Notice of Filing of Pesticide Petitions

Note: EPA no longer updates this information, but it may be useful as a reference or resource.

[Federal Register: August 26, 1998 (Volume 63, Number 165)]
[Notices]
[Page 45487-45497]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr26au98-58]

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ENVIRONMENTAL PROTECTION AGENCY

[PF-826; FRL-6023-5]

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-826, must
be received on or before September 25, 1998.
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

[[Page 45488]]

claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.

FOR FURTHER INFORMATION CONTACT: The product manager listed in the
table below:

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Office location/
Product Manager telephone number Address
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Beth Edwards (PM 3)........... Rm. 206, CM #2, 703- 1921 Jefferson
305-5400, e- Davis Hwy,
mail:edwards.beth@epa Arlington, VA
mail.epa.gov.
Sidney Jackson (PM 22)........ Rm. 233, CM #2, 703- Do.
305-7610, e-mail:
jackson.sidney@epamai
l.epa.gov.
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SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various food
commodities under section 408 of the Federal Food, Drug, and Comestic
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these petitions
contain data or information regarding the elements set forth in section
408(d)(2); however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of
the petition. Additional data may be needed before EPA rules on the
petition.
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-826] (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 pests, Reporting and recordkeeping
requirements.

Dated: August 13, 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. AgrEvo USA Company (acting as registered US agent for Hoechst
Schering AgrEvo, S.A.)

PP 7F4909

EPA has received a pesticide petition (PP 7F4909) from AgrEvo USA
Company (acting as registered U.S. agent for Hoechst Schering AgrEvo,
S.A.), 2711 Centerville Road, Wilmington, DE 19808 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 a tolerance
for residues of deltamethrin in or on various food and feed
commodities. Tolerances are currently established at 40 CFR 180.435 in
or on the following commodities for residues of deltamethrin [(1R, 3R)-
3(2,2-dibromovinyl)-2,2-dimethylcyclopropanecarboxylic acid (S)-alpha-
cyano-3-phenoxybenzyl ester] and relevant metabolites: cottonseed at
0.04 parts per million (ppm), cottonseed oil at 0.2 ppm, tomatoes at
0.2 ppm, and tomato products (concentrated) at 1.0 ppm.
EPA has determined that the petition contains data or information
regarding the elements set forth in section 408(d)(2) of the FFDCA;
however, EPA has not fully evaluated the sufficiency of the submitted
data at this time or whether the data supports granting of the
petition. Additional data may be needed before EPA rules on the
petition.
Based on the fact that tralomethrin, another synthetic pyrethroid
insecticide, is rapidly metabolized in plants and animals to
deltamethrin, and the toxicological profile of the two compounds is
similar, it is appropriate to consider a combined exposure assessment
for tralomethrin and deltamethrin.

A. Residue Chemistry

1. Plant metabolism. Deltamethrin metabolism studies in tomatoes,
corn, apples, and cotton demonstrate the same metabolic pathway.
Furthermore, plant metabolism studies have been conducted following
application of tralomethrin in cotton, corn, cabbage, and tomatoes.
These studies have demonstrated that the metabolism of tralomethrin
involves debromination to deltamethrin and its isomers. Thus, a similar
metabolic pathway has been shown to occur in a variety of crops
following either direct application of deltamethrin (cotton, corn,
apples, and tomatoes) or in-plant formation of deltamethrin via
debromination of applied tralomethrin (tomatoes, cotton, corn, and
cabbage). As a result of this substantial information base, it is
concluded that the residues of toxicological concern in/on growing
crops following application of tralomethrin or deltamethrin are
tralomethrin, cis-deltamethrin, and its isomers, trans-deltamethrin and
alpha-R-deltamethrin.
2. Analytical method. Analytical methods for determining residues
of tralomethrin and deltamethrin in various commodities for which
registrations have been approved, or are being sought, have been
submitted to the Agency. These methods, based on

[[Page 45489]]

gas chromatography (GLC) equipped with an electron capture detector
(ECD) and a DB-1 (or equivalent) capillary column, are used for the
determination of tralomethrin, cis-deltamethrin, trans-deltamethrin,
and alpha-R-deltamethrin in various raw agricultural, animal derived,
and processed commodities. These methods were independently validated
and are appropriate for the determination of residues of tralomethrin
and deltamethrin in various food and feed commodities after application
of these ingredients to target growing crops, and after use in food/
feed handling establishments.
3. Magnitude of residues. Residues of tralomethrin, deltamethrin,
and its metabolites are not expected to exceed the proposed tolerance
levels as a result of the use of these active ingredients on target
crops, or at target sites.

