UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, D.C.  20460

OFFICE OF

PREVENTION, PESTICIDES, AND

TOXIC SUBSTANCES

MEMORANDUM

DATE:	09-JUN-2009

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

PC Code:  079801	DP No.:  D365442

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

Risk Assessment Branch 1 (RAB1)

Health Effects Division (HED) (7509P)

THROUGH:	Dana M. Vogel, Branch Chief

				RAB1/HED (7509P)

Jess Rowland, Ph.D., Toxicologist

Science Information Management Branch (SIMB)/HED (7509P)

TO:		Bryant Crowe/Tony Kish, PM Team 22

		Registration Division (RD) (7505P)

NOTE:  This updated document supersedes “Thiram in/on Imported
Bananas.  Human-Health Risk Assessment,” (D356570, dated 11-NOV-2008).
 This assessment has been updated to include: 1) revisions to the hazard
profile and hazard characterization; 2) incorporation of the results of
a developmental neurotoxicity (DNT) study; and 3) the use of a benchmark
dose (BMD) dose for the acute dietary risk assessment.

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) and Jess Rowland
(SIMB).

Table of Contents

  TOC \o "1-3" \h \z \u    HYPERLINK \l "_Toc232318553"  2.0
PHYSICAL/CHEMICAL PROPERTIES CHARACTERIZATION	  PAGEREF _Toc232318553 \h
 9

  HYPERLINK \l "_Toc232318554"  2.1  Identification of Active Ingredient
  PAGEREF _Toc232318554 \h  9

  HYPERLINK \l "_Toc232318555"  2.2  Physical and Chemical Properties
PAGEREF _Toc232318555 \h  9

  HYPERLINK \l "_Toc232318556"  3.0  HAZARD CHARACTERIZATION/ASSESSMENT
 PAGEREF _Toc232318556 \h  9

  HYPERLINK \l "_Toc232318557"  3.1  Hazard and Dose-Response
Characterization	  PAGEREF _Toc232318557 \h  9

  HYPERLINK \l "_Toc232318558"  3.1.1  Database Summary	  PAGEREF
_Toc232318558 \h  9

  HYPERLINK \l "_Toc232318559"  3.1.2  Toxicological Effects	  PAGEREF
_Toc232318559 \h  10

  HYPERLINK \l "_Toc232318560"  3.2  Absorption, Distribution,
Metabolism, Excretion (ADME)	  PAGEREF _Toc232318560 \h  11

  HYPERLINK \l "_Toc232318561"  3.3  FQPA Considerations	  PAGEREF
_Toc232318561 \h  11

  HYPERLINK \l "_Toc232318562"  3.3.1  Adequacy of the Toxicity Database
  PAGEREF _Toc232318562 \h  12

  HYPERLINK \l "_Toc232318563"  3.3.2  Evidence of Neurotoxicity
PAGEREF _Toc232318563 \h  12

  HYPERLINK \l "_Toc232318564"  3.3.3  Developmental Toxicity Studies
PAGEREF _Toc232318564 \h  16

  HYPERLINK \l "_Toc232318565"  3.3.5  Additional Information from
Literature Sources	  PAGEREF _Toc232318565 \h  22

  HYPERLINK \l "_Toc232318566"  3.3.6  Pre-and/or Postnatal Toxicity
PAGEREF _Toc232318566 \h  22

  HYPERLINK \l "_Toc232318567"  3.3.7  Recommendation for a DNT Study
PAGEREF _Toc232318567 \h  22

  HYPERLINK \l "_Toc232318568"  3.4  FQPA SF for Infants and Children
PAGEREF _Toc232318568 \h  22

  HYPERLINK \l "_Toc232318569"  3.5  Hazard Identification and Toxicity
Endpoint Selection	  PAGEREF _Toc232318569 \h  23

  HYPERLINK \l "_Toc232318570"  3.5.1  Acute Reference Dose (aRfD) –
Females 13-49	  PAGEREF _Toc232318570 \h  23

  HYPERLINK \l "_Toc232318571"  3.5.2  aRfD – General Populations
PAGEREF _Toc232318571 \h  23

  HYPERLINK \l "_Toc232318572"  3.5.3  Chronic Reference Dose (cRfD)
PAGEREF _Toc232318572 \h  24

  HYPERLINK \l "_Toc232318573"  3.5.4-5  Incidental Oral Exposure
(Short- and Intermediate-Term)	  PAGEREF _Toc232318573 \h  25

  HYPERLINK \l "_Toc232318574"  3.5.6  Dermal Absorption	  PAGEREF
_Toc232318574 \h  25

