**UNITED STATES ENVIRONMENTAL PROTECTION AGENCY**

**WASHINGTON, D.C. 20460**

**TXR No. 0054204 OFFICE OF**

** PREVENTION, PESTICIDES AND**

** TOXIC SUBSTANCES**

April 4, 2006

**[Memorandum]{.underline}**

Subject: Toxicology Disciplinary Chapter for the Re-Registration
Eligibility Decision (RED) Risk Assessment

Active Ingredient: 2-(thiocyanomethylthio)benzothiazole (TCMTB)

PC Code 035603

DP Barcode: D328184

From: Deborah Smegal, Toxicologist/Risk Assessor

Re-Registration Branch 1 (RRB1)

Health Effects Division (7509C)

Through: Whang Phang , Branch Senior Scientist

Re-Registration Branch 1 (RRB1)

Health Effects Division (7509C)

To: Kathryn Jakob, Chemical Review Manager

Regulatory Management Branch II

Antimicrobials Division (7510C)

# [1.0]{#_Toc128905554}[ ]{#_Toc128905554}[HAZARD CHARACTERIZATION]{#_Toc128905554}

The toxicology data base for TCMTB is considered complete for a food use
pesticide. No additional studies are required at this time. TCMTB
exhibits low acute oral and dermal toxicity (toxicity category III).
However, it is highly irritating to the eyes and skin (toxicity category
I and II, respectively) and is also considered to be highly toxic via
the inhalation route of exposure (toxicity category I). TCMTB is a
dermal sensitizer.

Following subchronic oral exposures to rodents, TCMTB caused increased
incidence of mild to severe stomach lesions characterized by
inflammation, hyperplasia, necrosis, and ulceration. Inflammatory cells
infiltration and edema were also noted at a low incidence. TCMTB
resulted in decreased body weight gains (78 to 84% of control), food
consumption (87-95% of control) and food efficiency. In a 21-day rat
dermal toxicity study, TCMTB produced dose-dependant dermal irritation
in all dose groups beginning on treatment days 3-4, which progressed to
eschar formation. Rats in the mid and high dose group had ulcers,
hemorrhages and chronic dermatitis. Decreased body weight gain, food
consumption, and hematological (changes in hemoglobin, hematocrit, and
segmented neutrophils) and clinical chemistry changes (blood urea
nitrogen, glucose, globulins, and elevated serum aspartate
aminotransferase (AST) were also noted. However, the clinical chemistry
changes did not correspond to any treatment-related findings in the
liver or kidney.

Developmental toxicity studies were available in both the rat and rabbit
for TCMTB. Rabbits appear to be more sensitive to the toxicity of TCMTB
than rats. In rabbits, the maternal NOAEL and LOAEL were 16 and 32 mg
ai/kg/day, respectively. In rats, the maternal NOAEL and LOAEL were 21
and 64 mg ai/kg/day. No developmental effects were noted in the rabbit
at the highest dose tested (32 mg ai/kg/day). However, in the rat
adverse developmental effects including increased fetal and litter
incidence of fused/wavy ribs, rudimentary cervical, thoracic and lumbar
ribs and increased incidence of sternebrae and pelvic girdle anomalies
were noted at doses of 105 mg ai/kg/day, which was maternally toxic.

In a two-generation rat reproduction study, there were no treatment
related effects noted at the highest dose tested for parental toxicity
or on reproductive parameters examined in this study. Slight,
statistically significant effects were noted in mean body weight in the
high dose offspring in the second mating (F2B) around lactation day 21.
This must be considered as systemic toxicity as the litters began with
relatively similar mean body weights, and around lactation day 14 the
pups began to consume diet while continuing to nurse. Mean pup weight
was not significantly reduced at days 7 or 14 in the F2B pups, and there
were no consistent effects on pup weight in the F0 and F1a generation
pups. Thus, the Agency believes this finding in the F2B pups on day 21
is of questionable toxicological significance.

Dogs appear to be the most sensitive species to TCMTB toxicity following
chronic exposure. In the chronic dog toxicity study, adverse effects
were noted at the lowest dose tested of 3.8 mg/kg/day. Adverse effects
included decreased body weight gain, hematological effects (changes in
white blood cells, monocytes), alterations in clinical chemistry
parameters (plasma ALT) and decreased uterine weight in females.

In the chronic rat toxicity/carcinogenicity study, no adverse systemic
toxicity effects were noted at the highest dose tested of 20 mg/kg/day.
However, there was a statistically significant increase in the incidence
of testicular interstitial cell adenomas in males of mid (P=0.0155) and
high-dose (P=0.0087) levels, that had a highly significant positive
dose-related trend (P=0.0018).

Treatment was also associated with a possible increased incidence of
thyroid C-cell adenomas in females of the mid- and high-dose levels,
which had a highly significant (P=0.0067) positive dose-related trend,
but did not attain a statistically significant level in the pairwise
comparison with concurrent controls. No historical data were available
for review.

In the chronic mouse toxicity/carcinogenicity study, decreased body
weight gain was noted in both sexes, while there was a statistically
increased incidence of focal and diffuse hyperplasia of duodenal mucosa
in males (10/42 vs 1/41 in controls) at 150 mg TCMTB/kg/day (122 mg
ai/kg/day). There was no evidence of carcinogenicity.

The available toxicity data do no indicate neurotoxicity in the
experimental animals exposed to TCMTB by either oral or derma routes.

TCMTB was negative for mutagenicity in the gene mutation assay with
bacteria, and did not cause an increase in unscheduled DNA synthesis
(UDS) in rat primary hepatocytes assay. It was also negative for
chromosomal aberrations in the *in vivo* micronucleus assay in mice.

TCMTB has been classified as Group C - possible human carcinogen - and
the Agency recommended that for the purpose of risk characterization,
the Reference Dose (RfD) approach be used for quantitation of cancer
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.

# **[2.0]{#_Toc128905555}[ ]{#_Toc128905555}[REQUIREMENTS]{#_Toc128905555}**

The Toxicology Data Requirements (40CFR 158.340) for food uses of TCMTB
are in Table 1. Use of the new guideline numbers does not imply that the
new (1998) guideline protocols were used.

