[Federal Register Volume 62, Number 122 (Wednesday, June 25, 1997)]
[Notices]
[Pages 34261-34271]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-16655]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-736; FRL-5719-6]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-736, must
be received on or before July 25, 1997.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7506C), Office of Pesticides Programs, Environmental Protection
Agency, 401 M St., SW., Washington, DC 20460. In person bring comments
to: Rm. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically by following
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential
business information should be submitted through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: The product manager listed in the
table below:
[[Page 34262]]
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Product Manager/Regulatory Office location/
Leader telephone number Address
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Elizabeth Haeberer............ Rm. 207, CM #2, 703- 1921 Jefferson
308-2891, e- Davis Hwy,
mail:haeberer.elizabe Arlington, VA
[email protected].
Indira Gairola (Reg. Leader).. 4th floor, CS #1, 703- 2800 Crystal
308-8371, e-mail: Drive,
gairola.indira@epamai Arlington, VA
l.epa.gov.
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SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various food
commodities under section 408 of the Federal Food, Drug, and Comestic
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions
contain data or information regarding the elements set forth in section
408(d)(2); 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.
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-736] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
[email protected]
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number [PF-736] and appropriate petition
number. Electronic comments on this notice may be filed online at many
Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: June 9, 1997.
James Jones,
Acting Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Petitioner summaries of the pesticide petitions are printed below
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. EPA is publishing the petition summaries verbatim
without editing them in any way. The petition summary announces the
availability of a description of the analytical methods available to
EPA for the detection and measurement of the pesticide chemical
residues or an explanation of why no such method is needed.
1. Gaylord Chemical Corporation
PP 5E4592
EPA has received a Supplement to a Petition (PP 5E4592) from
Gaylord Chemical Corporation, P.O. Box 1209, Slidell, LA 70459-1209,
proposing, pursuant to section 408(d)(3) the Federal Food, Drug and
Cosmetic Act, 21 U.S. C. section 346a(d), to amend 40 CFR 180.1001(d)
to extend the existing exemption from a tolerance for residues of the
inert ingredient DMSO [dimethyl sulfoxide] by permitting its use in
pesticide formulations applied to the edible parts of food or feed
crops. DMSO may currently be used as a solvent or cosolvent in end-use
pesticides that are applied before crop emergence or prior to the
formation of edible parts of food plants.
Dimethyl sulfoxide (DMSO) is widely used as a solvent in industry,
in chemical and biochemical research, and in medicines. DMSO readily
penetrates the skin and has proven to be an effective carrier of
various pharmaceutical agents into the body. It is currently used in
veterinary medicinal formulations as well as being used medicinally in
its own right. DMSO has been shown to relieve pain and reduce swelling
when applied dermally to acute sprains and strains. It is approved for
a variety of human prescriptions in over 125 countries. In the United
States, DMSO is FDA-approved for treatment of musculoskeletal injuries
in horses, acute or chronic otitis in dogs, and interstitial cystitis
in humans. In Canada, DMSO is approved for the treatment of scleroderma
while in Germany it is approved for the treatment of sports injuries
and in the United Kingdom for treatment of herpes zoster.
On August 21, 1995, Gaylord Chemical Corporation (Gaylord)
submitted to the EPA a tolerance exemption petition (PP 5E4592)
entitled ``Petition for Extension of Existing Exemption from Tolerance
for the Inert Ingredient, DMSO''. That petition proposed to amend 40
CFR part 180.1001(d) by allowing DMSO to be applied to the edible parts
of food and feed crops when used in end-use pesticide formulations as a
solvent or a cosolvent at up to 10 percent of finished sprays or tank
mixes. Gaylord now proposes to amend their petition to clarify that
DMSO is intended for applications at not more than 5 lbs. DMSO per acre
when used as a solvent or cosolvent in end-use pesticide formulations
applied to the edible parts of food and feed crops.
Pursuant to the section 408(d)(2)(A)(i) of the FFDCA, as amended,
Gaylord Chemical Corporation has submitted the following summary of
information, data and arguments in support of their tolerance exemption
petition. This summary was prepared on behalf of Gaylord Chemical
Corporation and EPA has not fully evaluated the merits of the petition.
The summary may have been edited by EPA if the terminology used was
unclear, the summary contained extraneous material, or the summary was
not clear that it reflected the conclusion of the petitioner and not
necessarily EPA.
Based on petition PP 5E4592, as amended, by the supplemental
information presented herein, Gaylord Chemical Corporation concludes
that the expanded use of DMSO in pesticide end-use formulations applied
to the edible parts of food and feed crops will not result in DMSO
dietary exposures of toxicological consequence for the following
reasons: (1) DMSO is widely distributed and naturally-occurring in
plants and the environment; (2) DMSO is extensively metabolized by
plants following either root or foliar uptake; (3) When ingested or
dermally applied,
[[Page 34263]]
DMSO is practically non acutely toxic, nor is it genotoxic or
carcinogenic; (4) DMSO is rapidly metabolized and excreted by animals
and humans without any evidence of bioaccumulation; (5) DMSO is not
anticipated to cause any cumulative effects; and (6) There is no
evidence that DMSO is an endocrine disruptor.
A. Proposed Use Practices of DMSO
DMSO is a pesticidally inert ingredient that currently is exempted
[40 CFR (180.1001(d)] from the requirement of a tolerance for residues
when used as a solvent or cosolvent in pesticide formulations applied
before crop emergence from the soil or prior to formation of edible
parts of food plants. There are no other limits for DMSO expressed in
40 CFR (180.1001(d). The proposed amended use would allow DMSO
applications at not more than 5 lbs. DMSO per acre when used as a
solvent or cosolvent in end-use pesticide formulations applied to the
edible parts of food and feed crops.
B. Natural Occurrence of DMSO
Researchers have estimated that approximately 20 - 60 billion
pounds of DMSO are created in the atmosphere each year from naturally-
occurring, atmospheric dimethyl sulfide (DMS). DMSO is also found in
natural waters, where it is believed to be produced by photochemical
oxidation of dimethyl sulfide (DMS) generated by algae and
phytoplankton. There is also evidence that DMSO is found naturally in
soils and is metabolized by a variety of microorganisms, resulting in
volatilization of sulphur from soil.
Naturally-occurring DMSO has been identified in alfalfa, asparagus,
barley, beans, beets, cabbage, corn, cucumbers, oats, onions, Swiss
chard, tomatoes, apples, raspberries, spearmint, beer, milk, coffee and
tea. DMSO concentrations in fresh fruit, vegetables and grains ranged
from undetectable (<0.05 parts per million (ppm) to 1.8 ppm. In
processed products such as sauerkraut or tomato paste, concentrations
of DMSO ranged from <0.05 to 3.7 ppm. DMSO was also found in milk (0.13
ppm), lager beer (1.4 ppm), coffee (2.6 ppm) and black tea (16.0 ppm).
In forage crops such as alfalfa and corn silage, DMSO levels were 0.17
and 0.31 ppm, respectively.
C. Product Identity/Chemistry
1. Identity of inert compound and corresponding residues. Dimethyl
sulfoxide (CAS number 67-68-5) is commonly known and abbreviated as
DMSO. Other names for DMSO are sulfinylbismethane and methyl sulfoxide.
The molecular weight of DMSO is 78.13, the empirical formula is C2H6SO,
and the structural formula is (CH3)2SO. DMSO is a very hygroscopic
liquid with practically no odor or color. Residues of DMSO include
DMSO2 (dimethyl sulfone) and DMS (dimethyl sulfide).
