[Federal Register Volume 62, Number 168 (Friday, August 29, 1997)]
[Notices]
[Pages 45804-45810]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-23097]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-758; FRL-5738-2]
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-758, must
be received on or before September 29, 1997.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch (7506C), Information Resources and Services
Division, 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 contact person listed in the table
below:
[[Page 45805]]
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Office location/
Contact Person telephone number Address
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Beth Edwards,................. Rm. 211, CM #2, 703- 1921 Jefferson
305-5400, e- Davis Hwy,
mail:[email protected] Arlington, VA
mail.epa.gov.
Amelia Acierto................ 4th floor, CS1, 703- 2800 Crystal
308-8377, e-mail: Drive,
[email protected] Arlington, VA.
l.epa.gov.
Bipin Gandhi,................. Rm.4W53, CS1, 703-308- Do.
8380, e-mail:
gandhi.bipin@epamail..
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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-758] (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:
opp-docket@epamail.epa.gov
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-758] 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: August 20, 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. American Cyanamid Company
PP 3E4246
EPA has received a pesticide petition (PP 3E4246) from American
Cyanamid Company, Agricultural Products Research Division, P.O. Box
400, Princeton, NJ 08543-0400, proposing pursuant to section 408(d) of
the Federal Food, Drug and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40
CFR part 180 to establish an exemption from the requirement of a
tolerance for residues of Polyvinyl Chloride (PVC) when used as an
inert ingredient in pesticide formulations applied to growing crops or
to raw agricultural commodities after harvest, under 40 CFR
180.1001(c). 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. Toxicity Data
As part of the EPA policy statement on inert ingredients published
in the Federal Register of April 22, 1987 (52 FR 13305), the Agency set
forth a list of studies which would generally be used to evaluate the
risks posed by the presence of an inert ingredient in a pesticide
formulation. However, where it can be determined without the data that
the inert ingredient will present minimal or no risk, the Agency
generally does not require some or all of the listed studies to rule on
the proposed tolerance or exemption from the requirement of a tolerance
for an inert ingredient. Cyanamid believes that the data and
information described below is adequate to ascertain the toxicology and
characterize the risk associated with the use of PVC as an inert
ingredient in pesticide formulations applied to growing crops and raw
agricultural commodities after harvest.
In the case of certain chemical substances that are defined as
``polymers'', the EPA has established a set of criteria which identify
categories of polymers that present low risk. These criteria (described
in 40 CFR 723.250) identify polymers that are relatively unreactive and
stable compared to other chemical substances as well as polymers that
typically are not readily absorbed. These properties generally limit a
polymer's ability to cause adverse effects. In addition, these criteria
exclude polymers about which little is known. The EPA believes that
polymers meeting the criteria noted below will present minimal or no
risk.
Polyvinyl chloride (PVC) conforms to the definition of polymer
given in 40 CFR 723.250(b) and meets the following criteria that are
used to identify low risk polymers:
1. PVC is not a cationic polymer, nor is it reasonably anticipated
to become a cationic polymer in a natural aquatic environment.
2. PVC contains as an integral part of its composition the atomic
elements carbon, chlorine, and hydrogen.
3. PVC does not contain as an integral part of its composition,
except as impurities, any elements other than those listed in 40 CFR
723.250 (d)(2)(ii).
4. PVC is not designed, nor is it reasonably anticipated to
substantially degrade, decompose, or depolymerize.
5. PVC is not manufactured or imported from monomers and/or other
reactants that are not already included on the Toxic Substance Control
Act (TSCA) Chemical Substance Inventory or manufactured under an
applicable TSCA section 5 exemption.
6. PVC is not a water absorbing polymer.
[[Page 45806]]
7. PVC does not contain any group as reactive functional groups.
8. The minimum number-average molecular weight of PVC is listed as
29,000 daltons. Substances with molecular weights greater than 400
generally are not absorbed through the intact skin, and substances with
molecular weights greater than 1,000 generally are not absorbed through
the intact gastrointestinal (GI) tract. Chemicals not absorbed through
the skin or GI tract generally are incapable of eliciting a toxic
response.
9. PVC has a minimum number-average molecular weight of 29,000 and
contains less than 2 percent oligomeric material below molecular weight
500 and less than 5 percent oligomeric material below 1,000 molecular
weight.
