UNITED STATES ENVIRONMENTAL PROTECTION AGENCY WASHINGTON, D. C. 20460 OFFICE OF PREVENTION, PESTICIDES AND TOXIC SUBSTANCES December 20, 2005 MEMORANDUM SUBJECT: Metaldehyde: HED Chapter of the Reregistration Eligibility Decision Document ( RED). PC Code: 053001; DP Barcode: DP311884 FROM: Matthew Lloyd, Risk Assessor Linda Taylor Ph. D. Felecia Fort Jeffrey Dawson Reregistration Branch 1 Health Effects Division ( 7509C)

THROUGH: Whang Phang, Ph. D. Branch Senior Scientist Reregistration Branch 1 Health Effects Division ( 7509C)

TO: Jill Bloom, Chemical Review Manager Special Review and Reregistration Division ( 7508C)

DP Barcode: DP311884 PC Code: 053001 Attached is the revised Human Health Risk Assessment for the Metaldehyde Reregistration Eligibility Decision Document ( RED). Comments from the registrant, Lonza, Inc. have been reviewed and appropriately been incorporated into the current RED. Information was drawn from Health Effects Division ( HED) team members. Additional information was drawn from the Environmental Fate and Effects Division ( EFED) Tier 1& 2 Drinking Water Assessment and the review of Metaldehyde Incident Reports from HED, Chemistry and Exposure Branch. A complete list of team members can be found on page 3. Page 2 of 80 HUMAN HEALTH RISK ASSESSMENT Metaldehyde U. S. Environmental Protection Agency Office of Pesticide Programs Health Effects Division ( 7509C) Matthew Lloyd,  Risk Assessor Date: December 20, 2005 Page 3 of 80 Risk Assessment Team:

Risk Assessor: Matthew Lloyd Residue Chemistry: Felecia Fort Occupational and Residential Exposure: Jeffrey Dawson Epidemiology: Jerome Blondell, MPH, Ph. D.

Toxicology: Linda Taylor, Ph. D.

Drinking Water Estimates: Lucy Shanaman HUMAN HEALTH RISK ASSESSMENT Metaldehyde Page 4 of 80 Table of Contents 1.0 Executive Summary......................................................................................................... 7 2.0 Ingredient Profile............................................................................................................. 9 2.1. Summary of Registered/ Proposed Uses...................................................................... 9 2.2. Structure and Nomenclature .................................................................................... 12 2.3. Physical and Chemical Properties ............................................................................ 12 3.0 Metabolism Assessment................................................................................................. 13 3.1. Comparative Metabolic Profile ................................................................................ 13 3.2. Nature of the Residue in Foods................................................................................. 14 3.2.1. Description of Primary Crop Metabolism........................................................... 14 3.2.2. Description of Livestock Metabolism .................................................................. 14 3.2.3. Description of Rotational Crop Metabolism, including identification of major metabolites and specific routes of biotransformation ....................................................... 15 3.3. Environmental Degradation ..................................................................................... 15 3.4. Tabular Summary of Metabolites and Degradates.................................................. 15 3.5. Summary of Residues for Tolerance Expression and Risk Assessment.................. 17 3.5.1. Tabular Summary ................................................................................................ 17 3.5.2. Rationale for Inclusion of Metabolites and Degradates...................................... 17 4.0 Hazard Characterization/ Assessment........................................................................... 17 4.1. Hazard Characterization .......................................................................................... 17 4.2 FQPA Hazard Considerations.................................................................................... 22 4.1.1. Adequacy of the Toxicity Database...................................................................... 22 4.1.2. Evidence of Neurotoxicity .................................................................................... 23 4.1.3. Developmental Toxicity Studies........................................................................... 23 4.1.4. Reproductive Toxicity Study................................................................................ 23 4.1.5. Additional Information from Literature Sources ............................................... 24 4.1.6. Pre and/ or Postnatal Toxicity ............................................................................. 24 <IP_ADDRESS>. Determination of Susceptibility........................................................................ 24 <IP_ADDRESS>. Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Postnatal Susceptibility.................................................................................................... 24 4.2. Recommendation for a Developmental Neurotoxicity Study .................................. 24 4.2.1. Evidence in favor of retaining the 10X/ requiring further evaluation of neurobehavioral development............................................................................................ 24 4.2.2. Evidence against retaining the 10X/ requiring further evaluation of neurobehavioral development............................................................................................ 25 <IP_ADDRESS>. Rationale for the UFDB ( when a DNT is recommended).................................. 25 4.3. Hazard Identification and Toxicity Endpoint Selection .......................................... 25 4.3.1. Margins of Exposure ............................................................................................ 28 4.3.2. Recommendation for Aggregate Exposure Risk Assessments ............................ 28 4.3.3. Classification of Carcinogenic Potential .............................................................. 28 4.4. Endocrine disruption ................................................................................................ 29 5.0 Public Health Data......................................................................................................... 29 5.1. Incident Reports........................................................................................................ 29 6.0 Exposure Characterization/ Assessment........................................................................ 31 6.1. Dietary Exposure/ Risk Pathway............................................................................... 31 Page 5 of 80 6.1.1. Residue Profile...................................................................................................... 31 6.1.2. Acute and Chronic Dietary Exposure and Risk .................................................. 31 6.2. Water Exposure/ Risk Pathway................................................................................. 33 6.3. Residential ( Non Occupational) Exposure/ Risk Pathway....................................... 33 6.3.1. Home Uses............................................................................................................. 33 <IP_ADDRESS>. Residential Handler Risk Assessment.............................................................. 37 <IP_ADDRESS>. Residential Postapplication Risk Assessment .................................................... 43 6.3.2. Recreational Uses ................................................................................................. 48 6.3.3. Other ( Spray Drift, etc.)....................................................................................... 48 7.0 Aggregate Risk Assessments and Risk Characterization............................................. 48 7.1. Acute Aggregate Risk................................................................................................ 49 7.2. Short Term Aggregate Risk ..................................................................................... 50 7.3. Long Term Aggregate Risk ...................................................................................... 52 8.0 Cumulative Risk Characterization/ Assessment............................................................ 53 9.0 Occupational Exposure/ Risk Pathway.......................................................................... 53 9.1. Short/ Intermediate/ Long Term Handler Risk......................................................... 54 9.2. Short/ Intermediate/ Long Term Postapplication Risk............................................. 65 10.0 Data Needs and Label Requirements............................................................................ 65 10.1. Toxicology ............................................................................................................... 65 10.2. Residue Chemistry.................................................................................................. 65 10.3. Occupational and Residential Exposure ................................................................ 66 References: .............................................................................................................................. 66 Appendices: Appendix A: Relevant Toxicology Executive Summaries ..................................................... 67 Appendix B: Tolerance Reassessment Summary .................................................................. 78 List of Tables Table 1  Metaldehyde End Use Products ( EPs) with Registered Food/ Feed Uses. ............ 10 Table 2  Metaldehyde Nomenclature .................................................................................... 12 Table 3  Physicochemical Properties of Metaldehyde .......................................................... 12 Table 4  Tabular Summary of Metabolites and Degradates ................................................ 16 Table 5  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression............................................................................................... 17 Table 6  Acute Toxicity Profile  Metaldehyde ..................................................................... 19 Table 7  Subchronic, Chronic and Other Toxicity Profile ................................................... 20 Table 8  Summary of Toxicology Endpoint Selection for Metaldehyde .............................. 27 Table 9  Summary of Dietary Exposure and Risk for Metaldehyde.................................... 32 Table 10  Summary of Estimated Surface and Ground Water Concentrations for Metaldehyde .................................................................................................................... 33 Table 11  Summary of Registered Metaldehyde Residential Uses....................................... 34 Table 12  Metaldehyde Residential Non Cancer Inhalation Exposure and Risk................ 40 Table 13  Summary of Non Cancer Short term Postapplication MOEs for Toddlers ....... 47 Table 14  Aggregate Risk Assessment for Acute Dietary Exposure to Metaldehyde.......... 50 Table 15  Short Term Aggregate Risk.................................................................................. 51 Table 16  Aggregate Risk Assessment for Chronic Dietary Exposure to Metaldehyde ...... 52 Page 6 of 80 Table 17  Summary of Short and Intermediate term Occupational Handler Non cancer Risks................................................................................................................................. 58 Page 7 of 80 1.0 Executive Summary This risk assessment was performed to support the reregistration eligibility decision for metaldehyde [ 2,4,6,8 tetramethyl 1,3,5,7 tetraoxyacyclooctane]. Metaldehyde 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 concentrate ( FlC), and ready to use liquid ( RTU/ L) formulations. Formulated products generally contain 0.13 25% active ingredient.

The use of metaldehyde is being supported by Lonza, Inc., which manufactures the only technical grade product registered in the U. S. ( OPPIN query on 11/ 15/ 04). There are a total of 68 end use products with feed/ food uses that are registered or conditionally registered to 22 different registrants.

In the past, it was assumed that acetaldehyde, which can be formed in an acidic environment like the stomach, was responsible for the toxic effects observed following metaldehyde exposure. However, this seems unlikely since acetaldehyde was not found in the plasma or urine of dogs exposed to metaldehyde. Metaldehyde has been shown to cross the blood brain barrier and has been detected in the brain, blood, and liver of rodents. When molluscs and slugs are exposed to metaldehyde, the chemical causes the pests to be torpid, increasing the secretion of mucus leading to dehydration and death.

Metaldehyde has low acute toxicity via the dermal and inhalation routes of exposure [ Toxicity Category III] and via the oral route in males [ Toxicity Category III]. Moderate acute oral toxicity [ Toxicity Category II] is observed in females. Metaldehyde is a mild eye irritant [ Toxicity Category III] but is not a skin irritant [ Toxicity Category IV] or a dermal sensitizer. No dermal or systemic toxicity was observed at the limit dose [ 1000 mg/ kg/ day] in the 21 day dermal toxicity study in the rabbit.

The liver is a target organ following subchronic and chronic oral exposure, as evidenced by increased liver weight, increased incidence of liver lesions [ hepatocellular necrosis, hepatocellular hypertrophy, inflammation], and an increased incidence of hepatocellular adenomas/ carcinomas in female rats and hepatocellular adenomas in both sexes of mice. The testes and prostate are also target organs, as evidenced by atrophy of both organs following subchronic and chronic exposure in dogs.

There is a concern for neurotoxicity following oral exposure to metaldehyde, as evidenced by hindlimb paralysis, along with mortality, in rats following both acute [ one to two doses in pregnant rats] and repeated exposure ( lactation days 16 18), neurotoxic signs [ ataxia, tremors, twitching, salivation, and/ or prostration] in female rats [ 1 2 doses] and dogs of both sexes [ within first week of exposure and persisting through week 19], and neuropathology [ spinal cord necrosis and hemorrhage] in the maternal animal.

Developmental toxicity was not observed in either the rat or rabbit study at adequate dose levels. Reproductive toxicity was not observed. Offspring toxicity [ decreased pup body weight/ body weight gain] occurred at the same dose level producing mortality, clinical signs [ hindlimb paralysis] and histopathology [ spinal cord necrosis and hemorrhage] in the maternal animal. Page 8 of 80 The mutagenicity database is not complete, and a complete battery of studies is required.

The weight of evidence for metaldehyde is " Suggestive Evidence of Carcinogenic Potential", based on the presence of benign liver tumors in female rats, benign liver tumors in both sexes of mice, and a lack of adequate mutagenicity data. No quantification of cancer risk has been recommended.

The available toxicology data are adequate for toxicity endpoint selection for risk assessment as summarized below:

Dose Study Type/ Endpoint Acute dietary: NOAEL 75 mg/ kg Developmental toxicity in rats Chronic dietary: NOAEL 10 mg/ kg Chronic oral toxicity study in dogs Short term incidental oral: NOAEL 30 mg/ kg Chronic oral toxicity study in dogs ( ataxia, tremor, twitching from week 1) UF = 1000 for dietary and residential assessment There was no evidence of increased susceptibility following in utero exposure in rats and rabbits and pre/ postnatal exposure in the 2 generation reproduction study in rats. Since there are no residual uncertainties that indicate the need for a special safety factor, the FQPA special ( hazard) factor can be reduced to 1X. However, a developmental neurotoxicity study is recommended due to: 1) the neuropathology observed in the F0 dams that also displayed clinical signs of neurotoxicity, bilateral hindlimb paralysis, and death in the 2 generation reproduction study; 2) the clinical signs of neurotoxicity and death in dams in the rat developmental toxicity study; and 3) bilateral hindlimb paralysis observed in one high dose female sacrificed [ day 22] due to poor condition in the 90 day subchronic neurotoxicity study in rats. A database uncertainty factor of 10X was recommended to be applied to all exposure durations.

Dietary Exposure: Acute and chronic dietary exposure and risk assessments were conducted applying tolerance level residues. Food and water were considered in these assessments. Risk estimates were below HED's level of concern for both the acute and chronic assessments for the U. S. general population and various population subgroups. The highest exposed population subgroup was children 1 2 years old ( 25% aPAD and 49% cPAD for acute and chronic risks, respectively. The dietary risk estimates could be further refined with the incorporation of anticipated residues, cooking/ processing factors and usage information ( percent crop treated).

