[Federal Register Volume 63, Number 158 (Monday, August 17, 1998)]
[Notices]
[Pages 43937-43944]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-22012]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-819 FRL-6018-2]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various food commodities.
DATES: Comments, identified by the docket control number PF-819 must be
received on or before September 16, 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. 1132, CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically to: 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. 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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Joanne I. Miller.............. Rm. #227, CM #2, 703- 1921 Jefferson
305-6224, e- Davis Hwy,
mail:[email protected] Arlington, VA
amail.epa.gov.
Cynthia Giles-Parker.......... Rm. #247, CM #2, 703- Do.
305-7740,e-mail:parker.cynthia@epamai.
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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-819] (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 FRL-6018-2 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 4, 1998.
Arnold E. Layne,
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
[[Page 43938]]
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. BASF Corporation
PP 6F4640 and 3F4270
EPA has received pesticide petitions (PP 6F4640 and 3F4270) from
BASF Corporation, P.O. Box 13528, Research Triangle Park, NC 27709-3528
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 bentazon (3-isopropyl-1H-2,1,3-
benzothiadiazin-4(3H)-one 2,2-dioxide) and its 6- and 8-hydroxy
metabolites in or on the raw agricultural commodities succulent peas at
3.0 parts per million (ppm) and flax seed at 1.0 ppm. Bentazon is
currently registered for use in succulent peas with a 30-day preharvest
interval (PHI) and a tolerance has been established at 0.5 ppm. The
proposed increase in tolerance will allow for a reduction in the
preharvest interval (PHI) to 10 days. EPA has determined that the
petitions contain data or information regarding the elements set forth
in section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated
the sufficiency of the submitted data at this time or whether the data
supports granting of the petitions. Additional data may be needed
before EPA rules on the petitions.
A. Residue Chemistry
1. Plant metabolism. The qualitative nature of the residue in
plants is adequately understood. Bentazon is rapidly metabolized,
conjugated and incorporated into natural plant constituents. Metabolism
involves the hydroxylation of bentazon at the 6- and 8-position. The
terminal residues of regulatory concern are bentazon, 6-hydroxy
bentazon, and 8-hydroxy bentazon (as specified in 40 CFR 180.355 (a)).
2. Analytical method. Adequate enforcement methods are available in
the Pesticide Analytical Manual (PAM) Vol. II for the determination of
residues of bentazon and its 6- and 8-hydroxy metabolites in/on plant
commodities and for the determination of bentazon and AIBA metabolite
in animal commodities. The methods involve quantitation by gas
chromatography with flame photometric or nitrogen-specific Coulson
conductivity detectors. The limit of quantitation is 0.05 ppm in animal
tissues and eggs, 0.02 ppm in milk, and 0.05 ppm in plants. Residue
data submitted in support of the succulent pea and flax petitions were
collected using modifications of the available PAM Vol. II methods.
These modified methods, along with the methods listed in PAM Vol. II
are adequate for bentazon data collection and tolerance enforcement.
3. Magnitude of residues. Ten garden pea field trials were
conducted in 7 States. Experimental plots were treated with two
applications of bentazon at a rate of 1.0 lb ai/A/application. Samples
of pea pods and vines were harvested from each treated plot 10 days
after the second application. Samples were analyzed for the combined
residues of bentazon and its 6- and 8-hydroxy metabolites. Analysis of
treated samples showed that the maximum total combined residue was 2.9
ppm in pods and 26.6 ppm in vines.
Flax field trials were conducted in North Dakota (1 trial), South
Dakota (2 trials), and Minnesota (1 trial). Experimental plots of flax
were treated with two applications of bentazon at a rate of 1.0 lb ai/
A/ application. Samples of flax seed and straw were harvested at normal
maturity, resulting in a PHI range of 43 to 47 days. The maximum
combined residue (bentazon and its 6- and 8-hydroxy metabolites) in
flax seed samples was 0.63 ppm and in flax straw was 4.9 ppm. In the
processing study, there was no concentration of residue in flax meal.
In the flax petition (PP 3F4270) tolerances were proposed for the
combined residue of bentazon and its 6- and 8-hydroxy metabolites in or
on flax seed at 1.0 ppm and flax straw at 6.0 ppm. Since this
submission was made the regulations have changed and flax straw has
been removed as a raw agricultural commodity (Residue Chemistry Test
Guidelines, OPPTS 860.1000, August 1996) and a tolerance is no longer
required. Therefore, the tolerance statement for PP 3F4270 has been
amended proposing to establish a tolerance for the combined residues of
the herbicide bentazon and its metabolites in/on flax seed only. The
flax straw tolerance proposal has been removed.
B. Toxicological Profile
1. Acute toxicity. Technical bentazon has been evaluated for acute
toxicity effects. A summary of the acute toxicity studies follows:
Acute oral LD50 (rat) 1,100 mg/kg; M&F Toxicity category
III
Acute dermal LD50 (rat) >2,500 mg/kg Toxicity category
III
Eye irritation (rabbit) Slight irritation Toxicity category
III
Acute inhalation LC50 (rat) >4.8 mg/l Toxicity category
IV
Dermal irritation (rabbit) Minimal Toxicity category
III
Dermal sensitization (guin. Sensitizer.
pig)
2. Genotoxicty. Bentazon was not mutagenic in the tests for gene
mutations, which were reverse mutation assays in S. typhimurium and in
E. coli WP2 uvrA as well as forward mutation assays with in vitro
Chinese hamster ovary cell (HGPRT) cultures. Bentazon was also negative
in the mouse micronucleus test for assessing structural chromosomal
aberrations and the unscheduled DNA synthesis assay with primary mouse
hepatocytes for detecting DNA damage.
3. Reproductive and developmental toxicity. Teratogenicity study--
Rat. In pregnant Wistar rats gavaged with 0, 40, 100, or 250 mg/kg/day
of bentazon on gestation days 6-15, the maternal toxicity NOEL was over
250 mg/kg/day. The developmental toxicity NOEL was 100 mg/kg/day. The
LOEL was 250 mg/kg/day based upon an increase in postimplantation loss
and a reduction of fetal body weights. In addition, there was an
indication of delayed skeletal ossification of phalangeal nuclei of
fore- and hind-limb digits, sternebrae, and cervical vertebrae. The
delayed skeletal development was considered to be due
[[Page 43939]]
to a delayed maturation as indicated by the decreased fetal weight at
this dose.
