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ENVIRONMENTAL PROTECTION AGENCY
Environmental Protection Agency
CFR Citation: 40 CFR Part 180
OPP ID: [OPP-2003-0219; FRL-7313-6]
NOTICE: RULES
ACTION: Pesticides; tolerances in food, animal feeds, and raw agricultural commodities:
DOCUMENT ACTION: Final rule.
SUBJECT CATEGORY: Cymoxanil; Pesticide Tolerances
DATES: This regulation is effective July 16, 2003. Objections and requests for hearings, identified by docket ID number OPP20030219, must be received on or before September 15, 2003.
DOCUMENT SUMMARY: This regulation establishes tolerances for residues of cymoxanil in or on hop, dried cones; lettuce, head; imported lychee; vegetable, cucurbit, group 9; and vegetable, fruiting, group 8. The Interregional Research Project Number 4 (IR4), the Taipai Economic and Cultural Representative Office, and E.I du Pont Nemours and Company requested these tolerances under the Federal Food, Drug, and Cosmetic Act (FFDCA), as amended by the Food Quality Protection Act (FQPA) of 1996. EPA is also deleting the timelimited tolerance for hop, dried cones established in connection with use of the pesticide under section 18 emergency exemptions and the tolerance for imported tomato. These tolerances are no longer needed since this rule establishes tolerances in support of the U.S. registration for hops and tomato.
SUMMARY: Cymoxanil,
SUPPLEMENTAL INFORMATION
I. General InformationA. Does this Action Apply to Me?
You may be potentially affected by this action if you are an
agricultural producer, food manufacturer, or pesticide manufacturer.
Potentially affected entities may include, but are not limited to: [sbull] Crop production (NAICS 111)
[sbull] Animal production (NAICS 112)
[sbull] Food manufacturing (NAICS 311)
[sbull] Pesticide manufacturing (NAICS 32532)
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in this unit could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether this action might apply to certain entities. If you have any
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION CONTACT.
B. How Can I Get Copies of this Document and Other Related Information?
1. Docket. EPA has established an official public docket for this
action under docket identification ID number OPP20030219. The
official public docket consists of the documents specifically
referenced in this action, any public comments received, and other
information related to this action. Although a part of the official
docket, the public docket does not include Confidential Business
Information (CBI) or other information whose disclosure is restricted
by statute. The official public docket is the collection of materials
that is available for public viewing at the Public Information and
Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall
2. Electronic access. You may access this Federal Register document
electronically through the EPA Internet under the ``Federal Register''
listings at http://www.epa.gov/fedrgstr/. A frequently updated
electronic version of 40 CFR part 180 is available at http://www.access.gpo.gov/nara/cfr/cfrhtml_00/Title_40/40cfr180_00.html , a
beta site currently under development. To access the OPPTS Harmonized
Guidelines referenced in this document, go directly to the guidelines
at http://www.epa.gov/opptsfrs/home/guidelin.htm.
An electronic version of the public docket is available through
EPA's electronic public docket and comment system, EPA Dockets. You may
use EPA Dockets at http://www.epa.gov/edocket/ to submit or view public
comments, access the index listing of the contents of the official public docket, and to access those documents in the public
[[Page 41928]]
docket that are available electronically. Although not all docket
materials may be available electronically, you may still access any of
the publicly available docket materials through the docket facility
identified in Unit I.B.1. Once in the system, select ``search,'' then key in the appropriate docket ID number.
II. Background and Statutory Findings
In the Federal Register of July 6, 2001 (66 FR 130) (FRL67849)
and February 28, 2003 (68 FR 9660) (FRL72889), EPA issued notices
pursuant to section 408 of FFDCA, 21 U.S.C. 346a, as amended by FQPA
(Public Law 104170), announcing the filing of a pesticide petition
(1E6224) by IR4, 681 U.S. Highway
The World Wildlife Fund (WWF) submitted comments on August 7, 2001 in response to the notice of filing for hops and lychee. WWF urged EPA to apply the full 10X FQPA safety factor to cymoxanil ``because completed studies for this fungicide are inadequate to detect endocrine disruption and the endocrine disruptor data gap is of critical importance when determining a reasonable certainty of no harm to embryos, fetus, infants and children.'' In addition, WWF stated that there may be evidence of increased developmental susceptibility for cymoxanil. EPA reviewed the comments submitted by WWF and has addressed them in Unit III. D. of this document.
Section 408(b)(2)(A)(i) of the FFDCA allows EPA to establish a tolerance (the legal limit for a pesticide chemical residue in or on a food) only if EPA determines that the tolerance is ``safe.'' Section 408(b)(2)(A)(ii) of the FFDCA defines ``safe'' to mean that ``there is a reasonable certainty that no harm will result from aggregate exposure to the pesticide chemical residue, including all anticipated dietary exposures and all other exposures for which there is reliable information.'' This includes exposure through drinking water and in residential settings, but does not include occupational exposure. Section 408(b)(2)(C) of the FFDCA requires EPA to give special consideration to exposure of infants and children to the pesticide chemical residue in establishing a tolerance and to ``ensure that there is a reasonable certainty that no harm will result to infants and children from aggregate exposure to the pesticide chemical residue. . . .''
