UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
                            WASHINGTON, D.C.  20460
                                                                      OFFICE OF
                                                            CHEMICAL SAFETY AND
\* MERGEFORMAT
                                                           POLLUTION PREVENTION

MEMORANDUM

Date: June 20, 2013

SUBJECT:	Metaldehyde; Human Health Risk Assessment for Proposed Uses on Grass Grown for Seed, Leaf Petioles [Crop Subgroup 4B], Wetland Taro, Field & Sweet Corn, Mint, and Soybeans, and for Amendments to Existing Tolerances [Crop Subgroups 13-07A, B, & G].

PC Code: 053001
DP Barcode:  D404859
Decision No.: 468286
Registration No.: 61096-13
Petition No.: 2E8070
Regulatory Action: Section 3
Risk Assessment Type:  Single Chemical Aggregate
Case No.:  NA
TXR No.:  NA
CAS No.:  108-62-3
MRID No.:  NA
40 CFR:  180.523

FROM:	Matthew Lloyd, 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 assessments by Matt Lloyd (RABVII); the residue chemistry and dietary exposure assessment by William Donovan (RABV); the hazard characterization and endpoint selection by Linda Taylor (RABVII).
1.0	Executive Summary	4
2.0	HED Recommendations	6
2.1	Data 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	Physical/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/Degradate 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	Residential (Non-Occupational) Exposure/Risk Characterization	22
6.1	Residential Handler Exposure	23
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
Appendix B. Metabolism Summary Table	59
Appendix C.  Physical/Chemical Properties	60
Appendix D.  Review of Human Research	61

1.0	Executive Summary

Background:

Metaldehyde [2,4,6,8-tetramethyl-1,3,5,7-tetraoxyacyclooctane] is used to control slugs and snails on a wide variety of tree, fruit and vegetable crops.  Metaldehyde is formulated as granules (G), pelleted (P/T) baits, emulsifiable concentrate (EC), flowable concentrate (FlC), and ready-to-use liquid (RTU/L) formulations.  Formulated products generally contain 0.13-25% active ingredient.

The Registration Division (RD) of OPP has requested that HED evaluate hazard and exposure data and conduct dietary, occupational, residential, and aggregate exposure assessments, as needed, to estimate the risk to human health that will result from the proposed Section 3 registration uses of the active ingredient (ai), metaldehyde, for proposed uses on grass grown for seed, leaf petioles [Crop Subgroup 4B], wetland taro, field & sweet corn, mint, and soybeans, and for amendments to existing tolerances [crop subgroups  13-07A, B, & G].

Besides this risk assessment, the most recent human-health risk assessment for metaldehyde was the risk assessment to support metaldehyde reregistration completed in April, 2006 (M. Lloyd, et al.; D327385).

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

Developmental toxicity was not observed in the rat or rabbit developmental toxicity studies, and maternal toxicity was not observed in the rabbit. In the rat, maternal toxicity was observed, as evidenced by clinical signs (ataxia, tremors, and twitching) at the highest dose tested.  In the rat reproductive toxicity study, mortality and clinical signs (limb paralysis, spinal cord necrosis and hemorrhage) were observed in the maternal animals, and the effects on the 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 will adequately account for all chronic toxicity, including carcinogenicity, that could result from exposure to metaldehyde.

The carcinogenicity of metaldehyde has been evaluated by 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 analyses employed validated analytical methods and are supported by appropriate storage stability data.  Sufficient studies were submitted for corn, soybean, and mint to elucidate the fate of metaldehyde in processed commodities derived from these crops.  The Agency waived livestock metabolism and feeding studies; thus, all uses of metaldehyde are classified under 40 CFR §180.6 (a) (3), no reasonable expectation of finite residues with respect to residues in livestock commodities.  Limited rotational crop field trials demonstrate that residues are not expected in crops planted 30-days after metaldehyde is applied to soil; therefore, 30-day plant back intervals (PBIs) are appropriate for all crops in rotation to primary crops.

Exposure Profile and Risk Estimates:

Occupational exposures are expected from the proposed use of metaldehyde, although only 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 patterns, there is potential for short- and intermediate-term occupational exposure to metaldehyde during mixing, loading, applying, 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 level 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, and protective eyewear.

The updated residential assessment evaluated exposure to adults (handler assessment) and children (post-application assessment) as a result of use of metaldehyde products around the home (i.e., lawn and garden use). There were no risk estimates of concern identified for the residential handler or the post-application assessment (i.e., MOEs were >100).

Aggregate Risk Estimates:

In accordance with the FQPA, HED must consider and aggregate (add) pesticide exposures and risks from three major sources: food, drinking water, and residential exposures.  The acute and chronic aggregate risk assessments 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 only) 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, occupational, or toxicological 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 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/pesticides/regulating/immunotoxicity-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.

There are no data deficiencies in the occupational/residential exposure or residue chemistry databases.

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) containing sodium sulfate, filtered, concentrated, and analyzed by GC/MS using the m/z 89 and 45 ions for quantitation and confirmation, respectively.  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 partitioned 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 analysis.  For wheat grain, rape seed, and other oily matrices an additional cleanup step consisting of a hexane/methanol partition is also used.  The level of quantitation (LOQ) for metaldehyde in/on plant commodities is 0.05 ppm.

2.2.2	Recommended Tolerances

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 molluscicide metaldehyde, including 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-tetramethyl-1,3,5,7-tetroxocane, in or on the commodity.

Table 2.2.2 	Tolerance Summary for Metaldehyde.
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

Soybean, 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
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 metaldehyde in/on sweet corn.  Differences between the proposed and recommended tolerances for mint oil likely arise from the use of 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 immediately.

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	Introduction

3.1	Chemical Identity

TABLE 3.1.	Nomenclature of Metaldehyde.
Compound
Chemical Structure

Common name
Metaldehyde
Company experimental names
Not applicable
IUPAC name
r-2,c-4,c-6,c-8-tetramethyl-1,3,5,7-tetroxocane  (or)
2,4,6,8-tetramethyl-1,3,5,7-tetraoxacyclo-octane
CAS name
2,4,6,8-tetramethyl-1,3,5,7-tetroxocane
CAS #
108-62-3 (tetramer) and 9002-91-9 (homopolymer)
End-use products/EP
7.5% G (Durham Metaldehyde Granules; EPA Reg No. 5481-103);
4% P/T (Deadline MPs Mini-Pellets; EPA Reg. No. 5481-511); and
4% RTU/L (Deadline Force II; EPA Reg. No. 8119-6)

3.2	Physical/Chemical Characteristics

The physical/chemical properties of metaldehyde are summarized in Appendix C. Metaldehyde has a vapor pressure of 6.6 +- 0.3 Pa at 25 °C. Metaldehyde is expected to be mobile and moderately persistent in the environment.  Metaldehyde degrades aerobically with a reported half-life of 67 days, anaerobically with a reported half-life of 222 days, and is stable to abiotic degradation (hydrolysis and photolysis). There were no toxic residues of concern identified for the metaldehyde transformation products, and those transformation products were not considered in the EFED drinking water assessment. Acetaldehyde is an environmental degradate resulting from metaldehyde, although because acetaldehyde undergoes further degradation, it is not included in the tolerance expression or this risk assessment.

