Document ID: EPA-HQ-OPP-2007-0020-0008
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2009-10-06T04:00Z

UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES, AND

TOXIC SUBSTANCES

MEMORANDUM

DATE:		20-NOV-2008

SUBJECT:	Thiram in/on Imported Bananas.  Human-Health Risk Assessment.  

PC Code:  079801	DP No.:  356570

Decision No.:  372408	Registration No.:  NA

Petition No.:  6E7144	Regulatory Action:  NA

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

TXR No.:  NA	CAS No.:  137-26-8

MRID No.:  NA	40 CFR:  §180.132

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

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

Registration Action Branch 1 (RAB1)

Health Effects Division (HED) (7509P)

THROUGH:	Dana M. Vogel, Branch Chief

				Robert Mitkus, Ph.D., Toxicologist

RAB1/HED (7509P)

TO:		Bryant Crowe/Tony Kish, PM Team 22

		Registration Division (RD) (7505P)

The HED of the Office of Pesticide Programs (OPP) is charged with
estimating the risk to human health from exposure to pesticides.  The RD
of OPP has requested that HED evaluate hazard and exposure data and
conduct dietary, residential, and aggregate exposure assessments, as
needed, to estimate the risk to human health that will result from the
registered uses and the proposed tolerance for residues of thiram, per
se, without a U.S. registration, in/on bananas.

A summary of the findings and an assessment of human-health risk
resulting from the proposed uses of thiram are provided in this
document.  The risk assessment, dietary-exposure assessment, and the
residue chemistry data review were provided by George Kramer (RAB1); and
the hazard characterization by William Greear (RAB1).



Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc214776867"  1.0  EXECUTIVE
SUMMARY	  PAGEREF _Toc214776867 \h  4  

  HYPERLINK \l "_Toc214776868"  2.0  PHYSICAL/CHEMICAL PROPERTIES
CHARACTERIZATION	  PAGEREF _Toc214776868 \h  8  

  HYPERLINK \l "_Toc214776869"  2.1  Identification of Active Ingredient
  PAGEREF _Toc214776869 \h  8  

  HYPERLINK \l "_Toc214776870"  2.2  Physical and Chemical Properties	 
PAGEREF _Toc214776870 \h  8  

  HYPERLINK \l "_Toc214776871"  3.0  HAZARD CHARACTERIZATION/ASSESSMENT	
 PAGEREF _Toc214776871 \h  9  

  HYPERLINK \l "_Toc214776872"  3.1  Hazard and Dose-Response
Characterization	  PAGEREF _Toc214776872 \h  9  

  HYPERLINK \l "_Toc214776873"  3.1.1  Database Summary	  PAGEREF
_Toc214776873 \h  9  

  HYPERLINK \l "_Toc214776874"  3.1.2  Toxicological Effects	  PAGEREF
_Toc214776874 \h  10  

  HYPERLINK \l "_Toc214776875"  3.2  Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc214776875 \h  12  

  HYPERLINK \l "_Toc214776876"  3.3  FQPA Considerations	  PAGEREF
_Toc214776876 \h  13  

  HYPERLINK \l "_Toc214776877"  3.3.1  Adequacy of the Toxicity Database
  PAGEREF _Toc214776877 \h  13  

  HYPERLINK \l "_Toc214776878"  3.3.2  Evidence of Neurotoxicity	 
PAGEREF _Toc214776878 \h  13  

  HYPERLINK \l "_Toc214776879"  3.3.3  Developmental Toxicity Studies	 
PAGEREF _Toc214776879 \h  17  

  HYPERLINK \l "_Toc214776880"  3.3.4. Reproductive Toxicity	  PAGEREF
_Toc214776880 \h  20  

  HYPERLINK \l "_Toc214776881"  3.3.5  Additional Information from
Literature Sources	  PAGEREF _Toc214776881 \h  23  

  HYPERLINK \l "_Toc214776882"  3.3.6  Pre-and/or Postnatal Toxicity	 
PAGEREF _Toc214776882 \h  24  

  HYPERLINK \l "_Toc214776883"  3.3.7  Recommendation for a DNT Study	 
PAGEREF _Toc214776883 \h  25  

  HYPERLINK \l "_Toc214776884"  3.4  FQPA SF for Infants and Children	 
PAGEREF _Toc214776884 \h  25  

  HYPERLINK \l "_Toc214776885"  3.5  Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc214776885 \h  25  

  HYPERLINK \l "_Toc214776886"  3.5.1  Acute Reference Dose (aRfD) –
Females 13-49	  PAGEREF _Toc214776886 \h  25  

  HYPERLINK \l "_Toc214776887"  3.5.2  aRfD – All Populations	 
PAGEREF _Toc214776887 \h  25  

  HYPERLINK \l "_Toc214776888"  3.5.3.  Chronic Reference Dose (cRfD)	 
PAGEREF _Toc214776888 \h  26  

  HYPERLINK \l "_Toc214776889"  3.5.4-5 Incidental Oral Exposure (Short-
and Intermediate-Term)	  PAGEREF _Toc214776889 \h  26  

  HYPERLINK \l "_Toc214776890"  3.5.6  Dermal Absorption	  PAGEREF
_Toc214776890 \h  26  

  HYPERLINK \l "_Toc214776891"  3.5.7-8  Dermal Exposure (Short- and
Intermediate-Term)	  PAGEREF _Toc214776891 \h  26  

  HYPERLINK \l "_Toc214776892"  3.5.9  Level of Concern for MOEs	 
PAGEREF _Toc214776892 \h  27  

  HYPERLINK \l "_Toc214776893"  3.5.10  Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc214776893 \h  27  

  HYPERLINK \l "_Toc214776894"  3.5.11  Classification of Carcinogenic
Potential	  PAGEREF _Toc214776894 \h  27  

  HYPERLINK \l "_Toc214776895"  3.5.12  Summary of Toxicological Doses
and Endpoints for Thiram for Use in Human Risk Assessments	  PAGEREF
_Toc214776895 \h  27  

  HYPERLINK \l "_Toc214776896"  3.6  Endocrine Disruption	  PAGEREF
_Toc214776896 \h  29  

  HYPERLINK \l "_Toc214776897"  3.7  Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc214776897 \h  29  

  HYPERLINK \l "_Toc214776898"  4.0  EXPOSURE ASSESSMENT AND
CHARACTERIZATION	  PAGEREF _Toc214776898 \h  30  

  HYPERLINK \l "_Toc214776899"  4.1  Summary of Registered/Proposed Uses
  PAGEREF _Toc214776899 \h  30  

  HYPERLINK \l "_Toc214776900"  4.2  Dietary Exposure/Risk Pathway	 
PAGEREF _Toc214776900 \h  30  

  HYPERLINK \l "_Toc214776901"  4.2.1  Residue Profile	  PAGEREF
_Toc214776901 \h  31  

  HYPERLINK \l "_Toc214776902"  4.2.2  Dietary-Exposure Analyses	 
PAGEREF _Toc214776902 \h  33  

  HYPERLINK \l "_Toc214776903"  4.3  Water Exposure/Risk Pathway	 
PAGEREF _Toc214776903 \h  36  

  HYPERLINK \l "_Toc214776904"  4.4  Residential Exposure/Risk Pathway	 
PAGEREF _Toc214776904 \h  36  

  HYPERLINK \l "_Toc214776905"  5.0  AGGREGATE-RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc214776905 \h  36  

  HYPERLINK \l "_Toc214776906"  5.1  Acute Aggregate Risk	  PAGEREF
_Toc214776906 \h  36  

  HYPERLINK \l "_Toc214776907"  5.2  Short-and Intermediate-Term
Aggregate Risk	  PAGEREF _Toc214776907 \h  37  

  HYPERLINK \l "_Toc214776908"  6.0  CUMULATIVE RISK	  PAGEREF
_Toc214776908 \h  37  

  HYPERLINK \l "_Toc214776909"  7.0  DATA DEFICIENCIES/LABEL REVISIONS	 
PAGEREF _Toc214776909 \h  38  

  HYPERLINK \l "_Toc214776910"  7.1  Toxicology	  PAGEREF _Toc214776910
\h  38  

  HYPERLINK \l "_Toc214776911"  7.2  Residue Chemistry	  PAGEREF
_Toc214776911 \h  38  

  HYPERLINK \l "_Toc214776912"  Appendix A:  Toxicology Assessment	 
PAGEREF _Toc214776912 \h  39  

  HYPERLINK \l "_Toc214776913"  A.1  Toxicology Data Requirements	 
PAGEREF _Toc214776913 \h  39  

  HYPERLINK \l "_Toc214776914"  A.2  Toxicity Profiles	  PAGEREF
_Toc214776914 \h  39  

 

1.0  EXECUTIVE SUMMARY

Thiram is a dimethyl dithiocarbamate fungicide used to prevent crop
damage in the field and to protect harvested crops (apples, peaches, and
strawberries) from deterioration in storage or transport.  It is also
used as a seed protectant (e.g., small-seeded vegetables, large-seeded
vegetables, cereal grains, other seeds, coniferous seeds, cotton seed,
ornamental seeds, and soybeans) and as a turf protectant from fungal
diseases.  Tolerances for residues in/on food and feed commodities are
currently expressed in terms of residues of thiram per se (40 CFR
§180.132) and are established at 7 ppm for apples, peaches, and
strawberries.  The Update to the Residue Chemistry Chapter of the Thiram
Reregistration Standard was issued on 7/25/91 and the Revised HED
Chapter of the Reregistration Eligibility Decision (RED) Document was
issued on 12/16/03 (F. Fort; D293295) with an Addendum issued 6/6/05 (F.
Fort; D303131).

Taminco Corporation requests the establishment of the following
tolerances for residues of thiram, per se, without a U.S. registration,
in/on the following raw agricultural commodities (RACs):

Whole bananas	0.5 ppm

Banana pulp	0.3 ppm

Thiram is proposed for use on bananas with a maximum of 10 foliar
applications per growing season at 1.26 kg ai/ha/application (1.12 lb
ai/A/application) with retreatment intervals (RTIs) of 4-10 days and a
preharvest interval (PHI) of 0 days.

Hazard Assessment

Thiram has a low to moderate acute toxicity profile (generally Toxicity
Category IV to II).  The currently available toxicological database for
thiram suggests that this chemical has the potential to be a significant
neurotoxicant (in adults and children) as well as a developmental and
reproductive toxicant.  A 1976 study in rats by Lee and Peters, supports
the idea that thiram is a significant neurotoxicant.  In that study,
rats exposed to thiram in their diet, showed significant signs of
neurotoxicity such as ataxia and paralysis of the hind legs along with
histopathology changes in the nervous system (demyelination, macrophage
infiltration of the nerve bundle in the sciatic nerve, etc.).  The
neurotoxic effects of thiram reported in other studies submitted to the
Agency by the registrant include lethargy, reduced tail-pinch response,
no tail-pinch response, reduced brain weights, and reduced motor
activity.  Severe fetal malformations including central nervous system
(CNS) defects (hydrocephalus), as well as protruding tongues, unilateral
renal agenesis, cleft palate, and reduced ossifications have been
reported after in utero exposure to thiram at dose levels that did not
cause maternal toxicity.  Finally, the chronic toxicity profile
indicates that hematology and clinical chemistry parameters as well as
the liver, and kidneys are affected after prolonged exposure to this
compound.  However, after consideration and analysis of the currently
available toxicity data, it has been determined that thiram can be
classified as “not likely to be carcinogenic to humans.”

Dose-Response Assessment

Based on the toxicity profile, HED has selected an endpoint based on
neurotoxicity obtained from the acute neurotoxicity study in rats for
use in the acute dietary risk assessment.  The endpoint selected for
chronic risk assessment is based on changes in hematology, clinical
chemistry, incidences of bile duct hyperplasia, and reduction in body
weight seen in a combined chronic toxicity/carcinogenicity study in rats
in conjunction with elevated cholesterol levels and increased relative
liver weight reported in the chronic oral toxicity study in dogs.  Since
thiram has been classified as a chemical “not likely to be
carcinogenic to humans,” no cancer risk assessment has been conducted.
 In the case of short/intermediate-term dermal exposure, the
developmental neurotoxicity study in rats was used to obtain the
endpoint (increases in motor activity seen in female offspring on PND
17) and dose (1.4 mg/kg/day) to be used in the risk assessment.  The
registered uses for thiram do not indicate long-term
occupational/residential inhalation or dermal exposures.  Consequently,
long-term risk assessment via the inhalation or dermal routes were not
conducted.  HED also selected endpoints for short- and intermediate-term
incidental oral exposure.  The endpoints were based on increases in
motor activity seen in female offspring seen in a developmental
neurotoxicity study. .

Food Quality Protection Act (FQPA) Decision

The thiram risk assessment team recommended that the 10X FQPA Safety
Factor (SF) for increased sensitivity to the offspring be reduced to 1X 
(see D303131, memorandum of F. Fort, dated June 6, 2005).  The 10X FQPA
SF was not retained due to the submission of an adequate
developmental-neurotoxicity study (DNT) study.  Based upon uncertainty
factors (UFs) for inter- and intra-species variation, the level of
concern for human-health risk assessment is 100 (margin of exposure
(MOE) = 100).  

Note that while the new 40 CFR revised Part 158 requirement for an
immunotoxicity study has not yet been fulfilled, the existing data are
sufficient for endpoint selection for exposure/risk assessment scenarios
and for evaluation of the requirements under FQPA.  Further, the data
requirement pertaining to this study (see Section 7.1) should be
fulfilled as a condition of registration.

Residential Exposure Estimates

Thiram is not available for sale or use by homeowner applicators. 
However, there is potential for residential exposure from treated golf
course greens and tees.  All thiram turf uses that would conceivably
lead to children’s exposure on treated turf have been cancelled by the
registrant and as such are no longer included in this assessment. 
Therefore, residential exposures resulting from dermal contact with
thiram-treated turf were assessed for adults.  Inhalation
postapplication exposures for golf courses were not assessed since
inhalation exposures are thought to be negligible in outdoor
postapplication scenarios.  When use is restricted to greens and tees,
the duration of exposure is 1 hour to reflect the anticipated time a
player would be spending in contact with those areas.  Risks are not of
concern on the day of application for golfers (i.e., MOEs >100 on day of
application).

