[Federal Register Volume 62, Number 133 (Friday, July 11, 1997)]
[Notices]
[Pages 37246-37256]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-18085]
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ENVIRONMENTAL PROTECTION AGENCY
[PF-741; FRL-5723-1]
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 food commodities.
DATES: Comments, identified by the docket control number PF-741, must
be received on or before August 11, 1997.
ADDRESSES: By mail submit written comments to: Public Response and
Program Resources Branch, Field Operations Division (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: The product manager listed in the
table below:
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Office location/
Product Manager telephone number Address
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George LaRocca (PM 13)........ Rm. 204, CM #2, 703- 1921 Jefferson
305-6100, e- Davis Hwy,
mail:[email protected] Arlington, VA
v.
Mary Waller (PM 21)........... Rm. 265, CM #2, 703- Do.
308-9354, e-
mail:waller.mary@epam.
Cynthia Giles-Parker (PM 22).. Rm. 229, CM #2, 703- Do.
305-5540, e-mail:
parker.cynthia@epamai.
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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 food
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 granting 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-741 (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''.
Electronic comments can be sent directly to EPA at:
opp-docket@epamail.epa.gov
Electronic comments must be submitted as an ASCII file avoiding the
use of special characters and any form of encryption. Comment and data
will also be accepted on disks in Wordperfect 5.1 file format or ASCII
file format. All comments and data in electronic form must be
identified by the docket control number PF-741 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
[[Page 37247]]
additives, Feed additives, Pesticides and pests, Reporting and
recordkeeping requirements.
Dated: July 2, 1997.
Peter Caulkins,
Acting Director, Registration Division, Office of Pesticide Programs.
Summaries of Petitions
Below petitioner summaries of the pesticide petitions are printed
as required by section 408(d)(3) of the FFDCA. The summaries of the
petitions were prepared by the petitioners and represent the views of
the petitioners. EPA is publishing the petition summaries verbatim
without editing them in any way. The petition summary announces the
availability of a description of the analytical methods available to
EPA for the detection and measurement of the pesticide chemical
residues or an explanation of why no such method is needed.
1. ISK Biosciences Corporation
PP 6F4611
EPA has received a pesticide petition (PP 6F4611, (dated 6/25/95)
from ISK Biosciences Corporation (``ISK''), 5966 Heisley Road, P.O. Box
8000, Mentor, Ohio 44061-8000 proposing pursuant to section 408(d) of
the Federal Food, Drug and Cosmetic Act, 21 U.S.C. section 346a(d), to
amend 40 CFR part 180.275 by establishing tolerances for residues of 4-
hydroxy-2,5,6-trichloroisophthalonitrile (SDS-3701), a metabolite of
the fungicide chlorothalonil, in/on raw agricultural meat and milk
commodities as follows:
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Commodity Parts per million
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Cattle, fat............................... 0.1
Cattle, kidney............................ 0.5
Cattle, meat.............................. 0.03
Cattle, mbyp (except kidney).............. 0.05
Goats, fat................................ 0.1
Goats, kidney............................. 0.5
Goats, meat............................... 0.03
Goats, mbyp (except kidney)............... 0.05
Hogs, fat................................. 0.1
Hogs, kidney.............................. 0.5
Hogs, meat................................ 0.03
Hogs, mbyp (except kidney)................ 0.05
Horses, fat............................... 0.1
Horses, kidney............................ 0.5
Horses, meat.............................. 0.03
Horses, mbyp (except kidney).............. 0.05
Milk...................................... 0.1
Sheep, fat................................ 0.1
Sheep, kidney............................. 0.5
Sheep, meat............................... 0.03
Sheep, mbyp (except kidney)............... 0.05
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A. Residue Chemistry
1. Plant/Animal metabolism. The nature of the residue of
chlorothalonil in plants and animals, including ruminants, is
adequately understood. Chlorothalonil is not systemic in plants.
Chlorothalonil is rapidly metabolized in the ruminant and is not
transferred in animals to meat and milk through dietary consumption of
feedstuffs from crops treated with chlorothalonil products. Analytical
method development studies and storage stability studies with
chlorothalonil demonstrated that it is not stable in meat or milk.
Studies have determined that the chlorothalonil metabolite, 4-hydroxy-
2,5,6-trichloroisophthalonitrile, may be present in meat and milk from
dietary intake of animal feed items from chlorothalonil treated crops.
The metabolite, 4-hydroxy-2,5,6-trichloroisophthalonitrile, is stable
in meat and milk.
2. Analytical method. The analytical method (electron capture gas
chromatography) is adequate for analysis of 4-hydroxy-2,5,6-
trichloroisophthalo-nitrile in meat and milk and has been submitted to
the Agency for inclusion in PAM Vol. II. The method has undergone a
successful method validation by an independent laboratory.
3. Magnitude of the residues. Residue studies and metabolism
studies have shown that residues of chlorothalonil per se are not
expected to transfer from feed items to meat/milk but residues of 4-
hydroxy-2,5,6-trichloroisophthalonitrile could occur in these
commodities both from direct transfer of residues of the metabolite
found on feedstuffs in the diet and from a low percentage conversion of
chlorothalonil to the metabolite in the animal. Due to the instability
of chlorothalonil per se in meat and milk tissues, residues would not
be expected to occur even from misuse of chlorothalonil. The
chlorothalonil related residue found in meat and milk is 4-hydroxy-
2,5,6-trichloroisophthalonitrile. The submitted lactating dairy cow
feeding study is adequate to determine appropriate tolerance levels in
meat and milk. Analytical results are supported by frozen storage
stability data. No significant losses of 4-hydroxy-2,5,6-
trichloroisophthalonitrile occurred during frozen storage of spiked
analytical samples. Studies have shown that 4-hydroxy-2,5,6-
trichloroisophthalonitrile does not persist long in animals and that it
does not bioaccumulate in animal tissues.
The proposed tolerances are adequate to cover residues of 4-
hydroxy-2,5,6-trichloroisophthalonitrile that might occur in meat and
milk as a result of chlorothalonil uses on presently-registered crops
that may involve animal feed items.
B. Toxicological Profile
The following studies on file with the Agency support this
petition.
1. Acute toxicity. Acute toxicity studies include an acute oral rat
study on technical chlorothalonil with an LD50 >10,000 mg/
kg, an acute dermal toxicity study in the rabbit with an
LD50 >20,000 mg/kg, a four-hour inhalation study with finely
ground technical chlorothalonil resulting in a 4-hour LC50
of 0.092 mg/L (actual airborne concentration), a primary eye irritation
study with irreversible eye effects in the rabbit at 21 days, a primary
dermal irritation study showing technical chlorothalonil is not a
dermal irritant, and a dermal sensitization study showing technical
chlorothalonil is not a skin sensitizer.
Acute oral toxicity studies with the 4-hydroxy metabolite, indicate
the oral LD50s in male and female rats were 332 and 242 mg/
kg respectively.
2. Genotoxicity. The mutagenic potential of chlorothalonil has been
evaluated in a large number of studies covering a variety of endpoints.
The overall conclusion is that chlorothalonil is not mutagenic.
Mutagenicity studies with chlorothalonil include gene mutation
assays in bacterial and mammalian cells; in vitro and in vivo
chromosomal aberration assays; DNA repair assays in bacterial systems;
and cell transformation assays. All were negative with the following
two exceptions:
a. Chlorothalonil was positive in an in vitro chromosomal
aberration assay in (Chinese Hamster Ovary (CHO) cells without
metabolic activation but was negative with metabolic activation.
b. In vivo chromosomal aberration studies in rats and mice were
negative and one study in the Chinese hamster was equivocal. The
results of this study could not be confirmed in a subsequent study at
higher doses. The conclusion was that chlorothalonil does not cause
chromosome aberrations in bone marrow cells of the Chinese hamster. It
can be concluded that chlorothalonil
[[Page 37248]]
does not have clastogenic potential in intact mammalian systems.
In bacterial DNA repair tests, chlorothalonil was negative in
Bascillus subtilis, but was positive in Salmonella typhimurium. In an
in vivo DNA binding study in rats with 14C-chlorothalonil, there was no
covalent binding of the radiolabel to the DNA of the kidney, the target
organ for chlorothalonil toxicity in rodents.
c. The mutagenic potential of the 4-hydroxy metabolite has also
been evaluated for a variety of endpoints and it is concluded that it
is not mutagenic. The 4-hydroxy metabolite has been tested in gene
mutations assays in bacterial and mammalian cells; in vivo and in vitro
chromosome aberration studies; a DNA repair assay in the Salmonella
typhimurium; and a cell transformation assay.