EPA performs a number of analyses to determine the risks from aggregate exposure to pesticide residues. For further discussion of the regulatory requirements of section 408 of the FFDCA and a complete description of the risk assessment process, see the final rule on Bifenthrin Pesticide Tolerances November 26, 1997 (62 FR 62961) (FRL 57547).
III. Aggregate Risk Assessment and Determination of Safety
Consistent with section 408(b)(2)(D) of the FFDCA, EPA has reviewed the available scientific data and other relevant information in support of this action. EPA has sufficient data to assess the hazards of and to make a determination on aggregate exposure, consistent with section 408(b)(2) of the FFDCA, for tolerances for residues of cymoxanil on hop, dried cones at 1.0 ppm; lettuce, head at 4.0 ppm; vegetable, cucurbit, group 9 at 0.05 ppm; vegetable, fruiting, group 8 at 0.2 ppm; and imported lychee at 1.0 ppm. EPA's assessment of exposures and risks associated with establishing the tolerance follows.
A. Toxicological Profile
EPA has evaluated the available toxicity data and considered its
validity, completeness, and reliability as well as the relationship of
the results of the studies to human risk. EPA has also considered
available information concerning the variability of the sensitivities
of major identifiable subgroups of consumers, including infants and
children. The nature of the toxic effects caused by cymoxanil are
discussed in Table 1 of this unit as well as the no observed adverse
effect level (NOAEL) and the lowest observed adverse effect level (LOAEL) from the toxicity studies reviewed.
Table 1.Subchronic, Chronic, and Other Toxicity
Guideline No. Study Type Results
870.3100 90Day oral toxicity Systemic toxicity NOAEL = 47.6 milligrams/
rodents (rat) kilogram/day (mg/kg/day) in males and 59.9
mg/kg/day in females
Systemic toxicity LOAEL = 102 mg/kg/day in
males and 137 mg/kg/day in females, based
on decreases in body weights, body weight
gains and food efficiency in the females,
and body weight decreases and testicular
and epididymal changes in males.
870.3150 90Day oral toxicity in Systemic toxicity NOAEL not established
nonrodents (dog) Systemic toxicity LOAEL = 3 mg/kg/day,
based on decreased body weights (13%) and
food consumption in females.
870.3200 21/28Day dermal toxicity Systemic and dermal toxicity NOAEL = 1,000
(rat) mg/kg/day, highest dose tested (HDT)
Systemic and dermal toxicity LOAEL was not
established. [[Page 41929]]
870.3700 Prenatal developmental in Maternal NOAEL = 25 mg/kg/day
rodents (rat) Maternal LOAEL = 75 mg/kg/day, based upon
reduced body weight, body weight change
and food consumption
Developmental NOAEL = 10 mg/kg/day
Developmental LOAEL = 25 mg/kg/day, based
upon significant increase in overall
malformations, and generalized dose
related delay in skeletal ossification; at
75 and 150 mg/kg/day significant decrease
in fetal body weights; at 150 mg/kg/day
increased early resorptions resulting in
reduced litter size.
870.3700 Prenatal developmental in Maternal NOAEL 32 mg/kg/day
nonrodents (rabbit) Maternal LOAEL was not established
Developmental NOAEL = 4 mg/kg/day
Developmental LOAEL = 8 mg/kg/day, based
upon an increase in skeletal anomalies of
the cervical and thoracic vertebrae and
ribs; at 32 mg/kg/day, cleft palate was
also observed.
870.3800 2Generation reproduction Systemic toxicity NOAEL = 6.5 males and 7.9
and fertility effects females mg/kg/day
(rat) Systemic toxicity LOAEL = 32.1 males and
40.6 females mg/kg/day, based on reduced
premating body weight, body weight gain,
and food consumption for P males; and
decreased gestation and lactation body
weight for F1 females
Reproductive toxicity NOAEL 97.9 mg/kg/day
for males and 130 mg/kg/day for females.
Reproductive toxicity LOAEL was not
established
Offspring toxicity NOAEL = 6.5 males and
7.9 females mg/kg/day
Offspring toxicity LOAEL = 32.1 female and
40.6 females mg/kg/day, based upon
decreased F1 pup viability on postnatal
days 04 and on a significant reduction in
F2b pup weight.
870.4100 Chronic toxicity (dog) Systemic toxicity NOAEL = 3.0/3.1 mg/kg/day
for males/ and females
Systemic toxicity LOAEL = 5.7 mg/kg/day
(HDT in males), based upon depressed
weight gains through week 12 and changes
in the hematology and blood chemistry in
males
LOAEL was not established for females.
870.4300 Combined chronic toxicity/ Systemic toxicity NOAEL = 4.08 mg/kg/day
carcin ogenicity rodents for males and 5.36 mg/kg/day for females
(rat) Systemic toxicity LOAEL = 30.3 mg/kg/day
for males and 38.4 mg/kg/day for females,
based upon decreased body weight, body
weight gain, and food efficiency,
increased incidence of elongate spermatid
degeneration and increased aggressiveness
and/or hyperactivity in males and
increased incidence of nonneoplastic
lesions of the lungs, liver, sciatic nerve
and retinal atrophy in females
No evidence of carcinogenicity.
