[Federal Register Volume 62, Number 228 (Wednesday, November 26, 1997)]
[Rules and Regulations]
[Pages 63235-63244]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-30938]
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ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 180
[OPP-300577; FRL-5754-8]
RIN 2070-AB78
Zeta-Cypermethrin; Pesticide Tolerance
AGENCY: Environmental Protection Agency (EPA).
ACTION: Final rule.
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SUMMARY: This regulation establishes tolerances for residues of zeta-
cypermethrin in or on cabbage at 2.0 parts per million (ppm);
cottonseed at 0.5 ppm; lettuce, head at 10.0 ppm; onions, bulb at 0.10
ppm; pecans at 0.05 ppm; and the fat, meat, and meat byproducts (mbyp)
of cattle, goats, hogs, horses, and sheep at 0.05 ppm. It also removes
time limitations for tolerances for residues of zeta-cypermethrin on
the same commodities that expire on November 15, 1997. FMC Corporation
requested this tolerance under the Federal Food, Drug, and Cosmetic
Act, as amended by the Food Quality Protection Act of 1996.
DATES: This regulation is effective November 26, 1997. Objections and
requests for hearings must be received by EPA on or before January 26,
1998.
ADDRESSES: Written objections and hearing requests, identified by the
docket control number, OPP-300577, must 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, identified by the docket control
number, OPP-300577, must also be submitted to: Public Information and
Records Integrity Branch, Information Resources and Services Division
(7502C), Office of Pesticide Programs, Environmental Protection Agency,
401 M St., SW., Washington, DC 20460. In person, bring a copy of
objections and hearing requests to Rm. 1132, Crystal Mall #2, 1921
Jefferson Davis Hwy., Arlington, VA.
A copy of objections and hearing requests filed with the Hearing
Clerk may also be submitted electronically by sending electronic mail
(e-mail) to: opp-docket@epamail.epa.gov. Follow the instructions in
Unit VI. of this preamble. No Confidential Business Information (CBI)
should be submitted through e-mail.
FOR FURTHER INFORMATION CONTACT: By mail: Beth Edwards, Registration
Division (7505C), Office of Pesticide Programs, Environmental
Protection Agency, 401 M St., SW., Washington, DC 20460. Office
location, telephone number, and e-mail address: Crystal Mall #2, 1921
Jefferson Davis Hwy., Arlington, VA, (703) 305-5400, e-mail:
edwards.beth@epamail.epa.gov.
SUPPLEMENTARY INFORMATION: On June 15, 1984, EPA established time-
limited tolerances under section 408 of the Federal Food, Drug, and
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d) and 348 for residues of
cypermethrin on cottonseed; fat, meat, and mbyp of cattle, goats, hogs,
horses, poultry, and sheep; and milk (49 FR 24864). As additional crop
tolerances were established, they were also made time-limited. These
tolerances expire on November 15, 1997. FMC Corporation, on September
15, 1997, requested that the time limitation for tolerances established
for residues of the insecticide zeta-cypermethrin in these commodities
be removed based on environmental effects data that they had submitted
as a condition of the registration. FMC Corporation also submitted a
summary of its petition as required under the FFDCA, as amended by the
Food Quality Protection Act (FQPA) of 1996 (Pub. L 104-170).
In the Federal Register of September 25, 1997, (62 FR 50337) (FRL-
5748-2), EPA issued a notice pursuant to section 408 of the FFDCA, 21
U.S.C. 346a(e) announcing the filing of pesticide petitions (PP 2F2623,
4F2986, 3F2824, 7F3498, and 4F3011) for tolerances by FMC Corporation,
1735 Market St., Philadelphia, PA 19103. This notice included a summary
of the petition prepared by FMC Corporation, the registrant. There were
no comments received in response to the notice of filing.
The petition requested that 40 CFR 180.418 be amended by removing
the time limitation for tolerances for residues of the insecticide and
pyrethroid, zeta-cypermethrin in or on cabbage at 2.0 ppm; cottonseed
at 0.5 ppm; lettuce, head at 10.0 ppm; onions, bulb at 0.10 ppm; and
pecans at 0.05 ppm. Animal commodities were not
[[Page 63236]]
included in the notice of filing but are being included in this final
rule.
The basis for the time-limited tolerances, that expire November 15,
1997, was given in the October 20, 1993, Federal Register (58 FR
54094). These time-limited tolerances were predicated on the expiration
of pesticide product registrations that were made conditional due to
lack of certain ecological and environmental effects data. The
rationale for using time-limited tolerances was to encourage pesticide
manufacturers to comply with the conditions of registration in a timely
manner. There is no regulatory requirement to make tolerances time-
limited due to the conditional status of a product registration under
the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA), as
amended. It is current EPA policy to no longer establish time
limitations on tolerance(s) with expiration dates if none of the
conditions of registration have any bearing on human dietary risk. The
current petition action meets that condition and thus the expiration
dates associated with specific crop tolerances are being deleted.
I. Risk Assessment and Statutory Findings
New section 408(b)(2)(A)(i) of the FFDCA allows EPA to establish a
tolerance (the legal limit for a pesticide chemical residue in or on a
food) only if EPA determines that the tolerance is ``safe.'' Section
408(b)(2)(A)(ii) of the FFDCA defines ``safe'' to mean that ``there is
a reasonable certainty that no harm will result from aggregate exposure
to the pesticide chemical residue, including all anticipated dietary
exposures and all other exposures for which there is reliable
information.'' This includes exposure through drinking water and in
residential settings, but does not include occupational exposure.
Section 408(b)(2)(C) of the FFDCA requires EPA to give special
consideration to exposure of infants and children to the pesticide
chemical residue in establishing a tolerance and to ``ensure that there
is a reasonable certainty that no harm will result to infants and
children from aggregate exposure to the pesticide chemical residue. .
.''
EPA performs a number of analyses to determine the risks from
aggregate exposure to pesticide residues. 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. Second,
EPA examines exposure to the pesticide through the diet (e.g., food and
drinking water) and through exposures that occur as a result of
pesticide use in residential settings.
A. Toxicity
1. Threshold and non-threshold effects. For many animal 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 a study has 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. Thus, an aggregate daily exposure to a pesticide
residue at or below the RfD (expressed as 100% or less of the RfD) is
generally considered acceptable by EPA. EPA generally uses the RfD to
evaluate the chronic risks posed by pesticide exposure. For shorter
term risks, EPA calculates a margin of exposure (MOE) by dividing the
estimated human exposure into the NOEL from the appropriate animal
study. Commonly, EPA finds MOEs lower than 100 to be unacceptable. This
100-fold MOE is based on the same rationale as the 100-fold uncertainty
factor.
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 MOE 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.
2. Differences in toxic effect due to exposure duration. The
toxicological effects of a pesticide can vary with different exposure
durations. EPA considers the entire toxicity data base, and based on
the effects seen for different durations and routes of exposure,
determines which risk assessments should be done to assure that the
public is adequately protected from any pesticide exposure scenario.
Both short and long durations of exposure are always considered.
Typically, risk assessments include ``acute,'' ``short-term,''
``intermediate-term,'' and ``chronic'' risks. These assessments are
defined by the Agency as follows.
Acute risk, by the Agency's definition, results from 1-day
consumption of food and water, and reflects toxicity which could be
expressed following a single-oral exposure to the pesticide residues.
High-end exposure to food and water residues are typically assumed.
Short-term risk results from exposure to the pesticide for a period
of 1-7 days, and therefore overlaps with the acute risk assessment.
