[Federal Register Volume 62, Number 138 (Friday, July 18, 1997)]
[Rules and Regulations]
[Pages 38464-38474]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-19087]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Parts 180, 185 and 186
[OPP-300507; FRL-5727-9]
RIN 2070-AB78
Vinclozolin; Pesticide Tolerance
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final Rule.
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SUMMARY: This regulation establishes a time-limited tolerance for
residues of the pesticide vinclozolin, [3-(3,5-dichlorophenyl)-5-
ethenyl-5-methyl-2,4-oxazolidinedione] and its metabolites containing
the 3,5-dichloroanaline (3,5-DCA) moiety at 2.0 parts per million (ppm)
in or on the food commodity succulent beans. The tolerance will expire
and is revoked on October 1, 1999. A petition was submitted by BASF
Corporation to EPA under the Federal Food, Drug, and Cosmetic Act
(FFDCA) as amended by the Food Quality Protection Act of 1996 (Pub. L.
104-170) requesting the tolerance. BASF has requested that EPA revoke
the tolerances for prunes, plums, tomatoes, grapes (excluding grapes
grown for wine production), raisins, dried prunes and grape pomace. EPA
will publish a document in the Federal Register to remove the revoked
tolerances from the Code of Federal Regulations. BASF has deleted all
residential uses, as well as, turf in parks, school grounds and
recreational areas which would be expected to result in significant
exposure to children from its vinclozolin registrations under the
Federal Insecticide, Fungicide and Rodenticide Act (FIFRA).
DATES: This regulation becomes effective on May 30, 1997. Written
objections and hearing requests must be received on or before September
16, 1997.
ADDRESSES: Written objections and hearing requests, identified by the
docket control number, [OPP-30507], may be submitted to: Hearing Clerk
(1900), Environmental Protection Agency, Rm. M3708, 401 M St., SW.,
Washington, DC 20460. Fees accompanying objections and hearing requests
shall be labeled ``Tolerance Petition Fees'' and forwarded to: EPA
Headquarters Accounting Operations Branch, OPP (Tolerance Fees), P.O.
Box 360277M, Pittsburgh, PA 15251. A copy of any objections and hearing
requests filed with the Hearing Clerk should be identified by the
docket control number and submitted to: Public Information and Records
Integrity Branch, Information Resources and Services Division (7506C),
Office of Pesticide Programs, Environmental Protection Agency, 401 M
St., SW., Washington, DC 20460. In person, bring copy of objections and
hearing requests to: Rm. 1132, CM #2, 1921 Jefferson Davis Hwy.,
Arlington, VA 22202.
A copy of objections and hearing requests filed with the Hearing
Clerk may also be submitted electronically by sending electronic mail
(e-mail) to: [email protected]. Copies of objections and
hearing requests must be submitted as an ASCII file avoiding the use of
special characters and any form of encryption. Copies of objections and
hearing requests will also be accepted on disks in WordPerfect in 5.1
file
[[Page 38465]]
format or ASCII file format. All copies of objections and hearing
requests in electronic form must be identified by the docket control
number [OPP-300507]. No Confidential Business Information (CBI) should
be submitted through e-mail. Electronic copies of objections and
hearing requests on this rule may be filed online at many Federal
Depository Libraries.
FOR FURTHER INFORMATION CONTACT: By mail: Mary Waller, Acting Product
Manager (PM) 21, Registration Division (7505C), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., SW., Washington,
DC 20460. Office location and telephone number: Rm. 265, CM #2, 1921
Jefferson Davis Highway, Arlington, VA 22202, (703) 308-9354, e-mail:
[email protected].
SUPPLEMENTARY INFORMATION: EPA issued a notice, published in the March
19, 1997 Federal Register (62 FR 13000)(FRL-5592-6), which announced
that BASF Corporation had submitted a pesticide petition (PP) 9F3762 to
EPA requesting that the Administrator, pursuant to section 408 of the
Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C section 346a,
amend 40 CFR part 180 to establish a tolerance for residues of the
fungicide vinclozolin [3-(3,5-dichlorophenyl)-5-ethenyl-5-methyl-2,4-
oxazolidinedione; EPA Chemical No. 113201; CAS Reg. No. 50471-44-8] and
its metabolites containing the 3,5-dichloroanaline moiety in or on the
food commodity, succulent beans. The proposed tolerance levels for
vinclozolin and its metabolites were 5.0 ppm. As required by section
408(d) of the FFDCA, as recently amended by the Food Quality Protection
Act (FQPA), Pub. L. 104-170, BASF included in the notice of filing a
summary of the petition and authorization for the summary to be
published in the Federal Register in a notice of receipt of the
petition. The summary of the petition prepared by the petitioner
contained conclusions and assessments to support its contention that
the petition complied with the FQPA elements set forth in section
408(d)(3) of the FFDCA.
EPA has accepted these amendments to the vinclozolin registrations.
Revisions to existing tolerances and revocation of affected tolerances
will be addressed by the Agency in later actions.
I. Statutory Background
Section 408 of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21
U.S.C. 301 et seq., as amended by the Food Quality Protection Act of
1996 (FQPA), Pub. L. 104-170) authorizes the establishment of
tolerances (maximum residue levels), exemptions from the requirement of
a tolerance, modifications in tolerances, and revocation of tolerances
for residues of pesticide chemicals in or on food commodities and
processed foods. Without a tolerance or exemption, food containing
pesticide residues is considered to be unsafe and therefore
``adulterated'' under section 402(a) of the FFDCA, and hence may not
legally be moved in interstate commerce. For a pesticide to be sold and
distributed, the pesticide must not only have appropriate tolerances
under the FFDCA, but also must be registered under section 3 of the
Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA, 7 U.S.C.
136 et seq.).
Section 408 was substantially amended by the FQPA. Among other
things, the FQPA amends the FFDCA to bring all EPA pesticide tolerance-
setting activities under a new section 408 with a new safety standard
and new procedures. New section 408(b)(2)(A)(i) 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) 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 food, drinking water, and from pesticide use
in gardens, lawns, or buildings (residential and other indoor uses) but
does not include occupational exposure. Section 408(b)(2)(C) 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***.''
II. Discussion of Comments
Fifteen comments were received in response to the notice of filing
of this petition. Most of the commentors supported the tolerance
requested by BASF on economic grounds and thus raised issues outside
the scope of section 408. Only one commentor submitted comments in
opposition to the tolerance proposed in the notice of filing. The
principal objections to the proposed tolerance were:
1. The notice of filing was not sufficient to provide the public a
meaningful opportunity to comment.
2. The notice did not adequately address exposure to vinclozolin in
drinking water.
3. The notice did not adequately address residential and other non-
occupational exposures to vinclozolin.
4. The notice did not adequately address the issue of cumulative
exposures to pesticides with a common mechanism of toxicity.
5. The notice did not adequately address vinclozolin's carcinogenic
potential.
6. The notice did not adequately address risks to infants and
children.
Each of these principal objections is addressed below. In addition,
all of the scientific issues raised in the objections are addressed in
more detail elsewhere in this document.
A. Sufficiency of Notice to Allow for Public Comment
While it is clear that the commentor believed that the discussion
of various scientific issues in the summary provided by BASF was
unconvincing, it is unclear whether the commentor was contending that
the summary was legally insufficient for the Agency to proceed with the
publication of the notice of filing pursuant to section 408(d) of the
FFDCA or that EPA was obligated to include in the notice of filing any
additional analysis or information it might eventually rely upon in
determining whether to grant the tolerance. Whatever the basis for the
argument, the commentor's conclusion was that the notice of filing was
insufficient to allow for meaningful public comment.