The 4-hydroxy metabolite was positive in only one assay, an in
vitro chromosome aberration assay in CHO cells. In vivo, the 4-hydroxy
metabolite was negative in a bone marrow chromosome aberration study in
Chinese hamsters. Dominant lethal studies in rats and mice were clearly
negative in rats and equivocal in mice. Because it was negative in vivo
in studies to test for chromosome damage, it can be concluded that the
4-hydroxy metabolite does not have clastogenic potential in intact
mammalian systems
3. Developmental and reproductive toxicity. a. A developmental
toxicity study with rats given gavage doses of 0, 25, 100, and 400 mg/
kg body weight/day of chlorothalonil from days 6 through 15 of
gestation resulted in a no observed effect level (NOEL) for maternal
toxicity of 100 mg/kg/day based on increased mortality, reduced body
weight, and a slight increase in early resorptions at the highest dose.
There were no developmental effects observed at any dose in this study.
b. A developmental toxicity study in rabbits given gavage doses of
0, 5, 10, or 20 mg/kg/day of chlorothalonil on days 7 through 19 of
gestation resulted in a maternal NOEL of 10 mg/kg/day. Effects observed
in the dams in the high-dose group were decreased body weight gain and
reduced food consumption. There were no developmental effects observed
in this study.
c. A two-generation reproduction study in rats fed diets containing
0, 500, 1,500 and 3,000 ppm of chlorothalonil resulted in a
reproductive NOEL of 1,500 ppm (equivalent to 115 mg/kg/day) based on
lower neonatal body weights by day 21.
There were no effects seen on any reproductive parameter at any
dose level in this study.
d. A developmental toxicity study in rabbits receiving gavage doses
of 0, 1, 2.5 or 5 mg/kg/day of the 4-hydroxy metabolite on days 6
through 18 of gestation resulted in a maternal NOEL of 2.5 mg/kg/day.
Effects observed in the dams in the high-dose group were an increase in
the number of females with dead or resorbed fetuses and in the number
of aborted fetuses. There were no developmental effects observed in
this study.
e. A three-generation reproduction study in rats fed diets
containing 0, 10, 60 and 125 ppm of the 4-hydroxy metabolite, resulted
in a NOEL of 10 ppm (equivalent to 0.5 mg/kg/day) based on lower
neonatal body weights on days 14 and 21 of lactation. The reduction of
pup growth at the two highest dose levels during the later part of the
gestation period can be attributed to the direct ingestion of the adult
diet by the pups which resulted in inordinately high doses (per kg of
body weight) of the test material for the pups as compared to the
adults. There were no effects seen on any reproductive parameter at any
dose level in this study. The reproductive NOEL was the highest dose
tested.
f. A one generation reproduction study in rats was conducted to
further define the NOEL for the reduction in pup growth observed during
lactation in the three generation reproduction study with the 4-hydroxy
metabolite. Dietary levels of 0, 10, 20, 30, 60 and 120 ppm of the 4-
hydroxy metabolite were fed to rats. Two litters, F1a and F1b were
evaluated. The NOEL in this study was determined to be 30 ppm
(equivalent to 1.5 mg/kg/day).
4. Subchronic toxicity. a. A subchronic toxicity study (90-days)
was conducted in rats with chlorothalonil at doses of 0, 1.5, 3.0, 10
and 40 mg/kg bwt. Treatment-related hyperplasia and hyperkeratosis of
the forestomach were observed at the two highest dose levels. Although
the initial histopathological evaluation did not demonstrate any
nephrotoxicity, a subsequent evaluation observed a treatment-related
increase in hyperplasia of the proximal tubule epithelium at 40 mg/kg
bwt. in the male rats but not in the females. The no effect level for
renal histopathology was 10 mg/kg bwt. in males and 40 mg/kg bwt. in
females.
b. A 90-day oral toxicity study was conducted in dogs with dose
levels of technical chlorothalonil of 15, 150 and 750 mg/kg bwt./day.
The two highest dosages resulted in lower body weight gain in male
dogs. The NOAEL was 15 mg/kg/day. There were no macroscopic or
microscopic tissue alterations related to chlorothalonil and there were
no signs of renal toxicity.
c. A subchronic toxicity study (60-days) was conducted in rats with
the 4-hydroxy metabolite at doses of 0, 10, 20, 40, 75, 125, 250, 500,
and 750 mg/kg bwt. The NOEL was determined to be 20 mg/kg/day.
Treatment-related effects observed at higher doses included changes in
hematopoietic and clinical chemistry parameters, mild hemosiderosis,
toxic hepatitis, and microscopic degeneration in several organs.
d. Two 21-day dermal toxicity studies have been conducted with
technical chlorothalonil. In the initial study doses of 50, 2.5 and 0.1
mg/kg bwt./day were administered to rabbits. The NOEL for systemic
effects was greater than 50 mg/kg bwt./day and the NOEL for dermal
irritation was 0.1 mg/kg bwt./day.
e. A subsequent 21-day dermal study was conducted in male rats, to
specifically evaluate the potential for nephrotoxicity in this
laboratory species following dermal dosing. In this study the doses
were 60, 100, 250 and 600 mg/kg bwt./day. The NOEL for nephrotoxicity
was greater than 600 mg/kg bwt./day.
5. Estrogenic effects. Based upon all of the chronic toxicity,
teratogenicity, mutagenicity and reproductive studies conducted with
chlorothalonil and its metabolites, including the 4-hydroxy metabolite,
there were no results which indicate any potential to cause estrogenic
effects, or endocrine disruption. These effects would have manifested
themselves in these studies as reproductive or teratogenic effects, or
by producing histopathological changes in estrogen sensitive tissues
such as the uterus, mammary glands or the testes. Thus, it can be
concluded based upon the in vivo studies, that chlorothalonil does not
cause estrogenic effects.
6. Chronic toxicity. a. A 12-month chronic oral toxicity study in
Beagle dogs was conducted with technical chlorothalonil at dose levels
of 15, 150 and 500 mg/kg/day. The NOAEL was 150 mg/kg/day based on
lower blood albumin levels at the highest dose. There was no
nephrotoxicity observed at any dose in this study. This study replaced
an old outdated study that was not conducted under current guidelines
and did not use the current technical material.
b. A chronic feeding/carcinogenicity study with Fischer 344 rats at
dose levels of 0, 40, 80 or 175 mg/kg/day of technical chlorothalonil
for 116 weeks in males or 129 weeks in females, resulted in a
statistically higher incidence of combined renal adenomas and
carcinomas. At the high dose,
[[Page 37249]]
which was above the MTD, there was also a statistically significant
higher incidence of tumors of the forestomach in female rats.
c. In a second chronic feeding/carcinogenicity study with technical
chlorothalonil in Fischer 344 rats, designed to define the NOEL for
tumors and the preneoplastic hyperplasia, animals were fed diets which
resulted in dose levels of 0, 2, 4, 15 or 175 mg/kg/day. The NOEL in
this study, based on renal tubular hyperplasia, was a nominal dose of 2
mg/kg bwt./day. Because of the potential for chlorothalonil to bind to
diet, the 2 mg/kg bwt./day dose, expressed as unbound chlorothalonil is
1.8 mg/kg bwt./day. The NOEL for hyperplasia and hyperkeratosis of the
forestomach was 4 mg/kg bwt./day or a dose of 3.8 mg/kg bwt./day based
on unbound chlorothalonil.
d. A 2-year carcinogenicity study, conducted in CD-1 mice with
technical chlorothalonil at dietary levels of 0, 750 and 1,500 or 3,000
ppm (equivalent to 0, 107, 214 or 428 mg/kg/day), resulted in a
statistically higher incidence of squamous cell carcinoma of the
forestomach in both sexes, and a statistically higher incidence of
combined renal adenoma/carcinoma in only the male mice receiving the
low dose. There were no renal tumors in any female mouse in this study.
