................................ .................. 47

A.2 Toxicity Profiles

................................ ................................ ................................ ............ 48

A.3 Hazard Identification and Endpoint Selection

................................ .......................... 51 Appendix B. Physical/Chemical Properties

................................ ................................ ............. 55 Appendix C. Review of Human Research

................................ ................................ ................ 56Cyromazine Human Health Risk Assessment DP No. D387940

Page 4 of 56 1.0 Executive Summary

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

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

Use Profile

Cyromazine (N

- cyclopropyl

- 1,3,5

- triazine

- 2,4,6

- triamine) is a member of the triazine class of chemicals. While most of the chemicals of this class of chemicals are herbicides, cyromazine is an insecticide/larvicide. Tolerances are established (40 CFR §180.414) for residues of cyromazine in or on a variety of commodities ranging from 0.05 ppm (livestock commodities) to 10.0 ppm (brassica vegetables). Cyromazine works as an insect growth regulator. It exerts its toxic action by affecting the nervous system of the immature stages (larvae) of certain insects.

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

app lied to non

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

Hazard Identification

The studies available for consideration of cyromazine toxicity provide a comp rehensive database; however, t here are three outstanding studies according to the revised 40 CFR Part 158 Toxicology Data Requirement

. These studies include an acute neurotoxicity study, a subchronic neurotoxicity study, and an immunotoxicity study. (The registrant has notified the Agency of the conduct of an ACN study to be completed and submitted by Spring 2013).

Cyromazine is categorized as Toxicity Category III for acute oral, dermal and inhalation toxicity. Cyromazine is not an eye irritant or a der mal sensitizer but is a mild skin irritant. The liver and hematological parameters are the most commonly observed effects in both subchronic and chronic studies in the dog and subchronic study in the rat. Decrease s in body weight and food consumption are also common effects of cyromazine as observed in oral chronic dog, rat, mouse,

and developmental rabbit studies. Cyromazine is not absorbed via the dermal route since n o dermal or systemic toxicity was seen at the highest dose tested (>2000 mg/kg/day) in two 21

- day dermal toxicity studies in rabbits. In a 28

- day inhalation study in rats, cyromazine produced clinical signs of toxicity (hunched posture, piloerection, and reduced spontaneous activity) consistent with dyspnea at all concentrations. There is no evidence of developmental toxicity following in utero exposures or that offspring are more susceptible than adults based on developmental toxicity studies in rats and rabbits. In the two

- generation reproduction study in rats no reproductive ef

fects were observed. Cyromazine was shown not to be carcinogenic in mice or rats following long

- term dietary administration and is classified as a “not likely” human carcinogen. The available mutagenicity data suggest that cyromazine does not have genoto xic activity.Cyromazine Human Health Risk Assessment DP No. D387940

Page 5 of 56 T he acute and subchronic neurotoxicity studies are required in revised 40 CFR Part 158 Toxicology Data Requirements because they provide important scientific information on potential nervous system effects from pesticide exposure. These st udies can provide data on a wide range of functional tests for evaluating neurotoxicity including sensory effects, neuromuscular effects, learning and memory and histopathology of the nervous system. The Agency acknowledges that there are no clear signs o f neurotoxicity following acute, subchronic or chronic dosing in multiple species in the cyromazine database. However, the Agency also notes that the existing guideline studies are inadequate in their assessment of behavioral effects and do not use optima l methods to evaluate the potential toxicity to the nervous tissue structure and function. Because there is not sufficient information to remove the requirements for these studies, the HASPOC concluded that the acute and subchronic neurotoxicity studies a re required in accordance with revised 40 CFR Part 158 Toxicology Data Requirements. Consequently, a 10X database uncertainty factor (UF DB ) has been retained for the lack of these neurotoxicity

studies. This 10X database uncertainty factor will be reconsi dered upon receipt and evaluation of the neurotoxicity stud y(s) by the Agency.

The outstanding a cute and subchronic studies were recently considered in a weight

- of

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

TXR 0056148 ). Cyromazine contains a symmetrical triazine substructure like atrazine, propazine and simazine. However, atrazine, propazine and simazine are halotriazines (see the structures below); cyromazine is not a halotriazine. Atrazine, propazine an d simazine disrupt the hypothalamic

- pituitary

- gonadal (HPG) axis which results in neuroendocrine

- related effects in experimental toxicology studies. No such neuroendocrine effects have been observed for cyromazine. For cyromazine

, the liver and hematological system is the primary target organs

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

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

t he other triazines . Because cyromazine has a different toxicological profile from other triazines, it is not appropriate to infer or bridge information about the potential neurotoxic potential from atrazine, propazine, or simazine.

Cyromazine Atrazine Propazine Simazine

Dose Response Assessment

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

- and intermediate

- term occupational exposure scenarios. There were no toxicological effects attributable to a single exposure of cyromazineCyromazine Human Health Risk Assessment DP No. D387940

Page 6 of 56 observed in oral toxicity studies and an acute neurotoxicity (ACN) study is currently not
available . Therefore, a Point of Departure ( PO D ) for the acute (general population) dietary

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

was selected as the POD for the chronic dietary assessment

. No dermal or systemic toxicity was

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

A POD for the dermal scenario was therefore not selected. A POD for short

- and intermediate

term inhalation scenario was selected from a 28

- day inhalation rat study

. A NOAEL was not established in this inhalation rat study

.

The FQPA Safety Factor is retained in the form of a database uncertainty factor (UF DB ) due to the lack of the acute and subchronic neurotoxicity studies. Thus, the total uncertainty factor of

1 000x ( 10x for inter

- species extrapolation, 10x

- for intra

- species variation, and 10x for the data gaps) was applied to the POD for deriving the chronic Reference Dose (cRf d ). This 10X database uncertainty factor will be reconsidered upon receipt and evalua tion of the neurotoxicity

stud y(s) by the Agency. Quantification of dermal risk is not required since no dermal or systemic toxicity was seen following repeated dermal applications at twice the Limit Dose and there were no concerns for developmental or rep roductive toxicity. A Margin of Exposure of 3000 is required for assessing risk via inhalation exposure from occupational use; there are no current or proposed residential uses. The MOE of 3000 includes: 10x for inter

- species extrapolation, 10x

for intra

- species variation, 10x for the data gaps and 3x for the use a LOAEL (UF L ) as the POD. The 3000x UF is in accordance with the recommendation by the Agency’s RfC/RfD Technical Panel ( EPA/630/P

- 02/002F December, 2002 Final Report).

OPP is conducting an indep endent retrospective analysis of more than 120 immunotoxicity studies submitted to Agency. P reliminary findings of OPP’s retrospective analysis suggest that immunotoxicity studies have not yet provided lower PODs than are selected from other guideline experimental toxicology studies and thus, so far, immunotoxicity studies would not have impact ed the Agency’s risk assessment s . The OPP retrospective analysis is anticipated to be completed in the summer of 2012

. There are no indicators in the hazard database for cyromazine to suggest a concern for immunotoxicity, consequently a 10x UF DB would not be retained solely due to an outstanding immunotoxicity study

. HED believes preliminary results of the retrospective analyses support this approach of not retaining the UF DB for cyromazine.

Exposure/Risk Assessment and Risk Characterization

Risk assessments were conducted for dietary (food and water) and occupational exposure pathways based on registered uses of cyroma zine. Slightly refined chronic dietary and drinking

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

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

.

Occupational e xposure s and risks were estimated for short a nd intermediate

- term timeframes at
baseline attire and at some level of mitigation (i.e., PF 5 respirator). Most scenarios did not exceed HED’s level of concern (LOC) with baseline attire (i.e., single layer of clothing and no respirator)(i.e. , MOEs ≥ 3,000 for short

- and intermediate

- term exposure durations ) , except for

the m ixer/ l oader/ applicator m echanically pressurized h andgun s prayer scenario for fly control inCyromazine Human Health Risk Assessment DP No. D387940

Page 7 of 56 mushrooms, and fly larvae control in cattle, hog, and poultry operations. Both scenarios at baseline (no respirators) had MOEs of 2,400 and 720, respectively; when a PF 5 respirator was added, the MOEs increased to 12,000 and 3,600 and were therefore identified as not of concern.

Most s eed treatmen t (Trigard OMC; EPA Reg. No. 100

- 790) handler exposures resulted in

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

, except for the loader/applicator and “multiple activities” scenarios that presented MOEs of 97, and 2,600, respectively. The “multiple activities” scenario presented no risk of concern with

ad ditional Protective Personal Equipment (PPE) (i.e., PF 5 respirator; MOE = 13,000). However, the loader/applicator scenario, even at the highest level of P PE (i.e., PF 10 respirator) did not reach the level of concern of 3,000 (MOE = 970). For characterization purposes, note

that this chemical has 1) a low vapor pressure (1.3 x 10 - 9 mm Hg); 2) acute inhalation toxicity category of III; and a 10x dat abase un certainty factor ( UF ) for the lack of neurotoxicity battery

and immunotoxic i ty studies

. This 10X database uncertainty factor will be reconsidered upon receipt and evaluation of the neurotoxicity stud y(s) by the Agency.

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

HED's level of concern with baseline attire.

Although a quantitative occupational post

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

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

- application inhalation exposure scenarios.

A post

- application inhalation exposure assessment is not required as exposure is expected to be negligible. Seed treatment assessmen ts provide quantitative inhalation exposure assessments for seed treaters and secondary handlers (i.e. planters). It is expected that these exposure estimates would be protective of most postapplication inhalation exposure scenarios.

Use of Human Studi es

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. These studies, listed in Appendix 2.0, have been determined to require a review of their ethical conduc t. Some of these studies are also subject to review by the Human Studies Review Board. All of the studies used have received the appropriate review.

Tolerance Recommendation

Tolerances for inadvertent residues are required for crops grown in soil to wh ich livestock manure containing cyromazine has been applied. A tolerance of 0.6 0 ppm should be established for crops grown in soil amended with c y romazine treated fertilizer based on data from 1) a confined rotational crop study on crops grown in soil ame nded with chicken manure containingCyromazine Human Health Risk Assessment DP No. D387940

Page 8 of 56 cyromazine, and 2) a study on residues in poultry manure resulting from feed through and topical applications of cyromazine.

2.0 HED Recommendations

Deficiencies are outlined in Section 2.1 below. The specific tolerance recommendations are discussed in Section 2.2, and label modifications are discussed in Section 2.3.

2.1 Data Deficiencies

A cute and subchronic neurotoxicity stud ies (GLN 870.6200a and b )

. (The registrant has notified the Agency of the conduct of an ACN study to be completed and submitted by Spring 2013) An immunotoxicity study (GLN 870.7800)

.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

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

- Geigy 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 commodities.

Adequate methods are available in PAM , Vol. II for enforcement of the established tolerances for cyromazine in/on meat, milk, poultry, and eggs.

Cyromazine

, pe r se , was recov ered when analyzed through Protocol III (present Protocol D). HED concluded that the data were acceptable and no additional cyromazine MRM recovery data were required.

2.2.2 International Harmonization

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

HED recommends increasing established U.S. tolerances to harmonize with Codex, Canadian, and Mexican tolerances in cases where higher international tolerances have been established by these entities. Accordingly, established tolerances for the commodities established at 40 CFR §180.414 subsection (a) should be revised as follows to harmonize with Codex and Canadian

tolerances.Cyromazine Human Health Risk Assessment DP No. D387940

Page 9 of 56 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 1

Mango 0.3 0.5 1

Milk 0.05 0.1 1

Mushroom 1.0 8.0 2

Onion, bulb 0.2 0.3 2

Pepper 1.0 3.0 2

Poultry, meat (from chicken layer hens and chicken breeder hens only) 0.05 0.1 1

Poultry, meat byproducts (from chicken layer hens and chicken breeder hens only) 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

2.2.3 Recommended Tolerances

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

of 0. 6 0 ppm for all crops that are grown in soil amended with c y romazine treated fertilizer and that do not have current tolerances established based on direct application of cyromazine. The se tolerances would be established at 40 CFR §180.414 subsection (d) sho uld be revised as follows. Change existing subsection d to d(1). Add subsection d(2).