The short answer to this comment is that the depth and breadth of
the comments submitted by the commentor would seem to demonstrate that
significant meaningful public comment was not foreclosed by any alleged
inadequacies in the notice of filing. While the commentor asserted that
more information should have been provided on the various scientific
issues discussed below, the commentor did not explain why the failure
to supply such additional information rendered the summary provided by
BASF legally insufficient to meet the requirements set forth in section
408(d)(2) of the FFDCA. That section does not require the development
of the additional information adverted to in the comments, and the
Agency has not at this time required by regulation (or otherwise) the
development of such additional information. The Agency believes the
summary was legally sufficient to support publication of the notice of
filing.
[[Page 38466]]
As is clear from the remainder of this document, the Agency did not
agree with all the arguments propounded by BASF in its summary. Section
408(d) sets forth the procedures that must be followed in determining
whether to grant a petition for a tolerance; that section does not
require that the Agency publish its own analysis for comment before a
tolerance can be granted. In light of the facts that section 408(g)
provides an opportunity for a person objecting to the issuance of a
tolerance to file with the Administrator objections challenging the
issuance of a tolerance and the notice in this particular case allowed
interested parties an opportunity to meaningfully comment on the
significant issues raised by the petition (as demonstrated by the
comments submitted by this commentor), the Agency does not believe
publication of an additional notice was either necessary or
appropriate.
B. Exposure to Vinclozolin from Drinking Water
The commentor challenged BASF's argument that the Agency should
assume no exposure to vinclozolin from water, and instead argued that
the Agency should at least apply a default figure of 10% to represent
the portion of the allowable risk that could be attributed to residues
in water. As the discussion of this issue in this document makes clear,
the Agency did not ignore potential exposure to vinclozolin or its
toxic metabolites in water. Rather than use the default figure
identified in the comment, the Agency applied a more conservative model
to identify an upper bound to the contribution to overall risk from
vinclozolin and its metabolites in water. The use of this conservative
model actually resulted in an estimate of the contribution to overall
risk from water exposure greater than the 10% default that the
commentor urged the Agency to use.
The commentor also seemed to argue that, pursuant to the new FQPA,
BASF was obligated to submit additional data on water-related exposure
(and on other issues). Section 408(b)(2)(D) obligates the Agency to
consider ``available information'' concerning a number of factors,
including non-dietary, non-occupational exposures. The Agency does not
agree that the new section 408 requires that such information
automatically be developed (although the Agency does have the authority
to require that such information be developed and submitted to the
Agency).
C. Exposure to Vinclozolin from Residential/Non-Occupational Use
The commentor challenged BASF's treatment of exposure from
residential and other non-occupational uses of vinclozolin. Some time
after publication of the Notice of Filing, BASF agreed to remove all
residential uses from its labels and to request deletion of most of
them from the registration, with the others not being revived on labels
until such time as the Agency determines that any related exposures
would be safe. BASF also agreed to add label language that specifically
limits turf uses of vinclozolin to commercial and industrial sites,
golf courses, and greenhouses and nurseries. The language does not
permit use on turf in parks, school grounds, and recreational areas
that could be expected to be significant sources of exposure to
children; these uses have already been removed from BASF's new labels.
Consistent with the procedures set forth in FIFRA section 6(f), the
Agency expects to grant the requested use deletions later this year. In
light of the above described circumstances, the Agency does not expect
that residential and non-occupational uses will result in any further
meaningful exposure to vinclozolin.
D. Common Mechanism of Toxicity
The commentor argued that vinclozolin, iprodione and procymidone
should be treated as having a common mechanism of toxicity because the
chemicals share similar toxicological and structural properties.
Iprodione and vinclozolin share a common metabolite, and exposures to
the metabolite resulting from iprodione have been included in the
aggregate exposures considered in determining whether the requested
tolerance for vinclozolin on snap beans meets the safety standard set
forth in section 408(b)(2)(A). Although vinclozolin shares structural
and toxicological similarities with iprodione and procymidone, the
Agency does not have at this time sufficient methodologies in place to
resolve common mechanism issues in such circumstances in any meaningful
way. The Agency has therefore concluded that it does not have
sufficient available and reliable information concerning common
mechanism of toxicity of vinclozolin, iprodione, and procymidone to
analyze the common mechanism issue in a scientifically valid manner in
this tolerance decision. This tolerance decision was reached based upon
the best available and useful information for these chemicals and the
supporting risk assessment was performed assuming that no common
mechanism of toxicity exists. Furthermore, this tolerance decision will
be reexamined by the Agency after EPA establishes methodologies and
procedures for integrating information concerning common mechanism into
its risk assessments.
E. Carcinogenicity
The commentor argued that vinclozolin has more carcinogenic
potential than BASF asserted in its summary. The Agency's conclusions
on the carcinogenic potential of vinclozolin and its metabolite 3,5-DCA
are set forth in detail elsewhere in this Final Rule.
F. Risk to Children
The commentor argued that the discussion of risks to children in
the notice of filing was flawed for a number of reasons. The commentor
contended that exposures should be considered separately for separate
ages, rather than by considering children between the ages of one and
six together. They also asserted that BASF failed to adequately address
exposures in utero, breast milk, early infancy, or puberty, all periods
when protective measures may be necessary to protect against
vinclozolin's anti-androgenic effects. Finally, the commentor argued
that application of separate, additional tenfold safety factors are
compelled because of the lack of good data on exposure to children and
because of uncertainties associated with how endocrine disrupting
compounds actually work. Because of the need to include these
additional safety factors, the commentor asserted that the RfD proposed
for use in the notice of filing should be lowered by a factor of 100.
Given the completeness and reliability of the data base for
vinclozolin, the Agency concluded that a margin of safety of 100
(without the additional safety factors suggested by the commentor)
would be safe for children. In terms of different potential exposures
to children between the ages of one and six, it should be noted that
the most sensitive subgroup would be women of child-bearing age because
of the potential in utero and post-natal effects. The Agency has
determined that there is sufficient information to characterize the
risk to this subgroup, and that the tolerance announced in this Final
Rule is safe for this subgroup. The data on the anti-androgenic effects
of vinclozolin are of sufficient quantity and quality that an
additional uncertainty factor is not necessary in order to assure that
infants and children will be safe from such effects.
[[Page 38467]]
III. Risk Assessment and Statutory Findings--Background
EPA performs a number of analyses to determine the risks from
aggregate exposure to pesticide residues. First, EPA determines the
toxicity of pesticides based primarily on toxicological studies using
laboratory animals. These studies address many adverse health effects,
including (but not limited to) reproductive effects, developmental
toxicity, toxicity to the nervous system, and carcinogenicity. For many
of these studies, a dose response relationship can be determined, which
provides a dose that causes adverse effects (threshold effects) and
doses causing no observed effects (the ``no-observed effect level'' or
``NOEL'').
Once the studies have been evaluated and the observed effects have
been determined to be threshold effects, EPA generally divides the NOEL
from the study with the lowest NOEL by an uncertainty factor (usually
100 or more) to determine the Reference Dose (RfD). The RfD is a level
at or below which daily aggregate exposure over a lifetime will not
pose appreciable risks to human health. An uncertainty factor
(sometimes called a ``safety factor'') of 100 is commonly used since it
is assumed that people may be up to 10 times more sensitive to
pesticides than the test animals, and that one person or subgroup of
the population (such as infants and children) could be up to 10 times
more sensitive to a pesticide than another. In addition, EPA assesses
the potential risks to infants and children based on the weight of the
evidence of the toxicology studies and determines whether an additional
uncertainty factor is warranted. An aggregate daily exposure to a
pesticide residue at or below the RfD (expressed as 100 percent or less
of the RfD) is generally considered by EPA to pose a reasonable
certainty of no harm. For threshold effects other than those assessed
under the RfD, EPA generally calculates a margin of exposure (MOE). The
MOE is a measure of how close the exposure comes to the NOEL. The NOEL
is selected from a study of appropriate duration and route of exposure.
The MOE is the NOEL from the selected study divided by exposure. MOEs
greater than 100 are generally considered to show a reasonable
certainty of no harm.