Historically, this risk assessment was intended to address primarily
dermal and inhalation exposure which could result, for example, from
residential pesticide applications. However, since enaction of FQPA,
this assessment has been expanded to include both dietary and non-
dietary sources of exposure, and will typically consider exposure from
food, water, and residential uses when reliable data are available. In
this assessment, risks from average food and water exposure, and high-
end residential exposure, are aggregated. High-end exposures from all
three sources are not typically added because of the very low
probability of this occurring in most cases, and because the other
conservative assumptions built into the assessment assure adequate
protection of public health. However, for cases in which high-end
exposure can reasonably be expected from multiple sources (e.g.
frequent and widespread homeowner use in a specific geographical area),
multiple high-end risks will be aggregated and presented as part of the
comprehensive risk assessment/characterization. Since the toxicological
endpoint considered in this assessment reflects exposure over a period
of at least 7 days, an additional degree of conservatism is built into
the assessment; i.e., the risk assessment nominally covers 1-7 days
exposure,
[[Page 63237]]
and the toxicological endpoint/NOEL is selected to be adequate for at
least 7 days of exposure. (Toxicity results at lower levels when the
dosing duration is increased.)
Intermediate-term risk results from exposure for 7 days to several
months. This assessment is handled in a manner similar to the short-
term risk assessment.
Chronic risk assessment describes risk which could result from
several months to a lifetime of exposure. For this assessment, risks
are aggregated considering average exposure from all sources for
representative population subgroups including infants and children.
B. Aggregate Exposure
In examining aggregate exposure, section 408 of the FFDCA 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, residues in
ground water or surface water that is consumed as drinking water, and
other non-occupational exposures through pesticide use in gardens,
lawns, or buildings (residential and other indoor 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. In evaluating food
exposures, EPA takes into account varying consumption patterns of major
identifiable subgroups of consumers, including infants and children.
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% 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 (anticipated residue data
and/or percent of crop treated data) which show, generally, that
pesticide residues in most foods when they are eaten are well below
established tolerances.
II. Aggregate Risk Assessment and Determination of Safety
Consistent with section 408(b)(2)(D) of the FFDCA, EPA has reviewed
the available scientific data and other relevant information in support
of this action, EPA has sufficient data to assess the hazards of zeta-
cypermethrin and to make a determination on aggregate exposure,
consistent with section 408(b)(2) of the FFDCA, for residues of zeta-
cypermethrin in or on cabbage at 2.0 ppm; cottonseed at 0.5 ppm;
lettuce, head at 10.0 ppm; onions, bulb at 0.10 ppm; pecans at 0.05
ppm; and the fat, meat, and mbyp of cattle, goats, hogs, horses, and
sheep at 0.05 ppm. EPA's assessment of the dietary exposures and risks
associated with establishing the tolerances follows.
A. Toxicological Profile
EPA has evaluated the available toxicity data and considered its
validity, completeness, and reliability as well as the relationship of
the results of the studies to human risk. EPA has also considered
available information concerning the variability of the sensitivities
of major identifiable subgroups of consumers, including infants and
children. The nature of the toxic effects caused by zeta-cypermethrin
are discussed in this unit.
1. Acute toxicity studies with technical zeta-cypermethrin: oral
LD50 in the rat is 134.4 milligram (mg)/kilogram (kg) for
males and 86.0 mg/kg for females--Toxicity Category II.
2. Acute toxicity studies with cypermethrin bridged to zeta-
cypermethrin: dermal LD50 > 2460 mg/kg in rabbits and
LD50 > 4920 in rats--Toxicity Category III; inhalation
(LC50 2.5 mg/liter (L) for females and > 2.5 mg/L in males--
Toxicity Category III; primary eye irritation-- not irritating--
Toxicity Category IV; primary dermal irritation, primary irritation
score (PIS) 0.71 --Toxicity Category IV; dermal sensitization--moderate
sensitizer in two studies, negative in other studies; delayed type
neurotoxicity in hens--no evidence of delayed type neurotoxicity in
hens at dose levels of 0, 2,500, 5,000, or 10,000 mg/kg; neurotoxicity
screen in rats--NOEL and lowest-observed effect level (LOEL)
established as < 20="" mg/kg--at="" 20="" mg/kg="" decreased="" motor="" activity="" and="" gait="" abnormalities.="" 3.="" in="" a="" 90-day="" feeding="" study,="" rats="" were="" dosed="" at="" 0,="" 10,="" 50,="" 150,="" 250,="" 500,="" or="" 900="" ppm="" (0,="" 0.6,="" 2.7,="" 8.4,="" 13.8,="" 28.2,="" or="" 55.7="" mg/kg/day="" for="" males="" and="" 0,="" 0.6,="" 3.3,="" 9.6,="" 16.3,="" 32.2,="" or="" 65.2="" mg/kg/day="" for="" females).="" the="" noel="" is="" 250="" ppm="" (13.9="" mg/kg/day)="" and="" the="" loel="" is="" 500="" ppm="" (28.2="" mg/kg/day)="" based="" on="" decreases="" in="" bodyweight="" and="" bodyweight="" gains="" and="" food="" consumption="" at="" 28.2="" mg/kg/day="" and="" above="" and="" deaths;="" clinical="" signs="" of="" neurotoxicity;="" decreases="" in="" erythrocyte="" and="" leukocyte="" counts,="" hemoglobin,="" and="" hematocrit,="" and="" increases="" in="" blood="" urea="" nitrogen="" (bun)="" at="" 55.7="" mg/kg/day.="" 4.="" the="" 21-day="" dermal,="" subchronic="" oral="" study="" in="" the="" dog="" and="" the="" 21-="" day="" inhalation="" studies="" are="" bridged="" from="" cypermethrin.="" in="" a="" subchronic="" toxicity="" study,="" dogs="" were="" dosed="" at="" 0,="" 5,="" 50,="" 500,="" or="" 1,500="" ppm="" (corresponding="" to="" 0,="" 125,="" 1.25,="" 12.5,="" and="" 37.5="" mg/kg/day)="" for="" 13="" weeks.="" the="" loel="" is="" 1,500="" ppm="" (37.5="" mg/kg/day,="" based="" on="" clinical="" signs="" indicating="" neurotoxicity).="" the="" noel="" is="" 500="" ppm="" (12.5="" mg/kg/day).="" in="" a="" 21-day="" dermal="" toxicity="" study,="" rabbits="" were="" dosed="" at="" 2,="" 20,="" or="" 200="" mg/kg/day="" with="" daily="" applications="" for="" 3="" weeks="" for="" a="" total="" of="" 15="" applications.="" five/sex/group="" were="" abraded="" prior="" to="" application="" of="" the="" test="" material.="" the="" loel="" is="" 200="" mg/kg/day="" based="" on="" liver="" effects.="" the="" noel="" is="" 20="" mg/kg/day.="" in="" a="" 21-day="" subchronic="" inhalation="" toxicity="" study,="" rats="" were="" dosed="" by="" nose="" only="" exposure="" at="" concentrations="" of="" 0,="" 0.01,="" 0.05,="" or="" 0.25="" mg/l="" for="" 6="" hours="" per="" day,="" 5="" days="" per="" week="" for="" a="" total="" of="" 15="" exposures.="" additional="" satellite="" groups="" of="" five/sex="" were="" included="" for="" recovery="" assessment="" and="" analysis="" of="" cypermethrin="" in="" the="" brain.="" the="" loel="" is="" 0.05="" mg/l="" based="" mainly="" on="" bodyweight="" decrease.="" the="" noel="" is="" 0.01="" mg/l.="" 5.="" the="" chronic/oncogenicity="" studies="" are="" bridged="" from="" cypermethrin.="" in="" a="" chronic="" toxicity="" study,="" dogs="" were="" dosed="" at="" 0,="" 1,="" 5,="" or="" 15="" mg/="" kg/day="" for="" 52="" weeks.="" the="" loel="" is="" 5="" mg/kg/day="" based="" on="" gastrointestinal="" effects.="" the="" noel="" is="" 1="" mg/kg/day.