Date:Subject:UNITEDSTATESENVIRONMENTALPROTECTIONAGENCYWASHINGTON,D.C.20460November26,2014OFFICEOFCHEMICALSAFETYANDPOLLUTIONPREVENTIONDaminozide.DraftOccupationalandResidentialExposure/RiskAssessmentforRegistrationReview.PCCode:035101DecisionNo.:478436PetitionNo.:NADPBarcode:424016RegistrationNo.:NARegulatoryAction:RegReviewDRACaseNo.:0032RiskAssessmentType:ExposureAssessmentTXRNo.:NACASNo.:1596-84-5MRIDNo.:4901350040CFR:NAFrom:Through:To:IntroductionZaidaFigueroa,M.S.,IndustrialHygienistRiskAssessmentBranchIIHealthEffectsDivision(7509P)ChristinaSwartz,BranchChiefRiskAssessmentBranchIIHealthEffectsDivision(7509P)andMargaretHathaway,ChemicalReviewManagerPesticideRe-EvaluationDivision(7508P)ThePesticideRe-evaluationDivision(PRD)requestedthatHealthEffectsDivision(HED)conductanoccupationalexposure/riskassessmenttoestimatetherisktohumanhealththatwillresultfromthecurrentactivelyregisteredusesofdaminozide. ThismemorandumcontainsHED'soccupational/residentialexposureandriskassessmentrequiredduringregistrationreviewtoreflecttheupdateddaminozide'shazardassessment,sciencepoliciesandprocedures.Therearenoregisteredresidentialuses;therefore,thisriskassessmentonlyaddressespotentialoccupationalexposuresassociatedwiththedaminozide'sregistereduses.Page1of19It is HED policy

to use the best available data to assess exposure. Several sources
of generic data were used in this assessment

as surrogate data in the absence
of chemical-specific

data, including: Pesticide Handlers Exposure Database Version
1.1 (PHED
1.1 ); the Agricultural Handler Exposure Task Force (AHETF) database;
the Agricultural Reentry Task Force (ARTF) database; and an exposure monitoring degradation study (MRID No. 49013500); published literature study, etc]. Some of these data are proprietary,
and subject

to the data protection provisions

of the Federal Insecticide, Fungicide,
and Rodenticide
Act (FIFRA). Note: This memorandum
was reviewed

by the Exposure Science Advisory Committee (ExpoSAC)

on November 06,2014. Page

2 of19Table of Contents 1.0 Executive Summary .............................................................................................................

4 2.0 Risk Assessment Conclusions
and Recommendations ........................................................

6 2.1 Summary

of Risk Estimates .............................................................................................

6 2.2 Label Recommendations

from Occupational Assessment.. .............................................

6 2.3 Label Recommendations

from Residential Assessment ..................................................

6 2.4 Data Deficiencies
and Requirements

.. .. ................

. .............

. . . . ........... ................

.... ..........

6 3.0 Hazard Characterization .......................................................................................................

6 4.0 Use Profile .................

. ..............................

. ...........................................................................

9 5.0 Residential Exposure and Risk Estimates ..........................................................................

10 5.1 Residential Post-application Exposure
for Ornamentals from Retail Locations ............

10 5.2 Spray Drift ......................................................................................................................

10 6.0 Occupational Exposure and Risk Estimates ......................................................................

10 6.1 Occupational Handler Exposure/Risk Estimates ............................................................

1 0 6.1.1 Occupational Non-cancer Handler Exposure/Risk Estimates .................................

10 6.1.2 Occupational Cancer Handler Exposure/Risk Estimates .......

. .......................

.. ....... 11 6.2 Occupational Post-application Exposure/Risk Estimates ..............................................

12 6.2.1 Occupational Post-application Inhalation Exposure/Risk Estimates ......................

13 6.2.2 Occupational Post-application Non-Cancer Dermal Exposure/Risk Estimates ...... 13 6.2.3 Occupational Post-application Cancer Dermal Exposure/Risk Estimates ..............

13 Appendix

A. Summary

of Occupational Handler and Post-application Cancer Exposure/Risk Estimates
for UDMH ....................................................................................................................

14 Appendix

B. Summary

of Occupational Cancer Algorithms ......................................................

15 Appendix

C. Summary

of the Study (MRID# 49013500): Determination

of the Concentration

of Unsymmetrical Dimethyl Hydrazine (UDMH)

in a Mixture ofDaminozide

and Water over

a Storage Period of 24 Hours ...........................................................................................................

1 7 Page

3 of191.0 Executive Summary Daminozide (N-[dimethylamino] succinamic acid), also known by the trade name alar,
is a systemic plant growth regulator registered

for non-food use on containerized ornamental plants grown
in commercial greenhouses, shade houses, and nurseries. This memorandum provides

an occupational/residential exposure and risk assessment

for the currently registered uses of daminozide

for registration review. HED also considered exposure to unsymmetrical dimethyl hydrazine (UDMH),

a metabolite/degradate formed by the hydrolysis of daminozide.