+---------------------------------+-----------------+----------------+
| **Test **                       | **Technical**   |                |
+---------------------------------+-----------------+----------------+
|                                 |                 |                |
+---------------------------------+-----------------+----------------+
|                                 | **Required**    | **Satisfied**  |
+---------------------------------+-----------------+----------------+
|                                 |                 |                |
+---------------------------------+-----------------+----------------+
| 870.1100 Acute Oral Toxicity    | Y               | Y              |
|                                 |                 |                |
| 870.1200 Acute Dermal Toxicity  | Y               | Y              |
|                                 |                 |                |
| 870.1300 Acute Inhalation       | Y               | Y              |
| Toxicity                        |                 |                |
|                                 | Y               | Y              |
| 870.2400 Primary Eye Irritation |                 |                |
|                                 | Y               | Y              |
| 870.2500 Primary Dermal         |                 |                |
| Irritation                      | Y               | Y              |
|                                 |                 |                |
| 870.2600 Dermal Sensitization   | N               |                |
|                                 |                 |                |
| 870.6100 Acute Delayed          | N               |                |
| Neurotox. (Hen)                 |                 |                |
|                                 |                 |                |
| 870.6200a Acute Neurotox.       |                 |                |
| Screening Battery (Rat)         |                 |                |
+---------------------------------+-----------------+----------------+
| 870.3100 Oral Subchronic        | Y               | Y (by chronic) |
| (Rodent)                        |                 |                |
|                                 | Y               | Y (by chronic) |
| 870.3150 Oral Subchronic        |                 |                |
| (Non-Rodent)                    | N               | Y              |
|                                 |                 |                |
| 870.3200 21-Day Dermal          | N               |                |
|                                 |                 |                |
| 870.3250 90-Day Dermal          | Held in reserve |                |
|                                 |                 |                |
| 870.3465 90-Day Inhalation      |                 |                |
+---------------------------------+-----------------+----------------+
| 870.3700a Developmental         | Y               | Y              |
| Toxicity (rodent)               |                 |                |
|                                 | Y               | Y              |
| 870.3700b Developmental         |                 |                |
| Toxicity( non-rodent)           | Y               | Y              |
|                                 |                 |                |
| 870.3800 Reproduction           |                 |                |
+---------------------------------+-----------------+----------------+
| 870.4100a Chronic Toxicity      | Y               | Y              |
| (Rodent)                        |                 |                |
|                                 | Y               | Y              |
| 870.4100b Chronic Toxicity      |                 |                |
| (Non-rodent)                    | Y               | Y              |
|                                 |                 |                |
| 870.4200a Oncogenicity (Rat)    | Y               | Y              |
|                                 |                 |                |
| 870.4200b Oncogenicity (Mouse)  | Y               | Y              |
|                                 |                 |                |
| 870.4300 Chronic/Oncogenicity   |                 |                |
+---------------------------------+-----------------+----------------+
| 870.5100 MutagenicityGene       | Y               | Y              |
| Mutation - bacterial            |                 |                |
|                                 | Y               | Y              |
| 870.5300 MutagenicityGene       |                 |                |
| Mutation - mammalian            | Y               | N              |
|                                 |                 |                |
| 870.5395 MutagenicityMammalian  | N               |                |
| erythrocyte micronucleus        |                 |                |
|                                 |                 |                |
| 870.5xxx MutagenicityOther      |                 |                |
| Genotoxic Effects               |                 |                |
+---------------------------------+-----------------+----------------+
| 870.6100 90-Day Neurotoxicity   | N               | \--            |
| (hen)                           |                 |                |
|                                 | N               | \--            |
| 870.6200b 90 Day Neuro.         |                 |                |
| Screening Battery (Rat)         | N               | \--            |
|                                 |                 |                |
| 870.6300 Develop. Neuro         |                 |                |
+---------------------------------+-----------------+----------------+
| 870.7485 General Metabolism     | Y               | \--            |
|                                 |                 |                |
| 870.7600 Dermal Penetration     | N               |                |
+---------------------------------+-----------------+----------------+
| 870.7200 Companion Animal       | N               | \--            |
| Safety                          |                 |                |
+---------------------------------+-----------------+----------------+
|                                 |                 |                |
+---------------------------------+-----------------+----------------+
| Special Studies for Ocular      | N               | \--            |
| Effects                         |                 |                |
|                                 |                 |                |
| Acute Oral (Rat)                |                 |                |
|                                 |                 |                |
| Subchronic Oral (Rat)           |                 |                |
|                                 |                 |                |
| Six-month Oral (Dog)            |                 |                |
+---------------------------------+-----------------+----------------+
|                                 |                 |                |
+---------------------------------+-----------------+----------------+

**Y** - Yes; **N** -- no; \-- not necessary

# [3.0]{#_Toc128905556}[ ]{#_Toc128905556}[DATA GAP(S)]{#_Toc128905556}

There are no toxicology data gaps for TCMBT at this time. The
Antimicrobials Division Toxicology Endpoint Selection Committee (ADTC)
recommended that a repeated dose inhalation toxicity study for TCMTB be
held in reserve, pending the outcome of inhalation risk assessments
using the oral toxicity data.

# [4.]{#_Toc128905557}[0]{#_Toc128905557}[ ]{#_Toc128905557}[HAZARD ASSESSMENT]{#_Toc128905557}

## [4.1]{#_Toc128905558}[ ]{#_Toc128905558}Acute Toxicity

[Adequacy of data base for acute toxicity]{.underline}: The data base
for acute toxicity is considered complete. No additional studies are
required at this time. TCMTB exhibits low acute oral and dermal toxicity
(toxicity category III). However, it is highly irritating to the eyes
and skin (toxicity category I and II, respectively)) and is also
considered to be highly toxic via the inhalation route of exposure
(toxicity category I). TCMTB is a dermal sensitizer. The acute toxicity
data on the TCMTB Technical (80% ai), or Busan 72 (containing 60% ai) is
summarized below in Table 2.

+----------------+----------------+----------------+----------------+
| **Table 2.     |                |                |                |
| Acute Toxicity |                |                |                |
| Data on TCMTB  |                |                |                |
| Technical (80% |                |                |                |
| ai)**          |                |                |                |
+----------------+----------------+----------------+----------------+
|                |                |                |                |
+----------------+----------------+----------------+----------------+
| **Guideline    | **MRID No.**   | **Results**    | **Toxicity     |
| No./ Study     |                |                | Category**     |
| Type**         |                |                |                |
+----------------+----------------+----------------+----------------+
|                |                |                |                |
+----------------+----------------+----------------+----------------+
| 870.1100 Acute | 41583801       | LD~50~ = 750   | III            |
| oral toxicity  |                | mg/kg (M+F);   |                |
|                |                | 80% ai         |                |
+----------------+----------------+----------------+----------------+
|                |                |                |                |
+----------------+----------------+----------------+----------------+
| 870.1200 Acute | 41515401       | LD~50~ \> 2000 | III            |
| dermal         |                | mg/kg (M+F);   |                |
| toxicity       |                | 80% ai         |                |
+----------------+----------------+----------------+----------------+
| 870.1300 Acute | 41640601       | LC~50~=0.07    | I              |
| inhalation     |                | mg/L; 80% ai   |                |
| toxicity       |                |                |                |
+----------------+----------------+----------------+----------------+
| 870.2400 Acute | Acc No. 111991 | Diluted Busan  | I              |
| eye irritation |                | 72 (60 % ai):  |                |
|                |                | primary        |                |
|                |                | irritation     |                |
|                |                | score          |                |
|                |                | (PIS)=2/110    |                |
|                |                | (slight        |                |
|                |                | conjunctival   |                |
|                |                | redness, no    |                |
|                |                | corneal        |                |
|                |                | opacity);      |                |
|                |                | undiluted      |                |
|                |                | Busan 72 (60%  |                |
|                |                | ai) PIS=34/110 |                |
|                |                | (blanched      |                |
|                |                | conjunctivae,  |                |
|                |                | chemosis,      |                |
|                |                | corneal        |                |
|                |                | opacity not    |                |
|                |                | reversible by  |                |
|                |                | day 7)         |                |
+----------------+----------------+----------------+----------------+
| 870.2500 Acute | 41583701       | primary        | II             |
| dermal         |                | irritation     |                |
| irritation     |                | index=7.42     |                |
|                |                | with severe    |                |
|                |                | erythema and   |                |
|                |                | edema observed |                |
|                |                | at 72 hours;   |                |
|                |                | 80% ai         |                |
+----------------+----------------+----------------+----------------+
|                |                |                |                |
+----------------+----------------+----------------+----------------+
| 870.2600 Skin  | MRID 42349201  | Busan 74 (80%  | \--            |
| sensitization  |                | ai) caused     |                |
|                | Acc No. 259676 | delayed        |                |
|                |                | contact        |                |
|                |                | hy             |                |
|                |                | persensitivity |                |
|                |                | in guinea pigs |                |
|                |                | when induced   |                |
|                |                | and challenged |                |
|                |                | by a 40% w/v   |                |
|                |                | aqueous        |                |
|                |                | concentration  |                |
|                |                | of active      |                |
|                |                | ingredient.    |                |
|                |                | Sensitizer.    |                |
+----------------+----------------+----------------+----------------+
|                |                |                |                |
+----------------+----------------+----------------+----------------+

## [4.2]{#_Toc128905559}[ ]{#_Toc128905559}Subchronic Toxicity

[Adequacy of data base for subchronic toxicity]{.underline}: The data
base for subchronic toxicity is considered adequate for risk assessment
purposes. Although the subchronic rodent studies are unacceptable, there
are chronic studies available to fulfill the guideline requirements

Following repeat oral exposures to rodents, TCMTB caused increased
incidence of mild to severe stomach lesions characterized by
inflammation, hyperplasia, necrosis, and ulceration. Inflammatory cells
infiltration and edema were also noted at a low incidence. TCMTB
resulted in decreased body weight gains (78 to 84% of control), food
consumption (87-95% of control) and food efficiency. In a 21-day rat
dermal toxicity study, TCMTB produced dose-dependant dermal irritation
in all dose groups beginning on treatment days 3-4, which progressed to
eschar formation. Rats in the mid and high dose group had ulcers,
hemorrhages and chronic dermatitis. Decreased body weight gain, food
consumption, and hematological (changes in hemoglobin, hematocrit, and
segmented neutrophils) and clinical chemistry changes (blood urea
nitrogen, glucose, globulins, and elevated serum aspartate
aminotransferase (AST) were also noted. However, the clinical chemistry
changes did not correspond to any treatment-related findings in the
liver or kidney.