3.3	Pesticide Use Pattern
TABLE 3.3 CONTAINS A SUMMARY OF THE PROPOSED USES FOR METALDEHYDE.  The personal protective equipment proposed for the new uses direct mixers, loaders, applicators and other handlers to wear chemical resistant gloves in addition to baseline clothing (i.e., long sleeved shirt, long pants, and shoes with socks). This is identical to existing PPE requirements on currently registered labels.

Table 3.3.  Summary of Directions for Use of Metaldehyde Granular Formulation
                     Application Timing, Type, and  Equip.
                          Formulation [EPA Reg. No.]
                          Application Rate (lb ai/A)
                        Max. No. Application per Season
                   Max. Seasonal Application Rate (lb ai/A)
                                  PHI (days)
                        Use Directions and Limitations
                             Grass Grown for Seed
                  Broadcast (ground & handheld equipment)
                                   71096-13
                                      1.6
                                       4
                                      6.4
                                      21
                                 RTI = 14 days
                          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 soybeans 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 uses.  The proposed maximum application rates are supported by the submitted field trial data.  Refer to section 2.3 for recommended modifications to the proposed labels.

3.4	Anticipated Exposure Pathways

RD has requested an assessment of human health risk to support the proposed new and expanded uses of metaldehyde. Humans may be exposed to metaldehyde in food and drinking water, since metaldehyde may be applied directly to growing crops and application may result in metaldehyde reaching surface and ground water sources of drinking water.  In an occupational 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 identified for metaldehyde, 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 metaldehyde, residential handler inhalation exposures and post-application incidental oral exposure are assessed quantitatively. The other exposure routes are addressed qualitatively 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 pathways.

3.5	Consideration of Environmental Justice

Potential areas of environmental justice concerns, to the extent possible, were considered in this human health risk assessment, in accordance with U.S. Executive Order 12898, "Federal Actions to Address Environmental Justice in Minority Populations and Low-Income Populations," (http://www.eh.doe.gov/oepa/guidance/justice/eo12898.pdf.  As a part of every pesticide risk assessment, OPP considers a large variety of consumer subgroups according to well-established procedures.  In line with OPP policy, HED estimates risks to population subgroups from pesticide exposures that are based on patterns of that subgroup's food and water consumption, and activities in and around the home that involve pesticide use in a residential setting.  Extensive data on food consumption patterns are compiled by the USDA under the Continuing Survey of Food Intake by Individuals (CSFII) and are used in pesticide risk assessments for all registered food uses of a pesticide.  These data are analyzed and categorized by subgroups based on age, season of the year, ethnic group, and region of the country.  Additionally, OPP is able to assess dietary exposure to smaller, specialized subgroups and exposure assessments are performed when conditions or circumstances warrant.  Whenever appropriate, non-dietary exposures based on home use of pesticide products and associated risks for adult applicators and for toddlers, youths, and adults entering or playing on treated areas post-application are evaluated.  Further considerations are currently in development as OPP has committed resources and expertise to the development of specialized software and models that consider exposure to bystanders and farm workers as well as lifestyle and traditional dietary patterns among specific subgroups.

4.0	Hazard Characterization and Dose-Response Assessment

4.1	Toxicology Studies Available for Analysis

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

   * 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)

Metaldehyde is rapidly absorbed, distributed, and metabolized in the rat, with most of the administered dose (78-98%) being recovered as [14]CO2 in expired air within 24 hours for male rats and within 48 hours in female rats. Metaldehyde is absorbed intact in the stomach, distributed widely throughout the body, and readily crosses the blood-brain barrier. Recovery in urine/feces is low (2.5-5.1%), and the sexes differ slightly. In plasma, the ratio of metaldehyde to acetaldehyde was found to be 4:1 in males and 12: 1 in females at peak blood level (1-2 hrs in males and 2-4 hrs in female, post dosing). In addition, the half-life of metaldehyde was longer in females (8.8 hours) than in males (3.4 hours). 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 of 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 system effects observed in the subchronic and chronic oral toxicity studies include: ataxia; tremor; twitching; salivation; emesis; rapid respiration in dogs and maternal rats; and limb paralysis, spinal cord necrosis, and hemorrhage in maternal rats. The liver effects include increased liver weight, increased incidence of liver lesions (hepatocellular necrosis, hepatocellular hypertrophy and inflammation), and an increased incidence of hepatocellular adenomas in female rats and in both sexes of mice. In dogs, atrophy of the testes and prostate was observed following subchronic and chronic exposure. Toxicity was not observed in a rabbit 21-day dermal toxicity study at the limit dose. Acute lethality studies show that metaldehyde is not acutely toxic by the dermal and inhalation routes of exposure but is moderately toxic via the oral route. Metaldehyde is moderately irritating to the eyes and minimally irritating to the skin.

Developmental toxicity was not observed in the rat or rabbit developmental toxicity studies, and maternal toxicity was not observed in the rabbit. In the rat, maternal toxicity was observed, as evidenced by clinical signs (ataxia, tremors, and twitching) at the highest dose tested.  In the rat reproductive toxicity study, mortality and clinical signs (limb paralysis, spinal cord necrosis and hemorrhage) were observed in the maternal animals, and the effects on the offspring consisted of decreased 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 paralysis was observed in one female rat at the highest dose tested.  No acute neurotoxicity study on metaldehyde is available.  However, the Hazard and Science Policy Council (HASPOC) determined that the acute neurotoxicity study is not required since dogs appear to be the most sensitive species for neurotoxicity, and the 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 by liver hypertrophy 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 sexes (liver tumors, adenomas), and the rat study showed that metaldehyde was associated with liver adenomas in the female, HED has determined that quantification of risk using a non-linear approach; i.e., RfD, for metaldehyde will 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 were benign; (3) metaldehyde is not mutagenic; (4) no carcinogenic response was seen in the male rat; (5) incidence of adenomas at the high-dose in the female rat was within the historical control range of the testing lab.

4.4	Safety Factor 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:

The toxicity database is complete and adequate to assess safety for infants and children.  There is no evidence of increased qualitative or quantitative susceptibility in the developmental rat and rabbit studies or in the rat 2-generation reproduction study. These studies have clearly defined NOAEL/LOAELs. There is a subchronic neurotoxicity study on metaldehyde with a clearly defined NOAEL/LOAEL. Both the acute neurotoxicity study and the developmental neurotoxicity study have been waived.  The exposure assessment will not underestimate children's exposure to metaldehyde.  Further details may be found in the following sections.

4.4.1	Completeness of 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) determined that the acute neurotoxicity (ACN) study and the inhalation toxicity study may be waived.