As
a degradation product,

it exists
as a minor impurity

in technical and formulated products. The UDMH exposure assessment

is presented

in Appendix

A. Exposure Profile There are three registered daminozide products
for treatment

of containerized ornamental plants grown
in commercial greenhouses, shade houses, and outdoor nurseries. There

is a potential
for occupational exposure associated with handler activities (i.e., mixing, loading, and applying),

as well as post-application exposure

is expected
for workers re-entering treated areas. Based on the use pattern, the duration
of exposure

is expected

to be short-term

(1 to 30 days) and intermediate-term

(1 to 6 months) because:

1) plants grown
in commercial greenhouses, shade houses, and outdoor nurseries
are cyclical, and 2) product applications

are expected

to be rotated. There are no registered residential uses or scenarios that will result
in residential exposure; therefore, this risk assessment only addresses potential occupational exposures associated with the registered uses. Hazard Profile The toxicology database
for daminozide

is complete and sufficient
for risk assessment purposes. The toxicology database also includes toxicity studies conducted

on UDMH. No target organs for non-cancer effects were identified
for daminozide. There was no evidence

of susceptibility in the developmental

and reproduction studies. For short- and intermediate-term dermal and inhalation non-cancer occupational exposure,

no toxicological endpoints were selected for daminozide because
no hazard was identified and no effects were observed

in the database. These dermal and inhalation hazard considerations

are considered protective

of the UDMH that may be formed

as a tank mix metabolite/degradate

due to the low amount present. Daminozide
and UDMH were assessed
for carcinogenicity under the Agency's previous (1986) cancer guidelines and were classified

as Group B2 carcinogens (i.e., probable human carcinogen). Separate cancer potency (Q*) factors were calculated
for each compound.
For daminozide

a Q* of0.0087 (mg/kg/day)"

1 was calculated based on an increased incidence

of combined lung carcinomas
and adenomas

in male mice. For UDMH,

a Q* of0.46 (mg/kg/day)"

1 was calculated based on an increased incidence

of hemangiosarcomas

in male mice. Neither compound showed evidence

of genotoxicity

in a battery
of assays submitted

to the Agency; however there are published genotoxicity studies on UDMH showing positive results. Page

4 of19Residential Exposure There are no registered residential uses, or commercial/professional

uses at residential sites associated with daminozide

at this time. Therefore,

a quantitative residential exposure assessment

is not required. Furthermore, HED determined
that daminozide

is not registered

on use sites that are likely
to result
in spray drift. Therefore,

a quantitative spray drift assessment was not conducted

for daminozide. Non-Cancer Occupational Exposure Occupational non-cancer occupational handler and post-application

risk estimates were not quantitative assessed, because
no toxicological endpoints

of concern were identified. The current 24-hour REI specified
on the registered labels

is based on
a dislodgeable foliar residue (DFR) study on apples and chrysanthemums reviewed

as part of the reregistration eligibility decision (RED) document (MRID No. 40037001). However, since there
is no longer

a dermal toxicological endpoint

of concern, the REI should
be based on the current acute toxicity of the active ingredient.
The current toxicity database
for daminozide indicates low acute toxicity via oral, dermal and inhalation (Category
IV) routes of exposure. This compound causes mild eye irritation (Category III), and is not

a skin sensitizer. Based on the [156 subpart
K] Worker Protection Standard Statement,

a REI of 12 hours

is adequate

to protect agricultural workers from post-application exposures

to daminozide. HED recommends
that the REI be adjusted
on the registered labels from 24 hours
to 12 hours. Cancer Occupational Exposure Occupational handler cancer (dermal+ inhalation) risk estimates
for daminozide range from 1x1o-

7 to 4x10-

5
. The occupational post-application dermal cancer risk estimates
for daminozide range from 6x10-

6 to 5x10-

5
. Human Studies Review 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 data, which include studies from PHED 1.1; the AHETF database;
the AR TF database; and an exposure monitoring degradation study (MRID No. 49013500);

are (1) subject

to ethics review pursuant

to 40 CFR 26, (2) have received that review, and (3) are compliant with applicable ethics requirements.

For certain studies, the ethics review may have included review by the Human Studies Review Board. Descriptions

of data sources,

as well as guidance

on their use, can be found

at the Agency website

1 • 1 http:

/ / www .epa.gov

/ pesticides/science/handler-exposure-data.html

and http:
// www.epa.gov

/ pesticides/science

/ post-app-exposure-data.html Page

5 of192.0 Risk Assessment Conclusions
and Recommendations 2.1 Summary

of Risk Estimates HED has not identified any non-cancer risks associated with occupational exposures

of daminozide

or UDMH. Occupational handler cancer risk estimates
for both daminozide
and UDMH range from 2x10·

8 to 4x10-

5 and post-application dermal cancer risk estimates range from 6x10·

6 to 5x10·

5 . 2.2 Label Recommendations

from Occupational Assessment A degradation study (MRID No. 49013500) was submitted

by Chemtura Corporation

in response to the requirements

of a generic data call-in. The study confirmed that the degradation

to UDMH starts immediately after daminozide

is mixed with water, and increases steadily during the 24 hour storage period. Therefore,
the current restriction (i.e., **Solutions** prepared should not be held for more than 24 hours.")
on the labels
to prevent- workers from exposure

to increased levels ofUDMH forming

in the mixed solutions,

is adequate and should remain on the registered labels. Also, HED that the REI be adjusted
on the registered labels. 2.3 Label Recommendations

from Residential Assessment None. 2.4 Data Deficiencies
and Requirements There are no data deficiencies

or requirements identified
for daminozide

at this time. 3.0 Hazard Characterization The toxicology database
for daminozide

is complete and sufficient
for risk assessment.