(d)(2) Indirect or inadvertent residues. Tolerances are established for indirect or inadvertent residues of the insecticide cyromazine, including its metabolites and degradates, in or on the commodities in the table in this paragraph when present therein as a result of the application of fertilizer containing cyromazine to growing crops that do not have a higher tolerance in paragraph (a)(1) of this section. Complianc e with the tolerance levels specified in this paragraph is to be determined by measuring only cyromazine, N

- cyclopropyl

- 1,3,5

- triazine

- 2,4,6

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

Page 10 of 56 Table 2.2.3. Tolerance Summary for Cyromazine ppm Vegetable, Root and Tuber (except potato) 0. 6 0 Leaves of Root and Tuber Vegetables 0. 6 0 Vegetable, Bulb (except leek and green onion) 0. 6 0 Soybean 0. 6 0 Vegetable Fruit (except Pepper 0. 6 0 Strawberry 0. 6 0 Cereal Grain CG 15 (except small grain) 0. 6 0 Forage, fodder CG 16 (except small grain) 0. 6 0 Herbs and Spices (CG 19) 0. 6 0 Oil Seeds (CG 20) 0. 6 0

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

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

2.3.2 Recommendations from Occupational Assessment

The m ixer/ l oader/ applicator m echanically pressurized h andgun s prayer scenario for fly control in mushrooms, and fly larvae control in cattle, hog, and poultry operations had MOEs below 3000

. Both scenarios at baseline (no respirators) had MOEs of 2,400 and 720, respectively; when a PF 5 respirator was adde d, the MOEs increased to 12,000 and 3,600 and were therefore identified as

not of concern.

The loader/applicator and “multiple activities” scenarios presente d MOEs of 97, and 2,600, respectively. The “multiple activities” scenario presented no risk of concern with ad ditional Protective Personal Equipment (PPE) (i.e., PF 5 respirator; MOE = 13,000). However, the loader/applicator scenario, even at the highest level of PPE (i.e., PF 10 respirator) did not reach the level of concern of 3,000 (MOE = 970). For characterization purposes, note that this

chemical has 1) a low vapor pressure (1.3 x 10 - 9 mm Hg); 2) acute inhalation toxicity category of III; and a 10x d at abase uncertainty factor ( UF ) for the lack of neurotoxicity battery and

immunotoxic i ty studies

.

2.3.3 Recommendations f rom Residential Assessment

Cyromazine is not registered for residential uses.

3.0 In troduction

3.1 Chemical Identity

Structure and nomenclature are reported in Table 3. 1Cyromazine Human Health Risk Assessment DP No. D387940

Page 11 of 56 TABLE 3. 1 Cyromazine Nomenclature.

Chemical structure

Common name Cyromazine (ISO approved)

Company experimental name CGA

- 72662

IUPAC name N

- cyclopropyl

- 1,3,5

- triazine

- 2,4,6

- triamine

CAS name N

- cyclopropyl

- 1,3,5

- triazine

- 2,4,6

- triamine

CAS # 66215

- 27

- 8

End

- use product/EP Trigard®75WP

3.2 Physical/Chemical Characteristics

The physicochemical properties of cyromazine are reported in Appendix B

.

3.3 Pesticide Use Pattern

Cyromazine is an 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. Cyromazine belongs to the triazine cla ss of pesticides. Cyromazine is the only compound in this class that is used as an insecticide and larvicide

. Maximum application rates for existing and proposed uses are provided in Table 2. Maximum rates are based on a review of active and proposed la bels.Cyromazine Human Health Risk Assessment DP No. D387940

Page 12 of 56 Table 2 . Summary of Cyromazine End

- Use Products.

Reg No Formulation Max Application

Rate Target Use Sites Max. No. Applic. per Season Max No

Applic/

Season PHI

100

- 654 75% WP 0.125 lb ai/A Beans, dried, succulent

Brassica (Head and Stem) Vegetables Bulb Vegetables Cucurbit Vegetables Leafy Vegetables Peppers

Potatoes 6 0.75 lb

ai/A 7 day PHI

Label Directions: Apply 2.66 oz. (one packet) of Trigard Insecticide /A as a foliar spray when leafminers first appear. Apply with aircraft in a minimum of 5 gals. of water/A, or apply with ground application

E quipment in a minimum of 10 gals. of water/A, using sufficient carrier to achieve adequate coverage. Repeat application, as needed, at 7

- day Interva ls to maintain control. Do not make more than 6 applications to one crop of beans. Do not make the last application Within 7 days of harvest. (7

- day PHI). The following plant back intervals must be observed when planting ro t ational crops after an applic ation of Trigard Insecticide: All crops on the Trigard

insecticide label

– 0 days; Sweet corn, radishes, and cotton

– 30 days; any other crop

– 300 days.

100

- 656 5% L 6.29 lb ai/A Compost for mushroom

spawn NS NS NA

Label Directions: Apply Armor when preparing the mushroom substrate using a coarse drenching spray with low pressure to minimize the formation of mists. Apply in sufficient water for uniform distribution to the compost at label prescribed rates that result in a concentration of 5 parts per million (ppm) of active ingredient. Thoroughly incorporate with a spawning machine or similar equipment.

100

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

Label Directions: For control of Dipterous leafminers (Liriomyza spp.), apply 2.66 oz.lA in a minimum of 100 gals. of water as a foliar spray to the point of runoff when stippling first appears. Repeat applications at 7

- day intervals or as necessary to maintain control. Do not make more than a total of 6 applications to one crop. For contro l of fungus gnats (Bradysia spp.) and shore flies (Scatel/a spp.), apply 2.66 oz. of Citation in 100 gals. of water as a spray or drench to all surfaces where insect pests may breed. This includes the potting media surfaces, bench tops,

undersides of bench es, and the areas under benches that may be contaminated with potting media or algae. Repeat application on a 7 to 14

- day schedule to minimize reinfestation. Citation will not control adult ·stages of the insect pests. For control of adults, insecticides labeled for adult insect control should be used.

100

- 790 75% WP 4.95 lb ai/lb

seed Onion seed treatment NS NS 60 day PHI

Label Directions: Apply Trigard OMC to seed at the rate of 6.6 l bs . of product per 100 l bs. of seed (4.95 l bs. active ingredient per 100 l bs. of seed). Do not apply concurrent applications at planting time of insecticide products which have activity against onion maggot. Note: Do not harvest bulb vegetables grown from seed treated with Trigard

OMC within 60 da ys of planting. The following plant back intervals must be observed when planting ro t ational crops after an application of Trigard Insecticide: Leafy vegetables (except leafy Brassica), lima beans, peppers, cucurbits, tomatoes, Chinese cabbage, Chinese m ustard, onions, and potatoes

– 0 days; Sweet corn, radishes, and

cotton

– 30 days; any other crop

– 300 days.

1007

- 93 2.12% P/T 0.000028

lb/animal Feed through NS NS NA

Label Directions: Begin feeding in the spring before flies begin to appear and continue feeding throughout the summer and into the fall until cold weather inhibits fly development. Daily Dosage: Using 1/2 oz. scoop supplied with the product, mix one (1) scoop of SolitudeTM IGR in the horse's ration every day. Alternate Day Dosage: Using

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

42750

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

spawn NS NS NS

Label Directions: Apply Cyromazine 5% FL when preparing the mushroom substrate using a coarse drenching spray with low pressure to minimize the formation of mists. Apply in sufficient water for uniform distribution to the compost according to the rates in the following table. These rates result in a concentration of 5 parts perCyromazine Human Health Risk Assessment DP No. D387940

Page 13 of 56 Table 2 . Summary of Cyromazine End

- Use Products.

Reg No Formulation Max Application

Rate Target Use Sites Max. No. Applic. per Season Max No

Applic/

Season PHI

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

.

70585

- 1 1% G 0.000005

lb/lb Poultry Feed NS NS 3 day preslaughter

interval

Label Directions: If required based on label prescribed monitoring, f eed Larvadex 1 % Premix continuously as directed for 4 to 6 weeks. Usually, this is enough time for Larvadex 1 % Premix to thoroughly cover the droppings and break the fly population cycl e in the poultry house. After a minimum of 4 to 6 weeks of Larvadex 1% Premix feeding, carefully examine the manure pits. If little or no activity is observed in the manure, discontinue Larvadex 1 % Premix and continue the sanitary and management program. Continue monitoring the manure pits. If maggots become active again, repeat the procedure. Use bait, sprays, or fogs as needed during and between Larvadex 1 % Premix feeding periods to control any adult flies. During winter months or during periods of low fly pressure, discontinue Larvadex 1 % Premix use for at least 4 consecutive months per year. Consult with local extension service poultry entomologists or your State Agricultural Experiment station for additional localized fly control suggestions. Do not feed Larvadex 1 % Premix treated feed to broiler poultry. Larvadex 1 % Premix use in poultry

is limited to use as a feed

- through in chicken layer and breeder operations only and may not be fed to any other poultry species. To avoid illegal residues, Larvad ex 1 % Premix treated feed must be removed at least 3 days (72 hrs.) before slaughter. Manure from chickens fed Larvadex 1 % Premix may be used as a soil fertilizer supplement. Do not apply more than 3 tons of manure per acre per year. Do not apply to smal l grain crops that will be harvested or grazed or illegal residues may result. Do not feed manure from chickens fed Larvadex 1 % Premix to animals.

70585

- 2 2% L 4.36 lb ai/A Poultry Manure NS NS 1 day preslaughter

interval

Label Directions: First, monitor adult flies in and near the poultry house. When the population reaches a level to cause concern, use registered adulticide baits, sprays or fogs to reduce fly numbers and breeding potential. Then, examine manure and other fly breeding areas for mag got activity. If maggots are active, treat breeding sites with Larvadex 2SL. Mixing Application Dilute Larvadex 2SL with water to make a 0.1 % spray (see following Dilution Chart). Apply 1 gallon of finished spray per 100 sq. ft. of area over surface of ma nure, manure storage areas, spilled feed and other sites where maggots are active. Do not apply Larvadex 2SL more frequently than once every 21 days. Registered baits, sprays or fogs should be used to reduce adult flies present at the onset of

larvicide program and best management practices followed

70585

- 7 2% DF 4.36 lb ai/A Manure NS NS 1 day preslaughter

interval

Label Directions: Neporex 2SG is a water

- soluble granule suitable for dry scattering or spraying. The application

rate is 0.02 l b cyromazine per 200 sq. ft., independent of the method of application. Apply NEPOREX 2SG only on fly breeding sites. It is not intended for application to fly resting sites (walls, ceilings, etc.), as it has no effect on

adult flies. Prevent contamination o f feed troughs and water troughs.

75066

- 1 1% G .000005 lb /

lb Poultry Feed NS NS 3 day preslaughter

interval

Label Directions: If maggots are active, start Flyzine TM 1 % Premix in the ration. Feed Flyzine TM 1 % Premix continuously as directed for four (4) to six (6) weeks. Usually, this is enough time for Flyzine TM 1 % Premix to thoroughly cover the droppings and break the fly population cycle in the poultry house. After a minimum of four (4) to six (6) week s of Flyzine TM 1 % Premix feeding, carefully examine the manure pits. If little or no activity is observed in the manure, discontinue the use of Flyzine TM 1% Premix and continue the sanitary and management program. Continue monitoring the manure pits. If m aggots become active again, repeat the procedure. Use bait, sprays, or fogs as needed during and between Flyzine TM 1 % Premix feeding periods to control any adult flies. During the winter months or during periods of low fly pressure, discontinue Flyzine TM 1% Premix use for at least four (4) consecutive months per year.Cyromazine Human Health Risk Assessment DP No. D387940

Page 14 of 56 3.4 Anticipated Exposure Pathways

The Pesticide Re

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

application exposure for workers re

- entering treated fields. There are no residential uses of cyromazine . T here fore, there is no exposure in residential settings.

3.5 Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Execut ive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low

- Income Populations," ( http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf

. As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on pat terns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide. These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country. Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non

- dietary exposures based on home use of pesticide products and associated ri sks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas postapplication are evaluated. Further considerations are currently in development as OPP has committed resources and expertise to the development of speci alized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for Analysis

The studies available for consideration of cyromazine toxicity provide a comprehensive database; however, t here are three outstanding studies according to revised 40 CFR Part 158 Toxicology Data Requirement

. These studies include an acute neurotoxicity study, a subchronic neurotoxicity study, and an immunotoxicity study

. (The registrant has notified the Agency of the conduct of an ACN study to be completed and submitted by Spring 2013)Cyromazine Human Health Risk Assessment DP No. D387940

Page 15 of 56 Acute

- Oral rat, dermal rat, inhalation rat, eye ir ritation rabbit, dermal irritation rabbit, and skin sensitization guinea pig.