Residential Exposure: Residential handler scenarios and some residential post application scenarios have not been assessed because dermal exposure is not considered a hazard for metaldehyde and inhalation exposures are not anticipated. All of the residential handler scenarios have Margins of Exposure ( MOEs) that were not of concern (  5600). The post application residential exposure scenarios include hand to mouth, object to mouth, soil ingestion for toddlers, and the possible ingestion of metaldehyde granules. The combined risk estimate represents a high level of exposure based on what may be reasonably expected to occur in the metaldehyde user population. Short term risks from exposure to treated turf were not of concern ( combined MOE= 1600). . A rangefinder intermediateterm assessment was also completed resulting in risks that were not of concern. Page 9 of 80 Uncertainty related to the issue of a lack of residue dissipation data would be reduced if residue dissipation data were available.

Aggregate Exposures: HED considered and aggregated metaldehyde pesticide exposures and risks from several major sources: food, drinking water, residential, and other nonoccupational exposures. Intermediate term exposures were expected to occur infrequently, if at all. For the acute aggregate risk assessment with dietary and ground water, the highest subgroup was children ( 1 2 years old) with 29% of the aPAD at the 95th percentile. The short term aggregate risk was aggregated from oral and inhalation exposures, and was based on the same endpoint. None of the scenarios for the relevant population sub groups demonstrated risks of concern. Long term aggregate risk included only food and drinking water as there were no long term residential uses for metaldehyde. The most highly exposed sub group was children 1 2 years old where 69% of the cPAD was occupied in the chronic aggregate assessment.

Occupational Exposures: A variety of handler exposure scenarios were assessed including chemigation, groundboom application, airblast, various granular application scenarios, and various handheld sprayer scenarios ( e. g. handgun and hose end). For all short and intermediate term occupational handler scenarios, risks were not of concern.

Occupational post application exposures were not assessed for metaldehyde because no dermal hazard was identified. Inhalation exposures were expected to be negligible in outdoor post application scenarios since metaldehyde has low vapor pressure and the dilution factor outdoors is considered infinite.

2.0 Ingredient Profile 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 concentrate ( FlC), and ready to use liquid ( RTU/ L) formulations at concentrations ranging from 0.13 25% a. i. The use of metaldehyde is being supported by Lonza, Inc., which manufactures the only technical grade product registered in the U. S.

2.1. Summary of Registered/ Proposed Uses A summary of end use products is presented below in Table 1. Page 10 of 80 Table 1  Metaldehyde End Use Products ( EPs) with Registered Food/ Feed Uses.

EPA Reg. No. Formulation 1 Label Date Registrant Product Name 11656 20 2 2% P/ T 6/ 19/ 74 Western Farm Service, Inc Coastox Meta Carbaryl 2 4 Snail Pellets 19713 389 4% 4/ 24/ 96 Drexel Chemical Co Drexel Slug and Snail Bait 239 2373 3.25% P/ T 6/ 22/ 71 Bug geta Snail & Slug Pellets 239 2514 2 2% 1/ 24/ 85 Get a Bug Snail, Slug & Insect Killer 239 2651 2% P/ T 10/ 01/ 96 The ORTHO Business Goup Bug Geta Snail & Slug Pellets 3 2935 418 4% 10/ 28/ 82 Wilbur Ellis Co. Metaldehyde 4 Bait 34911 8 2 1% 9/ 15/ 76 Hi Yield Chemical Company Hi Yield Bug Bait 4 333 2 2% 8/ 21/ 86 Bonide Slug, Snail & Sowbug Bait 4 334 3.25% 8/ 21/ 86 Bonide Slug and Snail Beater 4 351 4% 7/ 31/ 89 Last Slime Slug n Snail Beater RTU 4 352 12.5% 12/ 14/ 89 Bonide Last Slime Slug n Snail Beater 4 442 0.13% 8/ 30/ 00 N Slugs N Snails 4 443 2 0.13% 2/ 22/ 96 Micro Flow Slug N Snail Plus 4 449 2 2% 11/ 01/ 02 Bonide Snail, Slug & Sowbug Bait 4 450 2 0.13% 10/ 29/ 02 Bonide Snail N Slug Plus 4 451 3.25% 10/ 29/ 02 Bonide Snail N Slug Beater 4 452 0.13% 3/ 26/ 03 N Snails N Slugs 4 453 12.5% 10/ 29/ 02 Bonide Products, Inc.

Bonide Snail n Slug Beater Concentrate 42057 39 2 4% 3/ 09/ 79 MORGRO Chemical Co MORGRO Pest Meal 49585 27 2% 7/ 02/ 93 Alljack, Division of United Industries Corp K Gro Snail & Slug Bait 5887 170 2 2.5% 11/ 16/ 87 Black Leaf Snailicide 769 643 3.25 P/ T 7/ 29/ 71 Value Gardens Supply, LLC Smcp Slug and Snail Bait Pellets 59639 53 4% P/ T 11/ 16/ 89 Valent U. S. A. Corporation Valent Metaldehyde 4% Bait 6973 10 1% P/ T 10/ 09/ 67 SOILSERV Inc SOILSERV Sevin Metaldehyde Bait 61282 10 2 3.5% P/ T 6/ 29/ 92 Snail and Slug Ag Pelleted Bait 61282 11 3.5% P/ T 6/ 29/ 92 Snail and Slug Ag Pelleted Bait 61282 34 2.75% P/ T 1/ 10/ 67 HACCO, Inc.

Hopkins Snail and Slug Pellets 5481 100 2 2.5% G 2/ 26/ 73 Durham carbaryl Metaldehyde Granules 5 2.5 5481 103 7.5% G 2/ 26/ 73 Durham Metaldehyde Granules 7.5 5481 318 20% G 7/ 23/ 86 Slugit 5481 451 2 3% 3/ 27/ 95 Snail, Slug & Sowbug Killer for Lawn & Garden 5481 507 4% P/ T 9/ 10/ 86 Deadline Bullets 5481 511 4% P/ T 2/ 03/ 98 Deadline M PS Mini Pellets! 5481 91 3.5% G 2/ 26/ 73 Durham Metaldehyde Granules 3.5 5481 95 2 3% G 2/ 26/ 73 Durham End of Trail Snail Slug & Insect Granules 5481 97 2 3% 2/ 26/ 73 AMVAC Chemical Corp Alco Snail, Slug and Sowbug Killer 71096 10 1.5% RTU 6/ 26/ 02 OR CAL Inc Slug Feast All Weather Formula RTU Page 11 of 80 Table 1  Metaldehyde End Use Products ( EPs) with Registered Food/ Feed Uses.

EPA Reg. No. Formulation 1 Label Date Registrant Product Name 71096 12 10.5% 4/ 25/ 73 Lilly/ Miller Go West Slug Killer 71096 13 4% P/ T 8/ 16/ 94 SOILSERV Metaldehyde Snail Bait 71096 4 2.1 lb/ gal FlC 10/ 10/ 73 Slug Fest Colloidal 25 71096 7 3.25% P/ T 10/ 01/ 80 OR CAL Slug & Snail Bait 71096 8 2.75% P/ T 10/ 01/ 80 ( OR CAL cont'd)

Snail & Slug Pellets 7401 265 2 1% P/ T 7/ 14/ 76 Ferti Lome Home Garden Bug Bait 7401 450 2.75% P/ T 9/ 25/ 00 Hi Yield Snail & Slug Killer Pellets 7401 72 2 1% 9/ 10/ 71 Voluntary Purchasing Group Inc Ferti Lome Improved Bug Bait 74941 1 2% 11/ 21/ 03 Metarex 2% Snail Slug Bait 74941 2 4% 5/ 08/ 03 De Sangosse UK Metarex 4% Snail and Slug Bait 33116 3 10.5% 11/ 06/ 02 Lilly Miller Slug & Snail Spray 802 351 2 2% 10/ 24/ 63 Miller's Slug, Snail and Insect Killer Bait 802 549 2% 1/ 03/ 83 Lilly/ Miller Slug, and Snail ' Em Bait 909 83 2 3% G 5/ 31/ 85 Central Garden & Pet D/ B/ A Lilly Miller Brands/ Excel Garden Cooke Slug N Snail Granules 8119 1 2% 9/ 26/ 63 Corry's Slug and Snail Death 8119 11 3.25% P/ T 12/ 05/ 02 Corry's Slug & Snail 3.25 8119 13 3.25% P/ T 12/ 05/ 02 Corry's Slug & Snail Pellets MP 8119 2 4% 1/ 16/ 87 Corry's Liquid Slug & Snail Control 8119 5 2 2% 4/ 11/ 88 Corry's Slug, Snail & Insect Killer 8119 6 4% 1/ 14/ 75 Deadline 40 8119 9 4% 11/ 13/ 98 Matson, LLC Deadline Rain Trough 8278 3 2 3.5% 8/ 03/ 90 Metro Tested All Purpose Bug Bait 8278 4 7.5% 4/ 30/ 93 Metro Biological Laboratory Metro That's It Dry 829 182 2 3.25% P/ T 11/ 17/ 67 Southern Agricultural Insecticides, Inc. SA 50 Brand Bait Pellets Kill Land Snails & Slugs 8660 196 2.75% 3/ 23/ 71 Pursell Snail & Slug Killer Meal 8660 197 2.75% P/ T 2/ 19/ 71 Snail & Slug Killer Pellets 8660 250 2% P/ T 2/ 24/ 99 Sta Gone Snail & Slug Killer Pellets 8660 251 2% 2/ 24/ 99 Sta Gone Snail & Slug Killer Meal 8660 73 3% 3/ 12/ 85 Vertagreen Slug & Snail Bait 8660 73 3% 3/ 12/ 85 SYLORR Plant Corp.

Vertagreen Slug & Snail Bait 869 119 2 1% 11/ 17/ 72 Green Light Company Green Light Bug & Snail Bait 1 Information on the formulation type for numerous EPs was not available to the reviewer. 2 These are MAI formulations also containing 4 5% carbaryl. Page 12 of 80 2.2. Structure and Nomenclature The nomenclature of metaldehyde are presented in Table 2.

Table 2  Metaldehyde Nomenclature Chemical structure O O O O C H 3 CH 3 CH 3 C H 3 Common name Metaldehyde ( PC Code   053001)

Molecular Formula C8H16O4 Molecular Weight 176.2 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 tetraoxacyclooctane CAS # 108 62 3 2.3. Physical and Chemical Properties The physicochemical properties of metaldehyde are listed below in Table 3.

Table 3  Physicochemical Properties of Metaldehyde Parameter Value Reference Melting point 246 EC MRID 00131972; Metaldehyde Registration Standard, 10/ 7/ 88, Chuck Trichilo.

pH Not applicable due to the low solubility of metaldehyde in water. N/ A Density, bulk density, or specific gravity 1.27 g/ cm3 Metaldehyde, IPCS Inchem, WHO/ FAO Data Sheet ( PDS 93).

Water solubility 0.222 g/ L at 20 EC MRID 40733901; RD letter dated 4/ 5/ 89 from D. Edwards to J. Conti, Lonza, Inc. Page 13 of 80 Table 3  Physicochemical Properties of Metaldehyde Parameter Value Reference Solvent solubility At 20.3 22.4 EC: 5.21 x 10 2 g/ L in hexane 0.53 g/ L in toluene 1.56 g/ L in tetrahydrofuran 1.73 g/ L in methanol MRID 00131972; Metaldehyde Registration Standard, 10/ 7/ 88, Chuck Trichilo.

Vapor pressure 6.6 ± 0.3 Pa at 25 EC MRID 40733902; Letter dated 4/ 5/ 89 from D. Edwards ( RD) to J. Conti ( Lonza, Inc.)

Dissociation constant, pKa 3.5 Pa ( m3/ mol) ( Henry's Law Constant) MRID 40733904; Letter dated 4/ 5/ 89 from D. Edwards ( RD) to J. Conti ( Lonza, Inc.)

Octanol/ water partition coefficient 1.33 ( log POW = 0.12) at 20 EC MRID 40733903; Letter dated 4/ 5/ 89 from D. Edwards ( RD) to J. Conti ( Lonza, Inc.)

UV/ visible absorption spectrum N/ A N/ A 3.0 Metabolism Assessment Previously, the toxicologically active substance was thought to be the degradation product acetaldehyde, which can be formed at a low pH in the stomach. However, the old theory that acetaldehyde is responsible for the toxic effects observed following metaldehyde exposure seems unlikely since acetaldehyde was not found in the plasma or urine of dogs exposed orally to metaldehyde. Metaldehyde has been shown to cross the blood brain barrier and has been detected in the brain, blood, and liver of rodents.

Metaldehyde is rapidly absorbed, distributed, and metabolized, with most of the radiolabel being recovered as 14CO2 in expired air within 24 hours for male rats and within 48 hours in female rats ( MRID 42300901). Recovery in urine/ feces is low [ 2.5% 5.1%], and the sexes differ slightly. In plasma, the ratio of metaldehyde to acetaldehyde was found to be 4: 1 in males and 12: 1 in females at peak blood level ( 1 2 hrs in males and 2 4 hrs in female, post dosing). In addition, the half life of metaldehyde was longer in females ( 8.8 hrs) than in males ( 3.4 hrs).