No target organs for non-cancer effects were identified

in subchronic

or chronic dietary studies on daminozide. Daminozide

did not show evidence

of neurotoxicity

in the rat or immunotoxicity

in the mouse. No offspring

or reproductive toxicity was observed

in a two-generation study
in the rat. Furthermore,

the toxicology database
for daminozide
also includes toxicity studies conducted

on UDMH,

a metabolite/degradate
found
in daminozide

(at 0.005%),

as well as a minor mammalian metabolite (estimated

at 1% of the dose). UDMH

is formed
by hydrolysis

of daminozide.
The rate of UDMH degradation

is approximately 0.1% of the parent and cmitinues to increase over time (D411596). Both daminozide
and UDMH are classified under the previous (1986) Agency cancer guidelines as B2, probable human carcinogens,
and separate cancer potency factors (Q*) were calculated

for each compound.
The carcinogenicity

of both compounds
has been extensively reviewed

by the Agency

in three Cancer Peer Reviews and by the Scientific Advisory Panel
to the Agency. Both compounds have been shown
to increase the incidence

of vascular and lung tumors

in mice. Page

6 of19Acute Toxicity The current toxicity database
for daminozide indicates low toxicity via the acute oral, dermal and inhalation routes of exposure (Category IV). This compound causes mild eye irritation (Category III), and is not

a skin sensitizer (Category IV).
A summary

of the acute toxicity profile

is sUillllUU'ized

in Table

3 .1. **1!.-~le ~.t_.**  **Acu~** 'fp*fti PI'QlUe (O,r **Jlandn~d'-**

fiWI " '(fte.of

-- **~~.: ~Me** 

•
Results **Stud_y/~~** line

..

n r:hiJJd,.

-" . -

:r. 870.1000 Acute Oral LDso, Rat 46164609
LDso => 5000 mglkg Category
IV 870.1200 Acute Dermal LDso, Rabbit 46164610
LDso

> 5,000 mglkg Category

IV 870.1300 Acute Inhalation Toxicity, Rat 46217101
LCso

> 2

. 20 mg/L Category

IV 870.2400 Primary Eye Irritation

, Rabbit 46164611
Mild irritant Category

III 870.2500 Primary Dermal Irritation, Rabbit 46164612 Non-irritant. Category
IV 870.2600 Dermal Sensitization, Guinea Pig 46164613

Not sensitizers Toxicological PODs Used for Risk Assessment For short- and intermediate-term non-cancer dermal and inhalation occupational exposure,

no endpoints were identified
for daminozide.

No systemic

or local dermal toxic effects were observed

in a 28-day dermal toxicity study in rats up to the limit dose.
In addition,

no significant findings were observed

in a rat 28-day inhalation toxicity study. Daminozide
and UDMH were assessed

for carcinogenicity under the Agency's previous (1986) cancer guidelines and were classified

as Group B2 carcinogens (i.e., probable human carcinogen). Separate cancer potency (Q*) factors were calculated

for each compound.
For daminozide

a Q* of 0.0087 (mg/kg/dayt

1 was calculated based on an increased incidence

of combined lung carcinomas
and adenomas

in male mice. For UDMH,

a Q* of 0.46 (mg/kg/dayt

1 was calculated based on an increased incidence

of hemangiosarcomas

in male mice. Neither compound showed evidence

of genotoxicity

in a battery
of assays submitted

to the Agency; however there are published genotoxicity studies on UDMH showing positive results. Summaries

of the toxicological doses and endpoints
for daminozide
and UDMH are summarized in Table 3.2.

Page

7 of19Table 3.2. Summary

of Toxicological Doses and Endpoints
for Daminozide
and UDMH for Use in Occupational Human Health Risk Assessments. Uncertainty/
Level of Study and Toxicological Effects Exposure/

Point of FQPASafety Concern
for

,, Scenario

.

,,_ Departure

Risk 'c
Factors Assessment

. Daminozide Dermal Short-term (1- 30 days) and

A dermal risk assessment was not conducted because
no hazard was identified
for dermal Intermediate-term exposure. (1-
6 months) Inhalation Shortterm (1-30 days)

An inhalation risk assessment was not conducted because
no hazard was identified
for inhalation and Intermediate- exposure. term (1-6 months) Classification:

B2 carcinogen, probable human carcinogen (Agency 1986 Cancer Guidelines) Cancer (all routes) based on an increase

in combined lung and vascular tumors

in mice. Cancer potency factor

= 0.0087 (mg!kglday)·

1 based on lung tumors

in male mice. UDMH Dermal Short-term

A separate risk assessment was not conducted

for UDMH. The contribution

to exposure from the (1- 30 days) and UDMH that
is formed

as a tank mix degradate

is negligible relative

to exposure

to UDMH formed Intermediate-term

as a metabolite

of daminozide, along with UDMH present

as an existing contaminant

of (1-
6 months) daminozide products. Inhalation Short-

A separate risk assessment was not conducted

for UDMH. The contribution

to exposure from the term (1-30 days) UDMH that
is formed

as a tank mix degradate

is negligible relative

to exposure

to UDMH formed and Intermediate-

as a metabolite

of daminozide, along with UDMH present

as an existing contaminant

of term (1-6 months) daminozide products. Cancer (oral, Classification:

B2 Carcinogen, probable human carcinogen (1986 Cancer Guidelines), based on an increased incidence

of vascular and lung tumors

in mice. Cancer potency factor

= 0.46 dermal, inhalation) (mg/kg/day)-

1 based on the incidence

of vascular tumors

in male mice. Q*= cancer potency factors. Absorption Daminozide

is poorly absorbed through the skin.
A dermal absorption
factor (DAF) of 2% was selected for cancer risk assessment based on in vivo dermal absorption study in the rat. The low absorption seen in the study
is consistent with the lack of systemic

or dermal toxicity observed

in a 28-day dermal toxicity study in the rat. This value

is considered

to be conservative

and an upper bound limit, based on selection

of the individual animal with the highest absorption. Furthermore,

an in vivo dermal absorption study was also conducted

in male rats using UDMH;

a DAF of23% was selected
for cancer risk assessment
and is considered conservative. Since no inhalation absorption data are available
for these compounds, toxicity by the inhalation route

is considered

to be equivalent

to the estimated toxicity
by the oral route of exposure. Body Weight The standard body weight for the general population
(80 kg) was used for all exposure scenarios covered

in this risk assessment since the endpoints selected were not developmental and/or fetal effects.

