[Federal Register Volume 62, Number 83 (Wednesday, April 30, 1997)]
[Notices]
[Pages 23455-23460]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-10893]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-728; FRL-5600-8]
Notice of Filing of Pesticide Petitions
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
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SUMMARY: This notice announces the initial filing of pesticide
petitions proposing the establishment of regulations for residues of
certain pesticide chemicals in or on various agricultural commodities.
DATES: Comments, identified by the docket control number PF-728, must
be received on or before May 30, 1997.
ADDRESSES: By mail submit written comments to: Public Response and
Program Resources Branch, Field Operations Divison (7505C), Office of
Pesticides Programs, Environmental Protection Agency, 401 M St., SW.,
Washington, DC 20460. In person bring comments to: Rm. 1132, CM #2,
1921 Jefferson Davis Highway, Arlington, VA.
Comments and data may also be submitted electronically 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. 1132 at the
address given above, from 8:30 a.m. to 4 p.m., Monday through Friday,
excluding legal holidays.
FOR FURTHER INFORMATION CONTACT: By mail, George LaRocca, Product
Manager, (PM 13), Registration Division (7506C), Office of Pesticide
Programs, Environmental Protection Agency, 401 M St., S.W., Washington,
DC 20460. Office location, telephone number and e-mail address: Crystal
Mall #2, 1921 Jefferson Davis Highway, Arlington, VA, 703-305-6100; e-
mail: [email protected].
SUPPLEMENTARY INFORMATION: EPA has received pesticide petitions as
follows proposing the establishment and/or amendment of regulations for
residues of certain pesticide chemicals in or on various raw
agricultural commodities under section 408 of the Federal Food, Drug,
and Comestic Act (FFDCA), 21 U.S.C. 346a. EPA has determined that these
petitions contain data or information regarding the elements set forth
in section 408(d)(2); however, EPA has not fully evaluated the
sufficiency of the submitted data at this time or whether the data
supports grantinig of the petition. Additional data may be needed
before EPA rules on the petition.
The official record for this notice, as well as the public version,
has been established for this notice of filing under docket control
number PF-728 (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:
[email protected]
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket control number (PF-728) and appropriate
petition number. Electronic comments on this notice may be filed online
at many Federal Depository Libraries.
Authority: 21 U.S.C. 346a.
List of Subjects
Environmental protection, Agricultural commodities, Food additives,
Feed additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: April 10, 1997.
Stephen L. Johnson,
Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Below summaries of the pesticide petitions are printed. The
summaries of the petitions were prepared by the petitioners. The
petition summary announces the availability of a description of the
analytical methods available to EPA for the detection and measurement
of the pesticide chemical residues or an explanation of why no such
method is needed.
1. Gowan Company
PP 6F4738
EPA has received a pesticide petition (PP 6F4738) from Gowan
Company, P. O. Box 5569, Yuma, AZ 85366-5569. The petition proposes,
pursuant to section 408 of the Federal Food, Drug and Cosmetic Act
(FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 to establish
tolerances for the acaricide hexythiazox (The chemical name of
hexythiazox is trans-5-(4-chlorophenyl)-N-cyclohexyl-4-methyl-2-
oxothiazolidine-3-carboxamide.) and its metabolites (Metabolites
containing the (4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety
are included in the tolerance expression.) in or on the raw
agricultural commodities stone fruits (except plums) at 1 part per
million (ppm), almonds at 0.2 ppm and almond hulls at 10 ppm, and also
in milk, cattle meat and cattle fat at 0.05 ppm and cattle meat
byproducts at 0.1 ppm. The proposed analytical method is high
performance liquid chromatography with an ultraviolet detector (HPLC
with UV detection).
A. Residue Chemistry
1. Plant metabolism. The metabolism of hexythiazox in apples,
pears, grapes and citrus has been studied. The major portion of the
residue is parent compound. The metabolites are hydroxycyclohexyl and
ketocyclohexyl analogs of hexythiazox and the amide formed by loss of
the cyclohexyl ring.
2. Animal metabolism. The metabolism of hexythiazox in goats, hens
and rats has been studied. Metabolic pathways in animals are similar to
those in plants.
3. Analytical method. An adequate analytical method (HPLC with UV
detection) is available for enforcement purposes. Parent compound and
all of its metabolites are converted to a common moiety before
analysis.