Subchronic

- Oral 90

- day rat and oral 90

- day dog;

Chronic

- Oral rat and dog; Reproductive/developmental

- Oral developmental rabbit and rat, 2

- generation reproductive rat

Other

- Or al rat and mouse cancer studies, 21

- day dermal rabbit toxicity, 28

- day rat inhalation, metabolism, mutagenicity screens.

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

Cyromazine was well absorbed after oral administration to rats . Excretion was rapid at the lower dose (3 mg/kg), but an apparent delay in excretion occurred at the high dose (300 mg/kg). Renal excretion was the primary route of elimination. Excretion was rapid with 54

- 82% of the

administered dose recovered in the urine and feces at 24 hours. Fecal elimination was equivalent among dose groups except the high dose males, where a greater percentage was eliminated by this route. The origin of fecal radioactivity was via biliary elimination. There was no evidence

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

fecal metabolites of 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 identified

.

Dermal a bsorption at 10 hrs = 13 %. Cyromazine is absorbed into the skin in an inverse dose related manner. The absorption into the skin is followed by a slower release into the body. Th e main route of excretion is in the urine. There is no evidence that the compound is s equestered in

the skin.

4.2.1 Dermal Absorption

No dermal or systemic toxicity was seen following repeated dermal applications to rabbits at 2000 mg/kg/day. In additio n, there are no concerns for developmental or reproductive toxicity. Therefore, quantification of dermal risk is not required.

4.3 Toxicological Effects

The liver and bone marrow (hematological system) are the primary targets for oral toxicity of cyromazine seen in a chronic dog study. Pronounced treatment

- related effects on hematological parameters were manifest in animals as decreases in hematocrit and hemoglobin levels at mid and high dose levels. Slight increases were also noted in relative brain, heart, and liver weights of the high dose males and females and the ovary weights of the high dose females. Decrease in body weight and food consumption are also common effects of cyromazine as observed in chronic dog, rat, mouse, and rabbit studies . No systemic toxicity was seen in rabbits following repeated dermal application at 2000 mg/kg/day for 21 days. A subchronic (28 day) inhalation study in rats is available where a NOAEL was not established. Clinical signs of toxicity such as hunched pos ture, piloerection, and reduced spontaneous activity were observed which is consistent with the dyspnea also observed at all concentrations.Cyromazine Human Health Risk Assessment DP No. D387940

Page 16 of 56 The available oral perinatal, prenatal and postnatal data demonstrated no indication of increased sensitivity of rats or rabbits to in utero exposure to cyromazine. No quantitative or qualitative susceptibility was observed in any study. In the prenatal developmental rat toxicity study, the NOAEL (300 mg/kg /day) for developmental effects was higher than the 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 clas sified as a “not likely” human carcinogen. The available mutagenicity data suggest that cyromazine does not have genotoxic activity.

Cyromazine is categorized as Toxicity Category III for acute oral, dermal and inhalation toxicity. Cyromazine is neith er an eye irritant nor a dermal sensitizer; however, it is mild skin irritant.

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

Although t here are no r esidual uncertainties or concerns for pre

- and/or post

- natal toxicity

, HED

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

- The toxicological data base is incomplete

. A neurotoxicity battery (acute and subchronic) and an immunotoxicity study are lacking

. (The registrant has notified the Agency of the conduct of an ACN study to be completed and submitted by Spring 2013)

4.4 .1 Completeness o f the Toxicology Database

T he toxicology database for cyromazine is partially adequate for evaluating and characterizing cyromazine toxicity and selecting endpoints for purposes of this risk assessment. A neurotoxicity battery of acute and subchronic duration is lacking. An immunot oxicity test is also

not available

. (The registrant has notified the Agency of the conduct of an ACN study to be completed and submitted by Spring 2013)

(see Appendixes for Toxicity Profile tables).

4.4.2 Evidence of N eurotoxicity

The outstanding a cute and subchronic studies were recently considered in a weight

- of

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

TXR 0056148 ). Cyromazine contains a symmetrical triazine substructure like atrazine, propazine a nd simazine. However, atrazine, propazine and simazine are halotriazines (see the structures below); cyromazine is not a halotriazine. Atrazine, propazine and simazine disrupt the hypothalamic

- pituitary

- gonadal (HPG) axis which results in neuroendocrine

- related effects in experimental toxicology studies. No such neuroendocrine effects have been observed for cyromazine. For cyromazine

, the liver and hematological system is the primary target organs

.Cyromazine Human Health Risk Assessment DP No. D387940

Page 17 of 56 The chronic point of departure (POD) is based on decre ased food consumption and body weight

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

the other triazines . Because cyromazine has a different toxicological profile from other triazines, it is not appro priate to infer or bridge information about the potential neurotoxic potential from atrazine, propazine, or simazine.

Cyromazine Atrazine Propazine Simazine

T he acute and subchronic neurotoxicity studies are require d in revised 40 CFR Part 158 Toxicology Data Requirements because they provide important scientific information on potential nervous system effects from pesticide exposure. These studies can provide data on a wide range of functional tests for evaluating n eurotoxicity including sensory effects, neuromuscular effects, learning and memory and histopathology of the nervous system. The Agency acknowledges that there are no clear signs of neurotoxicity following acute, subchronic or chronic dosing in multiple s pecies in the cyromazine database. However, the Agency also notes that the existing guideline studies are inadequate in their assessment of behavioral effects and do not use optimal methods to evaluate the potential toxicity to the nervous tissue structur e and function. Because there is not sufficient information to remove the requirements for these studies, the HASPOC concluded that the acute and subchronic neurotoxicity studies are required in accordance with revised 40 CFR Part 158 Toxicology Data Requ irements. Consequently, the 10X database uncertainty factor (UF DB ) has been retained for the lack of these neurotoxicity

studies

. This 10X database uncertainty factor will be reconsidered upon receipt and evaluation of the neurotoxicity stud y(s) by the Agency.

4.4.3 Evidence o f Sensitivity/Su sceptibility in the Developing o r Young Animal

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

- and post

- natal exposure to rats.

4.4.4 Re sidual Uncertainty in the Exposure Datab ase

The chronic dietary exposure analysis used tolerances and was refined with the use of percent crop treated data for some commodities

. The dietary assessment is not a highly refined

assessment. Therefore, dieta ry exposure to cyromazine will not be underestimated.

4.5 Toxicity Endpoint and Point of D eparture Selections

4.5.1 Dose

- Response AssessmentCyromazine Human Health Risk Assessment DP No. D387940

Page 18 of 56 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. There were no toxicological effects attributable to a single exposure of cyromazine

observed in the availabl e oral toxicity studies. Therefore, a POD for the acute (general population) dietary assessment was not selected. This may be revised upon the receipt of the ACN study currently being conducted by the registrant . A chronic/carcinogenicity rat study was selected as the POD for the chronic dietary assessment. No dermal or systemic toxicity was

observed following repeated dermal application at the highest dose tested for 21 days to rabbits. Additionally, there were no concerns for developmental or reproductive toxicity; t herefore a

POD for the dermal scenario was not selected. A POD for short

- and intermediate

- term
inhalation scenario was selected from a 28

- day inhalation rat study.

Chronic Dietary : UF= 1000x

- 10x for inter

- species extrapolation, 10x for intra

- species variation and 10x database UF for the lack of neurotoxicity battery. This 10X database uncertainty factor will be reconsidered upon receipt and evaluation of the neurotoxicity stud y(s) by the Agenc y.

Inhalation Occupational : MOE = 3000

– 10x for interspecies extrapolation, 10x for intraspecies variation, 3x for the use of a LOAEL (UF L ) and 10x for data gaps (UF DB ) for the lack of neurotoxicity battery. This 10X database uncertainty factor will be reconsidered upon receipt and evaluation of the neurotoxicity stud (y) by the Agency. The 3000x UF is in accordance with the recommendation by the Agency’s RfC/RfD Technical Panel ( EPA/630/P

- 02/0 02F December, 2002, Final Report).

OPP is conducting an independent retrospective analysis of more than 120 immunotoxicity studies submitted to Agency. There are no indicators in the hazard database for cyromazine to suggest a concern for immunotoxicity, consequently a 10x UF DB is not reta ined solely due to an outstanding immunotoxicity study . The preliminary results of the retrospective analyses support this approach of not retaining a database uncertainty factor for the lack of an immunotoxicity study.

4.5.2 Recommendation for Combinin g Routes of Exposures for Risk Assessment

When there are potential residential exposures to the pesticide, aggregate risk assessment must consider exposures from three major sources: oral, dermal and inhalation exposures. Since there

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

non

- food oral exposures is not required

.

4.5.3 Cancer Classification and Risk Assessment Recommendation

Cyromazine is classified as a “Not Likely Human Carcinogen” based on the lack of evidence of carcinogenicity in the mouse and rat c ancer studies (HED CPRC

, TXR No. 011384 , 1/6/95 ).

C yromazine was not mutagenic in three mutagenicity studies submitted to OPPCyromazine Human Health Risk Assessment DP No. D387940

Page 19 of 56 4. 5

. 4 Summary of Points of Departure and Toxicity Endpoints Used in Human Risk

Assessment

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

below:

Table 4. 5.4.1 Summary of Toxicological Doses and Endpoints for Cyromazine for Use in Dietary

Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty

/FQPA Safety

Factors RfD, PAD, LOC

for Risk

Assessment Study and Toxicological Effects

Acute Dietary (general population) A dose and an endpoint for acute dietary exposure were not identified for cyromazine.

Chronic Dietary (All Populations) NOAEL= 1.5

mg/kg/day UF A = 10x

UF H = 10x

UF DB = 10x Chronic RfD =

0.0015 mg/kg/day

cPAD = 0.0015 mg/kg/day Combined Chronic/Carcinogenicity

Toxicity in Rats, MRID 00103202

LOAEL = 15 mg/kg/day based on

food consumption and body weight decreases at 15 mg/kg/day ( LOAE L).

Cancer (all routes) Not likely human carcinogen

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

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

NOAEL = no 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 db = incomplete database. SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic).

RfD = reference dose.Cyromazine Human Health Risk Assessment DP No. D387940

Page 20 of 56 Table 4. 5. 4.2 Summary of Toxicological Doses and Endpoints for Cyromazine for Use in Occupati onal

Human Health Risk Assessments

Exposure/

Scenario Point of

Departure Uncertainty

Factors Level of

Concern for

Risk

Assessment Study and Toxicological Effects

Dermal

Short/intermediate

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.

Inhalation Short

to Intermediate

Term (1

- day

– 6 months ) LOAEL=

14.36 mg/kg/day * UF A = 10x

UF H =10x

UF DB = 10x

UF L = 3x Occupational

LOC for MOE

= 3000 28

- day Inhalation Toxicity study in

rats . MRID 47940804

LOAEL = 0.055 mg/L (equivalent

to 14.36 mg/kg/day oral dose)

based on impairment of the general

con dition with the symptoms of piloerection, dyspnea, hunched posture, and reduced spontaneous activity . This was the lowest

concentration tested. Cancer (all routes) Not likely human carcinogen

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

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

NOAEL = no 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 db =incomplete database. SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic).

RfD = reference dose. *mg/L conversion to mg/kg/day see A.3.6

. page 41 MOE = margin of exposure ; the maximum allowed by the Agency

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

4.6 Endocrine Disruption

As required by FIFRA and FFDCA, EPA reviews numerous studies to assess potential adverse outcomes from exposure to chemicals. Collectively, these studies include acute, subchronic and chronic toxicity, including assessments of carcinogenicity, neurotoxici ty, 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 maturati on, fertility, pregnancy rates, reproductive loss, and sex ratios in offspring. For ecological hazard assessments, EPA evaluates acute tests and chronic studies that assess growth, developmental and reproductive effects in different taxonomic groups. As part of its reregistration decision , EPA reviewed these data and selected the most sensitive endpoints for relevant risk assessment scenarios from the existing hazard database. However, as required by FFDCA section 408(p), cyromazine is subject to the

end ocrine screening part of the Endocrine Disruptor Screening Program (EDSP).

