Document ID: EPA-HQ-OPP-2004-0257-0004
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-07-27T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES, AND

TOXIC SUBSTANCES

MEMORANDUM

DATE:		16-MAR-2007

SUBJECT:	PP#3E6795.  Chlorothalonil:  Updated Revised Risk Assessment
for a Tolerance on Edible-Podded Peas Without a U.S. Registration.  DP#
337925.  PC Code 081901.  Decision# 373545.

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

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

Kelly M. Lowe, Environmental Scientist

Registration Action Branch 1 (RAB1)

Health Effects Division (HED) (7509P)

THROUGH:	P.V. Shah, Ph.D., Acting Branch Chief

RAB1/HED (7509P)

TO:		Tony Kish/Rosemary Kearns, RM 22

	Registration Division (RD; 7505P)

NOTE:  This document supersedes “Chlorothalonil:  Revised Risk
Assessment for a Tolerance on Edible-Podded Peas Without a U.S.
Registration,” G. Kramer, et al.; DP# 332752, dated 21-DEC-2006.  This
assessment has been updated to include a discussion of the reasons for
revisions to the toxicological endpoints from the RED and to include the
current policies for characterization of the FQPA safety factors.

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 Kelly Lowe (RAB1); 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 "1-4" \h \z \u    HYPERLINK \l "_Toc154470312"  1.0 EXECUTIVE
SUMMARY	  PAGEREF _Toc154470312 \h  4  

  HYPERLINK \l "_Toc154470313"  2.0 PHYSICAL/CHEMICAL PROPERTIES
CHARACTERIZATION	  PAGEREF _Toc154470313 \h  7  

  HYPERLINK \l "_Toc154470314"  2.1 Identification of Active Ingredient	
 PAGEREF _Toc154470314 \h  7  

  HYPERLINK \l "_Toc154470315"  2.2 Physical and Chemical Properties	 
PAGEREF _Toc154470315 \h  8  

  HYPERLINK \l "_Toc154470316"  3.0 HAZARD CHARACTERIZATION	  PAGEREF
_Toc154470316 \h  8  

  HYPERLINK \l "_Toc154470317"  3.1 Hazard and Dose-Response
Characterization	  PAGEREF _Toc154470317 \h  8  

  HYPERLINK \l "_Toc154470318"  3.1.1 Studies Considered in the Toxicity
and Dose-Response Evaluation	  PAGEREF _Toc154470318 \h  8  

  HYPERLINK \l "_Toc154470319"  3.1.2 Sufficiency of Studies/Data	 
PAGEREF _Toc154470319 \h  8  

  HYPERLINK \l "_Toc154470320"  3.1.3 Mode of Action and Mammalian
Toxicology	  PAGEREF _Toc154470320 \h  9  

  HYPERLINK \l "_Toc154470321"  3.1.4 Toxicological Effects	  PAGEREF
_Toc154470321 \h  10  

  HYPERLINK \l "_Toc154470322"  3.1.4.1 Chlorothalonil	  PAGEREF
_Toc154470322 \h  10  

  HYPERLINK \l "_Toc154470323"  3.1.4.2 Chlorolthalonil Plant Metabolite
SDS-3701	  PAGEREF _Toc154470323 \h  17  

  HYPERLINK \l "_Toc154470324"  3.1.4.3 Chlorothalonil Soil Metabolite
SDS-46851	  PAGEREF _Toc154470324 \h  20  

  HYPERLINK \l "_Toc154470325"  3.2 Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc154470325 \h  21  

  HYPERLINK \l "_Toc154470326"  3.2.a Dermal Absorption	  PAGEREF
_Toc154470326 \h  22  

  HYPERLINK \l "_Toc154470327"  3.2.b Mechanistic Data	  PAGEREF
_Toc154470327 \h  22  

  HYPERLINK \l "_Toc154470328"  3.3 FQPA Considerations	  PAGEREF
_Toc154470328 \h  23  

  HYPERLINK \l "_Toc154470329"  3.3.1 Adequacy of the Toxicity Database	
 PAGEREF _Toc154470329 \h  23  

  HYPERLINK \l "_Toc154470330"  3.3.2 Evidence of Neurotoxicity	 
PAGEREF _Toc154470330 \h  23  

  HYPERLINK \l "_Toc154470331"  3.3.2.1 Subchronic Neurotoxicity Study	 
PAGEREF _Toc154470331 \h  23  

  HYPERLINK \l "_Toc154470332"  3.3.2.2 Evidence of Neurotoxicity from
Other Related Studies	  PAGEREF _Toc154470332 \h  24  

  HYPERLINK \l "_Toc154470333"  3.3.3 Developmental Toxicity Studies	 
PAGEREF _Toc154470333 \h  24  

  HYPERLINK \l "_Toc154470334"  3.3.3.1.a. Rat (New Data)	  PAGEREF
_Toc154470334 \h  24  

  HYPERLINK \l "_Toc154470335"  3.3.3.1.b Rat (Old Data)	  PAGEREF
_Toc154470335 \h  25  

  HYPERLINK \l "_Toc154470336"  3.3.3.2.a. Rabbit (New Data)	  PAGEREF
_Toc154470336 \h  25  

  HYPERLINK \l "_Toc154470337"  3.3.3.2.b. Rabbit (Old Data)	  PAGEREF
_Toc154470337 \h  26  

  HYPERLINK \l "_Toc154470338"  3.3.3.a. Reproductive Toxicity Study
(Rat-New Data)	  PAGEREF _Toc154470338 \h  26  

  HYPERLINK \l "_Toc154470339"  3.2.3.b. Reproductive Toxicity Study
(Rat-Old Data)	  PAGEREF _Toc154470339 \h  28  

