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Chlorothalonil - Pesticide Tolerance Petition Filing 2/97

ENVIRONMENTAL PROTECTION AGENCY
[PF-708; FRL-5587-3]
ISK Biosciences Corporation; Pesticide Tolerance Petition Filing
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice of filing.
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SUMMARY: This notice announces the filing of a pesticide petition proposing
the establishment of a regulation for residues of chlorothalonil in or on
almonds and almond hulls. The notice includes a summary of the petition
prepared by the petitioner, ISK Biosciences Corporation.

DATES: Comments, identified by the docket number [PF-708], must be received
on or before March 17, 1997.

ADDRESSES: By mail, submit written comments to: Public Response and Program
Resources Branch, Field Operations Division (7506C), Office of Pesticide
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 sending electronic
mail (e-mail) to: opp-docket@epamail.epa.gov. Comments 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 docket number [PF-
708]. Electronic comments on this notice of filing may be filed online at many
Federal Depository Libraries. Additional information on electronic submissions
can be found in Unit II. of this document.

Information submitted as comments 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: Cynthia Giles-Parker, Product
Manager (PM 22), Registration Division (7505C), Office of Pesticide Programs,
Environmental Protection Agency, 401 M St., SW., Washington, DC 20460. Office
location, telephone number, and e-mail address: Crystal Mall #2, Room 229,
1921 Jefferson Davis Highway, Arlington, VA, 703-305-7740, e-mail: giles-
parker.cynthia@epamail.epa.gov.

SUPPLEMENTARY INFORMATION: EPA has received a pesticide petition (PP 5F4558),
originally published in the Federal Register on November 15, 1995 (60 FR
57419) (FRL-4971-5), from ISK Biosciences Corporation ("ISK"), 5966 Heisley
Road, P.O. Box 8000, Mentor, Ohio 44061, proposing pursuant to section 408(d)
of the Federal Food, Drug and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to
amend 40 CFR 180.275 by establishing tolerances for residues of the fungicide
chlorothalonil and its metabolite, 4-hydroxy-2,5,6-trichloroisophthalonitrile
(SDS- 3701) in or on the raw agricultural commodity (RAC) almonds (nutmeats)
at 0.05 parts per million (ppm) and almond hulls at 1.0 ppm. The proposed
analytical method is by electron capture gas chromatography. EPA has
determined that the petition contains data or information regarding the
elements set forth in section 408 (d)(2) of the FFDCA; however, EPA has not
fully evaluated the sufficiency of the submitted data at this time or whether
the data supports granting of the petition. Additional data may be needed
before EPA rules on the petition.

As required by section 408(d) of the FFDCA, as recently amended by the Food
Quality Protection Act (FQPA) Pub. L. 104-170, ISK included in the petition a
summary of the petition and authorization for the summary to be published in
the Federal Register in a notice of receipt of the petition. The summary
represents the views of ISK. EPA is in the process of evaluating the petition.
As required by section 408(d)(3) of the FFDCA, EPA is including the summary as
a part of this notice of filing. EPA has made minor edits to the summary for
the purpose of clarity.

I. Petition Summary

A. Residue Chemistry Data

1. Plant/animal metabolism. The nature of the residue of chlorothalonil in
plants and animals, including ruminants, is well understood. Chlorothalonil is
not systemic in plants. Any chlorothalonil residue found on almond nutmeats
occurs as a surface residue from transfer of the residue during harvesting and
shelling operations. Chlorothalonil is rapidly metabolized in the ruminant and
is not transferred to meat and milk from the dietary consumption by animals.
Furthermore, chlorothalonil is not stable in meat or milk.
2. Analytical method. An adequate analytical method (gas chromatography) is
available for enforcement purposes. The method is listed in the Pesticide
Analytical Manual, Vol. II (PAM II).
3. Magnitude of the residues. Residue data from studies conducted with
almonds support a tolerance of 0.05 ppm for combined residues of
chlorothalonil and its metabolite, 4-hydroxy-2,5,6- trichloroisophthalonitrile
in/on almond nutmeats and 1.0 ppm in/on almond hulls. Residues of
chlorothalonil on plants are surface residues. Nutmeats are not systemically
exposed to chlorothalonil since chlorothalonil is not a systemic fungicide in
plants. Chlorothalonil residues are not directly translocated to the nutmeats,
but residues from the hulls that contaminate the almond shells during harvest
may be transferred to the nutmeats during the shelling process.

