[Federal Register Volume 63, Number 42 (Wednesday, March 4, 1998)]
[Notices]
[Pages 10609-10614]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-5563]
-----------------------------------------------------------------------
ENVIRONMENTAL PROTECTION AGENCY
[PF-794; FRL-5774-1]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
-----------------------------------------------------------------------
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-794, must
be received on or before April 3, 1998.
ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch (7502C), 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. 119, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: opp-
[email protected]. Follow 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
[[Page 10610]]
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. 119 at the Virginia 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:
------------------------------------------------------------------------
Office location/
Product Manager telephone number Address
------------------------------------------------------------------------
Beth Edwards.................. Rm. 206, CM #2, 703- 1921 Jefferson
305-5400, e-mail: Davis Hwy,
edwards.beth@epamail. Arlington, VA
epa.gov.
Sidney Jackson................ Rm. 233, CM #2, 703- Do.
305-7610, e-mail:
jackson.sidney@epamai
l.epa.gov.
------------------------------------------------------------------------
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-794] (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 5.1/6.1 or ASCII file
format. All comments and data in electronic form must be identified by
the docket control number [PF-794] 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: February 24, 1998.
James Jones,
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. DowElanco
PP 8F4942
EPA has received a pesticide petition (PP 8F4942) from DowElanco,
9330 Zionsville Road, Indianapolis, IN 46254 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 the insecticide spinosad in or on the raw agricultural
commodity cotton gin byproducts at 1.5 parts per million (ppm). Because
of the amount of spinosad residue found in cotton gin byproducts as
well as wet apple pomace (pending tolerance under PP 6F4761) and almond
hulls and citrus dried pulp (pending tolerances under PP 7F4871) and
the amount of cotton gin byproducts, almond hulls, citrus dried pulp,
and apple pomace potentially included in livestock rations, a
livestock, fat residue tolerance of 0.8 ppm, a milk residue tolerance
of 0.05 ppm, and a milk fat residue tolerance of 0.7 ppm are also being
proposed. The following meat and milk tolerances for residues of
spinosad are presently pending under PP 6F4761 and PP 7F4871: meat at
0.04 ppm, kidney and liver at 0.2 ppm, fat at 0.7 ppm, milk at 0.04
ppm, and milk fat at 0.5 ppm. An adequate analytical method is
available for enforcement purposes. 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. The metabolism of spinosad in plants (apples,
cabbage, cotton, tomato, and turnip) and animals (goats and poultry) is
adequately understood for the purposes of these tolerances. A
rotational crop study showed no carryover of measurable spinosad
related residues in representative test crops.
2. Analytical method. There is a practical method (HPLC with UV
detection) for detecting (0.004 ppm) and measuring (0.01 ppm) levels of
spinosad in or on food with a limit of detection that allows monitoring
of food with residues at or above the levels set for these tolerances.
The method has had a successful method tryout in the EPA's
laboratories.
3. Magnitude of residues. Magnitude of residue studies were
conducted for cotton gin byproducts at seven sites. Residues found in
these studies ranged from less than the limit of quantitation of the
analytical method to 0.9 ppm on cotton gin byproducts.
B. Toxicological Profile
1. Acute toxicity. Spinosad has low acute toxicity. The rat oral
LD50 is 3,738 mg/kg for males and >5,000 milligrams/
kilograms (mg/kg) for females, whereas the mouse oral LD50
is >5,000 mg/kg. The rabbit dermal LD50 is >2,000 mg/kg and
the rat inhalation LC50 is >5.18 mg/l air. In addition,
spinosad is not a skin sensitizer in guinea pigs and does not produce
significant dermal or ocular irritation in rabbits. End use
formulations of spinosad that are water based suspension concentrates
have similar low acute toxicity profiles.
2. Genotoxicity. Short term assays for genotoxicity consisting of a
bacterial reverse mutation assay (Ames test), an
[[Page 10611]]
in vitro assay for cytogenetic damage using the Chinese hamster ovary
cells, an in vitro mammalian gene mutation assay using mouse lymphoma
cells, an in vitro assay for DNA damage and repair in rat hepatocytes,
and an in vivo cytogenetic assay in the mouse bone marrow (micronucleus
test) have been conducted with spinosad. These studies show a lack of
genotoxicity.
