[Federal Register Volume 64, Number 18 (Thursday, January 28, 1999)]
[Notices]
[Pages 4414-4418]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-1904]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-854; FRL-6056-3]
AgrEvo USA Company; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of a pesticide
petition proposing the establishment of regulations for residues of a
certain pesticide chemical in or on various food commodities.
DATES: Comments, identified by the docket control number PF-854, must
be received on or before March 1, 1999.
ADDRESSES: By mail submit written comments to: Information and Records
Integrity Branch, Public Information and Services Divison (7502C),
Office of Pesticides Programs, Environmental Protection Agency, 401 M
St., SW., Washington, DC 20460. In person bring comments to: Rm. 119,
CM #2, 1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically by following
the instructions under ``SUPPLEMENTARY INFORMATION.'' No confidential
business information should be submitted through e-mail.
Information submitted as a comment concerning this document may be
claimed confidential by marking any part or all of that information as
``Confidential Business Information'' (CBI). CBI should not be
submitted through e-mail. Information marked as CBI will not be
disclosed except in accordance with procedures set forth in 40 CFR part
2. A copy of the comment that does not contain CBI must be submitted
for inclusion in the public record. Information not marked confidential
may be disclosed publicly by EPA without prior notice. All written
comments will be available for public inspection in Rm. 119 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: Peg Perreault, Registration Support
Branch, Registration Division (7505C), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW,
[[Page 4415]]
Washington, DC 20460. Office location, telephone number, and e-mail
address: Rm. 207, Crystal Mall #2, 1921 Jefferson Davis Highway,
Arlington, VA 22202, (703) 305-5417; e-mail:
perreault.peg@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemical in or on various food
commodities under section 408 of the Federal Food, Drug, and Comestic
Act (FFDCA), 21 U.S.C. 346a. EPA has determined that this petition
contains data or information regarding the elements set forth in
section 408(d)(2); however, EPA has not fully evaluated the sufficiency
of the submitted data at this time or whether the data supports
granting of the petition. Additional data may be needed before EPA
rules on the petition.
The official record for this notice of filing, as well as the
public version, has been established for this notice of filing under
docket control number [PF-854] (including comments and data submitted
electronically as described below). A public version of this record,
including printed, paper versions of electronic comments, which does
not include any information claimed as CBI, is available for inspection
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The official record is located at the address in
``ADDRESSES'' at the beginning of this document.
Electronic comments can be sent directly to EPA at:
opp-docket@epamail.epa.gov
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1/6.1 file format or
ASCII file format. All comments and data in electronic form must be
identified by the docket control number (PF-854) and appropriate
petition number. Electronic comments on this notice may be filed online
at many Federal Depository Libraries.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: January 19, 1999.
James Jones,
Director, Registration Division, Office of Pesticide Programs.
Summary of Petition
The petitioner summary of the pesticide petition is printed below
as required by section 408(d)(3) of the FFDCA. The summary of the
petition was prepared by the petitioner and represents the views of the
petitioner. EPA is publishing the petition summaries verbatim without
editing them in any way. The petition summary announces the
availability of a description of the analytical methods available to
EPA for the detection and measurement of the pesticide chemical
residues or an explanation of why no such method is needed.
AgrEvo USA Company
PP 9F3705 and 9H5572
EPA has received pesticide petitions (PP 9F3705 and 9H5572) from
AgrEvo USA Company, Little Falls Center One, 2711 Centerville Road,
Wilmington, DE 19808, proposing pursuant to section 408(d) of the
Federal Food, Drug, and Cosmetic Act, 21 U.S.C.346a(d), to amend 40 CFR
part 180 by establishing a tolerance for residues of clofentezine in or
on the raw agricultural commodity apples at 0.5 parts per million
(ppm), in the processed feed commodity wet apple pomace at 10 ppm, and
in milk at 0.05 ppm. EPA has determined that the petition contains data
or information regarding the elements set forth in section 408(d)(2) of
the FFDCA; however, EPA has not fully evaluated the sufficiency of the
submitted data at this time or whether the data supports granting of
the petition. Additional data may be needed before EPA rules on the
petition.