870.4200 Carcinogenicity mice Systemic toxicity NOAEL = 4.19 mg/kg/day
for males and 5.83 mg/kg/day for females,
lowest dose tested (LDT)
Systemic toxicity LOAEL = 42 mg/kg/day for
males and 58.1 mg/kg/day for females HDT,
based upon increased frequency of sperm
cyst/cystic dilatation, tubular dilatation
and lymphoid aggregates in males and
hyperplastic gastropathy in females
No evidence of carcinogenicity.
870.5100 Gene mutation Cytotoxicity in all strains was seen at 750
[mu]g/plate S9 and 1.000 [mu]g/plate +S9.
The positive controls induced the expected
mutagenic responses in the appropriate
tester strain. There was, however, no
evidence that the test material induced a
mutagenic effect under any test condition.
870.5300 In vitro mammalian cell Severe cytotoxicity was seen at 750 [mu]g/
gene mutation assay (CHO) mL S9 and 1,000 [mu]g/mL +S9. The
positive controls induced the expected
mutagenic responses. There was, however,
no evidence that the test material was
mutagenic at the Hypoxanthine Guanine
Phophoribosyl Transferase locus at any
dose under any assay condition.
8 70.6200 Subchronic neurotoxicity No effects on the functional observation
screening battery (rat) battery, or motor activity were observed.
No treatmentrelated gross or microscopic
findings in the nervous system or skeletal
muscles of the male and female rats were
observed
The neurotoxicity NOAEL 3,000 ppm (224 mg/
kg/day in males and 333 mg/kg/day in
females; HDT). Neurotoxicity LOAEL was not
established. [[Page 41930]]
870.6300 Developmental Maternal toxicity NOAEL = 50 mg/kg/day
neurotoxicity (rat) Maternal toxicity LOAEL = 100 mg/kg/day,
based on slight decrease body weight, body
weight gains (17%) and food consumption.
Offspring NOAEL = 50 mg/kg/day
Offspring LOAEL = 100 mg/kg/day, based on
decreased pup survival, decreased pup
weight and body weight gain during early
lactation (less than 6%), increases in
morphometric measurements (anterior/
posterior cerebrum for males, cerebellar
height for females) at PND 7983, and
decreased retention in the water maze task
for adult females (latency 158% of control
levels) seen at the LOAEL of 100 mg/kg/
day.
870.7485 Metabolism and Cymoxanil was readily absorbed and 86 to
pharmacokinetics (rat) 94% of the administered dose was excreted
in 96 hours. The majority of the
administered dose was recovered in the
urine (64 57%) with smaller amounts
excreted in the feces (16 24%) and
carcass (<1%). There were no sexrelated
differences in the absorption,
distribution and metabolism of cymoxanil.
In urine about 37 55% of the dose was
free and/or conjugated [14C]glycine and 2
cyano2methoxyiminoacetic acid (INW3595;
about 7 to 33% of the dose). Intact
cymoxanil was not isolated in urine. In
feces intact 14C cymoxanil (<1%) and IN
W3595 was detected, but the majority of
radioactivity was 14C glycine (about 9
13%). Based on the data, the metabolic
pathway involves hydrolysis of cymoxanil
to IN W3595, which is then degraded to
glycine, which in turn is incorporated
into natural constituents or further
metabolized. B. Toxicological Endpoints
The dose at which the NOAEL from the toxicology study identified as appropriate for use in risk assessment is used to estimate the toxicological level of concern. However, the the LOAEL is sometimes used for risk assessment if no NOAEL was achieved in the toxicology study selected. An uncertainty factor (UF) is applied to reflect uncertainties inherent in the extrapolation from laboratory animal data to humans and in the variations in sensitivity among members of the human population as well as other unknowns. An UF of 100 is routinely used, 10X to account for interspecies differences and 10X for intra species differences.
For dietary risk assessment (other than cancer) the Agency uses the UF to calculate an acute or chronic reference dose (aRfD or cRfD) where the RfD is equal to the NOAEL divided by the appropriate UF (RfD = NOAEL/UF). Where an additional safety factors is retained due to concerns unique to the FQPA, this additional factor is applied to the RfD by dividing the RfD by such additional factor. The acute or chronic population adjusted dose (aPAD or cPAD) is a modification of the RfD to accommodate this type of FQPA SF.
For nondietary risk assessments (other than cancer) the UF is used to determine the lever of concern. For example, when 100 is the appropriate UF (10X to account for interspecies differences and 10X for intraspecies differences) the LOC is 100. To estimate risk, a ratio of the NOAEL to exposures (margin of exposure (MOE) = NOAEL/exposure) is calculated and compared to the lever of concern.
The linear default risk methodology (Q*) is the primary method
currently used by the Agency to quantify carcinogenic risk. The Q*
approach assumes that any amount of exposure will lead to some degree
of cancer risk. A Q* is calculated and used to estimate risk which
represents a probability of occurrence of additional cancer cases
(e.g., risk is expressed as 1 x 106 or one in a million).
