Meta]dehyde Hum an Health Risk Assessment DP No. 041750 6

UNITED STATES EN V IRON M ENTAL PROTECT I ON AGENCY

WASHINGTON, D.C. 20460



### MEMORANDUM

Date: December 17

, 20 14 O FFICE OF
CHEMICAL SA FET Y AND
POLLUTION PREVENT I ON



### SUBJECT: Metaldehyde. Human Health Ri sk Assessment for Propo se d New Uses on Vegetable, Legume

, Edib l e Podded [Sub g roup 6A], Pea and B ean , Succulent Shelled [Subgroup

6 B]

, Vege table

, Fo li age of Legume, Exc ept Soybean [Subgroup 7A]

, Clover Fo rage and Ha y , and Ginseng; and for Amendments to Existing Tolerances [ Toma to and Crop Group 1 0].

0417506

PC Code: 053001

Decis i on No.: 4864 2 6

Petitio n No.: 3E8223 DP Barcode: 0417506 Registrat i on No

. : 6 I 096-13 Regulato r y Action: Section 3

C aseNo.: NA R i sk Assessment Typ e : Sing l e C h e mical A gg r egate

TXR No.: NA CAS No

. : 108-62 -3

MRID No.: NA 40 CFR: 180.523



### FROM:

THROUGH: Matthew Lloyd

, C IH ; Ri sk Asse ss or
William Donovan, Chemist**~qt{** 

# ·**~** Linda Taylor

, Ph.D, Toxicologist 

# fFJ

Ri sk Assessmen t Bra nch e s V & VII

# -~

Health Effects Divis i on (7509P)

Id e li z Negron-Encarnacion, Ph.D.

,

# ~e 1 i s t 

## 1 7



# J a L /

John Liccione, Ph.D.

, Toxic o l og i st 

# tJ!I- ;{ 

# U

Mjchael Metzger, Chief 

## ; I f

, -**)att~v** m;lhtu/ 

## lh·b_L

Risk A s sessment Branches V & Vl f 

# V "'J 1 1 .t7l 

# t

- -;t c.--
Health Effects Di vision ( 7509P)



### T O : Laura No ll en / Barbara Madden

, RM 05

Risk Int eg r at ion and Minor Use E m e r ge ncy Respons e Branch Reg i st r at i o n Div i sion (7505P )

The Health Effects Di vis i o n ( HED ) of the Office of P es ticide Pro g ram s (OP P ) i s charged with

es tim at ing the risk to human health from exposure to pesticides.

The foll o w in g human h ealt h assessments were conducted in support of the r egistration act i on for

metal d e h yde: the aggregate risk

, and occupational and r esident ial exposure assessments by Matt

Pa ge I of59Metaldehyde Human Health Risk Assessment DP No. D4l 7506

Lloyd (RABVII); the residue chemistry and dietary exposure assessment by William Donovan (RABV); the hazard characterizatio n and endpoint se l ection b y Linda Tay l or (RABVII)

.

Pa ge 2 of 59Metaldehyde Human Health Risk Assessment DP No. D417506

Page 3 of 59 1.0 Executive Summary

................................ ................................ ................................ ........... 5
2.0 HED Recommendations

................................ ................................ ................................ .... 7
2.1 Data Deficiencies

................................ ................................ ................................ ............ 7
2.2 Tolerance Considerations

................................ ................................ .............................. 7
2.2.1 Enforcement Analytical Method

................................ ................................ ............... 7
2.2.2 Recommended Tolerances

................................ ................................ ......................... 8
2.2.3 Revisions to Petitioned

- For Tolerances

................................ ................................ .... 9
2.2.4 International Harmonization

................................ ................................ ..................... 9
2.3 Label Recommendations

................................ ................................ ................................ 9
2.3. 1 Recommendations from Residue Reviews

................................ ................................ 9
2.3.2 Recommendations from Occupational/Residential Assessment

............................. 9
3.0 Introduction

................................ ................................ ................................ ........................ 9
3.1 Chemical Identity

................................ ................................ ................................ ........... 9
3.2 Physical/Chemical Characteristics

................................ ................................ ............. 10
3.3 Pesticide Use Pattern

................................ ................................ ................................ .... 10
3.4 Anticipated Exposure Pathways

................................ ................................ ................. 11
3.5 Consideration of Environmental Justice

................................ ................................ .... 12
4.0 Hazard Characterization and Dose

- Response Assessment

................................ .......... 12
4.1 Toxicology Studies Available for Analysis

................................ ................................ . 12
4.2 Absorption, Distribution, Metabolism, & Eliminat ion (ADME)

............................. 13
4.2.1 Dermal Absorption

................................ ................................ ................................ ... 13
4.3 Toxicological Effects

................................ ................................ ................................ .... 13
4. 4 Safety Factor for Infants and Children (FQPA Safety Factor)

............................... 14
4.4.1 Completeness of the Toxicology Database

................................ .............................. 15
4.4.2 Evidence of Neurotoxicity

................................ ................................ ........................ 15
4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal

........ 15
4.4.4 Residu al Uncertainty in the Exposure Database

................................ ................... 16
4.5 Toxicity Endpoint and Point of Departure Selections

................................ .............. 16
4.5.1 Dose

- Response Assessment

................................ ................................ ...................... 16
4.5.3 Cancer Classification and Risk Assessment Recommendation

............................ 17
5.0 Dietary Exposure and Risk Assessment

................................ ................................ ......... 20
5.1 Metabolite/Degradate Residue Profile

................................ ................................ ....... 20
5.1.1 Summary of Plant and Animal Metabolism Studies

................................ ............. 20
5.1.2 Summary of Environmental Degradation

................................ .............................. 20
5.1.3 Comparison of Metabolic Pathways

................................ ................................ ....... 20
5.1.4 Residues of Concern Summary and Rationale

................................ ...................... 20
5.2 Food Residue Profile

................................ ................................ ................................ .... 21
5.3 Water Residue Profile

................................ ................................ ................................ .. 21
5.4 Dietary Risk Assessment

................................ ................................ .............................. 22
5.4.1 Description of Residue Data Used in Dietary Assessment

................................ .... 22
5.4.2 Acute Dietary Risk Assessment

................................ ................................ ............... 22
5.4.3 Chronic Dietary Risk Assessment

................................ ................................ ........... 23
5.4.4 Cancer Dietary Risk Assessment

................................ ................................ ............. 23
5.4.5 Summary Table

................................ ................................ ................................ ......... 23
6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

............................. 24
6.1 Residential Handler Exposure

................................ ................................ .................... 24Metaldehyde Human Health Risk Assessment DP No. D417506

Page 4 of 59 6.2 Post

- Application Exposure

................................ ................................ .......................... 25
6.4 Residential Risk Estimates for Use in Aggregate Assessment

................................ .. 25
6.5 Residential Bystander Post

- application Inhalation Exposure

................................ . 27
6.6 Spray Drift

................................ ................................ ................................ .................... 27
7.0 Aggregat e Exposure/Risk Characterization

................................ ................................ .. 28
7.1 Acute Aggregate Risk

................................ ................................ ................................ ... 28
7.2 Short

- and Intermediate Term Aggregate Risk

................................ ........................ 28
7.4 Chronic Aggregate Risk

................................ ................................ .............................. 30
8.0 Cumulative Exposure/Risk Characterization

................................ ............................... 30
9.0 Occupational Exposure/Risk Characterization

................................ ............................ 31
9.1 Short

- /Intermediate

- Term Handler Risk

................................ ................................ ... 31
9.2 Short

- /Intermediate

- Term Post

- Application Risk

................................ .................... 32
9.2.2 Inhalation Post

- application Risk

................................ ................................ ............. 33
10.0 References

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

................................ .................. 34
A.1 Toxicology Data Requirements

................................ ................................ ................... 34
A.2 Toxicity Profiles

................................ ................................ ................................ ............ 35
A.3 Hazard Identification and Endpoint Selection

................................ .......................... 40
A.4 Executive Summaries

................................ ................................ ................................ ... 42 Appendix B. Metabolism Summary Table

................................ ................................ ............... 56 Appendix C. Physical/Chemical Properties

................................ ................................ ............. 57 Appendix D. Review of Human Research

................................ ................................ ................ 58 Appendix E. Email message from Melanie Biscoe (EFED) to W. Donovan (HED), 15

- JUL

2014

. ................................ ................................ ................................ ................................ .............. 59Metaldehyde Human Health Risk Assessment DP No. D417506

Page 5 of 59 1.0 Executive Summary

Background:

Metaldehyde [2,4,6,8

- tetramethyl

- 1,3,5,7

- tetraoxyacyclooctane] is used to control slugs and snails on a wide variety of tree, fruit and vegetable crops. Metaldehyde is formulated as granules (G), pelleted (P/T) baits, emulsifiable concentrate (EC), flowable concentr ate (FlC), and ready

to

- use liquid (RTU/L) formulations. Formulated products generally contain 0.13

- 25% active ingredient.

The Registration Division (RD) of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the proposed Section 3 registration uses of the active ingredient (ai), metaldehyde, for proposed uses on vegetable, legume, edible podde d [subgroup 6A], pea and bean, succulent shelled [subgroup 6B], vegetable, foliage of legume, except soybean [subgroup 7A], clover forage and hay, and ginseng ; and for amendments to existing tolerances [ tomato and crop group 10 ].

Previous to this risk assessment, the next most recent human

- health risk assessment for metaldehyde was the risk assessment to support a variety of new crop uses of metaldehyde completed on June 20, 2013 (M. Lloyd, et al. ; D 404859 ).

Hazard Assessment:

The toxicological database for metaldehyde is considered complete for characterization of potential developmental, reproductive, carcinogenetic, mutagenic, neurotoxic, and immunotoxic effects. Based on a WOE approach considering all the available metaldehyde h azard and exposure information, the Hazard and Science Policy Council (HASPOC) concluded that the acute neurotoxicity study, a 28

- day inhalation toxicity study, and an immunotoxicity study may be waived for metaldehyde (TXR Nos. 0056524 and 0056825).

Th e toxicity profile of metaldehyde shows that the principal toxic effects are clinical signs of neurotoxicity, and changes in the liver and testes/prostate following repeated oral dosing

. T he dog is the most sensitive species for the neurotoxic effects. Th e nervous system effects observed

in the subchronic and chronic oral toxicity studies include : ataxia ; tremor ; twitching ; salivation ; emesis ; rapid respiration in dogs and maternal rats ; and limb paralysis, spinal cord necrosis

, and hemorrhage in maternal rats.

Developmental toxicity was not observed in the rat or rabbit developmental toxicity studies, and maternal toxicity was not observed in the rabbit. In the rat, maternal toxicity was observed, as evidenced by clinical signs (ataxia, tremors, and twitching) at the highest dose tested. In the rat reproductive toxicity study, mortality and clinical signs (limb paralysis, spinal cord necrosis and hemorrhage) were observed in the maternal animals, and the effects on the offsprin g consisted of decreased pup body weight and body weight gains. Reproductive toxicity was not observed.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 6 of 59 The Food Quality Protection Act ( FQPA ) safety factor was reduced to 1X for the relevant lifestages because the toxicity database is adequate to asses s safety for infants and children and

the exposure assessment will not underestimate children’s exposure.

The carcinogenicity of metaldehyde has been evaluated by HED and is classified as “suggestive evidence of carcinogenicity”. Metaldehyde is not m uta genic. HED has determined that quantification of risk using a non

- linear approach (i.e., the RfD) is appropriate and will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to metaldehyde.

Food Residu e Profile:

Adequate residue chemistry data have been provided for the requested new uses of metaldehyde. Field trials are of adequate number and geographic representation. Data analyses employed validated analytical methods and are supported by approp riate storage stability data. No processed commodities are associated with the new uses pro posed in the current petition. The Agency waived livestock metabolism and feeding studies because metaldehyde is expected to be rapidly metabolized in mammalian sy stems with subsequent incorporation of degradates into naturally occurring components. Thus , all uses of metaldehyde are classified under 40 CFR §180.6 (a) (3), no reasonable expectation of finite residues with respect to residues in livestock

commodities . Limi ted rotational crop field trial data demonstrate d that residues are not expected in crops planted 30

- days after metaldehyde is applied to soil; therefore,

30

- day plant back intervals (PBIs) are appropriate for unregistered crops in rotation to prim ary crops. Registered crops may be planted back at any time.

Exposure Profile and Risk Es t imates :

Occupational exposures are expected from the proposed use of metaldehyde

. The occupational

handler assessment of the proposed uses was completed assuming the maximum label application rate. Based on the proposed use pattern s, there is potential for short

- and

intermediate

- term occupational exposure to metaldehyde during mixing, loading, applying, and other handling tasks . As no dermal h azard was identified, only inhalation exposur e was quantitatively assessed. Chronic exposure is not expected for the proposed agricultural uses.

The level of concern (LOC) for occupational inhalation exposures is for margins of exposure (MOEs) <100 (i.e.

, MOEs ≥ 100 are not of concern to HED) . For the proposed uses, all occupational short

- and intermediate

- term handler (with standard work clothing and no respiratory protection ) MOEs were >100 . The proposed metaldehyde label includes a personal

protectiv e equipment (PPE) requirement that applicators and other handlers wear long

- sleeved shirts, long pants, chemical

- resistant gloves, shoes plus socks, and protective eyewear. Because no dermal point of departure was selected, occupational post

- application ex posures are addressed qualitatively.

Non

- occupational (residential) exposures are not expected from the proposed uses of metaldehyde. However, residential exposure is expected based on existing uses of metaldehyde.

T he residential exposure assessment comp leted as part of HED’s 2013 risk assessment is up

- to

-Metaldehyde Human Health Risk Assessment DP No. D417506

Page 7 of 59 date

. There were no risk estimates of concern identified for the residential handler or the post

application assessment (i.e., MOEs were >100 ).

Aggregate Risk Estimates:

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. The acute and

chronic aggregate risk assessment s takes into account exposure estima tes from dietary consumption of metaldehyde (food and drinking water). The acute dietary exposure estimates

are not of concern to HED (<100% aPAD ) at the 95 th exposure percentile for the general U.S. population and all other population subgroups

. The chr onic dietary exposure estimates are not of

concern to HED (<100% cPAD ) for the general U.S. population and all population subgroups

.

The short

- and intermediate

- term aggregate risk assessment combine s residentia l handler inhalation exposure (adult only) a nd oral post

- application exposures (children) with average food and water exposures. The risks estimated for adults and children are not of concern (i.e., MOEs are > 100)

.

This risk assessment relies in part on data from studies in which adult human subjects were intentionally exposed to a pesticide or other chemical. Please refer to Appendix D for a discussion of the human study data used in this risk assessment.

2.0 HE D Recommendations

Pending resolution of the deficiencies outlined below and submission of a revised Section F as specified in Section 2.2.3 , there are no other residue chemistry, occupational, or toxicolog ical data deficiencies that would preclude the est ablishment of permanent tolerances for residues of metaldehyde as outlined in Table 2.2.2.

2.1 Data Deficiencies

There are no data deficiencies in the toxicology database.

Additionally, t here are no data deficiencies in the occupational/residential e xposure or residue chemistry database s

.

2.2 Tolerance Considerations

2.2.1 Enforcement Analytical Method

The GC/MS method (EN

- CAS Method No. ENC

- 3/99, Revision 1) is acceptable for tolerance

enforcement of metaldehyde residues in plants. For this metho d, residues in homogenized plant matrices (except citrus and mint oil) are extracted with dichloromethane (DCM) containing sodium sulfate, filtered, concentrated, and analyzed by GC/MS using the m/z 89 and 45 ions for quantitation and confirmation, respect ively. For citrus and mint oil, the residue extraction step is slightly modified ; thus, residues in citrus oil are dissolved in methanol (MeOH), diluted withMetaldehyde Human Health Risk Assessment DP No. D417506

Page 8 of 59 hexane and partitioned with water. Residues in the resulting MeOH:water fraction are then partit ioned into DCM, concen trated, and analyzed by GC/MS. Mint oil samples are diluted with hexane and partitioned with 5% acetic acid and then DCM

, prior to GC/MS analysis. For wheat grain, rape seed, and other oily matrices an additional cleanup step consisting of a hexane/methanol partition is also used. The level of quantitation (LOQ) for metaldehyde in/on plant commodities is 0.05 ppm.

2.2. 2 Recommended Tolerances

The recommended tolerances for metaldehyde were derived by 1) use of the OECD MRL calculation procedures for crops with measurable residue levels, 2) use of the LOQ for crops where residues in the field trials were not measurable (ginseng), and 3) direct t ranslation where appropriate (subgroup 8

- 10A and group 10

- 10).

Table s 2.2.2 a and 2.2.2b summarize the registrant’s proposed tolerances and the Agency’s

tolerance recommendations. The tolerance expression for metaldehyde [40 CFR §180.523(a)] appropriatel y reads as follows:

Tolerances are established for residues of the molluscicide metaldehyde

, including its metabolites and degradates , in or on the commodities listed in the following table

. Compliance with the specified tolerance levels is to be determi ned by measuring only metaldehyde, 2 ,4,6,8

- tetramethyl

- 1,3,5,7

- tetr ox ocane , in or on the commodity.