4. Teratogenicity study-- Rabbit. When pregnant Chinchilla rabbits
were gavaged with 75, 150, or 375 mg/kg/day, on gestation days 6-18,
the maternal toxicity NOEL was 150 mg/kg/day. The maternal LOEL was 375
mg/kg/day due to the occurrence in a single doe of a partial abortion,
embryonic resorptions, and the absence of living fetuses. The
developmental toxicity NOEL was over 375 mg/kg/day.
5. Reproduction, 2-generation study-- Rat. A reproductive NOEL at
200 ppm (approximately 15 mg/kg/day; lowest dose tested (LDT)) was
found in a 2-generation study in Wistar rats. Doses were 0, 200, 800,
or 3,200 ppm bentazon in the diet. Higher levels of 800 ppm
(reproductive LOEL) and 3,200 ppm (approximately 62 and 249 mg/kg/day,
respectively) were associated with a decrease in the body weights of
the pups during lactation. For parental toxicity, the NOEL was 800 ppm,
and the LOEL was 3,200 ppm based on reductions in food consumption and
weight gain, and increased incidence of renal mineralization and liver
microgranuloma.
6. Subchronic toxicity--i. 90-day feeding study-- Rat. In a 13-week
dietary feeding study in Wistar rats, the doses were 0, 400, 1,200, or
3,600 ppm in the diet. The systemic toxicity NOEL was 1,200 ppm
(equivalent to 60 mg/kg/day). The LOEL was 3,600 ppm (180 mg/kg/day;
highest dose tested (HDT)) based on reductions in body weight gain,
increased thromboplastin and prothrombin times, diuresis, clinical
chemistry changes (e.g. increases in albumin, A/G ratios, and sodium),
and increased kidney and liver weights. In addition, females in the
3,600 ppm group showed suggestive evidence for the presence of lung
thrombi and dilated uterine horns.
ii. 21-day dermal. In a 21-day dermal study in rabbits, the doses
were 0, 250, 500 and 1,000 mg/kg/day applied daily for 6 hours. There
were no clinical signs of systemic toxicity at any dose level tested.
The no adverse effect level (NOAEL) was > 1,000 mg/kg/day for male and
female rabbits.
7. Chronic toxicity--i. Chronic feeding study- non-rodent--Dog.
Administration of bentazon in the feed of beagle dogs for 1 year at
levels of 0, 100, 400, or 1,600 ppm resulted in a systemic toxicity
NOEL of 100 ppm (approximately 3.2 mg/kg/day) and a LOEL of 400 ppm
(approximately 13.1 mg/kg/day). Adverse toxicological effects at the
two HDT consisted of clinical signs of toxicity (emaciation,
dehydration, loose and/or bloody stools, pale mucous membranes, and
reduced activity), hematological changes suggestive of anemia
(decreased red cells, hemoglobin and hematocrit, abnormal red cell
morphology, and increased reticulocytes, platelets, leukocytes, and
partial thromboplastin time), depressed body weight gains, intestinal
inflammation, and congestion of the small intestine and spleen. The
anemia appeared to be due to blood loss from the gastrointestinal
tract.
ii. Chronic feeding/oncogenicity study-- Rat. Fischer 344 rats were
given 0, 200, 800, or 4,000 ppm bentazon in the diet in a 2-year
combined chronic toxicity-carcinogenicity study. The systemic toxicity
NOEL was 200 ppm, equivalent to 10 mg/kg/day LDT. Adverse effects were
observed at levels of 800 ppm (40 mg/kg/day; LOEL) and 4,000 ppm (200
mg/kg/day) and consisted of increases in prothrombin time and partial
thromboplastin time, increases in urine volume, blood urea nitrogen,
and kidney weight along with reduced urinary specific gravity, a
reduction in body weight gain, and a decrease in thyroid gland weight.
No compound-related increase in tumors was observed.
iii. Oncogenicity study-- Mouse. B6C3F1 mice were fed 0, 100, 400,
or 2,000 ppm bentazon in a 2-year combined chronic toxicity-
carcinogenicity study. The systemic toxicity NOEL was 100 ppm,
equivalent to 15 mg/kg/day LDT. Adverse effects were observed at levels
of 400 ppm (60 mg/kg/day; LOEL) and 2,000 ppm (300 mg/kg/day). There
were an increased prothrombin time, calcification of the tunica
albuginea of the testes, hyperplasia of pancreatic islet cells and
liver, slight increase in mortality, reduced weight gain, areas of
hemorrhage in the liver and heart, and increased weights of the kidney,
thyroid gland, and pituitary gland. No compound- related increase in
tumors was observed.
8. Animal metabolism. The qualitative nature of the residue in
animals is adequately understood. Bentazon and its metabolite 2 amino-
N-isopropylbenzamide (AIBA) are the regulated terminal residues in
animal tissues, eggs and milk.
9. Endocrine disruption. No special studies investigating potential
estrogenic or endocrine effects of bentazon have been conducted.
However, the standard battery of required studies has been completed.
These studies include an evaluation of the potential effects on
reproduction and development, and an evaluation of the pathology
exposure. These studies are generally considered to be sufficient to
detect any endocrine effects but no such effects of the endocrine
organs following repeated or long-term were noted in any of the
studies.
10. Neurotoxicity. No specific neurotoxicity studies have been
conducted with bentazon. However, the results of acute, subchronic and
chronic studies with bentazon in different animal species did not
indicate evidence of any neurotoxic potential. It is assessed as being
very unlikely that bentazon would pose a specific neurotoxic hazard.
C. Aggregate Exposure
EPA has performed analyses to determine the risks from aggregate
exposure to bentazon residues. For purposes of assessing the potential
dietary exposure, EPA has estimated aggregate exposure based on the
Theoretical Maximum Residue Contribution (TMRC) from: (i) all existing
bentazon tolerances; and (ii) all existing tolerances plus the proposed
increase in tolerance in succulent peas. The TMRC is a ``worst case''
estimate of dietary exposure since it is assumed that 100% of all crops
for which tolerances are established are treated and that pesticide
residues are at the tolerance levels.