  HYPERLINK \l "_Toc232318575"  3.5.7-8  Dermal Exposure (Short- and
Intermediate-Term)	  PAGEREF _Toc232318575 \h  26

  HYPERLINK \l "_Toc232318576"  3.5.9  Inhalation Exposure	  PAGEREF
_Toc232318576 \h  26

  HYPERLINK \l "_Toc232318577"  3.5.10  Level of Concern for MOEs
PAGEREF _Toc232318577 \h  26

  HYPERLINK \l "_Toc232318578"  3.5.11  Recommendation for Aggregate
Exposure Risk Assessments	  PAGEREF _Toc232318578 \h  26

  HYPERLINK \l "_Toc232318579"  3.5.12  Classification of Carcinogenic
Potential	  PAGEREF _Toc232318579 \h  27

  HYPERLINK \l "_Toc232318580"  3.5.13  Summary of Toxicological Doses
and Endpoints for Thiram for Use in Human Risk Assessments	  PAGEREF
_Toc232318580 \h  27

  HYPERLINK \l "_Toc232318581"  3.6  Endocrine Disruption	  PAGEREF
_Toc232318581 \h  28

  HYPERLINK \l "_Toc232318582"  3.7  Public Health and Pesticide
Epidemiology Data	  PAGEREF _Toc232318582 \h  28

  HYPERLINK \l "_Toc232318583"  4.0  EXPOSURE ASSESSMENT AND
CHARACTERIZATION	  PAGEREF _Toc232318583 \h  29

  HYPERLINK \l "_Toc232318584"  4.1  Summary of Registered/Proposed Uses
  PAGEREF _Toc232318584 \h  29

  HYPERLINK \l "_Toc232318585"  4.2  Dietary Exposure/Risk Pathway
PAGEREF _Toc232318585 \h  29

  HYPERLINK \l "_Toc232318586"  4.2.1  Residue Profile	  PAGEREF
_Toc232318586 \h  30

  HYPERLINK \l "_Toc232318587"  4.2.2  Dietary-Exposure Analyses
PAGEREF _Toc232318587 \h  32

  HYPERLINK \l "_Toc232318588"  4.3  Water Exposure/Risk Pathway
PAGEREF _Toc232318588 \h  34

  HYPERLINK \l "_Toc232318589"  4.4  Residential Exposure/Risk Pathway
PAGEREF _Toc232318589 \h  35

  HYPERLINK \l "_Toc232318590"  5.0  AGGREGATE-RISK ASSESSMENTS AND RISK
CHARACTERIZATION	  PAGEREF _Toc232318590 \h  35

  HYPERLINK \l "_Toc232318591"  5.1  Acute Aggregate Risk	  PAGEREF
_Toc232318591 \h  35

  HYPERLINK \l "_Toc232318592"  5.2  Short- and Intermediate-Term
Aggregate Risk	  PAGEREF _Toc232318592 \h  35

  HYPERLINK \l "_Toc232318593"  6.0  CUMULATIVE RISK	  PAGEREF
_Toc232318593 \h  36

  HYPERLINK \l "_Toc232318594"  7.0  DATA DEFICIENCIES/LABEL REVISIONS
PAGEREF _Toc232318594 \h  36

  HYPERLINK \l "_Toc232318595"  7.1  Toxicology	  PAGEREF _Toc232318595
\h  36

  HYPERLINK \l "_Toc232318596"  7.2  Residue Chemistry	  PAGEREF
_Toc232318596 \h  36

  HYPERLINK \l "_Toc232318597"  Appendix A:  Toxicology Assessment
PAGEREF _Toc232318597 \h  38

  HYPERLINK \l "_Toc232318598"  A.1  Toxicology Data Requirements
PAGEREF _Toc232318598 \h  38

  HYPERLINK \l "_Toc232318599"  A.2  Toxicity Profiles	  PAGEREF
_Toc232318599 \h  38

