**COMPANY FEDERAL REGISTER DOCUMENT SUBMISSION TEMPLATE**

**EPA Registration Division contact: Laura Nollen, (703) 305**  **- 7390**  Interregional Research Project No. 4 (IR - 4) Pesticide Petition (PP#): 2E8070 EPA has received a pesticide petitio n, PP# 2E8070, f rom Interregional Research Project No. 4 (IR - 4), Rutgers, The State University o f New Jersey , 500 College Road East, Suite 201W, Princeton, NJ 0 8540, proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346 a(d), to amend 40 CFR § 180. 523 by e stablishing a tolerance for residues of Metaldehyde in or on the follow raw agricultural commodities: Grass , forage at 1.5 parts per million (ppm) ; Grass , hay

at 1.8 ppm ; L eaf petioles subgroup 4B at 0.8 0 ppm; P eppermi nt , tops at 3.5 ppm; Spearmint , tops at 3.5 ppm; P eppermint, oil at 14 ppm; S pearmint, oil at 14 ppm; C aneberry subgroup 13 - 07A at 0.15 ppm; B ushberry s ubgroup 13 - 07B at 0.15 ppm; B erry , low growing, subgroup 13 - 07G at 6.25 ppm ; T aro, corm at 0.25 ppm; T aro, leaves at 0.60 ppm; C orn, field, grain at 0.05 ppm; C orn, field, stover at 0.15 ppm; C orn, field, forage at 0.25 ppm; C orn, sweet , kernel plus cob with husks removed at 0.05 ppm; S oy bean , s eed at 0.05 ppm. EPA has determined that the petition contains data or information regarding the elements set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully e valuated the sufficiency o f the submitted data at this time or whether the data supports granting of the petition. A dditional data may be needed before EPA rules on the petition. A. **Residue Chemistry 1.**  **Plant metabolism** . Previously submitted studies sponsored by Lo nza Inc., established that Metaldehyde can translocate into plants and that the only re sidue of concern is parent Metaldehyde. The translocation studies using 14 C - Metaldehyde were conducted in leaf lettuce and sugar beets ( MRID Nos. 43923301 and 43923302). L SC analysis of the lettuce from the treated lettuce plot showed that the lettuce contained an average Total Radioactive Residue ( TRR) level (expressed as 14 C - Metaldehyde equivalents) of 2.44 ppm from the outer leaves and 2.36 ppm from the inner leaves. The corresponding values for the beet foliage and roots were 2.87 and 0.61 ppm, respec tively . HPL C analysis of treated lettuce and beet samples showed that 100% of the radioactivity in the lettuce and beet samples consisted of parent 14 C - Metaldehyde.

.2

2. **Analytical method** . A GC/MS analy tical method has been developed for analy zin g residues of Metaldehyde in food crops including all of the crops identified above. T he limit of quantitation (LOQ) for the method is 0.05 ppm. The method has been validated with respect to specificity and non - analy te interference, precision (repeatabil ity ), accuracy , sensitivity , linearity o f standards, stability o f standard solutions and precision (replicate injections) by EN - CAS Analy tical Laboratories Study

No. 99 - 0055 ( MRID# 46010501). 3. **Magnitude of residues** . Crop field trials were conducted i n all the crops identified in this petition , except for the crops covered by the revised crop groupings. A summary of the trials is shown below. All of the trials were conducted with the registered end - use product, Deadline M - P, which contains 4% Meta ld ehyde.

**Summary of Residue Studies Conducted with Metaldehyde Crop**  **Number of Trials Application Rate**  **Results** Celery 8 1 lb . a.i./A per application 4.0 lb . ai./A per season The treated samples from 5/8 trials showed no Metaldehyde residues above the LOQ of 0.05 pp m . For the other 3 trials, the total residues range from 0.146 - 0.334 ppm. Mint 5 1 - . 1.02 lb . a.i./A (per application) 4.0 - 4.08 lbs . a.i./A (per season ) Metaldehyde residues on mint tops ranged from 0.626 - 2.78 ppm . Soy beans 7 0.400 - 0.403 lb s . a.i./A (per application ) 1.200 - 1.203 lbs . a.i./A (per season ) There were no detectable residues of Metaldehyde above the LOQ of 0.05 ppm i n any treat ed soy