EPA published a dietary risk assessment for bentazon based on
existing uses supported through reregistration in the Reregistration
Eligibility Decision (RED) for bentazon dated January 27, 1995. EPA
also published an aggregate risk assessment for bentazon based on
existing tolerances plus a proposed increase in tolerance in succulent
peas in a final rule in the FR 33563 (FRL 5720-4) (June 20, 1997). This
final rule established a time-limited tolerance for bentazon and its
metabolites in/on succulent peas at 3 ppm in connection with EPA's
granting an emergency exemption under section 18 of the Federal
Insecticide, Fungicide, and Rodenticide Act authorizing use of bentazon
in/on succulent peas with a 10-day PHI in Minnesota, and Wisconsin.
BASF used information/data from these documents and performed
additional analyses in developing the following aggregate risk
assessment.
1. Dietary exposure. The TMRC for the overall U.S. population from
existing bentazon tolerances supported through reregistration is
estimated at 0.000651 mg/kg bwt/day, which represents 2.2% of the RfD.
The TMRC for the overall U.S. population from the existing bentazon
tolerances plus the proposed increase in tolerance for succulent peas
is estimated at 0.001079 mg/kg bwt/day, which represents 3.6%
[[Page 43940]]
of the RfD. Thus, dietary exposure to residues of bentazon in or on
food from the proposed tolerance increase in succulent peas will
increase the TMRC by 1.4% of the RfD for the overall U.S. population.
The TMRC from existing bentazon tolerances supported through
reregistration for the most highly exposed subpopulation (non-nursing
infants, <1- year="" old)="" is="" estimated="" at="" 0.002444="" mg/kg="" bwt/day,="" which="" represents="" 8.1%="" of="" the="" rfd.="" the="" tmrc="" from="" the="" existing="" bentazon="" tolerances="" plus="" the="" proposed="" increase="" in="" tolerance="" for="" succulent="" peas="" for="" non-nursing="" infants=""><1-year old)="" is="" estimated="" at="" 0.003755="" mg/kg="" bwt/day,="" which="" represents="" 12.5%="" of="" the="" rfd.="" dietary="" exposure="" to="" residues="" of="" bentazon="" in="" or="" on="" food="" from="" the="" proposed="" tolerance="" increase="" in="" succulent="" peas="" will="" increase="" the="" tmrc="" by="" 4.4="" %="" of="" the="" rfd="" for="" non-="" nursing="" infants=""><1-year old).="" these="" exposure="" assessments="" rely="" on="" very="" conservative="" assumptions-="" 100%="" of="" crops="" will="" contain="" bentazon="" residues="" and="" those="" residues="" would="" be="" at="" the="" level="" of="" the="" tolerance-="" which="" results="" in="" an="" overestimate="" of="" human="" exposure.="" basf="" believes="" that="" there="" will="" be="" no="" impact="" on="" the="" tmrc="" as="" a="" result="" of="" the="" use="" of="" bentazon="" in="" flax.="" no="" flax="" product="" is="" consumed="" by="" man="" as="" food="" and="" therefore="" the="" proposed="" tolerance="" will="" not="" directly="" impact="" the="" tmrc.="" 2.="" drinking="" water.="" to="" account="" for="" the="" exposure="" from="" drinking="" water,="" basf="" used="" an="" exposure="" level="" of="" 20="" ppb="" as="" previously="" used="" in="" the="" final="" rule="" establishing="" a="" time-limited="" tolerance="" for="" bentazon="" and="" its="" metabolites="" in/on="" succulent="" peas.="" this="" is="" a="" very="" conservative="" estimate="" since="" it="" is="" unlikely="" that="" a="" person="" would="" be="" exposed="" to="" this="" level="" daily="" for="" a="" life-time.="" basf="" estimates="" that="" consumption="" of="" 2="" liters="" of="" water="" per="" day="" by="" a="" 70="" kg="" adult="" at="" a="" water="" exposure="" level="" of="" 20="" ppb="" would="" result="" in="" an="" additional="" consumption="" of="" approximately="" 2.2%="" of="" the="" rfd.="" using="" these="" very="" conservative="" estimates="" for="" food="" (3.6%)="" and="" water="" (2.2%)="" results="" in="" a="" total="" of="" 5.8%="" of="" the="" rfd="" for="" the="" u.s.="" population.="" thus,="" basf="" believes="" that="" even="" if="" all="" the="" water="" consumed="" by="" a="" person="" over="" a="" lifetime="" contained="" bentazon="" at="" 20="" ppb="" there="" would="" still="" be="" nearly="" a="" twenty-fold="" level="" of="" safety.="" 3.="" non-dietary="" exposure.="" in="" the="" final="" rule="" establishing="" a="" time-="" limited="" tolerance="" for="" bentazon="" and="" its="" metabolites="" in/on="" succulent="" peas,="" epa="" discussed="" short-="" and="" intermediate-term="" exposure.="" according="" to="" epa,="" short-="" and="" intermediate-term="" aggregate="" exposure="" takes="" into="" account="" chronic="" dietary="" food="" and="" water="" (considered="" to="" be="" a="" background="" exposure="" level)="" plus="" indoor="" and="" outdoor="" residential="" exposure.="" although="" residential="" exposure="" data="" are="" not="" available="" for="" ornamentals="" and="" ornamental="" turf="" uses="" of="" bentazon,="" epa="" noted="" that="" large="" moes="" were="" calculated="" for="" acute="" aggregate="" risk="" (="">= 7,000) and occupational
exposure (> 6,000 for the most highly exposed group, aerial mixer
loader) and that EPA believes that short- and intermediate-term
aggregate risk is likely to be below EPA's level of concern.
Therefore, BASF believes that the proposed use of bentazon in
succulent peas in this petition also will not exceed the EPA's level of
concern for short- and intermediate exposure, since this use is
identical to the section 18 use of Bentazon. BASF also believes that
there will be no impact on short- and intermediate-term exposure as a
result of the use of bentazon in flax since flax is a minor
agricultural use with no flax product consumed by man as food.
