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Thiamethoxam - Pesticide Petition Filing 4/99

[Federal Register: May 5, 1999 (Volume 64, Number 86)]
[Notices]
[Page 24153-24160]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr05my99-57]

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ENVIRONMENTAL PROTECTION AGENCY
[PF-870; FRL-6072-7]
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-870, must
be received on or before June 4, 1999.

ADDRESSES: By mail submit written comments to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7502C), 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-
docket@epamail.epa.gov. 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 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
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
------------------------------------------------------------------------
Dani Daniel...................  Rm. 211, CM #2, 703-    1921 Jefferson
                                 305-5409, e-            Davis Hwy,
                                 mail:daniel.dani@epam   Arlington, VA
                                 ail.epa.gov.
Cynthia Giles-Parker (PM 22)..  Rm. 249, CM #2, 703-    Do.
                                 305-7740, e-mail:
                                 giles-
                                 parker.cynthia@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-870] (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. Comments 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 (insert docket number) and appropriate
petition number. Electronic comments on notice may be filed online at
many Federal Depository Libraries.

List of Subjects

    Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and

[[Page 24154]]

pests, Reporting and recordkeeping requirements.

    Dated: April 23, 1999.

Peter Caulkins, 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.

2. Novartis Crop Protection, Inc.

PP 9F5046

    EPA has received a pesticide petition (9F5046) from Novartis Crop
Protection, Inc., PO Box 18300, Greensboro, North Carolina 27419
proposing, pursuant to section 408(d) of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 by
establishing a tolerance for residues of Thiamethoxam in or on the raw
agricultural commodity (RAC) rape seed at 0.02 parts per million (ppm).
EPA has determined that the petition contains data or information
regarding the elements set forth in section 408(d)(2) of the FFDCA;
however, EPA

[[Page 24156]]

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 primary metabolic pathways of thiamethoxam
in plants (corn, rice, pears, and cucumbers) were similar to those
described for animals, with certain extensions of the pathway in
plants. Parent compound and CGA-322704 were major metabolites in all
crops. The metabolism of thiamethoxam in plants and animals is
understood for the purposes of the proposed tolerances. Parent
thiamethoxam and the metabolite, CGA-322704, are the residues of
concern for tolerance setting purposes.
    2. Analytical method. Novartis Crop Protection Inc. has submitted
practical analytical methodology for detecting and measuring levels of
thiamethoxam in or on RAC. The method is based on crop specific cleanup
procedures and determination by liquid chromatography with either
ultraviolet (UV) or mass spectrometry (MS) detection. The limit of
detection (LOD) for each analyte of this method is 1.25 nanogram (ng)
injected for samples analyzed by UV and 0.25 ng injected for samples
analyzed by MS, and the limit of quantitation (LOQ) is 0.005 ppm for
milk and juices and 0.01 parts per million (ppm) for all other
substrates.
    3. Magnitude of residues. A residue program was performed for
thiamethoxam on a full geography of canola, using a maximum application
rate of 400 g.a.i./100 kilogram (kg) seed (0.024 lbs. a.i./acre, at the
typical seeding rate). Two field trials also included seed treated at 3
times the normal rate for thiamethoxam. No residues were detected above
the method LOD for thiamethoxam. The proposed tolerance on canola is
0.02 ppm for thiamethoxam.