Page

8 of19

'4.0UseProfileTherearethreeseveraldaminozideend-useproducts(EP)registeredforuseonornamentalcropsincludesflowering,budding,andfoliageplantsgrownincommercialgreenhouses,shadehousesandnurseries.AlltheEPshavesimilarusedirectionsandmaybeappliedusinghandheldequipmentandnotthroughanytypeofirrigationsystem.Basedonthecurrentusepatternsandcurrentlabeling,typesofequipmentandtechniquesthatcanpotentiallybeused,occupationalhandlerexposure(i.e.,mixing,loading,andapplyingactivities),isexpectedfromtheregistereduses.Thedurationofexposureisexpectedtobeshort-term(1to30days)andintermediate-term(1to6months)because:1)plantsgrownincommercialgreenhouses,shadehouses,andoutdoornurseriesarecyclical,and2)productapplicationsareexpectedtoberotated.ThePersonalProtectiveEquipment(PPE)statementontheregisteredlabelsrequireapplicators,andotherhandlerstowear:longsleevedshirt,longpants,waterproofgloves,shoesplussocks.Alltheregisteredproductlabelshavearestrictedentryinterval(REI)of24hours.ThecurrentlyregisteredproductsandusedirectionscontainingdaminozidearelistedinTable4.1.Table4.1.SummaryofDirectionsforEnd-UseProductsofDaminozide.Applic.Timing,Type,andEquip.Foliarspray(directed)tocontainerizedplants;Handheldequipment(manuallypressurizedhandwand,backpack,sprayer,mechanicallypressurizedhandgun)Formulation[EPAReg.No.jlApplic.Rate(lbailA)MaLMax.No.S1.easonaApphc.perAliRatS2ppc.eeason(lbailA)UseDirectionsandLimitations2OrnamentalPlants(greenhouses,shadehouses,andnurseries)B-NineSP,•Use1galofdilutedsolutionto cover200Solublesq.ftareaofplants.Concentrate(SC),•Onesingleapplicationor2split85%aiapplicationsat112to2/3ratesareallowed.[400-110]B-NineWSG,WaterSolubleGranule(WSG),85%ai0.1-0.75%[1,000to1---[_40_0_-4_7_8]_--;7,500ppm]Dazide85WSG,WaterSolubleGranule(WSG),85%ai[62097-17]0.0084-0.063lbai!galMultiple3Notstated•Applicationintervalsarespecifiedbyplant.•Plantsshouldbedrywhensprayisapplied.•Donotoversprayfoliage,waitfor18-24hoursafterapplyinginordertoallowchemicaltoentertheplant.•Solutionspreparedshouldnotbeheldformorethan24hours.Repeatapplicationscanbemadeat1-2weekintervalsorasneeded.•Donotapplythisproductinawaythatwillcontactworkersorotherpersons,eitherdirectlyorthroughdrift.•Onlyprotectedhandlersmaybeintheareaduringapplication.1TopreventIncreasedlevelsofUDMHfromformtngInthesesolutions,thelabelsfordamtnoztdeEPsIncludetherestrictionstatementthat"Solutionspreparedshouldnotbeheldformorethan24hours."2SpecialrestrictionsareappliedtoFlorida(i.e.,specificmonthsoftheyeartheseproductscanbeapplieddependingontheplant).3Theregisteredproductscallforonesingleortwosplitapplicationsperbatchofplants.Page9of195.0 Residential Exposure and Risk Estimates There are no registered residential uses, or commercial/professional

uses at residential sites associated with daminozide

at this time. Therefore,

a quantitative residential exposure assessment

is not required. 5.1 Residential Post-application Exposure
for Ornamentals from Retail Locations HED notes that there are no direct homeowner applications

of daminozide

to ornamentals; however, there are registered commercial ornamental uses and the treated ornamentals could be subsequently purchased

at a retail location for use in a residential setting. HED considers postapplication exposure resulting from this scenario

to be negligible

for the following reasons: (1) Considering

the time from application

in a commercial setting
to consumer purchase

at a retail location, residues
are expected

to decline significantly. (2) Typical activities associated with residential ornamentals

(e

. g., picking fruit, thinning shrubs/bushes)

are anticipated

to occur
at some additional time after purchase and transplant, increasing
the time for residues

to decline. (3)
In many cases, transplanted trees (especially deciduous trees) may have little to no foliage available
for contact

at the time of purchase and transplanting,
thus decreasing
the potential
for dermal exposure. Therefore, quantitative residential non-cancer

or cancer post-application

risk assessments

for the use of daminozide

on commercial ornamentals were not performed

. because
of the lack of potential exposure.