B. Toxicological Profile

1. Acute toxicity. The acute oral LD<INF>50</INF> values for
deltamethrin in the rat are 66.7 milligram/kilograms (mg/kg) for males,
86 mg/kg for females, and for tralomethrin 99 mg/kg for males, 157 mg/
kg for females when administered in sesame oil. The oral
LD<INF>50</INF> for deltamethrin when administered in aqueous methyl
cellulose was greater than 5,000 mg/kg for both sexes. The dermal
LD<INF>50</INF> in rabbits was greater than 2,000 mg/kg for both
materials. Inhalation 4-hour LC<INF>50</INF> values in the rat are 2.2
mg/L for deltamethrin and greater than 0.286 mg/L for tralomethrin.
2. Genotoxicty. No indication of genotoxicity was noted in a
battery of in vivo and in vitro studies conducted with either
deltamethrin or tralomethrin.
3. Reproductive and developmental toxicity--i. Deltamethrin. A rat
developmental toxicity study conducted with deltamethrin indicated a
maternal no observed effect level (NOEL) of 3.3 mg/kg/day based on
clinical observations, decreased weight gain and mortality. The
developmental NOEL was 11 mg/kg/day higest dose tested (HDT).
In a rabbit developmental toxicity study with deltamethrin, the
maternal NOEL was considered to be 10 mg/kg/day based on decreased
defecation at 25 and 100 mg/kg/day, and mortality at 100 mg/kg/day. The
developmental NOEL was considered to be 25 mg/kg/day based on retarded
ossification of the pubic and tail bones at 100 mg/kg HDT.
A 3-generation rat reproduction study and a more recent, 2-
generation rat reproduction study with deltamethrin indicated the NOEL
for both parents and offspring was 80 ppm (4-12 mg/kg/day for adults
and 18-44 mg/kg/day for offspring) based on clinical signs of toxicity,
reduced weight gain and mortality at 320 ppm HDT.
ii. Tralomethrin. In a rat developmental toxicity study with
tralomethrin the NOEL for maternal and developmental toxicity was
judged to be greater than or equal to 18 mg/kg/day HDT.
No evidence of developmental toxicity was observed in either of two
rabbit developmental toxicity studies conducted with tralomethrin. In
one study, the maternal NOEL was 12.5 mg/kg/day based on mortality
while the developmental NOEL was judged to be greater than or equal to
25 mg/kg/day HDT. In the second study, the maternal NOEL was 8 mg/kg/
day based on body weight effects while the developmental NOEL was 32
mg/kg/day HDT.
In a 2-generation reproduction study with tralomethrin in rats, the
parental NOEL was 0.75 mg/kg/day based on body weight deficits while
the NOEL for offspring was 3.0 mg/kg/day, also based on body weight
deficits.
4. Subchronic toxicity-- i. Deltamethrin. A 90-day rat oral
toxicity study was conducted with deltamethrin which was administered
by gavage. The NOEL was judged to be 1.0 mg/kg/day based on reduced
body weight gain and slight hypersensitivity. In a more recent 90-day
rat dietary study with deltamethrin, the NOEL was judged to be 300 ppm
(23.9 mg/kg/day for males, 30.5 mg/kg/day for females) based on
uncoordinated movement, unsteady gait, tremors, increased sensitivity
to sound, shakes and spasmodic convulsions. The difference in the
NOEL's between the two studies is attributed to the different routes of
exposure (gavage in oil vs. administered in diet).
A 12-week study was conducted with deltamethrin in mice. The NOEL
was 300 ppm (61.5 mg/kg/day in males and 77.0 mg/kg/day in females)
based on chronic contractions, convulsions, poor condition, decreased
weight gain and mortality.
Two 13-week dog studies were conducted with deltamethrin. In the
first study, beagle dogs were administered deltamethrin by capsule
using PEG 200 as a vehicle. The NOEL for this study was 1 mg/kg/day
based on tremors, unsteadiness, jerking movements, salivation,
vomiting, liquid feces and/or dilatation of the pupils. In the second
study, deltamethrin was administered by capsule without a vehicle to
beagle dogs. The NOEL for this study was 10 mg/kg/day based on unsteady
gait, tremors, head shaking, vomiting and salivation. The difference in
toxicity between the two studies is attributed to the enhanced
absorption resulting from the use of PEG 200 as a vehicle in the first
study.
A 21-day dermal toxicity study was conducted with deltamethrin in
rats. The NOEL for systemic toxicity was determined to be 1,000 mg/kg/
day.
In a subchronic inhalation study, rats were exposed to aerosolized
deltamethrin for 6 hours per day, 5-days per week, for a total of 14-
days over 3 weeks. Based on slightly decreased body weights and
neurological effects at higher dose levels, it was concluded that 3
<greek-m>g/l was the NOEL for systemic effects in this study.
ii. Tralomethrin. Tralomethrin was administrated by gavage in corn
oil to rats for 13 weeks. Based on mortality, decreased activity and
motor control, soft stools, labored breathing and significantly lower
absolute and relative mean liver weights, the NOEL was considered to be
1 mg/kg/day.
Tralomethrin was administered by capsule to beagle dogs for 13
weeks. The NOEL for this study was 1.0 mg/kg/day based on refusal of
milk supplement, tremors, exaggerated patellar response, unsteadiness
and uncoordinated movement.
A 21-day dermal toxicity study was conducted with tralomethrin on
rats. No systemic effects were observed, therefore the systemic NOEL
for this study was 1,000 mg/kg/day.
5. Chronic toxicity and oncogenicity-- i. Deltamethrin.
Deltamethrin was administered in the diet to beagle dogs for 2 years.
No treatment-related effects were observed and the NOEL was judged to
be 40 ppm (1.1 mg/kg/day). In a more recent study, deltamethrin was
administered by capsule (without a vehicle) to beagle dogs for 1 year.
The NOEL in this study was considered to be 1 mg/kg/day based on
clinical signs, decreased food consumption and changes in several
hematology and blood chemistry parameters.
Two rat chronic toxicity/oncogenicity studies were conducted with
deltamethrin. In the first study, the test substance was administered
via the diet to rats for 2 years. The NOEL for this study was 20 ppm (1
mg/kg/day) based on slightly decreased weight gain. In a more recent
study, deltamethrin was administered to rats in the diet for 2 years.
The NOEL for this study was considered to be 25 ppm (1.1 and 1.5 mg/kg/
day for males and females, respectively), based on neurological signs,
weight gain effects and increased incidence and severity of
eosinophilic hepatocytes and/or balloon cells. No evidence of
carcinogenicity was noted in either study.

[[Page 45490]]

Two mouse oncogenicity studies were conducted with deltamethrin. In
the first study, deltamethrin was administered in the diet for 2 years.
No adverse effects were observed and the NOEL was judged to be 100 ppm
(12 and 15 mg/kg/day, respectively, for males and females). In a more
recent study, deltamethrin was administered in the diet to mice for 97
weeks. The NOEL was considered to be 1,000 ppm (15.7 and 19.6 mg/kg/
day) based on a higher incidence of poor physical condition and a
slight transient weight reduction. There was no evidence of
oncogenicity in either study.
ii. Tralomethrin. Tralomethrin was administered to beagle dogs by
capsule for 1 year at initial dosages of 0, 0.75, 3.0 and 10.0 mg/kg/
day. Due to trembling, ataxia, prostration and convulsions, the high
dosage was lowered to 8 mg/kg/day at study week 4 and lowered again to
6 mg/kg/day on study week 14. On the 14 week of study, the 0.75 mg/kg/
day dosage was raised to 1.0 mg/kg/day. Based on body weight changes,
convulsions, tremors, ataxia and salivation, the NOEL for this study
was considered to be 1 mg/kg/day.
Tralomethrin was administered by gavage to rats for 24 months. The
NOEL for this study was 0.75 mg/kg/day based on salivation,
uncoordinated movement, inability to support weight on limbs and
decreased body weight parameters. No evidence of carcinogenicity was
observed.
A 2 year mouse oncogenicity study was conducted with tralomethrin
administered by gavage. The NOEL was judged to be 0.75 mg/kg/day based
on higher incidences of dermatitis and mortality, salivation,
uncoordinated involuntary movements and aggressiveness. No evidence of
oncogenicity was observed.
6. Neurotoxicity. Acute delayed neurotoxicity studies in hens were
conducted for both deltamethrin and tralomethrin. In both cases, the
study results were negative indicating that neither material causes
delayed neurotoxicity.
In an acute neurotoxicity study with deltamethrin in rats, effects
were noted after a single oral administration of a dose of 50 mg/kg. In
addition, potential effects (limited to a single male and female) were
observed at a dose level of 15 mg/kg. Therefore, the no observed
adversed effect level (NOAEL) for neurotoxicity in this study was 5 mg/
kg.
In a subchronic neurotoxicity study with deltamethrin in rats,
effects were noted after daily dietary administration for 13
consecutive weeks at 800 ppm. The NOAEL for systemic toxicity and
neurotoxicity in this study was found to be 200 ppm (14 and 16 mg/kg/
day for males and females, respectively).
7. Animal metabolism-- i. Deltamethrin. The absorption of
deltamethrin appears to be highly dependent upon the route and vehicle
of administration. Once absorbed, deltamethrin is rapidly and
extensively metabolized and excreted, primarily within the first 48
hours.
ii. Tralomethrin. Tralomethrin is rapidly metabolized to
deltamethrin after debromination. The metabolic pattern of the
debrominated tralomethrin is exactly the same as that of the metabolic
pattern of deltamethrin.
8. Endocrine effects. No special studies have been conducted to
investigate the potential of deltamethrin or tralomethrin to induce
estrogenic or other endocrine effects. However, the standard battery of
required toxicity studies has been completed. These studies include an
evaluation of the potential effects on reproduction and development,
and an evaluation of the pathology of the endocrine organs following
repeated or long-term exposure. These studies are generally considered
to be sufficient to detect any endocrine effects, yet no such effects
were detected. Thus, the potential for deltamethrin or tralomethrin to
produce any significant endocrine effects is considered to be minimal.

