Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 1 of 61 UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C. 20460 **OFFICE OF CHEMICA**  **L SA FETY**  **AND POLLUTION PREVENTION**  **MEMORANDUM Date**  **: June**  **20 , 2013**  **SUBJECT: Metaldehyde**  **;** Human Health Risk Assessment for Proposed Uses on Grass Grown for Seed , Leaf P etioles [ Crop Subgroup 4B] , Wetland Taro, Field & Sweet C orn, Mint, and Soy beans, and for Amendments to Existing Tolerances [C rop Subgroups 13 - 07A , B , & G] . **PC Code:** 053001 **DP Barcode:** D404859 **Decision No.:** 468286 **Registration No. :**  61096 - 13 **Petition No.:** 2E8070 **Regulatory Action:** Section 3 **Risk A**  **ss essment Typ**  **e :**  Single Chemical Aggregate **Case No.:** NA **T XR No.:**  NA **CAS No.:** 108 - 62 - 3 **MRID No.:** NA **40 CFR:** 180.523 **FROM:** Matthew L loyd, CIH ; Risk Assessor

William Donovan , Chemist Linda Taylor, Toxicologist Risk Assessment Branch 57 Health Effects Division (7509P) **THROUGH:** Wade Britton, Industrial Hygienist

Michael Metzger , Chief Risk Assessment Branch VII Health Effects Division (7509P) **TO:** Laura Nollen/Barbara Madden , RM 05

Risk Integration and Minor Use Emergency Response Branch Registration Division (7505P) The Health Effects Division ( HED ) of the Office of Pesticide Programs (OPP) is charged with estimating the risk to human health from exposure to pesticides. The following human health assessments were conducted in support of the registration action for metaldehyde: the aggregate risk, and occupational and residential exposure assessment s by Matt Llo yd (RABVII); the residue chemistry and dietary exposure assessment by William Donovan (RAB V ); the hazard characterization and endpoint selection by Li nda Taylor (RABVII) .Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 2 of 61 **1.0 Executive Summary**  ................................ ................................ ................................ ........... 4 **2.0 HED Recommendations**  ................................ ................................ ................................ .... 6 **2.1 Da**  **ta Deficiencies** ................................ ................................ ................................ ............ 6 **2.2 Tolerance Considerations**  ................................ ................................ .............................. 6 **2.2.1 Enforcement Analytical Method**  ................................ ................................ ............... 6 **2.2.2 Recommended Tolerances**  ................................ ................................ ......................... 7 **2.2.3 Revisions to Petitioned**  **- For Tolerances**  ................................ ................................ .... 8 **2.2.4 International Harmonization**  ................................ ................................ ..................... 8 **2.3 Label Recommendations**  ................................ ................................ ................................ 8 **2.3. 1**  **Recommendations from Residue Reviews** ................................ ................................ 8 **2.3.2 Recommendations from Occupational/Residential Assessment**  ............................. 8 **3.0 Introduction**  ................................ ................................ ................................ ........................ 8 **3.1 Chemical Identity**  ................................ ................................ ................................ ........... 8 **3.2 Phys**  **ical/Chemical Characteristics** ................................ ................................ ............... 9 **3.3 Pesticide Use Pattern**  ................................ ................................ ................................ ...... 9 **3.4 Anticipated Exposure Pathways**  ................................ ................................ ................. 10 **3.5 Consideration of Environmental Justice**  ................................ ................................ .... 11 **4.0 Hazard Characterization and Dose**  **- Response Assessment**  ................................ .......... 11 **4.1 Toxicology Studies Available for Analysis**  ................................ ................................ . 12 **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  ............................. 12 **4.2.1 Dermal Absorption**  ................................ ................................ ................................ ... 12 **4.3 Toxicological Effects**  ................................ ................................ ................................ .... 12 **4.4 Safety Factor for Infants and Children (FQPA Safety Factor)**  ............................... 13 **4.4.1 Completeness of the Toxicology Database**  ................................ .............................. 14 **4.4.2 Evidence of Neurotoxicity**  ................................ ................................ ........................ 14 **4.4.3 Evidence of Sensitivity/Susceptibility in the Developing or Young Animal**  ........ 14 **4.4.4 Residual Uncertainty in the Exposure Database**  ................................ ................... 15 **4.5 Toxicity Endpoint and Point of Departure Selections**  ................................ .............. 15 **4.5.1 Dose**  **- Response Assessment**  ................................ ................................ ...................... 15 **4.5.3 Cancer Classification and Risk Assessment Recommendation**  ............................ 16 **5.0 Dietary Exposure and Risk Assessment**  ................................ ................................ ......... 19 **5.1 Metabolite/Degra**  **date Residue Profile** ................................ ................................ ....... 19 **5.1.1 Summary of Plant and Animal Metabolism Studies**  ................................ ............. 19 **5.1.2 Summary of Environmental Degradation**  ................................ .............................. 19 **5.1.3 Comparison of Metabolic Pathways**  ................................ ................................ ....... 19 **5.1.4 Residues of Concern Summary and Rationale**  ................................ ...................... 19 **5.2 Food Residue Profile**  ................................ ................................ ................................ .... 20 **5.3 Water Residue Profile**  ................................ ................................ ................................ .. 20 **5.4 Dietary Risk Assessment**  ................................ ................................ .............................. 21 **5.4.1 Description of Residue Data Used in Dietary Assessment**  ................................ .... 21 **5.4.2 Acute Dietary Risk Assessment**  ................................ ................................ ............... 21 **5.4.3 Chronic Dietary Risk Assessment**  ................................ ................................ ........... 21 **5.4.4 Cancer Dietary Risk Assessment**  ................................ ................................ ............. 22 **5.4.5 Summary Table**  ................................ ................................ ................................ ......... 22 **6.0 Resi**  **dential (Non -**  **Occupational) Exposure/Risk Characterization** ............................. 22 **6.1 Residential Handler Exposure**  ................................ ................................ .................... 23Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 3 of 61 **6.2 Post**  **- Application Exposure**  ................................ ................................ .......................... 25 **6.4 Residential Risk Estimates for Use in Aggregate Assessment**  ................................ .. 27 **6.5 Residential Bystander Post**  **- application Inhalation Exposure**  ................................ . 29 **6.6 Spray Drift**  ................................ ................................ ................................ .................... 29 **7.0 Aggregate Exposure/Risk Characterization**  ................................ ................................ .. 29 **7.1 Acute Aggregate Risk**  ................................ ................................ ................................ ... 30 **7.2 Short**  **- and Intermediate Term Aggregate Risk**  ................................ ........................ 30 **7.4 Chronic Aggregate Risk**  ................................ ................................ .............................. 33 **8.0 Cumulative Exposure/Risk Characterization**  ................................ ............................... 33 **9.0 Occupational Exposure/Risk Characterization**  ................................ ............................ 34 **9.1 Short**  **- /Intermediate**  **- Term Handler Risk**  ................................ ................................ ... 34 **9.2 Short**  **- /Intermediate**  **- Term Post**  **- Application Risk**  ................................ .................... 35 **9.2.2 Inhalation Post**  **- application Risk**  ................................ ................................ ............. 36 **10.0 References**  ................................ ................................ ................................ ......................... 36 **Appendix A. Toxicology Profile and Executive Summaries** ................................ .................. 37 **A.1 Toxicology Data Requirements**  ................................ ................................ ................... 37 **A.2 Toxicity Profiles**  ................................ ................................ ................................ ............ 38 **A.3 Hazard Identification and Endpoint Selection**  ................................ .......................... 43 **A.4 Executive Summaries**  ................................ ................................ ................................ ... 45 **Appe ndix B. Metabolism Summary Table**  ................................ ................................ ............... 59 **Appendix C. Physical/Chemical Properties** ................................ ................................ ............. 60 **Appendix D. Review of Human Research** ................................ ................................ ................ 61Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 4 of 61 **1.0 Executive Summary**  **Background:** Metaldeh yde [2,4,6,8 - tetramethyl - 1,3,5,7 - tetraox yac yclooctane] is used to control slugs and snails on a wide variety of tree, fruit and vegetable crops. Metaldeh yd e is formulated as granules (G), pelleted (P/T) baits, emulsifiable concentrate (EC), flowable concentrate (FlC), and readyto - use liquid (RTU/L) formulations. Formulated products generally contain 0.13 - 25% active ingredient. The Registration Division (RD) of OPP has requested that HED evaluate hazard and exposure data and conduct dietary , occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the proposed Secti on 3 registration uses of the active ingredient (ai), metaldehyde, for proposed uses on grass grown for seed , l eaf p etioles [Crop Subgroup 4B] , wetland t aro, f ield & sweet c orn, m int, and s oy beans, and for amendments to existing tolerances [c rop subgroups 13 - 07A , B, & G] . Besides this risk assessment, the most recent human - health risk assessment for metaldehyd e was the risk assessment to support metaldehyde reregistration completed in April, 2006 (M. Lloyd, et al. ; D 327385 ). **Hazard Assessment:** The hazard database for metaldehyde is extensive and sufficient for characterizing toxicity and hazard. Acceptable rat and rabbit developmental toxicity studies, a rat 2 - generation reproduction study , a subchronic neurotoxicity study in rats, are available, al though the immunotoxicity study remains as a datagap. The toxicity

profile of metaldehyde shows that the principal toxic effects are clinical signs of neurotoxicity, and changes in the liver and testes/prostate following repeated oral dosing . The dog is the most sensitive species for the neurotoxic effects. The nervous s ystem effects observed in the subchronic and chronic oral toxicity studies include : ataxia ; tremor ; twitching ; salivation ; emesis ; rapid respiration in dogs and maternal rats ; an d limb paraly sis, spinal cord necrosis , and hemorrhage in maternal rats. Developmental toxicity

was not observed in the rat or rabbit developmental toxicity studies, and maternal toxicity

was not observed in the rabbit. In the rat, maternal toxicity was o bserved, as evidenced b y clinical signs (ataxia, tremors, and twitching) at the highest dose tested. In the rat reproductive toxicity

study , mortality and clinical signs (limb paral ys is, spinal cord necrosis and hemorrhage) were observed in the maternal animals, and the effects on the offspring consisted of decreased pup body weight and body weight gains. Reproductive toxicity was not observed. The Food Quality

Protection Act ( FQPA ) safety factor was reduced to 1x for the relevant lifestages because the toxicity database is adequate to assess safety for infants and children and the exposure assessment will not underestimate children’s exposure. HED has determined that quantification of risk using a non - linear approach (i.e., the RfD) is appropriate and w illMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 5 of 61 adequatel y account for all chronic toxicity, including carcinogenicity , that could result from exposure to metaldehyde. The carcinogenicity of metaldeh yde has been evaluated b y HED and is classified as “suggestive evidence of carcinogenicity”. Mutagenicity is not a concern. **Food Residue Profile:** Adequate residue chemistry data have been provided for metaldehyde. Field trials are of adequate number and geographic representation. Data analy ses employed validated anal ytical methods and are supporte d by appropriate storage stability data. Sufficient studies were submitted for corn, so ybean, and mint to elucidate the fate of metaldehyde in processed commodities derived from these crops. The Agency waived livestock metabolism and feeding studies; thu s, all uses of metaldehyde are classified under 40 CFR §180.6 (a) (3), no reasonable expectation of finite residues with respect to residues in livestock commodities. L imited rotational crop field trials demonstrate that residues are not expected in crops planted 30 - day s after metaldehyde is applied to soil; therefore, 30 - day plant back intervals (PBIs) are appropriate for all crops in rotation to primary crops. **Exposure Profile**  **and Risk Es t**  **imates :**  Occupational exposures are expected from the proposed use of metaldehyde , although onl y inhalation exposure was quantitatively assessed because there is no dermal hazard. Because no dermal point of departure was selected, occupational post - application exposures are addressed qualitatively . Non - occupational (residential) exposures are not expected from the proposed uses of metaldehyde; however, an updated residential assessment has been conducted to assess existing uses of the chemical that include various liquid and granular products applied to lawns, turf, and around gardens, and ornamental plants. The occupational handler assessment of the proposed uses was completed assuming the maximum label application rate. Based on the proposed use pattern s, there is potential for short and intermediate - term occupati onal exposure to metaldehyde during mixing, loading, appl yi ng, and other handling tasks . As no dermal hazard was identified, only inhalation exposure was quantitatively

assessed. Chronic exposure is not expected for the proposed agricultural uses. The l evel of concern (LOC) for occupational inhalation exposures are for margins of exposure (MOEs) <100 (i.e., MOEs ≥ 100 are not of concern to HED) . For the proposed uses, all occupational short - and intermediate - term handler (with standard work clothing and no respiratory

protection) MOEs were >100 . The proposed metaldehyde label includes a personal protective equipment (PPE) requirement that applicators and other handlers wear long - sleeved shirts, long pants, chemical - resistant gloves, shoes plus socks, an d protective eyewear. The updated residential assessment evaluated exposure to adults (handler assessment) and children (post - application assessment) as a result of use of metaldehyd e products around the home (i.e., lawn and garden use). There were no ris k estimates of concern identified for the residential handler or the post - application assessment (i.e., MOEs were >100 ).Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 6 of 61 **Aggregate Risk Estimates:** In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. The acute and chronic aggregate risk assessment s takes into account exposure estimates from dietary consumption of metaldehyde (food and drinking water). The acute dietary exposure estimates are not of concern to HED (<100% aPAD ) at the 95 th exposure percentile for the general U.S. population and all other population subgroups . The chronic dietary exposure estimates are not of concern to HED (<100% cPAD ) for the general U.S. population and all population subgroups . The short - and intermediate - term aggregate risks combine residential handler (adult onl y) and post - application exposures ( children) with average food and water exposures. The risks estimated for adults and children are not of concern (i.e., MOEs are > 100) . This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. Please refer to Appendix D for a discussion of the human study data used in this risk assessment. **2.0 HED**  **Recommendations** Pending resolution of the deficiencies outlined below, there are no other residue chemistry , occu pational, or toxicolog ical data deficiencies that would preclude the establishment of permanent tolerances for residues of metaldehyde as outlined in Table 2.2.2. **2.1 Data Deficiencies**  The immunotoxicity

study (870.7800) is a toxicology data requirement for metaldehyde. Recently , OPP published the findings of its retrospective analy sis of immunotoxicity studies submitted to the Agency , concluding that none of the studies included in the anal ys is resulted in a Point of Departure (POD) that is l ower than the PODs selected from other available guideline toxicology

studies (http://www.epa.gov/pesticides/regulating/immunotoxicity- retro - anal ys is.pdf ) . EPA will consider requests for waivers for this study , particularl y in l ight of the retrospective anal ys is. A weight - of

- evidence rationale will be considered relative to the chemical’s toxicological profile, primary target organ s ys tem(s) and mode of toxic action, and any immuno related data available from structurally- related compounds. There are no data deficiencies in the occupational/residential exposure or residue chemistry database s . **2.2 Tolerance Considerations**  **2.2.1 Enforcement Analytical Method**  The GC/MS method (EN - CAS Method No. ENC - 3/99, Revision 1) is acceptable for tolerance enforcement of metaldehyde residues in plants. For this method, residues in homogenized plant matrices (except citrus and mint oil) are extracted with dichloromethane (DCM) containingMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 7 of 61 sodium sulfate, filtered, concentrated, and analyzed by GC/MS using the m/z 89 and 45 ions for quantitation and confirmation, respectivel y. For citrus and mint oil, the residue extraction step is slightly modified ; thus, residues in citrus oil are dissolved in methanol (MeOH), diluted with hexane and partition ed with water. Residues in the resulting MeOH:water fraction are then partitioned into DCM, concentrated, and analyzed by GC/MS. Mint oil samples are diluted with hexane and partitioned with 5% acetic acid and then DCM , prior to GC/MS analy sis. For wheat grain, rape seed, and other oily matrices an additional cleanup step consisting of a hexane/methanol partition is also used. The level of quantitation (LOQ) for metaldehyde in/on plant commodities is 0.05 ppm. **2.2. 2**  **Recommended Tolerances** Table 2.2.2 summarizes the registrant’s proposed tolerances and the Agency ’s tolerance recommendations. The tolerance expression in 40 CFR 180.523 for metaldehyde should be revised to read as follows: Tolerances are established for residues of the mollusc icide metal deh yd e , includin g its metabolites and degradates , in or on the commodities listed below. Compliance with the tolerance levels specified below is to be determined by measuring only metaldehyde, 2 ,4,6,8 - tetrameth yl - 1,3,5,7 - tetrox ocane , in or on the commodity . **Table 2**  **. 2.2**  **Tolerance Summary for M**  **etaldehyde .**  Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition Leaf petioles subgroup 4B 0.80 0.50 Peppermint, tops 3.5 4.0 Spearmint, tops 3.5 4.0 Peppermint, oil 14 12 Spearmint, oil 14 12 Caneberry subgroup 13 - 07A 0.15 0.15 Bushberry subgroup 13 - 07B 0.15 0.15 Berry, low

growing, subgroup 13 - 07G 6.25 6.25 Taro, corm 0.25 0.15 Taro, leaves 0.60 1.0 Corn, field, grain 0.05 0.05 Corn, sweet, kernel plus cob with husks removed 0.05 0.05 Soy bean, seed 0.05 0.05 Grass, forage 1.5 2.0 Grass, hay 1.8 2.0 Corn, field, forage 0.25 0.30 Corn, field, stover 0.15 0. 10 **Tolerances that need to be proposed**Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 8 of 61 **Table 2**  **. 2.2**  **Tolerance Summary for M**  **etaldehyde .**  Commodity Proposed Tolerance (ppm) Recommended