In addition, PVC is approved by the Food and Drug Administration
(FDA) under 21 CFR for contact with food as a component in adhesives
(21 CFR 175.105), coatings (21 CFR 175.320), and paper and paperboard
(21 CFR 176.180). PVC is also approved by FDA as an indirect food
additive used as a basic component of acrylic (21 CFR 177.1010) and
cellophane (21 CFR 177.1200) polymers.
PVC is also cleared for use as water pipe for potable water as per
FFDCA 201(s).
B. Aggregate Exposure
PVC was one of the earliest and still most widely used plastics.
The polymer is ubiquitous in our every day environment as it is
commonly used in building materials, furniture, and textiles. It is
also cleared by FDA as an indirect food additive due to its use in food
packaging materials.
Although exposure to PVC may occur through dietary (e.g., PVC-
containing food wrapping), non-occupational (e.g., contact with PVC
furniture), and drinking water (e.g., potable water piping, water
bottles, etc.) sources, the chemical characteristics of PVC lead to the
conclusion that there is a reasonable certainty of no harm from
aggregate exposure to the polymer. Given the existing widespread use of
PVC, any additional exposure resulting from the approval of the use of
PVC as an inert ingredient in pesticide formulations for use on growing
crops or to raw agricultural commodities after harvest would be
trivial.
C. Cumulative Effects
At this time there is no information to indicate that any toxic
effects produced by PVC would be cumulative with those of any other
chemical. Given the compound's categorization as a ``low risk polymer''
(40 CFR 723.250) and its proposed used as an inert ingredient in
pesticide formulations, there is no reasonable expectation of increased
risk due to cumulative exposure to PVC.
D. International Tolerances
Cyanamid is petitioning that PVC be exempt from the requirement of
a tolerance based upon its status as a low risk polymer as per 40 CFR
723.250. Therefore, an analytical method to determine residues of PVC
in raw agricultural commodities treated with pesticide formulations
containing PVC has not been proposed.
There are no Codex maximum residue levels (MRLs) established for
PVC.
Residues of PVC are currently exempt from the requirement of a
tolerance under 40 CFR 180.1001(e) for use in pesticide formulations
applied to animals. (Bipin Gandhi)
2. Merck Research Laboratories, Inc. (Merck)
PP 7F4845
EPA has received a pesticide petition (PP 7F4845) from Merck
Research Laboratories, Inc. (Merck), P.O. Box 450, Hillsborough Road,
Three Bridges, NJ 08887-0450, proposing pursuant to section 408(d) of
the Federal Food, Drug and Cosmetic Act, 21 U.S.C. 346a(d), to amend 40
CFR part 180 by establishing tolerances for residues of emamectin
benzoate and certain of its degradates in or on the fruiting vegetables
crop group (except cucurbits), which includes the raw agricultural
commodities eggplants, groundcherries, pepinos, peppers (bell, chili,
cooking, and sweet), tomatillos, and tomatoes. Emamectin benzoate is a
new insecticide designed for use against the larvae of various
Lepidoptera species when applied in the form of an emulsifaiable
concentrate formulation (PROCLAIM 0.16 EC Insecticide) or a
soluble granular formulation (PROCLAIM 5% SG Insecticide).
Merck Research Laboratories, Inc. (Merck) previously has applied
for the registration under section 3 of the Federal Insecticide,
Fungicide, and Rodenticide Act (FIFRA) of three products containing
emamectin benzoate: emamectin benzoate technical (EPA File Symbol 618-
RNI); PROCLAIM 0.16 EC Insecticide (EPA File Symbol 618-RNT); and
PROCLAIM 5% SG Insecticide (EPA File Symbol 618-RNA). Notice of filing
of these applications was published in the Federal Register on July 10,
1996 (61 FR 36372). In the previous petition, Merck proposed that the
end-use products be registered for use on broccoli, Brussels sprouts,
cabbage, cauliflower, celery, and head lettuce. Merck has also
submitted a petition under section 408 of the Federal Food, Drug, and
Cosmetic Act (FFDCA) for the establishment of permanent tolerances for
residues of emamectin benzoate on the raw agricultural commodities
(RACs) broccoli, Brussels sprouts, cabbage, cauliflower, celery, and
head lettuce. EPA has assigned this petition the number PP 6F4628.