bean sample s . Grass (seed crop) 12 1.59 - 1.62 lbs . a.i./A ( per application ) 6.40 - 6.43 lbs . a.i. /A (per season ) Metaldehyde residues ranged from 0.0721 - 1.42 ppm in forage samp l es and <0.050 - 1.29 ppm in hay samples .3 **Crop Number of Trials**  **Application Rate Results**  Taro 3 1.0 lb . a.i./A (per application) 15 lbs . a.i/A (per season) 3/6 of taro leaf sam ples had Metaldehyde residues below LOQ of 0.05 ppm. Of the remaining samples, the highest residue was 0.4511 ppm. 4/6 of the taro corm samples had residues below 0.05 ppm. Of the two remaining samples, the highest residue was 0.1047 ppm. Corn (field) 20 0.86 - 1.09 lbs . a.i//A (per application) 3.99 - 4.32 lbs a.i./A ( per season) 5 additional trials were conducted at a 5X rate (5.00 - 5.01 lbs a.i./A, per application) Among the 1X - treated grain samples, there were no detectable Metaldehyde residues above the LOQ of 0.05 ppm, except for a single sample that was at 0.06 ppm. At the 5X treament level, there were no detectable residues above the LOQ of 0.05 ppm. None of the treated samples of kernels plus cob with husks removed had a residues above 0.05 p pm though one sample had a residue at the LOQ. The total residues in the forage samples ranged from <0.05 to 0.409 ppm. The total residues in the stove samples ranged from <0.05 to 0.111 ppm.4

4. **M agnitude of the Residue in Animals**  . Metaldehyde is a cyclic tetramer of acetaldehyde. Therefore, metabolism in animal systems will result in the release of acetaldehyde, a normal body constituent. The metabolism of acetaldehyde, a normal body constituent and major degradate of ethanol, is well documented and understood. On the basis of this rationale the Agency granted waivers from conducting both nature and magnitude of the residue studies in animals with Metaldehyde. B. **Toxicological Profile** 1. **Acute toxicity**  . The acute oral LD 50 s in rats and mice were determined to be 283 and 425 mg/kg, respectively . T he acute dermal LD 50 and acute inhalation LC 50 in rats were determined to be > 5 g/kg and > 15 mg/l, respectively ( MRID# s 131434 and 131429). When instilled into the eye of the rabbit, slight transient iridial and conjunctival irritation were observed during the first 48 hours after instillation ( MRID# 42068801). No irritation was observed when Metaldehyde was applied to the skin of the rabbit ( MRID# 131971). In a dermal sensitization study c onducted in guinea pigs, Metaldehyde was shown to be nonsensitizing ( MRID# 153405). 2. **Genotoxicty**

**.** A battery

o f tests has been conducted including assays for gene mutation in bacterial cells ( MRID# s 131433 and 41553205), chromosomal aberrations in mamm alian cells ( MRID# 163832), an in vitro gene mutation assay i n mouse ly

mphoma L5 178Y cells ( MRID# s 41553206 and 42044007) an in vivo micronucleus test in the mouse ( MRID# 42044006 ). Metaldehyde was not active in any of these assays . 3. **Reproductive and developmental toxicity**  . A developmental toxicity study in rats was conducted at Metaldehyde dose levels of 0, 25, 75 and 150 mg/kg/day ( MRID# 41656001). The doses were administered via oral gavage on gestational days 6

– 15. T he maternal no - observed eff ect level (NOEL) was 75 mg/kg/day and the developmental NOEL was greater than the highest dose level tested of 150 mg/kg/day . A developmental toxicity study in New Zealand White rabbits was conducted at Metaldehyde dose levels of 0, 10, 40 and 80 mg/kg/ day ( MRID# 41590501). There was no impact on gestational parameters, or external, visceral or skeletal variations or malformations at any of the dose levels tested. The maternal and developmental toxicity NOEL was greater than the highest dose tested (80 mg/kg/day ).5