="" in="" a="" carcinogenicity="" study,="" mice="" were="" dosed="" at="" control-1,="" control-="" 2,="" 100,="" 400,="" and="" 1,600="" ppm="" (corresponding="" to="" 0,="" 0,="" 14,="" 57,="" or="" 229="" mg/="" kg/day)="" for="" 97="" weeks="" for="" males="" and="" 101="" weeks="" for="" females.="" the="" loel="" is="" 400="" ppm="" (57="" mg/kg/day)="" based="" on="" liver="" weight.="" the="" noel="" is="" 100="" ppm="" (14="" mg/kg/day).="" this="" study="" was="" determined="" to="" be="" positive="" for="" induction="" of="" benign="" alveologenic="" neoplasms.="" adequacy="" of="" dosing="" for="" carcinogenicity="" is="" based="" upon="" typically="" 9%="" decreases="" in="" males="" and="" 12%="" in="" females="" in="" the="" first="" months="" of="" the="" study.="" in="" a="" chronic="" toxicity/carcinogenicity="" study,="" rats="" were="" dosed="" at="" control-1,="" control-2,="" 20,="" 150,="" or="" 1,500="" ppm="" (corresponding="" to="" 0,="" 0,="" 1,="" 7.5,="" or="" 75="" mg/kg/day)="" for="" 2="" years.="" satellite="" groups="" of="" 12/sex="" were="" sacrificed="" after="" 1="" year="" of="" dosing.="" the="" loel="" is="" 1,500="" ppm="" (75="" mg/kg/day)="" based="" on="" bodyweight.="" the="" noel="" is="" 150="" ppm="" (7.5="" mg/kg/day).="" cypermethrin="" was="" not="" considered="" to="" be="" [[page="" 63238]]="" oncogenic="" in="" this="" study.="" a="" possible="" association="" with="" increased="" testicular="" interstitial="" tumors="" was="" not="" considered="" definite.="" 6.="" zeta-cypermethrin="" was="" tested="" in="" a="" developmental="" toxicity="" study="" in="" rats="" at="" the="" following="" dose="" levels:="" 0,="" 5,="" 12,="" 25,="" or="" 35="" mg/kg/day.="" groups="" of="" 25="" females="" were="" administered="" the="" test="" chemical="" by="" gavage="" on="" gestation="" days="" 6="" through="" 15="" in="" a="" volume="" of="" 5="" milliliter="" (ml)/kg="" bodyweight.="" no="" developmental="" toxicity="" was="" observed="" at="" any="" dose="" level.="" the="" maternal="" noel="" is="" 12.5="" mg/kg="" and="" the="" maternal="" loel="" is="" 25="" mg/kg="" based="" on="" decreases="" in="" bodyweight="" and="" bodyweight="" gain="" and="" food="" consumption="" and="" clinical="" signs="" of="" toxicity,="" particularly="" neurotoxicity.="" the="" developmental="" noel="" is="" 35="" mg/kg/day="" highest="" dose="" tested="" (hdt).="" the="" loel="" was="" not="" established.="" 7.="" the="" developmental="" toxicity="" study="" in="" the="" rabbit="" is="" bridged="" from="" cypermethrin.="" in="" a="" developmental="" toxicity="" study,="" rabbits="" were="" dosed="" at="" 0="" (empty="" capsule),="" 0="" (capsule="" plus="" corn="" oil),="" 3,="" 10,="" or="" 30="" mg/kg/day="" on="" days="" 6="" to="" 18="" inclusive="" of="" gestation.="" there="" were="" no="" effects="" of="" any="" kind="" reported="" on="" the="" does.="" the="" maternal="" loel="" is=""> 30 mg/kg/day. The maternal
NOEL is > 30 mg/kg/day. There were no treatment related effects on
either the skeletal or visceral structures reported. The developmental
LOEL is > 30 mg/kg/day. The developmental NOEL is > 30 mg/kg/day.
In a developmental toxicity study, rabbits were dosed at 0, 100,
450, or 700 mg/kg/day from days 7 through 19 of gestation. The does
were sacrificed on day 29 of gestation. The maternal LOEL is 450 mg/kg/
day, based on bodyweight gain. The maternal NOEL is 100 mg/kg/day.
There were no indications of developmental toxicity. The NOEL and LOEL
for developmental toxicity is > 700 mg/kg/day.
8. Zeta-cypermethrin was tested in a two-generation reproduction
study in groups of 30 male and 30 female rats at the following dose
levels: 0, 7.5, 25, 100, 375, or 750 ppm (0, 0.5, 1.8, 7, 27, or 45 mg/
kg/day). The parental and reproductive NOELs are 7 mg/kg/day and LOELs
are 27 mg/kg/day based on decreased parental and pup weight,
particularly during lactation, clinical signs of toxicity, and death at
45 mg/kg/day.
9. Zeta-cypermethrin was tested in a reverse mutation assay in
salmonella typhimurium strains TA1535, TA1537, TA100, TA1538, and TA98
at 0, 100, 333, 1,000, 3,333, 5,000, or 10,000 microgram (g)/
plate. It gave a very weak positive response (two-fold increase in
revertants/plate) in strain TA100 at 10,000 g/plate without S-
9 activation in two-separate experiments. Doses of 3,333 and 5,000
g/plate gave 1.5 and 1.6-fold increases in revertants/plate,
respectively. Strains TA98, TA1535, TA1537, and TA1538 treated in the
presence and absence of mammalian S-9 activation were not affected.
Zeta-cypermethrin is therefore considered a possible weak mutagen under
the conditions of the assay.
10. Zeta-cypermethrin was tested in an in vitro mammalian cell gene
mutation assay in Chinese hamster ovary (CHO) cells (CHO-K1-
BH4, subclone D1) at the following dose levels:
0, 1, 10, 25, 50, 100, 400, 700, or 1,000 g/ml, both in the
absence and presence of S-9 activation. No evidence of increased
forward mutation rate at the hypoxanthine guanine phosphoribose
transferase (HGPRT) locus was observed at any dose tested under the
conditions of these assays. The solubility limit of the test compound
in culture media was approximately 100 g/ml.
11. Zeta-cypermethrin was tested in an in vivo rat bone marrow
chromosomal aberration assay. Groups of 15 male and 15 female Sprague-
Dawley rats were administered single doses by gavage with 0, 31.25,
62.5, or 125 mg/kg zeta-cypermethrin in corn oil. Five rats/sex were
sacrificed at 6, 18, and 30 hours-post dosing. Cyclophosphamide was
used as the positive control (60 mg/kg). No evidence of structural
chromosomal aberrations was demonstrated at either 6, 18, or 30 hours-
post dosing.
12. Zeta-cypermethrin was tested in an unscheduled deoxyribonucleic
acid (DNA) synthesis assay in male Fischer 344 rat primary hepatocyte
cells. The dose levels tested were 0, 14, 45, 140, 450, 1,400, or 4,500
g/ml. No unscheduled DNA synthesis was observed at any dose
level up to 4,500 g/ml in the primary hepatocyte cultures
under the conditions of the assay. Minimal cytotoxicity was observed at
the highest doses. Incomplete solubility of the test compound in
culture media was observed, particularly at the higher doses. The
positive control gave clear positive responses. The study is acceptable
for regulatory purposes.
13. The metabolism studies are bridged from cypermethrin.
Several studies with both rats, dogs, and mice are available to
support the requirement for metabolism in mammals. Some of these
studies assess individual cis- and trans-radiolabeled isomers and other
studies assess the metabolism of cypermethrin with the label in either
the cyclopropyl of the phenoxybenzyl ring. In general the following has
been demonstrated from these studies:
Cypermethrin is readily absorbed from the gastrointestinal tract
and extensively metabolized. It is mostly excreted in the urine and
contains several characterized metabolites derived from conjugation of
the hydrolysis products of the parent compound following cleavage of
the esteratic linkage site. The following three executive summaries
describe the metabolism of cypermethrin in rats.
First study--First group. Six/sex rats, Wistar strain rats, were
dosed with a single dose 0.61 mg/animal of labeled cis-cypermethrin
isomers in 0.5 ml of corn oil. The rats were individually housed in
metabolism cages and their urine and fecal matter collected daily until
sacrifice. Two rats of each sex were sacrificed after 24 and 72 hours
and after 8 days. Samples of the blood and selected tissues were
assessed for radioactivity content.
Second group. Three/sex rats were dosed with 0.615 mg/animal of
labeled trans-cypermethrin in 0.8 ml of corn oil. In addition to the
urine and fecal collections, expired air was also collected from one
male and one female. Total recovery was from 97.2% to 100.5%. About 70%
of cis- and 80% of trans-cypermethrin was excreted in 24 hours.
