Document ID: EPA-HQ-OPP-2012-0706-0002
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2012-09-28T04:00Z

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 petition, PP# 2E8070, from Interregional
Research Project No. 4 

(IR-4), Rutgers, The State University of 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 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; Leaf
petioles subgroup 4B  at 0.80 ppm; Peppermint, tops at 3.5 ppm;
Spearmint, tops at 3.5 ppm; Peppermint, oil at 14 ppm; Spearmint, oil at
14 ppm; Caneberry subgroup 13-07A at 0.15 ppm; Bushberry subgroup 13-07B
at 0.15 ppm; Berry, low growing, subgroup 13-07G at 6.25 ppm; Taro, corm
at 0.25 ppm; Taro, leaves at 0.60 ppm; Corn, field, grain at 0.05 ppm;
Corn, field, stover at 0.15 ppm; Corn, field, forage at 0.25 ppm; Corn,
sweet, kernel plus cob with husks removed at 0.05 ppm; Soybean, seed 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 evaluated the sufficiency of the submitted
data at this time or whether the data supports granting of the petition.
 Additional data may be needed before EPA rules on the petition.

A. Residue Chemistry                                      

1.   Plant metabolism. Previously submitted studies sponsored by Lonza
Inc., established that Metaldehyde can translocate into plants and that
the only residue of concern is parent Metaldehyde. The translocation
studies using 14C-Metaldehyde were conducted in leaf lettuce and sugar
beets (MRID Nos. 43923301 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
14C-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, respectively.   HPLC analysis
of treated lettuce and beet samples showed that 100% of the
radioactivity in the lettuce and beet samples consisted of parent
14C-Metaldehyde.

.

2.   Analytical method.  A GC/MS analytical method has been developed
for analyzing residues of Metaldehyde in food crops including all of the
crops identified above.  The limit of quantitation (LOQ) for the method
is 0.05 ppm.  The method has been validated with respect to specificity
and non-analyte interference, precision (repeatability), accuracy,
sensitivity, linearity of standards, stability of standard solutions and
precision (replicate injections) by EN-CAS Analytical Laboratories 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.

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 ppm.  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. 

Soybeans	7	0.400-0.403 lbs. 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 in any treated soybean samples.

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 samples and <0.050-1.29 ppm in hay samples.

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 samples 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
ppm 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.  Magnitude 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 LD50s in rats and mice were
determined to be 283 and 425 mg/kg, respectively.  The acute dermal
LD50 and acute inhalation LC50 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 conducted in guinea pigs, Metaldehyde was
shown to be nonsensitizing (MRID# 153405).

2. Genotoxicty.  A battery of tests has been conducted including assays
for gene mutation in bacterial cells (MRID#s 131433 and 41553205),
chromosomal aberrations in mammalian cells (MRID# 163832), an in vitro
gene mutation assay in mouse lymphoma L5178Y 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.  The maternal no-observed effect
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). 

A two-generation reproduction study was conducted in rats fed diets
containing 0, 50, 1000 and 2000 ppm of Metaldehyde (MRID# 42823101). 
No effects on the reproductive parameters, litter viability or pup
survival were observed during either generation.  The 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 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 limb
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 first 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 toxicity 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 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 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
hypertrophy in 

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 oncogenicity
study was conducted in Charles River CD-1 mice (MRID# 44625101).  In
this 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 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, hematology or toxicologically
significant changes in food consumption.  Treatment-related increases in
liver weight and histopathological 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 hypertrophy in male and female mice and single cell
necrosis, focal and multifocal necrosis, pigment accumulation,
sinusoidal histiocytosis 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 hypertrophic response of the liver to an
increase in metabolic demand with subsequent development 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 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 observed in the mouse oncogenicity
study resulted from cell proliferative effects secondary to cytotoxicity
rather than a direct oncogenic effect of Metaldehyde. 