C. Aggregate Exposure

Based on the fact that tralomethrin is rapidly metabolized in
plants and animals to deltamethrin, and the toxicological profile of
the two compounds is similar, it is appropriate to consider combined
exposure assessments for tralomethrin and deltamethrin.
Deltamethrin and tralomethrin are broad spectrum insecticides used
to control pests of crops, ornamental plants and turf, and domestic
indoor and outdoor (including dog collars and direct application to
livestock), commercial, and industrial food use areas. Thus, aggregate
non-occupational exposure would include exposures resulting from non-
food use in addition to consumption of potential residues in food and
water. Exposure via drinking water is expected to be negligible since
deltamethrin binds tightly to soil and rapidly degrades in water.
1. Dietary exposure--Food. Food tolerances have been established
for residues of tralomethrin and/or deltamethrin and its metabolites in
or on a variety of raw agricultural commodities. These tolerances, in
support of registrations, currently exist for residues of tralomethrin
on broccoli, cottonseed, head lettuce, leaf lettuce, soybeans,
sunflower seed, and cottonseed oil. Also, tolerances in support of
registrations currently exist for deltamethrin on cottonseed and
cottonseed oil. Additionally, tolerances have been established for
tralomethrin to support its use in food/feed handling establishments,
and for deltamethrin on tomatoes and concentrated tomato products to
support the importation of tomato commodities treated with
deltamethrin. Further, a food/feed handling establishment use, and
associated tolerances, is pending for deltamethrin. Additional
tolerances are being proposed for deltamethrin in the subject pesticide
tolerance petition. Potential acute exposures from these relevant food
commodities were estimated using a Tier 3 acute dietary risk assessment
(Monte Carlo Analysis) following EPA guidance. Potential chronic
exposures from food commodities under the established food and feed
additive tolerances for deltamethrin and tralomethrin, plus the pending
tolerances for deltamethrin associated with use in food/feed handling
areas, and the tolerances proposed in this petition for deltamethrin,
were estimated using NOVIGEN's dietary exposure evaluation mode (DEEM).
This chronic risk assessment was conduced using anticipated residues
based on field trial or monitoring data, percent crop treated, and
percent food handling establishments treated.
2. Drinking water . Tralomethrin and deltamethrin are immobile in
soil and, therefore, will not leach into groundwater. Additionally, due
to the insolubility and lipophilic nature of deltamethrin and
tralomethrin, any residues in surface water will rapidly and tightly
bind to soil particles and remain with sediment, therefore not
contributing to potential dietary exposure from drinking water.
A screening evaluation of leaching potential of a typical
pyrethroid was conducted using EPA's pesticide root zone model (PRZM3).
Based on this screening assessment, the potential concentrations of a
pyrethroid in ground water at depths of 1 and 2 meters are essentially
zero <0.001 parts per billion (PPB). Surface water concentrations for
pyrethroids were estimated using PRZM3 and Exposure Analysis Modeling
System (EXAMS) using Standard EPA cotton runoff and Mississippi pond
scenarios. The maximum concentration predicted in the simulated pond
was 0.052 ppb. Concentrations in actual drinking water would be much
lower than the levels predicted in the hypothetical, small, stagnant
farm pond model since

[[Page 45491]]

drinking water derived from surface water would normally be treated
before consumption. Based on these analyses, the contribution of water
to the dietary risk estimate is negligible.
3. Non-dietary exposure. As noted above, deltamethrin and
tralomethrin are broad spectrum insecticides registered for use on a
variety of food and feed commodities. Additionally, registrations are
held for non-agricultural applications including turf and lawn care
treatments, broadcast carpet treatments (professional use only), indoor
fogger, spot, crack and crevice treatments, insect baits, lawn and
garden sprays and indoor and outdoor residential, industrial and
institutional sites including those for Food/Feed Handling
Establishments.
To evaluate non-dietary exposure, the ``flea infestation
control''senario was chosen to represent a plausible but worst case
non-dietary (indoor and outdoor) non-occupational exposure. This
scenario provides a situation where deltamethrin and/or tralomethrin is
commonly used and they can be used concurrently for a multitude of
uses, e.g., spot and/or broadcast treatment of infested indoor surfaces
such as carpets and rugs, treatment of pets and treatment of the lawn.
This hypothetical situation provides a very conservative, upper bound
estimate of potential non-dietary exposures. Consequently, if health
risks are acceptable under these conditions, the potential risks
associated with other more likely scenarios would also be acceptable.
Because tralomethrin is rapidly metabolized to deltamethrin, and
the toxicology profiles of deltamethrin and tralomethrin are virtually
identical, a non-dietary and aggregate (non-dietary + chronic dietary)
exposure/risk assessment has been conducted for the combination of both
active ingredients. The total exposure to both materials was expressed
as ``deltamethrin equivalents'' and these were compared to the
toxicology endpoints identified for deltamethrin.

D. Cumulative Effects

When considering a tolerance, the Agency must consider ``available
information'' concerning the cumulative effects of a particular
pesticide's residues and ``other substances that have a common
mechanism of toxicity''. AgrEvo USA Company, acting as registered U.S.
agent for Hoechst Schering AgrEvo SA, believes that ``available
information'' in this context includes not only toxicity, chemistry,
and exposure data, but also scientific policies and methodologies for
understanding common mechanisms of toxicity and conducting cumulative
risk assessments.
Further, AgrEvo does not have, at this time, available data to
determine whether tralomethrin and/or deltamethrin have a common
mechanism of toxicity with other substances. For the purposes of this
tolerance action, therefore, no assumption has been made that
tralomethrin and/or deltamethrin have a common mechanism of toxicity
with other substances.