e. A 2-year carcinogenicity study in male CD-1 mice for the purpose
of establishing the no effect level for renal and forestomach effects
associated with technical chlorothalonil, was conducted at dietary
levels of 0, 10/15, 40, 175, or 750 ppm (equivalent to 0, 1.4/2.1, 5.7,
25 or 107 mg/kg/day). The NOEL level for renal effects was 40 ppm and
the NOEL for forestomach effects was 15 ppm. This study did not
duplicate the results from the previous study where a statistically
higher incidence of renal tumors, when compared to controls, was
observed at 750 ppm. No tumors were observed at this dose level in this
study.
f. A chronic feeding/carcinogenicity study with CD rats at doses of
0, 0.5, 3.0, 15, or 30 mg/kg/day has been conducted with the 4-hydroxy
metabolite. Because of the severity of the toxicity observed during the
first six months of the study, the two highest dose levels were reduced
to 10 and 20 mg/kg/day. The animals receiving the highest dose were
terminated at 12 months. There were no neoplastic effects at any dose
level and the NOEL for chronic toxicity was 3 mg/kg/day. At the higher
dose levels, the treatment related effects included microcytic anemia
with an increased number of reticulocytes and metarubricytes,
hypocellular bone marrow, hemosiderin deposition in liver and bone
marrow and serum biochemistry changes and degenerative tissue changes
related to hypoxia.
g. A carcinogenicity study in CD-1 mice was conducted at dietary
levels of 0, 375, 750 and 1500 ppm of the 4-hydroxy metabolite. The
mean body weights of the high dose males and females were 4-15% and 5-
18% lower, respectively, when compared to controls. Liver weights were
also higher at the highest dietary level. There was no increase in the
incidence of any malignant or benign tumor at any dose in this study.
In 1987, the Office of Pesticide Programs' Toxicology Branch Peer
Review Committee classified chlorothalonil as a B2 (probable human
carcinogen), based on evidence of carcinogenicity in the forestomach
and kidneys of rats and mice. The Agency currently regulates
chlorothalonil as a B2 carcinogen although ISK Biosciences Corporation
has provided a significant amount of mechanistic data indicating that
the tumors result from a threshold mechanism. A potency factor,
Q1*, of 0.00766 (mg/kg/day)-1 has been used by the Agency
when conducting mathematical modeling to estimate carcinogenic risk to
man. ISK Biosciences Corporation believes that because the
nephrotoxicity seen in the rat is due to a threshold mechanism, any
risk associated with chlorothalonil can be managed using the margin of
safety (exposure) approach.
Numerous metabolism and toxicology studies indicate that
chlorothalonil is non-genotoxic, and produces a species specific renal
toxicity in the rat that eventually may lead to tumor formation through
an epigenetic mechanism. Studies comparing metabolism and toxicological
effects in dogs with those in rats demonstrate that the renal effects
observed in the rat are due to the exposure of the kidney of the rat to
significant levels of nephrotoxic thiol metabolites of chlorothalonil.
The 4-hydroxy metabolite was not tumorigenic in either the rat or
mouse. Reference Dose (RfD): The no effect level for chlorothalonil in
the rat is 1.8 mg/kg bwt. based on the nephrotoxicity observed in the
chronic study. The no effect level in the dog was 15 mg/kg bwt. in the
90-day study and 150 mg/kg bwt. based on the one-year study. No effect
levels for maternal toxicity from developmental studies are 10 mg/kg
bwt. in rabbits and 100 mg/kg bwt. in the rat. The no effect level for
pup growth in the reproduction study was 1,500 mg/kg bwt. which would
be most conservatively estimated as equating to approximately 75 mg/kg
bwt. The data indicate that the nephrotoxicity in the rat is produced
through a mechanism for which there is a clear threshold. In a study
which measured cell turnover in the rat kidney with BRDU, a NOEL was
established at 1.5 mg/kg bwt. Other chronic studies have established
the NOEL for hyperplasia in the kidney to be 1.8 mg/kg bwt. If all the
available toxicity data in laboratory animals are considered without
regard to applicability to humans, the lowest NOEL for any adverse
effect would be 1.5 mg/kg bwt./day. Because the mechanism of toxicity
which is related to the tumor formation in the kidney has been shown to
have a threshold, the use of the normal 100-fold safety factor in
conjunction with the 1.5 mg/kg no observable effect level would produce
a reference dose which would provide more than adequate safety for all
of the possible effects seen in any laboratory animal.
In the two reviews of chlorothalonil by the Joint Meeting of
Pesticide Residue Experts, and the review by the World Heath
Organization's International Program For Chemical Safety, these
esteemed groups concluded that the rat was not the appropriate species
to use in consideration of the risk assessment for man. They concluded
that the dog was the more appropriate species for determination of
subchronic and chronic effects. If the toxicological data for the dog
were used, the NOEL would be at least 15 mg/kg bwt., based on the most
recent 90-day study in the dog.
The NOEL for the 4-hydroxy metabolite based on the reduction of
weight gain late in the lactation period in a reproduction study would
be 30 ppm or 1.5 mg/kg/ day. This was not a reproductive effect. The
NOEL based on chronic toxicity in the rat would be 3.0 mg/kg bwt/day.
Therefore, under the most conservative scenario, the reference dose
for chlorothalonil including its 4-hydroxy metabolite would be 1.5 mg/
kg bwt./day divided by a 100-fold safety factor or 0.015 mg/kg bwt./day
with a threshold model being used for carcinogenic risk assessment. In
the scenario that uses the toxicological data in the dog, the reference
dose would be 15 mg/kg bwt./day. divided by a safety factor of 100 or
0.15 mg/kg bwt./day.
C. Aggregate Exposure
The following is a description of the likelihood of exposure to
chlorothalonil from various routes:
1. Dietary exposure (Food). No residues of chlorothalonil per se
will be added to the total exposure of chlorothalonil from consumption
of
[[Page 37250]]
meat or milk from livestock which were fed chlorothalonil-treated
commodities. Residues of 4-hydroxy-2,5,6-trichloroisophthalo-nitrile on
crops treated with products containing chlorothalonil are a very low
percentage of the total crop residue. Although 4-hydroxy-2,5,6-
trichloroisophthalonitrile will transfer to meat and milk, the levels
present on feedstuffs which are available for transfer are low.
Presently, there are very few uses of chlorothalonil which involve
livestock commodities. Meat and milk tolerances for 4-hydroxy-2,5,6-
trichloroisophthalonitrile are needed to support the reregistration of
chlorothalonil.
2. Drinking water. Chlorothalonil was included for monitoring in
the National Survey of Pesticides in Drinking Water Wells conducted by
EPA. No chlorothalonil residues were detected in any of the 1,300
community water systems and domestic wells (using methodology for
chlorothalonil having a limit of detection [LOD] of 0.06 mg/l and limit
of quantitation of 0.12 mg/l). The absence of chlorothalonil detections
in the National Survey provides adequate information to conclude that
chlorothalonil is not a contaminant in drinking water wells and that
the population is not exposed to chlorothalonil in these water sources.
These findings are consistent with the known physical/ chemical
properties of chlorothalonil including low water solubility (0.9 ppm)
and high affinity for organic matter including soil. It has also been
demonstrated that chlorothalonil does not leach into groundwater from
applications made to growing crops.
Aerobic aquatic metabolism studies with chlorothalonil establish a
half-life in natural aquatic habitats of less than 10 hours, depending
on environmental conditions. Considering the short half-life of
chlorothalonil in natural water/sediment systems and that surface water
is filtered and treated prior to consumption, chlorothalonil is not
likely to be present in drinking water obtained from natural surface
water systems.
If the exposure estimate is based on the surface water
concentration recently cited by EPA, it is concluded that the average
concentration in surface water would be less than 0.002 ppb. Assuming
that everyone in the US consumed untreated surface water, the exposure
to chlorothalonil to the general population would be less than 5.8 x
10-7 mg/kg bwt./day. This would be a worst case scenario.
The 4-hydroxy metabolite did not leach into ground water in a
prospective groundwater study, therefore, no intake of this metabolite
would be anticipated from drinking water.
3. Non-dietary exposure. Potential non-dietary exposures to
chlorothalonil may result from the following uses of chlorothalonil. In
each case, the exposure would be from the dermal route and only for an
intermittent duration. The two 21-day dermal studies that have been
conducted in the rabbit and rat indicate that there is no
nephrotoxicity associated with the dermal exposure to chlorothalonil at
dose levels up to 600 mg/kg/day. Therefore, the exposures from the uses
of chlorothalonil listed below, would not be expected to add to the
carcinogenic risk associated with chlorothalonil.