  HYPERLINK \l "_Toc154470340"  3.3.4 Additional Information from
Literature Sources	  PAGEREF _Toc154470340 \h  29  

  HYPERLINK \l "_Toc154470341"  3.3.5 Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc154470341 \h  29  

  HYPERLINK \l "_Toc154470342"  3.3.5.1 Determination of Susceptibility	
 PAGEREF _Toc154470342 \h  29  

  HYPERLINK \l "_Toc154470343"  3.3.5.2 Degree of Concern Analysis and
Residual Uncertainties	  PAGEREF _Toc154470343 \h  30  

  HYPERLINK \l "_Toc154470344"  3.3.6 Recommendation for a Developmental
Neurotoxicity Study	  PAGEREF _Toc154470344 \h  30  

  HYPERLINK \l "_Toc154470345"  3.4 FQPA SF	  PAGEREF _Toc154470345 \h 
30  

  HYPERLINK \l "_Toc154470346"  3.4.1 Adequacy of the Exposure Database	
 PAGEREF _Toc154470346 \h  30  

  HYPERLINK \l "_Toc154470347"  3.4.2 FQPA SF Conclusion	  PAGEREF
_Toc154470347 \h  30  

  HYPERLINK \l "_Toc154470348"  3.5 Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc154470348 \h  31  

  HYPERLINK \l "_Toc154470349"  3.5.1 aRfD - Females age 13-49	  PAGEREF
_Toc154470349 \h  32  

  HYPERLINK \l "_Toc154470350"  3.5.2 aRfD - General Population	 
PAGEREF _Toc154470350 \h  33  

  HYPERLINK \l "_Toc154470351"  3.5.3 cRfD	  PAGEREF _Toc154470351 \h 
33  

  HYPERLINK \l "_Toc154470352"  3.5.4 Incidental Oral Exposure (Short
and Intermediate Term)	  PAGEREF _Toc154470352 \h  33  

  HYPERLINK \l "_Toc154470353"  3.5.5 Dermal Absorption	  PAGEREF
_Toc154470353 \h  34  

  HYPERLINK \l "_Toc154470354"  3.5.6 Dermal Exposure (Short,
Intermediate and Long-Term)	  PAGEREF _Toc154470354 \h  34  

  HYPERLINK \l "_Toc154470355"  3.5.7 Inhalation Exposure (Short,
Intermediate and Long-Term)	  PAGEREF _Toc154470355 \h  35  

  HYPERLINK \l "_Toc154470356"  3.5.8 Level of Concern for Margin of
Exposure	  PAGEREF _Toc154470356 \h  35  

  HYPERLINK \l "_Toc154470357"  3.5.9 Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc154470357 \h  35  

  HYPERLINK \l "_Toc154470358"  3.5.10 Classification of Carcinogenic
Potential	  PAGEREF _Toc154470358 \h  35  

  HYPERLINK \l "_Toc154470359"  3.6 Endocrine disruption	  PAGEREF
_Toc154470359 \h  36  

  HYPERLINK \l "_Toc154470360"  3.7 Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc154470360 \h  37  

  HYPERLINK \l "_Toc154470361"  3.8 Data Proprietary Use/Gaps	  PAGEREF
_Toc154470361 \h  38  

  HYPERLINK \l "_Toc154470362"  4.0 EXPOSURE ASSESSMENT AND
CHARACTERIZATION	  PAGEREF _Toc154470362 \h  38  

  HYPERLINK \l "_Toc154470363"  4.1 Summary of Registered/Proposed Uses	
 PAGEREF _Toc154470363 \h  38  

  HYPERLINK \l "_Toc154470364"  4.2 Dietary Exposure/Risk Pathway	 
PAGEREF _Toc154470364 \h  38  

  HYPERLINK \l "_Toc154470365"  4.2.1 Residue Profile	  PAGEREF
_Toc154470365 \h  38  

  HYPERLINK \l "_Toc154470366"  4.2.2 Dietary-Exposure Analyses	 
PAGEREF _Toc154470366 \h  39  

  HYPERLINK \l "_Toc154470367"  4.2.2.1 Acute Dietary-Exposure Analysis	
 PAGEREF _Toc154470367 \h  40  

  HYPERLINK \l "_Toc154470368"  4.2.2.2 Chronic Dietary-Exposure
Analysis	  PAGEREF _Toc154470368 \h  40  

  HYPERLINK \l "_Toc154470369"  4.2.2.3 Cancer Dietary-Exposure Analysis
  PAGEREF _Toc154470369 \h  42  

  HYPERLINK \l "_Toc154470370"  4.3 Water Exposure/Risk Pathway	 
PAGEREF _Toc154470370 \h  42  

  HYPERLINK \l "_Toc154470371"  4.4 Residential Exposure/Risk Pathway	 
PAGEREF _Toc154470371 \h  43  

  HYPERLINK \l "_Toc154470372"  5.0 AGGREGATE-RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc154470372 \h  46  

  HYPERLINK \l "_Toc154470373"  6.0 CUMULATIVE RISK	  PAGEREF
_Toc154470373 \h  46  

  HYPERLINK \l "_Toc154470374"  7.0 OCCUPATIONAL EXPOSURE	  PAGEREF
_Toc154470374 \h  47  

  HYPERLINK \l "_Toc154470375"  8.0 DATA DEFICIENCIES / LABEL REVISIONS	
 PAGEREF _Toc154470375 \h  47  

  HYPERLINK \l "_Toc154470376"  Appendix 1. Toxicological Data
Requirements (Vischim S.r.l.)	  PAGEREF _Toc154470376 \h  48  

