Document ID: EPA-HQ-OPP-2007-1106-0005
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-12-03T05:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES, AND

TOXIC SUBSTANCES

MEMORANDUM

DATE:		09-OCT-2008

SUBJECT:	Chlorothalonil.  Petition For Tolerances on Brassica Head and
Stem Subgroup 5A, Cucurbit Vegetable Group 9, Fruiting Vegetable Group
8, Ginseng, Horseradish, Lentil, Lupin, Okra, Persimmon, Rhubarb, Yam,
Lychee, and Starfruit.  Human-Health Risk Assessment.  

PC Code:  081901	DP No.:  353243

Decision No.:  385118	Registration No.:  50534-188

Petition No.:  7E7270	Regulatory Action:  Section 3 Registration

Risk Assessment Type:  Single Chemical/Aggregate	Case No.:  NA

TXR No.:  NA	CAS No.:  1897-45-6

MRID No.:  NA	40 CFR:  §180.275

FROM:	George F. Kramer, Ph.D., Senior Chemist

William Greear, M.P.H., D.A.B.T., Toxicologist

Registration Action Branch 1 (RAB1)

Health Effects Division (HED) (7509P)

And

Mark I. Dow, Ph.D., Biologist

		Alternate Risk Integration Assessment Team (ARIA)

		Risk Integration Minor Use & Emergency Response Branch (RIMUERB)

Registration Division (RD) 7505P

THROUGH:	Dana M. Vogel, Branch Chief

				Robert Mitkus, Ph.D., Toxicologist

RAB1/HED (7509P)

TO:		Tony Kish/Rosemary Kearns, RM 22/RD; 7505P

The HED of the Office of Pesticide Programs (OPP) is charged with
estimating the risk to human health from exposure to pesticides.  The RD
of OPP has requested that HED evaluate hazard and exposure data and
conduct dietary, occupational/residential, and aggregate exposure
assessments, as needed, to estimate the risk to human health that will
result from the registered and proposed uses of the fungicide
chlorothalonil (2,4,5,6-tetrachloro-1,3-benzenedicarbonitrile).

A summary of the findings and an assessment of human-health risk
resulting from the proposed uses of chlorothalonil are provided in this
document.  The risk assessment, dietary-exposure assessment, and the
residue chemistry data review were provided by George Kramer (RAB1); the
occupational/residential exposure assessment by Mark Dow (ARIA); the
hazard characterization by William Greear (RAB1); and the drinking water
assessment by Lucy Shanaman of the Environmental Fate and Effects
Division (EFED).



Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc204498838"  1.0  EXECUTIVE
SUMMARY	  PAGEREF _Toc204498838 \h  5  

  HYPERLINK \l "_Toc204498839"  2.0  PHYSICAL/CHEMICAL PROPERTIES
CHARACTERIZATION	  PAGEREF _Toc204498839 \h  11  

  HYPERLINK \l "_Toc204498840"  2.1  Identification of Active Ingredient
  PAGEREF _Toc204498840 \h  11  

  HYPERLINK \l "_Toc204498841"  2.2  Physical and Chemical Properties	 
PAGEREF _Toc204498841 \h  12  

  HYPERLINK \l "_Toc204498842"  3.0  HAZARD CHARACTERIZATION	  PAGEREF
_Toc204498842 \h  12  

  HYPERLINK \l "_Toc204498843"  3.1  Hazard and Dose-Response
Characterization	  PAGEREF _Toc204498843 \h  12  

  HYPERLINK \l "_Toc204498844"  3.1.1  Studies Considered in the
Toxicity and Dose-Response Evaluation	  PAGEREF _Toc204498844 \h  12  

  HYPERLINK \l "_Toc204498845"  3.1.2  Sufficiency of Studies/Data	 
PAGEREF _Toc204498845 \h  13  

  HYPERLINK \l "_Toc204498846"  3.1.3  Mode of Action and Mammalian
Toxicology	  PAGEREF _Toc204498846 \h  13  

  HYPERLINK \l "_Toc204498847"  3.1.4  Toxicological Effects	  PAGEREF
_Toc204498847 \h  14  

  HYPERLINK \l "_Toc204498848"  3.2  Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc204498848 \h  26  

  HYPERLINK \l "_Toc204498849"  3.2.1  Dermal Absorption	  PAGEREF
_Toc204498849 \h  26  

  HYPERLINK \l "_Toc204498850"  3.2.2  Mechanistic Data	  PAGEREF
_Toc204498850 \h  27  

  HYPERLINK \l "_Toc204498851"  3.3  FQPA Considerations	  PAGEREF
_Toc204498851 \h  28  

  HYPERLINK \l "_Toc204498852"  3.3.1  Adequacy of the Toxicity Database
  PAGEREF _Toc204498852 \h  28  

  HYPERLINK \l "_Toc204498853"  3.3.2  Evidence of Neurotoxicity	 
PAGEREF _Toc204498853 \h  28  

  HYPERLINK \l "_Toc204498854"  3.3.3  Developmental Toxicity Studies	 
PAGEREF _Toc204498854 \h  29  

  HYPERLINK \l "_Toc204498855"  3.3.4  Additional Information from
Literature Sources	  PAGEREF _Toc204498855 \h  34  

  HYPERLINK \l "_Toc204498856"  3.3.5  Pre- and/or Postnatal Toxicity	 
PAGEREF _Toc204498856 \h  34  

  HYPERLINK \l "_Toc204498857"  3.3.6  Recommendation for a
Developmental Neurotoxicity Study (DNT)	  PAGEREF _Toc204498857 \h  34  

  HYPERLINK \l "_Toc204498858"  3.4  FQPA SF	  PAGEREF _Toc204498858 \h 
35  

  HYPERLINK \l "_Toc204498859"  3.4.1  Adequacy of the Exposure Database
  PAGEREF _Toc204498859 \h  35  

  HYPERLINK \l "_Toc204498860"  3.4.2  FQPA SF Conclusion	  PAGEREF
_Toc204498860 \h  35  

  HYPERLINK \l "_Toc204498861"  3.5  Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc204498861 \h  36  

  HYPERLINK \l "_Toc204498862"  3.5.1  aRfD - Females age 13-49	 
PAGEREF _Toc204498862 \h  37  

  HYPERLINK \l "_Toc204498863"  3.5.2  aRfD - General Population	 
PAGEREF _Toc204498863 \h  37  

  HYPERLINK \l "_Toc204498864"  3.5.3  cRfD	  PAGEREF _Toc204498864 \h 
38  

  HYPERLINK \l "_Toc204498865"  3.5.4  Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc204498865 \h  38  

  HYPERLINK \l "_Toc204498866"  3.5.5  Dermal Absorption	  PAGEREF
_Toc204498866 \h  39  

  HYPERLINK \l "_Toc204498867"  3.5.6  Dermal Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc204498867 \h  39  

  HYPERLINK \l "_Toc204498868"  3.5.7  Inhalation Exposure (Short-,
Intermediate- and Long-Term)	  PAGEREF _Toc204498868 \h  39  

  HYPERLINK \l "_Toc204498869"  3.5.8  LOC for MOEs	  PAGEREF
_Toc204498869 \h  40  

  HYPERLINK \l "_Toc204498870"  3.5.9  Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc204498870 \h  40  

  HYPERLINK \l "_Toc204498871"  3.5.10  Classification of Carcinogenic
Potential	  PAGEREF _Toc204498871 \h  40  

  HYPERLINK \l "_Toc204498872"  3.6  Endocrine disruption	  PAGEREF
_Toc204498872 \h  41  

  HYPERLINK \l "_Toc204498873"  3.7  Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc204498873 \h  41  

  HYPERLINK \l "_Toc204498874"  3.8  Data Proprietary Use/Gaps	  PAGEREF
_Toc204498874 \h  42  

  HYPERLINK \l "_Toc204498875"  4.0  EXPOSURE ASSESSMENT AND
CHARACTERIZATION	  PAGEREF _Toc204498875 \h  42  

  HYPERLINK \l "_Toc204498876"  4.1  Summary of Registered/Proposed Uses
  PAGEREF _Toc204498876 \h  42  

  HYPERLINK \l "_Toc204498877"  4.2  Dietary Exposure/Risk Pathway	 
PAGEREF _Toc204498877 \h  44  

  HYPERLINK \l "_Toc204498878"  4.2.1  Residue Profile	  PAGEREF
_Toc204498878 \h  44  

  HYPERLINK \l "_Toc204498879"  4.2.2  Dietary-Exposure Analyses	 
PAGEREF _Toc204498879 \h  48  

  HYPERLINK \l "_Toc204498880"  4.3  Water Exposure/Risk Pathway	 
PAGEREF _Toc204498880 \h  49  

  HYPERLINK \l "_Toc204498881"  4.4  Residential Exposure/Risk Pathway	 
PAGEREF _Toc204498881 \h  50  

  HYPERLINK \l "_Toc204498882"  5.0  AGGREGATE RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc204498882 \h  50  

  HYPERLINK \l "_Toc204498883"  5.1  Acute Aggregate Risk	  PAGEREF
_Toc204498883 \h  53  

  HYPERLINK \l "_Toc204498884"  5.2  Short- and Intermediate-Term
Aggregate Risk	  PAGEREF _Toc204498884 \h  53  

  HYPERLINK \l "_Toc204498885"  6.0  CUMULATIVE RISK	  PAGEREF
_Toc204498885 \h  53  

  HYPERLINK \l "_Toc204498886"  7.0  OCCUPATIONAL EXPOSURE	  PAGEREF
_Toc204498886 \h  54  

  HYPERLINK \l "_Toc204498887"  7.1  Occupational Handler	  PAGEREF
_Toc204498887 \h  54  

  HYPERLINK \l "_Toc204498888"  7.2  Occupational Post-Application
Exposure	  PAGEREF _Toc204498888 \h  56  

  HYPERLINK \l "_Toc204498889"  7.3  REI	  PAGEREF _Toc204498889 \h  57 

  HYPERLINK \l "_Toc204498890"  8.0  DATA DEFICIENCIES/LABEL REVISIONS	 
PAGEREF _Toc204498890 \h  57  

  HYPERLINK \l "_Toc204498891"  Appendix 1.  Toxicological Data
Requirements (Vischim S.r.l.)	  PAGEREF _Toc204498891 \h  59  

  HYPERLINK \l "_Toc204498892"  Appendix 2.  Toxicological Data
Requirements (Old Data)	  PAGEREF _Toc204498892 \h  60  

 

1.0  EXECUTIVE SUMMARY

Chlorothalonil (2,4,5,6-tetrachloro-1,3-benzenedicarbonitrile) is a
broad-spectrum, non-systemic protectant pesticide mainly used as a
fungicide to control fungal foliar diseases of vegetable, field, and
ornamental crops.  It is also used as a wood protectant, antimold and
antimildew agent, bactericide, microbiocide, algaecide, insecticide, and
acaricide.  The exact mechanism of action is not known.

The Interregional Research Project No. 4 (IR-4), on behalf of the
Agricultural Experiment Stations of AR, CA, DE, FL, GA, HI, ID, KY, LA,
MN, MS, NJ, NC, ND, OH, OK, OR, PR, SC, TN, TX, WA, WI, and VA, has
proposed to amend the use pattern for the 6 lb/gal flowable-concentrate
(FlC) formulation of chlorothalonil (Bravo Weather Stik®, EPA Reg. No.
50534-188-100) to add uses on ginseng, horseradish, lentil, lupin, okra,
persimmon, rhubarb, and yam.  In addition, IR-4 proposes to expand the
existing uses on broccoli, Brussels sprouts, cabbage, and cauliflower to
the Brassica head and stem subgroup (5A), the existing uses on cucumber,
melon, and squash to the cucurbit vegetable group (9), and the existing
uses on tomato to the fruiting vegetable group (8).  

Permanent and temporary tolerances have been established for
chlorothalonil and its 4-hydroxy metabolite (SDS-3701) as listed in 40
CFR §180.275.  Chlorothalonil is registered for use on a number of
agricultural commodities, including almond, apricot, asparagus, banana,
bean (dry), bean (snap, succulent), blueberry, broccoli, Brussels
sprouts, cabbage, carrot, cauliflower, celery, cherry (sweet and tart),
cocoa bean, coffee bean, corn (sweet), cranberry, cucumber, ginseng,
mango, melon, mushroom, nectarine, onion (dry bulb and green), papaya,
parsnip (root), passionfruit, peach, peanut, pepper (non-bell),
pistachio, plum (fresh and prune), potato, pumpkin, soybean, squash
(summer and winter) and tomato.  There are regional registrations for
chlorothalonil on filbert and mint hay.  Finally, there are tolerances
for the 4-hydroxy metabolite on fat, kidney, meat, and meat byproducts
of cattle, goat, hog, horse and sheep and in milk.  

Hazard Assessment

Chlorothalonil has a low order of acute toxicity by the oral and dermal
routes of exposure (Toxicity Category IV).  Chlorothalonil is severely
irritating to the eye (Toxicity Category I) and is moderately irritating
to the skin (Toxicity Category III).  Chlorothalonil is not a skin
sensitizer. 

Chlorothalonil is known to cause gastric irritation upon ingestion.  In
a subchronic dog study, both males and females exhibited decreased body
weights, body-weight gains and food consumption.  In a chronic dog
study, there were pathological findings in the stomach and in a second
toxicity study in dogs, vacuolated epithelium of the kidney was
observed.  In subchronic toxicity studies in mice and rats,
chlorothalonil produced hyperplasia and hyperkeratosis of the squamous
epithelium of the non-glandular region of the stomach (forestomach).  In
rodent chronic toxicity studies, there was an increased incidence of
epithelial hyperplasia of the limiting ridge and nonglandular region of
the stomach in rats and mice.  

Newly submitted genetic toxicology data (4 studies) were negative.  

There was no indication of a carcinogenic response in the rat chronic
toxicity/carcinogenicity study with the newer data set; however, an
increased incidence of renal adenomas and carcinomas, increased
incidence of papillomas and/or carcinomas of the forestomach in rats and
mice were observed in both sexes of rats and mice with the older data
set.  The new carcinogenicity study in mice also demonstrates that
chlorothalonil produces similar papillomas of the forestomach.  No
developmental toxicity was observed in two rat developmental toxicity
studies.  

In one of two rabbit developmental toxicity studies, there was an
increased incidence of thirteen ribs and reduced sternebrae.  No
qualitative evidence of increased susceptibility was seen following in
utero exposure to rats or rabbits in developmental studies or in the
reproduction study.  In the reproduction study, both parental animals
and offspring exhibited pathological effects involving the forestomach
consisting of thickened and/or roughening of the forestomach with
depressions in the epithelial aspect, and hyperplasia and hyperkeratosis
of the non-glandular epithelium of the stomach.  Based on
weight-of-evidence from all studies, HED concluded that there is no
evidence of increased susceptibility to offspring following pre-natal
exposure to chlorothalonil in rats and rabbits and pre- and postnatal
exposure in rats.

Dose-Response Assessment

The chlorothalonil risk assessment team evaluated the toxicology
database, selected doses and endpoints for chronic dietary exposures, as
well as occupational and residential exposure scenarios [short-,
intermediate-, and long-term exposure (dermal and inhalation)], assessed
the carcinogenic potential and addressed the sensitivity of infants and
children from exposure to chlorothalonil as required by the Food Quality
Protection Act (FQPA) of 1996.  

No appropriate acute endpoint was identified in the hazard database to
quantitate the risk to the general population or to females 13-50 years
old from single-dose administration of chlorothalonil.  Therefore, there
is no acute reference dose (aRfD) or acute population-adjusted dose
(aPAD).  

The cRfD has been changed since the previous hazard assessment.  The old
endpoint was based on forestomach lesions observed in the mouse
carcinogenicity study.  The new endpoint is based on kidney lesions
observed in the rat chronic toxicity/carcinogenicity study.  The chronic
RfD (cRfD) is established based on the lowest-observed-adverse-effect
level (LOAEL) from a chronic toxicity study in the rat.  The LOAEL of
4.0 mg/kg/day is based on epithelial cell hyperplasia, clear cell
hyperplasia and karyomegaly in the kidneys of male rats.  The
no-observed-adverse-effect level (NOAEL) is 2.0 mg/kg/day.  This NOAEL
is lower than any NOAEL in the database based on kidney effects. 
Although, lower NOAELs/LOAELs were observed for gastrointestinal
irritation in rodents, HED’s Hazard Assessment and Policy Committee
(HASPOC) determined that the forestomach lesions in rodent species
should not be used for risk assessment, based on the physiological
characteristics of that region of the stomach relative to other species.
 The study duration is appropriate for the duration of exposure; i.e.,
long-term.  The uncertainty factor (UF) used in determining the cRfD was
100 (10X for interspecies [animal-to-human] extrapolation; 10X for
intraspecies [human] variations).  

Overall, there was no clear evidence that chlorothalonil was mutagenic. 
The Scientific Advisory Panel (SAP) concluded that the forestomach
tumors chlorothalonil produced in mice involved sustained cytotoxicity
and regenerative cell proliferation as the mode of action and that a
margin-of-exposure (MOE) approach would be appropriate.  Quantification
of excess lifetime cancer risk using a linear approach is, therefore,
not required.  

Quantification of dermal risk (all exposure scenarios) is not required
since there is no systemic toxicity in a dermal toxicity study in rats
at doses up to 600 mg/kg/day and there are no developmental and/or
neurotoxicity concerns.  

The endpoint for short- and intermediate-term incidental oral and
inhalation exposures has been changed since the last hazard assessment. 
The old endpoint was based on forestomach and kidney effects observed in
the 2-generation reproduction study (LOAEL = 30.8 mg/kg/day).  The new
endpoint is based on kidney effects observed in a different study, the
90-day rat feeding study (LOAEL = 10.0 mg/kg/day).  Short- and
intermediate-term incidental oral and inhalation endpoints are based on
the LOAEL of 10.0 mg/kg/day established in a 90-day rat feeding study
(the NOAEL was 3.0 mg/kg/day).  A target MOE of 100 is considered
adequate for short and intermediate-term incidental oral and inhalation
exposure [10X for interspecies (animal-to-human) extrapolation; 10X for
intraspecies (human) variations].  

Long-term inhalation exposure to chlorothalonil is not expected to occur
based on the current use pattern.  

Food Quality Protection Act (FQPA) Decision

After evaluating the toxicological database, the chlorothalonil risk
assessment team has identified the following factors supporting
reduction of the cRfD’s FQPA Safety Factor (SF) from 10X to 1X:  1)
there are no significant data gaps in the hazard and exposure databases,
2) there are low concerns for pre- and/or postnatal toxicity, 3) there
are no residual uncertainties with regard to pre- and/or postnatal
toxicity, and 4) there are no neurotoxicity concerns.  There is
equivocal evidence of increased susceptibility in rabbits; however, the
degree of concern for prenatal susceptibility is low.  There is a
well-defined NOAEL of 10 mg/kg in the rabbit developmental toxicity
study protecting from these effects.  There are no residual
uncertainties with regard to pre- and/or post-natal susceptibility.  

Residential Exposure Estimates

There is potential for residential exposure from treated golf courses
and from using treated paint.  Note that all other residential turf uses
of chlorothalonil have been cancelled.  Therefore, residential exposures
resulting from contact with chlorothalonil treated turf were not
assessed.  HED has determined that there is no hazard via the dermal
route; therefore, quantification of a dermal risk assessment is not
required.  For this assessment, only inhalation and incidental oral
exposures from the use of treated paint were assessed.  Inhalation
postapplication exposures for golf courses were not assessed since
inhalation exposures are thought to be negligible in outdoor
postapplication scenarios.  The short- and intermediate-term inhalation
and incidental oral MOEs are greater than the target MOE of 100 and,
therefore, do not exceed HED’s level of concern (LOC).

Occupational Exposure and Risk Assessment  

Since there were no compound-specific data available with which to
assess pesticide handler exposure, the exposure estimates are based upon
surrogate exposure data in the Pesticide Handler Exposure Database
(PHED) Surrogate Exposure Guide (AUG, 1998).  Since no dermal endpoints
were identified, only short- and intermediate-term inhalation exposures
and risks are estimated.  A MOE of 100 is adequate to protect
occupational pesticide handlers from short- and intermediate-term
inhalation exposures to chlorothalonil.  All MOEs are greater than 100
except for a mixer/loader/applicator using high-pressure, hand-wand
sprayer.  Use of a dust/mist filtering respirator will reduce inhalation
exposure by about 80% and resulting MOEs will be >100.  With the use of
a dust/mist filtering respirator, the use pattern does not exceed the
LOC.  The remaining proposed use patterns do not exceed HED’s LOC at
baseline.  

There is a potential for post-application exposure to agricultural
workers during the course of typical agricultural activities.  The label
lists a 12-hour restricted-entry interval (REI).  Since no dermal
toxicological endpoints were identified, it is not necessary to conduct
assessments of post-application exposure and risk.  Title 40 of the Code
of Federal Regulations § 156.208 (c),(2) states “If a product
contains only one active ingredient and it is in Toxicity Category I by
the criteria in paragraph (c)(1) of this section, the REI shall be 48
hours.”  Chlorothalonil is classified in Toxicity Category I for
primary eye irritation.  It is classified in Category II for inhalation
toxicity.  The REI for Category II is 24 hours.  It is suggested that RD
confirm or correct the REI for chlorothalonil as may be appropriate.  