3.1. Comparative Metabolic Profile The major residue 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 waived since the metabolism in secondary crops is likely to be similar to the primary crops. Page 14 of 80 Livestock metabolism studies have been waived because metaldehyde is expected to be rapidly metabolized in mammalian systems with subsequent incorporation of degradates 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 as expired air within 24 hours as 14CO2 in the rat metabolism study ( MRID 42300901).

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

3.2. Nature of the Residue in Foods 3.2.1. Description of Primary Crop Metabolism The qualitative nature of metaldehyde residues in plants is understood based on the adequate 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, per se.

In the lettuce metabolism study, radioactive residues were taken up and translocated to leaves following a single directed application of [ 14C] metaldehyde to the soil at a rate equivalent to 13.76 lb ai/ A ( 10X). The maximum total radioactive residues ( TRR) were 4.43 ppm and 3.78 ppm in the inner and outer lettuce leaves, respectively, with a PHI of 28 days. Up to 95.3% of TRR was identified as the parent metaldehyde.

In the sugar beet metabolism study, a single directed application of [ 14C] metaldehyde was made to the soil at a rate equivalent to 13.76 lb ai/ A ( 10X). The TRR were 1.65 5.60 ppm in/ on sugar beet foliage and 0.30 1.13 ppm in/ on sugar beet root ( PHI = 48 days), indicating uptake and translocation to foliage. Metaldehyde was the only radioactive residue identified in the organic fractions of foliage ( 33% TRR, 1.84 ppm) and root ( 35% TRR, 0.39 ppm). Although no analytical analyses of the nonextractable residues of foliage ( 43.2% TRR, 2.42 ppm) and root ( 43.4% TRR, 0.49 ppm) were conducted, the aggregate of plant metabolism data for this chemical support the HED Metabolism Committee's decision to regulate only the parent in the tolerance expression for plant commodities.

3.2.2. Description of Livestock Metabolism Requirements for livestock metabolism and feeding studies have been waived. The Agency concluded that residues are unlikely to occur in livestock commodities based upon the rapid degradation of metaldehyde in mammalian systems and the subsequent incorporation of degradates into naturally occurring components. ( HED; 3/ 11/ 97). Page 15 of 80 3.2.3. Description of Rotational Crop Metabolism, including identification of major metabolites and specific routes of biotransformation A request for a data waiver of the confined rotational crop study for metaldehyde was submitted. The registrant is proposing to conduct a field accumulation in rotational crops study rather than the confined accumulation in rotational crop study.

The rationale for the waiver is that since the confined rotational crop study is essentially a metabolism study and metabolism is understood for metaldehyde, the confined study should not be required. The Agency made the determination that the only residue of interest is metaldehyde per se. For this reason, the Agency granted Lonza Inc. waivers for nature of residue studies in plants and livestock and required quantification of metaldehyde in plant translocation studies that were conducted with metaldehyde. The basis for this decision is that because of its chemical structure ( a tetramer of acetaldehyde), the primary metabolite would be acetaldehyde, a chemical whose metabolism in plants and animals is well documented in basic chemistry texts. The second reason is that it is very likely that total radioactive residues ( TRR) greater than 0.01 ppm would be found in the one month and four month rotational crops in a confined rotational crop study. This in turn would trigger the need for the field study anyway. Lonza, Inc. believes that the TRR would be greater than 0.01 because metaldehyde is a soil applied slug and snail bait that has been shown to translocate through the soil into plant matrices, and its half  life in soil under aerobic conditions is 67.2 days. The third reason is that residues ranging between 0.168 and 0.298 ppm have been found in several crops in the leafy vegetable crop group in the recent crop field trial program.

On December 9, 2004, the Chemistry Science Advisory Council ( CHEMSAC) granted a waiver for the confined accumulation in rotational crop study for the chemical metaldehyde.

3.3. 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, and those transformation products were not considered in the EFED drinking water assessment. Acetaldehyde is an environmental degradate resulting from metaldehyde, although because acetaldehyde undergoes further degradation, it is not included in the tolerance expression or this risk assessment.

3.4. Tabular Summary of Metabolites and Degradates A tabular summary of metabolites and degradates can be found below in Table 4. Page 16 of 80 Table 4  Tabular Summary of Metabolites and Degradates Percent TRR ( PPM) 1 Chemical Name Commodity Matrices  Major Residue2 (> 10% TRR) Matrices  Minor Residue2 (< 10% TRR) Structure Lettuce 95.3 Sugar beet  root 35 Sugar beet  top 33 Parent: Metaldehyde Rat * O O O O C H 3 CH 3 CH 3 C H 3 Lettuce < 5 Sugar beet  root 43.4 Sugar beet  top 43.2 Degradate: Non Extractable Residues Rat ND 2.5 5.1 CO2 Rat 78 98 N/ A 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 depuration * = metaldehyde and acetaldehyde detected in plasma; no quantification available at this time. ND = not detectable Note 1: Confined Rotational Crop waiver granted by CHEMSAC on 12/ 9/ 04. Note 2: Livestock metabolism and feeding studies ( ruminant & poultry) waiver granted Metaldehyde: 3/ 11/ 97) Page 17 of 80 3.5. Summary of Residues for Tolerance Expression and Risk Assessment 3.5.1. Tabular Summary Table 5  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression Matrix Residues included in Risk Assessment Residues included in Tolerance Expression All Primary Crops Parent Parent Plants Rotational Crop Parent Parent Ruminant Not Applicable Not Applicable Livestock Poultry Not Applicable Not Applicable Drinking Water Parent Not Applicable 3.5.2. Rationale for Inclusion of Metabolites and Degradates The major residue found in plant commodities was the parent compound, metaldehyde. Carbon dioxide and acetaldehyde are expected to be the terminal metabolites and/ or environmental degradates.

As mentioned in section 3.0, acetaldehyde previously was thought to be a major metabolite of metaldehyde. The recent data indicated that metaldehyde was found in greater concentrations in test animals than acetaldehyde. However, acetaldehyde occurs naturally, and is ubiquitous in the body. Acetaldehyde is used as a flavorant/ adjuvant and background levels occur in foods at up to 500 ppm. It is also listed as " Generally Recognized As Safe" ( GRAS) in 21 CFR 182.60. Therefore, acetaldehyde is not a residue of concern for either risk assessment or the tolerance expression.

4.0 Hazard Characterization/ Assessment 4.1. Hazard Characterization The required toxicological database on metaldehyde is not complete. The toxicological data gaps for metaldehyde include a developmental neurotoxicity study in rats, a subchronic inhalation study, and a mutagenicity battery. However, adequate information was available for establishing toxicity endpoints and doses for risk assessment.

In published articles on metaldehyde, signs and symptoms of toxicity in humans may be delayed several hours following ingestion. Depending upon the dose, initial effects may Page 18 of 80 be associated with gastrointestinal irritation, e. g. increased salivation, nausea, abdominal pain, vomiting and diarrhea. Other signs and symptoms may include elevated body temperature, mental confusion, muscle cramps and tremors, loss of consciousness, convulsions and coma. In case of severe poisoning, death may be due to cyanosis and respiratory failure. There may also be some liver and kidney involvement and recovery may take several weeks. It should be noted the gastrointestinal effect of metaldehyde in human was consistent with the necropsy found in the developmental rat study. In that study, dams dying on test had thinning of the stomach wall, ulceration of the glandular and nonglandular portion of the stomach. These results were seen at generally high dose levels.

When molluscs and slugs are exposed to metaldehyde, the chemical causes the pests to be torpid, increasing the secretion of mucus leading to dehydration and death.

Metaldehyde has low acute toxicity via dermal [ Toxicity Category III] and inhalation [ Toxicity Category IV] routes of exposure. The acute oral toxicity category is II. Metaldehyde is a mild eye irritant [ Toxicity Category III], but is not a skin irritant [ Toxicity Category IV] or a dermal sensitizer. No dermal or systemic toxicity was observed at the limit dose [ 1000 mg/ kg/ day] in the 21 day dermal toxicity study in the rabbit.

The liver is a target organ following subchronic and chronic oral exposure, as evidenced by increased liver weight, increased incidence of liver lesions [ hepatocellular necrosis, hepatocellular hypertrophy, inflammation], and an increased incidence of hepatocellular adenomas/ carcinomas in female rats and hepatocellular adenomas in both sexes of mice. In dogs, the testes and prostate are target organs, as evidenced by atrophy of both organs following subchronic and chronic exposure. With dermal application for 28 days in rabbits, no systemic effects were seen at doses as high as 1000 mg/ kg.

Chronic feeding studies in rats and mice indicated that metaldehyde produced liver effects characterized by liver hypertrophy and liver tumors. The carcinogenicity of metaldehyde had been evaluated by the Cancer Assessment Review Committee of OPP, and it classified metaldehyde as " suggestive evidence of carcinogenicity".

The developmental toxicity studies in rats and rabbits did not find any developmental effects at doses as high as 150 mg/ kg; however, in the rat, metaldehyde produced neurotoxic signs such as ataxia, tremors, and twitching in dams at 150 mg/ kg. The reproduction study in rats also indicated that metaldehyde did not affect any of the reproductive parameters, and the effects on the offspring consisted of decrease pup weight and body weight gains only at 133 mg/ kg or above. However, in dams, at 160 mg/ kg or above metaldehyde produced mortality and clinical signs ( limb paralysis, spinal cord necrosis and hemorrhage) similar to those seen in the rat developmental toxicity study.

No acute neurotoxicity study on metaldehyde is available. The 90 day neurotoxicity study demonstrated that this chemical produced increased motor activity at 39 mg/ kg or Page 19 of 80 above. At 185 mg/ kg, it produced bilateral hindlimb paralysis in one female rat. It appeared that metaldehyde at dose levels greater than 100 mg/ kg could produce neurotoxicity in adult rats as indicated in developmental and reproduction studies in rats.

A rat metabolism study showed that metaldehyde administered by gavage was rapidly absorbed, distributed, and metabolized. 78% 98% of the administered dose was recovered in expired air within 24 hours after dosing. More 14C was found in nervous tissues, fat, liver, and reproductive organs than other tissue.

The mutagenicity battery was not complete. In the mutagenicity studies where there were deficiencies in the tests, metaldehyde was suggested to be negative with mouse lymphoma assay and chromosomal aberrations in CHO cell, and micronucleus assay.

The acute toxicity profile for metaldehyde is summarized in Table 6. The chronic, subchronic and other toxicity profile for metaldehyde is summarized in Table 7.

Table 6  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 ] Page 20 of 80 Table 7  Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year) Classification / Doses Results 870.3100 90 Day oral toxicity [ rodents] 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], based 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 870.3250 90 Day dermal toxicity no study located/ not required no study located/ not required 870.3465 90 Day inhalation toxicity ( rat) no study located [ datagap] [ datagap]

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. Developmental 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 Maternal toxicity NOAEL = 80 mg/ kg/ day [ HDT] Maternal toxicity LOAEL = no effects observed. Developmental 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 increased 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; females 160 mg/ kg/ day], based on decreased pup body weight and body weight gain in both sexes/ both generations. Page 21 of 80 Table 7  Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year) Classification / Doses Results 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] 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 bodyweight 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 NOAEL = 10 mg/ kg/ day LOAEL = 30 mg/ kg/ day, based on deaths and atrophy of testes/ prostate 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] 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 bodyweight gain in females. evidence of carcinogenicity: females displayed a treatmentrelated increase in hepatocellular adenomas and adenomas and carcinomas combined [ positive trend at 5000 ppm] at the highdose 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 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] 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 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 0, 0.26, 1.28, 6.4, 32, 160 Fg/ plate (+/ S9; initial); 4, 8, 16, 32 Fg/ plate (+/ S9; repeat)

[ datagap] 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  mouse lymphoma L5178Y ( TK+/) cell line 870.5300 MRID 41553206 ( 1986) unacceptable 20, 50, 100, 200 Fg/ mL  S9 20, 50, 100, 167 Fg/ mL + S9 [ datagap] no conclusions can be drawn; doses evaluated were said to be " not completely dissolved in the selected solvent ( culture medium); all concentrations precipitated. Additionally, the. 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 42044007 ( 1986; revised 1991) clarification of MRID 41553206 unacceptable w/ S9  20, 50, 100, 167 Fg/ mL w/ out S9  20, 50, 100, 200 Fg/ mL [ datagap] negative for inducing forward gene mutation at TK locus in mouse lymphoma ( L5178Y) cell with/ without S9 activation up to precipitating concentrations ( 100 200 Fg/ mL ( S9); 100 167 Fg/ mL (+ S9), but the exposure time ( 2 hours) was shorter than the standard exposure time for this test system ( 4 hours).

Chromosomal aberrations in CHO cells 870.5375 MRID 00163832 ( 1986) unacceptable w/ S9  20, 50, 100, 167 Fg/ mL w/ out S9  20, 50, 100, 200 Fg/ mL [ datagap] Negative for inducing chromosome aberrations in CHO cells up to a precipitating concentration ( 200 Fg/ mL  S9). With S9, negative up to the highest dose tested ( 167 Fg/ mL) but no cytotoxicity or compound precipitation at this level. Page 22 of 80 Table 7  Subchronic, Chronic and Other Toxicity Profile Guideline No./ Study Type MRID No. ( year) Classification / Doses Results Micronucleus assay 870.5395 MRID 42044006 ( 1990) unacceptable 25, 50, 100 mg/ kg Negative up to HDT ( 100 mg/ kg) but MTD not reached 870.6200a Acute neurotoxicity screening battery no study located no study located 870.6200b Subchronic neurotoxicity screening battery MRID 46223401 ( 2003) unacceptable/ 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.