Table 2

. 2.2a Tolerance Summary for M etaldehyde , §180.523(a)

. Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition
Vegetable, legume, edible podded, subgroup 6A 0.80 0.80 Based on OECD calculator result using edible podded bean dataset

Pea and bean, succulent shelled, subgroup 6B 0.20 0.20 Based on OECD calculator result using succulent shelled pea and bean

datasets.
Vegetable, foliage of legume, except soybean, subgroup 7A 1.50 1.50 Based on OECD calculator result using edible podded bean foliage

dataset
Tomato subgroup 8

- 10A 0.24 0.24 Translated from tomato
Fruit, citrus, group 10

- 10 0.26 0.26 Translated from fruit, citrus, group

10
Ginseng 0.05 0.05 LOQ based tolerance level

Further, the tolerance expression in 40 CFR § 180.523(c) read s as follows:

“ Tolerances with a regional registration as defined in § 180.1(l) are established for

residues of the molluscicide metaldehyde , includin g its metabolites and degradates , in or
on the commodities listed below. Comp liance with the tolerance level specified be low is to be determined by measuring only metaldehyde, 2 ,4,6,8

- tetramethyl

- 1,3,5,7

- tetr ox ocane , in or on the commodity.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 9 of 59 Table 2

. 2.2b Tolerance Summary for M etaldehyde , §180.523(c)

. Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition
Clover, forage 0.5 0.60 Pacific Northwest
Clover, hay 0.5 0.60 Pacific Northwest

Note to RD: Upon establishment of the recommended subgroup 8

- 10A and group 10

- 10 tolerances, the existing tomato and group 10 tolerance listings should be deleted.

2.2. 3 Revisions to Petitioned

- For Tolerances

HED recommends tolerances of 0.60 ppm for clover hay and forage because of the determination that only three independent clover trials were conducted instead of the four trials assumed by the petitioner. Use of the OECD tolerance calculation procedures wi th three residue values each for clover hay and forage results in recommend ed tolerances of 0.60 ppm for both commodities. The petitioner should submit a revised Section F to reflect this change.

2.2. 4 International Harmonization

As there are no COD EX or Canadian MRLs established for metaldehyde, no international harmonization issues are expected to arise from establishment of the recommended tolerances.

2.3 Label Recommendations

2.3.1 Recommendations from Residue Reviews

The proposed labels shoul d contain the following restriction:

A 30

- day plant back interval (PBI) is appropriate for all rotational crops. Labeled crops may be replanted immediately.

All other metaldehyde labels should be amended in registration review to contain the

aforement ioned restriction.

2.3.2 Recommendations from Occupational /Residential Assessment

There are no recommendations for the assessment of occupational/residential exposures at this

time. As quantification of dermal risk is not required for metaldehyde, no dislodgeable foliar residue ( DFR ) or turf transferable residue ( TTR ) stud ies are required at this time. If future hazard database changes result in the identification of a dermal endpoint, HED will reassess the need for

these data.

3.0 In troduction

3.1 Chemical IdentityMetaldehyde Human Health Risk Assessment DP No. D417506

Page 10 of 59 TABLE 3 .1. Nomenclature of Metaldehyde.

Compound Chemical Structure

Common name Metaldehyde

Company experimental names Not applicable

IUPAC name r

- 2, c

- 4, c

- 6, c

- 8

- tetramethyl

- 1,3,5,7

- tetroxocane (or) 2,4,6,8

- tetramethyl

- 1,3,5,7

- tetraoxacyclo

- octane

CAS name 2,4,6,8

- tetramethyl

- 1,3,5,7

- tetroxocane

CAS # 108

- 62

- 3 (tetramer) and 9002

- 91

- 9 (homopolymer)

End

- use products/EP 7.5% G (Durham Metaldehyde Granules; EPA Reg No. 5481

- 103); 4% P/T (Deadline MPs Mini

- Pellets; EPA Reg. No. 5481

- 511); and 4% RTU/L (Deadline Force II; EPA Reg. No. 8119

- 6)

3.2 Physical/Chemical Characteristics

The physical/chemical properties of metaldehyde are summarized in Appendix C

. Metaldehyde has a vapor pressure of 6.6 ± 0.3 Pa at 25 °C. Metaldehyde is expected to be mobile and moderately persistent in the environment. Metaldehyde degrades aerobically with a reported

half

- life of 67 days, anaerobically with a reported half

- life of 222 days, and is stable to abiotic degradation (hydrolysis and photolysis).

3.3 Pesticide Use Pattern

Table 3.3 contains a summary of the proposed uses for metaldehyde. The personal protective equipment proposed for the new uses direct mixers, loaders, applicators and other handlers to

wear chemical resistant gloves in addition to baseline clothing (i.e., long sleeved shirt, long pants, and shoes with socks) . This is identical to existing PPE requirements on currently registered m etaldehyde labels.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 11 of 59 Table 3.3. Summary of Directions for Use of Metaldehyde Granular Formulation

Application Timing, Type, and Equip. Formulatio

n [EPA Reg. No.] Applica

tion Rate (lb ai/A) Max. No. Application per Season Max.

Seasonal Application Rate (lb ai/A) PHI (days) Use Directions and
Limitations

Vegetable, legume, edible podded (Subgroup 6A)

Broadcast (ground &

handheld equipment) 71096

- 13 1.0 3 3 Pre

- bloom RTI = 7 days

Pea and Bean, succulent shelled (Subgroup 6B)

Broadcast (ground &

handheld equipment) 71096

- 13 1.0 3 3 Pre

- bloom RTI = 7 days

Vegetable, foliage of legume, except soybean (Subgroup 7A)

Broadcast (ground &
handheld equipment) 71096

- 13 1.0 3 3 1 RTI = 7 days

Clover, forage*

Broadcast (ground &
handheld equipment) 71096

- 13 0.8 2 1.6 30 RTI = 10 days

Clover, hay*

Broadcast (ground &
handheld equipment) 71096

- 13 0.8 2 1.6 30 RTI = 10 days

Ginseng

Broadcast (ground &
handheld equipment) 71096

- 13 1.0 6 6 21 RTI = 21 days

* For use in the following states: Oregon, Idaho, and Washington

The use directions are adequate to allow evaluation of the residue data relative to the proposed

use s

. The proposed maximum application rates are supported by the submitted field trial data.

Refer to section 2.3 for recommended modifications to the proposed labels.

3.4 Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support the proposed new and expanded

uses of metaldehyde

. Humans may be exposed to metaldehyde in food and drinking water, sin ce metaldehyde may be applied directly to growing crops and application may result in metaldehyde reaching surface and ground water sources of drinking water. In an occupationalMetaldehyde Human Health Risk Assessment DP No. D417506

Page 12 of 59 setting, applicators may be exposed while handling the pesticide prior to app lication, as well as during application. There is a potential for post

- application exposure for workers re

- entering

treated fields. Because there is no dermal hazard identified for metaldehyde, occupational handler inhalation exposures are assessed quanti tatively ; post

- application exposures resulting from metaldehyde applications (dermal and inhalation) are assessed qualitatively.

While the request doesn’t include any residential uses of metaldehyde, residential exposure is possible . H umans may be expos ed to metaldehyde in residential settings, since it may be applied

around lawns/ ornamental plants in residences and public areas. Because there is no dermal hazard identified for metaldehyde

, a quantitative handler and post

- application dermal exposure

assessment has not been conducted. R esidential handler inhalation exposures and post

application incidental oral exposure were assessed quantitatively in 2013 and provide and up

- to

date non

- occupational exposure assessment

.

Therefore, this r isk assessm ent addresses both the existing and proposed residential uses of metaldehyde . This risk assessment considers all of the aforementioned exposure pathways

.

3.5 Consideration of Environmental Justice

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

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

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

- established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.
Extensive da ta 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 s ubgroups 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. Wh enever appropriate, non

- dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post

- application are evaluated. Further considerations a re currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgro ups.

4.0 Hazard Characterization and Dose

- Response Assessment

4.1 Toxicology Studies Available for AnalysisMetaldehyde Human Health Risk Assessment DP No. D417506

Page 13 of 59 The toxicology database on metaldehyde is sufficient for assessing the toxicity and characterizing the hazard of the chemical. The toxicology studies for metaldehyde are summarized in Table A.1 in Appendix A. The database includes the following studies.

 Acute/lethality studies (oral, dermal, inhalation, primary eye and dermal irritation, and dermal sensitization)

 Subchronic: 21

- day dermal toxicity (rabbit), 90

- day oral toxicity (dog)

 Developmental toxicity: rat and rabbit developmental toxicity studies

 Reproduction: 2

- generation reproduction study (rat)

 Chronic: combined oral chronic toxicity/carcinogenicity (rat), carcinogenicity (mouse), chronic oral toxicity (dog)

 Neurotoxicity: subchronic neurotoxicity (rat)

 Other: mutagenicity battery, metabolism

T he studies available for consideration of metaldehyde toxicity provide a comprehensive database, with routes of administration that are consistent with potential exposure scenarios.

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

Metaldeh yde is rapidly absorbed, distributed, and metabolized in the rat, with most of the

administered dose ( 78

- 98%) being recovered as 14 CO 2 in expired air within 24 hours for male
rats and within 48 hours in female rats

. Metaldehyde is readily absorbed into the bloodstream from the gastrointestinal tract

, distribute d widely throughout the body

, and readily crosses the

blood

- brain barrier. Reco very in urine/feces is low (2.5

- 5.1%) , and the sexes differ slightly

. In addition, the half

- life of metaldehyde was longer in females (8.8 h ou rs) than in males (3.4

h ou rs). More 14 C was found in nervous tissues, fat, liver, and reproductive organs than in other

tissues

.

4.2.1 Dermal Absorption

No dermal absorption studies are available. Quantification of dermal risk is not required , based on lack of toxicity in the rabbit dermal toxicity study at the limit dose , and the lack of pertinent effects in other toxicity studies not measured in the dermal toxicity study. Therefore, a dermal absorption factor is not required.

4.3 Toxicological Effects

T he principal toxic effects of metaldehyde are clinical signs of neurotoxicity, and changes in the

liver and testes/prostate following repeated oral dosing . The dog is the most sensitive species for

the neurotoxic effects. The nervous system effects observed in the subchronic and chronic oral toxicity studies include : ataxia ; tremor ; twitching ; salivation ; emesis ; rapid respiration in dogs

and maternal rats ; and limb paralysis, spinal cord necrosis

, and hemorrhage in materna l rats

. The
liver effects include increased liver weight, increased incidence of liver lesions ( hepatocellular necrosis, hepatocellular hypertrophy and inflammation ) , and an increased incidence ofMetaldehyde Human Health Risk Assessment DP No. D417506

Page 14 of 59 hepatocellular adenomas 1 in female rats and in both sexes o f mice. In dogs, atrophy of the testes and prostate was observed following subchronic and chronic exposure. Toxicity was not
observed in a rabbit 21

- day dermal toxicity study at the limit dose

. Acute lethality studies show that metaldehyde is not acutely t oxic by the dermal and inhalation routes of exposure but is moderately toxic via the oral route. Metaldehyde is moderately irritating to the eyes and minimally irritating to the skin.

D evelopmental toxicity was not observed in the rat or rabbit developmen tal toxicity studies , and maternal toxicity was not observed in the rabbit . In the rat, maternal toxicity was observed, as evidenced by clinical signs ( ataxia, tremors, and twitching ) at the highest dose tested. In the rat reproductive toxicity study, mor tality and clinical signs (limb paralysis, spinal cord necrosis and hemorrhage) were observed in the maternal animals, and the effects on the offspring consisted of

decrease d pup body weight and body weight gains. Reproductive toxicity was not observed

.

In the rat, clinical signs of neurotoxicity occur only at dose levels in excess of 100 mg/kg /day following repeat oral exposure. In t he 90

- day neurotoxicity study

, bilateral hindlimb paralysis
was observed in one female rat at the highest dose tested

. No acute neurotoxicity study on metaldehyde is available. However, the Hazard and Science Policy Council (HASPOC) determined that the acute neurotoxicity study is not required since dogs appear to be the most sensitive species for neurotoxicity, and the acu te neurotoxicity study in rats will not provide a point of departure or a more sensitive endpoint than those currently used in the overall risk assessment, which are based on the dog.

Chronic feeding studies in rats and mice indicated that metaldehyde pr oduced liver effects characterized by liver hypertrophy and liver tumors. HED has classified metaldehyde as “suggestive evidence of carcinogenicity”. Metaldehyde is not m utagenic. Although the mouse study showed that metaldehyde was associated with a com mon tumor in both sexes (liver tumors, adenomas), and the rat study showed that metaldehyde was associated with liver adenomas in the female, HED has determined that quantification of risk using a non

- linear approach; i.e., RfD, for metaldehyde will adequa tely account for all chronic toxicity, including carcinogenicity, that could result from exposure to metaldehyde. That conclusion is based on the following considerations: (1) the tumors found are commonly seen in the mouse; (2) the liver

tumors (adenomas) in both species were benign; (3) metaldehyde is not mutagenic; (4) no carcinogenic response was seen in the male rat; (5) incidence of adenomas at the high

- dose in the female rat was within the historical control range of the testing lab.

4.4 Safety F a ctor for Infants and Children (FQPA Safety Factor)

HED recommends that the 10X FQPA Safety Factor (for the protection of infants and children)

be reduced to 1X . An FQPA Safety Factor of 1X is appropriate for the following reasons:

1 The classification is driven by adenomas although one carcinoma was observed at the highest dose tested. The statistic for combined adenomas/carcinomas is statistically significant; however, no dose response was noted when
carcinomas were evaluated alone.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 15 of 59 The toxicity database is complete and adequate to assess safety for infants and children. There is no evidence of increased qualitative or quantitative susceptibility in the developmental rat and

rabbit studies or in the rat 2

- generation reproduction stud y. These studies have clearly defined NOAEL/LOAELs. There is a subchronic neurotoxicity study on metaldehyde with a clearly
defined NOAEL/LOAEL . Both the acute neurotoxicity study and the developmental neurotoxicity study have been waived. The exposure as sessment will not underestimate children’s exposure to metaldehyde. Further details may be found in the following sections.

4.4 .1 Completeness o f the Toxicology Database

The toxicology database for metaldehyde is complete and adequate to address the pro posed uses and to revisit the existing residential uses. Acceptable rat and rabbit developmental toxicity studies, a rat 2

- generation reproduction study, a subchronic neurotoxicity study in rats, are
available. The HED’s Hazard and Science Policy Council ( HASPOC) determined that the acute neurotoxicity (ACN) study , the immunotoxicity study, and the inhalation toxicity study can be
waived 2

.

4.4.2 Evidence of N eurotoxicity

There is a concern for neurotoxicity resulting from exposure to metaldehyde, based on (1) clinical signs [ataxia, twitching, tremors, prostration, paresis of hind legs] in female rats in the developmental toxicity study; (2) hindlimb paralysis, necrosis an d hemorrhage in the spinal cord and vertebra luxation in F0 dams during lactation period in the two

- generation reproduction study; (3) bilateral hindlimb paralysis observed initially on day 10 in one high

- dose female

sacrificed on day 22 due to poor condit ion in the 90

- day subchronic neurotoxicity study in rats; no neuropathology was evident; (4) clinical signs [ataxia, tremors, twitching, salivation] in the chronic dog study, which occurred within the first week of exposure and persisted through week 19; o ther signs included lateral position, reduced mobility, convulsions, and vocalization in one female, and agitation in another. It should be noted that most of the neurotoxic signs seen in rats

occurred at dose levels above 100 mg/kg.

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

There is no evidence of increased susceptibility following in utero exposure to metaldehyde in either the rat or rabbit developmental toxicity study, and there is no evidence of increased suscepti bility following in utero and/or pre

- /post

- natal exposure in the 2

- generation reproduction study in rats.

Metaldehyde has been evaluated for potential developmental effects in the rat and rabbit (gavage administration). Maternal toxicity in rats includ ed mortality, clinical signs of toxicity ( ataxia, tremors, twitching, and rapid respiration ) on days 7 and 8, and decreased body

- weight gain and food consumption during dosing . M aternal toxicity was not observed in rabbits. No developmental effects were o bserved in the rat or rabbit. M ortality, clinical signs (hindlimb paralysis in F0 females)

, gross/histopathol o gical lesions in females (spinal cord necrosis and hemorrhage, vertebra luxation in F0 females), and increased liver weight in both sexes were

2 K. Rury; February 21, 2013 ; TXR# 0056524Metaldehyde Human Health Risk Assessment DP No. D417506

Page 16 of 59 obs erved in the rat 2

- generation reproduction study at the same dose levels where decreased pup body weight and pup body

- weight gain w ere observed in both sexes/both generations.

4.4.4 Residual Uncertainty in the Exposure Datab ase

For all dietary risk assessments, the established and recommended tolerances were used and 100% crop treated was assumed. Modeling was used to derive estimated drinking water

concentrations. The occupational and residential exposure assessment was conduct ed such that

exposure s and risk s will not be underestimated. The aggregate exposure and risk estimates presented in this assessment are conservative and will not underestimate actual exposure and risk expected based on the current and proposed use patterns

.

4.5 Toxicity Endpoint and Point of D eparture Selections

4.5.1 Dose

- Response Assessment

A detailed description of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios is presented in A ppendi x A

.