 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

The available toxicological database for thiram suggests that this
chemical has a low to moderate acute-toxicity profile.  Thiram has been
shown to cause neurotoxicity following acute and subchronic exposures.
In the acute and subchronic neurotoxicity studies submitted to the
Agency, neurotoxicity is characterized as lethargy, reduced and/or tail
pinch response, changes in the functional-observation battery (FOB)
parameters, increased hyperactivity, changes in motor activity, and
increased occurrences of rearing events.  No treatment-related changes
were observed in brain weights or in the histopathology of the nervous
system.  In a non-guideline study published in the open literature,
chronic feeding of thiram to rats caused neurotoxicity, with onset of
ataxia in some animals 5-19 months after beginning of treatment.
However, no evidence of neurotoxicity was seen following chronic
exposures in mice or rats in guideline studies submitted to the Agency.
In addition, no adverse effects on the developing fetal nervous system
were seen in a DNT study.  The chronic toxicity profile for thiram
indicates that the liver, blood, and urinary system are the target
organs for this chemical in mice, rats, and dogs.  There is no evidence
for increased susceptibility following in utero exposures to rats or
rabbits and following pre- and post-natal exposures to rats for two
generations.  There is low concern for the increased susceptibility seen
in the developmental toxicity study since the dose response is well
defined and this endpoint is used for assessing the acute dietary risk
for the most sensitive population.  Thiram is classified as “not
likely to be a human carcinogen” based on lack of evidence for
carcinogenicity in mice or rats.  There are no mutagenic/genotoxic
concerns with thiram.

Dose-Response Assessment

Based on the toxicity profile, HED has selected neurotoxicity as the
endpoint for assessing acute dietary and dermal risks and systemic
toxicity as the endpoint for assessing chronic dietary risk.  Systemic
toxicity manifested as decreases in body weight, alterations in
hematology and clinical chemistry parameters, changes in organ weights,
and changes in liver and bileduct hisopathology in rats and/or dogs.
Since thiram has been classified as a chemical “not likely to be
carcinogenic to humans,” no cancer risk assessment has been conducted.
 The registered uses for thiram do not indicate long-term
occupational/residential inhalation or dermal exposures.  Consequently,
long-term risk assessments via the inhalation or dermal routes were not
conducted.

Food Quality Protection Act (FQPA) Decision

The thiram risk assessment team recommends that the 10X FQPA Safety
Factor (SF) be reduced to 1X.  This recommendation is based on the
following considerations.  The toxicological database for thiram is
complete with acceptable neurotoxicity, developmental, and reproductive
toxicity studies.  There are no residual uncertainties for pre and post
natal toxicity.  In accordance with the revised Part 158 an
immunotoxicity study in required.  There is no evidence of toxicity to
the immune organs in any study in the database.  In addition, thiram
does not belong to a class of chemicals (e.g., the organotins, heavy
metals, or halogenated aromatic hydrocarbons) that would be expected to
be immunotoxic.  Based on the above considerations, HED does not believe
that conducting a series 870.7800 immunotoxicity study will result in a
point of departure (PoD) lower than that used for overall risk
assessment.  Therefore an additional database uncertainty factor (UFDB)
does not need to be applied.  This study, however, should be submitted
as a condition of conversion of the time-limited tolerance to permanent
tolerance (see Section 7.1).

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)

A refined probabilistic acute dietary-exposure assessment was performed
using percent crop treated (%CT) provided by the Biological and Economic
Analysis Division (BEAD), distributions of field-trial residue values,
and empirical processing factors.  Dietary risk estimates were
determined considering exposures from food plus drinking water using
estimated drinking water concentrations (EDWCs) for surface water
sources provided by the Environmental Fate and Effects Division (EFED).
EDWC values were generated by the Pesticide Root Zone Model/Exposure
Analysis Modeling System (PRZM/EXAMS) for the turf application scenario,
since this crop yielded the highest EDWC values.  The resulting acute
dietary risk estimates for food and water combined are below HED’s
level of concern (i.e., <100% of the acute population-adjusted dose
(aPAD) of 0.6494 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).  Using the Dietary Exposure Evaluation Model
(DEEM-FCID™), 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 (3.3% of the aPAD); 0.053321 mg/kg/day (8.2% of
the aPAD) for children 1-2 years old, the population subgroup with the
highest estimated acute dietary exposure to thiram; and 0.013334
mg/kg/day (95% of the aPAD) for females 13-49 years old, the population
subgroup with the highest estimated acute dietary risk to thiram.

™ 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 Population The increased
susceptibility observed in a non-guideline study (1978) was determined
to be non-reliable because of deficiencies in study design, performance
and/or reporting and the results of that study were not replicated in a
recent study (1988) that was conducted in accordance with the Agency’s
Good Laboratory Practice (GLP) regulations.  Therefore, there is no
confidence in the results of the non-guideline study.  There is no
evidence of increased susceptibility following pre- and post-natal
exposures in the two-generation reproduction study in rats.  There is
low concern for the increased susceptibility seen in the developmental
toxicity study since the dose response is well defined and this endpoint
is used for assessing the acute dietary risk for the most sensitive
population

s and Low-Income Populations,"
(http://www.hss.energy.gov/nuclearsafety/env/guidance/justice/eo12898.pd
f).