870.6300 Developmental neurotoxicity no study available [ datagap] [ datagap]

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 dose females] as 14CO2; 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 [ T1/ 2 males 3.4 hrs.; females 8.8 hrs.]; recovery greater following low dose than highdose and repeat exposure; concentration of total 14C in blood at peak similar for sexes but concentration of intact metaldehyde was > 50% higher in females than in males at peak, first and second blood half lives; 14C in tissues/ carcass after 7 days similar for all groups [ 7% 11% of administered dose]; high concentrations 14C recovered in nervous tissue, fat, liver, female reproductive organs; 2 major peaks [ plasma] were metaldehyde and acetaldehyde 870.7600 Dermal penetration no study available no study available 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 incidence 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.

4.2 FQPA Hazard Considerations 4.1.1. Adequacy of the Toxicity Database The available toxicology database is adequate for toxicity endpoint selection. A developmental neurotoxicity study in rats is considered a datagap. The studies available for FQPA considerations are: Page 23 of 80   rat developmental toxicity study ( acceptable)   rabbit developmental toxicity study ( acceptable)   two generation reproduction study in rats ( acceptable)   90 neurotoxicity study in rats ( unacceptable)

4.1.2. Evidence of Neurotoxicity 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 and hemorrhage in the spinal cord and vertebra luxation in F0 dams during lactation period in the twogeneration reproduction study; ( 3) bilateral hindlimb paralysis observed initially on day 10 in one high dose female sacrificed [ day 22] due to poor condition in the 90 day subchronic neurotoxicity study in rats; ( 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; other signs included lateral position, reduced mobility, convulsions, and vocalization in one female, and agitation in another. It should be noted that most of these neurotoxic signs ( such limb paralysis, ataxia, and tremors) were seen in rats at dose levels above 100 mg/ kg except the increased motor activity at 39 mg/ kg in the 90 day neurotoxicity study.

4.1.3. Developmental Toxicity Studies In a developmental toxicity study in rats metaldehyde was tested up to 150 mg/ kg; no developmental effects were seen at any dose. However, there were increased mortality and clinical signs such as ataxia, tremors, twitching, and rapid respiration seen in 150 mg/ kg dams. In the developmental toxicity study in rabbits, metaldehyde was tested up to only 80 mg/ kg, no developmental and maternal toxicity was found. The developmental toxicity studies in rats and rabbits did not demonstrate an increase in sensitivity or susceptibility in developing fetuses of either species.

The executive summaries of the above are presented in Appendix A.

It should be noted that although no maternal or developmental effects were observed in rabbit developmental toxicity study, 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 was also supported by the results in the rat developmental toxicity study where no maternal effect was seen at 75 mg/ kg and no developmental effect was seen at 150 mg/ kg.

4.1.4. Reproductive Toxicity Study In a 2 generation reproduction study in rats, metaldehyde was administered in the diet at concentrations of 50, 1000, and 2000 ppm ( F1 males: 0, 3.23, 64.93, and 133.53 Page 24 of 80 mg/ kg/ day; F1 females: 0, 4.03, 80.51, and 164.15 mg/ kg/ day). Offspring toxicity was seen at 2000 ppm ( 133 mg/ kg) consisting of decreased pup weight and body weight gain, and parental toxicity consisted of increased mortality, clinical signs such as hindlimb paralysis, spinal cord necrosis and hemorrhage, and increased liver weights. As demonstrated in the developmental toxicity studies in rats and rabbits, the data of the 2 generation reproduction study also showed no increase in sensitivity or susceptibility in pups under the conditions of this study. The executive summary is presented in Appendix A.

4.1.5. Additional Information from Literature Sources The published literature noted that with oral exposure metaldehyde was hydrolyzed in the stomach acid to acetaldehyde polymers that readily enter the brain. Poisoning might result from reduced levels of brain serotonin, norepinephrine, and the inhibitory neurotransmitter (  aminobutyric acid [ GABA]. Clinical signs of toxicosis were similar in all mammals. Neurotoxicity signs are prominent and include severe muscle tremors, ataxia, hyperesthesia, nystagmus, and hyperpnea, followed by opisthotonos and continuous tonic convulsions.

4.1.6. Pre and/ or Postnatal Toxicity There is low/ no concern for pre and/ or postnatal toxicity resulting from exposure to metaldehyde. <IP_ADDRESS>. Determination of Susceptibility There is no evidence of increased susceptibility [ qualitative and quantitative] following in utero exposure to metaldehyde in either the rat or rabbit developmental toxicity study. There is no evidence of increased susceptibility [ qualitative or quantitative] following in utero and/ or pre/ postnatal exposure in the 2 generation reproduction study in rats.

<IP_ADDRESS>. Degree of Concern Analysis and Residual Uncertainties for Pre and/ or Postnatal Susceptibility There are no residual concerns for pre or post natal toxicity based on the currently available data.

4.2. Recommendation for a Developmental Neurotoxicity Study 4.2.1. Evidence in favor of retaining the 10X/ requiring further evaluation of neurobehavioral development Neurotoxicity was observed in both the F0 and F1 dams during the gestation and/ or lactation periods in the reproduction study following long term exposure and in the dams in the developmental toxicity study in rats following acute ( 1 2 days) exposure. Additionally, neuropathology was observed in those dams that displayed neurotoxicity in the reproduction study. There is no acute neurotoxicity study on metaldehyde, but there is Page 25 of 80 a subchronic neurotoxicity study. Although no neuropathological lesions were observed in the latter study, the high dose female that was sacrificed on day 22 due to hindlimb paralysis and poor condition was not subjected to a histopathological examination. There was an apparent increase in motor activity in females in the subchronic neurotoxicity study, although the adequacy of the procedures and reporting in that study are still under review. Based on the finding of neuropathy in the reproduction study in rats, a developmental neurotoxicity study [ DNT] in rats is recommended.

4.2.2. Evidence against retaining the 10X/ requiring further evaluation of neurobehavioral development There is no increased susceptibility and no developmental toxicity in either the rat or rabbit, and the apparent neurotoxic effects in adult animals occur at relatively high dose levels e. g., at 160 mg/ kg ( neuropathy and clinical signs observed in F0 dams during lactation days 16 18) in the reproduction study and 150 mg/ kg ( clinical signs) following exposure of rats during gestation days 7 8 [ 1 2 doses].

<IP_ADDRESS>. Rationale for the UFDB ( when a DNT is recommended)

Based on clinical signs indicating neurotoxicity seen in the several studies, a developmental neurotoxicity study is required for metaldehyde. A database uncertainty factor of 10X is required for risk assessment under the current policy to account for potential increase in response to the neurotoxic effects produced by metaldehyde in infants and children.

4.3. Hazard Identification and Toxicity Endpoint Selection The available toxicology data are adequate for toxicity endpoint selection for risk assessment as summarized below. A summary of selected toxicity endpoints and doses are presented in Table 8. A summary of each study used in selecting appropriate endpoints and doses are presented in Appendix A.

Acute dietary: The selected endpoint is mortality and clinical signs [ ataxia, tremors, twitching, rapid respiration] based on the developmental toxicity study in rats. The effects were seen at 150 mg/ kg ( LOAEL) or above after a single or more doses. The NOAEL was 75 mg/ kg. The route and duration of exposure were appropriate for acute dietary exposure assessment for all population. No developmental toxicity was seen in this study, and no single dose endpoint specific for females 13 49 years old could be identified. The selected endpoint applies to the general population including females 13+ subpopulation.

Chronic dietary: The chronic oral toxicity study in dogs was selected as the basis for selecting the NOAEL ( 10 mg/ kg) for the chronic RfD. The LOAEL was 30 mg/ kg which produced death and atrophy of testes and prostate. Also considered for this exposure scenario was the chronic toxicity/ carcinogenicity study in rats, which provided 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 Page 26 of 80 effect and not appropriate for selection of the chronic dietary endpoint. In addition the lower NOAEL seen in the rat study might be influenced by dose selection. The dog study was selected because the route and duration of exposure are appropriate for this risk assessment.

Incidental oral ( short term): The endpoint [ clinical signs ( ataxia, tremor, twitching, salivation, emesis] from a chronic oral toxicity study in dogs was selected for the shortterm incidental oral exposure scenario because the toxicity occurred from week one on at 90 mg/ kg and no effect was seen at 30 mg/ kg. It is appropriate for this exposure duration.

Incidental oral ( intermediate term): The endpoints [ death ( between weeks 37 and 46) and atrophy of the testes and prostate] from the chronic dog study was selected for the intermediate term incidental oral exposure scenario because the toxicity occurred in relatively young dogs and atrophy of the testes and prostate was observed at study termination in the 26 week dog study also. The NOAELs are 20 mg/ kg/ day [ subchronic]/ 10 mg/ kg/ day [ chronic], and the LOAELs are 60 [ subchronic]/ 30 mg/ kg/ day [ chronic].

Dermal ( short intermediate, and long term): 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 [ liver and testes] were evaluated, and there is no reproductive toxicity concern. It was concluded that no dermal exposure risk assessment is required.

Inhalation ( short and intermediate term): same as for short and intermediate term incidental oral. The inhalation exposure limits for all durations were based on the NOAELs from oral studies for each exposure scenario since no route specific study was available. Because no inhalation absorption data are available, toxicity by the inhalation route was considered to be equivalent to toxicity by the oral route of exposure. A subchronic inhalation toxicity study is required.

Inhalation ( long term): see chronic RfD. Page 27 of 80 Table 8  Summary of Toxicology Endpoint Selection for Metaldehyde Exposure Scenario Dose Used in Risk Assessment, UF Special FQPA SF* and Level of Concern for Risk Assessment Study and Toxicological Effects Acute Dietary ( All populations) NOAEL = 75 mg/ kg/ day UF = 1000 Acute RfD = 0.075 mg/ kg/ day FQPA SF = 1X aPAD = acute RfD ( 0.075) FQPA SF ( 1)

= 0.075 mg/ kg/ day developmental toxicity study in rats LOAEL = 150 mg/ kg/ day based on mortality, clinical signs [ ataxia, tremors, twitching, rapid respiration], decreased body weight gain during dosing in females Chronic Dietary ( All populations) NOAEL = 10 mg/ kg/ day UF = 1000 Chronic RfD = 0.01 mg/ kg/ day FQPA SF = 1X cPAD = chronic RfD ( 0.01) FQPA SF ( 1)

= 0.01 mg/ kg/ day dog chronic oral toxicity study LOAEL 30 mg/ kg/ day, based on death and atrophy of the testes and prostate Short Term Incidental Oral ( 1 30 days) NOAEL = 30 mg/ kg/ day Residential LOC for MOE = 1000 Occupational = NA dog chronic oral toxicity study LOAEL 90 mg/ kg/ day for clinical signs seen beginning the first week dosing.

Intermediate Term Incidental Oral ( 1 6 months) NOAEL = 10 mg/ kg/ day Residential LOC for MOE = 1000 Occupational = NA chronic oral toxicity study  dog LOAEL = 30 mg/ kg/ day based on deaths and atrophy of testes and prostate Short Term Inhalation ( 1 to 30 days) oral NOAEL= 30 ( inhalation absorption rate = 100%) Residential LOC for MOE = 1000 Occupational LOC for MOE = 100 dog chronic oral toxicity study LOAEL = 90 mg/ kg/ day for clinical signs Intermediate Term Inhalation ( 1 to 6 months) oral NOAEL = 10 mg/ kg/ day ( inhalation absorption rate = 100%) Residential LOC for MOE = 1000 Occupational LOC for MOE = 100 chronic oral toxicity study  dog LOAEL = 30 mg/ kg/ day based on deaths and testes/ prostate atrophy Long Term Inhalation (> 6 months) oral NOAEL= 10 mg/ kg/ day ( inhalation absorption rate = 100%) Residential LOC for MOE = 1000 Occupational LOC for MOE = 100 chronic oral toxicity study  dog LOAEL = 30 mg/ kg/ day, based on deaths and atrophy of the testes and prostate Cancer ( oral, dermal, inhalation) Classification: " Suggestive Evidence of Carcinogenic Potential"

A quantification of cancer risk for metaldehyde was not recommended.

UF = uncertainty factor, FQPA SF = Special FQPA safety factor, NOAEL = no observed adverse effect level, LOAEL = lowest observed adverse effect level, PAD = population adjusted dose ( a = acute, c = chronic) RfD = reference dose, MOE = margin of exposure, LOC = level of concern, N/ A = Not Applicable Page 28 of 80 4.3.1. Margins of Exposure Margins of exposure of 1000 ( 10X for intraspecies variability, 10X for interspecies variability, and 10X for a database uncertainty factor) should be applied to all appropriate exposure scenarios for metaldehyde.

4.3.2. Recommendation for Aggregate Exposure Risk Assessments As per FQPA ( 1996), when there are potential residential exposures to the pesticide, an aggregate risk assessment must consider exposures from three major sources: oral, dermal, and inhalation exposures. No endpoint was identified for dermal exposure, so dermal exposures need not be considered in the aggregate assessment. Inhalation exposures are not expected because of the use pattern ( typically a pellet formulation). Only food and water are generally aggregated for acute ( one day) exposures to metaldehyde. For short term oral exposure to metaldehyde, food, water, and residential exposures are aggregated.