Lifetime feeding studies in two species of laboratory animals are
conducted to screen pesticides for cancer effects. When evidence of
increased cancer is noted in these studies, the Agency conducts a
weight of the evidence review of all relevant toxicological data
including short term and mutagenicity studies and structure activity
relationship. Once a pesticide has been classified as a potential human
carcinogen, different types of risk assessments (e.g., linear low dose
extrapolations or margin of exposure calculation based on the
appropriate NOEL) will be carried out based on the nature of the
carcinogenic response and the Agency's knowledge of its mode of action.
In examining aggregate exposure, FFDCA section 408 requires that
EPA take into account available and reliable information concerning
exposure from the pesticide residue in the food in question, residues
in other foods for which there are tolerances, and other non-
occupational exposures, such as where residues leach into groundwater
or surface water that is consumed as drinking water and exposures
resulting from indoor and outdoor residential uses. Dietary exposure to
residues of a pesticide in a food commodity are estimated by
multiplying the average daily consumption of the food forms of that
commodity by the tolerance level or the anticipated pesticide residue
level. The Theoretical Maximum Residue Contribution (TMRC) is an
estimate of the level of residues consumed daily if each food item
contained pesticide residues equal to the tolerance. The TMRC is a
``worst case'' estimate since it is based on the assumptions that food
contains pesticide residues at the tolerance level and that 100 percent
of the crop is treated by pesticides that have established tolerances.
If the TMRC exceeds the RfD or poses a lifetime cancer risk that is
greater than approximately one in a million, EPA attempts to derive a
more accurate exposure estimate for the pesticide by evaluating
additional types of information which show, generally, that pesticide
residues in most foods when they are eaten are well below established
tolerances.
Consistent with sections 408(b)(2)(C) and (D), EPA has reviewed the
available scientific data and other relevant information in support of
this action. EPA has also assessed the toxicology data base for
vinclozolin in its evaluation of the application for registration on
succulent beans. EPA has sufficient data to assess the hazards of
vinclozolin and to make a determination on aggregate exposure,
consistent with section 408(b)(2), for granting a tolerance for
residues of vinclozolin on succulent beans at 2.0 ppm. EPA's assessment
of the database, dietary exposures and risks associated with
establishing this tolerance follows.
IV. Toxicology Database
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 vinclozolin are
discussed below.
A. Data Evaluated
1. Acute toxicity studies. A battery of acute toxicity studies
placing technical vinclozolin in toxicity category IV for acute oral
toxicity (LD50 of >10,000 millgrams per kilogram (mg/kg)),
and acute inhalation toxicity ((LD50 of 29.1 miligram per
liter (mg/l)); and toxicity category III for acute dermal toxicity
((LD50 of >5,000 mg/kg). Technical vinclozolin caused
minimal eye and dermal irritation and the technical material is a
positive skin sensitizer.
2. Chronic feeding--dog. A 1-year feeding study in dogs fed dosages
of 0, 1.1 , 2.4, 4.9, and 48.7 mg/kg/day with a No-Adverse-Effect Level
(NOAEL) of 2.4 mg/kg/day based on the following effects:
(i) Slight decrease in hematological and increase in clinical
chemistry values in the 48.7 mg/kg/day dose group (highest dose tested
- HDT).
(ii) Increased absolute and/or relative weights for the testes
(male only), adrenal, liver, spleen, and thyroids in the 4.9 or 48.7
mg/kg/day dose groups.
(iii) A dose-related atrophy of the prostate in the 4.9 or 48.7 mg/
kg/day dose groups; and (iv) microscopic findings in the adrenal and
testes (males) in the 48.7 mg/kg/day dose group and liver findings for
both male and female dogs in the 48.7 mg/kg/day dose groups and in the
females in the 4.9 mg/kg/day dose group, only.
3. Chronic feeding/carcinogenicity--rat. A combination of two
chronic feeding studies and one carcinogenicity study resulted in rats
being fed combined dosages of 0, 1.2, 2.4, 7.0, 23, 71, 143, and 221
mg/kg/day (males) and 0, 1.6, 3.1, 7.0, 23, 71, 180, and 221 mg/kg/day
(females) with a NOAEL of 1.2 mg/kg/day (males) and 1.6 mg/kg/day
(females) based on the following effects:
(i) Decreased body weights in both male and female rats at dose
levels >23 mg/kg/day with a progression of severity to the upper
levels.
(ii) Decreased food consumption in both male and female rats at
dose levels >71 mg/kg/day with a progression of severity to the upper
dose levels.
[[Page 38468]]
(iii) Cataracts with associative histopathology at dose levels >23
mg/kg/day and lenticular changes at dose levels >7.0 mg/kg/day for male
and female rats.
(iv) Hematological and clinical chemistry value changes at dose
levels >71 mg/kg/day dose groups with increase of severity at the
higher doses tested.
(v) Increased absolute and/or relative weights for adrenal at dose
levels >143 mg/kg/day, for the liver at dose levels >71 mg/kg/day, for
the testes at dose levels >23 mg/kg/day, and for the ovaries at dose
levels >143 mg/kg/day.
(vi) Microscopic findings were observed in the liver, adrenal,
pancreas, testes (males), ovaries and uterus (females) at dose levels
of >7.0 mg/kg/day with a progression of severity of histological
effects in the upper dose levels.
(vii) An increased incidence of neoplasms occurred at dose levels
greater than the maximum tolerated dose (MTD) of 23 mg/kg/day in the
liver, adrenal, pituitary, prostate (males), uterus (females), and
ovaries (females) at dose levels >143 mg/kg/day. In the testes (males),
Leydig cell adenomas were seen at the MTD for dose levels >23.0 mg/kg/
day due the antiandrogenic nature of vinclozolin.
4. Carcinogenicity-- mice. A carcinogenicity study in mice fed
dosages of 0, 2.1, 20.6, 432, and 1,225 (HDT) mg/kg/day (males) and 0,
2.8, 28.5, 557, and 1,411 (HDT) mg/kg/day (females) with a NOAEL of
20.6 mg/kg/day (males) and 28.5 mg/kg/day (females) based on the
following effects:
(i) Increased mortality in the highest dose tested (HTD) as
compared to controls.
(ii) Decreased body weights and significant signs of clinical
toxicity were observed in both male and female mice at the upper two
dose levels with a progression of severity.
(iii) Hematological and clinical chemistry value changes were
observed at the highest dose tested.
(iv) Increased absolute and/or relative weights for adrenal and
liver were observed at the upper two dose levels, atrophic seminal
vesicles and coagulation glands with reduction of the prostate (males)
and atrophic uteri were observed at the upper two dose levels.
(v) Microscopic findings were observed in the liver, adrenal,
testes (males), ovaries and uterus (females), and related sexual organs
in the upper two dose levels.
(vi) An increased incidence of neoplasms occurred at dose levels
greater than the maximum tolerated dose (>28.5 mg/kg/day) in the liver
of female mice.
5. Developmental toxicity-- rat. In four developmental toxicity
studies vinclozolin was given orally from gestational day (gd) 6
through 19 as follows: Study 4 - dose levels of 0, 15, 50, or 150 mg/
kg/day; study 5 - dose levels of 0, 50, 100, 200 mg/kg/day, study 6 -
dose levels of 0, 200, 400 mg/kg/day and study 8 - dose levels of 0,
600, 1,000 mg/kg/day. At the gd 20, the fetuses were evaluated.
Maternal toxicity was demonstrated at 600 and 1,000 mg/kg/day by
the statistically significant increase in absolute and relative adrenal
and liver weight in study 8. This was the only study where organ
weights were determined. A maternal NOEL could not be established and
therefore, the study was not considered to demonstrate any extra
sensitivity. No histology was conducted on the organs, but other
studies have demonstrated lipid accumulation in the adrenals, and
centrilobular cloudiness of the liver. In addition, a dermal
developmental study has indicated adrenal and liver weight increases
occurred at 180 mg/kg/day and higher. Statistically significant
increases and decreases occurred in the body weight gain and in food
consumption with no apparent dose relatedness in any of the studies.