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 Continuing Surveys
of Food Intakes by Individuals (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

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

870.7800 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.

Note to RD:  The domestic uses of thiram on apples have been cancelled
and that Taminco has requested that the apple tolerance be maintained in
order to allow importation of thiram-treated apples.  HED recommends
that the registrant be required to provide labels and residue data from
all countries which are significant sources of imported apples and in
which thiram is used.  These data are necessary to determine the
adequacy of the apple tolerance to support importation of thiram-treated
apples.

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.

<IP_ADDRESS>  Studies Available and Considered (animal, human, general
literature)

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

Subchronic toxicity – Oral studies in rats and dogs and a dermal
toxicity in rabbits.

Chronic toxicity – Combined chronic toxicity/carcinogenicity study in
rats and a carcinogenicity in mice.

Developmental toxicity – Pre-natal developmental toxicity studies in
rats and rabbits  Reproductive toxicity – Multigeneration
reproduction/fertility studies in rats.

Neurotoxicity - acute neurotoxicity rat, subchronic neurotoxicity rat,
and DNT in rats.

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).

<IP_ADDRESS>  Mode-of-Action, Metabolism, and Toxicokinetic Data

Thiram is a dimethyl dithiocarbamate compound used as a fungicide.  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.

<IP_ADDRESS>  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 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.

Thiram has been shown to cause neurotoxicity but not neuropathology
following acute and subchronic exposures.  In the acute and subchronic
neurotoxicity studies submitted to the Agency, neurotoxicity is
characterized as lethargy, reduced and/or tail pinch response, changes
in the FOB parameters, increased hyperactivity, changes in motor
activity, and increased occurrences of rearing events.  No
treatment-related changes were observed in brain weights or in the
histopathology of the nervous system.  In a non-guideline study
published in the open literature (1976), chronic feeding of thiram to
rats caused neurotoxicity, with onset of ataxia in some animals 5-19
months after beginning of treatment.  However, no evidence of
neurotoxicity was seen following chronic exposures in mice or rats in
studies (1993) submitted to the Agency.  In addition, no central nervous
system malformations or neuropathology were seen in the developing
fetuses in a DNT study.

The data available for evaluation indicated that there is no evidence of
increased quantitative or qualitative susceptibility of the offspring
after pre-natal (in utero) exposure in rats or in rabbits.  The
increased susceptibility observed in a non-guideline study (1978) was
determined to be non-reliable because of deficiencies in study design,
performance and/or reporting and the results of that study were not
replicated in a recent study (1988) that was conducted in accordance
with the Agency’s Good Laboratory Practice (GLP) regulations.
Therefore, there is no confidence in the results of the non-guideline
study.  There is no evidence of increased susceptibility following pre-
and post-natal exposures in the two-generation reproduction study in
rats.  There is low concern for the increased susceptibility seen in the
developmental toxicity study since the dose response is well defined and
this endpoint is used for assessing the acute dietary risk for the most
sensitive population

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, observations 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, toxicity
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 seen in a carcinogenicity study in mice
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 red blood corpuscle (RBC) counts,
hemoglobin, and hematocrit levels, as well as increased hemosiderin in
the spleen, were seen at the higher doses.  There was no evidence of
carcinogenicity and thiram is classified as “not likely to be
carcinogenic to humans.”  There is no mutagenicity concern for thiram.

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 recommends that the 10X FQPA SF be
reduced to 1X.  This recommendation is based on the following
considerations.  The toxicological database for thiram is complete.
There are no residual uncertainties for pre and post natal toxicity.  In
accordance with the revised Part 158 an immunotoxicity study in
required.  There is no evidence of toxicity to the immune organs in any
study in the database.  In addition, thiram does not belong to a class
of chemicals (e.g., the organotins, heavy metals, or halogenated
aromatic hydrocarbons) that would be expected to be immunotoxic.  Based
on the above considerations, HED does not believe that conducting a
special series 870.7800 immunotoxicity study will result in a PoD lower
than that used for overall risk assessment.  Therefore an additional
UFDB does not need to be applied.  This study, however, should be
submitted as a condition of conversion of the time-limited tolerance to
permanent tolerance (see Section 7.1).