**870.3100 90-Day Oral Toxicity - Rat**

In a 13 week range finding study (MRID 43112801), TCMTB (81.56% ai,
Batch 1517 MRID 46698604, 92179001)** **was administered to
Sprague-Dawley rats (n=10/sex/dose) in the diet at dose levels of 0, 10,
30, 70 or 100 mg/kg/day (actual doses: 10.2, 31, 70 and 100 mg
TCMTB/kg/day for males and 10.3, 31, 72 and 99 mgTCMTB/kg/day for
females using food consumption data). These doses are equivalent to
8.3/8.4 (M/F), 24.5, 57/59 (M/F), 80.8/81.6 (M/F) mg ai/kg/day,
respectively when considering the purity of the test substance as 81.56%
ai. This study examined limited parameters.

Systemic toxicity was noted at 30 mg/kg/day (24.5 mg ai/kg/day) and
above in the form of increased incidence of squamous epithelial
hyperplasia of the stomach. There were also treatment related decreases
in body weight gains (78 to 84% of control), food consumption (87-95% of
control) and food efficiency (89-94% of control) in both sexes of to 70
and 100 mgTCMTB/kg/day (57/59 (M/F) and 80.8/82.6 (M/F) mg ai/kg/day).
The LOAEL for systemic toxicity is 30 mg TCMTB/kg/day (24.5 mg
ai/kg/day) and the NOAEL for systemic toxicity is 10 mg TCMTB/kg/day
(8.3.8.4 mg ai/kg/day) based on increased incidences of stomach lesions.

This 90-day oral toxicity study in the rat is **UNACCEPTABLE-GUIDELINE**
and does not satisfy the guideline requirement for a subchronic (90-day)
oral toxicity study OPPTS 870.3100 in the rat because is was only a
range finding study, and based on major deficiencies (stability, diet
concentrations and homogeneity were not measured, and hematology and
clinical chemistry parameters were not measured). This study can not be
upgraded.

**870.3100 90-Day Oral Toxicity - Rat**

In a 90-day study (MRID 92179026), TCMTB (Lot 9-3573; approximately 80%
as supplied by the registrant via email correspondence) was administered
to Sprague-Dawley rats (n=30/sex/dose) in the diet at dose levels of 0,
333, 500 and 750 ppm for 90 days. Dietary doses were approximately 0,
16.7, 25, 37.5 mgTCMTB/kg/day, which is equivalent to 0, 13.4, 20 and 30
mg ai/kg/day, respectively based on a purity of approximately 80% ai.
(as supplied by the registrant).

There were no treatment-related effects on any of the parameters
measured except histopathology. Mild inflammatory changes were found in
the gastric mucosa of males in the high dose group. Mild to severe
changes in the stomach, including inflammation, necrosis and ulceration,
were found in the females in this group. Females in the mid-dose group
had a low incidence of inflammatory cells infiltration (5% vs. 0% in the
control) and edema (10% vs. 0% in the control).

The NOAEL is 500 ppm (25 mg TCMTB/kg/day or 20 mg ai/kg/day). The LOAEL
is 750 ppm (37.5 mg TCMTB/kg/day or 30 mg ai/kg/day). The Maximum
Tolerated Dose (MTD) in males is slightly higher than 750 ppm (based on
histopathology findings); females is slightly lower than 750 ppm (based
on incidence and severity of histopathology findings in the stomach).

This 90-day oral toxicity study in the rat is **UNACCEPTABLE-GUIDELINE**
and does not satisfy the guideline requirement for a subchronic (90-day)
oral toxicity study OPPTS 870.3100 in the rat because the percent
recovery of TCMTB in the diets was low (81, 82 and 84% for the low, mid-
and high dose groups, respectively), and ophthalmoscopic examinations
were not done. The approximate purity of 80% ai was submitted in late
2005 by the registrant.

**870.3200 21-Day Dermal Toxicity - Rat**

[Executive Summary:]{.underline} In a dermal toxicity study (MRID
41655801), TCMTB (82.33% a.i.** **Lot OB-8483 via fax submission dated
December 8, 2005) 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). These doses are equivalent to 0, 20.6, 82.3 and 206 mg
ai/kg/day. TCMTB produced slight to moderate 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) in the low dose group in all rats of the mid and high dose
groups. Blanching occurred in all rats of the high dose group and in all
females and 3/5 males in the mid dose group. Decreased body weight gain
was noted at the mid and high dose groups of male rats. Statistically
significant changes in hemoglobin, hematocrit, and segmented neutrophils
were observed in male and female rats of the high dose level. Several
clinical chemistry parameters were significantly increased in high dose
males and females (blood urea nitrogen, glucose and globulins); while
high dose females also had elevated serum aspartate aminotransferase
(AST). However, the clinical chemistry changes did not correspond to any
treatment-related findings in the liver or kidney.

The Systemic NOAEL = 20.6 mg ai/kg/day, and the Systemic LOAEL = 82.3 mg
ai/kg/day, based on decreased body weight gain, food consumption, and
hematological and clinical chemistry changes. A Dermal NOAEL was not
identified. The Dermal LOAEL is 20.6 mg ai/kg/day based on
dose-dependent irritation which progressed to eschar formation in 2 rats
of the low dose group and in all rats of the mid- and high-dose groups.
Mid- and high-dose groups exhibited ulcers, hemorrhages and chronic
dermatitis.

Based on the recent submission of purity information in 2005, this
21-day dermal toxicity study in the rat can be upgraded to
**ACCEPTABLE-GUIDELINE**, and satisfies the guideline requirement for a
subchronic dermal toxicity study OPPTS 870.3200 in the rat.

## [4.3]{#_Toc128905560}[ ]{#_Toc128905560}Prenatal Developmental Toxicity

[Adequacy of data base for Prenatal Developmental Toxicity]{.underline}:
The data base for prenatal developmental toxicity is considered
complete. Developmental toxicity studies were available in both the rat
and rabbit for TCMTB. No additional studies are required at this time.
Rabbits appear to be more sensitive to the toxicity of TCMTB than rats.
In rabbits, the maternal NOAEL and LOAEL were 16 and 32 mg ai/kg/day,
respectively. In rats, the maternal NOAEL and LOAEL were 21 and 64 mg
ai/kg/day. No developmental effects were noted in the rabbit at the
highest dose tested (32 mg ai/kg/day). However, in the rat adverse
developmental effects including increased fetal and litter incidence of
fused/wavy ribs, rudimentary cervical, thoracic and lumbar ribs and
increased incidence of sternebrae and pelvic girdle anomalies were noted
at doses of 105 mg ai/kg/day, which was maternally toxic. Thus, the
Agency concludes that these studies show no evidence of primary
developmental toxicity of TCMTB, which is consistent with the previous
conclusion of the Health Effects Division's RfD Peer Review committee
(September 29, 1994; document \# 011302).

