**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

WASHINGTON, D.C. 20460![](media/image1.png){width="1.5833333333333333in"
height="1.5402777777777779in"}

OFFICE OF

PREVENTION, PESTICIDES AND

TOXIC SUBSTANCES

**MEMORANDUM**

**DATE:** April 19, 2006

**SUBJECT:** ***2-(Thiocyanomethylthio) benzothiazole (TCMTB)***-Report
of the Antimicrobials Division Toxicity Endpoint Selection Committee
(ADTC).

**FROM:** Timothy F. McMahon, Ph.D.; Chair, ADTC

Michelle Centra, Pharmacologist; Executive Secretary, ADTC

Antimicrobials Division (7510C)

**TO**: Deborah Smegal, MPH, Toxicologist

Re-Registration Branch 1

Health Effects Division (7509C)

and

Kathryn Jakob, Chemical Review Manager

Ben Chambliss, Team Leader

Regulatory Management Branch II

Antimicrobials Division (7510C)

**PC Code:** 035603

On September 22, 2005, the Antimicrobials Division\'s Toxicity Endpoint
Selection Committee (ADTC) evaluated the toxicology data base of
**TCMTB,** and established toxicological endpoints for acute and chronic
dietary as well as occupational exposure risk assessments. The ADTC also
addressed the potential enhanced sensitivity of infants and children
from exposure to **TCMTB** as required by the Food Quality Protection
Act (FQPA) of 1996. The conclusions of this meeting are presented in
this report.

Committee Members in Attendance

Members present: Tim McMahon, Ph.D., John Redden, Stephen Dapson, Ph.D.,
Roger Gardner; Karen Hamernik, Ph.D, Melba Morrow, D.V.M., Sanyvette
Williams-Foy, D.V.M, Jonathan Chen, Ph.D.; Michelle Centra; Najm Shamim,
Ph.D., Timothy Leighton, Deborah Smegal, MPH.

DATA EVALUATION/PRESENTATION:
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
Deborah Smegal, MPH, Toxicologist

DRAFT DOCUMENT PREPARATION:
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_
Timothy F. McMahon, Ph.D., Chair

FINAL DOCUMENT PREPARATION:
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Michelle Centra, Pharmacologist, Executive Secretary

COMMITTEE MEMBERS (Signature indicates concurrence unless otherwise
stated)

Stephen Dapson \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Jonathan Chen \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Roger Gardner \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Karen Hamernik \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Tim McMahon (Chair)
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Melba Morrow \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

John Redden \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Sanyvette Williams-Foy
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Tim Leighton \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Michelle Centra

(Executive Secretary)
\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Najm Shamim \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

Deborah Smegal \_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_\_

I.  **[INTRODUCTION]{.underline}**

TCMTB is a pesticide chemical with both agricultural and antimicrobial
uses. As an agricultural pesticide, TCMTB is used as a contact fungicide
for the following grain crops: barley, oats, rice, sorghum, wheat; for
safflower as an oil crop, for all types of corn, field corn, cotton,
sorghum, sugar beets; on the following flowers: gladiolus, iris,
narcissus, tulips. As antimicrobial pesticide, TCMTB is used as a wood
preservative on the following woods: pine, white fur; for wood
protection treatment to existing buildings or parts of buildings,
unseasoned forest products, finished wood products, wooden containers
for growing plants, forest products by pressure; in pulp and paper mill
systems, commercial and industrial water cooling tower systems,
secondary oil recovery injection water, sewage systems; as a
preservative incorporation in adhesive, coatings, leather products and
hides, leather processing liquors, metalworking cutting fluids, oil
recovery drill muds and packer fluids, latex paints, paper and paper
products, textiles, fibers, cordage, wet-end industrial process
chemicals, applied film paints; as an additive to fuels, paper and paper
products, textiles, fibers, cordage; also for paper/paperboard surface
treatments and pesticide products for formulation of other products.

Structure:

![](media/image2.png){width="2.34375in" height="2.0833333333333335in"}

**Physical Chemical Properties**

The following characteristics have been reported for TCMTB:

Cas No. 21564-17-0

Melting Point \< 10 ^o^ C

Boiling Point: 120 ^o^C

Vapor pressure: 4.08 x 10^-6^ mm Hg at 25^o^ C

Solubility in Water: 125 mg/L at 24^o^ C

Log K~ow~ : 2.45

Specific Gravity 1.4 g/cm^3^

Physical State: Viscous liquid

II. **[HAZARD IDENTIFICATION]{.underline}**

> **A1. [Acute Reference Dose (aRfD)]{.underline}** \[general population
> including infants and children\]
>
> [Study Selected]{.underline}: Rat Developmental Toxicity (MRID
> 00154295, accession number 260491)

[Executive Summary]{.underline}: In a prenatal developmental toxicity
study (MRID 00154295, accession no. 260491), TCMTB (83.6% a.i.) was
administered to 5 groups of 29 mated female Sprague-Dawley rats per
group by oral gavage using technical TCMTB dissolved in corn oil/ 1%
Tween 80 at doses of 0, 25.1, 76.5, and 125.5 mg /kg/day from gestation
days 6 through 15. Maternal toxicity was evident at the 76.5 mg/kg/day
dose level as ventral alopecia, rough coat, dyspnea/wheezing, oral
discharge, nasal discharge, diarrhea/loose stool, urine staining,
piloerection, and hunched gait. Developmental toxicity was evident at
the 125.5 mg /kg/day dose level in the form of increased fetal and
litter incidence of fused/wavy ribs, rudimentary cervical, thoracic, and
lumbar ribs, and increased number of sternebrae and pelvic girdle
anomalies.

The Maternal NOAEL = 25.1 mg /kg/day, based on observations of clinical
toxicity at 76.5 mg /kg/day (LOAEL). The Developmental NOAEL = 76.5 mg
/kg/day, based on increased fetal and litter incidence of skeletal
anomalies.

This developmental toxicity study in the rat is classified as
acceptable/guideline and satisfies the requirement (OPPTS 870.3700) for
a developmental toxicity study in the rodent.

[Dose Selected for Risk Assessment]{.underline}: Maternal NOAEL of 25.1
mg /kg/day.