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 milligram/ kilogram
(mg/kg), an acute dermal toxicity study in the rabbit with an LD50
20,000 mg/kg, a 4-hour inhalation study with finely ground technical
chlorothalonil resulting in a 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.
2. Genotoxicity. The mutagenic potential of chlorothalonil has been evaluated
in a large number of studies covering a variety of endpoints. ISK concludes
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

[[Page 6781]]

transformation assays. All were negative with the following two exceptions:
i. Chlorothalonil was positive in an in vitro chromosomal aberration assay in
CHO cells without metabolic activation but was negative with metabolic
activation.
ii. 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 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, which is the target organ
for chlorothalonil toxicity in rodents.
3. Developmental and reproductive toxicity. A developmental toxicity study
with rats given gavage doses of 0, 25, 100, and 400 mg/ kg body weight
(bwt)/day 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.
A developmental toxicity study in rabbits given gavage doses of 0, 5, 10, or
20 mg/kg/day 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.
A 2-generation reproduction study in rats fed diets containing 0, 500, 1,500
and 3,000 ppm 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 other reproductive parameter at any dose level in this
study.
4. Subchronic toxicity. i. A 90-day subchronic toxicity study was conducted
in rats at doses of 0, 1.5, 3.0, 10, and 40 mg/kg bwt. Treatment related
hyperplasia and hyperkeratosis of the forestomach was 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 NOEL for renal histopathology
was 10 mg/kg bwt in males and 40 mg/kg bwt in females.
ii. 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 NOEL was 15
mg/kg/day. There were no macroscopic or microscopic tissue alterations related
to chlorothalonil and there were no signs of renal toxicity.
iii. 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.
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, ISK concludes that 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, ISK concludes based upon the in vivo studies, that
chlorothalonil does not cause estrogenic effects.
6. Chronic toxicity. i. 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 NOEL 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.
ii. A chronic feeding/carcinogenicity study with Fischer 344 rats fed diets
containing 0, 800, 1,600 or 3,500 ppm (equivalent to 0, 40, 80 or 175 mg/kg
bwt/day) 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, which was above the MTD, there was also a statistically
significant higher incidence of tumors of the forestomach in female rats.
iii. In a second chronic feeding/carcinogenicity study with Fischer 344 rats,
designed to define the NOEL for tumors and the preneoplastic hyperplasia,
animals were fed diets containing 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.
iv. A 2-year carcinogenicity study, conducted in CD-1 mice 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
carcinomas of the forestomach in both sexes and a statistically higher
incidence of combined renal adenomas/carcinomas in only the male mice
receiving the low dose. There were no renal tumors in any female mouse in this
study.
v. A 2-year carcinogenicity study, in male CD-1 mice for the purpose of
establishing the NOEL for renal and forestomach effects, 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 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.

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 has provided a significant amount of mechanistic data indicating
that the tumors result from a threshold mechanism. A potency factor, Q1* (Q1

[[Page 6782]]

star), of 0.00766 (mg/kg/day)1 has been used by the Agency when
conducting mathematical modeling to estimate carcinogenic risk to man. ISK
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.