Dietary Risk Estimates (Food + Water)

™), Version 2.03, software, acute dietary exposure at the 99.9th
exposure percentile is estimated at 0.021447 mg/kg/day for the general
U.S. population (43% of the aPAD) and 0.053321 mg/kg/day (107% of the
aPAD) for children 1-2 years old, the population subgroup with the
highest estimated acute dietary exposure to thiram. Fresh apples are the
largest contributor to overall dietary risk for children 1-2 years old
(52% of the aPAD); bananas contributed <0.5% of the aPAD.  Generally,
HED’s level of concern for acute dietary risk is 100% of the aPAD. 
However, HED does not consider the acute dietary risk for children 1-2
years old (107% of the aPAD) to be of concern because the residue
estimates in all foods were based on the results of field trials. 
Field-trial residues should exceed the residue levels found on food
commodities at the time of consumption.  When field trials are
performed, the maximum allowable application rate is used and crops are
harvested at the minimum PHI.  Samples are stored frozen until analysis
to ensure minimal degradation of residues.  In actual practice, however,
growers will not usually use the maximum application rates for economic
reasons.  In addition, most crops are not harvested and immediately
stored frozen.  For these reasons, HED is confident that this analysis
overestimates the actual risk.  

A conservative chronic dietary-exposure assessment was performed using
100% CT, average field-trial residues, and empirical processing factors.
 Dietary risk estimates were determined considering exposures from food
plus drinking water using EDWCs for surface water sources provided by
EFED.  The resulting chronic dietary risk estimates for food and water
combined are below HED’s level of concern (i.e., <100% of the chronic
population-adjusted dose (cPAD) of 0.015 mg/kg bw/day) for the overall
U.S. population and all population subgroups.  Using the DEEM-FCID™
software, dietary exposure is estimated at 0.001836 mg/kg/day for the
general U.S. population (12% of the cPAD) and 0.008502 mg/kg/day (57% of
the cPAD) for children 1-2 years old, the population subgroup with the
highest estimated chronic dietary exposure to thiram. 

Aggregate-Risk Estimates

Aggregate exposure risk assessments were assessed for the following
scenarios:  short- and intermediate-term (food + drinking water +
residential) and acute and chronic aggregate exposure (food + drinking
water).  Long-term and cancer aggregate-risk assessments were not
performed because there are no registered or proposed uses of thiram
which result in long-term residential exposures and thiram is considered
to be “not likely to be carcinogenic to humans,” respectively.

The total short- and intermediate-term food and residential aggregate
MOE is 580.  As this MOE is >100, the short- and intermediate-term
aggregate risk does not exceed the HED’s level of concern.  

Environmental-Justice Considerations

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

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

Review of Human Research

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

Recommendations for Tolerances/Registration

Pending submission of a revised Section F, there are no residue
chemistry or toxicological issues that would preclude establishing a
time-limited tolerance of 0.80 ppm for residues of thiram in/on banana.

HED recommends that conversion of the time-limited tolerance to
permanent tolerance may be considered upon submission of the following
outstanding residue chemistry and toxicology data:

Toxicology

Cholinesterase activity assessment screening assay.

Required as a result of the revisions of 40 CFR §158:

Guideline immunotoxicity study.

Residue Chemistry

860.1340 Residue Analytical Methods

Revision of enforcement method A7193 to address the comments from the
Analytical Chemistry Branch (ACB) (Memo, C. Stafford, D353875;
10/23/08).

860.1360 Multiresidue Methods

The requirement for multiresidue method testing of thiram remains
unfulfilled.  

860.1500 Crop Field Trials

HED requests that the petitioner conduct an additional 3 trials (1 each
in Guatemala, Colombia, and Honduras).  

860.1550 Proposed Tolerances

HED recommends a tolerance level of 0.80 ppm for banana.  Banana pulp is
not listed in Table 1 of OPPTS 860.1000; therefore, this entry should be
removed from the Section F. 

2.0  PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION

2.1  Identification of Active Ingredient

Common name	Thiram

IUPAC name	tetramethylthiuram disulfide

CAS name	tetramethylthioperoxydicarbonic diamide

CAS registry number	137-26-8

End-use products (EPs) used in residue field study 	Banguard 42 PLUS
(37.0% ai SC) or Banguard 60 (52.6% ai SC)

2.2  Physical and Chemical Properties

TABLE 2.	Physicochemical Properties of the Technical Grade of Thiram.

Parameter	Value	Reference

Melting range	142-150ºC	Revised Thiram Product and Residue Chemistry
Chapters for the RED Document, 12/16/03.

Density	0.32-0.35 g/mL

	Water solubility at 20-25ºC	0.00165 g/100 mL

	Solvent solubility at 20-25ºC	petroleum ether (0.0005 g/100 mL),
benzene (4.12 g/100 mL), acetone (6.97 g/100 mL), xylene (0.91 g/100
mL), and methanol (0.184 g/100 mL)

	Vapor pressure	1.6-1.8 x 10-5 Torr at 25°C

	Dissociation constant, pKa	Not applicable

	Octanol/water partition coefficient, POW	39.5-54.1

	

3.0  HAZARD CHARACTERIZATION/ASSESSMENT

3.1  Hazard and Dose-Response Characterization

3.1.1  Database Summary

Thiram is a dimethyl dithiocarbamate compound used as a fungicide to
prevent crop damage in the field and to protect harvested crops (apples,
peaches, and strawberries) from deterioration in storage or transport. 
It is also used as a seed protectant (e.g., small-seeded vegetables,
large seeded vegetables, cereal grains, other seeds, coniferous seeds,
cotton seed, ornamental seeds, and soybeans) and to protect turf from
fungal diseases.  In addition, thiram is used as an animal repellent to
protect crops from damage by rabbits, rodents, and deer. 

 

3.1.1.1  Studies Available and Considered (animal, human, general
literature)

Acute toxicity – oral, dermal, inhalation, eye irritation, skin
irritation, skin sensitization.

Subchronic toxicity – 21-day dermal toxicity in rabbit, oral 90-day
rat, oral 90-day dog.

Chronic toxicity - chronic oral dog, chronic toxicity/carcinogenicity
rat, carcinogenicity mouse.

Reproductive/developmental toxicity - oral developmental rat, oral
developmental rabbit, rat reproduction/fertility.

Neurotoxicity - acute neurotoxicity rat, subchronic neurotoxicity rat,
DNT rat.

Mutagenicity- in vitro mouse lymphoma gene mutation, in vitro mammalian
cytogenetics (chromosomal aberration assay in V79 cells), erythrocyte
micronucleus assay in mice, unscheduled DNA synthesis (UDS).

3.1.1.2  Mode-of-Action, Metabolism, and Toxicokinetic Data

Thiram is a dimethyl dithiocarbamate compound used as a fungicide. 
Thiram and other dithiocarbamates are metabolic poisons.  Their acute
toxic effects are largely similar to those of carbon disulfide,
supporting the conclusion that the common metabolite of these compounds
is responsible for their toxicity.  The exact mode of action of thiram
is unclear; it involves intracellular action of metabolites of carbon
disulfide, causing microsome injury and cytochrome P-450 injury
accompanied by increased heme-oxygenase activity.  A wide variety of
factors including monoamine-oxidase inhibition, abnormal vitamin B6 and
tryptophan metabolisms, and cellular deprivation of zinc and copper have
been cited as causes of the subcellular injuries. In contrast to carbon
disulfide, thiram also causes thyroid dysfunctions in vertebrates.  This
effect is thought to be a result of metabolic release of atomic sulfur
in the follicular cells, causing inhibition of tyrosine iodination and
ultimately hormone synthesis.  A single dose of thiram causes a
transient dysfunction; repeated doses can cause goiters.  Other cellular
enzymes may be similarly affected.  Thiram induces an alcohol
intolerance similar to that of Antabuse (disulfiram) either by
inhibiting acetaldehyde dehydrogenase or through the formation of a
quaternary compound with the ethanol.

3.1.1.3  Sufficiency of Studies/Data

The toxicity database is complete for thiram for risk assessment
evaluations and determination of FQPA.  

3.1.2  Toxicological Effects

Thiram is a neurotoxicant which can also act as a developmental
toxicant.  The neurotoxic effects of thiram include lethargy, reduced
tail-pinch response, no tail-pinch response, reduced brain weights, and
reduced motor activity.  Severe fetal malformations including CNS
defects (hydrocephalus), as well as protruding tongues, unilateral renal
agenesis, cleft palate, and reduced ossifications have been reported
after in utero exposure to thiram at dose levels that did not cause
maternal toxicity.

A DNT study has recently been conducted to provide further understanding
of the impact thiram exposure may have on the developing nervous system.
 The HED Hazard Identification Assessment Review Committee (HIARC) has
also recommended submission of a cholinesterase activity assessment
screening assay based on concerns for potential cholinesterase activity
inhibition by thiram as was seen in a structurally related
dithiocarbamate.  

Thiram has a low to moderate acute toxicity profile; the acute oral LD50
= 2.6 g/kg bw and the acute dermal LD50 (2.0 g/kg bw (Toxicity Category
III).  In an acute inhalation study, the LC50 for thiram was established
at (0.1 mg/L (the most concentrated suspension that could be nebulized).
 As a result, thiram is considered to be a Toxicity Category II chemical
via the inhalation route (i.e., moderately toxic).  Thiram is a moderate
eye irritant (Toxicity Category II), a slight dermal irritant (Toxicity
Category IV), and a moderate skin sensitizer.

The subchronic toxicity profile for thiram indicates that hematology,
clinical chemistry, and body weight are the parameters affected after
subchronic exposure to the compound for all species evaluated. 

The chronic toxicity profile for thiram indicates that the liver, blood
and urinary system are the target organs for this chemical.  In a
combined chronic/oncogenicity study in rats, effects were seen at a dose
level of 7.3 and 8.9 mg/kg/day for males and females, respectively.  The
effects described at these dose levels included changes in hematology
parameters, increased incidence of bile duct hyperplasia, and reduction
in body-weight gain.  At higher doses in this study, the severity of the
toxicity described above was increased and other signs of toxicity such
as an increased incidence in extramedullary hematopoiesis of the liver,
and changes in clinical chemistry parameters were reported.  In a
chronic oral toxicity study in dogs, effects were seen at doses >2.61
mg/kg/day.  Toxicity at this dose level was manifested as elevated
cholesterol levels and increases in liver-to-body weight ratio.  At
higher dose levels, the signs of toxicity were more severe.  Signs of
toxicity in a carcinogenicity study in mice were first reported at a
dose level of 24 mg/kg/day for males and included decreases in
body-weight gain, anemia, as well as non-neoplastic lesions in the eyes,
non-glandular stomach and urinary bladder.  At higher doses, the
severity of these signs of toxicity was greater.  In addition, decreases
in RBC counts, hemoglobin, and hematocrit levels, as well as increased
hemosiderin in the spleen, were seen at the higher doses.

The severity of developmental toxicity in the thiram database varied
considerably.  In one developmental toxicity study using Wistar rats,
severe fetal malformations including CNS defects (hydrocephalus) as well
as protruding tongues, unilateral renal agenesis, cleft palate, and
reduced ossification were reported at doses as low as 12.5 mg/kg/day
which was the no-observed adverse-effect level (NOAEL) for maternal
toxicity.  This study was classified unacceptable/guideline and could
not be upgraded.  In a subsequent developmental toxicity study using
Sprague-Dawley rats, the evidence of developmental toxicity was not as
severe (retarded growth, reduced ossification, and a rudimentary 13th
rib).  Furthermore, a developmental NOAEL of 7.5 mg/kg/day was
established in this latter study.  The potential impact of thiram
exposure on development in rabbits was examined in three studies [1
range-finding study, 2 definitive studies].  Independently, none of
these studies is acceptable for regulatory purposes.  However, when
considered as a group, they provide sufficient information to assess the
potential developmental toxicity of the test substance in rabbits.  The
results of these studies showed no developmental toxicity in rabbits in
the absence of maternal toxicity.  While maternal weight loss and
decreased fetal weights were reported at the 10 mg/kg/day dose in the
range-finding study, in the definitive study no maternal or
developmental effects were noted at this dose level (highest dose
tested; HDT).  However, at the HDT in the range-finding study (20
mg/kg/day), maternal death and complete litter loss were seen.

In addition to the studies submitted to the Agency, the International
Agency for Research on Cancer (IARC) profile for thiram (1991) provides
further evidence of thiram’s potential to act as a developmental
toxicant.  This report cites embryo lethality and embryotoxicity in rats
and hamsters and malformations in mice and hamsters.  Furthermore, in a
developmental toxicity study by Robens (1969), treatment at a dose level
of 100 mg/kg resulted in CNS malformations (exencephaly) thus providing
additional evidence of thiram’s potential for developmental toxicity.

While severe developmental effects were noted in a guideline, albeit
unacceptable, study in rats and in the published literature, effects
noted in the acceptable/guideline studies were less severe (reduced
ossification and rudimentary 13th rib), occurred at doses where maternal
toxicity was evident, or in the case of rabbits occurred at maternally
lethal doses.  Consequently, no quantitative or qualitative
susceptibility was noted in the acceptable/guideline developmental
toxicity studies submitted to the Agency for review.

Similarly, the results of two multigeneration reproduction toxicity
studies in rats did not reveal increased susceptibility of the young
after in utero and perinatal exposure to thiram.  In both studies, the
effects noted at the lowest-observed adverse-effect level (LOAEL) in the
offspring and parental animals were limited to decreases in body weight
and/or body-weight gain.  It is noteworthy, however, that although
reproductive parameters were not affected in the two guideline
multigeneration reproduction toxicity studies in rats, a 1996 study by
Stoker, et al. suggests that thiram may act as an endocrine disruptor by
interfering with the proestrus surge of lutenizing hormone.  

The mutagenicity database for thiram suggests that this chemical is a
clastogen.  It does not, however, induce unscheduled DNA synthesis nor
does it increase the mutation frequency at the HPRT locus.