[[Page 23456]]
4. Magnitude of residues. Twenty-four stone fruit residue trials
were conducted over three years. The geographic distribution of the
trials agrees with the recommendation given in the ``EPA Residue
Chemistry Guidance'' (1994). In these trials, the maximum combined
residues of hexythiazox and its metabolites were 0.52 ppm. Seven almond
residue trials were conducted over three years. In these trials, the
maximum combined residues of hexythiazox and its metabolites were 0.17
ppm in almond nutmeat and 7.5 ppm in the raw agricultural commodity
almond hulls.
B. Toxicological Profile
1. Acute toxicity. The acute oral and dermal LD50 of
technical hexythiazox is greater than 5,000 mg/kg, and the 4-hour acute
inhalation LC50 is greater than 2 mg/L. It is not a dermal
irritant or sensitizer and is a mild eye irritant.
2. Genotoxicity. The following genotoxicity tests were all
negative: Ames gene mutation, Chinese hamster ovary (CHO) gene
mutation, CHO chromosome aberration, mouse micronucleus and rat
hepatocyte unscheduled DNA synthesis.
3. Reproductive and developmental toxicity. Hexythiazox has not
been observed to induce developmental or reproductive effects. The
lowest reproductive or developmental NOEL (No Observed Effect Level)
observed was 200 mg/kg/day, the highest dose tested, in a 2-generation
rat reproduction study.
4. Chronic toxicity. The Office of Pesticide Programs has
established the Reference Dose (RfD) for hexythiazox at 0.025 mg/kg/
day. The RfD for hexythiazox is based on a 1-year dog feeding study
with a NOEL of 2.5 mg/kg/day and an uncertainty factor of 100. The
endpoint effect of concern was hypertrophy of the adrenal cortex in
both sexes, decreased red blood cell counts, hemoglobin content and
hematocrit in males.
5. Carcinogenicity. The Agency has classified hexythiazox as a
category C (possible human) carcinogen based on an increased incidence
of hepatocellular carcinomas (p = 0.028) and combined adenomas/
carcinomas (p = 0.024) in female mice at the highest dose tested (1,500
ppm) when compared to the controls as well as a significantly increased
(p <0.001) incidence of pre-neoplastic hepatic nodules in both males
and females at the highest dose tested. The decision supporting a
category C classification was based primarily on the fact that only one
species was affected and mutagenicity studies were negative. In
classifying hexythiazox as a category C carcinogen, the Agency
concluded that a quantitative estimate of the carcinogenic potential
for humans should be calculated because of the increased incidence of
liver tumors in the female mouse. A Q1* of 0.039 (mg/kg/day)-1 in human
equivalents was calculated.
C. Aggregate Exposure
Tolerances have been established (40 CFR 180.448) for combined
residues of hexythiazox [trans-5-(4-chlorophenyl)-N-cyclohexyl-4-
methyl-2-oxothiazolidine-3-carboxamide] and its metabolites containing
the (4-chlorophenyl)-4-methyl-2-oxo-3-thiazolidine moiety in or on
apples at 0.02 ppm and pears at 0.3 ppm. The nature and metabolism of
hexythiazox in plants and animals is adequately understood.
Hexythiazox is also registered for use on outdoor ornamental plants
by commercial applicators only. It is believed that non-occupational
exposure from this use is very low. Hexythiazox is not registered for
greenhouse, lawn, garden, or residential use. The environmental fate of
hexythiazox has been evaluated, and the compound is not expected to
contaminate groundwater or surface water to any measurable extent.
1. Chronic Exposure. The Agency has estimated in the Federal
Register of February 21, 1996, [61 FR 6552-6554] (FRL-5350-6), that
current uses on apples and pears would result in an exposure of
0.000051 mg/kg/day for the U.S. population, assuming that all residues
are at tolerance levels and 100 percent of the crops are treated. Non-
nursing infants, the subgroup having the highest exposure, would have
an exposure of 0.000600 mg/kg/day. Using the same conservative
assumptions, it is calculated that the current and proposed uses
together would result in an exposure of 0.001920 mg/kg for the U.S.
population and 0.006598 mg/kg/day for non-nursing infants, which
remains the most highly exposed subgroup.
Actual exposure will be much lower, however. Only a small fraction
of these crops will be treated with hexythiazox, and average residues
are far below the tolerance levels. For example, residues in apples
treated at 10 times the currently approved application rate remained
below the limit of quantitation, 0.01 ppm. Also, residues in apple
juice are expected to be less than 50 percent of the residue level in
the whole fruit. Average residues in stone fruits except cherries are
expected to be 7 percent of the proposed tolerance level, average
residues in cherries are expected to be 11 percent of the tolerance
level and average residues in almond nutmeat are expected to be below
20 percent of the proposed tolerance level. Furthermore, only a very
small percentage of crops (less than 1 percent up to 5 percent,
depending on the crop) are expected to be treated with hexythiazox.