B. Toxicological Profile

    1. Acute toxicity. Thiamethoxam has low acute toxicity. The oral
LD50 in rats is 1,563 millogram kilogram (mg/kg) for males
and females, combined. The rat dermal LD50 is > 2,000 mg/kg
and the rat inhalation LC50 is > 3.72 milligrams per liter
(mg/L) air. Thiamethoxam is not a skin sensitizer in guinea pigs and
does not produce dermal or eye irritation in rabbits. End-use
formulations of thiamethoxam have similar low acute toxicity profiles.
    2. Genotoxicty. Thiamethoxam did not induce point mutations in
bacteria (Ames assay in Salmonella typhimurium and Escherichia coli) or
in cultured mammalian cells (Chinese hamster V79) and was not genotoxic
in an in vitro unscheduled DNA synthesis assay in rat hepatocytes.
Chromosome aberrations were not observed in an in vitro test using
Chinese hamster ovary cells and there were no clastogenic or aneugenic
effects on mouse bone marrow cells in an in vivo mouse micronucleus
test. These studies show that thiamethoxam is not genotoxic.
    3. Reproductive and developmental toxicity. In rat and rabbit
teratology studies with thiamethoxam there was no evidence of
teratogenicity. In rabbits, thiamethoxam caused decreased body weights
(bwt), decreased food consumption and premature death of two females
administered 150 mg/kg/day during gestation. This maternal toxicity was
accompanied by reduced fetal bwts and an increase in the incidence of
minor skeletal anomalies or variations. Reduced maternal bwts and food
consumption were also noted in females administered 50 mg/kg/day
thiamethoxam during gestation. There was no indication of developmental
toxicity at 50 mg/kg/day. The no-observable adverse effect level
(NOAEL) in rabbits for maternal toxicity was 15 mg/kg/day. The NOAEL
for developmental toxicity was 50 mg/kg/day. In rats, thiamethoxam
caused decreased bwts, decreased food consumption and hypoactivity at
200 and 750 mg/kg/day. Reduced fetal bwts and an increase in the
incidence of minor skeletal anomalies and variations were observed only
at 750 mg/kg/day. There was no indication of developmental toxicity at
200 mg/kg/day. The NOAEL in rats for maternal toxicity was 30 mg/kg/day
and for developmental toxicity was 200 mg/kg/day. In a 2-generation
reproduction study in rats, parental bwts and food consumption were
decreased at 2,500 ppm highest dose tested (HDT). Hyaline changes in
the kidneys of adult males were observed at 2,500 and 1,000 ppm.
Reproductive parameters were not affected by treatment with
thiamethoxam. Effects on offspring were secondary to parental toxicity
and consisted of slightly reduced offspring bwts at 1,000 ppm and 2,500
ppm. The NOAEL for systemic toxicity in parental animals and for
offspring toxicity was 30 ppm (equivalent to 1.3 - 6.4 mg/kg/day).
    4. Subchronic toxicity Thiamethoxam was evaluated in 13-week
subchronic oral toxicity studies in rats, dogs and mice. Liver, kidneys
and spleen were identified as target organs. The NOAEL was 25 ppm (1.74
mg/kg/day) in male rats based on the finding of a hyaline change in the
kidney at 250 ppm (17.6 mg/kg/day). This kidney effect represents an
accumulation of alpha-2-microglobulin, which is unique to the male rat
and not relevant for human risk assessment. The NOAEL was 1,250 ppm
(92.5 mg/kg/day) for female rats. The NOAEL in dogs was 250 ppm (8.23
mg/kg/day). The NOAEL in mice was 10 ppm (1.41 mg/kg/day) for males and
100 ppm (19.2 mg/kg/day) for females. No dermal irritation was observed
in a 28-day repeated dose dermal toxicity study with thiamethoxam in
rats given 1,000 mg/kg/day. The dermal NOAEL for systemic toxicity in
rats was 250 mg/kg/day for males and 60 mg/kg/day for females.
    5. Neurotoxicity. Thiamethoxam did not cause neurotoxicity in an
acute neurotoxicity study in rats or in a subchronic 13-week
neurotoxicity study in rats. The NOAEL for systemic toxicity in the
acute neurotoxicity study was 100 mg/kg. The NOAEL for systemic
toxicity in the subchronic neurotoxicity study was 95.4 mg/kg/day for
males and 216.4 mg/kg/day for females.
    6. Chronic toxicity. The carcinogenic potential of thiamethoxam has
been evaluated in rats and mice. The proposed carcinogenic
classification for thiamethoxam is as a Group C carcinogen. This
classification is based on a liver tumor response in male and female
mice at dose levels exceeding the maximum tolerance dose (MTD) and/or
causing organ toxicity and induction of liver metabolizing enzymes. A
NOAEL for liver tumors in mice was established at 20 ppm (2.63 mg/kg/
day). No evidence of carcinogenicity was observed in rats. In the
absence of a mutagenic activity, it is concluded that the mechanism of
action leading to liver tumors in mice is not via genotoxic effects.
Therefore, mouse liver tumors associated with thiamethoxam treatment
have a threshold level.
    7. Animal metabolism. Metabolism of thiamethoxam has been well
characterized in animals. Metabolism in rats proceeds primarily via
hydrolysis of the oxadiazine ring, followed by N-demethylation. Several
minor pathways of metabolism of thiamethoxam were identified in
animals. In rats, the majority of the radioactive dose was absorbed and
then excreted in the urine. Parent compound was the major residue in
urine. In hens and goats, the metabolite profile was the same as in
rats, with certain extensions of the pathway.
    8. Metabolite toxicology. The metabolism profile for thiamethoxam
supports the use of an analytical enforcement method that accounts for
parent thiamethoxam and CGA-322704. Other metabolites are considered of