4.4.2	Evidence of Neurotoxicity

There is a concern for neurotoxicity resulting from exposure to metaldehyde, based on (1) clinical signs [ataxia, twitching, tremors, prostration, paresis of hind legs] in female rats in the developmental toxicity study; (2) hindlimb paralysis, necrosis and hemorrhage in the spinal cord and vertebra luxation in F0 dams during lactation period in the two-generation reproduction study; (3) bilateral hindlimb paralysis observed initially on day 10 in one high-dose female sacrificed on day 22 due to poor condition in the 90-day subchronic neurotoxicity study in rats; no neuropathology was evident; (4) clinical signs [ataxia, tremors, twitching, salivation] in the chronic dog study, which occurred within the first week of exposure and persisted through week 19; 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 of Sensitivity/Susceptibility in the Developing or 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.

Metaldehyde 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 days 7 and 8, and decreased 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. Mortality, clinical signs (hindlimb paralysis in F0 females), gross/histopathological lesions in females (spinal cord necrosis and hemorrhage, vertebra luxation in F0 females), and increased liver weight in both sexes were observed in the rat 2-generation reproduction study at the same dose levels where decreased pup body weight and pup body-weight gain were observed in both sexes/both generations.

4.4.4	Residual Uncertainty in the Exposure Database

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 exposures and risks 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 Departure 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 signs 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 days 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 exposures, 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 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. A 100X uncertainty factor was applied to account for inter- and intra-species variability resulting in a chronic reference dose (cRfD) of 0.10 mg/kg/day.  Since the FQPA factor is reduced to 1X, the cRfD is equivalent to the chronic population adjusted dose (cPAD).

The short-term incidental oral and inhalation endpoints for risk assessment were 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 signs occurred 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 endpoints for risk assessment were selected from the chronic oral toxicity study in the dog with a NOAEL of 10 mg/kg/day.  At the study LOAEL of 30 mg/kg/day, death and atrophy of the testes and prostate were observed. Atrophy of the testes and prostate was also observed in the subchronic dog study.

There was no  hazard observed via the dermal route with lack of systemic toxicity following 21 days of dermal exposure to rabbits. The endpoints of concern 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 of 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 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 in both species were benign; (3) metaldehyde is not mutagenic; (4) no carcinogenic response was seen in the male rat; (5) incidence of adenomas in the female rat was within the historical control range of the testing lab.

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

Table <IP_ADDRESS>   Summary of Toxicological Doses and Endpoints for Metaldehyde for Use in Dietary and Non-Occupational Human Health Risk Assessments
Exposure/ Scenario
Point of Departure
Uncertainty/FQPA Safety Factors
RfD, PAD, Level of Concern for Risk Assessment
Study and Toxicological Effects
Acute
Dietary (All Populations)
NOAEL = 30 mg/kg/day
UFA 10x
UFH 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
UFA 10x
UFH 10x

FQPA SF = 1X
cRfD = 0.10 mg/kg/day

cPAD = 0.10 mg/kg/day
Chronic dog oral toxicity study
LOAEL = 30 mg/kg/day, based on death and atrophy of the testes and prostate
Incidental Oral Short-Term (1-30 days)
NOAEL = 30 mg/kg/day
UFA 10x
UFH 10x

FQPA SF = 1x
Residential LOC for MOE < 100
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).
Incidental Oral Intermediate-Term (1-6 months)
NOAEL = 10 mg/kg/day
UFA 10x
UFH 10x

FQPA SF = 1x
Residential LOC for MOE < 100
Chronic 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 rabbits. The endpoints of concern were all assessed in this study, and there is no developmental or reproductive concern.
Inhalation Short- Term (1-30 days)
NOAEL = 30 mg/kg/day
UFA 10x
UFH 10x

FQPA SF = 1x
Residential LOC for MOE < 100
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).
Inhalation Intermediate-Term (1-6 months)
NOAEL = 10 mg/kg/day
UFA 10x
UFH 10x

FQPA SF = 1x
Residential LOC for MOE < 100
Chronic 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.  UFA = extrapolation from animal to human (interspecies).  UFH = 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 <IP_ADDRESS> Summary of Toxicological Doses and Endpoints for Metaldehyde for Use in Occupational Human Health Risk Assessments
                              Exposure/ Scenario
                              Point of Departure
                              Uncertainty Factors
                     Level of Concern for Risk Assessment
                        Study and Toxicological Effects
Dermal Short-Term (1-30 days)
No 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 months)

Inhalation Short-Term (1-30 days)
oral NOAEL= 30

Inhalation hazard assumed to be equivalent to oral hazard

UFA=10x
UFH=10x
Occupational LOC for MOE = 100

Chronic dog oral toxicity study
LOAEL = 90 mg/kg/day for clinical signs seen beginning the first week of dosing.
Inhalation Intermediate-term (1-6 months)
oral NOAEL = 10 mg/kg/day

Inhalation hazard assumed to be equivalent to oral hazard

UFA=10x
UFH=10x
Occupational LOC for MOE = 100

Chronic 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.  UFA = extrapolation from animal to human (interspecies).  UFH = potential variation in sensitivity among members of the human population (intraspecies).  UFL = use of a LOAEL to extrapolate a NOAEL.  UFS = use of a short-term study for long-term risk assessment.  UFDB = to account 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.

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

Metaldehyde is expected to be mobile and moderately persistent in the environment.  Metaldehyde degrades aerobically with a reported half-life of 67 days, anaerobically with a reported half-life of 222 days, and is stable to abiotic degradation (hydrolysis and photolysis). There were no toxic residues of concern identified for the metaldehyde transformation products, and those transformation products were not considered in the EFED drinking water assessment. Acetaldehyde is an environmental degradate resulting from metaldehyde, although because acetaldehyde undergoes further degradation, it is not included in the tolerance expression or this risk assessment.

5.1.3	Comparison of Metabolic Pathways

The major residue found in plant metabolism studies on lettuce and sugar beets was the parent compound, metaldehyde. There were considerable non-extractable residues in sugar beet root and tops that were not further characterized. The Confined Rotational Crop study was waived since the metabolism in secondary crops is likely to be similar to the primary crops.

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

Metaldehyde is rapidly absorbed, distributed, and metabolized in the rat. Between 78-98% of the administered dose was recovered as expired air within 24 hours as [14]CO2 in the rat metabolism study.

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

5.1.4	Residues of Concern Summary and Rationale

The qualitative nature of metaldehyde residues in plants is understood based on lettuce and sugar beet metabolism studies.  The HED Metabolism Committee (7/2/96) concluded that the regulated residue of concern in plants is parent metaldehyde.  This conclusion was confirmed in the Metaldehyde Reregistration Eligibility Decision (RED) document (D327385, M. Lloyd et. al., April 3, 2006).

Table 5.1.4  Summary of Metabolites and Degradates to be included in the Risk Assessment and Tolerance Expression
Matrix
Residues included in Risk Assessment
Residues included in Tolerance Expression
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 analyses employed validated analytical methods and are supported by appropriate storage stability data.  Sufficient studies were submitted for corn, soybean, and mint to elucidate the fate of metaldehyde in processed commodities derived from these crops:  metaldehyde residues were found to concentrate only in mint oil, with an average processing factor of 5.1x.  Multiplying the mint highest average field trial (HAFT) value [2.39 ppm] by the average processing factor resulted in the recommended tolerance level of 12 ppm 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 reasonable expectation of finite residues with respect to residues in livestock commodities.  Limited rotational crop field trials demonstrate that residues are not expected in crops planted 30-days after metaldehyde is applied to soil; therefore, 30-day plant back intervals (PBIs) are appropriate for 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 Fate and Effects Division (EFED).