Dietary Risk Estimates (Food + Water)

A conservative chronic dietary-exposure assessment was performed using
100% crop treated (CT), tolerance-level residues, and Dietary Exposure
Evaluation Model (DEEM™) 7.81 default processing factors for all foods
except for tomatoes (average field-trial residues and empirical
processing factors used), peppers (average field-trial residues used),
and snap beans (average field-trial residues used).  Dietary risk
estimates were determined considering exposures from food plus drinking
water using estimated drinking water concentrations (EDWCs) for surface
water sources provided by the Environmental Fate and Effects Division
(EFED).  EDWC values were generated by the PRZM (Pesticide Root Zone
Model)-EXAMS (Exposure Analysis Modeling System) for the FL horseradish
application scenario, since this crop yielded the highest EDWC values. 
Ground water sources were not included, as the EDWCs for this water
source are minimal in comparison to those for surface water.

The resulting chronic dietary exposure estimates for food and water
combined are below HED’s LOC (i.e., <100% of the cPAD of 0.02 mg/kg
bw/day) for the overall U.S. population and all population subgroups. 
Using the DEEM( software with the Food Commodity Intake Database
(DEEM-FCID(), dietary exposure is estimated at 0.008587 mg/kg/day for
the U.S. population (43% of the cPAD) and 0.018821 mg/kg/day (94% of the
cPAD) for children 1-2 years old, the population subgroup with the
highest estimated chronic dietary exposure to chlorothalonil.  Dietary
cancer risk concerns due to long-term consumption of chlorothalonil
residues are adequately addressed by the chronic exposure analysis using
the cPAD.

Aggregate-Risk Estimates

Aggregate exposure risk assessments were assessed for the following
scenarios:  short- and intermediate-term (food + drinking water +
residential) and chronic aggregate exposure (food + drinking water). 
Acute, long-term, and cancer aggregate-risk assessments were not
performed because no appropriate endpoint was available to determine the
aRfD for the general population or any population subgroup; there are no
registered or proposed uses of chlorothalonil which result in long-term
residential exposures; and aggregate cancer risk concerns are adequately
addressed by the chronic aggregate exposure (food + drinking water)
assessment.  

The total short- and intermediate-term food and residential aggregate
MOE is 270.  As this MOE is greater than 100, the short- and
intermediate-term aggregate risk does not exceed the HED’s LOC.  

Environmental-Justice Considerations

Potential areas of environmental-justice concerns, to the extent
possible, were considered in this human-health risk assessment, in
accordance with U.S. Executive Order 12898, "Federal Actions to Address
Environmental Justice in Minority Populations and Low-Income
Populations," (  HYPERLINK
"http://homer.ornl.gov/nuclearsafety/nsea/oepa/guidance/justice/eo12898.
pdf_" 
http://homer.ornl.gov/nuclearsafety/nsea/oepa/guidance/justice/eo12898.p
df ).

As a part of every pesticide risk assessment, OPP considers a large
variety of consumer subgroups according to well-established procedures. 
In line with OPP policy, HED estimates risks to population subgroups
from pesticide exposures that are based on patterns of that subgroup’s
food and water consumption, and activities in and around the home that
involve pesticide use in a residential setting.  Extensive data on food
consumption patterns are compiled by the USDA under CSFII and are used
in pesticide risk assessments for all registered food uses of a
pesticide.  These data are analyzed and categorized by subgroups based
on age, season of the year, ethnic group, and region of the country. 
Additionally, OPP is able to assess dietary exposure to smaller,
specialized subgroups and exposure assessments are performed when
conditions or circumstances warrant.  Whenever appropriate, non-dietary
exposures based on home use of pesticide products and associated risks
for adult applicators and for toddlers, youths, and adults entering or
playing on treated areas post-application are evaluated.  Further
considerations are currently in development as OPP has committed
resources and expertise to the development of specialized software and
models that consider exposure to bystanders and farm workers as well as
lifestyle and traditional dietary patterns among specific subgroups.

Review of Human Research

This risk assessment relies in part on data from PHED studies in which
adult human subjects were intentionally exposed to a pesticide or other
chemical.  These studies have been determined to require a review of
their ethical conduct, and have received that review.

Recommendations for Tolerances/Registration

Pending submission of revised Sections B (see requirements under
Directions for Use) and F (see requirements under Proposed Tolerances),
and submission of a reference standard for the 4-hydroxy metabolite (see
requirements under Submittal of Analytical Reference Standards), there
are no residue chemistry, toxicological, or occupational/residential
exposure issues that would preclude granting a conditional registration
for the requested uses of chlorothalonil on fruiting vegetables (Crop
Group 8), cucurbit vegetables (Crop Group 9), ginseng, horseradish, head
and stem Brassica (Subgroup 5A), lentil, okra, persimmon, rhubarb, and
yam; and establishment of the following permanent tolerances for
combined residues of chlorothalonil and its 4-hydroxy metabolite:  

	under 40 CFR §180.275(a)(1):

Brassica, head and stem, subgroup 5A	5.0 ppm

Ginseng	4.0 ppm

Horseradish	4.0 ppm

Lentil	0.10 ppm

Okra	6.0 ppm

Rhubarb	4.0 ppm

Vegetable, cucurbit, group 9	5.0 ppm

Vegetable, fruiting, group 8, except tomato	6.0 ppm

Yam	0.10 ppm

Lychee	15 ppm

Starfruit	3.0 ppm

	under 40 CFR §180.275(c):

Persimmon	1.5 ppm

Note to PM:  On establishment of the recommended tolerances, the
following tolerances should be removed from 40 CFR §180.275(a)(1):  

Broccoli	5 ppm

Brussels sprouts	5 ppm

Cabbage	5 ppm

Cauliflower	5 ppm

Cucumber	5 ppm

Melon	5 ppm

Pepper, non-bell	5 ppm

Pumpkin	5 ppm

Squash, summer	5 ppm

Squash, winter	5 ppm

and the following tolerance should be removed from 40 CFR §180.275(b): 

Ginseng	0.10 ppm (12/31/08 expiration date)

and the following tolerance should be removed from 40 CFR §180.275(b): 

Ginseng	0.10 ppm (12/31/08 expiration date)

860.1200 Directions for Use

The proposed uses on the Brassica head and stem subgroup should be
revised to specify a maximum seasonal application rate of 8.8 lb ai/A.

The proposed use on persimmon should be modified to specify that
chlorothalonil may only be applied to persimmon grown in Florida and
Hawaii, and that applications may be made with a minimum retreatment
interval (RTI) of 14 days.  In addition, the proposed use should specify
that aerial applications to persimmon be made in a minimum of 10 gal/A.

Use of a dust/mist filtering respirator should be specified for a
mixer/loader/applicator using high-pressure, hand-wand sprayer.  

Title 40 of the Code of Federal Regulations § 156.208 (c),(2) states
“If a product contains only one active ingredient and it is in
toxicity category I by the criteria in paragraph (c)(1) of this section,
the REI shall be 48 hours.”  Chlorothalonil is classified in Toxicity
Category I for primary eye irritation and Category II for inhalation
toxicity.  The REI for Category II is 24 hours.  It is suggested that RD
confirm or correct the REI for chlorothalonil as may be appropriate.  

860.1550 Proposed Tolerances

The petitioner should submit a revised Section F reflecting the
recommended tolerances and commodity definitions presented above and in
Table 4.2.1.

860.1650 Submittal of Analytical Reference Standards

The analytical reference standard for 4-hydroxy chlorothalonil at the
EPA National Pesticide Standards Repository has expired.  The registrant
should either recertify the lot in the repository and send in an updated
certificate of analysis (COA), or submit a new standard (different lot
#) if the previous lot will not be recertified.  

HED recommends that conversion of conditional registration to
unconditional registration for the requested uses may be considered upon
submission of the following outstanding residue chemistry and toxicology
data:

Residue Chemistry: 860.1500 Crop Field Trials

To support use of the FlC formulation on non-bell peppers, the
petitioner should conduct one additional side-by-side field trial with
non-bell peppers.  The trial should reflect side-by-side plots receiving
applications of the FlC and water-dispersible granule (WDG) formulations
at 1x the proposed maximum seasonal rate, and the trial should be
conducted in Zone 8.  If the trial indicates that residues in/on samples
treated with the FlC formulation are higher than in/on samples treated
with the WDG formulation, two additional field trials will be required,
so that a total of three field trials are available reflecting
application of the FlC formulation to non-bell peppers.  

Toxicology (required as a result of the revisions of 40 CFR §158)

Immunotoxicity studies.

Acute neurotoxicity study

2.0  PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

2.1  Identification of Active Ingredient

Common name	4-hydroxy-2,5,6-trichloroisophthalonitrile metabolite
(SDS-3701)

2.2  Physical and Chemical Properties

TABLE 2.2.  Physicochemical Properties of the Technical Grade Test
Compound:  Chlorothalonil. 

Parameter	Value	Reference

Melting range	250-251 (C	Chlorothalonil Reregistration Eligibility
Decision, April 1999

Water solubility	0.6 ppm (25 °C)	Chlorothalonil Reregistration
Eligibility Decision, April 1999

Solvent solubility	g/L at 25 °C:

acetone	20

dimethyl sulfoxide	20

cyclohexanone	30

dimethylformamide	30

kerosene	<10

xylene	80	The Pesticide Manual, 8th ed.

Octanol/water partition coefficient, Log(KOW)	4.37 x 102	TOXNET database

3.0  HAZARD CHARACTERIZATION

3.1  Hazard and Dose-Response Characterization

3.1.1  Studies Considered in the Toxicity and Dose-Response Evaluation

Data from the following studies were used to evaluate the hazard
potential of chlorothalonil:

Subchronic:  one rat (diet) neurotoxicity, one rat (dermal) toxicity,
one rabbit dermal toxicity, one dog (diet), one dog (capsule), one mouse
(diet) and three rat (diet) toxicity studies.

Chronic:  one 12-month dog (diet), one 24-month dog (diet), one 18- and
three 24-month mouse (diet) carcinogenicity studies, and four 24-month
rat (diet) carcinogenicity studies.

Reproduction/developmental:  two rat and two rabbit developmental
toxicity studies, and two rat 2-generation reproduction studies. 

Other:  a multitude of genotoxicity studies (in vivo/in vitro),
metabolism studies in rats and dogs and dermal penetration studies.

In addition, acute, subchronic, chronic, developmental toxicity studies
and reproduction studies are available on the plant/livestock metabolite
SDS-3701 (4-hydroxy metabolite) and the soil metabolite SDS-46851. 

3.1.2  Sufficiency of Studies/Data

There are two hazard databases that are available on chlorothalonil. 
One set is somewhat old and was provided by the Fermenta ASC
Corporation.  Vischim S.R.L provided the second and newer set of studies
as part of a “me-too” application.  In addition, GB Biosciences
Corporation (registrant of active ai) provided a new subchronic
neurotoxicity study in rats.  The hazard profile from both databases is
comparable.  The acute, subchronic, developmental, reproduction and
chronic studies were sufficient to determine whether human hazard could
exist within the context of dose, duration, timing, and
route-of-exposure for the old data, and the new and old data combined. 
The new database from Vischim had data gaps (see Appendix 1).  Data
quality is acceptable for the overall database, and the number of
species tested and endpoints measured is consistent with OPPTS
guidelines and 40 CFR §158.  Overall, there was no clear evidence that
chlorothalonil was mutagenic.  The SAP concluded that the forestomach
tumors chlorothalonil produced in mice involved sustained cytotoxicity
and regenerative cell proliferation as the mode of action and that a MOE
approach would be appropriate.  Quantification of excess lifetime cancer
risk using a linear approach is, therefore, not required.

When commercial production of chlorothalonil first began in the U.S. in
1969, certain production batches contained unacceptably high levels of
hexachlorobenzene (HCB).  The level of HCB in all chlorothalonil
products must be reduced to no greater than 0.004% (40 ppm).  This is
the lowest level that has been shown to be technologically feasible for
chlorothalonil.  HCB has been well characterized by the scientific
community.  HCB has been shown in animal studies to affect a wide range
of organ systems, including the liver, lungs, kidneys, thyroid,
reproductive tissues, nervous and immune systems.  Clinical toxicity,
including porphyria cutanea tarda in children and adults, and mortality
in nursing infants, has been observed in humans with high accidental
exposures.  HCB has a chronic oral RfD of 0.0008 mg/kg/day.  HCB is
currently a B2 possible human carcinogen.  The Q* for HCB is 1.02
(mg/kg/day)-1 based on a ¾ scaling factor (IRIS).  Risks associated
with HCB were assessed previously (Federal Register, Vol. 66: No. 48,
pp. 14330-14342, March 12, 2001).  Based on the low levels of HCB in
chlorothalonil, HED concludes that the cancer risk from the existing and
proposed uses of chlorothalonil are not of concern.

3.1.3  Mode of Action and Mammalian Toxicology

Chlorothalonil is a broad-spectrum, non-systemic protectant pesticide
mainly used as a fungicide to control fungal foliar diseases of
vegetable, field, and ornamental crops.  It is also used as a wood
protectant, antimold and antimildew agent, bactericide, algaecide,
insecticide, and acaricide.  Its mechanism of action as an antifungal
agent is by disrupting sulfur-containing enzymes and disrupting energy
production in the fungal organism.  Chlorothalonil is known to induce
rodent forestomach tumors through a non-genotoxic mechanism involving
irritation, cytotoxicity, cell necrosis, increased cell proliferation,
and restorative hyperplasia.  As to its kidney effects, chlorothalonil
acts by bioactivation of cysteine conjugate beta-lyase activity in the
kidney which leads to the formation of nephrotoxic
cysteine-S-conjugates.  Cysteine conjugate beta-lyase is a name applied
to enzymes which cleave the cysteine-S-conjugates of some xenobiotics to
form pyruvate, ammonia, and a thiol.  Metabolism studies on
chlorothalonil in rats have shown the presence in urine of dithiol-and
trithiol analogs of chlorothalonil, and it is these thiol metabolites
that lead to the renal toxicity.  “Mitochondrial respiratory control
has been shown to be disrupted by the di- and tri-thiol analogs of
chlorothalonil.  Osmotic changes occur within the renal cortical tubular
cells as a result of toxic insult by the thiol metabolites of
chlorothalonil, resulting in vacuolar degeneration followed by cellular
regeneration.”  (Excerpts from the Carcinogenicity of Chlorothalonil:
Data in Support of a Non-linear Mechanism of Carcinogenicity.  Presented
on July 29-30 by T. McMahon to the 1998 Federal Insecticide, Fungicide,
and Rodenticide Act (FIFRA) SAP.)  The vacuolar degeneration leads to
cell death followed by cellular regeneration (proliferation) which is
rapid and excessive to form adenomas/carcinomas.  With chlorothalonil,
the respiration of mitochondria is affected primarily in the cortex
region of the kidney, which eventually causes renal tubular cell
adenomas/carcinomas.  

3.1.4  Toxicological Effects 

3.1.4.1  Chlorothalonil 

Chlorothalonil has a low order of acute toxicity by the oral and dermal
routes of exposure (Toxicity Category IV).  Chlorothalonil is severely
irritating to the eye (Toxicity Category I) and is moderately irritating
to the skin (Toxicity Category III).  Chlorothalonil is not a skin
sensitizer.

Chlorothalonil causes gastric irritation upon ingestion.  In a
subchronic dog study, both males and females exhibited decreased body
weights, body-weight gains and food consumption.  In a chronic dog
study, there was one death (female), decreased body-weight gain and food
consumption, macroscopic and microscopic pathological findings in the
stomach including:  thickened appearance of the stomach, and
intra-epithelial nuclear pyknosis in the mucosal epithelium of the
antrum of the stomach and a very slight hypertrophy of the cells in the
zona fasciculata of the adrenal glands.  In a second chronic dog study,
vacuolated epithelium of the kidney was observed.  In a subchronic mouse
study, chlorothalonil produced hyperplasia and hyperkeratosis of the
squamous epithelium of the stomach.  In a subchronic rat study,
chlorothalonil increased relative kidney weights and produced dilated
renal medullary tubules, and hyperplasia and hyperkeratosis of the
non-glandular area of the stomach.  In rodent chronic toxicity studies,
there was an increased incidence of epithelial hyperplasia of the
limiting ridge and non-glandular region of the stomach in rats and mice.
 In addition, there was an increased incidence of benign squamous cell
papilloma of the non-glandular region of the stomach in male and female
mice.  

There was no indication of a carcinogenic response in the rat chronic
toxicity/carcinogenicity study.  Previously, and based on the extensive
“old” chlorothalonil database, “…HED/CPRC unanimously agreed
that the weight of the evidence supported a classification of
chlorothalonil as a “likely” human carcinogen by all routes of
exposure.  This conclusion was based on (1) the increased incidence of
renal adenomas and carcinomas observed in both sexes of rats and mice;
(2) the rarity of the tumor response in the kidney, and (3) the
increased incidence of papillomas and/or carcinomas of the forestomach
in rats and mice.  While it was recognized that the mechanistic data
supported a non-linear mode of action for tumor production by
chlorothalonil, the HED/CPRC also recognized that the kidney tumors were
the result of administration of test chemical, were considered rare, and
the submitted data supported the non-neoplastic pathology as directly
related to eventual neoplasia.  The HED/CPRC agreed that a non-linear
approach to risk assessment, using the MOE, should be used.”
(Extracted from HED document #012366, dated October 20, 1997.)  The
“new” mouse carcinogenicity study also demonstrates that the
sponsor’s [Vischim] chlorothalonil produces similar papillomas of the
forestomach.  Therefore, the previous HED/CPRC of 1997
decision/classification would be relevant.

 

No development toxicity was observed in two rat developmental toxicity
studies.  No qualitative evidence of increased susceptibility was seen
following in utero exposure to rats or rabbits in developmental studies
or in the reproduction study.  In one of two rabbit developmental
toxicity studies, there was an increased incidence of thirteen ribs and
reduced sternebrae.  There was a small (2x) quantitative difference in
susceptibility observed between fetal and maternal effect levels. 
However, the difference was due to an increase in two variations that
are often observed in this strain of rabbit; i.e., increased 13th rib
and reduced sternum and these findings were not reproduced in the other
rabbit developmental toxicity study.  No malformations, or increase in
malformations or reproductive effects attributable to administration of
chlorothalonil were observed.  In the reproduction study, both parental
animals and offspring exhibited pathological effects involving the
stomach consisting of thickened and/or roughening of the forestomach
with depressions in the epithelial aspect, and hyperplasia and
hyperkeratosis of the non-glandular epithelium of the stomach.  Newly
submitted genetic toxicology data (4 studies) were negative.

Based on overall weight of evidence, HED concluded that there is no
evidence of increased susceptibility to offspring following in utero
exposure to rats or rabbits in developmental studies or pre/post-natal
exposure to chlorothalonil in the reproduction studies in rats.  In a
90-day oral toxicity study with rats, a slight decreased in thymus
weight was observed at 529 mg/kg/day (highest-dose tested; HDT).  There
were no histopathological findings noted in the thymus.  There were no
effects on thymus in other subchronic and chronic carcinogenicity
studies in rats in the old and new data.  Therefore, decreases in thymus
weight in the 90-day study are considered equivocal and not a trigger
for immunotoxicity study.  

Table 3.1.4.1a.  Acute Toxicity Profile - Chlorothalonil Technical (96%
ai) (Old Data).

Guideline No./Study Type	

MRID No.	

Results	Toxicity Category

870.1100/Acute oral toxicity rat	00094941	LD50 >10,000 mg/kg	IV

870.1200/Acute dermal toxicity rat	00094940	LD50 >10,000 mg/kg	IV

870.1300/Acute inhalation toxicity rat	00094942	LC50 = 0.094 mg/L (M);
0.092 mg/L (F)	II

870.2400/Primary eye irritation rabbit	00246769	Severe irritation	I

870.2500/Primary dermal irritation rabbit	00094939	Slight erythema	III

870.2600/Dermal sensitization guinea pig	40546001	Not a sensitizer	N/A

Table 3.1.4.1b.  Subchronic and Chronic Toxicity and Genotoxicity
Profile - Chlorothalonil (New Data).  SEQ CHAPTER \h \r 1 

Guideline No./ Study Type	

MRID No. (Year)/Doses/ Classification	Results

870.3100

90-Day

rat - diet	45710205 (1994)

0, 30, 60, 300 or 1500 ppm (0/0, 2.3/2.7, 4.7/5.5, 23.6/28.8 or 117/130
mg/kg/day [M/F])

acceptable/guideline	  SEQ CHAPTER \h \r 1 NOAEL <2.3/2.7 mg/kg/day
(M/F). 

LOAEL = 2.3/2.7 mg/kg/day (M/F) based on minimal epithelial hyperplasia
and hyperkeratosis observed at the limiting ridge and/or non-glandular
region of the forestomach in males and females.

870.3150

90-Day

dog - diet	45710206 (1994)

0, 160, 1600 or 16,000 ppm (0/0, 5.6/6.1, 56.5/61.0 or 597/570 mg/kg/day
[M/F])

acceptable/guideline	  SEQ CHAPTER \h \r 1 NOAEL = 5.6/6.1 mg/kg/day
(M/F).  

LOAEL = 56.5/61.0 mg/kg/day (M/F) based on minimal foci of necrotic
hepatocytes with inflammatory cell infiltration in males, and minimal
parenchymal foci of inflammatory cells in both sexes.