[Uncertainty factors]{.underline}: 10x for interspecies extrapolation,
10x for intraspecies variation

[Comments about study selected and/or uncertainty factors]{.underline}:
The effects observed in offspring in this study occurred at doses higher
than those producing maternal toxicity. The ADTC further considered that
the developmental effects observed were not a primary developmental
effect. The maternal endpoint is appropriate for this risk assessment as
clinical signs are felt to be the result of a single dose.

**A2. [Acute Reference Dose]{.underline} (females 13-49)**

> [Study Selected]{.underline}: none.
>
> An endpoint for the female 13-49 subpopulation was not identified in
> the available database for TCMTB.

This risk assessment is not required.

**B. [Chronic Reference Dose (cPAD)]{.underline}**

[Study Selected]{.underline}: Chronic Toxicity Study in the Dog (MRID
41342201)

[Executive Summary]{.underline}: In a chronic toxicity study (MRID
41342201), tNumber range CHAPTERechnical TCMTB was administered to male
and female beagle dogs at dose levels of 0, 100ppm (3.8 mg/kg/day in
males; 4.0 mg/kg/day in females), 300ppm (11.7 mg/kg/day in males; 11.2
mg/kg/day in females), and 1000ppm (38.8 mg/kg/day in males; 43.2
mg/kg/day in females). Decreased body weight and body weight gain were
observed in male dogs at the 100 ppm dose level for weeks 0-13 of the
study, and overall body weight and weight gain were decreased greater
than 10% in both male and female dogs at the 1000 ppm dose level.
Significant decreases in circulating white cells and monocytes were also
observed in male dogs at all dose levels tested, while effects on
hematology in female dogs were limited. Plasma ALT was significantly
decreased in both sexes in a dose-related manner at all dose levels in
both male and female dogs for the duration of the study. Decreased
weight of the lung, thymus, and spleen were observed in male dogs at the
1000 ppm dose level, while decreased spleen, thymus, and uterine weight
were observed in female dogs. Involution of the thymus was the main
histologic finding, and the severity of this lesion appeared to increase
with increasing dose in both sexes. The Systemic NOAEL \< 100 ppm (males
and females). The Systemic LOAEL = 100 ppm \[3.8 mg /kg/day males; 4.0
mg /kg/day\] , based on decreased body weight gain, white cells,
monocytes and plasma ALT in males; decreased plasma ALT and uterine
weight in females.

[Dose Selected for Risk Assessment]{.underline}: LOAEL of 3.8 mg /kg/day

[Uncertainty factors]{.underline}: 10x interspecies extrapolation, 10x
intraspecies variation, 3x for lack of a NOAEL.

[Comments about study selected and/or uncertainty factors]{.underline}:
The study chosen by the ADTC for the chronic RfD is consistent with the
previous study selection by the HED RfD committee in 1994. However, the
ADTC chose a total uncertainty factor of 300 instead of the factor of
1000 chosen by the RfD Committee in 1994. The difference was that the
ADTC felt a factor of 3x for lack of a NOAEL was sufficient compared to
the 10x factor previously chosen.

**C. [Incidental Oral Exposure ]{.underline}**

1\. [Short-Term (1-30 days) **AND** Intermediate-term (30 days- 6
months)]{.underline}

> [Study Selected]{.underline}: Developmental toxicity study in the
> rabbit [(]{.underline}MRID No.:40075101, 40075102) (This summary is an
> update using re-calculated doses based on purity information provided
> by the registrant).

[Executive Summary:]{.underline} Number range CHAPTERIn a prenatal
developmental toxicity (teratology) study (MRID 40075102), TCMTB was
orally dosed to presumed pregnant rabbits (20 rabbits/group) at dose
levels of 0, 10, 20, and 40 mg/kg/day on gestation days 6-19 inclusive.
As confirmed by the registrant, actual doses were 0, 8, 16, and 32 mg
a.i./kg/day based on purity of TCMTB (81.0 % a.i).

Maternal toxicity was evidenced by decreased body weight gain and food
consumption in the 32 mg/kg/day dose group. **The Maternal Toxicity
NOAEL is 16 mg/kg/day and the Maternal Toxicity LOAEL is 32 mg/kg/day
based on decreased body weight gain and food consumption.**

No statistically significant or treatment-related changes were noted in
any treatment group for developmental anomalies. **The Developmental
Toxicity LOAEL is greater than 32 mg/kg/day and the Developmental
Toxicity NOAEL is greater than or equal to 32 mg/kg/day.**

This study is classified as **acceptable-guideline and** satisfies the
guideline requirement (§870.3700) for a developmental toxicity
(teratology) study in rabbits.

[Dose and Endpoint selected for Risk Assessment:]{.underline} Maternal
NOAEL of 16 mg/kg/day.

[Uncertainty factors]{.underline}: 10x for interspecies extrapolation,
10x for intraspecies variation

[Comments about Study/Endpoint:]{.underline} The maternal effect of
minimal body weight gain decreases during the dosing period coupled with
increased body weight gain after cessation of dosing is indicative of
maternal toxicity at the 16 and 32 mg /kg/day doses. There was no
evidence of developmental toxicity in this study.

**D. [Dermal Absorption]{.underline}**

A dermal absorption study was submitted by the registrant as an
unaudited draft report (MRID 42516601). This study was reviewed by the
Office of Pesticide Programs. The report was considered unacceptable for
review based on the unaudited nature of the submission and other errors
noted in the review. However, the executive summary of the unaudited
submission is of interest in noting that the dermal absorption of TCMTB
appears to increase with time of contact as well as dose level. This
study will require formal review of a final report to verify these
conclusions.

For TCMTB, a dermal absorption value is currently not needed based on
selection of dermal endpoints from a route-specific study (21-day dermal
toxicity study in rats, MRID 41655801).