**870.3700a Prenatal Developmental Toxicity Study - Rat**

In a prenatal developmental toxicity study (MRID 00154295, accession no.
260491); TCMTB (83.6% a.i. Lot 511230, MRID 46698601), 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.
These doses are equivalent to 0, 21, 64 and 105 mg ai/kg/day,
respectively. Maternal toxicity was evident at the 64 mg ai/kg/day (76.5
mg TCMTB/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 105 mg ai/kg/day (125.5 mg TCMTB/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 = 21 mg ai/kg/day (25.1 mg TCMTB/kg/day), based on
observations of clinical toxicity at 64 mg ai/kg/day (76.5
mgTCMTB/kg/day) (LOAEL). The Developmental NOAEL = 64 mg ai/kg/day (76.5
mg TCMTB/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.

**870.3700b Prenatal Developmental Toxicity Study - Rabbit**

In a prenatal developmental toxicity (teratology) study (MRID 40075102),
TCMTB (81.0 % a.i**., **Lot 5-13002, MRID 46698602) was orally dosed to
presumed pregnant rabbits at dose levels of 0, 10, 20 and 40 mg/kg/day
(20 rabbits/group) during gestation days 6-19 inclusive. These doses are
equivalent to 0, 8, 16, and 32 mg ai/kg/day, which were verified by the
registrant.

Maternal toxicity was evidenced by decreased body weight gain and food
consumption in the 32 mg ai/kg/day dose group. Statistically significant
(p\>0.01) body weight loss was noted in the high dose group on gestation
days 6-12, 6-19 and 19-29. Mean food consumption was significantly
reduced for the high dose group during gestation days 6-12 and 6-19. One
high dose and two mid-dose group rabbits died during the study. However,
only the high dose death, which occurred on gestation day 18, was
considered treatment related based on corroded gastric mucosa and
reddened duodenal mucosa. There were no clinical signs of toxicity in
any dose level during the study. Five dams aborted their litters prior
to scheduled sacrifice (1 control, 2 in the low dose group and 2 in the
mid-dose group). No animals in the high dose group aborted, therefore,
the abortions occurring in the lower dose groups were considered to be
spontaneous, which is not uncommon in rabbits. **The Maternal Toxicity
NOAEL is 16 mg ai/kg/day and the Maternal Toxicity LOAEL is 32 mg ai
/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 deaths/resorptions, altered growth,
developmental anomalies or malformations. **The Developmental Toxicity
LOAEL is greater than 32 mg ai/kg/day and the Developmental Toxicity
NOAEL is greater than or equal to 32 mg ai/kg/day.**

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

## [4.4]{#_Toc128905561}[ ]{#_Toc128905561}Reproductive Toxicity

[Adequacy of data base for Reproductive Toxicity]{.underline}: The data
base for reproductive toxicity is considered complete. No additional
studies are required at this time. The available data showed that TCMTB
did not cause reproductive effects in rats.

In a 2-generation reproduction toxicity study (MRID 41471401), TCMTB
(81.6% ai, Batch 1517; MRID 92179011, 46698604) 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 in the second
mating (F2B) around lactation day 21 (approximately 88% of control
pups). 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, and thus mostly
likely received more than 400 ppm TCMTB. Mean pup weight was not
significantly reduced at days 7 or 14 in the F2B pups, and there were no
consistent effects on pup weight in the F0 and F1a generation pups.
Thus, the Agency believes this finding in the F2B pups on day 21 is of
questionable toxicological significance.

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 offspring NOAEL is 400 ppm
(HDT) and the offspring LOAEL \> 400 ppm. The Reproductive toxicity
NOAEL [\>]{.underline} 400ppm and the Reproductive toxicity LOAEL \> 400
ppm.

This study is classified as** acceptable-guideline **and satisfies the
guideline requirement for a 2-generation reproductive study (§870.3800;
OECD 416) in rats

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.

## [4.5]{#_Toc128905562}[ ]{#_Toc128905562}Chronic Toxicity

[Adequacy of data base for chronic toxicity]{.underline}: The data base
for chronic toxicity is considered complete, and no additional studies
are required at this time.

In a chronic toxicity study (MRID 41342201), technical TCMTB (81.6% ai,
Batch 1517; MRID 92179008, 46698604) 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. Hematological
effects include significant decreases in circulating white blood cells
and monocytes 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 \[3.8 mg /kg/day for males;
4.0 mg /kg/day for females\], based on decreased body weight gain, white
blood cells, monocytes and plasma ALT in males; decreased plasma ALT and
uterine weight in females.

This chronic study in the dog is classified as**
acceptable-non-guideline **and does not** **satisfy the guideline
requirement for a chronic oral study (OPPTS §870.4100, OECD 452) in dogs
because a systemic NOAEL was not achieved. However, this study is
scientifically sound and adequate for use in risk assessment

## [4.6]{#_Toc128905563}[ ]{#_Toc128905563}Carcinogenicity

[Adequacy of data base for Carcinogenicity]{.underline}: The data base
for carcinogenicity is considered complete, and no additional studies
are required at this time. TCMTB produced an increase in testicular
interstitial adenomas in male rats and thyroid C-cell adenomas in female
rats.

1\. [Combined Chronic Toxicity/Carcinogenicity Study in
Rats]{.underline} (MRID No.: 42116301; 41529701; 41570301)

[Executive Summary]{.underline}: In a combined chronic/carcinogenicity
study (MRID 42116301; 41529701; 41570301), TCMTB (81.6% ai purity, MRID
46698604) 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}

Two 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.

Female 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}

The 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}: In a carcinogenicity study (MRID
42383001), TCMTB (81.6% ai, batch 1517/Lot number 6-14285, MRID
46698604) was administered to groups of CD-1 mice (50/sex) in the diet
at concentrations calculated to give dose levels of 0, 15, 50, or 150
mg/kg/day for 2 years. These doses are equivalent to 0, 4, 41 and 122 mg
ai/kg/day, respectively. No carcinogenic potential was seen. Body
weights were significantly reduced in high-dose males and high dose
females compared to controls. Weight gains in high dose males and
females were approximately 25% lower than controls at 78 weeks.
Cumulative weight gain was reduced 36% and 28% for high dose males and
females, respectively at week 104. There was no effect on food
consumption in this study. None of the gross findings were remarkable.
An 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 (41 mg ai/kg/day), and the Systemic LOAEL is determined to be
150 mg/kg/day (122 mg ai/kg/day), based on histologic changes in the
duodenum of high dose males and decreased weight gain in both sexes at
the high dose.

This carcinogenicity study in the mouse is **acceptable guideline** and
satisfies the guideline requirement for a carcinogenicity study (OPPTS
870.4200; OECD 451).

[Discussion of Tumor Data ]{.underline}

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

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

The 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 LOAEL is considered to be 150 mg/kg/day (122 mg
ai/kg/day) and the systemic toxicity NOAEL is 50 mg/kg/day (41 mg
ai/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}

The 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. 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, 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 cancer risk.

## [4.7]{#_Toc128905564}[ ]{#_Toc128905564}[Mutagenicity]{#_Toc128905564}

[Adequacy of data base for Mutagenicity]{.underline}: The data base for
Mutagenicity is considered adequate based on pre 1991 mutagenicity
guidelines. TCMTB was negative for mutagenicity in the gene mutation
assay with bacteria (MRID# 41386101), and did not cause an increase in
unscheduled DNA synthesis (UDS) in rat primary hepatocytes assay
(Accession No. 266150; MRID# 00165518). It was also negative for
chromosomal aberrations in the *in vivo* micronucleus assay in mice
(MRID# 00165520).

**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.: 1448-29). In the Rat Primary Hepatocyte Unscheduled DNA Synthesis
Assay

In an UDS assay (Accession No. 266150; MRID# 00165518), TCMTB did not
cause a significant increase in the unscheduled DNA synthesis (UDS) in
rat primary hepatocytes as measured in this study.

## [4.8]{#_Toc128905565}[ ]{#_Toc128905565}[Neurotoxicity]{#_Toc128905565}

[Adequacy of data base for Neurotoxicity]{.underline}: These studies are
not required at this time. The available data do not indicate
neurotoxicity in experimental animals exposed by oral or dermal
administration.