870.3700

Prenatal developmental toxicity - rabbit	45710208 (1994)

0, 5, 10 or 20 mg/kg/day

acceptable/guideline	  SEQ CHAPTER \h \r 1 Maternal NOAEL = 20
mg/kg/day.

Maternal LOAEL was not determined.

Developmental NOAEL = 10 mg/kg/day.

Developmental LOAEL = 20 mg/kg day based on incr. 13th rib and reduced
sternum.

870.3700

Prenatal developmental toxicity - rat	45710207 (1994)

0, 80, 200 or 500 mg/kg/day

acceptable/guideline	  SEQ CHAPTER \h \r 1 Maternal NOAEL = 200
mg/kg/day. 

Maternal LOAEL = 500 mg/kg/day, based on increased mortality, clinical
signs of toxicity, decreased body-weight gains and food consumption, and
increased water consumption.

Developmental NOAEL = 500 mg/kg/day. 

Developmental LOAEL was not determined.

870.3800

Reproduction and fertility effects rat - diet	45710209 (1995)

0, 400, 1200 or 3000 ppm (0/0, 30.8/34.3, 92.5/106.0 or 247.5/270.0
mg/kg/day [M/F])

acceptable/guideline	  SEQ CHAPTER \h \r 1 Parental NOAEL was not
established.

Parental LOAEL = 400 ppm (30.8/34.3 mg/kg/day [M/F]) based on
macroscopic and microscopic pathological findings in the stomach-
including: thickened, roughened, and white areas in forestomach with
depressions in the epithelial aspect, and hyperplasia and hyperkeratosis
of non-glandular epithelium in the stomach, and kidney effects; i.e.,
enlargement, relative weight increases and dystrophic mineralization at
the corticomedullary junction.

Offspring NOAEL was not established.

Offspring LOAEL = 400 ppm (30.8/34.3 mg/kg/day [(M/F]), based on
thickening and/or roughening of the forestomach with depressions in the
epithelial aspect, and hyperplasia and hyperkeratosis of the
non-glandular epithelium of the stomach.

Reproductive NOAEL = 3000 ppm (247.5/270.0 mg/kg/day (M/F)].

Reproductive LOAEL was not established.

870.4100

Chronic toxicity

dog - diet	45710210 (1995)

0, 160, 1280 or 10,240 ppm (0/0, 5.10/5.92, 43.26/45.30 or 374/354
mg/kg/day [M/F])

acceptable/guideline	  SEQ CHAPTER \h \r 1 NOAEL = 1280 ppm (43.5/45.3
mg/kg/day [M/F]).

LOAEL = 10,240 ppm (374/354 mg/kg/day [M/F]), based on death in a
female, decreased body-weight gain and food consumption, macroscopic and
microscopic pathological findings in the stomach including: thickened
appearance of the stomach, often with a catarrhal adhesion to the
mucosal surface, and intra-epithelial nuclear pyknosis in the mucosal
epithelium of the antrum of the stomach and a very slight hypertrophy of
the cells in the zona fasciculata of the adrenal glands.

870.4200

Carcinogenicity

mouse - diet	45710211 (1995)

0, 15, 60, 240 or 960 ppm (0/0, 1.9/2.5, 7.8/9.9, 30.4/40.6 or 130/157
mg/kg/day [M/F])

acceptable/guideline	  SEQ CHAPTER \h \r 1 NOAEL <15 ppm (1.9 mg/kg/day
[M]) and = 15 ppm (2.5 mg/kg/day [F]).

LOAEL = 1.9/9.9 mg/kg/day (M/F), based on epithelial hyperplasia of the
non-glandular region of the stomach and epithelial hyperplasia (limiting
ridge) of the stomach (M) and epithelial hyperplasia and of the
non-glandular region of the stomach (F).

870.4300

Chronic toxicity/carcinogenicity

rat - diet	45710212 (1996)

0, 15, 60, 240 or 1200 ppm (0/0, 0.7/0.9, 2.7/3.3, 10.6/13.9 or 54/70
mg/kg/day [M/F]

acceptable/guideline	  SEQ CHAPTER \h \r 1 NOAEL <15 ppm (0.9 mg/kg/day
[F]), and = 15 ppm [0.7 mg/kg/day [M]). 

LOAEL = 15 ppm 0.9 mg/kg/day [F]), and 60 ppm (2.7 mg/kg/day [M], based
on an increase in the incidence and severity of epithelial hyperplasia,
hyperkeratosis and ulceration of the non-glandular region of the stomach
(F), and an increase in the incidence and severity of epithelial
hyperplasia and hyperkeratosis of the non-glandular region of the
stomach (M). No evidence of carcinogenicity.

870.5300

In Vitro mammalian cells	45710214 (1996) 

0.01, 0.025, 0.05, 0.1, 0.2, 0.3, 0.4, or 0.5 μg/mL (Trial 1, -S9);
0.05, 0.1, 0.25, 0.5, 1.0, 1.5, 2.0, or 2.5 g/mL (Trial 1, +S9); 0.005,
0.01, 0.02, 0.04, 0.06, 0.08, 0.1, or 0.12 μg/mL (Trial 2, -S9); and
0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, or 5.0 μg/mL (Trial 2, +S9)

acceptable/guideline	No evidence of induced mutant colonies over
background in the presence or absence of S9-activation.  [Negative]

870.5395

In Vivo mammalian cytogenetics	45710215 (1992) 

0 or 1600 mg/kg

acceptable/guideline	No significant increase in the frequency of
micronucleated polychromatic erythrocytes in bone marrow compared to
controls.  [Negative]

870.5100

In Vitro bacterial gene mutation S. typhimurium/E. coli 	45710213 (1988)

0, 1.56, 3.13, 6.25, 12.5 or 25 µg/plate  (-S9 activation)

0, 3.13, 6.25, 12.5, 25 or 50 µg/plate (+S9 activation) cytotoxicity
was observed at 12.5-25 µg/plate -S9; 25-50 µg/plate +S9 

acceptable/guideline	No marked increases in the number of revertants
were observed at any concentration in any strain in either trial. 
[Negative]

870.6200b

Subchronic neurotoxicity rat

- diet	46526901 (2004)

0, 30, 300 or 3000 ppm (0/0, 2.1/2.4, 22.0/24.2 or 232.1/243.1 mg/kg/day
[M/F])

acceptable/guideline	NOAEL = 300 ppm (22.0/24.2 mg/kg/day [M/F]).

LOAEL = 3000 ppm (232.1/243.2 mg/kg/day [M/F]), based on decreased body
weights, food consumption and food utilization.

870.7485

Metabolism-rat	45710216 (1997)

1.5 or 50 mg/kg

acceptable/guideline	Chlorothalonil was readily absorbed.  Plasma
concentration peaked at 2-4 h at the low dose, increasing to 12 h at the
high dose.  The majority of the radioactivity was recovered in the
feces.  Males seem to excrete a greater proportion in the first 24 h,
whereas females excreted closer proportions in the 0-24 h and 24-48 h
intervals.  Urine accounted for a smaller percentage of the dose, with
females appearing to excrete a greater proportion of radioactivity than
males.  Bile was also a major excretion pathway accounting for 8.7-18.4%
of the dose by 48 h.  14-23% of the dose was absorbed by males.  The
test compound was not extensively retained by any tissue.  HPLC analysis
of the urine revealed 18 distinct peaks.  Unlike the dog, the presence
of mercapturic metabolites was discovered.

870.7485

Metabolism-dog	45710217 (1997)

1.5 mg/kg

acceptable/non-guideline	Chlorothalonil was readily absorbed by the oral
route.  Plasma concentration peaked at 6 h and the half life was
calculated to be 74.2 h.  One half of the administered dose was excreted
in the feces within 48 h; urine accounted for a lesser amount.  The
majority of the parent was found in the excreta within 48 h.  The test
compound was not extensively retained by any tissue.  Four major urinary
metabolites accounted for 1.2% of the dose. 

Non-guideline

Dermal penetration	46261901 (2004)

62 or 5000 µg/cm2 in a suspension concentration or a dispersible
granule concentrate

acceptable/non-guideline	The majority of radioactivity was unabsorbed
(89.1-97.5%).  Radioactivity was associated with the stratum corneum,
which was probably not available for absorption.  A greater proportion
of the applied low dose formulation was associated with the stratum
corneum compared to the high-dose formulations.  The different
formulation types had little effect on total absorption, or steady-state
absorption rates (7.1-8.2 ng/cm2/h for the low-dose formulations;
151.1-231.2 ng/cm2/h for the high-dose formulations).

Table 3.1.4.1c.  Subchronic and Chronic Toxicity and Genotoxicity
Profile - Chlorothalonil (Select Old Data).   SEQ CHAPTER \h \r 1 

Guideline No./ Study Type	MRID No. (Year)/ Doses/Classification	Results

870.3100

90-Day rat - diet	00127852, 00258768 (1981)

0, 1.5, 3, 10 or 40 mg/kg/day

acceptable/guideline	NOAEL = 3.0 mg/kg/day. 

LOAEL = 10.0 mg/kg/day, based on dilated renal medullary tubules and
hyperplasia and hyperkeratosis of the non-glandular area of the stomach.

870.3100

90-Day rat - diet	00127850 (1981)

0, 40, 80, 175, 375, 750 or 1500 mg/kg/day

acceptable/guideline	NOAEL <40 mg/kg/day. 

LOAEL = 40 mg/kg/day, based on increases in relative kidney weights.

870.3100

90-Day mouse - diet	00138148, 00258769 (1983)

0, 7.5, 15, 50, 275 or 750 ppm (equivalent to 0, 1.1, 2.3, 7.5 41.3 or
113 mg/kg/day)

acceptable/guideline	NOAEL = 15 ppm (2.3 mg/kg/day). 

LOAEL = 50 ppm (7.5 mg/kg/day), based on hyperplasia and hyperkeratosis
of the squamous epithelium of the stomach.

870.3150

90-Day dog - diet	43653602 (1993)

0, 15, 150 or 500/750 (750 reduced from 500 on day 5) mg/kg/day

acceptable/guideline	NOAEL = 15 mg/kg/day.  

LOAEL = 150 mg/kg/day, based on decreased body-weight gain.

870.3150

21-Day dermal rabbit 	00158254 (1986)

0, 0.1, 2.5 or 50.0 mg/kg/day

acceptable/guideline	NOAEL (systemic) = 50.0 mg/kg/day. 

LOAEL (systemic) was not determined.

NOAEL (dermal) = 2.5 mg/kg/day.

LOAEL (dermal) = 50.0 mg/kg/day, based on slight skin irritation
(erythema).

870.3150

21-Day dermal rat 	44119101 (1996)

0, 60, 100, 250 or 600 mg/kg/day

acceptable/guideline	NOAEL (systemic) = 600 mg/kg/day. 

LOAEL (systemic) was not determined.

NOAEL (dermal) <60 mg/kg/day.

LOAEL (dermal) = 60 mg/kg/day, based on erythema, desquamation,
hyperkeratosis and squamous epithelial hyperplasia of the skin.

870.3700 (b)

Prenatal developmental toxicity - rabbit	41250503 (1988)

0, 5, 10 or 20 mg/kg/day

acceptable/guideline	Maternal NOAEL = 10 mg/kg/day.

Maternal LOAEL = 20 mg/kg/day, based on decreases in body-weight gain
and food consumption.

Developmental NOAEL = 20 mg/kg/day.

Developmental LOAEL was not determined (HDT).

870.3700 (a)

Prenatal developmental toxicity - rat	00130733, 41679301 (1983)

0, 25, 100 or 400 mg/kg/day

acceptable/guideline	Maternal NOAEL = 100 mg/kg/day. 

Maternal LOAEL = 400 mg/kg bw/day, based on decreases in body-weight
gain and food consumption.

Developmental NOAEL = 100 mg/kg/day. 

Developmental LOAEL = 400 mg/kg/day based on an increase in total
resorptions per dam with a related increase in post-implantation loss. 

870.3800

Reproduction and fertility effects rat - diet	41706201 (1990)

0, 500, 1500 or 3000 ppm

(0, 38, 115 or 234 mg/kg/day)

acceptable/guideline	Parental NOAEL <500 ppm (38 mg/kg/day). 

Parental LOAEL = 500 ppm (38 mg/kg/day), based on kidney and forestomach
lesions. 

Offspring NOAEL = 1500 ppm (115 mg/kg/day).

Offspring LOAEL = 3000 ppm (234 mg/kg/day), based on lower pup body
weights on day 21.

Reproductive NOAEL = 3000 ppm (234 mg/kg/day).

Reproductive LOAEL was not determined.

870.4200

Carcinogenicity rat - diet	00052944 (1978)

0, 5063 or 10,126 ppm

0, 253 or 506 mg/kg/day	Renal adenomas and carcinomas were observed at
both dose levels (NCI).

870.4200

Carcinogenicity mouse - diet	00127858 (1979)

0, 750, 1500 or 3000 ppm

(0, 113, 225 or 450 mg/kg/day)

acceptable/guideline	NOAEL <750 ppm (113 mg/kg/day).

LOAEL = 750 ppm (113 mg/kg/day), based on increased kidney weights,
enlargement, discoloration, surface irregularities, pelvic dilation,
cysts, an increased incidence of tubular degeneration and cortical cysts
in males, an increased incidence of hyperplasia and hyperkeratosis of
the esophageal squamous mucosa and hyperplasia of the bone marrow and
splenic red pulp.

870.4200

Carcinogenicity mouse - diet	00052944 (1978)

0, 2688 or 5375 ppm

0, 429 or 851 mg/kg/day	No evidence of carcinogenicity (NCI).

870.4200

Carcinogenicity mouse - diet	40243701 (1987)

0, 10/15, 40, 175 or 750 ppm (0, 1.5/2.3, 6.0, 26.3 or 113 mg/kg/day
[the 10 ppm dose group was increased to 15 ppm at week 18])

acceptable/non-guideline	NOAEL <40 ppm (6.0 mg/kg/day).

LOAEL = 40 ppm (6.0 mg/kg/day), based on increased absolute and relative
kidney weights in males, tubular hyperplasia, hypertrophy and
karyomegaly of the kidney and hyperplasia and hyperkeratosis of the
squamous epithelium of the forestomach.

870.4200

Chronic toxicity dog - diet	00114034 (1970)

0, 60 or 120 ppm (0, 1.8 or 3.5 mg/kg/day) 

acceptable/non-guideline	NOAEL = 60 ppm (1.8 mg/kg/day).

LOAEL = 120 ppm (3.5 mg/kg/day), based on vacuolated epithelium of the
kidney in males.

870.4300

Chronic toxicity/carcinogenicity rat - diet	00146945 (1985)

0, 40, 80 or 175 mg/kg/day

acceptable/guideline	NOAEL <40 mg/kg/day.

LOAEL = 40 mg/kg/day based on an increased urine volume, decreased urine
specific gravity, increased relative kidney weights in males, chronic
glomerulonephritis, cortical tubular hyperplasia, increased incidence of
tubular cysts, increased incidence in males of hyperplasia of the
papillary/pelvic epithelium, hyperplasia/hyperkeratosis of the squamous
mucosa of the esophagus, mucosal hypertrophy of the duodenum,
hyperplasia/hyperkeratosis of the parathyroid in males,
hyperplasia/hyperkeratosis of the squamous mucosa of the stomach,
increased incidences of foci of necrosis or ulcers in the glandular
stomach, increased incidence of suppurative prostatitis in males and
complete involution of the thymus in females.

Increase in tumor incidence of renal adenomas and carcinomas and
papillomas of the stomach.

870.4300

Chronic toxicity/carcinogenicity rat - diet	41250502 (1989)

0, 2.0, 4.0, 15.0 or 175.0 mg/kg/day

acceptable/non-guideline	NOAEL = 2.0 mg/kg/day.

LOAEL = 4.0 mg/kg/day based on an increased incidence and/or severity of
hyperplasia, hyperkeratosis and ulcers or erosions of the squamous
mucosa of the forestomach in both sexes, and epithelial hyperplasia in
the proximal convoluted tubules of the kidney in the males.

Renal tubular adenomas and carcinomas and stomach papillomas and
carcinomas were observed.

870.5100

In vitro bacterial gene mutation S. typhimurium/E. coli 	00030288,
00030290, 00147949

 	No marked increases in the number of revertants were observed.

3.1.4.2  Chlorothalonil Metabolite SDS-3701 (4-hydroxy metabolite)

SDS-3701 is the major metabolite of chlorothalonil which is moderately
toxic via the oral route of exposure (Toxicity Category II).  The
primary effect in a 90-day toxicity study in dogs was on the kidney
(renal tubular degeneration and vacuolation).  The chronic
administration of SDS-3701 in dog produced hematopoietic effects
(alterations in RBCs, MCV, MCH and MCHC) and liver and kidney toxicity
at a higher dose.  

There are two subchronic toxicity studies in rats available.  In one
subchronic study in rats, decreases in body weights and increases in
liver weights were observed.  In another study in rats, anemia and renal
cortical atrophy was observed.  Chronic exposure to SDS-3701 produced
anemia in rats and liver effects in mice.  There was no evidence of
carcinogenicity in mice and rats.  It gave a mixed response in various
mutagenic assays.  The SDS-3701 metabolite of chlorothalonil did not
cause DNA damage or induce a mutagenic response in this microbial
species or in cultured Chinese hamster V 79 cells or BALB/3T3 mouse
fibroblasts.  No evidence of mutagenesis was found in a host-mediated
assay using S. typhimurium tester strains and mice exposed daily for 5
days to 6.5 mg/kg/day of the compound.  Phenotypic transformation was
not observed in rat embryo cells treated with SDS-3701; however, F1706
cells treated with SDS-3701 did induce late tumors in newborn Fischer
rats.  The latter finding was considered inconclusive since the more
sensitive cell line (H4536 P+2) was not tumorigenic under similar
conditions.  The S9-activated SDS-3701 metabolite induced reproducible,
significant and dose-related increases in the yield of cells with
abnormal chromosome morphology.  Clastogenic activity was, however, not
uncovered in bone marrow cytogenetic assays conducted in Chinese
hamsters or in mice.  Mouse and rat dominant lethal assays were also
negative.  Based on this evaluation, it was concluded that the SDS-3701
metabolite of chlorothalonil was positive for clastogenic activity in
cultured mammalian cells; however, damage to chromosomes was not
expressed in either the somatic or germinal cells of whole animals. 
Hence, the concern for genotoxic potential is diminished.  

No increased evidence of susceptibility was seen following in utero
exposure to rats or rabbits in developmental studies.  No reproductive
toxicity was observed in two reproduction studies in rats.  No evidence
of increased susceptibility was seen following pre and post-natal
exposure to SDS-3701 in two reproduction toxicity studies in rats. 

Of note is that in the chronic dog toxicity study the NOAELs for male
and females are 0.83/0.95 mg/kg/day, lower that the NOAEL of 2 mg/kg/day
established for kidney effects in the chlorothalonil chronic rat study
which was used to set the cRfD.  In the chronic dog study with SDS-3701,
the effects at 1.86 mg/kg/day were not statistically significant with
respect to female body-weight gain; probably attributable to a great
deal of variability among female dog weights.  However, the decrease in
male body weight gain was significant (p<0.05) at 1.80 mg/kg/day.  The
alterations in the hematological profile were not biologically
significant at 1.80/1.86 mg/kg/day, although there were several
hematological parameters that were statistically different from
controls.  These changes would indicate that the NOAEL was quite a bit
higher than 0.83/0.95 mg/kg/day, and probably closely approaches the
LOAEL of 1.80/1.86 mg/kg/day.  These values for the dog would be
considered numerically equivalent to the NOAEL of 2 mg/kg/day
established for kidney effects in rats, which is used as a basis for the
cRfD.  In this respect, chlorothalonil and the metabolite, SDS-3701,
have comparable quantitative toxicity in long-term studies.  

Since the quantitative subchronic and chronic toxicity of SDS-3701
appears to be similar to chlorothalonil, it is concluded that a separate
quantitative risk assessment of the plant/livestock metabolite SDS-3701
(4-hydroxy metabolite) is not necessary. 

Table 3.1.4.2.  Subchronic and Chronic Toxicity Profile - Chlorothalonil
Plant Metabolite SDS-3701 (Select Data)1  SEQ CHAPTER \h \r 1 .

Guideline No./ Study Type	MRID No. (Year)/ Doses/Classification	Results

870.3700 (a)

Prenatal developmental toxicity - rat	45331001 (1998)

0, 5, 15 or 25 mg/kg/day

	Maternal NOAEL = 5 mg/kg/day.

Maternal LOAEL = 15 mg/kg/day, based on clinical signs (red vaginal
exudate and/or red anogenital staining), decreased body weight,
decreased body-weight gain/body weight loss, and decreased food
consumption. 

Developmental NOAEL = 5 mg/kg/day.

Developmental LOAEL = 15 mg/kg/day, based on increased early
resorptions, increased total litter resorptions, decreased fetal weight
(both sexes), and an increased litter incidence of 14th rudimentary
ribs.

870.3700 (b)

Prenatal developmental toxicity - rabbit	00047944 (1976)

0, 1, 2.5 or 5 mg/kg/day

acceptable/guideline	Maternal NOAEL = 1 mg/kg/day.

Maternal LOAEL = 2.5 mg/kg/day based on a dose-dependent increase in
maternal death and abortion.

Developmental NOAEL >5 mg/kg/day.

Developmental LOAEL was not determined.