APOLLO SC Ovicide/Miticide (active ingredient
clofentezine) is registered for use on apples (early season through
tight cluster), pears, almonds, walnuts, apricots, cherries,
nectarines, and peaches to control European red mites and several
spider mite species. It is an environmentally-friendly, IPM-compatible
product used at low dose rates, and only once per season. Clofentezine
has been shown to be relatively non-toxic in studies conducted on
mammals, fish, birds, aquatic invertebrates, predacious and other
beneficial mites, bees, algae, and plants.
On February 23, 1995, EPA conditionally approved the use of
APOLLO SC on apples (early season through tight cluster) and
established a permanent tolerance for clofentezine on fresh apples of
0.01 ppm. The registration was made permanent February 19, 1998,
following the completion of a successful analytical method try-out
(MTO) by EPA (at the 0.01 ppm limit of quanitation (LOQ).
The information summarized below was previously submitted in
support of the requested label amendment for use on apples with a 45
day pre-harvest interval. The studies on which this summary is based
were thoroughly reviewed and approved by the Agency as part of previous
regulatory actions. However, the accuracy of this summary has not been
evaluated by the Agency.
Upon re-examination of this tolerance petition, AgrEvo trusts that
EPA will agree that the label amendment to allow the use of
APOLLO SC (clofentezine) on apples through a 45 day pre-
harvest interval would not pose a significant risk to human health,
including that of infants, and children, and is in compliance with the
requirements of the Food Quality Protection Act (FQPA) of 1996.
A. Residue Chemistry
1. Plant metabolism. The metabolism of clofentezine has been
studied in three crops representative of the use pattern for
APOLLO SC: apples (pome fruit), peaches (stone fruit), and
grapes (vines/small fruit). In each case, unchanged clofentezine was
the major extractable residue present. Non-extractable residues (fiber-
bound) were negligible. Minor amounts of 2-chlorobenzonitrile, the
major photo-degradation product, were detected, predominantly on the
fruit surface. Dissipation of this component may be a significant route
in the degradation of clofentezine on the surface of these crops. The
nature of the residue in apples, and in all the other registered crops,
is therefore adequately understood. The residue of concern is the
parent, clofentezine.
2. Analytical method. EPA recently approved an analytical method
for clofentezine on apples (MRID 43800801) at a LOQ of 0.01 ppm. In
support of that effort, AgrEvo submitted an independent laboratory
validation of the method (MRID 44038001) which involves organic
extraction and then cleanup, followed by high-pressure liquid
chromatography. This method is suitable for enforcement for the current
registration of APOLLO SC ovicide/miticide on apples through
the tight cluster timing.
For the requested use on apples with a 45 day PHI, an analytical
method similar to the above was previously approved during the review
of the petition, PP 9F3705/9H5572. This method was deemed suitable for
enforcement of the tolerances proposed
[[Page 4416]]
in the tolerance petition. Similar analytical methods suitable for
enforcement purposes are available for all the other registered crops
and relevant animal tissues/milk/fat.