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1"Mechanistic Interpretation of the Oncogenicity of Chlorothalonil in
Rodents and an Assessment of Human Relevance," by Drs. C. F. Wilkinson and J.
C. Killeen, Regulatory Toxicology and Pharmacology 24: 69-84 (1996), Article
No. 006.
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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. In the dog, no thio metabolites are found and
there are no toxic effects seen in kidneys of dogs dosed with high levels of
chlorothalonil.
7. Reference dose (RfD). The NOEL for chlorothalonil in the rat is
1.8 mg/kg bwt based on the nephrotoxicity observed in the chronic rat study.
The NOEL in the dog was 15 mg/kg bwt in the 90-day study and 150 mg/kg bwt
based on the 1-year study. NOEL for maternal toxicity from developmental
studies are 10 mg/kg bwt in rabbits and 100 mg/kg bwt in the rat. The NOEL 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. 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 proliferating cell nuclear antigen (PCNA)
immunohistochemical staining, 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 regards to its 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 NOEL would produce a reference dose which would
provide more than adequate safety for all of the possible effects seen in any
laboratory animal.

In two recent reviews of chlorothalonil by the Joint Meeting of Pesticide
Residue Experts (1990 and 1992) and the review by the World Health
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, which is based on the most recent 90-day study of the dog.
Therefore, under the most conservative scenario (using the toxicological data
in the rat), the reference dose would be 1.8 mg/kg bwt/day divided by a 100-
fold safety factor or 0.018 mg/kg bwt/day with a threshold model being used
for carcinogenic risk assessment. In the scenario that uses the toxicological
data of 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.-- i. Food. The Agency's Dietary Exposure Analysis dated
April 1, 1996, of ISK's petition (PP 5F4558), which requested tolerances for
chlorothalonil and its metabolite, 4-hydroxy- 2,5,6-trichloroisophthalonitrile
(SDS-3701) in/on almond nutmeats and almond hulls, determined the dietary
exposure from the proposed new anticipated residue contributed from almonds to
be 0.000001 mg/kg bwt/day to the U.S. population and also to children ages 1
to 6.
The Agency had calculated that the exposure of the general population from
existing published tolerances for chlorothalonil is 0.000133 mg/kg bwt/day and
0.00021 mg/kg bwt/day for infants and children ages 1 to 6. Unfortunately, the
Agency's calculation of the total exposure contained a significant error. The
Agency grossly overestimated the exposure from the use of chlorothalonil on
mushrooms by using an anticipated residue of 2.54 ppm which constitutes an
illegal residue. The tolerance is 1.0 ppm. There were also other overestimates
of less magnitude in the April 1996 EPA document. ISK believes that the
correct exposure, based on the current registered uses for chlorothalonil, is
0.0000642 mg/kg bwt/day for the general population and 0.000105 mg/kg bwt/day
for infants and children 1 to 6 years of age.
ii. 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 μg/l and limit of quantitation of
0.12 μg/l). The absence of chlorothalonil detections in the National
Survey of Pesticides in Drinking Water Wells 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.
An exposure estimate, based on surface water concentration recently cited by
EPA, would conclude that the average concentration in surface water would be
less than 0.002 ppm. Assuming that everyone in the United States consumed
untreated surface water, the exposure to chlorothalonil of the general
population would be less than 5.8 x 10-7 mg/kg bwt/day. This would be a
worse case scenario, which would greatly overestimate exposure.
2. 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

[[Page 6783]]

be expected to add to the carcinogenic risk associated with chlorothalonil.
i. Golf course uses. Chlorothalonil products are commonly applied to golf
course trees 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.
ii. 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.
iii. 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 interior paints in the United States contain chlorothalonil. In paints
chlorothalonil is tightly bound within the paint matrices; thus, effective
control of mildew may last for several years and the potential for exposure is
very limited.
iv. Grouts. Chlorothalonil is used in cement tile grouts and 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.
v. Wood treatment. Chlorothalonil is not currently 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 has considered the potential for cumulative effects of chlorothalonil and
other substances that have a common mechanism of toxicity. Chlorothalonil is a
halogenated benzonitrile which readily undergoes displacement of the 2, 4 and
6 chlorines by glutathione and other thiol containing amino acids and
proteins. In the rat, the thiol metabolites are sufficiently absorbed to
produce a nephrotoxic effect. In dogs where this absorption does not occur,
nephrotoxicity does not occur. ISK 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 chlorinated hydrocarbon pesticides
which have significantly different chemical and biological properties.