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:

	Acute and subchronic neurotoxicity studies in rats

Developmental toxicity study in rats

Developmental toxicity study in rabbits

Two-generation reproduction study in rats

DNT 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. A previous evaluation of this
study indicated a no-observed adverse-effect level (NOAEL) of 5 mg/kg
based on decreased motor activity and FOB findings.  Because of the poor
selection of the dose range (i.e, large dose spacing of 0, 5, 150, and
600 mg/kg) utilized in this study, the PoD can be higher than the NOAEL
of 5 mg/kg identified in the study, which is artificially low.  In order
to better evaluate this study, a BMD analysis was performed on the acute
neurotoxicity data to better assess the nature of the dose response
(Memo, J. Liccione, 5/6/09; TXR 0055174).  For this BMD analysis, a
standard 10% benchmark response (BMR) was considered (EPA 2000; EPA
Benchmark Dose Technical Guidance Document).  HED acknowledges the
variability of motor activity data, and that an alternative BMR might be
applicable; e.g., a 20% BMR.  However, because of the wide dose spacing
in the study and the uncertainty in the dose response between the NOAEL
of 5 mg/kg and the low dose of 150 mg/kg, a default 10% BMR was
considered.  It was recommended that the risk assessment team should use
the BMDL10 of 64.94 mg/kg as the PoD for assessing acute risk.

(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.

≥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 (highest dose tested; 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.

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 observation 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.

Developmental Neurotoxicity 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).

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 conducted in 1978 at the UCB-Pharmaceutical Division, Braine
L’Alleud, Belgium, is classified as unacceptable due to numerous
technical deficiencies that seriously compromised the interpretation of
the results.  There were no information on randomization procedures to
ensure homogenous initial body weight distribution, information
regarding the breeding, age, or housing conditions of the animals during
the study period, data on individual clinical observations, results of
individual fetal examinations, adequate, as well as quality assurance
statements (this study was conducted prior to the implantation of GLP).
Moreover, there is no confidence in the study or its findings
(quantitative susceptibility) since the results were not replicated in
the 1988 guideline study when tested at comparable doses (discussed
below).

(b) In a developmental toxicity study (MRID Nos. 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.

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, two 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 indicates 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.

These studies together satisfy the requirement for a developmental
toxicity study (OPPTS 870.3700; §83-3) 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 2-generation 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.

≤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.

This study is classified as acceptable/guideline and 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.

Premature deaths of several adults in each generation were considered
incidental to treatment.  No treatment-related clinical signs of
toxicity were observed in males or females during premating in any
generation.  No effects on body weights, body-weight gains, or food
consumption were seen in the low-dose groups of either generation.  No
treatment-related gross lesions were observed in the adults of either
generation at necropsy.  In adult animals, systemic toxicity was
primarily manifested as decreases in body weight, body-weight gain, and
food consumption.  With the exception of a statistically significant 10%
decrease in maternal body weight noted at the 180-ppm dose level during
gestation, body weight decreases in the F0 generation were minimal
(<6%).  Though these changes were on occasion statistically significant,
they were not considered toxicologically relevant since the magnitude of
the effect was not robust.  Body-weight gain was unaffected by treatment
during the pre-mating period but it was reduced by 15-22% during the
gestation period for the first littering [i.e., F0 (FIA)] at the mid-
and high-dose groups.  However, this decrease in body-weight gain did
not persist during the lactation period; in fact, body-weight gain
increased by 31-167% at dose levels ≥60 ppm.  Food consumption
decreases were noted in high-dose F0 animals during the pre-mating
(114-16%, p ≤0.01), gestation (19-15%, p ≤0.01), and lactation
(111-17%, p ≤0.01) periods of the first littering.  During the second
mating [i.e., F0(FIB)], body weights were unaffected.  As was the case
during the first mating, body-weight gains of high-dose females were
unaffected during the pre-mating period, reduced during gestation
(1-14%), and increased during lactation (193-270%). Body-weight gains of
mid- and low-dose females and food consumption in all groups were not
affected.  During the first mating, F1 adults exhibited statistically
significant decreases (15-21%) in body weight at all dose levels during
pre-mating.  However, due to the lack of a dose-response relationship
and the higher body weights noted for the control group relative to the
control for other generations, the changes at the low- and mid-dose were
not considered compound-related.  The body-weight decreases noted at the
high-dose during gestation and lactation were minimal (<6%) and not
considered biologically relevant; no changes were noted at any other
dose level.  Overall body-weight gain during gestation was reduced by 16
and 20% at the 60- and 180-ppm dose levels, respectively but increased
by 173 and 247% during lactation.  During the second mating, body weight
was decreased by 26% in high-dose males and 7-17% in high-dose females
during pre-mating.  The body weight decreases in high-dose females were
consistently statistically significant and were therefore considered
biologically relevant.  At the 60-ppm dose level, body-weight gain was
reduced by 11-17% during the second and third week of gestation (days
7-20) while high-dose females displayed a statistically significant
decrease (1-20%, p ≤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.