Essentially all was excreted in 8 days. Most of the label was excreted
in the urine (> 53%) with less in the feces and (< 20%)="" for="" the="" trans="" (males="" and="" females)="" and="" cis="" (males="" only)="" groups="" and="">< 1%="" in="" the="" air="" for="" all="" groups.="" a="" sex="" difference="" with="" respect="" to="" excretion="" in="" the="" urine="" from="" the="" cis-isomer="" was="" noted="" for="" females="" since="" about="" equal="" amounts="" (35%)="" were="" found="" in="" both="" the="" urine="" and="" feces.="" several="" urinary="" and="" fecal="" metabolites="" were="" tentatively="" characterized.="" second="" study.="" one="" group="" of="" three/sex="" wistar="" strain="" rats="" was="" dosed="" with="" a="" single-oral="" dose="" (approximately="" 1.3="" mg/kg)="" of="" 14c-cyclopropyl="" labeled="" cypermethrin="" in="" corn="" oil="" (0.8="" ml).="" the="" rats="" were="" then="" placed="" in="" glass="" metabolism="" cages="" and="" their="" urine="" and="" feces="" were="" collected.="" special="" metabolism="" cages="" for="" trapping="" any="" radioactivity="" expired="" through="" their="" respiratory="" system="" were="" used="" for="" one="" male="" and="" one="" female="" rat.="" the="" rats="" were="" sacrificed="" after="" 3="" days="" and="" their="" blood="" and="" selected="" tissues="" were="" assessed="" for="" radioactivity,="" 85.5%="" for="" males="" and="" 97.2%="" for="" females="" of="" 14c="" was="" excreted="" in="" 72="" hours.="" the="" urine="" (55.8%="" for="" males="" and="" 69.4%="" for="" females)="" was="" the="" major="" route="" of="" excretion="" with="" the="" feces="" containing="" the="" balance.="" the="" air="" contained="" only="" 0.1%="" or="" less.="" tissue="" [[page="" 63239]]="" retention="" was="" highest="" in="" the="" skin="" (1.2%)="" and="" liver="" (0.74%="" for="" males="" but="" only="" 0.18%="" for="" females)="" and="" fat="" (0.57="" to="" 0.66%).="" third="" study.="" in="" a="" series="" of="" nine="" different="" studies,="" labeled="" cypermethrin="" (1="" mg/kg="" or="" less)="" in="" corn="" oil="" or="" separated="" cis-="" or="" trans-="" cypermethrin="" isomers="" were="" given="" by="" gavage="" to="" single="" or="" groups="" of="" two="" or="" three="" wistar="" strain="" rats.="" their="" urine="" and="" in="" some="" cases="" fecal="" matter="" was="" collected="" at="" various="" intervals="" such="" as="" 18="" hours="" to="" 3="" days.="" in="" another="" set="" of="" experiments,="" labeled="" cypermethrin="" was="" administered="" to="" rats="" that="" were="" fitted="" with="" bile="" duct="" cannalulas="" and="" their="" bile="" collected="" for="" 4-5="" hours="" while="" the="" rat="" was="" under="" anesthesia.="" cis-="" and="" trans-14c-cyclopropyl="" labeled="" cypermethrin="" was="" demonstrated="" to="" form="" glucuronide="" conjugations="" of="" cis-="" and="" trans-acids="" and="" hydroxyacids.="" only="" 1.6%="" or="" less="" of="" the="" total="" dose="" is="" excreted="" in="" the="" bile.="" most="" of="" the="" cypermethrin="" in="" the="" feces="" was="" unmetabolized.="" the="" glucuronide="" conjugates="" in="" the="" urine="" were="" found="" to="" be="" unstable="" and="" subject="" to="" hydrolysis.="" 14.="" acute="" delayed="" type="" neurotoxicity-hens.="" cypermethrin="" was="" tested="" in="" the="" hen="" following="" a="" protocol="" similar="" to="" the="" series="" 81-7="" guideline.="" the="" dose="" levels="" tested="" were="" 0,="" 2,500,="" 5,000,="" and="" 10,000="" mg/kg="" but="" there="" was="" no="" indication="" of="" the="" delayed="" type="" neurotoxicity="" noted.="" 15.="" acute="" neurotoxicity="" screen-rats.="" there="" are="" two="" acute="" neurotoxicity="" studies="" with="" cypermethrin.="" first="" study.="" rats="" were="" dosed="" with="" cypermethrin="" at="" dose="" levels="" of="" 0,="" 20,="" 60,="" or="" 120/100="" mg/kg.="" the="" rats="" displayed="" gait,="" muscle="" effects,="" and="" choreoathetosis.="" motor="" activity="" was="" decreased="" for="" all="" dose="" groups="" for="" males="" (estimated="" 45%,="" 66%,="" and="" 85%="" for="" the="" 20,="" 60,="" and="" 100="" mg/kg="" dose="" group="" respectively)="" and="" gait="" abnormalities="" were="" present="" in="" the="" low-dose="" group.="" body="" temperature="" was="" increased="" about="" 1="" deg.c="" in="" the="" low-dose="" male="" group="" but="" decreased="" for="" the="" higher="" groups.="" some="" 10="" other="" parameters="" were="" affected="" at="" 60="" mg/kg="" and/or="" above.="" these="" included:="" salivation,="" urination,="" arousal,="" abnormal="" motor="" movement,="" forelimb,="" or="" hindlimb="" grip="" strength,="" landing="" foot="" splay,="" touch="" response,="" and="" tail="" pinch="" response.="" the="" loel="" and="" noels="" for="" neurotoxicity="" are="">< 20="" mg/kg.="" at="" 20="" mg/kg="" decreased="" motor="" activity="" and="" gait="" abnormalities="" resulted.="" second="" study.="" rats="" were="" dosed="" with="" cypermethrin="" in="" corn="" oil="" as="" control,="" 30,="" 100,="" or="" 200="" mg/kg.="" the="" rats="" were="" assessed="" at="" pretest,="" 4="" hours="" after="" treatment="" and="" on="" days="" 7="" and="" 14="" for="" functional="" observational="" battery="" (fob)="" and="" motor="" activity.="" after="" day="" 14,="" five/sex="" were="" prepared="" for="" neurohistopathology.="" at="" 100="" mg/kg,="" ataxia="" (two="" males="" and="" two="" females)="" and="" related="" conditions="" (staggered="" or="" impaired="" gait,="" decreased="" activity,="" splayed="" hindlimbs,="" and="" limp="" condition)="" and="" decreased="" motor="" activity="" (49%,="" p="">< 0.001="" for="" males="" and="" 33%,="" p="">< 0.01="" for="" females)="" resulted.="" in="" addition,="" some="" females="" had="" salivation,="" lacrimation="" and/or="" soiled="" fur.="" at="" 200="" mg/kg,="" deaths="" resulted="" (one="" male="" and="" two="" females)="" as="" well="" as="" several="" other="" parameters="" being="" affected.="" the="" lel="" is="" 100="" mg/kg="" based="" primarily="" on="" ataxia="" and="" related="" conditions.="" the="" noel="" is="" 30="" mg/kg.="" the="" first="" study="" in="" unit="" ii.="" a.15.="" of="" this="" preamble="" is="" considered="" to="" define="" the="" neurotoxicity="" to="" cypermethrin="" because="" responses="" were="" noted="" at="" lower-dose="" levels.="" the="" second="" study="" used="" a="" variable="" and="" large="" dose="" of="" corn="" oil="" and="" a="" different="" strain="" of="" rat.="" 16.="" subchronic="" neurotoxicity="" screen="" in="" rats.="" rats="" were="" dosed="" with="" cypermethrin="" as="" control,="" 500,="" 1,300="" or="" 1,700="" ppm="" (31,="" 77,="" or="" 102="" for="" males="" and="" 37,="" 95,="" or="" 121="" for="" females="" mg/kg/day)="" for="" 90="" days="" in="" a="" subchronic="" neurotoxicity="" study.="" at="" 1,300="" ppm,="" females="" displayed="" ataxia="" (1/10),="" splayed="" hindlimbs="" (5/16),="" impaired="" gait="" (4/10),="" and="" decreased="" feces="" (4/10)="" as="" well="" as="" decreased="" bodyweight="" gain="">41%).