> **D1. [Short-, Intermediate, and Long-Term Dermal (1 - 30 days; 30
> days-6months; 6 months)]{.underline}**
>
> [Study Selected:]{.underline} 21-Day Dermal Toxicity study in Rats
> (MRID No.: 41655801)

[Executive Summary:]{.underline} In a dermal toxicity study (MRID
41655801), TCMTB was applied to the skin of Sprague-Dawley rats
(5/sex/group) at dose levels of 0, 25, 100, or 250 mg/kg/day for 21 days
(6 hours/day). TCMTB produced significant dermal irritation in all dose
groups beginning on treatment days 3-4. Dermal irritation was
dose-dependent and progressed to eschar formation in 2 rats ( 1 male and
1 female) at 25 mg/kg/day and in all rats at the 100 and 250 mg/kg/day
dose groups. Blanching occurred in all rats at 250 mg/kg/day and in all
females and 3/5 males at 100 mg/kg/day. Decreased body weight gain was
noted at the 100 and 250 mg/kg/day dose groups of male rats.
Statistically significant changes in hemoglobin, hematocrit, and
segmented neutrophils were observed in male and female rats at the 250
mg/kg/day dose level. Increased AST, BUN, and glucose were observed in
female rats at 250 mg/kg/day; male rats showed increased BUN and glucose
at 250 mg/kg/day. However, the clinical chemistry changes did not
correspond to any treatment-related findings in the liver or kidney. The
Systemic NOAEL = 25 mg/kg/day, and the Systemic LOAEL = 100 mg/kg/day,
based on decreased body weight gain, food consumption, and hematological
and clinical chemistry changes.

> [Dose and Endpoint selected for Risk Assessment:]{.underline} Systemic
> NOAEL = 25 mg/kg/day
>
> [Uncertainty factors]{.underline}: For **short- and
> intermediate-term** risk assessments, the Margin of Exposure was
> determined to be 100 (10x interspecies extrapolation, 10x intraspecies
> variation). For **long-term** risk assessments, the Margin of Exposure
> was determined to be 300 (includes the two 10x factors just noted, and
> an additional 3x factor for extrapolation from a subchronic study to a
> chronic endpoint)
>
> [Comments about Study/Endpoint:]{.underline} A dermal irritation study
> of product grade TCMTB will not be requested because the committee
> felt that the systemic NOAEL for technical grade TCMTB is protective
> of dermal irritation (dermal and systemic effects occurred at the same
> dose level).
>
> **E. [Inhalation ]{.underline}**
>
> Note: where possible, the ADTC will employ the Agency's RfC guidance
> on calculation of human equivalent concentrations when there are
> animal data available that the ADTC considers scientifically
> acceptable. An example of this derivation can be found within the ADTC
> report on chlorine dioxide.

For TCMTB, there are no available inhalation toxicity studies from which
to select an endpoint. Therefore, oral data were used with the
understanding that additional uncertainty factors are applied for route
extrapolation.

> **E1. [Inhalation- Short- and Intermediate-term (1-30 days; 30 days-
> 6months)]{.underline}**
>
> [Study selected:]{.underline} Developmental Toxicity study in the
> Rabbit (MRID No. 0075101, 40075102)

[Executive Summary:]{.underline} Number range CHAPTERIn a prenatal
developmental toxicity (teratology) study (MRID 40075102), TCMTB was
orally dosed to presumed pregnant rabbits (20 rabbits/group) at dose
levels of 0, 10, 20, and 40 mg/kg/day on gestation days 6-19 inclusive.
As confirmed by the registrant, actual doses were 0, 8, 16, and 32 mg
a.i./kg/day based on purity of TCMTB (81.0 % a.i).

Maternal toxicity was evidenced by decreased body weight gain and food
consumption in the 32 mg/kg/day dose group. **The Maternal Toxicity
LOAEL is 32 mg/kg/day and the Maternal Toxicity NOAEL is 16 mg/kg/day
based on decreased body weight gain and food consumption.**

No statistically significant or treatment-related changes were noted in
any treatment group for developmental anomalies. **The Developmental
Toxicity LOAEL is greater than 32 mg/kg/day and the Developmental
Toxicity NOAEL is greater than or equal to 32 mg/kg/day.**

This study is classified as **acceptable-guideline and** satisfies the
requirement (§870.3700) for a developmental toxicity study in rabbits.

[Endpoint for Risk Assessment:]{.underline} Maternal NOAEL of 16
mg/kg/day

[Uncertainty Factors]{.underline}: 10x interspecies extrapolation, 10x
intraspecies variation

[Comments about Study/Endpoint:]{.underline} The results of two 90-day
oral toxicity studies in the rat (MRIDs 92179026 and 43112801) support
the NOAEL value chosen from the rabbit developmental toxicity study
(NOAELs of 25 and 10 mg/kg/day respectively).

**E2: [Inhalation: long-term (\> 6 months)]{.underline}**

[Study Selected:]{.underline} Chronic Toxicity study in Dogs (MRID No.:
41342201)

[Executive Summary]{.underline}: In a chronic toxicity study (MRID
41342201), tNumber range CHAPTERechnical TCMTB was administered to male
and female beagle dogs at dose levels of 0, 100ppm (3.8 mg/kg/day in
males; 4.0 mg/kg/day in females), 300ppm (11.7 mg/kg/day in males; 11.2
mg/kg/day in females), and 1000ppm (38.8 mg/kg/day in males; 43.2
mg/kg/day in females). Decreased body weight and body weight gain were
observed in male dogs at the 100 ppm dose level for weeks 0-13 of the
study, and overall body weight and weight gain were decreased greater
than 10% in both male and female dogs at the 1000 ppm dose level.
Significant decreases in circulating white cells and monocytes were also
observed in male dogs at all dose levels tested, while effects on
hematology in female dogs were limited. Plasma ALT was significantly
decreased in both sexes in a dose-related manner at all dose levels in
both male and female dogs for the duration of the study. Decreased
weight of the lung, thymus, and spleen were observed in male dogs at the
1000 ppm dose level, while decreased spleen, thymus, and uterine weight
were observed in female dogs. Involution of the thymus was the main
histologic finding, and the severity of this lesion appeared to increase
with increasing dose in both sexes. The Systemic NOAEL \< 100 ppm (males
and females). The Systemic LOAEL = 100 ppm \[3.8 mg /kg/day males; 4.0
mg /kg/day\] , based on decreased body weight gain, white cells,
monocytes and plasma ALT in males; decreased plasma ALT and uterine
weight in females.