3. Magnitude of residues. Extensive field residue trials have been
conducted with APOLLO SC on apples throughout the major
apple-growing regions of the United States. Application through 45 days
PHI at the maximum use rate resulted in residues of clofentezine on
fresh apples of < 0.01="" ppm="" to="" 0.44="" ppm.="" in="" processing="" studies="" on="" apples="" which="" had="" been="" treated="" with=""> SC at the maximum use rate
through 45 days PHI, residues in the processed commodity apple juice
were lower than those in the raw agricultural commodity; residues in
wet apple pomace ranged from < 0.01="" ppm="" to="" 0.03="" ppm.="" in="" tolerance="" petition="" pp="" 9f3705/9h5572="" tolerances="" were="" proposed="" and="" approved="" (although="" not="" enacted)="" for="" apples="" (0.5ppm),="" and="" apple="" pomace,="" wet="" and="" dry="" (10="" ppm).="" residue="" trials="" were="" conducted="" for=""> SC on pears,
apricots, cherries, nectarines, peaches, almonds, and walnuts at the
maximum use rates and minimum pre-harvest intervals (PHIs) throughout
the major growing regions of the United States. Residues in pears
ranged from < 0.01="" to="" 0.2="" ppm.="" residues="" in="" stone="" fruit="" ranged="" from="">< 0.01="" to="" 0.66="" ppm.="" residues="" on="" almond="" hulls="" ranged="" from="" 0.93="" to="" 2.4="" ppm,="" on="" almond="" nut="" meats="" from="">< 0.05="" to="" 0.3="" ppm,="" and="" on="" walnuts="">< 0.02="" ppm.="" tolerances="" were="" therefore="" established="" on="" pears="" (0.5="" ppm);="" apricots,="" cherries,="" nectarines,="" and="" peaches="" (1.0="" ppm);="" almond="" nutmeats="" (0.5="" ppm);="" almond="" hulls="" (5.0="" ppm);="" and="" walnuts="" (0.02="" ppm).="" ruminant="" feeding="" studies="" were="" conducted="" to="" determine="" the="" magnitude="" of="" the="" clofentezine-derived="" residues="" in="" the="" tissues="" and="" milk="" of="" cows.="" four="" groups="" of="" three="" dairy="" cattle="" were="" fed="" technical="" clofentezine="" in="" the="" diet="" at="" dose="" levels="" of="" 0,="" 10,="" 30,="" and="" 100="" ppm="" over="" a="" period="" of="" 28="" days.="" daily="" milk="" samples="" were="" taken="" and="" at="" the="" termination="" of="" the="" study,="" the="" following="" organs="" were="" analyzed:="" liver,="" kidney,="" heart,="" muscle,="" peritoneal="" fat="" and="" subcutaneous="" fat.="" at="" the="" feeding="" level="" of="" 10="" ppm,="" residues="" were="" 0.3="" ppm="" in="" liver="" and="">< 0.05="" ppm="" in="" kidney,="" milk,="" and="" other="" tissues.="" epa="" established="" tolerances="" for="" cattle,="" goats,="" hogs,="" horses,="" and="" sheep="" as="" follows:="" 0.05="" ppm="" in="" meat,="" fat,="" and="" meat="" by-="" products="" except="" liver;="" 0.4="" ppm="" in="" liver;="" and="" 0.01="" ppm="" in="" milk.="" the="" tolerances="" on="" meat,="" fat,="" meat="" by-products,="" and="" liver="" were="" also="" previously="" approved="" in="" tolerance="" petitions="" pp="" 9f3705/9h5572,="" the="" label="" amendment="" for="" use="" on="" apples="" through="" 45="" days="" phi.="" the="" tolerance="" for="" milk="" was="" approved="" (although="" not="" enacted)="" at="" 0.05="" ppm="" in="" this="" tolerance="" petition.="" b.="" toxicological="" profile="" the="" toxicology="" of="" clofentezine="" has="" been="" thoroughly="" evaluated="" by="" epa="" as="" part="" of="" previous="" regulatory="" actions.="" the="" studies="" are="" considered="" to="" be="" valid,="" reliable="" and="" adequate="" for="" the="" purposes="" of="" evaluating="" potential="" health="" risks="" and="" for="" establishing="" tolerances.="" the="" primary="" studies="" submitted="" in="" support="" of="" the="" registration="" of="" clofentezine="" are="" summarized="" below.="" the="" conclusions="" presented="" are="" those="" determined="" by="" the="" agency="" (as="" reported="" by="" the="" registrant).="" 1.="" acute="" toxicity.="" technical="" grade="" clofentezine="" has="" a="" relatively="" low="" degree="" of="" acute="" toxicity="" and="" irritation="" potential.="" it="" is="" classified="" as="" toxicity="" category="" iii="" for="" oral,="" dermal="" and="" inhalation="" toxicity,="" and="" toxicity="" category="" iv="" for="" eye="" and="" skin="" irritation.="" the="" acute="" oral="">50 of clofentezine was determined to be >5,200 milligram/
kilogram (mg/kg) in rats and mice, >3,200 mg/kg in hamsters, and >2,000
mg/kg in beagle dogs. The acute rat dermal LD50 was >2,100
mg/kg. Clofentezine is considered to be practically non-irritating to
eyes and skin but is considered to be a weak skin sensitizer in the
guinea pig maximization assay.