Males had only decreased bodyweight gain (27%) and
increased landing foot splay. At 1,700 ppm, males showed ataxia (8/10)
and additional related symptoms and females had decreased motor
activity (27%). The LEL is 1,300 ppm (77 mg/kg/day) based
on several effects. The NOEL is 500 ppm (31 mg/kg/day).
Because the studies in Units II. A.15. and 16. of this preamble are
screens, neurotoxicity studies will be required under a special Data
Call-In (DCI) letter pursuant to section 3(c)(2)(B) of FIFRA. Although
these data are lacking, EPA has sufficient toxicity data base to
support these tolerances and these additional studies are not expected
to significantly change its risk assessment.
B. Toxicological Endpoints
1. Acute toxicity. For acute dietary risk assessment, EPA
recommends use of a NOEL of 0.5 mg/kg/day based on the NOEL of 1.0 mg/
kg/day from the cypermethrin chronic toxicity study in dogs and a
correction factor of two to account for the differences in the
percentage of the biologically active isomer. The LOEL of this study of
5.0 mg/kg/day was based on gastrointestinal disturbances observed in
the first week of the study.
2. Short- and intermediate-term toxicity. For short- and
intermediate-term MOE's, EPA recommends use of a NOEL of 2.5 mg/kg/day
based on neurotoxic signs in dogs starting at week 1. The inhalation
NOEL is 5.0 with a correction factor of 2. Dermal absorption rate was
25%. A dermal absorption rate of 25% was recommended based on the
weight-of-the-evidence available for structurally related pyrethroids.
3. Chronic toxicity. EPA has established the RfD for zeta-
cypermethrin at 0.005 mg/kg/day. This RfD is based on gastrointestinal
disturbances in dogs with an uncertainty factor of 200 to account for
differences in percent biologically active isomers in enriched product.
Since insufficient data on zeta-cypermethrin are available to
establish an RfD, the data from cypermethrin were used in establishing
an RfD for zeta-cypermethrin. The NOELs from the cypermethrin studies
were divided by 2 as a correction factor, assuming the worst case that
the biologically active isomers are the ones which carry most of the
toxicity. The following paragraph summarizes the decision logic for
establishing the RfD for zeta-cypermethrin from the cypermethrin data
base.
In general, the most sensitive species for the 10 synthetic
pyrethroids appears to be the dog. For zeta-cypermethrin the Agency
does not have any toxicity data on the dog that can be compared with
the dog studies conducted with cypermethrin. In addition, the Agency
also does not have any chronic studies on zeta-cypermethrin that can be
compared with those conducted with cypermethrin. Therefore, although a
comparison of the LEL's from the zeta-cypermethrin studies with the
corresponding LEL's from the cypermethrin studies does not show a
pronounced difference in toxicity, for risk assessment purposes, the
Agency has decided to use the toxicity endpoints from cypermethrin with
a two-fold correction factor to account for the differences in the
percentages of the more biologically active isomers in the enriched
technical product (zeta-cypermethrin). This would also apply to the
inhalation endpoint because the Agency has no inhalation studies with
zeta-cypermethrin. The Agency is making a conservative assumption that
most of the toxicity for cypermethrin will be from the four more
biologically active isomers of zeta-cypermethrin. Based on previous
documentation, the Agency is assuming that the percentages of the
isomers are approximately as follows:
Cypermethrin, eight isomers with percentage compositions ranging
from 11-14% and zeta-cypermethrin, eight isomers with four
insecticidally less active ones at a concentration of 1% each. The
remaining four isomers, two
[[Page 63240]]
of which are regarded as being the most insecticidally active, will be
present at a concentration of 24% each.
4. Carcinogenicity. No carcinogenicity studies are available for
zeta-cypermethrin. Using its Guidelines for Carcinogen Risk Assessment
published September 24, 1986 (51 FR 33992) the Carcinogenicity Peer
Review Committee (CPRC) has classified cypermethrin as a weak Group C
(possible human carcinogen) based on the increased incidence in lung
adenomas in female CD-1 mice, but did not recommend assignment of a
cancer potency factor (Q*1) for a linear quantitative cancer risk
assessment. An RfD approach was recommended for human risk assessment
purposes. It is assumed that zeta-cypermethrin would also test
positively for lung adenomas in female CD-1 mice.
C. Exposures and Risks
1. From food and feed uses. Tolerances have been established (40
CFR 180.418) for the residues of zeta-cypermethrin in or on a variety
of raw agricultural commodities. Tolerances range from 0.05 ppm in
animal commodities to 10.0 ppm in head lettuce. Registered uses include
cabbage, cotton, head lettuce, onions, and pecans. Risk assessments
were conducted by EPA to assess dietary exposures and risks from zeta-
cypermethrin as follows:
i. Acute exposure and risk. Acute dietary risk assessments are
performed for a food-use pesticide if a toxicological study has
indicated the possibility of an effect of concern occurring as a result
of a 1 day or single exposure. The acute dietary exposure assessment
used Monte Carlo modeling incorporating anticipated residues and
percent crop treated refinements. The acute dietary MOE at the 99.9th
percentile for the overall U.S. population is 126. The MOE at the
99.9th percentile for children 1-6 years of age is 105. EPA concludes
that there is a reasonable certainty of no harm for MOEs of 100 or
greater. Therefore, the acute dietary risk assessment for zeta-
cypermethrin indicates a reasonable certainty of no harm.
ii. Chronic exposure and risk. The RfD used for the chronic dietary
analysis is 0.005 mg/kg/day based on a NOEL of 1.0 mg/kg/day from the
cypermethrin chronic dog study and an uncertainty factor of 200 (used
to account for the differences in the percentage of the biologically
active isomer). The endpoint effect of concern was based on
gastrointestinal disturbances observed in the first week of the study
at the LOEL of 5.0 mg/kg/day. The chronic dietary exposure assessment
used anticipated residues, monitoring data, and percent of crop treated
information . The chronic dietary exposure estimate for the overall
U.S. population was calculated to be 0.000018 mg/kg/day (0.4% RfD
utilized) and for children 1-6 years was calculated to be 0.00027 mg/
kg/day (0.5% RfD utilized).
EPA notes that the acute dietary risk assessments used Monte Carlo
modeling (in accordance with Tier 3 of EPA June 1996 ``Acute Dietary
Exposure Assessment'' guidance document) incorporating anticipated
residues and percent of crop treated refinements. The chronic dietary
risk assessments used anticipated residues and percent crop treated
information.
Section 408(b)(2)(E) authorizes EPA to consider available data and
information on the anticipated residue levels of pesticide residues in
food and the actual levels of pesticide chemicals that have been
measured in food. If EPA relies on such information, EPA must require
that data be provided 5 years after the tolerance is established,
modified, or left in effect, demonstrating that the levels in food are
not above the levels anticipated. Following the initial data
submission, EPA is authorized to require similar data on a timeframe it
deems appropriate. Section 408(b)(2)(F) allows the Agency to use data
on the actual percent of crop treated when establishing a tolerance
only where the Agency can make the following findings:
a. 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.
b. That the exposure estimate does not underestimate the exposure
for any significant subpopulation.
c. 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, the Agency must provide for periodic evaluation of any
estimates used.
The percent of crop treated estimates for zeta-cypermethrin 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, the Agency 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 the Agency to be reasonably certain that
no regional population is exposed to residue levels higher than those
estimated by the Agency. To meet the requirement for data on
anticipated residues, EPA will issue a DCI notice pursuant to FFDCA
section 408(f) requiring submission of data on anticipated residues in
conjunction with approval of the registration under the FIFRA.