3. Reproductive and developmental toxicity. Spinosad caused
decreased body weights in maternal rats given 200 milligrams/kilograms/
day (mg/kg/day) by gavage (highest dose tested). This was not
accompanied by either embryo toxicity, fetal toxicity, or
teratogenicity. The NOELs for maternal and fetal effects in rats were
50 and 200 mg/kg/day, respectively. A teratology study in rabbits
showed that spinosad caused decreased body weight gain and a few
abortions in maternal rabbits given 50 mg/kg/day (highest dose tested).
Maternal toxicity was not accompanied by either embryo toxicity, fetal
toxicity, or teratogenicity. The NOELs for maternal and fetal effects
in rabbits were 10 and 50 mg/kg/day, respectively. The NOEL found for
maternal and pup effects in a rat reproduction study was 10 mg/kg/day.
Neonatal effects at 100 mg/kg/day (highest dose tested in the rat
reproduction study) were attributed to maternal toxicity.
4. Subchronic toxicity. Spinosad was evaluated in 13-week dietary
studies and showed NOELs of 4.9 mg/kg/day in dogs, 6 mg/kg/day in mice,
and 8.6 mg/kg/day in rats. No dermal irritation or systemic toxicity
occurred in a 21-day repeated dose dermal toxicity study in rabbits
given 1,000 mg/kg/day.
5. Chronic toxicity. Based on chronic testing with spinosad in the
dog and the rat, the EPA has set a reference dose (RfD) of 0.0268 mg/
kg/day for spinosad. The RfD has incorporated a 100-fold safety factor
to the NOELs found in the chronic dog study. The NOELs shown in the dog
chronic study were 2.68 and 2.72 mg/kg/day, respectively for male and
female dogs. The NOELs shown in the rat chronic study were 2.4 and 3.0
mg/kg/day, respectively for male and female rats. Using the Guidelines
for Carcinogen Risk Assessment published September 24, 1986 (51 FR
33992), it is proposed that spinosad be classified as Group E for
carcinogenicity (no evidence of carcinogenicity) based on the results
of carcinogenicity studies in two species. There was no evidence of
carcinogenicity in an 18-month mouse feeding study and a 24-month rat
feeding study at all dosages tested. The NOELs shown in the mouse
oncogenicity study were 11.4 and 13.8 mg/kg/day, respectively for male
and female mice. The NOELs shown in the rat chronic/oncogenicity study
were 2.4 and 3.0 mg/kg/day, respectively for male and female rats. A
maximum tolerated dose was achieved at the top dosage level tested in
both of these studies based on excessive mortality. Thus, the doses
tested are adequate for identifying a cancer risk. Accordingly, a
cancer risk assessment is not needed.
6. Animal metabolism. There were no major differences in the
bioavailability, routes or rates of excretion, or metabolism of
spinosyn A and spinosyn D following oral administration in rats. Urine
and fecal excretions were almost completed in 48-hours post-dosing. In
addition, the routes and rates of excretion were not affected by
repeated administration.
7. Metabolite toxicology. The residue of concern for tolerance
setting purposes is the parent material (spinosyn A and spinosyn D).
Thus, there is no need to address metabolite toxicity.
8. Neurotoxicity. Spinosad did not cause neurotoxicity in rats in
acute, subchronic, or chronic toxicity studies.
9. Endocrine effects. There is no evidence to suggest that spinosad
has an effect on any endocrine system.
C. Aggregate Exposure
1. Dietary exposure. For purposes of assessing the potential
dietary exposure from use of spinosad on cotton gin byproducts as well
as from other existing or pending uses, a conservative estimate of
aggregate exposure is determined by basing the TMRC on the proposed
tolerance levels for spinosad and assuming that 100% of the cotton gin
byproducts and other existing and pending crop uses grown in the U.S.
were treated with spinosad. The TMRC is obtained by multiplying the
tolerance residue levels by the consumption data which estimates the
amount of crops and related foodstuffs consumed by various population
subgroups. The use of a tolerance level and 100% of crop treated
clearly results in an overestimate of human exposure and a safety
determination for the use of spinosad on crops cited in this summary
that is based on a conservative exposure assessment.