In addition,

no dermal
or inhalation non-cancer toxicological endpoints

of concern were identified. 5.2 Spray Drift All the daminozide uses were evaluated

as part of the Registration Review process

to ensure that the potential
for spray drift from all registered uses have been considered

in the risk assessment. Based on the use-pattern, HED determined that daminozide

is not registered

on use sites that would result
in spray drift. Therefore,

a quantitative spray drift assessment
was not conducted for daminozide. 6.0 Occupational Exposure and Risk Estimates 6.1 Occupational Handler Exposure/Risk Estimates 6.1.1 Occupational Non-cancer Handler Exposure/Risk Estimates Although there
is potential
for occupational non-cancer handler exposure, risk estimates
for daminozide were not quantitatively assessed because
no dermal
or inhalation toxicological endpoints

of concern were identified.
No additional PPE recommendations

are needed
on the registered labels. Furthermore,

a separate short- and intermediate-term non-cancer dermal and Page 10 of19inhalationoccupationalexposureassessmentwasnotconductedforUDMHbecausethetoxicologicaldeterminationofdaminozideisprotectiveofexposuretoUDMH,basedonlowlevelspresentasametabolite/degradate.Evaluation:ExposureStudySubmittedduringRegistrationReviewAstudyentitled"DeterminationoftheConcentrationofUnsymmetricalDimethylHydrazine(UDMH)inaMixtureofDaminozideandWateroveraStoragePeriodof24Hours,"wassubmittedbyChemturaCorporationinresponsetotherequirementsofagenericdatacall-infortheRegistrationReviewofdaminozide.ThestudyconfirmedthatthedegradationtoUDMHstartsimmediatelyafterdaminozideismixedwithwater,andincreasessteadilyduringthe24hourstorageperiod.Therefore,thecurrentrestriction(i.e.,"Solutionspreparedshouldnotbeheldformorethan24hours.")onthelabelstopreventworkersfromexposuretoincreasedlevelsofUDMHforminginthemixedsolutions,isadequateandshouldremainintheregisteredlabels.AsummaryofthestudyispresentedinAppendixC.6.1.2OccupationalCancerHandlerExposure/RiskEstimatesAlthoughanon-cancerriskassessmentwasnotperformedduetothelackofadverseeffectsinthenon-cancerdermalandinhalationstudies,acancerexposureandriskassessmentwasperformedbecauseacancerpotencyfactor(Q*)wasidentified.Dermalandinhalationexposuredoescontributetotheoverallcancerriskfordaminozide.Inaddition,cancerhandlerrisksofUDMHwerecalculatedandarepresentedinAppendixA.Thefollowingassumptionsareusedtoassesscancerrisk.DaysperYearofExposure:Toassesscancerrisk,itisassumedthatprivategrowerswouldbeexposed10daysperyearandcommercialapplicatorswouldbeexposed30daysperyear.Theterm"privategrower"meansthatthegroweroroneoftheworkerswouldapplythepesticidestolandownedoroperatedbythegrower.Commercialapplicatorsmeanstheapplicatorsarecompletingmultipleapplicationsincommercialsettings.YearsperLifetimeofExposure:Itisassumedthathandlerswouldbeexposedfor35yearsoutofa78yearlifespan.LifetimeExpectancy:Life expectancyvaluesarefrom theExposureFactorsHandbook2011EditionTable18-1(U.S.EPA,2011).Thetableshowsthattheoveralllifeexpectancyis78yearsbasedonlifeexpectancydatafrom2007.In2007,theaveragelifeexpectancyformaleswas75yearsand80yearsforfemales.Basedontheavailabledata,therecommendedvalueforuseincancerriskassessmentsis78years.OccupationalHandlerCancerExposureandRiskEquationsCancerriskestimateswerecalculatedusingalinearlow-doseextrapolationapproachinwhichaTotalLifetimeAverageDailyDose(LADD)isfirstcalculatedandthencomparedwithaQr*Page11of19that has been calculated

for daminozide based on dose response data in the appropriate toxicology study (Q1*

= 0.0087 (mg/kg/dayt

1 ). Absorbed average daily dose (ADD) levels were used as the basis for calculating

the LADD values. Dermal and inhalation ADD values were frrst added together

to obtain combined ADD values. LADD values were then calculated and compared

to the Q1 * to obtain cancer risk estimates. The algorithms used to estimate the LADD and cancer risk for occupational handlers can be found
in Appendix

B. Summary

of Occupational Handler Cancer Exposure and Risk Estimates An occupational handler cancer assessment was completed

for daminozide

at label required PPE (i.e., long sleeved shirt, long pants, waterproof gloves, shoes plus socks, no respirator).
For daminozide,

the occupational handler cancer risk estimates range from lxl0"

7 to 4x10-

5 (see Table 6.1.2). Table 6.1.2. Occupational Handler Cancer Exposure and Risk Estimates
for Daminozide. Private Handler
Commercial Handler LADD (mglkg/day)

LADD (mglkg/day) Crop or
Dermal

1

. Cancer Exposure Scenario Inhalation

1 Total

Inhalatio Total Target

[Single

[No LADJ>l Risk Dermal

1
nl LADJ>l Layer/

Estimate

4 [SUG] ....