When actual residues rather than tolerance levels and the percentage of
treated crop are taken into account, then the actual exposure is
estimated to be 0.0000013 mg/kg/day for the U.S. population.
Gowan has not conducted a detailed analysis of potential exposure
to hexythiazox via drinking water or outdoor ornamental plants.
However, it is believed that chronic exposure from these sources is
very small.
2. Acute exposure. No developmental, reproductive or mutagenic
effects have been observed with hexythiazox. Therefore, an analysis of
acute exposure has not been conducted.
3. Cumulative effects note. At this time Gowan has not reviewed
available information concerning the potentially cumulative effects of
hexythiazox and other substances that may have a common mechanism of
toxicity. For purposes of this petition only, Gowan is considering only
the potential risks of hexythiazox in its aggregate exposure.
D. Determination of Safety for U.S. Population
1. Chronic Risk. The Agency has calculated in the Federal Register
of February 21, 1996, [61 FR 6552-6554], (FRL-5350-6), assuming that
residues are at tolerance levels and 100 percent of crops are treated,
that the current use on apples and pears utilizes 0.2 percent of the
RfD for the U.S. population and 2.4 percent of the RfD for non-nursing
infants. Using these same assumptions, it is calculated that all
current and proposed uses would result in TMRCs equivalent to 7.7
percent of the RfD for the U.S. population and 26.4 percent of the RfD
for non-nursing infants. However, when actual residues rather than
tolerance levels and the percent of crop treated are taken into
account, actual chronic risk for the U.S. population is expected to be
only 0.005 percent of the RfD.
The actual dietary carcinogenic risk to the U.S. population is
calculated to be 5 x 10-8, which is well below the Agency's criterion
of 1 x 10-6.
2. Acute Risk. An estimate of acute risk with this compound has not
been conducted since no acute reproductive or developmental effects
have been observed.
[[Page 23457]]
E. Determination of Safety for Infants and Children
In assessing the potential for additional sensitivity of infants
and children to residues of hexythiazox, EPA considered data from
developmental toxicity studies in the rat and rabbit and a 2-generation
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.
No developmental or reproductive effects have been observed in any
study with hexythiazox. The lowest acute NOEL was 2,400 ppm in the diet
(200 mg/kg/day), the highest dose tested, in the 2-generation rat
reproduction study. In the rat developmental study, the maternal and
fetotoxic NOEL was 240 mg/kg/day and the developmental NOEL was 2,160
mg/kg/day, the highest dose tested. In the rabbit developmental study,
the maternal and developmental NOEL was 1,080 mg/kg/day, the highest
dose tested.
Taking into account current toxicological data requirements, the
database for hexythiazox relative to prenatal and postnatal effects is
complete. In the rat developmental study, the NOELs for maternal
toxicity and fetotoxicity were the same, which suggests that there is
no special prenatal sensitivity in the absence of maternal toxicity.
Furthermore, the lowest developmental or reproductive NOEL is two
orders of magnitude higher than the chronic NOEL on which the RfD is
based. It is concluded that there is a reasonable certainty of no harm
to infants and children from aggregate exposure to hexythiazox
residues.
F. International Tolerances
Codex maximum residue levels (MRLs) of 1 mg/kg (1 ppm) have been
established for residues of hexythiazox in cherries and peaches. The
U.S. tolerance proposal for stone fruits is in harmony with these MRLs.
There are no Codex MRLs for the other commodities in this petition.
2. AgroEvo Environmental Health
PP 7F4820
EPA has received a pesticide petition from AgroEvo Environmental
Health, 95 Chestnut Ridge Road, Montvale, NJ 07645. The petition
proposes, pursuant to section 408 of the Federal Food, Drug and
Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180 to
establish tolerances for deltamethrin in or on food and feed items as a
result of use in food and feed handling establishments at 0.05 part per
million (ppm). This petition was assigned Pesticide Petition Number
7F4820 (formerly 4H5710) and was initially announced in the Federal
Register of February 8, 1995 [60 FR 7539-7541], (FRL-4926-4). A
tolerance of 0.02 ppm was proposed for residues of deltamethrin in or
on food and feed items, and published for comment in the Federal
Register dated November 30, 1995 [60 FR 61504-61506], (FRL-4983-5). In
an effort to harmonize with a similar tolerance established in Germany,
the proposed tolerance was increased to 0.05 ppm per comments received
from the German Ministry of Health. The proposed analytical method is
high performance liquid chromatography with an ultraviolet detector.