D. Cumulative Effects
BASF has considered the potential for cumulative effects of
bentazon and other substances that have a common mechanism of toxicity.
BASF is unaware of any data indicating that some other active
ingredient produces toxic effects by a mechanism similar to that of
bentazon and that would result in cumulative toxicity. Thus, BASF is
considering only the potential risks of bentazon.
E. Safety Determination
1. U.S. population-- i. Acute risk. In the final rule establishing
a time-limited tolerance for bentazon and its metabolites in/on
succulent peas, EPA performed an acute dietary risk assessment and
selected the NOEL of 100 (mg/kg/day), based on developmental effects of
increased postimplantation loss and decreased fetal body weight at the
LOEL of 250 mg/kg/day, from the developmental toxicity study in rats.
EPA used tolerance level residues and assumed 100% crop-treated. EPA
has identified women of child bearing age (females 13+ years old) as
the most sensitive subpopulation. The resulting high-end exposure
estimate of 0.01125 mg/kg/day, results in a dietary (food only) MOE of
8,888 for females 13+ years old which EPA considered acceptable. EPA
used available monitoring data for groundwater to calculate a water
exposure estimate of 3 x 10-3 mg/kg/day for adults. Adding this water
exposure to the food exposure resulted in a MOE of 7,000 for females
13+ years.
In the final rule establishing a time-limited tolerance for
bentazon and its metabolites in/on succulent peas the following items
are noted: (a) the acute drinking water component of the risk
calculations presented are relevant to subpopulations with high-end
exposure within the United States (FL and CA); (b) because the
calculated risk, based on high-end exposure is acceptable, the overall
risk assessment is protective of the whole U.S. population; and (c) in
the best scientific judgment of the Office of Pesticide Programs, the
aggregate acute risk (food and water) from the currently registered
uses and section 18 (succulent peas) use of bentazon does not exceed
EPA's level of concern.
Therefore, BASF believes that the proposed use of bentazon in
succulent peas in this petition also will not exceed the EPA's level of
concern for acute exposure, since this use is identical to the section
18 use of bentazon. BASF also believes that there will be no impact on
acute exposure as a result of the use of bentazon in flax. No flax
product is consumed by man as food and therefore the proposed tolerance
will not impact the MOE. Furthermore, flax is considered a minor crop
with <100,000 acres="" harvested="" in="" the="" us="" in="" 1996.="" therefore,="" basf="" believes="" that="" the="" impact="" on="" groundwater="" exposure="" will="" be="" negligible="" as="" a="" result="" of="" bentazon="" use="" in="" flax="" and="" should="" not="" impact="" the="" moe.="" ii.="" short-="" and="" intermediate-term="" risk.="" in="" the="" final="" rule="" establishing="" a="" time-limited="" tolerance="" for="" bentazon="" and="" its="" metabolites="" in/on="" succulent="" peas,="" epa="" discussed="" short-="" and="" intermediate-term="" exposure.="" according="" to="" epa,="" short-="" and="" intermediate-term="" aggregate="" exposure="" takes="" into="" account="" chronic="" dietary="" food="" and="" water="" (considered="" to="" be="" a="" background="" exposure="" level)="" plus="" indoor="" and="" outdoor="" residential="" exposure.="" although="" residential="" exposure="" data="" are="" not="" available="" for="" ornamentals="" and="" ornamental="" turf="" uses="" of="" bentazon,="" epa="" noted="" that="" large="" moes="" were="" calculated="" for="" acute="" aggregate="" risk="" (="">= 7,000) and
occupational exposure (> 6,000 for the most highly exposed group,
aerial mixer loader) and that EPA believes that short- and
intermediate-term aggregate risk is likely to be below EPA's level of
concern.
Therefore, BASF believes that the proposed use of bentazon in
succulent peas in this petition also will not exceed the EPA's level of
concern for short- and intermediate exposure, since this use is
identical to the section 18 use of Bentazon. BASF also believes that
there will be no impact on short- and intermediate-term exposure as a
result of the use of bentazon in flax since flax is a minor
agricultural use with no flax product consumed by man as food.
iii. Chronic risk. Using the conservative TMRC exposure
[[Page 43941]]
assumptions described above, BASF has concluded that aggregate exposure
to bentazon from food will utilize 5.8% of the RfD for the U.S.
population. The major identifiable subgroup with the highest aggregate
exposure is non-nursing infants which is discussed below. EPA generally
has 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.
Despite the potential for exposure to bentazon, including all
anticipated dietary exposure and all other non-occupational exposure,
BASF does not expect the aggregate exposure to exceed 100% of the RfD.
BASF concludes that there is a reasonable certainty that no harm will
result from aggregate exposure to bentazon residues.
iv. Cancer risk. Bentazon was classified as a ``Group E''
carcinogen, which denotes evidence of non-carcinogenicity for humans,
by the Agency's Health Effects Division Carcinogenicity Peer Review
Committee, June 26, 1991.
2. Infants and children-- i. Developmental toxicity testing.
Developmental toxicity was observed in a developmental toxicity study
using rats but was not seen in a developmental toxicity study using
rabbits.
ii. Developmental toxicity study-- Rat. From the rat developmental
toxicity study, the maternal (systemic) NOEL was 250 mg/kg/day, the
HDT. The developmental (fetal) NOEL was 100 mg/kg/day, based on
increased postimplantation loss and decreased fetal body weight at the
LOEL of 250 mg/kg/day.
iii. Developmental toxicity study--Rabbit. From the rabbit
developmental toxicity study, the maternal (systemic) NOEL was 150 mg/
kg/day, based on abortion and embryonic resorptions at the LOEL of 375
mg/kg/day. The developmental (fetal) NOEL was 375 mg/kg/day, the HDT.
iv. Reproductive toxicity study-- Rat. From the rat reproductive
study, the parental (systemic) NOEL was 62 mg/kg/day, based on
increased incidences of kidney mineralization and liver microgranules
at the LOEL of 249 mg/kg/day. The reproductive (pup) NOEL was 15 mg/kg/
day, based on decreased body weight gain at the LOEL of 62 mg/kg/day.