E. Safety Determination

1. U.S. population. In EPA's Dietary Exposure Analysis, dated April 1, 1996,
for chlorothalonil and its metabolite in/on almond nutmeats and almond hulls,
the Agency determined that the oncogenic dietary risks associated with
potential exposure from anticipated residue of 0.05 ppm from almonds is
minimal. The risk assessment concluded that chlorothalonil does not pose a
significant chronic or acute dietary risk for uses that are currently
published or for uses recommended by EPA for registration. Unfortunately, the
Agency's calculation of the total exposure for existing published uses
contained a significant error. The Agency grossly overestimated the exposure
from the use of chlorothalonil on mushrooms by using an anticipated residue of
2.54 ppm which constitutes an illegal residue. The tolerance is 1.0 ppm.
The Agency has used a linearized model to estimate the carcinogenic risk
associated with chlorothalonil, whereas ISK believes that a threshold based
model is appropriate. If the linearized multistage model is used with the
corrected exposure estimates for food presented earlier, the carcinogenic risk
would be estimated at 4.9 x 107 for the general population and 8.0 x
107 for infants and children. Using the overestimated exposure estimates
of EPA, with a threshold based model and using the conservative RfD of 0.018
mg/kg bwt/day, the margin of safety for the general population would exceed
10,000 and the margin of safety for infants and children would exceed 7,000.
Using corrected exposure estimates would obviously yield larger margins of
exposure. Using a conservative RfD of 0.018 mg/kg/day, as the Agency has done
in recent Dietary Risk Evaluation System (DRES) analyses, and incorporating
corrections needed in exposure values for mushrooms and several other lesser
corrections, ISK calculated the overall dietary exposure to anticipated
residues of chlorothalonil, from all registered uses and pending uses of
chlorothalonil, to be 0.36% of the RfD for the general U.S. population and
0.59% of the RfD for children ages 1 to 6 years old, which is the group with
the highest exposure.
Because the worse case assumption for human exposure from drinking water
indicates 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 data base 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 2-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, which is 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 bwt/day (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 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 bwt caused maternal toxicity, but there were no developmental effects
and in the rat, a dose level of 400 mg/kg bwt caused maternal toxicity without
developmental toxicity.
The extensive data base that is available for chlorothalonil is devoid of any
indication that chlorothalonil would represent any unusual or disproportionate
hazard to infants or children. Therefore, there is no need to impose an
additional 10x safety factor

[[Page 6784]]

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.

F. International Tolerances

A maximum residue level has not been set for chlorothalonil on almonds by the
Codex Alimentarius Commission.

II. Public Record

EPA invites interested persons to submit comments on this notice of filing.
Comments must bear a notation indicating the docket number [PF- 708].
A record has been established for this notice of filing under docket number
[PF-708] 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 public record is located in Room 1132 of the
Public Response and Program Resources Branch, Field Operations Division
(7506C), Office of Pesticide Programs, Environmental Protection Agency,
Crystal Mall #2, 1921 Jefferson Davis Highway, Arlington, VA.
Electronic comments can be sent directly to EPA at: opp-docket@epamail.epa.gov

Electronic comments must be submitted as ASCII file avoiding the use of
special characters and any form of encryption.
The official record for this notice of filing, as well as the public version,
as described above will be kept in paper form. Accordingly, EPA will transfer
all comments received electronically into printed paper form as they are
received and will place the paper copies in the official record which will
also include all comments submitted directly in writing. The official record
is the paper record maintained at the address in "ADDRESSES" at the
beginning of this document.

List of Subjects

Environmental protection, Administrative practice and procedure, Agricultural
commodities, Pesticides and pests, Reporting and recordkeeping requirements.

Dated: February 7, 1997.

Donald R. Stubb,

Acting Director, Registration Division, Office of Pesticide Programs.

[FR Doc. 97-3646 Filed 2-12-97; 8:45 am] BILLING CODE 6560-50-F