Merck is now submitting this new petition for the issuance of a
tolerance for residues of emamectin on the ``fruiting vegetables
(except cucurbits)'' crop group, which includes eggplants,
groundcherriees, pepinos, peppers (bell, chili, cooking, and sweet),
tomatillos, and tomatoes.
The tolerances sought are for the total toxic residue, consisting
of the parent insecticide (emamectin benzoate) and four other
components that are plant metabolites or photodegradation products. For
each RAC the proposed tolerance level is 0.02 ppm. The pesticide
chemical that produces such residues is the parent insecticide
emamectin benzoate. Further information on the chemical identity and
composition of these compounds is set forth in the EPA files for the
three applications discussed in the previous paragraph above.
A. Residue Chemistry
1. Plant metabolism. The metabolism of emamectin benzoate in plants
has been studied in lettuce, cabbage, and sweet corn. The major portion
of the residue is parent compound and its delta 8,9- photoisomer.
Studies of the metabolism of emamectin in animals are not required
because the commodities that are the subject of the petition are not
significant animal feed items.
2. Analytical method. Adequate analytical methods (HPLC-
fluorescence methods) are available for enforcement purposes.
3. Magnitude of residues. Twenty-three field trials have been
conducted: 11 on peppers and 12 on tomatoes. A processing study was
also carried out with tomatoes. These trials were conducted in the
major U.S. growing areas for these crops.
All trials were conducted under maximum proposed use rates and
conditions. Raw agricultural commodity (RAC) samples from all trials
were collected a few hours after the last treatment (day 0) and on days
3, 7, and 14. In one trial samples were also collected for use in a
processing study.
In day 7 (and later) whole tomato samples, the highest level of the
B1a component and of the n-formyl component were each NQ (not
quantifiable, less than 5 ng/g); for the
[[Page 45807]]
other two components the residues were less than 1 ng/g. In day 7 (and
later) pepper samples, the highest B1a residue was 5 ng/g , the highest
n-formyl residue was NQ (less than 5 ng/g), and the other two
components were less than 1 ng/g in each sample. Thus, the maximum
combined residue was less than 12 ng/g (less than 0.012 ppm) in each
case. The processing study showed that the residues did not concentrate
in tomato puree or paste.
These data support the proposed tolerance of 0.02 ppm for total
toxic residues of emamectin benzoate on tomatoes, tomato puree, tomato
paste, or peppers, and by extension to remaining members of the
fruiting vegetables (except cucurbits) group.
B. Toxicological Profile
The primary toxic effect seen in animal studies of emamectin
benzoate is neurotoxicity. No-observed-effect-levels (NOELs) for this
effect have been well characterized in multiple studies. Emamectin
benzoate has not been shown to be oncogenic or teratogenic in animal
studies, it lacks mutagenic activity, and it is not selectively
developmentally toxic. The petition refers to toxicity data that
establish the following information about the toxicity of emamectin
benzoate:
1. Acute toxicity. Acute oral LD50: rat, 76-89 mg/kg;
CD-1 mouse 107-120 mg/kg; CF-1 mouse, 22-31 mg/kg. Acute oral
neurotoxicity: rat, NOEL = 5 mg/kg, LOEL = 10 mg/kg. Acute dermal
LD50: rat and rabbit, >2,000 mg/kg. Dermal irritation:
rabbit, not irritating to skin. Eye irritation: rabbit, severe eye
irritant. Acute inhalation 4-hour LC50: rat, 2.12-4.44 mg/l.
2. Mutagenicity. Emamectin benzoate was tested in a battery of in
vitro and in vivo mutagenicity assays and showed no evidence of
mutagenic potential. The photodegradates have also been tested in the
Ames bacterial mutagenicity assay and show no mutagenic potential in
this test system.
3. Reproductive and developmental toxicity. Developmental toxicity:
rat, maternal NOEL = 2 mg/kg/day, developmental NOEL = 4 mg/kg/day,
developmental LOEL = maternally toxic 8 mg/kg/day (HDT) for
developmental delay; rabbit, maternal NOEL = 3 mg/kg/day, developmental
NOEL = 6 mg/kg/day (maternally toxic HDT). Developmental neurotoxicity:
rat, maternal NOEL = 3.6/2.5 mg/kg/day (HDT), developmental NOEL = 0.6
mg/kg/day, developmental LOEL = 3.6/2.5 mg/kg/day for signs of
neurotoxicity in pups. 2-generation reproductive toxicity: rat,
parental and reproductive NOEL = 0.6 mg/kg/day, parental LOEL = 3.6/1.8
mg/kg/day (for decreased weight gain and neuronal lesions);
reproductive toxicity LOEL = 3.6/1.8 mg/kg/day (for decreased fecundity
and signs of neurotoxicity in pups).