v. Pre- and post-natal sensitivity. In the rat teratology study,
fetal effects were observed at the high dose of 250 mg/kg/day in the
absence of apparent maternal toxicity. However, it should be noted that
very few general toxicity parameters are investigated for the maternal
animals in rat teratology studies. Essentially body weight, food
consumption and clinical signs are all that are determined. Bentazon
typically does not produce any significant effects on these parameters
at doses around 250 mg/kg/day. However, other factors indicating
toxicity to adult animals were observed at a lower dose of 180 mg/kg/
day in the 90-day rat feeding study. These effects consisted of
increased thromboplastin and prothrombin times, diuresis, clinical
chemistry changes (e.g. increases in albumin, A/G ratios, and sodium)
and increased kidney and liver weights. The NOEL in this 90-day rat
feeding study was determined to be 60 mg/kg/day. A conclusion can be
drawn that the true NOEL for this study lies between 60 and 180 mg/kg/
day. Since the effects stated above were well defined and characterized
for the endpoints discussed, the data would suggest that the apparent
NOEL would be in the range of 80-120 mg/kg/day. Therefore, the maternal
NOEL and developmental NOEL in the rat study are similar if the same
parameters are measured in the rat developmental study as are measured
in the 90-day rat feeding study. Thus, since toxicity to adult animals
is observed at doses which are similar to or lower than that which
produced developmental toxicity, it can be concluded that bentazon does
not produce selective toxicity to fetuses.
No treatment-related developmental (fetal) toxicity was observed in
the rabbit teratology study despite testing to a maternally toxic
level.
In the rat reproduction study, pup effects were observed at the
high and mid doses of approximately 249 and 62 mg/kg/day, respectively,
with parental toxicity observed at the high dose only. However, the
only effect on offspring at both the mid and high doses was a slight
decrease in pup weight during the lactation period. These marginal to
slight differences from control were demonstrated to be transient. The
F1 pups were kept on the treated diets at the mid and high dose levels
after lactation. By 4 weeks of age, the F1 pup weights were the same
for the mid and high doses and control. At the mid dose, there was no
effect on body weight of the F1 generation animals through 123 days of
treatment prior to mating.
In summary, there was no developmental toxicity observed in the
rabbit teratology study, there was no selective toxicity to fetuses in
the rat teratology study, and the only effect noted in the reproductive
toxicity study at a dose below the parental toxicity was a slight and
transient decrease in pup weight. Based on these results no additional
safety factor is required for protection of infants and children.
BASF believes that the RfD used to assess safety to children should
be the same as that for the general population, 0.03 mg/kg/day. Using
the conservative exposure assumptions described above, BASF has
concluded that the most sensitive child population is that of non-
nursing infants (<1- year="" old).="" basf="" calculates="" the="" exposure="" to="" bentazon="" residue="" from="" all="" existing="" tolerances="" plus="" the="" proposed="" increase="" in="" tolerance="" in="" succulent="" peas="" and="" the="" tolerance="" for="" flax="" seed="" to="" be="" approximately="" 12.5%="" of="" the="" rfd="" for="" non-nursing="" infants="">< 1-="" year="" old).="" f.="" international="" tolerances="" 1.="" succulent="" peas.="" there="" is="" a="" codex="" mrl="" of="" 0.2="" ppm="" for="" bentazon="" and="" its="" metabolites="" established="" in/on="" garden="" peas="" (young="" pods),="" a="" canadian="" mrl="" for="" parent="" only="" of="" 0.1="" ppm="" (negligible)="" established="" in/on="" peas,="" and="" a="" mexican="" limit="" for="" parent="" (presumed)="" of="" 0.05="" ppm="" established="" in/on="" green="" peas.="" 2.="" flax.="" no="" maximum="" residue="" level="" (mrl)="" has="" been="" established="" for="" bentazon="" in/on="" flax="" by="" the="" codex="" alimentarius="" commission.="" austria="" has="" established="" a="" tolerance="" level="" for="" bentazon="" (including="" its="" hydroxy="" metabolites)="" in/on="" linseed="" (seed)="" of="" 1.5="" ppm.="" canada="" has="" a="" maximum="" residue="" level="" for="" parent="" only="" of="" 0.1="" ppm="" in/on="" linseed.="" (joanne="" i.="" miller)="" 2.="" novartis="" crop="" protection,="" inc.="" pp="" 8f4955="" epa="" has="" received="" a="" pesticide="" petition="" (pp="" 8f4955)="" from="" novartis="" crop="" protection,="" inc.,="" po="" box="" 18300,="" greensboro,="" nc="" 27419="" 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="" cga-279202="" in="" or="" on="" the="" raw="" agricultural="" commodity="" on="" pome="" fruit="" at="" 0.4,="" cucurbit="" vegetables="" at="" 0.25,="" grapes="" at="" 1.5,="" peanuts="" at="" 0.02,="" peanut="" hay="" at="" 4.0,="" apple="" pomace="" at="" 1.5="" and="" imported="" bananas="" at="" 0.1="" 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.="" a.="" residue="" chemistry="" 1.="" plant="" metabolism.="" the="" metabolism="" of="" cga-279202="" in="" plants="" (cucumbers,="" [[page="" 43942]]="" apples,="" wheat="" and="" peanuts)="" is="" well="" understood.="" identified="" metabolic="" pathways="" are="" substantially="" similar="" in="" plants="" and="" animals="" (goat,="" rat="" and="" hen).="" novartis="" proposes="" cga-279202,="" per="" se,="" as="" the="" residue="" of="" concern="" for="" tolerance="" setting="" purposes.="" 2.="" analytical="" method.="" novartis="" crop="" protection="" inc.="" has="" submitted="" practical="" analytical="" methodology="" for="" detecting="" and="" measuring="" levels="" of="" cga-279202="" in="" or="" on="" raw="" agricultural="" commodities.="" the="" limit="" of="" detection="" (lod)="" for="" each="" analyte="" of="" this="" method="" is="" 0.08="" ng="" injected,="" and="" the="" limit="" of="" quantitation="" (loq)="" is="" 0.02="" ppm.="" the="" method="" is="" based="" on="" crop="" specific="" cleanup="" procedures="" and="" determination="" by="" gas="" chromatography="" with="" nitrogen-phosphorus="" detection.