Tolerance (ppm) Comments; Correct Commodity

Definition Corn, sweet, forage None 0.30 Corn, sweet, stover None 0. 10 **2.2. 3**  **Revisions to Petitioned -**  **For Tolerances** For some commodities, the recommended tolerances are different than the proposed tolerance levels. Most of the recommended tolerance levels were based on use of the Organization for Economic Cooperation and Development ( OECD ) tolerance calculation procedures, while most of the proposed tolerance levels appear to be based on the North America Free Trade Agreement (NAFTA ) tolerance calculation procedures. Sweet corn forage and stover tolerances should be proposed to support the use of metaldehyd e in/on sweet corn. Differences between the proposed and recommended tolerances for mint oil likely arise from the use o f maximum residues and processing factors instead of highest average residues and average processing factors. **2.2. 4**  **International Harmonization** As there are no CODEX or Canadian MRLs established for metaldehyde, no international harmonization issues are expected to arise from establishment of the recommended tolerances. **2.3 Label Recommendations**  **2.3.1 Recommendations from Residue Reviews**  The proposed labels should contain the following restriction: A 30 - day plant back interval (PBI) is appropriate for all rotational crops. Labeled crops may be replanted immediatel y. All other metaldehyde labels should be amended in registration review to contain the aforementioned restriction. **2.3.2 Recommendations**  **from Occupational /Residential**  **Assessment** There are no recommendations for the assessment of occupational/residential exposures at this time. As quantification of dermal risk is not required for metaldehyde, no dislodgeable foliar residue ( DFR) or turf transferable residue ( TTR) studies are required at this time. If future hazard database changes result in the identification of a dermal endpoint, HED will reassess the need for these data. **3.0 In**  **troduction 3.1**  **Chemical Identity**Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 9 of 61 **TABLE 3**  **.1. Nom**  **enclature of Metaldehyde.** Compound Chemical Structure

Common name Metaldehyde Company experimental names Not applicable IUPAC name r- 2, c - 4, c - 6, c - 8 - tetramethyl - 1,3,5,7 - tetroxocane (or) 2,4,6,8 - tetramethyl - 1,3,5,7 - tetraoxacyclo - octane CAS name 2,4,6,8 - tetramethyl - 1,3,5,7 - tetroxocane CAS # 108 - 62 - 3 (tetramer) and 9002 - 91 - 9 (homopolymer) End -use products/EP 7.5% G (Durham Metaldehyde Granules; EPA Reg No. 5481 - 103); 4% P/T (Deadline MPs Mini - Pe llets; EPA Reg. No. 5481 - 511); and 4% RTU/L (Deadline Force II; EPA Reg. No. 8119 - 6) **3.2 Physical/Chemical Characteristics**  The phy sical/chemical properties of metaldehyde are summarized in Appendix C . Metaldehyde has a vapor pressure of 6.6 ± 0.3 Pa at 25 °C. Metaldehyde is expected to be mobile and moderatel y persistent in the environment. Metaldehyde degrades aerobically with a reported half - life of 67 day s, anaerobically with a reported half

- life of 222 day s, and is stable to abiotic degradation (h ydroly sis and photoly sis). 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 metaldeh yde, although because acetaldehyd e undergoes further degradation, it is not included in the tolerance expression or this risk assessment. **3.3 Pesticide Use Pattern**  Table 3.3 contains a summary of the proposed uses for metaldeh yde. The personal protective equipment proposed for the new uses direct mixers, loaders, applicators and other handlers to wear chemical resistant gloves in addition to baseline clothing (i.e., long sleeved shirt, long pants, and shoes with s ocks) . This is identical to existing PPE requirements on currentl y registered labels. **Table 3.3**  **. Summ ary of Directions for Use of**  **Metaldehyde Granular Formulation Applic**  **ation Timing, Type,**  **and Equip. Form**  **ulation**

**[EPA Reg. No.]**  **Applic at** 

**ion Rate**  **(lb ai/A)**  **Max. No.**

**Applic ation**  **per Season Max.** 

**Seasonal Applic**  **ation Rate (lb**  **ai/A) PHI** 

**(days) Use Directions and** 

**Limitations Grass**  **G rown for**  **S ee**  **d** Broadcast (ground & 71096 - 13 1.6 4 6.4 21 RTI = 14 days O O O O C H 3 C H 3

C H 3 C H 3Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 10 of 61 **Table 3.3**  **. Summ ary of Directions for Use of**  **Metaldehyde Granular Formulation Applic**  **ation Timing, Type,**  **and Equip. Form**  **ulation**

**[EPA Reg. No.]**  **Applic at** 

**ion Rate**  **(lb ai/A)**  **Max. No.**

**Applic ation**  **per Season Max.** 

**Seasonal Applic**  **ation Rate (lb**  **ai/A) PHI** 

**(days) Use Directions and** 

**Limitations** handheld equipment) **Leaf petioles (Subgroup**  **4B )**  Broadcast (ground & handheld equipment) 71096 - 13 1.0 4 4 1 RTI = 21 days **Mint (Peppermint and Spearmint)**  Broadcast (ground & handheld equipment) 71096 - 13 1.0 4 4 1 RTI = 21 days **Taro (wetland)** Broadcast (ground & handheld equipment) 71096 - 13 1.0 15 15.0 7 RTI = 21 days **Caneberry (**  **Subgroup 13**  **- 07A)**  **, Bushberry (Subgroup 13 -**  **07B, Low growing berry (Subgroup 13 -**  **07G)** Broadcast (ground & handheld equipment) 71096 - 13 0.8 3 2.4 0 RTI = 14 days **Sweet and Field Corn** Broadcast (ground & handheld equipment) 71096 - 13 1.0 4 4 N/A PHI = N/A because applications must be completed no later than flag stage. RTI = 7 days **Soybean** Broadcast (ground & handheld equipment) 71096 - 13 0.4 3 1.2 N/A PHI = N/A because applications must be completed prior to pod formation . Treated soy beans may not be fed to livestock, and livestock may not graze in the treated

fields. RTI = 7 days The use directions are adequate to allow evaluation of the residue data relative to the proposed use s . The proposed maximum application rates are supported b y the submitted field trial data. Refer to section 2.3 for recommended modifications to the proposed labels. **3.4 Anticipated Exposure Pathways** Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 11 of 61 RD has requested an assessment of human health risk to support the proposed new and expanded u ses of metaldehyde . Humans may be exposed to metaldehyde in food and drinking water, since metaldehyde may

be applied directly

to growing crops and application may result in metaldehyde reaching surface and ground water sources of drinking water. Inan oc cupational setting, applicators may

be exposed while handling the pesticide prior to application, as well as during application. There is a potential for post - application exposure for workers re - entering treated fields. Because there is no dermal hazard i dentified for metaldehyd e, occupational handler inhalation exposures are assessed quantitatively and post - application exposures (dermal and inhalation) are assessed qualitatively . While the RD request doesn’t include any residential uses of metaldehyde, residential exposure has been reassessed in this document based on existing uses of metaldehyde using the 2013 residential SOP revisions. Humans may be exposed to metaldehyde in residential settings, since it may be applied around lawns/ ornamental plants in residences and public areas. Because there is no dermal hazard identified for metaldehyd e , residential handler inhalation exposures and post - application incidental oral exposure are assessed quantitatively. The other exposure routes are addressed qualit atively in the residential exposure assessment. Therefore, this risk assessment addresses the proposed and existing residential uses of metaldehyde . This risk assessment considers all of the aforementioned exposure pathway s . **3.5 Consideration of Envir**  **onmental Justice** Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and L ow - Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf . As a part of every

pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well - established procedures. In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup’s food and water consumption, and activities in and around th e home that involve pesticide use in a residential setting. Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registere d food uses of a pesticide. These data are anal yz ed and categorized by subgroups based on age, season of the ye ar, ethnic group, and region of the country . Additionally , OPP is able to assess dietary

exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant. Whenever appropriate, non - dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing o n treated areas post - application are evaluated. Further considerations are currentl y in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to by standers and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups. **4.0 Hazard Characterization and Dose**  **- Response Assessment** Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 12 of 61 **4.1 Toxicology Studies Available for Analysis**  The toxicology

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

 Subchronic: 21 - day

dermal toxicity

(rabbit), 90 - day

oral toxicity

(dog)  Developmental toxicity : rat and rabbit developmental toxicity studies  Reproduction: 2 - generation reproduction study (rat)  Chronic: combined oral chronic toxicity /carcinogenicity

(rat), carcinogenicity

(mouse), chronic oral toxicity

(dog)  Neurotoxicity : subchronic neurotoxicity (rat)  Other: mutagenicity battery, metabolism The studies available for consideration of metaldehyde toxicity provide a comprehensive database, with routes of administration that are consistent with potential exposure scenarios. **4.2 Absorption, Distribution, Metabolism, & Elimination (ADME)**  Metaldeh yde is rapidl y absorbed, distributed, and metabolized in the rat, with most of the administered dose ( 78 - 98%) being recovered as 14 CO 2 in expired air within 24 hours for male rats and within 48 hours in female rats . Metaldeh yde is absorbed intact in the stomach , distribute d widely

throughout the body , and readily crosses the blood - brain barrier. Reco very in urine/feces is low (2.5 - 5.1%) , and the sexes differ slightly . In 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 h ours) than in males (3.4 h ours). More 14 C was found in nervous tissues, fat, liver, and reproductive organs than in other tissues . **4.2.1 Dermal Absorption**  No dermal absorption studies are available. Quantification of dermal risk is not required , based on lack of toxicity

in the rabbit dermal toxicity study at the limit dose , and the lack of pertinent effects in other toxicity

studies not measured in the dermal toxicity study . Therefore, a dermal absorption factor is not required. **4.3 Toxicological Effects**  The toxicity

profile o f metaldehyde shows that the principal toxic effects are clinical signs of neurotoxicity, changes in the liver and testes/prostate following repeated oral dosing . The dog is the most sensitive species for the neurotoxic effects. The nervous s ys tem effects observed in the subchronic and chronic oral toxicity studies include : ataxia ; tremor ; twitching ; salivation ; emesis ; rapid respiration in dogs and maternal rats ; and limb paraly sis, spinal cord necrosis , and hemorrhage in maternal rats . The liver effects include increased liver weight, increased incidence of liver lesions (hepatocellular necrosis, hepatocellular hy pertrophy and inflammation) , and anMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 13 of 61 increased incidence of hepatocellular adenomas 1 in female rats and in both sexes of mice. In dogs, atroph y o f the testes and prostate was observed following subchronic and chronic exposure. Toxicity

was not observed in a rabbit 21 - day dermal toxicity study at the limit dose . Acute lethality studies show that metaldehyde is not acutel y toxic by the dermal and inh alation routes of exposure but is moderatel y toxic via the oral route. Metaldehyde is moderatel y irritating to the eyes and minimally irritating to the skin. D evelopmental toxicity was not observed in the rat or rabbit developmental toxicity studies , and maternal toxicity

was not observed in the rabbit . In the rat, maternal toxicity was observed, as evidenced b y clinical signs ( ataxia, tremors, and twitching) at the highest dose tested. In the rat reproductive toxicity

study , mortality and clinical signs (limb paral ys is, spinal cord necrosis and hemorrhage) were observed in the maternal animals, and the effects on the offspring consisted of decrease d pup body

weight and body

weight gains. Reproductive toxicity was not observed . In the rat, clinical signs of neurotoxicity occur only

at dose levels in excess of 100 mg/kg/day following repeat oral exposure. In the 90 - day neurotoxicity

study , bilateral hindlimb paraly sis was observed in one female rat at the highest dose tested . No acute neurotoxicity study on metaldehyde is available. However, the Hazard and Science Policy Council (HASPOC) determined that the acute neurotoxicity study is not required since dogs appear to be the most sensitive species for neurotoxicity, and the acute neurotoxicity study in rats will not provide a point of departure or a more sensitive endpoint than those currently used in the overall risk assessment, which are based on the dog. Chronic feeding studies in rats and mice indicated that metaldehyde produced liver effects characterized b y liver h ypertroph y and liver tumors. HED has classified metaldehyde as “suggestive evidence of carcinogenicity”. Mutagenicity is not a concern. Although the mouse study showed that metaldehyde was associated with a common tumor in both se xes (liver tumors, adenomas), and the rat study showed that metaldehyde was associated with liver adenomas in the female, HED has determined that quantification of risk using a non - linear approach; i.e., RfD, for metaldehyde will adequately account for all chronic toxicity, including carcinogenicity , that could result from exposure to metaldehyde. That conclusion is based on the following considerations: (1) the tumors found are commonly seen in the mouse; (2) the liver tumors (adenomas) in both species wer e benign; (3) metaldehyde is not mutagenic; (4) no carcinogenic response was seen in the male rat; (5) incidence of adenomas at the high - dose in the female rat was within the historical control range of the testing lab. **4.4 Safety F**  **actor for Infants and Children (FQPA Safety Factor)**  HED recommends that the 10x FQPA Safety Factor (for the protection of infants and children) be reduced to 1x . An FQPA Safety Factor of 1x is appropriate for the following reasons:

1 The classification is driven by adenomas although one carcinoma was observed at the highest dose tested. The statistic for combined adenomas/carcinomas is statistically significant; however, no dose response was noted when carcinomas were evaluated alone.Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 14 of 61 The toxicity

database is complete and adeq uate to assess safety for infants and children. There is no evidence of increased qualitative or quantitative susceptibility in the developmental rat and rabbit studies or in the rat 2 - generation reproduction study . These studies have clearl y defined NOAE L/LOAELs. There is a subchronic neurotoxicity study on metaldehyde with a clearl y defined NOAEL/LOAEL . Both the acute neurotoxicity study and the developmental neurotoxicity

study have been waived. The exposure assessment will not underestimate children’s exposure to metaldehyde. Further details may be found in the following sections. **4.4 .1**  **Completeness o**  **f the**  **Toxicology Database** The toxicology

database for metaldehyde is adequate to address the proposed uses and to revisit the existing residential uses . Acceptable rat and rabbit developmental toxicity studies, a rat 2 - generation reproduction study , a subchronic neurotoxicity study in rats, are available. The immunotoxicity

study is a datagap . The HED’s Hazard and Science Policy Council (HASPOC) determin ed that the acute neurotoxicity (ACN) study and the inhalation toxicity study may

be waived. **4.4.2 Evidence of N**  **eurotoxicity** There is a concern for neurotoxicity resulting from exposure to metaldehyde, based on (1) clinical signs [ataxia, twitching, tremors, prostration, paresis of hind legs] in female rats in the developmental toxicity

study ; (2) hindlimb paraly sis, necrosis and hemorrhage in the spinal cord and vertebra luxation in F0 dams during lactation period in the two - generation reproduction study; (3) bilateral hindlimb paral ys is observed initially on day 10 in one high - dose female sacrificed on day

22 due to poor condition in the 90 - day subchronic neurotoxicity study in rats; no neuropathology

was evident; (4) clinical signs [ataxia, tremors, tw itching, 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 were seen in rats at dose levels above 100 mg/kg. **4.4.3 Evidence**  **o f Sensitivity/Su**  **sceptibility in the Developing o r Young Animal**  There is no evidence of increased susceptibility following in utero exposure to metaldehyde in either the rat or rabbit developmental toxicity study , and there is no evidence of increased susceptibility

following in utero and/or pre - /post - natal exposure in the 2 - generation reproduction study in rats. Metaldeh yde has been evaluated for potential developmental effects in the rat and rabbit (gavage administration). Maternal toxicity included mortality , clinical signs of toxicity ( ataxia, tremors, twitching, and rapid respiration) on day s 7 and 8, and dec reased body- weight gain and food consumption during dosing in rats, and maternal toxicity was not observed in rabbits. No developmental effects were observed in the rat or rabbit. M ortality , clinical signs (hindlimb paral ys is in F0 females) , gross/histopathol o gi cal lesions in females (spinal cord necrosis and hemorrhage, vertebra luxation in F0 females), and increased liver weight in both sexes wereMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 15 of 61 observed in the rat 2 - generation reproduction study at the same dose levels where decreased pup body weight and pup body- weight gain w ere observed in both sexes/both generations. **4.4.4 Residual**  **Uncertainty in the Exposure Datab ase**  For all dietary

risk assessments, the established and recommended tolerances were used and 100% crop treated was assumed. Modeling was used to derive estimated drinking water concentrations. The occupational and residential exposure assessment was conducted such that exposure s and risk s will not be underestimated. The aggregate exposure and risk estimates presented in this assessment are extremely conservative and will not underestimate actual exposure and risk expected based on the current and proposed use patterns. **4.5 Toxicity Endpoint and Point of**  **D eparture Selections**  **4.5.1 Dose**  **- Response Assessment**  A detailed description of the toxicity studies used for selecting toxicity endpoints and points of departure for various exposure scenarios is presented in Appendix A . No hazard or appropriate acute endpoint attributable to a single exposure was identified for females 13+ from the available oral toxicity database. An acute dietary endpoint for all populations was selected from the chronic oral toxicity study in the dog with a NOAEL of 30 mg/kg/day for clinical signs . At the LOAEL of 90 mg/kg/day , clinical s igns of neurotoxicity were observed in all dogs of each sex on the first day of dosing at this dose level . This endpoint is protective of the mortality and clinical signs seen in the maternal rats following 1 - 2 day s of dosing at the LOAEL of 150 mg/kg/day in the rat developmental toxicity study (NOAEL 75 mkd). The dog is the more sensitive species for the neurotoxicity observed following repeat oral exposure s, and this endpoint is consistent with endpoints for all the other exposure assessments , which are based on the dog chronic oral (diet) toxicity study . A 100X uncertainty factor was applied to account for inter- and intra - species variability resulting in an acute reference dose (aRfD) of 0.30 mg/kg/day. Since the FQPA factor is reduced to 1X, the aRfD is equivalent to the acute population adjusted dose (aPAD). The chronic dietary

endpoint was selected from the chronic oral toxicity study in the dog with a study NOAE L of 10 mg/kg/day. At the study LOAELof 30 mg/kg/day , death and atrophy of the tes tes and prostate were observed. A 100X uncertainty factor was applied to account for interand intra - species variability resulting in a chronic reference dose (cRfD) of 0.10 mg/kg/day . Since the FQPA factor is reduced to 1X, the cRfD is equivalent to the chronic population adjusted dose (cPAD). The short - term incidental oral and inhalation endpoint s for risk assessment w ere selected from the same chronic oral toxicity study in the dog described above for the chronic dietary endpoint but with a different NOAEL for clinical signs of neurotoxicity of 30 mg/kg/day . At the LOAEL of 90 mg/kg/day , the clinical signs of neurotoxicity were observed on the first day of exposure in all dogs at this dose level and throughout the first week of exposure . The clinical s igns occurredMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 16 of 61 initially and only at the high dose level and are considered appropriate for the short - term exposure duration. The intermediate - term incidental oral and inhalation endpoint s for risk assessment w ere selected from the chronic oral toxicity s tudy in the dog with a NOAEL of 10 mg/kg/day . At the study LOAEL of 30 mg/kg/day, death and atrophy of the testes and prostate were observed. Atrophy of the testes and prostate w as also observed in the subchronic dog study. Th ere was no hazard observed via the dermal route with lack of s ys temic toxicity following 21 day s of dermal exposure to rabbits. The endpoints of concern were all assessed in this study, and there is no developmental or reproductive concern ; therefore, quantification of dermal risk is not required . **4.5.3 Cancer Classification and Risk Assessment Recommendation**  The CARC classified metaldehyde as “Suggestive Evidence of Carcinogenicity” based on benign liver tumors seen in both sexes of mice and in female rats. Mutagenicity is not o f concern . Although the mouse study showed that metaldehyde was associated with a common tumor in both sexes (liver tumors, adenomas), and the rat study showed that metaldehyde was associated with liver adenomas in the female, HED has determined that quantification of risk using a non linear approach; i.e., RfD, for metaldehyd e will adequatel y account for all chronic toxicity, including carcinogenicity, that could result from exposure to metaldehyde. That conclusion is based on the following considerations: (1) the tumors found are commonly seen in the mouse; (2) the liver tumors in both species were benign; (3) metaldehyde is not mutagenic; (4) no carcinogenic response was seen in the male rat; (5) incidence of adenomas in the female rat was within the hist orical control range of the testing lab. A summary

of both carcinogenicity

studies is presented in Appendix A. **Table 4.**  **5 .4.1**  **Summary of Toxicological Doses and Endpoints**  **for Metaldehyde for Use in Dietary and Non**  **** **Occupational Hum an Health Risk Assessments**  **Exposure /**  **Scenario Point of** 