4. Subchronic and chronic toxicity and oncogenicity. With the
single exception of the chronic rat study, LOELs for the following
studies are based on clinical signs and/or histopathological evidence
of neurotoxicity (described further below). Subchronic (90-day)
toxicity: rat, NOEL = 0.5 mg/kg/day, LOEL = 2.5 mg/kg/day; CD-1 mouse,
NOEL = 5.4 mg/kg/day (TWA), LOEL = 0.5 mg/kg/day; dog, NOEL = 0.25 mg/
kg/day, LOEL = 0.5 mg/kg/day Subchronic (90-day) neurotoxicity; rat,
NOEL = 1 mg/kg/day, LOEL = 5 mg/kg/day. Chronic (105-week) toxicity/
oncogenicity, rat: NOEL = 0.25 mg/kg/day, LOEL = 1 mg/kg/day (based on
decreased body weight and clinical chemistry changes), neurotoxicity
NOEL = 1 mg/kg/day, not oncogenic. Chronic (79-week) toxicity/
oncogenicity, CD-1 mouse: NOEL = 2.5 mg/kg/day, LOEL = 5 mg/kg (males),
7.5 mg/kg/day (females), not oncogenic. Chronic (53-week) toxicity,
dog: NOEL = 0.25 mg/kg/day, LOEL= 0.5 mg/kg./day.
Exposure to sufficiently high doses of emamectin benzoate may be
associated with clinical signs of central nervous system (CNS) toxicity
and microscopic evidence of CNS/peripheral nervous system (PNS) damage.
Neurotoxicity has generally been the most sensitive endpoint for
toxicity in oral animal studies with emamectin benzoate. Clinical signs
of CNS toxicity resulting from emamectin benzoate exposure include
tremors, mydriasis, and changes in motor activity (e.g., lethargy,
hyperactivity, and/or ataxia). Nervous system lesions (generally focal
and of a low degree of severity) have been observed microscopically in
white and gray matter in the brain stem, spinal cord, and peripheral
nerves. Sporadic lesions of the optic nerve and/or retina have also
been seen at higher dose levels. NOELs have been determined in all
studies. The lowest toxic dose level of emamectin benzoate for CNS/PNS
lesions (0.5 mg/kg/day) was identified in a 1-year study in dogs (NOEL
of 0.25 mg/kg/day).
The CF-l mouse is uniquely sensitive to emamectin benzoate-induced
neurotoxicity. Studies have shown that a significant fraction of the
members of this strain inherit an inability to produce a P-
glycoprotein- one that most strains and species do produce- that
functions to resist the entrance of avermectin-type compounds into the
central nervous system. P-glycoprotein is also present in the gut of
most species and limits absorption of avermectin-type compounds
following oral exposure. In a 16-day feeding study in the CF-1 mouse,
tremors were seen at 0.3 mg/kg/day of emamectin benzoate with a NOEL of
0.1 mg/kg/day. No histopathologic evidence of neurotoxicity was seen in
this study up to the highest dose tested (0.9 mg/kg/day).
Emamectin benzoate photodegrades on plants and in soil. The major
photodegradates that are not animal metabolites were tested in a 15-day
neurotoxicity study in CF-1 mice. Only one photodegradate showed
neurotoxicity (Merck research number L-660,599, the N-formyl-N-methyl
degradate). Its NOEL was found to be 0.075 mg/kg/day, slightly lower
than the value for the parent compound in the same kind of study, and
both clinical signs and peripheral nerve lesions were observed at
levels of 0.1 mg/kg/day and higher.
5. Endpoint selection. Merck is proposing that the 0.075 mg/kg/day
NOEL from the CF-1 mouse 15-day neurotoxicity study with the L-660,599
photodegradate be used as the basis for acute dietary risk assessment.
For evaluation of chronic dietary risks, Merck is proposing that the 1-
year dog chronic study NOEL of 0.25 mg/kg/day be used. The dog appears
to be the most sensitive species to long-term exposure to emamectin
benzoate. Accordingly, chronic exposure is compared against a RfD of
0.0025 mg/kg/day, based on the dog study results and an uncertainty
factor of 100.