E. Safety Determination

1. U.S. population. The toxicity and residue data base for
deltamethrin and tralomethrin are considered to be valid, reliable and
essentially complete according to existing regulatory requirements. No
evidence of oncogenicity has been observed for either compound. In
accordance with EPA's ``Toxicology Endpoint Selection Process''
Guidance Document for acute exposures, the toxicology endpoint from the
deltamethrin rat acute neurotoxicity study, 5.0 mg/kg/day, is used. For
chronic exposures to deltamethrin and tralomethrin, the Reference Dose
(RfD) of 0.01 mg/kg bodyweight/day established for deltamethrin based
on the NOEL from the 2-year rat feeding study and a 100-fold safety
factor to account for interspecies extrapolation and intraspecies
variation is used.
For the overall U.S. population, acute dietary exposure at the
99.9th percentile results in a margin of exposure (MOE) of 1,406; the
MOE for the 99th percentile is 3,500; and at the 95th percentile the
MOE is 8,613. For the overall U.S. population, chronic dietary exposure
results in a utilization of 1.4% of the reference dose. Using an upper
bound estimate of potential non-dietary exposures for a worst case
scenario (flea treatment) results in an MOE of 160,000 for adults.
Utilizing the scenario of chronic dietary exposure plus an upper bound
estimate of potential non-dietary exposure from a worst case scenario
(flea treatment), it is shown that for aggregate exposure to
deltamethrin and tralomethrin there is an MOE of 31,100 for adults.
There is generally no concern for MOE's greater than 100. For chronic
exposure, there is generally no concern for exposure 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.
In conclusion, there is reasonable certainty that no harm will
result to the U.S. population, in general, from dietary or aggregate
exposure to deltamethrin and/or tralomethrin.
2. Infants and children. Data from developmental toxicity studies
in rats and rabbits, and multigeneration reproduction studies in rats
are generally used to assess the potential for increased sensitivity of
infants and children. 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 reproductive and other effects on
adults and offspring from pre-natal and post-natal exposure to the
pesticide. None of these studies conducted with deltamethrin or
tralomethrin indicated developmental or reproductive effects as a
result of exposure to these materials.
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 data requirements, the
database relative to pre- and post-natal effects in children is
complete. Although no indication of increased susceptibility to younger
animals was noted in any of the above studies, or in the majority of
studies with other pyrethroids, several recent publications have
reported that deltamethrin is more toxic to neonate and weanling
animals than to adults. However, a joint industry group currently
investigating this issue was unable to reproduce these findings.
Furthermore, the RfD (0.01 mg/kg/day) that has been established for
deltamethrin is already more than 1,000-fold lower than the lowest NOEL
from the developmental and reproduction studies. Therefore, the RfD of
0.01 mg/kg/day is appropriate for assessing chronic aggregate risk to
infants and children and an additional uncertainty factor is not
warranted. Also, the NOEL of 5.0 mg/kg/day from the rat acute
neurotoxicity study is appropriate to use in acute dietary, short term
non-dietary, and aggregate exposure assessments.
For the population subgroup described as non-nursing infants, less
than 1 year old, the MOE for acute dietary exposure at the 99.9th
percentile is 666; at the 99th percentile the MOE is 1,491; and at the
95th percentile the MOE is 8,755. For the population subgroup described
as children 1-6 years old, the MOE for acute dietary exposure is 871
for the 99.9th percentile; at the 99th percentile the MOE is 1,527; and
at the 95th percentile the MOE is 3,167. For non-nursing infants,
chronic dietary exposure results in a utilization of 1.9% of the RfD,
and

[[Page 45492]]

for children 1-6 years old 3.7% of the reference dose is utilized.
Using an upper bound estimate of potential non-dietary exposures for a
worst case scenario (flea treatment) results in an MOE of 6,100 for
infants less than 1 year old, and an MOE of 6,600 for children 1-6
years old. Utilizing the scenario of chronic dietary exposure plus an
upper bound estimate of potential non-dietary exposure from a worst
case scenario (flea treatment) it is shown that for aggregate exposure
to deltamethrin and tralomethrin, there is an MOE of 6,775 for infants
less than 1 year old, and an MOE of 5,700 for children 1-6 years old.
There is generally no concern for MOE's greater than 100. For chronic
exposure, there is generally no concern for exposure 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.
In summary, there is reasonable certainty that no harm will result
to infants and children from aggregate exposure to either deltamethrin
or tralomethrin.

F. International Tolerances

Deltamethrin is a broad spectrum insecticide used throughout the
world to control pests of livestock, crops, ornamentals plants and
turf, and household, commercial, and industrial food use areas. A
reevaluation of the maximum residue limits (MRL's) was conducted in
1994, in accordance with the EC Directive (91/414/EEC) Registration
Requirements for Plant Protection Products. A comparison of the
proposed/current CODEX MRL's and proposed/established tolerances for
deltamethrin is presented below:

----------------------------------------------------------------------------------------------------------------
Commodity Proposed Tolerance (USEPA) (PPM) Proposed/Current MRL (CODEX) (PPM)
----------------------------------------------------------------------------------------------------------------
Barley, grain........................... 0.50 1.0
Broccoli................................ 0.50 0.2
Cattle, fat............................. 0.15 ---
Cattle, mbyp............................ 0.05 ---
Cattle, meat............................ 0.05 ---
Cereal grain dust....................... 65.0 ---
Corn, field, grain...................... 1.0 1.0
Corn, pop, grain........................ 0.5 1.0
Corn, sweet, grain...................... 0.5 1.0
Corn, forage (field).................... 0.7 ---
Corn, fodder (field).................... 7.0 0.5
Cucurbits vegetables.................... 0.05 0.2
Eggs.................................... 0.02 ---
Goats, fat.............................. 0.15 ---
Goats, mbyp............................. 0.05 ---
Goats, meat............................. 0.05 ---
Hogs, fat............................... 0.15 ---
Hogs, mbyp.............................. 0.05 ---
Hogs, meat.............................. 0.05 ---
Horses, fat............................. 0.15 ---
Horses, mbyp............................ 0.05 ---
Horses, meat............................ 0.05 ---
Lettuce, head........................... 1.0 0.2
Lettuce, leaf........................... 3.0 0.5
Milk, Fat (reflecting 0.07 ppm in whole
milk).................................. 0.6 0.01 (milk)
Oats, grain............................. 0.5 1.0
Poultry, fat............................ 0.3 ---
Poultry, mbyp........................... 0.02 ---
Poultry, meat........................... 0.02 ---
Rice, grain............................. 0.5 1.0
Rye, grain.............................. 0.5 1.0
Sheep, fat.............................. 0.15 ---
Sheep, mbyp............................. 0.05 ---
Sheep, meat............................. 0.05 ---
Sorghum, grain.......................... 1.0 1.0
Sorghum, forage......................... 0.5 ---
Sorghum, fodder......................... 2.0 0.5
Soybeans................................ 0.05 0.1
Sunflower seed.......................... 0.05 0.1
Tomatoes................................ 0.3 0.2
Triticale, grain........................ 0.5 1.0
Wheat, forage........................... 8.0 ---
Wheat, grain............................ 1.0 1.0
Wheat, hay.............................. 8.0 0.5
Wheat, straw............................ 8.0 0.5
Corn, refined oil....................... 10.0 ---
Corn, flour............................. 3.0 ---
Corn, meal.............................. 2.0 ---
Tomato products (concentrated).......... 1.5 ---
Wheat bran.............................. 4.0 5.0
Wheat germ.............................. 8.0 ---
Soybean hulls........................... 0.25 0.5
Cereal bran............................. 2.0 ---
Rice hulls.............................. 6.0 ---

[[Page 45493]]

Corn, milled byproducts................. 3.0 ---
----------------------------------------------------------------------------------------------------------------

As far as can be determined, no CODEX MRL's are established or
proposed for tralomethrin.