**Departure Uncertainty/FQPA** 

**Safety Factors RfD, PAD,** 

**Level of Concern for**  **Risk Assessment**  **Study and Toxicological Effects**

Ac ute Dietary (All Populations ) NOAEL =

30 mg/kg/day UF A 10x

UF H 10x FQPA SF = 1X aRfD = 0.30

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

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

10 mg/kg/day UF A 10x

UF H 10x FQPA SF = 1X cRfD = 0.10

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

LOAEL = 30 mg/kg/day, based on death and atrophy of the testes and prostateMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 17 of 61 **Table 4.**  **5 .4.1**  **Summary of Toxicological Doses and Endpoints**  **for Metaldehyde for Use in Dietary and Non**  **** **Occupational Hum an Health Risk Assessments**  **Exposure /**  **Scenario Point of** 

**Departure Uncertainty/FQPA** 

**Safety Factors RfD, PAD,** 

**Level of Concern for**  **Risk Assessment**  **Study and Toxicological Effects**
Incidental Oral Short - Term (1 - 30 days) NOAEL =

30 mg/kg/day UF A 10x

UF H 10x FQPA SF = 1x Residential

LOC for MOE < 100 **C hronic**  **dog oral toxicity study** 

LOAEL = 90 mg/kg/day , based on clinical signs (ataxia, tremor, salivation, twitching) seen on day

1 of dosing (both sexes). Incidental Oral Intermediate Term (1 - 6 mo nths) NOAEL =

10 mg/kg/day UF A 10x

UF H 10x FQPA SF = 1x Residential

LOC for MOE < 100 **C hronic**  **dog oral toxicity study** 

LOAEL = 30 mg/kg/day , based on death and atrophy of the testes and prostate Dermal (All durations) No hazard observed via the dermal route, based on the lack of systemic effects following repeat

dermal exposure of rabbi ts. The endpoints of concern were all assessed in this study, and there is no developmental or reproductive conc ern. Inhalation Short - Term (1 - 30 days) NOAEL =

30 mg/kg/day UF A 10x

UF H 10x FQPA SF = 1x Residential

LOC for MOE < 100 **C hronic**  **dog oral toxicity study** 

LOAEL = 90 mg/kg/day , based on clinical signs (ataxia, tremor, salivation, twitching) seen on day

1 of dosing (both sexes). Inhalation Intermediate Term (1 - 6 mo nths) NOAEL =

10 mg/kg/day UF A 10x

UF H 10x FQPA SF = 1x Residential

LOC for MOE < 100 **C hronic**  **dog oral toxicity study** 

LOAEL = 30 mg/kg/day , based on death and atrophy of the testes and prostate Cancer (oral, inhalation) Classification : Suggestive Evidence of Carcinogenicity; EPA has determined that quantification

of risk using a non - linear approach (i.e., RfD) will adequately account for all chronic toxicity, including carcinogenicity . Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from animal to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). FQPA SF = FQPA Safety Factor. PAD = population adjusted dose (a = acute, c = chronic). RfD = reference dose. MOE = margin of exposure. LOC = level of concern. N/A = not applicable. **Table 4.5. 4**  **.2 Summary of Toxicological Doses and Endpoints for Metaldehyd**  **e for Use in Occupational**  **Hum an Health Risk Assessments**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty** 

**Factors Level of Concern** 

**for Risk Assessment**  **Study and Toxicological Effects** Dermal Short Term (1 - 30 days) No risk is expected from the exposure scenarios because no hazard was identified ;

based on the lack of systemic effects following repeat dermal exposure of rabbits at dose levels up to 1000 mg/kg/day . The endpoints of concern were all assessed in this study, and there is no developmental or reproductive concern. Dermal Intermediate Term (1 - 6 mo nths)Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 18 of 61 **Table 4.5. 4**  **.2 Summary of Toxicological Doses and Endpoints for Metaldehyd**  **e for Use in Occupational**  **Hum an Health Risk Assessments**  **Exposure/ Scenario**  **Point of**

**Departure Uncertainty** 

**Factors Level of Concern** 

**for Risk Assessment**  **Study and Toxicological Effects**

Inhalation Short - Term

(1 - 30 days) oral

NOAEL= 30 Inhalation hazard assumed to be equivalent to oral hazard UF A=10x

UF H =10x **Occupational**

LOC for MOE = 100 **C hronic**  **dog oral**  **toxicity study**

LOAEL = 90 mg/kg/day for clinical signs seen beginning the first week of dosing.

Inhalation Intermediate term (1 - 6 mo nths) oral

NOAEL = 10 mg/kg/day Inhalation hazard assumed to be equivalent to oral hazard UF A=10x

UF H =10x **Occupational**

LOC for MOE = 100 **C hronic**  **oral toxicity study** 
**– dog** 

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

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

quantification of risk using a non - linear approach (i.e., RfD) will adequately account for all chronic toxicity, including carcinogenicity . Point of Departure (POD) = A data point or an estimated point that is derived from observed dose - response data and used to mark the beginning of extrapolation to determine risk associated with lower environmentally relevant human exposures. NOAEL = no observed adverse effect level. LOAEL = lowest observed adverse effect level. UF = uncertainty factor. UF A = extrapolation from anima l to human (interspecies). UF H = potential variation in sensitivity among members of the human population (intraspecies). UF L = use of a LOAEL to extrapolate a NOAEL. UF S = use of a short - term study for long - term

risk assessment. UF DB = to acc ount for the absence of key data (i.e., lack of a critical study). MOE = margin of exposure. LOC = level of concern. N/A = not applicable.Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 19 of 61 **5.0 Dietary Exposure and Risk Assessment**  **5.1 Metabolite/Degradate Residue Profile**  **5.1.1 Summary of Plant and Animal**  **Metabolism Studies** No new metabolism studies were submitted in support of this petition. The residue of concern in plants consists only

of metaldehyde. Livestock metabolism studies have been waived. **5.1.2 Summary of Environmental Degradation**  Metaldeh yde is expected to be mobile and moderately persistent in the environment. Metaldeh yde degrades aerobically with a reported half - life of 67 day s, anaerobically with a reported half

- life of 222 day s, and is stable to abiotic degradation (hydrolysis and photoly sis). There were no toxic residues of concern identified for the metaldehyd e transformation products, and those transformation products were not considered in the EFED drinking water assessment. Acetaldeh yd e 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. **5.1.3 Comparison of Metabolic Pathways**  The major residue found in plant metabolism studies on lettu ce 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 likel y to be similar to the primary crops. Livestock metabolism studies have been waived because metaldehyde is expected to be rapidly metabolized in mammalian sy stems with subsequent incorporation of degradates into naturall y occurring components. T his conclusion is supported by the extensive metabolism observed in rat metabolism studies. Metaldeh yde is rapidl y absorbed, distributed, and metabolized in the rat. Between 78 - 98% of the administered dose was recovered as expired air within 24 hours as 14 CO 2 in the rat metabolism study . There was extensive metabolism of metaldehyde in both plants and animals. **5.1.4 Residues of Concern Summary and Rationale**  The qualitative nature of metaldehyde residues in plants is understood based on lettuce and sugar beet metabolism studies. The HED Metabolism Committee (7/2/96) concluded that the regulated residue of concern in plants is parent metaldehyde. This conclusion was confirmed in the Metaldeh yde Reregistration Eligibility Decision ( RED ) document (D32 7385, M. L loyd et. al., April 3, 20 06) .Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 20 of 61 **Table 5.1.4 Summary of Metabolites and Degradates to be included in th**  **e Risk Assessment and**  **Tolerance Expression** Matrix Residues included in Risk Assessment Residues included in Tolerance Expression Plants Primary Crop Metaldehyde Metaldehyde

Rotational Crop Metaldehyde Metaldehyde Livestock Not Applicable Not Applicable Drinking Water Metaldehyde Not Applicable **5 .2**  **Food Residue**  **Profile** Adequate residue chemistry data have been provided for metaldehyde. Field trials are of adequate number and geographic representation. Data analy ses employed validated anal ytical methods and are supported by a ppropriate storage stability data. Sufficient studies were submitted for corn , soy

bean, and mint to elucidate the fate of metaldehyde in processed commo dities derived from these crops: metal dehyde residues were found to concentrate only in mint oil, with an average processing factor of 5 .1 x. Multiplying the mint highest average field trial (HAFT) valu e [2.39 ppm] by the average processing factor resulted in the recommended tolerance level of 12 pp m for mint oil. The Agency waived livestock metabolism and feeding studies; thus, all uses of metaldehyde are classified under 40 CFR §180.6 (a) (3), no reas onable expectation of finite residues with respect to residues in livestock commodities. L imited rotational crop field trials demonstrate that residues are not expected in crops planted 30 - day s after metaldehyde is applied to soil; therefore, 30 - day plant back intervals ( PBIs ) are appropriate for all crops in rotation to primary crops. **5.3 Water Residue Profile**  The drinking water residues used in the dietary risk assessment were provided by the Environmental F ate and Effects Division (EFED) 2

. There are no monitoring data currentl y available for metaldeh yde in drinking water . E stimated drinking water concentrations (EDWCs) were generated using computer modeling procedures. The highest EDWCs resulted from the special mollusk eradication use on turf, and these values were used in the present dietary anal ys is. Surface water estimates were determined using the PRZM - EXAMS model and ground water estimates were determined using the PRZM - GW model. These latter values were recommended for use in th e human - health dietary risk assessment as they

were the highest values obtained. Additional information concerning the water models is available at the EPA web site 3

.

2 Personal communication (email message) from Melanie Biscoe (EFED) to W. Donovan (HED), 21 - MAY - 2013. 3 http://www.epa.gov/pesticides/science/models_pg.htm#aquaticMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 21 of 61 Maximum application rates for metaldehyd e as a high - end estimate of exposure in drinking water were modeled based on the proposed labels . C hemical specific and model input values were chosen in accordance with current EFED input parameter guidance (USEPA, 2009). The maximum surface and ground water EDWCs for use in the human - health risk assessment for metaldehyde are shown in Table 5.3. **Table 5.3.** Maximum Tier II estimated drinking water concentrations (EDWCs) in parts per billion (μg/L) resulting from 6 applications of 2 lb a.i./acre of metaldehyde to turf with a reapplication int erval of 14 day s. **Drinking water source (model)**  **1 -**  **in -**  **10 year 30**  **- year simulation**  Acute Chronic Acute Chronic Surface water (PRZM EXAMS) 205 136 - 83 Ground water (PRZM GW) - - 1740 635 Recommended for use in risk a ssessment: **1740 ppb** acute value, **635 ppb** chronic value **5.4 Dietary Risk Assessment**  **5.4.1 Description of Residue Data Used in Dietary Assessment**  For all dietary

risk assessments, the established and recommended tolerances were used and 100% crop treated was assumed. Proc essing studies for tomatoes and oranges indicate that metaldehyde residues do not concentrate in processed commodities derived from these crops. Exaggerated rates studies in corn and so ybean showed no detectable grain or seed residues at rates of 5 x and 1 0 x, respectivel y. Therefore, no processing factors were used in the anal ys es except for those processed commodities for which no processing studies are ty pically conducted (tomato, dried; tomato, juice; cranberry , juice; and high fructose corn s yrup), for which default factors were used. **5.4.2 Acute Dietary Risk Assessment**  A highl y conservative acute dietary assessment was conducted using tolerance - level residues, 100% crop treated assumptions, and modeled water numbers. Processing factors were assumed to be 1.0 for all commodities except for tomato, dried; tomato, juice; cranberry , juice; and high fructose corn s yrup; for these commodities, DEEM default processing factors were used. At the 95 th percentile of exposure, the estimated risk is ≤99% of the acute population adjusted dose (aPAD) for the U.S. population and all subpopulations. Results are shown in Table 5.4.5. **5.4.3 Chronic Dietary Risk Assessment**  A highl y conservative chronic dietary assessment was conducted using tolerance - level residues, 100% crop treated assumptions, and modeled water numbers. Processing factors were assumed to be 1.0 for all commodities except for tomato, dried; tomato, juice; cranberry , juice; and highMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 22 of 61 fructose corn s yrup; for these commodities, DEEM default processing factors were used. The estimated risk is ≤36% of the chronic population adjusted dose (cPAD) for the U.S. population and all subpopulations. Results are shown in Table 5.4.5. **5.4.4 Cancer Dietary Risk Assessment**  EPA has determined that quantification of risk using a non - linear approach (i.e., RfD) will adequatel y account for all chronic toxicity, including carcinogenicity . **5.4.5 Summary Table**  **Table 5 .**  **4.5. Summary of Dietary**  **(Food and Drinking Water) Exposure and Risk for**  **M etaldehyde**  **. 1**  Population Subgroup Ac ute Dietary ( 95th Percentile) Chronic Dietary Cancer Dietary Exposure (mg/kg/day) % aPAD Dietary Exposure (mg/kg/day) % cPAD Dietary Exposure (mg/kg/day) Risk General U.S. Population 0.099762 33 0.016044 16

N/A N/A **All Infants (< 1 year old) 0.298300**  **99 0.036060**  **36** Children 1 - 2 years old 0. 162635 54 0.026927 27 Children 3 - 5 years old 0.129865 43 0.022145 22 Children 6 - 12 years old 0.095292 32 0.015210 15 Youth 13 - 19 years old 0.082308 27 0.011935 12 Adults 20 - 49 years old 0.096014 32 0.015495 15 Adults 50 - 99 years old 0.087204 29 0.015637 16 Females 13 - 49 years old 0.098577 33 0.015638 16 1 Highest exposure identified in bold. **6.0 Residential (Non**  **- Occupational) Exposure/Risk Characterization**  There are no proposed non - occupational (residential ) uses or exposures associated with the current action ; however, there are existing residential uses that have been reassessed in this document to reflect updates to HED’s 2012 Residential SOPs 4 along with policy changes for bo dy weight assumptions. The revision of residential exposures will impact the human health aggregate risk assessment for metaldehyde . As no dermal hazard was identified for metaldehyde up to the limit dose, HED has quantitativel y assessed residential hand ler inhalation exposure (for adults applying metaldehyde) and incidental

4 Available: http://www.epa.gov/pesticides/science/residential - exposure - sop.htmlMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 23 of 61 oral postapplication exposure (for children) as a result of metaldehyde applications on turf around the home. **6.1 Residential Handler Exposure**  The quantitative exposure/risk assessment developed for residential handlers of metaldehyde i ncludes the following scenarios: loading/appl yi ng liquid ready- to - use products with (1) manually- pressurized handwands, (2) hose - end sprayers, and (3) sprinkler cans; and appl yi ng granules via ( 4 ) push - ty

pe rotary spreaders, ( 5 ) belly

grinders, ( 6 ) spoons, ( 7 ) cups, ( 8 ) hands, and ( 9 ) shaker cans. These residential use patterns were previousl y assessed (“ Metaldeh yd e : HED Chapter of the Reregistration Eligibility Decision Document (RED) ” . D327385 . April, 2006). Since that time, the unit exposures/exposure methodology has been updated to reflect current HED policies and is described in the 2012 Residential SOPs. At this time, no chemical - specific data for metaldehyde are available to assess res idential exposure. Detailed information on the assumptions used to assess residential handler exposure scenario s is available in the Metaldehyde Occupational and Residential Exposure Assessment memo ( D408747 ). Since there are no toxicity findings applicab le to the short - term dermal route of exposure up to the limit dose, the residential handler assessment onl y includes the inhalation route of exposure. Table 6.1 (below) summarizes the residential handler inhalation risk estimates for the relevant residential handler exposure scenarios. Handler risk estimates for all scenarios are not of concern (i.e., MOEs are >100) . **Table 6.1: Short -**  **Term Residential Handler Exposure and Risk Estimates for**  **Metaldehyde Exposure Scenario**  **Level of**

**Concern Inhalation Unit** 

**Exposure Application** 

**Rate 1**  **Am ount** 

**Treated or**  **Handled Daily**  **2 Inhalation** 

**Dose 3**  **MOE 4**  Mixer/L oader/Applicator Ornamentals, liquid; Manually- pressurized handwand 100 0.018 0.08 lb ai/gallon 5 gallons 0.00009 330,000 Lawn/turf

, liquid; Manually- pressurized handwand 100 0.018 0.023 lb ai/gallon 5 gallons 0.000026 1,200,000 Ornamentals, liquid; hose end sprayer 100 0.0014 0.0000 7 lb ai/ft2 1200 ft2 0.0000015 20,000,000 Turf

– spot; liquid; hose end sprayer 100 0.0014 0.00002 lb ai/ft2 1200 ft2 0.00000042 71,000,000 Turf

– broadcast; liquids; hose end sprayer 100 0.0014 1 lb ai/A 0.5 A 0.00014 220,000 Ornamentals; RTU; hose end sprayer 100 0.034 0.0000 7 lb ai/ft2 1200 ft2 0.000036 840,000 Ornamentals; granule; push - type spreader 100 0.0026 0.0000 7 lb ai/ft2 1200 ft2 0.0000027 11,000,000 Lawn/turf; granules; push - type spreader 100 0.0026 1 lb ai/A 0.5 A 0.000016 1,800,000Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 24 of 61 **Table 6.1: Short -**  **Term Residential Handler Exposure and Risk Estimates for**  **Metaldehyde Exposure Scenario**  **Level of**