2. From drinking water. Laboratory and field data have demonstrated
that cypermethrin is immobile in soil and will not leach into ground
water. Estimates of zeta-cypermethrin drinking water concentrations
were generated with the PRZM1 and EXAMS computer models. Based on these
analyses, the contribution of water to the dietary risk estimate is
negligible. Therefore, EPA concludes that together these data indicate
that residues are not expected to occur in drinking water.
i. Acute exposure and risk. The acute drinking water exposure and
risk estimates are 0.000126 mg/kg/day (MOE of 3,982) and 0.000242 mg/
kg/day (MOE of 2,069) for the overall U.S. population and non-nursing
infants < 1="" year="" old,="" respectively.="" ii.="" chronic="" exposure="" and="" risk.="" the="" chronic="" drinking="" water="" exposure="" and="" risk="" estimates="" are="" 0.000005="" mg/kg/day="" (0.1%="" of="" rfd="" utilized)="" and="" 0.000021="" mg/kg/day="" (0.4%="" of="" rfd="" utilized)="" for="" the="" overall="" u.s.="" population="" and="" non-nursing="" infants="">< 1="" year="" old,="" respectively.="" 3.="" from="" non-occupational="" non-dietary="" exposure.="" zeta-cypermethrin="" is="" registered="" for="" agricultural="" crop="" applications="" only;="" therefore,="" no="" non-="" occupational,="" non-dietary="" exposure="" is="" expected.="" 4.="" cumulative="" exposure="" to="" substances="" with="" common="" mechanism="" of="" toxicity.="" section="" 408(b)(2)(d)(v)="" of="" the="" ffdca="" requires="" that,="" when="" considering="" whether="" to="" establish,="" modify,="" or="" revoke="" a="" tolerance,="" the="" agency="" consider="" ``available="" information''="" concerning="" the="" cumulative="" effects="" of="" a="" particular="" pesticide's="" residues="" and="" ``other="" substances="" that="" have="" a="" common="" mechanism="" of="" toxicity.''="" 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="" [[page="" 63241]]="" mechanism="" of="" toxicity="" with="" any="" other="" substances,="" epa="" does="" not="" at="" this="" time="" have="" the="" methodologies="" to="" resolve="" the="" complex="" scientific="" issues="" 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="" be="" 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).="" four="" members="" of="" the="" insecticide="" class="" pyrethroids="" produce="" a="" common="" metabolite="" known="" as="" dcva="" (3-(2,2-dichloroethenyl)-2,2-="" dimethylcyclopropane="" carboxylic="" acid).="" these="" insecticides="" are="" cyfluthrin,="" cypermethrin,="" zeta-cypermethrin,="" and="" permethrin.="" although="" the="" residues="" of="" dcva="" can="" be="" estimated,="" no="" toxicology="" data="" on="" the="" compound="" per="" se="" are="" available="" to="" directly="" conduct="" a="" hazard="" evaluation="" and="" thereby="" establish="" an="" appropriate="" endpoint="" for="" use="" in="" a="" joint="" risk="" assessment.="" to="" date,="" for="" the="" purpose="" of="" assessing="" the="" risk="" of="" the="" parent="" compound,="" the="" toxicity="" of="" the="" dcva="" has="" been="" assumed="" to="" be="" equivalent="" to="" the="" parent="" compound.="" however,="" due="" to="" the="" markedly="" different="" toxicological="" profiles="" of="" cyfluthrin,="" cypermethrin,="" zeta-="" cypermethrin,="" and="" permethrin,="" epa="" does="" not="" believe="" that="" it="" would="" be="" appropriate="" to="" cumulate="" dcva="" residues="" from="" these="" pesticides,="" or="" dcva="" residues="" from="" one="" of="" these="" pesticides="" with="" the="" parent="" of="" another="" of="" these="" pesticides,="" in="" conducting="" the="" risk="" assessment="" for="" these="" pesticides.="" accordingly,="" epa="" does="" not="" have,="" at="" this="" time,="" available="" data="" to="" determine="" whether="" zeta-cypermethrin="" has="" a="" common="" mechanism="" of="" toxicity="" with="" other="" substances="" or="" how="" to="" include="" this="" pesticide="" in="" a="" cumulative="" risk="" assessment.="" for="" the="" purposes="" of="" this="" tolerance="" action,="" therefore,="" epa="" has="" not="" assumed="" that="" zeta-cypermethrin="" has="" a="" common="" mechanism="" of="" toxicity="" with="" other="" substances.="" d.="" aggregate="" risks="" and="" determination="" of="" safety="" for="" u.s.="" population="" 1.="" acute="" risk.="" the="" acute="" aggregate="" risk="" assessment="" takes="" into="" account="" exposure="" from="" food="" and="" water.="" the="" moe="" calculated="" at="" the="" 99.9th="" percentile="" for="" the="" overall="" u.s.="" population="" is="" 122.="" the="" agency="" has="" no="" cause="" for="" concern="" if="" total="" acute="" exposure="" calculated="" for="" the="" 99.9th="" percentile="" yields="" a="" moe="" of="" 100="" or="" larger.="" therefore,="" the="" agency="" has="" no="" acute="" aggregate="" concern="" due="" to="" exposure="" to="" zeta-cypermethrin="" through="" food="" and="" drinking="" water.="" 2.="" chronic="" risk.="" using="" the="" anticipated="" residue="" contribution="" (arc)="" exposure="" assumptions,="" epa="" has="" concluded="" that="" aggregate="" exposure="" to="" zeta-cypermethrin="" from="" food="" and="" water="" will="" utilize="" 0.5%="" of="" the="" rfd="" for="" the="" u.s.="" population.="" the="" major="" identifiable="" subgroup="" with="" the="" highest-="" aggregate="" exposure="" is="" children,="" ages="" 1-6="" years="" old,="" discussed="" in="" unit="" ii.="" f.="" of="" this="" preamble.="" epa="" generally="" has="" no="" concern="" for="" exposures="" below="" 100%="" of="" the="" rfd="" because="" the="" rfd="" represents="" the="" level="" at="" or="" below="" which="" daily="" aggregate="" dietary="" exposure="" over="" a="" lifetime="" will="" not="" pose="" appreciable="" risks="" to="" human="" health.="" epa="" concludes="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" aggregate="" exposure="" to="" zeta-cypermethrin="" residues.="" 3.="" short-="" and="" intermediate-term="" risk.="" short-="" and="" intermediate-term="" aggregate="" exposure="" takes="" into="" account="" chronic="" dietary="" food="" and="" water="" (considered="" to="" be="" a="" background="" exposure="" level)="" plus="" indoor="" and="" outdoor="" residential="" exposure.="" based="" on="" zeta-cypermethrin="" not="" being="" registered="" for="" residential="" non-food="" sites,="" epa="" concludes="" that="" the="" aggregate="" short-="" and="" intermediate-term="" risks="" do="" not="" exceed="" levels="" of="" concern="" (moe="" less="" than="" 100),="" and="" that="" there="" is="" reasonable="" certainty="" that="" no="" harm="" will="" result="" from="" aggregate="" exposure="" to="" zeta-cypermethrin="" residues.="" e.="" aggregate="" cancer="" risk="" for="" u.s.="" population="" no="" carcinogenicity="" studies="" are="" available="" for="" zeta-cypermethrin.="" however,="" cypermethrin="" has="" been="" classified="" as="" a="" weak="" group="" c="" carcinogen="" with="" no="" q*1="" based="" on="" the="" increased="" incidence="" in="" lung="" adenomas="" in="" female="" cd-1="" mice.="" based="" on="" the="" recommendation="" that="" the="" rfd="" approach="" be="" used,="" a="" quantitative="" dietary="" cancer="" risk="" assessment="" was="" not="" performed.="" dietary="" risk="" concerns="" due="" to="" long-term="" consumption="" of="" cypermethrin="" are="" adequately="" addressed="" by="" the="" dres="" chronic="" exposure="" analysis="" using="" the="" rfd.="" for="" the="" u.s.="" population,="" less="" than="" 1%="" of="" the="" rfd="" is="" occupied="" by="" aggregate="" chronic="" food="" and="" water="" exposure.="" f.="" aggregate="" risks="" and="" determination="" of="" safety="" for="" infants="" and="" children="" 1.="" safety="" factor="" for="" infants="" and="" children--i.="" in="" general.