G. Proposed Tolerances

This pesticide petition proposes to amend 40 CFR 180.435 for the
insecticide deltamethrin as it relates to the following raw
agricultural, food, or feed commodities:

------------------------------------------------------------------------
Commodity Parts per million
------------------------------------------------------------------------
Barley, grain....................... 0.5
Broccoli........................... 0.5
Cattle, fat........................ 0.15
Cattle, mbyp....................... 0.05
Cattle, meat....................... 0.05
Cereal bran........................ 2.0
Cereal grain dust.................. 65.0
Corn, field, grain................. 1.0
Corn, pop, grain................... 0.5
Corn, sweet, grain................. 0.5
Corn, forage (field)............... 0.7
Corn, fodder (field)............... 7.0
Corn, refined oil.................. 10.0
Corn, flour........................ 3.0
Corn, meal......................... 2.0
Corn, milled byproducts............ 3.0
Cottonseed......................... 0.04
Cottonseed oil..................... 0.2
Cucurbits vegetables............... 0.05
Eggs............................... 0.02
Goats, fat......................... 0.15
Goats, mbyp........................ 0.05
Goats, meat........................ 0.05
Hogs, fat.......................... 0.15
Hogs, mbyp......................... 0.05
Hogs, meat......................... 0.05
Horses, fat........................ 0.15
Horses, mbyp....................... 0.05
Horses, meat....................... 0.05
Lettuce, head...................... 1.0
Lettuce, leaf...................... 3.0
Milk, Fat (reflecting 0.07 ppm in
whole milk)........................ 0.6
Oats, grain......................... 0.5
Poultry, fat....................... 0.3
Poultry, mbyp....................... 0.02
Poultry, meat...................... 0.02
Rice, grain........................ 0.5
Rice, hulls........................ 6.0
Rye, grain......................... 0.5
Sheep, fat......................... 0.15
Sheep, mbyp........................ 0.05
Sheep, meat........................ 0.05
Sorghum, grain..................... 1.0
Sorghum, forage.................... 0.5
Sorghum, fodder.................... 2.0
Soybeans........................... 0.05
Soybean hulls...................... 0.25
Sunflower seed..................... 0.05
Tomatoes........................... 0.3
Tomato products (concentrated)...... 1.5
Triticale, grain................... 0.5
Wheat, bran........................ 4.0
Wheat, forage...................... 8.0
Wheat, germ........................ 8.0
Wheat, grain....................... 1.0
Wheat, hay......................... 8.0
Wheat, straw....................... 8.0
------------------------------------------------------------------------

[[Page 45494]]

H. Conclusions

The proposed establishment of food and food/feed additive
tolerances for deltamethrin resulting from application to growing
crops, stored grain, and direct application to livestock would not pose
a significant risk to human health, including that of children, and is
in compliance with the requirements of the Food Quality Protection Act
of 1996. Thus, the tolerances proposed for residues of deltamethrin can
be established.

2. Gowan Company

PP 8F4985

EPA has received a pesticide petition (PP 8F4985) from Gowan
Company, P.O. Box 5569, Yuma, AZ 85366-5569 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 a tolerance for
residues of the acaricide hexythiazox in or on strawberries, apples,
wet apple pomace, cottonseed and cotton gin byproducts. The chemical
name of hexythiazox is trans-5-(4-chlorophenyl)-N-cyclohexyl-4-methyl-
2-oxothiazolidine-3-carboxamide. Metabolites containing the (4-
chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety are included in the
tolerance expression. Time-limited tolerances for strawberries, cotton
seed and cotton gin byproducts are currently in effect. Gowan Company
has proposed that the tolerances for cotton seed and cotton gin
byproducts be geographically limited to California only. A permanent
tolerance exists for apples, but Gowan Company proposes to increase the
tolerance level in connection with a proposed change in the use
pattern. A tolerance for residues in wet apple pomace has not been
proposed previously.
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 support granting of the petition.
Additional data may be needed before EPA rules on the petition. The
proposed analytical method is high performance liquid chromatography
with an ultraviolet detector. As required by section 408(d) of the
FFDCA, as recently amended by the Food Quality Protection Act (FQPA)
Pub. L. 104-170, Gowan Company included in the petition a summary of
the petition and authorization for the summary to be published in the
Federal Register in a notice of receipt of the petition. The summary
represents the views of Gowan Company; EPA, as mentioned above, is in
the process of evaluating the petition. As required by section
408(d)(3) of the FFDCA, EPA is including the summary as a part of this
notice of filing.

A. Residue Chemistry

1. Plant metabolism. The metabolism of hexythiazox in apples,
pears, grapes, and citrus has been studied. The major portion of the
residue is parent compound. The metabolites are hydroxycyclohexyl and
ketocyclohexyl analogs of hexythiazox and the amide formed by loss of
the cyclohexyl ring.
2. Animal metabolism. The metabolism of hexythiazox in goats, hens
and rats has been studied. Metabolic pathways in animals are similar to
those in plants.
3. Analytical method. An adequate analytical method (HPLC with UV
detection) is available for enforcement purposes. Parent compound and
all of its metabolites are converted to a common moiety before
analysis.
4. Magnitude of residues--i. Strawberries. Seventy samples of
treated strawberries were analyzed. The maximum residue observed (MRO)
at a preharvest interval of 3-days was 2.06 ppm and the average residue
was 0.67 ppm. A tolerance of 3 ppm was proposed.
ii. Cotton. Twenty residue studies were conducted in the U.S.,
Brazil, and Spain. Four additional studies, including a processing
study, were conducted in California. The MRO in cotton seed was 0.097
ppm and the average residue was 0.065 ppm. A tolerance of 0.2 ppm was
proposed. The maximum residue observed in cotton gin byproducts was
2.29 ppm and the average residue was 1.07 ppm. A tolerance of 3 ppm was
proposed. The proposed tolerances are geographically limited to
California only. A field crop rotation study indicated that residues
would not be present in crops planted 4-months after application of
hexythiazox.
iii. Apples--a total of 20 trials were conducted. The maximum
residue in apples having a preharvest interval of 1-month was 0.38 ppm
and the average residue was 0.14 ppm. A tolerance of 0.4 ppm was
proposed. Processing studies indicated that hexythiazox residues
concentrate by a factor of 1.7 in wet apple pomace, and a tolerance of
0.7 ppm was proposed.