APOLLO SC is classified as Toxicity Category IV for oral
toxicity and skin irritation, and as Toxicity Category III for dermal
toxicity and eye irritation. The acute oral LD50 of
APOLLO SC was determined to be > 5,000 mg/kg in rats; the
acute dermal LD50 in rats was > 2,400 mg/kg.
APOLLO SC is considered slightly irritating to eyes and skin.
2. Genotoxicty. No evidence of genotoxicity was noted in a battery
of in vitro and in vivo studies. Studies submitted included Ames
Salmonella and mouse lymphoma gene mutation assays, a mouse
micronucleus assay, a rat dominant lethal assay, a gene conversion, and
mitotic recombination assay in yeast.
3. Reproductive and developmental toxicity. A multigeneration rat
reproduction study was conducted at dietary concentrations of 0, 4, 40
and 400 ppm. The parental no-observed adverse effect level (NOAEL) was
40 ppm based on slightly reduced body weights, increased liver weights
and hepatocellular hypertrophy at 400 ppm. No treatment related
reproductive effects were noted at any dose level.
In a rat developmental toxicity study, clofentezine was
administered by gavage at dose levels of 0, 320, 1,280 and 3,200 mg/kg/
day during gestation days 6 to 20. Evidence of maternal toxicity was
noted at 3,200 mg/kg/day and consisted of decreased weight gain,
increased liver weights and centrilobular hepatocellular enlargement.
No developmental effects were observed at any dose level.
In a rabbit developmental toxicity study, clofentezine was
administered by gavage at dose levels of 0, 250, 1,000 and 3,000 mg/kg/
day during gestation days 7 to 28. Slight maternal toxicity (decreased
maternal food consumption and weight gain) and a slight decrease in
fetal weight were noted at 3,000 mg/kg/day. Thus, the NOAEL was
considered to be 1,000 mg/kg/day for both maternal and developmental
effects.
4. Subchronic toxicity. In a preliminary 90 day feeding study
designed to select a suitable high dose level for a subsequent chronic
rat study, clofentezine was administered to rats at dietary
concentrations of 0, 3,000, 9,000 and 27,000 ppm. A significant
reduction in weight gain was noted at 9,000 and 27,000 ppm. In
addition, a marked, dose-related hepatomegaly and centrilobular
hepatocyte enlargement was noted in all treatment groups. In a
subsequent 90-day feeding study, clofentezine was administered to rats
at dietary concentrations of 0, 40, 400 and 4,000 ppm. Slightly reduced
weight gain, alterations in several clinical pathology parameters,
increased liver, kidney and spleen weights, and centrilobular
hepatocyte enlargement were noted at 400 and/or 4,000 ppm. Thus, 40 ppm
(2.8 mg/kg/day) was considered to be the NOAEL for this
study.
Clofentezine was administered to beagle dogs for 90 days at dietary
concentrations of 0, 3,200, 8,000 and 20,000 ppm. Increased liver
weights were noted at all dose levels but no histopathological changes
nor any other treatment-related effects were observed.