EPA has developed the EDSP to determine whether certain substances (including pesticide active and other ingredients) may have an effect in humans or wildlife similar to an effect produced by a “naturally occurring estrogen, or other such endocrine effects as the Administrator may designate.” The EDSP employs a two

- tiered approach to making the statutorily requiredCyromazine Human Health Risk Assessment DP No. D387940

Page 21 of 56 determinations. Tier 1 consists of a battery of 11 screening assay s to identify the potential of a chemical substance to interact with the estrogen, androgen, or thyroid (E, A, or T) hormonal systems. Chemicals that go through Tier 1 screening and are found to have the potential to interact with E, A, or T hormonal syst ems will proceed to the next stage of the EDSP where EPA will determine which, if any, of the Tier 2 tests are necessary based on the available data. Tier 2 testing is designed to identify any adverse endocrine

- related effects caused by the substance, and

establish a dose

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

Under FFDCA section 408(p), the Agency must screen all pesticide chemicals. Between October 2009 and February 2010, EPA issued test orders/data call

- ins for the first gro up of 67 chemicals, which contains 58 pesticide active ingredients and 9 inert ingredients. Cyromazine is not among the group of 58 pesticide active ingredients on the initial list to be screened under the EDSP. Accordingly, as part of registration revie w, EPA will issue future EDSP orders/data call

ins, requiring the submission of EDSP screening assays for cyromazine

. For further information on the status of the EDSP, the policies and procedures, the list of 67 chemicals, future lists, the test guidelin es and the Tier 1 screening battery, please visit our website: http://www.epa.gov/endo/

.

5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabol ism Studies

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

.

Data concerning the metabolism of cyromazine in lactating goats and laying hens have been previously submitted. The livestock metabolism data for cyromazine have been present ed to the HED Metabolism Assessment Review Committee (MARC, meeting date: 11/4/97). The MARC determined that the residue of concern in livestock commodities is the parent compound, cyromazine (Memo, 4/15/98 J.B. Stokes, D245214).

5.1.2 Summary of Environm ental Degradation

Based on previously submitted data, cyromazine is stable to hydrolysis and photolysis, and is persistent in aerobic soil (T 1⁄2 > 60 days). This was confirmed in the field studies, where dissipation half

- lives are as long as 250 days. Freu ndlich 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 the EFED Standardized Soil Mobility Classif ication Guidance (Bradbury, 2006). Cyromazine is also highly soluble (1.16 x 10 4 mg/L ). TheseCyromazine Human Health Risk Assessment DP No. D387940

Page 22 of 56 characteristics would suggest that cyromazine has the potential to leach through soils, especially sand, fine sands, and loamy sands, or to be transported in solu tion in runoff water.

5.1.3 Comparison of Metabolic Pathways

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

- methylcyromazine. The major

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

5.1.4 Residues of Concern Summary and Rationale

A summary of the metabolites and degradates to be included in the risk assessment and tolerance expression are presented below in Table 5.4.1. The residue of concern is the parent compound cyromazine as determined by the HED Metabolism Assessment Review Committee (MARC) (D245214, 11/4/97 )

. The MARC determined that the residue of concern in livestock commodities is the parent compound, cyromazine (D245214

, J.B. Stokes

, 4/15/98).

Table 5.4.1 : Summ ary of MARC Decisions for Cyromazine

Matrix Residues of Concern

For Risk Assessment For Tolerance Expression

Plants

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

.

5 .2 Food Residue Profile

Crop Field Trials

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

available for onion (green and dry bulb), broccoli, cabbage, mustard greens, tomato, lettuce (head and leaf), celery, spinach, cantaloupe, cucumber, honey dew melon, mushroom, pepper (b ell, chili, tabasco), corn (sweet K+CWHR, forage, fodder), radish (root, tops), mangoes, cottonseed, and bean (succulent). An adequate number of crop field trials conducted in appropriate ly representative locations are available for cyromazine for the cur rently registered crop applications and use patterns (application rate and PHI).Cyromazine Human Health Risk Assessment DP No. D387940

Page 23 of 56 Processed Food and Feed

The available processing data on tomatoes are adequate to support existing registered uses of cyromazine. Processing trials were conducted i n 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 processed commodities

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

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

cottonseed oils or soapstock even at the 5x rate.

Meat, Milk, Po ultry, and Eggs

Inadvertent tolerances need to be established for use of cyromazine treated manure as fertilizer on agricultural field s based on data submitted by Novartis Animal Health, U.S. Novartis submitted studies on cyromazine residues in poultry e xcreta from a poultry feed product and a product applied topically to poultry excreta. In the feed

- through study

, residues of cyromazine

were 3.6

- 5.8 ppm on Study Days 1

- 21 (before plateau) and 7.2

- 8.0 ppm on Study Days 28

- 42 (after plateau); correspondi ng 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 highest residues occurring immediately after each application and then declining. From Study Day 0 through Study Day 21 after the first application, residues of cyromazine and melamine declined from 49 to 3.0 ppm and from 0.53 to 0.18 ppm, respectively. After the second application on Study Day 21, residues of cyromazine and melamine increased to 39 ppm and 0.62 ppm, respectively, and then declined to 20 ppm and 0.51 ppm five days later. The second spray application did not result in residue buildup as compared to single treatment data.

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

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

2H5640. A maximum combined re sidue 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. D387940

Page 24 of 56 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 fer tilizer). A conservatively estimated residue of 40 ppm cyromazine is assumed based on results of a magnitude of the residue study in excreta topically treated with a 0.17 lb ai/gal soluble concentrate (SL). Residues from that study ranged from 49 ppm at day 0 to 20 ppm at day 26 with 40 ppm at day 24. Assuming 40 ppm cyromazine in treated manure, the calculated maximum label application rate of cyromazine at 4 tons treated manure per acre is 0. 33 lb a.i. per acre.Cyromazine Human Health Risk Assessment DP No. D387940

Page 25 of 56 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 rate used in the green house rotational crop study which resulted in a maximum residue level of 0.08 p pm in spring wheat straw. Adjusting the maximum residue level found in the greenhouse study in accordance with the maximum application rate derived from the magnitude of the residue study results in a

conservative tolerance level of 0. 6 0 ppm.

5.3 Water R esidue Profile

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

, applied using a feed

- through system in chi cken productions, or directly applied to manure generated by hogs and horses. Based on additional information included in a refinement performed by the Agency which incorporated suggestions by Novartis (2007 DP338467), an updated drinking water assessment (DWA) was performed for the manure applications (labels

70585

- 2, and 70585

- 7). The highest drinking water numbers resulted from direct application to succulent beans (refer to Table 5.3) and were previously estimated in the July 6, 2009 drinking

water assessment ( DWA

, DP 358724 ) ; for full details on this assessment, refer to Appendix B

.

Estimated Drinking Water Concentrations (EDWCs) Surface water concentrations were modeled using FIRST and groundwater concentrations were modeled using SCI

- GROW; refe r to http://www.epa.gov/pesticides/science/models_pg.htm#aquatic for additional information on these aquatic models.

Table 5.3 . Estimated drinking water concentrations (EDWCs ) for Cyromazine on Succulent Beans ( 2006, DP 317886).

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

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

Surface Water (FIRST)

0.125/6/7/1 47.1 15.8

Ground Water (SCI

- GROW)

0.125/6/7/1 1.1 1.1

* Applied as 6 applications at (0.125 lb ai/ac) rates, and a seasonal rate of 0.75 lb ai/acre. The concentrations have been adjusted with the Percent Crop Area (PCA) of 0.87 for a national assessment.Cyromazine Human Health Risk Assessment DP No. D387940

Page 26 of 56 5.4 Dietary Risk Assessment

5.4.1 Description of Residue Data Used in Dietary Assessment

A conservative chronic dietary exposure analysis was performed. Tolerance level residues and available average percent crop treated assumptions were used. DEEM default and empirical processing factors were used to modify the tolerance values. The chroni c analysis incorporated the 10 year average surface drinking water estimate from application of cyromazine to succulent

beans. As noted in the Executive Summary, although chronic dietary risk estimates significantly exceed OPP’s level of concern, HED did not attempt further refinement of the dietary exposure analysis because data that could be used to refine exposure estimates for the commodities that account for the highest contributions to dietary exposure (e.g., field trial data for inadvertent

toleran ces) are not available. [Note: an inadvertent tolerance of 0. 6 ppm is being established for all crops that are grown in soil amended with cyromazine treated manure and that do not have current tolerances established based on direct application of cyromazi ne ( D398364

, T. Morton &

B. Daiss

, 1 / 31 /1 3 ) ] Field trial and Pesticide Data Program data are available for a number of

commodities. Crop field trial data are available for onion (green and dry bulb), broccoli, cabbage, mustard greens, tomato, lettuce (he ad and leaf), celery, spinach, cantaloupe, cucumber, honey dew melon, mushroom, pepper (bell, chili, tabasco), corn (sweet K+CWHR, forage, fodder), radish (root, tops), mangoes, cottonseed, and bean (succulent).Cyromazine Human Health Risk Assessment DP No. D387940

Page 27 of 56 5.4.2 Percent Crop Treated Used in Dietary Assessment

February 16, 2011 Screening Level Estimates of Agricultural Uses of Cyromazine (121301) Sorted Alphabetically

Percent Crop T reate d

Crop Lbs. A.I. Avg. Max.

1 Beans, Green <500 <1 <2.5

2 Cantaloupes <500 <1 < 2.5

3 Celery 3,000 45 60

4 Chicory* <500 N/C N/C

5 Lettuce 5,000 10 25

6 Onions <500 <2.5 <2.5

7 Peppers <500 <2.5 5

8 Spinach 2,000 20 35

9 Tomatoes 2,000 5 25

10 Watermelons <500 <1 <2.5

All numbers rounded.

<500 Less than 500 pounds of active ingredient

<2.5 Less than 2.5 percent of crop treated

<1 Less than 1 percent of crop treated

N/C Only Lbs. A.I. available

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

SLUA data sources include:

USDA

- NA SS (United States Department of Agriculture's National Agricultural Statistics Service)

Private Pesticide Market Research California DPR (Department of Pesticide Regulation) These results reflect amalgamated data developed by the Agency and are releasable to the public.

5.4.3 Acute Dietary Risk Assessment

There were no toxicological effects attributable to a single exposure (dose) of cyromazine observed in oral toxicity studies including the developmental toxicity studies in rats or rabbits. Therefore, a dose and an endpoint for acute dietary exposure were not identified for cyromazine and an acute exposure assessment was not conducted

.Cyromazine Human Health Risk Assessment DP No. D387940

Page 28 of 56 5.4.4 Chronic Dietary Risk Assessment

Chronic dietary risk estimates are of concern for general population or other population subgroups. The subgroup with the highest risk estimate was children 1

- 2 years old with a %

cPAD of 93 0 %. The % cPAD for the general U.S. population was 42 0 %.

Although chronic dietary risk estimates significantly exceed OPP’s level of concern, HED did not attempt further refinement of the dieta ry exposure analysis (e.g., use of anticipated residues rather than tolerances) because data that could be used to refine exposure estimates for the commodities that account for the highest contributions to dietary exposure are not available.

5.4.5 Cancer Dietary Risk Assessment Cyromazine is classified as a “Not Likely Human Carcinogen” based on the lack of evidence of carcinogenicity in the mouse and rat c ancer studies (HED CPRC

, TXR No. 011384 , 1/6/95 ). Therefore, a cancer dietary risk assessment was n ot performed.

5.4.6 Summary Table

A dietary assessment was conducted for the registered uses of cyromazine. The dietary risk estimates are above HED’s level of concern; see Table 5.4. 6

. Table 5.4.6 includes the dietary risk estimates using tolerances ( both recommended tolerances in addition to highest field trial residues for some

commodities ) and with the tolerance for inadvertent residues

.