C. Aggregate Exposure
1. Dietary exposure. Except for a temporary tolerance associated
with an experimental use permit, no tolerances for residues of
emamectin benzoate have been established. Merck projects that by the
year 2,001, emamectin benzoate will be used on approximately 17% of the
acreage for the cole, leafy non-cole vegetable, and fruiting vegetable
crops. Chronic dietary exposure analyses were conducted for the overall
U.S. population and 26 population subgroups. Assuming 100% of the crops
are treated, chronic exposure for the overall U.S. population was
estimated to be 0.000005 mg/kg BW/day, and for the most highly exposed
subgroup, children 1 to 6 years of age, 0.000007 mg/kg BW/day.
2. Non-dietary exposure. No products containing emamectin benzoate
have yet been registered under the Federal Insecticide, Fungicide, and
Rodenticide Act (FIFRA) for any food or nonfood use. No significant
nondietary,
[[Page 45808]]
nonoccupational exposure is anticipated.
3. Drinking water. The environmental fate of emamectin has been
evaluated, and the compound is not expected to contaminate groundwater
or surface water to any measurable extent.
D. Cumulative Effects
Emamectin is a member of the avermectin family of natural and
synthetic compounds that includes the Merck products abamectin (a
naturally occurring compound that is the active ingredient of several
insecticides registered under FIFRA) and ivermectin (a human and animal
drug made from abamectin). Emamectin is made from abamectin but is less
similar to abamectin than is ivermectin. Other companies produce
certain other drugs that are members of the avermectin family. Some of
the effects seen in toxicity studies of abamectin and ivermectin are
similar to some of the effects seen in toxicity studies of emamectin.
See the discussion of abamectin and ivermectin in 61 FR 65043 (December
10, 1996). Merck is not aware of any information indicating what, if
any, cumulative effect would result from exposure to two or more of
these compounds.
E. Safety Determination
1. U.S. population-- i. Chronic risk. Chronic exposures were
analyzed with reference to the chronic effects RfD NOEL of 0.0025 mg/
kg/day. Assuming 100% of the crops are treated, the chronic exposure
estimate was 0.2% of the RfD for the overall U.S. population, and 0.3%
of the RfD for the most highly exposed subgroup, children 1 to 6 years
of age. If 25% crop treatment is assumed, exposure estimates were less
than 0.1% of the RfD for all population groups.
ii. Acute risk. Acute exposure analyses were conducted for the
overall U.S. population, and the population subgroups (1) women 13
years and older, (2) infants, and (3) children. In addition, Tier 2 and
Tier 3 acute analyses were conducted assessing acute exposures against
the 0.075 mg/kg/day NOEL. These analyses showed that the margins of
exposure (MOEs) calculated from the proposed uses of emamectin benzoate
are acceptable whether using a highly conservative approach (Tier 2) or
a more realistic (Tier 3) methodology. In the Tier 2 analysis, MOEs
were well over 1,000 up to the 95th percentile of exposure for all
population groups. In the Tier 3 analysis and assuming 100% of the
crops are treated, MOEs up to the 99.5th percentile of exposure were
greater than 1,000. Assuming 25% of the crop treated, MOEs were greater
than 1,000 up to the 99.9th percentile of exposure. Results of both the
chronic and acute dietary exposure analyses clearly demonstrate a
reasonable certainty that no harm will result from the proposed uses of
emamectin benzoate.
2. Infants and children. It is Merck's position that the
administration of emamectin benzoate has not been shown to cause
developmental or reproductive effects at dose levels below those that
are maternally toxic. Even if it were decided to use the 0.6 mg/kg NOEL
from the rat developmental neurotoxicity study as an endpoint from
which to calculate an RfD, the resulting RfD would not yield a
different regulatory outcome unless a very high additional uncertainty
factor were also employed. Use of such an extra uncertainty factor is
not justified for several reasons. Emamectin benzoate is not a
teratogen. In developmental toxicity testing, the compound caused no
developmental effects in rabbits; in rats, it caused no malformations,
and caused skeletal effects typical of developmental delay only at
severely maternally toxic doses. Likewise, no reproductive toxicity or
toxicity to pups was seen in the 2-generation reproductive toxicity
study except at parentally toxic doses. In the developmental
neurotoxicity study, tremors, hind-leg splay, and behavioral effects
were seen in pups at a dose level (3.6/2.5 mg/kg/day) at which no
maternal clinical signs were noted. However, the dams in the study were
discarded after the lactation period without gross necropsy or
microscopic examination. In studies in which rats dosed at similar
levels were examined microscopically, effects (central and peripheral
neural lesions) were seen.