An acute dietary endpoint for all populations was selected from the chronic oral toxicity study in

the dog with a NOAEL of 30 mg/kg/day for clinical signs . At the LOAEL of 90 mg/kg/day, clinical signs of neurotoxicity were observed in all dogs of eac h sex on the first day of dosing at
this dose level

. This endpoint is protective of the mortality and clinical signs seen in the maternal rats following 1

- 2 days of dosing at the LOAEL of 150 mg/kg/day in the rat developmental toxicity study (NOAEL 75 mkd)

. T he dog is the more sensitive species for the neurotoxicity
observed , and this endpoint is consistent with endpoints for a ll the other exposure assessments

, which are based on the dog chronic oral (diet) toxicity study. A 100X uncertainty factor was applied to account for inter

- and intra

- species variability resulting in an acute reference dose (aRfD) of 0.30 mg/kg/day. Since the FQPA factor is reduced to 1X, the aRfD is equivalent to the acute population adjusted dose (aPAD).

No developmental endpoint attributable to a single exposure was identified for females 13+ from the available oral toxicity database.

The chronic dietary endpoint was selected from the chronic oral toxicity study in the dog with a study NOAEL of 10 mg/kg/day. At the stud y LOAEL of 30 mg/kg/day, death and atrophy of the testes and prostate were observed. A 100X uncertainty factor was applied to account for inter

and intra

- species variability resulting in a chronic reference dose (cRfD) of 0.10 mg/kg/day. Since the FQPA f

actor is reduced to 1X, the cRfD is equivalent to the chronic population adjusted dose (cPAD).

The short

- term incidental oral and inhalation endpoint s for risk assessment w ere selected from

the same chronic oral toxicity study in the dog described above

, using the same NOAEL as used for acute dietary assessment ( 30 mg/kg/day ) . At the LOAEL of 90 mg/kg/day, clinical signs of neurotoxicity were observed on the first day of exposure in all dogs and throughout the first week of exposure

.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 17 of 59 The intermediate

- term incidental oral and inhalation endpoint s for risk assessment w ere selected from the chronic oral toxicity study in the dog with a NOAEL of 10 mg/kg/day. At the study LOAEL of 30 mg/kg/day, death and atrophy of the testes and prostate were observed. Atrophy of the testes and prostate w as also observed in the subchronic dog study.

Th ere was no hazard observed via the dermal route with lack of systemic toxicity following 21 days of dermal exposure to rabbits. The endpoints of concern we re all assessed in this study, and there is no developmental or reproductive concern ; therefore, quantification of dermal risk is not required

.

4.5.3 Cancer Classification and Risk Assessment Recommendation

The CARC classified metaldehyde as “Suggestive Evidence of Carcinogenicity” based on benign

liver tumors seen in both sexes of mice and in female rats. Metaldehyde is not m utagenic

. Although the mouse study showed that metaldehyde was associated with a common tumor in both sexes (liver tumors, adenomas), and the rat study showed that metaldehyde was associated with liver adenomas in the female, HED has determined that quantification o f risk using a non

linear approach; i.e., RfD, for metaldehyde will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to metaldehyde. That conclusion is based on the following considerations: (1) the tu mors found are commonly seen in the mouse; (2) the liver tumors in both species were benign; (3) metaldehyde is not mutagenic; (4) no carcinogenic response was seen in the male rat; (5) incidence of adenomas in the female rat was
within the historical cont rol range of the testing lab.

A summary of both carcinogenicity studies is presented in Appendix A.

Table 4. 5 .4.1 Summary of Toxicological Doses and Endpoints for Metaldehyde for Use in Dietary and

Non

- Occupational Human Health Risk Assessments

Exposure /
Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Acute Dietary (All Populations ) NOAEL =

30 mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1x aRfD = 0.30

mg/kg/day

aPAD = 0.30 mg/kg/day Chronic dog oral toxicity study

LOAEL = 90 mg/kg/day , based on clinical signs (ataxia, tremor, salivation, twitching) seen on day 1 of dosing (both sexes).

Chronic Dietary (All Populations) NOAEL =

10 mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1x cRfD = 0.10

mg/kg/day

cPAD = 0.10 mg/kg/day Chronic dog oral toxicity study

LOAEL = 30 mg/kg/day, based on death and atrophy of the testes and prostate

Incidental

Oral Short

Term (1

- 30 days) NOAEL =

30 mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1x Residential

LOC for

MOE < 100 C hronic dog oral toxicity study

LOAEL = 90 mg/kg/day , based on clinical signs (ataxia, tremor, salivation, twitching) seen on day 1 of dosing (both sexes).Metaldehyde Human Health Risk Assessment DP No. D417506

Page 18 of 59 Table 4. 5 .4.1 Summary of Toxicological Doses and Endpoints for Metaldehyde for Use in Dietary and

Non

- Occupational Human Health Risk Assessments

Exposure /
Scenario Point of

Departure Uncertainty/FQPA

Safety Factors RfD, PAD,

Level of
Concern for
Risk
Assessment Study and Toxicological Effects

Incidental

Oral

Intermediate

Term (1

- 6 months) NOAEL =

10 mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1x Residential

LOC for

MOE < 100 C hronic dog oral toxicity study

LOAEL = 30 mg/kg/day

, based on death and atrophy of the testes and prostate

Dermal (All durations) No hazard observed via the dermal route, based on the lack of systemic effects following repeat

dermal exposure of ra bbi ts. The endpoints of concern were all assessed in this study, and there is no developmental or reproductive concern.

Inhalation

Short

- Term (1

- 30 days) NOAEL =

30 mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1x Residential

LOC for

MOE < 100 C hronic dog oral toxicity study

LOAEL = 90 mg/kg/day , based on clinical signs (ataxia, tremor, salivation, twitching) seen on day 1 of dosing (both sexes).

Inhalation

Intermediate

Term (1

- 6 months) NOAEL =

10 mg/kg/day UF A 10x

UF H 10x

FQPA SF = 1x Residential

LOC for

MOE < 100 C hronic dog oral toxicity study

LOAEL = 30 mg/kg/day

, based on death

and atrophy of the testes and prostate

Cancer (oral, inhalation) Classification : Suggestive Evidence of Carcinogenicity; EPA has determined that quantification

of risk using a non

- linear approach (i.e., RfD) will adequately account for all chronic toxicity, including carcinogenicity

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adver se effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty f actor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable.

Table 4.5. 4 .2 Summary of Toxicological Doses and Endpoints for Metaldehyde for Use in Occupational
Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk
Assessment Study and Toxicological Effects

Dermal Short

Term (1

- 30 days) No hazard observed via the dermal route, based on the lack of systemic effects following repeat

dermal exposure of ra bbi ts. Th e endpoints of concern were all assessed in this study, and there is no developmental or reproductive concern. Dermal

Intermediate

Term (1

- 6 months)

Inhalation
Short

- Term (1

- 30 days) oral

NOAEL=

30

Inhalation

hazard

assumed to be equivalent

to oral hazard UF A =10x

UF H =10x Occupational

LOC for MOE =

100 C hronic dog oral toxicity study

LOAEL = 90 mg/kg/day for clinical signs seen beginning the first week of dosing.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 19 of 59 Table 4.5. 4 .2 Summary of Toxicological Doses and Endpoints for Metaldehyde for Use in Occupational
Human Health Risk Assessments

Exposure/
Scenario Point of

Departure Uncertainty

Factors Level of Concern

for Risk
Assessment Study and Toxicological Effects

Inhalation

Intermediate

term (1

- 6 months) oral

NOAEL =

10 mg/kg/day

Inhalation

hazard

assumed to be equivalent

to oral hazard UF A =10x

UF H =10x Occupational

LOC for MOE =

100 C hronic oral toxicity study

– dog

LOAEL = 30 mg/kg/day based on deaths and testes/prostate atrophy

Cancer (oral, dermal, inhalation) Classification : “Suggestive Evidence of Carcinogenic Potential”. EPA has determined that

quantification of risk using a non

- linear approach (i.e., RfD) will adequately account for all chronic toxicity, including carcinogenicity

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

- response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = l owest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a

NOAEL. UF S = use of a short

- term study for long

- term risk assessment. UF DB = to acc ount for the absence of key

data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 20 of 59 5.0 Dietary Exposure and Risk Assessment

5.1 Metabolite/Degradate Residue Profile

5.1.1 Summary of Plant and Animal Metabolism Studies

No new metabolism studies were submitted in support of this petition. The residue of concern in plants consists only of metaldehyde. Livest ock metabolism studies have been waived.

5.1.2 Summary of Environmental Degradation

Metaldehyde is expected to be mobile and moderately persistent in the environment. Metaldehyde degrades aerobically with a reported half

- life of 67 days, anaerobically with a reported half

- life of 222 days, and is stable to abiotic degradation (hydrolysis and photolysis). There were no toxic residues of concern identified for the metaldehyde transformation products,

so transformation products were not included in the EFED drinking water assessment.

5.1.3 Comparison of Metabolic Pathways

The major residu e found in plant metabolism studies on lettuce and sugar beets was the parent compound, metaldehyde. There were considerable non

- extractable residues in sugar beet root and tops that were not further characterized. The Confined Rotational Crop study was wa ived since the metabolism in secondary crops is likely to be similar to the primary crops.

Livestock metabolism studies have been waived because metaldehyde is expected to be rapidly metabolized in mammalian systems with subsequent incorporation of degra dates into naturally occurring components. This conclusion is supported by the extensive metabolism observed in rat

metabolism studies.

Metaldehyde is rapidly absorbed, distributed, and metabolized in the rat. Between 78

- 98% of the
administered dose was recovered in expired air within 24 hours as 14 CO 2 in the rat metabolism study

.

There was extensive metabolism of metaldehyde in both plants and animals.

5.1.4 Residues of Concern Summary and Rationale

The qualitative nature of metaldehyde residues in plants is understood based on lettuce and sugar beet metabolism studies. The HED Metabolism Committee (7/2/96) concluded that the regulated residue of concern in plants is parent metaldehyde. This conclusion was confirmed in the Metaldehyde Reregistrati on Eligibility Decision ( RED ) document (D327385, M. Lloyd et. al., April 3, 20 06)

.

The residue of concern for drinking water exposure assessment is metaldehyde.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 21 of 59 Table 5.1.4 Summary of Metabolites and Degradates to be included in th e Risk
Assessment and Tolerance Expression

Matrix Residues included in Risk

Assessment Residues included in Tolerance Expression

Plants Primary Crop Metaldehyde Metaldehyde

Rotational Crop Metaldehyde Metaldehyde

Livestock Not Applicable Not Applicable

Drinking Water Metaldehyde Not Applicable

5 .2 Food Residue Profile

D4 18047 , A. Doh, 10

- JUL

- 2014

Adequate residue chemistry data have been provided for metaldehyde. Field trials are of adequate number and geographic representation. Data analyses employed validated analytical methods and are supported by a ppropriate storage stability data. No processed commodities are associated with the new uses pro posed in the current petition. The Agency waived livestock metabolism and feeding studies ; thus, all uses of metaldehyde are classified under 40 CFR §180.6 (a) (3), no reasonable expectation of finite residues with respect to residues in livestock commodities. Limited rotational crop field trials demonstrate that residues are not expected in crops planted 30

- days after metaldehyde is applied to soil; therefore, 30

- day plant back intervals ( PBIs ) are appropriate for unregistered crops in rotation to primary crops. Registered crops may be planted back at any time.

5.3 Water Residue Profile

The drinking water residues used in the dietary risk assessment were provided by the
Environmental F ate and Effects Division (EFED) in a memo ( D404861, J. Hetrick and M. Biscoe, 7/17/13) and supplemented by updated calculations 3

. In addition to point estimat es for deterministic assessments, a full distribution of water values was provided for a probabilistic

assessment.

T here are no monitoring data currently available for metaldehyde in drinking water

. E stimated drinking water concentrations (EDWCs) were generated using computer modeling procedures. The highest EDWCs resulted from the special mollusk eradication use on turf, and these values were used in the present dietary analysis. Surface water estimates were determined using the

PRZM

- EXAMS model and ground water estimates were determined using the PRZM

- GW
model. These latter values were recommended for use in the human

- health dietary risk assessment as they were the highest values obtained. Additional information concerning the
water models is avai lable at the EPA web site 4

.

3 Email message from Melanie Biscoe (EFED) to W. Donovan (HED), 15

- JUL

- 2014. See Appendix E.

4 http://www.epa.gov/pesticides/science/models_pg.htm#aquaticMetaldehyde Human Health Risk Assessment DP No. D417506

Page 22 of 59 Maximum application rates for metaldehyde as a high

- end estimate of exposure in drinking water were modeled based on the proposed labels

. C hemical specific and generic model input
values were chosen in accordance with current EFED input parameter guidance (USEPA, 2009). The maximum surface and ground water EDWCs for use in the human

- health risk assessment for metaldehyde are shown in Table 5.3.

Table 5.3. Maximum Tier II estimated drinking water concentrations (EDWCs) in parts per billion (μg/L) resulting from 6 applications of 2 lb a.i./acre of metaldehyde to turf with a reapplication interval of 14 days.

Drinking water source (model) 1

- in

- 10 year 30

- year simulation

Acute Chronic Acute Chronic

Surface water (PRZM

EXAMS) 1 205 136

- 83

Ground water (PRZM

GW) 2 - - 1880 915

1 D404861, J. Hetrick and M. Biscoe, 7/17/13.

2 See Appendix E.

5.4 Dietary Risk Assessment

D420705, A. Doh, 28

- JUL

- 2014

5.4.1 Description of Residue Data Used in Dietary Assessment

Acute and chronic aggregate dietary (food and drinking water) exposure and risk assessments
were conducted using the Dietary Exposure Evaluation Model with the Food Commodity Intake

Database ( DEEM

- FCI D) Version 3.18. This software incorporates 2003

- 2008 food consumption

data from the U.S. Department of Agriculture’s National Health and Nutrition Examination Survey, What We Eat in America, (NHANES/WWEIA). For all dietary risk assessments, the

establis hed and recommended tolerances were used and 100% crop treated was assumed. Processing studies for tomatoes and oranges indicate that metaldehyde residues do not concentrate in processed commodities derived from these crops. Exaggerated rates studies in corn and soybean showed no detectable grain or seed residues at rates of 5 x and 10 x, respectively. Therefore, no processing factors were used in the analyses except for those processed commodities for which no processing studies are typically conducted (t omato, dried; tomato, juice; cranberry, juice; and high fructose corn syrup), for which default factors were

used.

5.4.2 Acute Dietary Risk Assessment

A n unrefined acute dietary assessment was conducted using tolerance

- level residues, 100% crop

treated a ssumptions, and modeled water numbers. The full distribution of modeled drinking
water estimates w as included in the acute analysis. Processing factors were assumed to be 1.0 for all commodities except for tomato, dried; tomato, juice; cranberry, juice; and high fructose corn syrup; for these commodities, DEEM default processing factors were used. At the 95 th percentile of exp osure, the estimated risk from food and water sources is ≤55 % of the acute population adjusted dose (aPAD) for the U.S. population and all subpopulations. For food onlyMetaldehyde Human Health Risk Assessment DP No. D417506

Page 23 of 59 exposures, the estimated risk is ≤11% of the aPAD for the U.S. population and all population subgroups. Comparison of food and drinking water results to the food only results demonstrat es that water is the primary contributor to risk. Results are shown in Tables 5.4.5a and 5.4.5b.

5.4.3 Chronic Dietary Risk Assessment

An unrefined chronic dietary assessment was conducted using tolerance

- level residues, 100% crop treated assumptions, and modeled water numbers. Drinking water was included in the analysis as a point estimate (915 ppb). Processing factors were assumed to be 1.0 for all commodities except for tomato, dried; tomato, juice; cranberry, juice; and high fructose corn syrup; for these commodities, DEEM default processing factors were used. The estimated risk
from food and water sources is ≤51 % of the chronic population adjusted dose (cPAD) for the U.S. population and all subpopulations. For food only exposures, the estimated ris k is ≤8.1% of the cPAD for the U.S. population and all population subgroups. Comparison of food and drinking water results to the food only results demonstrate s that water is the primary contributor

to risk. Results are shown in Tables 5.4.5a and 5.4.5b.

5.4.4 Cancer Dietary Risk Assessment

EPA has determined that quantification of risk using a non

- linear approach (i.e., RfD) will adequately account for all chronic toxicity, including carcinogenicity.