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

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

0.0015 0.006223 420 All Infants (< 1 year old) 0.008391 560

Children 1

- 2 years old 0.013987 930

Children 3

- 5 years old 0.011413 760

Children 6

- 12 years old 0.007749 520

Youth 13

- 19 years old 0.004756 320

Adults 20

- 49 years old 0.005329 360

Adults 50

- 99 years old 0.005944 400

Females 13

- 49 years old 0.005138 340

Although chronic dietary risk estimates significantly exceed OPP’s level of concern, HED did not attempt further refinement of the dietary exposure analysis because data that could be used to refine exposure estimates for the commodities that account for the highes t contributions to dietary exposure (e.g., field trial data for tolerances for inadvertent residues ) are not available.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

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

6.1 Residential Handler Exposure

The registered cyromazine uses are not expected to result in residential exposure.Cyromazine Human Health Risk Assessment DP No. D387940

Page 29 of 56 6.2 Post

- Application Exposure

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

6.3 Combined Exposure

The registered cyromazine uses are not expected to result in residential exposure , therefore, chronic aggregate exposures include food plus drinking water exposures only.

6.4 Residential Bys tander Postapplication Inhalation Exposure

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

- application inhalation

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

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

. However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

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

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

- application inhalation exposure data generated by the Agricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational

post

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

post

- application inhalation exposure assessment for cyromazine.

6. 5 Spra y Drift

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for [chemical]. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency’s Spray Drift website for more information at http://www.epa.gov/opp00001/factsheets/spraydrift.htm). On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product la bels/labeling. The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer mode l to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off

- target drift with specific pr oducts with significant risks

associated with drift.Cyromazine Human Health Risk Assessment DP No. D387940

Page 30 of 56 Although a quantitative residential postapplication inhalation exposure assessment was not performed as a result of pesticide drift from neighboring treated agricultural fields, an inhalation

exposure a ssessment was performed for flaggers. This exposure scenario is representative of a worse case inhalation (drift) exposure and may be considered protective of most outdoor agricultural and commercial postapplication inhalation exposure scenarios

.

7.0 Aggrega te Exposure/Risk Characterization

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures (dermal and residential) . In an aggregate assessm ent, exposures from relevant sources are added together and compared to quantitative estimates of hazard ( e.g. , a NOAEL or PAD), or the risks themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers

both the r oute and duration of exposure.

7.1 Acute Aggregate Risk

Current practice is to include only food and water in the acute aggre gate assessment. There were no toxicological effects attributable to a single exposure (dose) of cyromazine observed in oral toxicity studies including the developmental toxicity studies (r ats or rabbits ) . Therefore, a dose and an endpoint for acute dietary exposure were n ot identified for cyromazine and an acute aggregate exposure assessment is not required. Refer to section 5.4.3 for the acute dietary

assessment.

7.2 Short

- Term Aggregate Risk

There are no current or proposed residential uses of cyromazine. Therefore, the a cute and chronic exposure estimates provided in the dietary and drinking water exposure section represent

aggregate exposure.

7.3 Intermediate

- Term Aggregate Risk

There are no current or proposed residential uses of cyromazine. Therefore, the acute a nd chronic exposure estimates provided in the dietary and drinking water exposure section represent

aggregate exposure.

7.4 Chronic Aggregate Risk

There are no current or proposed residential uses of cyromazine. Therefore, the acute and chronic exposure estimates provided in the dietary and drinking water exposure section represent

aggregate exposure.Cyromazine Human Health Risk Assessment DP No. D387940

Page 31 of 56 7.5 Cancer Aggregate Risk

Cyromazine was not carcinogenic in mice or rats following long

- term dietary administration and

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

8.0 Cumulative Exposure/Risk Characterization

Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, E PA has not made a common mechanism of toxicity finding as

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

EPA has not assumed that cyromazine has a common mechanism of toxicity with other substances. For information regarding EPA’s efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA’s Office of Pesticide Programs concerning common mechanism determinations and proc edures for cumulating effects from substances found to have a common mechanism on EPA’s website at http://www.epa.gov/pesticides/cumulative/.

9.0 Occupational Exposure/Risk Characterization

9.1 Short

- /Intermediate

- Handler Risk

Occupational exposure to cyro mazine 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 assessmen ts (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

rate s for the assessed products

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

- assessed for the purp oses of this

document.

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

are expec ted :

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 ;

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

- s oluble p ackets for g roundboom

a pplication ;

• 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.Cyromazine Human Health Risk Assessment DP No. D387940

Page 32 of 56 Citation (75% ai) :

• Mixer/l oader

/applicator, manually

- pressurized handwand;

• mixer/l oader

/applicator, backpack sprayer; and

• mixer/l oader

/applicator

, mechanically

- pressurized handgun sprayer.

Liquid Formulations Armor (5% ai)

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

• Mixing/loading l iquids ;

• mixer/loader/applicator with m anually

- pressurized h andwan d; and

• mixer/loader/applicator with m echanica lly 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 ranules for feed through fly control

.

Neporex 2SG (2%) :

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

• applying granules by h and ;

• mixer/loader/applicator with backpack sprayer;

• mixer/loader/applicator with m anually

- pressurized h andwand ; and

• mixer/loader/applicator with mechanically

- pressurized handgun s prayer

.

Data and Assumptions for Handler Exposure Scenarios The assumptions and factors used for the exposure calculations include:

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

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

specific data, include the Pesticide Handlers Exposure Database Version 1.1 (PHED 1.1), the Agricultural Handler Exposure Task Force (AHETF) database, the Outdoor Residential Exposure Task Force (ORETF) database, or other registrant

- submitted occupational exposure studies. Some of these data are proprietary (e.g., AHETF data), and subject to the data protection provisions of FIFRA. The standard values recommended for use in predicting handler exposure that are used in this assessme nt, known as “unit exposures”, are outlined in the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (http://www.epa.gov/opp00001/science/handler

- exposure

- table.pdf), which, along with additional information on HED policy on use of s urrogate data, including descriptions of the various sources, can be found at http://www.epa.gov/pesticides/science/handler

- exposure

data.html

.

• The baseline clothing level was used as a starting point to calculate handler exposures, even though the proposed label recommends the use of baseline clothing plus water

- proof gloves.Cyromazine Human Health Risk Assessment DP No. D387940

Page 33 of 56 Depending upon the need for additional protection, additional PPE is added to obtain an MOE higher tha n the LOC. The baseline clothing level for occupational exposure scenarios generally represents an individual wearing long pants, a long

- sleeved shirt, shoes, socks, no

chemical

- resistant gloves, and no respirator. As reflected in the calculations includ ed herein, PPE may involve the addition of chemical

- resistant gloves or a respirator , which none of the registered labels currently requires

.

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

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

handled were de fined for each handler scenario by assuming an amount that can be reasonably treated by an individual in a single day. Area treated and amounts handled

assumed are as follows:

Wettable Powder Formulations Trigard (75% ai) :

• 350 acres/day for m ixing/ l oading and applying wettable powder packaged in water

soluble p ackets for a erial a pplicati on ;

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

- soluble

p ackets for g roundboom application; and

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

Citation (75% ai) :

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

- pressurized handwand ;

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

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

- pressurized h andgun

s prayer

.

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

• 576,000 sq ft/day for mixing/loading liquids ( 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 57,600 sq ft). 576,000 square feet (i.e., 10 football fields) was assessed as a high

- end assumption.);

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

- pressurized handwand and a mechanically pressurized handgun sprayer (from personal communications with the American Mushroom Institute an employee can apply the pesticide in the mushroom room when the casing layer is added. One employee wo uld treat a room of 8,000 sq ft once per crop. HED is not specific with respect to the number of rooms an employee might treat in one day, therefore the standard HED assumption of 1 acre (43,560 sq ft) was assessed. This is equivalent to 5

– 6 rooms of 8 000 square feet treated per day) ; and

Larvadex 2SL (2%) ( 1 Acre or 43,560 sq ft was assessed based upon HED standard assumptions):Cyromazine Human Health Risk Assessment DP No. D387940

Page 34 of 56 • 43

, 560 sq ft/day for mixing/loading liquids

• 43,560 sq ft

/day for for mixing/loading/applying with a manually

- pressurized handwand ; and

• 43,560 sq ft

/day for for mixing/loading/applying with a m echanically pressurized

h andgun sprayer.

Granular Formulations

Solitude IGR (2 .12 %) :

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

data r egarding how many horses a single worker may treat per day, a high

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

Larvadex 1% Premix and Flyzine 1% Premix :

• 1 00 tons feed/day for mixing/loading granules (l acking specific data regarding how many tons of chicken feed a single worker may handle per day, a high

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

Neporex 2SG (2%) :

• 1 acre/day for loading/app lying 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 press urized handgun

sprayer.

• Body Weight: In order to estimate risk, toxicological points of departure (POD) are compared with exposure estimates. These PODs are typically normalized by body weight (e.g., mg/kg). Therefore, to make an appropriate comparis on to estimate risk, exposure

estimates must also be normalized by body weight. Over the last 14 years, OPP has used the mean values for body weight as presented in the 1997 Exposure Factors Handbook in assessing occupational and residential risk. The bo dy weight values in the 1997 handbook are based on an analysis of data from the National Center for Health Statistics (NCHS, 1987). In October of 2011, EPA published a revised edition of the handbook (EPA, 2011) which provides the most up

- to

- date data on exposure factors, including body weight. The body weight values in the 2011 handbook are based on an analysis of 1999

- 2006 data from the National Health and Nutrition Examination Survey ( http://www.cdc.gov/ nchs/nhanes.htm )

. The average (male and female combined) body weight of 80 kg was used for this

assessment.

A POD for dermal exposure was not selected for cyromazine because no hazard was identified via the dermal route (i.e., no systemic toxicity was observed at the limit dose of 2,000 mg/kg/day). Therefore, the occupational risk assessment was based on inhala tion exposure only. Daily inhalation handler exposures are estimated for each applicable handler task with the application rate, amount handled or area treated in a day, and the applicable inhalation un it exposure using the following formulas:Cyromazine Human Health Risk Assessment DP No. D387940

Page 35 of 56 Daily Expos ure = Unit Exposure x Application Rate x Daily Area Treated

Where:

Daily Exposure = Amount (mg/day) inhaled that is available for inhalation absorption; Unit Exposure = Unit exposure value (mg/lb ai) derived from Sept 26, 2011

handler

expo sure data; Application Rate = Normalized application rate bas ed on a logical unit

treatment; Daily Area Treated = Normalized application area ba sed on a logical unit

treatment;

The daily inhalation dose is calculated by normalizing the daily exposure b y body weight and adjusting

.

Average Daily Dose = Da ily Exposure / Body Weight

Where:

Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given scenario; toxicity by the inhalation route is considered to be equivalent to the

estimated toxicity by the oral route of exposure (i.e., no inhalation absorption factor) ; Daily Exposure = A mount inhaled that is available for inhalation absorption; Body Weight = Body weigh t determined to represent the population of interest

.

Exposure and Risk Estimates

Table 9.1.1 presents the exposure/risks for short a nd intermediate

- term inhalation exposures at

baseline and with additional PPE as needed (i.e., a PF 5 respirator). With a PF 5 respirator the Agency assumes an 80% protection factor is provided by a NIOSH

- approved quarter

- face, cup

style respirator (it is similar to the paint masks painters often wear). This 80% PF respirator only provides dust/mist filtering capabili ty and is not assessed when the active ingredient has a vapor pressure in the range that organic vapors are a concern.

Mostly all scenarios were below HED’s level of concern (LOC) at baseline and therefore not of

concern (i.e. , MOEs ≥ 3,000 for short

- an d intermediate

- term exposure durations ) , except for the

m ixer/ l oader/ applicator m echanically pressurized h andgun s prayer scenario for fly control in mushrooms; and fly larvae control in cattle, hog, and poultry operations. Both scenarios at baseline (no r espirators) had MOEs of 2,400 and 720, respectively; when a PF 5 respirator was added, the MOEs increased to 12,000 and 3,600 and were therefore identified as not of concern.Cyromazine Human Health Risk Assessment DP No. D387940

Page 36 of 56Cyromazine Human Health Risk Assessment DP No. D387940

Page 37 of 56 Table 9.1

. 1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Cyromazine

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

- soluble packages ).