Under certain specific circumstances, MOE calculations will be used for
the carcinogenic risk assessment. In this nonlinear approach, a
``point of departure'' is identified below which carcinogenic effects
are not expected. The point of departure is typically a NOAEL based on
an endpoint related to cancer effects though it may be a different
value derived from the dose response curve. To estimate risk, a ratio
of the point of departure to exposure (MOE
Table 2.Summary of Toxicological Dose and Endpoints for Cymoxanil for Use in Human Risk Assessment
FQPA SF* and Level of
Exposure Scenario Dose Used in Risk Concern for Risk Study and Toxicological
Assessment, UF Assessment Effects
Acute dietary (females 1350 years of NOAEL = 4 mg/kg/day FQPA SF = 1X Developmental toxicity
age) UF = 100............... aPAD = aRfD............ study rabbit
aRfD = 0.04 mg/kg/day.. FQPA SF = 0.04 mg/kg/ Developmental LOAEL = 8
day. mg/kg/day based on
increased skeletal
anomalies of the
cervical and thoracic
vertebrae
(hemivertebrae) and
ribs; at 32 mg/kg/day,
cleft palate was also
observed. [[Page 41931]]
Acute dietary (general population NA NA An effect attributable
including infants and children) to a single exposure
was not observed in
the oral toxicity
studies, including the
developmental toxicity
studies in rats and
rabbits. Therefore, an
aRfD was not
established for this
population.
Chronic dietary (all populations) NOAEL = 4 mg/kg/day FQPA SF = 1X Combined chronic
UF = 100............... cPAD = chronic RfD..... toxicity/
cRfD = 0.04 mg/kg/day.. FQPA SF = 0.04 mg/kg/ carcinogenicity study
day. rat
Systemic LOAEL = 30.3
mg/kg/day based on
decreases in body
weight, body weight
gain, reduced food
efficiency and
histopathological
lesions in the eyes
and testes of males.
Shortterm dermal (1 to 30 days) Oral study NOAEL = 4 mg/ LOC for MOE = 100 Developmental toxicity
(Residential)........................ kg/day (Residential).......... study rabbit
(Dermal absorption rate Developmental LOAEL = 8
= 2.5%). mg/kg/day based on
increased skeletal
anomalies of the
cervical and thoracic
vertebrae
(hemivertebrae) and
ribs; at 32 mg/kg/day,
cleft palate was also
observed.
Intermediateterm dermal (1 to 6 Oral study NOAEL = 4 mg/ LOC for MOE = 100 Developmental toxicity
months) kg/day (Residential).......... study rabbit
(Residential)........................ (Dermal absorption rate Developmental LOAEL = 8
= 2.5%. mg/kg/day based on
increased skeletal
anomalies of the
cervical and thoracic
vertebrae
(hemivertebrae) and
ribs; at 32 mg/kg/day,
cleft palate was also
observed.
Longterm dermal (>6 months) Oral study NOAEL= 4 mg/ LOC for MOE = 100 Combined chronic
(Residential)........................ kg/day (Residential).......... toxicity/
(Dermal absorption rate carcinogenicity study
= 2.5% when rat
appropriate). Systemic LOAEL = 30.3
mg/kg/day based on
decreases in body
weight, body weight
gain, reduced food
efficiency and
histopathological
lesions in the eyes
and testes of males.
Shortterm inhalation (1 to 30 days) Oral study NOAEL= 4 mg/ LOC for MOE = 100 Developmental toxicity
(Residential)........................ kg/day (Residential).......... study rabbit
(Inhalation absorption Developmental LOAEL = 8
rate = 100%). mg/kg/day based on
increased skeletal
anomalies of the
cervical and thoracic
vertebrae and ribs; at
32 mg/kg/day, cleft
palate was also
observed.
Intermediateterm inhalation (1 to 6 Oral study NOAEL = 4 mg/ LOC for MOE = 100 Developmental toxicity
months) kg/day (Residential).......... study rabbit
(Residential)........................ (Inhalation absorption Developmental LOAEL = 8
rate = 100%). mg/kg/day based on
increased skeletal
anomalies of the
cervical and thoracic
vertebrae and ribs; at
32 mg/kg/day, cleft
palate was also
observed.
Longterm inhalation (> 6 months) Oral study NOAEL= 4 mg/ LOC for MOE = 100 Combined chronic
kg/day (Residential).......... toxicity/
(Residential)........................ (Inhalation absorption carcinogenicity study
rate = 100%). rat
Systemic LOAEL = 30.3
mg/kg/day based on
decreases in body
weight, body weight
gain, reduced food
efficiency and
histopathological
lesions in the eyes
and testes of males.
Cancer (oral, dermal, inhalation) NA NA Classification: not
likely human
carcinogen Q1* = none.
* The reference to the FQPA SF refers to any additional SF retained due to concerns unique to the FQPA. C. Exposure Assessment
1. Dietary exposure from food and feed uses. Tolerances have been
established (40 CFR 180.503) for the residues of cymoxanil, in or on a
variety of raw agricultural commodities. A permanent tolerance of 0.05
ppm for residues of cymoxanil per se in/on potatoes has been
established under 40 CFR 180.503(a). A timelimited tolerance of 1 ppm for residues of cymoxanil per se in/on hops, dried has
[[Page 41932]]
also been established under 40 CFR 180.503(b) in connection with EPA's
granting of a section 18 emergency exemption. The timelimited
tolerance for hops, dried cone was set to expire December 31, 2003.