A. Residue chemistry
1. Analytical Method. A practical analytical method using gas -
liquid chromatography is available for detecting and measuring levels
of deltamethrin in food and feed items. This method is used for the
determination of cis-deltamethrin, trans-deltamethrin, and alpha-R-
deltamethrin. The limit of quantitation (LOQ) is 0.02 mg/kg (ppm). The
enforcement methodology has been submitted to the Food and Drug
Administration for publication in the Pesticide Analytical Manual
Volume II (PAM II).
2. Nature and Magnitude of the Residue in Food and Feed Items. The
nature of the residues of deltamethrin in plants and animals relevant
to the establishment of food and feed additive tolerances is adequately
understood. The residue of concern is deltamethrin. In studies
conducted to support this use, residue levels of deltamethrin in food
and/or feed items after applications to food- and feed-handling
establishments were below the LOQ, i.e., below 0.02 ppm. There is no
reasonable expectation of secondary residues in eggs, meat, milk, or
poultry from the proposed use as delineated in 40 CFR 180.6(a)(3).
B. Toxicological Profile
1. Acute Toxicity. The acute rat oral LD50 of
deltamethrin technical was 66.7 mg/kg (males) and 86 mg/kg (females)
when administered in sesame oil and greater than 5,000 mg/kg in both
sexes when administered in 1 percent aqueous methylcellulose. The acute
dermal LD50 was greater than 2,000 mg/kg when administered
to rabbits in either polyethylene glycol or 1 percent aqueous
methylcellulose, and greater than 2,940 mg/kg when administered to rats
in 1 percent aqueous methylcellulose. The 4-hour rat inhalation
LC50 was 2.2 mg/l. Deltamethrin was slightly irritating to
rabbit eyes, non-irritating to rabbit skin, and did not induce skin
sensitization in guinea pigs.
2. Subchronic Toxicity. In a 90-day study, deltamethrin was mixed
with polyethylene glycol 200 (PEG 200) and administered by gavage to
rats at dose levels of 0, 0.1, 1, 2.5 and 10 mg/kg/day. The only
treatment-related effects observed were reduced body weight gain in
rats at 2.5 and 10 mg/kg/day and slight hypersensitivity in rats at 10
mg/kg/day at week 6, but not at week 13. The NOEL in this study was 1.0
mg/kg/day. In a more recent 90-day study (not yet submitted to the
Agency), deltamethrin was administered via the diet to rats at dietary
concentrations of 30, 300, 1,000, 3,000 and 6,000 ppm. All animals in
the 3,000 and 6,000 ppm groups and several animals from the 1,000 ppm
group died or were killed in extremis during the first few weeks of the
study. Decreased food and water consumption, decreased weight gain and
a variety of neurological signs of toxicity (including uncoordinated
movement, unsteady gait, tremors, increased sensitivity to sound, ``wet
dog shakes'' and spasmodic convulsions) were noted in these three dose
groups. A slight but statistically significant decrease in weight gain
was noted in females at 30 and 300 ppm but was considered to be of
equivocal significance because of the lack of a clear, consistent dose-
response relationship. There were no changes in clinical pathology
parameters, organ weights or gross or microscopic pathology at any dose
level. Thus, the NOEL for this study was considered to be 300 ppm (23.9
mg/kg/day in males and 30.5 mg/kg/day in females).
A 12-week feeding study of deltamethrin was conducted in mice at
dietary concentrations of 0, 30, 300, 3,000 and 6,000 ppm. Effects
noted at 3,000 and 6,000 ppm consisted of clinical signs of toxicity
(clonic contractions, convulsions and poor condition), decreased weight
gain and mortality. A very slight decrease in weight gain was noted in
males at 30 and 300 ppm but was considered to be of equivocal
significance. There were no effects on hematology, blood chemistry, or
organ weights.
The only histopathological lesions noted were thymic involution and
lipid depletion in the adrenal glands of animals at 3,000 and 6,000
ppm, which
[[Page 23458]]
were considered likely to be secondary effects of the stress induced by
the poor physical condition of the animals. Consequently, 300 ppm (61.5
mg/kg/day in males and 77.0 mg/kg/day in females) was considered to be
the NOEL.