The thiram database contains two acute neurotoxicity studies, one
subchronic neurotoxicity and one developmental toxicity study.  All four
of these studies provide evidence that this chemical has the potential
to be a significant neurotoxicant in adults.  In the acute neurotoxicity
studies in rats, functional-observational battery (FOB) effects such as
lethargy, lower temperature, reduced startle response, and no tail-pinch
response were reported as well as reduced motor activity, and decreased
brain weights.  Reduced motor activity was observed at 3½ hours, and 7
and 14 days after treatment with the test article suggesting that
thiram’s effects on the nervous system were not readily reversed.  In
the subchronic neurotoxicity study, rats exposed to thiram in their diet
exhibited a statistically significant increase in the incidence of
rearing events and hyperactivity in females and males; with the females
being affected at a lower dose level than males.  A statistically
significant decrease in body weight in both males and females was also
observed.  In a DNT study, thiram at the high-dose level increased the
incidence of slightly drooping eyes and moderate tremors in dams.  In
the open field, the mean activity count and the mean rearing count were
decreased in the high-dose dams.  A dose-related decrease in food
consumption occurred in all treated groups.  During pre-weaning, pup
body weight and body-weight gain were decreased at the high dose.  These
decreases were sustained during the post-weaning period.  The mean score
for surface righting reflex for male pups was increased at the high
dose, with one high-dose male failing the test.  The rearing count was
increased in male and female pups.  Flattened gait was noted for males
and females in the high-dose group.  Locomotor activity was increased in
males at the 90-ppm dose and in females at dose levels (45 ppm.  In
females, the increase in locomotor activity was seen in conjunction to
impaired habituation.  The auditory startle was decreased in males by
15-25% at the HDT.  Pre-pulse inhibition was also decreased at this dose
level.  In the Morris water maze, males and females from the high-dose
group had longer swimming times and greater number of sector entries
during the postnatal day (PND) 23/24 and PND 61/62 testing,
respectively.  During the PND 21 morphometric evaluation, a 7% increase
was observed in the hippocampus of males and in the neocortex of females
at the HDT.  

Further evidence of the potential neurotoxicant properties of thiram is
provided in the open literature.  A 1976 study in rats by Lee and Peters
supports the idea that thiram is a significant neurotoxicant at dose
levels of 65.8-66.9 mg/kg/day and higher in females.  In that study,
Charles River CD rats exposed to thiram in their diet, showed
significant signs of neurotoxicity such as ataxia and paralysis of the
hind legs along with histopathology changes in the nervous system
(demyelination, macrophage infiltration of the nerve bundle in the
sciatic nerve, etc.).  

There is no information in the submitted toxicology studies on thiram
that would indicate thiram was immunotoxic.

The HIARC has recommended submission of a cholinesterase activity
assessment screening assay based on concerns for potential
cholinesterase activity inhibition by thiram as was seen in ziram, a
structurally related dithiocarbamate. 

3.2  Absorption, Distribution, Metabolism, Excretion (ADME)

Thiram is readily absorbed (via the oral route), distributed,
extensively metabolized and eliminated primarily in the expired air and
urine of rats following single or repeated oral administrations.  Within
24 hours of administration of the compound, a high amount of
radioactivity was eliminated as expired air (14CO2, carbamyl sulfide,
and carbon disulfide).  The parent compound was not detected in the
urine. Fecal metabolites were not evaluated due to the low recovery of
radioactivity in the feces.  There is no apparent sex- or dose-related
difference in the distribution, metabolism, or excretion of 14C-thiram. 
Bioaccumulation of 14C-thiram in tissues was low (1.54-4.24% of the
administered dose).  Therefore, an appreciable accumulation of thiram is
not anticipated after repeated exposures.

3.3  FQPA Considerations

The thiram risk assessment team recommended that the 10X FQPA SF for
increased sensitivity to the offspring be reduced to 1X (see D303131,
memorandum of F. Fort, dated June 6, 2005).  The 10X FQPA SF was not
retained due to the submission of an adequate DNT study.  Based upon UFs
for inter- and intra-species variation, the level of concern for
human-health risk assessment is 100 (MOE = 100).  

Note that while the new 40 CFR revised Part 158 requirement for an
immunotoxicity study has not yet been fulfilled, the existing data are
sufficient for endpoint selection for exposure/risk assessment scenarios
and for evaluation of the requirements under FQPA.  Further, the data
requirement pertaining to this study (see Section 7.1) should be
fulfilled as a condition of registration.

3.3.1  Adequacy of the Toxicity Database

The toxicology database for thiram is adequate for evaluation of FQPA. 
The following acceptable studies are available:

Developmental toxicity study in rats

Developmental toxicity study in rabbits

Two-generation reproduction study in rats

DNT study in rats

3.3.2  Evidence of Neurotoxicity

Acute Neurotoxicity 

(a) Groups of 15 Sprague-Dawley rats/sex/dose were orally gavaged at 0,
5, 150, and 600 mg/kg, and were subsequently evaluated in FOB effects at
2 hours, 7 and 14 days, and motor function observations at 3 hours, 7
and 15 days.  FOB effects occurred at the two highest dose levels (150
and 600 mg/kg) 2 hours post-dosing.  More of the animals in those dose
groups were asleep relative to controls, and other findings (reduced
mean body weight, reduced temperatures, reduced startle response, more
animals showing no tail-pinch response) suggest lethargy.  Females were
more affected than males.  FOB findings at 7 and 14 days indicated
nothing remarkable.  Males and females of the two highest groups showed
reduced (usually significantly so) mean motor activities at 3 hours, and
7 and 14 days.  Absolute mean brain weights in 150- and 600-mg/kg males
were significantly decreased relative to their controls, (3.64 and 3.48%
lower for the 150- and 600-mg/kg groups, respectively).  Mean brain
weights for females in the two highest dose groups were also lower than
those of their controls, (3.65 and 3.26% lower for the 150- and
600-mg/kg groups, respectively, similar to what was observed in the male
groups), but there was apparently no statistical significance.  There
were no indications of any other adverse neuropathological effects in
the brains or in any of the central or peripheral nervous system tissue
which were examined following sacrifice.  The NOAEL for neurotoxicity is
5 mg/kg; the LOAEL (FOB effects at 2 hours post-dosing; reduced motor
activity at 3 hours, and at 7 and 14 days post-treatment) is 150 mg/kg.

(b) In a second acute neurotoxicity study (MRID 45589101), 5 groups of
Alpk:APfSD (Wistar derived) rats (10/sex/dose) were given a single oral
dose (by gavage) of thiram technical (98.7% a.i., batch no.:
V777R/G9605676) in corn oil at doses of 0, 10, 25, 60, or 150 mg/kg bw
and observed for 14 days.  Motor activity testing was performed on 10
rats/sex/dose 2.5 hours after dosing (day 1) and on days 8 and 15 of the
study period.  FOB evaluations were not conducted.  Cage-side
observations were conducted at least once daily with detailed clinical
examinations conducted on study days 1 (day of dosing), 8, and 15 (study
termination).  In addition, body weights and food consumption
assessments were conducted 1 week prior to study initiation, and on days
1 (prior to dosing and 2.5 hours post-dosing), 8, and 15 (end of study
period).  Cholinesterase activity was not determined.  At study
termination, all animals were euthanized, subjected to a gross necropsy
examination and the brains were weighed.  No neuropathology or
histopathology examinations were conducted. 

Mortality, clinical signs, brain weights, and gross necropsy parameters
were unaffected by treatment with the test article.  Males and females
exhibited minimal body-weight decreases at the 60 mg/kg bw dose level
(13-5% and 13-6%, respectively) on days 8 and 15 of the study period. 
Body-weight decreases reported at the 150 mg/kg/day dose level ranged
from 6-9% in males and 3-5% in females on days 8 and 15 of the study. 
Statistically significant and dose-dependent decreases in body-weight
gain were reported in males at dose levels ≥60 mg/kg bw on days 1-8
(121-28%, p ≤0.01) and days 1-15 (110-15%, p ≤0.05).  These
decreases occurred in conjunction with statistically significant (p =
0.01) decreases in food consumption during the first week of the study
period.  In males, 20% and 27% decreases in food consumption were noted
at the 60- and 150-mg/kg dose level, respectively.  Thiram exposure
elicited statistically significant (p ≤0.01) decreases in food
consumption in females at 25, 60, and 150 mg/kg (115, 18, and 22%,
respectively).  No decreases in food consumption were noted at the
10-mg/kg dose level or during the second week of the study period. 
Overall motor activity of females in the 150-mg/kg dose group (HDT) was
statistically significantly (p ≤0.05) decreased 2.5 hours post-dosing
and on days 8 and 15 of the study (44, 31, and 41% decreases,
respectively).  In males, motor activity was not affected by exposure to
the test compound.  Based on the limited data available in this study,
the NOAEL is set at 10 mg/kg and the LOAEL is established at 25 mg/kg
based on decreases in food consumption in males and females.

Independently, this neurotoxicity study is classified as
unacceptable/non-guideline and does not satisfy the guideline
requirement for an acute neurotoxicity study in rats (870.6200; OECD
424). Even when considered in conjunction with a previously submitted
acceptable/guideline study (MRID 42912401), this study does not provide
sufficient reliable data to warrant upgrading to an
acceptable/non-guideline status since FOB parameters (used as one of the
basis for the LOAEL in the guideline study) were not evaluated in this
study.

Subchronic Neurotoxicity Study 

In the subchronic neurotoxicity study in rats (MRID 43012701), 15
Sprague-Dawley rats/sex/dose were exposed to thiram technical (98.76%
a.i.) in their diet at doses of 0, 30, 125, or 500 ppm (0, 1.74, 7.26,
and 28.63 mg/kg/day for males and 0, 2.04, 8.07, and 31.82 mg/kg/day for
females).  A statistically significant decrease in weight gain in both
males and females (3 3.5% and 35.2%, respectively) was observed at
500-ppm (28.63 mg/kg/day) dose level.  This is consistent with the
concomitant decrease in food consumption observed at this dose level.

FOB observations revealed an increased incidence of hyperactivity along
with significantly increased occurrences of rearing events in males (at
weeks 8 and 13 of the study) treated at the 500-ppm (28.63 mg/kg/day)
dose level.  Similar observations were made on females starting at the
125-ppm (8.07 mg/kg/day) and higher dose levels.  Necropsy and
histopathology examinations of the 500-ppm animals revealed no
compound-related abnormalities.

The neurotoxicity LOAEL is 125 ppm (8.07 mg/kg/day), based on increased
numbers of rearing events and elevated incidences of hyperactivity in
females at weeks 8 and 13.  The NOAEL is 30 ppm (2.04 mg/kg/day) for
females, and 125 ppm (7.26 mg/kg/day) for males.

DNT Study

In a DNT study (MRID 46455201), thiram technical (99.6% a.i., batch #
G410050392) was administered to 24 female Crl:CD® (SD)BR IGS rats/dose
in the diet at concentrations of 0, 20, 45 or 90 ppm from gestation day
(GD) 3 through PND 20.  The average daily test article intake was 0,
1.4, 3.7, and 7.2 mg/kg/day from GD 3 through GD19 (based on analytical
data).  A FOB was performed on 10 dams/dose on GDs 12 and 18, and on
lactation days 4, 11, and 20.  On PND 4, litters were culled to yield
five males and five females (as closely as possible).  Offspring
representing at least 20 litters/dose were allocated for detailed
clinical observations (FOB), assessment of motor activity, assessment of
auditory startle response, habituation, assessment of auditory startle
pre-pulse inhibition, assessment of learning and memory, and
neuropathology at study termination (day 65 of age).  On PND 21, the
whole brain was collected from 10 pups/sex/dietary level for
micropathologic examination and morphometric analysis.  Pup sexual
maturation was assessed by age at vaginal opening for females and at
completion of balano-preputial separation for males.

All dams survived to scheduled termination.  Pale skin was observed in
eight high-dose dams during the second and third weeks of lactation. 
Three of these animals showed pale eyes and two had irregular
respiration.  During in-hand observations of the FOB, 4/12 high-dose
females showed pallor on PND 20; three of these animals had cold
extremities or were cold to the touch. Also noted at this dose level was
an increased incidence of slightly drooping eyes and moderate tremors
(4/12 each vs. 0 control) on PND 20.  In the open field on PND 20, for
the control, low-, mid-, and high-dose groups, the mean activity count
was 14.8±8.2, 10.2±4.0, 12.4±6.3, and 8.8±6.9 (p (0.05),
respectively, and the mean rearing count was 7.8±5.7, 6.0±5.0,
7.7±5.0, and 4.4±3.6, respectively.  Clinical signs noted at the
high-dose in dams during the exposure period consisted primarily of
effects on palpebral closure and tremors.  While the control animals
exhibited no clinical signs of toxicity on PND 11, 3/12 dams had
half-closed or closed eyes and 3/12 experienced slight tremors at the
high dose.  Similarly, on PND 20, 6/12 high-dose dams had either
drooping, half-closed, or closed eyes and 4/12 had moderate tremors vs.
0 incidences of these effects in controls.

Body weight of the high-dose dams was significantly less (p (0.01;
94-96% of controls) than that of controls on GDs 6-20 and lactation days
1 and 7-14.  Cumulative weight gain by the high-dose group was 8% and
83% (both p (0.01) of the control levels during GDs 3-6 and GDs 3-20,
respectively.  For the mid-dose group, body-weight gain was 75% (p
(0.05) of the control level for GDs 3-6, but was similar to the controls
thereafter.  During lactation, body-weight gain was not affected by
treatment in any group.  A dose-related decrease in food consumption
occurred in all treated groups on GD 3, the first day animals were
presented with the treated food.  No effects on food consumption were
observed in the low- and mid-dose groups during the remainder of
gestation.  Food consumption by the high-dose group was 69% and 83%
(both p (0.01) of the control level for GDs 3 and 4, respectively, was
(90% of the control level during GDs 5-16, and was 76-87% of the control
level for GDs 17-19.  Food consumption was similar between the treated
and control groups during lactation.  At maternal necropsy, findings in
the high-dose group included enlarged spleen (6/24), pale liver (3/24)
and kidneys (2/24), congested mesenteric lymph nodes (4/24), and dark
contents in the lower gastro-intestinal tract (5/24).  None of these
findings was seen in animals from the control, low-, or mid-dose groups.
 Mean brain weight was similar between the treated and control groups.  