[[Page 24157]]

equal or lesser toxicity than parent compound.
    9. Endocrine disruption. Thiamethoxam does not belong to a class of
chemicals known or suspected of having adverse effects on the endocrine
system. There is no evidence that thiamethoxam has any effect on
endocrine function in developmental or reproduction studies.
Furthermore, histological investigation of endocrine organs in chronic
dog, rat and mouse studies did not indicate that the endocrine system
is targeted by thiamethoxam.

C. Aggregate Exposure

    1. Dietary exposure--Food and drinking water. Chronic and acute
dietary exposure to thiamethoxam was based on the occurrence of no
detectable residues of thiamethoxam or its major metabolite resulting
from the use of Helix on canola. There is no adverse exposure to
thiamethoxam in the diet when chronic and acute assessments are made
using tolerance level residues for canola oil (analytical method limit
of quantitation (LOQ)), and 100% market share. The inclusion of the
maximum concentration of thiamethoxam in water, taken from the highest
estimated residue observed from the generic expected environmental
concentration (GENEEC) and screening concentration In GROund (SCI-GROW)
models, led to a maximum chronic exposure of 0.000019 mg/kg bwt/day in
the most sensitive population subgroup, non-nursing infants (< 1-year
old). This is only 0.1% of the proposed reference dose (RfD) of 0.013
mg/kg bwt/day. The inclusion of the water concentration estimate in the
acute exposure assessment led to a margin of exposure (MOE) (NOAEL/
exposure) of 264,491 at the 99.9th percentile of the most sensitive
population subgroup, all infants (< 1-year old). The results of these
analyses show that there is reasonable certainty that no harm will
result from the exposure to dietary residues of thiamethoxam (including
drinking water) from the use of Helix on canola.
    2. Non-dietary exposure. There are no other uses currently
registered for thiamethoxam that would lead to exposure from non-
dietary sources. The proposed uses involve application of thiamethoxam
to canola seed as part of the Helix product in an agricultural
environment. A discussion of exposure from non-dietary sources will be
made when future uses of thiamethoxam are proposed.

D. Cumulative Effects

    The potential for cumulative effects of thiamethoxam and other
substances that have a common mechanism of toxicity has also been
considered. Thiamethoxam belongs to a new pesticide chemical class
known as the neonicotinoids. There is no reliable information to
indicate that toxic effects produced by thiamethoxam would be
cumulative with those of any other chemical including another
pesticide. Therefore, Novartis believes it is appropriate to consider
only the potential risks of thiamethoxam in an aggregate risk
assessment.