="" 3="" magnitude="" of="" residues--residue="" trials.="" cga-279202="" was="" applied="" to="" apples="" in="" 10="" states="" and="" to="" pears="" in="" 4="" states="" for="" a="" total="" of="" 19="" field="" trials.="" twelve="" field="" trials="" were="" conducted="" in="" the="" following="" 8="" representative="" peanut-growing="" states:="" alabama,="" florida,="" georgia,="" north="" carolina,="" oklahoma,="" south="" carolina,="" texas,="" and="" virginia.="" eighteen="" cucurbit="" field="" trials="" in="" 10="" states="" were="" successfully="" harvested,="" including="" 8="" cucumber,="" 5="" cantaloupe,="" and="" 5="" summer="" squash="" field="" trials.="" twelve="" field="" trials="" in="" 5="" states,="" accounting="" for="" 94%="" of="" the="" u.s.="" grape="" production,="" were="" conducted="" to="" generate="" residue="" data="" on="" grapes,="" raisins,="" and="" raw="" and="" pasteurized="" juice.="" thirteen="" banana="" field="" trials="" were="" conducted="" in="" costa="" rica,="" ecuador,="" colombia,="" guatemala,="" mexico,="" honduras,="" and="" puerto="" rico.="" b.="" toxicological="" profile="" 1.="" acute="" toxicity.="" studies="" conducted="" with="" the="" technical="" material="" of="" cga-279202="" include="" a="" rat="" acute="" oral="" toxicity="" study="" with="" a="">50 >5,000 mg/kg; a mouse acute oral toxicity study with a
LD50 >5,000 mg/kg; a rabbit acute dermal toxicity study with
a LD50 >2,000 mg/kg; a rat acute dermal toxicity study with
a LD50 >2,000 mg/kg; a rat acute inhalation toxicity study
with a LC50 >4.65 mg/L; a rabbit eye irritation study
showing slight irritation (Category III); a rabbit dermal irritation
study showing slight irritation (Category IV); a Guinea pig dermal
sensitization study with the Buehler's method showing negative
findings; a Guinea pig dermal sensitization study with the maximization
method showing some positive findings.
2. Genotoxicty. No genotoxic activity is expected of CGA-279202
under in-vivo or physiological conditions. The compound has been tested
for its potential to induce gene mutation and chromosomal changes in 5
different test systems. The only positive finding was seen in the in
vitro test system (Chinese hamster V79 cells) as a slight increase in
mutant frequency at a very narrow range (250 - 278 g/ml) of
cytotoxic and precipitating concentrations (compound solubility in
water was reported to be 0.61 g/ml; precipitate was visually
noted in culture medium at 150 g/ml). The chemical was found
to be non-mutagenic in the in vivo system or all other in vitro
systems. Consequently, the limited gene mutation activity in the V79
cell line is considered a nonspecific effect under non-physiological in
vitro conditions and not indicative of a real mutagenic hazard.
3. Reproductive and developmental toxicity. 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 on CGA-279202
relative to pre- and post-natal effects for children is complete.
In assessing the potential for additional sensitivity of infants
and children to residues of CGA-279202, Novartis considered data from
teratogenicity studies in the rat and the rabbit and a 2-generation
reproduction studies in the rat. The teratogenicity studies are
designed to evaluate adverse effects on the developing embryo as a
result of chemical exposure during the period of organogenesis.
Reproduction studies provide information on effects from chemical
exposure on the reproductive capability of mating animals and systemic
and developmental toxicity from in-utero exposure.
In the rat teratology study, reductions in body weight gain (bwtg)
and food consumption were observed in the dam at 100 mg/kg. No
teratogenic effects or any other effects were seen on pregnancy or
fetal parameters except for the increased incidence of enlarged thymus,
which is a type of variation, at 1,000 mg/kg. The developmental NOEL
was 100 mg/kg.
In the rabbit teratology study, body weight loss and dramatically
reduced food consumption were observed in the dam at 250 mg/
kg. No teratogenic effects or any other effects were seen on pregnancy
or fetal parameters except for the increase in skeletal anomaly of
fused sternebrae-3 and -4 at the top dose level of 500 mg/kg. This
finding is regarded as a marginal effect on skeletal development that
could have resulted from the 40-65% lower food intake during treatment
at this dose level. The developmental NOEL was 250 mg/kg.
In the 2-generation rat reproduction study, bwtg and food
consumption were decreased at 750 ppm, especially in females
during lactation. Consequently, the reduced pup weight gain during
lactation (750 ppm) and the slight delay in eye opening
(1,500 ppm) are judged to be a secondary effect of maternal toxicity.
No other fetal effects or any reproductive changes were noted. The low
developmental NOEL, 50 ppm (5 mg/kg), seen in this study was probably
due to the lack of intermediate dose levels between 50 and 750 ppm.
Based on an evaluation of the dose-response relationship for pup weight
at 750 ppm and 1,500 ppm, the NOEL should have been nearly ten-fold
higher if such a dose was available.
Based on all these teratology and reproduction studies, the lowest
NOEL for developmental toxicity is 5 mg/kg while the lowest NOEL in the
subchronic and chronic studies is 2.5 mg/kg/day (from the rat chronic
study). Therefore, no additional sensitivity for infants and children
to CGA-279202 is suggested by the data base.
4. Subchronic toxicity. In subchronic studies, several mortality
related changes were reported for the top dose in dogs (500 mg/kg) and
rats (800 mg/kg). At these dose levels, excessive toxicity has resulted
in body weight loss and mortality with the associated and nonspecific
changes in several organs (such as atrophy in the thymus, pancreas,
bone marrow, lymph node, and spleen) which are not considered specific
target organs for the test compound. In the dog, specific effects were
limited to hepatocellular hypertrophy at 150 mg/kg and
hyperplasia of the epithelium of the gall bladder at 500 mg/kg. Target
organ effects in the rat were noted as hepatocellular hypertrophy
(200 mg/kg) and the related liver weight increase
(50 mg/kg). In the mouse, target organ effects included
single cell necrosis (300 mg/kg) and hypertrophy (1,050 mg/
kg) in the liver and extramedullary hematopoiesis (300 mg/
kg) and hemosiderosis in the spleen (1,050 mg/kg).
