**EPA**

**Registration Division contact: Laura Nollen, (703) 305**  **- 7390**  Interregional Research Project No. 4 (IR - 4) Pesticide Petition (PP#): 3E8223 EPA has received a pesticide petition ( PP# **3E8223** ) from Interregional Research Project No. 4 (IR - 4), Rutgers, The State University o f New Jersey , 500 College Road East, Suite 201W , Princeton, NJ 08540, proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR §180.523 by establishing a toleran ce for residues of m etaldehyde in or on the follow raw agricultural com mo dities: Clover, forage at 0.5 parts per m illion (ppm ); Clover, hay

at 0.5 ppm; Ginseng at 0.05 ppm; Vegetable legume, edible podded, subgroup 6A at 0.8 ppm; Pea and bean, succulent shelled, subgroup 6B at 0.2 ppm; Vegetable, foliage of legume, except soy bean, subgroup 7A at 1.5 ppm ; T om ato subgroup 8 - 10A at 0.24 ppm ; Fruit, citrus, group 10 - 10 at 0.26 ppm . Clover, forage and clover, hay

are proposed as tolerances with regional regist rations. Upon establishment of the tolerances proposed in “New Tolerances” the petition additionally requests to am end 40 CFR §180.523 by removing the established tolerances for residues of me taldehyde in or on the follow raw agricultural commodities: f ruit, citrus, group 10 at 0.26 ppm ; and tomato at 0.24 ppm. EPA has determined that the petition contains data or information regarding the elem ents set forth in section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated the sufficiency of the s ubm itted data at this tim e or whether the data supports granting of the petition. Additional data ma y b e needed before EPA r ules on the petition. A. **Residue Chemistry 1.**  **Plant metabolism**

. Previously submitted stu dies sponsored by Lonza Inc., established that Metaldehyde can translocate into plants and that the only residue of concern is parent Metaldehyde. The t ranslocation studies using 14 C - Metaldehyde were conducted in leaf lettuce and sugar beets (MRID Nos. 439 23301 and 43923302). LSC 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 fro m the inner leaves. The corresponding values for the beet foliage and roots were 2.87 and 0.61 ppm, respectively . HPLC 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. **Analytical method** 

. A GC/MS analy tical me thod has been developed for analy zing residues of Metaldehyde in food crops including all of the crops identified above. The lim it of quantitation (LOQ) for the me thod is 0.05 ppm . T he me t hod has been validated with respect to specificity a nd non - analy

te interference, precision (repeatability ), accuracy , sensitivity , linearity o f standards, stability o f standard solutions and precision (replicate injections) by EN - CAS Analy

tical Laboratorie s Study No. 99 - 0055 (MRID# 46010501). 3. **Magnitude of residues**

. Crop field trials were conducted in 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% Metaldehyde.

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**Summary of Residue Studies Conducted with Metaldehyde Crop**  **Number of Trials Ap**  **plication Rate Results**  Ginseng 4 1 lb. a.i./A per application 6.0 lb. ai./A per season There were no detectable residues of Metaldehyde (LLMV = 0.05 ppm) found in any treated or untreated dried ginseng root samples. Clover 4 0.798

– 0.838 lb. a.i./A (per application) 1.598

– 1.661 lbs. a.i./A (per season) The tota l residues of me taldehyde were in the ranges of <0.05

– 0.275 ppm in forage samples and <0.05 - 0.255 ppm in hay samples. Bean (Succulent Shelled) 6 0.997

– 1.000 lbs. a.i./A (per application) 2.991

– 3.000 lbs. a.i./A (per season) There were no detect able residues of Metaldehyde above the LLMV of 0.05 ppm in 4 of the 6 treated field trials. Remaining 2 field trials, quantifiable residues were found in the treated samples, with the m aximum residue measured 0.152 ppm . Bean and Pea (Edible Podded) 7 (bea n) 3 (pea) 0.988

– 1.004 lbs. a.i./A

( per application) 2.988

– 3.012 lbs. a.i./A (per season) Metaldehyde residues were in the range <0.05 - 0.432 ppm in edible podded beans and <0.050 - 0.258 ppm for edible podded peas, 0.0600 - 0.668 ppm for bean foliage, and <0.05

– 0.352 ppm for pea foliage. Pea (Succulent Shelled) 7 0.999

– 1.083 lb. a.i./A (per application) 2.997

– 3.246 lbs. a.i/A (per season) Metaldehyde residues were in the range <0.05

– 0.140 ppm

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4. **Magnitude of the Residue in Animals** . Metaldeh yd e is a cyclic tetramer of acetaldehyde. Therefore, me tabolism in animal systems will result in the release of acetaldehyde, a normal body constituent. The me tabolism of acetaldehyde, a normal body constituent and major degradate of ethanol, is well doc um ented 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 a nd mi ce were determined to be 283 and 425 mg /kg, respectively . T he acute derm al LD 50 and acute inhalation LC 50 in rats were determ ined to be > 5 g/kg and > 15 mg /l, respectively