5.4.5 Summary Table

Table 5

. 4.5 a Summary of Dietary (Food and Drinking Water) Exposure and Risk for M etaldehyde

. 1

Population Subgroup Acute Dietary ( 95th Percentile) Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk

General U.S. Population 0.053956 18 0.016151 22

N/A N/A All Infants (< 1 year old) 0.165402 55 0.051359 51

Children 1

- 2 years old 0.090370 30 0.035775 3 6

Children 3

- 5 years old 0.072701 24 0.029568 30

Children 6

- 12 years old 0.051399 17 0.020479 21

Youth 13

- 19 years old 0.041418 14 0.016263 16

Adults 20

- 49 years old 0.053415 18 0.021418 21

Adults 50

- 99 years old 0.051142 17 0.021529 22

Females 13

- 49 years old 0.054209 18 0.021545 22

1 Highest exposure identified in bold.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 24 of 59 Table 5

. 4.5b . Summary of Dietary (Food only ) Exposure and Risk for M etaldehyde

. 1

Population Subgroup Acute Dietary ( 95th Percentile) Chronic Dietary Cancer

Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk

General U.S. Population 0.011030 3.7 0.002854 2.9

N/A N/A All Infants (< 1 year old) 0.007663 2.6 0.001957 2.0

Children 1

- 2 years old 0.033819 11. 3 0.008137 8.1

Children 3

- 5 years old 0.022429 7.5 0.006282 6.3

Children 6

- 12 years old 0.014674 4.9 0.003686 3.7

Youth 13

- 19 years old 0.009390 3.1 0.002291 2.3

Adults 20

- 49 years old 0.009133 3.0 0.002302 2.3

Adults 50

- 99 years old 0.009830 3.3 0.002632 2.6

Females 13

- 49 years old 0.010292 3.4 0.002499 2.5

1 Highest exposure identified in bold.

6.0 Residential (Non

- Occupational) Exposure/Risk Characterization

There are no proposed non

- occupational ( residential ) uses associated with the current action . The most recent HED residential exposure assessment 5 is up to date and reflects
HED’s 2012 Residential SOPs 6 along with policy changes for body weight assumptions. There is no revision to the residential exposure assessment, and therefore only the residential contribution to the aggregate is presented in this risk assessment document . For additional details

on the residential exposure assessment, please see HED’s 2013 occupational and residential exposure memo, D 408747

.

6.1 Residential Handler Exposure

At this time, no chemical

- specific data for metaldehyde a re available to assess residential

exposure , and the re are no new scenarios to address since the 2013 risk assessment

. Since there

is no toxicity f

rom the dermal route of exposure, the residential handler assessment only includes the inhalation route of exposure. The 2013 assessment evaluated a number of residential exposure scenarios based on turf and ornamental uses with a variety of different equipment
types. Residential handler risk estimates for all scenarios were not of concern (i.e., MOEs are

≥ 100)

. The highest exposure residential handler scenario was “ hand dispersal of metaldehyde

5 Available: Metaldehyde Occupational and Residential Exposure Assessment memo ( D408747 )

6 Available: http://www.epa.gov/pesticides/science/residential

- exposure

- sop.htmlMetaldehyde Human Health Risk Assessment DP No. D417506

Page 25 of 59 granules for residential gardens ” ; the MOE for that scenario was 75,000 ( with an LOC of 100). Most other residential handler scenarios had MOEs >100,000.

6.2 Post

- Application Exposure

There is the potential for post

- application exposure for individuals exposed as a result of being in an environment that has been previously treated with metaldehyde. As no dermal hazard was identified, only incidental oral exposure for children was quant itatively assessed. Since metaldehyde is moderately persistent in the environment, intermediate

- term exposure is also possible for incidental soil ingestion exposure. These post

- application exposures were evaluated in the 2013 ORE memo (D408747) and are up

- to

- date. All residential post

- application risk estimates for metaldehyde were found to be “not of concern” (MOEs > LOC) for all exposure scenarios and lifestages. For liquid sprays on turf, short

- term residential incidental oral risk estimates ranged from 2,000 to 890,000

. For granular products applied to turf, short

- term risk estimates for the hand to mouth, object to mouth, and incidental soil ingestion ranged from 20,000 to 890,000 and were not of concern to HED.

6.4 Residential Risk Estimates for Use in Aggregate Assessment

Based on the 2013 ORE memo, there are residential contributions to the metaldehyde aggregate
risk assessment. R esidential exposure from granular applications to ornamentals/home gardens via hand dispersal) is use d in the adult (for both male and females) aggregate assessment

.

The residential exposure for use in the short

- /intermediate

- term aggregate assessment for

children 1 to <2 years old is short

- term hand

- to

- mouth (incidental oral) exposure from contacting

treated turf. Because of the long environmental half

- life of metaldehyde, there is also a n intermediate

- term residential aggregate assessment. The residential exposure for use in the

children 1 to <2 years old intermediate

- term aggregate assessment is (incidental oral) exposure from ingesting treated soil.

See Table 6.4.1 for additional information.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 26 of 59 Table 6 .4. 1 Residential Exposures for Use In the Metaldehyde Aggregate Assessment. 1

Lifestage Residential Handler Residential Post

- application

Dose (mg/kg/day) 2 MOE 3 Dose (mg/kg/day) 4 MOE 5

Dermal Inhalation Total Dermal Inhalation Total Dermal Inhalation Oral Total Dermal Inhalation Oral Total

Short

- Term

Adult Male N/A 0.0004 0.00 0 4 N/A 75,000 75,000 N/A N/A N/A N/A N/A N/A N/A N/A

Adult Female N/A 0.0004 0.00 0 4 N/A 75,000 75,000 N/A N/A N/A N/A N/A N/A N/A N/A

Child N/A N/A N/A 0.0152 0.0152 N/A N/A 2,000 2,000

Intermediate

- Term
Child N/A N/A N/A 0.00003 0.00003 3 3 0,000 3 3 0,000

1 Highlight ed risk estimates should contribute to the residential exposure porti on of the aggregate assessment;

2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed. Total = dermal (N/A) + inhalation.

3 Residential Handler MOE = the MOEs associated with the highest doses identified. Total = 1 ÷ (1/Inhalation MOE).

4 Residential Post

- application Dose = the highest post

- application dose for each applicable lifestage o f all scenarios assessed . Total = incidental oral exposure

. 5 Residential Post

- application MOE = the MOEs associated with the highest doses identified. Total = 1 ÷ (1/Incidental oral MOE).
Child 1 to < 2 years

- HTM contact with treated turf (ST); soil ingestion [because of long environmental half life] (IT).Metaldehyde Human Health Risk Assessment DP No. D417506

Page 27 of 59 6.5 Residential Bystander Post

- application Inhalation Exposure

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

- application inhalation exposure assessment was not performed for metaldehyde at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) and low vapor pressure ( 6.6 ± 0.3 Pa at 25 °C ) at ambient temperatures . However, volatilization of pesticides may be a source of post

- application inhalation exposure to individuals nearby pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Roden ticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 7 . The Agency is in the process of evaluating the SAP report and may, as appropriate, develop policies and procedures to identify the need for and, subsequently, the way to incorporate post

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

- application inhalation exposure assess ment for metaldehyde.

Although a quantitative residential post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for handlers (i.e., residential applicators ). Risks were not of concern for resid ential handlers. This exposure scenario is representative of a worse case inhalation exposure and should be considered protective of other
post

- application inhalation exposure scenarios.

6.6 Spray Drift

Spray drift is always a potential source of exposu re 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 metaldehyde. The Agency has been w orking 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 8 ) . The Agency h as 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 model to its risk assessments fo r 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 products with significant risk estimates associated with drift.

It is noted that the 1 lb ai/acre application rate for turf was modeled to estimate post

- application

residential (incidental oral) exposure of children. As this rate is comparable to the agricultural application rates, t his turf scenario is considered protective of any exposure from spray drift from agricultural metaldehyde applications.

7 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.html

8 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmMetaldehyde Human Health Risk Assessment DP No. D417506

Page 28 of 59 7.0 Aggregate Exposure/Risk Characterization

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

No endpoint was identified for dermal exposure, so dermal exposures need not be quantified in the metaldehyde aggregate assessment. Therefore, for the residential contribution to the aggregate assessment, the adult contribution is from the inhalation route of exposure and the child contribution is from the incidental oral route of exposure. Only food and water are generally aggregated for acute (one

- day) exposures to metaldehyde. For short

- and intermediate

term aggregate exposure to metaldehyde, contributions from food, water, and residential

incidental oral exposures are aggregated. Chronic exposures to metaldehy de are expected for food and water only.

7.1 Acute Aggregate Risk

The acute aggregate risk assessment takes into account exposure estimates from dietary consumption of metaldehyde (food and drinking water). While HED does calculate an acute granular ingestion scenario for pelletized pesticides, it is not appropriate to aggregate because it
represents episodic and sporadic ingestion, not a typical one day exposure pattern

. Further, these products contain a bi ttering agent which makes ingestion of metaldehyde formulations generally not palatable to children. The acute dietary exposure estimates are not of concern to HED (<100% aPAD ) at the 95 th exposure percentile for the general U.S. population and all other popul ation subgroups (see Table 5.4.5a ). The dietary exposure assessment utilized tolerance

level residues, 100% CT information for all crops , default processing factors , and a ground water EDWC generated by the PRZM

- GW Model

.

7.2 Short

- and Intermediate Term Aggregate Risk

The short

- and intermediate

- term aggregate risks combine duration appropriate residential handler (adult only) and /or post application exposures with average food and water exposures.

The residential contribution to the short

- and int ermediate

- term aggregate risk assessments are
summarized below in Table 7.2.1

.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 29 of 59 Table 7 .2.1. Short

- and Intermediate

- Term Residential Exposure Values and Sources
Used in the Metaldehyde Aggregate Risk Assessment

Population Handler Exposure (mg/kg/day) Postapplication Exposure (mg/kg/day) Residential Exposure (mg/kg/day) 1

Short

- Term

Adult Male 0.0004
Source: Table 6.1 3 Garden/tree, granule, hand dispersal N/A; no dermal endpoint 0.000 4

Adult Female 0.0004
Source: Table 6.1 Garden/tree, granule, hand dispersal N/A; no dermal endpoint 0.000 4

Child N/A; only adults are

assessed as handlers 3 0.0 152
Source: Table 5.2 .1 4

Hand

- to

- Mouth from
Treated Turf 0.0 152

Intermediate

- Term

Adult Male N/A; intermediate
term exposure not expected N/A; no dermal endpoint N/A

Adult Female N/A; intermediate
term exposure not expected N/A; no dermal endpoint N/A

Child N/A; only adults are
assessed as handlers 0.000034
Source: Table 5.2 5

Incidental Soil Ingestion 0.000034

1 Residential exposure is the representative residential contribution to the aggregate assessment

2 N/A is not applicable 3,4,5

- Lloyd, et al, D404859; Metaldehyde ; Human Health Risk Assessment for Proposed Uses on Grass Grown for Seed, Leaf Petioles [Crop Subgroup 4B], Wetland Taro, Field & Sweet Corn, Mint, and Soybeans, and for Amendments to Existing Tolerances [Crop Subgroups 13

- 07A, B, & G].

Short

- and intermediate

- term aggregate margins of exposure for adults and children are not of

concern (i.e., MOEs are > 100) . Shor t

- and intermediate

- term estimated aggregate exposures and risks are shown in Table 7.2.2, below.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 30 of 59 Table 7.2.2. Short

- Term and Intermediate

- Term Aggregate Risks

Population

NOAEL

mg/kg/day LOC 1 Max
Allowable Exposure 2 mg/kg/day Average

Food &

Water Exposure mg/kg/day Residential

Exposure 3 mg/kg/day Aggregate MOE

(food and residential) 4

Short

- Term Scenario

Adult Male 30 100 0.3 0.021529 0.000 4 1, 4 00

Adult Female 30 100 0.3 0.021545 0.000 4 1, 4 00

Child 30 100 0.3 0.035775 0.0 152 590

Intermediate

- Term Scenario

Adult Male N/A

Adult Female N/A

Child 10 100 0.1 0.035775 0.00003 4 280

1 The LOC of 100 is based on the standard inter

- and intra

- species uncertainty factors.

2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC = 30/100 = 0.3 mg/kg/day (ST)

. NOAEL/LOC = 10/100 = 0.1 mg/kg/day (IT).

3 Residential Ex posure values taken from Table 7 .2.1.Average food & wat er exposure taken from Table

5 .4.5 a

. 4 Aggregate MOE = [ Incidental Oral NOAEL [ST=30; IT=10] ÷ (Avg Food & Water Exposure + Residential Exposure)]

7.4 Chronic Aggregate Risk

The chronic aggregate risk assessment takes into account average exposure estimates from dietary consumption of metaldehyde (food and drinking water). The chronic dietary risk

estimates are n ot of concern to HED (<100% cPAD ) for the general U.S. population and all popul ation subgroups (see Table 5.4.5 ). The dietary exposure assessment utilized tolerance

- level

residues for all commodities, 100% crop treated

, def ault processing factors , and a chronic ground water EDWC generated by the PRZM

- GW model.

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

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

EPA has not assumed that metaldehyde 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 commonMetaldehyde Human Health Risk Assessment DP No. D417506

Page 31 of 59 mechanism determinations and procedures 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

HED completed an occupational ex posure assessment in a n HED memorandum dated 0 6 / 12 /13 ( M . L loyd ; D408747 ). Th at 2013 HED occupational assessment considers crops with use patterns identical to the proposed uses (legumes 6A/6B, 7A, clover, and ginseng) and uses up to date exposure methodologies and exposure assumptions . Therefore, no stand

- alone occupational and residential exposure disciplinary chapter was completed. This risk assessment presents the risk estimates from the proposed crops/crop groups, which are identical to the occupational assessment HED completed in 2013 for “l eaf petiole/mint/taro/13

- 07A .” For the proposed use sites, there is a potential for short

- and intermediate

- term occupational exposure to metaldehyde during mixing, loading, app lying, and other handling tasks

. Chronic exposure is not expected for the proposed agricultural uses.

9.1 Short

- /Intermediate

- Term Handler Risk

HED uses the term handlers to describe those individuals who are involved in the pesticide application proce ss. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each task. Job requirements (amount of chemical used in each application), the kinds of equipment used, the targe t being treated, and the level of protection used by a handler can cause exposure levels to differ in a manner specific to each application event.

Based on the anticipated use patterns and current labeling, types of equipment and techniques that can pot entially be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment (inhalation only) developed for occupational handlers

is based on the following scenarios:

 Mix/Load

- granular formulations for legumes 6A/6B, 7A, clover and ginseng

 Applicator

– granular formulations (ground equipment & hand dispersal)

 Load/Apply

– granular formulations (belly grinder/rotary spreader equipment)

The occupational and residential exposure assessmen t ( D408747 ) prov ides more detail on the assumptions used in the occupational assessment, specifically, details about the relevant application rates, the unit exposures, and assumptions about the area treated. As no dermal hazard was identified, only inhalation exposure wa s quantitatively assessed.

B ased on the proposed use, short

- and intermediate

- term exposures are expected for the following reasons: (1) the product can be applied multiple times per year (2) the product can be applied to multiple application sites and (3) there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks or months

.

All occupational handler scenarios are not of concern (i.e., inhalation MOEs are > 100) with baseline clothing (no respiratory protection) for both the short

- and intermediate

- term exposureMetaldehyde Human Health Risk Assessment DP No. D417506

Page 32 of 59 durations. While no quantification of dermal risk was appropriate based on the available toxicity information, it is relevant to note that the propo sed product labels include chemical

- resistant gloves.

Table 6.1.1. Occupational Handler Short

- /Intermediate

- Term Non

- Cancer Exposure and Risk Estimates for Metaldehyde

.

Exposure
Scenario Crop or

Target Dermal Unit

Exposure (μg/lb ai) 1 Inhalation Unit

E xposure (μg/lb ai) 1 Maximum

Application

Rate 2 Area

Treated or
Amount

Handled Daily 3 Inhalation

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

Mixer/Loader

M/L Granular

Product for
Ground Application legumes

6A/6B, 7A, clover, and ginseng N/A 1.7 1 80 0.0017 18,000 (ST)
5,900 (IT)

Applicator

Applicator

– Tractor Drawn spreader legumes

6A/6B, 7A, clover, and ginseng N/A 1.2

1 80 0.0012 25,000 (ST)
8,300 (IT)

Applicator

– Hand Dispersal Field crops N/A 470 1 1 0.006 5,100 (ST)
1,700 (IT)

Loader/Applicator

Belly Grinder Dispersal to

field crop rows N/A 62 1 1 0.000775 39,000 (ST) 13,000 (IT)

Rotary Spreader Dispersal to

field crop rows N/A 10 1 5 0.000625 48,000 (ST) 16,000 (IT)

1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” ( March 2013 ); Level of mitigation: Baseline, no respiratory protection

2 Based on registered or proposed label (Reg. No. 71096

- 13 ).
3 Exposure Science Advisory Council Policy #9.1.

4 Inhalation Dose = Dermal Unit Exposur e ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW ( 80 kg).

5 Inhalation MOE = Inhalation NOAEL (mg/kg/day) (30 ST/ 10 IT) ÷ Inhalation Dose (mg/kg/day).

9.2 Short

- /Intermediate

- Term Post

- Application Risk

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 re

entry exposure). Such exposures may occur when workers enter previ ously 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 c rop or target that was treated, the type of pesticide application, and the chemical’s degradation properties. No dermal toxicity is seen for metaldehyde and

, therefore, no post

- application dermal exposures and risks have been quantitatively assessed in

th is document. The potential for occupational post

- application inhalation exposures is discussed
below.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 33 of 59 9.2.2 Inhalation Post

- application Risk

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

- application inhalation exposure assessment was not performed for metaldehyde at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV ) and the low vapor pressure 6.6 ± 0.3 Pa at 25 °C)

. H owever, 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 resuspension 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, and received the SAP’s final report on March 2, 2010 9 . The Agency is in the process of evaluating the SAP report as well as available post

- application inhalation exposure data generated by the ARTF and may, as appropriate, develop polic ies 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 metaldehyde.