In general, definitive target organ toxicity, mostly in the liver,
was seen at high feeding levels of over 100 mg/kg for an extended
treatment period. At LOEL, no serious toxicity was observed other than
mostly non-specific effects including a reduction in body weight and
food consumption or liver hypertrophy.
5. Chronic toxicity. The liver appears to be the major primary
target organ based on the chronic studies conducted in mice, rats, and
dogs. It was identified as a target organ in both the mouse and
[[Page 43943]]
the dog studies with CGA-279202. However, no liver effect was seen in
the chronic rat study which produced the lowest NOEL of 2.5 mg/kg based
on reduced bwtg and food consumption seen at higher dose levels (HDL).
The compound did not cause any treatment-related increase in general
tumor incidence, any elevated incidence of rare tumors, or shortened
time to the development of palpable or rapidly lethal tumors in the 18-
month mouse and the 24-month rat studies. Dosages in both studies were
sufficient for identifying a cancer risk. In the absence of
carcinogenicity, Novartis believes that a Reference Dose (RfD)
rapproach is appropriate for quantitation of human risks.
6. Animal metabolism. CGA-279202 is moderately absorbed from the
gastrointestinal tract of rats and is rapidly distributed. Subsequent
to a single oral dose, the half life of elimination is about 2-days and
excretion is primarily via bile. CGA-279202 is extensively metabolized
by the rat into about 35 metabolites, but the primary actions are on
the methyl ester (hydrolysis into an acid), the methoxyimino group (O-
demethylation), and the methyl side chain (oxidation to a primary
alcohol). Metabolism is dose dependent as it was almost complete at low
doses but only about 60% complete at high doses.
In the goat, elimination of orally administered CGA-279202 is
primarily via the feces. The major residues were the parent compound
and the acid metabolite (CGA-321113) plus its conjugates. In the hen,
CGA-279202 is found as the major compound in tissues and in the
excreta, but hydroxylation of the trifluormethyl-phenyl moiety and
other transformations, including methyl ester hydrolysis and
demethylation of the methoxyimino group, are also seen. In conclusion,
the major pathways of metabolism in the rat, goat, and hen are the
same.
7. Metabolite toxicology. Metabolism of CGA-279202 has been well
characterized in plants, soil, and animals. In plants and soil,
photolytically induced isomerization results in a few minor metabolites
not seen in the rat; however, most of the applied materials remained as
parent compound as shown in the apple and cucumber studies. All
quantitatively major plant and/or soil metabolites were also seen in
the rat. The toxicity of the major acid metabolite, CGA-321113 (formed
by hydrolysis of the methyl ester), has been evaluated in cultured rat
hepatocytes and found to be 20-times less cytotoxic than the parent
compound. Additional toxicity studies were conducted for several minor
metabolites seen uniquely in plants and/or soil. The studies indicate
that these metabolites, including CGA-357261, CGA-373466, and NOA-
414412, are not mutagenic to bacteria and are of low acute toxicity
(LD50 >2,000 mg/kg). In conclusion, the metabolism and
toxicity profiles support the use of an analytical enforcement method
that accounts for parent CGA-279202.
8. Endocrine disruption. CGA-279202 does not belong to a class of
chemicals known for having adverse effects on the endocrine system.
Developmental toxicity studies in rats and rabbits and reproduction
study in rats gave no indication that CGA-279202 might have any effects
on endocrine function related to development and reproduction. The
subchronic and chronic studies also showed no evidence of a long-term
effect related to the endocrine system.
C. Aggregate Exposure
1. Dietary exposure. For the purposes of assessing the potential
dietary exposure under the proposed tolerances for the residue of CGA-
279202 and its metabolites, Novartis has estimated aggregate exposure
based upon the Theoretical Maximum Residue Concentration (TMRC). The
values range from 0.0031 ppm in milk to 1.5 ppm in grapes and include
tolerances for various crops; pome fruit - 0.4 ppm for the raw
agricultural commodities (RAC); cucurbits - 0.25 ppm for the RAC;
grapes - 1.5 ppm for the RAC; peanuts - 0.02 ppm for the RAC; banana -
0.1 ppm for the RAC. The TMRC is a ``worst case'' estimate of dietary
exposure since it assumes 100% of all crops for which tolerances are
established are treated and that pesticide residues are at the
tolerance levels, resulting in an overestimate of human exposure.