≥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

None

3.3.6  Pre-and/or Postnatal Toxicity

<IP_ADDRESS>  Determination of Susceptibility

The data available for evaluation indicated that there is no evidence of
increased quantitative or qualitative susceptibility of the offspring
after pre-natal (in utero) exposure in rats or in rabbits.  The
increased susceptibility observed in a non-guideline 1978 study was
determined to be non-reliable due to numerous technical deficiencies in
the study design, performance, and/or reporting and the results of that
study were not replicated in a 1988 guideline study that was conducted
in accordance with the Agency’s GLP regulations.  Therefore there is
no confidence in the results of the non-guideline study. There is no
evidence of increased susceptibility following pre- and post-natal
exposures in the two-generation reproduction study in rats.  There is
evidence of quantitative susceptibility in the DNT study.

<IP_ADDRESS>  Degree-of-Concern Analysis and Residual Uncertainties for Pre-
and/or Postnatal Susceptibility

There was no evidence of increased susceptibility following in utero
exposure to rats or rabbits or following pre-and post natal exposures to
rats.  There is low concern for the enhanced susceptibility seen in the
DNT study because:  1) clear NOAELs/LOAELs were established for the
offspring effects; 2) the dose-response is well defined; 3) behavioral
effect of concern was observed only in females on one evaluation time
period; 4) the dose/endpoint is used for acute dietary risk for the most
sensitive population subgroup (females 13-49); and 5) there are no
exposure to infants and children from residential uses.  Consequently,
there are no residual uncertainties for pre- and post-natal toxicity.

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 FQPA SF was not retained (i.e., 1X) due to the completeness of the
data base, absence of any residual uncertainties for pre and or
post-natal toxicity, the use of dose and endpoint of concern for
appropriate exposure scenarios, and the use of unrefined (field trial)
exposure data.

3.5  Hazard Identification and Toxicity Endpoint Selection

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

Study Selected:  DNT Study

MRID No.:  46455201

Executive Summary:  See Section 3.3.2

Dose and Endpoint for Establishing aRfD:  Offspring NOAEL of 1.4
mg/kg/day based increased locomotor activity in females on PND 17 at 3.7
mg/kg/day.

Uncertainty Factor (UF):  100X (10X interspecies extrapolation and 10X
intraspecies variation).

Comments about Study/Endpoint:  This behavioral effect is presumed to
occur after a single dose.

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

100 (UF)

3.5.2  aRfD – General Populations

Study Selected:  Acute Neurotoxicity Study

MRID No.:  42912401

Executive Summary:  See Section 3.3.2

Dose and Endpoint for Establishing aRfD:  A BMDL10 of 64.94 mg/kg/day
was calculated for deriving this acute RfD.

UF:  100X (10X interspecies extrapolation and 10X intraspecies
variation).

Comments about Study/Endpoint:  The BMDL10 of 64.94 mg/kg, based on
motor activity in female rats at the 3.5-hour time point, contrasts with
the identified NOAEL of 5 mg/kg.  The BMD approach makes full use of the
dose-response data, and is therefore more advantageous than the NOAEL
approach.  The PoD can be higher than the NOAEL of 5 mg/kg identified in
the study, which is artificially low because of the spacing of the dose
selection.  Based on the BMD analysis, the female rat provides the
lowest BMD10 and BMDL10 values.

For this BMD analysis, a standard 10% benchmark response (BMR) was
considered (EPA 2000; EPA Benchmark Dose Technical Guidance Document).
HED acknowledges the variability of motor activity data, and that an
alternative BMR might be applicable, e.g., a 20% BMR.  However, because
of the wide dose spacing in the study and the uncertainty in the dose
response between the NOAEL of 5 mg/kg and the low dose of 150 mg/kg, a
default 10% BMR was considered.  The BMDL10 of 64.94 mg/kg should be
used as the PoD for assessing acute risk.

aRfD = 64.94 mg/kg/day (NOAEL) = 0.6494 mg/kg/day

100 (UF)

3.5.3  Chronic Reference Dose (cRfD)

Study Selected:  Co-critical Studies:

  (A) Combined Chronic Toxicity/Carcinogenicity Study - Rat

  (B) Chronic Oral Toxicity Study - Dog

MRID No.:  42157601 & 41967901

(A) Executive Summary:  In a combined chronic/oncogenicity study (MRID
No: 42157601), Thiram technical (97.5% a.i.) was administered to albino
rats Crl:CD®(SD)BR (60/sex/dose) in the diet at concentrations of 0,
16.3, 119, 262 ppm (as suggested by the Tox Sac) (0, 1.5, 7.3, and 14.7
mg/kg/day for males; 0, 1.8, 8.9, and 18.6 mg/kg/day for females) for
104 weeks.  Eighty animals (10/sex/dose) were sacrificed 1 year after
initiation of the study.