[Dose Selected for Risk Assessment]{.underline}: LOAEL of 3.8 mg /kg/day

[Uncertainty factors]{.underline}: 10x interspecies extrapolation, 10x
intraspecies variation, 3x for lack of a NOAEL

**F. [Margins of Exposure for Occupational/Residential Exposure Risk
Assessments]{.underline}**

  ----------------- ----------------- ------------------- -----------------
  Route             Short-term (1-30  Intermediate-term   Long-term (\> 6
                    days)             (30 days- 6 months) months)

  Oral              100               100                 300

  Dermal            100               100                 300

  Inhalation        100               100                 300
  ----------------- ----------------- ------------------- -----------------

**G**. **[Recommendation for Aggregate Risk Assessments]{.underline}**

Acute dietary exposures can be aggregated with short-term and
intermediate-term incidental oral exposures as well as short-term and
intermediate-term inhalation exposures, as the study selected for these
endpoints (developmental toxicity study in rabbits) was the same. Dermal
and inhalation exposures can be aggregated since the effect of concern
is similar (decreased body weight gain). The total MOE approach should
be used since the target MOEs are both 100 for short- and intermediate
term durations, and 300 for long term durations.

Chronic dietary exposure can be aggregated with long-term inhalation
exposure as the study selected for these endpoints (chronic toxicity
study in the dog) is the same. Dermal exposures can also be aggregated
because the toxicological effect of concern is similar (decreased body
weight gain). The total MOE approach should be used since the target
MOEs is 300 for long term oral, dermal and inhalation exposures.

III. **[CLASSIFICATION OF CARCINOGENIC POTENTIAL]{.underline}**

> 1\. [Combined Chronic Toxicity/Carcinogenicity Study in
> Rats]{.underline} (MRID No. 2116301)

[Executive Summary]{.underline}: Number range CHAPTERTCMTB was
administered to Sprague Dawley rats of both sexes (50/sex/dose, main
group; and 20/sex/dose, interim kill group) for a period of up to 104
weeks in the diet at dose levels of 0, 2, 8, or 20 mg/kg/day. Mortality
was variable with survival rates of 80-100% in the interim kill group
and 38---82% in the carcinogenicity group. No treatment-related clinical
signs of toxicity were noted during the study. No dose-related or
significant effects were noted in the interim kill group. The only
significant reduction in body weight gains occurred in the 20 mg/kg/day
males at week 80, and these do not appear to be treatment-related. No
dose-related or significant effects were noted in the food consumption
of either the interim kill group or the carcinogenicity group.

A dose-related decrease in platelets was noted in all treated females at
week 104. All other changes in hematology parameters were not considered
to be toxicologically significant. No changes in the clinical chemistry
parameters were considered to be biologically significant due to the
lack of a dose---response relationship. No treatment-related changes
were noted in the organ weights of the interim kill group, but an
increasing trend was noted in the female absolute liver weights in all
treatment groups. Since a dose-response relationship was not present, it
was not considered to be biologically significant, Terminal organ
weights were not reported.

Only one finding displayed a dose-response relationship in the
microscopic pathology, interstitial cell tumors in the testes. The tumor
incidences were control group 4/50, low dose 5/50, mid dose 13/50 and
the high dose with 14/50. The mid and high doses were significantly
different (p\<0.05) from the controls. Additionally, the incidence of
thyroid C-cell adenomas was increased in female rats of the high dose
group, as compared to controls. The incidence of this lesion was 6/49,
4/49, 7/48 and 13/50 for the control, low, mid and high dose groups,
respectively. Thus, TCMTB appears to be carcinogenic inducing the
formation of interstitial cell tumors in the testes and thyroid C-cell
adenomas in female rats.

Although the current study did not appear to test to high enough doses
to produce systemic toxicity, on the basis of results from other
toxicity studies (noted below) as cited in the Cancer Peer Review
document, this study is classified as **acceptable-guideline** and
satisfies the OPPTS 870.4300 test guideline.

[Discussion of Tumor Data]{.underline}

Number range CHAPTERTwo findings displayed dose-response relationships
in the microscopic pathology, interstitial cell tumors in the testes and
thyroid C-cell adenomas in female rats. Male rats had a significant
dose-related increasing trend, as well as significant differences in the
pair-wise comparisons of the 8 and 20 mg/kg/day dose groups with the
controls, for testicular interstitial cell tumors.

Number range CHAPTERFemale rats had significant dose-related increasing
trends, and significant differences in the pair-wise comparisons of the
20 mg/kg/day dose group with the controls for thyroid C-cell adenomas
and adenomas and/or carcinomas combined; however, only adenomas were
present in treated groups (the control group had the single carcinoma
noted). Although there were no significant differences in the pair-wise
comparisons of the dosed groups with the controls, female rats did have
a significant increasing trend in thyroid C-cell hyperplasia at p \<
0.01.

[Adequacy of the Dose Levels Tested]{.underline}

Number range CHAPTERThe statistical evaluation of mortality indicated no
significant incremental changes with increasing doses of TCMTB in male
rats. Female rats showed a significant [decreasing]{.underline} trend in
mortality with increasing doses of TCMTB.

No treatment-related clinical signs of toxicity were noted during the
study. The only significant reduction in body weight gains occurred in
the 20 mg/kg/day males at week 80, and this did not appear to be
treatment-related. No dose-related or significant effects were noted in
the food consumption.

A dose-related decrease in platelets was noted in all treated females at
week 104. All other changes in hematology parameters were not considered
to be toxicologically significant. No changes in the clinical chemistry
parameters were considered to be biologically significant. An increasing
trend was noted in the female absolute liver weights in all treatment
groups; however, since a dose response relationship was not present it
was not considered to be biologically significant.

The systemic toxicity observed in this study in male and female rats was
minimal and there were no major differences between the treated and
control groups. However, data obtained from two subchronic feeding
studies in rats (the 13 week range finding study, MRID# 43112801 and the
90 day study in rats, MRID# 92179026) indicate that toxic effects
(decreased body weight gain and increased incidence of squamous
epithelial hyperplasia of the stomach) were observed at the dose level
of 30 mg/kg/day (a dose slightly higher than the HDT in this study). The
Systemic LOEL is greater than 20 mg/kg/day and the NOEL is equal to or
greater than 20 mg/kg/day. The study is considered in combination with
the 13 week range finding study (MRID# 43112801) and the 90 day study in
rats (MRID# 92179026). Based on this information, the dose levels used
in the chronic/carcinogenicity study in rats (MRID#'s 42116301,
41529701, and 41570301) were adequate for testing for the carcinogenic
potential of TCMTB.