2. Plant metabolism. The metabolism of DMSO in plants is well
understood. Extensive studies have shown that: (1) DMSO is absorbed by
plant roots and foliage; (2) translocation of DMSO is primarily upward
and associated with the transpirational stream; (3) metabolism of DMSO
is primarily occurs in the foliage; (4) DMSO is metabolized to DMSO2 by
oxidation, to volatile DMS by reduction and to components that are
incorporated into sulfur-containing amino acids and proteins; (5) DMSO
does not accumulate in plant tissues; and (6) the amount of residue is
dependent on the time since application.
3. Analytical methods. Validated analytical methods for residues of
DMSO in or on plant and animal tissues are available. DMSO is extracted
from the samples, analyzed by gas chromatography using a flame
photometric detector operating in the sulfur mode and quantified by
comparison to external standards.
4. Magnitude of the residues. In 1 study, 15 food or feed crops
were treated with DMS35O at a rate of 5 lbs per acre 24 hours before
harvest. The maximum total radioactive residue (TRR) found in forage
crops was 39.16 ppm. Among the food crops, grain from fall-planted
barley had maximum total S35 residues (5.38 ppm), while red raspberries
had residues of 1.81 ppm. All of the other treated crops had residues
less than 1 ppm with those in or on sweet corn, cabbage, apples, onions
and dried beans at less than 0.01 ppm.
A series of studies were also conducted to determine the types of
residues and the level of S35 in milk and tissues of lactating goats
and in eggs and tissues of chickens fed 20, 60 or 200 ppm DMS35O in the
diet for 28 days. Summary results are: (1) the maximum amounts of
DMS35O in milk, eggs, and goat and chicken tissues from the 20 ppm
DMS35O feeding level were 0.06, 0.28, 0.20 and 0.44 ppm, respectively,
and TRR was 0.64, 3.00, 3.86 and 2.13 ppm, respectively ; (2) most of
the DMS35O activity fed to the test animals was eliminated or
metabolized to DMS35O2 and higher molecular weight S35-bearing
compounds; (3) total S35 and DMS35O activities in milk and eggs
remained fairly constant within each feeding level for the 28-day
feeding period (i.e., no accumulation of S35 activity with time); (4)
there was no accumulation of total S35 activity in chicken and goat
tissues at any feeding level; and (5) the largest amounts of total S35
activity were found in goat liver and kidney and in chicken liver and
muscle.
D. Toxicological Profile
1. Acute toxicity. DMSO has low acute toxicity and is practically
non-toxic (LD50 > 5 g/kg) by ingestion or dermal
application. Rat oral LD50s are reported from 14.5 to 28.3
g/kg, whereas LD50s for mice have been reported from 16.5 to
24.6 g/kg. The acute dermal LD50 is 40 g/kg for the rat and
50 g/kg for the mouse, while dermal LD50s > 11 g/kg are
reported for both dogs (beagles) and primates (rhesus monkeys). The
acute rat inhalation LC50 > 1.6 mg/l, the only dose level
tested, and which is also the no-observed-effect-level (NOEL). Although
DMSO can cause skin and eye irritation, it is not a skin sensitizer.
2. Genotoxicity. DMSO is not mutagenic to Salmonella, Drosophila,
and fish cell cultures. Because DMSO is not considered to be mutagenic,
it is widely used as a solvent in mutagenicity testing. Although DMSO
is bacteriostatic or bactericidal at concentrations of 5-50 percent,
there is no evidence that DMSO causes chromosomal aberrations at levels
that are not directly toxic to cells. In vivo cytogenetic studies with
primates receiving orally or dermally administered DMSO showed no
abnormalities in bone marrow smears. There are no documented adverse
genetic effects reported as a result of medicinal DMSO uses (including
quasi-medicinal uses for treatment of arthritis or sprains and
strains). Additionally, no adverse genetic effects have been reported
from occupational exposure to DMSO in over 40 years of industrial use.
3. Reproductive and developmental toxicity. A mouse teratology NOEL
of 12 g/kg/day has been established based on research with a 50 percent
DMSO solution administered orally. Additional teratogenicity studies of
orally administered DMSO to pregnant mice, rats, rabbits and guinea
pigs have demonstrated that DMSO is not a teratogen in mammals except
at high levels that cause overt maternal toxicity and are coincident
with the maximum tolerated dose. The data suggest that DMSO is not
teratogenic at low levels regardless of the route of administration.
Finally, the teratogenic potential of DMSO is dependent on the route of
administration, the dose level and gestation stage at exposure.
[[Page 34264]]
4. Subchronic toxicity. A subchronic rat inhalation study
established a NOEL at 200 mg/m3 (0.2 mg/l), the only
concentration tested. Extensive monitoring of human patients have shown
that DMSO does not affect human renal function. DMSO is a diuretic but
no sign of kidney damage has been found in humans or laboratory animals
after repeated DMSO treatment.
5. Chronic toxicity. DMSO is not listed as a carcinogen by IARC,
NTP, OSHA or ACGIH, based on reviews of numerous studies. In fact, a
study supported by the US Public Health Services concluded that DMSO
was not a carcinogen and is a safe carrying agent analogous to mineral
oil. An 18-month study with rhesus monkeys established an oral NOEL of
3 g/kg/day. No tumors were observed and bone marrow smears from the
monkeys that received oral or topical doses of DMSO at up to 9 g/kg/day
for 18 months showed no DMSO effects. A 78-week rat study revealed no
increases in mortality or tumors and established an oral NOEL of 3.3 g/
kg/day based on hematology and ocular effects. If one considers the
rhesus monkey to be the most appropriate model for extrapolation to
humans, the oral monkey NOEL of 3 g/kg/day is comparable to an average
human (70 kg) consuming approximately 210 g DMSO per day. Continuing
research has demonstrated that the ocular effects reported from DMSO
treatment of dogs, rabbits, guinea pigs and swine are species-specific
and not reproducible in primates, including humans. In fact, 84 humans
that have received daily topical treatment of 2.6 g DMSO/kg/day for up
to 3 months showed no DMSO-related effects beyond occasional skin
irritation and garlicky breath and body odor.
6. Human and animal metabolism. DMSO is metabolized in humans by
oxidation to DMSO2 or by reduction to DMS. DMSO and DMSO2 are excreted
in the urine and feces. DMS is eliminated through the breath and skin
with a characteristic garlicky or oyster-like odor. Human excretion of
orally administered DMSO is complete within 120 hours, with up to 68
percent as unchanged DMSO and 21-23 percent as DMSO2 excreted in the
urine. The rate of renal clearance has been shown to be similar for
chronic and singly administered doses regardless of dose concentration.
No residual accumulation of DMSO has been reported in humans or lower
animals who have received DMSO treatment for protracted periods of
time, regardless of route of dose administration.
7. Metabolite toxicity. The metabolites of DMSO are DMSO2, which is
naturally-occurring at low levels in human urine, and DMS, which is
naturally-occurring in plants, the atmosphere, and lakes and oceans.
Both of these metabolites are readily excreted from the body. Based on
their widespread natural occurrence and ready degradation and/or
excretion, the production of these metabolites from the proposed use of
DMSO on food producing plants is not expected to pose any toxicological
concern.
E. Aggregate Exposure
1. Dietary exposure. While potential dietary exposure is usually
determined by multiplying the residue tolerance level for each exposed
food or feed crop by its dietary consumption data then summing the
residue contributions from all dietary sources, this method is not
possible for DMSO for the following reasons: (1) because DMSO is
naturally-occurring in many plants as well as in natural waters, the
daily intake of endogenous DMSO is unknown; (2) residue data are only
available for some of the raw agricultural commodities (RAC) that may
potentially be exposed to DMSO from its proposed use in pesticides; and
(3) it is unknown at this time which RACs will be exposed to DMSO used
in pesticides applied to edible crop parts.