There are no monitoring data currently available for metaldehyde in drinking water.  Estimated drinking water concentrations (EDWCs) were generated using computer modeling procedures.  The highest EDWCs resulted from the special mollusk eradication use on turf, and these values were used in the present dietary analysis.  Surface water estimates were determined using the PRZM-EXAMS model and ground water estimates were determined using the PRZM-GW model.  These latter values were recommended for use in the human-health dietary risk assessment as they were the highest values obtained.   Additional information concerning the water models is available at the EPA web site.

Maximum application rates for metaldehyde as a high-end estimate of exposure in drinking water were modeled based on the proposed labels.  Chemical 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 interval of 14 days.
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 assessment: 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.  Processing studies for tomatoes and oranges indicate that metaldehyde residues do not concentrate in processed commodities derived from these crops.  Exaggerated rates studies in corn and soybean showed no detectable grain or seed residues at rates of 5x and 10x, respectively.  Therefore, no processing factors were used in the analyses except for those processed commodities for which no processing studies are typically conducted (tomato, dried; tomato, juice; cranberry, juice; and high fructose corn syrup), for which default factors were used.

5.4.2	Acute Dietary Risk Assessment

A highly 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 syrup; 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 highly 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 high fructose corn syrup; 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 adequately 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 Metaldehyde.[1]
                              Population Subgroup
                                 Acute Dietary
                               (95th Percentile)
                                Chronic Dietary
                                     Cancer

                          Dietary Exposure (mg/kg/day)
                                     % aPAD
                                Dietary Exposure
                                  (mg/kg/day)
                                     % cPAD
                                Dietary Exposure
                                  (mg/kg/day)
                                      Risk
 General U.S. Population
                                    0.099762
                                       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 along with policy changes for body 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 quantitatively assessed residential handler inhalation exposure (for adults applying metaldehyde) and incidental 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 includes the following scenarios:  loading/applying liquid ready-to-use products with (1) manually-pressurized handwands, (2) hose-end sprayers, and (3) sprinkler cans; and applying granules via (4) push-type rotary spreaders, (5) belly grinders, (6) spoons, (7) cups, (8) hands, and (9) shaker cans. These residential use patterns were previously assessed ("Metaldehyde: 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 residential exposure.  Detailed information on the assumptions used to assess residential handler exposure scenarios is available in the Metaldehyde Occupational and Residential Exposure Assessment memo (D408747). Since there are no toxicity findings applicable to the short-term dermal route of exposure up to the limit dose, the residential handler assessment only 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]
                     Amount Treated or Handled  Daily [2]
                                  Inhalation

                                   Dose [3]
                                    MOE[4]
                            Mixer/Loader/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
                              0.00007 lb ai/ft[2]
                                  1200  ft[2]
                                   0.0000015
                                  20,000,000
                    Turf  -  spot; liquid; hose end sprayer
                                      100
                                    0.0014
                              0.00002 lb ai/ft[2]
                                  1200  ft[2]
                                  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
                              0.00007 lb ai/ft[2]
                                  1200  ft[2]
                                   0.000036
                                    840,000
                   Ornamentals; granule; push-type spreader
                                      100
                                    0.0026
                              0.00007 lb ai/ft[2]
                                  1200  ft[2]
                                   0.0000027
                                  11,000,000
                    Lawn/turf; granules; push-type spreader
                                      100
                                    0.0026
                                   1 lb ai/A
                                     0.5 A
                                   0.000016
                                   1,800,000
                       Lawn/turf, granule; belly grinder
                                      100
                                     0.039
                              0.00007 lb ai/ft[2]
                                  1200  ft[2]
                                   0.000041
                                    730,000
                         Garden/trees, granule; spoon
                                      100
                                     0.087
                              0.00007 lb ai/ft[2]
                                  1200  ft[2]
                                   0.000091
                                    330,000
                           Lawn/turf, granule; spoon
                                      100
                                     0.087
                              0.0008 lb ai/ft[2]
                                   100 ft[2]
                                   0.000087
                                    340,000
                           Garden/tree, granule, cup
                                      100
                                     0.013
                              0.00007 lb ai/ft[2]
                                  1200  ft[2]
                                   0.000014
                                   2,200,000
                            Lawn/turf, granule; cup
                                      100
                                     0.013
                              0.0008 lb ai/ft[2]
                                   100 ft[2]
                                   0.000013
                                   2,300,000
                     Garden/tree, granule, hand dispersal
                                      100
                                     0.032
                              0.00007 lb ai/ft[2]
                                  1200  ft[2]
                                    0.0004
                                    75,000
1   Based on application rates determined from EPA registered labels for metaldehyde & May, 2005 Use Closure Memo (details available D327385)
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) x Application Rate (lb ai/acre or gal) x Area Treated or Amount Handled (A/day, ft[2]/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 = 100

6.2	Post-Application Exposure

There is the potential for post-application exposure for individuals exposed as a result of being in an environment that has been previously treated with metaldehyde.  As no dermal hazard was identified, only incidental oral exposure for children was quantitatively assessed. Since metaldehyde is moderately persistent in the environment, intermediate-term exposure is also possible for incidental soil ingestion exposure. No dislodgeable foliar residue 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 (D408747).

The quantitative exposure/risk assessment for residential post-application exposures includes 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
   * Incidental Ingestion of granules (as a result of turf/lawn applications).
                                     Acute

The lifestages selected for each post-application scenario are based on an analysis provided as an Appendix in the 2012 Residential SOPs.  These lifestages are not the only 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 assessment) 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 for residential post-application exposure scenarios to metaldehyde (i.e, MOEs are >100).  For liquid sprays on turf, short-term residential incidental oral risk estimates ranged from 2,000 to 890,000. For granular products applied to turf, short-term risk estimates for the hand to mouth, object to mouth, and incidental soil ingestion ranged from 20,000 to 890,000 and were not of concern to HED.

Because metaldehyde is moderately 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 of metaldehyde was 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 days.   The estimated risk is an MOE = 300,000 and does not contribute significantly to the short- and intermediate-term aggregate risks for metaldehyde.   Intermediate-term child incidental soil ingestion from the granular and liquid turf products are not of concern to HED.

Table 6.2.1:      Residential Post-Application 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 cm[2])) x (exposure time (1.5 hrs/day)*number of replenishment intervals/hr (4 intervals/hr) x (1-(1-saliva extraction 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 (150 cm[2]).
     Object-to-Mouth = ((Object Residue (ug/cm[2]) x CF1 (1.0E-3 mg/ug) x Object Surface Area Mouthed/Event (10 cm[2]/event)) x (Exposure  Time (1.5 hrs/day) x #Replenishment Intervals/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         Incidental ingestion of granules based on an acute exposure scenario; acute dietary POD = 30 mg/kg/day

Ingestion of metaldehyde formulations such as mini-pellets or granules is a possible source of exposure because children could potentially ingest them if they were found in treated lawns.  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 by 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 adults 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 greatly 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

Residential exposure from granular applications to ornamentals/home gardens via hand dispersal) is  used in the adult aggregate assessment.