The clinical signs of avermectin-family neurotoxicity seen in
neonatal rats are unlikely to be useful predictors of human risk. Young
rats are considerably more sensitive to avermectin-type compounds than
either adult rats or humans and other primates. (In neonatal rats,
unlike humans, the P-glycoprotein levels are only a small fraction of
the levels seen in adult rats.) Moreover, data from clinical experience
with ivermectin, a related human drug, and studies on ivermectin and
abamectin, a related pesticide, demonstrate that both the neonatal rat
and the CF-1 mouse overpredict the toxicity of the avermectin-type
compounds to humans and to non-human primates.
F. International Tolerances
No Codex maximum residue levels (MRLs) have been established for
residues of emamectin benzoate. (Beth Edwards)
3. Milliken & Company
PP 5E4597
EPA has received a pesticide petition (PP 5E4597) from Milliken &
Company, M-400, P.O Box 1927, Spartanburg, SC 29304-1927, proposing
pursuant to section 408(d) of the Federal Food, Drug and Cosmetic Act,
21 U.S.C. 346a(d), to amend 40 CFR 180.1001(c) to establish an
exemption from the requirement of a tolerance for Poly(ethylene glycol)
modified FD&C Blue No. 1, Methyl-Poly(ethylene glycol) modified FD&C
Blue No. 1; Poly(ethylene glycol) modified Methyl Violet 2B; when used
as inert ingredients at the rate not to exceed 0.6 parts per billion
(ppb) to impart color to pesticidally-treated seeds. 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. No specific residue studies have been
conducted on the colorants in raw agricultural commodities or in
processed foods. However, the aggregate exposure estimates, discussed
above, are based on the assumption that an exaggerative level of PEG-
modified FD&C Blue No. 1, Methyl-PEG-modified FD&C Blue No. 1, and PEG-
modified Methyl Violet 2B applied to seeds will be absorbed by growing
plants and enter the diet. Even based on this exaggerative assumption,
the maximum potential dietary exposure to the colorants is minuscule.
2. Analytical method. Section 408(c)(3)(B) provides for
circumstances where no need exists for a practical method for detecting
and measuring levels of pesticide residue in or on food. In this
instance, because the colorants of interest are inert ingredients and
since the exemption from the requirement of a tolerance has no
numerical limitation, analytical methods are not required for
enforcement purposes for these colorants.
B. Toxicological Profile
1. Acute toxicity. The results of acute oral toxicity studies
indicate that PEG-modified FD&C Blue No. 1 has very low
[[Page 45809]]
toxicity by the oral route. Specifically, PEG-modified FD&C Blue No. 1
has an acute oral LD50 of greater than 5,000 milligrams per
kilogram in rats. An additional test material having slightly smaller
side chain lengths than PEG-modified FD&C Blue No. 1 also showed an
acute oral LD50 of greater than 5,000 milligrams per
kilogram in rats. PEG-modified FD&C Blue No. 1 is closely related to
FD&C Blue No. 1; however, the PEG-modified FD&C Blue No. 1 is of a
higher molecular weight than FD&C No. 1. FD&C Blue No. 1, itself, is
exempt from the requirement of a tolerance under 40 CFR 180.1001 and
also is cleared by the Food and Drug Administration for use in coloring
food and for coloring drugs under 21 CFR 74.101 and 74.1101,
respectively. The acute oral LD50 for FD&C Blue No. 1 has
been determined to be greater than 2,000 mg/kg in rats (Lu and
Lavallee, 1964). Thus, the acute toxicity data submitted in support of
this petition support the conclusion that PEG-modified FD&C Blue No. 1
is of a lower order of toxicity than FD&C Blue No. 1, itself. Such a
result could be expected since, in general, compounds of higher
molecular weights are more poorly absorbed and consequently are
typically less toxic than closely related lower molecular weight
materials.