However, one can broadly estimate dietary exposure based on certain
assumptions and/or generalizations, the available residue data to
estimate conservative residue levels in broad crop groupings, and
dietary consumption information for categories of food commodities. For
example, information on per capita consumption data provided by food
and nutrition specialists allows the following estimate of daily food
consumption: meat - 0.5 lbs, dairy - 1.0 lbs, fruit and vegetables -
2.0 lbs and grains - 2.0 lbs, for a daily food consumption of 5.5 lbs
or 2.5 kg food per day.
2. Food. When DMSO is applied at up to 5.0 lbs/acre to the edible
parts of food and feed crops, dietary exposure to DMSO can be estimated
from naturally-occurring DMSO levels in various food and feedstuffs in
combination with those from crops harvested 24 hours after DMSO
application. Maximum theoretical DMSO residues were 0.5 to 4 ppm in or
on fruits and vegetables, up to about 10 ppm in or on small grains, and
up to about 40 ppm in or on forage grasses and legumes.
Theoretical residues of DMSO in the human diet from meat and dairy
products were determined from theoretical animal diets, the available
crop residue data converted to dry weight basis and residue data from
animal feeding studies. Based on these estimates of DMSO in bovine and
poultry diets, bovine meat (liver) and milk would contribute 19.2 ppm
and 8.0 ppm DMSO to the human diet, respectively, while poultry meat
(liver) and eggs would contribute 2.1 ppm and 3.0 ppm DMSO to the diet.
Using the available residue data for DMSO in the raw agricultural
commodities (RACs) and animal products in concert with dietary
consumption information, total daily dietary intake of DMSO in human
diet would be 0.0207 g (20.7 mg) DMSO. DMSO levels (ppm) in the human
diet from endogenous sources and the proposed uses of DMSO in pesticide
formulations are estimated to be 8.66 ppm. For dietary risk
calculations, a more conservative value of 10.0 ppm will be used for
estimated DMSO levels in human diet.
3. Drinking water. Based on the natural occurrence of DMSO in the
environment, its chemical and biological characteristics and little-to-
no mobility in soil, the expanded agronomic usage of DMSO is not
expected to significantly increase drinking water exposures to DMSO.
DMSO is found in many natural waters but concentrations are dependent
on DMSO producing algae and other natural variables. It is unknown if
or at what levels DMSO would be found in municipal or private water
systems. Any DMSO that may be oversprayed to the soil from applications
to crops would be rapidly metabolized by a wide variety of
microorganisms, thereby diminishing ground or surface water exposure to
DMSO. Additionally, environmental studies have shown little-to-no
mobility of DMSO in the soil. Finally, DMSO is already cleared as a
pesticidal inert for use in products applied to crops. Therefore, the
proposal to expand the application timing of DMSO from early in the
cropping season to include the entire cropping season would not be
expected to significantly increase exposure of drinking water sources
to DMSO.
4. Non-dietary exposure. The only anticipated human exposure to
DMSO from non-dietary sources would be through occupational exposure,
medicinal or quasi-medicinal uses of DMSO. DMSO applied to plants is
rapidly absorbed and metabolized. When oversprayed to soils during
agronomic use, DMSO is metabolized by a wide variety of soil
microorganisms. DMSO is legally and readily available in health stores
in many states and is reportedly used as a unregistered topical
treatment for arthritis, muscle strains and sprains and bursitis.
However, while these uses are not FDA-approved,
[[Page 34265]]
they have been practiced for 30 to 40 years with no documented ill
effects beyond skin irritation to humans. Dermal exposure to very low
levels of naturally-occurring DMSO may also occur from swimming in
lakes or in the ocean.
F. Cumulative Effects
There is no reliable information to indicate that DMSO has a common
mechanism of toxicity with any other chemical compound. Therefore, for
cumulative exposure considerations, Gaylord believes it is appropriate
to consider only the potential risks of DMSO.
Metabolism studies in humans and animals have shown that DMSO is
not bioaccumulative. Since DMSO is naturally-occurring in many if not
most fruits, vegetables and grains, is readily metabolized and
eliminated, and has low toxicity, there would not be any anticipated
increased human risk or adverse effects from DMSO applied to edible
parts of plants. Plant-eating animals, including humans, ingest
endogenous DMSO on a daily basis throughout their life as part of the
normal diet. Ingestion of low-level DMSO residues resulting from
agronomic use of DMSO will not increase the body burden of this
efficiently metabolized and excreted compound.
G. Endocrine Effects
In light of the ubiquitous natural occurrence of this compound and
the absence of any reported endocrine effects from any of the toxicity
studies (even at very high dose levels), DMSO is not considered to be
an endocrine disruptor. DMSO is found naturally in the environment, in
natural waters and in most foods and feeds. Studies have shown that
DMSO applied to plants is metabolized and incorporated into amino acids
and other sulfur-containing plant components. Animal and human
metabolism studies have shown that DMSO is predominantly eliminated
``as is'' or metabolized to DMSO2 and DMS prior to elimination. Several
studies in which different species (i.e. rat, mouse, rabbit, hamster)
were administered DMSO at high levels (up to lethal levels) have shown
no effect on the time-to-mating or on mating and fertility indices.
Radiolabeled DMS35O fed to chickens (laying hens) for 28 days had no
effect on the ability of the hens to produce eggs. This wealth of data
suggests that there are no effects on the estrous cycle, on mating
behavior, or on male or female fertility. Chronic and subchronic
studies in rhesus monkeys, mice, rats and dogs have not demonstrated
any evidence of toxicity to the male or female reproductive tracts.
H. Safety Determination
1. US population. Based on the human NOEL of 2.6 g/kg/day and very
conservative assumptions about DMSO residue levels in food/feed from
natural occurrence and from the proposed expanded agronomic usage of
DMSO, it would be impossible for humans to ingest toxicologically
consequential levels of DMSO. DMSO is naturally present in most edible
plants and animal products (i.e. milk, eggs, etc.). The proposed use of
DMSO on edible parts of food crops would not add appreciably to
naturally-occurring DMSO levels except for forage crops. Even when
residues in or on forage crops and maximum anticipated residues from
animal tissues/products are considered, total theoretical maximum
levels of DMSO in the diet are still considerably below levels that
would be of toxicological concern.
There is ample information to determine a reference dose (RfD) of
0.03 g DMSO/kg body weight/day based on data from chronic oral studies
with rhesus monkeys. NOELs established by chronic oral studies vary
from 3.0 g/kg/day for a monkey oral study to 12 g/kg/day for a mouse
teratology study. Since dogs are the most sensitive specie tested using
the oral route of exposure, based on lenticular effects, it would seem
appropriate to use a dog study to establish the RfD for conducting a
dietary exposure assessment. However, since rhesus monkeys are
physiologically more closely related to humans than dogs, and the
lenticular effect observed in dogs has never been documented in
primates or humans in over 30 years of testing, the primate oral NOEL
of 3 g/kg/day would be more relevant for use in human dietary risk
assessments. Since the NOEL was established in a non-human it is
appropriate to use an uncertainty factor (UF) of 100X (using current
EPA criteria of 10X for intra-species variability and 10X for inter-
species variability, 10 x 10 = 100). The data from the multigeneration
studies indicate that there is no increased risk to neonates or young
when DMSO is administered orally; therefore, an extra safety factor for
the protection of infants and children is not warranted. This would
result in a UF of 100X and a RfD of 0.03 g/kg/day or 30 mg/kg/day DMSO.
For an average adult (70 kg) this is equivalent to 2.1 g DMSO/day,
which is lower than therapeutic levels (i.e., 2.6 g/kg/day) that have
shown no adverse effects in humans.