B. Toxicological Profile

1. Acute toxicity. The acute oral and dermal LD<INF>50</INF> of
technical hexythiazox is > 5,000 mg/kg, and the 4-hour acute inhalation
LC<INF>50</INF> is > 2 mg/L. It is not a dermal irritant or sensitizer
and is a mild eye irritant.
2. Genotoxicity. The following genotoxicity tests were all
negative: Ames gene mutation, CHO gene mutation, CHO chromosome
aberration, mouse micronucleus and rat hepatocyte unscheduled DNA
synthesis.
3. Reproductive and developmental toxicity. Hexythiazox has not
been observed to induce developmental or reproductive effects. The
lowest reproductive or developmental no-observed effected level (NOEL)
was 200 milligram/kilogram/day (mg/kg/day), the highest dose tested
(HDT), in a 2-generation rat reproduction study.
4. Chronic toxicity. The Office of Pesticide Programs has
established the Reference Dose (RfD) for hexythiazox at 0.025 mg/kg/
day. The RfD for hexythiazox is based on a 1-year dog feeding study
with a NOEL of 2.5 mg/kg/day and an uncertainty factor of 100. The
endpoint effect of concern was hypertrophy of the adrenal cortex in
both sexes, decreased red blood cell counts, hemoglobin content and
hematocrit in males.
5. Carcinogenicity. The Agency has classified hexythiazox as a
category C (possible human) carcinogen based on an increased incidence
of hepatocellular carcinomas (p = 0.028) and combined adenomas/
carcinomas (p = 0.024) in female mice at the HDT (1,500 ppm) when
compared to the controls as well as a significantly increased (p
<0.001) incidence of pre-neoplastic hepatic nodules in both males and
females at the HDT. The decision supporting a category C classification
was based primarily on the fact that only one species was affected and
mutagenicity studies were negative. In classifying hexythiazox as a
category C carcinogen, the Agency concluded that a quantitative
estimate of the carcinogenic potential for humans should be calculated
because of the increased incidence of liver tumors in the female mouse.
A Q1* of 0.039 (mg/kg/day)-1 in human equivalents was calculated.

C. Aggregate Exposure

Tolerances have been established (40 CFR 180.448) for combined
residues of hexythiazox [trans-5-(4-chlorophenyl)-N-cyclohexyl-4-
methyl-2-oxothiazolidine-3-carboxamide] and its metabolites containing
the (4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety in or on
apples at 0.02 ppm and pears at 0.3 ppm. Use on several other crops had
been previously proposed [PP 6F4738], and an aggregate exposure
analysis has taken into consideration all current and proposed uses.
The nature and metabolism of

[[Page 45495]]

hexythiazox in plants and animals is adequately understood.
Hexythiazox is also registered for use on outdoor ornamental plants
by commercial applicators only. It is believed that non-occupational
exposure from this use is very low. Hexythiazox is not registered for
greenhouse, lawn, garden, or residential use. The environmental fate of
hexythiazox has been evaluated, and the compound is not expected to
contaminate groundwater or surface water to any measurable extent.
1. Chronic exposure. A chronic dietary exposure analysis was
conducted for the general U.S. population and 26 population subgroups.
In this analysis it was assumed that 100% of crops were treated. A
chronic exposure of 0.000172 mg/kg/day was calculated for the average
U.S. population. Non-nursing infants, the most heavily exposed
subgroup, had a calculated exposure of 0.000972 mg/kg/day. Actual
exposure would be much lower, however, because far less than 100% of
crops would be treated.
The Agency has not conducted a detailed analysis of potential
exposure to hexythiazox via drinking water or outdoor ornamental
plants. However, it is believed that chronic exposure from these
sources is very small.
2. Acute exposure. No developmental, reproductive or mutagenic
effects have been observed with hexythiazox. Therefore, an analysis of
acute exposure has not been conducted.

D. Cumulative Effects

At this time the Agency has not reviewed available information
concerning the potentially cumulative effects of hexythiazox and other
substances that may have a common mechanism of toxicity. For purposes
of this petition only, the Agency is considering only the potential
risks of hexythiazox in its aggregate exposure.

E. Safety Determination

1. U.S. population--i. Chronic risk. Chronic risk was calculated
using anticipated residue concentrations from all current and proposed
uses of hexythiazox and assuming that 100% of each crop is treated.
Dietary exposure of the general U.S. population was equivalent to 0.7%
of the RfD. Exposure of the most heavily exposed subgroup, non-nursing
infants, was equivalent to 3.9% of the RfD.
ii. Oncogenic risk. Oncogenic risk was evaluated using anticipated
residue concentrations and taking into account the percent of crop
known or expected to be treated. Lifetime oncogenic risk for the U.S.
population was calculated to be 4.5 x 10-7.
iii. Acute risk. An estimate of acute risk with this compound has
not been conducted since no acute reproductive or developmental effects
have been observed.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of hexythiazox, EPA
considered data from developmental toxicity studies in the rat and
rabbit and a 2-generation study in the rat. The developmental toxicity
studies are designed to evaluate adverse effects on the developing
organism resulting from pesticide exposure during prenatal development
to one or both parents. Reproduction studies provide information
relating to effects from exposure to the pesticide on the reproductive
capability of mating animals and data on systemic toxicity.
No developmental or reproductive effects have been observed in any
study with hexythiazox. The lowest acute NOEL was 2,400 ppm in the diet
(200 mg/kg/day), the HDT, in the 2-generation rat reproduction study.
In the rat developmental study, the maternal and fetotoxic NOEL was 240
mg/kg/day and the developmental NOEL was 2,160 mg/kg/day, the HDT. In
the rabbit developmental study, the maternal and developmental NOEL was
1,080 mg/kg/day, the HDT.
Taking into account current toxicological data requirements, the
database for hexythiazox relative to prenatal and postnatal effects is
complete. In the rat developmental study, the NOELs for maternal
toxicity and fetotoxicity were the same, which suggests that there is
no special prenatal sensitivity in the absence of maternal toxicity.
Furthermore, the lowest developmental or reproductive NOEL is two
orders of magnitude higher than the chronic NOEL on which the RfD is
based. It is concluded that there is a reasonable certainty of no harm
to infants and children from aggregate exposure to hexythiazox
residues.

F. International Tolerances

Codex MRLs of 0.5 mg/kg for residues of hexythiazox in strawberries
and apples have been established. The U.S. tolerance proposals are
somewhat at variance with the Codex MRLs because they are based upon
different preharvest intervals. Also, it is believed that the U.S.
proposed tolerance levels allow for a greater margin of safety than the
Codex MRLs. There are no Codex MRLs for the other commodities in this
petition. There are no Canadian or Mexican MRLs for hexythiazox. (Beth
Edwards).

3. Interregional Research Project

PP 7E4833

EPA has received a pesticide petition (PP 7E4833) 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
residues of the herbicide glyphosate [N-phosphonomethyl)glycine] in or
on the raw agricultural commodities (RACs) durian at 0.2 ppm,
mangosteen at 0.2 ppm, and rambutan at 0.2 ppm. Durian, mangosteen, and
rambutan are tree fruits which are grown commercially in Hawaii and
Puerto Rico.
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 support granting of the petition.
Additional data may be needed before EPA rules on the petition. This
notice includes a summary of the petition prepared by Monsanto
Agricultural Group (MAG), the registrant.