2. Drinking water. Another potential source of dietary exposure are
residues in drinking water. Based on the available environmental
studies conducted with spinosad wherein it's properties show little or
no mobility in soil, there is no anticipated exposure to residues of
spinosad in drinking water. In addition, there is no established
Maximum Concentration Level for residues of spinosad in drinking water.
3. Non-dietary exposure. Spinosad is currently registered for use
on cotton with several crop registrations pending all of which involve
applications of spinosad in the agriculture environment. Spinosad is
also currently registered for use on turf and ornamentals at low rates
of application (0.04 to 0.54 lb a.i. per acre). Thus, the potential for
non-dietary exposure to the general population is not expected to be
significant.
D. Cumulative Effects
The potential for cumulative effects of spinosad and other
substances that have a common mechanism of toxicity is also considered.
In terms of insect control, spinosad causes excitation of the insect
nervous system, leading to involuntary muscle contractions, prostration
with tremors, and finally paralysis. These effects are consistent with
the activation of nicotinic acetylcholine receptors by a mechanism that
is clearly novel and unique among known insecticidal compounds.
Spinosad also has effects on the GABA receptor function that may
contribute further to its insecticidal activity. Based on results found
in tests with various mammalian species, spinosad appears to have a
mechanism of toxicity like that of many amphiphilic cationic compounds.
There is no reliable information to indicate that toxic effects
produced by spinosad would be cumulative with those of any other
pesticide chemical. Thus it is appropriate to consider only the
potential risks of spinosad in an aggregate exposure assessment.
E. Safety Determination
1. U.S. population. Using the conservative exposure assumptions and
the proposed RfD described above, the aggregate exposure to spinosad
use on cotton gin byproducts and other existing or pending crop uses
will utilize 20.6% of the RfD for the U.S. population. A more realistic
estimate of dietary exposure and risk relative to a chronic toxicity
endpoint is obtained if average (anticipated) residue values from field
trials are used. Inserting the average residue values in place of
tolerance residue levels produces a more realistic, but still
conservative risk assessment. Based on average or anticipated residues
in a dietary risk analysis, the use of spinosad on cotton gin
byproducts and other existing or pending crop uses will utilize 4.5% of
the RfD for the U.S. population. EPA generally has no concern for
exposures below 100% of the RfD because the RfD represents the level at
or below which daily aggregate dietary exposure over a lifetime will
not pose appreciable risks to human health.
[[Page 10612]]
Thus, it is clear that there is reasonable certainty that no harm will
result from aggregate exposure to spinosad residues on cotton gin
products and other existing or pending crop uses.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of spinosad, data from
developmental toxicity studies in rats and rabbits and a 2-generation
reproduction study in the rat are considered. The developmental
toxicity studies are designed to evaluate adverse effects on the
developing organism resulting from pesticide exposure during prenatal
development. Reproduction studies provide information relating to
effects from exposure to the pesticide on the reproductive capability
and potential systemic toxicity of mating animals and on various
parameters associated with the well-being of pups.
Section 408 of the FFDCA provides that EPA may apply an additional
safety factor for infants and children in the case of threshold effects
to account for pre- and post-natal toxicity and the completeness of the
database. Based on the current toxicological data requirements, the
database for spinosad relative to pre- and post-natal effects for
children is complete. Further, for spinosad, the NOELs in the dog
chronic feeding study which was used to calculate the RfD (0.0268 mg/
kg/day) are already lower than the NOELs from the developmental studies
in rats and rabbits by a factor of more than 10-fold.
Concerning the reproduction study in rats, the pup effects shown at
the highest dose tested were attributed to maternal toxicity.
Therefore, it is concluded that an additional uncertainty factor is not
needed and that the RfD at 0.0268 mg/kg/day is appropriate for
assessing risk to infants and children.
Using the conservative exposure assumptions previously described
(tolerance level residues), the percent RfD utilized by the aggregate
exposure to residues of spinosad on cotton gin byproducts and other
existing or pending crop uses is 38.1% for children 1 to 6 years old,
the most sensitive population subgroup. If average or anticipated
residues are used in the dietary risk analysis, the use of spinosad on
these crops will utilize 11.1% of the RfD for children 1 to 6 years
old. Thus, based on the completeness and reliability of the toxicity
data and the conservative exposure assessment, it is concluded that
there is a reasonable certainty that no harm will result to infants and
children from aggregate exposure to spinosad residues on cotton gin
byproducts and other existing or pending crop uses.