Since the RfD of 0.26 g/kg/day calculated from human data is based
on a 3-month exposure period, the more conservative RfD of 0.03 g/kg/
day calculated from monkey data, based on a 18-month exposure period,
will be used in conducting the DMSO lifetime risk assessment. Using the
compounded and extremely conservative exposure assumptions described
above and the very conservative RfD of 0.03 g DMSO/kg/day, the
aggregate human exposure to DMSO from its proposed agronomic use will
utilize only 0.99 percent [(0.0207 g DMSO/day in diet) ( (0.03 g/kg/day
x 70 kg body wt) = 0.0207g DMSO/day anticipated ( 2.1 g/day DMSO
allowed = 0.00985] of the RfD for the US population (based on estimated
average consumption of 2.5 kg food/day for an average 70 kg adult). EPA
generally has little concern for exposures below 100 percent of the RfD
because the RfD represents the level at or below which daily aggregate
dietary exposure over a lifetime will not pose appreciable health risks
to humans. Thus, based on the natural occurrence of DMSO in the human
diet, DMSO's low toxicity, the ability of humans to readily metabolize
DMSO, and very low aggregate dietary exposure, Gaylord concludes with
reasonable certainty that no harm will result from aggregate human
exposure to residues from the proposed use of DMSO in pesticide
products applied to the edible parts of food and feed crops.
2. Infants and children. The proposed use of DMSO in pesticide
products applied to the edible parts of plants will pose no additional
risk of adverse effects to infants or children. Human infants and
children are exposed to endogenous levels of DMSO and readily
metabolize and excrete this compound. Even so, when assessing the
potential for additional sensitivity of infants and children to DMSO
and its residues, it is appropriate to consider the results of the
developmental and reproductive studies, chronic studies and human
health studies. The available data provide a clear picture of possible
toxic effects and indicate that there is no increased risk to neonates
or young when DMSO is ingested. Therefore, Gaylord concludes that an
additional safety factor for the protection of infants and children is
not needed and that the RfD of 0.03 g/kg/day is appropriate for
assessing DMSO risks to infants and children.
Using the conservative exposure assumptions previously described,
the percent RfD utilized by the aggregate human exposure to residues of
DMSO from natural occurrence and from the proposed use would be 1.2
percent
[[Page 34266]]
[(0.0207 g DMSO/day in diet) x (0.25 percent of adult intake) ( (0.03
g/kg/day x 14 kg body wt) = 0.0052 g DMSO/day anticipated ( 0.42 g/day
DMSO allowed = 0.0123] for children 1 to 6 years old, based on
estimated average consumption of 0.625 kg food/day (1/4 of adult
consumption) and average body weight of 14 kg. Therefore, based on this
conservative exposure assessment, Gaylord concludes with reasonable
certainty that no harm will result to infants and children from
aggregate human exposure to residues from the proposed use of DMSO in
pesticide products applied to the edible parts of food and feed crops.
I. Existing Tolerances
DMSO is a pesticidally inert ingredient that currently is exempted
[40 CFR (180.1001(d)] from the requirement of a tolerance for residues
when used as a solvent or cosolvent in pesticide formulations applied
before the crop emergence from the soil or prior to formation of edible
parts of food plants. There are no other limits for DMSO expressed in
40 CFR (180.1001(d).
J. International Tolerances
There are no Codex maximum residue levels established for residues
of DMSO on food or feed crops.
2. Gustafson Incorporation
PP 5F4584
EPA has received a pesticide petition (PP 5F4584) pursuant to
section 408(d) of the Federal Food, Drug and Cosmetic Act, as amended,
21 U.S.C. 346a(d), by the Food Quality Protection Act of 1996 (Pub. L.
104-170, 110 Stat. 1489) from Gustafson, Inc., 1400 Preston Road, Suite
400, Plano, Texas 75093 requesting that the time limited tolerances for
wheat, barley and sugar beet RACs be made permanent for residues of the
insecticide, imidacloprid: 1-[(6-chloro-3-pyridinyl)methyl]-N-nitro-2-
imidazolidinimine and its metabolites containing the 6-chloro-pyridinyl
moiety. In September 1995, the EPA revised Table II of the Pesticide
Assessment Guidelines, Subdivision O, Residue Chemistry. At that time,
forage was removed as a raw agricultural commodity of barley. It is
proposed that tolerances of 0.20 ppm for wheat, hay, and 0.20 ppm for
barley, hay, be added. It is proposed that the tolerance for barley,
straw, be increased from 0.20 ppm to 0.30 ppm. It is proposed that the
tolerance for beets, sugar (tops) be increased from 0.20 ppm to 0.30
ppm. The original time-limited tolerances were published in the
December 13, 1995 and in the August 30, 1995 Federal Registers.
Imidacloprid is a broad-spectrum insecticide with excellent systemic
and contact toxicity characteristics which is used primarily for
sucking insects. The nature of the imidacloprid residue in plants and
livestock is adequately understood. The analytical method for
determining residues is a common moiety method for imidacloprid and its
metabolites containing the 6-chloro-pyridinyl moiety using oxidation,
derivatization, and analysis by capillary gas chromatography with a
mass-selective detector. Pursuant to section 408(d)(2)(A)(i) of the
FFDCA, as amended, Gustafson has submitted the following summary of
information, data and arguments in support of its pesticide petition.
The summary was proposed by Gustafson, and EPA has not yet fully
evaluated the merits of the petition. The conclusions and arguments
presented are those of the petitioner and not of the EPA although the
EPA has edited the summary for clarification as necessary.
A. Plant Metabolism and Analytical Method
The metabolism of imidacloprid in plants is adequately understood
for the purposes of these tolerances. The residues of concern are
combined residues of imidacloprid and its metabolites containing the 6-
chloro-pyridinyl moiety, all calculated as imidacloprid. The analytical
method is a common moiety method for imidacloprid and its metabolites
containing the 6-chloro-pyridinyl moiety using a permanganate
oxidation, silyl derivatization, and capillary GC-MS selective ion
monitoring. This method has successfully passed a petition method
validation in EPA labs. There is a confirmatory method specifically for
imidacloprid and several metabolites utilizing GC/MS and HPLC-UV which
has been validated by the EPA as well. Imidacloprid and its metabolites
are stable for at least 24 months in the commodities when frozen.
B. Magnitude of the Residue
1. Wheat. When the conditional registrations and the time-limited
tolerances were issued for wheat grain, wheat forage and wheat straw,
the EPA requested additional residue field trials and residue testing
to support a tolerance for wheat hay. Wheat seed was treated with
imidacloprid, formulated as Gaucho 480 FS at a rate of 2.0 oz. a.i./cwt
seed. Field trials were conducted at seven locations: Colorado,
Nebraska (two locations), North Dakota, Oklahoma, Texas and Wyoming.
The wheat seed was planted and the RACs were harvested at the
appropriate growth stages. Maximum residues in wheat grain, wheat
forage and wheat straw were less than the time-limited tolerances. The
maximum residue level in wheat hay was 0.187 ppm. A tolerance of 0.20
ppm for wheat hay is proposed.
2. Barley. When the conditional registrations and the time-limited
tolerances were issued for barley grain, barley forage and barley
straw, the EPA requested additional residue field trials and residue
testing to support a tolerance for barley hay. Barley seed was treated
with imidacloprid, formulated as Gaucho 480 FS at a rate of 2.0 oz.
a.i./cwt seed. Field trials were conducted at five locations: Colorado,
Nebraska, North Dakota, Pennsylvania and Wyoming. The barley seed was
planted and the RACs were harvested at the appropriate growth stages.
The maximum residue in barley grain was less than the time-limited
tolerance. The maximum residue level in barley straw was 0.221 ppm,
which was above the time- limited tolerance of 0.20 ppm. A revised
tolerance of 0.30 ppm for barley straw is proposed. The maximum residue
level in barley hay was 0.181 ppm. A tolerance of 0.20 ppm for barley
hay is proposed.