="" in="" assessing="" the="" potential="" for="" additional="" sensitivity="" of="" infants="" and="" children="" to="" residues="" of="" zeta-cypermethrin,="" epa="" considered="" data="" from="" developmental="" toxicity="" studies="" in="" the="" rat="" and="" rabbit="" and="" a="" two-="" generation="" reproduction="" study="" in="" the="" rat.="" the="" developmental="" toxicity="" studies="" are="" designed="" to="" evaluate="" adverse="" effects="" on="" the="" developing="" organism="" resulting="" from="" pesticide="" exposure="" during="" prenatal="" development="" to="" one="" or="" both="" parents.="" reproduction="" studies="" provide="" information="" relating="" to="" effects="" from="" exposure="" to="" the="" pesticide="" on="" the="" reproductive="" capability="" of="" mating="" animals="" and="" data="" on="" systemic="" toxicity.="" section="" 408="" of="" the="" ffdca="" provides="" that="" epa="" shall="" apply="" an="" additional="" 10-fold="" 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="" data="" base="" unless="" epa="" determines="" that="" a="" different="" margin="" of="" safety="" will="" be="" safe="" for="" infants="" and="" children.="" margins="" of="" safety="" are="" incorporated="" into="" epa="" risk="" assessments="" either="" directly="" through="" use="" of="" a="" moe="" analysis="" or="" through="" using="" uncertainty="" (safety)="" factors="" in="" calculating="" a="" dose="" level="" that="" poses="" no="" appreciable="" risk="" to="" humans.="" epa="" believes="" that="" reliable="" data="" support="" using="" the="" standard="" moe="" and="" uncertainty="" factor="" (usually="" 100="" for="" combined="" inter-="" and="" intra-species="" variability)="" and="" not="" the="" additional="" 10-fold="" moe/="" uncertainty="" 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="" moe/safety="" factor.="" ii.="" developmental="" toxicity="" studies.="" in="" a="" prenatal="" developmental="" toxicity="" study="" in="" rats,="" there="" was="" no="" evidence="" of="" developmental="" toxicity="" at="" the="" hdt="" (35="" mg/kg/day).="" maternal="" toxicity="" (ataxia,="" urine="" and="" feces="" stained="" fur,="" decreased="" bodyweight="" gain="" and="" food="" consumption)="" was="" observed="" at="" the="" maternal="" loel="" (25="" mg/kg/day),="" and="" the="" maternal="" noel="" was="" established="" at="" 12.5="" mg/kg/day.="" in="" [[page="" 63242]]="" addition,="" an="" acceptable="" prenatal="" developmental="" toxicity="" study="" in="" rabbits="" conducted="" with="" cypermethrin="" was="" submitted.="" iii.="" reproductive="" toxicity="" study.="" in="" the="" two-generation="" reproduction="" study="" in="" rats,="" offspring="" toxicity="" (decreased="" pup="" weight="" gain="" during="" lactation)="" was="" observed="" at="" the="" same="" treatment="" level="" which="" resulted="" in="" parental="" systemic="" toxicity="" (noel="100" ppm="" or="" 27="" mg/kg/day;="" loel="375" ppm="" or="" 45="" mg/kg/day).="" iv.="" pre-="" and="" post-natal="" sensitivity.="" there="" is="" no="" evidence="" of="" additional="" sensitivity="" to="" young="" rats="" following="" pre-="" or="" post-natal="" exposure="" to="" zeta-cypermethrin.="" v.="" conclusion.="" the="" data="" base="" related="" to="" pre-="" and="" post-natal="" sensitivity="" is="" complete.="" based="" on="" the="" information="" in="" unit="" ii.="" f.="" of="" this="" preamble,="" epa="" concludes="" that="" reliable="" data="" support="" use="" of="" the="" standard="" 100-fold="" uncertainty="" factor,="" and="" that="" an="" additional="" uncertainty="" factor="" is="" not="" needed="" to="" protect="" the="" safety="" of="" infants="" and="" children.="" 2.="" acute="" risk.="" the="" acute="" aggregate="" risk="" assessment="" takes="" into="" account="" exposure="" from="" food="" and="" water.="" the="" moe="" calculated="" at="" the="" 99.9th="" percentile="" for="" children="" age="" 1-6="" is="" 102.="" the="" agency="" has="" no="" cause="" for="" concern="" if="" total="" acute="" exposure="" calculated="" for="" the="" 99.9th="" percentile="" yields="" an="" moe="" of="" 100="" or="" larger.="" therefore,="" the="" agency="" has="" no="" acute="" aggregate="" concern="" due="" to="" exposure="" to="" zeta-cypermethrin="" through="" food="" and="" drinking="" water.="" 3.="" chronic="" risk.="" using="" conservative="" exposure="" assumptions,="" epa="" has="" concluded="" that="" aggregate="" exposure="" to="" zeta-cypermethrin="" from="" food="" and="" water="" will="" utilize="" 0.6%="" of="" the="" rfd="" for="" children,="" ages="" 1-6="" years="" old.="" epa="" generally="" has="" no="" concern="" for="" exposures="" below="" 100%="" of="" the="" rfd="" because="" the="" rfd="" represents="" the="" level="" at="" or="" below="" which="" daily="" aggregate="" dietary="" exposure="" over="" a="" lifetime="" will="" not="" pose="" appreciable="" risks="" to="" human="" health.="" epa="" concludes="" that="" there="" is="" a="" reasonable="" certainty="" that="" no="" harm="" will="" result="" to="" infants="" and="" children="" from="" aggregate="" exposure="" to="" zeta-cypermethrin="" residues.="" 4.="" short-="" or="" intermediate-term="" risk.="" based="" on="" zeta-cypermethrin="" not="" being="" registered="" for="" residential="" non-food="" sites,="" epa="" concludes="" that="" the="" aggregate="" short-="" and="" intermediate-term="" risks="" do="" not="" exceed="" levels="" of="" concern,="" and="" that="" there="" is="" reasonable="" certainty="" that="" no="" harm="" will="" result.="" 5.="" special="" docket.="" the="" complete="" acute="" and="" chronic="" exposure="" analyses="" (including="" dietary,="" non-dietary,="" drinking="" water,="" and="" residential="" exposure,="" and="" analysis="" of="" exposure="" to="" infants="" and="" children)="" used="" for="" risk="" assessment="" purposes="" can="" be="" found="" in="" the="" special="" docket="" for="" the="" fqpa="" under="" the="" title="" ``risk="" assessment="" for="" extension="" of="" tolerances="" for="" synthetic="" pyrethroids.''="" further="" explanation="" regarding="" epa's="" decision="" regarding="" the="" additional="" safety="" factor="" can="" also="" be="" found="" in="" the="" special="" docket.="" g.="" endocrine="" disrupter="" effects="" epa="" is="" required="" to="" develop="" a="" screening="" program="" to="" determine="" whether="" certain="" substances="" (including="" all="" pesticides="" and="" inerts)="" ``may="" have="" an="" effect="" in="" humans="" that="" is="" similar="" to="" an="" effect="" produced="" by="" a="" naturally="" occurring="" estrogen,="" or="" such="" other="" endocrine="" effect....''="" 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.="" at="" that="" time,="" epa="" may="" require="" further="" testing="" of="" this="" active="" ingredient="" and="" end="" use="" products="" for="" endocrine="" disrupter="" effects.="" iii.="" other="" considerations="" a.="" metabolism="" in="" plants="" and="" animals="" the="" metabolites="" found="" in="" plants="" and="" livestock="" also="" are="" formed="" in="" the="" rat.="" it="" was="" concluded="" that="" 3-phenoxybenzoic="" acid="" (pba)="" and="" its="" conjugates="" are="" not="" of="" concern="" based="" on="" toxicology="" data="" for="" pba.="" in="" the="" absence="" of="" toxicology="" data,="" the="" cis-="" and="" trans-isomers="" of="" dcva="" are="" considered="" to="" be="" of="" comparable="" toxicity="" to="" the="" parent.="" in="" light="" of="" codex="" maximum="" residue="" limits="" (mrls)="" including="" only="" the="" parent="" compound,="" the="" parent="" being="" recoverable="" by="" the="" food="" and="" drug="" administration="" (fda)="" multi-residue="" methods="" i="" and="" ii,="" and="" the="" dcva="" is="" not="" likely="" to="" be="" measured="" by="" these="" methods,="" it="" was="" concluded="" that="" tolerances="" should="" be="" set="" in="" terms="" of="" cypermethrin="" only.