4.3.3. Classification of Carcinogenic Potential In a chronic toxicity/ carcinogenicity study, Sprague Dawley CD ® rats were administered metaldehyde in the diet at concentrations of 0, 50, 1000, and 5000 ppm for 104 weeks. An increase in liver tumors was seen in mid and high dose males and in high dose female. In a mouse carcinogenicity study, CD 1 mice received metaldehyde in the diet at concentrations of 0, 25, 100, and 300 ppm for 18 months. There was no statisticallysignificant increase in the incidence of liver tumors in either sex. A supplemental mouse carcinogenicity study using the same strain of mice and a single dose ( 1000 ppm) was conducted. Under the conditions of this study, increased liver weight ( both sexes), hepatocellular hypertrophy ( both sexes), liver single cell/ focal/ multifocal necrosis ( males), liver pigment accumulation ( males), sinusoidal histiocytosis ( males), hepatocellular eosinophilic cell foci ( females), and hepatocellular adenomas ( both sexes) were observed. The Cancer Assessment Review Committee evaluated all the available carcinogenicity and other toxicology data and classified metaldehyde in accordance with the EPA Final Guidelines for Carcinogen Risk Assessment ( March 29, 2005), as " Suggestive Evidence of Carcinogenic Potential" based on the presence of benign liver tumors in female rats, benign liver tumors in both sexes of mice, and a lack of adequate mutagenicity data.

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

Special FQPA Safety Factor Based on the hazard data, the metaldehyde risk assessment team recommended the special FQPA SF be reduced to 1X because there are no residual uncertainties with regard to pre and/ or postnatal toxicity. A clear dose response relationship was observed in the toxicity studies selected for risk assessment endpoints, and clear NOAEL's were Page 29 of 80 established which were used as risk assessment points of departure. The recommendation is also based on the following:

The dietary food exposure assessment utilizes proposed tolerance level or higher residues and 100% CT information for all commodities. By using these screening level assessments, chronic exposures/ risks will not be underestimated.

The dietary drinking water assessment ( Tier 1 estimates) utilizes values generated by model and associated modeling parameters which are designed to provide conservative, health protective, high end estimates of water concentrations.

The residential exposure assessment relies on sufficiently protective default assumptions that are unlikely to underestimate exposure/ risk.

4.4. Endocrine disruption EPA is required under the FFDCA, as amended by FQPA, to develop a screening program to determine whether certain substances ( including all pesticide active and other ingredients) " may have an effect in humans that is similar to an effect produced by a naturally occurring estrogen, or other such endocrine effects as the Administrator may designate." Following recommendations of its Endocrine Disruptor and Testing Advisory Committee ( EDSTAC), EPA determined that there was a scientific basis for including, as part of the program, the androgen and thyroid hormone systems, in addition to the estrogen hormone system. EPA also adopted EDSTAC's recommendation that the Program include evaluations of potential effects in wildlife. For pesticide chemicals, EPA will use FIFRA and, to the extent that effects in wildlife may help determine whether a substance may have an effect in humans, FFDCA authority to require the wildlife evaluations. As the science develops and resources allow, screening of additional hormone systems may be added to the Endocrine Disruptor Screening Program ( EDSP).

In the available toxicity studies on metaldehyde, there was no apparent estrogen, androgen, and/ or thyroid mediated toxicity. However, atrophy of the testes and prostate occurred in both the subchronic [ 26 week] and chronic oral toxicity studies in the dog.

When additional appropriate screening and/ or testing protocols being considered under the Agency's EDSP have been developed, metaldehyde may be subjected to further screening and/ or testing to better characterize effects related to endocrine disruption.

5.0 Public Health Data 5.1. Incident Reports The following databases have been consulted for the poisoning incident data on the active ingredient metaldehyde: OPP Incident Data System ( IDS), Poison Control Centers, California Department of Pesticide Regulation, National Pesticide Information Center ( NPIC), and the National Institute of Occupational Safety and Health's Sentinel Event Notification System for Occupational Risks ( NIOSH SENSOR). Page 30 of 80 There are 35 cases documented from IDS between 1994 and 2004. Another 8 10 lawsuits were reported but excluded from tabulation because of lack of medical documentation. Fifty one percent of cases reported either irritation to the skin or allergic type reaction. A total of 2268 cases were located in the Poison Control Center records from 1993 through 2003. Of these 2268 cases, 9 were of moderately or life threatening concern, and those cases were due to ingestion. Children under age six were involved in 1648 cases, 594 were adults exposed in a non occupational setting and 26 were adults in an occupational setting.

Incident data on domestic animals allegedly exposed to metaldehyde were reviewed from two sources, the National Pesticide Information Center ( NPIC) and EPA's Incident Data System for 6( a)( 2) reporting. Data for the period January 1, 2000 to December 31, 2004 were reported from the NPIC, a toll free telephone service that provides pesticide information without treatment advice to the general public and medical and veterinary professionals. If an animal is in need of immediate veterinary care, the caller is referred to the ASPCA's Animal Poison Control Center ( APCC). The APCC is a 24 hour emergency hotline for animals similar to human poison control centers. The NPIC determines if a pesticide product is responsible for clinical signs and assigns the following categories: definite, probable, possible or unlikely. Only probable and possible cases were included with the metaldehyde data. A probable case has a clearly documented and highly plausible exposure pathway with specific health effects that are consistent with exposure to the active ingredient( s). With possible cases, there is a report of exposure and clinical signs, but there is uncertainty with respect to the likelihood of exposure, the circumstances surrounding the exposure or the consistency of the reported signs based upon the active ingredient( s).

The metaldehyde data from NPIC were analyzed and tabulated to determine the product type ( bait, liquid, etc.) involved, the outcome of the case ( died, referred to APCC, unknown, recovered) and species affected ( dog, cat). For the five year period, there were 104 cases in the probable and 156 in the possible categories for a total of 260 cases involving 274 animals. The number of probable cases increased yearly from 8 in 2000 to 43 in 2004. The number of possible cases was similar from 2000 2003 but increased in 2004. Ingestion was the most common route of exposure. Most animals were exposed to metaldehyde products applied to yards/ gardens; however, dogs also chewed into bags or boxes in storage areas. Granular and bait formulations were the most common form ingested. A total of 17 animals in the probable and five in the possible categories died during the five year period, while 10 animals in the probable and possible categories recovered. A total of 35 animals in the probable and 46 in the possible categories were referred to APCC. The outcome was unknown in 54 animals in the probable and 108 in the possible categories. Most of the outcomes were unknown because the NPIC advised that the caller consult a veterinarian about the animal. The NPIC has no follow up capabilities for these cases. Animals affected include both dogs ( 252/ 274) and cats ( 22/ 274). Data reviewed from the APCC confirm that the clinical signs in the cases referred by the NPIC were compatible with metaldehyde exposure. Page 31 of 80 6.0 Exposure Characterization/ Assessment 6.1. Dietary Exposure/ Risk Pathway 6.1.1. Residue Profile The qualitative nature of metaldehyde residues in plants is understood based on the adequate 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, per se. Requirements for animal metabolism and feeding studies have been waived. The Agency concluded that residues are unlikely to occur in livestock commodities based upon the rapid degradation of metaldehyde in mammalian systems and the subsequent incorporation of degradates into naturally occurring components. The tolerance reassessment summary for metaldehyde is presented in Appendix B.

A tolerance of " zero" has been established for residues of metaldehyde on strawberry [ 40 CFR § 180.523( a)( 2)]. There are currently no other tolerances on other primary crops, animal commodities or rotational crops. No analytical methods are listed in the Pesticide Analytical Manual ( PAM Vol. II) for the enforcement of the established tolerance.

An adequate GC/ MS method ( EN CAS Method No. ENC 3/ 99, Revision 1) is available for collecting data on metaldehyde residues in/ on plant commodities. This method has been validated using a wide variety of plant matrices, and it has a validated method LOQ of 0.05 ppm. The method has also undergone a successful independent laboratory validation trial and has been proposed as the tolerance enforcement method.

Adequate field trial data are available to support the use of metaldehyde on Brassica leafy vegetables ( group 5), citrus fruits ( group 10), berries ( group 13), tomato, artichoke, lettuce, strawberry, prickly pear cactus and watercress. An adequate number of tests were conducted on these crops in the appropriate geographical regions using representative formulations applied at the maximum supported use rates. These studies are also supported by adequate storage stability data. The residue data from these field trials will support permanent tolerances on the above crops or crop groups The available residue data from the limited field trials indicate that detectable residues ($ 0.05 ppm) of metaldehyde are likely to occur on a wide variety of plant commodities following application( s) of metaldehyde formulations at the maximum supported label rates. Therefore, tolerances for metaldehyde and supporting field trial data are required on all crops and/ or crop groups with registered uses of metaldehyde.

The available processing studies on tomatoes and oranges are adequate and indicate that metaldehyde residues do not concentrate in processed commodities derived from these crops.

6.1.2. Acute and Chronic Dietary Exposure and Risk Page 32 of 80 An unrefined Tier 1 [ tolerance level and 100% crop treated (% CT)] acute dietary risk assessment was conducted for all supported metaldehyde food uses. Dietary risk estimates are provided for the general U. S. population and various population subgroups. This assessment showed that at the 95th percentile of exposure, the acute risk estimates are below the Agency's level of concern (< 100% aPAD) for the general U. S. population ( 11% of the aPAD) and all population subgroups (< 25% of the aPAD). The highest exposed population subgroup was children 1 2 years old.

Tolerance level residues and 100% CT were also used to determine the chronic dietary exposure and risk estimates. This assessment showed that for all included commodities, the chronic risk estimates were below the Agency's level of concern (< 100% cPAD) for the general U. S. population ( 22% of the cPAD) and all population subgroups (< 49% cPAD). The highest exposed population subgroup was children 1 2 years old.

Table 9 contains a summary of dietary exposure and risks for metaldehyde for a number of population sub groups.

Table 9  Summary of Dietary Exposure and Risk for Metaldehyde Acute Dietary ( 95th Percentile) Chronic Dietary DEEM FCID DEEM FCID Population Subgroup* Dietary Exposure ( mg/ kg/ day) % aPAD* Dietary Exposure ( mg/ kg/ day) % cPAD General U. S. Population 0.008551 11 0.002215 22 All Infants (< 1 year old) 0.003560 4.8 0.000674 6.7 Children 1 2 years old 0.018514 25 0.004890 49 Children 3 5 years old 0.016881 23 0.004442 44 Children 6 12 years old 0.011224 15 0.003002 30 Youth 13 19 years old 0.007551 10 0.001843 18 Adults 20 49 years old 0.007251 9.7 0.001830 18 Adults 50+ years old 0.007776 10 0.002067 21 Females 13 49 years old 0.007320 9.8 0.001910 19 Page 33 of 80 6.2. Water Exposure/ Risk Pathway When surface water modeling residues are included in the acute and chronic assessments, HED's level of concern is not exceeded (< 100% aPAD and cPAD). The most highly exposed population subgroup was children 1 2 years old at 26% aPAD ( 95th percentile) and 59% cPAD, respectively. When ground water modeling residues are included in the acute and chronic assessments, HED's level of concern is not exceeded (< 100% aPAD and cPAD). For ground water, children 1 2 years old were also the most highly exposed population subgroup. For children 1 2 years old, 29% and 69% of the aPAD and cPAD were occupied in the acute and chronic aggregate assessment, respectively. For groundwater, EDWCs were generated from a Tier I SCI GROW analysis. A EDWC of 62.5 ppb from a scenario based on use of metaldehyde on ornamental plants was used in both the chronic and acute aggregate assessments. The EDWCs are considered to be somewhat conservative, although it can not be precluded that higher concentrations in drinking water will not be found based on uncertainties in the half life determined from a single soil aerobic metabolism study. The Commodity Contribution Analysis shows that water is the most significant contributor.

Table 10  Summary of Estimated Surface and Ground Water Concentrations for Metaldehyde Metaldehyde Exposure Duration Surface Water Conc., ppb a Ground Water Conc., ppb b Acute 110 62.5 Chronic ( non cancer) 55.8 62.5 Chronic ( cancer) 31.9 62.5 a From the Tier II PRZM EXAMS  Index Reservoir model. Input parameters are based on use on Brassica and leafy vegetables in FL & CA. b From the SCI GROW model assuming a maximum seasonal use rate of 6.4 lb ai/ A, a Koc of 57 ( loam soil), and a half life of 67 days.

6.3. Residential ( Non Occupational) Exposure/ Risk Pathway The residential risk assessment addresses exposures that individuals receive through their use of consumer products that contain metaldehyde and through exposures they could receive from frequenting areas that have been previously treated with metaldehyde, such as a home lawn or a park.

6.3.1. Home Uses Page 34 of 80 Metaldehyde is available as a consumer product for snail and slug control on lawns and around fruit, vegetable, and ornamental gardens in the following formulations: liquid concentrate, ready to use liquid/ paste, and ready to use granules/ pellets/ minipellets/ meal baits. The methods of application include hose end sprayers, trigger pump sprayers, low pressure handwand sprayers, sprinkling cans, belly grinders, push type spreaders, and applying ready to use products by hand.