E. Safety Determination

    1. U.S. population. Using the exposure assumptions and the proposed
RfD described above, the aggregate exposure (including drinking water)
to thiamethoxam from the application of helix to canola will utilize <
0.1% of the RfD for the U.S. population. Therefore, Novartis concludes
that there is reasonable certainty that no harm will result from
aggregate exposure to thiamethoxam residues from the use of helix on
canola.
    2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of thiamethoxam, data
from developmental toxicity studies in the rat and rabbit and a 2-
generation reproduction study in the rat have been considered.
    In teratology studies, delayed fetal development was apparent only
at maternally toxic doses of thiamethoxam in rats and rabbits. In
rabbits, 150 mg/kg/day was clearly toxic to does, causing death, weight
loss, reduced food consumption and perineal or vaginal discharge.
Developmental toxicity occurred secondary to maternal toxicity and
consisted of reduced fetal bwts and an increase in minor skeletal
anomalies or variations. Maternal toxicity was also noted at 50 mg/kg/
day, consisting of reduced bwts and food consumption and total
resorptions in one female. There was no indication of developmental
toxicity at 50 mg/kg/day. The NOAEL for maternal toxicity was 15 mg/kg/
day and for developmental toxicity was 50 mg/kg/day in rabbits. In
rats, 200 and 750 mg/kg/day caused maternal toxicity, but developmental
toxicity secondary to maternal toxicity was observed only at 750 mg/kg/
day. The NOAEL for maternal toxicity was 30 mg/kg/day and for
developmental toxicity was 200 mg/kg/day.
    In a rat multigeneration study, parental toxic effects were noted
at 2,500 ppm (250 mg/kg/day). and 1,000 ppm (100 mg/kg/day). Offspring
bwts were reduced in males and females at 2,500 ppm (250 mg/kg/day) and
in females (F1 only) at 1,000 ppm (100 mg/kg/day). The NOAEL for
systemic toxicity in adult males was 30 ppm (approximately 3 mg/kg/day,
range = 1.3 - 4.3 mg/kg/day) and in adult females was 1,000 ppm
(approximately 100 mg/kg/day, range = 59.3 - 219.6 mg/kg/day). The
NOAEL for toxicity to offspring was 30 ppm (approximately 3 mg/kg/day,
range = 1.3 - 4.3 mg/kg/day). These studies show no evidence that
developing offspring are more sensitive to than adults to the effects
of thiamethoxam.
    FFDCA section 408 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 requirements, the database
for thiamethoxam relative to pre- and post-natal effects for children
is complete. Further, for thiamethoxam, the developmental studies
showed no increased sensitivity in fetuses as compared to maternal
animals following in utero exposures in rats and rabbits, and no
increased sensitivity in pups as compared to the adults in the multi-
generation reproductive toxicity study. Therefore, it is concluded that
an additional uncertainty factor is not warranted to protect the health
of infants and children and that an RfD of 0.013 mg/kg/day is
appropriate for assessing aggregate risk to infants and children of
thiamethoxam.
    Assuming tolerance level residues and 100% of crops treated, only
0.1% of the thiamethoxam chronic RfD is utilized in the population
subgroup all infant (< 1-year old) when helix is used as a seed
treatment on canola. Therefore, based on the completeness and
reliability of the toxicity database, Novartis concludes that there is
reasonable certainty that no harm will result to infants and children
from aggregate exposure to thiamethoxam residues.

F. International Tolerances

    There are no Codex maximum residue level (MRLs) established for
residues of thiamethoxam on canola.

3. Norvartis Crop Protection, Inc.

PP 9F5051

    EPA has received a pesticide petition (PP 9F5051) from Novartis
Crop Protection, Inc. Greensboro, North Carolina, 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

[[Page 24158]]

a tolerance for residues of Thiamethoxam in or on the raw agricultural
commodity (RAC) fruiting vegetables at 0.25 parts per million (ppm),
tomato paste at 0.80 ppm, head and stem brassica vegetables at 1.0 ppm,
leafy brassica greens at 2.0 ppm, cucurbit vegetables at 0.2 ppm, leafy
vegetables, tuberous and corm vegetables at 0.02 pm, barley hay at 0.05
ppm, barley straw at 0.03 ppm, cottonseed at 0.05 ppm, cotton gin by-
products at 1.0 ppm, pome fruit at 0.2 ppm, wheat forage at 0.5 ppm,
wheat grain, wheat straw, wheat hay, barley grain, sorghum grain,
sorghum forage and sorghum fodder at 0.02 ppm and milk at 0.02 ppm. EPA
has 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 primary metabolic pathways of thiamethoxam
in plants (corn, rice, pears, and cucumbers) were similar to those
described for animals, with certain extensions of the pathway in
plants. Parent compound and CGA-322704 were major metabolites in all
crops. The metabolism of thiamethoxam in plants and animals is
understood for the purposes of the proposed tolerances. Parent
thiamethoxam and the metabolite, CGA-322704, are the residues of
concern for tolerance setting purposes.
    2. Analytical method. Novartis Crop Protection Inc. has submitted
practical analytical methodology for detecting and measuring levels of
thiamethoxam in or on RAC. The method is based on crop specific cleanup
procedures and determination by liquid chromatography with either
ultraviolet (UV) or mass spectrometry (MS) detection. The limit of
detection (LOD) for each analyte of this method is 1.25 nanogram (ng)
injected for samples analyzed by UV and 0.25 ng injected for samples
analyzed by MS, and the limit of quantitation (LOQ) is 0.005 ppm for
milk and juices and 0.01 ppm for all other substrates.
    3. Magnitude of residues. A residue program was performed for
thiamethoxam on a full geography of cucumbers, cantaloupes and squash
as representative cucurbit crops, tomatoes and peppers as
representative fruiting vegetable crops, head lettuce, leaf lettuce,
celery and spinach as representative leafy vegetable crops, broccoli
and cabbage as representative head and stem brassica vegetable crops,
mustard greens as a representative leafy brassica green vegetable crop,
potatoes as a representative crop of tuberous and corm vegetables, and
apples and pears as representative pome fruit crops. A seed treatment
residue program was performed for thiamethoxam on sorghum, wheat,
barley and cotton where seed was treated using specific seed treatment
formulations. Cotton was also treated via foliar application. Field
residue trials were performed for thiamethoxam on tobacco using both an
in-furrow transplant drench and a post-foliar spray. Novartis also
completed a three-level dairy study and calculated the rate of transfer
of residues of thiamethoxam from residues in the animal feed to beef
and dairy commodities.