The relative efficiency of food utilization was too variable to be
definitive.
Statistically significant male and female fetal body weight
decrement occurred at 1,000 mg/kg/day. These weight decrements were
considered test material related. A statistically significant decrease
occurred in anogenital distance (ambiguous sex) among male fetuses. The
term pseudohermaphroditism was used to describe the effect because
these males exhibited decreased anogenital distances, but exhibited
superficially normal internal testes. The anogenital distance in male
fetuses was statistically decreased at 50 mg/kg/day and higher in
studies 4, 6, and 8. (The anogenital index was statistically
significantly depressed at 150 mg/kg/day and higher). The anogenital
distance and index were not determined in study 5. The response was
dose related. Although anogential index was not statistically
significantly depressed at 50 mg/kg/day, it was nominally depressed.
Considering the significantly depressed anogenital distance at 50 mg/
kg/day and higher and the nominally depressed anal-genital index at 50
mg/kg/day, the NOEL for this study was considered to be 15 mg/kg/day,
the LDT. These results are consistent with hormonal or anti-hormonal
effects from the test material.
Soft tissue examination of fetuses indicated that increased
incidence occurred in dilated renal pelvis and hydro-ureter at 400 mg/
kg/day in study 6. At higher dose levels in study 8, the incidence of
dilated renal pelvis and hydro-ureter was nominally increased. The
failure of the dilated renal pelvis, and hydro-ureter to be
significantly increased in study 8 was attributed to the fewer litters
used (7, 5, and 8 in controls, 600, and 1000 mg/kg/day). The NOEL for
these renal effects is considered to be 200 mg/kg/day.
Skeletal examination of fetuses indicated increased incidence of
accessory 14th rib at 400 mg/kg/day and in fetuses and litters at 600,
and 1,000 mg/kg/day. These effects on the 14th rib may be related to
dose administration. Evaluation of the Preliminary Study suggested a
dose related increase in 14th ribs at these high dose levels. No other
dose related effects were reported.
The developmental toxicity NOEL was set at 15 mg/kg/day and the
developmental LOEL was 50 mg/kg/day based on decreased anogenital
distance in males (ambiguous sex). Increased incidence of dilated renal
pelvis, hydro-ureter, and accessary 14th rib may have occurred at 400
mg/kg/day and higher. The maternal toxicity LOEL was < 600 mg/kg/day
based on increases in absolute and relative adrenal and liver weight.
Organ weights were not determined at lower dose levels.
A developmental study in rats via dermal exposure for 6 hours/day
on intact skin with dosages of 0, 60, 180, and 360 mg/kg/day (HDT) had
a developmental NOAEL of 60 mg/kg/day and a maternal NOAEL of 60 mg/kg/
day based on the following: (1) increased absolute liver weights at
dose levels > 180 mg/kg/day; and (2) decreased anogenital distance and
index at dose levels > 180 mg/kg/day.
6. Developmental toxicity--rabbit. A developmental study in rabbits
via oral gavage resulted in dosages of 0, 20, 80, and 300 mg/kg/day
(HDT) with a developmental NOAEL of 300 mg/kg/day and a maternal NOAEL
of 300 mg/kg/day based on no signs of maternal or meaningful fetal
toxicity observed at any of the dose levels mentioned.
A second developmental study in rabbits via oral gavage resulted in
dosages of 0, 50, 200, and 800 mg/kg/day (HDT) with a development
toxicity NOAEL of 200 mg/kg/day and a maternal toxicity NOAEL of 50 mg/
kg/day based on the following: (1) severe maternal toxicity with
simultaneous change in hematological values and high number of
abortions at the HDT; and (2) increased absolute and/or
[[Page 38469]]
relative weights for adrenal in the mid and high dose groups.
7. Two-generation reproduction-- rat. A two-generation reproduction
study (consisting of two studies: study A - dose levels of 0, 2.0 and
4.1 mg/kg/day; study B - dose levels of 0, 4.9, 29, 100, and 307 mg/kg/
day) with rats fed dosages of 0, 2.0, 4.1, 4.9, 29, 100, and 307 mg/kg/
day with a reproductive NOAEL of 4.9 mg/kg/day based on feminization of
males and their inability to mate at dose levels >100 mg/kg/day and pup
effects at 29 mg/kg/day; and with a parental NOAEL of 4.9 mg/kg/day
based on general toxicity consistent with previous rat studies at
levels >29 mg/kg/day. Study A was performed to clarify an equivocal
finding of decreased absolute and relative weight of the epididymides
without any morphological correlation in the male FY and FZ generations
in Study B. However, the Agency concluded that the effects at the 4.9
mg/kg/day dose level were minimal and considered sufficiently close to
the NOAEL. The study is acceptable and 4.9 mg/kg/day dose level was
considered to be the NOEL.
8. Mutagenicity. A Modified Ames Test (three studies, point
mutation): a Host-Mediated Assay (point mutation), a Mouse Lymphoma
Test (point mutation), In Vitro CHO Cells (point mutation), In Vitro
Cytogenetics - CHO Cells (Chromosome Aberrations), In Vivo Dominant
Lethal Test - Male NMRI Mouse (Chromosome Aberrations), Rec Assay (two
test, DNA damage and repair) In Vitro UDS Test Using Hepatocyte (DNA
damage and repair), In Vivo SCE Using Chinese Hamster (DNA damage and
repair) showed no evidence of mutagenic activity.
9. Mechanistic studies --anti-androgenicity activity. A series of
mechanistic studies (In Vivo and In Vitro) were conducted to define the
anti-androgenic properties of vinclozolin. The results of these studies
showed that vinclozolin elicits the inhibition of the androgen receptor
in androgen sensitive organs.
B. Toxicology Profile
1. Toxicity endpoint for dietary exposure-- i. Acute toxicity. To
assess acute dietary exposure, the Agency used a NOEL of 3.0 mg/kg/day
from a rat developmental toxicity study for evaluating acute risk to
females 13+ years. The dose of 5.5 mg/kg/day was calculated using the
bracketed conversion (3 mg/kg/day x 3.91/2.12 = 5.5 mg/kg/day), in
order to obtain the single day internal dose corresponding to the NOEL
of 3 mg/kg/day.
ii. Chronic effects. A RfD of 0.012 mg/kg/day was established based
on a 2-year rat feeding study with a NOEL of 1.2 mg/kg/day and an
uncertainty factor of 100.
iii. Carcinogenicity. Using its Guidelines for Carcinogen Risk
Assessment published September 24, 1986 (51 FR 33992), EPA has
classified vinclozolin as a Group C chemical - possible human
carcinogen. The Agency Cancer Peer Review Committee (CPRC) chose a non-
linear approach [MOE] based on a NOEL of 4.9 mg/kg/day for hormone-
related effects [decreased epididymal weight at 30 mg/kg/day] in the 2-
generation oral rat reproductive toxicity study to quantify human risk.
The MOE approach was chosen because the remaining tumors [Leydig cell]
were benign at dose levels which were not considered to be excessive.
2. Toxicity endpoints for non-dietary exposure--i. Short- and
intermediate term risk for infants and children ages 1-12. For short-
and intermediate-term MOE calculations, the Agency decided to use of a
NOEL of 5.0 mg/kg/day from an oral rat study based on delayed puberty
in young rats at the LOEL of 15 mg/kg/day based on available data.
ii. Short and intermediate term risk for females age 13 and older.