A. Residue Chemistry

1. Plant metabolism. The nature of the residue in plants and
animals is adequately understood. The residue to be regulated is the
parent glyphosate.
2. Analytical method. There is a practical analytical method for
detecting and measuring levels of glyphosate in or on food with a
limits of detection (0.05 ppm) that allows monitoring of food with
residues at or above the levels set in these tolerances. EPA has
provided information on this method to FDA.
3. Magnitude of residues. The proposed use for glyphosate is for
orchard floor treatment. The registrant referenced extensive experience
and data with glyphosate in/on tree fruit and nuts crops which show
that when orchard floor applications are made, no detectable residues
of the herbicide are recovered in the harvested fruit. Based on these
data Monsanto expects no detectable residues of glyphosate in durian,
mangosteen or rambutan when glyphosate is applied in a similar manner.
Tolerances for the combined residues of glyphosate and its
metabolite, aminomethylphosphonic acid (AMPA), have been established at
0.2 ppm on a number of tree fruit and nuts, as well as a variety of
tropical fruit: acerola, atemoya, avocado, banana, breadfruit,
canistel, carambola, cherimoya cocoa beans, coconuts, dates, figs,
genip, jaboticaba, jackfruit, longan, lychee,

[[Page 45496]]

mango, mayhaw, passion fruit, persimmon, pomegranate, sapodilla,
sapote, soursop, sugar apple and tamarind. Any secondary residues
occurring in milk, eggs, meat, fat, liver and kidney of cattle, goats,
horses, hogs, poultry and sheep are covered by existing tolerances.
The Agency's Health Effects Division - Metabolism Committee has
determined that AMPA should be dropped from the tolerance expression.
Tolerances that are the subject of this notice are based solely on
residues of glyphosate.

B. Toxicological Profile

1. Acute toxicity. Results from an acute oral study in rats show a
combined lethal dose (LD)<INF>50</INF> for glyphosate of >5,000
milligram/kilogram (mg/kg).
An acute dermal study in rabbit resulted in a LD<INF>50</INF> of >
5,000 mg/kg.
The results of a primary eye irritation study in the rabbit showed
severe irritation for glyphosate acid. However, glyphosate is normally
formulated as one of several salts and eye irritation studies on the
salts showed essentially no irritation.
A primary dermal irritation study showed essentially no irritation.
A primary dermal sensitization study showed no sensitization. Based
on these data, Monsanto concludes that the acute toxicity and
irritation potential of glyphosate is low.
2. Genotoxicity. A number of mutagenicity studies were conducted
and were all negative. These studies included: chromosomal aberration
in vitro (no aberrations in Chinese hamster ovary cells were caused
with or without S9 activation); deoxyribonucleic acid(DNA) repair in
rat hepatocyte; in vivo bone marrow cytogenic test in rats; rec-assay
with B. subtilis; reverse mutation test with S. typhimurium; Ames test
with S. typhimurium; and dominant-lethal mutagenicity test in mice.
Negative results were obtained when glyphosate was tested in a
dominant-lethal mutation assay. While this assay was designed as a
genetic toxicity test, agents that can affect male reproduction
function will also cause effects in this assay. More importantly, the
multi-generation reproduction study in rodents is a complex study
design which measures a broad range of endpoints in the reproductive
system and in developing offspring that are sensitive to alterations by
chemical agents. Glyphosate has been tested in two separate multi-
generation studies and each time the results demonstrated that
glyphosate is not a reproductive toxin.
3. Reproductive and developmental toxicity. An oral developmental
toxicity study with rats given doses of 0, 300, 1,000 and 3,500
milligram/kilogram/day (mg/kg/day) with a maternal no-observed-effect
level (NOEL) of 1,000 mg/kg/day based on clinical signs of toxicity,
body weight effects and mortality, and a fetal NOEL of 1,000 mg/kg/day
based on reduced body weights and delayed sternebrae maturation at the
highest dose tested (HDT) of 3,500 mg/kg/day.
An oral developmental toxicity study with rabbits given doses of
0,75, 175 and 350 mg/kg/day with a maternal of NOEL of 175 mg/kg/day
based on clinical signs of toxicity and mortality, and a fetal NOEL of
350 mg/kg/day based on no developmental toxicity at any dose tested.
A 3-generation reproduction study with rats fed dosage levels of 0,
3, 10 and 30 mg/kg/day with a NOEL for systemic and reproductive/
developmental parameters of 30 mg/kg/day based on no adverse effects
noted at any dose level.
A 2-generation reproduction study with rats fed dosage levels of 0,
100, 500 and 1,500 mg/kg/day with a NOEL for systemic and developmental
parameters of 500 mg/kg/day based on body weight effects, clinical
signs of toxicity in adult animals and decreased pup body weights, and
a reproductive NOEL of 1,500 mg/kg/day.
4. Subchronic toxicity. A 90-day feeding study in mice fed dosage
levels of 0, 5,000, 10,000 and 50,000 with a NOEL of 10,000 ppm based
on body weight effects at the high dose.
A 90-day feeding study in rats fed dosage levels of 0, 1,000, 5,000
and 20,000 ppm with a NOEL of 20,000 ppm based on no effects even at
the HDT.
A 90-day feeding study in dogs given glyphosate, via capsule, at
doses of 0, 200, 600 and 2,000 mg/kg/day with a NOEL of 2,000 mg/kg/day
based on no effects even at the HDT.
5. Chronic toxicity. The reference dose (RfD) for glyphosate based
on maternal effects in a developmental study with rabbits (NOEL of 175
milligram/killogram/body weight day (mg/kg/bwt/day)) and using a
hundred-fold safety factor is calculated to be 2.0 mg/kg/bwt/day.
The EPA Carcinogenicity Peer Review Committee has classified
glyphosate in Group E (evidence of non-carcinogenicity for humans),
based upon lack of convincing carcinogenicity evidence in adequate
studies in two animal species. There was no evidence of carcinogenicity
in an 18-month feeding study in mice and a 2 year feeding study in rats
at the dosage levels tested (DLT). The doses tested were adequate for
identifying a cancer risk.
A mouse carcinogenicity study with mice fed dosage levels of 0,
150,750 and 4,500 mg/kg/day with a NOEL of 750 mg/kg/day based on body
weight effects and microscopic liver changes at the high dose. There
was no carcinogenic effect at the HDT of 4,500 mg/kg/day.
A 12-month oral study in dogs given glyphosate, via capsule, at
doses of 0, 20, 100 and 500 mg/kg/day with a NOEL of 500 mg/kg/day
based on no adverse effects at any dose level.
A 24-month chronic/feeding carcinogenicity study with rats fed
dosage levels of 0, 89, 362 and 940 mg/kg/day (males) and 0, 113, 457
and 1,183 mg/kg/day (females) with a systemic NOEL of 362 mg/kg/day
based on body weight effects in the female and eye effects in males.
There was no carcinogenic response at any dose level.
A 26-month chronic/feeding carcinogenicity study with rats fed
dosage levels of 0, 3, 10 and 31 mg/kg/day (males) and 0, 3, 11 and 34
mg/kg/day (females) with a systemic NOEL of 31 mg/kg/day (males) and 34
mg/kg/day (females) based on no carcinogenic or other adverse effects
at any dose level.
Monsanto believes that these data support their conclusion that
glyphosate does not produce adverse reproductive effects and is not a
developmental toxin, mutagen, carcinogen or a neurotoxin.
6. Animal metabolism. Animal metabolism data were not submitted
with this petition. However, Monsanto believes that the treated
commodities are not fed to animals, therefore, there will be no
residues transferred to meat, milk, poultry, or eggs.