B. Toxicological Profile

    1. Acute toxicity. Thiamethoxam has low acute toxicity. The oral
LD50 in rats is 1,563 milligram kilogram (mg/kg) for males
and females, combined. The rat dermal LD50 is > 2,000 mg/kg
and the rat inhalation LC50 is > 3.72 milligrams per liter
(mg/L) air. Thiamethoxam is not a skin sensitizer in guinea pigs and
does not produce dermal or eye irritation in rabbits. End-use
formulations of thiamethoxam have similar low acute toxicity profiles.
    2. Genotoxicty. Thiamethoxam did not induce point mutations in
bacteria (Ames assay in Salmonella typhimurium and Escherichia coli) or
in cultured mammalian cells (Chinese hamster V79) and was not genotoxic
in an in vitro unscheduled DNA synthesis assay in rat hepatocytes.
Chromosome aberrations were not observed in an in vitro test using
Chinese hamster ovary cells and there were no clastogenic or aneugenic
effects on mouse bone marrow cells in an in vivo mouse micronucleus
test. These studies show that thiamethoxam is not genotoxic.
    3. Reproductive and developmental toxicity. In rat and rabbit
teratology studies with thiamethoxam there was no evidence of
teratogenicity. In rabbits, thiamethoxam caused decreased body weights
(bwts), decreased food consumption and premature death of two females
administered 150 mg/kg/day during gestation. This maternal toxicity was
accompanied by reduced fetal bwts and an increase in the incidence of
minor skeletal anomalies or variations. Reduced maternal body weights
(bwts) and food consumption were also noted in females administered 50
mg/kg/day thiamethoxam during gestation. There was no indication of
developmental toxicity at 50 mg/kg/day. The no-observable adverse
effect level (NOAEL) in rabbits for maternal toxicity was 15 mg/kg/day.
The NOAEL for developmental toxicity was 50 mg/kg/day. In rats,
thiamethoxam caused decreased bwts, decreased food consumption and
hypoactivity at 200 and 750 mg/kg/day. Reduced fetal bwts and an
increase in the incidence of minor skeletal anomalies and variations
were observed only at 750 mg/kg/day. There was no indication of
developmental toxicity at 200 mg/kg/day. The NOAEL in rats for maternal
toxicity was 30 mg/kg/day and for developmental toxicity was 200 mg/kg/
day. In a 2-generation reproduction study in rats, parental bwts and
food consumption were decreased at 2,500 ppm highest dose tested (HDT).
Hyaline changes in the kidneys of adult males were observed at 2,500
and 1,000 ppm. Reproductive parameters were not affected by treatment
with thiamethoxam. Effects on offspring were secondary to parental
toxicity and consisted of slightly reduced offspring bwts at 1,000 ppm
and 2,500 ppm. The NOAEL for systemic toxicity in parental animals and
for offspring toxicity was 30 ppm (equivalent to 1.3 - 6.4 mg/kg/day).
    4. Subchronic toxicity. Thiamethoxam was evaluated in 13-week
subchronic oral toxicity studies in rats, dogs and mice. Liver, kidneys
and spleen were identified as target organs. The NOAEL was 25 ppm (1.74
mg/kg/day) in male rats based on the finding of a hyaline change in the
kidney at 250 ppm (17.6 mg/kg/day). This kidney effect represents an
accumulation of alpha-2-microglobulin, which is unique to the male rat
and not relevant for human risk assessment. The NOAEL was 1,250 ppm
(92.5 mg/kg/day) for female rats. The NOAEL in dogs was 250 ppm (8.23
mg/kg/day). The NOAEL in mice was 10 ppm (1.41 mg/kg/day) for males and
100 ppm (19.2 mg/kg/day) for females. No dermal irritation was observed
in a 28-day repeated dose dermal toxicity study with thiamethoxam in
rats given 1,000 mg/kg/day. The dermal NOAEL for systemic toxicity in
rats was 250 mg/kg/day for males and 60 mg/kg/day for females.
    5. Neurotoxicity. Thiamethoxam did not cause neurotoxicity in an
acute neurotoxicity study in rats or in a subchronic 13-week
neurotoxicity study in rats. The NOAEL for systemic toxicity in the
acute neurotoxicity study was 100 mg/kg. The NOAEL for systemic
toxicity in the subchronic neurotoxicity study was 95.4 mg/kg/day for
males and 216.4 mg/kg/day for females.
    6. Chronic toxicity. Chronic toxicity studies with thiamethoxam
have been conducted in rats and dogs. In the dog,