A Use Closure Memo was issued for metaldehyde on March 1, 2005. Subsequently on March 21, 2005, EPA's metaldehyde team met with representatives of Lonza, the sole technical registrant of metaldehyde. On April 14, 2005, an addendum ( addendum 1) to the original use closure memo was issued that contained a listing of the agricultural crop uses supported by Lonza and a listing of the formulations supported by Lonza. That addendum stated Lonza's decisions regarding the maximum application rates, the maximum seasonal ( yearly) application rates, minimum retreatment intervals, and the pre harvest intervals for each supported use pattern. The addendum stated that for home and garden products, only those fruit and vegetable crops listed for agricultural use may be listed on product labels. [ Note: All assessments contained herein are based on the aforementioned use closure memo and associated addenda per personal communication with Chemical Review Manager, Jill Bloom.] On May 25, 2005, a second addendum ( addendum 2) to the original use closure memo was issued that contained the Lonza proposed maximum application rates, the maximum seasonal ( yearly) application rates, minimum retreatment intervals, and the maximum applications per year for ornamentals and turf/ dichondra use patterns.

Table 11 provides a summary of residential use sites, product formulations, maximum application rates, frequency of application, and application equipment.

Table 11  Summary of Registered Metaldehyde Residential Uses Crop Target Formulation Maximum Application Ratea and Frequency of Applicationb Application Equipmentc Granular push type spreader, belly grinder, by hand, shaker can RTU solution/ paste squeeze solution/ paste from bottle or tube Ornamentals Soluble concentrate 3.5 lb ai/ A Maximum number of applications/ yr: 12 Minimum retreatment interval: 21 days hose end sprayer, low pressure handwand sprayer, trigger pump sprayer, and sprinkler can Granular push type spreader, belly grinder, by hand, shaker can Lawns and Recreational Turfgrass Snails and slugs Soluble concentrate 1 lb ai/ A Maximum number of applications/ yr: 12 Minimum retreatment interval: 21 days hose end sprayer, low pressure handwand sprayer, trigger pump sprayer, and sprinkler can Page 35 of 80 Table 11  Summary of Registered Metaldehyde Residential Uses Crop Target Formulation Maximum Application Ratea and Frequency of Applicationb Application Equipmentc Citrus Granular 1 lb ai/ A Apply when needed ( winter through spring) up to day of harvest Minimum retreatment interval: 2 weeks Maximum amount applied per year: 6 lb ai/ A push type spreader, belly grinder, by hand, shaker can Granular push type spreader, belly grinder, by hand, shaker can Brassica RTU solution/ paste 1 lb ai/ A Apply when needed up to 72 hours before harvest Minimum retreatment interval: 2 weeks Maximum amount applied per year: 4 lb ai/ A squeeze solution/ paste from bottle or tube Granular push type spreader, belly grinder, by hand, shaker can Lettuce RTU solution/ paste 1 lb ai/ A Apply when needed up to 72 hours before harvest Minimum retreatment interval: 2 weeks Maximum amount applied per year: 4 lb ai/ A squeeze solution from bottle Granular push type spreader, belly grinder, by hand, shaker can Tomato RTU solution/ paste 1 lb ai/ A Apply when needed up to 72 hours before harvest Minimum retreatment interval: 2 weeks Maximum amount applied per year: 4 lb ai/ A squeeze solution/ paste from bottle or tube Strawberry Granular 1 lb ai/ A push type spreader, belly grinder, by hand, shaker can Page 36 of 80 Table 11  Summary of Registered Metaldehyde Residential Uses Crop Target Formulation Maximum Application Ratea and Frequency of Applicationb Application Equipmentc RTU solution/ paste Apply when needed up to 72 hours before harvest Minimum retreatment interval: 2 weeks Maximum amount applied per year: 5 lb ai/ A ( perennials) and 3 lb ai/ A ( annuals) squeeze solution/ paste from bottle or tube Granular push type spreader, belly grinder, by hand, shaker can Berries RTU solution/ paste 0.8 lb ai/ A Apply up to day before harvest Minimum retreatment interval: 2 weeks Maximum amount applied per year: 4 lb ai/ A squeeze solution/ paste from bottle or tube Granular push type spreader, belly grinder, by hand, shaker can Artichoke RTU solution/ paste 0.8 lb ai/ A Apply up to day before harvest Minimum retreatment interval: 18 days Maximum amount applied per year: 5.6 lb ai/ A squeeze solution/ paste from bottle or tube Prickly pear cactus Snails and slugs Granular 0.8 lb ai/ A Apply up to day before harvest Minimum retreatment interval: 30 days Maximum amount applied per year: 5.6 lb ai/ A push type spreader, belly grinder, by hand, shaker can a Application rates are the maximum application rates determined from EPA registered labels for metaldehyde b Amount handled per day values are HED estimates of acres, square feet, or cubic feet treated or gallons applied based on Exposure SAC SOP # 9 " Standard Values for Daily Acres Treated in Agriculture," industry sources, and HED estimates. Page 37 of 80 <IP_ADDRESS>. Residential Handler Risk Assessment The anticipated use patterns and current labeling indicate several major residential exposure scenarios, based on the types of equipment and techniques, in which homeowners can be exposed to metaldehyde during the application process. The quantitative exposure/ risk assessment developed for residential handlers is based on these scenarios. The major scenarios include:

( 1) Mixing/ loading/ applying liquid concentrates with low pressure handwand sprayer ( ORETF data for ground directed applications), ( 2) Mixing/ loading/ applying liquid concentrates with hose end sprayer ( ORETF data for hose end sprayer applications to turfgrass), ( 3) Mixing/ loading/ applying liquid concentrates with sprinkling can ( using ORETF data for hose end sprayer applications to turfgrass as surrogate data), ( 4) Mixing/ loading/ applying liquid concentrates with pump trigger sprayer ( ORETF pump trigger data), ( 5) Applying granulars by hand ( PHED data), ( 6) Loading/ applying granulars via push type spreader ( ORETF data) ( 7) Loading/ applying granulars via belly grinder ( PHED data), and ( 8) Applying ready to use liquid/ paste formulations via squeeze bottle or tube ( using ORETF pump trigger data as surrogate data)

Data and Assumptions A series of assumptions and exposure factors served as the basis for completing the residential handler risk assessments, as described below.

$ Label maximum use rates and use information specific to residential products as specified in the use closure memo ( Bloom, 2005) served as the basis for the risk calculations.

$ The unit exposure values used in this assessment were based on the Outdoor Residential Exposure Task Force ( ORETF) and the Pesticide Handlers Exposure Database ( Version 1.1 August 1998) ( PHED) 1. The quality of the data in PHED varies from scenarios that meet study guideline requirements to others where a limited number of poor quality data points are available. However, in all cases, the data used represent the best available for the scenario. The PHED unit exposure values range between geometric mean and median of available exposure data. When data from other studies were used, the appropriate statistical measure of central tendency was used. Central tendency values, coupled with other inputs used by HED, are thought to result in conservative, deterministic estimates of risk. [ Note: Lonza, the technical registrant is not a member of the ORETF and as such, the use of ORETF data may be subject to data compensation.]

1 PHED is a generic database, which includes the results of over 100 exposure studies, developed by US EPA, Pest Management Regulatory Agency/ Health Canada and the California Department of Pesticide Regulation, in cooperation with the pesticide industry. Page 38 of 80 $ Average body weight of adult handlers is assumed to be 70 kg because the toxicological endpoint of concern used for the risk assessments is appropriate for average adult body weight representing the general population. No specific effects were observed consistently in the toxicology studies to indicate an increased sensitivity of one gender over another.

$ Homeowner handler assessments were completed based on individuals wearing shorts and short sleeved shirts.

$ Homeowner handlers are expected to complete all tasks associated with the use of a pesticide product including mixing/ loading, if needed, as well as the application.

$ Calculations were based on scenarios in the home that would reasonably be treated in a day ( but would not take more than an hour or two) such as the size of a lawn, the size of a garden, or the amount that can be applied with a piece of equipment and are based on Agency Exposure SAC Policy 12: Recommended Revisions To The Standard Operating Procedures For Residential Exposure Assessment.

Residential Handler Non cancer Risks Non cancer risks are calculated using the Margin of Exposure ( MOE) approach, which is a ratio of the body burden to the toxicological endpoint of concern. Since no toxicological endpoint of concern was selected to assess risk from short term dermal exposures, no short or intermediate term dermal risks are calculated. Short term inhalation risks were calculated using a NOAEL of 30 mg/ kg/ day from a chronic oral toxicity study in dogs. The level of concern for inhalation risks to residential handlers is 1000, based on a 10X factor to account for interspecies extrapolation to humans from the animal test species, a 10X factor to account for intraspecies sensitivity, and a database uncertainty factor ( 10X). Intermediate and long term exposures are not expected for residential handlers, because of the sporadic nature of applications by homeowners.

Body burden values were determined by first calculating daily exposures using application parameters ( i. e., application rate and area treated) along with unit exposure levels. Exposures were then normalized by body weight and adjusted for absorption factors ( 100 percent for inhalation) as appropriate to calculate average daily dose levels ( i. e., body burdens) as illustrated in equation below.

Daily Exposure ( mg ai/ day) =

Unit Exposure ( mg ai/ lb ai) x Application Rate ( lb ai/ A or lb ai/ gal)) x Daily Area Treated ( A or Gal/ day)

Where:

Daily Exposure = Amount that is inhaled, also referred to as potential dose ( mg ai/ day); Unit Exposure = Normalized exposure value derived from August 1998 PHED Surrogate Page 39 of 80 Exposure Table and ORETF Surrogate Exposure Data ( µ g ai/ lb ai); Application Rate = Normalized application rate based on a logical unit treatment such as acres or gallons, maximum values are generally used ( lb ai/ A or lb ai/ gal); and Daily Area Treated = Normalized application area based on a logical unit treatment such as acres ( A/ day) or gallons per day ( gal/ day).

No specific inhalation absorption factor is available for metaldehyde. Therefore, a factor of 100 percent was used for route to route calculations. MOEs were calculated using the following formula.

MOE = NOAEL ( mg ai/ kg/ day)________ Average Daily Dose ( mg ai/ kg/ day)

Where:

MOE = Margin of exposure, value used to represent risk or how close a chemical exposure is to being a concern ( unitless); Average Daily Dose = The amount as absorbed dose received from exposure to a pesticide in a given scenario ( mg pesticide active ingredient/ kg body weight/ day); and NOAEL = No observed adverse effect level or dose level in a toxicity study where no observed adverse effects occurred in the study ( mg pesticide active ingredient/ kg body weight/ day).

Short term risks for residential handlers are presented in Table 12. For all scenarios, residential handler risks are not of concern, because MOEs meet or exceed HED's uncertainty factor of 1000 ( i. e., MOEs range from 56000 to ~ 34 million). Page 40 of 80 Table 12  Metaldehyde Residential handler Non Cancer Inhalation Exposure and Risk Baseline Short term Exposure Scenario Crop or Target Application Rate ( lb ai/ acre) a Area Treated Daily ( acres) b Baseline Inhalationc Unit Exposure ( µ g/ lb ai) Inhalation Dose ( mg/ kg/ day) Inhalation MOE Mixer/ Loader/ Applicator ornamentals 3.5 0.023 2.7 0.0000031 9700000 Mixing/ Loading/ Applying Liquid Concentrates with Low Pressure Handwand ( ORETF ground directed) ( 1) turf  spot 1 0.023 2.7 0.00000089 34000000 ornamentals 3.5 0.023 17 0.00002 1500000 turf  spot 1 0.023 17 0.0000056 5400000 Mixing/ Loading/ Applying Liquid Concentrates with Hose End Sprayer ( ORETF data  turfgrass application) ( 2) turf  broadcast 1 1 17 0.000243 124000 ornamentals 3.5 0.023 17 0.00002 1500000 Mixing/ Loading/ Applying Liquid Concentrates with a Watering Can ( using ORETF hose end data for turfgrass application) ( 3) turf 1 0.023 17 0.0000056 5400000 Page 41 of 80 Table 12  Metaldehyde Residential handler Non Cancer Inhalation Exposure and Risk Baseline Short term Exposure Scenario Crop or Target Application Rate ( lb ai/ acre) a Area Treated Daily ( acres) b Baseline Inhalationc Unit Exposure ( µ g/ lb ai) Inhalation Dose ( mg/ kg/ day) Inhalation MOE ornamentals 3.5 0.023 19 0.000022 1400000 Brassica, lettuce,

tomato, strawberry 1 0.023 19 0.0000062 4800000 Applying Ready to Use Formulations via Trigger Pump Sprayer ( ORETF) ( 4) berries, artichoke 0.8 0.023 19 0.000005 6000000 ornamentals 3.5 0.023 467 0.00054 56000 citrus, Brassica,

lettuce, tomato,

strawberry 1 0.023 467 0.00015 200000 Loading/ Applying Granulars via Hand ( PHED) ( 5) berries, artichoke,

prickly pear cactus 0.8 0.023 467 0.00012 240000 ornamentals 3.5 0.5 0.88 0.000022 1400000 Loading/ Applying Granulars via Push Type Spreader ( ORETF data) ( 6) turf, citrus, Brassica,

lettuce, tomato,

strawberry 1 0.5 0.88 0.0000063 4800000 Page 42 of 80 Table 12  Metaldehyde Residential handler Non Cancer Inhalation Exposure and Risk Baseline Short term Exposure Scenario Crop or Target Application Rate ( lb ai/ acre) a Area Treated Daily ( acres) b Baseline Inhalationc Unit Exposure ( µ g/ lb ai) Inhalation Dose ( mg/ kg/ day) Inhalation MOE berries, artichoke,

prickly pear cactus 0.8 0.5 0.88 0.000005 6000000 ornamentals 3.5 0.023 62 0.000071 420000 citrus, Brassica,

lettuce, tomato,

strawberry 1 0.023 62 0.00002 1500000 Loading/ Applying Granulars via Belly Grinder ( 7) berries, artichoke,

prickly pear cactus 0.8 0.023 62 0.000016 1800000 ornamentals 3.5 0.023 19 0.000022 1400000 Brassica, lettuce,

tomato, strawberry 1 0.023 19 0.0000062 4800000 Applying Ready to Use Liquid/ Paste Formulations via Squeeze Bottle or Tube ( using ORETF pump trigger data as surrogate data) ( 8) berries, artichoke 0.8 0.023 19 0.000005 6000000 a Application rates are the maximum application rates determined from EPA registered labels for metaldehyde b Amount handled per day values are HED estimates of acres, square feet, or cubic feet treated or gallons applied based on Exposure SAC SOP # 9 " Standard Values for Daily Acres Treated in Agriculture," industry sources, and HED estimates.

c Baseline Inhalation: no respirator. Page 43 of 80 Residential Handler Cancer Risks Metaldehyde is classified as " suggestive evidence of carcinogenic potential @

however, cancer risks were not calculated, since no cancer toxicological endpoint or potency factor was identified for metaldehyde.