Exposure Scenario Crop or Target Inhalation Unit Exposure 1
(mg/lb ai) Maximum

Application Rate

2 Amount Treated

Daily 3 Inhalation

Mitigation

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

(LOC = 3,000)

Mixer/Loader

Mixing/Loading Wettable Powder packaged in

Water

- Soluble Packets for Aerial Application B rassica (cole) leafy vegetables group 5 (including: abyssinian cabbage; bok choy; broccoli; broccoli, Chinese; broccoli raab; Brussels sprouts; cabbage; cabbage, Chine se; cabbage Chinese mustard; cabbage, seakale; cauliflower; cavalo broccolo; collards; Hanover salad; kale, common; kohlrabi; mustard, wild; mustard, Chinese; mustard greens; mustard spinach; and rape greens) and turnip greens 0.00024 (Eng. Control) 0.125

(lbs ai/A) 350

(A/day) 0.00013 109,000

Mixing/Loading Wettable Powder packaged in

Water

- Soluble Packets for Groundboom Application 80 (A/day) 0.00003 0 480,000

Mixing/Loading Liquids Sciard fly control in

mushrooms

0.000219 0.00014 (lbs ai/sq ft) 576,000

(sq ft) 0.00022 65

, 000

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

(A) 0.000010 1

, 40 0

, 000

Mixing/Loading Granules Feed

- Through Fly Control in and around horses, horse barns,

horse stables and paddocks,

horse race tracks 0.0017 0.00066 (lb ai/horse) 1,000

(horses/day) 0.000014 1,020,000

For fly control in and around 1) caged or slatted flooring layer chicken operations 2) Breeder Chicken Operations 0.010 (lb ai/ton feed) 100

(tons feed/day) 0.00002 1 67 0 ,000

Applicator

Applying Sprays with B rassica (cole) leafy vegetables 0.000068 0.125 350 0.000037 380,000Cyromazine Human Health Risk Assessment DP No. D387940

Page 38 of 56 Table 9.1

. 1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Cyromazine

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

- soluble packages ).

Exposure Scenario Crop or Target Inhalation Unit Exposure 1
(mg/lb ai) Maximum

Application Rate

2 Amount Treated

Daily 3 Inhalation

Mitigation

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

(LOC = 3,000)

Fixed

- wing Aircraft group 5 (including: abyssinian cabbage; bok choy; broccoli; broccoli, Chinese; broccoli

raab ; Brussels sprouts; cabbage; cabbage, Chinese; cabbage Chinese mustard; cabbage, seakale; cauliflower; cavalo broccolo; collards; Hanover salad; kale, common; kohlrabi; mustard, wild; mustard, Chinese; mustard greens; mustard spinach; and rape greens) and turnip greens (Eng. Control) (lbs ai/A) (A/day)

Applying Sprays with Open Cab Groundboom Sprayer 0.00034 80 (A/day) 0.000043 340,000

Loading/Applying Granules, Belly Grinder Control of fly larvae in cattle, hog, and poultry operations 0.062 4.36 (lb ai/A) 1

(A) 0.0034 4,200

Applicator, Granules by Hand (No Respirator) 0.47 0.00010 (lb ai/sq ft) 1,000

(sq ft) 0.00059 24,000

Flagger

Flagging (Sprays) for Aerial Operations B rassica (cole ) leafy vegetables group 5 (including: abyssinian cabbage; bok choy; broccoli; broccoli, Chinese; broccoli raab; Brussels sprouts; cabbage; cabbage, Chinese; cabbage Chinese mustard; cabbage, seakale; cauliflower; cavalo broccolo; collards; Hanover salad; kale, common; kohlrabi; mustard, wild; mustard, Chinese; mustard greens; mustard spinach; and 0.00035 0.125 (lbs ai/A) 350

(A/day) 0.00019 75,000Cyromazine Human Health Risk Assessment DP No. D387940

Page 39 of 56 Table 9.1

. 1. Short

- /Intermediate

- Term Occupational Exposure and Risk Estimates for Cyromazine

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

- soluble packages ).

Exposure Scenario Crop or Target Inhalation Unit Exposure 1
(mg/lb ai) Maximum

Application Rate

2 Amount Treated

Daily 3 Inhalation

Mitigation

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

(LOC = 3,000) rape greens) and turnip greens

Mixer/Loader/Applicator
Manually

- pressurized

Handwand For control of selected insects,

including Dipterous leafminers, and fungus gnats in landscape ornamentals; container grown ornamentals; greenhouse, lath and shadehouse grown ornamental bedding plants, and ornamental crops; and interiorscapes; and shore fl ies, only in greenhouse ornamental crops and interiorscapes. 0.030

0.125 (lbs ai/A) 40

(gal/day) 0.000019 760,000

Backpack Sprayer 0.14 40 (gal/day) 0.000088 160,000

Mechanically

- pressurized Handgun Sprayer 0.0039 1,000 (gal/day) 0.000061 230,000

Mechanically

- pressurized Handgun Sprayer (General Broadcast/Foliar Applications

- Greenhouses) 0.12 1,000 (gal/day) 0.0019 7,600

Manually

- pressurized

Handwand Sciard fly control in

mushrooms 0.030 6.10 (lb ai/A) 1

(A) 0.0023 6,300

Mechanically pressurized Handgun Sprayer 0.079

PF 5 = 0.0158 0.0060

PF 5 = 0.0012 2,400

PF 5 = 12,000 Manually

- pressurized

Handwand fly control in and around

chicken layer and breeder operations 0.030 3.75 (lb ai/A) 1

(A) 0.0014 10,100

Mechanically pressurized Handgun Sprayer 0.079 0.0037 3,900

Backpack Sprayer

Control of fly larvae in cattle, hog, and poultry operations 0.030 0.020 (lb ai/gal) 40

(gal/day) 0.00030 48,000 Manually

- pressurized

Handwand Mechanically pressurized Handgun Sprayer 0.079

PF 5 =0.0158 1,000 (gal/day) 0.020

PF 5 = 0.0040 724

PF 5 = 3,600

1. PHED/ORETF (level of mitigation: Baseline, PPE, Eng. Controls = water

- soluble packages, PF 5 = 80% protection factor provided by a NIOSH

- approved quarter

- face, cup

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

2. Based on registered label.

3. Exposure Science Advisory Council Policy #9.1 and other assumptions based on specific product and scenario (described in section 4.1)

. 4. Inhalation Dose = Dermal Unit Exposure (mg/kg) x Application Rate (lb ai/acre or gal) x Amount Treated (A/day) /BW (kg)Cyromazine Human Health Risk Assessment DP No. D387940

Page 40 of 56 5. Inhalation MOE = Inhalation NOAEL (mg/kg/day)/ Inhalation Dose (mg/kg/day)Cyromazine Human Health Risk Assessment DP No. D387940

Page 41 of 56 Based upon the proposed seed treatment use, occupational handler exposure is expected for individuals involved in commercial seed treatment and planting

. The registered label specifies that this use is permitted only to licensed commercial seed treatment companies. Therefore, on

farm treatment was not assessed

.

Post

- application exposure to agricultural workers is possible if they perform tasks that involve the soil subsurface following planting of treated seeds.

Commercial seed treatment equipment is designed to apply accurately measured quantities of pesticides to a given weight or quantity of seed. For all crops, potential occupational exposure

scenarios from use of cyromazine as a commercial seed treatment inc lude:

Mixing, loading, applying wettable powder formulations; Bagging treated seed; Sewing bags; Multiple activities; and Planting treated seed.

Typically for large

- scale commercial seed treatments, handlers perform only those specific

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

Chemical

- specific data for assessing expo sure from the proposed uses of cyromazine were not submitted to the Agency in support of this Section 3 application. Unit exposure data from PHE D and HED ExpoSAC Policy 14: Standard Operating Procedures (SOPs) for Seed Treatment were used in this assessment. Unit exposure data for mixing/loading wettable powder formulations from PHED was used as a surrogate for the loader/applicator seed treatmen t scenarios, since no

seed

- treatment

- specific unit exposure values are available for wettable powder formulations. Table 9.1.2 provides a summary of the unit exposure values used to assess commercial seed treaters and planters.

Table 9.1

. 2 . Unit Exposure Values Used for Assessing Commercial Seed Treaters and

Planters

. Scenario Inhalation (mg/lb ai) PPE Level Loader/Applicator 1 0.0434 Baseline, no respirator Loader/Applicator 0.0087 Baseline + PF 5 Respirator 3

Loader/Applicator 0.0043 Baseline + PF 10 Respirator 4

Sewer 2 0.00023 Baseline, no respirator
Bagger 2 0.00016 Baseline, no respirator Multiple Activities 2 0.0016 Baseline, no respirator Multiple Activities 0.0003 Baseline + PF 5 Respirator 3

1. Based on unit exposure for mixing/loading wettable powder formulations from PHED.

2 . Based on unit exposures from HED Policy #14.

3. PF 5 : 80% protection factor is provided by a NIOSH

- approved quarter

- face, cup

- style respirator; 4. PF 10: 90% protection factor is provided by a NIOSH

- approved half

- face cartridge or canister respirator or a powered air

purifying respirator (PAPR). This 90% PF respirator can be fitted with a dust/mist filter only or with an organic

- vapor

- removing

fi lter with a dust/mist filter.Cyromazine Human Health Risk Assessment DP No. D387940

Page 42 of 56 For purposes of performing commercial seed treatment assessments, HED used ExpoSAC Policy 15 to estimate amount of seeds treated per day and seeds planted per day. The amount assessed was 5,500 seeds treated per day assume d for bulb onion seeds.

Daily Exposure

Daily handler exposures are estimated for each applicable handler task with the application rate, the amount of seed treated/planted in a day, and the applicable unit exposure using the following

formula:

Daily Exposure (mg ai/day) = Unit Exposure (μg ai/lb ai handled) * Application Rate (lbs ai/lb seed) * Daily Amount Handled (lbs seed/day) * Conversion Factor (mg/1,000 μg)

Where:

Daily Exposure = Amount (mg ai/day) inhaled that is available for inhalation absorption ; Unit Exposure = Unit exposure value (μg ai/day); Application Rate = Normalized application rate based on a logical unit

treatment, such as lb ai/lb seed; a nd, Daily Amount Handled = Amount seed treated/planted per day (lb seed/day).

Daily Dose

Daily dose (inhalation) was calculated by normalizing the daily inhalation exposure value by body weight and accounting for inhalation absorption:

Average Daily Dose (mg/kg/day) = Daily Exposure (mg ai/day) x { Absorption Factor (%/100) } Body Weight (kg)

Where:

Average Daily Dose = Absorbed dose received from exposure to a pesticide in a given

scenario (mg pesticide active ingredient/kg body weight/day); Daily Exposure = Amount (mg ai/day) inhaled that is a vai lable for inhalation absorption; Absorption Factor = A measure of the amount of chemical that crosses a biological boundary such as the lungs; and Body Weight = Body weight determined to represent the population of interest in a

risk

assessment.Cyromazine Human Health Risk Assessment DP No. D387940

Page 43 of 56 Margin of Exposure (MOE)

The daily inhalation doses received by occupational handlers were compared to the appropriate points of departure (i.e., NOAEL) to assess the inhalation risks to occupational handlers.

MOE = _____NOAEL (mg/kg /day)____ Average Daily Dose (mg/kg/day)

Where:

MOE = Margin of exposure value used by HED to represent risk or how

close a chemical exposure i s to being a concern (unitless);

ADD = Average daily dose (AD D) is absorbed dose recei ved from

exposure to pesticide;

NOAEL = Dose level in a toxicity study, where no observed adverse effects

occurred in the study.

Commercial Seed Treatment Exposure and Risk Estimates

Most s eed treatmen t (Trigard OMC; EPA Reg. No. 100

- 790) handler exposures resulted in

MOEs that do not exceed HED's level of concern (i.e. , MOEs ≥ 3,000 ) at baseline attire (i.e., single layer of clothing and no respirator)

, except for the loader/applicator and “multiple

activities” scenarios that presented MOEs of 97, and 2,600, respectively. The “multiple activities” scenario presented no risk of concern with ad ditional Protective Personal Equipment (PPE) (i.e., PF 5 respirator; MOE = 13,000). However, the loader/applicator scenari o, even at the highest level of PPE (i.e., PF 10 respirator) did not reach the level of concern of 3,000 (MOE = 970). For characterization purposes, note that this chemical has 1) a low vapor pressure (1.3 x

10 - 9 mm Hg); 2) acute inhalation toxicity categ ory of III; and a 10x dat abase uncertainty factor ( UF ) for the lack of neurotoxicity battery and immunotoxic i ty studies

.