[[Page 24159]]

minor changes in blood chemistry parameters, including increased plasma
creatinine and plasma urea levels, and decreased alanine
aminotransferase activities, occurred at the lowest-observable adverse
effect level (LOAEL) of 750 ppm (21.0 mg/kg/day). The NOAEL in the dog
was 150 ppm (4.05 mg/kg/day). The NOAEL established in the rat chronic
toxicity study was 30 ppm (1.29 mg/kg/day) for males, based on kidney
changes, (hyaline change, chronic tubular lesions, basophilic
proliferation and lymphocytic infiltration) at the LOAEL of 500 ppm
(21.0 mg/kg/day). These kidney changes are attributed to an
accumulation of alpha-2-microglobulin, which is specific to the male
rat, and not relevant to humans. In the female rat, the NOAEL was 1,000
ppm (50.3 mg/kg/day) based on decreased bwts and hemosiderosis of the
spleen at the LOAEL of 3,000 ppm (155 mg/kg/day).
    7. Carcinogenicity. The carcinogenic potential of thiamethoxam has
been evaluated in rats and mice. The proposed carcinogenic
classification for thiamethoxam is as a Group C carcinogen. This
classification is based on a liver tumor response in male and female
mice at dose levels exceeding the maximum tolerance dose (MTD) and/or
causing organ toxicity and induction of liver metabolizing enzymes. A
NOAEL for liver tumors in mice was established at 20 ppm (2.63 mg/kg/
day). No evidence of carcinogenicity was observed in rats. In the
absence of a mutagenic activity, it is concluded that the mechanism of
action leading to liver tumors in mice is not via genotoxic effects.
Therefore, mouse liver tumors associated with thiamethoxam treatment
have a threshold level.
    8. Animal metabolism. Metabolism of thiamethoxam has been well
characterized in animals. Metabolism in rats proceeds primarily via
hydrolysis of the oxadiazine ring, followed by N-demethylation. Several
minor pathways of metabolism of thiamethoxam were identified in
animals. In rats, the majority of the radioactive dose was absorbed and
then excreted in the urine. Parent compound was the major residue in
urine. In hens and goats, the metabolite profile was the same as in
rats, with certain extensions of the pathway.
    9. Metabolite toxicology. The metabolism profile for thiamethoxam
supports the use of an analytical enforcement method that accounts for
parent thiamethoxam and CGA-322704. Other metabolites are considered of
equal or lesser toxicity than parent compound.
    10. Endocrine disruption. Thiamethoxam does not belong to a class
of chemicals known or suspected of having adverse effects on the
endocrine system. There is no evidence that thiamethoxam has any effect
on endocrine function in developmental or reproduction studies.
Furthermore, histological investigation of endocrine organs in chronic
dog, rat and mouse studies did not indicate that the endocrine system
is targeted by thiamethoxam.