The residential exposure for use in the short-/intermediate-term aggregate assessment for children 1 to <2 years old is short-term hand-to-mouth (incidental oral) exposure from contacting treated turf. Because of the long environmental half life of metaldehyde, there is also an intermediate-term residential aggregate assessment. The residential exposure for use in the children 1 to <2 years old intermediate-term aggregate assessment is (incidental oral) exposure from ingesting treated soil.

See Table 6.4.1 for additional information.

Table 6.4.1  Residential Exposures for Use In the Metaldehyde Aggregate Assessment.[1]
                                   Lifestage
                              Residential Handler
                         Residential Post-application

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

                                    Dermal
                                  Inhalation
                                     Total
                                    Dermal
                                  Inhalation
                                     Total
                                    Dermal
                                  Inhalation
                                     Oral
                                     Total
                                    Dermal
                                  Inhalation
                                     Oral
                                     Total
                                  Short-Term
Adult Male
                                      N/A
                                    0.0004
                                    0.0004
                                      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
                                    0.0004
                                      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	Highlighted risk estimates should contribute to the residential exposure portion 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 assessed 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/Incidental oral MOE).
Child 1 to <2 years - HTM contact with treated turf  (ST); soil ingestion [because of long environmental half life] (IT).
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 nearby 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 Advisory Panel (SAP) in December 2009, and received the SAP's final report on March 2, 2010.  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 always a potential source of exposure to residents nearby to spraying operations.  This is particularly the case with aerial application, but, to a lesser extent, could also be a potential source of exposure from the ground application method employed for metaldehyde.  The Agency has been working with the Spray Drift Task Force, EPA Regional Offices and State Lead Agencies for pesticide regulation and other parties to develop the best spray drift management practices (see the Agency's Spray Drift website for more information).  The Agency has completed its evaluation of the new database submitted by the Spray Drift Task Force, a membership of U.S. pesticide registrants, and is developing a policy on how to appropriately apply the data and the AgDRIFT computer model to its risk assessments for pesticides applied by air, orchard airblast and ground hydraulic methods.  After the policy is in place, the Agency may impose further refinements in spray drift management practices to reduce off-target drift with specific products with significant risk estimates associated with drift.

It is noted that the 1 lb ai/acre application rate for turf was modeled to estimate post-application residential (incidental oral) exposure of children.  As this rate is comparable to the agricultural application rates, this scenario is considered protective of any exposure of farm children via spray drift from agricultural metaldehyde applications.

6.0 Aggregate Exposure/Risk Characterization

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

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

7.1	Acute Aggregate Risk

The acute aggregate risk assessment takes into account exposure estimates from dietary consumption of metaldehyde (food and drinking water). While HED does calculate an acute granular ingestion scenario for pelletized pesticides, it is not appropriate to aggregate because it represents episodic and sporadic ingestion, not a typical one day exposure pattern.  Further, these products contain a bittering agent which makes ingestion of metaldehyde formulations generally not palatable to children.  The acute dietary exposure estimates are not of concern to HED (<100% aPAD) at the 95[th] exposure percentile for the general U.S. population and all other 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 by the PRZM-GW Model.

1.2 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.  Short- and Intermediate-Term Residential Exposure Values and Sources Used in the Metaldehyde Aggregate Risk Assessment
Population
                         Handler Exposure (mg/kg/day)
                           Postapplication Exposure
                                  (mg/kg/day)
                              Residential Exposure
                                  (mg/kg/day)[1]
                                  Short-Term
Adult Male
                                    0.0004
                               Source: Table 6.1
                     Garden/tree, granule, hand dispersal
                            N/A; no dermal endpoint
                                    0.0004
Adult Female
                                    0.0004
                               Source: Table 6.1
                     Garden/tree, granule, hand dispersal
                            N/A; no dermal endpoint
                                    0.0004
Child
                 N/A; only adults are assessed as handlers[3]
                                    0.0152
                             Source:  Table 5.2.1
                        Hand-to-Mouth from Treated Turf
                                    0.0152
                               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
                                   0.000034
                              Source:  Table 5.2
                           Incidental Soil Ingestion
                                   0.000034
[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 concern (i.e., MOES are > 100).  Short- and intermediate-term estimated exposures and risks are shown in Table 7.2.2, below.

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
                                    0.0004
                                     1,900
Adult Female
                                      30
                                      100
                                      0.3
                                   0.015638
                                    0.0004
                                     1,900
Child
                                      30
                                      100
                                      0.3
                                   0.036060
                                    0.0152
                                      590

                          Intermediate-Term Scenario
Adult Male
                                      N/A
Adult Female
                                      N/A
Child
                                      10
                                      100
                                      0.1
                                   0.036060
                                   0.000034
                                      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 chronic 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, default processing factors, and a chronic ground water EDWC generated by the PRZM-GW model.

6.0 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 produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that metaldehyde has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/.

7.0 Occupational Exposure/Risk Characterization

An occupational exposure assessment of the proposed uses was provided in an HED memorandum dated 06/12/13 (M. Lloyd; D408747).  For the proposed use sites, there is a potential for short- and intermediate-term occupational exposure to metaldehyde during mixing, loading, applying, and other handling tasks. Chronic exposure is not expected for the proposed agricultural uses.

9.1	Short-/Intermediate-Term Handler Risk

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

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

   * Mix/Load - granular formulations for ornamentals, sod, mint, taro, blackberry, leaf petioles, and high acreage crops (i.e., corn, soybeans)
   * Applicator  -  granular formulations (ground equipment & 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, specifically, details about the relevant application rates, the unit exposures, and assumptions about the area treated. As no dermal hazard was identified, only inhalation exposure was quantitatively assessed.

For metaldehyde, based on the proposed use, short- and intermediate-term exposures are expected for the following reasons:  (1) the product can be applied multiple times per year (2) the product can be applied to multiple application sites and (3) there may be a large agribusiness and/or commercial applicators who may apply a product over a period of weeks.