**Concern Inhalation Unit** 

**Exposure Application** 

**Rate 1**  **Am ount** 

**Treated or**  **Handled Daily**  **2 Inhalation** 

**Dose 3**  **MOE 4**  Lawn/turf, granule; belly grinder 100 0.039 0.0000 7 lb ai/ft2 1200 ft2 0.000041 730,000 Garden/trees, granule; spoon 100 0.087 0.0000 7 lb ai/ft2 1200 ft2 0.000091 330,000 Lawn/turf, granule; spoon 100 0.087 0.0008 lb ai/ft2 100 ft2 0.000087 340,000 Garden/tree, granule, cup 100 0.013 0.0000 7 lb ai/ft2 1200 ft2 0.000014 2,200,000 Lawn/turf, granule; cup 100 0.013 0.0008 lb ai/ft2 100 ft2 0.000013 2,300,000 Garden/tree, granule, hand dispersal 100 0.032 0.0000 7 lb ai/ft2 1200 ft2 0.0004 75,000 1 Based on application rates determined from EPA registered labels for metaldehyde & May , 2005 Use Closure Memo (details available D 327385 ) 2 Based on HED’s 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential - exposure - sop.html ). 3 Inhalation Dose = Inhalation Unit Exposure (mg/lb ai) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled (A

/day, ft2/day, or gallons/day) ÷ BW ( 80 kg). 4 Inhalation MOE = Inhalation NOAEL ( 30 mg/kg/day) ÷ Inhalation Dose (mg/kg/day). LOC is an MOE = 100Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 25 of 61 **6.2 Post**  **- Application Exposure**  There is the potential for post - application exposure for individuals exposed as a result of being in an environment that has been previousl y treated with metaldehyde. As no dermal hazard was identified, only

incidental oral exposure for children was quantitativel y assessed. Since metaldehyde is moderately persistent in the environment, intermediate - term exposure is also possible for incidental soil ingestion exposure. No dislodgeable f oliar r esidue or turf transferable residue data were available to assess residential post - application exposure; therefore, default residue availability

assumptions were used in the assessment. Additional details about the residue assumptions, and the assumptions used in the exposure assessment are available in the ORE memo ( D4 08747 ). The quantitative exposure/risk assessment for residential post - application exposures i nclude s the following scenarios and corresponding durations of exposure : **Residential Post -**  **Application Exposure**

**Scenario Exposure Duration**   Hand - to - mouth exposure to treated turf Short - term  Object - to - mouth exposure to treated turf  Treated soil ingestion Short /Intermediate - term  In cidental Ingestion of granules (as a result of turf/lawn applications). Acute The lifestages selected for each post - application scenario are based on an analy sis provided as an Appendix in the 2012 Residential SOPs 5 . These lifestages are not the onl y that could be potentially

exposed for these post - application scenarios; however, the assessment of these lifestages is health protective for the exposures and risk estimates for any other potentially exposed lifestages. The dermal route of exposure does not need to be combined with the assessed hand - to - mouth route of exposure ( or included in the aggregate risk assessm ent) because there is no identified dermal hazard. Table 5.2.1. (below) presents the short - and intermediate - term incidental oral risk estimates from post - application residential exposure to metaldehyde. There were no risk estimates of concern identified f or residential post - application exposure scenarios to metaldehyde (i.e, MOEs are >100). For liquid spray s on turf, short - term residential incidental oral risk estimates ranged from 2,000 to 890,000 . For granular products applied to turf, short term risk e stimates for the hand to mouth, object to mouth, and incidental soil ingestion ranged from 20,000 to 890,000 and were not of concern to HED. Because metaldehyde is moderatel y persistent in the environment (i.e., the aerobic soil half life of metaldehyde is 67 days), HED has determined there is the potential for intermediate - term exposures from children 1 to < 2 years old via incidental ingestion of soil following granular and liquid turf treatment. The assessment of short - term incidental soil ingestion o f metaldehyde was

5 Available: http://www.epa.gov/pesticides/science/residential - exposure - sop.htmlMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 26 of 61 conducted using day

of application (Day

0) soil residues because of the potential for children’s exposures to occur on the initial day . Intermediate - term incidental soil ingestion was also conducted assuming Day 0 soil residues as a screen , and did not account for the potential for residue dissipation for subsequent day s. The estimated risk is an MOE = 300,000 and does not contribute significantly

to the short - and intermediate - term aggregate risk s for metaldeh yd e. Intermedi ate - term child incidental soil ingestion from the granular and liquid turf products are not of concern to HED. **Table 6**  **. 2.1**  **: Residential Post**  **- A**  **pplication Non**  **- cancer**  **Exposure and Risk Estimates for Metaldehyde.**  Lifestage Post - application Exposure Scenario Dose 1 MOEs 2 Child: 1 to <2 years old Turf - sprays Hand to Mouth 0.0152 2,000 Object to Mouth 0.00046 65,000 Incidental Soil Ingestion (ST) 3.4E - 05 890,000 Incidental Soil Ingestion (IT) 3.4E - 05 300,000 Child: 1 to <2 years old Turf

– solids (granules) Hand to Mouth 0.0015 20,000 Object to Mouth 0.00009 320,000 Incidental Soil Ingestion (ST) 3.4E - 05 890,000 Incidental Soil Ingestion (IT) 3.4E - 05 300,000 Incidental Ingestion of Granules/Pellets (7.5%) 3 0.01 4,400 **1 Hand**  **- to**  **- Mouth**  = [Hand residue loading (mg/cm 2 ) x (fraction hand surface area mouthed/event (0.127/event) x typical surface area of one hand (150 cm2 )) x (exposure time (1.5 hrs/day)*number of replenishment intervals/hr (4 intervals/hr) x (1 - (1 - saliva extra ction factor (0.5)^(number of hand - to - mouth contact events per hour (13.9 events/hr); Hand Residue Loading = (fraction of ai on hands compared to total surface residue from dermal TC study (0.06) x dermal exposure (mg))/typical surface area of one hand (15 0 cm2 ). **Object -**  **to -**  **Mouth =** ((Object Residue (μg/cm 2 ) x CF1 (1.0E - 3 mg/μg) x Object Surface Area Mouthed/Event (10 cm2/event)) x (Exposure Time (1.5 hrs/day) x #Replenishment I ntervals/hr (4)) x (1 - ((1 - Extraction by Saliva (0.48))^(#Object - to - Mouth Events /hr (8.8 events/hr)/#Replenishment intervals/hr))))/Body Weight (11kg). **Soil Ingestion =**  adjusted for application rate based on 11 kg bodyweight child; See Appendix: Table A- 5 of ORE Chapter ( D408747 ). **2 MOE**  = NOAEL/Daily Dose (mg ai/kg/day); Oral NOAEL = 30 mg/kg/day (Short - term incidental oral & acute dietary POD) **3** In cidental ingestion of granules based on an acute exposure scenario; acute dietary POD = 30 mg/kg/day In gestion 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. 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). Regardless, in order to characterize the potential risks if such ingestion events did occur an exposure and risk assessment was conducted for this scenario. Because ingestion of formulated material is considered episodic, risks were calculated using the acute dietary endpoint (NOAEL = 30 mg/kg/day and UF=100). The exposure from ingestion of metaldehyde formulations is based on homeowner solid formulation products where the maximum w/w concentration in a formulation is 7.5 percent b y weight. The risk estimate (i.e., MOE) for ingestion of the highest percent w/w formulation (7.5%) based on ingestion of 0.001 grams of product is 4,400. As a standard practice, post - application non - dietary ingestion exposure (i.e., hand - to - mouth, object - to - mouth, soil ingestion, etc.) for adult s is not assessed. It is assumed that an adult would not place pesticide - contaminated hands, objects, or soil in their mouth. Additionally, post application non - dietary

ingestion exposure is also not assessed for young children for ornamental/home garden pesticide applications. Unlike treated grass at home or in recreational areas, the potential for exposure via non - dietary ingestion for young children is greatlyMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 27 of 61 diminished. Since the extent to which young children engage in gardening activities associated with these areas or utilize these areas for prolonged periods of play is low, significant non dietary ingestion exposure is not expected. **6.4 Residential Risk Estimates for Use in Aggregate Assessment**  R esidential exposure from granular applications t o ornamentals/home gardens via hand dispersal) is use d in the adult aggregate assessment . The residential exposure for use in the short - /intermediate - term aggregate assessment for children 1 to <2 ye ars old is short - term hand - to - mouth (incidental oral) exposure from contacting treated turf. Because of the long environmental half life of metaldehyd e, there is also an intermediate - term residential aggregate assessment. The residential exposure for use in the children 1 to <2 ye ars old intermediate - term aggregate assessment is (incidental oral) exposure from ingesting treated soil. See Table 6.4.1 for additional information.Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 28 of 61 **Table 6**  **.4. 1**  **Residential Exposures for Use In**  **the Metaldehyde Aggregate Assessment.**  **1 Lifestage**  **Residential Handler Residential**  **Post -**  **application**

**Dose (m**  **g/k g/day)**  **2 MOE**  **3 Dose**  **(m g/k** **g/day) 4**  **MOE 5**  **Dermal Inhalation**  **Total Dermal**  **Inhalation Total**  **Dermal Inhalation**  **Oral Total**  **Dermal Inhalation**  **Oral Total**  **Short -**  **Term** Adult Male N/A 0.0004 0.00 0 4 N/A 75,000 75,000 N/A N/A N/A N/A N/A N/A N/A N/A Adult Female N/A 0.0004 0.00 0 4 N/A 75,000 75,000 N/A N/A N/A N/A N/A N/A N/A N/A Child N/A N/A N/A 0.0152 0.0152 N/A N/A 2,000 2,000 Intermediate - Term Child N/A N/A N/A 0.00003 0.00003 300,000 300,000 1 Highlight ed risk estimates should contribute to the residential exposure porti on of the aggregate assessment; 2 Residential Handler Dose = the highest handler dose for each applicable lifestage of all scenarios assessed from Table 5.1.1. Total = dermal (N/A) + inhalation . 3 Residential Handler MOE = the MOEs associated with the highest doses identified in Table 5.1.1. Total = 1 ÷ (1/Inhalation MOE). 4 Residential Post - application Dose = the highest post - application dose for each applicable lifestage of all scenarios as sessed from Table 5.2.1. Total = incidental oral exposure . 5 Residential Post - application MOE = the MOEs associated with the highest doses identified in Table 5.2.1. Total = 1 ÷ (1/I ncidental oral MOE). Child 1 to <2 years - HTM contact with treated turf (ST); soil ingestion [because of long environmental half life] (IT).Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 29 of 61 **6.5 Residential Bystander**  **Post -**  **application Inhalation Exposure**  Based on the Agency's current practices, a quantitative post - application inhalation exposure assessment was not performed for metaldehyde at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV) and low vapor pressure ( 1.5E - 03 Pa at 25 oC ) . However, volatilization of pesticides may be a source of post - application inhalation exposure to individuals nearb y pesticide applications. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advi sory

Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 6 . The Agency is in the process of evaluating the SAP report and may , as appropriate, develop policies and procedures to identify the need for and, subsequently , the way to incorporate post - application inhalation exposure into the Agency's risk assessments. If new policies or procedures are developed, the Agency may revisit the need for a quantitative post application inhalation exposure assessment for metaldehyde. Although a quantitative residential post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for handlers (i.e., residential applicators ). This exposure scenario is representative of a worse case inhalation exposure and should be considered protective of other post - application inhalation exposure scenarios. **6.6 Spray Drift**  Spray drift is alway s a potential source of exposure to residents nearby to spraying operations. This is particularly

the case w ith aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for metaldehyd e. The Agency

has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency ’s Spray Drift website for more information 7 ) . The Agency has completed its evaluation of the new database submitted by the Spray

Drift Ta sk Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriatel y apply

the data and the AgDRIFT computer model to its risk assessments for pesticides applied b y air, orchard airblast and ground hydraulic methods. Af ter the policy

is in place, the Agency

may impose further refinements in spray drift management practices to reduce off - target drift with specific products with significant risk estimates associated with drift. It is noted that the 1 lb ai/acre applicatio n rate for turf was modeled to estimate post - application residential (incidental oral) exposure of children. As this rate is comparable to the agricultural application rates, this scenario is considered protective of any exposure of farm children via spray drift from agricultural metaldehyde applications. **7.0 Aggregate Exposure/Risk Characterization** 

6 Available: http://www.ep a.gov/scipoly/SAP/meetings/2009/120109meeting.html 7 Available: http://www.epa.gov/opp00001/factsheets/spraydrift.htmMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 30 of 61 In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures. 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 vario us sources, HED considers both the route and duration of exposure. No endpoint was identified for dermal exposure, so dermal exposures need not be quantified in the metaldehyde aggregate assessment. Therefore, for the residential contribution to the aggre gate assessment, the adult contribution is from the inhalation route of exposure and the child contribution is from the incidental oral route of exposure. Onl y food and water are generall y aggregated for acute (one - day) exposures to metaldehyde. For short - and intermediate term oral exposure to metaldehyde, food, water, and residential exposures are aggregated. Chronic exposures to metaldehyde are expected for food and water onl y. **7.1 Acute Aggregate Risk**  The acute aggregate risk assessment takes into account exposure estimates from dietary consumption of metaldehyde (food and drinking water). While HED does calculate an acute granular ingestion scenario for pelletized pesticides, it is not appropriate to aggregate because it represents episodic and sporadic ingestion, not a ty pical one day

exposure pattern . Further, these products contain a bittering agent which makes ingestion of metaldehyde formulations generall y not palatable to children. The acute die tary exposure estimates are not of concern to HED (<100% aPAD ) at the 95 th exposure percentile for the general U.S. population and all other population subgroups (see Table 5.4.6). The dietary exposure assessment utilized tolerance - level residues, 100% CT information for all crops , default processing factors , and a ground water EDWC generated b y the PRZM - GW Model . **7.2 Short**  **- and Intermediate**  **Term Aggregate Risk** The short - and intermediate - term aggregate risks combine duration appropriate residential handler (adult only) and

/or post application exposures with average food and water exposures. The residential estimated exposures used in the short - and intermediate - term aggregate risk assessments are shown in Table 7.2.1, below. **Table 7**  **.2.1. S**  **hort -**  **and Intermediate**  **- Term**  **Residential Exposure**  **Values and**  **Sources Used in the Metaldehyde**  **Aggregate Risk Assessment Population**  **Handler Exposure (m**  **g/kg/day) Postapplication**  **Exposure (m**  **g/kg/day) Residential Exposure**  **(m g/kg/day)**  **1 Short**  **- Term**  Adult Male 0.0004 Source: Table 6 .1 Garden/tree, granule, hand dispersal N/A ; no dermal endpoint 0.000 4Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 31 of 61 **Table 7**  **.2.1. S**  **hort -**  **and Intermediate**  **- Term**  **Residential Exposure**  **Values and**  **Sources Used in the Metaldehyde**  **Aggregate Risk Assessment Population**  **Handler Exposure (m**  **g/kg/day) Postapplication**  **Exposure (m**  **g/kg/day) Residential Exposure**  **(m g/kg/day)**  **1** Adult Female 0.0004 Source: Table 6 .1 Garden/tree, granule, hand dispersal N/A ; no dermal endpoint 0.000 4 Child N/A ; only adults are assessed as handlers 3 0.0 152 Source: Table 5.2 .1 Hand - to - Mouth from Treated Turf 0.0 152Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 32 of 61 **Table 7**  **.2.1. S**  **hort -**  **and Intermediate**  **- Term**  **Residential Exposure**  **Values and**  **Sources Used in the Metaldehyde**  **Aggregate Risk Assessment Population**  **Handler Exposure (m**  **g/kg/day) Postapplication**  **Exposure (m**  **g/kg/day) Residential Exposure**  **(m g/kg/day)**  **1 Intermediate**  **- Term**  Adult Male N/A ; intermediate term exposure not expected N/A ; no dermal endpoint - Adult Female N/A ; intermediate term exposure not expected N/A ; no dermal endpoint - Child N/A ; only adults are assessed as handlers 0.0000 34 Source: Table 5.2 Incidental Soil Ingestion 0.0000 34 1 Residential exposure is the representative residential contribution to the aggregate assessment 2 N/A is not applicable 3 HED’s 2012 Residential SOPs (http://www.epa.gov/pesticides/science/residential - exposure - sop.html ) Short - and intermediate - term aggregate margins of exposure for adults and children are not of co ncern (i.e., MOES are > 100) . Short - and intermediate - term estimated exposures and risks are shown in Table 7.2.2, below.Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 33 of 61 **Table 7.2.2. Short**  **- Term and/or Intermediate**  **- Term Aggregate Risk Calculations**  **Population NOAEL** 

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

**Food & Water**  **Exposure mg/kg/day**  **Residential**

**Exposure 3**  **mg/kg/day Aggregate MOE** 

**(food and residential)**  **4** Short - Term

Scenario Adult Male 30 100 0.3 0.015637 0.000 4 1, 9 00 Adult Female 30 100 0.3 0.015638 0.000 4 1, 9 00 Child 30 100 0.3 0.036060 0.0 152 590 **Intermediate -**  **Ter m**  **Scenario** Adult Male N/A Adult Female N/A Child 10 100 0.1 0.036060 0.00003 4 280 1 The LOC of 100 is based on the standard inter - and intra - species uncertainty factors. 2 Maximum Allowable Exposure (mg/kg/day) = NOAEL/LOC = 30/100 = 0.3 mg/kg/day (ST) . NOAEL/LOC = 10/100 = 0.1 mg/kg/day (IT). 3 Residential Exposure values taken from Table 7 .2.1.Average food & water exposure taken from Table 5 .3.3. 4 Aggregate MOE = [ Incidental Oral NOAEL [ST=30; IT=10] ÷ (Avg Food & Water Exposure + Residential Exposure)] **7.4 Chronic Aggregate Risk**  The chronic aggregate risk assessment takes into account average exposure estimates from dietary consumption of metaldehyde (food and drinking water). The c hronic dietary risk estimates are not of concern to HED (<100% cPAD ) for the general U.S. population and all population subgroups (see Table 5.4.6). The dietary exposure assessment utilized tolerance - level residues for all commodities, 100% crop treated , def ault processing factors , and a chronic ground water EDWC generated by the PRZM - GW model. **8.0 Cumulative Exposure/Risk Characterization**  Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to metaldehyde and any

other substances and metaldehyde does not appear to pro duce a toxic metabolite produced b y 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/ .Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 34 of 61 **9.0 Occupational Exposure/Risk Characterization**  An occupational exposure assessm ent of the proposed uses was provided in an HED memorandum dated 0 6 / 12 /13 ( M . L loyd ; D408747 ). For the proposed use sites, there is a potential for short - and intermediate - term occupational exposure to metaldehyde during mixing, loading, appl yi ng, and oth er handling tasks . Chronic exposure is not expected for the proposed agricultural uses. **9.1 Short**  **- /Intermediate**  **- Term**  **Handler Risk** HED uses the term handlers to describe those individuals who are involved in the pesticide application process. HED believes that there are distinct job functions or tasks related to applications and exposures can vary depending on the specifics of each t ask. Job requirements (amount of chemical used in each application), the kinds of equipment used, the target being treated, and the level of protection used b y a handler can cause exposure levels to differ in a manner specific to each application event. Based on the anticipated use patterns and current labeling, typ es of equipment and techniques that can potentially

be used, occupational handler exposure is expected from the proposed uses. The quantitative exposure/risk assessment (inhalation only) dev eloped for occupational handlers is based on the following scenarios:

 Mix/L oad - granular formulations for ornamentals, sod, mint, taro, blackberry , leaf petioles, and high acreage crops (i.e., corn, so yb eans)  Applicator

– granular formulations (ground e quipment & hand dispersal)  Load/Apply

– granular formulations (backpack/belly grinder/rotary

spreader equipment) The occupational and residential exposure assessment ( D408747 ) provides more detail on the assumptions used in the occupational assessment, sp ecificall y, details about the relevant application rates, the unit exposures, and assumptions about the area treated. As no dermal hazard was identified, only inhalation exposure was quantitatively assessed. For metaldeh yd e, based on the proposed use, s hort - and intermediate - term exposures are expected for the following reasons: (1) the product can be applied multiple times per year (2) the product can be applied to multiple application sites and (3) there may be a large agribusiness and/or commercial a

pplicators who may

appl y a product over a period of weeks. All occupational handler scenarios are not of concern (i.e., inhalation MOEs are > 100) with baseline clothing (no respiratory protection) for both the short - and intermediate - term exposure durations. While no quantification of dermal risk was appropriate based on the available toxicity information, it is relevant to note that the proposed product labels include chemical - resistant gloves. **Table 6.1.1. Occupational Handler Short**  **- /Intermediat**  **e -**  **Term Non**  **- Cancer Exposure and Risk Estimates for**  **Me taldehyde**  **.**Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 35 of 61 **Exposure Scenario**  **Crop or**

**Target Dermal Unit** 

**Exposure ( μ**  **g/lb ai)**  **1 Inhalation Unit** 

**Exposure ( μ**  **g/lb ai)**  **1 Ma** **xim um** 

**Application Rate**  **2 Area** 

**Treated or Am**  **ount Handled**  **Daily 3**  **Inhalation Mitigation**  **Level Mitigation Level**  **Dose (m**  **g/k g/day)**  **4 MOE**  **5** Mixer/Loader

M/L Granular P roduct for Ground A pplication Corn/ soybean N/A 1.7 1 200 0.00425 7,100 (ST) 2,400 (IT) S od N/A 1.7 1.6 80 0.00273 11,000 (ST) 3,700 (IT) Leaf petiole/mint/tar o/13 - 07A N/A 1.7 1 80 0.0017 18,000 (ST) 5,900 (IT) Applicator Applicator

– Tractor D rawn spreader Corn/soybeans N/A 1.2 1 200 0.003 10,000 (ST) 3,300 (IT) S od N/A 1.2 1.6 80 0.00193 16,000 (ST) 5,200 (IT) Leaf petiole/mint/ta ro/13 - 07A N/A 1.2 1 80 0.0012 25,000 (ST) 8,300 (IT) Applicator

– Hand Dispersal Field crops N/A 470 1 1 0.006 5,100 (ST) 1,700 (IT) Loader/Applicator Backpack S od N/A 23.8 1.6 1 0.000476 63,000 (ST) 21,000 (IT) Belly Grinder Dispersal to

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

field crop rows N/A 10 1 5 0.000625 48,000 (ST) 16,000 (IT) 1 Based on the “Occupational Pesticide Handler Unit Exposure Surrogate Reference Table” (March 2013 ); Level of mitigation: Baseline, no respiratory protection 2 Based on registered or proposed label (Reg. No. 71096 - 13 ). 3 Exposure Science Advisory Council Policy #9.1. 4 Inhalation Dose = Dermal Unit Exposure ( μ g/lb ai) × Conversion Factor (0.001 mg/ μ g) × Application Rate (lb ai/acre or gal) × Area Treated or Amount Handled Daily (A or gal/day) ÷ BW (kg). 5 Inhalation MOE = I

nhalation NOAEL (mg/kg/day) (30 ST/ 10 IT) ÷ Inhalation Dose (mg/kg/day). **9.2 Short**  **- /Intermediate**  **- Term**  **Post -**  **Application Risk**  HED uses the term post - application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re entry exposure). Such exposures may occur when workers enter previ ously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting. Post - application exposure levels vary over time and depend on such things as the ty pe of activity , the nature of the c rop or target that was treated, the ty pe of pesticide application, and the chemical’s degradation properties. No dermal point of departure was selected for metaldehyde and , therefore, no post - application dermal exposures and risks have been quantitatively assessed in this document. The potential for occupational post - application inhalation exposures is discussed below.Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 36 of 61 **9.2.2 Inhalation**  **Post -**  **application Risk**  Based on the Agency's current practices, a quantitative post - application inhalation exposure asses sment was not performed for metaldehyde at this time primarily because of the low acute inhalation toxicity

(Toxicity Category IV ) and the low vapor pressure ( 1.5E - 03 Pa at 25 oC) 8

. H owever, there are multiple potential sources of post - application inhalation exposure to individuals performing post - application activities in previously treated fields. These potential sources include volatilization of pesticides and resuspension of dusts and/or particulates that contain pesticides. The Agency sought expert advice and input on issues related to volatilization of pesticides from its Federal Insecticide, Fungicide, and Rodenticide Act Scientific Advisory Panel (SAP) in December 2009, and received the SAP’s final report on March 2, 2010 9 . The Agency is in the process of evaluating the SAP report as well as available post - application inhalation exposure data generated by the ARTF and may , as appropriate, develop policies and procedures, to identify

the need for and, subsequently , the way to incorporate occupational post application inhalation exposure into the Agency's risk assessments. If new policies or procedures are put into place, the Agency may revisit the need for a quantitative occupational post - application inhalation exposure assessment for metaldehyde. Although a quantitative occupational post - application inhalation exposure assessment was not performed, an inhalation exposure assessment was performed for occupational/commercial handlers , and all risks were below the level of concern (MOE > 100) . Handler exposure resulting from application of pesticides outdoors is likely to result in higher exposure than post application exposure. Therefore, it is expected that these handler inhalation exposure estimates would be protective of most occupational post - ap plication inhalation exposure scenarios. **10.0 References**  Previous Risk Assessments: M. L loyd, et al, “ Metaldehyde : HED Chapter of the Reregistration Eligibility Decision Document (RED). PC Code: 053001; DP Barcode: DP 327385” 04/03/06 ; D327385 HASPOC Memo: K. Rury ; February 21, 2013 ; TXR# 0056524. Chemistry Memo: W. Donovan ; in preparation ; D 408745 Drinking W

ater Memo: M. Biscoe ; in preparation. Dietary Memo: W. Donovan ; 2 3 - MAY - 2013; D 408746 Occupational & Residential Exposure Memo : M. Llo yd; 0 6 / 12 /13; D408747

8 MRID 40733902; Letter dated 4/5/89 from D. Edwards (RD) to J. Co nti (Lonza, Inc.) 9 Available: http://www.epa.gov/scipoly/SAP/meetings/2009/120109meeting.htmlMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 37 of 61 **A ppendix**  **A .**  **Toxicology Profile and Executive Summaries A.1**  **Toxicology Data Requirements** The requirements (40 CFR 158.340) for food use for me taldehyde are in Table 1. Use of the new guideline numbers does not imply that the ne w (1998) guideline protocols were used. **Study Technical**  **Required Satisfied**  870.1100 Acute Oral Toxicity ................................ ....................... 870.1200 Acute Dermal Toxicity ................................ .................. 870.1300 Acute Inhalation Toxicity ................................ .............. 870.2400 Primary Eye Irritation ................................ .................... 870.2500 Primary Dermal Irritation ................................ .............. 870.2600 Dermal Sensitization ................................ ...................... yes yes yes yes yes yes yes

yes yes yes yes no 870.3100 Oral Subchronic (rodent) ................................ ............... 870.3150 Oral Subchronic (nonrodent) ................................ ......... 870.3200 21 - Day Dermal ................................ .............................. 870.3250 90 - Day

Dermal ................................ .............................. 870.3465 90 - Day

Inhalation ................................ .......................... y es yes yes CR y es y es

yes yes

- yes A 870.3700a Developmental Toxicity (rodent) ................................ ... 870.3700b Developmental Toxicity (nonrodent) ............................. 870.3800 Reproduction ................................ ................................ . y es yes yes y es

yes yes 870.4100a Chronic Toxicity (rodent) ................................ .............. 870.4100b Chronic Toxicity (nonrodent) ................................ ........ 870.4200a Oncogenicity (rat) ................................ .......................... 870.4200b Oncogenicity (mouse) ................................ .................... 870.4300 Chronic/Oncogenicity ................................ .................... yes yes yes yes yes y es

yes yes yes yes 870.5100 Mutagenicity

—Gene Mutation - bacterial ..................... 870.5300 Mutagenicity

—Gene Mutation - mammalian ................ 870. 5385 Mutagenicity

— Structural Chromosomal Aberrations ... yes yes yes y es

yes yes 870.6100a Acute Delayed Neurotox icity (hen) ............................... 870.6100b 90 - Day

Neurotoxicity (hen) ................................ ........... 870.6200a Acute Neurotox icity Screening Battery (rat) ................. 870.6200b 90 - Day

Neuro toxicity Screening Battery (rat) ............... 870.6300 Develop. Neuro toxicity ................................ ................. no no yes yes CR -

- y es A yes A

- B 870.7485 General Metabolism ................................ ...................... 870.7600 Dermal Penetration ................................ ........................ 870.7800 Immunotoxicity ................................ ............................. yes CR yes y es

- no AWaived by HASPOC (TXR# 0056524) ; B EP A concluded there was no need for DNT ( TXR# 0055119, June 10, 2009).Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 38 of 61 **A.2 Toxicity Profile**  **s Table A.2.1**  **- Acute Toxicity Profile** 
**– Me**  **taldehyde Guideline**  **No. Study Type**  **MRID(s) Results**  **Toxicity Category**  870.1100 Ac ute oral [Sprague - Dawley rat] LD50 = 283 mg/kg II 870.1200 Ac ute dermal [CFY rat] 00131434 LD50 = >5000 mg/kg III 870.1300 Ac ute inhalation [Sprague Dawley rat] 00131429 LC50 = 13.5 mg/L/4 hrs IV 870.2400 Ac ute eye irritation [rabbit] 42068801 mild irritant III 870.2500 Ac ute dermal irritation [rabbit] 00131971 not an irritant IV 870.2600 Skin sensitization [guinea pig] N/A [N/A ] [N/A ]
**Table 2 -**  **Subchronic, Chronic and Other Toxicity Profile**
**– Metaldehyde**  **Guideline No./ Study Type**  **MRID No. (year) Classification /Doses**  **Results** 870.3100 90 - Day oral toxicity (mouse) 43297701 (1990)

mo use [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] Sy stemic NOAEL not established Sy stemic 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 pro state; at HDT, follicular hyperplasia of mesenteric lymph node in both sexes 870.3200 21/28 - Day dermal toxicity (rabbit) 42063401 (1991)

acceptable/guideline 0, 100, 300, 1000 mg/kg/day NOAEL = 1000 mg/kg/day [highest dose tested] LOAEL = no effects observed 870.3465 90 - Day inhalation toxicity (rat) HASPOC determined that an inhalation toxicity study was not required, based on MOEs that

were >1000Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 39 of 61 **Table 2 -**  **Subchronic, Chronic and Other Toxicity Profile**
**– Metaldehyde**  **Guideline No./ Study Type**  **MRID No. (year) Classification /Doses**  **Results** 870.3700a Prenatal developmental in rodent (rat) 41656001 (1990)

acceptable/guideline 0, 25, 75, 150 mg/kg/day gestation days 6 - 15 **Maternal** NOAEL = 75 mg/kg/day ] LOAEL = 150 mg/kg/day, based on mo rtality, clinical signs of

t oxicity [ataxia, tremors, twitching, rapid respiration] on days 7 and 8, and decreased body- weight gain during dosing, and decreased food consumption during dosing. **Developm ental**  NOAEL = 150 mg/kg/day [HDT] LOAEL = no effects. 870.3700b Prenatal developmental in nonrodent (rabbit) 41590501 (1990)

acceptable/guideline 0, 10, 40, 80 mg/kg/day gestation days 6 - 18 **Materna** l **toxicity NOAEL** = 80 mg/kg/day [HDT] **Maternal toxicity LOAEL** = no effects observed. **Developm enta**  l **toxicity NOAEL** = 80 mg/kg/day [HDT] **Developm ental 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 mo rtality, clinical signs (hindlimb paralysis in F0 females) on lactation day s 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]; **Offspr ing**  **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. 870.4100a Chronic toxicity rodents (SD rat) MRID 42203601 (1992)

acceptable/guideline 0, 50, 1000, 5000 ppm M 0, 2, 44, 244 mg/kg/day F 0, 3, 60, 314 mg/kg/day NOAEL = 50 ppm [ males 2 mg/kg/day; females 3 mg/kg/day] **A** LOAEL = 1000 ppm

[ males 44 mg/kg/day; females 60 mg/kg/day], based on increased incidence of hepatocellular hypertrophy (both sexes) and increased cholesterol (females), and decreased body- weight gain in females. [see under 870.4200 below] 870.4100b Chronic toxicity nonrodent (dogs) MRID 46378401 (2003)

acceptable/guideline 0, 10, 30, 90 mg/kg/day Overall NOAEL = 10 mg/kg/day LOAEL = 30 mg/kg/day, based on deaths and atrophy of testes/prostate NOAEL = 30 mg/kg/day LOAEL = 90 mg/kg/day, based on clinical signs of neurotoxicity in all dogs on the first day o f exposure and throughout the first week.Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 40 of 61 **Table 2 -**  **Subchronic, Chronic and Other Toxicity Profile**
**– Metaldehyde**  **Guideline No./ Study Type**  **MRID No. (year) Classification /Doses**  **Results** 870.4200 Carcinogenicity rats MRID 42203 601 (1992)

acceptable/guideline 0, 50, 1000, 5000 ppm M 0, 2, 44, 244 mg/kg/day F 0, 3, 60, 314 mg/kg/day NOAEL = 50 ppm [ 2 mg/kg/day; females 3 mg/kg/day] **A** LOAEL = 1000 ppm

[ males 44 mg/kg/day; females 60 mg/kg/day], based on increased incidence of hepatocellular hypertrophy (both sexes) and increased cholesterol (females), and decreased body- weight gain in females. **evidence of**  **carcinogenicity: fem**  **ales displayed**  **a treatm**  **ent -**  **related increase**  **in hepatocellular**  **adenom as**  **and adenomas**  **and carcinom**  **as com** **bi ned [positive trend at 5000 ppm**  **] at the high**   ** dose level [adenom** **as 6/60, 10%] com pared to both**  **control groups**  **[0/60 and**  **1/60]; carcinom**  **as 1/60,**  **1.7% compared**  **to both**  **controls [**  **0/60 and**  **1/60]; and**  **com bined**  **7/60, 11.7%**  **com pared**  **to both**  **controls [0/60**  **and 2/6**  **0]; the**  **incidence was**  **within the**  **historical control**  **range [adenom**  **as 0%**  **- 10%;**  **carcinom as 0%; combined 0%**  **- 10%].**  870.4300 Carcinogenicity mice 42737201 (1993)

acceptable/guideline when combined with MRID 44625101 2 control groups 25, 100, 300 ppm M 4.0, 15.9, 48.9 mg/kg/day F 4.8, 19.7, 59.8 mg/kg/day NOAEL = 100 ppm [ males 15.9/females 19.7 mg/kg/day] **A** LOAEL = 300 ppm

[ ma les 48.9/females 59.8 mg/kg/day based on increased incidence of hepatocellular hypertrophy in both sexes. Dose levels not adequate to a ssess carcinogenicity potential; **slight increase**  **in hepatocellular**  **adenom as**  **in both**  **sexes compared to both control groups** 870.4300 Carcinogenicity mice MRID 44625101 (1998)

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

h epatocellular adenomas in both sexes Gene Mutation - Ames assay 870.5265 MRID 415 53205 (1978)

unacceptable 0, 0.26, 1.28, 6.4, 32, 160 , 0 . 2 6 , 1.28, 6.4, 32, 160 ease in incidence of hepatocellular hy does not provide sufficient evidence of an egative response in strains TA 98, TA100, TA 1535, TA 1537, TA 1538 with and without metabolic activation; no MTD; poor performance of some strains Gene Mutation - Ames assay 870.5100 MRID 48666101 (2011)

tested up to limit dose (5000 μg/plate);insoluble at ≥2500 μg/plate +/ - S9. Acceptable/guideline No evidence of cy totoxicity; no appreciable incr eases in mean number of revertants/plate in any strain in either trial (+/ - S9). Th e positive controls induced the appropriate response in all strains in the presence and absence of S9 - activation. **There was**  **no evidence**  **of induced mutant colonies over back** **ground.**Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 41 of 61 **Table 2 -**  **Subchronic, Chronic and Other Toxicity Profile**
**– Metaldehyde**  **Guideline No./ Study Type**  **MRID No. (year) Classification /Doses**  **Results** Gene Mutation - mo use lymphoma L5178Y (TK+/ - ) cell line 870.5300 MRID 41553206 (1986)

unacceptable 20, 50, 100, 200 0 , 5 0 , 1 20, 50, 100, 167 0 , 5 0 , 1 no conclusions can be drawn; doses “not com pletely dissolved in the selected solvent (culture medium); all concentrations precipitated. Additionally, exposure time (2 hours) was shorter than the standard exposure time for this test system (4 hours). Gene Mutation - mo use lymphoma L5178Y (TK+/ - ) cell line 870.5300 MRID 48721401 (2011)

tested up to solubility limit ( ≥ 600 μg/mL +/ - S9) Acceptable/guideline N o evidence of induced mutant colonies over background.