870.3800

Reproduction and fertility effects rat - diet	00127845 (1982)

0, 10, 20, 30, 60 or 120 ppm (0, 0.5, 1.0, 1.5, 3.0 or 6.0 mg/kg/day)

acceptable/guideline	Parental NOAEL = 30 ppm (1.5 mg/kg/day). 

Parental LOAEL = 60 ppm (3.0 mg/kg/day).

Offspring NOAEL = 30 ppm (1.5 mg/kg/day).

Offspring LOAEL = 60 ppm (3.0 mg/kg/day), based on a reduction in
weanling body weight. 

Reproductive NOAEL = 120 ppm (6.0 mg/kg/day). 

Reproductive LOAEL was not determined.

870.4200

Chronic toxicity dog - diet	45491101 (2000)

0, 30, 60 or 120 ppm (0/0, 0.83/0.95, 1.80/1.86 and 3.26/3.35 mg/kg/day
in males/females, respectively)	NOAEL = 30 ppm (0.83/0.95 mg/kg bw/day
[M/F]). 

LOAEL = 60 ppm (1.80/1.86 mg/kg/day [M/F]), based on decreased food
consumption in females, decreased body-weight gain in both sexes and
decreased erythrocyte parameters (red blood cell count, hemoglobin
concentration, hematocrit, and reticulocyte count in females and
abnormal erythrocyte morphology in males. 

870.4300

Chronic toxicity/carcinogenicity

rat - diet	00127848, 00137124 (1983)

0, 0.5, 3.0 or 15 (reduced to 10 at week 30) or 30 (reduced to 20 at
week 30) mg/kg/day 

acceptable/guideline	  SEQ CHAPTER \h \r 1 NOAEL = 3.0 mg/kg/day.

LOAEL = 10 mg/kg/day based on reduced body weight, microcytic anemia,
hemosiderin and decreased serum potassium. There was no evidence of
carcinogenicity in either sex.

870.4200

Carcinogenicity

mouse - diet	00127849 (1982)

0, 375, 750 or 1500 ppm (0, 54, 107 or 214 mg/kg/day)

acceptable/guideline	  SEQ CHAPTER \h \r 1 NOAEL <375 ppm (54
mg/kg/day).

LOAEL = 375 ppm (54 mg/kg/day), based on increased liver-to-body weight
ratios in males and increased RBC values in females.  There was no
evidence of carcinogenicity in either sex.

1-Data obtained from 1) HED Doc No. TXR 012213 (The HED Chapter of the
RED for Chlorothalonil (Case No. 0097; Chemical No. 081901), and 2) HED
TB-1 TOX ONELINERS /Caswell 215B/CAS-REG# 1897-45-6, dated 01/12/94).

3.1.4.3  Chlorothalonil Soil Metabolite SDS-46851

SDS-46851 is the major soil metabolite of chlorothalonil.  The primary
effect of SDS-46851 in a 90-day toxicity study in rats was increased
adrenal, kidney and liver weights and increased urinary specific
gravity.  In the 90-day dog study, liver weights, urinary pH and blood
glucose levels were increased.  No adverse findings were observed in a
90-day mouse study.  The chronic administration of SDS-46851 to rats for
65 weeks produced no toxic effects at the HDT of 1000 mg/kg/day.  In a
developmental toxicity study in rats, neither maternal nor fetal adverse
effects were observed at the HDT of 2000 mg/kg.  In a rabbit
developmental toxicity study, maternal adverse effects were expressed as
a decrease in body-weight gain and reduced food consumption. No adverse
fetal effects were observed at a dose of 1000 mg/kg.  In a 1-generation
reproduction study, parental animals were observed to have increased
liver and kidney weights.  The pups experienced reduced body weight on
day 21 postpartum.  The SDS-46851 metabolite of chlorothalonil did not
cause UDS.  SDS-46851 produced no evidence of mutagenicity in a
bacterial gene mutation assay using S. typhimurium, in a mammalian gene
mutation assay using mouse lymphoma L5178Y cells, or in a sister
chromatid exchange assay.  No increased evidence of susceptibility was
seen following in utero exposure to rats or rabbits in developmental
studies. No evidence of increased susceptibility was seen in two
developmental toxicity studies or following pre and post-natal exposure
to SDS-46851 in a 1-generation reproduction study in rats. 

Table 3.1.4.3.  Subchronic and Chronic Toxicity and Genotoxicity Profile
- Chlorothalonil Soil Metabolite SDS-46851 (Select Old Data)1  SEQ
CHAPTER \h \r 1 .

Guideline No./ Study Type	MRID No. (Year)/ Doses/Classification	Results

870.3100

90-Day rat - diet	41564806

0, 250, 750 or 2000 mg/kg/day

acceptable/guideline	NOAEL = 250 mg/kg/day. 

LOAEL = 750 mg/kg/day in males based on increases in relative liver and
kidney weights.

870.3100

90-Day mouse - diet	42090103 

0, 44, 134, 412 or 1401 mg/kg/day

acceptable/non-guideline	NOAEL = 1401 mg/kg/day.

LOAEL was not determined.

870.3150

90-Day dog - diet	41564805 

0, 5, 15 or 100 mg/kg/day

acceptable/guideline	NOAEL = 15 mg/kg/day.  

LOAEL = 50 mg/kg/day based on increases in liver weights and blood
glucose levels, and decreases in urinary pH.

870.3700 (b)

Prenatal developmental toxicity - rabbit	41564810 

0, 250, 500 or 1000 mg/kg/day

acceptable/guideline	Maternal NOAEL = 250 mg/kg/day.

Maternal LOAEL = 500 mg/kg/day based on decreased body-weight gain and
food consumption.

Developmental NOAEL = 1000 mg/kg/day.

Developmental LOAEL was not determined.

870.3700 (a)

Prenatal developmental toxicity - rat	41564808 

0, 500, 1000 or 2000 mg/kg/day

acceptable/guideline	Maternal NOAEL = 2000 mg/kg/day.

Maternal LOAEL was not determined.

Developmental NOAEL = 2000 mg/kg/day.

Developmental LOAEL was not determined.

870.3800

Reproduction and fertility effects rat - diet	41564806 

0, 250, 750 or 2000 mg/kg/day

acceptable/guideline	Parental NOAEL <250 mg/kg/day.

Parental LOAEL = 750 mg/kg/day based on increased liver and kidney
weights. 

Offspring NOAEL = 750 mg/kg/day.

Offspring LOAEL = 2000 mg/kg/day based on lower pup body weights on day
21.

870.4100

Chronic toxicity - rat	42090104

0, 80, 200, 500 and 1000 mg/kg/day

Acceptable/guideline	NOAEL = 1000 mg/kg/day.

LOAEL was not established.

870.5100

In Vitro bacterial gene mutation S. typhimurium/E. coli 	41564812 

acceptable/guideline 	No marked increases in the number of revertants
were observed with or without metabolic activation.  (Negative).

870.5300 

In vitro mammalian cell gene mutation test (L5178Y mouse lymphoma)
41564813 

unacceptable	No mutagenic effect at any dose level without activation. 
Mutagenic effects were observed at all dose levels with activation. 
(Negative).

870.5550 Unscheduled DNA synthesis in mammalian cells in culture
41564815 

24 to 240 µg/mL

acceptable/guideline	No evidence of mutagenicity reported at any dose
with or without activation.  (Negative).

870.5915

In vivo sister chromatid exchange assay	41564816 

200 to 2000 µg/mL

unacceptable	No evidence of mutagenicity reported at any dose with or
without activation.  (Negative).

870.7485

Metabolism-rat

	41564818 

10 and 1000 mg/kg/day

acceptable/guideline	The test material was quickly excreted through both
the urine and feces with the half-life for elimination being 2.5 and 6.2
hours in the low and high doses, respectively.

1-Data obtained from HED Doc No. TXR 013558 (Chlorothalonil:
Determination of toxicological concern under FQPA for the
3-carbamyl-2,4,5-trichlorobenzoic acid (SDS-46851) soil metabolite;
7/12/1999).

3.2  Absorption, Distribution, Metabolism, Excretion (ADME)

Disposition studies of chlorothalonil were conducted in male and female
rats in which either single oral doses (5-200 mg/kg) or multiple oral
doses (1.5-160 mg/kg/day for 5 days) of 14C-labeled chlorothalonil were
used.  Oral absorption of the test material was low (approximately 33%
of the administered dose).  Peak blood levels were observed between 2-9
hours post-dose and were considered low (i.e., less than 1% of the dose
present in blood).  Apparent saturation of kinetics occurred at doses
between 5 and 50 mg/kg, with prolonged elimination and increased blood
levels observed at higher dose levels.  Chlorothalonil-derived
radioactivity was eliminated primarily by the gastrointestinal tract,
with 80-90% of the administered dose observed in feces.  Approximately
15-20% of the dose was observed in bile, with a reduced rate of biliary
excretion observed at high doses.  Tissue residues of chlorothalonil
were highest in the gastrointestinal tract, blood, liver, and kidneys. 
Available data on metabolism of chlorothalonil in rats and dogs indicate
that the parent chemical is conjugated in liver to glutathione or
cysteine-S-conjugates.  These conjugates are then absorbed from the
gastrointestinal tract via the bile.  Cysteine-S-conjugates, glutathione
conjugates, or mercapturic acids reaching the kidney come into contact
with proximal tubular cells, where eventual "activation" of
pre-mercapturic acids occurs through the action of cysteine conjugate
(-lyase, an enzyme found in the cytosol and mitochondria of the cells of
the renal proximal tubules.  Nephrotoxicity of cysteine-S-conjugates
through activation to thiol metabolites is related to renal cortical
mitochondrial dysfunction.  Respiratory control has been shown to be
disrupted by the di- and tri-thiol analogs of chlorothalonil.  Osmotic
changes occur within the renal cortical tubular cells as a result of
toxic insult by the thiol metabolites of chlorothalonil, resulting in
vacuolar degeneration followed by cellular regeneration.  This mechanism
has been proposed to explain the carcinogenicity of chlorothalonil in
rats, and formed the basis for the recent reconsideration of the
carcinogenic potential of chlorothalonil.

3.2.1  Dermal Absorption

In a dermal-absorption study, 1% 14C chlorothalonil in latex base paint
or in alkyd covering stain (0.1µg/cm2) was applied to the back of male
rats for periods of 8 hours (washed and terminated), 24 hours (washed
and terminated) and 24 hours (washed and maintained for an additional 24
hours).  For the paint, total recovery was 99-105% with 97-102% being in
skin washes, 0.64-1.62% in skin and 0.58-0.99% absorbed (urine, feces,
cage wash, blood and carcass).  For the stain, total recovery was
89-96%, with 84-95% being in skin washes, 0.56-1.52% in skin and
0.78-2.97% absorbed.  In all other (non-paint and non-stain) scenarios
that result in skin contact during the workday, an upper limit of 0.15%
of chlorothalonil is estimated to be absorbed.  This dermal-absorption
rate was estimated using the lowest LOAEL from the subchronic oral
dosing studies in rats, the oral-absorption rate obtained from the rat
metabolism study, and the LOAEL from the 21-day dermal toxicity study. 
In a dermal-penetration study, the majority of radioactivity was
unabsorbed (89.1-97.5%).  Radioactivity was associated with the stratum
corneum, which was probably not available for absorption.  A greater
proportion of the applied low-dose formulation was associated with the
stratum corneum compared to the high-dose formulations.  The different
formulation types had little effect on total absorption, or steady-state
absorption rates (7.1-8.2 ng/cm2/h for the low-dose formulations;
151.1-231.2 ng/cm2/h for the high-dose formulations).

3.2.2  Mechanistic Data

GB Biosciences submitted several studies which address the mechanism of
carcinogenicity of chlorothalonil.  In a cell-proliferation study, 28
male Fischer 344 rats received technical chlorothalonil (97.9% a.i) in
the diet at 175 mg/kg/day for up to 91 days.  Scheduled sacrifices
occurred on Days 7 (14 rats), 28 (7 rats), and 91 (7 rats) for the
purpose of assessing the effect of chlorothalonil administration on cell
proliferation in the kidney.  Rats were implanted with Alzet minipumps
containing bromodeoxyuridine (BrdU) 3.5 and 6.5 days prior to sacrifice
(Day 7), or 3.5 days prior to sacrifice (Days 28 and 91).  Mean labeling
index was statistically increased in the kidneys of male rats treated
with 175 mg/kg/day chlorothalonil at all scheduled sacrifice times. 
From Day 7 to Day 28, the increase in labeling index was relatively
stable (approximately 10-fold over control), with a decrease to
approximately 3.5-fold over control on Day 91.  Increased cell
proliferation correlated with histopathological lesions of degeneration
of the proximal convoluted tubules and epithelial hyperplasia.  The
results of this study demonstrate a sustained cell-proliferative
response as a result of dietary administration of technical
chlorothalonil at a dose of 175 mg/kg/day.  The apparent lack of
cytotoxicity compared to the hypertrophic response in this study is not
readily explained by the available data (MRID 44223002).  

In another study, 96 male SPF rats were divided into test groups of 6
animals per group.  Rats received technical chlorothalonil (98.98% ai)
in the diet at dose levels of 0, 1.5, 15, or 175 mg/kg/day for either 7,
14, 21, or 28 days (total of 24 rats per time point).  Histological
examination of kidney and stomach tissue was performed for each group
after the appropriate exposure.  In addition, kidneys were subjected to
PCNA staining and stomachs to BrdU staining, and the labeling index and
labeling count of cell nuclei were performed.  Duodenum was used as a
negative control for PCNA and BrdU staining.  Increased absolute and
relative weight of the kidneys was observed at 175 mg/kg/day at all time
points, and in one animal at 15 mg/kg/day on Day 28.  Increased
incidence of vacuolization of the epithelium of the proximal convoluted
tubules was observed at all time points at 175 mg/kg/day and on Days 7,
14, and 21 at 15 mg/kg/day.  PCNA immunostaining of the proximal
convoluted tubule epithelial cells showed increased labeling of cells at
the 175-mg/kg/day dose level at all time points, and increased labeling
at 15 mg/kg/day on Days 7, 14, and 21.  BrdU labeling of the rat
forestomach showed marked labeling at 175 mg/kg/day at all time points,
and increased labeling on Day 28 at 15 mg/kg/day.  The results of this
study demonstrate a toxic response of the kidney and forestomach to
repeated dietary administration of chlorothalonil at doses of 15 and 175
mg/kg/day (MRID 44240901).  

3.3  FQPA Considerations

3.3.1  Adequacy of the Toxicity Database

The toxicology database used to assess pre- and/or postnatal exposure to
chlorothalonil is adequate.  The following acceptable studies are
available:

Two developmental toxicity studies in rats.

Two developmental toxicity studies in rabbits.

Two 2-generation reproduction studies in rats.

One subchronic neurotoxicity study in rats.

In addition, developmental toxicity studies in rats and rabbits and two
reproduction toxicity studies in rats are available on SDS-3701
(plant/livestock metabolite).  Developmental toxicity studies in rats
and rabbits and a one 1-generation reproduction study in rats are also
available for the soil metabolite SDS-46851 for FQPA assessment.

3.3.2  Evidence of Neurotoxicity

No evidence of neurotoxicity was observed in the database.  No evidence
was observed in a newly conducted subchronic neurotoxicity study in
rats.  

3.3.2.1  Subchronic Neurotoxicity Study

In an acceptable/guideline subchronic neurotoxicity study (  SEQ CHAPTER
\h \r 1 MRID 46526901), chlorothalonil [(technical, 99.52%), batch #
3E10D1] was administered to 12 Alpk:APfSD (Wistar-derived)
rats/sex/group at dose levels of 0, 30, 300, or 3000 ppm (equivalent to
0, 2.1, 22.0, or 232.1 mg/kg bw/day for males and 2.4, 24.2 or 243.2 for
females) for 90 days.  Neurobehavioral assessment (functional
observational battery and motor activity testing) was performed in 11-12
animals/sex/group at weeks -1, 2, 5, 9 and 14.  At study termination,
five animals/sex/group were euthanized, perfused in situ for
neuropathological examination, and subjected to histopathological
evaluation of brain and peripheral nervous system tissues. 

Non-specific yellow staining of the skin coat of ears, paws, nose and
mouth, and tray papers under the cages was observed in all males and
females from 3000 ppm group.  No other treatment-related clinical
observations were noticed.  Body weights were significantly (p<0.01)
decreased at the high dose (3000 ppm) in males (12-18%) and females
(6-12%) as compared to controls.  Food consumption and food utilization
were also significantly reduced in high dose group animals.

Although motor activity changed in males (increased) and in females
(decreased) fed 3000 ppm chlorothalonil as compared to controls at a
number of isolated time periods, this was considered an isolated finding
and not considered toxicologically significant.  

No treatment-related macro and/or microscopic findings were observed.

The LOAEL was established at 3000 ppm (232.1/243.2 mg/kg bw/day [M/F])
based on decreased body weights, food consumption and food utilization
in both sexes.  The NOAEL was 300 ppm (22.0/24.2 mg/kg bw/day [M/F]).

3.3.2.2  Evidence of Neurotoxicity from Other Related Studies

There was no evidence of clinical signs of neurotoxicity in the
chlorothalonil database.

3.3.3  Developmental Toxicity Studies

3.3.3.1.a  Rat (New Data)

In an acceptable/guideline developmental toxicity study (MRID 45710207),
chlorothalonil (Batch # NF 28/01; 99.15% ai) in 1.0% methylcellulose was
administered daily by gavage at a dose volume of 15 mL/kg bw to 25
female (Crl: CD®[SD] BR VAF/Plus) rats/group at dose levels of 0, 80,
200, or 500 mg/kg/day on gestation days (GD) 6 through 15.  All dams
were killed on GD 20; their fetuses were removed by cesarean section and
examined.

At 500 mg/kg/day, one dam was found dead on GD 9.  This animal exhibited
noisy respiration prior to dosing on the previous day, and post-mortem
examination revealed red/brown staining of the perinasal and perioral
regions, enlarged cervical lymph nodes, firm lungs with patchy
congestion, and gaseous distension of the gastrointestinal tract.  Also
at the above dose level, two dams were killed for humane reasons on GD
12.  These dams exhibited loss of body tone, noisy/irregular
respiration, piloerection, and brown perinasal staining immediately
prior to death, as well as lethargy, distended abdomen, and yellow
stained urogenital region.  Post-mortem examination revealed enlarged
cervical lymph nodes and severe gaseous distension of the
gastrointestinal tract in both animals; one animal was also found to
have a roughened forestomach.  All other animals survived to study
termination.  Wet feces were noted on GD 7 or 8 to GD 16, post-dosing
salivation was observed in 6/22 dams on GD 11/12, and noisy/irregular
respiration was noted in 2/22 dams on GD 10-16 and 13-19.  Body-weight
gains were decreased (p<0.05) during treatment on GD 6-8 and 6-14 (decr.
19-41%).  Body-weight gains continued to be decreased (p<0.05) to
termination (GD 6-20; decr. 9%) and for the overall (GD 2-20) study
(decr. 7%; not significant [NS]).  Food consumption was decreased
(p<0.05) during GD 6-7 (decr. 13%), and water consumption was increased
(p<0.05) during GD 8-9, 12-13, 14-15, and 18-19 (incr. 21-33%).  No
evidence of neurotoxicity was observed.  

The maternal LOAEL is 500 mg/kg bw/day, based on increased mortality,
clinical signs of toxicity, decreased body-weight gains and food
consumption, and increased water consumption.  The maternal NOAEL is 200
mg/kg bw/day.

There were no abortions, premature deliveries, or dead fetuses.  No
effects of treatment were noted on numbers of litters, live fetuses,
resorptions (early, late, or complete litter), or on sex ratio or
post-implantation losses.  No effects of treatment were observed on
fetal growth.  There were no treatment-related external, visceral, or
skeletal malformations or variations.

The developmental LOAEL was not observed.  The developmental NOAEL is
500 mg/kg bw/day.

3.3.3.1.b  Rat (Old Data)

In a developmental toxicity study (MRID 00130733) chlorothalonil (98%
ai) was administered to 25 females Sprague-Dawley rats/dose by gavage at
dose levels of 0, 25, 100 or 400 mg/kg bw/day from days 6 through 15 of
gestation.  Dams were sacrificed on day 20.

No maternal or developmental toxicity was observed at the 25 or 100
mg/kg dose levels.  At the high-dose level (400 mg/kg), maternal
toxicity was manifested by mortality in 3 dams; the presence of loose
stools and staining of the urogenital region of dams, statistically
significant decreases in body weight, and decreased food consumption
during the period of dosing.  No evidence of neurotoxicity was observed.
 No other treatment-related maternal effects were observed.  The
maternal LOAEL is 400 mg/kg bw/day, based on decreases in body-weight
gain and food consumption.  The maternal NOAEL is 100 mg/kg bw/day.

No treatment-related effects were observed on fetal body weights or sex
ratios.  Chlorothalonil did not induce any external, visceral or
skeletal malformations or increase the incidence of variations.  There
was a significant increase in the number of early resorptions as well as
an increase in the number of post-implantation losses in the high-dose
group.  The developmental LOAEL is 400 mg/kg bw/day, based on an
increase in total resorptions per dam with a related increase in
post-implantation loss.  The developmental NOAEL is 100 mg/kg bw/day. 