## [4.9]{#_Toc128905566}[ ]{#_Toc128905566}[Metabolism]{#_Toc128905566}

2-Mercaptobenzothiazole (2-MBT) is the main mammalian urinary metabolite
of TCMTB, and has been suggested as a biological marker of exposure to
TCMTB (Manninen et al. 1996). In this study, three doses of TCMTB in
olive oil were given to male rats by gavage for 3 weeks. Urine was
collected daily and the metabolites were analyzed as thioethers by
derivatization with pentafluorobenzylbromide by gas chromatography-mass
spectrometry. The parent chemical was not detected in urine samples, but
two metabolites of TCMTB were identified.

2-Mercaptobenzothiazole (2-MBT) was the main metabolite, and its
excretion varied according to the dose. The second metabolite was
2-(mercaptomethylthio)benzothiazole. The amount of 2-MBT excreted in rat
urine was 66 12% (SD), 51 20% and 44 9% for TCMTB doses of 15, 75, and
150 mg/kg, respectively. Two doses, 75 and 150 mg/kg , caused diuresis
in rats during the 1 week of dosing. During the 3-week TCMTB treatment,
rat liver microsomal CYP enzyme profile was not significantly changed.
Urine samples for sawmill workers exposed to TCMTB were collected after
their work shifts for exposure assessment. TCMTB could not be detected
in the urine samples of exposed workers. Most concentrations of 2-MBT
were below the limit of detection, 0.12 mol/l, the concentrations were
0.12-0.15 mol/l only in few cases. The authors conclude that the
determination of 2-MBT in urine, when a sample is taken immediately
after a work shift, is a suitable indicator of workers' exposure to
TCMTB.

In a rat metabolism study (MRID 40884801) 14C-TCMTB as administered to
Sprague Dawley rats (5/sex/dose) by oral gavage at single doses of 3 and
30 mg/kg, and at a repeated oral dose of 3 mg/kg. Excretion of TCMTB
derived radioactivity was monitored, as well as measurement of plasma
levels and excretion of TCMTB derived radioactivity in bile. Metabolites
of TCMTB in urine, plasma, and bile were characterized using thin layer
chromatography. Absorption of TCMTB was rapid, with 80% excreted in
urine by 24 hours post-dose at both the 3 and 30 mg/kg dose levels. In
bile, cannulated rats, there was a marked reduction in 0-24 hour urinary
excretion (25-35%).

Distribution data indicated that red blood cells and kidney were the
only sites of significant retention of residual radioactivity. However,
these levels were low (0.02-2.41 g equiv./g tissue). Measurement of
elimination of radioactivity from blood showed that the half-life in red
cells might be in excess of 7 days.

Excretion of TCMTB derived radioactivity was mainly in urine, with
between 80-85% of the total dose excreted in non-cannulated rats. Fecal
excretion comprised about 5% of an administered dose, and was not
altered in cannulated rats, suggesting reabsorption of radioactivity
from the gastrointestinal tract and excretion in urine. Pharmacokinetic
data indicated that clearance was approximately equal at both the low
and high dose, and the AUC was proportional to the dose, suggesting
first order elimination at both the low and high dose.

Metabolite characterization using radio-TLC showed the presence of one
and possibly 2 metabolites of TCMTB in urine and bile. However,
definitive identification was not made, other than to suggest that at
least one metabolite could be a glucuronide conjugate.

This metabolism study in the rat is classified as **unacceptable
guideline** and does not satisfy the guideline requirement for a
metabolism study \[OPTTS 870.7485, OECD 417\] in rats because there are
incomplete data for the repeated low oral dose group, incomplete
identification of metabolites and the purity of TCMTB was not reported.

# [5.0]{#_Toc128905567}[ ]{#_Toc128905567}[H]{#_Toc128905567}AZARD CHARACTERIZATION FOR 2-MERCAPTOBENZOTHIAZOLE (2-MBT)

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 conduced 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

2-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, 2-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.` `

2-MBT was negative in a salmonella (Ames) assay, a rat dominant lethal
test, a CHO/HGPRT test \[gene mutation\], and a mouse micronucleus test
\[chromosomal aberration\]. 2-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. 2-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.

# [6.0]{#_Toc128905568}[ ]{#_Toc128905568}[TOXICITY ENDPOINT SELECTION]{#_Toc128905568}

## [6.1]{#_Toc128905569}[ ]{#_Toc128905569}[See Section 9.2 for Endpoint Selection Table.]{#_Toc128905569}

## **[6.2]{#_Toc128905570}[ ]{#_Toc128905570}[Dermal Absorption]{#_Toc128905570} **

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).

A dermal absorption study was submitted by the registrant as an
unaudited draft report (MRID NR42516601). 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.

## [6.3]{#_Toc128905571}[ ]{#_Toc128905571}[Classification of Carcinogenic Potential]{#_Toc128905571}

**See Section 4.6. **

# [7.0]{#_Toc128905572}[ ]{#_Toc128905572}[FQPA CONSIDERATIONS]{#_Toc128905572}

## [7.1]{#_Toc128905573}[ ]{#_Toc128905573}[Special Sensitivity to Infants and Children]{#_Toc128905573}

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, the ADTC recommended that the hazard-based FQPA safety
factor be reduced to 1x.

## [7.2]{#_Toc128905574}[ ]{#_Toc128905574}[Recommendation for a Developmental Neurotoxicity Study]{#_Toc128905574}

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

# **[8.0]{#_Toc128905575}[ ]{#_Toc128905575}[REFERENCES]{#_Toc128905575}**

MRID 00154295, 92179009. Goad P. T., et al. 1985. Teratogenicity study
of TCMTB in rats. HED Doc no. 005769.

MRID No. 40075101, 40075102, 92179011. Adam, C. P. 1986. TCMTB---A
teratology study in rabbits.

MRID 40884801. Cameron, B.D. Scott, G. 1987. The Metabolism of
2-(Thiocyanomethylthio)benzothiazole (TCMTB) in the rat. Buckman
Laboratories, Inc., Memphis TN. Inveresk Research International Ltd.,
Scotland.

MRID No. 41342201, 92179008. Goburdhun, R., and Greenough, R.J. 1989.
2-(Thiocyanomethylthio)benzothiazole (TCMTB): 52-Week dietary toxicity
study in dogs.

MRID No. 41471401, 92179011. Hazelden, K., Pl. and Wilson, J.A. 1988.
TCMTB-Two generation reproduction study in rats. HED Doc 010607

MRID No. 41529701, 41570301, 421165301. Everett, D. J. et al. 1989.
104-Week dietary toxicity/carcinogenicity study n rats with 52-week
interim kill.

MRID No. 42383301. Everett, D.J., et al. 1990.
2-(Thiocyanomethylthio)benzothiazole- 104-Week dietary carcinogenicity
study in mice. HED Doc. 010332.

MRID No. 43112801. Atkinson, C., et al. 1987.
2-(Thiocyanomethylthio)benzothiazole (TCMTB). 13-Week dietary dose range
finding study in rats.

MRID No. 92179026. Rao, G., No. 1980. 90-Day subchronic oral toxicity
study of TCMTB in rats.

Manninen, A., Auriola S, Vartiainen M., Leisivuori J., Turunen, T.,
Pasanen M. 1996. Determination of urinary 2-mercaptobenzothiazole
(2-MBT), the main metabolite of 2-(thiocyanomethylthio)benzothiazole
(TCMTB) in humans and rats.