' Gloves] Respirator]

[NoR] Mixer/Loader/Applicator

for WDG/Lic uids Ornamentals Backpack Sprayer 0.0000867 0.0000542 0.000141 lxl0-6 0.00026 0.000163 0.000424 Ornamentals Ornamentals Manually-pressurized 0.00000332 0.0000116 0.000015 lxl0-

7 0.00000996 0.0000349 0.000045 Hand wand Mecanically-pressurized 0.000486 0.00116 0.00165 lxto

- s 0.00146 0.00349 0.00494 Handgun 1 Dermal LADD (mg/kg/day)- Dermal dose (mglkg/day)

x [Days per year of exposure (days/yr)
365 days/year]

x [Years per hfetlme
of exposure (yrs)
-T Lifetime expectancy (yrs)]. 2 Inhalation LADD (mglkglday) =Inhalation Dose (mglkglday)

x [Days per year of exposure (days/yr)

I 365 days/year]

x [Years per lifetime of exposure (yrs)
-T Lifetime expectancy (yrs)]. 3 Total LADD (mg/kg/day) =Dermal LADD (mg/kg/day)

+ Inhalation LADD (mg/kg/day). 4 Cancer risk estimates= Total LADD

x Ot•, where Q1• = 0

. 0087 (mglkg/day)·

1 . Cancer risk estimates were calculated

at label required PPE

. 6.2 Occupational Post-application Exposure/Risk Estimates HED uses the term post-application

to describe exposures that occur when individuals

are present

in an environment
that has been previously treated with

a pesticide (also referred

to as reentry exposure). Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related

to crop production, such as scouting
for pests or harvesting. Post-application exposure levels vary over time and depend
on such things
as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.

In addition, the timing of pesticide applications, relative

to harvest activities, can greatly reduce the potential
for post-application **~xposure.** Page 12 of19

Cancer Risk Estimate

4 4xio-

6 4xl0"

7 4xi0-

56.2.1OccupationalPost-applicationInhalationExposure/RiskEstimatesAlthoughworkersenteringdaminozidetreatedgreenhouseandnurseryareasforhandlingtreatedornamentalplantsmaybeexposedtopesticideresiduesaftertreatmentstoornamentalplants,occupationalnon-cancerpost-applicationriskestimatesforagriculturalworkerswerenotquantitativeassessed,becausenoinhalationendpointofconcernwasidentified.TheWorkerProtectionStandardforAgriculturalPesticidescontains requirementsforprotectingworkersfrominhalationexposuresduringandaftergreenhouseapplicationsthroughtheuseofventilationrequirements[40CFR170.110,(3)(Restrictionsassociatedwithpesticideapplications)].Thoserequirementsaretobeprotectiveofanypotentiallow-levelnon-cancerpost-applicationinhalationexposurethatcouldresultfromthesetypesofapplications.6.2.2OccupationalPost-applicationNon-CancerDermalExposure/RiskEstimatesAlthoughpost-applicationexposuresareexpectedforworkersenteringtreatedgreenhouseand/ornurseryareasandhandlingtreatedornamentalplants,occupationalnon-cancerpost-applicationriskestimateswerenotquantitativeassessed,becausenodermalendpointofconcernwasidentified.RestrictedEntryIntervalThecurrent24-hourREIspecifiedontheregisteredlabelsisbasedonadislodgeablefoliarresidue(DFR)studyonandchrysanthemumsthatwasreviewedaspartofthereregistrationeligibilitydecision(RED)documentandjudgedsupplemental(MRIDNo.40037001).However,sincethereisnolongeradermaltoxicologicalendpointofconcern,theREIshouldbebasedonthecurrentacutetoxicityoftheactiveingredient.Thecurrenttoxicitydatabasefordaminozideindicateslowacutetoxicityviaoral,dermalandinhalation(CategoryIV)routesofexposure.Thiscompoundcausesmildeyeirritation(CategoryIII),andisnotaskinsensitizer.Basedonthe[40CFR156subpartK]WorkerProtectionStandardStatement,aREIof12hoursisadequatetoprotectagriculturalworkersfrompost-applicationexposurestodaminozide.HEDrecommendsthattheREIbeadjustedontheregisteredlabelsfrom24hoursto12hours.6.2.3OccupationalPost-applicationCancerDermalExposure/RiskEstimatesPost-applicationoccupationalhandlercancerriskestimateswerecalculatedusingalinearlowdoseextrapolationapproachinwhichaTotalLADDisfirstcalculatedandthencomparedwithaQ1*thathasbeencalculatedfordaminozidebasedondoseresponsedataintheappropriatetoxicologystudy(Q1*=0.0087(mg/kg/dayt1).ThealgorithmsusedtoestimatetheLADDandcancerriskforoccupationalworkerscanbefoundinAppendixB.Thefollowingassumptionsareusedtoassesscancerpost-applicationrisk:DaysperYearofExposure:Toassesscancerrisk,itisassumedthatprivategrowerswouldbeexposed10daysperyearandcommercialapplicatorswouldbeexposed30daysperyear.Theterm"privategrower"means.thatthegroweroroneoftheworkerswouldapplythepesticidestoPage13of19land owned
or operated

by the grower. Commercial applicators means the applicators

are completing multiple applications

for multiple clients. Years per Lifetime
of Exposure: HED assumes that post-application workers would be exposed for 35 years out of a 78 year lifespan. Lifetime Expectancy: Based on available data from EPA's Exposure Factors Handbook 2011 Edition, the recommended lifespan
for use in cancer risk assessments

is 78 years. Life expectancy values are derived from the Exposure Factors Handbook 2011 Edition Table 18-1 (U.S. EPA, 2011). The table shows that the overall life expectancy

is 78 years based on life expectancy data from 2007.
In 2007, the average life expectancy

for males was 75 years and 80 years for females. Occupational Post-application Cancer Dermal Risk Estimates An occupational post-application cancer assessment was completed

for daminozide (Table 6.2.3). The occupational post-application cancer risk estimates range from 6x10-

6 to 5x1o-

5
. Table 6.2.3. Occupational Post-Application Cancer Exposure and Risk Estimates
for Daminozide.