3.3.3.2.a  Rabbit (New Data)

In an acceptable/guideline developmental toxicity study (MRID 45710208),
chlorothalonil (Batch NF 28/01; 99.15% ai) in 1.0% (w/v) aqueous
methylcellulose was administered daily by gavage at a dose volume of 5
mL/kg bw to 16 female New Zealand White rabbits/group at dose levels of
0, 5, 10 or 20 mg/kg/day on GD 6 through 18.  All does were killed on GD
29; their fetuses were removed by cesarean section and examined.

No effects of treatment were observed on mortality, clinical signs, body
weights, body-weight gains, food consumption, or gross pathology.

At 5 mg/kg/day, one doe died prior to dosing on GD 8.  One 10-mg/kg/day
female aborted her litter on GD 29; this animal exhibited cold ears
during dosing, and anorexia/few feces, cold ears, red material/blood on
tray paper, and no feces post-dosing.  One 20-mg/kg/day aborted her
litter on GD 25-26; this animal exhibited anorexia/few feces prior to
dosing, anorexia/few feces, cold ears, and no feces during dosing, and
anorexia/few feces, cold ears, dark eyes, no feces, fouled anogenital
region, nasal exudate, soft/liquid feces, and thin appearance
post-dosing.  It was stated that similar findings were not observed in a
preliminary developmental toxicity study in rabbits, and in view of the
low incidence of animals aborting prior to terminal sacrifice, these
findings are considered to be incidental to treatment.  No evidence of
neurotoxicity was observed.  

The maternal LOAEL was not observed.  The maternal NOAEL is 20 mg/kg
bw/day.

No effects of treatment were noted on numbers of litters, live fetuses,
resorptions (early, late, or complete litter), or post-implantation
losses.  Fetal growth was unaffected by treatment.

There were no treatment-related external, visceral, or skeletal
malformations.

At 20 mg/kg/day, increased (p<0.05) incidence of thirteen ribs, a
variant, was observed (75.0% fetuses; 100% litters) compared to
concurrent controls (49.2% fetuses; 93.3% litters), and reduced
sternebrae, a variant, was observed (17.8% fetuses; 76.9% litters)
compared to concurrent controls (8.3% fetuses; 40.0% litters).  In the
absence of historical control data, these findings are considered
treatment-related.

The developmental LOAEL is 20 mg/kg bw/day based on increased incidence
of 13th ribs and reduced sternum.  The developmental NOAEL is 10 mg/kg
bw/day.

3.3.3.2.b  Rabbit (Old Data)

In a developmental toxicity study (MRID 41250503), chlorothalonil (98.1%
ai, lot #D-5840923 was administered to 20 mated females New Zealand
white rabbits/dose suspended in 0.5% aqueous methyl cellulose by gavage
at dose levels of 0, 5, 10 or 20 mg/kg bw/day from days 7 through 19 of
gestation.  Dams were sacrificed on day 30.

No maternal or developmental toxicity was observed at the 5- or 10-mg/kg
dose levels.  At the high-dose level (20 mg/kg), maternal toxicity was
manifested by statistically significant (p<0.05) decreases in
body-weight gain and food consumption only during the period of dosing. 
No evidence of neurotoxicity was observed.  No other treatment-related
maternal effects were observed.  The maternal LOAEL is 20 mg/kg bw/day,
based on decreases in body-weight gain and food consumption.  The
maternal NOAEL is 10 mg/kg bw/day.

No treatment-related effects were observed on fetal body weights or sex
ratios.  Chlorothalonil did not induce any external, visceral or
skeletal malformations or increase the incidence of variations.  The
developmental LOAEL was not determined.  The developmental NOAEL is 20
mg/kg bw/day. 

3.3.3.3.a  Reproductive Toxicity Study (Rat-New Data)

In an acceptable/guideline two-generation reproduction toxicity study
(MRID 45710209), chlorothalonil (Batch # NF 28/01; 99.16% ai) was
administered continuously in the diet to Crl: CD®BR VF/Plus rats (32
animals/sex/dose) at dose levels of 0, 400, 1200, or 3000 ppm
(equivalent to 0/0, 30.8/34.3, 92.5/106.0, and 247.5/270.0 mg/kg bw/day
[M/F]).  The P and F1 parents were dosed for 10 weeks and 12 weeks,
respectively, before they were mated to produce the F1 and F2 litters. 
The F1 pups were weaned on postnatal day (PND) 21, and 28 pups/sex/group
(1 pup/sex/litter as nearly as possible) were randomly selected as
parents of the F2 generation.

In the parental animals, no treatment-related effects were observed on
survival, or food or water consumption.

In the 3000-ppm P animals, body-weight gains during Weeks 0-1 were
decreased, and food consumption for Week 1 was decreased.  Body-weight
gains were decreased during Week 1-10 in the males in this generation,
but cumulative food consumption was comparable for Weeks 2-10 in both
sexes in this generation.  In the 3000-ppm F1 males, body weights were
decreased throughout treatment (Weeks 4-26), resulting in decreased
body-weight gains during pre-mating (Weeks 4-16), that continued to
termination (Weeks 17-26).  Similarly in the 3000-ppm F1 females, body
weights were decreased during premating (Weeks 4-16), resulting in
decreased body-weight gains during this period.  In the males, food
consumption was not affected, while food consumption was slightly
decreased during Week 1 in the females.

Treatment-related effects were observed on the kidney at 1200 and 3000
ppm.  Adjusted (to terminal body weight) kidney weights were increased
in both sexes in both generations.  Enlarged kidney was observed in the
P and F1 males compared to controls, and the following microscopic
pathological findings were noted:  i) trace to moderate
dilated/basophilic cortical tubules containing colloidal material in the
P males compared to controls; ii) trace to moderate
hyperplasia/hypertrophy of the inner cortical tubules in both sexes in
both generations compared to controls; and iii) trace to minimal
dystrophic mineralization at the corticomedullary junction in the P
females compared to controls.  Bright yellow/orange urinary staining and
wetter than normal feces on the cage tray paper under the cages of the P
and F1 parents; and cage sawdust yellow stained and wet during lactation
phase in the P and F1 females was observed. 

In the 400-ppm and above P and F1 animals, the forestomach was observed
to be thickened and roughened, compared to controls, with depressions in
the epithelial aspect compared to controls.  At 1200 ppm and above,
white areas in the forestomach were noted in the P animals, and the
limiting ridge of the forestomach was prominent in the F1 animals both
compared to controls.  In the 400-ppm and above P and F1 males and
females, trace to moderate hyperplasia and hyperkeratosis of the
non-glandular epithelium of the stomach was observed compared to
controls.  At 3000 ppm, minimal focal ulceration of the non-glandular
epithelium of the stomach was observed in the P females, and trace to
moderate erosion of the non-glandular epithelium of the stomach was
noted in the F1 females, both compared to controls.  Increases were
observed in relative kidney weights (~9-13%) in the 400 ppm P and F1
males.  The kidney was enlarged in 3 males in the P generation and in 7
males in the F1 generation.  Microscopically, there was an increased
incidence of trace to minimal dystrophic mineralization at the
corticomedullary junction of the kidneys in the P females (34%) when
compared to controls (13%).  

The LOAEL for parental toxicity is 400 ppm (equivalent to 30.8/34.3
mg/kg bw/day male/female), based on macroscopic and microscopic
pathological findings in the stomach- including: thickened, roughened,
and white areas in forestomach with depressions in the epithelial
aspect, and hyperplasia and hyperkeratosis of non-glandular epithelium
in the stomach, and kidney effects; i.e., enlargement, relative weight
increases and dystrophic mineralization at the corticomedullary
junction.  The NOAEL was not established.

In the offspring, no treatment-related effects were observed on
post-implantation survival, live birth, viability, or lactation indices,
on the sex ratio, clinical signs, gross pathology, or microscopic
pathology.

At 3000 ppm, pup body weights were decreased during PND 12-21 in the F1
and F2 pups, resulting in decreased overall (PND 0-21) pup body-weight
gains.  Litter weights were decreased in the F1 pups during PND 16-21,
and in the F2 pups during PND 8-21, resulting in decreased overall
litter weight gains.  Additionally, balano-preputial skinfold cleavage
was delayed and vaginal opening was delayed compared to controls. 
However, since no differences were observed in the subsequent mating and
reproductive performance of these animals, these effects were considered
equivocal and were attributed to the reduction in body-weight gain
observed during lactation.  This assertion is supported by the
comparable body weight at attainment of criterion in all treatment
groups.

At 400 ppm, a dose-dependent increase in the incidence of thickening
and/or roughening of the forestomach was observed in both generations,
and increased incidence and severity of trace to moderate hyperplasia
and hyperkeratosis of the non-glandular epithelium of the stomach and
trace to marked subepithelial edema in the non-glandular region of the
stomach were observed compared to controls.  Additionally, in the F1
group, trace to moderate inflammatory cells in the non-glandular region
of the stomach was noted compared to controls.  No evidence of
neurotoxicity was observed.  

The LOAEL for offspring toxicity is 400 ppm (equivalent to 30.8/34.3
mg/kg bw/day male/female), based on thickening and/or roughening of the
forestomach with depressions in the epithelial aspect, and hyperplasia
and hyperkeratosis of the non-glandular epithelium of the stomach.  The
NOAEL was not established.

No treatment-related effects were observed on estrous cycle length or
periodicity, pre-coital interval, duration of gestation, or on mating,
gestation, or parturition indices.

The LOAEL for reproductive toxicity was not observed.  The NOAEL for
reproductive performance is 3000 ppm (equivalent to 247.5/270.0 mg/kg
bw/day males/females).

3.3.3.3.b  Reproductive Toxicity Study (Rat-Old Data)

In a 2-generation reproduction study (MRID 41706201), chlorothalonil
(98.1% ai, lot #D-5840923) was administered to 35 Sprague-Dawley
(CD-VAF) rats/sex/dose in the diet at dose levels of 0, 500, 1500, or
3000 ppm (equivalent to 0, 38, 115, or 234 mg/kg bw/day).  Two litters
(a and b) were produced per generation. 

Body weights were decreased in F0 and F1 males (11%, both generations)
and females (8% and 13%, respectively) in the 3000 ppm group when
compared to controls.  Body-weight gain was decreased by 5, 8 and 15% in
the F0 males and 6, 7 and 11%, respectively, in the F1 males at 500,
1500 and 3000 ppm, respectively.  Body-weight gain for F0 and F1 females
was comparable among the treated and control groups.  Epithelial
hyperplasia, tubular, hypertrophy, clear cell hyperplasia, pigmentation
and/or karyomegaly were observed in the kidney of males and females in
the 500-, 1500-, and 3000-ppm groups.  Hyperkeratosis and squamous
epithelial hyperplasia of the forestomach was observed in males and
females in the 500-, 1500-, and 3000-ppm groups.  No evidence of
neurotoxicity was observed.  The parental systemic LOAEL is 500 ppm (38
mg/kg bw/day), based on kidney and forestomach lesions.  The parental
systemic NOAEL is less than 500 ppm (38 mg/kg bw/day). 

There was a decrease in pup weights compared to controls for litters
(F1a, F1b, F2a, F2b) produced from all generations of rats treated at
3000 ppm.  The offspring LOAEL is 3000 ppm (234 mg/kg bw/day), based on
lower pup body weights on day 21.  The offspring NOAEL is 1500 ppm (115
mg/kg bw/day). 

No reproductive effects were observed.  The reproductive LOAEL was not
determined.  The reproductive NOAEL is 3000 ppm (234 mg/kg bw/day).  

3.3.4  Additional Information from Literature Sources

There is no additional relevant information on the toxicity of
chlorothalonil that is currently available in the literature as
demonstrated by an internet TOXNET search.

3.3.5  Pre-and/or Postnatal Toxicity

3.3.5.1  Determination of Susceptibility

There was no evidence of increased susceptibility in the two
developmental toxicity studies in rats and two 2-generation reproduction
studies in rats.  There was evidence of increased susceptibility
(quantitative) in the “new” rabbit developmental toxicity study.  In
the rabbit developmental study, there was a slight increase in the
incidence of two variations in fetuses in the high-dose (20 mg/kg)
group; i.e., 13th rib (75%/100%; fetal/litter incidence) compared to
concurrent controls (49.2%/93.3%; fetal/litter incidence) and reduced
sternebrae (17.8%/76.9%; fetal/litter incidence) when compared to
concurrent controls (8.3%/40.0%; fetal/litter incidence) without the
presence of maternal toxicity.  However, these are variations that occur
spontaneously within this strain (New Zealand White) of rabbit.  There
was no evidence of increased susceptibility in rabbits (old study). 
Both developmental toxicity studies were conducted in the same strain of
rabbits (New Zealand White) and at the same high dose level.  The
concurrent controls had high incidences of these two variations.  In
addition, the developmental toxicity studies conducted with the soil
metabolite (SDS-46851) and the plant/livestock metabolite (SDS-3701) did
not show any developmental effects that could be attributed to
administration of the soil or plant metabolite.  HED concluded that the
occurrence of these two variations in the one rabbit developmental
toxicity study do not constitute significant increased susceptibility.

No evidence of increased susceptibility was seen following in utero
exposure to rats or rabbits in developmental studies and pre and/or
post-natal exposure to the metabolite SDS-3701 and the soil metabolite
SDS-46851.  Therefore, based on overall weight-of-evidence, HED
concluded that there is no increased susceptibility following exposure
to chlorothalonil and its metabolite (SDS-3701) and the soil metabolite
(SDS-46851). 

3.3.5.2  Degree-of-Concern Analysis and Residual Uncertainties

HED concluded that there is no increased susceptibility following
pre-natal or post-natal exposure to chlorothalonil in rats (two
studies).  There is equivocal evidence of increased susceptibility in
rabbits; however, the degree of concern for prenatal susceptibility is
low.  There is a well-defined NOAEL of 10 mg/kg in the rabbit
developmental toxicity study protecting from these effects.  In
addition, developmental effects were only observed in only one of the
two developmental toxicity studies conducted in the same strain of
rabbit at the same dose levels.  Therefore, there are no residual
uncertainties with regard to pre- and/or post-natal susceptibility. 

3.3.6  Recommendation for a Developmental Neurotoxicity Study (DNT)

The usual triggers for a DNT were not observed in any study.  There was
no neuropathology, central nervous system (CNS) malformations, and
effects on brain weights, abnormal behavior or effects on offspring
sexual maturation observed in the studies that were attributed to
treatment with chlorothalonil.  Additionally, the subchronic
neurotoxicity study provided no indication of chlorothalonil-induced
neurotoxicity.  The overall weight of the evidence in the hazard
database supports the conclusion that a DNT study is not required.  

3.4  FQPA SF

After evaluating the toxicological database, the chlorothalonil risk
assessment team has identified the following factors supporting
reduction of the FQPA SF from 10X to 1X for the chronic RfD: 1) there
are no significant data gaps in the hazard and exposure databases, 2)
there are low concerns for pre- and/or postnatal toxicity, 3) there are
no residual uncertainties with regard to pre- and/or postnatal toxicity,
and 4) there are no neurotoxicity concerns.  There is equivocal evidence
of increased susceptibility in rabbits; however, the degree of concern
for prenatal susceptibility is low.  There is a well-defined NOAEL of 10
mg/kg in the rabbit developmental toxicity study protecting from these
effects.  There are no residual uncertainties with regard to pre- and/or
post-natal susceptibility.  

In a 90-day oral toxicity study with rats, a slight decreased in thymus
weight was observed at 529 mg/kg/day (HDT).  There were no
histopathological findings noted in the thymus.  There were no effects
on thymus in other subchronic and chronic carcinogenicity studies in
rats in the old and new databases.  Therefore, decreases in thymus
weight in the 90-day study are considered a spurious finding and not a
trigger for an immunotoxicity study.  Since an immunotoxicity study is
now a data requirement in the 40 CFR revised Part 158, it will be
required as a condition of registration.  However, a database
uncertainty factor is not warranted since the effects (decreased in
thymus weight) were seen only in the 90-day study which is considered as
a spurious finding since no other study in the database had effects on
the thymus.  Therefore, HED does not believe that conducting a special
series 870.7800 immunotoxicity study will result in a point of departure
less than the cRfD NOAEL of 2 mg/kg/day for chlorothalonil, and
therefore, an additional UF for database uncertainties (UFDB) does not
need to be applied.  Similarly, given the lack of an acute neurotoxicity
study (also required in the new Part 158 guidelines) and the lack of
neurotoxicity in the data available, including a subchronic
neurotoxicity study, no additional UFDB is warranted to account the lack
of these data.  

3.4.1  Adequacy of the Exposure Database

Exposure pathways resulting from the use of chlorothalonil are dietary
(food and drinking water), residential, and occupational.  The database
is considered adequate to characterize the risks (including aggregate)
associated with potential exposure to chlorothalonil in all three
exposure pathways.

3.4.2  FQPA SF Conclusion

The chlorothalonil risk assessment team recommends that the FQPA SF be
reduced from 10X to 1X for chronic oral risk assessment and to 1X for
residential exposure assessments.  Reducing the FQPA SF from 10X to 1X
is appropriate for several reasons:  1) there are no significant data
gaps in the hazard and exposure databases, 2) there are low concerns for
pre- and/or postnatal toxicity, 3) there are no residual uncertainties
with regard to pre- and/or postnatal toxicity, and 4) there are no
neurotoxicity concerns.  There is equivocal evidence of increased
susceptibility in rabbits; however, the degree of concern for prenatal
susceptibility is low.  There is a well-defined NOAEL of 10 mg/kg in the
rabbit developmental toxicity study protecting from these effects. 
There are no residual uncertainties with regard to pre- and/or
post-natal susceptibility.

3.5  Hazard Identification and Toxicity Endpoint Selection

A summary of the toxicological endpoints and doses chosen for the
relevant exposure scenarios for human risk assessment are found in Table
3.5.  

Table 3.5.  Summary of Toxicological Doses and Endpoints for
Chlorothalonil Used in Human-Health Risk Assessments.

Exposure Scenario	Dose Used in Risk Assessment, UF	FQPA SF1 and LOC for
Risk Assessment	Study and Relevant Toxicological Effects

Acute Dietary-

general population, including infants and children	N/A	N/A	An endpoint
of concern (effect) attributable to a single dose was not identified in
the database.  Quantification of acute risk to general population
including infants and children is not required.

Acute Dietary-

females 13-49 years old	N/A	N/A	An endpoint of concern (effect)
attributable to a single dose was not identified in the database. 
Quantification of acute risk to females 13-49 years old is not required.

Chronic Dietary-

general population, including infants and children	NOAEL = 2.0 mg/kg/day

UF = 100

	FQPA SF = 1X

cRfD = cPAD 

 = 0.02 mg/kg/day	Chlorothalonil chronic toxicity - rat

LOAEL = 4.0 mg/kg/day, based on epithelial cell hyperplasia, clear cell
hyperplasia and karyomegaly in the kidneys of male rats.

Short-Term 

(1-30 days) 

Incidental Oral 

	NOAEL = 3.0 mg/kg/day (M/F) 	LOC = MOE = 100

(residential/recreational; includes the FQPA SF = 1X)	Chlorothalonil
90-day - rat

LOAEL = 10.0 mg/kg/day, based on dilated renal medullary tubules and
hyperplasia and hyperkeratosis of the non-glandular area of the
stomach.3

Intermediate-Term (1-6 months) Incidental Oral 	NOAEL = 3.0 mg/kg/day
(M/F)	LOC = MOE = 100

(residential/recreational; includes the FQPA SF = 1X)	Chlorothalonil
90-day - rat

LOAEL = 10.0 mg/kg/day, based on dilated renal medullary tubules and
hyperplasia

Short-Term 

(1-30 days) 

Dermal	N/A	N/A	Quantification of dermal risk is not required.

Intermediate-Term (1-6 months) Dermal	N/A	N/A	Quantification of dermal
risk is not required.

Long-Term

(>6 months) Dermal	N/A	N/A	Long-term dermal exposures are not expected
to occur.

Short-Term 

(1-30 days)

Inhalation	NOAEL = 3.0 mg/kg/day (M/F)	LOC = MOE = 100

(residential/recreational; includes the FQPA SF = 1X)

LOC (occupational) = 100

Inhalation absorption factor = 100%2	Chlorothalonil 90-day - rat

LOAEL = 10.0 mg/kg/day, based on dilated renal medullary tubules and
hyperplasia

Intermediate-Term (1-6 months) Inhalation	NOAEL = 3.0 mg/kg/day (M/F) 
LOC = MOE =100

(residential/recreational; includes the FQPA SF = 1X)

LOC (occupational) = 100

Inhalation absorption factor = 100%2	Chlorothalonil 90-day - rat

LOAEL = 10.0 mg/kg/day, based on dilated renal medullary tubules and
hyperplasia.

Long-Term

(>6 months)

Inhalation 	N/A	N/A	Long-term inhalation exposures are not expected to
occur.

Cancer (oral, dermal, inhalation)	Classification:  “Likely” to be a
human carcinogen by all routes of exposure (HED CPRC, 4th Meeting,
6/11/1997); however, the SAP decision (6/30/98) supports the use of an
MOE approach in risk assessment for chlorothalonil.  The HASPOC
deliberated on 3/12/08 and supported the MOE approach.

UF = uncertainty factor, FQPA SF = FQPA Safety Factor, NOAEL =
no-observed-adverse-effect level, LOAEL = lowest-observed-adverse-effect
level, RfD = reference dose (a = acute, c = chronic), PAD =
population-adjusted dose, MOE = margin of exposure, LOC = level of
concern, N/A = Not Applicable.