> 2\. [Carcinogenicity Study in Mice]{.underline} (MRID No.: 42383001)

[Executive Summary]{.underline}: Number range CHAPTERGroups of CD-1 mice
(50/sex) were dosed with TCMTB at dietary concentrations calculated to
give dose levels of 0, 15, 50, or 150 mg/kg/day for 2 years. Body
weights were significantly reduced in high-dose males and high dose
females compared to controls. Weight gain in high dose males and females
were approximately 25% lower than controls at 78 weeks. Cumulative
weight gain was reduced 36% and 28% for males and females at week 104
respectively. There was no effect on food consumption in this study.
Number range CHAPTERAn increase in focal and diffuse hyperplasia of the
duodenal mucosa was seen microscopically in males receiving 150
mg/kg/day: the incidence was 10/42 compared to 1/41 in controls
(p\<0.01). A nonsignificant increase was seen for mucosal hyperplasia of
the duodenum in high-dose females (8/45 compared to 4/46 in controls).
No other pathologic findings were considered treatment related. The
Systemic NOAEL is determined to be 50 mg/kg/day, and the Systemic LOAEL
is determined to be 150 mg/kg/day, based on histologic changes in the
duodenum of high dose males and decreased weight gain in both sexes at
the high dose.

[Discussion of Tumor Data]{.underline}

Number range CHAPTERThere were no compound-related tumors observed in
male or female mice. All tissues were examined.

[Adequacy of the Dose Levels Tested]{.underline}

Number range CHAPTERThe statistical evaluation of mortality indicated no
significant incremental changes with increasing doses of TCMTB in male
mice. Female mice showed a significant [decreasing]{.underline} trend in
mortality with increasing doses of TCMTB.

Body weights were significantly reduced in high-dose males and high-dose
females as compared to controls. Weight gains in high-dose groups were
about 88% of control in males and 97% of control in females at 13 weeks;
however at 80 weeks the weight gains were 67% of control in the males
and 78% of control in the females and cumulative mean gains for the
entire treatment period (weeks 0-104) were 64% and 72% of the controls
for the high-dose males and females, respectively. No marked effects on
food consumption were observed. None of the gross findings were
remarkable. Based on the histologic changes in the duodenum in high-dose
males and the decreased weight gain in both sexes at the high-dose, the
systemic toxicity LOEL is considered to be 150 mg/kg/day and the
systemic toxicity NOEL is 50 mg/kg/day.

The high dose tested (150 mg/kg/day) is considered to be an adequate
dose for assessing the carcinogenic potential of TCMTB in male and
female CD-1 mice.

> 3\. [Classification of Carcinogenic Potential]{.underline}

Number range CHAPTERThe Health Effects Division Carcinogenicity Peer
Review Committee (CPRC) met on June 28, 1995 to discuss and evaluate the
weight-of-the-evidence on 2-(Thiocyanomethylthio) benzothiazole (TCMTB)
with particular reference to its carcinogenic potential. The CPRC
concluded that TCMTB should be classified as Group C - possible human
carcinogen - and recommended that for the purpose of risk
characterization, the Reference Dose (RfD) approach should be used for
quantitation of human risk. This was based on statistically significant
increases in tumors in both sexes of the Sprague-Dawley rat: testicular
interstitial cell adenomas in males and thyroid c-cell adenomas in
females.

IV. **[MUTAGENICITY]{.underline}**

**Study Type:** Mutagenicity Test on TCMTB in the
Salmonella/Mammalian-Microsome Reverse Mutation (Ames Test) with
Confirmatory Assay

In an Ames assay (MRID# 41386101) TCMTB was [negative]{.underline} for
inducing reverse gene mutations in *Salmonella typhimurium* strains
TA1535, TA1537, TA1538, TA98, or TA100 exposed in the presence or
absence of S9 activation up to cytotoxic doses (33.3 g/plate -S9;
66.7 g/plate +S9). The results were confirmed in an independently
performed trial.

**Study Type:** Evaluation for Structural Chromosomal Aberration of
TCMTB (EPA Reg. No.1448-29): Clastogenic Evaluation in the In Vivo Mouse
Micronucleus Assay

In a structural chromosomal aberration assay (MRID# 00165520), the high
dose of TCMTB (500 mg/kg) exhibited mortality and signs of clinical
toxicity. No evidence of an increase in micronucleated polychromatic
erythrocytes was noted at the dose levels tested in this study (50, 167
and 500 mg/kg). There was evidence of some PCE depression at the high
dose in the 48 and 72 hour animals.

**Study Type:** Evaluation of Other Genotoxic Effects of TCMTB (EPA Reg.
No.: 1448-290: In the Rat Primary Hepatocyte Unscheduled DNA Synthesis
Assay

In an UDS assay (MRID# 00165518), TCMTB did not cause a significant
increase in the unscheduled DNA synthesis (UDS) in rat primary
hepatocytes as measured in this study.

V.  **[FQPA CONSIDERATIONS]{.underline}**

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1.  [Neurotoxicity]{.underline}

There are no studies that specifically examined neurotoxicity of TCMTB
in the available database. From examination of the available data,
however, the ADTC concluded that there was no evidence of neurotoxicity
of TCMTB and that neurotoxicity studies would not be required.

2\. [Developmental Toxicity]{.underline}

Developmental toxicity studies were available in both the rat and rabbit
for TCMTB. The results of both of these studies (noted in this document
under the endpoint selection section) show no evidence of primary
developmental toxicity of TCMTB. This conclusion is consistent with the
previous conclusion of the Health Effects Division's RfD Peer Review
committee (September 29, 1994; document \# 011302)

3\. [Reproductive Toxicity]{.underline}

[Executive Summary:]{.underline} (note: this summary is an update of the
original, based on discussions by the ADTC; the parental NOAEL and LOAEL
values are changed)

In a 2-generation reproduction toxicity study (MRID 41471401), Number
range CHAPTERTCMTB was administered to Sprague Dawley CD outbred albino
rats from Charles River UK Ltd. in the diet at dose levels of 0, 25,
100, or 400 ppm (2.4, 9.6, and 38.4 mg/kg/day for males and 3.0, 11.7,
and 45.5 mg/kg/day for females for the 25, 100, and 400 ppm groups,
respectively) for 2 generations with 1 litter in the first generation
and 2 litters in the second generation. No treatment related effects
were noted on reproductive parameters examined in this study. Slight,
statistically significant effects were noted in mean body weight in the
high dose offspring around lactation day 24. This must be considered as
systemic toxicity as the litters began with relatively equal mean body
weights and around lactation day 14, the pups began to consume diet
while continuing to nurse. The parental/systemic NOAEL = 400 ppm
(38.4/45.5 mg /kg/day \[males/females\]) and the parental/systemic LOAEL
\> 400 ppm (\> 38.4/45.5 mg /kg/day \[males/females\]). The Reproductive
toxicity NOAEL [\>]{.underline} 400ppm and the Reproductive toxicity
LOAEL \> 400 ppm.