F. International Tolerances
There are no Codex maximum residue levels established for residues
of spinosad on cotton gin byproducts or any other food or feed crop.
(Beth Edwards)
2. Interregional Research Project
PP 4E4420 and 6E4638
EPA has received pesticide petitions (PP 4E4420 and 6E4638) from
the Interregional Research Project Number 4 (IR-4), 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
combined residues (free and bound) of the herbicide metolachlor and its
metabolites, CGA- 37913 and CGA- 49751, expressed as the parent
compound, in or on the raw agricultural commodities (RACs) peppers at
0.5 ppm, forage of the grass forage, fodder and hay group (excluding
Bermudagrass), forage at 12 ppm and hay of the grass forage, fodder and
hay group (excluding Bermudagrass) at 0.3 ppm. Time-limited tolerances
are being proposed for peppers and grass grown for seed to allow time
to developed magnitude of residue data from an additional three field
trials for bell pepper and five additional field trials for grass
forage and hay. EPA has determined that the petitions contain 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 support granting of the
petitions. Additional data may be needed before EPA rules on the
petitions. This notice contains a summary of the petitions submitted by
Novartis Crop Protection, Inc. (Novartis), the registrant.
A. Residue Chemistry
1. Plant and animal metabolism. The qualitative nature of the
metabolism of metolachlor in plants and animals is well understood.
Metabolism in plants involves conjugation of the chloroacetyl side
chain with glutathione, with subsequent conversion to the cysteine and
thiolactic acid conjugates. Oxidation to the corresponding sulfoxide
derivatives occurs and cleavage of the side chain ether group, followed
by conjugation with glucose. In animals, metolachlor is rapidly
metabolized and almost totally eliminated in the excreta of rats,
goats, and poultry. Metabolism in plants and animals proceeds through
common Phase 1 intermediates and glutathione conjugation.
2. Analytical method. IR-4 has submitted a practical analytical
method involving extraction by acid reflux, filtration, partition and
cleanup with analysis by gas chromatography using nitrogen specific
detection. The methodology accounts for residues of CGA-37913 and CGA-
49751 which are formed from metolachlor and its metabolites under acid
hydrolysis. The limit of quantitation (LOQ) for the method is 0.03 ppm
for CGA-37913 and 0.05 ppm for CGA-49751. Residues of CGA-37913 and
CGA-49751 are reported as metolachlor equivalents.
3. Magnitude of residues. For peppers - This petition for the
establishment of a 0.5 ppm tolerance for metolachlor on peppers is
supported by the individual tolerances already established in a number
of pepper varieties: bell (0.1 ppm), chili (0.5 ppm), Cubanelle (0.1
ppm), and tabasco (0.5 ppm).
In four field trials, 1.5 to 3.5 lbs. metolachlor per acre, was
applied 48 hours after transplanting of bell peppers. Residues from
these samples were less than 0.1 ppm. Metolachlor was also applied at
2.0 to 4.0 lbs active per acre to Cubanelle peppers shortly after
transplanting. Residues recovered from these samples were also below
the 0.1 ppm level. In tabasco peppers, 4 lbs metolachlor per acre was
applied as a directed spray to the pepper plants and peppers were
harvested either 7 or 14 days after treatment. Residues of nearly 0.5
ppm were recovered 7 days after treatment, however, the residue levels
dropped to approximately 0.25 ppm when harvested 14 days after
treatment. For chili peppers, metolachlor was applied post-emergence as
a foliar application at 2.0 lbs active per acre. Samples harvested at
approximately 40 days after treatment had residues of 0.36 ppm (as CGA-
49751), however, samples taken later than this date had residues below
0.03 ppm. In one additional chili pepper trial, metolachlor was applied
at rates of 1 to 4 lbs active ingredient per acre to direct seeded
peppers. No residues were recovered from the peppers harvested 204 days
after the application. The proposed label would allow one surface
broadcast application of metolachlor at 1.25 to 2.0 pints (1.25 to 2.0
lbs. active) per acre within 48 hours after transplanting peppers and
with a pre-harvest interval of 63 days.