5. Chronic toxicity. In a 12 month feeding study, clofentezine was
administered to beagle dogs at dietary concentrations of 0, 50, 1,000
and 20,000 ppm. An increase in adrenal and thyroid weights, as well as
moderate hepatotoxicity consisting of minimal periportal hepatocyte
enlargement with cytoplasmic eosinophilia, hepatomegaly and increased
plasma cholesterol, triglycerides and alkaline phosphatase levels, were
noted at 20,000 ppm. Evidence of slight hepatotoxicity was also noted
at 1,000 ppm. Thus, the NOAEL for this study was considered to be 50
ppm (1.25 mg/kg/day1).
In a 27 month feeding study, clofentezine was administered to rats
at dietary concentrations of 0, 10, 40 and 400 ppm. Effects noted at
400 ppm were
[[Page 4417]]
limited to the liver and thyroid, primarily of males, and consisted of
increased liver weights, a variety of microscopic liver lesions
(centrilobular hepatocyte hypertrophy and vacuolation, focal cystic
hepatocellular degeneration and diffuse distribution of fat deposits),
increased serum thyroxine levels, and a slight but statistically
significant increase in the incidence of thyroid follicular cell
tumors. The NOAEL was considered to be 40 ppm (2 mg/kg/
day).
Clofentezine was not oncogenic to mice when administered for 2
years at dietary concentrations of 0, 50, 500 and 5,000 ppm. Decreased
weight gain, increased liver weights, and increased mortality were
noted at 5,000 ppm. An increased incidence of eosinophilic or
basophilic hepatocytes was noted at 5,000 ppm, and possibly 500 ppm.
6. Special studies. Numerous studies were conducted to investigate
the mechanism for the increased incidence of male thyroid follicular
tumors that was observed in the chronic rat study. These studies
suggest that the tumors may have been caused by increased thyroid
stimulating hormone (TSH) levels, which, in turn, resulted from
clofentezine's liver toxicity.
7. Animal metabolism. The metabolism, tissue distribution and
excretion of clofentezine have been evaluated in a number of species.
In all species, almost all of the administered dose was recovered
within 24 to 48 hours after treatment, primarily via the feces. The
major route of metabolism was found to be ring hydroxylation, sometimes
preceded by the replacement of a chlorine atom with a methyl-thio
group. Blood and tissue levels in the fetuses of pregnant rats that had
been treated with clofentezine were much lower than the levels found in
the mother, indicating that clofentezine does not readily pass across
the placenta. In addition, less than 1% of the administered dose was
absorbed through the skin of rats following a 10 hour exposure to a 50
SC (50% suspension concentrate) formulation of clofentezine.
Following oral dosing of a cow and three goats with 14C-
labeled clofentezine, the residue in milk was identified as a single
metabolite, 4-hydroxyclofentezine. Similarly, 4-hydroxyclofentezine has
been shown to be the only metabolite present in fat, liver, and kidney.
No unchanged clofentezine or other metabolites were found. Therefore,
the nature of the residue in animals is adequately understood. The
residues of concern are the combined residues of the parent,
clofentezine, and the 4-hydroxyclofentezine metabolite.
8. Endocrine disruption. Except for the thyroid mechanistic studies
mentioned above, no special studies have been conducted to investigate
the potential of clofentezine to induce estrogenic or other endocrine
effects. However, the standard battery of required toxicity studies has
been completed. These studies include an evaluation of the potential
effects on reproduction and development, and an evaluation of the
pathology of the endocrine organs following repeated or long-term
exposure. These studies are generally considered to be sufficient to
detect any endocrine effects. However, with the exception of a slightly
increased incidence of thyroid tumors in male rats, no such effects
were noted in any of the studies with clofentezine. The male rat is
known to be much more susceptible than humans to the carcinogenic
effects resulting from thyroid hormone imbalance and/or increased
levels of TSH. Therefore, the alterations in thyroid hormone and
subsequent thyroid pathological changes, which have been noted
following administration of high doses of clofentezine, are considered
to be of minimal relevance to human risk assessment, particularly
considering the low levels of clofentezine to which humans are likely
to be exposed.