Although a quantitative occupational post

- application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for oc cupational/commercial

handlers , and all risks were below the level of concern ( i.e.

, MOE s ≥ 100) . Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post

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

- application inhalation exposure scenarios.

10.0 References
Previous Risk Assessments: M. Lloyd, et al, “ Metaldehyde ; Human Health Risk Assessment for Proposed Uses on Grass

Grown for Seed , Leaf P etioles [Crop Subgroup 4B]

, Wetland Taro, Field & Sweet

C orn, Mint, and Soybeans, and for Amendments to Existing Tolerances [C rop Subgroups 13

- 07A , B, & G]

. ” D404859, 06/20/2013.

M. Lloyd, et al, “ Metaldehyde : HED Chapter of the Reregistration Eligibility Decision

Document (RED). ” PC Code: 053001; DP Barcode: DP 327385, 04/03/06

.

HASPOC Memo: K. Rury; February 21, 2013 ; TXR# 0056524.

HASPOC Memo : K. Rury; November 12, 2013; TXR# 0056825.

Chemistry Memo: A. Doh ; 10

- JUL

- 2014 ; D 41 8 047

Drinking Water Memo: J. Hetrick and M. Biscoe, 17

- JUL

- 2013; D404861

.

Dietary Memo: A. Doh ; 2 8

- JUL

- 2014 ; D 420705.

Occupational & Residential Exposure Memo : M. Lloyd; 0 6 / 12 /13; D408747

9 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meet ing.htmlMetaldehyde Human Health Risk Assessment DP No. D417506

Page 34 of 59 A ppendix A

. Toxicology Profile and Executive Summaries
A.1 Toxicology Data Requirements The requirements (40 CFR 158.340) for food use for metaldehyde are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

Study Technical

Required Satisfied

870.1100 Acute Oral Toxicity

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

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

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

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

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

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

yes

yes

yes

yes

yes y es

yes

yes

yes

yes

no

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

................................ .......................... y es

yes

yes CR

y es y es

yes

yes

- yes A

870.3700a Developmental Toxicity (rodent)

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

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

................................ ................................ . y es

yes

yes y es

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

yes

yes

yes

yes y es

yes

yes

yes

yes

870.5100 Mutagenicity

— Gene Mutation

- bacterial

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

— Gene Mutation

- mammalian

................ 870. 5385 Mutagenicity

— Structural Chromosomal Aberrations

... yes

yes

yes y es

yes

yes 870.6100a Acute Delayed Neurotox icity (hen)

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

- Day Neurotoxicity (hen)

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

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

- Day Neuro toxicity Screening Battery (rat)

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

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

no

yes

yes CR -

- y es A

yes A

- B

870.7485 General Metabolism

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

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

................................ ............................. yes CR

yes y es

- yes C

A Waived by HASPOC (TXR# 0056524) ; B EPA concluded there was no need for DNT ( TXR# 0055119, June 10, 2009) ;

C Waived by HASPOC (TXR# 0056825).Metaldehyde Human Health Risk Assessment DP No. D417506

Page 35 of 59 A.2 Toxicity Profile s

Table A.2.1

- Acute Toxicity Profile

– Metaldehyde

Guideline

No. Study Type MRID(s) Results Toxicity Category

870.1100 Acute oral [Sprague

- Dawley rat] LD50 = 283 mg/kg II

870.1200 Acute dermal [CFY rat] 00131434 LD50 = >5000 mg/kg III

870.1300 Acute inhalation [Sprague

Dawley rat] 00131429 LC50 = 13.5 mg/L/4 hrs IV

870.2400 Acute eye irritation [rabbit] 42068801 mild irritant III

870.2500 Acute dermal irritation [rabbit] 00131971 not an irritant IV

870.2600 Skin sensitization [guinea pig] N/A [N/A ] [N/A ]

Table 2

- Subchronic, Chronic and Other Toxicity Profile

– Metaldehyde

Guideline No./ Study Type MRID No. (year)
Classification /Doses Results

870.3100
90

- Day oral toxicity (mouse) 43297701 (1990)

mouse [range

- finding study] 0, 100, 300, 1000, 3000, and 10000 ppm [19, 54, 178, 560, and 1918 mg/kg/day (males); 24, 70, 235, 742, and 2296 mg/kg/day (females)] NOAEL = 300 ppm [54/70 mg/kg/day] LOAEL = 1000 ppm [178/235 mg/kg/day], based on increased liver weight and increased incidence of liver lesions [hepatocellular necrosis, hepatocellular hypertrophy, inflammation, and anisokaryosis in both

sexes.

Non

- guideline

28

- Day oral toxicity ( rat ) 44237704 (1989)

acceptable/non

- guideline 0, 2500, 5000, 10000, 20000 ppm [m/f]

- [0, 197/233, 382/454, 761/875 1545 (males only) mg/kg/day] Systemic NOAEL not established Systemic LOAEL = 2500 ppm [200 mg/kg/day], b ased on increased absolute and relative liver weights at all
dose levels in both sexes Mortality, hindlimb paralysis [females at 10000 ppm; both sexes at 20000 ppm]; fracture/luxation of vertebra, hemorrhage of spinal cord

870.3150

Subchronic oral toxicity in nonrodents (dog) MRID 00131432 (1980)

acceptable/guideline 0, 20, 60, 90 mg/kg/day [26 weeks] NOAEL = 20 mg/kg/day LOAEL = 60 mg/kg/day based on diffuse or focal atrophy of the testes and prostate; at HDT, follicular hyperplasia of mesenteric lymph node in both sexes

870.3200

21/28

- Day dermal toxicity (rabbit) 42063401 (1991)

acceptable/guideline 0, 100, 300, 1000 mg/kg/day NOAEL = 1000 mg/kg/day [highest dose tested]
LOAEL = no effects observed

870.3465

90

- Day inhalation toxicity (rat) HASPOC determined that an inhalation toxicity study was not required, based on MOEs that

were >1000Metaldehyde Human Health Risk Assessment DP No. D417506

Page 36 of 59 Table 2

- Subchronic, Chronic and Other Toxicity Profile

– Metaldehyde

Guideline No./ Study Type MRID No. (year)
Classification /Doses Results

870.3700a
Prenatal developmental in rodent (rat) 41656001 (1990)

acceptable/guideline 0, 25, 75, 150 mg/kg/day gestation days 6

- 15 Maternal NOAEL = 75 mg/kg/day ] LOAEL = 150 mg/kg/day, based on mortality, clinical signs of toxicity [ataxia, tremors, twitching, rapid respiration] on days 7 and 8, and decreased body

weight gain during dosing, and decreased food consumption during dosing.

Devel opmental NOAEL = 150 mg/kg/day [HDT]

LOAEL = no effects.

870.3700b

Prenatal developmental in nonrodent (rabbit) 41590501 (1990)

acceptable/guideline 0, 10, 40, 80 mg/kg/day gestation days 6

- 18 Materna l toxicity NOAEL = 80 mg/kg/day [HDT] Maternal toxicity LOAEL = no effects observed. Developmenta l toxicity NOAEL = 80 mg/kg/day [HDT] Developmental toxicity LOAEL = no effects.

870.3800 Reproduction and fertility effects (rats) MRID 42823101 (1993)

acceptable/guideline

0, 50, 1000, 2000 ppm males: F0 0, 3.4, 69.37, 138.36; F1 0, 3.23, 64.93, 133.53 mg/kg/day females: F0 0, 4.16, 80.81, 160.42; F1 0, 4.03, 80.51, 164.15 mg/kg/day Parental toxicity NOAEL = 1000 ppm [males 65 mg/kg/day; females 81 mg/kg/day] Parental toxicity LOAEL = 2000 ppm [males 133 mg/kg/day; females 160 mg/kg/day], based on mortality, clinical signs (hindlimb paralysis in F0 females) on lactation days 16

- 18, gross/histopatholigical lesions in females (spinal cord necrosis and hemorrhage, vertebra luxation in F0 females), and increas ed liver weight in both sexes.

Reproductive NOAEL =2000 ppm [males 133 mg/kg/day; females 160 mg/kg/day], the highest dose

tested.

Offspring NOAEL = 1000 ppm [males 65 mg/kg/day; females 81 mg/kg/day]; Offspring LOAEL = 2000 ppm [males 133 mg/kg/day; fem ales 160 mg/kg/day], based on decreased pup body weight and body

- weight gain in both sexes/both generations.

870.4100a Chronic toxicity rodents (SD rat) MRID 42203601 (1992)

acceptable/guideline 0, 50, 1000, 5000 ppm M 0, 2, 44, 244 mg/kg/day F 0, 3, 60, 314 mg/kg/day NOAEL = 50 ppm [males 2 mg/kg/day; females 3
mg/kg/day] A
LOAEL = 1000 ppm [males 44 mg/kg/day; females 60 mg/kg/day], based on increased incidence of hepatocellular hypertrophy (both sexes) and increased cholesterol (females), and decreased body

- weight gain in females. [see under 870.4200 below]

870.4100b Chronic toxicity nonrodent (dogs) MRID 46378401 (2003)

acceptable/guideline 0, 10, 30, 90 mg/kg/day Overall NOAEL = 10 mg/kg/day LOAEL = 30 mg/kg/day, based on deaths and atrophy

of testes/prostate
NOAEL = 30 mg/kg/day
LOAEL = 90 mg/kg/day, based on clinical signs of neurotoxicity in all dogs on the first day of exposure and throughout the first week.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 37 of 59 Table 2

- Subchronic, Chronic and Other Toxicity Profile

– Metaldehyde

Guideline No./ Study Type MRID No. (year)
Classification /Doses Results

870.4200 Carcinogenicity

rats MRID 42203601 (1992)

acceptable/guideline 0, 50, 1000, 5000 ppm M 0, 2, 44, 244 mg/kg/day F 0, 3, 60, 314 mg/kg/day NOAEL = 50 ppm [2 mg/kg/day; females 3
mg/kg/day] A
LOAEL = 1000 ppm [males 44 mg/kg/day; females 60 mg/kg/day], based on increased incidence of hepatocellular hypertrophy (both sexes) and increased cholesterol (females), and decreased body

- weight gain
in females. evidence of carcinogenicity: females displayed a

treatment

- related increase in hepatocellular
adenomas and adenomas and carcinomas combined [positive trend at 5000 ppm] at the high

dose level [adenomas 6/60, 10%] compared to both control groups [0/60 and 1/60]; carcinomas 1/60, 1.7% compared to both controls [0/60 and 1/60]; and combined 7/60, 11.7% compared to both controls [0/60 and 2/60]; the incidence was within
the historical control range [adenomas 0%

- 10%; carcinomas 0%; combined 0%

- 10%].

870.4300 Carcinogenicity

mice 42737201 (1993)

acceptable/guideline when combined

with MRID 44625101 2 control groups 25, 100, 300 ppm M 4.0, 15.9, 48.9 mg/kg/day F 4.8, 19.7, 59.8 mg/kg/day NOAEL = 100 ppm [males 15.9/females 19.7
mg/kg/day] A
LOAEL = 300 ppm [males 48.9/females 59.8 mg/kg/day based on increased incidence of hepatocellular hypertrophy in both sexes. Dose levels not adequate to assess carcinogenicity potential; slight increase in hepatocellular adenomas in both sexes compared to both control groups

870.4300 Carcinogenicity

mice MRID 44625101 (1998)

Acceptable/guideline when
combined with MRID 42737201 2 control groups, 1000 ppm increased liver weight, increase in incidence of hepatocellular hypertrophy (both sexes), single cell/focal/multifocal necrosis (males), and an increase in the incidence of hepatocellular adenomas in both

sexes

Gene Mutation

- Ames assay

870.5265 MRID 41553205 (1978)

unacceptable

1.28, 6.4, 32, 160 ease in incidence of hepatocellular hy does not provide sufficient evidence of a negative response in strains TA98, TA100, TA1535, TA1537, TA1538 with and without metabolic activation; no MTD; poor performance of some strains

Gene Mutation

- Ames assay

870.5100 MRID 48666101 (2011)

tested up to limit dose (5000 μg/plate);insoluble at ≥2500 μg/plate

+/

- S9.

Acceptable/guideline No evidence of cytotoxicity; no appreciable increases

in mean number of re vertants/plate in any strain in either trial (+/

- S9). The positive controls induced the appropriate response in all strains in the presence and
absence of S9

- activation. There was no evidence of induced mutant colonies over background.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 38 of 59 Table 2

- Subchronic, Chronic and Other Toxicity Profile

– Metaldehyde

Guideline No./ Study Type MRID No. (year)
Classification /Doses Results

Gene Mutation

- mouse lymphoma L5178Y (TK+/

- )

cell line

870.5300 MRID 41553206 (1986)

unacceptable no conclusions can be drawn; doses “not completely dissolved in the selected solvent (culture medium); all

concentrati ons precipitated. Additionally, exposure time (2 hours) was shorter than the standard exposure time for this test system (4 hours).

Gene Mutation

- mouse lymphoma L5178Y (TK+/

- )

cell line

870.5300 MRID 48721401 (2011)

tested up to solubility limit (≥ 600 μg/mL +/

- S9)

Acceptable/guideline N o evidence of induced mutant colonies over background.

Gene Mutation

- mouse lymphoma L5178Y (TK+/

- )

cell line

870.5300 MRID 42044007 (1986; revised

1991)
clarification of MRID 41553206 unacceptable

w/S9

- w/out S9

- No evidence for inducing forward gene mutation at TK locus in mouse lymphoma (L5178Y) cell with/without S9 activation up to precipitating concentrations (100

- mut ation at TK locus in mouse lymphoma (L5178Y)

cell with/with st andard exposure time for this test system (4 hours).

Chromosomal

aberrations in

CHO cells

870.5375 MRID 00163832 (1986)

unacceptable

w/S9

- w/out S9

- 20, 50, 100, 200 N o evidence for inducing chromosome aberrations in CHO cells up to a precipitating concentration (200

μ g /mL

- S9). With S9, no evidence up to the highest

in CHO cells up to a precipitat

Chromosom e Aberration Assay

870.5385 MRID 48788201 (2012)

0, 62.5, 125, and 250 mg/kg (M) or 0, 31.25, 62.5, and 125 mg/kg (F)

Acceptable/guideline No evidence of cytogenicity in this in vivo rat bone
marrow chromosome aberration assay.

Micronucleus

assay 870.5395 MRID 42044006 (1990)

unacceptable 25, 50, 100 mg/kg H ighest dose tested (100 mg/kg ); MTD not reached

870.6200a

Acute neurotoxicity screening battery HASPOC (TXR# 0056524) determined that a rat ACN was not required, based on the fact

that neurotoxicity effects observed in the rat occur only at high dose levels; the dog is the more sensitive species for neurotoxic effects and points of departure based on the dog study are protective of any neurotoxicity at higher dose levels.

870.6200b
Subchronic neurotoxicity screening battery MRID 46223401 (2003)

Unacceptable (did not demonstrate ability to detect neurotoxic effects) /guideline 0 [basal diet], 100, 500, and 2500 ppm (equivalent to 0, 8, 39, 185 mg/kg bw/day) NOAEL = 100 ppm [8 mg/kg/day]

LOAEL = 500 ppm [39 mg/kg/day], based on increased motor activity in females. At the HDT [185 mg/kg], bilateral hindlimb paralysis [one female] and decreased body

- weight gains in females during the first week of the study.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 39 of 59 Table 2

- Subchronic, Chronic and Other Toxicity Profile

– Metaldehyde

Guideline No./ Study Type MRID No. (year)
Classification /Doses Results

870.6300 Developmental neurotoxicity DNT Workgroup (2009) determined that DNT was not required, based on a weight

- of

evidence: (1) no evidence of ↑ susceptibility following in utero exposures to rats/rabbits or following pre

- /postnatal exposure in rat reproduction study; (2) no treatment

- rela ted effects on any reproductive parameters; offspring effects were ↓ pup body weight/gain only at ≥133 mkd; (3) most of the neurotoxic signs; e.g., limb paralysis, ataxia, and tremors, were seen in adult rats at dose levels of 150 mkd to 185 mkd; (4) pharm acokinetic profile indicates a short half

life with primary metabolite being its degradation/metabolism to acetaldehyde , an endogenous chemical; (5) based on offspring LOAEL of 133 mkd, in order to elicit effects in the offspring,
the DNT would need to be tested at high doses (>100 mkd), which would not yield lower POD than those currently used for overall risk assessment.

870.7485

Metabolism and pharmacokinetics (Sprague

- Dawley rat) MRID 42300901 (1992)

single gavage dose 10 or 100 mg/kg repeated dose 10 mg/kg/day for 14 days, then single dose 14C [10 mg/kg]

Classification: acceptable/guideline rapidly absorbed, distributed, metabolized; most recovered in expired air [78%

- 98% of administered dose] within 24 hours [48 hr high

- dos e females] as

14 CO 2 ; recovery in urine/feces low [2.5%

- 5.1%] ; sexes differ slightly; peak blood levels [males 1

- 2 hrs;

females 2

- 4 hrs] and excretion faster in males [T 1/2 males 3.4 hrs.; females 8.8 hrs.]; recovery greater following low

- dose than high

- dose and repeat exposure; concentration of total 14 C in blood at peak

similar for sexes but concentration of intact metaldehyde was >50% higher in females than in males at pe ak, first and second blood half

- lives; 14 C in tissues/carcass after 7 days similar for all groups [7%

- 11% of administered dose]; high concentrations 14 C recovered in nervous tissue, fat, liver, female reproductive organs; 2 major peaks [plasma] were

metald ehyde and acetaldehyde

870.7600
Dermal penetration no study available no study available

.