Consistent with both the RfD Peer Review's conclusion and that of the
California Environmental Protection Agency's summary of TCMTB (February
22, 2001), there was no evidence of reproductive toxicity of TCMTB.

4\. [Recommendation for Developmental Neurotoxicity Study]{.underline}

A developmental neurotoxicity study for TCMTB is not required at this
time.

5\. [Hazard-based Recommendation for the FQPA safety factor]{.underline}

On the basis of the results of developmental and reproductive toxicity
testing as well as consideration of the conclusions of the RfD Peer
Review committee and CAL EPA's findings, the ADTC recommended that the
hazard-based FQPA safety factor be reduced to 1x.

VI. **[DATA GAPS / REQUIREMENTS]{.underline}**

A repeated dose inhalation toxicity study with TCMTB is held in reserve
at this time, pending the outcome of inhalation risk assessments using
the oral toxicity data.

VII. **[OTHER ISSUES]{.underline}**

2-mercaptobenzothiazole (2-MBT) is the main mammalian metabolite of
TCMTB (Manninen et al., Arch. Toxicol. 70: 579-584, 1996). Although the
current uses of 2-MBT have been cancelled, it is instructive to
summarize the hazard of 2-MBT relative to that of TCMTB, as this will be
the main metabolite that mammalian organisms are exposed to when exposed
to TCMTB.

2-MBT shows low acute toxicity by the oral route (Toxicity Category IV,
MRID 41571901) and dermal route (LC50 \> 2000 mg/kg, Toxicity Category
III, MRID 41571902). 2-MBT was minimally irritating to the eyes
(Toxicity Category III, MRID 41571903) and slightly irritating to the
skin (Toxicity Category IV, MRID 41571904). A dermal sensitization study
submitted for the zinc salt of 2-MBT showed no evidence of
hypersensitivity when tested using the modified Buehler test method
(MRID 41571905).

A 90-day oral toxicity study conducted with 2-MBT (96.3% a.i.) by the
National Toxicology Program at doses of 187.5, 375, 750, and 1500
mg/kg/day (technical report no. 332) in rats showed decreased body
weight gain at 1500 mg/kg/day in both sexes compared to control, and
increased liver weight at 1500 mg/kg/day. A 90-day toxicity study by the
NTP with 2-MBT in mice at doses of 0, 94, 188, 375, 750, and 1500
mg/kg/day showed mortality at the high dose (5/10 males and 7/10
females), clonic seizures, lacrimation, and salivation at 750 and 1500
mg/kg/day, and lethargy and rough coat at 375 and 750 mg/kg/day. There
were no gross or microscopic pathological effects noted in mice.

In a 13-week dermal toxicity study with 2-MBT (98.22%), administration
of 2-MBT at doses of 0, 200, 1000, and 2000 mg/kg/day resulted in
increased relative liver weight at 1000 and 2000 mg/kg/day, the only
effect noted in this study (MRID 42146301).

In a developmental toxicity study in rats (MRID 41422202), 2-MBT (98.5%
a.i.) was administered to mated female SD Crl:COBS CD BR VAF rats
(26/dose) at doses of 0, 300, 1200, and 1800 mg/kg/day on gestation days
6 through 15 inclusive. At 1200 mg/kg/day, maternal toxicity was
observed in the form of salivation and urine staining. There was no
evidence of developmental toxicity related to administration of 2-MBT in
this study. The Maternal NOAEL = 300 mg/kg/day and the Maternal LOAEL =
1200 mg/kg/day, based on increased salivation and urine staining. The
Developmental NOAEL [\>]{.underline} 1800 mg/kg/day and the
Developmental LOAEL \> 1800 mg/kg/day.

In a 2-generation reproduction toxicity study (MRID 41912501),
2-MBT(98.0-98.5% a.i.) was administered in the diet to groups of COBS BR
rats at doses of 0, 194, 695, and 1195 mg/kg/day \[males\] and 0, 218,
783, and 1327 mg/kg/day \[females\]). At the high dose, decreased body
weight and weight gain were observed as well as increased incidence of
microscopic changes in the kidney. Fertility, length of gestation, and
pup viability were unaffected by 2-MBT treatment. Pup growth (in the
form of decreased body weight) was decreased at the 695/783 and
1195/1327 mg/kg/day dose levels by 9% and 15% respectively on day 14 and
by 13% and 21% on day 21 in the first generation, and was decreased
significantly (9-13%) at all dose levels in the second generation on
days 14 and 21. The systemic/reproductive toxicity NOAEL = 194 mg/kg/day
and the systemic/reproductive toxicity LOAEL = 695 mg/kg/day based on
decreases in body weight in parental animals and in offspring at this
dose.

In carcinogenicity studies conducted by the NTP, there was some evidence
of carcinogenicity for

MBT in male and female rats. The evidence included increased incidences
of pituitary

adenomas/adeno-carcinomas and adrenal gland pheochromocytomas in both
female dosed groups

and increased incidences of adrenal gland pheochromocytomas/malignant
pheochromocytomas and

preputial gland adenomas/carcinomas in both male dosed groups along with
an increased incidence

of mononuclear cell leukemia and pancreatic acinar cell adenomas in the
low dose males. For both

male dosed groups, however, the treatment levels appeared to be
excessive.

Based on the available data from the NTP report, MBT appears to be
carcinogenic in female mice

based on increased incidences of hepatocellular adenomas or carcinomas
(combined) in the low

dose females. The high dose tested in this study was excessive based on
the increased mortality

noted in high dose females.

MBT was negative in a salmonella (Ames) assay, a rat dominant lethal
test, a CHO/HGPRT test \[gene mutation\], and a mouse micronucleus test
\[chromosomal aberration\]. MBT was positive both with and without
metabolic activation in a mouse lymphoma test \[gene mutation\].
MBT-sodium salt was negative in a rat hepatocyte unscheduled DNA
synthesis assay.