For Grass Grown for Seed - This petition is supported by six field
residue tests conducted on grasses grown for seed. Quantitative
measurements of the metolachlor hydrolysates, CGA-37913 and CGA-49751,
were made for all
[[Page 10613]]
samples and reported as metolachlor equivalents. In all residue tests,
metolachlor (Dual 8E) was applied post-emergence at a maximum
of 2.0 lbs. a.i./A at the early regrowth stage prior to weed emergence.
The maximum residue in forage was 27 ppm (60-day PHI). Residues in
forage declined with increasing PHI. Maximum residues in straw,
screenings, and seed were 0.11 ppm, 0.04 ppm, and <0.08 ppm,
respectively.
B. Toxicological Profile
1. Acute toxicity. Metolachlor has a low order of acute toxicity.
The combined rat oral lethal dose (LD)50 is 2,877
milligrams(mg)/kilogram(kg). The acute rabbit dermal LD50 is
>2,000 mg/kg and the rat inhalation lethal concentration
(LC)50 is >4.33 mg/liter (L). Metolachlor was not irritating
to the skin and eye. It was shown to be positive in guinea pigs for
skin sensitization. End use formulations of metolachlor also have a low
order of acute toxicity and cause slight skin and eye irritation.
2. Genotoxicity. Assays for genotoxicity were comprised of tests
evaluating metolachlor's potential to induce point mutations
(Salmonella assay and an L5178/TK+/- mouse lymphoma assay), chromosome
aberrations (mouse micronucleus and a dominant lethal assay) and the
ability to induce either unscheduled or scheduled deoxyribonucleic acid
(DNA) synthesis in rat hepatocytes or DNA damage or repair in human
fibroblasts. The results indicate that metolachlor is not mutagenic or
clastogenic and does not provoke unscheduled DNA synthesis.
3. Reproductive and developmental toxicity. Adverse developmental
and reproductive potential of metolachlor was investigated in rats and
rabbits. The results indicate that metolachlor is not embyrotoxic or
reproductive toxic in either species at maternally toxic doses. The no-
observed-effect level (NOEL) for developmental toxicity for metolachlor
was 360 mg/kg/day for both the rat and rabbit while the NOEL for
maternal toxicity was established at 120 mg/kg/day in the rabbit and
360 mg/kg/day in the rat.
A 2-generation reproduction study was conducted with metolachlor in
rats at feeding levels of 0, 30, 300 and 1,000 ppm. The reproductive
NOEL of 300 ppm (equivalent to 23.5 to 26 mg/kg/day) was based upon
reduced pup weights in the F1a and F2a litters at the 1,000 ppm dose
level (equivalent to 75.8 to 85.7 mg/kg/day). The NOEL for parental
toxicity was equal to or greater than the 1,000 ppm dose level.
4. Subchronic toxicity. Metolachlor was evaluated in a 21-day
dermal toxicity study in the rabbit and a 6-month dietary study in
dogs; NOELs of 100 mg/kg/day and 7.5 mg/kg/day were established in the
rabbit and dog, respectively. The liver was identified as the main
target organ.
5. Chronic toxicity. A 1-year dog study was conducted at dose
levels of 0, 3.3, 9.7, or 32.7 mg/kg/day. The Agency-determined
reference dose(RfD) for metolachlor is based on the one year dog study
with a NOEL of 9.7 mg/kg/day. The RfD for metolachlor is established at
0.1 mg/kg/day using a 100-fold uncertainty factor. A combined chronic
toxicity/carcinogenicity study was also conducted in rats at dose
levels of 0. 1.5, 15 or 150 mg/kg/day. The NOEL for systemic toxicity
was 15 mg/kg/day.
6. Carcinogenicity. An evaluation of the carcinogenic potential of
metolachlor was made from two sets of carcinogenicity studies conducted
with metolachlor in rats and mice. EPA has classified metolachlor as a
Group C (possible human) carcinogen and uses a Margin of Exposure (MOE)
approach to quantify risk. This classification is based upon the
marginal tumor response observed in livers of female rats treated with
a high (cytotoxic) dose of metolachlor (3,000 ppm). The two studies
conducted in mice were negative for carcinogenicity.