Gene Mutation - mo use lymphoma L5178Y (TK+/ - ) cell line 870.5300 MRID 42044007 (1986; revised

1991) clarification of MRID 41553206 unacceptable w/S9 - 20, 50, 100, 167 / S 9 w/out S9 - 20, 50, 100, 200 /o uL No evidence for inducing forward gene mutation at TK locus in mouse lymphoma (L5178Y) cell with/without S9 activation up to precipitating concentrations (100 - 200 f o r in duc i n g f

o rward gene mutation at TK locus in mouse lymphoma (L5178Y) cell with/with st andard exposure time for this test system (4 hours). Chromosomal aberrations in CHO cells 870.5375 MRID 00163832 (1986)

unacceptable w/S9 - 20, 50, 100, 167 / S 9 w/out S9 - 20, 50, 100, 200 /o ut N o evidence for inducing chromosome aberrations in CHO cells up to a precipitating concentration (200 μ g/mL - S9). With S9, no evidence up to the highest dose tested (167 u

p t o th e hi gh e s t d o s e t e s t e d ( 1 6 7 in CHO cells up to a precipitat Chromosome Aberration Assay 870.5385 MRID 48788201 (2012)

0, 62.5, 125, and 250 mg/kg (M) or 0, 31.25, 62.5, and 125 mg/kg (F) Acceptable/guideline No evidence of cytogenicity in this in vivo rat bone marrow chromosome aberration assay.
Micronucleus assay 870.5395 MRID 42044006 (1990)

unacceptable 25, 50, 100 mg/kg H ighest dose tested (100 mg/kg ); MTD not reached 870.6200a Ac ute neurotoxicity screening battery HASPOC (TXR# 0056524) determined that a rat ACN was not required, based on the fact

that neurotoxicity effects observed in the rat occur only at high dose levels; the dog is the mo re sensitive species for neurotoxic effects and points of departure based on the dog study are protective of any neurotoxicity at higher dose levels. 870.6200b Subchronic neurotoxicity screening battery MRID 46223401 (2003)

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

[ 39 mg/kg/day], based on increased mo tor 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.Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 42 of 61 **Table 2 -**  **Subchronic, Chronic and Other Toxicity Profile**
**– Metaldehyde**  **Guideline No./ Study Type**  **MRID No. (year) Classification /Doses**  **Results** 870.6300 Developmental neurotoxicity DNT Workgroup (2009) determined that DNT wa s not required, based on a weight - ofevidence: (1) no evidence of ↑ susceptibility following in utero exposures to rats/rabbits or following pre - /postnatal exposure in rat reproduction study; (2) no treatment - related effects on any reproductive parameters; offspring effects were ↓ pup body weight/gain only at ≥133 mkd; (3) mo st of

the neurotoxic signs; e. g., limb paralysis, ataxia, and tremors, were seen in adult rats at dose levels of 150 mkd to 185 m kd; (4) pharmacokinetic profile indicates a short half - life with primary

m etabolite being its degradation/metabolism to acetaldehyde , an endogenous chemical; (5) based on offspring LOAEL of 133 m kd, in order to elicit effects in the offspring, the DNT wo uld need to be tested at high doses (>100 mkd), which wo uld not yield lower POD than those currently used for overall risk assessment. 870.7485 Metabolism and pharmacokinetics (Sprague - Dawley rat) MRID 42300901 (1992)

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

Classification: acceptable/guideline rapidly absorbed, distributed, metabol ized; mo st recovered in expired air [78% - 98% of administered dose] within 24 hours [48 hr high - dose females] as 14 CO 2 ; recovery in urine/feces low [ 2.5% - 5.1%] ; sexes differ slightly; peak blood levels [males 1 - 2 hrs; females 2 - 4 hrs] and excretion faster in males [T 1/2 males 3.4 hrs.; females 8.8 hrs.]; recovery greater following low - dose than high - dose and repeat exposure; concentration of t otal 14 C 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; 14 C in tissues/carcass after 7 days similar for all groups [7% - 11% of administered dose]; high concentrations 14 C recovered in nervous tissue, fat, liver, female reproductive organs; 2 major peaks [plasma] we re metaldehyde and acetaldehyde 870.7600 Dermal penetration no study available no study available . 870.7800 Immunotoxicity no study available Recently, OPP published the findings of its retrospective analysis of immunotoxicity studies submitted to the Agency, concluding that none of the studies included in the analysis resulted in a Point of Departure (POD) that is lower than the PODs selected from other available guideline toxicology studies ( http://www.epa.gov/pesticid es/regulating/immunoto xicity - retro - analysis.pdf

) . EPA will consider requests for waivers for this study, particularly in light of the retrospective analysis. A weight - of - evidence rationale will be considered relative to the chemical’s toxicological profile , primary target organ system(s) and mode of toxic action, and any immuno - related data available from structurally - related compounds.Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 43 of 61 **Table 2 -**  **Subchronic, Chronic and Other Toxicity Profile**
**– Metaldehyde**  **Guideline No./ Study Type**  **MRID No. (year) Classification /Doses**  **Results** 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 mo de of carcinogenic action [liver tumors]; no data on whether proliferative response sustained. A Regarding the lower NOAELs observed in both the rat and mouse long - term studies, discussion was included in the endpoint selection section of the RED. For the chronic dietary scenario, it was noted that the chronic toxicity/carcinogenic ity study in rats provided a lower NOAEL (2 mg/kg). However, the endpoint of concern [liver effects (hepatocellular hy pertrophy)] was seen at 44 mg/kg (LOAEL); the effects were considered an adaptive effect and not appropriate for selection of the chronic dietary endpoint. In addition, the lower NOAEL seen in the rat study mi ght be influenced by dose selection. Although the mouse study was not discussed, a similar conclusion is appropriate; i.e., the endpoint of concern in the mouse study [increased inciden ce of hepatocellular hypertrophy in both sexes] was seen at 48 mg/kg/day (LOAEL); the lower NOAEL (16/20 mkd) in the mouse study might be influenced by dose selection; and the effects might also be considered adaptive and not appropriate for selection of the dietary endpoint. **A.3 Hazard Identification and Endpoint Selection**  **A.3.1 Acute Reference Dose (aRfD)**  **- All populations**  **Study Selected:** Chronic oral toxicity study - dog **MRID No.:** 46378401 **Executive Summary :**  See Appendix A, Guideline [§ 870. 3100 ] **Dose and**  **Endpoint for**  **Risk Assessment:**  NOAEL= 3 0 mg/kg/day b ased on clinical signs (ataxia, tremors, salivation, twitching) seen on day 1 o f dosing in both sexes at LOAEL = 9 0 mg/kg/day . **Comments about**  **Study/Endpoint/Uncertainty Factors:**  Since the signs of neurotoxicity w ere observed on the first day of dosing, the study i s appropriate for an acute assessment. The dog is the most sensitive species for the neurotoxic effects observed, and neurotoxicity i s the most sensitive endpoint in the toxicity database. The dose and endpoint are appropriate for all populations. No endpoint appropriate for females 13+ was identified in the database. Although maternal deaths occurred following 1 - 2 exposures in the rat and rabbit developmental toxicity studies, the deaths occurred at dose levels ≥100 mg/kg/day . The dose and endpoint selected from the chronic dog study

are protective of these findings and of potential acute toxicity f or all populations. Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability). **A.3. 2**  **Chronic Reference Dose (cRfD )**  **` Study Selected:**  Chronic oral toxicity study - dog **MRID No.:** 46378401Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 44 of 61 **Executive Summary :**  See Appendix A, Guideline [§ 870.3100] **Dose and Endpoint for Risk Assessment:**  NOAEL=10 mg/kg/day based on death and atrophy of the testes and prostate seen on at LOAEL = 30 mg/kg/day . **Comments about Study/Endpoint/Uncertainty Factors:** The selected endpoint provides the most sensitive NOAELavailable from a study of appropriate duration and exposure (oral). Atrophy of the testes and prostate were observed in the dog subchronic oral toxicity study also at a dose of 60 mg/kg/day

(NOAEL = 20 mg/kg/day). Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability) . **A.3. 3**  **Incidental Oral Exposure (Short -**  **Term) Study Selected:**  Chronic oral toxicity study - dog **MRID No.:** 46378401 **Executive Summary :**  See Appendix A, Guideline [§ 870.3100] **Dose and**  **Endpoint for**  **Risk Assessment:**  NOAEL=3 0 mg/kg/day b ased on clinical signs (ataxia, tremors, salivation, twitching) seen on day 1 o f dosing in both sexes at LOAEL = 90 mg/kg/day . **Comments about Study/Endpoint/Uncertainty Factors:** The study is appropriate for the short term assessment since the signs of neurotoxicity were observed on the first day o f dosing and throughout the first week of exposure . The dog is the most sensitive species for the neurotoxic effects observed, and neurotoxicity i s the most sensitive endpoint in the toxicity d atabase. The dose and endpoint are protective of effects observed in postnatal animals (population of concern) in the reproduction toxicity study (decreased pup body

weight/gain). Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability). **A.3.4 Incidental Oral Exposure (Intermediate**  **- Term)**  **Study Selected:** Chronic oral toxicity study - dog **MRID No.:** 46378401 **Executive Summary :**  See Appendix A, Guideline [§ 870.3100] **Dose and Endpoint for Risk Assessment:**  NOAEL=10 mg/kg/day b ased on death and atroph y of the testes and prostate seen on at LOAEL = 30 mg/kg/day . **Comments about Study/Endpoint/Uncertainty Factors:** The selected endpoint provides the most sensitive NOAELavailable from a study of appropriate duration and exposure (oral). Atrophy of the testes and prostate were observed in the dog subchronic oral toxicity study also at a dose of 60 mg/kg/day

(NOAEL = 20 mg/kg/day). Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability). **A.3.5 Dermal Exposure (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 observe d, the target organs [liver and testes] were evaluated, and there is no reproductive toxicity concern. Since n o hazard was identified , no risk from dermal exposure is expected . **A.3.6 Inhalation Exposure (Short**  **- Term)**  **Study Selected:** Chronic oral toxicity study - dogMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 45 of 61 **MRID No.:** 46378401 **Executive Summary :**  See Appendix A, Guideline [§ 870.3100] **Dose and**  **Endpoint for**  **Risk Assessment:**  NOAEL=3 0 mg/kg/day b ased on clinical signs (ataxia, tremors, salivation, twitching) seen on day 1 of dosing in both sexes at LOAEL = 90 mg/kg/day . **Comments about Study/Endpoint/Uncertainty Factors:** The study is appropriate for the short term assessment since the signs of neurotoxicity w ere observed on the first day o f dosing and throughout the first we ek of exposure. The dog is the most sensitive species for the neurotoxic effects observed, and neurotoxicity i s the most sensitive endpoint in the toxicity d atabase. The dose and endpoint are protective of effects observed in postnatal animals (population of concern) in the reproduction toxicity study (decreased pup body

weight/gain). Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability). **A.3.7 Inhalation Exposure (** **Intermediate -**  **and Long -**  **Term) Study Selected:**  Chronic oral toxicity study - dog **MRID No.:** 46378401 **Executive Summary :**  See Appendix A, Guideline [§ 870.3100] **Dose and Endpoint for Risk Assessment:**  NOAEL=10 mg/kg/day b ased on death and atrophy of the testes and prostate seen on at LOAEL = 30 mg/kg/day . **Comm ents about Study/Endpoint/Uncertainty Factors:**  The selected endpoint provides the most sensitive NOAELavailable from a study of appropriate duration and exposure (oral). Atrophy of the testes and prostate were observed in the dog subchronic oral toxicity study also at a dose of 60 mg/kg/day

(NOAEL = 20 mg/kg/day). Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability). **A.4 Executive Summaries**  **A.4.1 Subchronic Toxicity**  **870.3100 90**  **- Day Oral Toxicity**  **- Rat**  In a subchronic oral toxicity s tudy ( MRID 44237704), metaldehyde (99.0% a.i.) was fed to 10 Sprague - Dawley

CD rats/sex/dose at dietary c oncentrations of 0, 2,500, 5,000, 10,000, or 20,000 ppm (equivalent to approximately 0, 200, 400, 800, or 1550 mg/kg/day) for 28 consecutive day s. The study w as to be used as a range - finding study f or a chronic oncogenicity and a 2 - generation study that were scheduled to be conducted. Mortality , either as spontaneous death or moribund sacrifice, occurred in 6/10 10,000 - ppm fem ales and 10/10 20,000 - ppm females, and in 4/10 20,000 - ppm males. In decedent animals, hind limb paral ys is was the predominant effect observed prior to death, although tonic convulsions, excessive vocalization, gasping, and hy peractivity

w ere also observed in one high dose female. In creases (  10 - 28%) in blood urea nitrogen concentrations in all treated females were observed, with significance (p<0.05 or 0.01) at the 2,500 - and 10,000 - ppm levels. Slight decreases (6 - 8%, p<0.05) in ery

throcy tes were observ ed in the  10,000 - ppm males.Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 46 of 61 Treatment - related increases (p< 0.01) in absolute (up to 67%) and relative (up to 69%) liver weights were observed in both sexes and all test groups. F urthermore, histopathological examination revealed hepatocellular hypertroph y in both sexes at all test levels. Findings upon gross n ecropsy w ere limited to animals that died or were sacrificed during the study and included fracture/luxation of the vertebra, hemorrhage of the spinal cord, abnormal coloration of various organs, hydronephrosis and/or hemorrhage of the kidney s, and dilatation/distention and/or hemorrhage of the urinary b ladder. The urinary

tract abnormalities were presumably

s econdary

t o urine stasis resulting from paral ys is. S imilarly, microscopic examination revealed luxation of the vertebra; hemorrhaging of the vertebra and spinal cord; spinal cord compression, vacuolization, and malacia; hydronephrosis; and general congestion and/or hemorrhaging of various organs, including the thy mic region, lungs, kidney s, and urinary bladder. **The systemic**  **LOAEL is**  **2,500 ppm**  **(equi valent**  **to approximately**  **200 mg/kg/day)**  **based on**  **increased absolute**  **and relative**  **liver weights**  **in all**  **dose groups**  **and hepatocellular**  **hypertrophy at all dose levels in both sexes. The systemic NOAEL was not established.** This 28 - day

o ral (dietary) study

i s classified **acceptable (Non**  **Guideline)** as it is not a required guideline study . It is acceptable for the purposes for which it was intended [range - finding study]. **870.3150 90**  **- Day Oral Toxicity**  **- Dog**  In a 26 - week oral toxicity study (MRID 00131432) ; beagle dogs were administered 0, 20, 60 or 90 mg/kg/day m etaldeh yde in the diet. All animals survived the 26 - week period and no clinical signs of toxicity

were observed. No effects were observed for food consumption, body weight, drinking water intake, he matology , clinical chemistry , ophthalmology , or organ weights. Diffuse or focal atroph y of the prostate and testes were observed in the 60 and 90 mg/kg/day groups. There were increases in follicular hy perplasia of the mesenteric ly mph node in the 90 mg/kg/ day group. Animals in the 90 mg/kg/group had slight increases in periportal infiltration of ly mphocy tes, histiocy

tes and eosinophilic granulocy tes in the liver and very

slight hydropic swelling in focal areas of the liver , which are probably of no toxicolo gical significance. The NOEL/LEL were determined to be 20 mg/kg/day / 60 mg/kg/day , based on diffuse or focal atrophy of the testes and prostate. The study is core - minimum and satisfies the requirements for a Guideline Series 83 - 1(b) chronic toxicity study in dogs. **870.3200 21/28**  **- Day Dermal Toxicity** 
**– Rat**  In a 21 - day

dermal toxicity

study ( MRID 42063401 ) , 5 New Zealand White rabbits/sex/group were administered metaldehyde [99.0%] via dermal application [dry powder covered with a gauze patch moistened with Milli - Q® filtered water; once a day for 6 hours, 5 days/week] for 22 day s at concentrations of 0, 100, 300, and 1000 mg/kg/day . Treatment had no adverse effect on survival, clinical signs, mean body weight, body- weight gain, food consumption, hematology , clinical chemistry , organ weights, or gross and microscopicMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 47 of 61 pathology . There was no dose - related increase in the incidence or severity of signs of dermal toxicity . **The NOAEL for sys temic and dermal toxicity is 1000 mg/kg/day, the highest dose tested**  This guideline 21 - day

dermal toxicity

study is classified ACCEPTABLE, and it satisfies the guideline requirement [§82 - 2; 870.3200] for a 21 - day dermal toxicity

study. Although fewer rabbits/sex/group were utilized than specified in the Guideline, this does not by itself diminish the finding of no effect at the limit dose. **870.3465 90**  **- Day Inhalation** 
**– Rat**  Study waived by

HASPOC (TXR# 0056524, dated 2/21/13) **A.4.2 Prenatal De** **velopmental Toxicity 870.3700a Prenatal Developmental Toxicity Study**  **- Rat**  In a developmental toxicity study [MRID 41656001], female Sprague - Dawley Crl:CD(SD)BR rats [25/group] were administered metaldehyde [99%] via gavage at dose levels of 0 [Mazola® c orn oil], 25 mg/kg/day , 75 mg/kg/day , and 150 mg/kg/day from gestation day

6 through gestation day

15. There were six deaths [all pregnant; high - dose level only], which occurred between gestation day s 7 and 8. Clinical signs attributed to treatment were observed at the high - dose level in those dams that died and included ataxia [all six], rapid respiration [5 dams], twitching [4 dams], tremors [3 dams], prostration [1 dam], abdominal breathing [1 dam], hy peractivity

[1 dam], paresis of the hind legs [1 dam], pallor [2 dams], perioral encrustation [3 dams], and perinasal encrustation [2 dams]. Decreased body weight [96% of control] was observed at the high - dose level only on gestation day

[GD] 9. Body- weight gain was significantl y decreased [74% of control] initially