  HYPERLINK \l "_Toc154470378"  Appendix 2. Toxicological Data
Requirements (Old Data)	  PAGEREF _Toc154470378 \h  49  

 

1.0 EXECUTIVE SUMMARY

The purpose of this risk assessment is to support the establishment of a
tolerance without a registered use in the U. S. for residues of
chlorothalonil and its 4-hydroxy-2,5,6-trichloroisophthalonitrile
metabolite (SDS-3701) in or on edible-podded peas (including snow peas
and sugar snaps).  The assessment is prompted by the submission of
petition 3E6795 from the Snowpea Commission of Guatemala, the Guatemala
Ministry of Agriculture, and Partnerships for Food Industry Development
- Fruits and Vegetables of Michigan State University.  This risk
assessment was performed for the use of the compound chlorothalonil on
edible-podded peas (including snow peas and sugar snaps) that are
imported to the U. S. Chlorothalonil is the active ingredient (a.i.) in
the registered product Bravo® 500 (EPA Reg. No. 50534-8-10182) which
contains 40.4% active ingredient, 4.17 lb a.i./gallon.

Permanent and temporary tolerances have been established for
chlorothalonil and its 4-hydroxy metabolite 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. It 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 a subchronic toxicity studies in mice and rats,
chlorothalonil produced hyperplasia and hyperkeratosis of the squamous
epithelium of the stomach and/or non-glandular region of the
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 the
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 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.  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 post natal
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 chronic RfD (cRfD) was
established based on the lowest-observed-adverse-effect level (LOAEL)
from the chronic toxicity study in the rat.  The LOAEL of 0.9 mg/kg/day
is based on an increased incidence and severity of epithelial
hyperplasia, hyperkeratosis and ulceration of the non-glandular region
of the stomach in females.  The no-observed-adverse-effect level (NOAEL)
was not established.  This LOAEL is lower than any NOAEL in the
database.  In addition, the study duration is appropriate for the
duration of exposure.  The uncertainty factor used in determining the
cRfD was 300 [10X for interspecies (animal-to-human) extrapolation; 10X
for intraspecies (human) variations; and 3X for use of a LOAEL instead
of a NOAEL].  The uncertainty factor of 3X for use of LOAEL instead of
the NOAEL is considered appropriate since an increased incidence and
severity of epithelial hyperplasia, hyperkeratosis and ulceration of the
non-glandular region of the stomach in females were seen in few animals
and were minimal in severity and observed in one sex only.  Overall,
there was no clear evidence that chlorothalonil was mutagenic.  The
Science 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) of 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 neurotoxic concerns.  Short and intermediate-term incidental oral
and inhalation endpoints are 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 seen at the LOAEL of 30 mg/kg/day in a two generation
reproduction study in rats.  A target MOE of 1000 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; and 10X for use of a LOAEL instead of a
NOAEL].  Long-term inhalation exposure to chlorothalonil is not expected
based on the current use pattern.  

Food Quality Protection Act (FQPA) Decision

The chlorothalonil risk assessment team recommends that the FQPA SF be
reduced to 3X for chronic risk assessment but retained at 10X for
residential assessments.  As explained in section 3.5.3, the data from
the chronic toxicity study in rats show that a 3X factor in the chronic
risk assessment will be protective of infants and children despite the
lack of a NOAEL in that study.  As to the residential risk assessment,
there are insufficient reliable data to conclude that a reduction of the
10X FQPA safety factor is safe for infants and children given the lack
of a NOAEL in the study upon which the residential risk assessment is
based.  Other than the lack of NOAELs in these two critical studies,
other considerations raise no concern for the safety of infants and
children.  Specifically, the chlorothalonil risk assessment team found
that 1) the hazard and exposure databases are complete, 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 neurotoxic concerns. 

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.  RD should ensure that all turf labels prohibit use in
recreational areas (including, but not limited to, daycare centers,
playgrounds, parks, athletic fields, campgrounds, schools, churches,
etc.).  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 1000 and, therefore, do not exceed
HED’s level of concern (LOC).

Occupational Exposure and Risk Assessment  

The proposed tolerance on edible-podded peas is not associated with a
registered use in the U.S.  Therefore, an updated occupational exposure
and risk assessment is not necessary. 

Dietary Risk Estimates (Food + Water)

The Tier 3, chronic dietary-exposure assessment was refined by making
use of monitoring data from the Pesticide Data Program (PDP) and Food
and Drug Administration surveillance monitoring (FDA), percent crop
treated (%CT) estimates provided by the Office of Pesticide Programs
Biological and Economic Analysis Division (BEAD, J. Alsadek, 8/24/04),
and processing factors as tabulated in the Reregistration Eligibility
Decision (RED) for Chlorothalonil (Document # EPA 738-R-99-004, April
1999).  Drinking water was incorporated directly into the dietary
assessment.  EFED has provided Tier II estimated drinking water
concentrations (EDWCs) for use in drinking water assessments when
chlorothalonil is used according to registered labeling.  Because
monitoring data are unavailable, estimates of chlorothalonil and the
major degradate SDS-3701 concentrations were made only with mathematical
models.  The models Pesticide Root Zone Model/Exposure Analysis Modeling
System (PRZM/EXAMS) with regional percent crop area adjustment factors
were used to conduct surface water exposure assessments.  The highest
estimated surface water concentrations occurred with the PA turf (sod
farm) scenario.  Based on preliminary analyses, the maximum allowable
EDWC was estimated to be 42 ppb; i.e., a value of >42 ppb resulted in a
chronic dietary (food + water) risk which exceeded 100% of the chronic
population-adjusted dose (cPAD).  Other than turf (sod farms), all
registered uses result in EDWCs of <42 ppb. EFED has conducted a
sensitivity analysis on the effect of application rate and
re-application interval for sod farms on the EDWCs of chlorothalonil
total toxic residues in surface water (Memo, L. Shanaman, 01-SEP-2006,
D328340).  This sensitivity analysis identifies several scenarios that
result in water exposure below 42 ppb. 