Because the 4-hydroxy metabolite is a soil metabolite, no
significant exposure would be anticipated through non-dietary routes.
Although some hydrolysis of chlorothalonil to the 4-hydroxy metabolite
may occur at a basic pH in some paint or wood treatment products, the
anticipated exposure when the products dry would be negligible.
a. Golf course uses. Chlorothalonil products are commonly applied
to golf course tees and greens to control a broad complex of turf
diseases. Application to golf course fairways is much less common. Golf
is not a game played by infants or small children, therefore no
exposure to infants and children would be anticipated.
b. Residential owner uses. Applications of chlorothalonil products
to home lawns are rare. Thus, there is very little exposure to
chlorothalonil related to use on residential turf. Applications to
roses and other ornamentals in home gardens is also a minor use of
chlorothalonil.
c. Paint. Chlorothalonil is used in paints and stains for control
of mildew and molds on exterior surfaces of buildings. Chlorothalonil
is also occasionally used for interior paints, but this use represents
only a small proportion of the chlorothalonil used in paints. About 2%
of the chlorothalonil used in paint is used in interior paint; however,
only 0.2% or less of the interior paints in the United States contain
chlorothalonil. In paints, chlorothalonil is tightly bound within the
matrices of the paint; thus, effective control of mildew may last for
several years.
d. Grouts. Chlorothalonil is used in cement tile grouts for control
of mildew and molds. Chlorothalonil is bound within the grout matrices
and very little is available for exposure. This is a minor use of
chlorothalonil and non-occupational dermal exposure of humans to
chlorothalonil from this source is extremely low.
e. Wood treatment. Chlorothalonil is not used for pressure-treating
wood. It is used for control of sapstain as a surface treatment on
rough-cut, newly-sawn lumber to protect it from molds and mildews while
drying. Being a surface residue, it is removed during the finishing
operations prior to sale of the wood. Chlorothalonil does not occur in
structural wood used for residential or occupational scenarios.
D. Cumulative Effects
ISK Biosciences has considered the potential for cumulative effects
of chlorothalonil and other substances that have a common mechanism of
toxicity. Chlorothalonil is a halogenated benzonitrile fungicide which
readily undergoes displacement of the chlorines in the 2, 4 and 6
positions by glutathione and other thiol containing amino acids and
proteins. In the rat, the glutathione binding, absorption and
subsequent metabolism to form the di- and tri-thiol metabolites occur
at sufficient levels to produce a nephrotoxic effect. In dogs where
this mechanism does not occur to produce thiol metabolites,
nephrotoxicity does not occur. ISK Biosciences does not have any
information to indicate that toxic effects observed in rats occur
through a mechanism which is common to any other agricultural chemical.
Thus, consideration of common mechanisms of toxicity is not appropriate
at this time.
Chlorothalonil should not be confused with chemicals classified as
chlorinated hydrocarbon pesticides which have significantly different
chemical and biological properties.
There would be no cumulative effects expected between
chlorothalonil and its 4-hydroxy metabolite because each affects a
different toxicological endpoint.
E. Safety Determination
1. U.S. population. The majority of exposure to chlorothalonil and
its 4-hydroxy metabolite would be expected to occur from the diet. In
EPA's Dietary Exposure Analysis for the Use of Chlorothalonil in/on
Meat and Milk Products, dated April 23, 1996, the Agency determined
that ``Chlorothalonil does not pose a significant chronic or acute
dietary risk for uses that are currently published or for uses
recommended by CBRS for registration''. The Agency concluded that
because of the instability of chlorothalonil in meat and milk, that
even in misuse, residues of chlorothalonil would not transfer from
[[Page 37251]]
animal feed items to meat and milk. The EPA determined that the 4-
hydroxy metabolite would be a residue in meat and milk and that the
chronic RfD for chlorothalonil would be sufficient for the metabolite.
The Agency calculated that the Anticipated Residue Contribution
when the tolerances for meat and milk are approved, would be 6.8% for
the general population and 37% for non-nursing infants (<1 yr.="" old).="" in="" estimating="" the="" carcinogenic="" risk,="" the="" agency="" indicated="" that="" since="" the="" 4-hydroxy="" metabolite="" was="" not="" carcinogenic,="" and="" that="" no="" residues="" of="" chlorothalonil="" would="" transfer="" to="" meat="" and="" milk,="" the="" carcinogenic="" risk="" calculated="" for="" chlorothalonil="" would="" not="" be="" affected="" by="" this="" tolerance.="" the="" agency="" has="" used="" a="" linearized="" model="" to="" estimate="" the="" carcinogenic="" risk="" associated="" with="" chlorothalonil,="" whereas="" isk="" biosciences="" believes="" that="" a="" threshold="" based="" model="" is="" appropriate.="" because="" the="" worst="" case="" assumptions="" for="" human="" exposure="" from="" drinking="" water="" indicate="" that="" exposure="" would="" be="" only="" 1%="" of="" the="" dietary="" exposure,="" the="" risk="" assessment="" is="" not="" significantly="" altered="" by="" considering="" the="" exposure="" from="" drinking="" water.="" 2.="" infants="" and="" children.="" there="" is="" a="" complete="" database="" for="" chlorothalonil="" which="" includes="" pre-="" and="" post-natal="" developmental="" toxicity="" data="" as="" well="" as="" mechanistic="" data="" related="" to="" the="" rodent="" specific="" nephrotoxicity="" observed="" in="" subchronic="" and="" chronic="" studies.="" the="" toxicological="" effects="" of="" chlorothalonil="" in="" rodents="" are="" well="" understood.="" chlorothalonil="" has="" a="" low="" level="" of="" toxicity="" in="" dogs.="" in="" a="" two-generation="" reproduction="" study="" in="" rats,="" all="" reproductive="" parameters="" investigated="" showed="" no="" treatment-related="" effects="" except="" pup="" weight="" gain.="" specifically,="" the="" weights="" of="" pups="" exposed="" to="" chlorothalonil="" were="" comparable="" to="" controls="" at="" parturition="" through="" day="" four="" of="" lactation.="" it="" was="" only="" after="" day="" four="" of="" lactation,="" when="" the="" pups="" begin="" to="" consume="" the="" test="" diet,="" that="" body="" weight="" gain="" lags="" behind="" controls.="" this="" only="" occurred="" at="" the="" highest="" dose="" tested,="" 3,000="" ppm.="" the="" dose="" of="" chlorothalonil="" the="" pups="" would="" receive="" would="" be="" far="" in="" excess="" of="" the="" estimated="" adult="" dose="" of="" 150="" mg/kg="" (3,000="" ppm/20).="" the="" doses="" for="" the="" pups="" could="" have="" easily="" exceeded="" 500="" mg/kg="" bwt./day.="" dose="" levels="" of="" 375="" mg/kg="" bwt.="" and="" above="" have="" been="" shown="" to="" significantly="" affect="" body="" weight="" in="" the="" rat.="" therefore,="" the="" reduction="" of="" body="" weight="" gain="" observed="" in="" the="" reproduction="" study="" is="" considered="" to="" be="" comparable="" to="" the="" effects="" that="" have="" been="" observed="" in="" older="" rats.="" the="" noel="" for="" this="" effect="" was="" 1,500="" ppm.="" in="" a="" three="" generation="" reproduction="" study="" and="" a="" subsequent="" one="" generation="" study="" with="" the="" 4-hydroxy="" metabolite,="" there="" were="" no="" reproductive="" effects="" even="" at="" a="" dose="" that="" produced="" parental="" toxicity.="" although="" a="" reduction="" in="" pup="" growth="" was="" noted="" at="" dietary="" concentrations="" of="" 60="" ppm="" and="" higher,="" it="" could="" be="" attributed="" to="" an="" inordinately="" high="" dose="" of="" the="" test="" material="" received="" by="" the="" pups="" when="" compared="" to="" adults.="" in="" developmental="" toxicity="" studies="" conducted="" in="" the="" rat="" and="" the="" rabbit,="" chlorothalonil="" did="" not="" cause="" any="" developmental="" effects="" even="" at="" dose="" levels="" that="" produced="" significant="" maternal="" toxicity.