A NOEL of 15 mg/kg/day from the 2 year rat feeding study was
determined to be appropriate for use in the MOE carcinogenic risk
assessment. However, because the chronic reference dose is lower (9.7
mg/kg/day) than the carcinogenic NOEL (15 mg/kg/day), the EPA is using
the Reference Dose for quantification of human risk.
7. Estrogenic potential/endocrine disruption. Metolachlor does not
belong to a class of chemicals known or suspected of having adverse
effects on the endocrine system. There is no evidence that metolachlor
has any effect on endocrine function in developmental or reproduction
studies. Furthermore, histological investigation of endocrine organs in
the chronic dog, rat and mouse studies conducted with metolachlor did
not indicate that the endocrine system is targeted by metolachlor, even
at maximally tolerated doses administered for a lifetime. Although
residues of metolachlor have been found in raw agricultural
commodities, there is no evidence that metolachlor bioaccumulates in
the environment.
C. Aggregate Exposure
1. Dietary (food) exposure. For purposes of assessing the potential
dietary exposure to metolachlor, aggregate exposure has been estimated
based on the Theoretical Maximum Residue Contribution (TMRC) from the
use of metolachlor in or on raw agricultural commodities for which
tolerances have been previously established (40 CFR 180.368). The
incremental effect on dietary risk resulting from the addition of
peppers to the label was assessed by assuming that exposure would occur
at the proposed tolerance level of 0.5 ppm with 100% of the crop
treated. The potential human dietary exposure from grasses grown for
seed comes from the consumption of grass forage and hay by animals.
Based on the tolerances proposed in forage (12 ppm) and hay (0.3 ppm),
it has been determined that tolerances previously established for
metolachlor in animal commodities of milk and meat, fat, kidney, liver
and meat byproducts are adequate to cover secondary residues resulting
from animal consumption of grass forage and hay.
The TMRC is obtained by multiplying the tolerance level residue for
all these raw agricultural commodities by the consumption data which
estimates the amount of these products consumed by various population
subgroups. Some of these raw agricultural commodities (e.g. corn forage
and fodder, peanut hay) are fed to animals; thus exposure of humans to
residues in these fed commodities might result if such residues are
transferred to meat, milk, poultry, or eggs. Therefore, tolerances of
0.02 ppm for milk, meat and eggs and 0.2 ppm for kidney and 0.05 ppm
for liver have been established for metolachlor.
In conducting this exposure assessment, it has been conservatively
assumed that 100% of all raw agricultural commodities for which
tolerances have been established for metolachlor will contain
metolachlor residues and those residues would be at the level of the
tolerance--which results in an overestimation of human exposure.
2. Drinking water. Another potential source of exposure of the
general population to residues of pesticides are residues in drinking
water. Based on the available studies used by EPA to assess
environmental exposure, Novartis anticipates that exposure to residues
of metolachlor in drinking water will not exceed 20% of the RfD (0.02
mg/kg/day), a value upon which the Health Advisory Level of 70 parts
per billion (ppb) for metolachlor is based. In fact, based on
experience with metolachlor,
[[Page 10614]]
it is believed that metolachlor will be infrequently found in
groundwater (less than 5% of the samples analyzed), and when found, it
will be in the low ppb range.
3. Non-dietary exposure. Although metolachlor may be used on turf
and ornamentals in a residential setting, that use represents less than
0.1 percent of the total herbicide market for residential turf and
landscape uses. Currently, there are no acceptable, reliable exposure
data available to assess any potential risks from non-dietary exposure.
However, given the small amount of material that is used, Novartis
believes that the potential for non-occupational exposure to the
general population is unlikely.
D. Cumulative Effects
The potential for cumulative effects of metolachlor and other
substances that have a common mechanism of toxicity has also been
considered. Novartis believes that consideration of a common mechanism
of toxicity with other registered pesticides in this chemical class
(chloroacetamides) is not appropriate. EPA concluded that the
carcinogenic potential of metolachlor is not the same as other
registered chloroacetamide herbicides, based on differences in rodent
metabolism (EPA Peer Review of metolachlor, 1994). Novartis maintains
that only metolachlor should be considered in an aggregate exposure
assessment.