A significant decrease in food consumption in the 119 and 262 ppm dose
animals (males and females) was seen.  This observation is consistent
with the concomitant reduction in mean body weight gain.  However, this
decrease in mean body weight gain was only statistically and
biologically significant at the 262-ppm dose level.  Females and males
in this group had a 75% or 71% mean body weight gain, respectively, when
compared to the controls.  Mean RBC counts, hemoglobin (HGB), and
hematocrit (HCT) were decreased in the 10- and 119-ppm females.  In
contrast, the mean corpuscular volume (MCV) and mean corpuscular
hemoglobin (MCH) in these animals was higher (sometimes significantly
so) when compared to animals in the control group.  These observations
may bear some relation to the increased incidence of extramedullary
hematopoiesis of the liver in 262-ppm females as well as higher levels
of splenic extramedullary hematopoiesis observed in all females exposed
to the test article.  For their part, only males exposed to 262 ppm of
thiram had significantly lower RBC counts and higher MCV at week 27 of
the study, but not thereafter.

Clinical chemistry analysis revealed significantly lower (p (0.05)
glucose levels in animals treated with 262 ppm of the test article
(females at week 27 and males at week 53) when compared to the controls.
 Additionally, when compared to their control group counterparts,
females in the two higher dose groups (119 and 262 ppm) had higher blood
urea nitrogen levels.

An increase in the incidence of hepatocellular adenoma was seen in both
sexes.  While the incidence in the terminally sacrificed 300-ppm dose
group was statistically significant (17% and 20% in females and males,
respectively), when considered in conjunction with the unscheduled death
animals the incidences observed were not statistically significant (10%
and 15% for females and males, respectively) according to the Fisher’s
Exact Test.

A treatment-related and statistically significant increase in the
incidence of bile duct hyperplasia was seen in 119- and 262-ppm females.
 An increase in steatosis/fatty infiltration of the pancreas was also
seen in 119- and 262-ppm males and females.  Furthermore, males in the
two higher dose groups had a higher incidence of multifocal acinar
atrophy of the pancreas.  A statistically significant, but not
dose-related, increase in thyroid C-cell hyperplasia was seen in 119-
and 262-ppm females.

Based on changes in hematology, clinical chemistry, incidences of bile
duct hyperplasia, and reduction in mean body weight gain, the LOAEL is
set at a nominal concentration of 119 ppm (7.3 mg/kg/day for males and
8.9 mg/kg/day for females).  The NOAEL is set at a nominal concentration
of 16.3 ppm (1.8 mg/kg/day for females and 1.5 mg/kg/day males).

(B) Executive Summary:  In a chronic toxicity study (MRID No. 41967901),
thiram (97.5% a.i.) was administered to 6 beagle dogs/sex/dose in the
diet at levels of 0, 30, 90, and 250 ppm (0, 0.84, 2.61, and 7.35
mg/kg/day in males and 0, 0.90, 2.54, and 7.23 mg/kg/day in females) for
52 weeks.  Beginning on week 13 of the study, statistically significant
(p >0.05) elevated cholesterol levels were noted at the mid- and
high-dose ((44% and (47%, respectively vs. concurrent controls).
Toxicity was observed at 52 weeks in mid- and high-dose males as
significantly elevated mean cholesterol levels ((46.3% and 55.8%,
respectively vs. concurrent controls and 34.5% and 43.2% respectively,
vs historical controls), associated with increased incidences of high
(>200 mg/dL) cholesterol (mid-dose: 3/6; high-dose 4/6; concurrent
controls: 0/6; historical controls: 1/20).  In high-dose males there was
a significantly (both with respect to concurrent and historical
controls) increased mean liver-to-body weight ratio (high-dose: 3.1;
concurrent controls: 2.2, historical controls: 2.4).  Mean body weight
of high-dose males was significantly lower (-21.5%) than that of
historical controls, and lower (-11.2%; not significant) than that of
concurrent controls.  High-dose females had elevated mean cholesterol
levels (+60.1% vs. concurrent controls and +22.2% vs. historical
controls) and an increased mean liver-to-body weight ratio (high-dose:
3.0; concurrent controls: 2.4; historical controls: 2.5), but these were
significant only with respect to concurrent and not historical controls.
 However, one female in the high-dose group had a liver weight (396 g)
which was outside the established normal range of 163-361 g.