="" in="" the="" rabbit="" a="" dose="" level="" of="" 20="" mg/kg="" caused="" maternal="" toxicity,="" but="" there="" were="" no="" developmental="" effects,="" and="" in="" the="" rat="" a="" dose="" level="" of="" 400="" mg/kg="" caused="" maternal="" toxicity="" without="" developmental="" toxicity.="" in="" a="" developmental="" toxicity="" study="" conducted="" with="" the="" 4-hydroxy="" metabolite="" there="" were="" no="" developmental="" effects="" even="" at="" doses="" that="" produced="" significant="" maternal="" toxicity.="" a="" dose="" of="" 5="" mg/kg="" produced="" maternal="" toxicity="" but="" there="" were="" no="" developmental="" effects.="" the="" extensive="" database="" that="" is="" available="" for="" chlorothalonil="" and="" its="" 4-hydroxy="" metabolite="" is="" devoid="" of="" any="" indication="" that="" either="" material="" would="" represent="" any="" unusual="" or="" disproportionate="" hazard="" to="" infants="" or="" children.="" therefore,="" there="" is="" no="" need="" to="" impose="" an="" additional="" 10x="" safety="" factor="" for="" infants="" or="" children.="" the="" standard="" uncertainty="" factor="" of="" 100x="" should="" be="" used="" for="" all="" segments="" of="" the="" human="" population="" when="" calculating="" risks="" associated="" with="" chlorothalonil="" or="" its="" 4-hydroxy="" metabolite.="" f.="" international="" tolerances="" a="" maximum="" residue="" level="" has="" not="" been="" set="" for="" the="" 4-hydroxy="" metabolite="" of="" chlorothalonil="" in="" milk="" and="" meat="" by="" the="" codex="" alimentarius="" commission.="" the="" data="" indicate="" that="" no="" tolerance="" would="" be="" necessary="" for="" chlorothalonil="" on="" milk="" and="" meat="" since="" it="" would="" not="" be="" expected="" to="" transfer="" from="" animal="" feed="" items="" to="" these="" commodities.="" (pm="" 22)="" 2.="" novartis="" pp="" 9f3740,="" pp="" 5f4424,="" pp="" 5f4591,="" pp="" 5f4498="" epa="" has="" received="" pesticide="" petitions="" (pp)="" 9f3740,="" 5f4424,="" 5f4591,="" 5f4498="" from="" novartis="" crop="" protection="" inc.,="" po="" box="" 18300,="" greensboro,="" nc="" 27419.="" the="" petition="" proposes,="" to="" amend="" 40="" cfr="" part="" 180,="" by="" establishing="" a="" tolerance="" for="" the="" residues="" of="" the="" fungicide="" propiconazole,="" which="" is="" a="" triazole="" fungicide="" registered="" for="" use="" on="" many="" crops,="" including="" bananas,="" celery,="" corn,="" grasses="" grown="" for="" seed,="" mint="" (west="" of="" the="" cascade="" mountains),="" pecans,="" peanuts,="" rice,="" small="" grains="" (barley,="" oats,="" rye,="" wheat),="" stone="" fruit,="" and="" wild="" rice.="" use="" rates="" range="" from="" 0.07="" to="" 0.22="" pound="" (lb.)="" active="" ingredient="" per="" acre.="" petitions="" currently="" pending="" for="" propiconazole="" include:="" the="" tree="" nuts="" (pp="" 9f3740);="" drybean="" and="" soybeans="" (pp="" 5f4424);="" berry="" crop="" grouping,="" carrots,="" and="" onions="" (pp="" 5f4591);="" and="" alfalfa="" and="" sorghum="" (pp="" 5f4498).="" a.="" residue="" chemistry="" 1.="" metabolism.="" novartis="" believes="" the="" studies="" supporting="" propiconazole="" adequately="" characterize="" metabolism="" in="" plants="" and="" animals.="" the="" metabolism="" profile="" supports="" the="" use="" of="" an="" analytical="" enforcement="" method="" that="" accounts="" for="" combined="" residues="" of="" propiconazole="" and="" its="" metabolites="" which="" contain="" the="" 2,4-dichlorobenzoic="" acid="" (dcba)="" moiety.="" 2.="" analytical="" methodology.="" novartis="" has="" submitted="" a="" practical="" analytical="" method="" involving="" extraction,="" filtration,="" conversion,="" partition,="" derivitization,="" and="" solid="" phase="" cleanup="" with="" analysis="" by="" confirmatory="" gas="" chromatography="" using="" electron="" capture="" detection="" (ecd).="" the="" total="" residue="" method="" is="" used="" for="" determination="" of="" propiconazole="" and="" its="" metabolites.="" the="" limit="" of="" quantitation="" (loq)="" for="" the="" method="" is="" 0.05="" part="" per="" million="" (ppm).="" 3.="" magnitude="" of="" residue.="" field="" residue="" trials="" have="" been="" conducted="" at="" various="" rates,="" timing="" intervals,="" and="" applications="" methods="" to="" represent="" the="" use="" patterns="" which="" would="" most="" likely="" result="" in="" the="" highest="" residues.="" for="" all="" samples,="" the="" total="" residue="" method="" was="" used="" for="" determination="" of="" the="" combined="" residues="" of="" parent="" and="" its="" metabolites="" which="" contain="" the="" dcba="" moiety.="" b.="" toxicological="" profile="" the="" following="" mammalian="" toxicity="" studies="" have="" been="" conducted="" to="" support="" the="" tolerances="" of="" propiconazole:="" a="" rat="" acute="" oral="" study="" with="" a="">50 of 1,517 mg/kg.
A rabbit acute dermal study with a LD50 > 6,000 mg/kg.
A rat inhalation study with a LC50 > 5.8 mg/liter air.
A primary eye irritation study in rabbits which showed mild
irritation.
A primary dermal irritation study in rabbits which showed slight
irritation.
A skin sensitization study in guinea pigs which showed no
sensitization.
A 21-day dermal study in the rabbit with a No Observed Effect Level
(NOEL) of 200 mg/kg based on clinical signs of systemic toxicity.
[[Page 37252]]
A 28-day oral toxicity study in the rat with a No Observed Adverse
Effect Level (NOAEL) of 50 mg/kg based on increased liver weight.
A subchronic feeding study in the mouse with a NOEL of 20 ppm (3
mg/kg) based on liver pathologic changes.
A 13-week feeding study in the male mouse with a NOEL of 20 ppm (3
mg/kg) based on liver pathologic changes.
A 90-day feeding study in the rat with a NOEL of 240 ppm (24 mg/kg)
based on reduction in body weight gain.
A 90-day feeding study in the dog with a NOEL of 250 ppm (6.25 mg/
kg) based on reduced food intake and stomach histologic changes.
A 12-month feeding study in the dog with a NOEL of 50 ppm (1.25 mg/
kg) based on stomach histologic changes.
A 24-month oncogenicity feeding study in the mouse with a NOEL of
100 ppm (15 mg/kg). The MTD was exceeded at 2,500 ppm in males based on
decreased survival and body weight. Increased incidence of liver tumor
was seen in these males but no evidence of carcinogenicity was seen at
the next lower dose of 500 ppm in either sex.
A 24-month chronic feeding/oncogenicity study in the rat with a
NOEL of 100 ppm (5 mg/kg) based on body weight and blood chemistry. The
MTD was 2,500 ppm based on reduction in body weight gain and no
evidence of oncogenicity was seen.
An oral teratology study in the rabbit with a maternal NOEL of 30
mg/kg based on reduced food intake but without any fetotoxicity even at
the top dose of 180 mg/kg.
An oral teratology study in the rabbit with a maternal NOEL of 100
mg/kg based on reductions in body weight gain and food consumption and
a fetal NOEL of 250 mg/kg based on increased skeletal variations at 400
mg/kg.
An oral teratology study in the rat with a maternal and fetal NOEL
of 100 mg/kg based on decreased survival, body weight gain, and food
consumption in the dams and delayed ossification in the fetuses at 300
mg/kg.
A second teratology study in the rat with a maternal and fetal NOEL
of 30 mg/kg based on reductions in body weight gain and food
consumption in the dams and delayed development in the fetuses at 90
and 360/300 mg/kg.
A supplemental teratology study in the rat involving eight times as
many animals pergroup as usually required and showing no teratogenic
potential for the compound.
A 2-generation reproduction study in the rat showing excessive
toxicity at 5,000 ppm without any teratogenic effects.
A 2-generation reproduction study in the rat with no effects on
reproductive or fetal parameters at any dose level. Postnatal growth
and survival were affected at the top dose of 2,500 ppm, where parental
toxicity was also evident. The NOEL for development toxicity is 500
ppm.