Tolerances for residues of cymoxanil per se in/on imported grapes and
tomatoes at 0.1 ppm are established under 40 CFR 180.503(e). Risk
assessments were conducted by EPA to assess dietary exposures from cymoxanil in food as follows:
i. Acute exposure. Acute dietary risk assessments are performed for a fooduse pesticide if a toxicological study has indicated the possibility of an effect of concern occurring as a result of a 1day or single exposure. In conducting the acute dietary exposure assessment EPA used the Dietary Exposure Evaluation Model software with the Food Commodity Intake Data base (FCDI DEEMTM) which incorporates food consumption data as reported by respondents in the United States Department of Agriculture (USDA) 19941996, and 1998 nationwide Continuing Surveys of Food Intake by Individuals (CSFII) and accumulated exposure to the chemical for each commodity. The acute dietary exposure analyses assumed tolerance level residues, 100% crop treated and DEEMTM (ver. 7.76) default processing factors for all registered/proposed commodities.
ii. Chronic exposure. In conducting the chronic dietary exposure
assessments EPA used the DEEMTM software with the FCID which
incorporates food consumption data as reported by respondents in the
USDA 1994l996, and 1998 nationwide CSFII and accumulated exposure to
the chemical for each commodity. The following assumptions were made
for the chronic exposure assessments: The chronic dietary exposure analyses assumed tolerance level residues, 100% CT, and
DEEMTM (ver. 7.76) default processing factors for all registered/proposed commodities.
iii. Cancer. In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (July 1999), the Agency classified cymoxanil as a ``not likely'' human carcinogen. Therefore, a cancer dietary exposure analysis was not performed.
2. Dietary exposure from drinking water. The Agency lacks sufficient monitoring exposure data to complete a comprehensive dietary exposure analysis and risk assessment for cymoxanil in drinking water. Because the Agency does not have comprehensive monitoring data, drinking water concentration estimates are made by reliance on simulation or modeling taking into account data on the physical characteristics of cymoxanil.
The Agency uses the Generic Estimated Environmental Concentration (GENEEC) or the Pesticide Root Zone Model/Exposure Analysis Modeling System (PRZM/EXAMS) to estimate pesticide concentrations in surface water and Screening Concentration in Ground water (SCIGROW), which predicts pesticide concentrations in ground water. In general, EPA will use GENEEC (a tier 1 model) before using PRZM/EXAMS (a tier 2 model) for a screeninglevel assessment for surface water. The GENEEC model is a subset of the PRZM/EXAMS model that uses a specific highend runoff scenario for pesticides. GENEEC incorporates a farm pond scenario, while PRZM/EXAMS incorporate an index reservoir environment in place of the previous pond scenario. The PRZM/EXAMS model includes a percent crop area factor as an adjustment to account for the maximum percent crop coverage within a watershed or drainage basin.
Since the models used are considered to be screening tools in the risk assessment process, the Agency does not use estimated environmental concentrations (EECs) from these models to quantify drinking water exposure and risk as a %RfD or %PAD. Instead, drinking water levels of comparison (DWLOCs) are calculated and used as a point of comparison against the model estimates of a pesticide's concentration in water. DWLOCs are theoretical upper limits on a pesticide's concentration in drinking water in light of total aggregate exposure to a pesticide in food, and from residential uses. Since DWLOCs address total aggregate exposure to cymoxanil they are further discussed in the aggregate risk sections in Unit II.E.
Cymoxanil appears to be mobile in soils. However, the rapid dissipation of cymoxanil in the environment precludes the possibility of extensive leaching. No detections of cymoxanil were observed below the 015 cm soil depth at any of the test sites. Though the degradates of cymoxanil are mobile, the aerobic soil metabolism study showed that the degradates are shortlived. Cymoxanil and its degradates should not pose a threat to ground water. Therefore, ground water EEC values were not included in the risk assessment.
Based on the GENEEC model the EECs of cymoxanil for surface water are estimated to be 4.13 parts per billion (ppb) for acute exposures and 0.19 ppb for chronic exposure.
3. From nondietary exposure. The term ``residential exposure'' is used in this document to refer to nonoccupational, nondietary exposure (e.g., for lawn and garden pest control, indoor pest control, termiticides, and flea and tick control on pets).
Cymoxanil is not registered for use on any sites that would result in residential exposure.
4. Cumulative exposure to substances with a common mechanism of toxicity. Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering whether to establish, modify, or revoke a tolerance, the Agency consider ``available information'' concerning the cumulative effects of a particular pesticide's residues and ``other substances that have a common mechanism of toxicity.''