870.7800 Immunotoxicity HASPOC (TXR# 0056825) determined that an immunotoxicity study was not required,

b ased on a WOE approach considering all the available metaldehyde hazard and exposure

information.

Special studies (CD

- 1 mouse) MRID 44810901 (1999)

retrospective analysis of cell proliferation/apoptosis [liver tissue] males

- correlation between cell proliferation, liver weight increase, and an increased in cidence of liver necrosis and/or hypertrophy at 1000 ppm and 3000 ppm]; clear evidence of cell proliferation and hepatotoxicity not evident at lower doses; females

- suggestive evidence of a similar correlation at 1000 ppm and 3000 ppm; however, lack of a dose

- response and extreme variability of data renders findings equivocal for proposed mode of carcinogenic action [liver tumors]; no data on whether proliferative response sustained.

A Regarding the lower NOAELs observed in both the rat and mouse long

- term studies, discussion was included in the endpoint selection section of the RED. For the chronic dietary scenario, it was noted that the chronic toxicity/carcinogenicity study in rats

pr ovided a lower NOAEL (2 mg/kg). However, the endpoint of concern [liver effects (hepatocellular hypertrophy)] was seen at 44 mg/kg (LOAEL); the effects were considered an adaptive effect and not appropriate for selection of the chronic dietary endpoi nt.
In addition, the lower NOAEL seen in the rat study might be influenced by dose selection. Although the mouse study was notMetaldehyde Human Health Risk Assessment DP No. D417506

Page 40 of 59 discussed, a similar conclusion is appropriate; i.e., the endpoint of concern in the mouse study [increased incidence of hepa tocellular hypertrophy in both sexes] was seen at 48 mg/kg/day (LOAEL); the lower NOAEL (16/20 mkd) in the mouse study might be influenced by dose selection; and the effects might also be considered adaptive and not appropriate for selection of the diet ary endpoint.

A.3 Hazard Identification and Endpoint Selection

A.3.1 Acute Reference Dose (aRfD)

- All populations

Study Selected: Chronic oral toxicity study

- dog

MRID No.: 46378401 Executive Summary : See Appendix A, Guideline [§ 870. 3100 ] Dose and Endpoint f

or Risk Assessment: NOAEL = 3 0 mg/kg/day based on clinical signs (ataxia, tremors, salivation, twitching) seen on day 1 of dosing in both sexes at LOAEL = 9 0 mg/kg/day

. Comments about Study/Endpoint/Uncertainty Factors: Since the signs of neurotoxicity were observed on the first day of dosing, the study is appropriate for an acute assessment. The dog is the most sensitive species for the neurotoxic effects observed, and neurotoxicity is the most sensitive endpoint in the toxicity database. The dose and e ndpoint are appropriate for all populations. No endpoint appropriate for females 13+ was identified in the database. Although maternal deaths occurred following 1

- 2 exposures in the rat and rabbit developmental toxicity studies, the deaths occurred at dose levels ≥100 mg/kg/day. The dose and endpoint selected from the chronic dog study are protective of these findings and of potential acute toxicity for all populations. Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability).

A.3. 2 Chronic Reference Dose (cRfD ) ` Study Selected: Chronic oral toxicity study

- dog

MRID No.: 46378401 Executive Summary : See Appendix A, Guideline [§ 870.3100] Dose and Endpoint for Risk Assessment: NOAEL = 10 mg/kg/day based on death and atrophy of the testes and prostate seen on at LOAEL = 30 mg/kg/day. Comments about Study/Endpoint/Uncertainty Factors: The selected endpoint provides the most sensitive NOAEL available from a study of appropriate duration and exposure (oral).

At rophy of the testes and prostate were observed in the dog subchronic oral toxicity study also at a dose of 60 mg/kg/day (NOAEL = 20 mg/kg/day). Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability).

A.3. 3 Incidental Oral Exposure (Short

- Term) Study Selected: Chronic oral toxicity study

- dog

MRID No.: 46378401 Executive Summary : See Appendix A, Guideline [§ 870.3100] Dose and Endpoint for Risk Assessment: NOAEL = 30 mg/kg/day based on clinical signs (ataxia, tremors, salivation, twitching) seen on day 1 of dosing in both sexes at LOAEL = 90 mg/kg/day.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 41 of 59 Comments about Study/Endpoint/Uncertainty Factors: The study is appropriate for the short

term assessment since t he signs of neurotoxicity were observed on the f irst day of dosing and throughout the first week of exposure . The dog is the most sensitive species for the neurotoxic effects observed, and neurotoxicity is the most sensitive endpoint in the toxicity database. The dose and endpoint are protective of effe cts observed in postnatal animals (population of concern) in the reproduction toxicity study (decreased pup body weight/gain). Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability).

A.3.4 Incidental Oral Exposure (Intermediate

- Term) Study Selected: Chronic oral toxicity study

- dog

MRID No.: 46378401 Executive Summary : See Appendix A, Guideline [§ 870.3100] Dose and Endpoint for Risk Assessment: NOAEL = 10 mg/kg/day based on death and atrophy

of the testes and prostate seen on at LOAEL = 30 mg/kg/day. Comments about Study/Endpoint/Uncertainty Factors: The selected endpoint provides the most sensitive NOAEL available from a study of appropriate duration and exposure (oral). Atrophy of the testes and prostate we re observed in the dog subchronic oral toxicity study also at a dose of 60 mg/kg/day (NOAEL = 20 mg/kg/day). Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability).

A.3.5 Dermal Exposure (Short

- , Intermediate

- and Long

- Te rm ) The repeated [21

- day] dermal toxicity study was considered for these exposure scenarios because the route of exposure is appropriate. Although no effects were observed, the limit dose was tested, no clinical signs were observed, the target organs [liv er and testes] were evaluated, and

there is no reproductive toxicity concern. Since n o hazard was identified , no risk from dermal exposure is expected

.

A.3.6 Inhalation Exposure (Short

- Term) Study Selected: Chronic oral toxicity study

- dog

MRID No.: 4 6378401 Executive Summary : See Appendix A, Guideline [§ 870.3100] Dose and Endpoint for Risk Assessment: NOAEL = 30 mg/kg/day based on clinical signs (ataxia, tremors, salivation, twitching) seen on day 1 of dosing in both sexes at LOAEL = 90 mg/kg/day. Comments about Study/Endpoint/Uncertainty Factors: The study is appropriate for the short

term assessment since the signs of neurotoxicity were observed on the first day of dosing and throughout the first week of exposure. The dog is the most se nsitive species for the neurotoxic effects observed, and neurotoxicity is the most sensitive endpoint in the toxicity database. The dose and endpoint are protective of effects observed in postnatal animals (population of concern) in the reproduction toxici ty study (decreased pup body weight/gain). Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability).

A.3.7 Inhalation Exposure ( Intermediate

- and Long

- Term) Study Selected: Chronic oral toxicity study

- dog

MRID No.: 4637 8401Metaldehyde Human Health Risk Assessment DP No. D417506

Page 42 of 59 Executive Summary : See Appendix A, Guideline [§ 870.3100] Dose and Endpoint for Risk Assessment: NOAEL = 10 mg/kg/day based on death and atrophy of the testes and prostate seen on at LOAEL = 30 mg/kg/day. Comments about Study/Endpoint/Uncertainty Factors: The selected endpoint provides the most sensitive NOAEL available from a study of appropriate duration and exposure (oral). Atrophy of the testes and prostate were observed in the dog subchronic oral toxicity study also at a dose of 60 mg/kg/day (NOAEL = 20 mg/kg/day). Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability).

A.4 Executive Summaries

A.4.1 Subchronic Toxicity

870.3100 90

- Day Oral Toxicity

- Rat In a subchronic oral toxicity study (MRID 44237704), metaldehyde (99.0% a.i.) was fed to 10 Sprague

- Dawley CD rats/sex/dose at dietary concentrations of 0, 2,500, 5,000, 10,000, or 20,000 ppm (equivalent to approximately 0, 200, 400, 800, or 1550 mg/kg/day) for 28 consecutive days. The study was to be used as a range

- finding study for a chronic oncogenicity and a 2

- generation study that were scheduled to be conducted.

Mortality, either as spontaneous death or moribund sacrifice, occurred in 6/10 10,000

- ppm females and 10/10 20,000

- ppm females, and in 4/10 20,000

- ppm males. In decedent animals, hind limb paralysis was the predominant effect observed prior to death, although tonic convulsions, excessive vocalization, gasping, and hyperactivity were also observed in one high

- dose female.

Increases (  10

- 28%) in blood urea nitrogen concentrations in all treated females were observed, with significance (p<0.05 or 0.01) at the 2,500

- and 10,000

- ppm levels. Slight decreases (6

- 8%, p<0.05) in erythrocytes were observed in the  10,000

- ppm males.

Treatment

- related increases (p<0.01) in absolute (up to 67%) and relative (up to 69%) liver weights were observed in both sexes and all test groups. Furthermore, histopathological examination revealed hepatocellular hypertrophy in both sexes at all test l evels.

Findings upon gross necropsy were limited to animals that died or were sacrificed during the study and included fracture/luxation of the vertebra, hemorrhage of the spinal cord, abnormal coloration of various organs, hydronephrosis and/or hemorrh age of the kidneys, and dilatation/distention and/or hemorrhage of the urinary bladder. The urinary tract abnormalities were presumably secondary to urine stasis resulting from paralysis. Similarly, microscopic examination revealed

luxation of the verteb ra; hemorrhaging of the vertebra and spinal cord; spinal cord compression, vacuolization, and malacia; hydronephrosis; and general congestion and/or hemorrhaging of various organs, including the thymic region, lungs, kidneys, and urinary bladder.

The sy stemic LOAEL is 2,500 ppm (equivalent to approximately 200 mg/kg/day) based on increased absolute and relative liver weights in all dose groups and hepatocellular hypertrophy at all dose levels in both sexes. The systemic NOAEL was not established.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 43 of 59 Thi s 28

- day oral (dietary) study is classified acceptable (Non Guideline) as it is not a required guideline study. It is acceptable for the purposes for which it was intended [range

- finding study].

870.3150 90

- Day Oral Toxicity

- Dog
In a 26

- week oral t oxicity study (MRID 00131432) ; beagle dogs were administered 0, 20, 60 or 90 mg/kg/day m etaldehyde in the diet. All animals survived the 26

- week period and no clinical signs of toxicity were observed. No effects were observed for food consumption, body we ight, drinking water intake, hematology, clinical chemistry, ophthalmology, or organ weights. Diffuse or focal atrophy of the prostate and testes were observed in the 60 and 90 mg/kg/day groups. There were increases in follicular hyperplasia of the mesente ric lymph node in the 90 mg/kg/day group. Animals in the 90 mg/kg/group had slight increases in periportal infiltration of lymphocytes, histiocytes and eosinophilic granulocytes in the liver and very slight hydropic swelling in focal areas of the liver

, wh ich are probably of no toxicological significance.

The NOEL/LEL were determined to be 20 mg/kg/day / 60 mg/kg/day, based on diffuse or focal atrophy of the testes and prostate. The study is core

- minimum and satisfies the requirements for
a Guideline Ser ies 83

- 1(b) chronic toxicity study in dogs.

870.3200 21/28

- Day Dermal Toxicity

– Rat
In a 21

- day dermal toxicity study ( MRID 42063401 ) , 5 New Zealand White rabbits/sex/group were administered metaldehyde [99.0%] via dermal application [dry powder covered with a gauze patch moistened with Milli

- Q® filtered water; once a day for 6 hours, 5 days/week] for 22 days at concentrations of 0, 100, 300, and 1000 mg/kg/day.

Treatment had no adverse effect on survival, clinical signs, mean body weight, body

- weight gain, food consumption, hematology, clinical chemistry, organ weights, or gross and microscopic pathology. There was no dose

- related increase in the incidence or severity of signs of dermal toxicity.

The NOAEL for sys temic and dermal toxicity is 1000 mg/kg/day, the highest dose tested

This guideline 21

- day dermal toxicity study is classified ACCEPTABLE, and it satisfies the guideline requirement [§82

- 2; 870.3200] for a 21

- day dermal toxicity study. Although fewer rabbits/sex/group were utilized than specified in the Guideline, this does not by itself diminish the finding of no effect at the limit dose.

870.3465 90

- Day Inhalation

– Rat

Study waived by HASPOC (TXR# 0056524, dated 2/21/13)

A.4.2 Prenatal De velopmental Toxicity

870.3700a Prenatal Developmental Toxicity Study

- Rat In a developmental toxicity study [MRID 41656001], female Sprague

- Dawley Crl:CD(SD)BR rats [25/group] were administered metaldehyde [99%] via gavage at dose levels of 0 [Mazola®Metaldehyde Human Health Risk Assessment DP No. D417506

Page 44 of 59 c orn oil], 25 mg/kg/day, 75 mg/kg/day, and 150 mg/kg/day from gestation day 6 through gestation day 15.

There were six deaths [all pregnant; high

- dose level only], which occurred between gestation days 7 and 8. Clinical signs attributed to treatment were observed at the high

- dose level in those dams that died and included ataxia [all six], rapid respiration [5 dams], twitching [4 dams], tremors [3 dams], prostration [1 dam], abdominal breathing [1 dam], hyperactivity [1 dam], paresis of the hind legs [1 dam], pallor [2 dams], perioral encrustation [3 dams], and perinasal encrustation [2 dams]. Decreased body weight [96% of control] was observed at the high

- dose level only on gestation day [GD] 9. Body

- weight gain was significantly decreased [74% of control] initially [GD 6

- 9] and throughout the dosing period at the high

- dose level. Although

dams at the mid

- do se level displayed only a slightly lower body

- weight gain during the dosing period [91% of control] compared to the control, based on their pre

- dose body

- weight gain [115% of control], the decrease is considered treatment

- related. A compensatory weight gai n was noted during the post

- dosing period at the high

- dose level. Corrected body

- weight gain at the high

- dose level was slightly [94% of control] lower than the control value. Food consumption was decreased at the high

- dose level during the dosing period a nd increased significantly during the post

- dosing period at the mid

- and high

- dose levels.

Treatment

- related necropsy findings in the dams dying on test included thinning of the stomach wall [1 dam], ulceration of the glandular [2 dams] and nonglandular [2 dams] portion of the stomach, red/brown lungs [6 dams], dilated renal pelvis [2 dams], and hydronephrosis [1 dam]. Additionally, perioral encrustation [6 dams], perinasal encrustation [5 dams], and paravertebral hemorrhage [1 dam] were observed in thos e dying on test. There were no adverse effects observed on maternal liver weight or gravid uterine weight.

There were no abortions, and the pregnancy rate was comparable among the groups. The numbers of corpora lutea, implantation, live fetuses, and reso rptions [both total and per dam], as well as pre

- and post

- implantation losses were comparable among the groups. There was one dead fetus [high dose]. Fetal body weights and the sex ratio were comparable among the groups. There were no statistically

- signif icant or dose

- related differences in the incidence of fetal malformations or variations [external, visceral, and skeletal].

The maternal toxicity NOAEL is 75 mg/kg/day, and the maternal toxicity LOAEL is 150 mg/kg/ day , based on mortality, clinical signs o f toxicity [ataxia, tremors, twitching, rapid respiration], decreased body

- weight gain during dosing, and decreased food consumption during dosing. The NOAEL for developmental toxicity is 150 mg/kg/day, the highest dose

tested.

This guideline developmen tal toxicity study is classified Acceptable, and it satisfies the guideline [OPPTS 870.3700; §83

- 3(a)] for a developmental toxicity study in the rodent.

870.3700b Prenatal Developmental Toxicity Study

- Rabbit In a developmental toxicity study [MRID 41590501], female New Zealand white rabbits [16/group] were administered metaldehyde [99%] via gavage at dose levels of 0 [Mazola® cornMetaldehyde Human Health Risk Assessment DP No. D417506

Page 45 of 59 oil], 10 mg/kg/day, 40 mg/kg/day, and 80 mg/kg/day from gestation day 6 through gestation day

18.

There were no treatment

- related deaths or clinical signs of toxicity. Body

- weight gains were extremely variable, and there was no dose

- response. All groups, including the control, displayed negative corrected body

- weight gains but ther e was no dose

- response. Food consumption was decreased at all dose levels during the dosing period compared to the control, but there was no

dose

- response.

Necropsy findings were comparable among the groups. There were no adverse effects observed

on mater nal liver weight or gravid uterine weight.