In vitro gene mutation test: Ames assay - negative; rat hepatocyte
DNA repair test - negative; human fibroblast DNA repair test -
negative.
In vitro chromosome test: human lymphocyte cytogenetic test -
negative.
In vivo mutagenicity test: Chinese hamster bone marrow cell nucleus
aunomaly test -negative; Chinese hamster bone marrow cell micronucleus
test - negative; mouse dominant lethal test - negative.
Other mutagenicity test: BALB/3T3 cell transformation assay -
negative.
C. Threshold Effects
1. Chronic effects. Based on the available chronic toxicity data,
Novartis believes the Reference dose (RfD) for propiconazole is 0.0125
mg/kg/day. This RfD is based on a 1-year feeding study in dogs with a
No-Observed Effect Level of 1.25 mg/kg/day (50 ppm) and an uncertainly
factor of 100. No additional modifying factor for the nature of effects
was judged to be necessary as stomach mucosa hyperemia was the most
sensitive indicator of toxicity in that study.
2. Acute toxicity. The risk from acute dietary exposure to
propiconazole is considered to be very low. The lowest NOEL in a short
term exposure scenario, identified as 30 mg/kg in the rat teratology
study, is 24-fold higher than the chronic NOEL (see above). Based on
worst-case assumptions the chronic exposure assessment (see below) did
not result in any margin of exposure less than 150 for even the most
impacted population subgroup. Novartis believes that the margin of
exposure for acute exposure would be more than one hundred for any
population groups; margins of exposure of 100 or more are considered
satisfactory.
3. Non-threshold effects. Using the Guidelines for Carcinogenic
Risk Assessment published on September 24, 1986 (51 FR 33992), the
USEPA has classified propiconazole in group C for carcinogenicity
(evidence of possible carcinogenicity for humans). The compound was
tested in 24-month studies with both rats and mice. The only evidence
of carcinogenicity was an increase in liver tumor incidence in male
mice at a dose level that exceeded the maximum tolerated dose (MTD).
Dosage levels in the rat study were appropriate for identifying a
cancer risk. The Cancer Peer Review Committee recommended the RfD
approach for quantitation of human risk. Therefore, the RfD is deemed
protective of all chronic human health effects, including cancer.
D. Aggregate Exposure
1. Dietary exposure. For the purposes of assessing the potential
dietary exposure under the existing, pending, and proposed tolerances
for the residue of propiconazole and its metabolites determined as 2,4-
dichlorobenzoic acid, Novartis has estimated aggregate exposure based
upon the Theoretical Maximum Residue Concentration (TMRC). The TMRC is
a ``worst case'' estimate of dietary exposure since it assumes 100
percent of all crops for which tolerances are established are treated
and that pesticide residues are at the tolerance levels, resulting in
an overestimate of human exposure.
Currently established tolerances range from 0.05 ppm in milk to 60
ppm in grass seed screenings and include: apricots (1.0 ppm); bananas
(0.2 ppm); barley grain (0.1 ppm); barley straw (1.5 ppm); cattle
kidney and liver (2.0 ppm); cattle meat, fat, and meat by products
except kidney and liver (0.1 ppm); celery (5.0 ppm); corn forage and
fodder (12.0 ppm); corn grain and sweet (0.1); eggs (0.1 ppm); goat
kidney and liver (2.0 ppm); goat meat, fat, and meat by products except
kidney and liver (0.1 ppm); grass forage (0.5 ppm); grass hay/straw
(40.0 ppm); grass seed screenings (60.0 ppm); hogs kidney and liver
(2.0 ppm); hog meat, fat, and meat by products except kidney and liver
(0.1 ppm); horses kidney and liver (2.0 ppm); horse meat, fat, and meat
by products except kidney and liver (0.1 ppm); milk (0.05 ppm); mint
tops (0.3 ppm - regional tolerance west of Cascade Mountains);
mushrooms (0.1 ppm); nectarines (1.0 ppm); oat forage (10.0 ppm); oat
grain (0.1 ppm); oat hay (30.0 ppm); oat straw (1.0 ppm); peaches (1.0
ppm); peanut hay (20.0 ppm); peanut hulls (1.0 ppm); peanuts (0.2
ppm);, pecans (0.1 ppm); pineapple (0.1 ppm); pineapple fodder (0.1
ppm); plums (1.0 ppm); poultry liver and kidney (0.2 ppm); poultry
meat, fat, and meat by products except kidney and liver (0.1 ppm);
prunes, fresh (1.0 ppm); rice grain (0.1 ppm); rice straw (3.0 ppm);
wild rice (0.5 ppm regional tolerance Minnesota); rye grain (0.1 ppm);
rye straw (1.5 ppm); sheep kidney and liver (2.0 ppm); sheep meat, fat,
and meat by products except kidney and liver (0.1 ppm); stone fruit
crop group 12 (1.0 ppm); wheat grain (0.1 ppm); and wheat straw (1.5
ppm). In addition, time-limited regional tolerances for
[[Page 37253]]
sorghum grain and stover at 0.1 ppm and 1.5 ppm, respectively were
established to support a section 18 Crisis exemption in Texas
(expiration date 10/31/98).
Additional uses of propiconazole have been requested in several
pending petitions.
Proposed tolerances include: PP 5F4424 for use of propiconazole on
drybean and soybean -- dry bean forage (8.0 ppm); dry bean hay (8.0
ppm); dry bean vines (0.5 ppm); dry bean (0.5 ppm), soybeans (0.5 ppm);
soybean fodder (8.0 ppm); soybean forage (8.0 ppm); soybean hay (25.0
ppm); and soybean straw (0.1 ppm).
PP 5F4591 for use of propiconazole on berries, carrots and onions -
- berry crop grouping (1.0 ppm); dry bulb onion (0.3 ppm); green onion
(8.0).
PP 9F3740 -- tree nut crop grouping (0.1 ppm);
PP 5F4498 -- inadvertent/rotational crop tolerances for alfalfa
forage (0.1 ppm), alfalfa hay (0.1 ppm), grain sorghum fodder (0.3
ppm), grain sorghum forage (0.3 ppm) and grain sorghum grain (0.2 ppm).
Other potential sources of exposure of the general population to
residues of propiconazole are residues in drinking water and exposure
from non-occupational sources. Review of environmental fate data by the
Environmental Fate and Effects Division of USEPA indicates that
propiconazole is persistent and moderately mobile to relatively
immobile in most soil and aqueous environments. No Maximum
Concentration Level (MCL) currently exists for residues of
propiconazole in drinking water and no drinking water health advisory
levels have been established for propiconazole.
2. Drinking water exposure. The degradation of propiconazole is
microbially mediated with an aerobic soil metabolism half-life of 70
days. While propiconazole is hydrolytically and photochemically stable
(T1/2 >100 days), it binds very rapidly and tightly to soil particles
following application. Adsorption/desorption and aged leaching data
indicate that propiconazole and its degradates will primarily remain in
the top 0-6 inches of the soil. It has been determined that under field
conditions propiconazole will degrade with a half-life of approximately
100 days.
3. Non-dietary exposure. Propiconazole is registered for
residential use as a preservative treatment for wood and for lawn and
ornamental uses. At this time, no reliable data exist which would allow
quantitative incorporation of risk from these uses into a human health
risk assessment. The exposure to propiconazole from contacting treated
wood products is anticipated to be very low since the surface of wood
is usually coated with paint or sealant when used in or around the
house. The non-occupational exposure from lawn and ornamental
applications is also considered to be minor. It is estimated that less
than 0.01 percent of all households nationally use propiconazole in a
residential setting.
Consideration of a common mechanism of toxicity is not appropriate
at this time since there is no reliable information to indicate that
toxic effects produced by propiconazole would be cumulative with those
of any other types of chemicals. While other triazoles are available on
the commercial or consumer market, sufficient structural differences
exist among these compounds to preclude any categorical grouping for
cumulative toxicity. Consequently, Novartis is considering only the
potential risks of propiconazole in its aggregate exposure assessment.
E. Safety Determiniation
1. U.S. population. Reference dose. Using the conservative exposure
assumptions described above (100 percent stone fruit acres treated and
tolerance level residues) and based on the completeness and reliability
of the toxicity data base for propiconazole, Novartis has calculated
aggregate exposure levels for this chemical. The calculation shows that
only 16 percent of the RfD will be utilized for the U.S. population
based on chronic toxicity endpoints. EPA generally has no concern for
exposures below 100 percent 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. Novartis
concludes that there is a reasonable certainty that no harm will result
from aggregate exposure to propiconazole residues.