EPA does not have, at this time, available data to determine whether cymoxanil has a common mechanism of toxicity with other substances. Unlike other pesticides for which EPA has followed a cumulative risk approach based on a common mechanism of toxicity, EPA has not made a common mechanism of toxicity finding as to cymoxanil and any other substances and cymoxanil does not appear to produce a toxic metabolite produced by other substances. For the purposes of this tolerance action, therefore, EPA has not assumed that cymoxanil has a common mechanism of toxicity with other substances. For information regarding EPA's efforts to determine which chemicals have a common mechanism of toxicity and to evaluate the cumulative effects of such chemicals, see the policy statements released by EPA's Office of Pesticide Programs concerning common mechanism determinations and procedures for cumulating effects from substances found to have a common mechanism on EPA's website at http://www.epa.gov/pesticides/cumulative/ .
D. Safety Factor for Infants and Children
1. In general. Section 408 of the FFDCA provides that EPA shall apply an additional tenfold margin of safety for infants and children in the case of threshold effects to account for prenatal and postnatal toxicity and the completeness of the data base on toxicity and exposure unless EPA determines that a different margin of safety will be safe for infants and children. Margins of safety are incorporated into EPA risk assessments either directly through use of a MOE analysis or through using uncertainty (safety) factors in calculating a dose [[Page 41933]]
level that poses no appreciable risk to humans.
2. Prenatal and postnatal sensitivity. There is an indication of increased susceptibility (qualitative and quantitative) of rats and rabbits to in utero exposure to cymoxanil. In the rat developmental toxicity study, decreased fetal body weights and skeletal malformations were observed at 25 mg/kg/day LOAEL, which is below the maternal toxicity of 75 mg/kg/day LOAEL. In the rabbit developmental study increased skeletal malformations were observed at 8 mg/kg/day LOAEL, also below the maternal NOAEL of 32 mg/kg/day. In the 2generation reproduction study there was an indication of increased qualitative susceptibility in the offspring, since there was decreased pup viability at a maternally toxic dose.
3. Conclusion. There is a complete toxicity data base for cymoxanil and exposure data are complete or are estimated based on data that reasonably accounts for potential exposures. EPA determined that the 10X SF to protect infants and children should be reduced to 1X. The FQPA factor is reduced to 1X because in the developmental and postnatal studies (including a developmental neurotoxicity study in rats) the effects are well characterized and conservative NOAELs were established for all developmental and offspring effects. In addition, the doses selected for risk assessment are lower than the NOAELs from these studies and are protective of any potential prenatal and postnatal effects. Therefore, there are low levels of concern and no residual uncertainties for prenatal and postnatal toxicity.
In response to the notice of filing of July 6, 2001, WWF urged EPA to apply the full 10X FQPA safety factor to cymoxanil. According to WWF the data for cymoxanil is inadequate to address potential endocrine disruption and there is evidence of increased susceptibility in the prenatal developmental rabbit study. WWF claimed the multigeneration reproduction study in rats is inadequate because it was conducted before the 1996 guideline changes which added additional endpoints responsive to estrogenic and/or androgenic endocrine disruption. In addition, WWF noted that inferences about endocrine disruption based on current guidelines are still not fully adequate to evaluate endocrine disruption. In particular, the Endocrine Disruptor Screening and Testing Advisory Committee (EDSTAC) recommended the inclusion of more endpoints relevant to thyroid disruption and measurement of estradiol, testerone, luteinizing hormone, follicle stimulating hormone, T4 and thyroid stimulating hormone levels in multigeneration studies. WWF further argued for the inclusion of certain adrenal hormones such as ACTH and corticosterone (the primary glucocorticoid in rodents) to fully address the endocrine disruption issue. In addition, WWF believes that there is an increased developmental susceptibility to rabbits fetuses. WWF questioned the conclusions reached by the Office of Pesticide Programs' Hazard Identification Assessment Review Committee (HIARC) Jan 20, 1998 that there is no sensitivity in fetuses compared to maternal animals. Developmental malformations were observed at 8 mg/ kg/day, which is below the maternal NOAEL of 16 mg/kg/day. These results were discounted due to uncertainties regarding the source of the parental rabbits. In another rabbit study, developmental malformations were observed at the same dose (8 mg/kg/day) as in the previous study, however, HIARC did not consider this to show increased susceptibility because the effects were observed at 8 mg/kg/day, which is also a maternal toxic dose.
On June 18, 2002, HIARC reviewed the WWF comments and concluded that possible endocrinerelated effects on testicular and/or epididymal tissues are fully characterized and well defined in mouse, subchronic and chronic rat and dog studies with clear NOAELs. Further, in the reproduction toxicity study in rats, testicular effects were seen, however, these effects did not affect any measured reproductive parameters, indicating no adverse effects on reproduction. Additional measurements recommended by EDSTAC and WWF are unlikely to provide any significant additional information for cymoxanil since NOAELs are clearly defined for the testicular and/or epididymal effects and there are no indications of endocrine disruption in other organs e.g., thyroid (thyroid weight changes and hyperplasia), adrenal toxicity.
Prior to receipt of WWF letter, the HIARC on August 21, 2001,
reevaluated the toxicology data base and modified certain study reviews
resulting in the selection of new endpoints. The reevaluations resulted in the qualitative and quantitative evidence of increased
susceptibility to rabbit fetuses (as suggested by WWF) and rat fetuses.