A chronic toxicity/oncogenicity study was conducted for a period of
104 weeks in Sprague-Dawley CD® rats (MRID# 42203601).  Metaldehyde
dietary concentrations of 0, 50, 1000 or 5000 ppm (equivalent to 0, 2,
44, and 224 mg/kg/day for the males and 0, 3, 60 and 314 mg/kg/day for
the females) were evaluated.  No biologically significant differences in
mortality, clinical signs of toxicity, palpable masses or food
consumption were observed in any of the treatment groups.  Treatment of
both male and female rats with 5000 ppm Metaldehyde resulted in
decreased body weight and weight gain throughout the test 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, hepatocellular hypertrophy
for males and females, and a questionable increase in the incidence of
females with hepatocellular adenomas were observed in the high-dose
group.  These benign neoplasms occurred late in the course of the study
and were within the range of historical control incidences for the same
tumor.  Therefore, this small numerical increase in hepatocellular
adenomas was attributed to an uncommonly low number of such tumors in
the concurrent control animals.  Treatment-related effects in animals
fed diets containing 1000 ppm Metaldehyde were lower body weight and
body weight gain in the males and females for the first year of the
study, increased serum cholesterol for females only, and hepatocellular
hypertrophy for males and females.  The NOEL 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 data base assembled for Metaldehyde, the acute
NOAEL is considered to be 75 mg/kg/day and the acute Reference Dose
(RfD), using a 100x safety factor is 0.75 mg/kg/day.  The 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.

 rats to determine the absorption, distribution, metabolism and
excretion patterns of 14C-Metaldehyde following oral dose administration
(MRID# 42300901).  The results of the study showed that orally
administered Metaldehyde is readily absorbed from the gastrointestinal
tract and quantitatively metabolized to acetaldehyde, which in turn is
converted to acetyl-C0A as it enters the Krebs cycle.  This allowed the
14C label to be eliminated as 14C-C02 and to enter the two carbon pool
resulting in persistent 14C residues in tissue.  The majority of the
Metaldehyde was eliminated as 14C-CO2.  

7. Metabolite toxicology. The only residue found in plants was parent
Metaldehyde.  In animal systems, Metaldehyde is metabolized to
acetaldehyde (a normal body constituent) and CO2.  Therefore, only
parent 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.  However, the standard battery of required toxicology studies
has been completed.  These include an evaluation of the potential
effects on reproduction and development, and an evaluation of the
pathology of 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. Aggregate Exposure

1. Dietary 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
(CSFII, for 1994 to 1996, as contained in DEEM). Existing crop
tolerances 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 Exposure.  

Based on the DEEM acute dietary risk assessment, exposure at the 95th
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 Permissible Acceptable Dose (aPAD).  The highest
exposed population subgroup, children 1-2 years, had an acute exposure
at the 95th 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 Dietary Exposure.  

i. Food:  Based on the DEEM chronic dietary risk assessment, the
exposure for the overall U.S. population was estimated to be 0.0028
mg/kg bw/day, which is 2.8% of the cPAD .  The highest exposed subgroup,
children 1-2 years, had a chronic exposure 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).  

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 (residential) 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 care 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
Metaldehyde-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
toxic 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 estimate results in
intake of approximately 1.3% of the aRfD at the 95th percentile (MOE =
7668).  The predicted chronic exposure for the overall U.S. population
is 0.0028 mg/kg bw/day, or 2.8% of the cRfD (based on the chronic NOAEL
of 10 mg/kg bw/day).

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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.  

2.   Infants and children. The population subgroup with the highest
level of acute exposure at the 95th percentile is children 1-2 years of
age.  The estimated acute exposure is 0.02171 mg/kg bw/day, or 2.9% of
the aRfD (MOE =3454).  The 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 with the highest level of exposure (children 1-2
years) from dietary exposure to Metaldehyde.  

F. International Tolerances

No incompatibilities with international tolerances are expected.

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