.. . Crop or Target Anticipated Activity

Days After DermalLADD Cancer Risk Transfer Coefficients
(cm

2 /hr) Treatment (mglkglday)

1 Estimate2 Hand Pruning; Scouting; Container Moving; Hand Weeding; Grafting; Hand Harvesting; Propagating;

0 0.0006
**6x10~** Ornamentals/ Transplanting; Pinching; Nurseries Tying/Training TC=230
cm

2 /hr Irrigation (hand set)

0

. 0

. 0053

5xi0·

5 TC=I,900
cm

2 /hr Dermal LADD (mglkg/day) =Dermal Dose (mglkg/day)

x [Days per year of exposure (days/yr)

+ 365 days/year]

x [Years per lifetime
of exposure (yrs) +Lifetime expectancy (yrs)]. 2 Cancer risk estimate= Dermal LADD (mglkg/day)

x Q

1 ', where
Q

1
' = 0.0087 (mglkg/day)'

1 . Appendix

A. Summary

of Occupational Handler and Post-application Cancer Exposure/Risk Estimates
for UDMH Occupational handler cancer assessments were completed

for UDMH

at label required PPE (i.e., long sleeved shirt, long pants, waterproof gloves, shoes plus socks, no respirator). Occupational cancer exposures were calculated using the maximum application
rate of daminozide (parent) multiplied

by 0.1% to adjust for the ratio of parent (assuming 100%)

to UDMH

to account for how much degrada:te will be in the tank mix. The algorithms used to estimate the LADD and cancer risk for occupational workers can be found
in Appendix

A. A Total LADD was also calculated

for UDMH and compared

to a Q1 * that has been calculated based on dose response data in the appropriate toxicology study (Q1 * = 0.46 (mg/kg/dayt

1 ).

Page 14 of19OccupationalhandlercancerriskestimatesforUDMH atlabelrequiredPPE(i.e.,long sleevedshirt,longpants,waterproofgloves,shoesplussocks,norespirator)rangefrom2x10·8to9x10-6(TableB.1).ThesecancerriskestimatesareconsideredprotectiveofanypotentialUDMHoccupationalpost-applicationcancerrisksbecause,basedonthephysicochemicalpropertiesofUDMH(e.g.,13.7kPaat20°Cor102.76mmHg),thiscompoundisnotexpectedtobeavailablefordermalpost-applicationexposure.TableA.l.Occu1ationalHandlerCancerExposureandRiskEstimatesforUDMH.-,_,-PrivateHandlerCommercialHandlerCroporTargetExposureLADD(mglkg/day)TotalCancerLADD(mglkg/day)TotalCancerRiskScenarioRiskDermal1Inhalation2LADWEstimate4Dermal1lnhalation2LADWEstimate4Mixer/Loader/ApplicatorforWDG/LiquidsSpraysusingOrnamentalsBackpack9.97xl0·75.42xl0·81.05x10-6sxto·72.99x10-61.36xl0·83.15x10-6SprayerSpraysusingOrnamentalsManually-3.82xl0·81.16xl0·84.99xl0·82xlo.s1.15x10·73.49xi0·81.50x10·7pressurizedHandwandSpraysusingOrnamentals.Mecanically-5.58x10-61.16x10-66.75xl0·63xl0-61.67x10·53.49x10-62.02x10·5pressurizedHandgun1DermalLADD(mglk:glday)-DermalDose(mglk:glday)x[Daysperyearofexposure(days/yr)365days/year]x[Yearsperhfet1meofexposure(yrs)+Lifetimeexpectancy(yrs)].2InhalationLADD(mglk:glday)=InhalationDose(mglk:glday)x[Daysperyearofexposure(days/yr)I365days/year]x[Yearsperlifetimeofexposure(yrs)+Lifetimeexpectancy(yrs)].3TotalLADD(mglk:glday)=DermalLADD(mglk:glday)+InhalationLADD(mglk:glday).4CancerRiskEstimates=TotalLADDxQ1",whereQ1"=0.46(mglk:glday)"1.CancerriskestimateswerecalculatedatlabelrequiredPPE.AppendixB.SummaryofOccupationalCancerAlgorithmsPotentialdailyexposuresforoccupationalhandlersarecalculatedusingthefollowingformulas:where:EUE=ARA=E=UE*AR*A*0.001mg/ugexposure(mgai/day),unitexposure(Jlgai/lbai),maximumapplicationrateaccordingtoproposedlabel(lbaiAorlbailgal),andareatreatedoramounthandled(e.g.,A/day,gal/day).Potentialdailyexposuresforoccupationalpost-applicationworkersarecalculatedusingthefollowingformulas:DFR1=AR*F*(1-D/* (4.54E8;:)* (2.47E-8Page15of19lxl0-67xto-s9x10-6where: DFRt AR F D t where: E TC DFRt ET

= = = dislodgeable foliage residue on day "t" (J..Lg/cm

2 ), application rate (lb ai/acre), fraction
of ai retained
on foliage
or 25% (unitless), fraction
of residue that dissipates daily or 10% (unitless), and number
of days after application
day (days)

. E=TC

* DFR

t
. * ET
* 0. 001 mg ug exposure (mg ai/day), transfer coefficient (cm

2 /hr), dislodgeable foliar residue
on day "t" (J..Lg/cm

2 ), and exposure time (hours/day). The daily doses for both occupational handlers and post-application workers are calculated using the following formula:

ADD= where:

E*AF BW ADD average daily dose absorbed

in a given scenario (mg ai/kg/day), E exposure (mg ai/day), AF absorption factor (dermal and/or inhalation),
and BW body weight (kg). After the development

of the ADD values, the next step required

to calculate carcinogenic
risk estimates

is to amortize these values over the anticipated lifetime, which results
in the LADD. LADD values are calculated using the following equation: where: LADD ADD

Days per Year of Exposure Years per Lifo time of Exposure LADD

= ADD* ---------

* 365 Days per Year Lifetime Expectancy absorbed dose over

a lifetime (mg ai/kg/day), average daily dose absorbed

in a given scenario (mg ai/kg/day), Days per Year of Exposure
annual frequency

of an application

by an individual (days/year), Page 16 of19Years per Lifetime

of Exposure

= amount
of a lifetime that an individual would be expected

to use pesticides (years), and Lifetime Expectancy

average life expectancy

of an individual (years). Cancer risk estimate calculations

are completed

by comparing
the LADD values calculated above
to the Q1 * for the chemical. Cancer risk estimates
are calculated using the following equation: Total Cancer Risk Estimate= {Dermal LADD +Inhalation LADD)

* Q
1 * where: Cancer Risk Estimate

= DermalLADD

= Inhalation LADD

= = probability

of incidence

of cancer cases over

a lifetime (unitless), absorbed dose from dermal exposure over

a lifetime (mg ailk:g/day), absorbed dose from inhalation exposure over

a lifetime (mg ailk:g/day),
and quantitative dose response factor used for linear, low-dose response cancer risk estimate calculations (mg/kg/day)"

1 • Appendix

C. Summary

of the Study (MRID# 49013500): Determination

of the Concentration

of Unsymmetrical Dimethyl Hydrazine (UDMH)

in a Mixture

of Daminozide
and Water over

a Storage Period
of 24 Hours The study entitled "Determination

of the Concentration

of Unsymmetrical Dimethyl Hydrazine (UDMH)

in a Mixture ofDaminozide

and Water Over

a Storage Period of24 Hours," was submitted

by Chemtura Corporation

in response

to the requirements

of a generic data call-in for the Registration Review
of daminozide (Case No. 0032). Summary The study entitled "Determination ofthe Concentration

of Unsymmetrical Dimethyl Hydrazine (UDMH)

in a Mixture ofDaminozide

and Water over

a Storage Period of24 Hours," was submitted

by Chemtura Corporation

in response

to the requirements

of a generic data call-in for the Registration Review
of daminozide (Case No. 0032). The purpose
of the study was to quantify the amount ofUDMH present

as an impurity

in the formulation,

as well as characterize its potential
for formation after mixing over time. As stated
in MRID 490135-00,

the study
is an Adverse Effects Report that was conducted under the requirements found
at 40 CFR

§ Section 159.179 (a)(2)(i)(D), "Metabolites, degradates, contaminants

and impurities." This study was designed

to determine
the concentration

of unsymmetrical dimethyl hydrazine (UDMH)

in a mixture
of daminozide (parent) and water over

a 24 hour storage period

at ambient temperature.
The daminozide solution was prepared

at a concentration of3,750 ppm. Two aliquots
of the solution were collected and analyzed
for UDMH

at Time

0 (immediately
after solution preparation),

1, 2, 4, 6, and 24 hours. Page 17 of19Analysis
for UDMH was conducted using Method GRL-GM-1281

_ (Version 1.0, dated 8/24/12), a high performance liquid chromatography (HPLC) method with UV detection and external standard quantification. Method validation results were provided; however,

it could not be determined from the report
if validation occurred prior or after sample analysis. Raw analytical data sheets were not provided

to verify reported concentrations

or to assess quality control and instrument performance. Degradation

to UDMH started immediately after daminozide
was mixed with water, and the concentration

of UDMH rose steadily during the 24 hour storage period. The results show that UDMH concentrations

in the daminozide solution increased steadily with time. Average UDMH concentrations
were 0.043, 0.16, 0.36, 0.67, 1.1, and 3.7 mg/L
at Time
0, 1, 2, 4, 6, and 24 hours, respectively. Expected levels ofUDMH cannot be predicted accurately beyond the 24 hour time period. Based on V ersar'

s linear regression analysis, the data fit a linear regression model with an R 2 value of0.998 (see Figure
1). The study author compared
the UDMH concentration

at each storage period after dilution

to those concentrations occurring immediately after solution preparatfon (Time
0) using at-test

at the 95% confidence interval. The t-tests indicated

a significant difference

in the UDMH concentration

at each time interval from the Time

0 value. Some limitations

of the study include:

1) no mention
on storage conditions

of sample extracts

or on storage stability testing;

2) ambient temperatures during the storage duration, dates of sample collection, extraction and analysis were not reported, and 3) the sampling was not performed

to simulate actual field conditions (e.g., temperature range, exposure

to sunlight

or no exposure

to sunlight, possible agitation

of tank mix, etc.). Page 18 of19Figure1.UDMHConcentrationsinDaminozideSolution(preparedintapwater)OverTime4.000.---------------------:::i'"iia3.500+----------------:>IlL-----.§.=0.1525x+0.06483.000R2=0.998"'.::.2.5001:62.000v::1:::!!:1.500c::Icu1.0001111l!0.500+---...,.f!C-----------------<051015202530TimeInterval(hours)Page19of19·-Linear(Series1)