For short- and intermediate-term MOE calculations, the Agency decided
to use a NOEL of 3 mg/kg/day from an oral rat developmental study based
on the occurrence of pseudohermaphroditism (reduced anogenital
distance) in male fetuses and nipple development. The maternal toxicity
NOEL/LOEL were also 3 and 6 mg/kg/day respectively based on reduced sex
organ weights.
iii. Chronic non-dietary exposure. A chronic risk exposure scenario
has not been identified for the proposed use, although the chronic
tolerance endpoint selection is based on the NOEL of 1.2 mg/kg/day.
C. Dietary Exposure
1. Food and feed uses. For purposes of assessing the potential
chronic dietary exposure (food only) from the use of vinclozolin, EPA
has used the percent of crop treated/percent imported data to refine
the risk estimates for selected commodities (apricots, beans,
raspberries, cherries, cucumbers, lettuce, nectarines, onions, peaches,
peppers, and strawberries), while other commodities were assumed to be
100% treated/imported (caneberries (other than raspberries),
cranberries, endive, garlic, wine/sherry, kiwifruit, and shallots). No
chronic anticipated residue refinement has been performed. Therefore,
the resulting exposure (food only) estimates should be viewed as
partially refined; further refinement using anticipated residues and
additional percent of crop treated/percent imported data would result
in lower chronic dietary exposure estimates. The Anticipated Residue
Contribution (ARC) for chronic dietary exposure estimates is equivalent
to 12% of the RfD for the U.S. population (48 states). The ARC for
infants and children and other subgroups ranged from 7 to 15% of the
RfD. In the best judgement of the Agency, the vinclozolin dietary (food
source only) chronic risk from the currently registered uses and this
section 3 registration on snap beans does not exceed the level of
concern. No feed items are associated with succulent beans. Therefore,
secondary residues are not expected as a result of this proposed
section 3 registration.
Section 408(b)(2)(F) allows EPA to use data on the actual percent
of crop treated when establishing a tolerance only where the Agency can
make the following findings:
(1) That the data used are reliable and provide a valid basis for
showing the percentage of food derived from a crop that is likely to
contain residues.
(2) That the exposure estimate does not underestimate the exposure
for any significant subpopulation.
(3) Where data on regional pesticide use and food consumption are
available, that the exposure estimate does not understate exposure for
any regional population. In addition, EPA must provide for periodic
evaluation of any estimates used.
The percent of crop treated estimates for vinclozolin were derived
from Federal and market survey data. EPA considers these data reliable.
A range of estimates are supplied by this data and the upper end of
this range was used for the exposure assessment. By using this upper
end estimate of percent crop treated, EPA is reasonably certain that
exposure is not underestimated for any significant subpopulation.
Further, regional consumption information is taken into account through
EPA's computer-based model for evaluating the exposure of significant
subpopulations including several regional groups. Review of this
regional data allows EPA to be reasonably certain that no regional
population is exposed to residue levels higher than those estimated by
the Agency. To provide for the periodic evaluation of these estimates
of percent crop treated, EPA has issued a data call-in under section
408(f) to all vinclozolin registrants for data on percent crop treated.
That data call-in requires such data to be
[[Page 38470]]
submitted every 5 years as long as the tolerances remain in force.
The acute dietary (food only) risk assessment used Monte Carlo
analysis which creates an exposure distribution by randomly pairing a
distribution of residue chemistry data with a distribution of food
consumption and percent of crop treated or percent imported data for
selected commodities (apricots, beans, raspberries, cherries,
cucumbers, lettuce, nectarines, onions, peaches, peppers, and
strawberries.), while other commodities were assumed to be 100%
treated/imported (caneberries, other than raspberries; cranberries;
endive; garlic; wine/sherry; kiwifruit; and shallots). Tier 2
anticipated residue refinement was performed for the mixed commodity
wine/sherry. For imported, single-serving commodities, acute
anticipated residue refinement was performed by using the highest field
trial value in the Monte Carlo analysis. For all commodities which have
a corresponding Section 3 registration, the Monte Carlo analysis used
the full range of field trial residue data which reflected the existing
(or proposed) use directions.
For the subgroup of concern, females 13+ years, the resulting high-
end (99.9th percentile) dietary (food only) exposure estimate of
0.013587 mg/kg/day resulting in a MOE of 405. This estimate should be
viewed as a refined risk estimate; further refinement using additional
percent of crop treated or percent imported data may result in a
slightly lower acute dietary exposure estimate.
2. Potable water. The Agency does not have drinking water
monitoring data available to perform a quantitative drinking water risk
assessment for vinclozolin at this time. Tier 1 estimated environmental
concentrations (EEC's) were produced for surface water using the
Generic Expected Environmental Concentration (GENEEC) model to estimate
the human health risk to vinclozolin. The calculated acute EEC is 27.04
g/L and the calculated chronic EEC is 1.06 g/L. The model was performed
using residues of vinclozolin per se. However, due to the very
conservative nature of the Tier 1 GENEEC run and the low estimated
metabolite level in relation to the parent compound, this estimate
should be applicable to the sum total of vinclozolin and its
metabolites containing the 3,5-dichloroaniline moiety.
Exposure from surface water was calculated for various subgroups of
the population from which risk estimates were developed. For acute
risk, the MOE was estimated to be 6,100 for females 13 years and older
which was the only subgroup of concern. For chronic risk, exposure was
less than 1% of the RfD of 0.012 mg/kg/day for all subgroups. For
cancer, an MOE (dietary water only) of 160,000 was calculated for the
U.S. population from the exposure value of 0.0000303 mg/kg/day.
3. Non-dietary uses. Exposure in this category has been
significantly reduced through elimination of all residential uses from
product labeling. Therefore, any non-dietary, non-occupational exposure
is expected to be minimal particularly for infants and children.
An approximation of the aggregate risk from the remaining non-
dietary use (postapplication exposure to vinclozolin-treated produce at
``U-pick'' farms indicates that the calculated MOE's are
100 for children and adults. These are considered conservative risk
estimates. The exposure estimates are based on studies of workers
harvesting produce as wage earners. This may overestimate the exposure
for non-occupational harvesters picking produce at ``U-pick'' farms for
non-monetary purposes.
4. Cumulative exposure to substances with common mechanism of
toxicity. Section 408(b)(2)(D)(V) 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.'' The Agency believes that ``available
information'' in this context might include not only toxicity,
chemistry, and exposure data, but also scientific policies and
methodologies for understanding common mechanisms of toxicity and
conducting cumulative risk assessments. For most pesticides, although
the Agency has some information in its files that may turn out to be
helpful in eventually determining whether a pesticide shares a common
mechanism of toxicity with any other substances, EPA does not at this
time have the methodologies to resolve the complex scientific
concerning common mechanism of toxicity in a meaningful way. EPA has
begun a pilot process to study this issue further through the
examination of particular classes of pesticides. The Agency hopes that
the results of this pilot process will increase the Agency's scientific
understanding of this question such that EPA will be able to develop
and apply scientific principles for better determining which chemicals
have a common mechanism of toxicity and evaluating the cumulative
effects of such chemicals. The Agency anticipates, however, that even
as its understanding of the science of common mechanisms increases,
decisions on specific classes of chemicals will heavily dependent on
chemical specific data, much of which may not be presently available.
Although at present the Agency does not know how to apply the
information in its files concerning common mechanism issues to most
risk assessments, there are pesticides as to which the common mechanism
issues can be resolved. These pesticides include pesticides that are
toxicologically dissimilar to existing chemical substances (in which
case the Agency can conclude that it is unlikely that a pesticide
shares a common mechanism of activity with other substances) and
pesticides that produce a common toxic metabolite (in which case common
mechanism of activity will be assumed).
Vinclozolin, iprodione, and procymidone are structurally-related
pesticides belonging to the imide class. Each of these three pesticides
can metabolize to 3,5-dichloroaniline (3,5-DCA). Under FQPA, EPA is
also required to estimate the risk for consumption of food and water
containing 3,5-DCA across vinclozolin, iprodione, and procymidone.