1 Refer to Section 3.4.

2 Default, because no inhalation studies are available.

3.5.1  aRfD - Females age 13-49

An acute dietary endpoint for females 13-49 years of age was not
established since an endpoint of concern attributable to a single dose
was not identified in the database.  In the RED, the acute RfD was based
on the results of a of 90-day study in rats in which gastric and renal
lesions were observed beginning at 7 days of continuous dosing.  These
type of lesions and in particular, the time frame at which they occurred
(after 7 days of continuous high-dose administrations), do not meet the
criteria of a single-dose effect.  Therefore, this study would not be
appropriate for this type of determination.  The effects on the kidney
were minimal and transient within a 14-day period.  The kidney lesions
consisted of nuclear pyknosis, karyomegaly, loss of brush border and
tubular epithelial vacuolation and degeneration (grade
2-3/slight-moderate) on day 4.  After 14 days, the kidney morphology
appeared nearly normal.  The kidney lesions were reduced to showing
regenerative epithelium (grade 1/minimal) and tubular hypertrophy (grade
1-2/minimal-slight).  The gastric lesions of the forestomach were
described as squamous epithelial hyperplasia and hyperkeratosis and
ulcer.  These findings were not considered a single dose effects because
the kidney lesions appeared after 4 days of dosing (transient and very
minimal severity) and gastric lesions after 7 days of dosing.  

3.5.2  aRfD - General Population

An acute dietary endpoint for all populations, including infants and
children, was not established since an endpoint of concern attributable
to a single dose was not identified in the database.  In the RED, the
acute RfD was based on the results of a of 90-day study in rats in which
gastric and renal lesions were observed beginning at 7 days of
continuous dosing.  These type of lesions and in particular, the time
frame at which they occurred (after 7 days of continuous high-dose
administrations), do not meet the criteria of a single-dose effect. 
Therefore, this study would not be appropriate for this type of
determination.  The effects on the kidney were minimal and transient
within a 14-day period.  The kidney lesions consisted of nuclear
pyknosis, karyomegaly, loss of brush border and tubular epithelial
vacuolation and degeneration (grade 2-3/slight-moderate) on day 4. 
After 14 days, the kidney morphology appeared nearly normal.  The kidney
lesions were reduced to showing regenerative epithelium (grade
1/minimal) and tubular hypertrophy (grade 1-2/minimal-slight).  The
gastric lesions of the forestomach were described as squamous epithelial
hyperplasia and hyperkeratosis and ulcer.  These findings were not
considered single-dose effects because the kidney lesions appeared after
4 days of dosing (transient and very minimal severity) and gastric
lesions after 7 days of dosing.

3.5.3  cRfD

The cRfD has been changed since the previous hazard assessment.  The old
endpoint was based on forestomach lesions observed in the mouse
carcinogenicity study.  The new endpoint is based on kidney lesions
observed in the rat chronic toxicity/carcinogenicity study.  The LOAEL
of 4.0 mg/kg/day is based on epithelial cell hyperplasia, clear cell
hyperplasia and karyomegaly in the kidneys of male rats.  The NOAEL is
2.0 mg/kg/day.  This NOAEL is lower than any NOAEL in the database based
on kidney effects.  Although, lower NOAELs/LOAELs were observed for
gastrointestinal irritation, HED’s HASPOC determined that the
forestomach lesions in rodent species should not be used for risk
assessment, based on the physiological characteristics of this region of
the stomach relative to other species.  Humans and dogs do not have
forestomachs.  In addition, the study duration is appropriate for the
duration of exposure.  The UFs used in determining the cRfD was 100 (10X
for interspecies [animal-to-human] extrapolation; 10X for intraspecies
[human] variations).

3.5.4  Incidental Oral Exposure (Short- and Intermediate-Term)

The endpoint for short- and intermediate-term incidental oral exposures
has been changed since the last hazard assessment.  The old endpoint was
based on forestomach and kidney effects observed in the 2-generation
reproduction study (LOAEL = 30.8 mg/kg/day).  The new endpoint is based
on kidney effects observed in a different study, the 90-day rat feeding
study (LOAEL = 10.0 mg/kg/day).  This change in endpoint provides the
lowest NOAEL/LOAEL in the database that is appropriate for short- and
intermediate-term exposures.  The NOAEL in the 90-day rat study is very
similar to the NOAEL in the chronic rat study.  The kidney is the target
organ in both subchronic and chronic rat studies.  Kidney lesions
demonstrated in the 90-day oral rat study was chosen for the short- and
intermediate-term incidental oral exposure scenarios, because it is more
protective of the population of concern; i.e., infants and children,
than the kidney lesions demonstrated in the 2-generation reproduction
study.  The effects of concern that are relevant to the selection of the
short- and intermediate-term incidental oral doses are based solely on
kidney effects; i.e., dilated renal medullary tubules.  Hyperplasia and
hyperkeratosis of the non-glandular area of the stomach were also
observed at the LOAEL.  However, the HASPOC has determined that
hyperplasia and hyperkeratosis of the forestomach in rodents is not an
appropriate endpoint for human risk assessments.  A NOAEL of 3.0
mg/kg/day was established for kidney toxicity.  The study length is the
most appropriate for the durations of exposure; namely, 1-30 days
(short-term) and 1-6 months (intermediate-term) and is protective of the
population of concern (infants and children).  A MOE of 100 is
considered adequate for short- and intermediate-term incidental oral
exposure scenarios.  

3.5.5  Dermal Absorption

Due to the lack of adequate dermal-penetration studies a
dermal-absorption factor was calculated. An upper limit of 0.15% of
chlorothalonil is estimated to be absorbed (MRID 44493601).  This
dermal-absorption rate was calculated using the lowest LOAEL from the
subchronic oral dosing studies in rats, the oral absorption rate
obtained from the rat metabolism study, and the LOAEL from the 21-day
dermal toxicity study (R. Zendzian, D244482, 3/30/1998).  A
dermal-absorption factor is not needed since quantification of cancer
risk is not required.

3.5.6  Dermal Exposure (Short-, Intermediate- and Long-Term)

Two route-specific studies, 21-day dermal toxicity, exist in the
database.  One was conducted in rats and a second was conducted in
rabbits.  The study conducted in rabbits was tested only at dose levels
up to 50 mg/kg bw/day and produced only slight dermal irritation.  The
study conducted in rats was tested at dose levels up to 600 mg/kg bw/day
and also only produced slight dermal irritation but no systemic
toxicity.  The study chosen for short- and intermediate-term dermal risk
assessment was the rat 21-day dermal toxicity study because it is most
appropriate for these durations.  Long-term exposures are not expected
to occur.  However, it was decided that quantitation of dermal risk was
not required for the following reasons:

    1. There are no developmental and neurotoxicity concerns.

    2. There is no systemic toxicity in the dermal toxicity study up to
600 mg/kg bw/day.

3. Quantitation of dermal risk using data obtained from oral toxicity
studies would not                 accurately reflect the actual toxic
effects expressed by the dermal route of exposure.

3.5.7  Inhalation Exposure (Short-, Intermediate- and Long-Term)

The endpoint for short- and intermediate-term inhalation exposures has
been changed from the last hazard assessment.  The old endpoint was
based on forestomach and kidney effects observed in the 2-generation
reproduction study (LOAEL = 30.8 mg/kg/day).  The new endpoint is based
on kidney effects observed in a different study, the 90-day rat feeding
study (LOAEL = 10.0 mg/kg/day).  This change in endpoint provides the
lowest NOAEL/LOAEL in the database that is appropriate for short- and
intermediate-term exposures.  The NOAEL in the 90-day rat study is very
similar to the NOAEL in the chronic rat study.  The kidney is the target
organ in both subchronic and chronic rat studies.  Repeated dose
inhalation toxicity studies are not available in the database.  Kidney
lesions demonstrated in the 90-day oral rat study was chosen for the
short- and intermediate-term incidental oral exposure scenarios, because
it is more protective than the kidney lesions demonstrated in the
2-generation reproduction study.  The effects of concern that are
relevant to the selection of the short- and intermediate-term incidental
oral doses are based solely on kidney effects; i.e., dilated renal
medullary tubules.  Hyperplasia and hyperkeratosis of the non-glandular
area of the stomach were also observed at the LOAEL.  However, the
HASPOC has determined that hyperplasia and hyperkeratosis of the
forestomach in rodents is not an appropriate endpoint for human risk
assessments.  A NOAEL of 3.0 mg/kg/day was established for kidney
toxicity.  The study length is the most appropriate for the durations of
exposure; namely, 1-30 days (short-term) and 1-6 months
(intermediate-term).  A MOE of 100 is considered adequate for short- and
intermediate-term incidental oral exposure scenarios.  

3.5.8  LOC for MOEs

The target MOEs for occupational and residential exposure risk
assessments are as follows:

Route	Duration

	Short-Term

(1-30 days)	Intermediate-Term

(1-6 Months)	Long-Term

(>6 Months)

Occupational (Worker) Exposure

Dermal	-	-	-

Inhalation	100a	100a

	Residential (Non-Dietary) Exposure

Oral	100a	100a	-

Dermal	-	-	-

Inhalation	100a	100a	-

a Based on the conventional UF of 100X (10X for interspecies
extrapolation; 10X for intraspecies variation).

3.5.9  Recommendation for Aggregate Exposure Risk Assessments

Aggregate risk consists of residential exposure and exposure from food
and drinking water sources.  Chronic aggregate risks were also assessed.
 

3.5.10  Classification of Carcinogenic Potential

In the two “new" rodent chronic toxicity studies, there was an
increased incidence of epithelial hyperplasia of the limiting ridge and
non-glandular region of the stomach in rats and mice.  In addition,
there was an increased incidence of benign squamous cell papilloma of
the non-glandular region of the stomach in male and female mice.  There
was no indication of a carcinogenic response in the rat chronic
toxicity/carcinogenicity study.  Previously, and based on the extensive
“old” chlorothalonil database, “…HED/CPRC unanimously agreed
that the weight of the evidence supported a classification of
chlorothalonil as a “likely” human carcinogen by all routes of
exposure.  This conclusion was based on (1) the increased incidence of
renal adenomas and carcinomas - observed in both sexes of rats and mice;
(2) the rarity of the tumor response in the kidney, and (3) the
increased incidence of papillomas and/or carcinomas of the forestomach
in rats and mice.  While it was recognized that the mechanistic data
supported a non-linear mode of action for tumor production by
chlorothalonil, the HED/CPRC also recognized that the kidney tumors were
the result of administration of test chemical, were considered rare, and
the submitted data supported the non-neoplastic pathology as directly
related to eventual neoplasia.  The HED/CPRC agreed that a non-linear
approach to risk assessment, using the MOE, should be used.”
(Extracted from HED document #012366, dated October 20, 1997.)  The
“new” mouse carcinogenicity study also demonstrates that the
sponsor’s [Vischim] chlorothalonil produces similar papillomas of the
forestomach.  Therefore, the previous HED/CPRC of 1997
decision/classification would be relevant. 

The SAP met on June 30, 1998 to discuss the carcinogenicity issues
surrounding chlorothalonil.  “There was a majority view of Panel
members that the cytotoxicity/regenerative cell proliferation pathway
was plausible and the likely mode of action for chlorothalonil.  In
addition, risk assessment based on differential enzyme activities in
rats vs. humans is not appropriate.  There was a majority view amongst
Panel members that the mode of action for chlorothalonil’s activity in
the rodent kidney, based on sustained cytotoxicity and regenerative cell
proliferation during compound administration, as presented by the
Agency, was plausible and likely to be valid.  For the rodent
forestomach tumors induced by chlorothalonil, there was general
agreement amongst the Panel that chlorothalonil was similar to a group
of non-genotoxic rodent forestomach carcinogens that were either mucosal
irritants or disruptors of the gastric mucosal barrier, causing repeated
injury to the forestomach lining with inflammation, and sustained
increased cell proliferation.  This leads to hyperplasia and ultimately,
neoplasia, representing an indirect or secondary mechanism of
carcinogenesis.  Assuming a mode of action involving sustained
cytotoxicity and regenerative cell proliferation, a MOE approach would
be in order.”  The SAP decision is relevant in that the cancer risk
can be quantitated using an MOE approach.

HED recommends that a MOE approach be used in this risk assessment.

3.6  Endocrine disruption

EPA is required under the Federal Food, Drug, and Cosmetic Act (FFDCA),
as amended by FQPA, to develop a screening program to determine whether
certain substances (including all pesticide active and other
ingredients) “may have an effect in humans that is similar to an
effect produced by a naturally occurring estrogen, or other such
endocrine effects as the Administrator may designate.”  Following
recommendations of its Endocrine Disruptor and Testing Advisory
Committee (EDSTAC), EPA determined that there was a scientific basis for
including, as part of the program, the androgen and thyroid hormone
systems, in addition to the estrogen hormone system.  EPA also adopted
EDSTAC’s recommendation that the Program include evaluations of
potential effects in wildlife.  For pesticide chemicals, EPA will use
FIFRA and, to the extent that effects in wildlife may help determine
whether a substance may have an effect in humans, FFDCA authority to
require the wildlife evaluations.  As the science develops and resources
allow, screening of additional hormone systems may be added to the
Endocrine Disruptor Screening Program (EDSP). 

When additional appropriate screening and/or testing protocols being
considered under the Agency’s EDSP has been developed, chlorothalonil
may be subjected to further screening and/or testing to better
characterize effects related to endocrine disruption.  

3.7  Public Health and Pesticide Epidemiology Data

The majority of information derived from toxnet and other relevant
databases search conducted by W. Greear (2/22/2006) provided the
following general information:  “Contact dermatitis has been reported
for personnel working in chlorothalonil manufacturing and in farmers and
horticultural workers.  Workers in the manufacture of wood products have
also developed contact dermatitis on the hands and face when wood
preservatives containing chlorothalonil were used.”  The dermatitis
observed may have been the result of the presence of relatively large
amounts of a known contaminant of older formulations of chlorothalonil;
i.e., HCB.

Chlorothalonil was among the 50 chemicals examined for cancer and
non-cancer symptoms in humans in the Agricultural Health Study (AHS)
[see <www.aghealth.org> for publications referenced below]. 
Dermatological symptom results have not yet been but eventually will be
published by AHS scientists. 

For wheeze (n = 3,838), and non-wheeze symptoms (n = 16,630) in
certified applicators, the chlorothalonil results were not statistically
significant, according to Hoppin, 2006.  In the wheeze analysis, only
fungicide exposures by boom on tractor and hand spray were associated
with excess respiratory disease symptoms. 

For eye disease, farmer applicators exposed to chlorothalonil had a
statistically significant elevated odds ratio of 2.4 (CI 1.1-5.2), or
140% excess of macular degeneration, according to Kamel et al., 2000. 
Kirrane, 2005 reported that chlorothalonil results for ever and never
use of the chemical was not statistically significant for increased
retinal degeneration in spouses.  As a class, fungicides were
statistically significant for macular degeneration in wives of farmer
pesticide applicators at odds ratio 1.9 (CI 1.2-3.1).  This is a 90%
excess disease.  AHS chemical-specific fungicide results are being
studied further in ongoing studies, and EPA will review and evaluate new
AHS results, as they are published.

Chlorothalonil not was among the chemicals previously reviewed for acute
incident findings by the pesticide epidemiology group.  It will be added
to the priority list for completion by checking the standard incident
data bases used by HED for risk assessment.

3.8  Data Proprietary Use/Gaps

It should be noted that a relatively recent subchronic neurotoxicity
study (MRID 46526901, 2004) submitted by GB Biosciences Corporation was
used to support Vischim S.r.l. in this hazard assessment.  Much of the
older toxicity data used in the hazard assessment of chlorothalonil was
supplied by SDS Biotech Corporation.  The 21-day dermal toxicity study
in rats (MRID 4419101) was supplied by ISK Biosciences Corporation.

Vischim S.r.l. has not provided a 21/28-day dermal toxicity study
(870.3200), subchronic neurotoxicity battery (870.6200b) or mutagenicity
data in the category “other genotoxic effects” (870.5500) to support
new food uses.

4.0  EXPOSURE ASSESSMENT AND CHARACTERIZATION

4.1  Summary of Registered/Proposed Uses

IR-4 included a copy of an existing label for the 6 lb/gal FlC
formulation (EPA Reg. No. 50534-188-100), and provided a description of
the proposed use patterns for the Brassica head and stem subgroup, the
cucurbit vegetable group, the fruiting vegetable group, ginseng,
horseradish, lentil, lupin, okra, persimmon, rhubarb, and yam.  The
proposed uses are summarized in Table 4.1.

Table 4.1.  Summary of Directions for Use of Chlorothalonil.

Applic. Timing, Type, and Equip.	Formulation

[EPA Reg. No.]	Applic. Rate 

(lb ai/A)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(lb ai/A)	PHI

(days)	Use Directions and Limitations

Brassica, head and stem, subgroup 5A

Postemergence

Broadcast foliar	6 lb/gal FlC

[50534-188-100]	1.13-1.5	Not specified	12	7	A minimum RTI of 7 days is
proposed.

Cucurbit vegetable, group 9

Postemergence

Broadcast foliar	6 lb/gal FlC

[50534-188-100]	1.13-2.25	Not specified	15.8	0	A minimum RTI of 7 days
is proposed.

Fruiting vegetables, group 8 and Okra

Postemergence

Broadcast foliar	6 lb/gal FlC

[50534-188-100]	1.13	8 (implied)	9	3	A minimum RTI of 7 days is
proposed.

Ginseng

Postemergence

Broadcast foliar	6 lb/gal FlC

[50534-188-100]	1.5	8 (implied)	12	14	A minimum RTI of 7 days is
proposed.

Horseradish

Postemergence

Broadcast foliar	6 lb/gal FlC

[50534-188-100]	2.25	8 (implied)	18	14	A minimum RTI of 7 days is
proposed.

Lupin and lentil

Postemergence

Broadcast foliar	6 lb/gal FlC

[50534-188-100]	0.75-1.13	Not specified	6	14	A minimum RTI of 7 days is
proposed.

Persimmon

Postemergence

Broadcast foliar	6 lb/gal FlC

[50534-188-100]	0.94	5 (implied)	4.7	14	A minimum RTI of 10 days is
proposed.

Rhubarb

Postemergence

Broadcast foliar	6 lb/gal FlC

[50534-188-100]	2.25	6 (implied)	13.5	30	A minimum RTI of 7 days is
proposed.

Yam

Postemergence

Broadcast foliar	6 lb/gal FlC

[50534-188-100]	0.75-1.13	Not specified	11.3	7	A minimum RTI of 7 days
is proposed.

The proposed use directions do not include any information pertaining to
application equipment or volumes; the petitioner referred to the
registered label for general product information.  The product label
included in the submission for EPA Reg. No. 50534-188-100 specifies that
applications may be made using ground or aerial equipment.  A minimum
spray volume of 5 gal/A for ground and aerial equipment is specified for
applications to field and row crops.  For tree and orchard crops, the
label specifies that the product should be applied in sufficient volume
to obtain adequate coverage of the tree canopy.  The general use
directions on the parent label do not specify minimum spray volumes for
tree and orchard crops [the individual directions for these crops
include spray volume information].

Conclusions.  Label revisions are required for some crops to reflect
the field-trial parameters.  The proposed uses on the Brassica head and
stem subgroup should be revised to specify a maximum seasonal
application rate of 8.8 lb ai/A.  The proposed use on persimmon should
be modified to specify that chlorothalonil may only be applied to
persimmon grown in Florida and Hawaii and that applications may be made
with a minimum RTI of 14 days.  In addition, the proposed use should
specify that aerial applications to persimmon be made in a minimum of 10
gal/A.

HED notes that use of the 6 lb/gal FlC formulation (EPA Reg. No.
50534-188) on lupin exists on the current label (label accepted
9/27/05), as part of the uses on dry beans.

The submitted data for pepper (bell and non-bell) support the proposed
use pattern for the fruiting vegetables crop group.  However, existing
product labels allow a less restrictive use on tomatoes, which is
supported by adequate data:  multiple foliar applications to tomatoes at
up to 2.1 lb ai/A/application, with a maximum seasonal rate of 15 lb
ai/A and a 0-day PHI.  HED concludes that the product label for the 6
lb/gal FlC formulation (EPA Reg. No. 50534-188) should have separate use
directions for “Tomato” and “Fruiting vegetables, other than
tomato.”  

4.2  Dietary Exposure/Risk Pathway

The residue chemistry data submitted in support of the proposed
petitions were evaluated by HED (Memo, G. Kramer, DP# 346319).  The
drinking water assessment was completed by EFED (Memo, L. Shanaman,
4/2/08; DP# 346321).  The dietary-exposure assessment was completed by
HED (Memo, G. Kramer, DP# 353241).