Table 9.1.3 presents summaries of the short

- and intermediate

- term occupational handler risk

estimate s for commercial seed treatment.Cyromazine Human Health Risk Assessment DP No. D387940

Page 44 of 56 Table 9.1.3. Short

- and Intermediate

- Term Occupational Handler Exposures and Risks for Treating 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 5

(mg/kg/day) Short /Int

Term

Inhalation

MOE 6
(LOC = 3,000) Mitigation

Level 4 Mitigation

Level 4

Commercial Loader/applicator

0.050 5,500 0.0434

PF 5 = 0.0087

PF 10 = 0.0087 0.1477

PF 5 = 0.0295

PF 10 = 0.0148 97

PF 5 = 480

PF 10 = 970

Sewer 0.00023 0.0008 18,000
Bagger 0.00016 0.0005 26,000

Multiple Activities 0.0016

PF 5 = 0.0003 0.0054

PF 5 = 0.0011 2,600

PF 5 = 13,000

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

- 790) ; 2. Assumption for pounds of small vegetable seeds treated per day from Policy #15 was used for all vegetable seeds on label whic h included: bulb vegetables;

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

4. PF 5: 80% protection factor is provided by a NIOSH

- approved quarter

- face, cup

- style respirator;

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

6. Short

- and Intermediate

- term I nhalation MOE = NOAEL (14.33 mg/kg/day for short

- term exposure ) / inhalation daily dose (mg/ kg/

- day). Level of concern = 3,000.

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

scenario.

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

level of concern when baseline attire is worn. Table 9.1.4 presents the short

- and intermediate

term risk estimate s for planters.

Table 9.1.4. Short

- and Intermediate

- Term Occupational Handler Exposures and Risks f or 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 5

(mg/kg/day) Short /Int

Term

Inhalation

MOE 6

(LOC = 3,000) Mitigation

Level 4 Mitigation

Level 4

Planters Seed

Planter 0.050 320 0.0034 0.00067 21,000

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

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

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

4. PF 5: 80% protection factor is provided by a NIOSH

- approved quarter

- face, cup

- style respirator;

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

6. Short

- and Intermediate

- term I nhalation MOE = NOAEL (14.33 mg/kg/day for short

- term exposure ) / inhalation daily dose (mg/ kg/

- day). Level of concern = 3,0 00.Cyromazine Human Health Risk Assessment DP No. D387940

Page 45 of 56 9.2 Short

- /Intermediate

- /Long

- Term/Cancer (if needed) Post

- Application Risk

9.2.1 Dermal Postapplication Risk

No hazard was identified via the dermal route of exposure and therefore quantificat ion of risk via this route of exposure is not required.

9.2.2 Inhalation Postapplication Risk

Dermal Post

- Application Risk There are no concerns regarding exposure through the dermal route for post

- application workers conducting post

- application activities since no toxicological endpoint was selected.

Inhalation Post

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

- application inhalation

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

. However, there are multiple potential sources of post

- application inhalation exposure to individuals performing post

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

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

- application inhalation exposure data generated by the Ag ricultural Reentry Task Force and may, as appropriate, develop policies and procedures, to identify the need for and, subsequently, the way to incorporate occupational

post

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

post

- application inhalation exposure assessment for cyromazine.

Although a quantitative occupational post

- application inhalation exposure assessment was no t performed, an inhalation exposure assessment was performed for agricultural occupational/commercial handlers. Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

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

- application inhalation exposure scenarios.

Furthermore, the Worker Protection Standard for Agricultural Pesticides contains requirements

f or protecting workers from inhalation exposures during and after greenhouse applications through the use of ventilation requirements. [40 CFR 170.110, (3) (Restrictions associated with pesticide applications)].Cyromazine Human Health Risk Assessment DP No. D387940

Page 46 of 56 Bulb Onion Seed Treatment Occupational Post

- application Exposure and Risk (Trigard
OMC; EPA Reg. No. 100

- 790)

A post

- application inhalation exposure assessment is not required as exposure is expected to be negligible. Seed treatment assessments provide quantitative inhalation exposure assessm ents for seed treaters and secondary handlers (i.e.planters). It is expected that these exposure estimates would be protective of most post

- application inhalation exposure scenarios.

Occupational dermal post

- application risks to agricultural workers foll owing the planting of treated seeds were not assessed, since a dermal endpoi nt was not selected for cyromazine

.

10.0 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.

R

. Daiss & T. Morton

, 1 / 3 0 /201 3 , D 398366, Cyromazine

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

Ivan Nieves

, 1 / 31 /201 3

, D 398369

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

.

Tiffany Dowen, James Hetrick, & Rosanna Louie

- Juzwiak, 2/10/ 2012 , D 398026

, Drinking Water Assessment for All Currently Registered Uses of Cyromazine

.

Deborah Smega l , 1/3/2012, TXR0056148, Cyromazine: Summary of Hazard and Science Policy Council (HASPOC) Meeting of December 8, 2011: Recommendations on data requirements for immunotoxicity and acute and subchronic neurotoxicity studies for cyromazine.

Steve Dapson & Esther Rinde, 1/6/95, Carcinogenicity Peer Review of Cyromazine.Cyromazine Human Health Risk Assessment DP No. D387940

Page 47 of 56 A ppendix A

. Toxicology Profile and Executive Summaries

Table A.1. Cyro mazine Toxicology Data Requirements

Table 1. Guideline Data Requirements

Test Technical

Required Satisfied

870.1100 Acute Oral Toxicity

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

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

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

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

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

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

yes

yes

yes

yes

yes yes

yes

yes

yes

yes

yes

870.3100 Oral Subchronic (rodent)

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

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

- Day Dermal

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

- Day Dermal

................................ .............................. 870.3465 90

- Day Inhalation

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

yes

yes

no

no yes

yes

yes

no

no

870.3700a Developmental Toxicity (rodent)

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

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

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

yes

yes yes

yes

yes

870.4100a Chronic Toxicity (rodent)

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

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

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

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

................................ .................... yes a

yes

yes a

yes

yes yes

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

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

— Gene Mutation

- mammalian

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

— Structural Chromosomal Aberrations

... 870.5900 Mutagenicity

— Other Genotoxic Effects

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

yes

yes

yes yes

yes

yes

yes

870.6100a Acute Delayed Neurotox. (hen)

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

- Day Neurotoxicity (hen)

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

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

- Day Neuro. Screening Battery (rat)

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

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

no

yes

yes

no -

-

no

no

no

870.7485 General Metabolism

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

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

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

no

yes yes

yes

no

a Guideline 870.4300 satisfies guideline 870.4100a and 870.4200a.Cyromazine Human Health Risk Assessment DP No. D387940

Page 48 of 56 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. Toxicology profile for Cyromazine Study Type /

Guideline No. MRID (Year) /

Classification / Doses Results

Subchronic oral

- Dog 870.3100 (82

- 1) 00135432 (1979)

Acceptable/Guideline 0, 30, 300, 1000 or 3000 ppm (0, 0.75, 7.5, 25 and 75 mg/kg/day) The systemic toxicity LOAEL is 1000 ppm (25 mg/kg/day) based on alteration in liver weight in males. The systemic toxicity NOAEL is 300 ppm (7.5 mg/kg/day).

Subchronic oral

- Rat 870.3100 (82

- 1) 00135433 (1979)

Acceptable/Guideline 0, 30, 100 and 300 ppm (0, 3, 10, and 30 mg/kg/day) The systemic toxicity LOAEL is 300 ppm (30 mg/kg/day), based on alteration in the liver weight changes in males. The systemic t oxicity NOAEL is 30 ppm (3 mg/kg/day).

28

- day Inhalation

- Rat

870.3465 47940804 (1988)

Acceptable/Guideline Nominal 55, 210, or 710 mg/m 3 The LOAEL is 0.055 mg/L/day based on impairment of the general condition with the symptoms of piloerection, dyspnea, hunched posture, and reduced spontaneous activity.

The NOAEL was not observed.

21

- day dermal toxicity

- Rabbit 870.3200 (82

- 2) 44060901 (1992)

Acceptable/Guideline 0, 50, 200 & 2000 mg/kg/day No treatment related systemic toxicity was noted. The systemic toxicity NOAEL > 2000 mg/kg/day and the systemic toxicity LOAEL > 2000 mg/kg/day. No dermal irritation was noted. The dermal toxicity NOAEL > 2000 mg/kg/day and the dermal toxicity LOAEL > 2 000 mg/kg/day.

21

- day dermal toxicity

- Rabbit 870.3200 (82

- 2) 44060902 (1984)

Acceptable/Guideline 0 & 2010 mg/kg/day No treatment related systemic toxicity was noted. The systemic toxicity NOAEL > 2010 mg/kg/day and the systemic toxicity LOAEL > 2010 mg/kg/day. No dermal irritation was noted. The dermal toxicity NOAEL > 2010 mg/kg/day and the dermal toxicity LOAEL > 2010 mg/kg/day.

Chronic oral (6

- months)

- Dog 870.4100 (83

- 1) 00103193 (1982)

Acceptable/Guideline 0, 30, 300 or 3000 pp m (0, 0.75, 7.5 and 75 mg/kg/day) The systemic toxicity LOAEL is 3000 ppm (75 mg/kg/day) based on alteration in hematological parameters (hemoglobin, and hematocrit). The systemic toxicity NOAEL is 300 ppm (7.5 mg/kg/day).

Combine Chronic/ Carcinogenici ty

- Rat 870.4300 (83

- 5) 00103202 (1982)

Acceptable/Guideline 0, 30, 300 and 3000 ppm (0, 1.5, 15, and 150 mg/kg/day) The systemic toxicity LOAEL is 300 ppm (15 mg/kg/day) based on decreased body weight. The systemic toxicity NOAEL is 30 ppm. (1.5 mg/kg/day). There is no evidence of carcinogenicity.

Carcinogenicity

Mouse 870.4200 (83

- 2) 00115736 (1982)

Acceptable/Guideline 0, 50, 1000, and 3000 ppm (0, 7.5, 150, and 450 mg/kg/day) The systemic toxicity LOAEL is 1000 ppm (150 mg/kg/day) based on decreased body weight. The systemic toxicity NOAEL is 50 ppm. (7.5 mg/kg/day). There is no evidence of carcinogenicity.Cyromazine Human Health Risk Assessment DP No. D387940

Page 49 of 56 Table A.2. 2. Toxicology profile for Cyromazine Study Type /

Guideline No. MRID (Year) /

Classification / Doses Results

Cancer Classification:

The HED CPRC TXR

No. 011384 Jan. 6, 1995 The HED CPRC re

- evaluated the weight

- of

- evidence on Cyromazine

with particular reference to its carcinogenic potential. The HED CPRC concluded that cyromazine should be re

- classified as Group E, based on

a submission of data from a re

- examination of the tissues from the mouse and rat studies. Cyromazine is classified as a “Not Likely Human Carcinogen” based on the lack of evidence of carcinogenicity in the

mouse and rat cancer studies. Developmental toxicity

- Rabbit 870.3700 (83

- 3b) 00150471 (1985)

Acceptable/Guideline 0, 10, 30, and 60 mg/kg/day The maternal toxicit y LOAEL is 30 mg/kg/day, based on reduced body weight gain and food consumption, and the maternal toxicity NOAEL is 10 mg/kg/day. The developmental toxicity LOAEL was not established and the developmental toxicity NOAEL = 60 mg/kg/day (HDT). Developmenta l toxicity

- Rat 870.3700 (83

- 3a) 00027488 (1979)

Acceptable/Guideline 0, 100, 300 and 600 mg/kg/day The maternal toxicity LOAEL is 300 mg/kg/day, based on clinical signs (red or clear nasal discharge) and decreased body weights. The

maternal toxicity NOAEL = 100 mg/kg/day. The developmental toxicity LOAEL is 600 mg/kg/day (HDT), based on increased incidence of minor skeletal variations. The developmental toxicity NOAEL is 300 mg/kg/day. Two generation reproduction

- Rat 870.3800 (83

- 4) 001031 97 (1981)