[GD 6 - 9] and throughout the dosing period at the high - dose level. Although dams at the mid - do se level displayed onl y a slightly lower body- weight gain during the dosing period [91% of control] compared to the control, based on their pre - dose body- weight gain [115% of control], the decrease is considered treatment - related. A compensatory weight gai n was noted during the post - dosing period at the high - dose level. Corrected body- weight gain at the high - dose level was slightly [94% of control] lower than the control value. Food consumption was decreased at the high - dose level during the dosing period and increased significantl y during the post - dosing period at the mid - and high - dose levels. Treatment - related necropsy findings in the dams dyingon test included thinning of the stomach wall [1 dam], ulceration of the glandular [2 dams] and nonglandular [2 dams] portion of the stomach, red/brown lungs [6 dams], dilated renal pelvis [2 dams], and hydronephrosis [1 dam]. Additionally , perioral encrustation [6 dams], perinasal encrustation [5 dams], and paravertebral hemorrhage [1 dam] were observed in thos e dyi ng on test. There were no adverse effects observed on maternal liver weight or gravid uterine weight. There were no abortions, and the pregnancy rate was comparable among the groups. The numbers of corpora lutea, implantation, live fetuses, and reso rptions [both total and per dam], asMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 48 of 6 1 well as pre - and post - implantation losses were comparable among the groups. There was one dead fetus [high dose]. Fetal body weights and the sex ratio were comparable among the groups. There were no statistically- signif icant or dose - related differences in the incidence of fetal malformations or variations [external, visceral, and skeletal]. **The maternal toxicity NOAEL is 75 mg/kg/day, and the maternal toxicity LOAEL is 150 mg/kg/**  **day , based on mortality, clinical signs o**  **f toxicity [ataxia, tremors, twitching, rapid respiration], decreased body**  **- weight gain during dosing, and decreased food consumption**  **during dosing. The NOAEL for developmental toxicity is 150 mg/kg/day, the highest dose tested.**  This guideline developmental toxicity study is classified Acceptable, and it satisfies the guideline [OPPTS 870.3700; §83 - 3(a)] for a developmental toxicity study in the rodent. **870.3700b Prenatal Developmental Toxicity Study -**  **Rabbit** In a developmental toxicity study [MRID 41 590501], female New Zealand white rabbits [16/group] were administered metaldehyde [99%] via gavage at dose levels of 0 [Mazola® corn oil], 10 mg/kg/day , 40 mg/kg/day , and 80 mg/kg/day from gestation day

6 through gestation day 18. There were no treatment - related deaths or clinical signs of toxicity . Body- weight gains were extremely variable, and there was no dose - response. All groups, including the control, displayed negative corrected body- weight gains but there was no dose - response. Food consumption w as decreased at all dose levels during the dosing period compared to the control, but there was no dose - response. Necrops y findings were comparable among the groups. There were no adverse effects observed on maternal liver weight or gravid uterine weight. There were no abortions, and the pregnancy rate was not adversel y affected by treatment. The numbers of corpora lutea, implantation, live fetuses, resorptions [both total and per dam], and dead fetuses, as well as pre - and post - implantation losses were c omparable among the groups. Fetal body weights and the sex ratio were comparable among the groups. There were no statistically- significant or dose - related differences in the incidence of external or visceral malformations, but a slightly higher incidence o f skeletal malformations [5 fetuses in 3 litters] was observed at the high - dose level compared to the control and lower dose groups [1 fetus/group]. This latter finding is considered attributable to the greater number of fetus examined at the high - dose lev el [140 fetuses in 16 litters] compared to the other groups [112 fetuses/12 litters; 104 fetuses/13 litters; and 107 fetuses/13 litters in the control, low - and mid dose groups, respectivel y]. External, visceral, and skeletal variations were comparable amo ng the groups. The maternal toxicity

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

is 80 mg/kg/day , the highest dose tested.Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 49 of 61 This guideline developmental toxicity study is classified Acceptable, and it satisfies the guideline [OPPTS 870.3700; §83 - 3(b)] for a developmental toxicity study in the rodent. NOTE: Although no maternal or developmental effects were observed, the dose levels are considered adequate based on effects observed in the range - finding study . All does [5/group] in the 200, 350 and 500 mg/kg/day

groups died [following 1 or 2 doses] or were sacrificed moribund [gestation day s 8 - 12], and one doe at 100 mg/kg/day died. A repeat study

at higher dose levels would not provide useful data. This is supporte d by the results in the rat. The maternal NOAEL in the rat developmental toxicity

study is 75 mg/kg/day , based on mortality , clinical signs of toxicity [ataxia, tremors, twitching, rapid respiration], decreased body- weight gain during dosing, and decreased food consumption during dosing at the LOAEL of 150 mg/kg/day . The NOAEL for developmental toxicity

is 150 mg/kg/day , the highest dose tested. **A.4.3 Reproductive Toxicity**  **870.3800 Reproduction and Fertility Effects -**  **Rat** In a 2 - generation reproduction s tudy [MRID 42823101], 28 male/28 female F0 CD ® rats/sex/group were administered metaldehyd e [>99% a.i.] via the diet for 10 weeks prior to mating and through gestation and lactation of one litter at dose levels of 0 ppm, 50 ppm, 1000 ppm, and 2000 ppm [F0 males: 0, 3.4, 69.37, and 138.36mg/kg/day ; F0 females: 0, 4.16, 80.81, and 160.42 mg/kg/day ; F1 males: 0, 3.23, 64.93, and 133.53 mg/kg/day ; F1 females: 0, 4.03, 80.51, and 164.15 mg/kg/day]. Rats were mated, one male with one female. The resulting F1 litt ers were weaned at day 28 post partum . The F1 generation [28 rats/sex/group] was administered the test material at the same dose levels as F0 animals and mated in a similar manner, avoiding sibling matings. The resulting F2 litters were weaned at day 28 post partum . No treatment - related clinical signs of toxicity or mortality

were observed in F0 males at any time point or in F0 females during the pre - mating and mating periods or during gestation. However, at 2000 ppm, three F0 dams were sacrificed moribund during the lactation period [lactation day s 16 - 18; days 110, 110, 113 on test] due to bilateral hindlimb paraly sis. No treatment - related clinical signs of toxicity

or mortality

were observed in F1 males at any time point or in F1 females during the pre - mating and mating periods. However, during gestation/lactation, three F1 dams [2000 ppm] were found dead [days 95, 101, and 125]. The 2000 ppm F1 dam that was found dead on day

95 displayed ataxia, labored breathing, cold extremities, and pallor on day 94. An additional 2000 ppm F1 female [nongravid] displayed prostration, tremors, abdominal breathing, and rapid respiration on day 102 but survived until terminal sacrifice [day 134]. The author stated that the relationship of these latter signs to treatment w as unclear. The cause of death of two of the F1 females was not determined [third female due to septic emboli to various organs]. None of the other deaths [ F0 male and 2 F0 females at 50 ppm, 2 F1 females at 50 ppm, and one F1 male at 1000 ppm] was consid ered treatment - related. No additional treatment - related clinical signs were noted. **F0 parental animals** Body weights for the treatment groups were similar to control throughout the study for both sexes. During the pre - mating dosing period, there were no c onsistent adverse effects on body- weight gain in either sex. Body- weight gains of the F0 high - dose males were decreased initially

[weeks 0 - 1 (91% of control)] and during weeks 5 - 6 (89% of control) and weeks 8 - 9 (75% of control). During weeks 2 - 3, there was an apparent dose - related increase inMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 50 of 61 body- weight gain in males at the mid - (112% of control) and high - dose (114% of control) levels. F0 females displayed a decrease in body- weight gain [66% of control] during weeks 2 - 3 at the high - dose level, although st atistical significance was not attained, and the standard deviation exceeded the group mean. Food consumption was not affected in either sex. There were no consistent, treatment - related, adverse effects on body weights or body- weight gains of the F1 parental animals during the pre - mating dosing period, although both sexes at the high dose displayed a smaller body- weight gain during weeks 9 - 10 [males 83%; females 65% of control] than control. Food consumption was comparable among the groups [both sexes] throughout the study. At sacrifice, necrosis and hemorrhage in the spinal cord and vertebra luxation were observed in the three high - dose F0 dams that displayed hindlimb paral ys is. An additional F0 dam at 2000 ppm displayed spinal cord lesions microscopically . At necrops y, no treatment - related adverse effects were observed in F1 animals at any dose level. At 2000 ppm, F1 males displayed increased relative liver weights [15%] and F1 females displayed increased absolute [12%] and relative [11%] liver weights. These organ - weight changes were not accompanied b y histopathological lesions and may be attributed to adaptation to the test material. NOTE: Liver weights were not determined for F0 animals. **F0 Generation.** No apparent adverse effect was observed on fertility , and the mating and gestation indices were comparable among the groups. Pre - coital intervals were not reported. The duration of gestation was comparable among the groups. The number of live pups was comparable among the groups. The number of p ups born dead/dying by day 1 was not affected by treatment. Litter size was slightl y lower at the high - dose level [Day 0 (13.6), Day

4 precull (13.3), Day

21 (7.5)] compared to the control [Day 0 (13.7), Day

4 precull (13.5), Day

21 (7.8)] and other dose groups [Day 0 (14.0 and 13.8), Day 4 precull (13.7 and 13.8), Day 21 (7.7 and 7.9) for low - and mid - dose groups, respectivel y] throughout the weaning period. The live birth index and the viability

index were comparable among the groups, but the lactation in dex was slightly lowered [89%] at the high - dose level compared to the control [99%] and other dose groups [99%]. At the high - dose level, a slightly lower pup body

weight was observed on lactation day s 7 [males 96%/females 95% of control] and 21 [95% of co ntrol], although statistical significance was not attained for either timepoint. Body- weight gains were slightly lower for both sexes at the high - dose level [94% - 95% of control] compared to the control throughout lactation. The sex ratio was comparable amo ng the groups. **F1 Generation.** No apparent, treatment - related, adverse effect was observed on fertility , and the mating and gestation indices were comparable among the groups. Pre - coital intervals were not reported. The duration of gestation was comparable among the groups. The high - dose group had the fewest females [22] with live born pups [27 control and 23 each at the low - and mid - dose levels]. The number of live pups was comparable among the groups. The number of pups born dead/dyi ng by day 1 was not af

fected by treatment. Litter size was comparable among the groups, and the live birth index, viability

index, and the lactation index were comparable among the groups. At the high - dose level, a slightly lower pup body

weight was observed on lactation day s 1 [males 93%/females 93% of control], 7 [females 95% of control], and 21 [males 93%/females 92% ofMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 51 of 61 control], although statistical significance was attained only at the day

21 time point. Body- weight gains were slightly

lower for both sexes at the high - dose level [91% - 93% of control] compared to the control throughout lactation. The sex ratio was comparable among the groups. **The NOAEL for parental toxicity is 1000 ppm [males 65 mg/kg/day; females 81 mg/kg/day) and the parental LOAEL is 2000 ppm [males 133**  **mg/kg/day; females 160 mg/kg/day], based on mortality (F0 and F1 females), clinical signs (hindlimb paralysis in F0 females),**  **and histopathology (spinal cord necrosis and hemorrhage, and vertebra luxation in F0 females and increased liver weight in both se**  **xes [F1]. The NOAEL for reproductive toxicity is 2000 ppm [males 133 mg/kg/day; females 160**  **mg/kg/day], the highest dose tested. The NOAEL for offspring toxicity is 1000 ppm [males 65 mg/kg/day; females 81**  **mg/kg/day) and the LOAEL for offspring toxicity is 2000 ppm [males 133 mg/kg/day;**  **females 160 mg/kg/day], based on decreased pup body weight/body -** **weight gain [F1 and F2 pups].**  This 2 - generation reproduction study is classified Acceptable/Guideline. This study satisfies the guideline requirement (OPPTS 870.3800; §83 - 4) for a 2 - generation reproduction study . The original DER set the reproductive toxicity L OEL at 2000 ppm, based on decreased pup body weight and weight gain in both sexes, which is not a reproductive toxicity endpoint but an offspring endpo int. Reproductive toxicity was not observed in this study , based on the parameters examined. It is to be noted that several parameters in the current protocol that measure reproductive effects, such as age of vaginal opening and preputial separation; anog enital distance for F2 pups; implantations sites; estrous cycle length and periodicity (F1 weanlings); and sperm measures, were not evaluated. These are included in the new protocol, which was not in effect at the time of the study . **A.4.4 Chronic Toxicit** **y 870.4100a (870.4300) Chronic Toxicity** 
**– Rat**  See below under 870.4200 **870.4100b Chronic Toxicity -**  **Dog** In a chronic oral toxicity

study (MRID 46378401), metaldehyde (98.3% a.i.; batch # 30202) was administered once daily

for 52 consecutive weeks to groups of 4 male and 4 female Beagle dogs at dose levels of 10, 30, and 90 mg/kg/day . The amount of test material given was adjusted to each dog’s actual body weight weekl y. There were three deaths [one each sex at 30 mg/kg/day and one female at 90 mg/kg/ day], which occurred between weeks 37 and 46. Treatment - related clinical signs were observed from week one on at the high dose and included ataxia, emesis, tremor, twitching, and salivation. The incidence and severity

of these clinical signs lessened with time from week 19, although 1 or 2 animals continued to display salivation throughout the study . One high - dose female displayed lateral position earl y in the study , reduced motility during most of the study , and convulsion andMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 52 of 61 vocalization during week 46. Agitation was displayed b y one high - dose female during weeks 6 - 9 and 24 - 52. Body weight was slightl y lower in the treated dogs [males ↓7% - 17% ; females ↓6% - 19% ] throughout most of the study , although a dose - response was not alway s evident. At study termination, male body

weights were ↓16 %, ↓12 %, and ↓17 % and female body weights were ↓4 %, ↓1 0%, and ↓ 1 9 % with increasing dose. During the first week on test, males displayed decreased body- weight gains at all dose levels, although the decrease was inversel y relat ed to dose [ ↓53 %, ↓34 %, and ↓26 % with increasing dose]. Only the mid - dose females displayed a decrease in body- weight gain initially [ ↓ 6 4 %]. During the 0 - 13 week interval, males at all dose levels [ ↓2 5%, ↓17 %, and ↓43 % with increasing dose] and females at the mid - [63%] and high - [79%] dose levels displayed decreased body- weight gains compared to the controls. Food consumption was not adversel y affected. Food efficiency values were not provided. No lesions of the eyes or optic region were found, and there were no differences in the urinal ys is parameters monitored in either sex. During the 13 - week assessment, one high - dose dog of each sex did not react to the noise test, but no effects were noted in either sex at the 26 - and 52 - week assessments. Increases in hemoglobin, RBC, and hematocrit were observed in both sexes at the high - dose level at week 13, but only in females at week 26. Alkaline phosphatase was increased throughout the study in both sexes at the high - dose level, with the magnitude of the respon se from control increasing with time [both sexes]. High - dose females displayed an increase in gamma - GT throughout the study , but other liver enzy me activities [AST, ALT] were not affected by treatment. Trigl ycerides were increased in the high - dose females throughout the study compared to the control values. At the high - dose level in both sexes, liver weight was increased significantly compared to the control values. There was a dose - related decrease in absolute prostate weight [ ↓1 8%, ↓29 %, and ↓32 % with i ncreasing dose], a decrease in testes weight at the low - and high - dose level, and an increase in absolute and relative lung weight in high - dose males. Increased brain weight ( ↑ 5 %) was observed in females at the high - dose level compared to the control. There were no apparent microscopic lesions in the liver, but atrophy and/or degeneration was observed in the testes and prostate. **The lowest -**  **observed -**  **adverse -**  **effect level (LOAEL) for metaldehyde in the dog is 30 mg/kg/day, based on death and atrophy of the te**  **stes and prostate. The NOAEL is 10 mg/kg/day.**  **The LOAEL for clinical signs of neurotoxicity is 90 mg/kg/day, based on ataxia, emesis,**  **tremor, twitching, and salivation that occurred in all dogs of both sexes during days 1 -**  **7. The NOAEL for clinical signs o**  **f neurotoxicity is 30 mg/kg/day.** This chronic oral toxicity study in the dog is **Acceptable/Guideline** , and it satisfies the guideline requirement for a chronic oral toxicity study [OPPTS 870.4100); OECD 452] in the dog. **A.4.5 Carcinogenicity**  **870.4200a Carcinogenicity Study**  **- rat** Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 53 of 61 In a chronic toxicity