3. Sugar Beets. When the conditional registrations and the time-
limited tolerances were issued for beets, sugar (tops); beets, sugar
(roots); and beets, sugar, molasses; the EPA requested additional
residue field trials. Sugar beet seed was treated with imidacloprid,
formulated as Gaucho 75 ST at a rate of 90 g ai/kg raw seed. Field
trials were conducted at four locations: California, Colorado, Idaho
and Nebraska. The sugar beet seed was planted and the RACs were
harvested at the appropriate growth stages. The maximum residue in the
sugar beet roots was less than the time-limited tolerances. The maximum
residue level in the sugar beet tops was 0.255 ppm, which was above the
time-limited tolerance of 0.10 ppm. A revised tolerance of 0.30 ppm for
sugar beet tops is proposed.
C. Toxicological Profile of Imidacloprid
1. Acute toxicity. The acute oral LD50 values for
imidacloprid technical ranged from 424 - 475 mg/kg bwt in the rat. The
acute dermal LD50 was greater than 5,000 mg/kg in rats. The
4-hour inhalation LC50 was less than 69 mg/m3 air
(aerosol). Imidacloprid was not irritating to rabbit skin or eyes.
Imidacloprid did not cause skin sensitization in guinea pigs.
[[Page 34267]]
2. Genotoxicity. Extensive mutagenicity studies conducted to
investigate point and gene mutations, DNA damage and chromosomal
aberration, both using in vitro and in vivo test systems show
imidacloprid to be non-genotoxic.
3. Reproductive and developmental toxicity. A 2-generation rat
reproduction study gave a no-observed-effect level (NOEL) of 100 ppm (8
mg/kg/bwt). Rat and rabbit developmental toxicity studies were negative
at doses up to 30 mg/kg/bwt and 24 mg/kg/bwt, respectively.
4. Subchronic toxicity. 90-day feeding studies were conducted in
rats and dogs. The NOELs for these tests were 14 mg/kg/bwt/day (150
ppm) and 5 mg/kg/bwt/day (200 ppm), for the rat and dog studies,
respectively.
5. Chronic toxicity/oncogenicity. A 2-year rat feeding/
carcinogenicity study was negative for carcinogenic effects under the
conditions of the study and had a NOEL of 100 ppm (5.7 mg/kg/bwt in
males and 7.6 mg/kg/bwt in females for noncarcinogenic effects that
included decreased body weight gain in females at 300 ppm and increased
thyroid lesions in males at 300 ppm and females at 900 ppm. A 1-year
dog feeding study indicated a NOEL of 1,250 ppm (41 mg/kg/bwt). A 2-
year mouse carcinogenicity study was negative for carcinogenic effects
under conditions of the study and had a NOEL of 1,000 ppm (208 mg/kg/
day).
Imidacloprid has been classified under ``Group E'' (no evidence of
carcinogenicity) by EPA's OPP/HED's Reference Dose (RfD) Committee.
There is no cancer risk associated with exposure to this chemical. The
reference dose (RfD) based on the 2-year rat feeding/carcinogenic study
with a NOEL of 5.7 mg/kg/bwt and hundredfold uncertainty factor, is
calculated to be 0.057 mg/kg/bwt. The theoretical maximum residue
contribution (TMRC) from published uses is 0.008358 mg/kg/bwt/day
utilizing 14.7 percent of the RfD.
6. Endocrine effects. The toxicology database for imidacloprid is
current and complete. Studies in this database include evaluation of
the potential effects on reproduction and development, and an
evaluation of the pathology of the endocrine organs following short or
long term exposure. These studies revealed no primary endocrine effects
due to imidacloprid.
7. Mode of action. Imidacloprid exhibits a mode of action different
from traditional organophosphate, carbamate, or pyrethroid
insecticides. Imidacloprid acts by binding to the nicotinergic receptor
sites at the postsynaptic membrane of the insect nerve. Due to this
novel mode of action, imidacloprid has not shown any cross resistance
to registered alternative insecticides and is a valuable tool for use
in IPM or resistance management programs.
D. Aggregate Exposure
Imidacloprid is a broad-spectrum insecticide with excellent
systemic and contact toxicity characteristics with both food and non-
food uses. Imidacloprid is currently registered for use on various food
crops including seed treatments, tobacco, turf, ornamentals, buildings
for termite control, and cats and dogs for flea control. Those
potential exposures are addressed below:
1. Dietary. The EPA has determined that the reference dose (RfD)
based on the 2-year rat feeding/carcinogenicity study with a NOEL of
5.7 mg/kg/bwt and hundredfold uncertainty factor, is calculated to be
0.057 mg/kg/bwt. As published in the Federal Register June 12, 1996 (61
FR 29674) (petition to establish tolerances on leafy green vegetables
(PP 5F4522/R2237)), the theoretical maximum residue contribution (TMRC)
from published uses is 0.008358 mg/kg/bwt utilizing 14.7 percent of the
RfD for the general population. For the most highly exposed subgroup in
the population, non-nursing infants (less than 1 year old), the TMRC
for the published tolerances is 0.01547 mg/kg/day. This is equal to
27.1 percent of the RfD.
The TMRC for wheat is calculated to be 0.000066 mg/kg/bwt/day for
the general population, which represents 0.1 percent of the RfD. The
TMRC for the most highly exposed subgroup in the population, children 1
to 6 years of age, is 0.000149 mg/kg/bwt/day, which represents 0.3
percent of the RfD. The TMRC for nursing infants is 0.000009 mg/kg/bwt/
day, which represents 0.0 percent of the RfD, and for non-nursing
infants is 0.000033 mg/kg/bwt/day, which represents 0.1 percent of the
RfD. Therefore, dietary exposure from wheat will not exceed the
reference dose for any subpopulation (including infants and children).
The TMRC for barley is calculated to be 0.000004 mg/kg/bwt/day for
the general population, which represents 0.0 percent of the RfD. The
TMRC for the most highly exposed subgroup in the population, non-
nursing infants, is 0.000009 mg/kg/bwt/day, which represents 0.0
percent of the RfD. The TMRC for nursing infants is 0.000000 mg/kg/bwt/
day, which represents 0.0 percent of the RfD. The TMRC for children 1
to 6 years of age is 0.000001 mg/kg/bwt/day, which represents 0.0
percent of the RfD. Therefore, dietary exposure from barley will not
exceed the reference dose for any subpopulation (including infants and
children).
The TMRC for sugar beets is calculated to be 0.000012 mg/kg/bwt/day
for the general population, which represents 0.0 percent of the RfD.
The TMRC for the most highly exposed subgroup in the population,
children 1 to 6 years of age, is 0.000027 mg/kg/bwt/day, which
represents 0.0 percent of the RfD. The TMRC for non-nursing infants is
0.000017 mg/kg/bwt/day, which represents 0.0 percent of the RfD. The
TMRC for nursing infants is 0.000005 mg/kg/bwt/day, which represents
0.0 percent of the RfD. Therefore, dietary exposure from sugar beets
will not exceed the reference dose for any subpopulation (including
infants and children).
The additive TMRC from exposure to wheat, barley and sugar beets
for the general population, is 0.000082 mg/kg/bwt/day, which represents
0.1 percent of the RfD. The additive TMRC from exposure to wheat,
barley and sugar beets to children, 1 to 6 years of age, is 0.000177
mg/kg/bwt/day, which represents 0.3 percent of the RfD. For non-nursing
infants, the additive TMRC is 0.000029 mg/kg/bwt/day, which is 0.1
percent of the RfD. For nursing infants, the additive TMRC is 0.000014
mg/kg/bwt/day, which is 0.0 percent of the RfD.