C. Aggregate Exposure
Clofentezine is a miticide used on apples, pears, almonds, walnuts,
apricots, cherries, peaches, and nectarines. Clofentezine has also been
registered recently for use on ornamental plants, however, the product
registered for use on ornamental plants (OVATION miticide/
insecticide) is not being marketed at this time. There are no other
non-crop uses. Thus, potential sources of non-occupational exposure to
clofentezine would consist only of any potential residues in food and
drinking water. There are no acute toxicity concerns with clofentezine.
Therefore, only chronic exposures are addressed here.
1. Dietary exposure--Food. A worst case dietary exposure assessment
was performed for clofentezine using the Exposure 1 software
system (TAS, Inc.) and the 1977-78 USDA consumption data. This
assessment assumed that 100% of all apples, pears, almonds, walnuts,
apricots, cherries, nectarines, peaches, milk, and the fat, meat, and
meat by-products of cattle, goats, horses, sheep, and hogs contained
residues at the established and proposed tolerance levels. specify here
or previously. A more realistic assessment was also conducted using
estimates of market share.
2. Drinking water. All EPA environmental fate data requirements
have been satisfied. The potential for clofentezine to leach into
groundwater was assessed in terrestrial field dissipation studies
conducted in several locations and in varying soil types. Half-lives
ranged from 32.4 to 83 days. No evidence of leaching of parent or
degradation products was observed. Based upon these and other studies,
EPA concluded that ``clofentezine is a relatively short-lived, non-
mobile compound which does not pose a risk to groundwater, and will not
be expected to accumulate in rotational crops.'' Thus, the potential
for finding significant clofentezine residues in drinking water is
minimal and the contribution of any such residues to the total dietary
intake of clofentezine will be negligible. No Maximum Contaminant Level
for clofentezine has been established.
D. Cumulative Effects
The primary effects observed in the toxicity studies conducted with
clofentezine appear to be a result of its potency as an enzyme inducer.
Although many other chemicals are also known to induce microsomal
enzymes, insufficient information is available at this time to
determine whether or not the potential toxic effects from these
chemicals are cumulative. Furthermore, realistic estimates of potential
non-occupational exposure to clofentezine indicate that such exposures
are minimal and far below the levels that might be expected to produce
any effects. Thus, any contribution of clofentezine to cumulative risk
will not be significant. Therefore, only exposure from clofentezine is
being addressed at this time.
E. Safety Determination
1. U.S. population. The toxicity and residue data bases for
clofentezine are considered to be valid, reliable and essentially
complete. Although clofentezine has been classified by EPA as Category
C for oncogenicity, quantitative oncogenic risk assessment was
considered inappropriate for the following reasons:
i. Evidence of tumors was limited to a single site in one sex of
one species and occurred only at the high-dose level.
ii. The increased incidence of thyroid follicular tumors was only
marginally increased above both concurrent and historical control
levels.
[[Page 4418]]
iii. No evidence of genotoxicity has been observed.
iv. Mechanistic data indicate that the thyroid tumors were likely a
secondary, threshold-mediated effect associated with clofentezine's
liver toxicity. Furthermore, humans are believed to be much less
susceptible to this effect than rats. Therefore, no effect on the
thyroid-pituitary axis or oncogenic response would be expected at
exposure levels which did not affect #the liver.
Thus, a standard margin of safety approach is considered
appropriate to assess the potential for clofentezine to produce both
oncogenic and non-oncogenic effects. Based on the previously described
data, EPA has adopted an reference dose (RfD) value for clofentezine of
0.0125 mg/kg/day, which was calculated using the NOAEL of 1.25 mg/kg/
day from the 1 year dog feeding study and a 100-fold safety factor.