( MRID#s 131434 and 131429). W hen instilled into the eye of the rabbit, sligh t 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). I n a dermal sensitization study conducted in guinea pigs, Metaldehyde was shown to be nonsensitizing (MRID# 153405). 2. **Genotoxic i** **ty.** A battery o f tests has been conducted including assays for gene mu tation in bacterial cells (MRID#s 131433 and 41553205), chromosomal aberrations in m am ma lian cells (MRID# 163832), an in vitro gene mu tation assay

i n mo use ly mp hom a L5178Y cells (MRID#s 41553206 and 42044007) an in vivo mi cronucleus test in the mouse (MRID# 42044006 ). Metaldehyde was not active in any of these assays 3. **Reproductive an d developmental toxicity** 

. A developm ental toxicity study in rats was conducted at Metaldehyde dose levels of 0, 25, 75 and 150 mg /kg/day (MRID# 41656001). The doses were adm inistered via oral gavage on gestational days 6

– 15. The maternal no - observed e ffect level (NOEL) was 75 mg /kg/day

and the developm ental NOEL was greater than the highest dose level tested of 150 mg /kg/day

. A developm ental toxicity study in New Zealand W hite rabbits was conducted at Metaldehyde dose levels of 0, 10, 40 and 80 mg /k g/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 developm ental toxicity NOEL was greater than the highest dose tested ( 80 mg /kg/day ). A two - generation reproduction study was conducted in rats fed diets containing 0, 50, 1000 and 2000 ppm o f Metaldehyde (MRID# 42823101). No effects on the reproductive parameters, litter viability o r pup survival were observed during eith er generation. T he NOEL for adult toxicity was 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

C D ® 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). W ith the exception of one female in the 2500 ppm treatment group that showed loss of hind li mbfunction, 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 firs t 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 ).

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5. **Chronic toxicity**

. A six - mo nth chronic toxi city study was conducted in Beagle dogs (MRID# 131432). Metaldehyde dose levels of 0, 20, 60 and 90 mg/kg/day were adm inistered 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 hem atological and biochemical parameters and in increased absolute and relative liver weight also were noted for the animals in this group. Histopathology revealed m orphological changes in the testes and prostate of the animals treated 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 deaths 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 o r 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 ® mi ce (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 in the 300 ppm dose group. Pair wise comparisons and/or l ife 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 oncogenicity study was conducted in Charles River CD - 1 ® mi ce (MRID# 44625101) **.** In this study , Metaldehyde dietary concentrations of 0 and 1000 ppm were evaluated (equivalent to 0 and 135 m g/kg/day for the males and 0 and 163 mg /kg/day for the females). The exposure of mice to 1000 ppm of Metaldehyde in the diet did not result in clinical signs of toxicity or changes in survival, body weight, hem atology

or toxicologically

significant changes in food consumption. Treatment- related increases in liver weight and histopa thological 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 m ale and female mice and single cell necros is, focal and multifocal necrosis, pigment accumulation, sinusoidal histiocytosis and hepatocellular adenoma in ma le m ice. A small increase in the incidence of hepatocellular eosinophilic cell foci or hepatocellular adenom a 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 dem and with subsequent developm ent of proliferative changes and hepatocellular toxicity . There 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 fro m 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 observ ed in the m ouse oncogenicity study resulted from cell proliferative effects secondary to cy totoxicity rather than a direct oncogenic effect of Metaldehyde. A chronic toxicity

/oncogenicity

study was conducted for a period of 104 weeks in Sprague - Dawley C D ® rats (MRID# 42203601). Metaldehyde dietary c oncentrations of 0, 50, 1000 or 5000 ppm ( equivalent to 0, 2, 44, and 224 mg /kg/day

for the ma les and 0, 3, 60 and 314 mg /kg/day for the females) were evaluated. N o biologically

s ignificant differences in mo rtality , clinical signs of toxicity , palpable ma sses or food consumption were observed in any

o f the treatment groups. T reatment of both ma le and female rats with 5000 ppm Metaldehyde resulted in decreased body weight and weight gain throughout the test pe riod, increases in both absolute and relative liver weights, and an a num erical increase in the incidence of females at necropsy w ith liver ma sses and/or nodules at necropsy . I ncreased serum globulin and increased serum cholesterol for