There is no toxicological database; thus no RfD or Q1*
for 3,5-DCA. However, EPA has used the Q1* for p-
chloroaniline (PCA) to assess the carcinogenic risk for other
structurally related chloroanilines because EPA does not have any
evidence that 3,5-DCA is not carcinogenic. In 1988, the Q1*
for PCA was estimated to be 0.039 (mg/kg/day)-1. However, a
revised Q1* of 0.059 (mg/kg/day)-1 for PCA has
been used for this assessment based on more recent data on male and
female tumors.
The following routes of exposure for 3,5-DCA were evaluated: In
food as a result of application of iprodione, in food as a result of
application of vinclozolin, in imported wine as a result of application
of procymidone, in water as a result of application of iprodione to a
crop, and in water as a result of application of vinclozolin to a crop.
There are no U.S. registrations for procymidone; therefore, an
evaluation of exposure to procymidone in water was not appropriate.
Metabolism data of iprodione indicated that 3,5-DCA represented 1%
TRR (total radioactive residue) in eggs, smaller proportions in other
livestock commodities, and was not detected in primary or rotational
crops. Metabolism data of vinclozolin indicated that 3,5-DCA
represented 9.6% TRR in peaches, smaller proportions in strawberries
and
[[Page 38471]]
was not detected in lettuce or grapes. Wine grapes were also included
in the analysis even though the metabolism studies for procymidone
indicated that the 3,5-DCA metabolite was not detected in grapes, but
was formed in wine.
Two models were used for estimating potential concentrations of
3,5-DCA in surface water. PRZM/EXAMS was used to estimate 3,5-DCA
concentrations as a result of applications of vinclozolin or iprodione
on peaches. A conservative screening model, GENEEC, was used to
estimate 3,5-DCA concentrations as a result of application of
vinclozolin on strawberries. The estimation process also used surrogate
fate data, a molecular weight conversion, proportion of acreage
treated, and assumptions of the percent conversion of parent chemical
to metabolite.
The following risk values were estimated for 3,5-DCA:
------------------------------------------------------------------------
Route of Exposure Dose Estimated Risk
------------------------------------------------------------------------
In food as a result of application 0.00000009219 5.4 x 10-9
of iprodione.
In food as a result of application 0.0000143224 8.4 x 10-7
of vinclozolin.
In imported wine as a result of 0.0000058 2.5 x 10-7
application of procymidone.
In water as a result of 0.0000189 1.1 x 10-6
application of iprodione to
peaches.
In water as a result of 0.0000005 3.0 x 10-8
application of vinclozolin to
strawberries (not in California).
In water as a result of 0.000007 4.1 x 10-7
application of vinclozolin to
peaches.
------------------------------------------------------------------------
Total Food and Wine only.......... 1.1 x 10-6
------------------------------------------------------------------------
Total Water as a result of 1.5 x 10-6
application at a peach site.
------------------------------------------------------------------------
Total Food, Wine and Water........ 2.6 x 10-6
------------------------------------------------------------------------
The total carcinogenic risk for consumption of food and wine
containing residues of 3,5-DCA as a result of applications of
iprodione, vinclozolin, and procymidone is 1.1 x 10-6.
This can be considered to be a slight over-estimate since metabolism
studies were used to estimate the TRRs to convert iprodione or
vinclozolin to 3,5-DCA used in the calculations. There is also an
uncertainty to the risk estimate because a surrogate Q1* was
used for 3,5-DCA.
The total carcinogenic risk for drinking water containing residues
of 3,5-DCA as a result of applications of iprodione and vinclozolin was
estimated at 1.5 x 10-6 for the most highly exposed
populations. Although, there is a high degree of uncertainty to this
analysis, these are the best available estimates of concentrations of
3,5-DCA in drinking water. EPA believes that these risk numbers do
justify asking for fate data and monitoring data for 3,5-DCA in both
ground and surface water from both the registrants of iprodione and
vinclozolin.
EPA believes that the total risk estimate estimated for 3,5-DCA for
food, wine, and drinking water of 2.6 x 10-6 generally
represents a negligible risk, as EPA has traditionally applied that
concept. EPA has commonly referred to a negligible risk as one that is
at or below 1 in 1 million (1 x 10-6). Quantitative cancer
risk assessment is not a precise science. There are a significant
number of uncertainties in both the toxicology used to derive the
cancer potency of a substance and in the data used to measure and
calculate exposure. Thus, EPA generally does not attach great
significance to numerical estimates for carcinogenic risk that differ
by approximately a factor of 2\1/2\.
The registrant must submit, upon EPA's request and according to a
schedule determined by the Agency, such information as the Agency
directs to be submitted in order to evaluate issues related to whether
vinclozolin shares a common mechanism of toxicity with any other
substance and, if so, whether any tolerances for vinclozolin need to be
modified or revoked.
V. Determination of Safety for Infants and Children
FFDCA section 408 provides that EPA shall apply an additional
tenfold margin of safety for infants and children in the case of
threshold effects to account for pre- and post-natal toxicity and the
completeness of the database 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 margin of exposure analysis or through using
uncertainty (safety) factors in calculating a dose level that poses no
appreciable risk to humans. In either case, EPA generally defines the
level of appreciable risk as exposure that is greater than 1/100 of the
no observed effect level in the animal study appropriate to the
particular risk assessment. This hundredfold uncertainty (safety)
factor/margin of exposure (safety) is designed to account for combined
inter- and intra-species variability. EPA believes that reliable data
support using the standard hundredfold margin/factor not the additional
tenfold margin/factor when EPA has a complete data base under existing
guidelines and when the severity of the effect in infants or children
or the potency or unusual toxic properties of a compound do not raise
concerns regarding the adequacy of the standard margin/factor.
In assessing the potential for additional sensitivity of infants
and children to residues of vinclozolin, EPA considered data from
developmental toxicity studies in the rat and rabbit and a reproductive
toxicity study in rats. The developmental toxicity studies are designed
to evaluate adverse effects on the developing organism resulting from
pesticide exposure during prenatal development to the mother.
Reproduction studies provide information relating to effects from
exposure to the pesticide on the reproductive capability of mating
animals and data on systemic toxicity.
1. Developmental toxicity--rats. In oral developmental toxicity
study in rats, the developmental NOEL was 3 mg/kg/day based on the
occurrence of pseudohermaphroditism (reduced anogenital distance) in
male fetuses and nipple development. The maternal toxicity NOEL/LOEL
were not determined in this segment of the study.
2. Developmental toxicity--rabbits. From the developmental toxicity
study in rabbits the maternal (systemic) NOEL was 50 mg/kg/day, based
on increased absolute and relative liver weight, reduced defecation,
and reddish-brown urine at the LOEL of 200 mg/kg/day. The developmental
(fetal) NOEL was 200 mg/kg/day, based on early resorptions, fetal
weight increase, decreased live litter size and possible increased
skeletal anomalies at the LEL of 400 mg/kg/day.
3. Reproductive toxicity-- rats. From the reproductive toxicity
studyin rats, the parental (systemic) NOEL was 4.9 mg/kg/day, based on
decreased epididymal weights at the LOEL of 30 mg/kg/day. The
reproductive/developmental (pup) NOEL was 4.9 mg/kg/day, based on
reduced epididymal
[[Page 38472]]
weights and lenticular degeneration at the LEL of 30 mg/kg/day.
Based on current toxicological data requirements, the database
relative to pre- and post natal toxicity is complete. From these data
EPA concludes that extra (greater than 100) uncertainty factors were
not necessary when used with the developmental toxicity endpoint of 3
mg/kg/day. Agency documents are available through the docket which
detail this decision. The bases of the Agency's finding is as follows:
Vinclozolin has an adequate and extensive toxicity data
base including mechanistic data.
Mechanistic data (androgen receptor inhibition) showing
that vinclozolin probably results in analogous developmental effects in
the rat and human.