Using the worst-case assumptions of 100% of crop treated and that
all crops and animal commodities contain residues of clofentezine at
the current tolerance levels, the aggregate exposure of the general
population to clofentezine from the established tolerances utilizes
about 5% of the RfD. Using more realistic estimates of percent crop
treated and adjusting for contribution from livestock diet, this
decreases to less than 0.5% of the RfD. Repeating these assessments
with the proposed tolerances, the percent RfD for the worst case is
less than 10%, and for the more realistic case the percent RfD
decreases to less than 1.2%. There is generally no concern for
exposures which utilize less than 100% of the RfD because the RfD
represents the level at or below which daily aggregate exposure over a
lifetime would not pose significant risks to human health. Therefore,
there is a reasonable certainty that no harm will result to the general
population from aggregate exposure to clofentezine residues.
2. Infants and children. Data from rat and rabbit developmental
toxicity studies and rat multi generation reproduction studies are
generally used to assess the potential for increased sensitivity of
infants and children. The developmental toxicity studies are designed
to evaluate adverse effects on the developing organism resulting from
pesticide exposure during prenatal development. Reproduction studies
provide information relating to reproductive and other effects on
adults and offspring from prenatal and postnatal exposure to the
pesticide.
No indication of increased sensitivity to infants and children was
noted in any of the studies with clofentezine. No developmental effects
were noted in rats, even at a dose level (3,200 mg/kg/day) that
exceeded the 1,000 mg/kg/day limit dose and produced maternal toxicity.
In addition, no evidence of reproductive toxicity was noted in the rat
multigeneration reproduction study. Slight developmental toxicity
(decreased fetal weights) was noted in rabbits, but only at a dose
level (3,000 mg/kg/day) that exceeded the EPA limit dose and also
produced maternal toxicity.
FFDCA Section 408 provides that EPA may apply an additional safety
factor for infants and children to account for pre- and post-natal
toxicity and the completeness of the data base. The toxicology database
for clofentezine regarding potential pre- and post-natal effects in
children is complete according to existing Agency data requirements and
does not indicate any developmental or reproductive concerns.
Furthermore, the existing RfD is based on a NOAEL of 1.25 mg/kg/day
(from the 1 year dog study) which is already more than 800-fold lower
than the NOAEL in the rabbit developmental toxicity study. Thus, the
existing RfD of 0.0125 mg/kg/day is considered to be appropriate for
assessing potential risks to infants and children and an additional
uncertainty factor is not warranted.
Using the conservative exposure assumptions described above
(proposed tolerances, 100% crop treated, and no adjustments for percent
contribution from livestock diet), aggregate exposure to residues of
clofentezine are expected to utilize about 65% of the RfD in non-
nursing infants, 33% of the RfD in nursing infants, and 25% of the RfD
in children aged 1 to 6 years old.
Using more realistic estimates of percent crop treated and
adjusting for the percent contribution from livestock diet, the percent
of RfD utilized is less than 8% for these population subgroups. These
numbers would be lowered further if anticipated residues were utilized
rather than tolerance values. Therefore, there is a reasonable
certainty that no harm will result to infants or children from
aggregate exposure to clofentezine residues.
F. International Tolerances
Codex tolerances have been established for clofentezine on a wide
variety of crops, including apples. The following MRLs were adopted by
the Codex Committee on Pesticide Residues (CCPR) in April, 1988, except
as noted in parentheses:
------------------------------------------------------------------------
Commodity MRL (mg/kg)
------------------------------------------------------------------------
Cattle meat............................... 0.05
Cattle, edible offal,..................... 0.1
Cattle, milk.............................. 0.01
1Citrus fruits............................ 0.5 (1995)
Cucumber.................................. 1.0 (1991)
Currants.................................. 0.01 (1993)
Eggs (poultry)............................ 0.05
Grapes.................................... 1.0 (1995)
Pome fruits............................... 0.5
Poultry, edible offal..................... 0.05
Poultry meat.............................. 0.05
Stone fruits.............................. 0.2
Strawberry................................ 2.0
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[FR Doc. 99-1904 Filed 1-27-99; 8:45 am]
BILLING CODE 6560-50-F