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females only , hepat ocellular hy pertrophy for ma les and females, and a questionable increase in the incidence of females with hepatocellular adenom as were observed in the high - dose group. These benign neoplasm s occurred late in the course of the study a nd were within the ran ge of historical control incidences for the same tumor. T herefore, this small num erical increase in hepatocellular adenom as was attributed to an uncommonly low num ber of such tumors in the concurrent control anim als. T reatment- related effects in anim als fed diets containing 1000 ppm M etaldehyde were lower body weight and body

weight gain in the ma les and females for the first year of the study , increased serum cholesterol for females only , and hepatocellular hy pertrophy for ma les and females. T he NOEL fo r systemic toxicity a fter 104 weeks of dietary a dm inistration 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

and th e acute Reference Dose (RfD), using a 100x safety factor is 0.75 m g/kg/day . T he chronic NOEL is considered to be 10 mg/kg/day and the chronic RfD, using a 100x safety factor, is 0.1 mg/kg/day

. 6. **Animal metabolism** 

. A study was conducted in Charles River CD ® rats to determine the absorption, distribution, me tabolism and excretion patterns of 14 C - Metaldehyde following oral dose adm inistration (MRID# 42300901). T he results of the study s howed that orally

a dm inistered Metaldehyde is readily a bsorbed from th e gastrointestinal tract and quantitatively metabolized to acetaldehyde, which in turn is converted to acety l - C 0A 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. T he ma jority of the Metaldehyde was elim inated as 14 C - CO 2 . 7. **Metabolite toxicology** 

. The only residue found in plants was parent Metaldehyde. I n anim al systems, Metaldehyde is me tabolized to acetaldehyde (a normal body consti tuent) 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 Metaldehyde have been conducted. H owever, the standard battery of required toxicology

s tudies has been completed. These include an evaluation of the potential effects on reproduction and development, and an evaluation of the pathology o f the endocrine organs 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. C. **Ag gregate Exposure**  1. **Dietary expo sure**  . Acute and chronic dietary risk assessments were conducted for Metaldehyde using the Cumulative and Aggravate Risk Evaluation System (CARES) and the USDA Continuing Survey of Food Intake by

Individuals (CSFII, for 1987 through 1994). Existing crop tol erances and the proposed tolerances noted in this document were used. The results of both the chronic and acute dietary and clearly demonstrate a reasonable certainty that no harm will result from the proposed uses of Metaldehyde. A. Acute Dietary Exp osure. Based on the CARES acute dietary risk assessment, exposure at the 95 th percentile for the overall U.S. population was estim ated to be 0.00314 mg/kg/day , which results in a Margin of Exposure (MOE) of 23876, which is 0.42% of the acute Permissible Acceptable Dose (aPAD).

### 6 The highest exposed population subgroup, children 1 - 2 years, had an acute exposure at the 95 th percentile that was estimated to be 0.00801 mg/kg/day , which results in an MOE of 9364 and 1.07% of aPAD. B. Chronic Dietary Exposure. i. Food : Based on the CARES chronic dietary risk assessment, the exposure for the overall U.S. population was estimated to be 0.0010 mg/kg bw/day , which is 1.03% of the cPAD. The highest exposed subgroup, children 1 - 2 years, had a chronic exposure of 0.0027 mg/kg bw/day , which is 2.67% 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). 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 appli cator (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 (residential) consume r 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 care methods evaluated, i.e., spot treatment of lawns via hand dispersion of granules or low pressure hand -wand spray ing, 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 Metaldehyde - based products for slug and snail control are associated with a “reasonable certainty

of no harm.”

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D. **Cumulative Effects** There is no evidence to indicate or suggest that Metaldehyde has any toxic effects on ma mma ls 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 0.00314 mg/kg day . Based on the acute NOAEL and reference dose (75 and 0.75 mg/kg bw/day , respectively ), this exposure estimate results in intake of approximately 0.42% of the aPAD at the 95 th percentile (MOE = 23876). The predicted chronic exposure for the overall U.S. population is 0.0010 mg/kg bw/day , or 1.03% of the cPAD (based on the chronic NOAEL of 10 mg/kg bw/day ). Because the predicted exposures, expressed as percentages of the aPAD and cPAD 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.

2. **Infants and**  **children**

. The p opulation 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 0.00801 mg /kg bw/day , or 1.07% of the aPAD (MOE =9364). T he estimated chronic exposure is 0.0027 mg /kg bw/day equivalent to 2.67% of the cPAD. Because the predicted exposures, expressed as percentages of the aPAD and cPAD are well below 100%, there is reasonable certainty that no acute or chronic effects would result in the population subgroup with the highest l evel of exposure (children 1 - 2 years) from dietary exposure to Metaldehyde. F. **International Tolerances** No incompatibilities with international tolerances are expected.