In addition, reevaluation of rat reproduction toxicity study resulted
in the qualitative increased susceptibility to offspring. A
conservative NOAEL from the rabbit developmental study was used for
establishing the aRfD. Nonetheless, it was concluded that reliable data
supported applying no additional safety factor since endpoints chosen
for risk assessments adequately protect infants and children with
regard to the prenatal and/or postnatal toxicity that has been identified.
E. Aggregate Risks and Determination of Safety
To estimate total aggregate exposure to a pesticide from food, drinking water, and residential uses, the Agency calculates DWLOCs which are used as a point of comparison against the model estimates of a pesticide's concentration in water (EECs). DWLOC values are not regulatory standards for drinking water. DWLOCs are theoretical upper limits on a pesticide's concentration in drinking water in light of total aggregate exposure to a pesticide in food and residential uses. In calculating a DWLOC, the Agency determines how much of the acceptable exposure (i.e., the PAD) is available for exposure through drinking water e.g., allowable chronic water exposure (mg/kg/day) = cPAD (average food + residential exposure). This allowable exposure through drinking water is used to calculate a DWLOC.
A DWLOC will vary depending on the toxic endpoint, drinking water consumption, and body weights. Default body weights and consumption values as used by the USEPA Office of Water are used to calculate DWLOCs: 2 liter (L)/70 kg (adult male), 2L/60 kg (adult female), and 1L/10 kg (child). Default body weights and drinking water consumption values vary on an individual basis. This variation will be taken into account in more refined screeninglevel and quantitative drinking water exposure assessments. Different populations will have different DWLOCs. Generally, a DWLOC is calculated for each type of risk assessment used: Acute, shortterm, intermediateterm, chronic, and cancer.
When EECs for surface water and ground water are less than the calculated DWLOCs, OPP concludes with reasonable certainty that exposures to the pesticide in drinking water (when considered along with other sources of exposure for which EPA has reliable data) would not result in unacceptable levels of aggregate human health risk at this time. Because EPA considers the aggregate risk resulting from multiple exposure pathways associated with a pesticide's uses, levels of comparison in drinking water may vary as those uses change. If new uses are added in the future, EPA will reassess the potential impacts of residues of the pesticide in drinking water as a part of the aggregate risk assessment process.
[[Page 41934]]
1. Acute risk. Using the exposure assumptions discussed in this
unit for acute exposure, the acute dietary exposure from food to
cymoxanil will occupy <71% of the aPAD for females 13 to 49 years old.
This is the only population for which an acute toxicological endpoint
has been determined. In addition, there is potential for acute dietary
exposure to cymoxanil in drinking water derived from surface water.
After calculating DWLOCs and comparing them to the EECs for surface and
ground water, EPA does not expect the aggregate exposure to exceed 100% of the aPAD, as shown in the following Table 3.
Table 3.Aggregate Risk Assessment for Acute Exposure to Cymoxanil
Surface
Population Subgroup aPAD (mg/ % aPAD Water EEC Acute DWLOC
kg) (Food) (ppb) (ppb)
Females (1349 years old) 0.04 <71 4.13 350
2. Chronic risk. Using the exposure assumptions described in this
unit for chronic exposure, EPA has concluded that exposure to cymoxanil
from food will utilize 13% of the cPAD for the U.S. population, and all
population subgroups. Adults 2049 years old and females 1349 years
old were the most highly exposed subpopulations. There are no
residential uses for cymoxanil that result in chronic residential
exposure. In addition, there is potential for chronic dietary exposure
to cymoxanil in drinking water derived from surface water. After
calculating DWLOCs and comparing them to the EECs for surface water and
ground water, EPA does not expect the aggregate exposure to exceed 100% of the cPAD, as shown in the following Table 4.
Table 4.Aggregate Risk Assessment for Chronic (NonCancer) Exposure to Cymoxanil
Surface
Population Subgroup cPAD mg/kg/ % cPAD Water EEC Chronic
day (Food) (ppb) DWLOC (ppb)
U.S. population 0.04 <13 0.19 1,200
5. Aggregate cancer risk for U.S. population. In accordance with the EPA Draft Guidelines for Carcinogen Risk Assessment (July, 1999), the Agency classified cymoxanil as a ``not likely'' human carcinogen. Cymoxanil is not expected to pose a cancer risk to humans.
6. Determination of safety. Based on these risk assessments, EPA
concludes that there is a reasonable certainty that no harm will result
to the general population, and to infants and children from aggregate exposure to cymoxanil residues.
IV. Other Considerations
A. Analytical Enforcement Methodology
Cymoxanil was shown to be recoverable using Protocol D of FDA's Pesticide Analytical Manual I methodology. The residue of concern in plants was previously determined to be parent only. In addition, Method AMR 306094 Revision 2, a High Performance Liquid Chromotography Ultraviolet (HPLC/UV) method, should be adequate for lychee tolerance enforcement purposes.
B. International Residue Limits
There are no CODEX, Canadian or Mexican Maximum Residue Levels established for cymoxanil on hops, lychee, or cucurbit vegetables. The U.S. tolerance for fruiting vegetables is compatible with Codex. Therefore, no compatibility problems exist for the tolerances established by this rule.