Assuming that water exposure is no higher than 42 ppb, the resulting
chronic dietary-exposure estimates for combined food and drinking water
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
Dietary Exposure Evaluation Model software with the Food Commodity
Intake Database (DEEM-FCID() software, dietary exposure is estimated to
be 0.000984 mg/kg/day for the U.S. population (33% of the cPAD) and
0.002967 mg/kg/day (99% of the cPAD) for all infants (<1 year 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 by incorporating the
drinking water directly into the dietary-exposure assessment 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 8600.  As this MOE is greater than 1000, the short- and
intermediate-term aggregate risk does not exceed the HED’s LOC.  

Recommendations for Tolerances/Registration

Provided that RD ensures that the directions for use of chlorothalonil
on sod farms are modified to result in EDWCs of <42 ppb and that all
turf labels are modified to prohibit use in recreational areas,   SEQ
CHAPTER \h \r 1 HED concludes there are no residue chemistry or
toxicology data requirements that would preclude the establishment of
the HED-recommended tolerance of 5.0 ppm for residues of chlorothalonil
and its 4-hydroxy metabolite in/on “Pea, edible podded.”

2.0 PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

2.1 Identification of Active Ingredient

TABLE 2.1.1.	Chlorothalonil Nomenclature.

Compound	

Common Name	Chlorothalonil

IUPAC Name	tetrachloroisophthalonitrile

CAS Name	2,4,5,6-tetrachloro-1,3-benzenedicarbonitrile

CAS Registry Number	1897-45-6

End-Use Products (EP)	Bravo® 500 (EPA Reg. No. 50534-8-10182)

Regulated Metabolite	

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

2.2 Physical and Chemical Properties

  SEQ CHAPTER \h \r 1 Technical chlorothalonil is a white crystalline
solid with a melting point of 250-251 °C.  Chlorothalonil is
practically insoluble in water at 25 °C (~0.6 ppm) and only slightly
soluble in acetone, chloroform, ethanol, kerosene, methyl ethyl ketone,
mineral oil, toluene, and xylene (≤8.0% by weight).  The technical
product is stable under normal storage temperatures, on exposure to
ultraviolet radiation, and in moderate alkaline or acidic aqueous media.

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 metabolite SDS-3701
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 a.i.) provided a new subchronic
neurotoxicity study in rats.  The hazard profile from both databases is
comparable.  Each database in and of itself is adequate for a food use
pesticide.  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.  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.). 

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 S-cysteine 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
to the July 29-30, 1998 FIFRA Scientific Advisory Panel).  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; however, it does 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 including a
thickened appearance of the stomach, often with a catarrhal adhesion to
the mucosal surface and prominent apoptotic bodies in the antrum of
males and females, mucus and cell debris adherent to lumenal surface,
and foci of mineralization in the stomach mucosa of males.  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.  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.  There was a small (2x) quantitative difference in
susceptibility observed between fetal and maternal effect levels. 
However, the difference was due an increase in two variations that are
often observed in this strain of rabbit; i.e., increased 13th rib and
reduced sternum.  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.

Table 3.1.4.1a. Acute Toxicity Profile - Chlorothalonil Technical (96%
A.I.) (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 g/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	is 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 = 30.8/34.3 mg/kg bw/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 = 30.8/34.3 mg/kg bw/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 = 247.5/270.0 mg/kg bw/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 = 5.10/5.92 mg/kg/day
(M/F).

LOAEL = 43.3/45.3 mg/kg/day (M/F) based on macroscopic and microscopic
pathological findings in the stomach including:  thickened appearance of
the stomach, often with a catarrhal adhesion to the mucosal surface, and
prominent apoptotic bodies in the antrum of males and females; mucus and
cell debris adherent to lumenal surface and foci of mineralization in
the stomach mucosa of males.

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 < 1.9 (M) and = 2.5
mg/kg/day (F).

LOAEL = 1.9/9.9 mg/kg bw/day 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 < 0.9 mg/kg/day (F),
and = 0.7 mg/kg/day (M). 

LOAEL = 0.9/2.7 mg/kg bw/day (F/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) 

g/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 g/mL (Trial 2, -S9); and 0.25, 0.5, 1.0, 1.5, 2.0, 3.0, 4.0, or
5.0 g/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 = 22.0/24.2 mg/kg/day (M/F).

LOAEL = 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 = 2.3 mg/kg/day. 

LOAEL = 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 bw/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 bw/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 < 38 mg/kg/day. 

Parental LOAEL = 38 mg/kg/day based on kidney and forestomach lesions. 

Offspring NOAEL = 115 mg/kg/day.

Offspring LOAEL = 234 mg/kg/day based on lower pup body weights on day
21.

Reproductive NOAEL = 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 < 113 mg/kg/day.

LOAEL = 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 < 6.0 mg/kg/day.

LOAEL = 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 = 1.8 mg/kg bw/day.

LOAEL = 3.5 mg/kg bw/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 Plant Metabolite SDS-3701

SDS-3701 is the major metabolite of chlorothalonil which is moderately
toxic via 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. 

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 metabolite SDS-3701 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

“NEW DATA” UNREVIEWED AT THIS TIME 	Maternal NOAEL = 5 mg/kg/day

Maternal LOAEL = 15 mg/kg/day based on reduced body weight and body
weight gain during gestation, reduced food consumption and
altered/reduced hematological parameters.