There were no abortions, and the pregnancy rate was not adversely affected by treatment. The numbers of corpora lutea, implantation, live fetuses, resorptions [both total and per dam], and dead fetuses, as well a s pre

- and post

- implantation losses were comparable among the groups. Fetal body weights and the sex ratio were comparable among the groups. There were no statistically

- significant or dose

- related differences in the incidence of external or visceral

malfor mations, but a slightly higher incidence of skeletal malformations [5 fetuses in 3 litters] was observed at the high

- dose level compared to the control and lower dose groups [1 fetus/group]. This latter finding is considered attributable to the greater num ber of fetus examined at the high

- dose level [140 fetuses in 16 litters] compared to the other groups [112 fetuses/12 litters; 104 fetuses/13 litters; and 107 fetuses/13 litters in the control, low

- and mid

dose groups, respectively]. External, visceral, a nd skeletal variations were comparable among the

groups.

The maternal toxicity NOAEL is 80 mg/kg/day, the highest dose tested. The NOAEL for developmental toxicity is 80 mg/kg/day, the highest dose tested.

This guideline developmental toxicity study is classified Acceptable, and it satisfies the guideline [OPPTS 870.3700; §83

- 3(b)] for a developmental toxicity study in the rodent. NOTE: Although no maternal or developmental effects were observed, the dose levels are considered adequate

based on effects observed in the range

- finding study. All does [5/group] in the 200, 350 and 500 mg/kg/day groups died [following 1 or 2 doses] or were sacrificed moribund [gestation days 8

- 12], and one doe at 100 mg/kg/day died. A repeat study at higher dose levels would not provide useful data. This is supported by the results in the rat. The maternal NOAEL in the rat developmental toxicity study is 75 mg/kg/day, based on mortality, clinical signs of toxicity [ataxia, tremors, twitching, rapid respiration], decreased body

- weight gain during dosing, and decreased food consumption during dosing at the LOAEL of 150 mg/kg/day. The NOAEL for developmental toxicity is 150 mg/kg/day, the highest dose tested.

A.4.3 Reproductive Toxicity

870.3800 Reproduction and Fertility Effec ts

- Rat
In a 2

- generation reproduction study [MRID 42823101], 28 male/28 female F0 CD ® rats/sex/group were administered metaldehyde [>99% a.i.] via the diet for 10 weeks prior to mating and through gestation and lactation of one litter at dose levels of 0 ppm, 50 ppm, 1000Metaldehyde Human Health Risk Assessment DP No. D417506

Page 46 of 59 ppm, and 2000 ppm [F0 males: 0, 3.4, 69.37, and 138.36mg/kg/day; F0 females: 0, 4.16, 80.81, and 160.42 mg/kg/day; F1 males: 0, 3.23, 64.93, and 133.53 mg/kg/day; F1 females: 0, 4.03, 80.51, and 164.15 mg/kg/day]. Rats were mated, one ma le with one female. The resulting F1 litters were weaned at day 28 post partum . The F1 generation [28 rats/sex/group] was
administered the test material at the same dose levels as F0 animals and mated in a similar manner, avoiding sibling matings. The resu lting F2 litters were weaned at day 28 post partum

.

No treatment

- related clinical signs of toxicity or mortality were observed in F0 males at any time point or in F0 females during the pre

- mating and mating periods or during gestation. However, at 2000 pp m, three F0 dams were sacrificed moribund during the lactation period [lactation days

16

- 18; days 110, 110, 113 on test] due to bilateral hindlimb paralysis. No treatment

- related clinical signs of toxicity or mortality were observed in F1 males at any time point or in F1 females during the pre

- mating and mating periods. However, during gestation/lactation, three F1 dams [2000 ppm] were found dead [days 95, 101, and 125]. The 2000 ppm F1 dam that was found dead on day 95 displayed ataxia, labored breathing, cold extremities, and pallor on day 94. An additional 2000 ppm F1 female [nongravid] displayed prostration, tremors, abdominal breathing, and rapid respiration on day 102 but survived until terminal sacrifice [day 134]. The

author stated that the relation ship of these latter signs to treatment was unclear. The cause of
death of two of the F1 females was not determined [third female due to septic emboli to various organs]. None of the other deaths [ F0 male and 2 F0 females at 50 ppm, 2 F1 females at 50 ppm

, and one F1 male at 1000 ppm] was considered treatment

- related. No additional treatment

- related clinical signs were noted.

F0 parental animals Body weights for the treatment groups were similar to control throughout the study for both sexes. During the pre

- mating dosing period , there were no consistent adverse effects on body

- weight gain in either sex. Body

- weight gains of the F0 high

- dose males were decreased initially [weeks 0

- 1 (91% of control)] and during weeks 5

- 6 (89% of control) and
weeks 8

- 9 (75% of control). During weeks 2

- 3, there was an apparent dose

- related increase in body

- weight gain in males at the mid

- (112% of control) and high

- dose (114% of control) levels. F0 females displayed a decrease in body

- weight gain [66% of control] during weeks 2

- 3 at the high

- dose level, although statistical significance was not attained, and the standard deviation exceeded the group mean. Food consumption was not affected in either sex.

There were no consistent, treatment

- related, adverse effects on body we ights or body

- weight gains of the F1 parental animals during the pre

- mating dosing period, although both sexes at the high dose displayed a smaller body

- weight gain during weeks 9

- 10 [males 83%; females 65% of control] than control. Food consumption was co mparable among the groups [both sexes] throughout the study.

At sacrifice, necrosis and hemorrhage in the spinal cord and vertebra luxation were observed in the three high

- dose F0 dams that displayed hindlimb paralysis. An additional F0 dam at 2000 ppm d isplayed spinal cord lesions microscopically.

At necropsy, no treatment

- related adverse effects were observed in F1 animals at any dose level.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 47 of 59 At 2000 ppm, F1 males displayed increased relative liver weights [15%] and F1 females displayed increased absolute [12%] and relative [11%] liver weights. These organ

- weight changes were not accompanied by histopathological lesions and may be attributed to adaptation to the test material. NOTE: Liver weights were not determined for F0 animals.

F0 Generation. No apparent adverse effect was observed on fertility, and the mating and gestation indices were comparable among the groups. Pre

- coital intervals were not reported. The duration of gestation was comparable among the groups. The number of live pups was

comp arable among the groups. The number of pups born dead/dying by day 1 was not affected by treatment. Litter size was slightly lower at the high

- dose level [Day 0 (13.6), Day 4 precull (13.3), Day 21 (7.5)] compared to the control [Day 0 (13.7), Day 4 precu ll (13.5), Day 21 (7.8)] and other dose groups [Day 0 (14.0 and 13.8), Day 4 precull (13.7 and 13.8), Day 21 (7.7 and 7.9) for low

- and mid

- dose groups, respectively] throughout the weaning period. The live birth index and the viability index were comparabl e among the groups, but the lactation index was slightly lowered [89%] at the high

- dose level compared to the control [99%] and other dose groups [99%]. At the high

- dose level, a slightly lower pup body weight was observed on lactation days 7 [males 96%/f emales 95% of control] and 21 [95% of control], although statistical significance was not attained for either timepoint. Body

- weight gains were slightly lower for both sexes at the high

- dose level [94%

- 95% of control] compared to the control throughout lac tation. The sex ratio was comparable among the groups. F1 Generation. No
apparent, treatment

- related, adverse effect was observed on fertility, and the mating and gestation indices were comparable among the groups. Pre

- coital intervals were not reported. T he duration of gestation was comparable among the groups. The high

- dose group had the fewest females [22] with live born pups [27 control and 23 each at the low

- and mid

- dose levels]. The number of live pups was comparable among the groups. The number of pups born dead/dying by day 1 was not affected by treatment. Litter size was comparable among the groups, and the live birth index, viability index, and the lactation index were comparable among the groups. At the high

- dose level, a slightly lower pup body weight was observed on lactation days 1 [males 93%/females 93% of control], 7 [females 95% of control], and 21 [males 93%/females 92% of control], although statistical significance was attained only at the day 21 time point. Body

- weight gains were slightl y lower for both sexes at the high

- dose level [91%

- 93% of control] compared to the control throughout lactation. The sex ratio was comparable among the groups.

The NOAEL for parental toxicity is 1000 ppm [males 65 mg/kg/day; females 81 mg/kg/day)

and th e parental LOAEL is 2000 ppm [males 133 mg/kg/day; females 160 mg/kg/day], based on mortality (F0 and F1 females), clinical signs (hindlimb paralysis in F0 females), and histopathology (spinal cord necrosis and hemorrhage, and vertebra luxation in F0
femal es and increased liver weight in both sexes [F1].

The NOAEL for reproductive toxicity is 2000 ppm [males 133 mg/kg/day; females 160 mg/kg/day], the highest dose tested.

The NOAEL for offspring toxicity is 1000 ppm [males 65 mg/kg/day; females 81 mg/kg/d ay) and the LOAEL for offspring toxicity is 2000 ppm [males 133 mg/kg/day; females 160 mg/kg/day], based on decreased pup body weight/body

- weight gain [F1 and F2 pups].Metaldehyde Human Health Risk Assessment DP No. D417506

Page 48 of 59 This 2

- generation reproduction study is classified Acceptable/Guideline. This study sa tisfies the guideline requirement (OPPTS 870.3800; §83

- 4) for a 2

- generation reproduction study. The original DER set the reproductive toxicity LOEL at 2000 ppm, based on decreased pup body weight and weight gain in both sexes, which is not a reproductive toxicity endpoint but an offspring endpoint. Reproductive toxicity was not observed in this study, based on the parameters examined. It is to be noted that several parameters in the current protocol that measure reproductive effects, such as age of vagina l opening and preputial separation; anogenital distance for F2 pups; implantations sites; estrous cycle length and periodicity (F1 weanlings); and sperm measures, were not evaluated. These are included in the new protocol,
which was not in effect at the t ime of the study.

A.4.4 Chronic Toxicity

870.4100a (870.4300) Chronic Toxicity

– Rat
See below under 870.4200

870.4100b Chronic Toxicity

- Dog In a chronic oral toxicity study (MRID 46378401), metaldehyde (98.3% a.i.; batch # 30202) was

administered once daily for 52 consecutive weeks to groups of 4 male and 4 female Beagle dogs at dose levels of 10, 30, and 90 mg/kg/day. The amount of test material given was adjusted to each dog’s actual body weight weekly.

There were three deaths [one each sex at 3 0 mg/kg/day and one female at 90 mg/kg/day], which
occurred between weeks 37 and 46. Treatment

- related clinical signs were observed from week one on at the high dose and included ataxia, emesis, tremor, twitching, and salivation. The incidence and severity of these clinical signs lessened with time from week 19, although 1 or 2 animals continued to display salivation throughout the study. One high

- dose female displayed lateral position early in the study, reduced motility during most of the study, and convu lsion and vocalization during week 46. Agitation was displayed by one high

- dose female during weeks 6

- 9
and 24

- 52. Body weight was slightly lower in the treated dogs [males ↓7%

- 17% ; females ↓6%

- 19% ] throughout most of the study, although a dose

- response wa s not always evident. At study termination, male body weights were ↓16 %, ↓12 %, and ↓17 % and female body weights were ↓4 %, ↓1 0%, and ↓ 1 9 % with increasing dose. During the first week on test, males displayed decreased body

- weight gains at all dose levels, al though the decrease was inversely related to dose [ ↓53 %, ↓34 %, and ↓26 % with increasing dose]. Only the mid

- dose females displayed a decrease in body

- weight gain initially [ ↓ 6 4 %]. During the 0

- 13 week interval, males at all dose levels [ ↓2 5%, ↓17 %, and ↓43 % with increasing dose] and females at the mid

- [63%] and high

- [79%] dose levels displayed decreased body

- weight gains compared to the controls. Food consumption was not adversely affected. Food efficiency values were not provided.

No lesions of the ey es or optic region were found, and there were no differences in the urinalysis parameters monitored in either sex. During the 13

- week assessment, one high

- dose dog of each sex did not react to the noise test, but no effects were noted in either sex at the 26

- and 52

- week assessments. Increases in hemoglobin, RBC, and hematocrit were observed in both sexes at the high

- dose level at week 13, but only in females at week 26. Alkaline phosphatase was increasedMetaldehyde Human Health Risk Assessment DP No. D417506

Page 49 of 59 throughout the study in both sexes at the high

- dose level, with the magnitude of the response from control increasing with time [both sexes]. High

- dose females displayed an increase in

gamma

- GT throughout the study, but other liver enzyme activities [AST, ALT] were not affected by treatment. Triglycerides w ere increased in the high

- dose females throughout the study compared to the control values.

At the high

- dose level in both sexes, liver weight was increased significantly compared to the
control values. There was a dose

- related decrease in absolute prost ate weight [ ↓1 8%, ↓29 %, and ↓32 % with increasing dose], a decrease in testes weight at the low

- and high

- dose level, and an increase in absolute and relative lung weight in high

- dose males. Increased brain weight (↑ 5 %) was observed in females at the high

- d ose level compared to the control. There were no apparent microscopic lesions in the liver, but atrophy and/or degeneration was observed in the testes and
prostate.

The lowest

- observed

- adverse

- effect level (LOAEL) for metaldehyde in the dog is 30 mg/kg/da y, based on death and atrophy of the testes and prostate. The NOAEL is 10 mg/kg/day.

The LOAEL for clinical signs of neurotoxicity is 90 mg/kg/day, based on ataxia, emesis, tremor, twitching, and salivation that occurred in all dogs of both sexes during d ays 1

- 7. The NOAEL for clinical signs of neurotoxicity is 30 mg/kg/day.

This chronic oral toxicity study in the dog is Acceptable/Guideline , and it satisfies the guideline requirement for a chronic oral toxicity study [OPPTS 870.4100); OECD 452] in the do g.

A.4.5 Carcinogenicity

870.4200a Carcinogenicity Study

- rat In a chronic toxicity/carcinogenicity study [MRID 42203601], 60 Sprague

- Dawley CD® rats/sex/dose were administered metaldehyde [99 %] via the diet at concentrations of 0 ppm and 0 ppm (2 control groups), 50 ppm [males 2 mg/kg/day; females 3 mg/kg/day], 1000 ppm [males 44 mg/kg/day; females 60 mg/kg/day], 5000 ppm [males 224 mg/kg/day; females 314 mg/kg/day] for 104 weeks.

There was no adve rse effect of treatment on survival of either sex, although females at the mid

- [60%] and high

- [58%] dose levels displayed a slightly greater mortality than the control groups [50% and 48%]. There were no apparent treatment

- related clinical signs of toxic ity. There was a slight reduction in body weight [ ↓ 5%] throughout most of the study in both sexes at the high

dose level compared to the control groups. During the first week, females in all treated groups displayed a dose

- related [statistically

- significan t at all dose levels] decrease in body

- weight gain compared to the 2 control groups [86%/94%, 69%/75%, and 60%/66% of control with increasing dose]. During the same time

- frame, males displayed a similar dose

- related decrease in body

weight gain, which was statistically significant at the mid

- [87% of control] and high

- [78% of control] dose level compared to one of the control groups. Food consumption was decreased at the high

- dose level in both sexes during the first few weeks of the study, which suggests a palatability problem.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 50 of 59 There were no apparent, treatment

- related, effects on the ophthalmological or hematological parameters monitored in either sex. Mid

- and high

- dose females displayed a statistically

significant, dose

- related, increase in cholester ol levels throughout most of the study. Globulin values were elevated in the high

- dose females throughout most of the study [weeks 26, 52, and 78] and in mid

- dose females only at week 78. There were no treatment

- related alterations in the liver enzymes mon itored. There was a dose

- related increase in urine volume in females [37%, 40%, and 54% with increasing dose] at week 77 only.

Increased liver weight [males ↑ 11%

- 18%; females ↑ 21%

- 32%] was observed in both sexes at the high

- dose level, although the value s in males did not attain statistical significance. Females at all dose levels displayed an increase in ovarian weight, but there was no dose

- response, and the
standard deviation of the low

- and high

- dose female groups exceeded the means.

In the liver, th ere was a dose

- related increase in hepatocellular hypertrophy in both sexes, which was statistically

- significant at the mid

- dose level in males and at the high

- dose level in both sexes. There was a statistically

- significant increase in hepatocellular adeno mas in high

- dose females [10%] compared to the control and other dose groups. The majority of the liver adenomas were observed at the terminal sacrifice, and the incidence is within the historical control incidence of the testing facility [0%

- 10%]. One hep atocellular carcinoma was observed in one of the control groups and in one high

- dose female. The combined incidence [adenomas and carcinomas] of liver tumors in the high

- dose females [11.7%] is slightly outside the

historical control incidence of the testi ng facility [0%

- 10%]. Males did not display an increase in
liver tumors.

The systemic toxicity NOAEL is 50 ppm [males 2 mg/kg/day; females 3 mg/kg/day], based on hepatocellular hypertrophy and increased cholesterol in both sexes and decreased body

weight gain in females at the systemic LOAEL of 1000 ppm [males 44 mg/kg/day; females 60 mg/kg/day].

This guideline chronic toxicity/carcinogenicity study is classified ACCEPTABLE, and it satisfies the guideline [OPPTS 870.4300; §83

- 5] for a chronic toxicity/ carcinogenicity study in

the rat.

870.4200b Carcinogenicity (feeding)

- Mouse In a carcinogenicity study [MRID 42737201], 60 CD

- 1 mice/sex/dose were administered metaldehyde [>99%; Lot # 5448] via the diet at concentrations of 0 ppm [2 control groups], 25 ppm [males 4.0 mg/kg/day; females 4.8 mg/kg/day], 100 ppm [males 15.9 mg/kg/day; females 19.7 mg/kg/day], and 300 ppm [males 48.9 mg/kg/day; females 59.8 mg/kg/day] for 18 months.