There are probably only minor differences in kinetics and
metabolism of vinclozolin between rats and humans.
Postnatal studies show effects in parents and offsprings
at similar dose levels, although, the effects in offsprings are more
severe.
The 3 mg/kg/day NOEL for decreased ano-genital distance
(AGD) as a measure of developmental effects is a very sensitive measure
of decreased androgenization of the fetus/offspring.
The decreased AGD has only been seen in rat studies.
Neither the rabbit nor the mouse developmental toxicity studies show
obvious anti-androgen related effects.
The 3 mg/kg/day endpoint may be overprotective since the
next higher dose level (6 mg/kg/day) was not statistically
significantly different from the control. Based on additional analysis
by the Science Advisory Board (SAB) statisticians, the NOEL may be as
high as 12 mg/kg/day.
VI. Determination of Safety for U.S. Population Including Infants
and Children
1. Chronic dietary exposure/risk. Based of the exposure assumptions
discussed above and the completeness and reliability of the toxicity
database, the Agency estimates that the food only exposure to
vinclozolin for the subgroup of concern, Non-Nursing Infants < 1 year
old, will utilize 14% of the RfD. The population subgroup with the
largest percentage of the RfD occupied is U.S. Population, Western
Region at 15% of the RfD. EPA generally has no concern for exposure
below 100 percent of the RfD.
2. Aggregate risk--i. Acute aggregate risk. For the subgroup of
concern, females 13+ years, the calculated dietary (food only) MOE
value is 405. This estimate should be viewed as a refined risk
estimate; further refinement using additional percent of crop treated
or percent imported data may result in a slightly lower acute dietary
exposure estimate. When the surface water exposure estimate (it appears
the surface water estimate is worst case) is added (based on limited
data for ground water and environmental fate data), the aggregate acute
dietary risk (food + water) estimate results in an MOE of 380. This MOE
value does not exceed the Agency's level of concern for acute dietary
exposure.
ii. Chronic aggregate risk. The aggregate chronic risk is equal to
the sum of the chronic risk from food + water + non-dietary exposure.
Vinclozolin is not currently registered for any residential uses and no
other chronic exposure scenario's have been identified from the
registered uses of vinclozolin. Therefore, the aggregate chronic risk
for vinclozolin is equal to the sum of the chronic risk from food +
water, and is equivalent to less than 13% of the RfD for the U.S.
population. Other subgroups ranged from 8 to 16% of the RfD.
iii. Short- and intermediate-term aggregate risk. The aggregate
short- and intermediate-term risk is equal to the sum of the chronic
risk from food + water (considered to be a background exposure level) +
non-dietary exposure (exposure from ``U-pick'' farms). The calculated
MOE values for the aggregate short- and intermediate-term risk from
vinclozolin range from 140 for children 1 to 6 years old to 150 for
children 7 to 12 years old. The MOE's do not exceed the Agency's level
of concern. EPA concludes that there is a reasonable certainty that no
harm will result from aggregate exposure to vinclozolin residues.
iv. Cancer aggregate risk. The aggregate cancer risk for
vinclozolin is equal to the sum of the chronic risk from food + water.
The Anticipated Residue Contribution (ARC) for the U.S. Population was
calculated to be 0.001383 mg/kg/day from food and 0.0000303 from
dietary water, for a total dietary exposure (food + water) of 0.001413.
Using the formula where the Margin of Exposure (MOE) = NOEL (mg/kg/day)
Exposure (mg/kg/day), or 4.9 mg/kg/day 0.001413 mg/
kg/day, the calculated MOE (food + water) is 2,100.
VII. Other Considerations
A. Endocrine Effects
EPA is required to develop a screening program to determine whether
certain substances (including all pesticides and inerts) may effect
humans similar to an effect produced by a naturally occurring estrogen,
or such other endocrine effects. The Agency is currently working with
interested stakeholders, including other government agencies, public
interest groups, industry and research scientists in developing a
screening and testing program and a priority setting scheme to
implement this program. Congress has allowed 3 years from the passage
of FQPA (August 3, 1999) to implement this program. The endocrine
modulating effects of vinclozolin are adequately understood.
The in vivo studies show that vinclozolin or it's metabolites/
degradation products disrupt the androgen endocrine system through
inhibition of androgen receptors. This receptor inhibition results in
reduced androgen to androgen sensitive organs, such as the prostate
seminal vesicles and epididymides (anti-androgen effects). In the
pituitary gland, this inhibition results in increased luteinizing
hormone which in turn stimulates the testicular Leydig cells.
Continuous stimulation of the testicular Leydig cells result in the
Leydig cell adenomas seen in the chronic and carcinogenicity studies.
The in vitro data are studies on androgen receptor inhibition by
two metabolism/degradation products (M1 and M2) of the vinclozolin.
This androgen receptor inhibition results in the reduced ano-genital
distance seen in the developmental toxicity studies with vinclozolin.
B. Metabolism in Plants and Animals
The metabolism of vinclozolin in plants and animals is adequately
understood for the purpose of this tolerance. A CODEX Maximum Residue
Limit (MRL) for residues of vinclozolin and its metabolites containing
the 3,5-dichloroaniline moiety has been established for common beans at
2.0 ppm. Residue data were examined at the Joint meeting of the FAO
Panel of Experts on Pesticide Residues in Food and the Environment and
the WHO Expert Group on Pesticide Residues. The field trials were
conducted in Germany, the Netherlands, Japan, United Kingdom, and
France. It was concluded that a 2.0 ppm MRL should be established based
on rates of 0.19 (3 applications) to 1.0 kg a.i./ha. (three(3)
applications) and a PHI of 7 days. These rates are equivalent to 0.17
to 0.89 lbs a.i./A.
Residues of vinclozolin and its metabolites containing the 3,5-
dichloroaniline (DCA) moiety are not expected to exceed 2.0 ppm in/on
snap beans as a result of this Section 3
[[Page 38473]]
registration. There are no processed commodities or feed items
associated with snap beans. Therefore, secondary residues are not
expected as a result of this proposed Section 3 registration.
There is a practical analytical method available for determination
of residues of vinclozolin. Adequate enforcement methodology (gas
chromatography/electron capture detector) for plant and animal
commodities is available to enforce the tolerances. As a condition of
registration, EPA has requested that revisions and clarifications be
made to the submitted methodology, and that the animal commodity method
be improved by eliminating the use of hazardous materials. Once this
method has been submitted, EPA will provide information on this method
to FDA. In the interim, the analytical method is available to anyone
who is interested in pesticide residue enforcement from: By mail,
Calvin Furlow, Public Information and Records Integrity Branch,
Information Resources and Services Division (7506C), Office of
Pesticide Programs, Environmental Protection Agency, 401 M St. SW.,
Washington, DC 20460. Office location and telephone number: Crystal
Mall #2, Rm 1128, 1921 Jefferson Davis Hwy., Arlington, VA 22202, 703-
305-5805.
C. Tolerance Revocation and Data Requirements
1. Tolerance Revocation. BASF has requested that EPA revoke the
tolerances for prunes, plums, tomatoes, grapes (excluding grapes grown
for wine production), raisins, dried prunes and grape pomace, and that
all residential uses, as well as, turf in parks, school grounds and
recreational areas which would be expected to result in significant
exposure to children be deleted from its vinclozolin registrations
under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA).
EPA accepts these amendments to the vinclozolin registrations.
Revisions to existing tolerances and revocation of affected tolerances
will be addressed by the Agency in later actions.
2. Data Requirements. In accordance with section 408(b)(2)(E)(ii)
of the Federal Food, Drug, and Cosmetic Act(FFDCA), the Agency is
requiring, pursuant to subsection (f)(1), that data be provided five
years after the date on which the tolerance is established, modified,,
or left in effect, and thereafter as the Administrator deems
appropriate, demonstrating that such residue levels are not above the
levels so relied on. If such data are not so provided, or if the data
do not demonstrate that the residue levels are not above the levels so
relied on, the Administrator shall, not later than 180 days after the
date on which the data were required to be provided, issue a regulation
under subsection (e)(1), or an order under subsection (f)(2), as
appropriate, to modify or revoke the tolerance.