2. Water. Although the various imidacloprid labels contain a
statement that this chemical demonstrates the properties associated
with chemicals detected in groundwater, the Registrant is not aware of
imidacloprid being detected in any wells, ponds, lakes, streams, etc.
from its use in the United States. Imidacloprid is hydrolytically
stable at pH 5 and 7 with photolytic degradation in water having a
half-life of 4.2 hours. Under aerobic soil conditions in laboratory
studies, imidacloprid has a half-life of 188 to >366 days. Under
laboratory anaerobic aquatic conditions, the half-life was 27 days.
Adsorption/desorption studies indicate that aged imidacloprid residues
do not leach into the soil. Imidacloprid dissipates under actual field
conditions with a half-life of 7 to 196 days. Imidacloprid remained in
the top six inches of the soil in U.S. tests for the duration of nine
of ten field dissipation studies. The presence of growing vegetation
significantly increased the rate of degradation of imidacloprid. In
studies conducted in 1995, imidacloprid was not detected in seventeen
wells on potato farms in Quebec, Canada. In addition, groundwater
monitoring
[[Page 34268]]
studies are currently underway in California and Michigan. Therefore,
contributions to the dietary burden from residues of imidacloprid in
water would be inconsequential.
3. Non-occupational-- i. Residential turf. Bayer Corporation has
conducted an exposure study to address the potential exposures of
adults and children from contact with imidacloprid treated turf. The
population considered to have the greatest potential exposure from
contact with pesticide treated turf soon after pesticides are applied
are young children.
Margins of safety (MOS) of 7,587 - 41,546 for 10 year old children
and 6,859 - 45,249 for 5 year old children were estimated by comparing
dermal exposure doses to the imidacloprid no-observable effect level of
1,000 mg/kg/day established in a 15-day dermal toxicity study in
rabbits. The estimated safe residue levels of imidacloprid on treated
turf for 10 year old children ranged from 5.6 - 38.2 g/cm2
and for 5 year old children from 5.1 - 33.3 g/cm2. This
compares with the average imidacloprid transferable residue level of
0.080 g/cm2 present immediately after the sprays have dried.
These data indicate that children can safely contact imidacloprid-
treated turf as soon after application as the spray has dried.
ii. Termiticide. Imidacloprid is registered as a termiticide. Due
to the nature of the treatment for termites, exposure would be limited
to that from inhalation and was evaluated by EPA's Occupational and
Residential Exposure Branch (OREB) and Bayer Corporation. Data indicate
that the Margins of Safety for the worst case exposures for adults and
infants occupying a treated building who are exposed continuously (24
hours/day) are 8.0 x 107 and 2.4 x 108,
respectively, and exposure can thus be considered negligible.
iii. Tobacco smoke. Studies have been conducted to determine
residues in tobacco and the resulting smoke following treatment.
Residues of imidacloprid in cured tobacco following treatment were a
maximum of 31 ppm (7 ppm in fresh leaves). When this tobacco was burned
in a pyrolysis study only 2 percent of the initial residue was
recovered in the resulting smoke (main stream plus side stream). This
would result in an inhalation exposure to imidacloprid from smoking of
approximately 0.0005 mg per cigarette. Using the measured subacute rat
inhalation NOEL of 5.5 mg/m3, it is apparent that exposure
to imidacloprid from smoking (direct and/or indirect exposure) would
not be significant.
iv. Pet treatment. Human exposure from the use of imidacloprid to
treat dogs and cats for fleas has been addressed by EPA's Occupational
and Residential Exposure Branch (OREB) who have concluded that due to
the fact that imidacloprid is not an inhalation or dermal toxicant and
that while dermal absorption data are not available, imidacloprid is
not considered to present a hazard via the dermal route.
4. Cumulative Effects. No other chemicals having the same mechanism
of toxicity are currently registered, therefore, there is no risk from
cumulative effects from other substances with a common mechanism of
toxicity.
E. Safety Determinations
1. U.S. Population in general. Using the conservative exposure
assumptions described above and based on the completeness and
reliability of the toxicity data, it can be concluded that total
aggregate exposure to imidacloprid from all current uses including
those currently proposed will utilize little more than 15 percent of
the RfD for the U.S. population. EPA generally has no concerns for
exposures below 100 percent of the RfD, because the RfD represents the
level at or below which daily aggregate exposure over a lifetime will
not pose appreciable risks to human health. The TMRC from exposure to
wheat, barley and sugar beets for the general population, is 0.000082
mg/kg/bwt/day, which represents 0.1 percent of the RfD. Thus, it can be
concluded that there is a reasonable certainty that no harm will result
from aggregate exposure to imidacloprid residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of imidacloprid, the
data from developmental studies in both rat and rabbit and a 2-
generation reproduction study in the rat have been considered. The
developmental toxicity studies evaluate potential adverse effects on
the developing animal resulting from pesticide exposure of the mother
during prenatal development. The reproduction study evaluates effects
from exposure to the pesticide on the reproductive capability of mating
animals through 2 generations, as well as any observed systemic
toxicity.
FFDCA Section 408 provides that the EPA may apply an additional
safety factor for infants and children in the case of threshold effects
to account for pre- and post-natal effects and the completeness of the
toxicity database. Based on current toxicological data requirements,
the toxicology database for imidacloprid relative to pre- and post-
natal effects is complete. Further for imidacloprid, the NOEL of 5.7
mg/kg/bwt from the 2-year rat feeding/ carcinogenic study, which was
used to calculate the RfD (discussed above), is already lower than the
NOELs from the developmental studies in rats and rabbits by a factor of
4.2 to 17.5 times. Since a hundredfold uncertainty factor is already
used to calculate the RfD, it is surmised that an additional
uncertainty factor is not warranted and that the RfD at 0.057 mg/kg/
bwt/day is appropriate for assessing aggregate risk to infants and
children.
Using the conservative exposure assumptions described above, EPA
has concluded that the TMRC from use of imidacloprid from published
uses is 0.008358 mg/kg/bwt/day utilizing 14.7 percent of the RfD for
the general population. For the most highly exposed subgroup in the
population, non- nursing infants (less than 1 year old), the TMRC for
the published tolerances is 0.01547 mg/kg/day. This is equal to 27.1
percent of the RfD. The additive TMRC from exposure to wheat, barley
and sugar beets to children, 1 to 6 years of age, is 0.000177 mg/kg/
bwt/day, which represents 0.3 percent of the RfD. For non-nursing
infants, the additive TMRC is 0.000029 mg/kg/bwt/day, which is 0.1
percent of the RfD. For nursing infants, the additive TMRC is 0.000014
mg/kg/bwt/day, which is 0.0 percent of the RfD. Thus, it can be
concluded that there is a reasonable certainty that no harm will result
from additional exposure of infants and children.
F. Other Considerations
The nature of the imidacloprid residue in plants and livestock is
adequately understood. The residues of concern are combined residues of
imidacloprid and its metabolites containing the 6-chloropyridinyl
moiety, all calculated as imidacloprid. The analytical method is a
common moiety method for imidacloprid and its metabolites containing
the 6-chloropyridinyl moiety using a permanganate oxidation, silyl
derivatization, and capillary GC-MS selective ion monitoring. There is
an additional confirmatory method available. Imidacloprid and its
metabolites have been shown to be stable for at least 24 months in
frozen storage.
G. International Tolerances
No CODEX Maximum Residue Levels (MRLs) have been established for
residues of imidacloprid on any crops at this time.
[[Page 34269]]
3. Gustafson Incorporation
PP 6F4682
EPA has received a pesticide petition (PP 6F4682) pursuant to
section 408(d) of the Federal Food, Drug and Cosmetic Act, as amended,
21 U.S.C. 346a(d), by the Food Quality Protection Act of 1996 (Pub. L.
104-170, 110 Stat. 1489) from Gustafson, Inc., 1400 Preston Road, Suite
400, Plano, Texas 75093 requesting that tolerances be established for
residues of the insecticide, imidacloprid: 1-[(6-chloro-3-
pyridinyl)methyl]-N-nitro-2-imidazolidinimine and its metabolites
containing the 6-chloro-pyridinyl moiety. It is proposed that
tolerances of 0.05 parts per million (ppm) for field corn, grain, 0.02
ppm for field corn, fodder and 0.10 ppm for field corn, forage be
established. The nature of the imidacloprid residue in plants and
livestock is adequately understood. The analytical method for
determining residues is a common moiety method for imidacloprid and its
metabolites containing the 6-chloro-pyridinyl moiety using oxidation,
derivatization, and analysis by capillary gas chromatography with a
mass-selective detector.