E. Safety Determination
1. U.S. population. Using the exposure assumptions described above,
based on the completeness and reliability of the toxicity data,
Novartis has concluded that aggregate exposure to metolachlor including
the proposed new uses on peppers and grasses grown for seed will
utilize approximately 3.0% of the RfD for the U.S. population. EPA
generally has no concern for exposures below 100% of the RfD because
the RfD represents the level at or below which daily aggregate dietary
exposure over a lifetime will not pose appreciable risks to human
health. Therefore, Novartis believes that there is a reasonable
certainty that no harm will result from aggregate exposure to
metolachlor or metolachlor residues.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of metolachlor, data
from developmental toxicity studies in the rat and rabbit and a 2-
generation reproduction study in the rat have been considered. The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from chemical exposure during
prenatal development to one or both parents. Reproduction studies
provide information relating to effects from exposure to a chemical on
the reproductive capability of mating animals and data on systemic
toxicity.
Developmental toxicity (reduced mean fetal body weight, reduced
number of implantations/dam with resulting decreased litter size, and a
slight increase in resorptions/dam with a resulting increase in post-
implantation loss) were observed in studies on metolachlor in rats and
rabbits. The NOEL's for developmental effects in both rats and rabbits
were established at 360 mg/kg/day. The developmental effect observed in
the metolachlor rat study is believed to be a secondary effect
resulting from maternal stress (lacrimation, salivation, decreased body
weight gain and food consumption and death) observed at the limit dose
of 1,000 mg/kg/day.
A 2-generation reproduction study was conducted with metolachlor at
feeding levels of 0, 30, 300 and 1,000 ppm. The reproductive NOEL of
300 ppm (equivalent to 23.5 to 26 mg/kg/day) was based upon reduced pup
weights in the F1a and F2a litters at the 1,000 ppm dose level
(equivalent to 75.8 to 85.7 mg/kg/day). The NOEL for parental toxicity
was equal to or greater than the 1,000 ppm dose level.
Section 408 of the FFDCA provides that EPA may apply an additional
safety factor for infants and children in the case of threshold effects
to account for pre- and post-natal toxicity and the completeness of the
database. Based on the current toxicological data requirements, the
database relative to pre- and post-natal effects for children is
complete. Further, for the chemical metolachlor, the NOEL of 9.7 mg/kg/
day from the metolachlor chronic dog study, which was used to calculate
the RfD (discussed above), is already lower than the developmental
NOEL's of 360 mg/kg/day from the metolachlor developmental toxicity
studies in rats and rabbits. In the metolachlor reproduction study, the
lack of severity of the pup effects observed (decreased body weight) at
the systemic lowest-observed-effect level (LOEL) (equivalent to 75.8 to
85.7 mg/kg/day) and the fact that the effects were observed at a dose
that is nearly 10 times greater than the NOEL in the chronic dog study
(9.7 mg/kg/day) suggest there is no additional sensitivity for infants
and children. Therefore, Novartis concludes that an additional
uncertainty factor is not warranted to protect the health of infants
and children and that the RfD at 0.1 mg/kg/day based on the chronic dog
study is appropriate for assessing aggregate risk to infants and
children from use of metolachlor.
Using the exposure assumptions described above, Novartis concludes
that the approximate percentages of the RfD that will be utilized by
aggregate exposure to residues of metolachlor including published and
pending tolerances is 1% for U. S. population, for nursing infants less
than 1%, 3% for non-nursing infants, 3% for children 1 to 6 years old
and 2% for children 7 to 12 years old.
Therefore, based on the completeness and reliability of the
toxicity data and the conservative exposure assessment, Novartis
concludes that there is a reasonable certainty that no harm will result
to infants and children from aggregate exposure to metolachlor
residues.
F. International Tolerances
There are no Codex Alimentarius Commission (CODEX) maximum residue
levels (MRL's) established for residues of metolachlor in or on raw
agricultural commodities. (Sidney Jackson)
[FR Doc. 98-5563 Filed 3-3-98:45 am]
BILLING CODE 6560-50-F