C. Aggregate Exposure

1. Dietary exposure--Food. For purposes of assessing the potential
dietary exposure, Monsanto has estimated aggregate exposure based on
the tolerances for glyphosate on jackfruit, sugar apple and lychee, all
with established 0.2 ppm tolerances. As the consumption of durian,
mangosteen and rambutan is so limited, the theoretical maximum residue
contribution (TMRC) calculations were based on similar or related
tropical fruit: durian and jackfruit are similar in size, with thick
rinds and similar growth habit; mangosteen and sugar apple fruit are
also similar in size and growth habit: and rambutan and lychee are from
the same botanical family, the Sapindaceae. The fruit are not fed to
animals, therefore, there will be no exposure of humans to residues
transferred to meat, milk, poultry, or eggs. Other potential sources of
exposure of the general population to residues of pesticides are

[[Page 45497]]

residues in drinking water and exposure from non-occupational sources.
Based on the available acute toxicity data, Monsanto believes that
glyphosate does not pose any acute dietary risks.
2. Drinking water. A Maximum Concentration Level (MCL) has been
established for residues of glyphosate in drinking water at 0.7 mg/l
since glyphosate is approved for direct application to water. The MCL
represents the level at which no known or anticipated adverse health
effects occur, allowing for an adequate margin of safety (MOE), and is
based on the RfD.
Monsanto reports that glyphosate adsorbs strongly to soil and is
not expected to move vertically below the 6-inch soil layer; residues
are expected to be immobile in soil. Glyphosate is readily degraded by
soil microbes to AMPA, which is degraded to carbon dioxide. Monsanto
believes that glyphosate and AMPA are not likely to move to ground
water due to their strong adsorptive characteristics. However, due to
its aquatic use patterns and through erosion, glyphosate does have the
potential to enter surface waters, where, according to Monsanto, it
will adsorb to sediment and undergo microbial degradation.
3. Non-dietary exposure. Exposure (non-occupational) of the general
population to glyphosate is expected based on the currently-registered
uses; however, due to the low acute toxicity and lack of other
toxicological concerns, Monsanto believes that the risk posed by non-
occupational exposure (NOE) to glyphosate is minimal.

D. Cumulative Effects

Because the existing data base is insufficient to fully assess
cumulative toxic effects that may be caused by glyphosate along with
other chemical compound(s) that may share a common mechanism of
toxicity, Monsanto believes that any consideration of such an analysis
of toxicity is inappropriate at this time.

E. Safety Determination

1. U.S. population. The TMRC for existing, published tolerances for
glyphosate is 0.021460 mg/kg/bwt/day or 1.0% of the RfD for the overall
U.S. population. Even using conservative exposure assumptions and
substituting the more widely consumed jackfruit, sugar apple and
lychee, there is not enough exposure to calculate a significant
contribution to the TMRC. As the exposure from durian, mangosteen and
rambutan would be even less, the aggregate exposure of these three
fruits will not add to the RfD for the overall U.S. population. EPA
generally has no concern for exposures below 100% of the RfD.
Therefore, based on the completeness and reliability of the toxicity
data and the conservative exposure assessment, Monsanto concludes that
there is a reasonable certainty that no harm will result from aggregate
exposure to residues of glyphosate, including all anticipated dietary
exposure and all other non-occupational exposures.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of glyphosate, data
were considered from developmental toxicity studies in the rat and
rabbit and multi-generation reproduction studies in rats.
No birth defects were observed in the offspring of rats given
glyphosate by gavage at dose levels of 0, 300, 1,000, and 3,500 mg/kg/
day on days 6 through 19 of gestation. The NOEL for this study was
1,000 mg/kg/day based on maternal and developmental toxicity observed
at the HDT, 3,500 mg/kg/day. The high-dose in this study was 3.5 times
higher than the limit dose that is currently required by the
guidelines.
No birth defects were observed in the offspring of rabbits given
glyphosate by gavage at dose levels of 0, 75, 175, and 350 mg/kg/day on
days 6 through 27 of gestation. The NOEL for this study is considered
to be 175 mg/kg/day based on maternal toxicity at the high-dose of 350
mg/kg/day. Because no developmental toxicity was observed at any dose
level, the developmental NOEL is considered to be 350 mg/kg/day.
Male and female rats were fed glyphosate at dose levels of 0, 3,
10, and 30 mg/kg/day every day throughout the production of three
successive generations. No adverse treatment-related effects on
reproduction were observed. Because no toxicity was noted even at the
HDT, a second reproduction study at higher dose levels (HDLs) was
performed and is described below.
Male and female rats were fed glyphosate at dose levels of 0, 100,
500, and 1,500 mg/kg/day every day throughout the production of two
successive generations. Reduced body weights and soft stools occurred
at 1,500 mg/kg/day (3% of the diet); therefore, the systemic NOEL is
considered to be 500 mg/kg/day. Glyphosate did not affect the ability
of rats to mate, conceive, carry or deliver normal offspring at any
dose level.
3. Reference dose. The TMRC for existing, published and pending
tolerances (including durian, mangosteen, and rambutan) for glyphosate
range from 0.015 for nursing infants to 0.049 for non-nursing infants
(0.8 to 2.5% of the RfD). EPA generally has no concern for exposures
below 100% of the RfD. Therefore, based on the completeness and
reliability of the toxicity data and the conservative exposure
assessment, Monsanto concludes that there is a reasonable certainty
that no harm will result from aggregate exposure to residues of
glyphosate, including all anticipated dietary exposure and all other
non-occupational exposures.
4. Endocrine effects. No known factors were identified in sub-
chronic, chronic or developmental toxicity studies to indicate any
endocrine-modulating activity by glyphosate.

F. International Tolerances

Codex maximum residue levels (MRLs) have not been established for
residues of glyphosate on durian, mangosteen and rambutan. (Sidney
Jackson).
[FR Doc. 98-22430 Filed 8-25-98; 8:45 am]
BILLING CODE 6560-50-F

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