The maternal systemic and neurotoxicity LOAEL for thiram in rats is 90
ppm in the diet (7.2 mg/kg/day) based on decreased body weight,
body-weight gain, and food consumption, clinical signs of toxicity, and
FOB findings.  The maternal NOAEL is 45 ppm (3.7 mg/kg/day).

No treatment-related effect on the number of litters, live litter size,
sex ratio, live birth, viability, or lactation indices was observed.  No
dam had total litter loss.  No treatment-related clinical signs of
toxicity were observed in the offspring during lactation or during the
post-weaning period.

During pre-weaning, pup body weight and body-weight gain were decreased
((6-13% and 14%, respectively) at the high dose.  These decreases were
sustained during the post-weaning period and were considered
toxicologically relevant.  In contrast, the decreases in pup body weight
and weight gain seen at the mid-dose (((7%) were not sustained during
the post-weaning period (((4%) and were not considered sufficiently
robust to be toxicologically relevant.  No differences in the mean day
to preputial separation for males or vaginal opening for females were
observed between the treated and control groups.  No treatment-related
effects were found during in-hand observations of offspring on any test
day (PND 35, 45, or 60).  On PND 4, no differences were seen between
pups in the treated and control groups on performance in the open arena.
 On PND 11, the mean score for surface righting reflex for male pups in
the control, low-, mid-, and high-dose groups was 1.0, 1.1, 1.2, and
1.5, respectively, with one high-dose male failing the test. No effects
on surface-righting reflex were observed in females.  On PND 21, rearing
count for the control, low-, mid-, and high-dose groups was 3.3, 3.8,
2.9, and 4.8, respectively, for males, and 2.6, 3.3, 3.8, and 4.9,
respectively, for females.  On PND 21, two females from the high-dose
group were observed with occasional chewing movements.  Flattened gait
was noted for 2, 3, 5, and 4 males in the control, low-, mid-, and
high-dose groups, respectively, on PND 60.  No treatment-related effects
were noted in the open arena on PNDs 35 or 45. 

Locomotor activity was increased in males on PND 13 ((73%) at the 90-ppm
dose and in females on PND 17 at dose levels (45 ppm ((46-60%).  While
an increase was also noted in males at the 45 ppm dose level, the
toxicological relevance of the effect was considered equivocal due to
the high variability (CV = 47%) which was comparable to the magnitude of
the change observed ((43%).  In females, the increase in locomotor
activity was seen in conjunction to impaired habituation as evidenced by
the observation that locomotor activity was higher during the last
sub-sessions than it was during the first sub-sessions.  Motor activity
was unaffected at other time periods.

On PND 23/24 and 61/62, auditory startle was decreased in males by
15-25% at the HDT.  Pre-pulse inhibition was also decreased at this dose
level (19.1 ± 8.2% vs. 31.5 ± 10.8% in control).  Auditory startle and
pre-pulse inhibition were unaffected in females.

In the Morris water maze, males and females from the high-dose group had
longer swimming times and greater number of sector entries during the
PND 23/24 and PND 61/62 testing, respectively.  No other
treatment-related effects on learning and memory were observed in males
or females.

During the PND 21 morphometric evaluation, a 7% increase was observed in
the hippocampus of males and in the neocortex of females at the HDT. 
These effects are considered compound-related and toxicologically
relevant.  Consequently, it is requested that measures for these brain
regions at the low- and mid-dose be submitted to the Agency for
evaluation.

The offspring systemic and neurotoxicity LOAEL for thiram in rats is 45
ppm in the diet (3.7 mg/kg/day) based on increased locomotor activity in
females on PND 17.  The offspring NOAEL is 20 ppm (1.4 mg/kg/day).

A developmental study in Wistar rats (MRID 00259810) revealed severe
fetal malformations including CNS defects (hydrocephalus) as well as
protruding tongues, unilateral renal agenesis, cleft palate, and reduced
ossification.

3.3.3  Developmental Toxicity Studies

Rat  

(a) In a developmental toxicity study (MRID No: 00259810), groups of
pregnant Wistar rats (26/dose) were given thiram technical (99.5% a.i.)
in 0.5% methyl cellulose (by gavage) at dose levels of 12.5, 25, 50, and
100 mg/kg bw from days 6 through 15 of gestation.  The test article was
administered at a volume of 2.5 mL/kg body weight.  Seventy eight
pregnant rats were divided into 3 groups (26/group) receiving either 250
mg/kg aspirin, 0.9% NaC1, or 0.5% MC4 and used as controls.

Maternal signs of toxicity observed on animals treated with 50 or 100
mg/kg/day of the test article included lethargy, rough hair coat, nasal
bleeding, and periocular incrustation.  A dose-dependent and
statistically significant reduction in body-weight gain was reported in
animals at the 25-, 50-, and 100-mg/kg/day dose groups.  In fact, dams
in the 100-mg/kg/day dose group lost weight during the dosing period GD
6-15.  These observations were consistent with the statistically
significant decrease in food consumption reported at these dose levels. 
Animals in the 12.5-, 50-, and 100-mg/kg/day dose groups continued to
exhibit lower food intake that persisted until the end of the study
period.  Three animals died during the study period.  These deaths,
however, were considered incidental and not compound-related.  All
animals were sacrificed at the end of the study period.  Gross necropsy
examination revealed no abnormalities. 

Based on reduced body-weight gains and food consumption observed at the
25-mg/kg dose level and higher, the maternal NOAEL is 12.5 mg/kg/day. 
The LOAEL for maternal toxicity is 25 mg/kg/day, based on the
observation of lethargy, rough hair coat, nasal bleeding, and periocular
encrustation observed at 50-mg/kg and higher dose levels.

Developmental signs of toxicity were observed at all dose levels.  While
the pregnancy rates were not affected by treatment with the test
article, a statistically significant increased incidence of
pre-implantation loss was reported at the 25- and 100-mg/kg/day dose
levels.  Both pre- and post-implantation losses were significantly
higher in the 100-mg/kg dose group.  This test group also had smaller
litter size, and significantly higher number of early reabsorptions. 
Furthermore, the increase in pre-implantation loss was also
statistically significant at the 25-mg/kg dose level and litter sizes
were slightly but significantly smaller at the 12.5-mg/kg dose level.  A
dose-dependent and statistically significant pattern of decreased fetal
body weight at 25-, 50-, and 100-mg/kg dose levels was also observed. 
In fact, the fetal and litter incidences of fetuses weighing less than
2.6 g at the 100-mg/kg dose group were statistically significant as
well.  Gross external examination of the fetuses revealed severe
malformations such as anophthalmia, protruding tongue, unilateral renal
agenesis and cleft palate even at the lowest dose level of 12.5 mg/kg. 
In addition to these malformations, other abnormalities detected in the
25-mg/kg and higher dose groups included hydrocephalus, cranial
hematoma, unilateral lung atrophy, diaphragmatic hernia, soft
consistency of the head and a stunted appearance.  These last two
observations are consistent with the skeletal examination findings that
revealed reduced ossification at all doses, particularly in the skull
(frontal, parietal, and occipital bones), sternum, ribs, vertebrae, and
metacarpals.  Also detected during the skeletal examination were wider
cranial sutures, rudimentary 13th rib, and the absence of sternebral
ossification center. 

Given the significant extent of malformations and reduced ossification
observed at the lowest dose tested (12.5 mg/kg), no developmental NOAEL
could be established for this study.  The LOAEL is 12.5 mg/kg, under the
conditions of this study.

This study in the rat is unacceptable, does not satisfy the guideline
requirement for a developmental toxicity study (OPPTS 870.3700; §83-3)
in rats, and cannot be upgraded.  This study had numerous deficiencies
that seriously compromised the interpretation of the results.  Perhaps
most significant, is the inability to establish a developmental NOAEL
since the lowest dose used gave rise to severe malformations
(anophthalmia, unilateral renal agenesis, protruding tongue and cleft
palate) and reduced ossification.  Moreover, no information regarding
the breeding, age, or housing conditions during the study period was
provided.  Also missing from the report were quality assurance
statements, individual clinical observations, results of individual
fetal examinations, and adequate randomization procedures to ensure a
homogeneous initial body weight distribution.

(b) In a developmental toxicity study (MMD No. 40534101 and 41498301), a
group of pregnant Sprague-Dawley rats (25/dose) were given thiram
technical (99.82%) in 0.5% carboxymethylcellulose (by gavage) at dose
levels of 0, 7.5, 15, and 30 mg/kg/day from days 6 through 15 of
gestation.  The test article was administered at a volume of 10 mL/kg
body weight. The animals were observed twice a day for mortality or
signs of toxicity.  Maternal body weight was measured on GD5 0, 3, 6-16,
18, and 20.

Maternal signs of toxicity were observed at all dose levels ranging from
decrease in body-weight gain, alopecia, scars, damaged digits,
red-stained paws, and excessive salivation.  Alopecia and decreased
body-weight gain were the only maternal signs of toxicity that appeared
to be dose-dependent (1, 3, 8, and 11 dams in the 0-, 7.5-, 15-, and
30-mg/kg dose groups, respectively for alopecia; and 11, 27, and 55%
reduction in body-weight gain during the dosing period at the 

low-, mid-, and high-dose levels, respectively).  No mortality was
reported during the study period.  Gross necropsy examination revealed
no abnormalities. 

The LOAEL for maternal toxicity is 7.5 mg/kg/day (lowest dose tested),
based on reduced body-weight gains and the observation of alopecia,
scars, damaged digits, red-stained paws, and excessive salivation.  No
maternal NOAEL could be established.

Signs of developmental toxicity:  While fetal body weight was
significantly reduced in the high-dose group only, placental weight was
significantly reduced at all dose levels when compared to controls
(statistically significant at the high-dose level only).  At the 15- and
30-mg/kg dose levels, compound-related signs of absent/incomplete
ossification were observed in the thoracic, vertebral centra, and limb
bones.  Moreover, an increased incidence in reduced 13th rib was
reported at all dose levels though it was considered statistically
significant at the mid- and high-dose levels only. 

The LOAEL for developmental toxicity is 15 mg/kg/day based on retarded
growth and rudimentary 13th rib; the NOAEL is 7.5 mg/kg/day.

This study in the rat is acceptable/guideline and satisfies the
requirements for a developmental toxicity study (OPPTS 870.3700; §83-3)
in rats.  It is noteworthy that in a previous teratology study
(Accession No. 259810) conducted in Wistar rats severe fetal
malformations (anophthalmia, protruding tongue, unilateral renal
agenesis and cleft palate) and reduced ossification were reported at
doses as low as 12.5 mg/kg/day.  Maternal signs of toxicity included
lethargy, nasal bleeding, and periocular encrustation.  Although it was
deemed unacceptable, the results of that study suggest a potential for
maternal and developmental toxicity which appear to corroborate the
findings of the current study.

Rabbit

Three developmental toxicity studies in rabbits (MRID No. 40444702,
40577301, 42223601) were submitted by the registrant.  These studies are
a range-finding study (1987) and two full studies (1987 and 1992). 
Independently, none of these studies is acceptable since no maternal or
developmental toxicity was seen at the HDTs (5 and 10 mg/kg/day). 
However, when considered as a group they provide sufficient information
to assess the potential developmental toxicity of the test substance in
rabbits.  In general, the results of these three studies showed that at
doses of 10 mg/kg/day or lower, no dose-related effects were seen in
either maternal or developmental data.  At 20 mg/kg/day, 1/4 dams died
and 2/3 surviving females had total litter loss.  An increase in
post-implantation loss (46%) was also seen at this dose level.  The
executive summaries for these three studies are presented below.

(a) Range-Finding Study (MRID 40444702):  In a range-finding study,
inseminated New Zealand White rabbits (4/dose) were given oral
administration of thiram (99.1% a.i.) in 0.5% (w/v) aqueous
carboxymethylcellulose mucilage + 0.5% Tween at 0, 1, 3, 5, 7.5, 10, 20,
40, or 80 mg/kg/day during GDs 6-19. 

All animals treated at the two highest dose levels died.  At 20
mg/kg/day, one dam died and 2/3 surviving dams exhibited transitional
decreases in body-weight gain, decreased food consumption, and increased
fecal retention and water intake.  At 10 mg/kg/day, 2 females lost
weight during the early part of the treatment period.  A decrease in
body-weight gain was also reported in animals treated at the
7.5-mg/kg/day dose level during the majority of the treatment period. 
During GDs 8-10, dams in the 5-mg/kg/day dose group, exhibited a slight
decrease in maternal body-weight gain.  The changes in body-weight gain
observed at the 7.5-mg/kg/day level and lower were not statistically
significant.  No treatment-related effects in the fetus were seen at the
1, 3, or 5 mg/kg/day doses.  One dam treated at 7.5 mg/kg/day had total
litter loss, but the post-implantation loss in the 2 remaining surviving
females was comparable to the controls (15.8% treated animals vs. 20.8%
control).  No litter loss was seen at the 10-mg/kg/day dose level. 
While there was a slight increase in post-implantation loss (20%) when
compared to the concurrent control (4.3%), the loss observed in the
treated animals was comparable to a second control (20.8%) and well
within the historical control range (1.0-20.5%).  In the 20-mg/kg/day
dose group, 2 females had total litter loss as well as considerable
increase in post-implantation loss (45.5%) when compared to the control
group (4.3%).  No other litter parameters were affected by treatment.

Based on these findings, dose levels selected for the main study were 1,
2.5, and 5 mg/kg/day.

(b) Definitive Study (1987) (MRID 40577301):  In a developmental
toxicity study (MRID 40577301), inseminated New Zealand White rabbits
(15-20/group) were given thiram technical (99.5% a.i.) in 0.5%
methylcellulose + 0.5% Tween (by gavage) at dose levels of 0, 1, 2.5,
and 5 mg/kg/day during GDs 6-19.  No compound-related mortalities or
clinical signs were observed at any dose levels.  Fetal parameters were
comparable between the control and treated groups.  The lack of maternal
and/or developmental effects at the HDT indicate that the high dose was
not adequate to assess the developmental toxicity of thiram. 

Based on these findings the maternal and developmental NOAEL is 5
mg/kg/day (HDT); a LOAEL could not be established.