Acceptable/Guideline 0, 30, 1000 and 3000 ppm (0, 1.5, 50, and 150 mg/kg/day) The parental systemic toxicity LOAEL is 3000 ppm (150 mg/kg/day) based on decreased body weights that were associated with decreased food efficiency. The parental sy stemic toxicity NOAEL is 1000 ppm (50 mg/kg/day). The offspring systemic/developmental toxicity LOAEL is 3000 ppm (150 mg/kg/day), based on decreased body weights at birth and through weaning. The systemic/developmental toxicity NOAEL is 1000 ppm (50 mg/k g/day). No effects were noted on reproductive parameters and no reproductive toxicity LOAEL was determined. The reproductive toxicity NOAEL is

Metabolism

- Rat 870.7485 (85

- 1) 41442101 (1989)

Acceptable/Guideline

3 and 300 mg/kg Cyromazine was well absorbed after oral administration. Excretion was rapid at the lower dose (3 mg/kg), but an apparent delay in excretion occurred at the high dose (300 mg/kg). Fecal elimination was equivalent among dose groups except the high d ose males, where a greater percentage was eliminated by this route. The origin of fecal radioactivity was via biliary elimination. Residual radioactivity in tissues was minimal in all dose groups. Urinary and fecal metabolites of 14C_cyromazine were iso lated 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. D387940

Page 50 of 56 Table A.2. 2. Toxicology profile for Cyromazine Study Type /

Guideline No. MRID (Year) /

Classification / Doses Results

Dermal Absorption

- Rat 870.7600 (85

- 3) 40168601 (1987)

Acceptable/Guideli ne 0.10, 1.00, and 10 mg/rat Absorption at 10 hrs = 13 %. Cyromazine apparently rapidly absorbed into the skin in an inverse dose related manner. The absorption into the skin is followed by a slower release into the body. The main route of

excretion is apparently by the urine. There is no evidence that the compound is sequestered in the skin. Mean absorption based on blood, urinary/fecal excretion, and carcass, ranged from 0.6 to 7% for animals sacrificed at the end of the exposure periods. For anim als exposed for 10 and 24 hours and followed for 48 hours post

- exposure, mean absorption ranged from 8 to 14.5%. Total radioactivity absorbed generally decreased as dose increased indicating saturation of absorption with increasing dose. Amounts remaining in/on the skin at termination ranged from 4.5% (10 mg dose/2 h exposure) to 24% ( 0.1 mg dose/24 hour exposure). The majority of the absorbed radioactivity was found in the urine and carcass. Most of the unabsorbed radioactivity was found in the skin was hes from each

dose/duration. Dermal Absorption

- Rat 870.7600 (85

- 3) Accession No: 257488

(1987) Acceptable/Guideline 0.10, 1.00, and 100 mg/rat Absorption at 10 hrs = 10%. Mean total recoveries of applied radioactivity from all dose groups ranged from 85 to 101%. Mean absorption based on blood, urinary/fecal excretion, and carcass, ranged from 2% to 11%. Total radioactivity absorbed generally increased with increasing exposure time but decreased with increasing dose indicating saturation of penetr ation with increasing dose. The majority of the absorbed radioactivity was found in the urine and carcass. Most of the unabsorbed radioactivity was found in the skin washes from each dose/duration (35

- 90%). However, based on measurements of skin absorp tion, a significant amount of radioactive dose was also found in the skin itself (9

- 40%). Mean absorption with inclusion of radioactivity in dissolved skin ranged from

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

to the radioac tivity in the skin itself decreased with time indicating penetration into the subsurface of the skin with time after treatment. Mutagenicity

Gene mutation in Hamster (Chinese)

- (84

- 4.) Mutagenic

- Nucleus Anomaly) MRID: 00103199 (1980)

Minimum acceptable/Guideline Lavardex tech. 98.9% pure 2000, 4000, and 8000 mg/kg in 20 mL/kg 0.7% CMC

solution Negative mutagen.

Mutagenic

- Point

Mutation Salmonella typhimurium (84

- 4) MRID: 0089923 (1978)

limited/Guideline 25, 75, 255, 675 and 2025

plate in DMSO,

+

- S

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

TA100 with and without activation.

84

- 2b. Mutagenic.

- Dominant lethal test species: Mouse (84

- 2b) MRID:00103198 (1981)

limited/Guideline 226 and 678 mg/kg in PEG400 vehicle (0.2 mL/log of body weight) Negative mutagen.Cyromazine Human Health Risk Assessment DP No. D387940

Page 51 of 56 A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD)

– All Population s

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

observed in the available oral toxicity studies including the developmental toxicity studies in rats

or rabbits. An acute neurotoxicity study that could provide an e ndpoint for assessing acute dietary exposure is not available. Therefore, a dose and an endpoint for acute dietary exposure is not identified for cyromazine and an acute aggregate exposure assessment is not required.

A.3. 2 Chronic Reference Dose (cRfD ) `

Selected Study: Combined chronic/c arcinogenicity in the r at ; MRID 00103202

In a 24

- month chronic toxicity/oncogenicity study in rats, 60 Charles River Sprague

- Dawley rats sex/dose were administered 0, 30, 300 and 3000 ppm of cyromazine. An additional 1 0 animals per sex in the control and 3000 ppm groups were designated for interim sacrifice at one year. The study design allocated groups of 60 rats per sex to dose levels of 0, 30, 300 or 3000 ppm (0, 1.5, 15, 150 mg/kg/day) of cyromazine (95.5%). An ad ditional 10 animals per sex in the control and 3000 ppm groups were designated for interim sacrifice at one year. The statistical evaluation of mortality provided by the registrant indicated no significant incremental charges with increasing doses of cyro mazine in male or female rats (41% survival in HDT vs. 42% survival in controls). Survival in males and females were excellent in all groups after 24 months. There were no statistically significant differences between the control and treated groups in be nign tumors (adenomas and fibroadenomas), malignant tumors (adenocarcinomas) or combined benign and malignant tumors (adenomas and/or fibroadenomas and/or adenocarcinomas); there were no statistical trends and no dose response. Hence, there was no evidenc e of carcinogenicity at the dose levels tested in this study. Female rats had decreased body weight gain at doses of 300 and 3000 ppm, as did males at doses of 3000 ppm. Body weight gains were reduced by 22% in the high

- dose males and 33% in females, and in the mid

- dose females body weight gain was reduced by about 10% from week 49 until termination. Food consumption was also decreased at these dose levels; however food efficiency was unchanged from control. The systemic toxicity LOAEL is 300 ppm (15 mg /kg/day) based on decreased body weight. The systemic toxicity NOAEL is 30 ppm (1.5 mg/kg/day). There wa s no evidence of carcinogenicity.

Dose and Endpoint for Establishing a POD : NOAEL = 1 .5 mg/kg/day day based on food consumption and body weight decreases at 1 5 mg/kg/day (LOAEL).

Uncertainty Factor (UF) : 1000x (10x for interspecies variation and 10x for intraspecies variation and 10x database UF)

Chronic RfD = 1 .5 mg/kg (NOAEL) = 0.0 01 5 mg/kg

100 0 (UF)

[Note: T he chronic RfD has been revised from previous risk assessments based on reevaluation of the existing data .]Cyromazine Human Health Risk Assessment DP No. D387940

Page 52 of 56 A.3. 3 Incidental Oral Exposure (Short

- and Intermediat e

- Term)

Cyromazine has not been registered for residential uses; therefore, selection of a toxicity endpoint is not necessary for this exposure scenario at this time.

A.3. 4 Dermal Exposure (Short

- , Intermediate

- and Long

- Term )

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

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

A.3.6 Inhalation Expo sure (Short

- and Intermediate

- Term)

Inhalation Exposure ( Short

- Term)

Selected Study : 28

- day inhalation toxicity study; MRID 47940804

. In this subchronic inhalation toxicity study (28

- Day), 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 con centrations 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 (5 males and 5 females) were allowed to survive for 3

additional weeks then sacrificed to obs erve 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, hun ched 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 in males of all treatment groups were sligh tly (but not significantly) decreased when compared with the controls. This decrease was independent of the aerosol concentration. No exposure

- related changes were observed in food consumption.

Hematology investigation revealed slightly higher values of r ed 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 returned back to normal. Blood chemistry data revealed no evidence of treatment

- induced significant changes to the parameters measured.

Pituitary glands weight of the test article

- exposed males was dose

- dependently lower compared

to controls after 4 weeks, however; in the satellite groups that were sacrificed at week 8, both weights were similar. Also, no corroborating microscopic effects on the pituitary were observed. Therefore, this effect was not considered adverse. The liver of the females of the mid (0.210Cyromazine Human Health Risk Assessment DP No. D387940

Page 53 of 56 mg/L) and high (0.710 mg/L) dose gr oups showed a significantly higher weight than that of the controls. However, in the recovered satellite animals of the 0.710 mg/L group, liver weights returned back to normal. Also, no corroborating microscopic effects in the liver were observed.

Therefo re, this effect was not considered adverse. Gross examination revealed no changes which could be attributed to test article toxicity. Microscopic examination revealed 3 females from the 0.710 mg/L group and one female from the 0.055 mg/L group with small foci of lymphocytic infiltration in the adrenal cortex. This change was absent in control female rats and was not dose dependent. Therefore, it was not considered adverse.

The LOAEL is 0.055 mg/L/day based on impairment of the general condition with

th e 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 condit ion with the symptoms of piloerection, dyspnea, hunched posture, and reduced spontaneous activity. The NOAEL was not
observed. This study is appropriate for use since it is route specific and the duration coincides

with the short

- (1

- 30 days) and intermed iate

- (1

- 6 mos) term scenarios. The study also provided a recovery group of animals which showed that adverse effects did reverse within 3 weeks.

The inhalation L OAEL of 0.055 mg/L /day is equivalent to 14

. 3 6 mg/kg/day oral dose using the following formula:

mg/kg/day = mg/L x A x CF x D x AF (0.055 x 1 x 43.5 x 6 x 1 = 14.3 6 )

where

A is absorption factor . Default value of was used.

CF is a conversion factor in L/hr/kg to account for respiratory volume and body weight for a given species and strain. For the rat strain used in this study it is 43.5

D is duration of daily exposure in hours. A 6 hour daily exposure was used.

AF is activity factor. The animal default factor of 1 was used.

Uncertainty F actor (UF ): 3000

– 10x for interspecies extrapolation, 10x for intraspecies variation, 3x for extrapolation of the study LOAEL to NOAEL

, and 10x data base UF for the lack of neurotoxicity battery and immunotoxic i ty studies. The Agency’s RfD/RfC Technical Panel limits the total UF applied for any particular chemical to be 3000 (EPA/630/P

- 002F). ,

C linical signs observed (piloerection, dyspnea, hunched posture, and reduced spontaneous activity) at the lowest concentration t ested were not as severe as at the mid

- and highest concentrations. The severity of the clinical signs at this lowest dose was slight and the observed clinical signs appeared mostly after 7 days of exposure. Piloerection increased to moderate after

23 da ys of exposure at this lowest concentration. In contrast, the clinical signs at the mid and high exposure groups were more severe and appeared within 1

-- 3 days after exposure. Following cessation of exposure during recovery, all the clinical signs in the high exposure group disappeared except for decreasing slight dyspnea and hunched posture. Although t hereCyromazine Human Health Risk Assessment DP No. D387940

Page 54 of 56 were no recovery groups in the mid and low exposure groups , it would also be expected that clinical signs would have resolved as in the high dose grou p, especially since the clinical signs

were much less severe than in the high dose group . There were also no biologically significant changes in the hematological parameters at the lowest concentration tested of 0.055 mg/L , unlike

the mid

- and high

- dose g roups

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

- response curve, suggesting the low concentration is near a true no effect level.

MOE: 30 00 for short

- and intermediate

- term duration.

Comments about Study/Endpoint : S ince 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

.Cyromazine Human Health Risk Assessment DP No. D387940

Page 55 of 56 Appendix B

. Physical/Chemical Properties

Table C1

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

- 632 PAI ).

Parameter Value Reference

Melting point/range 224

- 225 C MRID 40594903

pH 8.0 @ 25 C MRID 40594903

Density 1.35 g/mL @ 20 C MRID 40594903

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

Solvent solubility( g/mL @25 C) Hexane, not soluble Cyclohexane, not soluble

Methanol , 1.49 Toluene, not soluble Acetone, 0.16

2

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

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

Dissociation constant 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 40594903Cyromazine Human Health Risk Assessment DP No. D387940

Page 56 of 56 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 F ebruary, 1995.

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