# [9.0 APPENDICES]{#_Toc128905576}

**Tables for Use in Risk Assessment**

## [9.1]{#_Toc128905577}[ ]{#_Toc128905577}[Toxicity Profile Summary Tables]{#_Toc128905577}

**9.1.1 Acute Toxicity Table  - See Section 4.1**

**9.1.2 Subchronic, Chronic and Other Toxicity Tables**

+----------------------+----------------------+----------------------+
| **Guideline No./     | **MRID No. (year)/   | **Results**          |
| Study Type**         | Classification       |                      |
|                      | /Doses**             |                      |
+----------------------+----------------------+----------------------+
|                      |                      |                      |
+----------------------+----------------------+----------------------+
| 870.3100             | 43112801 (1987)      | NOAEL = 10.2         |
|                      |                      | mg/kg/day(M); 10.3   |
| 13-week oral         | unacceptable/        | mg/kg/day (F) (8.3   |
| toxicity rodents     |                      | mg ai/kg/day)        |
| (Range finding)      | guideline (range     |                      |
|                      | finding study)       | LOAEL = 31 mg/kg/day |
| (Diet)               |                      | (M+F) (25 mg         |
|                      | 0, 10, 30, 70 and    | ai/kg/day) based on  |
| Batch 1517           | 100 mgTCMTB/kg/day   | increased incidence  |
|                      | in diet (0, 8.2,     | of squamous          |
|                      | 24.5, 57 and 81.6 mg | epithelial           |
|                      | ai/kg/day)           | hyperplasia of the   |
|                      |                      | stomach and          |
|                      | M: 0, 10.2, 31,70    | decreased in body    |
|                      | and 100 mg/kg/day    | weight gains, food   |
|                      |                      | consumption and food |
|                      | F: 0, 10.3, 31, 72,  | efficiency in both   |
|                      | 99 mg /kg/day        | sexes of the 70 and  |
|                      |                      | 100 mg/kg/day dose   |
|                      | 81.56% ai purity     | groups.              |
|                      | (46698604, 92179001) |                      |
+----------------------+----------------------+----------------------+
| 870.3100             | 92179026 (1980)      | NOAEL = 25 mg        |
|                      |                      | TCMTB/kg/day (20 mg  |
| 90-Day oral toxicity | unacceptable/        | ai/kg/day)           |
| rodents (diet)       |                      |                      |
|                      | guideline            | LOAEL = 37.5 mg      |
| Lot 9-3573           |                      | TCMTB/kg/day(30 mg   |
|                      | 0, 333, 500, 750 ppm | ai/kg/day) based on  |
|                      | in diet              | increased incidence  |
|                      |                      | of histopathology of |
|                      | 0, 16.7, 25, 37.5    | the stomach,         |
|                      | mgTCMTB/kg/day which | including            |
|                      | is equivalent to     | inflammation,        |
|                      |                      | necrosis and         |
|                      | 13.4, 20 and 30 mg   | ulceration.          |
|                      | ai/kg/day            |                      |
|                      |                      |                      |
|                      | Purity approximately |                      |
|                      | 80% ai. (as supplied |                      |
|                      | by the registrant    |                      |
|                      | via email)           |                      |
+----------------------+----------------------+----------------------+
| 870.3700a            | 00154295, 92179009   | **Maternal** NOAEL = |
|                      | (1985)               | 21 mg ai/kg/day      |
| Prenatal             |                      | (25.1 mg             |
| developmental in     | 0, 25.1, 76.5, 125.5 | TCMTB/kg/day)        |
| rodents              | mg/kg via gavage     |                      |
|                      |                      | LOAEL = 64 mg        |
| Lot 511230           | acceptable guideline | ai/kg/day (76.5 mg   |
|                      |                      | TCMTB/kg/day) based  |
|                      | 83.6% ai purity      | on clinical signs of |
|                      | (46698601)           | ventral alopecia,    |
|                      |                      | rough coat,          |
|                      | Equivalent to 21, 64 | dyspnea/wheezing,    |
|                      | and 105 mg ai/kg/day | oral discharge,      |
|                      |                      | diarrhea/loose       |
|                      |                      | stool, urine         |
|                      |                      | staining,            |
|                      |                      | piloerection and     |
|                      |                      | hunched gait along   |
|                      |                      | with reduced body    |
|                      |                      | weight gain.         |
|                      |                      |                      |
|                      |                      | **Developmental**    |
|                      |                      | NOAEL =64 mg         |
|                      |                      | ai/kg/day (76.5 mg   |
|                      |                      | TCMTB/kg/day)        |
|                      |                      |                      |
|                      |                      | LOAEL = 105 mg       |
|                      |                      | ai/kg/day (125.5 mg  |
|                      |                      | TCMTB/kg/day) based  |
|                      |                      | on skeletal anomaly  |
|                      |                      | observations         |
|                      |                      | consisting of        |
|                      |                      | fused/wavy ribs,     |
|                      |                      | rudimentary cervical |
|                      |                      | thoracic and lumbar  |
|                      |                      | ribs, increased      |
|                      |                      | number of sternebrae |
|                      |                      | and pelvic girdle    |
|                      |                      | anomalies.           |
+----------------------+----------------------+----------------------+
| 870.3700b            | 40075101, 40075102,  | **Materna**l NOAEL = |
|                      | 92179011 (1986)      | 16 mg ai/kg/day (20  |
| Prenatal             |                      | mg TCMTB/kg/day )    |
| developmental in     | acceptable guideline |                      |
| nonrodents           |                      | LOAEL = 32 mg       |
|                      | 0, 10, 20, 40        | ai/kg/day (40 mg     |
| Lot 5-13002          | mgTCMTB/kg/day via   | TCMTB/kg/day) based  |
|                      | gavage of 81% ai     | on decreased body    |
|                      | purity (MRID         | weight gain and food |
|                      | 46698602)            | consumption.         |
|                      |                      |                      |
|                      | Equivalent to 0, 8,  | **Developmenta**l    |
|                      | 16 and 32 mg         | NOAEL≥  32 mg       |
|                      | ai/kg/day            | ai/kg/day (40 mg     |
|                      |                      | TCMTB /kg/day)       |
|                      |                      |                      |
|                      |                      | LOAEL=.32 mg         |
|                      |                      | ai/kg/day (40 mg     |
|                      |                      | TCMTB /kg/day).      |
+----------------------+----------------------+----------------------+
| Two generation       | 41471401, 92179011   | **Offspring NOAEL**  |
| reproduction study   | (1988)               | (HDT) =38.4          |
| in rats              |                      | mg/kg/day (M); 45.5  |
|                      | acceptable guideline | mg/kg/day (F)        |
| Batch 1517           |                      | mg/kg/day (400 ppm)  |
|                      | 0, 25, 100 and 400   |                      |
|                      | ppm;                 | **Offspring LOAEL**  |
|                      |                      | = Not identified     |
|                      | M: 0, 2.4, 9.6, 38.4 |                      |
|                      | mg/kg/day;           | **Parental/systemic  |
|                      |                      | NOAEL** =38.4        |
|                      | F: 0, 3, 11.7, 45.5  | mg/kg/day (M); 45.5  |
|                      | mg/kg/day            | mg/kg/day (F) (HDT)  |
|                      |                      | (400 ppm)            |
|                      | 81.6% ai purity      |                      |
|                      | (MRID 46698604)      | **Parental/systemic  |
|                      |                      | LOAEL** = Not        |
|                      |                      | identified.          |
|                      |                      |                      |
|                      |                      | **Reproductive **    |
|                      |                      |                      |
|                      |                      | NOAEL =38.4          |
|                      |                      | mg/kg/day (M); 45.5  |
|                      |                      | mg/kg/day (F) (HDT)  |
|                      |                      | (400 ppm)            |
|                      |                      |                      |
|                      |                      | LOAEL = Not          |
|                      |                      | identified.          |
+----------------------+----------------------+----------------------+
| 83-1a                | 41529701, 41570301,  | NOAEL=20 mg/kg/day   |
|                      | 42116301 (1989)      |                      |
| Chronic toxicity in  |                      | LOAEL= not           |
| rats                 | acceptable guideline | identified.          |
|                      |                      |                      |
| Batch 1517           | 0, 2, 8 and 20       | Statistically        |
|                      | mg/kg/day            | significant increase |
|                      |                      | in the incidence of  |
|                      | 81.6% ai purity(MRID | testicular           |
|                      | 46698604)            | interstitial cell    |
|                      |                      | adenomas in males of |
|                      |                      | mid (P=0.0155) and   |
|                      |                      | high-dose (P=0.0087) |
|                      |                      | levels, that had a   |
|                      |                      | highly significant   |
|                      |                      | positive             |