VIII. Summary of Findings
The risk analysis for vinclozolin shows that there is reasonable
certainty that no harm will result from aggregate exposure to
vinclozolin. This analysis includes all current tolerances including
the tolerances that BASF requested to be cancelled. All population
subgroups examined by EPA are exposed to vinclozolin residues at levels
below 100 percent of the RfD for chronic effects. Based on the
information and data considered, EPA concludes that the proposed
tolerances will be safe. Therefore the tolerances are established as
set forth below.
FQPA has eliminated all distinctions between tolerances for raw
agricultural commodities and processed foods. Therefore, EPA is
combining the tolerances that now appear in Sec. Sec. 185.1850 and
186.1850 with the tolerances in Sec. 180.380 and is eliminating
Sec. Sec. 185.1850 and 186.1850.
IX. Objections and Hearing Requests
The new FFDCA section 408(g) provides essentially the same process
for persons to ``Object'' to a tolerance regulation issued by EPA under
the new section 408(d) as was provided in the old section 408 and in
section 409. However, period for filing objections is 60 days, rather
than 30 days. EPA currently has procedural regulations which given the
submission of objections and hearing requests. These regulations will
require some modification to reflect the new law. However, until those
modifications can be made, EPA will continue to use its current
procedural regulations with appropriate adjustments to reflect the new
law.
Any person may, by September 16, 1997, file written objections to
any aspect of this regulation and may also request a hearing on those
objections. Objections and hearing requests must be filed with the
Hearing Clerk, at the address given above (40 CFR 178.20). A copy of
the objections and/or hearing requests filed with the Hearing Clerk
should be submitted to the OPP docket for this rulemaking. The
objections submitted must specify the provisions of the regulation
deemed objectionable and the grounds for the objections (40 CFR
178.25). Each objection must be accompanied by the fee prescribed by 40
CFR 180.33(I). If a hearing is requested, the objections must include a
statement of the factual issues on which a hearing is requested, the
requestor's contentions on such issues, and a summary of any evidence
relied upon by the requestor (40 CFR 178.27). A request for a hearing
will be granted if the Administrator determines that the material
submitted shows the following: There is 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 in the manner sought by the requestor would be adequate
to justify the action requested (40 CFR 178.32). Information submitted
in connection with an objection or hearing request may be claimed
confidential by marking any part or all of that information as
Confidential Business Information (CBI). Information so marked will not
be disclosed except in accordance with procedures set forth in 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.
X. Public Docket
The official record for this rulemaking, as well as the public
version, has been established for this rulemaking under docket control
number [OPP-300507] (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 rulemaking record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
[email protected]
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket number (insert docket number). Electronic
comments on this proposed rule may be filed online at many Federal
Depository Libraries.
[[Page 38474]]
XI. Regulatory Assessment Requirements
This final rule establishes a tolerance under FFDCA section 408(d)
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, entitled Regulatory Planning and
Review (58 FR 51735, October 4, 1993). This final rule does not contain
any information collections subject to OMB approval under the Paperwork
Reduction Act (PRA), 44 U.S.C. 3501 et seq., or impose any enforceable
duty or contain any unfunded mandate as described under Title II of the
Unfunded Mandates Reform Act of 1995 (UMRA) (Pub. L. 104-4). Nor does
it require any prior consultation as specified by Executive Order
12875, entitled Enhancing the Intergovernmental Partnership (58 FR
58093, October 28, 1993), or special considerations as required by
Executive Order 12898, entitled Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations (59 FR 7629, February 16, 1994), or require OMB review in
accordance with Executive Order 13045, entitled Protection of Children
from Environmental Health Risks and Safety Risks (62 FR 19885, April
23, 1997).
In addition, since tolerances and exemptions that are established
on the basis of a petition under FFDCA section 408(d), such as the
tolerance in this final rule, do not require the issuance of a proposed
rule, the requirements of the Regulatory Flexibility Act (RFA) (5
U.S.C. 601 et seq.) do not apply. Nevertheless, the Agency previously
assessed whether establishing tolerances, exemptions from tolerances,
raising tolerance levels or expanding exemptions might adversely impact
small entities and concluded, as a generic matter, that there is no
adverse economic impact. The factual basis for the Agency's generic
certification for tolerance actions published on May 4, 1981 (46 FR
24950), and was provided to the Chief Counsel for Advocacy of the Small
Business Administration.
XII. Submission to Congress and the General Accounting Office
Under 5 U.S.C. 801(a)(1)(A), as added by the Small Business
Regulatory Enforcement Fairness Act of 1996, the Agency has submitted a
report containing this rule and other required information to the U.S.
Senate, the U.S. House of Representatives, and the Comptroller General
of the General Accounting Office prior to publication of this rule in
today's Federal Register. This is not a ``major rule'' as defined by 5
U.S.C. 804(2).
List of Subjects in 40 CFR Parts 180, 185 and 186
Environmental protection, Animal feeds, Administrative practice and
procedure, Agricultural commodities, Food additive, Pesticides and
pest, Reporting and recordkeeping requirements.
Dated: July 14, 1997.
Stephen L. Johnson,
Acting Director, Office of Pesticide Programs.
Therefore, 40 CFR Chapter I is amended as follows:
PART 180--[AMENDED]
1. In part 180:
a. The authority citation for part 180 continues to read as
follows:
Authority: 21 U.S.C. 346a and 371.
b. By revising Sec. 180.380 to read as follows:
Sec. 180.380 Vinclozolin; tolerances for residues.
(a) General. Tolerances are established for the combined residues
of the fungicide vinclozolin (3-(3,5-dichlorophenyl)-5-ethenyl-5-
methyl-2,4-oxazolidinedione) and its metabolites containing the 3,5-
dichloroaniline moiety in or on the food commodities in the table
below. There are no U.S. registrations for Belgian endive, cucumbers,
grapes, peppers and tomatoes as of (May 30, 1997). The time-limited
tolerance will expire and is revoked on the date(s) listed in the
following table.
------------------------------------------------------------------------
Parts per Expiration/Revocation
Commodity million Date
------------------------------------------------------------------------
Beans, succulent.................. 2.0 10/1/99
Belgian endive, tops.............. 5.0 None
Cucumbers......................... 1.0 None
Grapes............................ 6.0 None
Grape, pomace, dry (as a result of
application to grapes)........... 42.0 None
Kiwifruit......................... 10.0 None
Lettuce, head..................... 10.0 None
Lettuce (leaf).................... 10.0 None
Onions (dry bulb)................. 1.0 None
Peppers (bell).................... 3.0 None
Prunes............................ 75 None
Raisins (as a result of
application to grapes)........... 30 None
Raspberries....................... 10.0 None
Stonefruits....................... 25.0 None
Strawberries...................... 10.0 None
Tomatoes.......................... 3.0 None
------------------------------------------------------------------------
(b) Section 18 emergency exemptions. [Reserved]
(c) Tolerances with regional registrations. [Reserved]
(d) Indirect or inadvertent residues. [Reserved]
PART 185--[AMENDED]
2. In part 185:
a. The authority citation continues to read as follows:
Authority: 21 U.S.C. 346a and 348.
Sec. 185.1850 [Removed]
b. Section 185.1850 is removed.
PART 186--[AMENDED]
3. In part 186:
a. The authority citation continues to read as follows:
Authority: 21 U.S.C. 342, 348 and 701.
Sec. 186.1850 [Removed]
b. Section 186.1850 is removed.
[FR Doc. 97-19087 Filed 7-16-97; 1:30 pm]
BILLING CODE 6560-50-F