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-/Intermediate-Term Non-Cancer Exposure and Risk Estimates for Metaldehyde.
                               Exposure Scenario
                                Crop or Target
                      Dermal Unit Exposure (μg/lb ai)[1]
                    Inhalation Unit Exposure (μg/lb ai)[1]
                                    Maximum
                              Application Rate[2]
                    Area Treated or Amount Handled Daily[3]
                                  Inhalation

                               Mitigation Level
                               Mitigation Level

                              Dose (mg/kg/day)[4]
                                    MOE[5]
                                 Mixer/Loader
                  M/L Granular Product for Ground Application
                                 Corn/ soybean
                                      N/A
                                      1.7
                                       1
                                      200

                                    0.00425

                                  7,100 (ST)
                                  2,400 (IT)

                                      Sod
                                      N/A
                                      1.7
                                      1.6
                                      80
                                    0.00273
                                  11,000 (ST)
                                  3,700 (IT)

                         Leaf petiole/mint/taro/13-07A
                                      N/A
                                      1.7
                                       1
                                      80
                                    0.0017
                                  18,000 (ST)
                                  5,900 (IT)
                                  Applicator
                     Applicator  -  Tractor Drawn spreader
                                 Corn/soybeans
                                      N/A
                                      1.2
                                       1
                                      200
                                     0.003
                                  10,000 (ST)
                                   3,300 (IT)

                                      Sod
                                      N/A
                                      1.2
                                      1.6
                                      80
                                    0.00193
                                  16,000 (ST)
                                  5,200 (IT)

                         Leaf petiole/mint/taro/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
                                     Sod
                                      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 (μg/lb ai) x Conversion Factor (0.001 mg/μg) x Application Rate (lb ai/acre or gal) x Area Treated or Amount  Handled Daily (A or gal/day) / BW (kg).
5	Inhalation MOE = Inhalation NOAEL (mg/kg/day) (30  ST/ 10 IT) / Inhalation Dose (mg/kg/day).

9.2	Short-/Intermediate-Term Post-Application Risk

HED uses the term post-application to describe exposures that occur when individuals are present in an environment that has been previously treated with a pesticide (also referred to as re-entry exposure).  Such exposures may occur when workers enter previously treated areas to perform job functions, including activities related to crop production, such as scouting for pests or harvesting.  Post-application exposure levels vary over time and depend on such things as the type of activity, the nature of the crop or target that was treated, the type of pesticide application, and the chemical's degradation properties.  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.

9.2.2	Inhalation Post-application Risk

Based on the Agency's current practices, a quantitative post-application inhalation exposure assessment was not performed for metaldehyde at this time primarily because of the low acute inhalation toxicity (Toxicity Category IV) and the low vapor pressure (1.5E-03 Pa at 25 ºC).  However, there are multiple potential sources of post-application inhalation exposure to individuals performing post-application activities in previously treated fields.  These potential sources include volatilization of pesticides and 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. 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-application inhalation exposure scenarios.

10.0	References

Previous Risk Assessments:
M. Lloyd, et al, "Metaldehyde: HED Chapter of the Reregistration Eligibility Decision Document (RED). PC Code: 053001; DP Barcode: DP327385" 04/03/06; D327385

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

Chemistry Memo:  W. Donovan; in preparation; D408745

Drinking Water Memo:  M. Biscoe; in preparation.

Dietary Memo:  W. Donovan; 23-MAY-2013; D408746

Occupational & Residential Exposure Memo:  M. Lloyd; 06/12/13; D408747
Appendix A.  Toxicology Profile and Executive Summaries
A.1	Toxicology Data Requirements
The requirements (40 CFR 158.340) for food use for metaldehyde are in Table 1. Use of the new guideline numbers does not imply that the new (1998) guideline protocols were used.

                                     Study
                                   Technical

                                   Required
                                   Satisfied
870.1100    Acute Oral Toxicity
870.1200    Acute Dermal Toxicity
870.1300    Acute Inhalation Toxicity
870.2400    Primary Eye Irritation
870.2500    Primary Dermal Irritation
870.2600    Dermal Sensitization
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      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
                                      yes
                                      yes
                                      yes
                                      CR
                                      yes
                                      yes
                                      yes
                                      yes
                                       -
                                    yes[A]
870.3700a  Developmental Toxicity (rodent)
870.3700b  Developmental Toxicity (nonrodent)
870.3800    Reproduction
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
870.4100a  Chronic Toxicity (rodent)
870.4100b  Chronic Toxicity (nonrodent)
870.4200a  Oncogenicity (rat)
870.4200b  Oncogenicity (mouse)
870.4300    Chronic/Oncogenicity
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      yes
                                      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
                                      yes
                                      yes
                                      yes
870.6100a  Acute Delayed Neurotoxicity (hen)
870.6100b  90-Day Neurotoxicity (hen)
870.6200a  Acute Neurotoxicity Screening Battery (rat)
870.6200b  90-Day Neurotoxicity Screening Battery (rat)
870.6300    Develop. Neurotoxicity
                                      no
                                      no
                                      yes
                                      yes
                                      CR
                                       -
                                      -
                                    yes[A]
                                    yes[A]
                                     -[B]
870.7485    General Metabolism
870.7600    Dermal Penetration
870.7800    Immunotoxicity
                                      yes
                                      CR
                                      yes
                                      yes
                                       -
                                      no
[A]Waived by HASPOC (TXR# 0056524);  B EPA concluded there was no need for DNT (TXR# 0055119, June 10, 2009).

A.2	Toxicity Profiles
             Table A.2.1 - Acute Toxicity Profile  -  Metaldehyde
                                 Guideline No.
                                  Study Type
                                    MRID(s)
                                    Results
                               Toxicity Category
870.1100
Acute oral [Sprague-Dawley rat]

LD50 = 283 mg/kg

                                      II

870.1200
Acute dermal [CFY rat]
                                   00131434
LD50 = >5000 mg/kg
                                      III
870.1300
Acute inhalation [Sprague-Dawley rat]
                                   00131429
LC50 = 13.5 mg/L/4 hrs
                                      IV
870.2400
Acute eye irritation [rabbit]
                                   42068801
mild irritant
                                      III
870.2500
Acute dermal irritation [rabbit]
                                   00131971
not an irritant
                                      IV
870.2600
Skin sensitization [guinea pig]
                                      N/A
[N/A ]
                                    [N/A ]