(c) Definitive Study (1992) (MRID 42223601):  In a developmental
toxicity study (MRID 42223601), inseminated New Zealand White rabbits
(20/group) were given thiram technical (98.26% a.i.) in 0.5%
methylcellulose + 0.5% Tween (by gavage) at dose levels of 0, 1, 5, and
10 mg/kg/day during GD 7-19.  No maternal toxicity was seen at any dose;
the 2 deaths seen at the 0 mg/kg/day and the single death at the 10
mg/kg/day dose levels can be attributed to trauma during gavage
procedure.  Treatment with the test article had no effect on pregnancy
rate, post-implantation loss, resorption rate, fetal viability, fetal
sex ratio, and fetal weight.  No treatment-related external, visceral,
or skeletal malformations or variations were seen in any of the fetuses.

No maternal or developmental toxicity was seen at any dose level,
consequently the NOAEL = 10 mg/kg/day (HDT).  No LOAEL could be
established.

Although the HDT (10 mg/kg/day) in the 1992 study (MRID 42223601) was
twice the HDT (5 mg/kg/day) of the 1987 (MRID 40577301) study, it failed
to elicit any signs of toxicity in the dams or the developing fetus. 
Given that significant toxicity to dams seen at the 20 mg/kg/day dose
level during the range-finding study, it was determined that titration
of a maximum-tolerated dose is unnecessary.  While it would be
preferable to obtain some evidence of toxicity in rabbits, the data
gathered in these 3 studies is sufficient to evaluate the developmental
toxicity potential of thiram in rabbits.

3.3.4. Reproductive Toxicity

Two acceptable/guideline multigeneration toxicity studies are available
in the thiram database.  The executive summaries for these studies are
presented below:

(a) In a \ rat reproduction study (MRID 42095901) thiram, 97.5% was
administered to 26 Charles River (Crl:CDR VAF/PlusR)
rats/sex/dietary-exposure level at dietary levels of 0, 30, 60, and 180
ppm.  Since the Agency has data showing that rats can utilize at least
84% of the thiram in their diet, the corresponding values are 0, 25, 50,
and 150 ppm [0, 1.2, 2.4, and 8.5 mg/kg/day for F0 males and 0, 1.9,
3.9, and 11.8 mg/kg/day for F0 females; 0, 1.5, 3.2, and 9.2 mg/kg/day
for F1 males and 0, 2.0, 4.3, and 13.4 for F1 females].  The parental
(F0) animals were given the diet for 81 days before the first mating. 
There were 3 matings for the F0 generation and 2 matings for the
generation (the generation was selected from pups of the third mating). 
Selection of parents for the F1 generation was made when the pups were
22 days old, and they were at least 106 days old when first mated.

Systemic toxicity was observed in mid- and high-dose F0 females in the
form of significantly decreased mean body weights during the premating
period (week 11: mid-dose: -7.6% with a p ≤0.05 ; high-dose: -9.5%
with a p ≤0.0l), significantly reduced mean food consumption during
the first two gestations, but not the third (first gestation: mid-dose:
-7.4%; high-dose: -11.3%; second gestation: mid-dose: -15%; high-dose:
-18.1%).  Systemic toxicity was observed in high-dose F1 females at
weeks 11 of age (but not week 16) as a significantly reduced mean weight
(-6%).  Mean maternal body-weight gains and food consumption during
gestation tended to be somewhat lower (sometimes significantly so) in
the mid- and high-dose groups both for F0 and F1 females.  There were no
significant body weight differences between groups of F0 and F1 males at
the end of the premating period. 

The systemic toxicity LOAEL for adult females is 3.9 mg/kg/day based on
decreased body-weight gain and decreased food consumption.  The systemic
toxicity NOAEL for adult females is 1.9 mg/kg/day.

Reproductive parameters were unaffected by treatment.  Significantly
elevated fertility indices for high-dose F0 females following the second
and third matings (second mating:  65.4% vs. a control value of 23.1%;
third mating: 76.2% vs. a control value of 33.3%) were presumably due to
heavier mean body weights of the control animals, which adversely
affected their fertility.  Systemic toxicity was consistently noted in
the offspring of the high-dose group in the form of reduced mean pup
weights, which were usually statistically significant.  Occurrences of
significantly lower mean pup weights in the low- and mid-dose groups
occurred sporadically without dose-related trends and/or involved
relatively high- control values (as in the second matings of the F0 and
F1 generations).  The reproductive toxicity NOAEL is greater than 8.9
mg/kg/day. 

The systemic toxicity LOAEL for pups is 11.8 mg/kg/day based on reduced
mean body weights.  The systemic toxicity NOAEL for pups is 3.9
mg/kg/day.

The classification of this study is upgraded to acceptable.  This study
satisfies the guideline requirement for a 2-generation reproduction
study (83-4) in rats.

(b) In a two-generation reproduction study, thiram (99.44% a.i.; Lot No.
4712AB) was administered to groups of 26 male and 26 female
Sprague-Dawley (Crl:CD®VAF/Plus®) rats in the diet at concentrations
of 0, 20, 60, or 180 ppm (MRID 45441203).  Two litters were produced by
each generation.  Time-weighted average premating doses for the low-,
mid-, and high-dose groups were 1.4, 4.2, and 12.2 mg/kg/day,
respectively, for the F0 males, 1.6, 4.7, and 14 mg/kg/day,
respectively, for the F0 females, 1.7, 4.9, and 14.9 mg/kg/day,
respectively, for the F1 males, and 1.8, 5.4, and 16.4 mg/kg/day,
respectively, for the F1 females.  F0 and F1 parental animals were
administered test or control diet for 90 or 81 days, respectively, prior
to mating, throughout mating, gestation, and lactation, and until
sacrifice.  After the premating interval, the adult animals were mated
to produce the A litters.  Approximately 10 days after the last A
litters were weaned, the parental animals were mated again within the
same dose group to produce the B litters.  F1 parental animals were
selected from the FIb litters.

≤0.01) in body-weight gain during the third week of gestation (days
14-20) and an overall body-weight gain reduction of 16% (p ≤0.01)
during gestation.  Lactational body weight and body-weight gains were
not affected by treatment with the test article during the second
mating.  At the 180-ppm dose level, microscopic evaluations revealed a
slight increase in the incidence of suppurative inflammation of the
prostate gland in F0 males (35% vs. 12% control) and increased incidence
of angiectasis of the pituitary in F0 females (15% incidence vs. 0%
control).  No other compound-related microscopic findings were reported
in the F0 or F1 adults. 

Therefore, the LOAEL for parental toxicity is 60 ppm (4.7 mg/kg/day)
based on reduced body weights gains during gestation (F0 and F1
females).  The NOAEL for parental toxicity is established at 20 ppm (1.4
mg/kg/day).

No differences in mating, fertility, or gestation indices were seen
between the treated and control groups of either generation.  The
copulatory interval and gestation length of the treated groups were
comparable to the control groups in both generations.  No
treatment-related differences were noted for offspring survival in
either litter of both generations.  Live birth, viability, and lactation
indices were similar between the treated and control groups.  The sex
ratio at birth was not affected by treatment.

Therefore, the reproductive toxicity NOAEL is ≥180 ppm (12.2
mg/kg/day) and the reproductive toxicity LOAEL was not identified.

No treatment-related clinical signs of toxicity were observed in the
pups during lactation.  However, dose-dependent decreases in pup body
weights were noted in the F1A (19-20%) and F1B generations (11-21%) at
doses ≥60 ppm beginning on PND 4.  In addition, F1B offspring
exhibited statistically significant decreases (113-26%, p ≤0.01) in
pup weight at the 20-ppm dose level.  Similarly, dose-related decreases
in body-weight gain were observed in the FIA (19-31%) and FIB (111-35%)
generations at dose levels ≥60 ppm.  F1 offspring also exhibited a
12-43% decrease in body-weight gain at the 20-ppm dose level during
lactation.  The decreases in body weight and body-weight gain at the
lowest dose tested were not considered compound-related as they did not
reflect a dose-response relationship.  Moreover, the larger litter size
of the low-dose FIB group may have contributed to the initial lower pup
weight.  Decreased pup weights were also noted in the second generation
at the mid- and high-dose.  At the 60-ppm dose level, F2A offspring body
weight was 5-8% lower than control beginning on PND 7 while F2B pup
weight was 7% lower than control beginning on PND 14.  At the 180-ppm
dose, F2A and F2B pup weights were reduced by 13-24% beginning on PND 7
and 9-14% beginning on PND 0, respectively.  Body-weight gains by F2A
were reduced by 5-12% and 10-28% at the 60- and 180-ppm doses,
respectively.  F2B pup body-weight gain was reduced by 8% at the 60-ppm
dose level and 20% at the 180-ppm dose level.

The offspring NOAEL is established at 20 ppm (1.4 mg/kg/day).  The LOAEL
is established at 60 ppm (4.2 mg/kg/day) based on statistically
significant decreases in pup weight and body-weight gain.

This study is classified as acceptable/guideline and satisfies the
requirements for a reproduction study (870.3800 [83-4]) in rats.

3.3.5  Additional Information from Literature Sources

In addition to the studies submitted to the Agency, the IARC profile for
thiram (1991) provides further evidence of thiram’s potential to act
as a developmental toxicant.  This report cites embryo lethality and
embryotoxicity in rats and hamsters and malformations in mice and
hamsters.  Furthermore, in a developmental toxicity study by Robens
(1969), treatment at a dose level of 100 mg/kg resulted in CNS
malformations (exencephaly) thus providing additional evidence of
thiram’s potential for developmental toxicity.

3.3.6  Pre-and/or Postnatal Toxicity

3.3.6.1  Determination of Susceptibility

The data available for evaluation suggest that there is no evidence of
increased quantitative or qualitative susceptibility of the offspring
after in utero or early postnatal exposure.  A quantitative
susceptibility was reported in an unacceptable/guideline prenatal
developmental toxicity study in rats.  However, no susceptibility was
observed in a subsequent acceptable/guideline study in the rat.  Three
developmental toxicity studies in rabbits (considered acceptable when
evaluated together) did not reveal enhanced susceptibility of the fetus
after in utero exposure.  Similarly, the results of two multigeneration
reproduction toxicity studies do not indicate an enhanced susceptibility
to the test article in utero or during early post-natal exposure.

3.3.6.2  Degree-of-Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility

Since there is quantitative evidence of increased susceptibility of the
young following exposure to thiram in the (unacceptable) prenatal
developmental study in rats and reported in the open literature, HIARC
performed a degree-of-concern analysis to:  1) determine the level of
concern for the effects observed when considered in the context of all
available toxicity data; and 2) identify any residual uncertainties
after establishing toxicity endpoints and traditional UFs to be used in
the risk assessment of this chemical.  If residual uncertainties are
identified, HIARC examines whether these residual uncertainties can be
addressed by a special FQPA SF and, if so, the size of the factor
needed.  The results of the HIARC degree-of-concern analysis for thiram
follow:

Although there is a high degree of concern for the quantitative
susceptibility seen in the unacceptable developmental toxicity study in
rats, there is no residual uncertainty since the results were not
replicated in a subsequent acceptable developmental study in rats and
when doses are used for regulatory purposes are taken into
consideration.  Concerns for the potential developmental toxicity of
thiram were also raised by reports in the published literature. 
However, the level of concern is low when the doses and endpoints
selected for regulatory purposes are taken into consideration.  This
determination was based on a weight-of-evidence analysis that takes into
consideration the following factors:  

• No evidence of increased quantitative/qualitative susceptibility in
the available acceptable/guideline studies.

• Clear NOAELs/LOAELs have been identified for the effects of concern.

• Dose-response relationships for the effects of concern are
well-characterized.

• The doses used for regulatory purposes are at least 10X lower than
the doses where developmental and reproductive toxicity effects were
reported in the published literature.

• An acceptable/guideline DNT study has been submitted and reviewed by
the Agency.  The study results have been incorporated into the risk
assessment and are the basis for the point of departure for the acute
females 13+ dietary assessment and all short- and intermediate-term
(incidental oral, dermal, inhalation, and aggregate) assessments.

• There are no residual uncertainties in the hazard database.

Note that while the new 40 CFR revised Part 158 requirement for an
immunotoxicity study has not yet been fulfilled, the existing data are
sufficient for endpoint selection for exposure/risk assessment scenarios
and for evaluation of the requirements under FQPA.  Further, the data
requirement pertaining to this study (see Section 7.1) should be
fulfilled as a condition of registration.

3.3.7  Recommendation for a DNT Study

An acceptable DNT study has been completed, submitted, and evaluated.

3.4  FQPA SF for Infants and Children

The HIARC concluded that the FQPA SF could be reduced to 1X.  This
conclusion is based on the outcome of the degree of concern analysis
that failed to identify any residual uncertainties.

The FQPA SF recommended by the HIARC assumes that the exposure databases
(dietary food, drinking water, and residential) are complete and that
the risk assessment for each potential exposure scenario includes all
metabolites and or degradates of concern and does not underestimate the
potential risk for infants and children.

3.5  Hazard Identification and Toxicity Endpoint Selection

3.5.1  Acute Reference Dose (aRfD) – Females 13-49

The aRfD was established based on the NOAEL of 1.4 mg/kg bw from a DNT
study.  Increases in motor activity seen in female offspring on PND 17
at the LOAEL of 3.7 mg/kg/day were observed.  The dose and endpoint
selected for this risk assessment are relevant since they evaluate the
effects of thiram exposure on the fetus during the appropriate time of
exposure.  The UFs applied were 10X for intraspecies variation and 10X
for interspecies extrapolation.  Consequently, the calculated acute RfD
is 0.014 mg/kg bw.  The study was selected since the effects observed in
the neurotoxicity study occurred after multiple doses were administered.

aRfD = 1.4 mg/kg/day (NOAEL) = 0.014 mg/kg/day

                        100 (UF) 

3.5.2  aRfD – All Populations

The aRfD was established based on the NOAEL of 5 mg/kg bw from an acute
neurotoxicity study.  Lethargy, reduced tail-pinch response, reduced
brain weights, and reduced motor activity were the effects seen at the
LOAEL of 150 mg/kg bw.  The UFs applied were 10X for intraspecies
variation and 10X for interspecies extrapolation.  Consequently, the
calculated acute RfD is 0.05 mg/kg bw.  The study was selected since the
effects observed in the neurotoxicity study occurred after a single dose
administration.  

aRfD = 5 mg/kg/day (NOAEL) = 0.05 mg/kg/day

                     100 (UF) 

3.5.3.  Chronic Reference Dose (cRfD) 

The cRfD was established based on a combined chronic
toxicity/carcinogenicity study in rats.  Use of this study to establish
the cRfD would address the effects of concern noted in the developmental
and reproduction toxicity studies.  While the NOAELs for all
acceptable/guideline developmental studies are higher than the NOAEL
selected for this risk assessment, the lowest NOAEL (1.4 mg/kg/day) for
a multigeneration reproduction toxicity study in rats is equivalent to
the 1.5 mg/kg/day in the combined chronic toxicity/carcinogenicity study
(the difference of 0.1 mg/kg/day in these studies is within the margin
of error for the estimation of compound intake from dietary
administration).  A 10X factor for interspecies extrapolation and 10X
factor for intraspecies variation is applicable to this risk assessment.
 

cRfD = 1.5 mg/kg/day (NOAEL) = 0.015 mg/kg/day

                         100 (UF) 

3.5.4-5 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 exposure are based on the results
of the DNT study (NOAEL of 1.4 mg/kg/day).  A MOE of 100 is considered
adequate for short- and intermediate-term incidental oral exposure
scenarios.