="" crop="" field="" trials="" should="" continue="" to="" include="" analyses="" for="" residues="" of="" cis-="" and="" trans-dcva.="" b.="" analytical="" enforcement="" methodology="" adequate="" enforcement="" methodology="" gas="" chromatography/electron="" capture="" detector="" (gc/ecd)="" is="" available="" in="" pesticide="" analytical="" method="" ii="" (pam="" ii)="" as="" method="" i="" to="" enforce="" the="" tolerance="" expression.="" c.="" magnitude="" of="" residues="" residue="" data="" from="" field="" trials="" and="" the="" fda="" monitoring="" program="" (1992-1995)="" and="" the="" pdp="" monitoring="" program="" (1994)="" were="" used="" to="" estimate="" chronic="" dietary="" exposure.="" for="" the="" chronic="" analyses,="" mean="" residues="" from="" fda="" monitoring="" were="" used="" for="" lettuce="" and="" onions="" (dry="" bulb).="" residue="" field="" trial="" data="" were="" used="" for="" broccoli,="" cabbage,="" cotton,="" green="" onions,="" mustard="" greens,="" and="" pecans.="" for="" acute="" dietary="" exposure="" analysis,="" field="" trial="" residue="" data,="" along="" with="" percent="" of="" crop="" treated="" data,="" were="" used="" in="" the="" monte="" carlo="" analysis.="" d.="" international="" residue="" limits="" codex="" mrls="" for="" cypermethrin="" have="" been="" established="" which="" are="" in="" harmony="" with="" the="" u.s.="" tolerances="" for="" meat="" and="" mbyp="" of="" cattle,="" goats,="" hogs,="" horses,="" and="" sheep="" (0.05="" ppm);="" milk="" (0.05="" ppm);="" and="" onions,="" bulb="" (0.10="" ppm).="" codex="" mrls="" have="" been="" established="" which="" exceed="" the="" u.s.="" tolerances="" for="" meat="" (fat="" basis)="" of="" cattle,="" goats,="" hogs,="" horses,="" and="" sheep="" (0.2="" vs.="" 0.05="" ppm).="" codex="" mrls="" have="" been="" established="" which="" are="" below="" their="" u.s.="" counterparts="" for="" cabbage="" (brassica="" vegetables)="" (1.0="" vs.="" 2.0="" ppm)="" and="" lettuce,="" head="" (2.0="" vs.="" 10.0="" ppm).="" no="" canadian="" mrls="" have="" been="" established="" for="" residues="" of="" cypermethrin.="" mexico="" has="" established="" a="" tolerance="" for="" residues="" of="" cypermethrin="" on="" cottonseed="" (0.5="" ppm)="" which="" is="" in="" harmony="" with="" the="" u.s.="" tolerance.="" as="" indicated="" in="" this="" unit,="" there="" are="" differences="" between="" the="" ffdca="" section="" 408="" tolerances="" and="" the="" codex="" mrl="" values="" for="" specific="" commodities.="" these="" differences="" could="" be="" caused="" by="" differences="" in="" methods="" to="" establish="" tolerances,="" calculations="" of="" animal="" feed="" dietary="" exposure,="" and="" as="" a="" result="" of="" different="" agricultural="" practices.="" epa="" will="" specifically="" address="" these="" differences="" when="" the="" pesticides="" are="" reregistered="" and="" the="" tolerances="" made="" permanent.="" iv.="" conclusion="" therefore,="" the="" tolerances="" are="" established="" for="" residues="" of="" zeta-="" cypermethrin="" (s-cyano(3-phenoxyphenyl)="" methyl="">) cis, trans
3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate) in or on
cabbage at 2.0 ppm; cottonseed at 0.5 ppm; lettuce, head at 10.0 ppm;
onions, bulb at 0.10 ppm; pecans at 0.05 ppm; and fat, meat, and mbyp
of cattle, goats, hogs, horses, and sheep at 0.05 ppm.
V. Objections and Hearing Requests
The new section 408(g) of the FFDCA provides essentially the same
process for persons to ``object'' to a tolerance regulation issued by
EPA under new section 408(e) and (l)(6) of the FFDCA as was provided in
the old section 408 and in section 409 of the FFDCA. However, the
period for filing objections is 60 days, rather than 30 days. EPA
currently has procedural regulations
[[Page 63243]]
which govern 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 those procedural regulations with appropriate adjustments to
reflect the new law.
Any person may, by January 26, 1998 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 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.
VI. Public Record and Electronic Submissions
The official record for this rulemaking, as well as the public
version, has been established for this rulemaking under docket control
number OPP-300577 (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 the paper record maintained at the
Virginia address in ``ADDRESSES'' at the beginning of this document.
Electronic comments may be sent directly to EPA at:
opp-docket@epamail.epa.gov.
Electronic objections and hearing requests must be submitted as an
ASCII file avoiding the use of special characters and any form of
encryption. Objections and hearing requests will also be accepted on
disks in WordPerfect 5.1/6.1 or ASCII file format. All copies of
objections and hearing requests in electronic form must be identified
by the docket control number, OPP-300577. No 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.
VII. Regulatory Assessment Requirements
This final rule establishes tolerances under section 408(d) of the
FFDCA in response to a petition submitted to the Agency. The Office of
Management and Budget (OMB) has exempted these types of actions from
review under Executive Order 12866, 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 FR7 629,
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 these tolerances and exemptions that are
established on the basis of a petition under section 408(d) of the
FFDCA, such as the tolerances 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 has 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.
VIII. 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 Part 180
Environmental protection, Administrative practice and procedure,
Agricultural commodities, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: November 14, 1997.
James Jones,
Acting Director, Registration Division, Office of Pesticide Programs.
Therefore, 40 CFR chapter I is amended as follows:
PART 180--[AMENDED]
1. The authority citation for part 180 continues to read as
follows:
Authority: 21 U.S.C. 346a and 371.
2. Section 180.418 is amended by adding a new paragraph (a)(2) to
read as follows:
Sec. 180.418 Cypermethrin and an isomer zeta-cypermethrin; tolerances
for residues.
(a) * * *
(2) Tolerances are established for residues of the insecticide
zeta-cypermethrin (s-cyano(3-phenoxyphenyl) methyl () cis,
trans 3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylate) in
or on the following commodities:
[[Page 63244]]
------------------------------------------------------------------------
Commodity Parts per million
------------------------------------------------------------------------
Cabbage........................................ 2.0
Cattle, fat.................................... 0.05
Cattle, mbyp................................... 0.05
Cattle, meat................................... 0.05
Cottonseed..................................... 0.5
Goats, fat..................................... 0.05
Goats, mbyp.................................... 0.05
Goats, meat.................................... 0.05
Hogs, fat...................................... 0.05
Hogs, mbyp..................................... 0.05
Hogs, meat..................................... 0.05
Horses, fat.................................... 0.05
Horses, mbyp................................... 0.05
Horses, meat................................... 0.05
Lettuce, head.................................. 10.0
Milk........................................... 0.05
Onions, bulb................................... 0.10
Pecans......................................... 0.05
Sheep, fat..................................... 0.05
Sheep, mbyp.................................... 0.05
Sheep, meat.................................... 0.05
------------------------------------------------------------------------
* * * * *
[FR Doc. 97-30938 Filed 11-25-97; 8:45 am]
BILLING CODE 6560-50-F