Imidacloprid is a broad spectrum insecticide with excellent
systemic and contact toxicity characteristics which is used primarily
for sucking insects. Pursuant to section 408(d)(2)(A)(i) of the FFDCA,
as amended, Gustafson has submitted the following summary of
information, data and arguments in support of its pesticide petition.
The summary was proposed by Gustafson, and EPA has not yet fully
evaluated the merits of the petition. The conclusions and arguments
presented are those of the petitioner and not of the EPA although the
EPA has edited the summary for clarification as necessary.
A. Plant Metabolism and Analytical Method
The metabolism of imidacloprid in plants is adequately understood
for the purposes of these tolerances. The residues of concern are
combined residues of imidacloprid and its metabolites containing the 6-
chloro-pyridinyl moiety, all calculated as imidacloprid. The analytical
method is a common moiety method for imidacloprid and its metabolites
containing the 6-chloro-pyridinyl moiety using a permanganate
oxidation, silyl derivatization, and capillary GC-MS selective ion
monitoring. This method has successfully passed a petition method
validation in EPA labs. There is a confirmatory method specifically for
imidacloprid and several metabolites utilizing GC/MS and HPLC-UV which
has been validated by the EPA as well. Imidacloprid and its metabolites
are stable for at least 24 months in the commodities when frozen.
B. Magnitude of the Residue
Corn seed was treated with imidacloprid, formulated as Gaucho 480
FS at a rate of 8.0 oz.ai/cwt seed. Field trials were conducted at
twenty locations, one in Region 1, one in Region 2, seventeen in Region
5, and one in Region 6. The corn seed was planted and the RACs were
harvested at the appropriate growth stages. The highest average residue
level found in field corn forage was 0.064 ppm. The highest average
residue level found in the field corn grain was less than the Limit of
Quantitation, which was 0.05 ppm. The highest average residue level
found in the field corn fodder was 0.150 ppm. The proposed tolerance
for field corn forage is 0.10 ppm. The proposed tolerance for the field
corn fodder is 0.20 ppm. The proposed tolerance for the field corn
grain is 0.05 ppm.
Since there were no quantifiable residues in the field corn grain
RAC samples analyzed in the processing study or in the RAC study,
neither a section 409 food/feed additive tolerance or a section 701
maximum residue level is required for the processed commodities.
C. Toxicological Profile of Imidacloprid
1. Acute toxicity. The acute oral LD50 values for
imidacloprid technical ranged from 424 - 475 mg/kg bwt in the rat. The
acute dermal LD50 was greater than 5,000 mg/kg in rats. The
4 hour inhalation LC50 was less than 69 mg/m3 air
(aerosol). Imidacloprid was not irritating to rabbit skin or eyes.
Imidacloprid did not cause skin sensitization in guinea pigs.
2. Genotoxicity. Extensive mutagenicity studies conducted to
investigate point and gene mutations, DNA damage and chromosomal
aberration, both using in vitro and in vivo test systems show
imidacloprid to be non-genotoxic.
3. Reproductive and developmental toxicity. A 2-generation rat
reproduction study gave a no-observed-effect level (NOEL) of 100 ppm (8
mg/kg/bwt). Rat and rabbit developmental toxicity studies were negative
at doses up to 30 mg/kg/bwt and 24 mg/kg/bwt, respectively.
4. Subchronic toxicity. 90-day feeding studies were conducted in
rats and dogs. The NOELs for these tests were 14 mg/kg/bwt/day (150
ppm) and 5 mg/kg/bwt/day (200 ppm), for the rat and dog studies,
respectively.
5. Chronic toxicity/oncogenicity. A 2-year rat feeding/
carcinogenicity study was negative for carcinogenic effects under the
conditions of the study and had a NOEL of 100 ppm (5.7 mg/kg/bwt in
males and 7.6 mg/kg/bwt in females for noncarcinogenic effects that
included decreased body weight gain in females at 300 ppm and increased
thyroid lesions in males at 300 ppm and females at 900 ppm. A 1-year
dog feeding study indicated a NOEL of 1,250 ppm (41 mg/kg/bwt). A 2-
year mouse carcinogenicity study was negative for carcinogenic effects
under conditions of the study and had a NOEL of 1,000 ppm (208 mg/kg/
day).
Imidacloprid has been classified under ``Group E'' (no evidence of
carcinogenicity) by EPA's OPP/HED's Reference Dose (RfD) Committee.
There is no cancer risk associated with exposure to this chemical. The
reference dose (RfD) based on the 2-year rat feeding/carcinogenic study
with a NOEL of 5.7 mg/kg/bwt and hundredfold uncertainty factor, is
calculated to be 0.057 mg/kg/bwt. The theoretical maximum residue
contribution (TMRC) from published uses is 0.008358 mg/kg/bwt/day
utilizing 14.7 percent of the RfD.
6. Endocrine effects. The toxicology database for imidacloprid is
current and complete. Studies in this database include evaluation of
the potential effects on reproduction and development, and an
evaluation of the pathology of the endocrine organs following short or
long term exposure. These studies revealed no primary endocrine effects
due to imidacloprid.
7. Mode of action. Imidacloprid exhibits a mode of action different
from traditional organophosphate, carbamate, or pyrethroid
insecticides. Imidacloprid acts by binding to the nicotinergic receptor
sites at the postsynaptic membrane of the insect nerve. Due to this
novel mode of action, imidacloprid has not shown any cross resistance
to registered alternative insecticides and is a valuable tool for use
in IPM or resistance management programs.
D. Aggregate Exposure
Imidacloprid is a broad-spectrum insecticide with excellent
systemic and contact toxicity characteristics with both food and non-
food uses. Imidacloprid is currently registered for use on various food
crops including seed treatments, tobacco, turf, ornamentals, buildings
for termite control, and cats and dogs for flea control. Those
potential exposures are addressed below:
[[Page 34270]]
1. Dietary. The EPA has determined that the reference dose (RfD)
based on the 2-year rat feeding/carcinogenicity study with a NOEL of
5.7 mg/kg/bwt and hundredfold uncertainty factor, is calculated to be
0.057 mg/kg/bwt. As published in the Federal Register June 12, 1996 (61
FR 29674) (petition to establish tolerances on leafy green vegetables
(PP 5F4522/R2237), the theoretical maximum residue contribution (TMRC)
from published uses is 0.008358 mg/kg/bwt utilizing 14.7 percent of the
RfD for the general population. For the most highly exposed subgroup in
the population, non-nursing infants (less than 1 year old), the TMRC
for the published tolerances is 0.01547 mg/kg/day. This is equal to
27.1 percent of the RfD.
The TMRC for corn is calculated to be 0.000055 mg/kg/bwt/day for
the general population, which represents 0.1 percent of the RfD. The
TMRC for the most highly exposed subgroup in the population, non-
nursing infants is 0.000131 mg/kg/bwt/day, which represents 0.2 percent
of the RfD. The TMRC for children ages 1 to 6 years is 0.000130 mg/kg/
bwt/day, which represents 0.2 percent of the RfD, and for nursing
infants is 0.000032 mg/kg/bwt/day, which represents 0.1 percent of the
RfD. For children 7 to 12 years of age, the TMRC is 0.000098 mg/kg/bwt/
day, which represents 0.2 percent of the RfD. Therefore, dietary
exposure from field corn will not exceed the reference dose for any
subpopulation (including infants and children).