Table 2 - Subchronic, Chronic and Other Toxicity Profile  -  Metaldehyde
                           Guideline No./ Study Type
                                MRID No. (year)
                             Classification /Doses
                                    Results
870.3100
90-Day oral toxicity (mouse)
43297701 (1990)
mouse [range-finding study] 0, 100, 300, 1000, 3000, and 10000 ppm
[19, 54, 178, 560, and 1918 mg/kg/day (males); 24, 70, 235, 742, and 2296 mg/kg/day (females)]
NOAEL = 300 ppm [54/70 mg/kg/day]
LOAEL = 1000 ppm [178/235 mg/kg/day],  based on increased liver weight and increased incidence of liver lesions [hepatocellular necrosis, hepatocellular  hypertrophy, inflammation, and anisokaryosis in both sexes.
Non-guideline
28-Day oral toxicity (rat)
44237704 (1989)
acceptable/non-guideline
0, 2500, 5000, 10000, 20000 ppm
[m/f]-[0, 197/233, 382/454, 761/875  1545 (males only) mg/kg/day]
Systemic NOAEL not established
Systemic LOAEL = 2500 ppm [200 mg/kg/day], based on increased absolute and relative liver weights at all dose levels in both sexes
Mortality, hindlimb paralysis [females at 10000 ppm; both sexes at 20000 ppm]; fracture/luxation of vertebra, hemorrhage of spinal cord
870.3150
Subchronic oral toxicity in nonrodents (dog)
MRID 00131432 (1980)
acceptable/guideline
0, 20, 60, 90 mg/kg/day
[26 weeks]
NOAEL = 20 mg/kg/day
LOAEL = 60 mg/kg/day based on diffuse or focal atrophy of the testes and prostate; at HDT, follicular hyperplasia of mesenteric lymph node in both sexes
870.3200
21/28-Day dermal toxicity (rabbit)
42063401 (1991)
acceptable/guideline
0, 100, 300, 1000 mg/kg/day
NOAEL = 1000 mg/kg/day [highest dose tested]
LOAEL = no effects observed
870.3465
90-Day inhalation toxicity (rat)
HASPOC determined that an inhalation toxicity study was not required, based on MOEs that were >1000
870.3700a
Prenatal developmental in rodent (rat)
41656001 (1990)
acceptable/guideline
0, 25, 75, 150 mg/kg/day
gestation days 6-15
Maternal NOAEL = 75 mg/kg/day ]
LOAEL = 150 mg/kg/day, based on mortality, clinical signs of toxicity [ataxia, tremors, twitching, rapid respiration] on days 7 and 8, and decreased body-weight gain during dosing, and decreased food consumption during dosing.
Developmental NOAEL = 150 mg/kg/day [HDT]
LOAEL = no effects.
870.3700b
Prenatal developmental in nonrodent (rabbit)
41590501 (1990)
acceptable/guideline
0, 10, 40, 80 mg/kg/day
gestation days 6-18
Maternal toxicity NOAEL = 80 mg/kg/day [HDT]
Maternal toxicity LOAEL = no effects observed.
Developmental toxicity NOAEL = 80 mg/kg/day [HDT]
Developmental toxicity LOAEL = no effects.
870.3800
Reproduction and fertility effects (rats)
MRID 42823101 (1993)
acceptable/guideline

0, 50, 1000, 2000 ppm
males: F0 0, 3.4, 69.37, 138.36; F1 0, 3.23, 64.93, 133.53 mg/kg/day
females: F0 0, 4.16, 80.81, 160.42; F1 0, 4.03, 80.51, 164.15 mg/kg/day
Parental toxicity NOAEL = 1000 ppm [males 65 mg/kg/day; females 81 mg/kg/day]
Parental toxicity LOAEL = 2000 ppm [males 133 mg/kg/day; females 160 mg/kg/day], based on mortality, clinical signs (hindlimb paralysis in F0 females) on lactation days 16-18, gross/histopatholigical lesions in females (spinal cord necrosis and hemorrhage, vertebra luxation in F0 females), and increased liver weight in both sexes.

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

Offspring NOAEL = 1000 ppm [males 65 mg/kg/day; females 81 mg/kg/day]; Offspring LOAEL = 2000 ppm [males 133 mg/kg/day; females 160 mg/kg/day], based on decreased pup body weight and body-weight gain in both sexes/both generations.
870.4100a
Chronic toxicity rodents (SD rat)
MRID 42203601 (1992)
acceptable/guideline
0, 50, 1000, 5000 ppm
M 0, 2, 44, 244 mg/kg/day
F 0, 3, 60, 314 mg/kg/day
NOAEL = 50 ppm [males 2 mg/kg/day; females 3 mg/kg/day] A
LOAEL = 1000 ppm [males 44 mg/kg/day; females 60 mg/kg/day], based on increased incidence of hepatocellular hypertrophy (both sexes) and increased cholesterol (females), and decreased body-weight gain in females. [see under 870.4200 below]
870.4100b
Chronic toxicity nonrodent (dogs)
MRID 46378401 (2003)
acceptable/guideline
0, 10, 30, 90 mg/kg/day
Overall NOAEL = 10 mg/kg/day
LOAEL = 30 mg/kg/day, based on deaths and atrophy of testes/prostate
NOAEL = 30 mg/kg/day
LOAEL = 90 mg/kg/day, based on clinical signs of neurotoxicity in all dogs on the first day of exposure and throughout the first week.
870.4200
Carcinogenicity rats
MRID 42203601 (1992)
acceptable/guideline
0, 50, 1000, 5000 ppm
M 0, 2, 44, 244 mg/kg/day
F 0, 3, 60, 314 mg/kg/day
NOAEL = 50 ppm [2 mg/kg/day; females 3 mg/kg/day] [A]
LOAEL = 1000 ppm [males 44 mg/kg/day; females 60 mg/kg/day], based on increased incidence of hepatocellular hypertrophy (both sexes) and increased cholesterol (females), and decreased body-weight gain in females.
evidence of carcinogenicity: females displayed a treatment-related increase in hepatocellular adenomas and adenomas and carcinomas combined [positive trend at 5000 ppm] at the high-dose level [adenomas 6/60, 10%] compared to both control groups [0/60 and 1/60]; carcinomas 1/60, 1.7% compared to both controls  [0/60 and 1/60]; and combined 7/60, 11.7% compared to both controls [0/60 and 2/60]; the incidence was within the historical control range [adenomas 0%-10%; carcinomas 0%; combined 0%-10%].
870.4300
Carcinogenicity mice
42737201 (1993)
acceptable/guideline when combined with MRID 44625101
2 control groups 25, 100, 300 ppm
M 4.0, 15.9, 48.9 mg/kg/day
F 4.8, 19.7, 59.8 mg/kg/day
NOAEL = 100 ppm [males 15.9/females 19.7 mg/kg/day][A]
LOAEL = 300 ppm [males 48.9/females 59.8 mg/kg/day based on increased incidence of hepatocellular hypertrophy in both sexes.
Dose levels not adequate to assess carcinogenicity potential;
slight increase in hepatocellular adenomas in both sexes compared to both control groups
870.4300
Carcinogenicity mice
MRID 44625101 (1998)
Acceptable/guideline when combined with MRID 42737201
2 control groups, 1000 ppm
increased liver weight, increase in incidence of hepatocellular hypertrophy (both sexes), single cell/focal/multifocal necrosis (males), and an increase in the incidence of hepatocellular adenomas in both sexes
Gene Mutation - Ames assay
870.5265
MRID 41553205 (1978)
unacceptable
0, 0.26, 1.28, 6.4, 32, 160 , 0.26, 1.28, 6.4, 32, 160 ease in incidence of hepatocellular hy
does not provide sufficient evidence of a negative response in strains TA98, TA100, TA1535, TA1537, TA1538 with and without metabolic activation; no MTD; poor performance of some strains
Gene Mutation - Ames assay
870.5100
MRID 48666101 (2011)
tested up to limit dose (5000 ug/plate);insoluble at >=2500 ug/plate +/-S9.
Acceptable/guideline
No evidence of cytotoxicity; no appreciable increases in mean number of revertants/plate in any strain in either trial (+/-S9).  The positive controls induced the appropriate response in all strains in the presence and absence of S9-activation.  There was no evidence of induced mutant colonies over background.
Gene Mutation - mouse lymphoma L5178Y (TK+/-) cell line
870.5300
MRID 41553206 (1986)
unacceptable
20, 50, 100, 200 0, 50, 1
20, 50, 100, 167 0, 50, 1
no conclusions can be drawn; doses "not completely 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 - mouse lymphoma L5178Y (TK+/-) cell line
870.5300
MRID 48721401 (2011)
tested up to solubility limit (>= 600 ug/mL +/-S9)
Acceptable/guideline
No evidence of induced mutant colonies over background.
Gene Mutation - mouse lymphoma L5178Y (TK+/-) cell line
870.5300
MRID 42044007 (1986; revised 1991)
clarification of MRID 41553206
unacceptable
w/S9 - 20, 50, 100, 167 /S9
w/out S9 -20, 50, 100, 200 /ouL
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 for inducing forward gene mutation at TK locus in mouse lymphoma (L5178Y) cell with/with standard exposure time for this test system (4 hours).
Chromosomal aberrations in  CHO cells
870.5375
MRID 00163832 (1986)
unacceptable
w/S9 - 20, 50, 100, 167 /S9
w/out S9 -20, 50, 100, 200 /out