2. Infants and children. Developmental toxicity (e.g., reduced pup
weight and ossification) was observed in the rat teratology studies and
2-generation rat reproduction studies at maternally toxic doses. Some
of these findings are judged to be nonspecific, secondary effects of
maternal toxicity. The lowest NOEL for developmental toxicity was
established in the rat teratology study at 30 mg/kg, a level 24-fold
higher than the NOEL of 1.25 mg/kg on which the RfD is based.
Reference dose. Using the same conservative exposure assumptions as
employed for the determination in the general population, Novartis has
calculated that the percent of the RfD that will be utilized by
aggregate exposure to residues of propiconazole is 26 percent for
nursing infants less than 1 year old, 65 percent for non-nursing
infants less than 1 year old, 35 percent for children 1-6 years old,
and 23 percent for children 7-12 years old. Therefore, based on the
completeness and reliability of the toxicity data base and the
conservative exposure assessment, Novartis concludes that there is a
reasonable certainty that no harm will result to infants and children
from aggregate exposure to propiconazole residues.
F. Estrogenic Effects
Propiconazole does not belong to a class of chemicals known or
suspected of having adverse effects on the endocrine system.
Developmental toxicity studies in rats and rabbits and reproduction
studies in rats gave no indication that propiconazole might have any
effects on endocrine function related to development and reproduction.
The subchronic and chronic studies also showed no evidence of a long-
term effect related to the endocrine system.
G. International Tolerances
International CODEX values are established for almond, animal
products, bananas, barley, coffee, eggs, grapes, mango, meat, milk,
oat, peanut-whole, peanut grains, pecans, rape, rye, stone fruit, sugar
cane, sugar beets, sugar beet tops, and wheat. The U.S. residue
definition includes both propiconazole and metabolites determined as
2,4-dichlorobenzoic acid (DCBA), while the CODEX definition is for
propiconazole, per se, i.e. parent only. This difference results in
unique tolerance expressions with the U.S. definition resulting in the
higher tolerance levels. (PM 21)
3. Novartis Crop Protection, Inc.
PP 5E4450, 6F3332, 5F4546, 5F4576, and 6F4613
EPA has received pesticide petitions (PP) 5E4450, 6F3332, 5F4546,
5F4576, and 6F4613) from Novartis Crop Protection, Inc., 410 Swing
Road, Greensboro, NC 27419, proposing to amend 40 CFR part 180 by
establishing a tolerance for residues of the insecticide, cyromazine,
and its metabolite, melamine, in or on the raw agricultural commodities
of potatoes (potato tubers) at 1.5 ppm, green onions at 3 ppm, dry bulb
onions at 0.3 ppm, cottonseed at 0.2 ppm, sweet corn (kernels plus cobs
with husks removed, forage, and fodder) at 0.5 ppm, radishes (roots and
tops) at 0.5 ppm, and
[[Page 37254]]
mangoes at 0.3 ppm. A tolerance of 0.04 ppm is requested for residues
of cyromazine in milk; a tolerance of 0.02 ppm is requested for
residues of melamine in milk.
Residues of cyromazine and its metabolite, melamine, were
determined by Analytical Methods AG-408 and AG-417A which, combined,
are the EPA tolerance enforcement method published in the Pesticide
Analytical Manual, Volume II. Cyromazine is determined by High
Performance Liquid Chromatography (HPLC) on a LiChrosorb-NH2 column at
214 nm. The limit of determination in potatoes is 0.05 ppm.
Method AG-417A has been validated as reported in report ABR-84069
and by the EPA method trial reported in the Pesticide Analytical Manual
(PAM). EPA has accepted AG-408, 417A as the regulatory enforcement
method for crops.
Storage stability data for cyromazine have been reported in ABR-
92019 and Special Study 134/93: Interim Report. Stability of field-
incurred residues of cyromazine was demonstrated for 23 months in head
and leaf lettuce, 24 months in celery, 9\1/2\ months in tomatoes, and
11 months in mushrooms. In Special Study 134/93: Interim report, no
degradation of laboratory-spiked cyromazine was observed for 6 months
in mangoes (the time period required to validate the mango analyses).
No deterioration of cyromazine residues has been observed in any
substrate under freezer storage conditions. In this study, the storage
period for potatoes ranged from 3.5 to 24 months, which is within the
demonstrated freezer stability period.
A. Chemical Uses
Cyromazine, the active ingredient in Trigard Insecticide, is a
synthetic insect growth regulator. Cyromazine is highly efficacious
against dipterous leafminer larvae developing in the foliage of certain
agronomic, vegetable, and ornamental crops, and it can be used to
control flies in mushroom houses. Cyromazine is compatible with
integrated pest management (IPM) programs.
B. Residue Chemistry
Six field trials were conducted in three mango production areas of
Mexico. Residues of cyromazine ranged from less than the detection
limit (0.03 ppm) to 0.25 ppm. These data support the proposed tolerance
of 0.3 ppm in mangoes.
The maximum combined residue of cyromazine and melamine in
cottonseed from cotton grown as a rotational crop following lettuce
treated six times at the 1X use rate was 0.18 ppm. These data support
the proposed tolerance of 0.2 ppm in cottonseed.
Application of Trigard OMC to onion seed (pelletization) resulted
in maximum residues in immature whole onion plants of 2.71 ppm. These
data support the proposed tolerances for combined residues of
cyromazine and melamine at 3.0 ppm in green onions and 0.3 ppm in dry
bulb onions.
Residue data in rotational sweet corn and radishes and potatoes
have been previously submitted to EPA for review and have been found by
EPA to support tolerances of 0.5 ppm in sweet corn (kernels & cobs with
husks removed), sweet corn forage, sweet corn fodder, radish roots and
radish tops and to support tolerances of 1.5 ppm in/on potatoes. The
proposed 1.5 ppm for the RAC potatoes will cover any expected residues
including residues in processed potato wastes.
C. Toxicological Profile
Novartis has submitted toxicology studies in support of tolerances
for cyromazine. Cyromazine has low acute toxicity, no indication of
irritation potential and no sensitization potential. Cyromazine is not
genotoxic, fetotoxic, embryolethal, or teratogenic. It is not a
reproductive toxin. High-dose chronic toxicity included bronchiectasis
in male and female rats, testicular degeneration in dogs, and decreased
body weights in rats, dogs, and mice. No tumorigenic effects were noted
in any species tested and EPA has classified cyromazine as Group E, no
evidence of carcinogenicity in humans. Therefore, Novartis proposes
that a Margin of Exposure (MOE) or percentage of reference dose (RfD)
approach be used for characterizing human risk. For cyromazine,
Novartis concludes that aggregate MOE's are acceptable for the U.S.
population and all population subgroups for both acute toxicity and
chronic effects.
The following mammalian toxicity studies were conducted to support
proposed tolerances for cyromazine:
A rat acute oral toxicity study with an LD50 of
approximately 3,387 mg/kg.
A rat acute dermal toxicity study with an LD50 >3,100
mg/kg.
A rat acute inhalation study with an LC50 >3,600 mg/
m3.
A primary eye irritation study in the rabbit that showed no eye
irritation.
A primary dermal irritation study in the rabbit that showed no
dermal irritation.
A dermal sensitization study in the guinea pig that showed no
sensitization.
A 21-day dermal study in rabbits demonstrated no target organ
toxicity at doses up to 2,000 mg/kg/day.
A 13-week rat feeding study demonstrated no specific target organ
toxicity and a no observed effect level (NOEL) of 300 ppm (25 mg/kg/
day).
A 13-week feeding study in dogs demonstrated no specific target
organ toxicity, although some red blood cell parameters were affected
in high-dose males. The NOEL was 1,000 ppm (34 mg/kg/day).
A six-month feeding study in dogs showed reversible red blood cell
effects and transient changes in clinical parameters in high dose
males. No specific target organs were identified histologically,
although changes in some organ to body weight ratios were observed. The
NOEL was 30 ppm (0.75 mg/kg).
A 24-month feeding study in rats identified no specific target
organs. There was no oncogenic effect and the NOEL for the study was 30
ppm (1.5 mg/kg/day).