3.5.6  Dermal Absorption

No adequate dermal absorption studies are currently available.  The
dermal-absorption factor was calculated to be 1% based on the LOAELs in
a range-finding study for the developmental toxicity study in rabbits
and the 21-day dermal toxicity study in rabbits.  The range-finding
study was used in conjunction with two definitive studies to establish
the developmental rabbit LOAEL since no LOAEL could be established in
either of the definitive studies.  The LOAEL for the range-finding study
was established at 10 mg/kg/day based on maternal weight loss coupled
with a marked decrease in fetal weight.  Thus, the LOAEL for the
developmental range-finding study in rabbits (10 mg/kg/day) and the
LOAEL for the 21-day dermal toxicity study in rabbits (1000 mg/kg/day)
are based on decreased body-weight gain (common endpoint) 

3.5.7-8  Dermal Exposure (Short- and Intermediate-Term) 

The effects of concern that are relevant to the selection of the short-
and intermediate-term dermal exposure are based on the results of the
DNT study.  The DNT study is relevant for both the short- and
intermediate term risk assessments.  Although a study conducted via the
most relevant route of exposure (21-day dermal toxicity study in
rabbits) was available for consideration, the DNT was selected since it
evaluated endpoints of concern (neurotoxicity) that were not assessed in
the dermal toxicity study.  If a dermal-absorption factor of 1% is
applied to the NOAEL obtained in the DNT, then the derived
dermal-equivalent dose (DED) would be 140 mg/kg/day.  Since the NOAEL
from the dermal study is 300 mg/kg/day, use of the DNT would be
protective of the effects of concern seen in the dermal toxicity study
(decreases in body weight and food consumption; and alterations in
clinical chemistry).  The dermal-absorption factor should be considered
to be 1% when extrapolating from an oral exposure to a dermal exposure. 
A MOE of 100 is considered adequate for short- and intermediate-term
dermal exposure scenarios.

3.5.9  Level of Concern for MOEs

Table 3.5.9.  Summary of LOC for Risk Assessment.

Route	Short-Term MOE

(1-30 Days)	Intermediate-Term MOE

(1-6 Months)	Long-Term MOE

(>6 Months)

Residential Exposure1

Oral	100	100	100

Dermal	100	100	100

1	LOC based on UFA = 10X [(extrapolation from animal to human
(intraspecies)], UFH = 10X [potential variation in sensitivity among
members of the human population (interspecies)], and FQPA Factor = 1X.

3.5.10  Recommendation for Aggregate Exposure Risk Assessments

As per FQPA, 1996, when there are potential residential exposures to the
pesticide, aggregate risk assessment must consider exposures from three
major sources: oral, dermal and inhalation exposures.  The toxicity
endpoints selected for these routes of exposure may be aggregated as
follows:

Short-, intermediate-, and long-term aggregate exposure risk assessment
the MOEs derived for oral, dermal, and inhalation exposures may be
combined since common endpoints (decreases in body weight and
alterations in clinical chemistry parameters) were identified via the
dermal route (short- and intermediate-term dermal exposures) and the
oral equivalent doses used for the incidental oral, dermal (long-term),
and inhalation risk assessments (all durations).

3.5.11  Classification of Carcinogenic Potential

Thiram is considered to be “not likely to be carcinogenic to humans”
based on the results of a rat chronic toxicity/carcinogenicity study and
a mouse carcinogenicity study.   

3.5.12  Summary of Toxicological Doses and Endpoints for Thiram for Use
in Human Risk Assessments

A summary of the toxicological endpoints and doses chosen for the
relevant exposure scenarios for human risk assessment are found in Table
3.5.12.



Table 3.5.12.  Summary of Toxicological Doses and Endpoints for Thiram
for Use in Dietary and Non-Occupational Human Health Risk Assessments.

Exposure/

Scenario	Point of Departure	Uncertainty/FQPA SFs	RfD, PAD, LOC for Risk
Assessment	Study and Toxicological Effects

Acute Dietary

(All Populations)

	NOAEL = 5 mg/kg

	UFA = 10x

UFH = 10x

FQPA SF = 1x

	Acute RfD = 0.05

mg/kg/day

aPAD =0.05 mg/kg/day	Acute Neurotoxicity Study - Rat

LOAEL = 150 mg/kg/day based on FOB effects (lethargy, lower temperature,
reduced startle response, no tail-pinch response), reduced motor
activity, and reduced brain weights.

Acute Dietary

(Females 13-49 years old)

	NOAEL = 1.4 mg/kg

	UFA = 10x

UFH = 10x

FQPA SF = 1x

	Acute RfD = 0.014

mg/kg/day

aPAD =0.014 mg/kg/day	Dev. Neurotoxicity Study - Rat

LOAEL = 3.7 mg/kg/day based on increases in motor activity seen in
female offspring on PND 17.

Chronic Dietary

(All populations)

	NOAEL = 1.5 mg/kg

	UFA = 10x

UFH = 10x

FQPA SF = 1x

	Chronic RfD = 0.015 mg/kg/day

cPAD =0.015 mg/kg/day

	Combined Chronic Toxicity/Carcinogenicity Study - 

LOAEL = 7.3 mg/kg/day based on changes in hematology, clinical
chemistry, incidences of bile duct hyperplasia, and reduction in mean
body-weight gain seen at 7.9 mg/kg/day.

Short-Term

Incidental Oral (1-30 days)	NOAEL = 1.4 mg/kg/day

	UFA = 10x

UFH = 10x

FQPA SF = 1x	Residential LOC for MOE = 100

Occupational = NA	Dev. Neurotoxicity Study - Rat

LOAEL = 3.7 mg/kg/day based on increases in motor activity seen in
female offspring on PND 17.

Intermediate-Term

Incidental Oral (1- 6 months)	NOAEL = 1.4 mg/kg/day

	UFA = 10x

UFH = 10x

FQPA SF = 1x	Residential LOC for MOE = 100

Occupational = NA	Dev. Neurotoxicity Study - Rat

LOAEL = 3.7 mg/kg/day based on increases in motor activity seen in
female offspring on PND 17.

Short-Term Dermal (1 to 30 days)	NOAEL = 1.4 mg/kg/day

	UFA = 10x

UFH = 10x

FQPA SF = 1x

(Dermal-absorption factor = 1%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	Dev. Neurotoxicity Study - Rat

LOAEL = 3.7 mg/kg/day based on increases in motor activity seen in
female offspring on PND 17.

Intermediate-Term

Dermal (1 to 6 months)	NOAEL =1.4 mg/kg/day

	UFA = 10x

UFH = 10x

FQPA SF = 1x

(Dermal-absorption factor = 1%)	Residential LOC for MOE = 100

Occupational LOC for MOE = 100	Dev. Neurotoxicity Study - Rat

LOAEL = 3.7 mg/kg/day based on increases in motor activity seen in
female offspring on PND 17.

Cancer (oral, dermal, inhalation)	“Not Likely to be Carcinogenic to
Humans”

Point of Departure (POD) = A data point or an estimated point that is
derived from observed dose-response data and used to mark the beginning
of extrapolation to determine risk associated with lower environmentally
relevant human exposures. NOAEL = no-observed adverse-effect level. 
LOAEL = lowest-observed adverse-effect level.  UF = uncertainty factor. 
UFA = extrapolation from animal to human (intraspecies).  UFH =
potential variation in sensitivity among members of the human population
(interspecies).  FQPA SF = FQPA Safety Factor.  PAD =
population-adjusted dose (a = acute, c = chronic).  RfD = reference
dose.  MOE = margin of exposure.  LOC = level of concern.  N/A = not
applicable.

3.6  Endocrine Disruption

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

When additional appropriate screening and/or testing protocols being
considered under the Agency’s EDSP have been developed, thiram 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 

There were 17 cases reported from the Incident Data System since 1992. 
Although all of the reported cases occurred since 1995, approximately
half of these cases (8 of 17) were reported in 1998.  Three of the cases
reported affected adults following the occupational handling or clean-up
of thiram products.  Thirteen of the cases reported affected the general
public (3 children and 10 adults) following the non-occupational
handling of thiram products.  One serious incident (a seizure episode)
occurred following the use of thiram after alcohol had been consumed the
evening prior to exposure.  It was unclear if this was an occupational
or non-occupational incident.  Recorded dermal effects for the reported
cases were skin rashes, skin reddening, itching and tingling of the
hands, thickened skin on the palms and blisters under the skin, small
bumps on the hands and other parts of the body, and burning and redness
on the face.  One case recorded a dry cough following an inhalation
exposure while a splash incident to the face resulted in burning of the
eyes.  During the period 1982-1996, 15 cases involving the sole use of
thiram were reported.  Thiram ranked 122nd as a cause of systemic
poisoning in California.  A total of four persons had systemic illnesses
from thiram exposure, four experienced eye illnesses, six experienced
skin illnesses, and one person experienced a combination of these
illnesses.  Of the 15 cases, two persons were disabled for one day.  The
15 persons were exposed to thiram in the following manner:  eight of the
persons affected were applicators; one was cleaning or repairing
pesticide contaminated equipment; one experienced exposure
coincidentally; two were exposed during the shipping, warehousing or
retailing of thiram; two were packing, processing or retailing thiram;
and one worker was exposed to thiram residue which was neither
agricultural or structural.  According to these statistics,
applicator’s exposures accounted for the majority of the recorded
illnesses.  The illnesses included symptoms of rashes, dermatitis, and
itchy, watery or burning eyes.  On the list of the top 200 chemicals for
which National Pesticide Information Center received calls from
1984-1991 inclusively, thiram ranked number 101 and was reported to be
involved in 33 human incidents and six animal incidents, mostly pets. 

4.0  EXPOSURE ASSESSMENT AND CHARACTERIZATION

4.1  Summary of Registered/Proposed Uses

A summary of the proposed end-use products is presented in Table 4.1.1. 
Table 4.1.2 lists the summary of proposed use patterns.

Table 4.1.1.  Summary of Proposed End-Use Products.

Trade Name	

Reg. No.	% ai (formulation)	Formulation Type	

Target New Crops	

Target Pests	Label Date

Banguard 42 PLUS

37.0	Soluble concentrate (SC)	Banana	Black Sigatoka	Undated specimen
label

Banguard 60

52.6	SC	Banana	Black Sigatoka	Undated specimen label

Table 4.1.2.  Summary of Proposed Directions for Use of Thiram.

Applic. Timing, Type, 

Equipment.	Formulation

[EPA Reg. No.]	Applic. Rate

kg ai/ha

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

(RTI, days)	Max. Seasonal Applic. Rate

kg ai/ha (lb ai/A)	PHI

(days)

Foliar Ground (60-120 L/Ha)

Aerial (10-30 L/Ha)	Banguard 42 PLUS	1.26

(1.12)	10

(every 4-10 days)	12.6

(11.2)	0

	Banguard 60

The submitted data for banana support the proposed use pattern.  

4.2  Dietary Exposure/Risk Pathway

The residue chemistry data submitted in support of the proposed
petitions were evaluated by HED (Memos, G. Kramer, DP# 334946; 9/13/07
and DP# 356632).  The drinking water assessment was completed by EFED
(Environmental Fate and Ecological Effects Assessment and
Characterization Chapter for the Thiram Reregistration Eligibility
Decision Document (J. Carleton and F. Jenkins; 12/11/03)).  The
dietary-exposure assessment was completed by HED (Memo, G. Kramer, DP#
356633).

4.2.1  Residue Profile

Background

Thiram is a dimethyl dithiocarbamate fungicide used to prevent crop
damage in the field and to protect harvested crops (apples, peaches, and
strawberries) from deterioration in storage or transport.  It is also
used as a seed protectant (e.g., small-seeded vegetables, large-seeded
vegetables, cereal grains, other seeds, coniferous seeds, cotton seed,
ornamental seeds, and soybeans) and to protect turf from fungal
diseases.  Tolerances for residues in/on food and feed commodities are
currently expressed in terms of residues of thiram per se (40 CFR
§180.132) and are established at 7 ppm for apples, peaches, and
strawberries.  The Update to the Residue Chemistry Chapter of the Thiram
Reregistration Standard was issued on 7/25/91 and the Revised HED
Chapter of the RED Document was issued on 12/16/03 (F. Fort; D293295).

Taminco Corporation requests the establishment of the following
tolerances for residues of thiram per se, without a U.S. registration,
in/on the following RACs:

Whole bananas	0.5 ppm

Banana pulp	0.3 ppm

Nature of the Residue in Plants 

HED previously concluded that the common-moiety (CS2) method determined
all thiram residues of toxicological concern (F. Fort, 12/16/03;
D293295).  A total 67 field-trial samples of strawberry, peach, apple,
pear, cherry, lettuce, and plum bearing quantifiable residues of thiram
were analyzed by the single-analyte high-performance liquid
chromatography (HPLC) and common-moiety (CS2) methods.  The results were
comparable (the average results from the CS2 method were 1% higher than
the HPLC method.  As the HPLC (single-analyte) and common-moiety (CS2)
methods gave comparable results, the parent thiram is an adequate marker
of the total residues of toxicological concern.  Note that this
conclusion pertains to bananas only.  