Along the same lines, it should be noted that Methyl-PEG-modified
FD&C Blue No. 1, is another material that is closely related to FD&C
Blue No. 1, but is of a higher molecular weight. Similarly, PEG-
modified Methyl Violet 2B is closely related to Methyl Violet 2B, but
is of a higher molecular weight. Methyl Violet 2B, itself, currently is
exempted from the requirement of a tolerance under 40 CFR 180.1001.
Additional acute toxicity studies on the polymeric colorants of
interest include skin and eye irritation studies. Primary dermal
irritation studies in rabbits on PEG-modified FD&C Blue No. 1 show
``minimally irritating'' results and primary eye irritation studies in
rabbits show ``practically non-irritating'' results. The dermal
sensitization studies on PEG-modified FD&C Blue No. 1 show that this
material is not a skin sensitizer. In addition, primary dermal
irritation studies on the test material having slightly shorter side
chain lengths than PEG-modified FD&C Blue No. 1, show no effects.
Finally, primary dermal irritation studies in rabbits on PEG-modified
Methyl Violet 2B show barely perceptible erythema on abraded sites
only, and primary eye irritation studies in rabbits show ``non-
irritating'' results.
2. Genotoxicity. In Vitro Transformation Studies and Mouse Lymphoma
Forward Mutation Studies on PEG-modified FD&C Blue No. 1 both show that
this test material is inactive. Furthermore, an Ames study on Methyl-
PEG-modified FD&C Blue No. 1 shows non-mutagenic results. Mutagenicity
studies have not been conducted on Methyl Violet 2B, PEG Analog.
3. Reproductive and developmental toxicity. In Vitro Transformation
Studies and Mouse Lymphoma Forward Mutation Studies on PEG-modified
FD&C Blue No. 1 both show that this test material is inactive.
Furthermore, an Ames study on Methyl-PEG-modified FD&C Blue No. 1 shows
non-mutagenic results. Mutagenicity studies have not been conducted on
Methyl Violet 2B, PEG Analog.
4. Chronic toxicity. Chronic toxicity studies have not been
conducted on the three colorants of interest; however, studies have
been conducted on FD&C Blue No. 1, which is closely related to the FD&C
Blue No. 1 PEG and methyl PEG analogs. For this substance, a chronic
dietary No-Observed-Adverse-Effect Level (NOAEL) in mice has been shown
to be 7,354 milligrams per kilogram body weight per day for males, and
8,966 milligrams per kilogram per day for females. A chronic dietary
NOAEL for rats has been shown to be 1,072 for milligrams per kilogram
body weight per day for males and 631 milligrams per kilogram body
weight per day for females, showing a low order of chronic toxicity.
C. Aggregate Exposure
1. Dietary exposure. Dietary exposure to the polymeric colorants,
if at all, will be at de minimis levels. The colorants are intended to
be used as inert ingredients in pesticides that will be applied to
seeds. (The purpose of the colorants is to signal users that the seeds
have been treated with a pesticide that is not the subject of a
tolerance or an exemption from tolerance.) Because the colorants are
polymeric, they are not expected to be taken up by the growing plants.
Indeed, a determination of the octanol/water partition coefficient for
a test material identical to PEG-modified FD&C Blue No. 1, but with
slightly longer side chain lengths, resulted in low values that
demonstrate that the colorant would have little or no tendency to
concentrate in the fatty portions of animals or in plants. Even
assuming, however, that the polymeric colorants are taken up by growing
plants, the potential dietary exposure to these materials is less than
0.6 parts per billion (ppb) of the diet. This estimate is based on data
presented in Knott's Handbook for Vegetable Growers, O. Lorenz and D.
Maynard (c1988), which provides data with respect to the ``Approximate
Number of Seeds per Ounce and per Gram and Seeding Rates for
Traditional Plant Densities,'' and ``Yields of Vegetable Crops.''
Although the calculated dietary exposure to the colorants is
minuscule, it is important to note that even this extremely low
calculated exposure clearly is a gross overestimate, given the
polymeric nature of the colorants. Furthermore, although an acceptable
daily intake (ADI) for the colorants of interest has not been
established, the Joint FAO/WHO Expert Committee on Food Additives
(JECFA) has established an ADI for FD&C Blue No. 1 of 5 mg/kg body
weight/day, or 100 ppm of the diet. Furthermore, JECFA has established
an ADI for PEG of 10 mg/kg/person/day, or 200 ppm of the diet. (See
``World Health Organization Technical Report Series'', Nos. 557 and
648.) The estimated dietary exposure to the colorants of interest is
over two orders of magnitude below these ADIs for related compounds.