 

Developmental NOAEL = 5 mg/kg/day

Developmental LOAEL = 15 mg/kg/day based on reduced fetal body weights
and an increase in the incidence of 14th rudimentary rib.

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 = 1.5 mg/kg/day 

Parental LOAEL = 3.0 mg/kg/day

Offspring NOAEL = 1.5 mg/kg/day

Offspring LOAEL = 3.0 mg/kg/day based on a reduction in weanling body
weight. 

Reproductive NOAEL = 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)

“NEW DATA” UNREVIEWED AT THIS TIME 	NOAEL = 0.95 mg/kg bw/day (F);
1.8 mg/kg/day (M)

LOAEL = 1.86 mg/kg/day (F) based on decreased body weight gain; 3.26 (M)
based on decreased body weight and body weight gain.

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 bw/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 < 54 mg/kg/day

LOAEL = 54 mg/kg bw/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

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.

870.5100

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.

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.

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.

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.

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.  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.a 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.b 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% a.i.)
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
metabolite).  Developmental toxicity studies in rats and rabbits and two
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 wk -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% a.i.) 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%
a.i.) 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% a.i.) 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%
a.i., 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.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% a.i.) 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).

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

In a 2-generation reproduction study (MRID 41706201), chlorothalonil
(98.1% a.i., 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 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 a internet TOXNET search of 01/05/2006.

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 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 plant 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 plant 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

The usual triggers for a developmental neurotoxicity study (DNT) were
not observed in any study.  There was no neuropathology, 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 to 1X:  1) the hazard and exposure databases
are complete, 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 neurotoxic concerns. 
However, there is still some uncertainty concerning the toxicological
findings because both the chronic RfD and dose level of concern for
residential risk assessments are based on LOAELs not NOAELs.

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 chronic
dietary analysis incorporated monitoring data from the PDP and FDA
surveillance monitoring, %CT estimates provided by BEAD, and observed
processing factors.  Provided that RD ensures that the directions for
use of chlorothalonil on sod farms are modified to result in EDWCs of
<42 ppb, chronic exposures/risks will not be underestimated.  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 to 3X for chronic risk assessment but retained at 10X for
residential assessments.  As explained in section 3.5.3, the data from
the chronic toxicity study in rats show that a 3X factor in the chronic
risk assessment will be protective of infants and children despite the
lack of a NOAEL in that study. As to the residential risk assessment,
there is insufficient reliable data to conclude that a reduction of the
10X FQPA safety factor is safe for infants and children given the lack
of a NOAEL in the study upon which the residential risk assessment is
based.  The database do not support reduction 10X FQPA safety factor for
infants and children for residential exposure since the gastric lesions
were seen in other 90 day dietary study at doses around 3 mg/kg/day.  

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 3.5.1.  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 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 <0.9 mg/kg/day

UF = 300

Chronic RfD = 0.003 mg/kg/day	FQPA SF = 1X

cPAD = NOAEL/PAD SF

 = 0.003 mg/kg/day	Chronic toxicity - rat

LOAEL = 0.9 mg/kg/day based on an increased incidence and severity of
epithelial hyperplasia, hyperkeratosis and ulceration of the
non-glandular region of the stomach in females.

Short-Term 

(1-30 days) 

Incidental Oral 

	NOAEL < 30.8 mg/kg/day

	LOC = MOE = 1000

(residential/recreational; includes the FQPA SF = 1X)	2-Gen reproduction
- rat

LOAEL (offspring) = 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.

Intermediate-Term (1-6 months) Incidental Oral 	NOAEL < 30.8 mg/kg/day

	LOC = MOE = 1000

(residential/recreational; includes the FQPA SF = 1X)	2-Gen reproduction
- rat

LOAEL (offspring) = 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.

Short-Term 

(1-30 days) 

Dermal

	Quantification of dermal risk is not required.

Intermediate-Term (1-6 months) Dermal

	Quantification of dermal risk is not required.

Dermal 

Long-Term

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

Short-Term 

(1-30 days)

Inhalation	NOAEL < 30.8 mg/kg/day	LOC = MOE = 1000

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

LOC (occupational) = 1000

Inhalation absorption factor = 100%2	Reproduction - rat

LOAEL (offspring) = 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.

Intermediate-Term (1-6 months) Inhalation	NOAEL <30.8 mg/kg/day	LOC =
MOE = 1000

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

LOC (occupational) = 1000

Inhalation absorption factor = 100%2	Reproduction - rat

LOAEL (offspring) = 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.

Inhalation 

Long-Term

(>6 months)	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.

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 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
(grade1-2/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 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 (grade1-2/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.

3.5.3 cRfD

The cRfD was established based on the LOAEL from the chronic toxicity
study in the rat.  The LOAEL of 0.9 mg/kg/day is based on an increased
incidence and severity of epithelial hyperplasia, hyperkeratosis and
ulceration of the non-glandular region of the stomach in females. The
NOAEL was not established.  This LOAEL is lower than any NOAEL in the
database.  In addition, the study duration is appropriate for the
duration of exposure.  The uncertainty factors used in determining the
cRfD was 300 [10X for interspecies (animal-to-human) extrapolation; 10X
for intraspecies (human) variations; and 3X for use of a LOAEL instead
of a NOAEL].  The uncertainty factor of 3 for use of LOAEL instead of
the NOAEL is considered appropriate since an increased incidence and
severity of epithelial hyperplasia, hyperkeratosis and ulceration of the
non-glandular region of the stomach in females were seen in few animals
and were minimal in severity and observed in one sex only. 