<IP_ADDRESS>. Residential Postapplication Risk Assessment Metaldehyde uses include home gardens, ornamentals, and turf ( lawns). As a result, a wide array of individuals of varying ages can potentially be exposed when they do activities in areas that have been previously treated. However, since dermal exposure is not considered a hazard for metaldehyde and inhalation exposures are not anticipated ( i. e., due to low volatility and dilution outdoors), the only risks which were quantitatively addressed were those associated with the oral exposure of toddlers who played on treated turf ( i. e., hand to mouth activities, object to mouth activities, and ingestion of treated soil were included) and those associated with the possible ingestion of metaldehyde granules.

The exposures from treated turf were assessed using the short term incidental oral endpoint defined in a chronic dog study ( NOAEL = 30 mg/ kg/ day). Granular ingestion was assessed using the acute dietary endpoint which was defined in a developmental toxicity study in rats ( NOAEL = 75 mg/ kg/ day). Short term noncancer risks were calculated using the MOE approach as described under Section <IP_ADDRESS> ( Residential Handler Risk Assessment). The level of concern is established by the total uncertainty factor ( or target MOE) of 1000. This factor is based on a 10X factor to account for interspecies extrapolation to humans from the animal test species, a 10X factor to account for intraspecies sensitivity, and an additional 10X database uncertainty factor.

Methodology The Agency relied on a standardized approach for completing residential risk assessments that is based on current metaldehyde labels and guidance contained in the following documents [ Note: No exposure data were available for metaldehyde.]:

  Standard Operating Procedures For Residential Exposure Assessment ( Dec. 1997) This document provides the overarching guidance for developing residential risk assessments including scenario development, algorithms, and values for inputs.

  Science Advisory Council For Exposure Policy 12 ( Feb. 2001): Recommended Revisions To The Standard Operating Procedures ( SOPs) For Residential Exposure Assessment This document provides additional, revised guidance for completing residential exposure assessments.

Several different types of calculations were used in this assessment. In essence, all can be summarized by saying that a source of some sort ( e. g., residue on turf) comes in contact with a toddler as they are doing an activity ( e. g., playing on treated lawns). Exposures were then calculated by multiplying the source concentration by some factor ( e. g., frequency of hand to mouth events and saliva extraction Page 44 of 80 factors) and the duration of exposure. The procedures and algorithms incorporated in these documents used to address the specific scenarios are presented below:

  Dose from ingestion of metaldehyde granules from treated turf calculated using SOP 2.3.1: Postapplication dose among toddlers from episodic nondietary ingestion of residues from a child potentially ingesting solid metaldehyde formulations ( e. g., granulars or pellets) after they have been applied to areas such as lawns or gardens.

  Dose from hand to mouth activity from treated turf calculated using SOP 2.3.2: Postapplication dose among toddlers from incidental nondietary ingestion of pesticide residues on treated turf from hand to mouth transfer ( i. e., those residues that end up in the mouth from a child touching turf and then putting their hands in their mouth);

  Dose from object to mouth activity from treated turf calculated using SOP 2.3.3: Postapplication dose among toddlers from incidental nondietary ingestion of pesticide residues on treated turf from object to mouth transfer ( i. e., those residues that end up in the mouth from a child mouthing a handful of treated turf or object that has been in contact with such turf); and   Dose from soil ingestion activity from treated turf calculated using SOP 2.3.4: Postapplication dose among toddlers from incidental nondietary ingestion of pesticide residues from ingesting soil in a treated turf area ( i. e., those soil residues that end up in the mouth from a child touching treated soil and turf then putting their hands in their mouth).

Dose from ingestion of metaldehyde granules from treated turf calculated using SOP 2.3.1: The following illustrates the approach used to calculate exposures that are attributable to the ingestion of metaldehyde formulations such as pellets or granules:

Where:

D = dose from ingesting solid formulation ( mg/ kg/ day); IgR = ingestion rate for granule ingestion per day ( g/ day); F = fraction of active ingredient in granules ( unitless); and BW = body weight ( kg).

Dose from hand to mouth activity from treated turf calculated using SOP 2.3.2: Nondietary ingestion from hand to mouth behaviors considers the environmental concentrations and the mouthing behaviors of children. The following equation describes how these exposures have been calculated.

D = {( TR * ( SE/ 100) * SA * Freq * Hr * ( 1mg/ 1000Fg))}/ BW Where:

D = dose from hand to mouth activity ( mg/ kg/ day); TR = transferable residues, TR is assumed to be 5% of the application rate on day 0 for treatments to lawns or other turf ( Fg/ cm2); D ={( IgR * F * ( 1000 mg/ 1g))}/ BW Page 45 of 80 SE = saliva extraction factor (%); SA = surface area of the hands ( cm2); Freq = frequency of hand to mouth events ( events/ hour); Hr = exposure duration ( hours); and BW = body weight ( kg).

Dose from object to mouth activity from treated turf calculated using SOP 2.3.3: The following illustrates the approach used to calculate exposures that are attributable to object to mouth behavior on treated turf:

Where:

D = dose from mouthing activity ( mg/ kg/ day); TR = transferable residues, TR is assumed to be 20% of the application rate on day 0 for treatments to lawns or other turf ( Fg/ cm2); IgR = ingestion rate for mouthing per day ( cm2/ day); and BW = body weight ( kg).

Dose from soil ingestion activity from treated turf calculated using SOP 2.3.4: The following illustrates the approach used to calculate exposures that are attributable to the ingestion of soil on treated turf:

Where:

D = dose from mouthing activity ( mg/ kg/ day); SR = soil residues, SR is based on soil density and considering 100% of the application rate in top 1 cm of soil on day 0 for treatments to turf ( Fg/ g or ppm); IgR = ingestion rate for mouthing per day ( g/ day); and BW = body weight ( kg).

Combining Appropriate Risk Estimates: HED combines risk values resulting from separate postapplication exposure scenarios when it is toxicologically appropriate and it is likely they can occur simultaneously based on the use pattern and the behavior associated with the exposed population. The risks from hand to mouth, object to mouth, and soil ingestion scenarios were combined, since they could logically co occur. The following formula is used to calculate total MOE values by combining the route specific MOEs: MOE total = 1/(( 1/ MOE a) + ( 1/ MOE b) + ( 1/ MOE c)). Where: MOE a represents hand to mouth risk, MOE b represents object to mouth risks, and MOE c represents soil ingestion risks.

Inputs The inputs used in the risk calculations are consistent with current Agency policy for completing residential exposure assessments ( i. e., SOPs for Residential Exposure Assessment and related D ={( TR * IgR *( 1mg/ 1000Fg))}/ BW D ={( SR * IgR *( 1mg/ 1000Fg))}/ BW Page 46 of 80 documents). A series of standard exposure factors served as the basis for assessing the residential post application risks from children's. These included:

$ 5 percent of the application rate ( 1 lb ai/ acre) has been used to calculate the 0 day transferable residue levels for defining risks from hand to mouth behaviors ( i. e., 5 percent of the application rate lb ai/ acre after it has been converted to µ g/ cm2 is used);

$ hand to mouth exposures are based on a frequency of 20 events/ hour and a surface area per event of 20 cm2 representing the palmar surfaces of three fingers;

$ saliva extraction efficiency is 50 percent which indicates that every time the hand goes in the mouth approximately ½ of the residues on the hand are removed;

$ a dissipation rate of 10 percent/ day for metaldehyde residues was used to complete a rangefinder intermediate term assessment;

$ 20 percent of the application rate has been used to calculate the 0 day transferable residue levels for defining risks from object to mouth behaviors for short term exposures ( i. e., 20 percent of the application rate lb ai/ acre after it has been converted to µ g/ cm2 is used);

$ object to mouth exposures are based on a 25 cm2 surface area;

$ when soil ingestion is considered, 100 percent of the application rate and a soil density of 0.67 cm3/ gram have been used to calculate day 0 concentrations in the top centimeter of soil ( i. e., the application rate is converted to µ g/ cm2, then it is converted to a density µ g/ cm3 based on the premise residues are found in the top 1 cm of soil, finally w/ w soil concentrations were calculated by adjusting for soil density);

$ various formulations were considered in the calculation of the risks associated with the ingestion of metaldehyde formulations, a concentration range for all homeowner solid formulations of 2 to 7.5 percent active ingredient was considered and to specifically evaluate the amount ingested 2 specific formulations were considered with a particle size of 35 to 50 mini pellets/ gram ( EPA Reg 8119 9 which contains 4% ai) and 450 particles/ gram ( EPA Reg 8278 3 which contains 3.5% ai);

$ an ingestion rate of 100 mg per day was used for defining risks from soil ingestion behaviors for acute oral exposures;

$ an ingestion rate of 0.3 grams per day was used for defining risks from possible ingestion of metaldehyde granules; and $ the average weight of toddlers is 15 kg.

Summary of Residential Post application Non Cancer Risks Table 13 summarizes the post application non cancer risks to toddlers following applications of metaldehyde to turf. In this table, risks for each scenario considered, as well as a combined risk estimate are presented. To summarize, short term risks from mouthing exposures on treated turf were not of concern ( i. e., the combined MOE on the day of application = 1600 and the major exposure component is hand to mouth activity with an associated MOE = 2000). It should be noted that the approaches and inputs used are generally thought to result in high calculated levels of exposure ( and hence risk) for each distinct scenario. As a result, the combined risk estimate is thought to represent an extremely high level of exposure based on what may be reasonably expected to occur in the metaldehyde user population. A rangefinder intermediate term assessment was also completed resulting in risks that were not of concern ( i. e., MOE = 2900). However, no metaldehyde residue dissipation data were available so the dissipation estimate of 10 percent per day has uncertainty Page 47 of 80 associated with it especially given its half life of 67 days and the intended nature of the formulations to provide residual pest control over extended periods. Uncertainty related to this issue would be reduced if residue dissipation data were available.

Table 13  Summary of Non Cancer Short term Postapplication MOEs for Toddlers Exposure Scenario Route of Exposure Formulation App. Rate ( lb ai/ A) MOE on Day 0 Combined MOE Granular Hand to Mouth Activity on Turf Spray 2000 Granular Object to Mouth Activity on Turf Spray 8000 Granular Incidental Soil Ingestion Oral Spray 1.0 600000 1600 Note: To ensure that the Agency adequately addressed all nature of exposures, an intermediate term " rangefinder" assessment was also completed based on a 10% residue decline per day over a month ( no residue decline data were available for metaldehyde). The resulting combined MOE = 2900.

Ingestion of metaldehyde formulations such as mini pellets or granules is a possible source of exposure because children could potentially ingest them if they were found in treated lawns or gardens. This scenario, however, is considered to be episodic in nature and is also further thought to be unlikely because of the use of a bittering agent which makes ingestion of metaldehyde formulations generally not palatable to toddlers ( i. e., who are the population most likely to ingest such materials). However, it is of interest to examine such a scenario in the interest of public health in order to characterize the potential risks if such ingestion events did occur. These potential risks can be estimated in 2 distinct manners including ( 1) calculating the risks based on the SOP 2.3.1 described above and ( 2) describing how much formulation one would be required to ingest at the level of concern defined by the hazard endpoint and associated uncertainty factor. Because ingestion of formulated material is considered episodic, risks were calculated using the acute dietary endpoint ( NOAEL = 75 mg/ kg/ day and UF= 1000). The exposure from ingestion of metaldehyde formulations is based on homeowner solid formulation products where, as indicated above, w/ w concentration ranges from 2 to 7.5 percent by weight. Additionally, in order to provide an illustration of how much one may be required to ingest to achieve a level of concern, 2 specific formulations were considered.