In a 13-week study, deltamethrin was administered to beagle dogs by
capsule at dose levels of 0, 0.1, 2, 2.5 and 10 mg/kg/day, using PEG
200 as a vehicle. There was no mortality but animals at the top two
dose levels exhibited various clinical signs of toxicity (e.g.,
tremors, unsteadiness, jerking movements, excessive salivation,
vomiting, liquid feces, and/or dilatation of the pupils) and modified
EEG patterns. No histopathological findings were observed. The NOEL for
this study was considered to be 1.0 mg/kg/day.
In a more recent study, deltamethrin was administered dry (without
vehicle) via capsule to beagle dogs for 13 weeks at dose levels of 0,
2, 10 and 50 mg/kg/day. No mortality occurred during the study but
animals at 50 mg/kg/day exhibited decreased food consumption and weight
gain and a variety of clinical signs including unsteady gait, tremors,
shaking of the head, vomiting and salivation. There were no effects on
clinical pathology, ophthalmoscopy, organ weights or pathology. The
NOEL for this study was 10 mg/kg/day. The difference in toxicity
between the two dog studies is attributed to the enhanced absorption
resulting from the use of PEG 200 as a vehicle in the first study.
In a 21-day dermal toxicity study, deltamethrin was admixed with
polyethylene glycol and applied dermally to rats for 6 hours per day
for 21 successive days at dose levels of 0, 100, 300 and 1,000 mg/kg/
day. Signs of local dermal irritation were noted at all dose levels. No
conclusive evidence of systemic toxicity was noted at any dose level.
However, because of slight, non-statistically significant decreases in
weight gain and food consumption in males at 300 and 1,000 mg/kg/day,
the EPA concluded that the NOEL for this study was 100 mg/kg/day.
In a subchronic inhalation study, rats were exposed to aerosolized
deltamethrin at concentrations of 0, 3, 9.6 and 56.3 g/l for 6 hours
per day, 5 days per week, for a total of 14 days over 3 weeks. Signs of
local irritation (agitated grooming and scratching) and excessive
salivation were noted in all treated groups. Peripheral vasodilation
was noted at 9.6 and 56.3 g/l. Ataxia and walking with arched back were
noted at 56.3 g/l. Based on slightly decreased body weights and
neurological effects at higher dose levels, AgroEvo Environmental
Health concluded that 3 g/l was the NOEL for systemic effects in this
study.
3. Chronic Toxicity/Oncogenicity. In a 2-year feeding study,
deltamethrin was administered to beagle dogs at dietary concentrations
of 0, 1, 10 and 40 ppm. No treatment-related effects were noted in any
animal. Thus, 40 ppm (1.1 mg/kg/day) was considered to be the NOEL. In
a more recent study, deltamethrin was administered dry, via capsule, to
beagle dogs for 1 year at dose levels of 0, 1, 10 and 50 mg/kg/day.
Effects observed at 10 and 50 mg/kg/day included clinical signs of
toxicity (e.g., unsteadiness, abnormal gait, tremors, chewing/
scratching of extremities and liquid feces), decreased food consumption
(high dose only) and changes in several hematology and blood chemistry
parameters. There were no treatment related gross or histopathological
findings. The NOEL in this study was also considered to be 1 mg/kg/day.
No evidence of oncogenicity was noted in either of two chronic rat
feeding studies. In the first study, deltamethrin was administered to
rats for 2 years at dietary concentrations of 0, 2, 20 and 50 ppm. The
NOEL was considered to be 20 ppm (1 mg/kg/day) based on slightly
decreased weight gain at 50 ppm. In a more recent study, deltamethrin
was administered to rats for 2 years at dietary concentrations of 0,
25, 125, 500 and 800 ppm. Neurological effects (uncoordinated movement
of limbs, abnormal gait and unsteady gait) were noted at 500 and 800
ppm during the first week of the study but subsided and were no longer
apparent by Week 8. Minor effects on weight gain were also noted at
these two dose levels. Microscopic evidence of slight hepatotoxicity
(increased incidence and severity of eosinophilic hepatocytes and/or
ballooned cells) was noted in males at 125 mg/kg/day and above. The
NOEL for this study was considered to be 25 ppm (1.1 and 1.5 mg/kg/day
for males and females, respectively).