3.5.4 Incidental Oral Exposure (Short and Intermediate Term)

The effects of concern that are relevant to the selection of the short-
and intermediate-term incidental oral doses are 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 of parental animals at the lowest dose tested;
i.e.; 30.8/34.3 mg/kg/day (M/F) in a 2-generation reproduction study in
rats.  Effects on the stomach were also seen in the offspring upon
necropsy shortly after weaning.  A NOAEL could not be established.  The
study length is appropriate for the durations of exposure, namely, 1-30
days (short-term) and 1-6 months (intermediate-term); and the LOAEL of
30.8 mg/kg/day is protective of the population of concern, namely,
infants and children.  A MOE of 1000 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 to assess short- and
intermediate-term dermal exposure scenarios since HED is using the
21-day dermal study in rats and 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.  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)

Repeated dose inhalation toxicity studies are not available in the
database.  The 2-generation reproduction study in rats was also chosen
for the short- and intermediate-term inhalation exposure scenarios (as
it was for the short- and intermediate-term incidental oral exposure
scenarios), because it is protective of potential adverse effects
following inhalation exposure of both adults and children.  The effects
of concern that are relevant to the selection of short-and
intermediate-term inhalation endpoints are 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 reported for parental animals at the lowest dose
tested; i.e., 30.8/34.3 mg/kg/day (M/F) in a 2-generation reproduction
study in rats.  The effects observed in the stomach of parents were also
observed in the stomach of offspring when the pups were necropsied
shortly after weaning.  A NOAEL could not be established.  Although the
route of exposure is not ideal, the study length is appropriate for the
durations of exposure.  Long-term exposures are not expected to occur. 
An MOE of 1000 is considered adequate for short- and intermediate-term
inhalation exposure scenarios.

3.5.8 Level of Concern for Margin of Exposure

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	1000a	1000a	-

Residential (Non-Dietary) Exposure

Oral	1000a	1000a	-

Dermal	-	-	-

Inhalation	1000a	1000a	-

a based on the conventional UF of 100X (10X for interspecies
extrapolation; 10X for intraspecies variation)  and 10X for use of a
LOAEL instead of a NOAEL.

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 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 the
Federal Insecticide, Fungicide, and Rodenticide Act (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). 

In a two-generation reproduction study in rats with chlorothalonil (new
data), at the high dose, balano-preputial skinfold cleavage of males was
delayed and vaginal opening was delayed compared to controls, suggesting
the possibility of endocrine mediated effects.  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
the lactation period.  This assertion is supported by the comparable
body weight at attainment of criterion in all treatment groups. 
Histopathological examinations of reproductive organs did not show
treatment-related effects.  Based on the available data, it can be
concluded that chlorothalonil does not cause endocrine disruption.

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 supplied acute toxicity data (870.1000-870.2000),
a 21/28-day dermal toxicity study (870.3200) or mutagenicity data in the
category “other genotoxic effects” (870.5500) to support food use.

4.0 EXPOSURE ASSESSMENT AND CHARACTERIZATION

4.1 Summary of Registered/Proposed Uses

Table 4.1.1 provides the proposed use pattern for edible-podded peas.  

Table 4.1.1.  Summary of Proposed Directions for Use of Chlorothalonil.

Applic. Timing, Type, 

Equipment.	Formulation	Applic. Rate 

(kg ai/ha)	Max. No. Applic. per Season	Max. Seasonal Applic. Rate

(kg ai/ha)	PHI

(days)

Edible-Podded Peas

Foliar broadcast (spray)	Use Directions and Limitations:  Reapply every
7 to 14 days, particularly during wet weather and periods of rapid
disease growth.

	Bravo 500	1.1-1.5	4	6.0	7

Conclusions.  The submitted labels are adequate to allow evaluation of
the residue data relative to the proposed use.

4.2 Dietary Exposure/Risk Pathway

The residue chemistry data submitted in support of the proposed
petitions were evaluated by ARIA on 9-FEB-2005 (Memo, J. R. Tomerlin,
D310791).  The drinking water assessment was completed by EFED (Memos,
L. Shanaman, 29-JUN-2006, D306584; and 01-SEP-2006, D328340).  The
dietary-exposure assessment was completed by HED (Memo, G. Kramer,
14-SEP-2006, D332540).

4.2.1 Residue Profile

Background

The Snowpea Commission of Guatemala, the Guatemala Ministry of
Agriculture, and Partnerships for Food Industry Development - Fruits and
Vegetables of Michigan State University, supported by technical data
provided by GB Biosciences of Greensboro, NC submitted Petition 3E6795
requesting that a tolerance of 5.0 ppm be established for residues of
chlorothalonil on edible-podded peas.  The tolerance is being sought
without a registered use in the U. S.

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).

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

At this time, there are no residue data for edible-podded peas. 
However, the proposed use pattern for the Bravo 500 formulation
corresponds to the current Bravo 500 label for snap beans.  Therefore,
residue data from snap bean field trials was used to support the
tolerance on edible-podded peas.  For purposes of the tolerance on
edible podded peas without a registered use in the U. S., residue data
from snap beans were used because of the similarities in use patterns.
It should be noted that the translation of snap bean residue data to
snow peas is approved only for this action for snow peas grown in
Guatemala (Minutes of 2/9/05 HED’s Chemistry Science Advisory Council
(ChemSAC) meeting).  The similarity in growth conditions of snap beans
and Guatemalan snow peas might not occur in other regions where snow
peas are grown, and the Agency is not approving the general translation
of snap bean data to snow peas.

Tolerance Summary

A summary of tolerance reassessment is presented in Table 4.2.1.1.   
SEQ CHAPTER \h \r 1 The CODEX MRL for common beans, podded is 5 ppm. 