2. Water. Although the various imidacloprid labels contain a
statement that this chemical demonstrates the properties associated
with chemicals detected in groundwater, the Registrant is not aware of
imidacloprid being detected in any wells, ponds, lakes, streams, etc.
from its use in the United States. Imidacloprid is hydrolytically
stable at pH 5 and 7 with photolytic degradation in water having a
half-life of 4.2 hours. Under aerobic soil conditions in laboratory
studies, imidacloprid has a half-life of 188 to >366 days. Under
laboratory anaerobic aquatic conditions, the half-life was 27 days.
Adsorption/desorption studies indicate that aged imidacloprid residues
do not leach into the soil. Imidacloprid dissipates under actual field
conditions with a half-life of 7 to 196 days. Imidacloprid remained in
the top six inches of the soil in U.S. tests for the duration of nine
of ten field dissipation studies. The presence of growing vegetation
significantly increased the rate of degradation of imidacloprid. In
studies conducted in 1995, imidacloprid was not detected in seventeen
wells on potato farms in Quebec, Canada. In addition, groundwater
monitoring studies are currently underway in California and Michigan.
Therefore, contributions to the dietary burden from residues of
imidacloprid in water would be inconsequential.
3. Non-occupational-- i. Residential turf. Bayer Corporation has
conducted an exposure study to address the potential exposures of
adults and children from contact with imidacloprid treated turf. The
population considered to have the greatest potential exposure from
contact with pesticide treated turf soon after pesticides are applied
are young children.
Margins of safety (MOS) of 7,587 - 41,546 for 10 year old children
and 6,859 - 45,249 for 5 year old children were estimated by comparing
dermal exposure doses to the imidacloprid no-observable effect level of
1,000 mg/kg/day established in a 15 day dermal toxicity study in
rabbits. The estimated safe residue levels of imidacloprid on treated
turf for 10 year old children ranged from 5.6 - 38.2 g/cm2
and for 5 year old children from 5.1 - 33.3 g/cm2. This
compares with the average imidacloprid transferable residue level of
0.080 g/cm2 present immediately after the sprays have dried.
These data indicate that children can safely contact imidacloprid-
treated turf as soon after application as the spray has dried.
ii. Termiticide. Imidacloprid is registered as a termiticide. Due
to the nature of the treatment for termites, exposure would be limited
to that from inhalation and was evaluated by EPA's Occupational and
Residential Exposure Branch (OREB) and Bayer Corporation. Data indicate
that the Margins of Safety for the worst case exposures for adults and
infants occupying a treated building who are exposed continuously (24
hours/day) are 8.0 x 107 and 2.4 x 108,
respectively, and exposure can thus be considered negligible.
iii. Tobacco smoke. Studies have been conducted to determine
residues in tobacco and the resulting smoke following treatment.
Residues of imidacloprid in cured tobacco following treatment were a
maximum of 31 ppm (7 ppm in fresh leaves). When this tobacco was burned
in a pyrolysis study only two percent of the initial residue was
recovered in the resulting smoke (main stream plus side stream). This
would result in an inhalation exposure to imidacloprid from smoking of
approximately 0.0005 mg per cigarette. Using the measured subacute rat
inhalation NOEL of 5.5 mg/m3, it is apparent that exposure
to imidacloprid from smoking (direct and/or indirect exposure) would
not be significant.
iv. Pet treatment. Human exposure from the use of imidacloprid to
treat dogs and cats for fleas has been addressed by EPA's Occupational
and Residential Exposure Branch (OREB) who have concluded that due to
the fact that imidacloprid is not an inhalation or dermal toxicant and
that while dermal absorption data are not available, imidacloprid is
not considered to present a hazard via the dermal route.
4. Cumulative effects. No other chemicals having the same mechanism
of toxicity are currently registered, therefore, there is no risk from
cumulative effects from other substances with a common mechanism of
toxicity.
E. Safety Determinations
1. U.S. Population in general. Using the conservative exposure
assumptions described above and based on the completeness and
reliability of the toxicity data, it can be concluded that total
aggregate exposure to imidacloprid from all current uses including
those currently proposed will utilize little more than 15 percent of
the RfD for the U.S. population. EPA generally has no concerns for
exposures below 100 percent of the RfD, because the RfD represents the
level at or below which daily aggregate exposure over a lifetime will
not pose appreciable risks to human health. The TMRC from exposure to
field corn for the general population, is 0.000055 mg/kg/bwt/day, which
represents 0.1 percent of the RfD. Thus, it can be concluded that there
is a reasonable certainty that no harm will result from aggregate
exposure to imidacloprid residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of imidacloprid, the
data from developmental studies in both rat and rabbit and a 2-
generation reproduction study in the rat have been considered. The
developmental toxicity studies evaluate potential adverse effects on
the developing animal resulting from pesticide exposure of the mother
during prenatal development. The reproduction study evaluates effects
from exposure to the pesticide on the reproductive capability of mating
animals through 2 generations, as well as any observed systemic
toxicity.
FFDCA section 408 provides that the EPA may apply an additional
safety factor for infants and children in the case of threshold effects
to account for pre- and post-natal effects and the completeness of the
toxicity database. Based on current toxicological data requirements,
the toxicology database for imidacloprid relative to pre- and
[[Page 34271]]
post-natal effects is complete. Further for imidacloprid, the NOEL of
5.7 mg/kg/bwt from the 2-year rat feeding/ carcinogenic study, which
was used to calculate the RfD (discussed above), is already lower than
the NOELs from the developmental studies in rats and rabbits by a
factor of 4.2 to 17.5 times. Since a hundredfold uncertainty factor is
already used to calculate the RfD, it is surmised that an additional
uncertainty factor is not warranted and that the RfD at 0.057 mg/kg/
bwt/day is appropriate for assessing aggregate risk to infants and
children. Using the conservative exposure assumptions described above,
EPA has concluded that the TMRC from use of imidacloprid from published
uses is 0.008358 mg/kg/bwt/day utilizing 14.7 percent of the RfD for
the general population. For the most highly exposed subgroup in the
population, non-nursing infants (less than 1 year old), the TMRC for
the published tolerances is 0.01547 mg/kg/day. This is equal to 27.1
percent of the RfD. The TMRC from exposure to field corn to non-nursing
infants is 0.000131 mg/kg/bwt/day, which represents 0.2 percent of the
RfD. The TMRC for children ages 1 to 6 years is 0.000130 mg/kg/bwt/day,
which represents 0.2 percent of the RfD. For nursing infants, the TMRC
is 0.000032 mg/kg/bwt/day, which is 0.1 percent of the RfD. For
children ages 7 to 12 years, the TMRC is 0.000098 mg/kg/bwt/day, which
is 0.2 percent of the RfD. Thus, it can be concluded that there is a
reasonable certainty that no harm will result from additional exposure
of infants and children.
F. Other Considerations
The nature of the imidacloprid residue in plants and livestock is
adequately understood. The residues of concern are combined residues of
imidacloprid and its metabolites containing the 6-chloropyridinyl
moiety, all calculated as imidacloprid. The analytical method is a
common moiety method for imidacloprid and its metabolites containing
the 6-chloropyridinyl moiety using a permanganate oxidation, silyl
derivatization, and capillary GC-MS selective ion monitoring. There is
an additional confirmatory method available. Imidacloprid and its
metabolites have been shown to be stable for at least 24 months in
frozen storage.
G. International Tolerances
No CODEX Maximum Residue Levels (MRLs) have been established for
residues of imidacloprid on any crops at this time.
[FR Doc. 97-16655 Filed 6-24-97; 8:45 am]
BILLING CODE 6560-50-F