The first formulation is a mini pellet type with a particle size of 35 to 50 mini pellets/ gram or 0.029 grams/ pellet based on the 35 count ( EPA Reg 8119 9 contains 4% a. i. so each 35 count mini pellet contains 1 mg metaldehyde). The second is a small granular formulation with a particle size of 450 granules/ gram or 0.0022 grams/ granule ( EPA Reg 8278 3 contains 3.5% ai so each granule contains 0.078 mg metaldehyde). Risks ( i. e., MOEs) for ingestion of the 2 and 7.5 percent w/ w formulations based on SOP 2.3.1 are 188 and 50, respectively. These values represent potential risks of concern since the total uncertainty factor ( i. e., target MOE) that is applicable to this scenario is 1000. Page 48 of 80 However, it is important to consider these results in the context described above ( i. e., episodic events and use of a bittering agent). It is also important to consider these results in the context of how much formulation would be required to be ingested at the Agency's level of concern ( i. e., 1.125 mg metaldehyde based on NOAEL 75 mg/ kg/ day/ UF = 1000 and the 15 kg body weight of a toddler) in order to further characterize the MOE results presented above. Ingestion of 2 mini pellets would exceed the Agency's level of concern while ingestion of 15 small granules would exceed the Agency's level of concern ( e. g., 1.125 mg metaldehyde at level of concern/ 1 mg metaldehyde in each minipellet

6.3.2. Recreational Uses The use patterns supported by the technical registrant, Lonza, include uses on turf, dichondra, and ornamentals on sites such as parks, recreation areas, golf courses, etc. These applications would be applied by occupational handlers; therefore, no residential handler assessment is needed. Postapplication exposures to children are likely to occur. However, a separate risk assessment for these exposures was not completed, since the application rates and other application parameters are identical to uses on home lawns and home ornamentals. Therefore the exposure and risk assessment conducted in <IP_ADDRESS> is considered representative of post application exposures to toddler from uses in recreational settings.

6.3.3. Other ( Spray Drift, etc.)

Spray drift is always a potential source of exposure to residents nearby to spraying operations. This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for metaldehyde. The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices. On a chemical by chemical basis, the Agency is now requiring interim mitigation measures for aerial applications that must be placed on product labels/ labeling. The Agency has completed its evaluation of the new data base 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 for pesticides applied by air, orchard airblast and ground hydraulic methods. After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off target drift with specific products with significant risks associated with drift. However, metaldehyde is primarily applied in a granular form and spray drift is unlikely.

7.0 Aggregate Risk Assessments and Risk Characterization In accordance with the FQPA, HED must consider and aggregate metaldehyde pesticide exposures and risks from several major sources: food, drinking water, residential, and other non occupational 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 themselves can be aggregated. When aggregating exposures and risks from various sources, HED considers both the route and duration of exposure. Page 49 of 80 No endpoint was identified for dermal exposure to metaldehyde, so dermal exposures need not be considered in the aggregate assessment.

For metaldehyde, a screening level assessment indicated that short term risks will be higher than intermediate term risks. For this reason, and because intermediate term exposures ( continuous exposures for 1 6 month in duration) are likely to occur only infrequently, if at all, aggregate assessment was completed only for the short term duration.

No quantification of cancer risk is required, based on the " Suggestive Evidence of Carcinogenicity, but Not Sufficient to Assess Human Carcinogenic Potential" classification.

7.1. Acute Aggregate Risk Only food and water are generally aggregated for acute ( one day) exposures to pesticides. The following section elaborates on the probabilistic dietary assessment that includes both food and water exposures.

When surface water modeling residues are included in the acute assessments, HED's level of concern is not exceeded (< 100% aPAD). The most highly exposed population subgroup was children 1 2 years old at 26% aPAD ( 95th percentile). For ground water, children 1 2 years old were also the most highly exposed population subgroup. For children 1 2 years old, 29% of the aPAD was occupied in the acute aggregate assessment. HED is generally not concerned unless the exposure substantially exceeds 100% of the aPAD.

The Commodity Contribution Analysis shows that water is the most significant contributor to the risk. SCI GROW is a Tier 1 conservative modeling analysis; therefore, water concentration estimates could be significantly lower with additional refinements. Page 50 of 80 Table 14  Aggregate Risk Assessment for Acute Dietary Exposure to Metaldehyde Acute Scenario ( 95th percentile) Dietary Only Dietary + Surface Water Dietary + Ground Water Population Subgroup1 aPAD mg/ kg/ day Food Exp mg/ kg/ day % aPAD Agg. Exp mg/ kg/ day % aPAD Agg. Exp mg/ kg/ day % aPAD U. S. Population 0.075 0.008551 11 0.008809 12 0.010396 14 All Infants (< 1 year old) 0.075 0.003560 4.8 0.005713 7.6 0.013840 18 Children 1 2 years old 0.075 0.018514 25 0.019321 26 0.021634 29 Children 3 5 years old 0.075 0.016881 23 0.017325 23 0.019125 26 Children 6 12 years old 0.075 0.011224 15 0.011484 15 0.013144 18 Youth 13 19 years old 0.075 0.007551 10 0.007750 10 0.009096 12 Adults 20 49 years old 0.075 0.007251 9.7 0.007549 10 0.008890 12 Adults 50+ years old 0.075 0.007776 10 0.008007 11 0.009326 12 Females 13 49 years old 0.075 0.007320 9.8 0.007610 10 0.008932 12 1  This footnote should indicate the selected subgroups and provide rationale for selection. Indicate body weights ( 70 kg adult male; 60 kg adult female; 10 kg child). * Dietary Only   based on DEEM FCID ( version 2.00) * Dietary + Surface/ Ground Water values   based on DEEM FCID ( version 2.00) and PRZM EXAMS analysis. * PRZM EXAMS acute assessment ( n= 11000) based on max. application of Brassica leafy vegetables in California. * EDWC of 295ppb generated from a Tier I SCI GROW analysis based on use of metaldehyde on ornamental plants ( chronic and acute aggregate assessments).

7.2. Short Term Aggregate Risk Incidental oral and inhalation exposures may be expected as a result of the residential use of metaldehyde. The same study was selected for short term risk assessment for both the oral and inhalation routes, so the risks may be aggregated. Since the same study was used and an inhalation absorbtion factor of 100% was used, the exposures were added and divided into the NOAEL in order to calculate aggregate MOEs. Page 51 of 80 Exposures via the oral route may be expected from food, water, and incidental oral exposures around the residence. Inhalation exposure is not expected because of the use patterns ( pellet formulation). Average food and water exposure values were used to aggregate the MOEs. Incidental oral exposures may result from children playing on treated turf and ingesting soil or inserting their hands in their mouths during or after playing on treated turf. Since these activities are likely to occur simultaneously, the combined MOE was used in the aggregate assessment.

The short term aggregated risks can be found below in Table 15 aggregated from oral and inhalation exposures. The target MOE for all short term aggregated risks is 1000 for all scenarios; none exceed the Agency target MOE.

Table 15  Short Term Aggregate Risk Exposure ( mg/ kg/ day) Aggregate MOE Population Food only Residential Food & water food/ residential3 food/ drinking water/ residential4 Aggregate MOE using chronic surface water EDWC Children playing on turf1 0.00489 0.019 0.0059 1300 1200 Residential Handler   adults2 0.002215 0.00054 0.0029 11000 8700 Aggregate MOE using chronic ground water EDWC Children playing on turf1 0.00489 0.019 0.0069 1300 1200 Residential Handler   adults2 0.002215 0.00054 0.003533 11000 7400 Target MOE for all short term aggregate risks = 1000 Note: To ensure the Agency adequately addressed all nature of exposures, an intermediate term " rangefinder" assessment was also completed based on a 10% residue decline per day over a month ( MRID 4657801 shows a daily dissipation of ~ 0.1% per day although it has not been completely reviewed by HED. Once a review is completed, the result may be incorporated in to the RA. However, incorporating any lower residue decline values will only increase resulting MOEs). The resulting combined MOE = 2900 1 ` Children playing on turf' dietary exposures ( food & food and drinking water) from children 1 2 years old 2 Residential Handler adult dietary exposures ( food & food and drinking water) from General U. S. population Page 52 of 80 3 Food/ residential Aggregate MOEs = Short Term Incidental Oral NOAEL ( 30 mg/ kg/ day)/[ dietary exposure + residential exposure ( in mg/ kg/ day)] 4 Food/ drinking water/ residential Aggregate MOEs = Short Term Incidental Oral NOAEL ( 30 mg/ kg/ day)/[ dietary ( food & surface water drinking water) exposure + residential exposure ( in mg/ kg/ day)]

7.3. Long Term Aggregate Risk There are no long term residential exposures expected for metaldehyde, therefore, long term aggregate risk incorporates only food and drinking water.

Tolerance level residues and 100% CT were used to determine the chronic dietary exposure and risk estimates. This assessment showed that for food only, the chronic risk estimates were below the Agency's level of concern (< 100% cPAD) for the general U. S. population ( 22% of the cPAD). The highest exposed population subgroup was children 1 2 years old (< 49% cPAD).

When surface water modeling residues are included in the chronic assessment, HED's level of concern is not exceeded (< 100% cPAD). The most highly exposed population subgroup was children 1 2 years old at 59% cPAD ( 95th percentile). For ground water, children 1 2 years old were also the most highly exposed population subgroup. For infants, 69% of the cPAD was occupied in the chronic aggregate assessment. The Commodity Contribution Analysis shows that water is the most significant contributor.

Table 16  Aggregate Risk Assessment for Chronic Dietary Exposure to Metaldehyde Chronic Scenario ( 95th percentile) Food Only Food + Surface Water Food + Ground Water Population Subgroup1 cPAD mg/ kg/

day Food Exp mg/ kg/ day % cPAD Agg. Exp ( Food+ SW) mg/ kg/ day % cPAD Agg. Exp ( Food+ GW)

mg/ kg/ day % cPAD U. S. Population 0.01 0.002215 22 0.002888 29 0.003533 35 All Infants (< 1 year old) 0.01 0.000674 6.7 0.002878 29 0.004993 50 Children 1 2 years old 0.01 0.004890 49 0.005888 59 0.006846 69 Children 3 5 years old 0.01 0.004442 44 0.005377 54 0.006274 63 Page 53 of 80 Table 16  Aggregate Risk Assessment for Chronic Dietary Exposure to Metaldehyde Chronic Scenario ( 95th percentile) Food Only Food + Surface Water Food + Ground Water Population Subgroup1 cPAD mg/ kg/

day Food Exp mg/ kg/ day % cPAD Agg. Exp ( Food+ SW) mg/ kg/ day % cPAD Agg. Exp ( Food+ GW) mg/ kg/ day % cPAD Children 6 12 years old 0.01 0.003002 30 0.003646 37 0.004265 43 Youth 13 19 years old 0.01 0.001843 18 0.002329 23 0.002795 28 Adults 20 49 years old 0.01 0.001830 18 0.002458 25 0.003060 31 Adults 50+ years old 0.01 0.002067 21 0.002728 27 0.003362 34 Females 13 49 years old 0.01 0.001910 19 0.002536 25 0.003135 31 1  This footnote should indicate the selected subgroups and provide rationale for selection. Indicate body weights ( 70 kg adult male; 60 kg adult female; 10 kg child). * Dietary Only   based on DEEM FCID ( version 2.00) * Dietary + Surface/ Ground Water values   based on DEEM FCID ( version 2.00) and PRZM EXAMS analysis. * PRZM EXAMS chronic assessment ( n= 11000) based on average residues for Brassica leafy vegetables in CA. * EDWC of 295ppb generated from a Tier I SCI GROW analysis based on use of metaldehyde on ornamental plants ( chronic and acute aggregate assessments).

8.0 Cumulative Risk Characterization/ Assessment 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 produce 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 common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http:// www. epa. gov/ pesticides/ cumulative/.

9.0 Occupational Exposure/ Risk Pathway Page 54 of 80 This section of the risk assessment addresses exposures to individuals who are exposed as part of their employment. These exposures can occur because people have contact with metaldehyde residues while using commercial products containing metaldehyde ( i. e., handlers) or by being in areas that have been previously treated ( post application workers). A thorough understanding of how metaldehyde is used is critical to the development of a quality risk assessment.

Because this information is also critical to the dietary and residential exposure assessments presented above, available use information has already been summarized. Please refer to Section 2.1: Summary of Registered/ Proposed Uses for further information on this topic. All calculations for occupationally exposed people are based on this information.

9.1. Short/ Intermediate/ Long Term Handler Risk The Agency completes occupational handler risk assessments using scenarios as the basis for the calculations as described in the U. S. EPA Guidelines for Exposure Assessment. For commercial pesticide products, the Agency categorizes handler exposures based on the kinds of formulations ( e. g., liquids or various solids), the kinds of equipment used to make applications ( e. g., airblast, tractor drawn spreader, or handheld equipment), the nature of the task ( e. g., mixing/ loading, applying, or both combined), and the level of personal protection used. Identifying the duration of exposure is also a critical element in the development of a risk assessment to ensure that the proper hazard component is used.