The HED RfD/Peer Review committee met in April of 1994 to establish a
Reference Dose for 2-MBT. The committee recommended that the RfD be
established on the basis of the 2-generation reproduction toxicity study
using the NOAEL value of 194 mg/kg/day. Using a total uncertainty factor
of 300 (10x interspecies extrapolation, 10x intraspecies variation, 3x
for lack of a chronic toxicity study in non-rodents \[per the RfD peer
review committee memo\]), the RfD committee calculated a Reference Dose
for 2-MBT of 0.6 mg/kg/day. Note that this chronic RfD value is
considerably higher than that for the parent TCMTB, consistent with the
toxicity database which shows lower toxicity for 2-MBT than TCMTB.

The HED Carcinogenicity Peer Review Committee decided that 2-MBT should
be classified as Group-C possible human carcinogen and recommended that
for the purpose of risk characterization the Reference Dose (RfD)
approach should be used for quantification of human risk. This decision
to use the RfD approach was based on some evidence of adrenal gland
tumors in male and female rats and some evidence of preputial gland
tumors in male rats. There is equivocal evidence for pituitary gland
tumors in male rats. The evidence for hepatocellular tumors in mice was
also equivocal. MBT was also considered to have genotoxic activity. The
q~1~\* approach to risk assessment was not used since the tumors were
found in only 1 species and there was no clear evidence of
carcinogenicity from any of the tumor types.

**Table 1. Acute Toxicity of TCMTB**

+--------+----------------+----------+-----------------+--------------+
| Gui    | Study Type     | MRID     | Results         | Toxicity     |
| deline |                | #(s)     |                 | Category     |
|        |                |          |                 |              |
| No.    |                |          |                 |              |
+--------+----------------+----------+-----------------+--------------+
| 81-1   | Acute Oral     | 41583801 | LD~50~ = 750    | III          |
|        |                |          | mg/kg           |              |
+--------+----------------+----------+-----------------+--------------+
| 81-2   | Acute Dermal   | 41515401 | LD~50~ \> 2000  | III          |
|        |                |          | mg/kg           |              |
+--------+----------------+----------+-----------------+--------------+
| 81-3   | Acute          | 41640601 | LC~50~ = 0.07   | I            |
|        | Inhalation     |          | mg/L            |              |
+--------+----------------+----------+-----------------+--------------+
| 81-4   | Primary Eye    |          | No acceptable   | I            |
|        | Irritation     |          | studies; all    |              |
|        |                |          | show            |              |
|        |                |          | corrosivity     |              |
+--------+----------------+----------+-----------------+--------------+
| 81-5   | Primary Skin   | 41583701 | Severe erythema | II           |
|        | Irritation     |          | at 72 hrs.      |              |
+--------+----------------+----------+-----------------+--------------+
| 81-6   | Dermal         | 111991   |                 | Positive     |
|        | Sensitization  |          |                 | Sensitizer   |
+--------+----------------+----------+-----------------+--------------+