A two - generation reproduction study w as conducted in rats fed diets containing 0, 50, 1000 and 2000 ppm of Metaldehyde ( MRID# 42823101). N o effects on the reproductive parameters, litter viability or pup survival were observed during either generation. T he NOEL for adult toxicity w as 50 ppm; the NOEL for offspring was 1000 ppm and the NOEL for reproductive effects was greater than 2000 ppm. 4. **Subchronic toxicity** . A 90 - day repeated dose dietary

neurotoxicity

study in Sprague - Dawley CD ® rats was conducted at Metaldehyde dietary concentrations of 0, 100, 500 and 2500 ppm (equivalent to 0, 8, 39 and 185 mg/kg/day , respectively ) ( MRID# 46223401). With the exception of one female in the 2500 ppm treatment group that showed loss of hind l imb function, increased respiration, wet fur, and red/brown staining around the anogenital region, no clinical signs of toxicity were observed in any

of the dose groups. Females in the 2500 ppm treatment group had decreased body

weight gain during the fir st week of the study . No treatment - related effects were observed in the behavioral, functional or sensory assessments of neurotoxicity . The NOEL for neurotoxicity

was considered to be 500 ppm (39 mg/kg/day ). 5. **Chronic toxicity** . A six - month chronic tox icity study was conducted in Beagle dogs ( MRID# 131432). Metaldehyde dose levels of 0, 20, 60 and 90 mg/kg/day were administered via the diet. No clear evidence of systemic toxicity was observed in any

of the treatment groups. A 52 - week chronic toxicity study in dogs was conducted by administering Metaldehyde via the diet at concentrations of 0, 10, 30 and 90 mg/kg/day ( MRID# 46378401). Clinical signs observed in the high - dose group included ataxia, emesis, salivation, tremor and twitching. Reduced body weight gain, changes in hematological and biochemical parameters and in increased absolute and relative liver weight also were noted for the animals in this group. Histopathology

revealed morphological changes in the testes and prostate of the animals t reated with 90 mg/kg/day

in the form of an atrophy and/or degeneration of the germinative epithelium with giant cells. One mid - and high - dose female and one mid - dose male died prior to the terminal sacrifice. The study director attributed all three death s to treatment with Metaldehyde and defined the no - observed adverse effect level (NOAEL) as 10 mg/kg/day on this basis. Since there were no other treatment - related effects observed in the 30 mg/kg/day dose group, it is somewhat questionable as to whether or not the two deaths in the mid dose group should be attributed to Metaldehyde treatment. An oncogenicity

study was conducted for a period of 78 weeks in Charles River CD - 1  mice ( MRID# 42737201). Metaldehyde dietary concentrations of 0, 25, 100 and 300 ppm were evaluated (equivalent to 4, 16 and 49 mg/kg/day for the males and 0, 5, 20 and 60 mg/kg/day for the females, respectively

). The only

treatment - related effect was hepatocellular hy pertrophy in6

the 300 ppm dose group. Pair wise comparisons and/ or life table analyses did not indicate any treatment - related effects on survival, tumor incidence or time to tumor. Because the criteria for a maximum tolerated dose was not satisfied in the initial oncogenicity study , a second 78 - week chronic oncogeni city study was conducted in Charles River CD - 1  mice ( MRID# 44625101)**.** Inthis study , Metaldehyde dietary concentrations of 0 and 1000 ppm were evaluated (equivalent to 0 and 135 mg/kg/day for the males and 0 and 163 mg/kg/day for the females). The expos ure of mice to 1000 ppm of Metaldehyde in the diet did not result in clinical signs of toxicity

or changes in survival, body weight, hematology

or toxicologically

significant changes in food consumption. Treatment - related increases in liver weight and his topathological lesions in the liver of male mice, and to a lesser extent, of female mice were observed. Significant histopathologic lesions observed in Metaldehyde treated mice included hepatocellular hy pertrophy in male and female mice and single cell ne crosis, focal and multifocal necrosis, pigment accumulation, sinusoidal histiocy tosis and hepatocellular adenoma in male mice. A small increase in the incidence of hepatocellular eosinophilic cell foci or hepatocellular adenoma in female mice treated with 1000 ppm Metaldehyde also was observed. The nature of these changes was consistent with an adaptive hy pertrophic response of the liver to an increase in metabolic demand with subsequent development of proliferative changes and hepatocellular toxicity . Th ere were no other treatment - related findings. A cell proliferation assay ( MRID# 44810901) was conducted in order to further investigate the mechanism by

which the increase in benign liver tumors occurred in the mouse oncogenicity study . Archival material from a mouse 90 - day dose range - finding study was used for this evaluation. A clear dose response for cell proliferation in the liver was observed in this assay . These findings support the conclusion that the increased incidence of benign liver tumors ob served in the mouse oncogenicity study resulted from cell proliferative effects secondary to cy totoxicity rather than a direct oncogenic effect of Metaldehyde. A chronic toxicity