No evidence of oncogenicity was noted in two mouse oncogenicity
studies. In the first study, deltamethrin was administered to mice for
2 years at dietary concentrations of 0, 1, 5, 25 and 100 ppm. No
adverse effects were noted at any dose level. Thus, the NOEL was
considered to be 100 ppm (12 and 15 mg/kg/day in males and females,
respectively). In a more recent study, deltamethrin was administered to
mice for 97 weeks at dietary concentrations of 0, 10, 100, 1,000 and
2,000 ppm. Effects noted at 2,000 ppm consisted of a slightly higher
incidence of mice in poor physical condition and a slight, transient
reduction in weight gain. Increased incidences of macroscopic and
microscopic skin lesions, which were attributed to excessive
scratching, were noted in animals at 1,000 and 2,000 ppm. The NOEL was
considered to be 100 ppm (15.7 and 19.6 mg/kg/day for males and
females, respectively).
4. Genotoxicity. No evidence of genotoxicity was noted in a battery
of in vitro and in vivo studies, including Salmonella and E. coli
reverse bacterial mutation assays, an in vitro chromosomal aberration
assay in Chinese hamster ovary (CHO) cells, an unscheduled DNA
synthesis assay in rat hepatocytes, and a dominant lethal assay in
mice.
5. Reproductive and Developmental Toxicity. In a rat developmental
toxicity study, deltamethrin was mixed with corn oil and administered
by gavage during gestation days 6 through 15 at dose levels of 0, 1,
3.3, 7 and 11 mg/kg/day. Maternal toxicity, as evidenced by clinical
observations, decreased weight gain and mortality was noted at 7 and 11
mg/kg/day. No evidence of developmental toxicity was noted at any dose
level. Thus, the No Observable Effect Level (NOEL) was considered to be
3.3 mg/kg/day for maternal toxicity and 11 mg/kg/day (highest dose
tested) for developmental toxicity.
In a rabbit developmental toxicity study, deltamethrin was
administered by gavage in a vehicle of 0.5 percent aqueous
carboxymethyl cellulose at dose levels of 0, 10, 25 and 100 mg/kg/day
during gestation days 7 through 19. The maternal NOEL was considered to
be 10 mg/kg/day based on decreased defecation at 25 and 100 mg/kg/day
and mortality at 100 mg/kg/day. The developmental NOEL was considered
to be 25 mg/kg/day based on retarded ossification of the pubic and tail
bones at 100 mg/kg/day.
In a 3-generation reproduction study, deltamethrin was suspended in
corn oil and administered to rats at dietary concentrations of 0, 2, 20
and 50 ppm. No treatment related effects were noted in either parents
or offspring at any dose level. In a more recent 2-generation study
(not yet submitted to the Agency), deltamethrin was administered to
rats at dietary concentrations of 0, 5, 20, 80 and 320 ppm. The NOEL
for both the parents and offspring was 80 ppm (equivalent to
approximately 4 to 12 mg/kg/day in adults and 18 to 44 mg/kg/day in the
offspring), based on clinical signs of toxicity, reduced weight gain,
and mortality in both parents and offspring at 320 ppm. However, there
were no effects on mating, fertility or developmental behavior at any
dose level.
[[Page 23459]]
6. Endocrine Effects. No special studies have been conducted to
investigate the potential of deltamethrin 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, yet no such effects were detected. Thus,
the potential for deltamethrin to produce any significant endocrine
effects is considered to be minimal.
7. Metabolism. The absorption of deltamethrin appears to be highly
dependent upon the route and vehicle of administration. Once absorbed,
deltamethrin is rapidly and extensively metabolized and excreted,
primarily within the first 48 hours.
C. Aggregate Exposure
Deltamethrin is a broad spectrum insecticide used to control pests
of crops, ornamental plants and turf, and domestic indoor and outdoor
(including dog collars), commercial, and industrial food use areas.
Thus, aggregate non-occupational exposure would include exposures
resulting from non-food uses in addition to consumption of potential
residues in food and water. Exposure via drinking water is expected to
be negligible since deltamethrin binds tightly to soil and rapidly
degrades in water. Because of the variety and nature of the non-food
uses of deltamethrin, and the unavailability of reliable exposure data,
we cannot fully evaluate potential exposure from these non-food uses.
However, deltamethrin binds tightly to organic matter, is not easily
dislodged from indoor surfaces, has very low vapor pressure, and is
poorly absorbed through the skin. Furthermore, the formulations to
which the general public would be exposed are relatively dilute and
non-toxic. Thus, non-food exposures are not expected to pose a
significant risk to the general public, or to infants and children.