|                      |                      | dose-related trend   |
|                      |                      | (P=0.0018).          |
|                      |                      | Treatment was also   |
|                      |                      | associated with a    |
|                      |                      | possible increased   |
|                      |                      | incidence of thyroid |
|                      |                      | C-cell adenomas in   |
|                      |                      | females of the mid-  |
|                      |                      | and high-dose        |
|                      |                      | levels, which had a  |
|                      |                      | highly significant   |
|                      |                      | (P=0.0067) positive  |
|                      |                      | dose-related trend,  |
|                      |                      | but did not attain a |
|                      |                      | statistically        |
|                      |                      | significant level in |
|                      |                      | the pairwise         |
|                      |                      | comparison with      |
|                      |                      | concurrent controls. |
|                      |                      | No historical data   |
|                      |                      | were available for   |
|                      |                      | review.              |
+----------------------+----------------------+----------------------+
| 83-2                 | 42383001 (1990)      | NOAEL=50 mg          |
|                      |                      | TCMTB/kg/day (41 mg  |
| Chronic toxicity/    | acceptable guideline | ai/kg/day)           |
|                      |                      |                      |
| Carcinogenicity in   | 0, 5, 50, 150        | LOAEL= 150 mg        |
| mice                 | mg/kg/day which is   | TCMTB/kg/day (122 mg |
|                      |                      | ai/kg/day) based on  |
| Batch 1517           | equivalent to 4, 41  | decreased body       |
|                      | and 122 mg           | weight gain in both  |
|                      | ai/kg./day based on  | sexes, statistically |
|                      |                      | increased incidence  |
|                      | 81.6% ai purity(MRID | of focal and diffuse |
|                      | 46698604)            | hyperplasia of       |
|                      |                      | duodenal mucosa in   |
|                      |                      | males (10/42 vs 1/41 |
|                      |                      | in controls). No     |
|                      |                      | evidence of          |
|                      |                      | carcinogenicity.     |
+----------------------+----------------------+----------------------+
| One-year dog         | 41342201, 92179008   | NOAEL= not           |
|                      | (1989)               | identified (\<100    |
| Batch 1517           |                      | ppm or 3.8           |
|                      | unacceptable         | mg/kg/day)           |
|                      | guideline (No NOAEL) |                      |
|                      |                      | LOAEL= 3.8 mg/kg/day |
|                      | 0, 100, 300 and 1000 | (M) and 4 mg/kg/day  |
|                      | ppm;                 | (F) based on         |
|                      |                      | decreased body       |
|                      | M: 0, 3.8, 11.7 and  | weight gain, white   |
|                      | 38.8 mg/kg/day       | cells, monocytes and |
|                      |                      | plasma ALT in males  |
|                      | F:0, 4, 11.2, 43.2   | and decreased plasma |
|                      | mg/kg/day            | ALT and uterine      |
|                      |                      | weight in females.   |
|                      | 81.6% ai purity(MRID |                      |
|                      | 46698604)            |                      |
+----------------------+----------------------+----------------------+
| 21-Day dermal        | 41655801 (1990)      | Systemic NOAEL=20.6  |
| toxicity study       |                      | mg ai/kg/day (25     |
|                      | 0, 25, 100 and 250   | mgTCMTB/kg/day)      |
| Lot OB-8483          | mg/kg/day which is   |                      |
|                      | equivalent to        | Systemic LOAEL=82.3  |
|                      |                      | mg ai/kg/day (100 mg |
|                      | 0, 20.6, 82.3 and    | TCMTB/kg/day) based  |
|                      | 206 mg ai/kg/day     | on decreased body    |
|                      | based on             | weight gain and food |
|                      |                      | consumption in       |
|                      | 82.33% ai purity     | males, in addition   |
|                      |                      | to significant       |
|                      |                      | hematalogical        |
|                      |                      | (increased           |
|                      |                      | neutrophils,         |
|                      |                      | decreased            |
|                      |                      | hemoglobin,          |
|                      |                      | hematocrit and       |
|                      |                      | erythrocytes) and    |
|                      |                      | clinical chemistry   |
|                      |                      | changes (increased   |
|                      |                      | urea nitrogen,       |
|                      |                      | glucose and          |
|                      |                      | globulins)           |
|                      |                      |                      |
|                      |                      | Dermal NOAEL= not    |
|                      |                      | identified           |
|                      |                      |                      |
|                      |                      | Dermal LOAEL= 20.6   |
|                      |                      | mg ai/kg/day (25 mg  |
|                      |                      | T CMTB/kg/day) for   |
|                      |                      | dermal effects based |
|                      |                      | on dose-dependent    |
|                      |                      | irritation which     |
|                      |                      | progressed to eschar |
|                      |                      | formation in 2 rats  |
|                      |                      | of the low dose      |
|                      |                      | group, and in all    |
|                      |                      | rats of mid- and     |
|                      |                      | high-dose group. Mid |
|                      |                      | and high dose group  |
|                      |                      | exhibited ulcers,    |
|                      |                      | hemorrhages and      |
|                      |                      | chronic dermatitis.  |
+----------------------+----------------------+----------------------+
|                      |                      |                      |
+----------------------+----------------------+----------------------+
| 870.5100/84-2        | MRID 41386101        | TCMTB was negative   |
|                      |                      | for inducing reverse |
| Mutagenicity study:  | acceptable           | gene mutations in    |
| Gene mutation (S.    |                      | Salmonella           |
| Typhimurium)         |                      | typhimurium strains  |
|                      |                      | TA1535, TA1537,      |
|                      |                      | TA1538, TA 98 or TA  |
|                      |                      | 100 exposed in the   |
|                      |                      | presence of absence  |
|                      |                      | of S9 activation up  |
|                      |                      | to cytotoxic         |
|                      |                      | concentrations       |
|                      |                      | (33.3 ug/plate -S9; |
|                      |                      | 66.7 ug/plate +S9). |
|                      |                      | The results were     |
|                      |                      | confirmed in an      |
|                      |                      | independently        |
|                      |                      | performed trial.     |
+----------------------+----------------------+----------------------+
| 870.5395/84-2        | MRID 00165520        | In a structural      |
|                      |                      | chromosomal          |
| Structural           | Acceptable; EPA      | aberration assay,    |
| Chromosomal          | Accession No. 266152 | the high dose of     |
| Aberrations:         |                      | TCMTB (500 mg/kg)    |
| Clastogenic          | TRID 470330-022      | exhibited mortality  |
| Evaluation in [in    |                      | and signs of         |
| vivo]{.underline}    | Purity not provided  | clinical toxicity.   |
| mouse micronucleus   |                      | No evidence of an    |
| assay                |                      | increase in          |
|                      |                      | micronucleated       |
|                      |                      | polychromatic        |
|                      |                      | erythrocytes (PCE)   |
|                      |                      | 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. |
+----------------------+----------------------+----------------------+
|                      |                      |                      |
+----------------------+----------------------+----------------------+
| 870.5550/84-4        | MRID 00165518        | TCMTB did not cause  |
|                      |                      | a significant        |
| Rat Primary          | Acceptable;          | increase in the      |
| Hepatocyte           |                      | unscheduled DNA      |
| Unscheduled DNA      | TRID 470330-020      | synthesis (UDS) in   |
| Synthesis Assay      |                      | rat primary          |
|                      | EPA Accession No.    | hepatocytes as       |
|                      | 266150               | measured in this     |
|                      |                      | study.               |
|                      | Purity not provided; | Concentrations used  |
|                      | Lot No. 5-13002      | were 0.05-25 ug/ml   |
|                      |                      | in DMSO.             |
+----------------------+----------------------+----------------------+
|                      |                      |                      |
+----------------------+----------------------+----------------------+