/carcinogenicity study [MRID 42203601], 60 Sprague - Dawley CD® rats/sex/dose were administered metaldehyd e [99 %] via the diet at concentrations of 0 ppm and 0 ppm (2 control groups), 50 ppm [males 2 mg/kg/day; females 3 mg/kg/day], 1000 ppm [males 44 mg/kg/day ; females 60 mg/kg/day], 5000 ppm [males 224 mg/kg/day ; females 314 mg/kg/day] for 104 weeks. There was no adverse effect of treatment on survival of either sex, although females at the mid- [60%] and h igh - [58%] dose levels displayed a slightl y greater mortality than the control groups [50% and 48%]. There were no apparent treatment - related clinical signs of toxicity . There was a slight reduction in body weight [ ↓ 5%] throughout most of the study in both sexes at the high dose level compared to the control groups. During the first week, females in all treated groups displayed a dose - related [statistically- significant at all dose levels] decrease in body- weight gain compared to the 2 control groups [86%/94 %, 69%/75%, and 60%/66% of control with increasing dose]. During the same time - frame, males displayed a similar dose - related decrease in bodyweight gain, which was statistically significant at the mid - [87% of control] and high - [78% of control] dose lev el compared to one of the control groups. Food consumption was decreased at the high - dose level in both sexes during the first few weeks of the study , which suggests a palatability

problem. There were no apparent, treatment - related, effects on the ophthalmological or hematological parameters monitored in either sex. Mid - and high - dose females displayed a statisticallysignificant, dose - related, increase in cholesterol levels throughout most of the study . Globulin values were elevated in the high - dose females throughout most of the study [weeks 26, 52, and 78] and in mid - dose females only at week 78. There were no treatment - related alterations in the liver enzy mes monitored. There was a dose - related increase in urine volume in females [37%, 40%, and 54% with increasing dose] at week 77 only . In creased liver weight [males ↑ 11% - 18%; females ↑ 21% - 32%] was observed in both sexes at the high - dose level, although the values in males did not attain statistical significance. Females at all dose levels displayed an increase in ovarian weight, but there was no dose - response, and the standard deviation of the low - and high - dose female groups exceeded the means. In the liver, there was a dose - related increase in hepatocellular hypertroph y in both sexes, which was statistically- significant at the mid - dose level in males and at the high - dose level in both sexes. There was a statistically- significant increase in hepatocellular adenomas in high - dose females [10%] compared to the control and other dose groups. The majority of the liver adenomas were observed at the terminal sacrifice, and the incidence is within the historical control incidence of the testing facility [0% - 10%]. One hepatocellular carcinoma was observed in one of the control groups and in one high - dose female . The combined incidence [adenomas and carcinomas] of liver tumors in the high - dose females [11.7%] is slightly outside the historical control incidence of the testing facility [0% - 10%]. Males did not display an increase in liver tumors. **The systemic tox icity NOAEL is 50 ppm [males 2 mg/kg/day; females 3 mg/kg/day], based**  **on hepatocellular hypertrophy and increased cholesterol in both sexes and decreased body -** Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 54 of 61 **weight gain in females at the systemic LOAEL of 1000 ppm [males 44 mg/kg/day; females 60 mg/kg/da** **y].** This guideline chronic toxicity /carcinogenicity study

is classified ACCEPTABLE, and it satisfies the guideline [OPPTS 870.4300; §83 - 5] for a chronic toxicity / carcinogenicity

study in the rat. **870.4200b Carcinogenicity (feeding) -**  **Mouse** In a carcinogenicity

study [MRID 42737201], 60 CD - 1 mice/sex/dose were administered metaldehyde [>99%; Lot # 5448] via the diet at concentrations of 0 ppm [2 control groups], 25 ppm [males 4.0 mg/kg/day ; females 4.8 mg/kg/day], 100 ppm [males 15.9 mg/kg/d ay ; females 19.7 mg/kg/day], and 300 ppm [males 48.9 mg/kg/day ; females 59.8 mg/kg/day] for 18 months. There were no treatment - related effects on survival or clinical signs in either sex, and body weights, body- weight gains, and food consumption were comp arable among the groups for both sexes. The hematologic parameters monitored were comparable among the groups [both sexes]. Clinical chemistry

and urinaly sis parameters were not monitored. At necrops y, there were no gross lesions attributed to treatment in either sex. With the exception of liver weights in males, which displayed a dose - related increase (although statistical significance was not attained), organ weights were comparable among the groups [both sexes]. Non - neoplastic lesions: The incidence [overall: high - dose males 62% vs 30% - 33% control; high dose females: 30% vs 7% - 15% control] and severity of hepatocellular hy

pertrophy were increased in both sexes at the high - dose level compared to the control groups. The majority of the mice with hepato cellular hy pertrophy were diagnosed at terminal sacrifice. Neoplastic lesions : There was no statistically- significant increase in the incidence of liver tumors in either sex, although the high - dose males displayed a slight increase [15 adenomas and 3 carc inomas] compared to both control groups [8 adenomas/1 carcinoma and 8 adenomas/3carcinomas]. The sy stemic toxicity

NOAEL is 100 ppm [15.9 mg/kg/day (males); 19.7 mg/kg/day (females)], based on a significantl y i ncreased incidence of hepatocellular hypertro phy in both sexes at the LOAEL of 300 ppm [48.9 mg/kg/day (males); 59.8 mg/kg/day (females)]. **No other toxicological effects were observed in either sex. The incidence of tumors was comparable**  **among the groups [both sexes].** This guideline carcinogenicity study is classified ACCEPTABLE/Guideline. However, the dose levels were not considered adequate for assessing the carcinogenic potential of metaldehyde, and a supplementary

study was performed [MRID 44625101; separate DER]. In the 90 - day mouse study [not s ubmitted to the Agency] performed to determine dose levels to be used in the current study , mortality

was said to have been observed at 3000 ppm and 10000 ppm and dose - related increases in liver weight and hepatic lesions were reported in both sexes at ≥ 30 0 ppm. TheMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 55 of 61 supplemental carcinogenicity study [MRID 44625101] was performed using one dose level of metaldehyde [1000 ppm]. At 1000 ppm, there was a treatment - related increase in the incidence of hepatocellular adenomas in both sexes when compared to controls. Dosing was considered adequate based on the increased incidence of liver lesions [liver single cell/focal/multifocal necrosis (males) and hepatocellular eosinophilic cell foci (females)] in both sexes, in addition to hepatocellular h yp ertrophy (both s exes ), which was the only treatment - related finding in the current study at 300 ppm. When all the information, including the 90 - day study (MRID 43297701), are considered together, MRID 42737201 and MRID 44625101 satisfy the guideline requirement [OPPTS 870 .4200; §83 - 2] for a carcinogenicity study in the mouse. In a carcinogenicity

study [MRID 44625101], metaldehyde was administered to 60 Crl:CD - 1® - (I CR)BR mice/sex/dose via the diet at dose levels of 0, 0, and 1000 ppm [equivalent to 0, 0, 135 mg/kg bw/day (males)/163 mg/kg bw/day (females)] for at least 78 weeks. There were no compound - related effects on mortality , clinical signs, body weight, food consumption, or hematology in either sex. With the exception of the liver, organ weights were comparable to those of the control groups for both sexes. Liver weights were increased significantl y in both sexes at 1000 ppm compared to both of their respective control groups. Gross and histologic pathology findings were comparable among the groups for both sexes, with the exception of the liver. Hepatocellular hypertrophy was observed in both sexes at 1000 ppm. Males at 1000 ppm displayed single cell necrosis, focal or multifocal necrosis, pigment accumulation, and sinusoidal. Females at 1000 ppm displayed a small increase in the incidence of hepatocellular eosinophilic cell foci. There was a significant increase in the incidence of hepatocellular adenomas in both sexes [males: 4 and 5 vs 14; females: 1 and 0 vs 5], with the males displaying the greater effect. Mal es also displayed a slight increase in hepatocellular carcinomas [2 and 2 vs 4] compared to both control groups. Under the conditions of this study, at the onl y dose of metaldehyd e tested [1000 ppm; 135 (males)/163 (females) mg/kg/day)], increased liver weight (both sexes), hepatocellular hy pertrophy (both sexes), liver single cell/focal/multifocal necrosis (males), liver pigment accumulation (males), sinusoidal histiocy tosis (males), hepatocellular eosinophilic cell foci (females), and hepatocellular adenomas (both sexes) were observed. The NOAEL is not established in the current study . However, based on a previous mouse carcinogenicity study in the same strain of mouse [MRID 42737201], in which an increased incidence of hepatocellular hy pertrophy was obs erved in both sexes at the highest dose tested [300 ppm; 48.9 (males)/59.8 (females) mg/kg/day], the NOAEL is 100 ppm [15.9 (males)/19.7 (females) mg/kg/day], with the LOAEL based on an increased incidence of hepatocellular hypertroph y in both sexes. At the dose tested in the current study, there was a treatment related increase in the incidence of hepatocellular adenomas in both sexes when compared to the controls. Dosing was considered adequate based on the increased incidence of liver lesions [liver si ngle cell/focal/multifocal necrosis (males) and hepatocellular eosinophilic cell foci (females)] in both sexes, in addition to the hepatocellular hypertrophy observed in the previous study at 300 ppm. This carcinogenicity

study in the mouse is Acceptable/non - guideline. It is non - guideline since only one dose level was tested. The study was performed as a supplement to a previous 18 -Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 56 of 61 month mouse carcinogenicity study [MRID 42737201] and should be considered along with the previous study . Together, the two studies satisfy the guideline requirement for a carcinogenicity study [OPPTS 870.4200; OECD 451] in mice. **A.4.6 Mutagenicity**  **Gene Mutation** Guideline 870.5100 , r everse gene mutation assay in bacteria MRID 48666101 (2011) C lassification : acceptable/guideline Salmonella typhimurium strains TA98, TA100, TA102, TA1535, and TA 1537; concentrations of 0, 3, 10, 33, 100, 333, 1000, 2500, or 5000 μg/plate (+/ - S9 - activation); insoluble at ≥2500 μg/plate +/ - S9. N o evidence of induced mutant colonies over background. **Cytogenetics** Guideline 870.5300 , in vitro mutagenicity (mammalian forward gene mutation) MRID 48721401 ( 2011) C lassification : acceptable/guideline T ested up to solubility limit ( ≥ 600 μg/mL +/ - S9) ; failed to induce either a cytotoxic or a mutagenic effect. There was no evidence of induced mutant colonies over background.

Guideline 870.5385 , in v iv o cy togenetic mutagenicity assay MRID 48788201 ( 2012) Classification : acceptable/guideline in vivo rat bone marrow chromosome aberration test at doses of 0, 62.5, 125, and 250 mg/kg (M) or 0, 31.25, 62.5, and 125 mg/kg (F) ; no evidence of cytogenicity in this whole animal chromosome aberration assay. **Other Genotoxicity** Guideline 870.5395 , micronucleus assay MRID 42044006 (1990) C lassification ; Unacceptable/guideline highest dose tested (100 mg/kg); MTD not reached

**A.4.7 Neurotoxicity**  **870.6200 Acute Neurotoxicity Screening Battery** Study was w aived by

HASPOC ( TXR# 0056524 ; dated 2/21/13 ) . **870.6200 Subchronic Neurotoxicity Screening Battery** In a subchronic neurotoxicity s tudy ( MRID 46223401), metaldehyde (98.3% a.i., batch # 31509) was administered via the diet to 10 Sprague - Dawley C rl:CD® (SD) IG S BR rats/sex/group at dose levels of 0 [basal diet], 100, 500, and 2500 ppm (equivalent to 0, 8, 39, 185 mg/kg bw/day) for 90 consecutive day s. Clinical signs, body- weight development, food and water consumption were monitored during the study , and ophthalmoscopic examination of the control and high - dose rats was performed pre - test and during final week of the study . Neurobehavioral assessment (functional observational battery and motor activity

t esting) was performed in all rats/sex/groupMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 57 of 61 prior to the start of dosing and during weeks 2, 4, 8, and 12. At study t ermination, 5 animals/sex/group were euthanized and perfused with gluteraldehyde: paraformaldehyde via the heart, following initial whole - body p erfusion with heparinz ed saline, for neuropathological examination. Of the perfused animals, al l control and high - dose rats were subjected to histopathological evaluation of brain and peripheral nervous system tissues. One high - dose female was sacrificed [day 2 2] due to poor condition [bilateral hindlimb paral ys is], which was observed initially

o n day 10. There were no other treatment - related deaths. Body w eights and body- weight gains of the males were comparable among the groups throughout the study. Females at the mid - and high - dose levels displayed slightl y lower body w eights [ ↓5 % - 6 %] throughout th e study . Body- weight gains of the mid - dose females [80% of control; not statistically

significant] and high - dose females [ ↓3 0%; statistically significant] were lower during the first week and remained lower than control throughout the study , although statistical significance was not attained and a dose - response was not alway s apparent. Food consumption was comparable among the male groups but lower than control in the high - dose females throughout the study . Food efficiency w as comparable among the groups for both sexes. No ocular effects were observed in either sex. Differences in motor activity parameters were observed sporadically , but there was no consistent dose response, some standard deviations were greater than the means, and statistical signifi cance was rarel y attained. Differences in grip strength and startle reflex values were observed sporadicall y also, but there was no consistent dose response and statistical significance was rarel y attained. At termination, no macroscopic abnormalities were reported for either sex. No treatment - related changes were observed in brain weight for either sex, and no treatment - related histopathological alterations were reported in either sex. NOTE: The positive control data [February- April, 2003] bring into qu estion the capability the testing facility

h ad to adequatel y assess neurotoxicity at the time the metaldehyde study w as performed [February- October, 2002]. Additionally , the available positive control data do not provide adequate evidence of the ability o f the testing facility

to identify

a neurotoxic compound. Since the trimethyltin [1 mg/kg] animals did not survive to study t ermination, no FOB assessment was performed on these animals [no motor activity, grip strength, startle reflex]. Neuropathology

w as demonstrated following trimethyltin exposure, however. The onl y neuropathological findings in the acryl amide - treated animals [15 mg/kg] were contraction vacuoles in the sciatic and/or tibial nerves, mainly i n females. No axonal degeneration was observed. Findings in the acrylamide females were not observed in the acrylamide males, and a sex difference following acrylamide exposure is not expected. Individuals performing the various assessment s were not identified in either the metaldehyde study or the posi tive control study , and methodology

and apparatus descriptions are not adequate. Further, a more definitive explanation/presentation of the data, especiall y the motor activity data are required. **Provisionally, the**  **LOAEL for**  **neurotoxicity can**  **be set**  **at 50**  **0 ppm**  **[39 mg/kg/day],**  **based on**  **increased motor**  **activity in**  **females. The**  **NOAEL can**  **be set**  **at 100**  **ppm [8**  **mg/kg/day]. At**  **the highest**  **dose tested**  **[2500 ppm**  **(185 mg/kg)],**  **bilateral hindlimb**  **paralysis was** Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 58 of 61 **observed in one female, and females displayed decreased b ody**  **- weight gains during the first**  **week of the study.** The study

i s classified as **Unacceptable (guideline)**  , and it does not satisfy the guideline requirement for a subchronic neurotoxicity s tudy i n rats (870.6200b). The study i s classified Unacceptable sinc e the results suggest little neurotoxicity f ollowing exposure to metaldehyde; more importantly , the positive control data submitted do not demonstrate proficiency o f the testing facility

to detect alterations in the neurotoxicity parameters monitored. **A.4 .8**  **Metabolism 870.7485**  **Metabolism -**  **Rat** In a metabolism study

in rats (MRID 42300901),the absorption, distribution, metabolism and excretion of m etaldeh yde were studied in groups of male and female Sprague - Dawley rats administered a single oral gavage dose of 10 or 100 mg/kg 14C - metaldehyd e or following repeated oral dosing of 10 mg/kg non - labeled m etaldehyde for 14 day s followed by a single dose o f labeled m etaldehyde on day 15. In addition, the pharmacokinetics of m etaldehyde was evaluated in rats receiving a single oral dose of 10 mg/kg labeled m etaldehyde. Metaldeh yde was rapidl y absorbed, distributed, and metabolized in rats for all dosing regimens. The 7 - day

recoveries were >94% for all groups. Most of the radioactivity was recovered in expired air (78 - 98% of administered dose) within 24 hours (48 hours for high - dose females) , the majority of which was reported to be 14 CO 2 . Recovery in urine and feces was low for all dosing groups (2.5 - 5.1 %). Slight sex - , dose - , and regimen - related effects on m etaldehyde excretion were found. The recovery

of administered radioactivity was greater in low - dose animals than in high dose and repeated dose animals. The pharmacokinetics study showed that males reached peak blood levels and excreted radioactivity faster than females. The concentration of total radioactivity

in the blood at peak levels was similar for both sexes, but the concentration of intact m etaldeh yde was >50% higher in females than in males at peak, first and second blood halflives. Recovered radioactivity

in tissues/carcass after 7 day s was similar for all dose groups (7 - 11% of administered dose). High concentrations of radioactivity were recove red in nervous tissue, fat, liver, and reproductive organs. Tissue examination of low - dose animals showed that radioactive residues (percent of administered dose) were highest in the carcass at peak, first and second blood half

- lives. At second blood half - life, percent dose in the liver exceeded that of any other tissue (except carcass) in both males and females. No clinical signs of toxicity were observed. Classified acceptable for a metabolism study under Guideline series 85 - 1. **A.4.9 Immunotoxicity**  **870.7800 Immunotoxicity**  The immunotoxicity

s tudy ( 870.7800) is a data gap and toxicology data requirement for metaldehyde.Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 59 of 61 **A ppendix**  **B. Metabolism Summary Table** 

**Table B.1 -**  **Tabular Summary of Metabolites and Degradates Chemical**  **Name Commodity**  **Percent TRR (PPM) 1**  **Structure Matrices**  **- Major**  **Residue 2**  **(>10%TRR) Matrices**  **-**

**Minor Residue**  **2 (<10%TRR)**  Parent: Metaldeh yde Lettuce 95.3

Sugar beet - root 35 Sugar beet - top 33 Rat * Degradate: Non Extractable Residues Lettuce <5 N/A

Sugar beet - root 43.4 Sugar beet - top 43.2 Rat ND 2.5 - 5.1 CO 2 Rat 78 - 98 Lettuce; 43923301; 13.8 lb ai/A; 10x; single directed application; 28 day s. Sugar beets; 43923302; 13.76 lb ai/A; 10x; single directed application; 48 day s. Rat: 42300901; single gavage dose 10 or 100 mg/kg, repeated dose 10 mg/kg/day for 14 day s, 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) O O O O C H 3 C H 3

C H 3 C H 3Metaldeh yde Human Health Risk Assessment DP No. D404859

Page 60 of 61 **Appendix C. Physical/Chemical Properties** 

**TABLE C.1. Physicochemical Properties of**  **Metaldehyde** Parameter Value Reference Melting point/range 246°C Metaldehyde RED, PC Chapter pH Not applicable due to the low solubility of metaldehyde in water. N/A Density 1.27 g/cm3
Metaldehyde RED, PC Chapter Water solubility (20°C) 0.222 g/L at 20°C Solvent solubility (g/L at 20.3 - 22.4°C) 5.21 x 10 - 2 in hexane 0.53 in toluene 1.56 in tetrahydrofuran 1.73 in methanol Vapor pressure 1 mm Hg at 20°C 6.6 ± 0.3 Pa at 25°C Dissociation constant (pK a) 3.5 Pa (m3 /mol) (Henry’s Law Constant) Octanol/water partition coefficient, Kow 1.33 (log K ow = 0.12) at 20°CMetaldeh yde Human Health Risk Assessment DP No. D404859

Page 61 of 61 **Appendix D. Review of Human Research**  This risk assessment relies in part on data from studies in which adult human subjects were intentionally

exposed to a pesticide or other chemical. These data, which include studies from the PHED 1.1, the AHETF database, and the ARTF database are (1) subject to ethics review pursuant to 40 CFR 26, (2) have received that revi ew, and (3) are compliant with applicable ethics requirements. For certain studies, the ethics review may have included review b y the Human Studies Review Board. Descriptions of data sources, as well as guidance on their use, can be found at the Agency w ebsite 10

.

10 http://www.epa.gov/pesticides/science/handler - exposure - data.html and http://www.epa.gov/pesticides/science/post - app - exposure - data.html