Potential dietary exposures from food commodities under the
proposed tolerances for deltamethrin, plus the established tolerances
for deltamethrin (40 CFR 180.435 and 185.1580) on cotton and tomato
commodities, plus the pending temporary tolerances (under an
Experimental Use Permit) on soybean commodities for deltamethrin were
estimated using the Exposure 1 software system (TAS, Inc.) and the
1977-78 USDA consumption data. Two scenarios were evaluated. In the
first, worst case scenario, it was assumed that 100 percent of the
crops for which a tolerance for deltamethrin is established or pending
are treated with deltamethrin, all food and feed handling
establishments are treated with deltamethrin, and that all residues
resulting from these treatments are at tolerance level. In a second,
slightly more realistic-case scenario, anticipated residues and percent
crop treated adjustments were used, but again the unrealistic
assumption was made that 100 percent of all food and feed handling
establishments were treated with deltamethrin.
D. Safety Determinations
1. US Population in General. AgrEvo Environmental Health considers
the toxicity and residue data base for deltamethrin to be valid,
reliable and essentially complete according to existing regulatory
requirements. No evidence of oncogenicity has been observed. A
Reference Dose (RfD) of 0.01 mg/kg bodyweight/day has been established
for deltamethrin based on the NOEL from the two-year rat feeding study
and a 100-fold safety factor to account for interspecies extrapolation
and intraspecies variation.
Using the dietary exposure assumptions described above in section
D, chronic dietary exposures utilize 17 percent of the deltamethrin
Reference Dose in the worst-case scenario, and only 2.6 percent of the
Reference Dose in the slightly more realistic-case scenario for the
general population. Thus, even utilizing a number of unrealistic
assumptions, the total of the RfD utilized for deltamethrin did not
exceed 17 percent. There is generally no concern for exposures below
100 percent of the RfD since it represents the level at or below which
no appreciable risks to human health is posed. Therefore, there is
reasonable certainty that no harm will result to the U.S. population in
general from aggregate exposure to deltamethrin.
2. Infants and Children. Data from developmental toxicity studies
in rats and rabbits, and multigeneration reproduction studies in rats
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 developmental effects were noted in a rat developmental toxicity
study with deltamethrin, even at dose levels that produced clinical
signs of toxicity, reduced body weight, and death in the dams. The
maternal and developmental NOEL's in this study were 3.3 mg/kg/day and
11 mg/kg/day (highest dose tested), respectively. The only
developmental effect noted in the rabbit developmental toxicity study
was possibly retarded ossification at 100 mg/kg/day, a dose level which
also produced maternal mortality. The maternal and developmental NOEL's
in this study were 10 mg/kg/day and 25 mg/kg/day, respectively. No
effects were noted in either parents or offspring at the high dose
level (50 ppm) in a 3-generation rat reproduction study. In a more
recent 2-generation rat reproduction study (not yet submitted to the
Agency), the NOEL for both the parents and offspring was 80 ppm
(equivalent to approximately 4 to 12 mg/kg/day in adults and 18 to 44
mg/kg/day in the offspring), based on a variety of toxic effects
(clinical signs of toxicity, reduced weight gain, and mortality) in
both parents and offspring at 320 ppm. However, there were no effects
on mating, fertility, or developmental behavior at any dose level.
Thus, these data do not provide any evidence of increased
susceptibility to infants or children.
FFDCA section 408 provides that EPA may apply an additional safety
factor for infants and children in the case of threshold effects to
account for pre- and post-natal toxicity and the completeness of the
database. Based on the current toxicological data requirements, the
database relative to pre- and post-natal effects in children is
complete. Although no indication of increased susceptibility to younger
animals was noted in any of the above studies, or in the majority of
studies with other pyrethroids, several recent publications have
reported that deltamethrin is more toxic to neonate and weanling
animals than to adults. However, a joint industry group currently
investigating this issue was unable to reproduce these findings.
Furthermore, the RfD (0.01 mg/kg/day) that has been established for
deltamethrin is already more than 1,000-fold lower than the lowest NOEL
from the developmental and reproduction studies. Therefore, the RfD of
0.01 mg/kg/day is appropriate for assessing aggregate risk to infants
and children and an additional uncertainty factor is not warranted.
Using the dietary exposure assumption described above in section D,
chronic dietary exposures utilize 54 percent of the deltamethrin RfD in
the
[[Page 23460]]
worst-case scenario, and only 10.2 percent of the RfD in the slightly
more realistic-case scenario for the population subgroup described as
non-nursing infants, less than 1 year old. Thus, even utilizing a
number of unrealistic assumptions, the total of the RfD utilized for
deltamethrin did not exceed 54 percent . There is generally no concern
for exposures below 100 percent of the RfD since it represents the
level at or below which no appreciable risks to human health is posed.