**Table 2. Summary of Toxicity Endpoints Selected for TCMTB**

+------------+---------------+---------------+------------------------+
| **         | **Dose Used   | **Target      | **Study and            |
| Exposure** | in Risk       | MOEs/UFs FQPA | Toxicological          |
|            | Assessment**  | safety factor | Effects**              |
| **         |               | for Risk      |                        |
| Scenario** | **            | Assessment**  |                        |
|            | (mg/kg/day)** |               |                        |
+------------+---------------+---------------+------------------------+
| **Acute    | **NOAE        | **Target      | DevelopmentalToxicity  |
| Dietary**  | L(maternal)** | MOE** = 100   | Study in Rats          |
|            | = 25.1        |               | (accession no. 260491) |
| (general   | mg/kg/day     | **UF** = 100  |                        |
| population |               | (10x          | **LOAEL(maternal)** =  |
| including  |               | inter-species | 76.5 mg /kg/day, based |
| infants    |               | e             | on clinical signs of   |
| and        |               | xtrapolation, | toxicity (ventral      |
| children)  |               | 10x           | alopecia, rough coat,  |
|            |               | intra-species | dyspnea/wheezing, oral |
|            |               | variation)    | discharge,             |
|            |               |               | diarrhea/loose stool,  |
|            |               | **FQPA SF** = | urine staining,        |
|            |               | 1x            | piloerection, and      |
|            |               |               | hunched gait).         |
|            |               | **Acute PAD** |                        |
|            |               | = 0.25        |                        |
|            |               |               |                        |
|            |               | mg/kg/day     |                        |
+------------+---------------+---------------+------------------------+
| **Acute    | An endpoint   |               |                        |
| Dietary**  | for females   |               |                        |
|            | 13-49 was not |               |                        |
| (females   | identified in |               |                        |
| 13-49)     | the available |               |                        |
|            | database for  |               |                        |
|            | TCMTB. This   |               |                        |
|            | risk          |               |                        |
|            | assessment is |               |                        |
|            | not required. |               |                        |
+------------+---------------+---------------+------------------------+
| **Chronic  | **LOAEL** =   | **Target      | Chronic Toxicity Study |
| Dietary**  | 3.8 mg/kg/day | MOE** = 300   | in Dogs (MRID          |
|            |               |               | 41342201)              |
| (all       |               | **UF** = 100  |                        |
| po         |               | (10x          | **LOAEL** = 3.8        |
| pulations) |               | inter-species | mg/kg/day (males),     |
|            |               | e             | based on decreased     |
|            |               | xtrapolation, | body weight gain,      |
|            |               | 10x           | decreased white cells, |
|            |               | intra-species | monocytes, and plasma  |
|            |               | variation)    | ALT in males;          |
|            |               |               | decreased plasma ALT   |
|            |               | **DB UF** =3  | and uterine weight in  |
|            |               | (3x for use   | females.               |
|            |               | of a LOAEL)   |                        |
|            |               |               |                        |
|            |               | **FQPA SF** = |                        |
|            |               | 1x            |                        |
|            |               |               |                        |
|            |               | **Chronic     |                        |
|            |               | PAD** = 0.013 |                        |
|            |               |               |                        |
|            |               | mg/kg/day     |                        |
+------------+---------------+---------------+------------------------+
| **         | **NOAEL**= 16 | **Target      | Developmental Toxicity |
| Incidental | mg/kg/day     | MOE** = 100   | Study in Rabbits (MRID |
| Oral**     |               |               | 40075102)              |
| Short- and |               | **UF** = 100  |                        |
| Interme    |               | (10x          | **LOAEL** = 32         |
| diate-Term |               | inter-species | mg/kg/day, based on    |
|            |               | e             | decreased body weight  |
| (1-30      |               | xtrapolation, | gain and food          |
| days; 30   |               | 10x           | consumption in         |
| days-6     |               | intra-species | maternal animals.      |
| months)    |               | variation)    |                        |
|            |               |               |                        |
|            |               | **FQPA SF** = |                        |
|            |               | 1x            |                        |
+------------+---------------+---------------+------------------------+
| **Dermal** | **NOAEL**= 25 | **Target      | 21-Day Dermal Toxicity |
|            | mg/kg/day     | MOE** = 100   | Study in Rats (MRID    |
| All        |               | (ST and IT)   | 41655801)              |
| Durations  |               |               |                        |
|            |               | **Target      | **LOAEL** = 100        |
| (1-30      |               | MOE** = 300   | mg/kg/day, based on    |
| days; 1-6  |               | (LT)          | decreased body weight  |
| months; \> |               |               | gain, food             |
| 6 months)  |               | **UF** = 100  | consumption, and       |
|            |               | (10x          | hematological and      |
|            |               | inter-species | clinical chemistry     |
|            |               | e             | changes.               |
|            |               | xtrapolation, |                        |
|            |               | 10x           |                        |
|            |               | intra-species |                        |
|            |               | variation)    |                        |
|            |               |               |                        |
|            |               | **DB UF** = 3 |                        |
|            |               | (3x for use   |                        |
|            |               | of a          |                        |
|            |               | subchronic    |                        |
|            |               | endpoint)     |                        |
|            |               |               |                        |
|            |               | **FQPA SF** = |                        |
|            |               | 1x            |                        |
+------------+---------------+---------------+------------------------+
| **In       | **NOAEL** =   | **Target      | Developmental Toxicity |
| halation** | 16 mg/kg/day  | MOE** = 100   | Study in Rabbits (MRID |
|            |               |               | 40075102)              |
| Short- and |               | (ST and IT)   |                        |
| Interme    |               |               | **LOAEL** = 32         |
| diate-Term |               | **UF** = 100  | mg/kg/day, based on    |
|            |               | (10x          | decreased body weight  |
| (1-30      |               | inter-species | gain and food          |
| days; 1-6  |               | e             | consumption in         |
| months)    |               | xtrapolation, | maternal animals       |
|            |               | 10x           |                        |
|            |               | intra-species |                        |
|            |               | variation)    |                        |
|            |               |               |                        |
|            |               | **Note:** an  |                        |
|            |               | additional    |                        |
|            |               | 10x is        |                        |
|            |               | necessary for |                        |
|            |               | route         |                        |
|            |               | e             |                        |
|            |               | xtrapolation. |                        |
|            |               | If results    |                        |
|            |               | are below a   |                        |
|            |               | MOE of 1,000, |                        |
|            |               | a             |                        |
|            |               | confirmatory  |                        |
|            |               | inhalation    |                        |
|            |               | study may be  |                        |
|            |               | required      |                        |
+------------+---------------+---------------+------------------------+
| **In       | **LOAEL** =   | **Target      | Chronic Toxicity Study |
| halation** | 3.8 mg/kg/day | MOE** = 300   | in Dogs (MRID          |
|            |               | (LT)          | 41342201)              |
| Long-Term  |               |               |                        |
|            |               | **UF** = 100  | **LOAEL** = 3.8        |
| (\> 6      |               | (10x          | mg/kg/day (males),     |
| months)    |               | inter-species | based on decreased     |
|            |               | e             | body weight gain,      |
|            |               | xtrapolation, | decreased white cells, |
|            |               | 10x           | monocytes, and plasma  |
|            |               | intra-species | ALT in males;          |
|            |               | variation)    | decreased plasma ALT   |
|            |               |               | and uterine weight in  |
|            |               | **Note:** an  | females.               |
|            |               | additional    |                        |
|            |               | 10x is        |                        |
|            |               | necessary for |                        |
|            |               | route         |                        |
|            |               | e             |                        |
|            |               | xtrapolation. |                        |
|            |               | If results    |                        |
|            |               | are below a   |                        |
|            |               | MOE of 1,000, |                        |
|            |               | a             |                        |
|            |               | confirmatory  |                        |
|            |               | inhalation    |                        |
|            |               | study may be  |                        |
|            |               | required      |                        |
+------------+---------------+---------------+------------------------+
| **Carcino  | The CPRC      |               |                        |
| genicity** | concluded     |               |                        |
|            | that TCMTB    |               |                        |
|            | should be     |               |                        |
|            | classified as |               |                        |
|            | Group C -     |               |                        |
|            | possible      |               |                        |
|            | human         |               |                        |
|            | carcinogen -  |               |                        |
|            | and           |               |                        |
|            | recommended   |               |                        |
|            | that for the  |               |                        |
|            | purpose of    |               |                        |
|            | risk          |               |                        |
|            | char          |               |                        |
|            | acterization, |               |                        |
|            | the Reference |               |                        |
|            | Dose (RfD)    |               |                        |
|            | approach      |               |                        |
|            | should be     |               |                        |
|            | used for      |               |                        |
|            | quantitation  |               |                        |
|            | of human      |               |                        |
|            | risk. This    |               |                        |
|            | was based on  |               |                        |
|            | statistically |               |                        |
|            | significant   |               |                        |
|            | increases in  |               |                        |
|            | tumors in     |               |                        |
|            | both sexes of |               |                        |
|            | the           |               |                        |
|            | S             |               |                        |
|            | prague-Dawley |               |                        |
|            | rat:          |               |                        |
|            | testicular    |               |                        |
|            | interstitial  |               |                        |
|            | cell adenomas |               |                        |
|            | in males and  |               |                        |
|            | thyroid       |               |                        |
|            | c-cell        |               |                        |
|            | adenomas in   |               |                        |
|            | females.      |               |                        |
+------------+---------------+---------------+------------------------+