Currently, there are no established tolerances or exemptions from
tolerance for any of the colorants. However, the colorants are simply
polyethylene glycol-modified versions of dyes that currently are exempt
from the requirement of a tolerance (i.e., FD&C Blue No. 1 and Methyl
Violet 2B).
2. Drinking water. There is no available information regarding
exposure to PEG-modified FD&C Blue No. 1, Methyl-PEG-modified FD&C Blue
No. 1, or PEG-modified Methyl Violet 2B via drinking water. However,
aerobic soil metabolism studies on PEG-modified FD&C Blue No. 1 and
PEG-modified Methyl Violet 2B demonstrate that these colorants are
``inherently biodegradable.'' Furthermore, the results of aerobic soil
metabolism studies on all three colorants show that between 19% and 25%
of each colorant degrades within 42 days. Based on these results and
the low use levels of the colorants, significant exposure to these
colorants in drinking water is not anticipated. Furthermore, there is
no established Maximum Concentration Level for the polymeric colorants
in drinking water.
3. Non-dietary exposure. The proposed use of PEG-modified FD&C Blue
No. 1, Methyl-PEG-modified FD&C Blue No. 1, and PEG-modified Methyl
Violet 2B involves either application to turf grass seeds or
application to seeds grown in an agricultural environment. Thus, there
is no potential for significant non-occupational exposure of the
colorants to the general population.
[[Page 45810]]
D. Cumulative Effects
There is no reason to suspect that toxic effects of PEG-modified
FD&C Blue No. 1, Methyl-PEG-modified FD&C Blue No. 1, PEG-modified
Methyl Violet 2B would be cumulative with those of any other pesticide
inert or active chemical, and there are no data to indicate that this
would be the case. Thus, Milliken considers it appropriate to evaluate
the potential risks of the colorants solely in the context of the
aggregate exposure assessment.
E. Safety Determination
1. U.S. population. Data from acute toxicity studies show FD&C Blue
No. 1, PEG and Methyl PEG Analogs and PEG-modified Methyl Violet 2B to
be of a very low order of toxicity. Furthermore, two compounds that are
closely related to the colorants of interest, FD&C Blue No. 1 and
Methyl Violet 2B, currently are exempt from the requirement of a
tolerance under 40 CFR 180.1001 paragraphs (b) and (c), respectively.
In addition, FD&C Blue No. 1 is cleared by FDA for use in coloring food
and drugs. Use of the polymeric colorants of interest as inert
ingredients in pesticides applied to turf grass seeds and seeds for
edible plants such as beans, squash, and soybeans is not expected to
result in significant dietary exposures. Furthermore, there currently
are no other registered pesticidal uses in which these polymeric
colorants are used.
Because of the de minimis potential dietary exposures to the
polymeric colorants, there are no dietary risk concerns associated with
the intended use of the colorants, and there is a reasonable certainty
that no harm will result from such use.
2. Infants and children. The toxicity and exposure data in the
petition are sufficiently complete to adequately address the potential
for additional sensitivity to infants and children. Specifically, as
discussed above, developmental and reproductive effects studies on PEG-
modified and Methyl-PEG-modified FD&C Blue No. 1 have shown no
developmental/reproductive effects. Based on these data, together with
the low potential dietary exposure to the colorants, there is a
reasonable certainty that no harm will result to infants and children
from aggregate exposure to PEG-modified FD&C Blue No. 1, and Methyl-
PEG-modified FD&C Blue No. 1. Furthermore, although developmental
effects studies have not been conducted on PEG-modified Methyl Violet
2B, the potential dietary exposure to this colorant is sufficiently low
as to establish that there is a reasonable certainty that no harm will
result to infants and children from aggregate exposure to PEG-modified
Methyl Violet 2B.
F. International Tolerances
There are no Codex maximum residue levels established for residues
of PEG-modified FD&C Blue No. 1, Methyl-PEG-modified FD&C Blue No. 1,
or PEG-modified Methyl Violet 2B. (Amelia Acierto)
[FR Doc. 97-23097 Filed 8-28-97; 8:45 am]
BILLING CODE 6560-50-F