Therefore, there is reasonable certainty that no harm will result to
the most sensitive population subgroup described as non-nursing
infants, less than one year old, from aggregate exposure to
deltamethrin.
E. Cumulative Effects
At the present time, there are insufficient data available to allow
AgrEvo to properly evaluate the potential for cumulative effects from
the various pyrethroids now being used, or from any other chemicals
that may have similar mechanisms of toxicity. Furthermore, because of
the need to utilize data from multiple registrants, such an analysis
cannot be conducted by a single registrant. AgrEvo is currently
participating in a joint industry effort to evaluate the potential
aggregate risks from exposure to all pyrethroids but the results from
this evaluation are not yet available. As an interim measure, AgrEvo
has performed an initial evaluation of the potential combined
effectsfrom exposure to two pyrethroids, deltamethrin and tralomethrin,
that are currently registered by AgrEvo Environmental Health and AgrEvo
USA Companies. A combined assessment of these two active ingredients is
considered appropriate because tralomethrin is rapidly debrominated
into deltamethrin and because the two molecules have essentially
identical toxicology profiles.
For the same reasons previously discussed for deltamethrin, non-
dietary exposures to tralomethrin are not expected to pose a
significant risk to human health and, therefore, have not been
evaluated. Potential dietary exposures to tralomethrin are, however,
considered here. The RfD established for tralomethrin is 0.0075 mg/kg
bodyweight/day based on a two-year rat feeding study and a 100 fold
safety factor to account for interspecies extrapolation and
intraspecies variation. Using the dietary exposure assumptions
described above in section D, chronic dietary exposures utilize 16.9
percent of the tralomethrin RfD in the worst-case scenario, and only
3.9 percent of the tralomethrin RfD in the slightly more realistic-case
scenario for the general population. For the population subgroup
described as non-nursing infants, less than one year old, 32 percent of
the RfD for tralomethrin is utilized in the worst-case scenario, and
only 11 percent of the RfD for tralomethrin in the slightly more
realistic-case scenario. (The crops/uses considered for tralomethrin
are those for which tolerances have been established for experimental
use permits and those listed in 40 CFR 180.422, 185.5450, and
186.5450.)
A simple cumulative risk assessment can be made by adding the
percent RfD utilized for deltamethrin and tralomethrin. However, this
is a gross overestimate because, based on efficacy, economics, and/or
label restrictions, crops and food/feed handling establishments would
not be concurrently treated with both products. This is especially
important in considering food/feed handling uses because all foods are
considered to contain residues of both deltamethrin and tralomethrin.
Nonetheless, looking at this simple summation, it is shown that in the
worst-case scenario described in section D, chronic dietary exposures
utilize 33.9 percent of the RfDs for tralomethrin/deltamethrin, while
in the slightly more realistic-case scenario only 6.5 percent of the
RfDs for tralomethrin/deltamethrin are utilized. For the population
subgroup described as non-nursing infants, less than one-year old, 86
percent of the RfDs for tralomethrin/deltamethrin are utilized in the
worst-case scenario, while only 21.2 percent of the RfDs for
tralomethrin/deltamethrin are utilized in the slightly more realistic-
case scenario. Thus, even utilizing a number of unrealistic
assumptions, and using a simple summation of percent RfD utilized for
each active ingredient, the total of percent RfD utilized for
deltamethrin/tralomethrin did not exceed 86 percent, and is actually
less than 21.2 percent, for the population subgroup non-nursing
infants, less than one year old. Therefore, there is reasonable
certainty that no harm will result from cumulative aggregate exposures
to deltamethrin and tralomethrin for the general population and/or
infants and children.
G. International Tolerances
Deltamethrin is a broad spectrum insecticide used throughout the
world to control pests of livestock, crops, ornamental plants and turf,
and household, commercial, and industrial food use areas. A
reevaluation of the maximum residue limits (MRL s) was conducted in
1994, in accordance with the EC Directive (91/414/EEC) Registration
Requirements for Plant Protection Products. A comparison of the
proposed CODEX MRLs and proposed tolerances for deltamethrin is
presented below:
------------------------------------------------------------------------
Proposed/Current Proposed/
MRL Established
Commodity ---------------------------------------
(CODEX) Tolerance (USEPA)
------------------------------------------------------------------------
Food/Feed Handling Uses......... 0.05 ppm.......... 0.05 ppm
------------------------------------------------------------------------
[FR Doc. 97-10893 Filed 4-29-97; 8:45 am]
BILLING CODE 6560-50-F