C. Aggregate Exposure

    1. Dietary exposure. Chronic dietary exposure was estimated using a
Tier I approach by inputting tolerance level residues into the dietary
exposure evaluation model (DEEMTM) software. The Tier I
assessment was partially refined by adjusting for projected percent
crop-treated information, and was made using the department of
agriculture (USDA) National Food consumption Survey, Continuing Survey
of Food Intakes by Individuals (CSFII) 1994-96. The maximum total
exposure to the U. S. population (48 States, all seasons) was
calculated to be 4.1% of the reference dose of 0.013 mg/kg bwt/day. The
maximum exposure to the most sensitive population sub-group, children
(1-6 years) was 9.5% of the reference dose (RfD). The inclusion of the
maximum concentration of thiamethoxam in water, taken from the highest
estimated concentration observed from the generic expected
environmental concentration (GENEEC) and screening concentration In
GROund water (SCI GROW) models, led to a maximum chronic dietary
exposure of 4.5% in the United States population and 10.0% in children
(1-6 years old).
    Acute dietary exposure was calculated using a Tier III,
probabilistic assessment. A distribution of residue data points was
included for the typically non-blended commodities of vegetables
(tuberous, fruiting, cucurbit, brassica and leafy), pome fruits, meat
and milk, while the average field trial value was used for the
typically blended commodities of grains (wheat, sorghum, and barley),
seed oil (cotton and canola), apple juice and tomato paste and puree.
The acute assessment used adjustment for percent of crop treated, and
was made using the DEEM software with the Monte Carlo analysis and the
CSFII 1994-96 food consumption survey. The margin of exposure (MOE)
(NOAEL/exposure) for the United States population (all seasons) at the
99.9th percentile of the exposure distribution was 4,995 using the
NOAEL value of 15 mg/kg bwt/day. At the 99.9th percentile, the MOE for
the most sensitive population sub-group (non-nursing infants < 1-year
old) was 1,012. Inclusion of the drinking water value to the acute
assessment led to an MOE of 4,904 at the 99.9th percentile of the
United States population, and 1,008 for the population sub-group non-
nursing infants < 1-year old. The results of these analyses show that
there is reasonable certainty that no harm will result from exposure to
dietary residues (including drinking water) of thiamethoxam.
    2. Non-dietary exposure. Novartis also requests registrations for
the use of thiamethoxam on dogs, turf and ornamentals. Novartis has
identified potential non-dietary exposures to toddlers for these uses.
These exposures include the following scenarios:
    i. Incidental non-dietary ingestion of residues on lawns from hand-
to-mouth transfer.
    ii. Ingestion of thiamethoxam treated grass.
    iii. Incidental ingestion of pesticide residues on pets from hand-
to-mouth transfer.
    According to current EPA policy, these exposures are considered to
be short-term oral exposures. EPA does not expect incidental ingestion
of pesticide residues on pets from hand-to-mouth transfer to occur
during the same period as the exposures from the turf uses. Thus,
Novartis considered these exposures in separate estimates of risk.
According to current EPA policy, if an oral endpoint is needed for
short-term risk assessment (for incorporation of food, water, or oral
hand-to-mouth type exposures into an aggregate risk assessment), the
acute oral endpoint (acute RfD = 15 mg/kg bwt/day) will be used to
incorporate the oral component into aggregate risk. Short-term
aggregate exposure is defined by EPA to be average food and water
exposure (chronic exposure) plus residential exposure. The short-term
risk estimates for the population subgroup children, 1 to 6-years old,
is summarized below. This population subgroup was chosen because it has
the highest chronic food exposure and because toddlers have the highest
exposure from the residential uses. From the results below, Novartis
concludes there is no concern associated with the aggregate exposure to
thiamethoxam.
    3. Short-term aggregate exposure and risk including turf for
children 1 to 6- years old--i. Dietary exposure estimate including
water is 0.001296 mg/kg bwt/day.
    ii. Residential exposure from turf is calculated to be 0.00497 mg/
kg bwt/day.
    iii. Total exposure equals 0.0063 mg/kg bwt/day.

[[Page 24160]]

    iv. Percent Acute RfD consumed is 0.04%
    4. Short-term aggregate exposure and risk including pet use for
children 1 to 6-years old--i. Dietary exposure estimate including water
is 0.001296 mg/kg bwt/day.
    ii. Predicted hand to mouth transfer is 0.0341 mg/kg bwt/day.
    iii. Total exposure equals 0.035 mg/kg bwt/day.
    iv. Percent Acute RfD consumed is 0.23%.