Under the conditions of this study, the NOAEL is established at 30 ppm
(0.84 mg/kg/day) and the LOAEL is set at 90 ppm (2.6 mg/kg/day) based on
elevated cholesterol levels and increases in liver-to-body weight ratio.

Dose and Endpoint for Establishing cRfD:  1.5 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 in
conjunction with elevated cholesterol levels and increased liver weights
reported in the chronic oral toxicity study in dogs at 2.6 mg/kg/day.

UF(s):  100X (10X interspecies extrapolation and 10X intraspecies
variation).

Comments about Study/Endpoint:  Hepatotoxicity seen following chronic
exposures in two species at comparable doses.

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)

Toxicity endpoints were not selected for this exposure scenario since
there are no residential uses which result in this exposure scenario
associated with this action.

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  Inhalation Exposure

Toxicity endpoints for assessing risk via inhalation were not selected
since the use pattern (i.e., from use on golf courses) indicates low
exposure potential via this route.

3.5.10  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 (golf course use only) Exposure1

Oral	100	100	NA

Dermal	100	100	NA

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.

3.5.11  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:

For short- and intermediate-term aggregate exposure risk assessments,
the MOEs derived for oral, dermal, and inhalation exposures may be
combined since common endpoints (increases in motor activity seen in
female offspring) were identified via the dermal route (short- and
intermediate-term dermal exposures) and inhalation risk assessments (all
durations).

3.5.12  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.

3.5.13  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
3.5.13.

Table 3.5.13.  Summary of Toxicological Doses and Endpoints for Thiram
for Use in Dietary and Non-Occupational Human Health Risk Assessments.

Exposure/

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

Acute Dietary

(General Population)

	BMDL10 = 64.94 mg/kg

	UFA = 10x

UFH = 10x

FQPA SF = 1x

	Acute RfD = 0.6494

mg/kg/day

aPAD = 0.6494 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- and Intermediate- Term Incidental Oral 	No incidental oral
residential exposure.

Short-Term Dermal (1-30 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.

Short- and Intermediate-Term Inhalation	Toxicity endpoints not used due
to low exposure potential.

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.

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#
365915).

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.

<IP_ADDRESS>  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.

The resulting acute dietary risk estimates for food and water combined
are below HED’s level of concern (i.e., <100% of the aPAD of 0.6494
mg/kg bw/day) for the general U.S. population and all population
subgroups (including females 13-49 years old; aPAD of 0.014 mg/kg
bw/day).  Using DEEM-FCID™, acute dietary exposure at the 99.9th
exposure percentile is estimated at 0.021447 mg/kg/day for the general
U.S. population (3.3% of the aPAD); 0.053321 mg/kg/day (8.2% of the
aPAD) for children 1-2 years old, the population subgroup with the
highest estimated acute dietary exposure to thiram; and 0.013334
mg/kg/day (95% of the aPAD) for females 13-49 years old, the population
subgroup with the highest estimated acute dietary risk to thiram.  The
estimated exposures/risks for combined food and water are summarized in
Table <IP_ADDRESS> for all populations.

Table <IP_ADDRESS>.  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	0.6494	0.003077	<1	0.006913	1.0	0.021447	3.3

All Infants (<1 year old)	0.6494	0.010241	1.6	0.016334	2.5	0.032281	5.0

Children 1-2 years old	0.6494	0.006571

0.018851	2.9	0.053321	8.2

Children 3-5 years old	0.6494	0.005181	<1	0.015580	2.4	0.048814	7.5

Children 6-12 years old	0.6494	0.003337	<1	0.007901	1.2	0.029802	4.6

Youth 13-19 years old	0.6494	0.002283	<1	0.004941	<1	0.013688	2.1

Adults 20-49 years old	0.6494	0.002620	<1	0.005133	<1	0.012240	1.9

Adults 50+ years old	0.6494	0.002409	<1	0.004489	<1	0.012935	2.0

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

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

<IP_ADDRESS>  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 <IP_ADDRESS> for all populations.

Table <IP_ADDRESS>.  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

<IP_ADDRESS>  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.  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.  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 <IP_ADDRESS>).

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 (dimethyl dithiocarbamate) 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

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

870.7800 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)

RDI:  RAB1 Chemists (10/29/08)

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

Table A.2.1.  Acute Toxicity Profile – Thiram.

Guideline No.	Study Type	MRID(s)	Results	Toxicity Category

870.1100	Acute oral (rat)	00163854	LD50 = 2.6 g/kg 	III

870.1200	Acute dermal 	00259250	LD50 ≥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 = 20 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, 5, 150, or 600 mg/kg bw	BMDL10 = 64.94 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

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摧弩÷Ѐnated 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# 365442

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