2. Food--i. Chronic. The RfD of 0.025 mg/ kg/day is derived from
the 24-month rat NOEL of 2.5 mg/kg/day. Even under worst-case
assumptions, dietary exposure analysis for CGA-279202 in the most
exposed population (non-nursing infants <1-year old)="" shows="" the="" percent="" rfd="" utilization="" to="" be="" only="" 18.9%.="" although="" tolerances="" in="" meat="" and="" milk="" are="" not="" required="" for="" these="" uses,="" anticipated="" residues="" in="" meat="" and="" milk="" were="" also="" included="" in="" this="" exposure="" analysis.="" for="" average="" u.s.="" populations="" (48="" states),="" dietary="" exposure="" for="" cga-279202="" shows="" a="" minimal="" utilization="" of="" 3.4%="" of="" the="" rfd.="" ii.="" acute.="" for="" cga-279202,="" the="" appropriate="" noel="" for="" acute="" exposure="" is="" 2,000="" mg/kg/day="" from="" the="" acute="" oral="" neurotoxicity="" study="" in="" rats.="" acute="" dietary="" exposure="" analysis="" predicted="" the="" general="" population="" will="" be="" exposed="" to="" less="" than="" 0.0045="" mg/kg/day="" of="" cga-279202,="" which="" corresponds="" to="" a="" moe="" of="" 44,237="" at="" the="" 99.9="" percentile.="" children="" 1-6="" years="" constitute="" the="" sub-population="" with="" the="" highest="" predicted="" exposure.="" predicted="" acute="" exposure="" for="" this="" subgroup="" is="" less="" than="" 0.026="" mg/kg/day,="" corresponding="" to="" a="" moe="" of="" at="" least="" 7,797="" for="" 99.9%="" of="" the="" individuals.="" 3.="" drinking="" water.="" the="" potential="" for="" exposure="" to="" cga-279202="" through="" drinking="" water="" (surface="" or="" ground="" water)="" is="" low;="" this="" is="" due="" to="" the="" strong="" binding="" affinity="" of="" cga-279202="" to="" soil="" and="" to="" its="" low="" use="" rates="" (0.04-0.125="" lb="" ai/acre/application).="" the="" highest="" average="" (56-days)="" surface="" water="" concentration="" due="" to="" runoff="" predicted="" by="" the="" geneec="" model="" is="" 0.06="" ppb,="" resulting="" from="" application="" on="" turf.="" assuming="" a="" daily="" water="" consumption="" rate="" of="" 2="" l/day="" for="" an="" adult="" (70="" kg),="" this="" would="" lead="" to="" an="" adult="" intake="" of="" 0.0000017="" mg/kg/day="" which="" is="" only="" 0.007%="" of="" the="" chronic="" reference="" dose="" of="" 0.025="" mg/kg/day.="" assuming="" a="" three-fold="" increase="" in="" water="" consumption="" per="" unit="" body="" weight="" for="" children,="" the="" potential="" exposure="" increases="" only="" to="" 0.02%="" of="" rfd="" for="" this="" population="" subgroup.="" estimated="" concentrations="" for="" treating="" other="" crops="" or="" for="" ground="" water="" are="" even="" lower="" and="" do="" not="" indicate="" any="" cause="" for="" concern.="" 4.="" non-dietary="" exposure.="" non-dietary="" exposure="" to="" cga-279202="" is="" considered="" negligible="" as="" the="" chemical="" is="" intended="" primarily="" for="" commercial="" and="" agricultural="" use.="" exposure="" due="" to="" professional="" use="" on="" turf="" is="" considered="" negligible.="" for="" workers="" handling="" this="" chemical,="" acceptable="" margins="" of="" exposure="" (in="" the="" range="" of="" thousands)="" have="" been="" obtained="" for="" both="" acute="" and="" chronic="" scenarios.="" d.="" cumulative="" effects="" consideration="" of="" a="" common="" mechanism="" of="" toxicity="" is="" not="" appropriate="" at="" this="" time="" since="" there="" is="" no="" information="" to="" indicate="" that="" toxic="" effects="" produced="" by="" cga-279202="" would="" be="" cumulative="" with="" those="" of="" any="" other="" types="" of="" chemicals.="" furthermore,="" the="" oximinoacetate="" is="" a="" new="" type="" of="" fungicide="" and="" no="" compound="" in="" this="" general="" chemical="" class="" currently="" has="" a="" significant="" market="" share.="" consequently,="" novartis="" is="" considering="" only="" the="" potential="" exposure="" to="" cga-279202="" in="" its="" aggregate="" risk="" assessment.="" e.="" safety="" determination="" 1.="" u.s.="" population.="" using="" the="" conservative="" exposure="" assumptions="" described="" above="" and="" based="" on="" the="" completeness="" and="" reliability="" of="" the="" toxicity="" data="" base="" for="" cga-279202,="" [[page="" 43944]]="" novartis="" has="" calculated="" aggregate="" exposure="" levels="" for="" this="" chemical.="" the="" calculation="" shows="" that="" only="" 3.4%="" of="" the="" rfd="" will="" be="" utilized="" for="" the="" u.s.="" population="" based="" on="" chronic="" toxicity="" endpoints.="" epa="" generally="" has="" no="" concern="" for="" exposures="" below="" 100%="" of="" the="" rfd="" because="" the="" rfd="" represents="" the="" level="" at="" or="" below="" which="" daily="" aggregate="" dietary="" exposure="" over="" a="" lifetime="" will="" not="" pose="" appreciable="" risks="" to="" human="" health.="" novartis="" concludes="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" aggregate="" exposure="" to="" cga-279202="" residue.="" 2.="" infants="" and="" children.="" developmental="" toxicity,="" manifested="" as="" reduced="" weaning="" pup="" weight,="" enlarged="" thymus,="" or="" fused="" sternabrae,="" was="" observed="" in="" the="" teratology="" study="" and="" 2-generation="" rat="" reproduction="" studies="" at="" maternally="" toxic="" doses.="" all="" of="" these="" findings="" are="" judged="" to="" be="" non-specific,="" secondary="" effects="" of="" maternal="" toxicity.="" the="" lowest="" noel="" for="" developmental="" toxicity="" was="" established="" in="" the="" rat="" reproduction="" study="" at="" 5="" mg/kg,="" a="" level="" that="" is="" likely="" to="" be="" an="" overly="" low="" estimate="" (as="" a="" result="" of="" dose="" gap)="" but="" is="" still="" higher="" than="" the="" chronic="" noel="" of="" 2.5="" mg/kg="" on="" which="" the="" rfd="" is="" based.="" using="" the="" same="" conservative="" exposure="" assumptions="" as="" employed="" for="" the="" determination="" in="" the="" general="" population,="" novartis="" has="" calculated="" that="" the="" percent="" of="" the="" rfd="" that="" will="" be="" utilized="" by="" aggregate="" exposure="" to="" residues="" of="" cga-279202="" is="" only="" 19%="" for="" non-nursing="" infants="" less="" than="" 1-year="" old="" (the="" most="" impacted="" sub-population).="" therefore,="" based="" on="" the="" completeness="" and="" reliability="" of="" the="" toxicity="" data="" base="" and="" the="" conservative="" exposure="" assessment,="" novartis="" concludes="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" to="" infants="" and="" children="" from="" aggregate="" exposure="" to="" cga-279202="" residues.="" f.="" international="" tolerances="" no="" codex="" mrls="" have="" been="" established="" for="" residues="" of="" cga-279202.="" (janet="" whitehurst).="" [fr="" doc.="" 98-22012="" filed="" 8-14-98;="" 8:45="" am]="" billing="" code="" 6560-50-f="">