D. Cumulative Effects

    The potential for cumulative effects of thiamethoxam and other
substances that have a common mechanism of toxicity has also been
considered. Thiamethoxam belongs to a new pesticide chemical class
known as the neonicotinoids. There is no reliable information to
indicate that toxic effects produced by thiamethoxam would be
cumulative with those of any other chemical including another
pesticide. Therefore, Novartis believes it is appropriate to consider
only the potential risks of thiamethoxam in an aggregate risk
assessment.

E. Safety Determination

    1. U. S. population. Using the chronic exposure assumptions and the
proposed RfD described above, the aggregate exposure (including
drinking water) to thiamethoxam to the U. S. population (48 States, all
seasons) was calculated to be 4.5% of the RfD of 0.013 mg/kg bwt/day.
Therefore, Novartis concludes that there is reasonable certainty that
no harm will result from aggregate chronic exposure to thiamethoxam
residues.
    2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of thiamethoxam, data
from developmental toxicity studies in the rat and rabbit and a 2-
generation reproduction study in the rat have been considered.
    In teratology studies, delayed fetal development was apparent only
at maternally toxic doses of thiamethoxam in rats and rabbits. In
rabbits, 150 mg/kg/day was clearly toxic to does, causing death, weight
loss, reduced food consumption and perineal or vaginal discharge.
Developmental toxicity occurred secondary to maternal toxicity and
consisted of reduced fetal bwts and an increase in minor skeletal
anomalies or variations. Maternal toxicity was also noted at 50 mg/kg/
day, consisting of reduced bwts and food consumption and total
resorptions in one female. There was no indication of developmental
toxicity at 50 mg/kg/day. The NOAEL for maternal toxicity was 15 mg/kg/
day and for developmental toxicity was 50 mg/kg/day in rabbits. In
rats, 200 and 750 mg/kg/day caused maternal toxicity, but developmental
toxicity secondary to maternal toxicity was observed only at 750 mg/kg/
day. The NOAEL for maternal toxicity was 30 mg/kg/day and for
developmental toxicity was 200 mg/kg/day.
    In a rat multigeneration study, parental toxic effects were noted
at 2,500 ppm (250 mg/kg/day) and 1,000 ppm (100 mg/kg/day). Offspring
bwts were reduced in males and females at 2,500 ppm (250 mg/kg/day) and
in females (F1 only) at 1,000 ppm (100 mg/kg/day). The NOAEL for
systemic toxicity in adult males was 30 ppm (approximately 3 mg/kg/day,
range = 1.3 - 4.3 mg/kg/day) and in adult females was 1,000 ppm
(approximately 100 mg/kg/day, range = 59.3 - 219.6 mg/kg/day). The
NOAEL for toxicity to offspring was 30 ppm (approximately 3 mg/kg/day,
range = 1.3 - 6.4 mg/kg/day). These studies show no evidence that
developing offspring are more sensitive to than adults to the effects
of thiamethoxam.
    FFDCA section 408 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 requirements, the database
for thiamethoxam relative to pre- and post-natal effects for children
is complete. Further, for thiamethoxam, the developmental studies
showed no increased sensitivity in fetuses as compared to maternal
animals following in utero exposures in rats and rabbits, and no
increased sensitivity in pups as compared to the adults in the multi-
generation reproductive toxicity study. Therefore, it is concluded that
an additional uncertainty factor is not warranted to protect the health
of infants and children and that an RfD of 0.013 mg/kg/day is
appropriate for assessing aggregate risk to infants and children of
thiamethoxam.
    Assuming tolerance level residues and adjusting for the percent of
crops treated, only 7.0% of the thiamethoxam chronic RfD is utilized in
the population subgroup all infant (> 1-year old). Therefore, based on
the completeness and reliability of the toxicity database, Novartis
concludes that there is reasonable certainty that no harm will result
to infants and children from aggregate exposure to thiamethoxam
residues.

F. International Tolerances

    There are no Codex maximum residue levels (MRLs) established for
residues of thiamethoxam on fruiting vegetables, tomato paste, head and
stem brassica vegetables, leafy brassica greens, cucurbit vegetables,
leafy vegetables, tuberous and corm vegetables, barley grain, barley
hay, barley straw, cottonseed, cotton gin by-products, pome fruit,
wheat grain, wheat forage, wheat straw, wheat hay, sorghum grain,
sorghum forage, sorghum fodder, or milk. (Dani Daniel)
[FR Doc. 99-11169 Filed 5-4-99; 8:45 am]
BILLING CODE 6560-50-F