There were no treatment

- related effects on survival or clinical signs in either sex, and body weights, body

- weight gains, and food consumption were comparable among the groups for both

sexes.

The hematologic parameters monitored were comparable among the groups [both s exes]. Clinical chemistry and urinalysis parameters were not monitored.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 51 of 59 At necropsy, there were no gross lesions attributed to treatment in either sex. With the exception of liver weights in males, which displayed a dose

- related increase (although statis tical significance was not attained), organ weights were comparable among the groups [both sexes].

Non

- neoplastic lesions: The incidence [overall: high

- dose males 62% vs 30%

- 33% control; high

dose females: 30% vs 7%

- 15% control] and severity of hepatocel lular hypertrophy were increased in both sexes at the high

- dose level compared to the control groups. The majority of the mice with hepatocellular hypertrophy were diagnosed at terminal sacrifice.

Neoplastic lesions : There was no statistically

- significant increase in the incidence of liver tumors in either sex, although the high

- dose males displayed a slight increase [15 adenomas and 3 carcinomas] compared to both control groups [8 adenomas/1 carcinoma and 8 adenomas/3carcinomas].

The systemic toxicity NO AEL is 100 ppm [15.9 mg/kg/day (males); 19.7 mg/kg/day (females)], based on a significantly increased incidence of hepatocellular hypertrophy in both sexes at the LOAEL of 300 ppm [48.9 mg/kg/day (males); 59.8 mg/kg/day (females)]. No other toxicological e ffects were observed in either sex. The incidence of tumors was comparable among the groups [both sexes].

This guideline carcinogenicity study is classified ACCEPTABLE/Guideline. However, the dose levels were not considered adequate for assessing the carc inogenic potential of metaldehyde, and a supplementary study was performed [MRID 44625101; separate DER]. In the 90

- day mouse study [not submitted to the Agency] performed to determine dose levels to be used in the current study, mortality was said to have been observed at 3000 ppm and 10000 ppm and dose

- related increases in liver weight and hepatic lesions were reported in both sexes at ≥ 300 ppm. The supplemental carcinogenicity study [MRID 44625101] was performed using one dose level of metaldehyde [1000 ppm]. At 1000 ppm, there was a treatment

- related increase in the incidence of hepatocellular adenomas in both sexes when compared to controls. Dosing was considered adequate based on the increased incidence of liver lesions [liver single cell/focal/multifo cal necrosis (males) and hepatocellular eosinophilic cell foci (females)] in both sexes, in addition to hepatocellular hypertrophy ( both sexes ), which was the only treatment

- related finding in the current study at 300 ppm. When all the information, includi ng the 90

- day study (MRID 43297701), are considered together, MRID 42737201 and MRID 44625101 satisfy the guideline requirement [OPPTS 870.4200; §83

- 2] for a carcinogenicity study in the mouse.

In a carcinogenicity study [MRID 44625101], metaldehyde was administered to 60 Crl:CD

- 1®

- (ICR)BR mice/sex/dose via the diet at dose levels of 0, 0, and 1000 ppm [equivalent to 0, 0, 135 mg/kg bw/day (males)/163 mg/kg bw/day (females)] for at least 78 weeks.

There were no compound

- related effects on mortality, cli nical signs, body weight, food consumption, or hematology in either sex. With the exception of the liver, organ weights were comparable to those of the control groups for both sexes. Liver weights were increased significantly in both sexes at 1000 ppm comp ared to both of their respective control groups. Gross and histologic pathology findings were comparable among the groups for both sexes, withMetaldehyde Human Health Risk Assessment DP No. D417506

Page 52 of 59 the exception of the liver. Hepatocellular hypertrophy was observed in both sexes at 1000 ppm. Males at 1000 ppm displayed single cell necrosis, focal or multifocal necrosis, pigment accumulation, and sinusoidal. Females at 1000 ppm displayed a small increase in the incidence of hepatocellular eosinophilic cell foci. There was a significant increase in the incidence of hepatocellular adenomas in both sexes [males: 4 and 5 vs 14; females: 1 and 0 vs 5], with the males displaying the greater effect. Males also displayed a slight increase in hepatocellular carcinomas [2 and 2 vs 4] compared to both control groups.

Und er the conditions of this study, at the only dose of metaldehyde tested [1000 ppm; 135 (males)/163 (females) mg/kg/day)], increased liver weight (both sexes), hepatocellular hypertrophy (both sexes), liver single cell/focal/multifocal necrosis (males), liv er pigment accumulation (males), sinusoidal histiocytosis (males), hepatocellular eosinophilic cell foci (females), and hepatocellular adenomas (both sexes) were observed. The NOAEL is not established in the current study. However, based on a previous mous e carcinogenicity study in the same strain of mouse [MRID 42737201], in which an increased incidence of hepatocellular hypertrophy was observed in both sexes at the highest dose tested [300 ppm; 48.9 (males)/59.8 (females) mg/kg/day], the NOAEL is 100 ppm [15.9 (males)/19.7 (females) mg/kg/day], with the LOAEL based on an increased incidence of hepatocellular hypertrophy in both sexes.

At the dose tested in the current study, there was a treatment related increase in the incidence of hepatocellular adenomas in both sexes when compared to the controls. Dosing was considered adequate based on the increased incidence of liver lesions [liver single cell/focal/multifocal necrosis (males) and hepatocellular eosinophilic cell foci (females)] in both sexes, in addition to the hepatocellular hypertrophy observed in the previous study at 300 ppm.

This carcinogenicity study in the mouse is Acceptable/non

- guideline. It is non

- guideline since only one dose level was tested. The study was performed as a supplement to a previous 18

- month mouse carcinogenicity study [MRID 42737201] and should be considered along with the previous study. Together, the two studies satisfy the guideline requirement for a carcinogenicity study [OPPTS 870.4200; OECD 451] in mice.

A.4.6 Mutagenicity

Gene Mutation

Guideline 870.5100

, r everse gene mutation assay in bacteria

MRID 48666101 (2011)

C lassification : acceptable/guideline Salmonella typhimurium strains TA98, TA100, TA102, TA1535, and TA1537; concentrations of 0, 3, 10, 33, 100, 333, 1000, 2500, or 5000 μg/plate (+/

- S9

- activation); insoluble at ≥2500 μg/plate +/

- S9.

N o evidence of induced mutant colonies over background.

Cytogenetics

Guideline 870.5300

, in vitro mutagenicity (mammalian forward gene mutation)

MRID 48721401 ( 2011)

C lassification : acceptable/guideline T ested up to solubility limit (≥ 600 μg/mL +/

- S9) ; failed to induce either a cytotoxic or a mutagenic effect. There was no evidence of induced mutant colonies over background.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 53 of 59 Guideline 870.5385

, in v iv o cytogenetic mutagenicity assay MRID 48788201 ( 2012)

Classification : acceptable/guideline in vivo rat bone marrow chromosome aberration test at doses of 0, 62.5, 125, and 250 mg/kg (M) or 0, 31.25, 62.5, and 125 mg/kg (F) ; no evidence of cytogenicity in this whole animal chromosome aberration

assay.

Other Genotoxicity

Guideline 870.5395

, micronucleus

assay MRID 42044006 (1990)

C lassification ; Unacceptable/guideline highest dose tested (100 mg/kg); MTD not reached

A.4.7 Neurotoxicity

870.6200 Acute Neurotoxicity Screening Battery

Study was w aived by HASPOC ( TXR# 0056524 ; dated 2/21/13 )

.

870.6200 Subchronic Neurotoxicity Screening Battery In a subchronic neurotoxicity study (MRID 46223401), metaldehyde (98.3% a.i., batch # 31509)
was administered via the diet to 10 Sprague

- Dawley Crl:CD® (SD) IGS BR rats/sex/group at dose
levels of 0 [basal diet], 100, 500, and 2500 ppm (equivalent to 0, 8, 39, 185 mg/kg bw/day) for 90 consecutive days. Clinical signs, body

- weight development, food and water consumption were monitored during the study, and ophthalmoscopic examination of the control and high

- dose rats was performed pre

- test and during final week of the study. Neurobehavioral assessment (functional observational battery and motor activity testing) was performed in all rats/sex/group prior to the start of dosing and during weeks 2, 4, 8, a nd 12. At study termination, 5 animals/sex/group were euthanized and perfused with gluteraldehyde: paraformaldehyde via the heart, following initial
whole

- body perfusion with heparin z ed saline, for neuropathological examination. Of the perfused animals, al l control and high

- dose rats were subjected to histopathological evaluation of brain and peripheral nervous system tissues. One high

- dose female was sacrificed [day 22] due to poor condition [bilateral hindlimb paralysis], which was observed initially on da y 10. There were no

other treatment

- related deaths. Body weights and body

- weight gains of the males were comparable among the groups throughout the study. Females at the mid

- and high

- dose levels displayed slightly lower body weights [ ↓5 %

- 6 %] throughout th e study. Body

- weight gains of the mid

- dose females [80% of control; not statistically significant] and high

- dose females [ ↓3 0%; statistically significant] were lower during the first week and remained lower than control throughout the study, although stati stical significance was not attained and a dose

- response was not always apparent. Food consumption was comparable among the male groups but lower than control in the high

- dose females throughout the study. Food efficiency was comparable among the groups fo r both sexes.
No ocular effects were observed in either sex.

Differences in motor activity parameters were observed sporadically, but there was no consistent dose response, some standard deviations were greater than the means, and statistical significance was rarely attained. Differences in grip strength and startle reflex values were observedMetaldehyde Human Health Risk Assessment DP No. D417506

Page 54 of 59 sporadically also, but there was no consistent dose response and statistical significance was rarely

attained.

At termination, no macroscopic abnormalities were rep orted for either sex. No treatment

- related changes were observed in brain weight for either sex, and no treatment

- related histopathological alterations were reported in either sex.

NOTE: The positive control data [February

- April, 2003] bring into questio n the capability the testing facility had to adequately assess neurotoxicity at the time the metaldehyde study was performed [February

- October, 2002]. Additionally, the available positive control data do not provide adequate evidence of the ability of the testing facility to identify a neurotoxic compound. Since the trimethyltin [1 mg/kg] animals did not survive to study termination, no FOB assessment was performed on these animals [no motor activity, grip strength, startle reflex]. Neuropathology

was demo nstrated following trimethyltin exposure, however. The only neuropathological findings in the acrylamide

- treated animals [15 mg/kg] were contraction vacuoles in the sciatic and/or tibial nerves, mainly in females. No axonal degeneration was observed. Findi ngs in the acrylamide females were not observed in the acrylamide males, and a sex difference following acrylamide exposure is not expected. Individuals performing the various assessment s were not identified in either the metaldehyde study or the positive control study, and methodology and apparatus descriptions are not adequate. Further, a more definitive explanation/presentation of the data, especially the motor activity data are require d.

Provisionally, the LOAEL for neurotoxicity can be set at 500 ppm [39 mg/kg/day], based on increased motor activity in females. The NOAEL can be set at 100 ppm [8 mg/kg/day]. At the highest dose tested [2500 ppm (185 mg/kg)], bilateral hindlimb paralys is was observed in one female, and females displayed decreased body

- weight gains during the first week of the study.

The study is classified as Unacceptable (guideline) , and it does not satisfy the guideline requirement for a subchronic neurotoxicity stud y in rats (870.6200b). The study is classified Unacceptable since the results suggest little neurotoxicity following exposure to metaldehyde; more importantly, the positive control data submitted do not demonstrate proficiency of the testing facility to de tect alterations in the neurotoxicity parameters monitored.

A.4.8 Metabolism

870.7485 Metabolism

- Rat In a metabolism study in rats (MRID 42300901),t he absorption, distribution, metabolism and

excretion of m etaldehyde were studied in groups of male and female Sprague

- Dawley rats administered a single oral gavage dose of 10 or 100 mg/kg 14C

- metaldehyde or following repeated oral dosing of 10 mg/kg non

- labeled m etaldehyde for 14 days followed by a single dose

o f labeled m etaldehyde on day 15. In addition, the pharmacokinetics of m etaldehyde was evaluated in rats receiving a single oral dose of 10 mg/kg labeled m etaldehyde.

Metaldehyde was rapidly absorbed, distributed, and metabolized in rats for all dosing reg imens.

The 7

- day recoveries were >94% for all groups. Most of the radioactivity was recovered inMetaldehyde Human Health Risk Assessment DP No. D417506

Page 55 of 59 expired air (78

- 98% of administered dose) within 24 hours (48 hours for high

- dose females)

, the majority of which was reported to be 14 CO 2 . Recovery in urine a nd feces was low for all dosing groups (2.5

- 5.1 %). Slight sex

- , dose

- , and regimen

- related effects on m etaldehyde excretion were found. The recovery of administered radioactivity was greater in low

- dose animals than in high

dose and repeated dose animals. The pharmacokinetics study showed that males reached peak blood levels and excreted radioactivity faster than females. The concentration of total radioactivity in the blood at peak levels was similar for both sexes, but the concentration of intact

m etaldeh yde was >50% higher in females than in males at peak, first and second blood half

lives.

Recovered radioactivity in tissues/carcass after 7 days was similar for all dose groups (7

- 11% of administered dose). High concentrations of radioactivity were recove red in nervous tissue, fat, liver, and reproductive organs. Tissue examination of low

- dose animals showed that radioactive residues (percent of administered dose) were highest in the carcass at peak, first and second

blood half

- lives. At second blood half

- life, percent dose in the liver exceeded that of any other tissue (except carcass) in both males and females. No clinical signs of toxicity were observed.

Classified acceptable for a metabolism study under Guideline series 85

- 1.Metaldehyde Human Health Risk Assessment DP No. D417506

Page 56 of 59 A ppendix B. Metabolism Summary Table

Table B.1

- Tabular Summary of Metabolites and Degradates

Chemical

Name Commodity Percent TRR (PPM) 1

Structure Matrices

- Major
Residue 2 (>10%TRR) Matrices

-

Minor
Residue 2 (<10%TRR)

Parent: Metaldehyde Lettuce 95.3

Sugar beet

- root 35

Sugar beet

- top 33

Rat *
Degradate:

Non

Extractable

Residues Lettuce <5

N/A

Sugar beet

- root 43.4

Sugar beet

- top 43.2

Rat ND 2.5

- 5.1

CO 2 Rat 78

- 98
Lettuce; 43923301; 13.8 lb ai/A; 10x; single directed application; 28 days.

Sugar beets; 43923302; 13.76 lb ai/A; 10x; single directed application; 48 days.

Rat: 42300901; single gavage dose 10 or 100 mg/kg, repeated dose 10 mg/kg/day for 14 days, then single dose 14C [10 mg/kg], Sprague

- Dawley, 1 day depur ation

* = metaldehyde and acetaldehyde detected in plasma; no quantification available at this time.

ND = not detectable
Note 1: Confined Rotational Crop study waiver granted by CHEMSAC on 12/9/04.
Note 2: Livestock metabolism and feeding studies (ruminan t & poultry) waiver granted Metaldehyde: 3/11/97)Metaldehyde Human Health Risk Assessment DP No. D417506

Page 57 of 59 Appendix C. Physical/Chemical Properties

TABLE C.1. Physicochemical Properties of Metaldehyde

Parameter Value Reference
Melting point/range 246°C Metaldehyde RED, PC Chapter

pH Not applicable due to the low solubility of metaldehyde in water. N/A

Density 1.27 g/cm 3

Metaldehyde RED, PC Chapter Water solubility (20°C) 0.222 g/L at 20°C

Solvent solubility (g/L at 20.3

- 22.4°C) 5.21 x 10

- 2 in hexane
0.53 in toluene

1.56 in tetrahydrofuran
1.73 in methanol

Vapor pressure 6.6 ± 0.3 Pa at 25°C
Dissociation constant (pK
a ) 3.5 Pa (m 3 /mol) (Henry’s Law Constant)
Octanol/water partition coefficient, K
ow 1.33 (log K
ow = 0.12) at 20°CMetaldehyde Human Health Risk Assessment DP No. D417506

Page 58 of 59 Appendix D. 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 data, which include studies from the PHED 1.1, the AHETF database, and the ARTF database 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 10

.

10 http://www.epa.gov/pesticides/science/handler

- exposure

- data.html and http://www.epa.gov/pesticides/science/post

- app

- exposure

- data.htmlMetaldehyde Human Health Risk Assessment DP No. D417506

Page 59 of 59 Appendix E. Exerpt from e mail message from Melanie Biscoe (EFED) to W. Donovan (HED), 15

- JUL

- 2014.

Metaldehyde ground water modeling comparison 30

- year simulation (metaldehyde applied first 6 years only)

Acute (Peak) ug/L Chronic

(Post

- Breakthrough Average)

ug/L

2013 Drinking Water

Assessment

PRZM

- GW v. 1.0 1,740 (WI Sands) 635 (WI Sands)

Initial Scenarios

PRZM

- GW v. 1.07

1,880 (FL Citrus) 915 (NC Coastal) Revised Scenarios distributed
March 2014