A 24-month mouse feeding study identified no specific target
organs. There was no oncogenic effect and the NOEL was 50 ppm (7.0 mg/
kg/day).
A rat teratology study demonstrated no developmental toxicity. The
maternal NOEL is 100 mg/kg/day and the developmental NOEL was 300 mg/
kg/day.
Several rabbit teratology studies were conducted. Based on a weight
of the evidence, no teratogenic effect was demonstrated. The maternal
NOEL was 10 mg/kg/day, whereas the developmental NOEL was 60 mg/kg/day.
A multigeneration study in rats demonstrated no impairment of
reproductive performance or fetal and/or pup effects, although pup body
weights were slightly decreased at the highest dose. The parental NOEL
and developmental NOEL's were 1,000 ppm (50 mg/kg/day).
There was no evidence of induction of point mutations in an Ames
test.
There was no indication of a mutagenic effect in a dominant lethal
test.
There was no evidence of a mutagenic effect in a nucleus anomaly
test in Chinese hamsters.
D. Threshold Effects
1. Chronic effects. EPA has established a reference dose for
cyromazine at 0.0075 mg/kg/day based on the 6 month dog study using the
NOEL of 0.75 mg/kg/day (30 ppm) and an uncertainty factor of 100.
2. Acute toxicity. Based on the low degree of acute toxicity, it
can be
[[Page 37255]]
concluded that cyromazine does not pose any acute dietary risks.
Non-threshold effects (Carcinogenicity). Based on the Guidelines
for Carcinogenic Risk Assessment published by EPA September 24, 1986
(51 FR 33992), EPA has classified cyromazine as not carcinogenic (Group
E). This classification was issued by the Health Effects Division
Carcinogenicity Peer Review Committee on September 14, 1994.
E. Aggregate Exposure
1. Dietary exposure. For purposes of assessing the potential
dietary exposure to cyromazine, Novartis has estimated aggregate
exposure based on the TMRC from the use of cyromazine in or on raw
agricultural commodities for which tolerances have been established (40
CFR 180.368) or are pending.
The TMRC is obtained by multiplying the tolerance level residue for
all these raw agricultural commodities by the consumption data that
estimate the amount of these products consumed by various population
subgroups. Since these raw agricultural commodities (e.g. soybean
forage and fodder) are fed to animals, the transfer of residues in
these fed commodities to meat, milk, poultry, or eggs has been
calculated and tolerances have either been proposed or established.
In conducting this exposure assessment, Novartis has used either
EPA's estimate of market share or used best estimates provided by
Novartis Product Management which assume plateau market share values.
In addition, the dietary exposure assessment includes residue
assumptions for meat and milk that provide very conservative estimates.
2. Drinking Water. The environmental fate database for cyromazine
indicates that, when used according to label directions, the compound
is not likely to be found in ground or surface water at biologically
significant concentrations. To date, cyromazine has never been detected
in ground or surface water. The primary environmental degradate of
cyromazine, melamine, has rarely been detected, and melamine detections
have always been less than 0.3 ppb in water. To evaluate the potential
impact of exposure to cyromazine in drinking water, Novartis calculated
a theoretical lifetime Maximum Contaminant Level (MCL). The theoretical
MCL, 50 ppb, is orders of magnitude greater than levels that are likely
to be found in the environment under current conditions of use.
3. Non-dietary exposure. Non-occupational exposure to the general
population is unlikely since cyromazine is not used in or around the
home, including home lawns.
F. Cumulative Effects
Novartis considered the potential for cumulative effects of
cyromazine and other chemicals in this class that may have a common
mechanism of toxicity. Consideration of a common mechanism of toxicity
is not appropriate for cyromazine since the existing data do not
suggest a common mechanism.
G. Safety Determination
1. U.S. population. Using the conservative exposure assumptions
described above, and based on the completeness and reliability of the
toxicity data, Novartis has concluded that aggregate exposure to
cyromazine will utilize approximately 35% percent of the RfD for the
U.S. population based on chronic toxicity endpoints. 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.
Therefore, Novartis concludes that there is reasonable certainty that
no harm will result from aggregate exposure to cyromazine or residues
of cyromazine that may appear in raw agricultural commodities.
2. Infants and children. In assessing the potential for additional
sensitivity of infants and children to residues of cyromazine, Novartis
has considered data from developmental toxicity studies in the rat and
rabbit, and a 2-generation reproduction study in the rat. The
developmental toxicity studies are designed to evaluate adverse effects
on the developing organism resulting from chemical exposure during
prenatal development. Reproduction studies provide information relating
to effects from exposure to a chemical on the reproductive capability
of mating animals, on postnatal development, and systemic toxicity,
particularly to the reproductive system.
Developmental toxicity (reduced mean fetal body weight and an
increased incidence of skeletal variations due to delayed ossification)
was observed in the rat only at the maternally toxic dose of 600 mg/kg/
day. The no observed effect level for developmental toxicity in the rat
was 300 mg/kg/day, a dose that was still maternally toxic. Similarly,
the developmental no observed effect level in the rabbit (60 mg/kg/day)
was higher than the maternal no observed effect level (10 mg/kg/day),
which suggests that the developmental toxicity associated with high
doses of cyromazine occurs secondarily to maternal toxicity.
A 2-generation reproduction study was conducted with cyromazine at
feeding levels of 0, 30, 1,000, and 3,000 ppm. Reproductive performance
was unaffected by treatment with cyromazine at feeding levels up to
3,000 ppm. Evidence of parental toxicity, as indicated by decreased
body weight gain, was observed in males and females at feeding levels
>1,000 ppm. Similar effects were noted in the offspring at 3,000 ppm.
The maternal and developmental no observed effect levels were
established at 1,000 ppm (50 mg/kg/day).
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 for children is
complete. Furthermore, the NOEL of 0.75 mg/kg/day from the chronic dog
study used to calculate the RfD, is approximately 100 fold lower than
the lowest developmental NOEL in the teratology studies (Rabbit
Developmental NOEL = 60 mg/kg/day) and the developmental NOEL (50 mg/
kg/day) established in the multigeneration reproduction study. Based on
these data, Novartis concludes that there is no evidence to suggest
that developing organisms are more sensitive to the effects of
cyromazine than are adults.
The percentage of the RfD utilized by the U.S. population for 48
states using aggregate exposure estimates is approximately 70%, if
drinking water intake is assumed to be 100% of the MCL for the
respective subgroup. It is highly unlikely that concentrations in
drinking water will approach the MCL for even short periods of time.
Consequently, this calculation of the percentage of the RfD that would
be utilized is extremely conservative.
The percentage of the RfD that is utilized is somewhat higher for
non-nursing infants if the chronic NOEL is used to estimate exposure
using the conservative exposure assumptions described above. Novartis
has determined that the percentage of the lowest developmental NOEL (50
mg/kg/day from the rat multigeneration study) utilized by aggregate
exposure to residues of cyromazine is approximately 20% for nursing
infants less than 1 year old, approximately 21% for non-nursing infants
and for children 1 to six years old, and 62% for children 7 to 12 years
old.
[[Page 37256]]
Therefore, based on the completeness and reliability of the
toxicity data and the conservative exposure assessment, Novartis
concludes that there is reasonable certainty that no harm will result
to infants and children from aggregate exposure to cyromazine residues.
H. Estrogenic Effects
Cyromazine does not belong to a class of chemicals known to have or
suspected of having adverse effects on the endocrine system. No adverse
effects on fertility or reproduction were observed in high dose females
(3000 ppm) in the rat reproduction study. Although residues of
cyromazine have been found in raw agricultural commodities, there is no
evidence that cyromazine bioaccumulates in the environment.
I. Environmental Fate
Soil metabolism and soil dissipation studies on various soil types
have shown that cyromazine dissipates moderately over time, while
melamine is slightly more stable.
J. International Tolerances
Compatibility problems exist between Codex limits, Mexican limits,
and the proposed US tolerances. In Codex and Mexican limits, cyromazine
is the only residue of concern; the metabolite melamine is not included
in the residue expression. There are no established cyromazine limits
for the RAC potato, or the processed commodities, potato granules/
flakes, or chips, or the feedstuff, processed potato waste. There is a
0.01 ppm (at or about the limit of determination) Codex limit in milk.
(PM 13)
[FR Doc. 97-18085 Filed 7-10-97; 8:45 am]
BILLING CODE 6560-50-F