4.2.1  Residue Profile

Background

The Interregional Research Project No. 4 (IR-4), on behalf of the
Agricultural Experiment Stations of AR, CA, DE, FL, GA, HI, ID, KY, LA,
MN, MS, NJ, NC, ND, OH, OK, OR, PR, SC, TN, TX, WA, WI, and VA, has
proposed to amend the use pattern for the 6 lb/gal FlC formulation of
chlorothalonil (Bravo Weather Stik®, EPA Reg. No. 50534-188-100) to add
uses on ginseng, horseradish, lentil, lupin, okra, persimmon, rhubarb,
and yam.  In addition, IR-4 proposes to expand the existing uses on
broccoli, Brussels sprouts, cabbage, and cauliflower to the Brassica
head and stem subgroup (5A), the existing uses on cucumber, melon, and
squash to the cucurbit vegetable group (9), and the existing uses on
tomato to the fruiting vegetable group (8).  In conjunction with the
requested amended uses, IR-4 has submitted a petition, PP#7E7270, for
the establishment of permanent tolerances for the combined residues of
the fungicide chlorothalonil (tetrachloroisophthalonitrile) and its
metabolite 4-hydroxy-2,5,6-trichloroisophthalonitrile in or on the
following raw agricultural commodities:

Vegetables, fruiting, group 8	5.0 ppm

Vegetable, cucurbit, group 9	5.0 ppm

Okra	5.0 ppm

Persimmon	1.9 ppm

Horseradish	4.0 ppm

Rhubarb	5.0 ppm

Ginseng	3.0 ppm

Yam	5.0 ppm

Lupin	0.1 ppm

Lentil	0.1 ppm

Brassica, head and stem, subgroup 5A	5.0 ppm

RD has also requested that HED recommend levels for tolerances on lychee
and starfruit in order to alleviate trade irritant issues with the
government of Taiwan.  

Tolerances for chlorothalonil residues are established under 40 CFR
§180.275.  Tolerances are established in 40 CFR §180.275(a)(1) for the
combined residues of chlorothalonil and its 4-hydroxy metabolite
(4-hydroxy-2,5,6-trichloroisophthalonitrile) for various plant
commodities.  Tolerances range from 0.05 ppm (almonds and dried cocoa
bean) to 15 ppm (celery and papaya). Tolerances for livestock
commodities are established under 40 CFR §180.275(a)(2) and expressed
in terms of the 4-hydroxy metabolite; tolerances range from 0.03 ppm
(meat of cattle, goat, hog, horse, and sheep) to 0.5 ppm (kidney of
cattle, goat, hog, horse, and sheep).  A time-limited tolerance is
established in 40 CFR §180.275(b) for the combined residues of
chlorothalonil and its 4-hydroxy metabolite (expressed as
chlorothalonil) in/on ginseng at 0.10 ppm; the tolerance has an
expiration date of 12/31/08.  Tolerances with regional registration are
established in 40 CFR §180.275(c) for the combined residues of
chlorothalonil and its metabolite in/on hazelnut at 0.1 ppm and mint hay
at 2 ppm.

Nature of the Residue in Plants 

The qualitative nature of the residues in plants is adequately
understood based on metabolism studies with carrots, celery, lettuce,
snap beans, and tomatoes.  The residues of concern are chlorothalonil
and its 4-hydroxy metabolite (SDS-3701).

Nature of the Residue in Livestock 

The qualitative nature of the residue in livestock is adequately
understood.  The residue of concern in meat and milk is the 4-hydroxy
metabolite of chlorothalonil (SDS-3701).  Chlorothalonil per se has been
shown to be so unstable in ruminant tissues that it is impractical to
establish tolerances that include the parent.

Residue Analytical Methods

Adequate residue analytical methods are available for purposes of
reregistration.  The Pesticide Analytical Manual (PAM) Vol. II lists
Method I, a gas chromatography (GC) method with electron-capture
detection (ECD), for the enforcement of tolerances for plant
commodities.

The FDA PESTDATA database dated 1/94 (PAM Vol. I, Appendix I) indicates
that chlorothalonil is completely recovered (>80%) using multiresidue
methods PAM Vol. I Sections 303 (Mills, Onley, Gaither method) and 304
(Mills fatty food method) and has a low recovery (<50%) using Section
302 (Luke method).

Magnitude of Residues in Plants

To support the proposed uses, IR-4 submitted crop field trial data for
ginseng, horseradish, bell and non-bell pepper, persimmon, and rhubarb. 
Adequate storage stability data have been submitted previously which
support the submitted crop field trial studies with horseradish, bell
and non-bell pepper, persimmon, and rhubarb.  A concurrent storage
stability study was conducted with ginseng which indicated the potential
for decline of chlorothalonil during storage; sample results for ginseng
were corrected for this decline.  

Adequate field trial data have been submitted to support the requested
new uses of the 6 lb/gal FlC formulation (EPA Reg. No. 50534-188-100) on
ginseng, horseradish, persimmon, and rhubarb.  Label amendments for
persimmon are required before the requested uses may be approved. 
Additional crop field trial data are required for non-bell pepper to
support the proposed use; submission of these data may be considered a
condition of registration.  The submitted data for bell and non-bell
peppers and the existing residue data for tomato may be used to support
the proposed uses on fruiting vegetables and okra.  

The petitioner is relying on existing residue data for broccoli,
Brussels sprouts, cabbage, and cauliflower to support the proposed uses
on the Brassica head and stem subgroup; for cucumber, melon, pumpkin,
and summer and winter squash to support the proposed uses on the
cucurbit vegetable group; for dry bean to support the proposed use on
lentil; and for potato to support the proposed use on yam.  The existing
residue data are adequate to support proposed uses provided the proposed
use on the Brassica head and stem subgroup is modified to specify a
lower maximum seasonal rate.  

RD has also requested that HED recommend levels for tolerances on lychee
and starfruit in order to alleviate trade irritant issues with the
government of Taiwan.  Based on translation from existing tolerances on
tropical fruits, HED is recommending for tolerances of 15 ppm for lychee
(translated from papaya) and 3 ppm for starfruit (translated from
passionfruit; personal communication from B. Schneider, 7/16/08).  

Tolerance Summary

A summary of tolerance reassessment is presented in Table 4.2.1.    SEQ
CHAPTER \h \r 1 The Codex Alimentarius Commission has established
maximum residue limits (MRLs) for chlorothalonil per se at 7 ppm for
sweet pepper; 5 ppm each for broccoli, Brussels sprouts, cucumber,
tomato, and squash (summer and winter); 2 ppm for melons (except
watermelon); 1 ppm each for cabbage, heads and cauliflower; and 0.2 ppm
for dry beans.  Mexican MRLs for “clorotalonil” have been
established at 0.1 ppm for bean and 5 ppm each for broccoli, Brussels
sprouts, cabbage, cauliflower, cucumber, melon, squash, and tomato.  As
the U.S. tolerance definition differs from the Codex and Mexican
definitions, harmonization is not possible.  Canadian MRLs for
chlorothalonil and its 4-hydroxy metabolite are established at 5 ppm
each for beans, broccoli, Brussels sprouts, cabbage, cauliflower,
cucumber, melons, pumpkins, squash, and tomatoes.  With the exception of
beans (which presumably includes dried beans), the Canadian MRLs are
harmonized with U.S. tolerances.  

Table 4.2.1.  Tolerance Summary for Chlorothalonil.

Commodity	Established Tolerance (ppm)1	Proposed Tolerance (ppm)
Recommended Tolerance (ppm)	Comments; Correct Commodity Definition

Brassica, head and stem, subgroup 5A	--	5.0	5.0	Tolerance recommendation
is based on residue data translated from broccoli, Brussels sprouts,
cabbage, and cauliflower and pending label revision to specify a 7-day
PHI and a maximum seasonal rate of 8.8 lb ai/A.

Broccoli	5	--	Remove from 180.275(a)(1)	Covered by tolerance for
Brassica head and stem subgroup.

Brussels sprouts	5	--

Cabbage	5	--

Cauliflower	5	--

Cucumber	5	--	Remove from 180.275(a)(1)	Covered by tolerance for
cucurbit vegetable group.

Ginseng	0.102	3.0	4.0	Established tolerance under 180.275(b) should be
removed when 4.0-ppm tolerance is established under 180.275(a)(1).

Horseradish	--	4.0	4.0

	Lentil	--	0.1	0.10	Tolerance recommendation based on residue data
translated from dry bean seed.

Lupin	--	0.1	None	Covered by the established tolerance for dry bean
seed. 

Melon	5	--	Remove from 180.275(a)(1)	Covered by tolerance for cucurbit
vegetable group.

Okra	--	5.0	6.0	Tolerance recommendation based on residue data for
representative crops of fruiting vegetables crop group.

Persimmon	--	1.9	1.5	Tolerance should be established under 40 CFR
§180.275(c) and proposed use should be amended to restrict use to FL
and HI.

Pepper, non-bell	53	--	Remove from 180.275(a)(1)	Covered by tolerance
for fruiting vegetable crop group.

Pumpkin	5	--	Remove from 180.275(a)(1)	Covered by tolerance for cucurbit
vegetable group.

Rhubarb	--	5.0	4.0

	Squash, summer	5	--	Remove from 180.275(a)(1)	Covered by tolerance for
cucurbit vegetable group.

Squash, winter	5	--

Tomato	5

5.0

	Vegetable, cucurbit, group 9	--	5.0	5.0	Tolerance recommendation is
based on residue data for cucumber, melon, summer squash, and winter
squash.

Vegetables, fruiting, group 8	--	5.0	6.0	Tolerance recommendation is
based on residue data for bell pepper.

Vegetable, fruiting, group 8, except tomato.

Yam	--	5.0	0.10	Tolerance recommendation is based on residue data
translated from potato.

Lychee 	--	--	15	Recommended at the request of RD.

Starfruit	--	--	3.0

	1  Established under 40 CFR §180.275(a)(1) unless otherwise specified.

2  Established under 40 CFR §180.275(b). 

3  No U.S. registrations.

4.2.2  Dietary-Exposure Analyses

™, Version 2.03, which incorporates consumption data from USDA’s
CSFII, 1994-1996 and 1998.  The 1994-96, 98 data are based on the
reported consumption of more than 20,000 individuals over two
non-consecutive survey days.  Foods “as consumed” (e.g., apple pie)
are linked to EPA-defined food commodities (e.g. apples, peeled fruit -
cooked; fresh or N/S; baked; or wheat flour - cooked; fresh or N/S,
baked) using publicly available recipe translation files developed
jointly by USDA/ARS and EPA.  Consumption data are averaged for the
entire U.S. population and within population subgroups for chronic
exposure assessment, but are retained as individual consumption events
for acute exposure assessment.

™ analysis evaluated the individual food consumption as reported by
respondents in the USDA 1994-1996 and 1998 nationwide CSFII and
accumulated exposure to the chemical for each commodity.  

For chronic exposure and risk assessment, an estimate of the residue
level in each food or food-form (e.g., cranberry or cranberry juice) on
the food commodity residue list is multiplied by the average daily
consumption estimate for that food/food form.  The resulting residue
consumption estimate for each food/food form is summed with the residue
consumption estimates for all other food/food forms on the commodity
residue list to arrive at the total average estimated exposure. 
Exposure is expressed in mg/kg body weight/day and as a percent of the
cPAD.  This procedure is performed for each population subgroup.

4.2.2.1  Acute Dietary-Exposure Analysis

An acute dietary-exposure assessment was not performed because there
were no toxic effects attributable to a single dose.  Thus, an endpoint
of concern was not identified to quantitate acute dietary risk to the
general population or to any population subgroup.

4.2.2.2  Chronic Dietary-Exposure Analysis

™ analyses estimate the dietary exposure of the U.S. population and
various population subgroups.  The results reported in Table 4.2.2.2 are
for the general U.S. Population, all infants (<1 year old), children
1-2, children 3-5, children 6-12, youth 13-19, females 13-49, adults
20-49, and adults 50+ years.  

A conservative chronic dietary-exposure assessment was performed using
100% CT, tolerance-level residues, and DEEM™ 7.81 default processing
factors for all foods except for tomatoes (average field-trial residues
and empirical processing factors used), peppers (average field-trial
residues used), and snap beans (average field-trial residues used). 
Chlorothalonil chronic dietary (food + water) exposure estimates using
the DEEM-FCID™ software are below HED’s LOC for the U.S. population
and each of the population subgroups.  Dietary exposure was estimated at
0.008587 mg/kg/day for the U.S. population (43% of the cPAD) and
0.018821 mg/kg/day (94% of the cPAD) for children 1-2 years old, the
population subgroup with the highest estimated chronic dietary exposure
to chlorothalonil.  

Table 4.2.2.2.  Summary of Chronic Dietary Exposure and Risk for
Chlorothalonil (Food + Water).

Age Group	cPAD (mg/kg/day)	Exposure (mg/kg/day)	% cPAD

	General U.S. Population	0.02	0.008587	43

All Infants (<1 year old)	0.02	0.013143	66

Children 1-2 years old	0.02	0.018821	94

Children 3-5 years old	0.02	0.015688	78

Children 6-12 years old	0.02	0.010345	52

Youth 13-19 years old	0.02	0.006170	31

Adults 20-49 years old	0.02	0.007151	36

Adults 50+ years old	0.02	0.008517	43

Females 13-49 years old	0.02	0.007187	36

4.2.2.3  Cancer Dietary-Exposure Analysis

Dietary cancer risk concerns due to long-term consumption of
chlorothalonil residues are adequately addressed by the chronic exposure
analysis using the cPAD.  Previously, and based on the extensive
“old” chlorothalonil database, “…HED/CPRC unanimously agreed
that the weight of the evidence supported a classification of
chlorothalonil as a “likely” human carcinogen by all routes of
exposure.  While it was recognized that the mechanistic data supported a
non-linear mode of action for tumor production by chlorothalonil, the
HED/CPRC also recognized that the kidney tumors were the result of
administration of test chemical, were considered rare, and the submitted
data supported the non-neoplastic pathology as directly related to
eventual neoplasia.  The HED/CPRC agreed that a non-linear approach to
risk assessment, using the MOE, should be used.”  

4.3  Water Exposure/Risk Pathway

Chlorothalonil degrades through both photolytic and microbial processes.
 Chlorothalonil degrades rapidly in clear, shallow water through aqueous
photolysis.  Chlorothalonil is more persistent under terrestrial aerobic
conditions, and even more persistent under aquatic conditions. Biotic
degradation rates for chlorothalonil are sensitive to the biogeochemical
environment and ambient conditions, and may depart from first-order
kinetics.  Apparent initial aquatic "half-lives" ranging from a few
hours to around two weeks, while overall half-lives for the total system
are much longer.  An identified major metabolite, SDS-3701, which is
considered to be of toxicological concern, forms under differing test
conditions, and appears to be persistent.  As is true in any fate
assessment, total toxic residues are more persistent than the parent
alone.  Mobility data for the degradation product, SDS-3701, are not
available.  Therefore, it is assumed, for modeling purposes, that the
mobility of this metabolite is equal to that of the parent compound.  

™ into the food categories “water, direct, all sources” and
“water, indirect, all sources” for both the acute and chronic
assessment.

4.4  Residential Exposure/Risk Pathway

Chlorothalonil is a broad-spectrum fungicide applied to turfgrass
(including sod farms, golf courses, and other non-residential turf), and
formulated into paints for interior and exterior applications.  There is
potential for residential exposure from treated golf courses and from
using treated paint.  Note that all other residential turf uses of
chlorothalonil have been cancelled.  Therefore, residential exposures
resulting from contact with chlorothalonil treated turf were not
assessed.  HED has determined that there is no hazard via the dermal
route; therefore, quantification of a dermal risk assessment is not
required.  For this assessment, only inhalation and incidental oral
exposures from the use of treated paint were assessed.  Inhalation
postapplication exposures for golf courses were not assessed since
inhalation exposures are thought to be negligible in outdoor
postapplication scenarios.

Risk from Short-Term and Intermediate-Term Exposures:  For the purposes
of this assessment, short-term exposures are of 1-30 days duration and
intermediate-term exposures are of 1-6 months duration.  Because the
endpoints are the same, short- and intermediate-term risk estimates are
derived from the same daily (short/intermediate-term) exposures.  Short-
and intermediate-term handler risk estimates are presented in Table
4.4.1.  

Risk from Short-Term and Intermediate-Term Dermal Exposures:  Dermal
exposures were not assessed.  A 21-day dermal toxicity study with the
rat was chosen that included dose levels up to 600 mg/kg/day, but only
produced slight dermal irritation.  There is no systemic hazard via the
dermal route; therefore, quantification of the dermal risk assessment is
not required.

Risk from Short-Term and Intermediate-Term Inhalation Exposure:  Except
for an acute inhalation toxicity study, no inhalation toxicity studies
were available for this assessment.  The dose identified for assessing
inhalation risk is from a 90 day oral rat study.  A NOAEL of 3.0
mg/kg/day was used based on dilated renal medullary tubules seen at the
LOAEL of 10 mg/kg/day.  An inhalation-absorption factor of 100% was
used.  Inhalation MOEs for all durations for occupational and
residential handlers are calculated as follows:

MOEI = (NOAELoral / Dose) = (3.0 mg/kg/day / Inhalation Exposure
(mg/kg/day))

HED’s LOC for chlorothalonil exposure is 100 (i.e., a MOE less than
100 exceeds HED’s LOC).  The LOC is based on 10X to account for
interspecies extrapolation to humans from the animal test species and
10X to account for intraspecies sensitivity.  Exposure risk estimates
for short- and intermediate-term exposures are summarized in Table
4.4.1.  The estimates in these tables are based on a 70-kg default body
weight.  The short-and intermediate-term inhalation MOEs are greater
than the target MOE of 100 and, therefore, do not exceed HED’s LOC.

Carcinogenic Risk to Handlers:  Chlorothalonil has been classified as
“likely” to be a human carcinogen by all routes of exposure (HED
CPRC, 4th Meeting, 6/11/1997); however, the SAP decision (6/30/98)
supports the use of an MOE approach for cancer risk assessment.  Based
on the use pattern, HED has determined that long-term residential
exposures to chlorothalonil are not expected; therefore, cancer risks
were not assessed.

Table 4.4.1.  Estimated Short- and Intermediate-Term Residential
Exposures and Risks for Chlorothalonil.

Exposure Scenario	Target	Application Rate (lb ai/gallon)	Amount handled
(gallons)	Baseline Inhalation Unit Exposure (mg/lb ai)	Baseline
Inhalation Dose (mg/kg/day)	Baseline Inhalation MOE

Mixer/Loader/Applicator

Mixing/Loading/Applying Liquid Concentrates with a Paint Brush (PHED)
painting with latex interior paint	0.048	2	0.284	0.00039	7,700

Mixing/Loading/Applying Liquid Concentrates with a Paint Brush (using
chlorothalonil data from MRID 43600102)

0.048	2	0.507	0.0007	4,300

Mixing/Loading/Applying Liquid Concentrates with an Airless Sprayer
(PHED)

0.048	2	0.83	0.0011	2,600

Mixing/Loading/Applying Liquid Concentrates with a Paint Brush (PHED)
painting with latex exterior paint	0.096	2	0.284	0.00078	3,900

Mixing/Loading/Applying Liquid Concentrates with a Paint Brush (using
chlorothalonil data from MRID 43600102)

0.096	2	0.507	0.0014	2,200

Mixing/Loading/Applying Liquid Concentrates with an Airless Sprayer
(PHED)

0.096	2	0.83	0.0023	1,300

Mixing/Loading/Applying Liquid Concentrates with a Paint Brush (PHED)
painting with alkyd exterior paint	0.11	2	0.284	0.00089	3,400

Mixing/Loading/Applying Liquid Concentrates with a Paint Brush (using
chlorothalonil data from MRID 43600102)

0.11	2	0.507	0.0016	1,900

Mixing/Loading/Applying Liquid Concentrates with an Airless Sprayer
(PHED)

0.11	2	0.83	0.0026	1,200

Post-application exposure and risk:  Incidental oral exposure was
assessed for children from ingestion of paint chips containing pesticide
residues.  The dose identified for assessing incidental oral exposure to
children is from an oral toxicity study in rats.  A NOAEL of 3.0
mg/kg/day was used based on dilated renal medullary tubules and
hyperplasia and hyperkeratosis of the non-glandular area of the stomach
at a LOAEL of 10 mg/kg/day.  

The assumptions and factors used in the risk calculations are consistent
with current HED policy for assessing residential exposure and risk
(SOPs For Residential Exposure Assessment, 2000) and include:  (1) the
ingestion rate for paint chips is 0.04 g/day for children based on the
assumption that a child ingests a paint chip with an overall size of 1
square inch and an average weight of 6.5 mg/cm2 for a paint chip that is
one layer thick; and (2) the paint chips contain 20% of the active
ingredient, which is available for ingestion.  Ingestion of paint chips
is considered an episodic event and not a routine behavior.  Because HED
does not believe that this would occur on a regular basis, our concern
for human health is related to acute poisoning rather than short -term
residue exposure.  

This scenario was assessed using the residential SOP 2.3.1,
Postapplication Potential Among Toddlers from Ingestion of Pesticide
Granules from Treated Areas.  This SOP provides a standard method for
estimating postapplication doses among toddlers from incidental
ingestion of pesticide granules.

Incidental Oral MOE = NOAEL (3.0 mg/kg/day) ( PDR

Where

PDR = Potential Dose Rate (mg/day) = IgR x (P/100) x F x CF1 / BW

And

IgR	=	ingestion rate of paint chips containing pesticide residues
(g/day);

P	=	% of ai in paint;

F	=	fraction of ai available for ingestion (unitless);

CF1	=	weight unit conversion factor (1,000 mg/g); and

BW	=	body weight.

Table 4.4.2 summarizes the short- and intermediate-term oral MOEs for
children’s ingestion of paint chips containing chlorothalonil
residues.  The short- and intermediate-term oral MOE (1,200) is greater
than the target MOE of 100 and, therefore, does not exceed HED’s LOC. 