/oncogenicity

s tudy w as conducted for a period of 104 weeks in Sprague - Dawle y CD ® rats ( MRID# 42203601). M etaldehyde dietary c oncentrations of 0, 50, 1000 or 5000 ppm (equivalent to 0, 2, 44, and 224 mg/kg/day f or the males and 0, 3, 60 and 314 mg/kg/day f or the females) were evaluated. N o biologically s ignificant differences in mortality , clinical signs of toxicity , palpable masses or food consumption were observed in any o f the treatment groups. Treatment of both male and female rats with 5000 ppm Metaldehyde resulted in decreased body weight and weight gain throughout the tes t period, increases in both absolute and relative liver weights, and an a numerical increase in the incidence of females at necropsy with liver masses and/or nodules at necropsy . Increased serum globulin and increased serum cholesterol for females only , h epatocellular hy

pertrophy f or males and females, and a questionable increase in the incidence of females with hepatocellular adenomas were observed in the high - dose group. T hese benign neoplasms occurred late in the course of the study and were within the range of historical control incidences for the same tumor. T herefore, this small numerical increase in hepatocellular adenomas was attributed to an uncommonly l ow number of such tumors in the concurrent control animals. Treatment - related effects in anim als fed diets containing 1000 ppm Metaldehyde were lower body7

weight and body

w eight gain in the males and females for the first ye ar of the study , increased serum cholesterol for females only , and hepatocellular hy pertrophy f or males and females. T he NOE L for systemic toxicity

after 104 weeks of dietary administration to rats was 50 ppm (2.0 mg/kg/day for males and 3.0 mg/kg/day

for females). Based on the toxicology

d ata base assembled for Metaldehyde, the acute NOAEL is considered to be 75 mg/kg/day

an d the acute Reference Dose (RfD), using a 100x safety f actor is 0.75 mg/kg/day . The chronic NOEL is considered to be 10 mg/kg/day a nd the chronic RfD, using a 100x safety f actor , is 0.1 mg/kg/day . 6. **Animal metabolism**  . A study w as conducted in Charles River CD  rats to determine the absorption, distribution, metabolism and excretion patterns of 14 C - Metaldehyde following oral dose administration ( MRID# 42300901). T he results of the study s howed that orally

a dministered Metaldehyde is readily

a bsorbed from the g astrointestinal tract and quantitatively m etabolized to acetaldehyde, which in turn is converted to acetyl - C 0 A as it enters the Krebs cycle. T his allowed the 14 C label to be eliminated as 14 C - C0 2 and to enter the two carbon pool resulting in persistent 14 C residues in tissue. The majority of the Metaldehyde was eliminated as 14 C - CO 2 . 7. **Metabolite toxicology**  . The only r esidue found in plants was parent Metaldehyde. In animal systems, Metaldehyde is metabolized to acetaldehyde (a normal body c onstitue nt) and CO 2. Therefore, only

p arent Metaldehyde is included in the proposed tolerance expressions and in the risk exposure assessment. 8. **Endocrine disruption**  . No special studies investigating the potential estrogenic or other endocrine effects of Met aldehyde have been conducted. H owever, the standard battery o f required toxicology studies has been completed. T hese include an evaluation of the potential effects on reproduction and development, and an evaluation of the pathology o f the endocrine organ s following repeated or long term exposure to doses that far exceed likely human exposures. Based on these studies there is no evidence to suggest that Metaldehyde has an adverse effect on the endocrine system.8

C. **Aggregate Exposure** 1. **Dietar y exposure**  . Acute and chronic dietary risk assessments were conducted for Metaldehyde using the Dietary Exposure Evaluation Model (DEEM) and the USDA Continuing Survey of Food Intake by

