EPA REGISTRATION DIVISION - COMPANY NOTICE OF FILING FOR PESTICIDE
PETITION

Docket ID Number: EPA-HQ-OPP-2015-0558

EPA Registration Division (RD) Contact: RD

Interregional Research Project Number 4 

Pesticide Petition Number: 5E8377

EPA has received a pesticide petition (PP# 5E8377) 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
residue of the molluscicides, metaldehyde,
2,4,6,8-tetramethyl-1,3,5,7-tetroxocane, 

in or on the follow raw agricultural commodities:   wheat, forage at
0.05 parts per million (ppm); wheat, grain at 0.05 ppm; wheat, hay at
0.05 ppm; wheat, straw at 0.05 ppm; beet, garden, roots at 0.05 ppm;
beet, garden, tops (greens) at 0.08 ppm; rutabaga, roots at 0.05 ppm;
turnip, roots at 0.05 ppm; turnip, tops at 0.08 ppm; hop, dried cones 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 these data support 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).  Laser scanning cytometer
(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.   High
Performance Liquid Chromatography (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 Gas Chromatography–Mass Spectrometry
(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

Root Vegetables (garden beet, rutabaga and turnip)	6	1.001 – 1.003
pounds of active ingredient/acre (lbs. a.i./A) per application

2.002 -2.006 lbs. a.i./A (per season)	No detectable residues of
Metaldehyde (LLMV =  0.05 ppm) were found in any treated roots collected
in any trial.

Only one of the eight treated samples of top leaves collected in the
garden beet and turnip trials had a residue higher than the LLMV (0.0512
ppm)



Wheat	4	Trt 02 Plot:

0.999 – 1.002 lbs. a.i./A (per application)

2.997 – 3.006 lbs. a.i./A (per season)

Trt 03 plot:

10.039 lbs a.i./A             (per application)

30.117 lbs a.i./A             (per season)	No residues above the LLMV of
Metaldehyde were found in any treated samples of grain, straw, hay or
forage collected in the field trials in this study.

Hops	4	1.600 – 1.680 lbs. a.i./A (per application)

6.400 – 6.720 lbs. a.i./A (per season)

	No detectable residues of Metaldehyde were found in hop samples taken
at 58-64 days after application.





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 lethal dose (LD)50s in rats and mice
were determined to be 283 and 425 milligrams per kilogram (mg/kg),
respectively.  The acute dermal LD50 and acute inhalation lethal
concentration (LC)50 in rats were determined to be > 5 grams (g)/kg)
and > 15 mg/liter (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. Genotoxicity.  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 adverse
effect level (NOAEL) was 75 mg/kg/day and the developmental NOAEL 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 NOAEL 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 ppm of Metaldehyde (MRID# 42823101).  No
effects on the reproductive parameters, litter viability or pup survival
were observed during either generation.  The NOAEL for adult toxicity
was 50 ppm; the NOAEL for offspring was 1000 ppm and the NOAEL 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 NOAEL 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 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 NOAEL 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 NOAEL
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, metabolism and excretion
patterns of 14Carbon (C)-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-Carbon Dioxide(C0)2 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 Cumulative and Aggravate Risk
Evaluation System (CARES) and the USDA Continuing Survey of Food Intake
by Individuals (CSFII, for 1987 through 1994). 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 CARES acute dietary risk assessment, exposure at the 95th
percentile for the overall U.S. population was estimated to be 0.000273 
mg/kg/day, which results in a Margin of Exposure (MOE) of 275,000, which
is 0.036% 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 0.000531 mg/kg/day,
which results in an MOE of 141,180 and 0.071% 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 0.000097
mg/kg body weight (bw)/day, which is 0.10% of the c(chronic)PAD.  The
highest exposed subgroup, children 3-5 years, had a chronic exposure of
0.000240 mg/kg bw/day, which is 0.24% 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 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=
3,950) 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
0.000273 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 0.036% of the aPAD at the 95th percentile (MOE =
275,000).  The predicted chronic exposure for the overall U.S.
population is 0.000097 mg/kg bw/day, or 0.10% 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 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 0.000531 mg/kg bw/day, or 0.071%
of the aPAD (MOE =141,180).  The population subgroup with the highest
level of chronic exposure at the 95th percentile is children 3-5 years
of age. The estimated chronic exposure is 0.000240 mg/kg bw/day
equivalent to 0.24% 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 level of exposure (children 1-2
years) from dietary exposure to Metaldehyde.  

F. International Tolerances

No incompatibilities with international tolerances are expected.

 PAGE  1 