## [9.2]{#_Toc128905578} Summary of Toxicological Dose and Endpoints for 2-(Thiocyanomethylthio)benzothiazole (TCMTB) for Use in Human Risk Assessment^[1]{.underline}^

+----------------+----------------+----------------+----------------+
| **Exposure**   | **Dose Used in | **Target       | **Study and    |
|                | Risk           | MOEs/UFs FQPA  | Toxicological  |
| **Scenario**   | Assessment**   | safety factor  | Effects**      |
|                |                | for Risk       |                |
|                | *              | Assessment**   |                |
|                | *(mg/kg/day)** |                |                |
+----------------+----------------+----------------+----------------+
|                |                |                |                |
+----------------+----------------+----------------+----------------+
| Acute Dietary  | NOAEL= 25.1    | UF = 100 (10x  | Developmental  |
|                | mg/kg/day      | inter-species  | toxicity study |
| (general       |                | extrapolation, | in rats (MRID  |
| population     | 83.55% ai      | 10x            | 00154295,      |
| including      | purity         | intra-species  | 92179009       |
| infants and    |                | variation)     | (1985))        |
| children)      |                |                |                |
|                |                | FQPA SF = 1x   | Maternal LOAEL |
|                |                |                | = 76.5 mg      |
|                |                | **Acute PAD**  | TCMTB/kg/day,  |
|                |                | = 0.25         | based on       |
|                |                |                | clinical signs |
|                |                | mg             | of toxicity    |
|                |                | TCMTB/kg/day   | (ventral       |
|                |                |                | alopecia,      |
|                |                |                | rough coat,    |
|                |                |                | dys            |
|                |                |                | pnea/wheezing, |
|                |                |                | oral           |
|                |                |                | discharge,     |
|                |                |                | diarrhea/loose |
|                |                |                | stool, urine   |
|                |                |                | staining,      |
|                |                |                | piloerection,  |
|                |                |                | and hunched    |
|                |                |                | gait).         |
+----------------+----------------+----------------+----------------+
|                |                |                |                |
+----------------+----------------+----------------+----------------+
| Acute Dietary  | An endpoint    |                |                |
|                | for females    |                |                |
| (females       | 13-49 was not  |                |                |
| 13-49)         | identified in  |                |                |
|                | the available  |                |                |
|                | database for   |                |                |
|                | TCMTB. This    |                |                |
|                | risk           |                |                |
|                | assessment is  |                |                |
|                | not required.  |                |                |
+----------------+----------------+----------------+----------------+
|                |                |                |                |
+----------------+----------------+----------------+----------------+
| Chronic        | LOAEL = 3.8    | UF = 300 (10x  | Chronic        |
| Dietary        | mg/kg/day      | inter-species  | toxicity study |
|                |                | extrapolation, | in dogs (MRID  |
| (all           | 81.6% ai       | 10x            | 41342201,      |
| populations)   | purity         | intra-species  | 92179008       |
|                |                | variation, 3x  | (1989))        |
|                |                | for use of a   |                |
|                |                | LOAEL)         | LOAEL = 3.8    |
|                |                |                | mg/kg/day      |
|                |                | FQPA SF = 1x   | (males), based |
|                |                |                | on decreased   |
|                |                | **Chronic      | body weight    |
|                |                | PAD** = 0.01   | gain,          |
|                |                |                | decreased      |
|                |                | mg ai/kg/day   | white cells,   |
|                |                |                | monocytes, and |
|                |                |                | plasma ALT in  |
|                |                |                | males;         |
|                |                |                | decreased      |
|                |                |                | uterine weight |
|                |                |                | in females.    |
+----------------+----------------+----------------+----------------+
| Short- and     | NOAEL=16.2 mg  | MOE = 100      | Developmental  |
| Int            | ai/kg/day      |                | toxicity study |
| ermediate-Term |                |                | in rabbits     |
|                | 81% ai purity  |                | (MRID          |
| Incidental     |                |                | 40075101,      |
| Oral           | (20 mg         |                | 40075102,      |
|                | TCMTB/kg/day)  |                | 92179011       |
| (1-30 days; 30 |                |                | (1986))        |
| days-6 months) |                |                |                |
|                |                |                | LOAEL = 32 mg  |
|                |                |                | ai/kg/day (40  |
|                |                |                | mg             |
|                |                |                | TCMTB/kg/day), |
|                |                |                | based on       |
|                |                |                | decreased body |
|                |                |                | weight gain    |
|                |                |                | and food       |
|                |                |                | consumption in |
|                |                |                | maternal       |
|                |                |                | animals.       |
+----------------+----------------+----------------+----------------+
| Dermal^\ ^(all | NOAEL= 25      | MOE = 100 (ST  | 21-Day dermal  |
| durations)     | mg/kg/day      | and IT)        | toxicity study |
|                |                |                | in rats (MRID  |
| (1-30 days; 30 | 82.33% ai      | MOE = 300 (LT) | 41655801)      |
| days-6 months; | purity         |                |                |
| \> 6 months)   |                |                | LOAEL = 100 mg |
|                | (20.6 mg       |                | TCMTB/kg/day   |
|                | ai//kg/day)    |                | (82.3 mg       |
|                |                |                | ai/kg/day),    |
|                |                |                | based on       |
|                |                |                | decreased body |
|                |                |                | weight gain,   |
|                |                |                | food           |
|                |                |                | consumption,   |
|                |                |                | and            |
|                |                |                | hematological  |
|                |                |                | and clinical   |
|                |                |                | chemistry      |
|                |                |                | changes        |
+----------------+----------------+----------------+----------------+
| Inhalation     | NOAEL=16.2 mg  | MOE = 300 (ST  | Developmental  |
|                | ai/kg/day      | and IT)        | toxicity study |
| (short- and    |                |                | in rabbits     |
| inte           | 81% ai purity  |                | (MRID          |
| rmediate-term) |                |                | 40075102)      |
|                | (20 mg         |                |                |
|                | TCMTB/kg/day)  |                | LOAEL = = 32   |
|                |                |                | mg ai/kg/day   |
|                | A              |                | (40 mg         |
|                | bsorption=100% |                | TCMTB/kg/day), |
|                | (inhalation    |                | based on       |
|                | and oral       |                | decreased body |
|                | equivalent)    |                | weight gain    |
|                |                |                | and food       |
|                |                |                | consumption in |
|                |                |                | maternal       |
|                |                |                | animals        |
+----------------+----------------+----------------+----------------+
| Inhalation     | LOAEL = 3.8    | MOE = 1000     | Chronic        |
| (long-term)    | mg/kg/day      |                | toxicity study |
|                |                |                | in dogs (MRID  |
|                | 81.6% ai       |                | 41342201,      |
|                | purity         |                | 92179008       |
|                |                |                | (1989))        |
|                | A              |                |                |
|                | bsorption=100% |                | LOAEL = 3.8    |
|                | (inhalation    |                | mg/kg/day      |
|                | and oral       |                | (males), based |
|                | equivalent)    |                | on decreased   |
|                |                |                | body weight    |
|                |                |                | gain,          |
|                |                |                | decreased      |
|                |                |                | white cells,   |
|                |                |                | monocytes, and |
|                |                |                | plasma ALT in  |
|                |                |                | males;         |
|                |                |                | decreased      |
|                |                |                | uterine weight |
|                |                |                | in females.    |
+----------------+----------------+----------------+----------------+
|                |                |                |                |
+----------------+----------------+----------------+----------------+
| C              | The CPRC       |                |                |
| arcinogenicity | concluded that |                |                |
|                | TCMTB should   |                |                |
|                | be classified  |                |                |
|                | as Group C -   |                |                |
|                | possible human |                |                |
|                | carcinogen -   |                |                |
|                | and            |                |                |
|                | recommended    |                |                |
|                | that for the   |                |                |
|                | purpose of     |                |                |
|                | risk           |                |                |
|                | cha            |                |                |
|                | racterization, |                |                |
|                | 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.       |                |                |
+----------------+----------------+----------------+----------------+
|                |                |                |                |
+----------------+----------------+----------------+----------------+