Individuals (CSFI I, for 1994 to 1996, as contained in DEEM). E xisting crop tolerances and the p roposed tolerances noted in this document were used. The results of both the chronic and acute dietary and c learly

demonstrate a reasonable certainty that no harm will result from the proposed uses of Metaldehyde. A. Acute Die tary Exposure. Based on the DEEM acute dietary risk assessment, exposure at the 95 th percentile for the overall U.S. population was estimated to be 0. 00978 mg/kg/day , which results in an Margin of Exposure (MOE) of 7668 , which is 1.3% of the acute Permi ssible Acceptable Dose (aPAD) . The highest exposed population subgroup, children 1 - 2 ye ars, had an acute exposure at the 95 th percentile that was estimated to be 0. 02171 mg/kg bw/day , which results in an MOE of 3454 and 2.9% of aPAD . B. Chronic Dieta ry Exposure. i. Food : Based on the DEEM chronic dietary risk assessment, the exposure for the overall U.S. population was estimated to be 0.00 28 mg/kg bw/day , which is 2.8% of the cPAD . The highest exposed subgroup, children 1 - 2 years, had a chronic e xposure of 0. 0058 mg/kg bw/day , which is 5.8% of the cPAD. 2. **Non -**  **dietary exposure** . A deterministic non - dietary (non - occupational) risk assessment using the Residential Exposure Assessment (Rex) model was performed for Metaldehyde applied to the ground in and around ornamental plants, small fruit and berry plants, fruit trees, vegetable garden areas ( MRID# 46524302). The maximum application rate of 3.5 lbs of active ingredient (a.i.) per acre was used. A separate assessment for use of Metaldehyde in lawn care applications was also performed ( MRID# 46524304).9

The results for the non - dietary (non - occupational) risk assessment indicate that acceptable MOEs exist for the vegetable garden (and by inference small fruits and berries), ornamental, and tree care hand dispersion scenarios. Using worst - case conditions (e.g., no gloves during application, maximum application rates, 1,000 square feet being treated for each setting, i.e., gardens, ornamentals and trees), the overall aggregate MOE for the adult applicator (dermal and inhalation routes) was approximately 400 assuming the same person applied granules to all three settings (vegetable gardens, ornamentals, and trees) on the same day . The results of the screening - level, non - dietary (resident ial) consumer applicator (dermal and inhalation) and post - application (adult dermal, and child dermal and incidental ingestion) risk analysis for Metaldehyde use for lawn care, demonstrate that acceptable Margins of Exposure (MOEs) exist for various lawn c are methods evaluated, i.e., spot treatment of lawns via hand dispersion of granules or low pressure hand - wand spraying, or granular broadcast treatment of lawns via push - spreaders. Using worst - case conditions (e.g., no gloves during application, maximum application rates, high contact reentry activities on the day

of broadcast treatment), the overall total intake ranged from approximately 0.232 mg/kg/day

for the adult applicator (dermal and inhalation routes; MOE= 3950) for granular lawn broadcast treatment (push spreader) to 0.0328 mg/kg/day

(MOE = 30,370) for spot treatment using a low pressure hand - wand sprayer. Based on this assessment, it can be concluded that the potential residential/consumer application exposures associated with the use of Metal dehyde - based products for slug and snail control are associated with a “reasonable certainty of no harm.” D. **Cumulative Effects** There is no evidence to indicate or suggest that Metaldehyde has any t oxic effects on mammals that would be cumulative with those of any other chemicals. E. **Safety Determination** 1. **U.S. population** . As indicated above, the predicted acute exposure is 0.00978 mg/kg day . Based on the acute NOAEL and reference dose (75 and 0.75 mg/kg bw/day, respectively ), this exposure estimat e results in intake of approximately 1.3% of the aRfD at the 95 th percentile (MOE = 7668 ). The predicted chronic exposure for the overall U.S. population is 0.00 28 mg/kg bw/day , or 2.8% of the cRfD (based on the chronic NOAEL of 10 mg/kg bw/day ) . Because the predicted exposures, expressed as percentages of the aRfD and cRfD are well below 100%, there is reasonable certainty that no acute or chronic effects in the U.S. population would result from dietary

exposure to Metaldehyde.10

2. **Infants a nd children**  . The population subgroup with the highest level of acute exposure at the 95 th percentile is children 1 - 2 ye ars of age. T he estimated acute exposure is 0.02171 mg/kg bw/day , or 2.9 % of the aRfD (MOE =3454 ). T he estimated chronic exposure is 0. 0058 mg/kg bw/day equivalent to 5.8 % of the cRfD. Because the predicted exposures, expressed as percentages of the aRfD and cRfD are well below 100%, there is reasonable certainty that no acute or chronic effects would result in the population subgroup wi th the highest level of exposure (children 1 - 2 ye ars) from dietary exposure to Metaldehyde. F. **International Tolerances** No incompatibilities with international tolerances are expected.