Residue Analytical Methods

The Pesticide Analytical Manual (PAM) Vol. II lists Method I, II, III,
IV, and A for the determination of dithiocarbamate residues in/on plant
commodities.  These methods are based on the decomposition of
dithiocarbamates with release of CS2.  Using these methods, the CS2 is
swept through a trap to remove any H2S and into a reaction tube
containing a solution of copper acetate and an amine.  A colored copper
dithiocarbamate complex is formed and its absorbance read as a measure
of the original dithiocarbamate.  The stated limit of detection (LOD)
for Method I is 0.5-4.0 ppm.

The Update to the Residue Chemistry Chapter of the Thiram Reregistration
Standard noted that the current enforcement methodology is nonspecific
for CS2-generating compounds.  The Update required enforcement method(s)
capable of quantifying residues of thiram per se and distinguishing it
from other CS2-generators (e.g., EBDCs).

Taminco has submitted a new HPLC enforcement method, A7193, for the
determination of residues of thiram per se in banana commodities.  This
method and the independent laboratory validation (ILV) were forwarded to
ACB for a petition method validation (PMV) (DP# 302799; 6/26/08, G.
Kramer).  ACB has successfully validated method A7193 (Memo, C.
Stafford, D353875; 10/23/08).  However, ACB made the following
recommendation:

3.  Page 12 of the ILV laboratory report notes that they received
guidance to make some modifications to the original method.  ACB
believes that one of the ILV modifications, involving the sample
evaporation step, could have a significant impact on overall method
performance.  We recommend that Taminco evaluate the significance of the
ILV modification, and if they agree that the modification is warranted
then the method should be revised to reflect the change.

Submission of method A7193 fulfills the requirement for an enforcement
method for bananas.  Provided that Taminco addresses the comments from
ACB in the PMV, this deficiency is now resolved.  

The Update to the Residue Chemistry Chapter of the Thiram Reregistration
Standard reported that it is unlikely for thiram to be recovered through
any of the FDA multiresidue protocols.  The 10/99 PESTDATA database
(PAM, Vol. I, Appendix I) does not contain any entry information for
thiram or dithiocarbamates.  Therefore, the registrant is required to
follow the decision tree for multiresidue method testing in PAM Vol. I,
Appendix II.  If the registrant believes that thiram should not be
subjected to multiresidue tests, then appropriate rationales as to why
such requirements are not needed should be submitted.  

Magnitude of Residues in Plants

Taminco Corporation has submitted residue data for thiram on bananas
from field trials conducted in Central and South America.  A total of 9
banana field trials were conducted in Central and South America during
2006, with 3 trials conducted in Costa Rica, 3 trials conducted in
Ecuador, 1 trial conducted in Colombia, 1 trial conducted in Honduras,
and 1 trial conducted in Mexico.  The test formulation used in all
trials was Banguard 42, a SC formulation containing 37.0% thiram.  The
Costa Rican trials also included plots treated with Banguard 60 (52.6%
ai SC).  All trials contained plots with unbagged bananas; in five
trials both bagged and unbagged bananas were treated.  Bananas received
ten broadcast foliar applications of the test formulation   SEQ CHAPTER
\h \r 1 at ~1.26 kg ai/ha/application (1.12 lb ai/A/application) for
total rates of 12.08-12.79 kg ai/ha (10.75-11.38 lb ai/A).  All
applications were made with 5- to 7-day RTIs, using ground equipment in
~3 gal/A (25-31 L/ha) spray volumes; an adjuvant was added to the spray
mixture (spray oil, plus emulsifier).  Bagged and unbagged bananas were
harvested at a 0-day PHI.  Addition samples were harvested at a 1-, 3-,
5-, and 7-day PHIs to measure residue decline.

  SEQ CHAPTER \h \r 1 The maximum storage interval of whole banana
samples from harvest to analysis was 72 days and the maximum storage
interval for pulp was 64 days.  Supporting storage stability data were
included in the current study submission.  Thiram is stable in/on whole
bananas for up to 91 days and in/on banana pulp for up to 78 days.

  SEQ CHAPTER \h \r 1 Banana (whole) and pulp samples were analyzed for
residues of thiram, as CS2, using a gas chromatography/flame photometric
detection (GC/FPD) method (Morse Method #Meth-100, Rev. 4).  Briefly,
CS2 was released from thiram by heating the samples with stannous
chloride in   SEQ CHAPTER \h \r 1 hydrochloric acid.  The liberated CS2
was collected from the headspace, and CS2 residues were quantitated
using GC/FPD.  The stated limit of quantitation (LOQ) was 0.05 ppm.

The maximum residues of thiram, determined as CS2, in/on samples
harvested 0 days following the last of 10 broadcast foliar applications
of the Banguard 42 formulation for total seasonal rates of 12.08-12.79
kg ai/ha (10.75-11.38 lb ai/A) were:  (i) 0.16 ppm in/on bagged whole
bananas, (ii) 0.523 ppm in/on unbagged whole bananas, (iii) 0.276 ppm
in/on pulp from bagged bananas, and (iv) 0.225 ppm in/on pulp from
unbagged bananas.  Residues were significantly lower in whole bananas
and pulp treated with the Banguard 60 formulation.  In the residue
decline study, residues generally increased in whole bananas and
remained constant in pulp.

For imported bananas, the Agency recommends a total of 12 field trials
(North American Free Trade Agreement (NAFTA) Guidance Document on Data
Requirements for Tolerances on Imported Commodities, 4/2003).  As only 9
banana field trials were submitted, HED requests that the petitioner
conduct an additional 3 trials (1 each in Guatemala, Colombia, and
Honduras). 

Tolerance Summary

The submitted data for whole unbagged banana (Banguard 42 formulation
only) were entered into the tolerance spreadsheet (see Appendix I). 
Using the rounding procedure as outlined in the Guidance for Setting
Pesticide Tolerances Based on Field Trial Data SOP, HED recommends
tolerance levels of 0.80 ppm for banana.  Banana pulp is not listed in
Table 1 of OPPTS 860.1000; therefore, this entry should be removed from
the Section F.  A summary of tolerance reassessment is presented in
Table 4.2.1.  The Codex Alimentarius has established maximum residue
limits (MRL), for “total dithiocarbamates, determined and expressed as
mg carbon disulfide per kg” in banana of 2 mg/kg.  As U.S. tolerances
are established on the individual dithiocarbamates, compatibility is not
possible with the proposed tolerances.    SEQ CHAPTER \h \r 1 

Table 4.2.1.  Tolerance Summary for Thiram.

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

[Correct Commodity Definition]

Whole bananas	0.5	0.80	Banana

Banana pulp	0.3	Delete	Not a RAC as per Table 1 of OPPTS 860.1000.

4.2.2  Dietary-Exposure Analyses

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

For chronic exposure and risk assessment, an estimate of the residue
level in each food or food-form (e.g., orange or orange 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.

For acute exposure assessments, individual one-day food consumption data
are used on an individual-by-individual basis.  The reported consumption
amounts of each food item can be multiplied by a residue point estimate
and summed to obtain a total daily pesticide exposure for a
deterministic (Tier 1 or Tier 2) exposure assessment, or “matched”
in multiple random pairings with residue values and then summed in a
probabilistic (Tier 3/4) assessment.  The resulting distribution of
exposures is expressed as a percentage of the aPAD on both a user (i.e.,
those who reported eating relevant commodities/food forms) and a
per-capita (i.e., those who reported eating the relevant commodities as
well as those who did not) basis.  In accordance with HED policy, per
capita exposure and risk are reported for all tiers of analysis. 
However, for Tiers 1 and 2, significant differences in user vs. per
capita exposure and risk are identified and noted in the risk
assessment.

4.2.2.1  Acute Dietary-Exposure Analysis

A refined probabilistic acute dietary-exposure assessment was performed
using %CT provided by BEAD, distributions of field-trial residue values,
and empirical processing factors.  Dietary risk estimates were
determined considering exposures from food plus drinking water using
EDWCs for surface water sources provided by EFED.  EDWC values were
generated by the PRZM-EXAMS for the turf application scenario, since
this crop yielded the highest EDWC values.  Ground water sources were
not included, as the EDWCs for this water source are minimal in
comparison to those for surface water.

The resulting acute dietary risk estimates for food and water combined
are <100% of the aPAD of 0.05 mg/kg bw/day for the overall U.S.
population and all population subgroups (including females 13-49 years
old; aPAD of 0.014 mg/kg bw/day), except for children 1-2 years old. 
Using the DEEM-FCID™ software, acute dietary exposure at the 99.9th
exposure percentile is estimated at 0.021447 mg/kg/day for the general
U.S. population (43% of the aPAD) and 0.053321 mg/kg/day (107% of the
aPAD) for children 1-2 years old, the population subgroup with the
highest estimated acute dietary exposure to thiram.  Fresh apples are
the largest contributor to overall dietary risk for children 1-2 years
old (52% of the aPAD); bananas contributed <0.5% of the aPAD. 
Generally, HED’s level of concern for acute dietary risk is 100% of
the aPAD.  However, HED does not consider the acute dietary risk for
children 1-2 years old (107% of the aPAD) to be of concern because the
residue estimates in all foods were based on the results of field
trials.  Field-trial residues should exceed the residue levels found on
food commodities at the time of consumption.  When field trials are
performed, the maximum allowable application rate is used and crops are
harvested at the minimum PHI.  Samples are stored frozen until analysis
to ensure minimal degradation of residues.  In actual practice, however,
growers will not usually use the maximum application rates for economic
reasons.  In addition, most crops are not harvested and immediately
stored frozen.  For these reasons, HED is confident that this analysis
overestimates the actual risk.  Further refinement to the analyses could
be made through the use of monitoring data; however, as monitoring data
for thiram are not currently available, a more highly refined acute
analysis is not possible at this time.  



Table 4.2.2.1.  Results of Acute Dietary Exposure and Risk Analysis for
Thiram (Food + Water).

Population Subgroup	aPAD (mg/kg/day)	95th Percentile	99th Percentile
99.9th Percentile

Exposure (mg/kg/day)	% aPAD	Exposure (mg/kg/day)	% aPAD	Exposure
(mg/kg/day)	% aPAD

General U.S. Population	0.05	0.003077	6.2	0.006913	14	0.021447	43

All Infants (<1 year old)	0.05	0.010241	20	0.016334	33	0.032281	65

Children 1-2 years old	0.05	0.006571	13	0.018851	38	0.053321	107

Children 3-5 years old	0.05	0.005181	10	0.015580	32	0.048814	98

Children 6-12 years old	0.05	0.003337	6.7	0.007901	16	0.029802	60

Youth 13-19 years old	0.05	0.002283	4.6	0.004941	9.9	0.013688	27

Adults 20-49 years old	0.05	0.002620	5.2	0.005133	10.3	0.012240	25

Adults 50+ years old	0.05	0.002409	4.8	0.004489	9.0	0.012935	26

Females 13-49 years old 	0.014	0.002679	19	0.005181	37	0.013334	95

** The values for the highest exposed population for each percentile are
bolded.

4.2.2.2  Chronic Dietary-Exposure Analysis

™ software, dietary exposure is estimated at 0.001836 mg/kg/day for
the general U.S. population (12% of the cPAD) and 0.008502 mg/kg/day
(57% of the cPAD) for children 1-2 years old, the population subgroup
with the highest estimated chronic dietary exposure to thiram.  The
estimated exposures/risks for combined food and water are summarized in
Table 4.2.2.2 for all populations.

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

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

	General U.S. Population	0.015	0.001836	12

All Infants (<1 year old)	0.015	0.004760	32

Children 1-2 years old	0.015	0.008502	57

Children 3-5 years old	0.015	0.006677	44

Children 6-12 years old	0.015	0.003059	20

Youth 13-19 years old	0.015	0.001042	7

Adults 20-49 years old	0.015	0.000957	6

Adults 50+ years old	0.015	0.001316	9

Females 13-49 years old	0.015	0.001081	7

4.2.2.3  Cancer Dietary-Exposure Analysis

Thiram is considered to be “not likely to be carcinogenic to humans”
based on the results of a rat chronic toxicity/carcinogenicity study and
a mouse carcinogenicity study.

4.3  Water Exposure/Risk Pathway

™ into the food categories “water, direct, all sources” and
“water, indirect, all sources” for the dietary assessments.

Table 4.3.  EDWCs for Use in the Human-Health Risk Assessment.

Crop 	Annual App Rate (lbs ai/acre/yr) 	SCIGROW concentration (ppb) 
PRZM/EXAMS* Acute EEC (ppb) 	PRZM/EXAMS* non-cancer chronic EEC (ppb) 
PRZM/EXAMS* cancer chronic EEC (ppb) 

Turf farm 	146.6 	0.84 	47.8 	2.5 	2.2 

Golf course 	146.6 	0.84 	14.8 	0.78 	0.67 

Apples 	22.5 	0.13 	16.3 	1.2 	1.1 

* Index Reservoir environment 

4.4  Residential Exposure/Risk Pathway

Reference:  RED Addendum (F. Fort; 6/6/05, D303131).

Thiram is not available for sale or use by homeowner applicators. 
However, there is potential for residential exposure from treated golf
course greens and tees.  All thiram turf uses that would conceivably
lead to children’s exposure on treated turf have been cancelled by the
registrant and as such are no longer included in this assessment. 
Therefore, residential exposures resulting from dermal contact with
thiram-treated turf were assessed for adults.  Inhalation
postapplication exposures for golf courses were not assessed since
inhalation exposures are thought to be negligible in outdoor
postapplication scenarios.  When use is restricted to greens and tees,
the duration of exposure is 1 hour to reflect the anticipated time a
player would be spending in contact with those areas.  Risks are not of
concern on the day of application for golfers (i.e., MOEs >100 on day of
application) (Table 4.4).

Table 4.4.  Summary of Thiram Noncancer Postapplication Residential MOEs
For Adults.