V. Conclusion
Therefore, the tolerance is established for residues of cymoxanil, [2cyanoN[(ethylamino)carbonyl]2(methoxyimino) acetamide], in or on hop, dried cones at 1.0 ppm; lettuce, head at 4.0 ppm; vegetable, cucurbit group 9 at 0.05 ppm; vegetable, fruiting, group 8 at 0.2 ppm; and lychee at 1.0 ppm.
VI. Objections and Hearing Requests
Under section 408(g) of the FFDCA, as amended by the FQPA, any
person may file an objection to any aspect of this regulation and may
also request a hearing on those objections. The EPA procedural
regulations which govern the submission of objections and requests for
hearings appear in 40 CFR part 178. Although the procedures in those
regulations require some modification to reflect the amendments made to
the FFDCA by the FQPA, EPA will continue to use those procedures, with
appropriate adjustments, until the necessary modifications can be made.
The new section 408(g) of the FFDCA provides essentially the same
process for persons to ``object'' to a regulation for an exemption from
the requirement of a tolerance issued by EPA under new section 408(d)
of FFDCA, as was provided in the old sections 408 and 409 of the FFDCA.
However, the period for filing objections is now 60 days, rather than 30 days.
A. What Do I Need to Do to File an Objection or Request a Hearing?
You must file your objection or request a hearing on this regulation in accordance with the instructions provided in this unit and in 40 CFR part 178. To ensure proper receipt by EPA, you must identify docket ID number OPP20030219 in the subject line on the first page of your submission. All requests must be in writing, and must be mailed or delivered to the Hearing Clerk on or before September 15, 2003.
1. Filing the request. Your objection must specify the specific
provisions in the regulation that you object to, and the grounds for
the objections (40 CFR 178.25). If a hearing is requested, the
objections must include a statement of the factual issues(s) on which a
hearing is requested, the requestor's contentions on such issues, and a
summary of any evidence relied upon by the objector (40 CFR 178.27).
Information submitted in connection with an objection or hearing
request may be claimed confidential by marking any part or all of that
information as CBI. Information so marked will not be disclosed except in accordance with procedures set forth in
[[Page 41935]]
40 CFR part 2. A copy of the information 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.
Mail your written request to: Office of the Hearing Clerk (1900C),
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 204600001. You may also deliver your request to the
Office of the Hearing Clerk in Rm.
2. Tolerance fee payment. If you file an objection or request a hearing, you must also pay the fee prescribed by 40 CFR 180.33(i) or request a waiver of that fee pursuant to 40 CFR 180.33(m). You must mail the fee to: EPA Headquarters Accounting Operations Branch, Office of Pesticide Programs, P.O. Box 360277M, Pittsburgh, PA 15251. Please identify the fee submission by labeling it ``Tolerance Petition Fees.''
EPA is authorized to waive any fee requirement ``when in the judgement of the Administrator such a waiver or refund is equitable and not contrary to the purpose of this subsection.'' For additional information regarding the waiver of these fees, you may contact James Tompkins by phone at (703) 3055697, by email at tompkins.jim@epa.gov, or by mailing a request for information to Mr. Tompkins at Registration Division (7505C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460 0001.
If you would like to request a waiver of the tolerance objection fees, you must mail your request for such a waiver to: James Hollins, Information Resources and Services Division (7502C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 204600001.
3. Copies for the Docket. In addition to filing an objection or hearing request with the Hearing Clerk as described in Unit VI.A., you should also send a copy of your request to the PIRIB for its inclusion in the official record that is described in Unit I.B.1. Mail your copies, identified by docket ID number OPP20030219, to: Public Information and Records Integrity Branch, Information Resources and Services Division (7502C), Office of Pesticide Programs, Environmental Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460 0001. In person or by courier, bring a copy to the location of the PIRIB described in Unit I.B.1. You may also send an electronic copy of your request via email to: oppdocket@epa.gov. Please use an ASCII file format and avoid the use of special characters and any form of encryption. Copies of electronic objections and hearing requests will also be accepted on disks in WordPerfect 6.1/8.0 or ASCII file format. Do not include any CBI in your electronic copy. You may also submit an electronic copy of your request at many Federal Depository Libraries. B. When Will the Agency Grant a Request for a Hearing?
A request for a hearing will be granted if the Administrator determines that the material submitted shows the following: There is a genuine and substantial issue of fact; there is a reasonable possibility that available evidence identified by the requestor would, if established resolve one or more of such issues in favor of the requestor, taking into account uncontested claims or facts to the contrary; and resolution of the factual issues(s) in the manner sought by the requestor would be adequate to justify the action requested (40 CFR 178.32).
VII. Statutory and Executive Order Reviews
This final rule establishes a tolerance under section 408(d) of the FFDCA in response to a petition submitted to the Agency. The Office of Management and Budget (OMB) has exempted these types of actions from review under Executive Order 12866, entitl
FOR FURTHER INFORMATION CONTACT Shaja R. Brothers, Registration
Division (7505C), Office of Pesticide Programs, Environmental
Protection Agency, 1200 Pennsylvania Ave., NW., Washington, DC 20460 0001; telephone number: (703) 3083194; email address:
brothers.shaja]@epa.gov.
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