No evidence for inducing chromosome aberrations in CHO cells up to a precipitating concentration (200 ug/mL -S9). With S9, no evidence up to the highest dose tested (167 up to the highest dose tested (167  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
Highest dose tested (100 mg/kg); MTD not  reached
870.6200a
Acute neurotoxicity screening battery
HASPOC (TXR# 0056524) determined that a rat ACN was not required, based on the fact that neurotoxicity effects observed in the rat occur only at high dose levels; the dog is the more sensitive species for neurotoxic effects and points of departure based on the dog study are protective of any neurotoxicity at higher dose levels.
870.6200b
Subchronic neurotoxicity screening battery
MRID 46223401 (2003)
Unacceptable (did not demonstrate ability to detect neurotoxic effects) /guideline
0 [basal diet], 100, 500, and 2500 ppm (equivalent to 0, 8, 39, 185 mg/kg bw/day)
NOAEL = 100 ppm [8 mg/kg/day]
LOAEL = 500 ppm [39 mg/kg/day], based on increased motor activity in females. At the HDT [185 mg/kg], bilateral hindlimb paralysis [one female] and decreased body-weight gains in females during the first week of the study.
870.6300
Developmental neurotoxicity
DNT Workgroup (2009) determined that DNT was not required, based on a weight-of-evidence: (1) no evidence of ↑ susceptibility following in utero exposures to rats/rabbits or following pre-/postnatal exposure in rat reproduction study; (2) no treatment-related effects on any reproductive parameters; offspring effects were ↓ pup body weight/gain only at >=133 mkd; (3) most of the neurotoxic signs; e.g., limb paralysis, ataxia, and tremors, were seen in adult rats at dose levels of 150 mkd to 185 mkd; (4) pharmacokinetic profile indicates a short half-life with primary metabolite being its degradation/metabolism to acetaldehyde, an endogenous chemical; (5) based on offspring LOAEL of 133 mkd, in order to elicit effects in the offspring, the DNT would need to be tested at high doses (>100 mkd), which would not yield lower POD than those currently used for overall risk assessment.
870.7485
Metabolism and pharmacokinetics (Sprague-Dawley rat)
MRID 42300901 (1992)
single gavage dose 10 or 100 mg/kg
repeated dose 10 mg/kg/day for 14 days, then single dose 14C [10 mg/kg]

Classification: acceptable/guideline
rapidly absorbed, distributed, metabolized; most recovered in expired air [78%-98% of administered dose] within 24 hours [48 hr high-dose females] as [14]CO2; recovery in urine/feces low [2.5%-5.1%] ; sexes differ slightly; peak blood levels [males 1-2 hrs; females 2-4 hrs] and excretion faster in males [T1/2 males 3.4 hrs.; females 8.8 hrs.]; recovery greater following low-dose than high-dose and repeat exposure; concentration of total [14]C in blood at peak similar for sexes but concentration of intact metaldehyde was >50% higher in females than in males at 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] were 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/pesticides/regulating/immunotoxicity-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.
Special studies (CD-1 mouse)
MRID 44810901 (1999)
retrospective analysis of cell proliferation/apoptosis [liver tissue]
males - correlation between cell proliferation, liver weight increase, and an increased incidence of liver necrosis and/or hypertrophy at 1000 ppm and 3000 ppm]; clear evidence of cell proliferation and hepatotoxicity not evident at lower doses; females - suggestive evidence of a similar correlation at 1000 ppm and 3000 ppm; however, lack of a dose-response and extreme variability of data renders findings equivocal for proposed mode of carcinogenic action [liver tumors]; no data on whether proliferative response sustained.
[A] Regarding the lower NOAELs observed in both the rat and mouse long-term studies, discussion was included in the endpoint selection section of the RED. For the chronic dietary scenario, it was noted that the chronic toxicity/carcinogenicity study in rats provided a lower NOAEL (2 mg/kg). However, the endpoint of concern [liver effects (hepatocellular hypertrophy)] was seen at 44 mg/kg (LOAEL); the effects were considered an adaptive effect and not appropriate for selection of the chronic dietary endpoint. In addition, the lower NOAEL seen in the rat study might be influenced by dose selection. Although the mouse study was not discussed, a similar conclusion is appropriate; i.e., the endpoint of concern in the mouse study [increased incidence 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 = 30 mg/kg/day based on clinical signs (ataxia, tremors, salivation, twitching) seen on day 1 of dosing in both sexes at LOAEL = 90 mg/kg/day.
Comments about Study/Endpoint/Uncertainty Factors: Since the signs of neurotoxicity were observed on the first day of dosing, the study is appropriate for an acute assessment. The dog is the most sensitive species for the neurotoxic effects observed, and neurotoxicity is the most sensitive endpoint in the toxicity database. The dose and 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 for all populations.
Uncertainty Factor: 100X (10X interspecies extrapolation, 10X intraspecies variability).

A.3.2	Chronic Reference Dose (cRfD) `
Study Selected: Chronic oral toxicity study - dog
MRID No.:  46378401
Executive Summary:  See Appendix A, Guideline [§ 870.3100]
Dose and Endpoint for Risk Assessment: NOAEL = 10 mg/kg/day based on death and atrophy of the testes and prostate seen on at LOAEL = 30 mg/kg/day.
Comments about Study/Endpoint/Uncertainty Factors:  The selected endpoint provides the most sensitive NOAEL available from a study of appropriate duration and exposure (oral). 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 = 30 mg/kg/day based on clinical signs (ataxia, tremors, salivation, twitching) seen on day 1 of dosing in both sexes at LOAEL = 90 mg/kg/day.
Comments about Study/Endpoint/Uncertainty Factors: The study is appropriate for the short-term assessment since the signs of neurotoxicity were observed on the first day of dosing and throughout the first week of exposure. The dog is the most sensitive species for the neurotoxic effects observed, and neurotoxicity is the most sensitive endpoint in the toxicity database. The dose and endpoint are protective of 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 based on death and atrophy of the testes and prostate seen on at LOAEL = 30 mg/kg/day.