Table 4.2.1.1.  Tolerance Summary for Chlorothalonil.

Commodity	Proposed Tolerance (ppm)	Recommended Tolerance (ppm)	Comments;

[Correct Commodity Definition]

Edible-podded peas	5	5.0	Pea, edible podded 

4.2.2 Dietary-Exposure Analyses

A chlorothalonil chronic dietary risk assessment was conducted using
DEEM-FCID™, Version 2.03, which incorporates consumption data from
USDA’s Continuing Surveys of Food Intakes by Individuals (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.

The DEEM-FCIDTM 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
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As stated above, for chronic assessments, HED is concerned when dietary
risk exceeds 100% of the cPAD.  The DEEM-FCID™ analyses estimate the
dietary exposure of the U.S. population and various population
subgroups.  The results reported in Table 3 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.  

The Tier 3, chronic dietary-exposure assessment was refined by making
use of monitoring data from the PDP and FDA surveillance monitoring, %CT
estimates provided by BEAD (J. Alsadek, 8/24/04), and processing factors
as tabulated in the RED for Chlorothalonil (Document # EPA 738-R-99-004,
April 1999).  Chlorothalonil chronic dietary (food only) 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 0.000099 mg/kg/day for the U.S. population (3% of the
cPAD) and 0.000238 mg/kg/day (8% of the cPAD) for children 1 to 2 years
old, the population subgroup with the highest estimated chronic dietary
exposure to chlorothalonil.  The estimated exposures/risks for combined
food only are summarized in Table 4.2.2.2.1 for all populations.  

corporated directly into the dietary assessment using the DEEM-FCID™
software.  EFED has provided Tier II estimated drinking water
concentrations (EDWCs) for use in drinking water assessments when
chlorothalonil is used according to registered labeling.  Because
monitoring data are unavailable, estimates of chlorothalonil and the
major degradate SDS-3701 concentrations were made only with mathematical
models.  The models Pesticide Root Zone Model/Exposure Analysis Modeling
System (PRZM/EXAMS) with regional percent crop area adjustment factors
were used to conduct surface water exposure assessments.  The highest
estimated surface water concentrations occurred with the PA turf (sod
farm) scenario.  Based on preliminary analyses, the maximum allowable
EDWC was estimated to be 42 ppb; i.e., a value of >42 ppb resulted in a
chronic dietary (food + water) risk which exceeded 100% of the chronic
population-adjusted dose (cPAD).  Other than turf (sod farms), all
registered uses result in EDWCs of <42 ppb. However, EFED has conducted
a sensitivity analysis on the effect of application rate and
re-application interval for sod farms on the EDWCs of chlorothalonil
total toxic residues in surface water (Memo, L. Shanaman, 01-SEP-2006,
D328340).  This sensitivity analysis identifies several scenarios that
result in water exposure below 42 ppb (i.e., reduction of the seasonal
application rate to 11 lbs. a.i./A (2 x 5.5 lbs. a.i./A) will result in
a maximum EDWC of 40 ppb).  Assuming that water exposure is no higher
than 42 ppb, chlorothalonil chronic dietary (food + water) exposure
estimates are below HED’s LOC for the U.S. population and each of the
population subgroups.  Dietary exposure was estimated at 0.000984
mg/kg/day for the U.S. population (33% of the cPAD) and 0.002967
mg/kg/day (99% of the cPAD) for all infants (<1 year old), the
population subgroup with the highest estimated chronic dietary exposure
to chlorothalonil.  The estimated exposures/risks for combined food and
water are summarized in Table 4.2.2.2.2 for all populations.

Table 4.2.2.2.1.  Summary of Chronic Dietary Exposure and Risk for
Chlorothalonil (Food Only).

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

	General U.S. Population	0.003	0.000099	3

All Infants (<1 year old)	0.003	0.000065	2

Children 1-2 years old	0.003	0.000238	8

Children 3-5 years old	0.003	0.000214	7

Children 6-12 years old	0.003	0.000146	5

Youth 13-19 years old	0.003	0.000094	3

Adults 20-49 years old	0.003	0.000083	3

Adults 50+ years old	0.003	0.000074	2

Females 13-49 years old	0.003	0.000073	2

Table 4.2.2.2.2.  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	0.003	0.000984	33

All Infants (<1 year old)	0.003	0.002967	99

Children 1-2 years old	0.003	0.001552	52

Children 3-5 years old	0.003	0.001445	49

Children 6-12 years old	0.003	0.000995	33

Youth 13-19 years old	0.003	0.000734	25

Adults 20-49 years old	0.003	0.000910	30

Adults 50+ years old	0.003	0.000943	31

Females 13-49 years old	0.003	0.000896	30

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.”  At that time, for
the purposes of risk assessment (RED, 1999) for chronic life-time
dietary non-cancer risk, the MOE was determined using the 1.5-mg/kg/day
dose as the “point of departure” as no tumor response or cell
proliferation response was observed at this dose level in the rodent
carcinogenicity studies.  Tumor response in the kidney as well as cell
proliferation was observed at the next higher dose level tested (15
mg/kg/day).  Currently, the MOE approach utilizes the current cPAD which
is based on a new chronic/carcinogenicity study that provides a lower
endpoint with a LOAEL of 0.9 mg/kg/day.  Therefore, the cPAD is
protective of any cancer and noncancer effects.

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.  