Table 4.4.2.  Postapplication Exposure and Risk Ingestion of Paint Chips
Containing Pesticide Residues.

Scenario	IgR (g/day)	Percent of ai in painta	Fraction of ai available
for ingestion	CF1 (mg/g)	BW (kg)	PDRb (mg/kg/day)	MOEc

Incidental paint chip ingestion	0.04	0.48%	0.2	1,000	15	0.0026	1,200

a. % of ai in product is 40.4% however the % of ai in a gallon of paint
is 0.48% (153.6 oz/12,800 oz x 40.4%

= 0.48%).

b. PDR = potential dose rate = IgR x (Percent ai in paint) x Fraction of
ai available for ingestion x CF1 / BW.

c. MOE = NOAEL (3.0 mg/kg/day)/PDR.

5.0  AGGREGATE RISK ASSESSMENTS AND RISK CHARACTERIZATION

5.1  Acute Aggregate Risk

An acute aggregate-risk assessment was not performed because no
appropriate endpoint was available to determine the aRfD for the general
population or any population subgroup.  

5.2  Short- and Intermediate-Term Aggregate Risk

In aggregating short- and intermediate-term risk, the Agency routinely
combines background chronic dietary exposure (food + water) with short-
and intermediate-term residential exposure.  Because there is no
systemic hazard via the dermal route, and since incidental oral exposure
from treated paint is considered to be episodic, only inhalation (see
Table 4.4.1) exposures for homeowners applying chlorothalonil products
were included in the short- and intermediate-term aggregate risk
assessment.  

Dietary (food + water) exposure can be added to the estimated
residential exposure because the short-term oral and inhalation
endpoints are the same.  The combined exposure may then be used to
calculate an MOE for aggregate risk.  Using the scenario with highest
exposure (mixing/loading/applying liquid concentrates with an airless
sprayer at the 0.11 lb/gal rate (MOE = 1200)), combined with
subpopulation with the greatest dietary exposure for those applying
paint – i.e., adults 50+ years old, the total short- and
intermediate-term food and residential aggregate MOE is 270.  As this
MOE is greater than 100, the short- and intermediate-term aggregate risk
does not exceed the HED’s LOC.  Table 5.2 summarizes the
short/intermediate-term aggregate exposure to chlorothalonil residues.

Table 5.2.  Short-Term and/or Intermediate-Term Aggregate Risk.

Population	Short- or Intermediate-Term Scenario

	NOAEL

mg/kg/day	Target

MOE1	Max

Exposure2

mg/kg/day	Average Food + Water Exposure mg/kg/day	Residential Exposure3

mg/kg/day	Aggregate MOE (food and residential)4

Adults 50+ years old5	3.0	100	0.030	0.008517	0.0026	270

1 The target MOE is based on the 10X for interspecies extrapolation and
the 10X for intraspecies variations, totaling 100.

2 Maximum Exposure (mg/kg/day) = NOAEL/Target MOE.

3 Residential Exposure = [Inhalation Exposure].

4 Aggregate MOE = [NOAEL/(Avg Food Exposure + Residential Exposure)].

5 Relevant population subgroup with highest exposure (Table 4.2.2.2).

6.0  CUMULATIVE RISK

Section 408(b)(2)(D)(v) of the FFDCA requires that, when considering
whether to establish, modify, or revoke a tolerance, the Agency consider
"available information” concerning the cumulative effects of a
particular pesticide's residues and "other substances that have a common
mechanism of toxicity.” 

In the RED, chlorothalonil was grouped in the polychlorinated fungicide
class of pesticides.  Other members of this class include HCB,
pentachlorophenol (PCP), and pentachloronitrobenzene (PCNB).  This is a
very loose classification, the only thing they have common is that they
are polychlorinated compounds used as fungicides.  Available data do not
support a finding for a common mechanism of toxicity for chlorothalonil
and the other pesticides in the polychlorinated fungicide class. 
Chlorothalonil produces renal (kidney) tubular adenomas and carcinomas
and papillomas of the stomach in rats.  Chlorothalonil also produces
gastric lesions and kidney toxicity due to perturbation of mitochondrial
respiration.  The other pesticides in the class do not have the same
toxic effects and do not have the same mode of action.  

For the purposes of this tolerance action, therefore, EPA has not
assumed that chlorothalonil has a common mechanism of toxicity with
other substances.  For information regarding EPA’s efforts to
determine which chemicals have a common mechanism of toxicity and to
evaluate the cumulative effects of such chemicals, see the policy
statements released by EPA’s OPP concerning common mechanism
determinations and procedures for cumulating effects from substances
found to have a common mechanism on EPA’s website at   HYPERLINK
"http://www.epa.gov/pesticides/cumulative/" 
http://www.epa.gov/pesticides/cumulative/ .

7.0  OCCUPATIONAL EXPOSURE

An occupational exposure assessment for chlorothalonil was prepared in
an ARIA memorandum dated 7/14/08 (M. Dow, DP# 346460).

7.1  Occupational Handler

For the proposed new uses (Table 4.1), the most highly exposed
occupational pesticide handlers are expected to be mixer/loaders using
open-pour loading of liquid formulations, mixer/loader/applicators using
high-pressure hand-wand sprayers, mixer/loader/applicators using
backpack sprayers, applicators using open-cab, ground-boom sprayers,
applicators using open-cab airblast sprayers, aerial applicators and
handlers preparing for use in chemigation systems.  

Occupational pesticide handlers preparing to apply pesticides via
chemigation systems are believed to experience exposures similar to
mixer/loaders supporting aerial or large scale ground operations. 
Handlers preparing chemigation systems are not expected to be more
highly exposed. Typically, concentrate is metered into the irrigation
stream via “siphon” tubes.  Those preparing for use in center pivot
or similar types are not expected to be more highly exposed than
mixer/loaders supporting aerial operations.  The total acres treated per
day are believed to be similar.

It is anticipated that most ground applications will be applied by the
grower.  Although treatment blocks may be quite large, it is unlikely
that pesticide handlers would be exposed continuously for 30 days or
more (short-term duration exposures).  The HED Science Advisory Council
for Exposure (ExpoSAC) maintains it is possible for handlers to have
intermediate-term exposure; therefore, estimates of intermediate-term
exposures (1-6 months) are presented.

Particularly for ground applications, private (i.e., grower) applicators
may perform all functions; that is, mix, load and apply the material. 
HED standard procedure directs that although the same individual may
perform all those tasks, they shall be assessed separately.  The
available exposure data for combined mixer/loader/applicator scenarios
are limited in comparison to the monitoring of these two activities
separately.  These exposure scenarios are outlined in the PHED Surrogate
Exposure Guide (August 1998).  HED has adopted a methodology to present
the exposure and risk estimates separately for the job functions in some
scenarios and to present them as combined in other cases.  Most exposure
scenarios for hand-held equipment (such as hand wands, backpack
sprayers, and push-type granular spreaders) are assessed as a combined
job function.  With these types of hand-held operations, all handling
activities are assumed to be conducted by the same individual.  The
available monitoring data support this and HED presents them in this
way.  Conversely, for equipment types such as fixed-wing aircraft,
groundboom tractors, or air-blast sprayers, the applicator exposures are
assessed and presented separately from those of the mixers and loaders. 
By separating the two job functions, HED determines the most appropriate
levels of personal-protective equipment (PPE) for each aspect of the job
without requiring an applicator to wear unnecessary PPE that might be
required for a mixer/loader (e.g., chemical-resistant gloves may only be
necessary during the pouring of a liquid formulation).  

No chemical-specific data were available with which to assess potential
exposure to pesticide handlers.  The estimates of exposure to pesticide
handlers are based upon surrogate study data available in the PHED (v.
1.1, 1998).  For pesticide handlers, it is HED standard practice to
present estimates of dermal exposure for “baseline;” that is, for
workers wearing a single layer of work clothing consisting of a
long-sleeved shirt, long pants, shoes plus socks and no protective
gloves as well as for “baseline” and the use of protective gloves or
other PPE as might be necessary.  

The label directs:  “Mixers, Loaders, Applicators and all other
handlers must wear:  Long-sleeved shirt and long pants,
chemical-resistant gloves made of any waterproof material and shoes plus
socks.”

Chlorothalonil has a low order of acute toxicity by the oral and dermal
routes of exposure (Toxicity Category IV).  It is toxic via the
inhalation route (Toxicity Category II).  Chlorothalonil is severely
irritating to the eye (Toxicity Category I) and is moderately irritating
to the skin (Toxicity Category III).  Chlorothalonil is not a skin
sensitizer.  

The RAB1 toxicology team did not identify short-term (1-30 days) or
intermediate-term (1-6 months) exposure duration dermal toxicological
endpoints.  Two route-specific 21-day dermal toxicity studies exist, one
in the rat and one in the rabbit.  The rat study was conducted to dose
levels up to 600 mg ai/kg bw/day which produced slight dermal irritation
but NO signs of systemic toxicity.  The team found that there were no
developmental or neurotoxicity concerns.  As stated, there was no
systemic toxicity in doses up to 600 mg ai/kg bw/day.  Quantitation of
dermal risk using data obtained from oral toxicity studies would not
accurately reflect actual toxic effects expressed by the dermal route of
exposure.  Therefore, an assessment of dermal exposure and risk is not
necessary.

The toxicology team did identify toxicological endpoints via the
inhalation route of exposure.  The endpoints were identified from a 90
day oral rat study where the effects were based on dilated renal
medullary tubules.  The NOAEL is 3.0 mg ai/kg bw/day.  HED’s LOC for
chlorothalonil exposure is 100 (i.e., a MOE less than 100 exceeds
HED’s LOC).  The LOC is based on 10X to account for interspecies
extrapolation to humans from the animal test species and 10X to account
for intraspecies sensitivity.  HED and RD assume 100% absorption via the
inhalation route of exposure.  

Chlorothalonil was classified as “Likely” to be a human carcinogen
by all routes of exposure (HED Cancer Peer Review Meeting, 6/11/1997). 
However the SAP decision (6/30/98) supports the use of an MOE approach
in cancer risk assessment for chlorothalonil.  The HED HASPOC reviewed
the approach on 3/12/08 and supported the MOE approach.  Since long-term
(i.e., chronic) exposures are not expected, it is not necessary to
perform a cancer risk assessment.  

Table 7.1.  Estimated Handler Exposure and Risk from the Proposed Uses
of Chlorothalonil.

Unit Exposure1

mg ai/lb handled	Applic. Rate2	Units Treated3

Per Day	Average Daily

Dose4

mg ai/kg bw/day	NOAEL5

mg ai/kg bw/day	MOE6

Inhalation

Mixer/Loader - Liquid - Open-pour

Inhal             0.0012 	2.25 lb ai/A	350 A/day	Inhal           0.0135
3.0	220

Applicator - Ground-boom - Open Cab

Inhal           0.00074	2.25 lb ai/A	80 A/day	Inhal          0.0019	3.0
1,600

Applicator - Fixed-wing - Aerial (Pilots not required to wear gloves)

Inhal         0.000068	2.25 lb ai/A	350 A/day	Inhal        0.000765	3.0
3,900

Applicator – Open-cab Airblast (persimmon)

Inhal              0.45 	0.9375 lb ai/A	40 A/day	Inhal          0.0024
3.0	1,200

Mixer/Loader/Applicator - High-pressure Hand-Wand (Ginseng)

Inhal             0.12 

PF5-Resp    0.024	1.5 lb ai/A	1,000* gal/day = 50 A/day	Inhal         
0.13

                  0.026	3.0	23

120

Mixer/Loader/Applicator – Backpack (Ginseng)

Inhal              0.03	1.5 lb ai/A	40* gal/day = 2 A/day	Inhal         
0.0013	3.0	2,300

1.  Unit Exposures are taken from “PHED SURROGATE EXPOSURE GUIDE.” 
Estimates of Worker Exposure from the PHED Version 1.1, August 1998. 
Inhal. = Inhalation.  Units = mg ai/pound of active ingredient handled. 

2.  Applic. Rate. = Taken from Sections B of the IR-4 submissions.

3.  Units Treated are taken from “Standard Values for Daily Acres
Treated in Agriculture;” SOP No. 9.1 ExpoSAC; Revised 5 July 2000.  It
is assumed that chlorothalonil is applied to ginseng in 20 gal spray/A. 
There were no directions regarding volume of spray for ginseng.  The
Bravo Weather Stik® label indicates 25-50 gal spray per acre for
asparagus and 20–100 gal spray per acre for blueberries.

4.  Average Daily Dose = Unit Exposure * Applic. Rate * Units Treated (
Body Weight (70 kg).

5.  NOAEL = No-Observable Adverse-Effect Level:  3.0 mg ai/kg bw/day for
short- and intermediate–term inhalation exposures.

6.  MOE = Margin of Exposure = NOAEL ( ADD.  

A MOE of 100 is adequate to protect occupational pesticide handlers from
short- and intermediate-term inhalation exposures to chlorothalonil. 
All MOEs are greater than 100 except for a mixer/loader/applicator using
high-pressure, hand-wand sprayer.  Use of a dust/mist filtering
respirator will reduce inhalation exposure by about 80% and resulting
MOEs will be >100.  With the use of a dust/mist filtering respirator,
the use pattern does not exceed the LOC.  The remaining proposed use
patterns do not exceed HED’s LOC.  

7.2  Occupational Post-Application Exposure

It is possible for agricultural workers to have post-application
exposures to pesticide residues during the course of typical
agricultural activities.  HED assumes post-application inhalation
exposure is negligible.  The label lists a 12-hour REI.  By that time
sprays have likely dried.  Chlorothalonil has a vapor pressure of 3.47
mm HG at 25ºC.  Volatilization is not considered to be a factor.  

Since no dermal toxicological endpoints were identified, it is not
necessary to conduct assessments of post-application exposure and risk. 

7.3  REI

Chlorothalonil is classified in Acute Toxicity Category IV for acute
dermal toxicity.  It is classified in Toxicity Category III for primary
dermal irritation.  It is classified in Toxicity Category II for acute
inhalation toxicity and is classified in Toxicity Category I for primary
eye irritation.  

Title 40 of the Code of Federal Regulations § 156.208 (c),(2) states
“If a product contains only one active ingredient and it is in
Toxicity Category I by the criteria in paragraph (c)(1) of this section,
the REI shall be 48 hours.”  Chlorothalonil is classified in Toxicity
Category I for primary eye irritation and Category II for inhalation
toxicity.  The REI for Category II is 24 hours.  It is suggested that RD
confirm or correct the REI for chlorothalonil as may be appropriate.  

8.0  DATA DEFICIENCIES/LABEL REVISIONS

860.1200 Directions for Use

The proposed uses on the Brassica head and stem subgroup should be
revised to specify a maximum seasonal application rate of 8.8 lb ai/A.

The proposed use on persimmon should be modified to specify that
chlorothalonil may only be applied to persimmon grown in Florida and
Hawaii, and that applications may be made with a RTI of 14 days.  In
addition, the proposed use should specify that aerial applications to
persimmon be made in a minimum of 10 gal/A.

Use of a dust/mist filtering respirator should be specified for a
mixer/loader/applicator using high-pressure, hand-wand sprayer.  

Title 40 of the Code of Federal Regulations § 156.208 (c),(2) states
“If a product contains only one active ingredient and it is in
toxicity category I by the criteria in paragraph (c)(1) of this section,
the REI shall be 48 hours.”  Chlorothalonil is classified in Toxicity
Category I for primary eye irritation and Category II for inhalation
toxicity.  The REI for Category II is 24 hours.  It is suggested that RD
confirm or correct the REI for chlorothalonil as may be appropriate.  

860.1550 Proposed Tolerances

The petitioner should submit a revised Section F reflecting the
recommended tolerances and commodity definitions presented above and in
Table 6.

860.1650 Submittal of Analytical Reference Standards

The analytical reference standard for 4-hydroxy chlorothalonil at the
EPA National Pesticide Standards Repository has expired.  The registrant
should either recertify the lot in the repository and send in an updated
COA, or submit a new standard (different lot #) if the previous lot will
not be recertified.  

860.1500 Crop Field Trials

To support use of the FlC formulation on non-bell peppers, the
petitioner should conduct one additional side-by-side field trial with
non-bell peppers.  The trial should reflect side-by-side plots receiving
applications of the FlC and WDG formulations at 1x the proposed maximum
seasonal rate, and the trial should be conducted in Zone 8.  If the
trial indicates that residues in/on samples treated with the FlC
formulation are higher than in/on samples treated with the WDG
formulation, two additional field trials will be required, so that a
total of three field trials are available reflecting application of the
FlC formulation to non-bell peppers.  

Toxicology (required as a result of the revisions of 40 CFR §158)

Immunotoxicity studies

Acute neurotoxicity study

cc: G. Kramer (RAB1), W. Greear (RAB1), M. Dow (RD)

RDI: Branch (7/30/08); RAB1 Chemists (7/30/08); RAB1 Toxicologists
(6/17/08)

G.F. Kramer:S10781:PY-S:(703)305-5079:7509P:RAB1 

Appendix 1.  Toxicological Data Requirements (Vischim S.r.l.)

The requirements (40 CFR 158.340) for Food Use for chlorothalonil are
presented below.  Use of the new guideline numbers does not imply that
the new (1998) guideline protocols were used.

Test 	Technical

	Required	Satisfied

870.1100	Acute Oral Toxicity

870.1200	Acute Dermal Toxicity

870.1300	Acute Inhalation Toxicity

870.2400	Primary Eye Irritation

870.2500	Primary Dermal Irritation

870.2600	Dermal Sensitization	yes

yes

yes

yes

yes

yes	yes

no

yes

no

no

no

870.3100	Oral Subchronic (rodent)

870.3150	Oral Subchronic (nonrodent)

870.3200	21-Day Dermal

870.3250	90-Day Dermal

870.3465	90-Day Inhalation	yes

yes

yes

no

no	yes

yes

no

-

-

870.3700a	Developmental Toxicity (rodent)

870.3700b	Developmental Toxicity (nonrodent)

870.3800	Reproduction	yes

yes

yes	yes

yes

yes

870.4100a	Chronic Toxicity (rodent)

870.4100b	Chronic Toxicity (nonrodent)

870.4200a	Oncogenicity (rat)

870.4200b	Oncogenicity (mouse)

870.4300	Chronic/Oncogenicity	yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.5100	Mutagenicity—Gene Mutation - bacterial

870.5300	Mutagenicity—Gene Mutation - mammalian

870.5400	Mutagenicity—Structural Chromosomal Aberrations

870.5500	Mutagenicity—Other Genotoxic Effects	yes

yes

yes

yes	yes

yes

yes

no

870.6100a	Acute Delayed Neurotox. (hen)

870.6100b	90-Day Neurotoxicity (hen)

870.6200a	Acute Neurotox. Screening Battery (rat)

870.6200b	90-Day Neuro. Screening Battery (rat)

870.6300	Develop.
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Appendix 2.  Toxicological Data Requirements (Old Data)

	

The requirements (40 CFR 158.340) for previously approved food Use for
chlorothalonil are presented below.  Use of the new guideline numbers
does not imply that the new (1998) guideline protocols were used.

Test 	Technical

	Required	Satisfied

870.1100	Acute Oral Toxicity

870.1200	Acute Dermal Toxicity

870.1300	Acute Inhalation Toxicity

870.2400	Primary Eye Irritation

870.2500	Primary Dermal Irritation

870.2600	Dermal Sensitization	yes

yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

yes

870.3100	Oral Subchronic (rodent)

870.3150	Oral Subchronic (nonrodent)

870.3200	21-Day Dermal

870.3250	90-Day Dermal

870.3465	90-Day Inhalation	yes

yes

yes

no

no	yes

yes

yes

-

-

870.3700a	Developmental Toxicity (rodent)

870.3700b	Developmental Toxicity (nonrodent)

870.3800	Reproduction	yes

yes

yes	yes

yes

yes

870.4100a	Chronic Toxicity (rodent)

870.4100b	Chronic Toxicity (nonrodent)

870.4200a	Oncogenicity (rat)

870.4200b	Oncogenicity (mouse)

870.4300	Chronic/Oncogenicity	yes

yes

yes

yes

yes	yes

yes

yes

yes

yes

870.5100	Mutagenicity—Gene Mutation - bacterial

870.5300	Mutagenicity—Gene Mutation - mammalian

870.5400	Mutagenicity—Structural Chromosomal Aberrations

870.5500	Mutagenicity—Other Genotoxic Effects	yes

yes

yes

yes	yes

yes

yes

yes

870.6100a	Acute Delayed Neurotox. (hen)

870.6100b	90-Day Neurotoxicity (hen)

870.6200a	Acute Neurotox. Screening Battery (rat)

870.6200b	90-Day Neuro. Screening Battery (rat)

870.6300	Develop. Neurotoxicity	no

no

yes

yes

no	-

-

no

no

-

870.7485	General Metabolism

870.7600	Dermal Penetration

870.7800	Immunotoxicity	yes

no

yes	yes

-

no

Special Studies for Ocular Effects

Acute Oral (rat)	

Subchronic Oral (rat)	

Six-month Oral (dog)		

no

no

no	

-

-

-

Chlorothalonil	Dietary Exposure Assessment		DP# 327261

Chlorothalonil	                       Human-Health Risk Assessment		DP#
353243

Page   PAGE  1  of   NUMPAGES  60 

Chlorothalonil	                       Human-Health Risk Assessment		DP#
327261

Page   PAGE  46  of   NUMPAGES  60