Scenario	Descriptor	MOE on Day 0

Golfing	16.3 lb ai/A - California Data	1840

	24.5 lb ai/A - California Data	1220

5.0  AGGREGATE-RISK ASSESSMENTS AND RISK CHARACTERIZATION

5.1  Acute Aggregate Risk

The acute aggregate risk assessment takes into account exposure
estimates from dietary consumption of thiram (food and drinking water). 
The acute dietary-exposure estimates, are not of concern to HED (<100%
aPAD) at the 99th exposure percentile for the general U.S. population
and all other population subgroups, except for children 1-2 years old
(see Table 4.2.2.1).  The refined probabilistic acute dietary-exposure
assessment was performed using %CT provided by BEAD, distributions of
field-trial residue values, and empirical processing factors. 
Generally, HED’s level of concern for acute dietary risk is 100% of
the aPAD.  However, HED does not consider the acute dietary risk for
children 1-2 years old (107% of the cPAD) to be of concern because the
residue estimates in all foods were based on the results of field trials
(see Section 4.2.2.1).  Therefore, the acute aggregate risk associated
with the proposed uses of thiram is not of concern to HED for the
general U.S. population or any population subgroups.

5.2  Short-and Intermediate-Term Aggregate Risk

In aggregating short- and intermediate-term risk, the Agency routinely
combines background chronic dietary exposure (food + water) with short-
and intermediate-term residential exposure.  Dietary (food + water)
exposure can be added to the estimated residential exposure because the
endpoints are the same.  The combined exposure may then be used to
calculate an MOE for aggregate risk.  Using the golfer scenario,
combined with applicable subpopulation with the greatest dietary
exposure– i.e., adults 50+ years old, the total short- and
intermediate-term food and residential aggregate MOE is 580.  As this
MOE is greater than 100, the short- and intermediate-term aggregate risk
does not exceed the HED’s LOC.  Table 5.2 summarizes the
short/intermediate-term aggregate exposure to thiram residues.

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

Population	Short- or Intermediate-Term Scenario

	NOAEL

mg/kg/day	Target

MOE1	Max

Exposure2

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

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

Adults 50+ years old5	1.4	100	0.014	0.001316	0.0011	580

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

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

3 Residential Exposure = [Oral exposure + Dermal exposure + Inhalation
Exposure].

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

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

6.0  CUMULATIVE RISK

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

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

7.0  DATA DEFICIENCIES/LABEL REVISIONS

7.1  Toxicology

Cholinesterase activity assessment screening assay.

Required as a result of the revisions of 40 CFR §158:

Guideline immunotoxicity study.

7.2  Residue Chemistry

860.1340 Residue Analytical Methods

Revision of enforcement method A7193 to address the comments from ACB
(Memo, C. Stafford, D353875; 10/23/08).

860.1360 Multiresidue Methods

The requirement for multiresidue method testing of thiram remains
unfulfilled.  

860.1500 Crop Field Trials

HED requests that the petitioner conduct an additional 3 trials (1 each
in Guatemala, Colombia, and Honduras).  

860.1550 Proposed Tolerances

The submitted data for whole unbagged bananas were entered into the
tolerance spreadsheet (see Appendix I).  Using the rounding procedure as
outlined in the Guidance for Setting Pesticide Tolerances Based on Field
Trial Data SOP, HED recommends tolerance levels of 0.80 ppm for banana. 
Banana pulp is not listed in Table 1 of OPPTS 860.1000; therefore, this
entry should be removed from the Section F.  

Revision of the tolerance level for banana may be required once the
requested field-trial data are available.

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

RDI: Branch (10/29/08); RAB1 Chemists (10/29/08); RAB1 Toxicologists
(8/28/08)

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

Appendix A:  Toxicology Assessment

A.1  Toxicology Data Requirements

The HIARC has recommended submission of a cholinesterase activity
assessment screening assay based on concerns for potential
cholinesterase activity inhibition by thiram as was seen in a
structurally related dithiocarbamate.  Currently, immunotoxicity studies
are being required on all pesticides under 870.7800.

A.2  Toxicity Profiles

 ≥2.0 g/kg 	III

870.1300	Acute inhalation (rat)	00165855	LC50 ≥0.1 mg/L	II

870.2400	Primary eye irritation (rabbit)	00259250	Moderate eye irritant
II

870.2500	Primary dermal irritation (rabbit)	00259250	Very slight dermal
irritant	IV

870.2600	Dermal sensitization 	00153068	Moderate skin sensitizer	N/A

Table A.2.2	Subchronic and Chronic Toxicity and Genotoxicity Profile –
Thiram

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

870.3100	90-Day oral toxicity (rat)	40773601 (1988)

Unacceptable/guideline

0, 50, 500, or 1000 ppm

(0, 2.5, 25, or 50 mg/kg bw/day)	NOAEL = could not be determined due to
lack of information on stability. 

LOAEL = 25 mg/kg/day, based on decreases in body-weight gain, hematology
and clinical chemistry parameters.

870.3150

	90-Day oral toxicity (dog)	461503608 (1990) Acceptable/guideline

0, 75, 250, or 500 ppm 

(0, 1.94-2.58, 6.17-7.85, or 10.55-14.69 mg/kg bw/day) 	NOAEL = 1.9
mg/kg/day. 

LOAEL = 6.3 mg/kg/day, based on adverse changes in clinical chemistry,
and decreases in mean body weight and food consumption.

870.3200

	21-Day dermal toxicity (rabbit)	42642501 (1992)

Acceptable/guideline

0, 250, 500, or 1000 mg/kg bw/day	NOAEL = 300 mg/kg/day.

LOAEL = 1000 mg/kg/day, based on decreases in body-weight gain and food
consumption as well as alterations in clinical chemistry.

870.3700a

	Prenatal developmental (rat)	00151610 (1978)

Unacceptable/guideline

0, 12.5, 25, 50, or 100 mg/kg bw	Maternal NOAEL = 12.5 mg/kg.

LOAEL = 25 mg/kg, based on reduced body-weight gains and food
consumption.

Developmental NOAEL could not be determined.

LOAEL = 12.5 mg/kg, based on reduced ossification.

870.3700a

	Prenatal developmental (rat)	40534101; 41498301 (1988)

Acceptable/guideline

0, 7.5, 15, or 30 mg/kg bw

	Maternal NOAEL could not be determined. 

LOAEL = 7.5 mg/kg, based on decreases in body-weight gain, alopecia,
scars, damaged digits, red-stained paws and excessive salivation.

Developmental NOAEL = 7.5 mg/kg. 

LOAEL = 15 mg/kg based on retarded growth and rudimentary 13th rib, and
reduced ossification.

870.3700b

	Prenatal developmental (rabbit)	40444702(1987)

Acceptable

0, 1, 3, 5, 7.5, 10, 20, 40, or 80 mg/kg bw

(range-finding)	Maternal NOAEL = 3 mg/kg bw/day.

LOAEL = 5 mg/kg/day, based on decreased maternal body-weight gains. 

Developmental NOAEL was not determined.

LOAEL was not determined. 

870.3700b

	Prenatal developmental (rabbit)	40577301 (1988)

Acceptable

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

(range-finding)	Maternal NOAEL = 5 mg/kg bw/day.

LOAEL was not determined. 

Developmental NOAEL = 5 mg/kg.

LOAEL was not determined.

870.3700b

	Prenatal developmental (rabbit)	42223601 (1992)

Acceptable

0, 1, 5, or 10 mg/kg bw	Maternal NOAEL = 10 mg/kg bw/day

LOAEL was not determined 

Developmental NOAEL = 10 mg/kg

LOAEL was not determined.

870.3800

	2-Gen. reproduction and fertility effects

(rat)	42095901 (1991)

Acceptable/guideline

0, 30, 60, or 180 ppm

(F0: 0/0, 1.2/1.9, 2.4/3.9, or 8.5/11.8 mg/ kg bw/day [M/F])

(F1: 0/0, 1.5/2.0, 3.24.3, or 9.2/13.4 mg/kg bw/day [M/F]

	Parental/Systemic NOAEL = 30 ppm (1.9 mg/kg/day [M/F]).

LOAEL = 60 ppm (2.6/3.1.7 mg/kg/day [M/F]) based on decreases in
body-weight gain and food consumption.

Reproductive NOAEL was not determined.

LOAEL >180 ppm (8.9 mg/kg/day).

Offspring NOAEL = 180 ppm (11.8 mg/kg/day).

LOAEL = 60 ppm (3.9 mg/kg/day), based on decreased mean body weight.

870.3800

	2-Gen. reproduction and fertility effects

(rat)	45441203 (1997)

Acceptable/guideline

0, 20, 60, or 180 ppm

(0, 1.4, 4.2, or 12.2 mg/kg bw/day)	Parental/Systemic NOAEL = 30 ppm
(1.4 mg/kg/day).

LOAEL = 60 ppm (4.7 mg/kg/day) based on reduced body-weight gains during
gestation.

 NOAEL ≥ 180 ppm (12.2 mg/kg/day).

LOAEL was not determined.

Offspring NOAEL = 20 ppm (1.4 mg/kg/day).

LOAEL = 60 ppm (4.2 mg/kg/day), based on decreases in pup body weight
and body-weight gain.

870.4100

	Chronic toxicity (1 year; dog)	41967901 (1991)

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0, 30, 90, or 250 ppm

M; 0, 0.84, 2.61, or 7.35 mg/kg bw/day 

F: 0, 0.90, 2.54, or 7.23 mg/kg bw/day	NOAEL (M) = 30 ppm (0.84
mg/kg/day).

NOAEL (F) = 90 ppm (2.54 mg/kg/day).

LOAEL (M) = 90 ppm (2.61 mg/kg/day, based on increased mean cholesterol
levels.

LOAEL (F) = 250 ppm (7.23 mg/kg/day), based on increased mean
cholesterol levels and increased liver-to-body weight ratios. 

870.4200

	Carcinogenicity

(mouse)	42313401 (1992)

Acceptable/guideline

M: 0, 15, 150, or 300 ppm F:  0, 15, 300, or 600 ppm

M: 0, 2.5, 24, and 57 mg/kg bw/day

F: 0, 3.1, 57, and 112 mg/kg bw/day	NOAEL = 15 ppm (M/F: 2.5/3.1 mg/kg
bw/day).

LOAEL (M) = 150 ppm (24 mg/kg bw/day.

LOAEL (F) = 300 ppm (57 mg/kg/day), based on decreases in mean body
weight and mean body-weight gain, anemia, and non-neoplastic lesions in
the eyes, non-glandular stomach and urinary bladder.

No evidence of carcinogenicity.

870.4300

	Combined chronic toxicity/

carcinogenicity

(rat)	42157601 (1991)

Acceptable/guideline

0, 30, 150, or 300 ppm (0, M: 0, 1.5, 7.3, and 14.7 mg/kg bw/day

F: 0, 1.8, 8.9, and 18.6 mg/kg bw day 	NOAEL = 30 ppm (M/F: 1.5/1.8
mg/kg/day).

LOAEL = 150 ppm (M/F: 7.3/8.9 mg/kg/day), based on changes in
hematology, clinical chemistry, incidences of bile duct hyperplasia and
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0.001-56.0 μg/mL (±S9)	No evidence of mutagenicity with or without
metabolic activation.

870.5375	In Vitro Mammalian Cytogenetics (Chromosomal Aberration Assay
in Chinese Hamster Ovary Cells) 	40510901 ( 1987)

Acceptable/guideline

0.56, 1.0, or 2.4 μg/mL (-S9)

1.8, 5.6, or 18.0 μg/mL (+S9)	Significant dose-related increases in
chromosomal aberrations with and without metabolic activation. 
Classified as a clastogen.

870.5395	Mammalian erythrocyte micronucleus test	40510902 (1987)

Acceptable/guideline

38, 189, or 377 mg/kg

 or 10.0 μg/mL	Did not induce DNA repair.

870.6200a

	Acute neurotoxicity screening battery	45589101 ( 1993)

Unacceptable/non-guideline

0, 10, 25, 60, or 150 mg/kg bw	NOAEL = 10 mg/kg.

LOAEL = 25 mg/kg, based on decreases in food consumption in males and
females. 

870.6200a

	Acute neurotoxicity screening battery	42912401 ( 1993)

Acceptable/guideline

0, 2, 150, or 600 mg/kg bw	NOAEL = 5 mg/kg.

LOAEL = 150 mg/kg, based on FOB effects at 21/2 hours post-dosing;
reduced motor activity at 31/2 hours, and at 7 and 14 days
post-treatment.  

870.6200b 	Subchronic neurotoxicity – feeding study in rats	43012701
(1993)

Acceptable/guideline

0, 30, 125 or 500 ppm (0/0, 1.74/2.04, 7.26/8.07, and 28.63/31.82 mg/kg
bw/day [M/F])	NOAEL = 30 ppm (1.74/2.04 mg/kg/day [M/F]).

LOAEL = 125 ppm (7.26/8.07 mg/kg/day [M/F]), based on increased numbers
of rearing events and elevated incidences of hyperactivity in females at
weeks 8 and 13. 

870.6300

	DNT	46455201 (2004)

Acceptable/guideline

0, 20, 45, or 90 ppm

0, 1.4, 3.7, or 7.2 mg/kg bw/day	Maternal NOAEL = 45 ppm (3.7
mg/kg/day).

LOAEL = 90 ppm (7.2 mg/kg/day), based on decreased body weight,
body-weight gain, and food consumption, clinical signs of toxicity, and
FOB findings.

Offspring NOAEL = 20 ppm (1.4 mg/kg/day.

LOAEL = 45 ppm (3.7 mg/kg/day) based on increased locomotor activity in
females on PND17.

870.7485

	Metabolism and pharmacokinetics

摧粬]ЀC was eliminated in the urine, 2.6-5.3% in the feces and 47-48%
in the expired air.  The nature of the volatile 14C was not investigated
in detail, but 75-85% of it was collected in a KOH trap suggesting CO2,
or COS, with the remainder collected in a reagent for CS2.  Norris
(1991) identified by HPLC the metabolites in the urine of the rats from
the single dose study of Gay (1987) and the multiple dose study of
Nomeir and Markham (1990).  There were no sex differences in the
metabolism but the proportions of some of the metabolites depended on
the dosage level and the time after dosing.
[www.fao.org/docrep/W5897E/w5897e5a.htm]

Thiram	                       Human-Health Risk Assessment		DP# 356570

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