EFED has provided Tier II EDWCs for use in drinking water assessments
when chlorothalonil is used according to registered labeling.  Because
monitoring data are unavailable, estimates of chlorothalonil and the
major degradate SDS-3701 concentrations were made only with mathematical
models.  The models PRZM/EXAMS with regional percent crop area
adjustment factors were used to conduct surface water exposure
assessments.  EDWCs were generated for the total toxic residue which
includes parent chlorothalonil and the major degradate SDS-3701.  The
highest estimated surface water concentrations were associated with the
PA turf (sod farm) scenario.  Based on preliminary analyses, the maximum
allowable EDWC was estimated to be 42 ppb; i.e., a value of >42 ppb
resulted in a chronic dietary (food + water) risk which exceeded 100% of
the cPAD.  Other than turf (sod farms), all registered uses result in
EDWCs of <42 ppb (Memo, L. Shanaman, 29-JUN-2006, D306584; Tables 1f &
1h).  However, EFED has conducted a sensitivity analysis on the effect
of application rate and re-application interval for sod farms on the
EDWCs of chlorothalonil total toxic residues in surface water (Memo, L.
Shanaman, 01-SEP-2006, D328340).  This sensitivity analysis identifies
several scenarios that result in water exposure below 42 ppb (i.e.,
reduction of the seasonal application rate to 11 lbs. a.i./A (2 x 5.5
lbs. a.i./A) will result in a maximum EDWC of 40 ppb).

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.  RD should ensure that all turf labels prohibit use in
recreational areas (including, but not limited to, daycare centers,
playgrounds, parks, athletic fields, campgrounds, schools, churches,
etc.).  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.  According to RAB1 toxicologists,
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 an oral toxicity study.  A LOAEL of 30.8
mg/kg/day was used from a reproduction study based on thickening and/or
roughening of the forestomach with depressions in the epithelial aspect,
and hyperplasia and hyperkeratosis of the nonglandular epithelium of the
stomach.  An inhalation-absorption factor of 100% was used.  Inhalation
MOEs for all durations for occupational and residential handlers are
calculated as follows:

MOEI = (LOAELoral / Dose) = (30.8 mg/kg/day / Inhalation Exposure
(mg/kg/day))

HED’s LOC for chlorothalonil exposure is 1000 (i.e., a MOE less than
1000 exceeds HED’s LOC).  The LOC is based on 10X to account for
interspecies extrapolation to humans from the animal test species, 10X
to account for intraspecies sensitivity and 10X to account for the
uncertainty in using a LOAEL versus a NOAEL.  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 1000 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	79,000

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

0.048	2	0.507	0.0007	44,000

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

0.048	2	0.83	0.0011	27,000

Mixing/Loading/Applying Liquid Concentrates with a Paint Brush (PHED)
painting with latex exterior paint	0.096	2	0.284	0.00078	40,000

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

0.096	2	0.507	0.0014	22,000

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

0.096	2	0.83	0.0023	14,000

Mixing/Loading/Applying Liquid Concentrates with a Paint Brush (PHED)
painting with alkyd exterior paint	0.11	2	0.284	0.00089	35,000

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

0.11	2	0.507	0.0016	19,000

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

0.11	2	0.83	0.0026	12,000

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 LOAEL of 30.8
mg/kg/day was used from a reproduction study in rats based on thickening
and/or roughening of the forestomach with depressions in the epithelial
aspect, and hyperplasia and hyperkeratosis of the nonglandular
epithelium of the stomach.  

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.  HED believes that if a
toddler were to ingest paint chips, the exposure would most likely to be
“episodic”; that is, a one time occurrence that is not likely to be
repeated on a routine basis.

Short- and intermediate-term incidental oral MOEs for occupational and
residential handlers are calculated as follows:

Short- and Intermediate-term Oral MOE = LOAEL (30.8 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 (12,000) is greater
than the target MOE of 1000 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	12,000

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 (30.8 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 considered
background chronic dietary exposure (food + water) and short- and
intermediate-term inhalation or incidental oral exposures from the use
of treated paint.  However, as incidental oral exposure from treated
paint is considered to be episodic, only inhalation (see Table 4.4.1)
exposures 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 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),
the total short- and intermediate-term food and residential aggregate
MOE is 8600. As this MOE is greater than 1000, the short- and
intermediate-term aggregate risk does not exceed the HED’s LOC. Table
5.2.1 summarizes the short/intermediate-term aggregate exposure to
chlorothalonil residues.

Table 5.2.1.  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

General U.S. Population	30.8	1000	0.0308	0.000984	0.0026	8600

1 The target MOE is based on the10X for interspecies extrapolation; 10X
for intraspecies variations; and 10X for use of a LOAEL instead of a
NOAEL totaling 1000.

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

3 Residential Exposure = [Inhalation Exposure]

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

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 Office of Pesticide Programs 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

The proposed tolerance on edible podded peas is not associated with a
registered use in the U.S.  Therefore, an occupational exposure and risk
assessment is not necessary. 

8.0 DATA DEFICIENCIES / LABEL REVISIONS

The directions for use of chlorothalonil on sod farms should be modified
to result in EDWCs of <42 ppb.

All turf labels should be modified to prohibit use of chlorothalonil in
recreational areas.

cc: G. Kramer (RAB1), W. Greear (RAB1), K. Lowe (RAB1)

RDI: Branch (12/6/06); RAB1 Chemists (12/6/06); RAB1 Toxicologists
(1/31/06, 2/28/06, & 10/26/06)

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	no

no

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)

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Appendix 2. Toxicological Data Requirements (Old Data)

	

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

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

no

no

no	-

-

-

-

-

870.7485	General Metabolism

870.7600	Dermal Penetration	yes

no	yes

-

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#
337925

Page   PAGE  1  of   NUMPAGES  49 

Chlorothalonil	                       Human-Health Risk Assessment		DP#
327261

Page   PAGE  49  of   NUMPAGES  49