UNITED ST ATES ENVIRONMENT AL PROTECTION AGENCY WASHINGTON, D.C. 20460

OFFICE OF CHEMICAL SAFETY
AND POLLUTION PREVENTION

MEMORANDUM

DATE: August 27, 2015

SUBJECT: Diethofencarb: Report of the Cancer Assessment Review Committee

PC Code : 112102
Decision No.: N I A
Petition No.: N I A
Risk Assessment Type: NA

TXR No.: 0057298

MRID No.: N I A DP Barcode: N I A Registration No.: N I A Regulatory Action: N I A
Case No.: N I A

CASNo.: N I A

40 CFR: N I A

FROM: Jess Rowland

, Chair

### de-~~~ Deputy Division Director 

# U

Karlyn Middleton

, Co-Chair

### /"-~ Cancer Assessment Re ¥ iew Committee

Health Effects Division (7509P)

TO: Myron Ottley

, Toxicologist

Risk Assessment Branch III
Health Effects Division (7509P)

And

Driss Benmhend

Rachel Holloman Fungicide-Herbicide Branch Registration Division (RD) (7505P)

On May 20

, 2015

, the Cancer Assessment Review Committee (CARC) of the Health Effects

Division

, evaluated the carcinogenic potential of diethofencarb in accordance with the

EPA ' s Final Guidelines for Carcinogen Ri s k Assessment (March

, 2005)

. Attached please

find the final Cancer Assessment Document.

Page 1 of34Diethofencarb (PC Code 112102) FINA L

Page 2 of 34 CANCER ASSESSMENT DOCUMENT

EVALUATION OF THE CARCINOGENIC POTENTIAL OF
Diethofencarb

PC Code: 112102

August 27, 2015



### C ANCER 

### A SSESSMENT 

### R EVIEW 

### C OMMITTEE
HEALTH EFFECTS DIVISION
OFFICE OF PESTICIDE PROGRAMSPage 3 of 34 Table of Contents

I. EXECUTIVE SUMMARY .................................................................................................... 4

II. INTRODUCTION .................................................................................................................. 5

III. BACKGROUND INFORMATION .................................................................................... 5

IV. EVALUATION OF CARCINOGE NICITY STUDIES ...................................................... 5 A. Combined Chronic Toxicity/Carcinogeni city Study in Sprague Dawley Rats ..................... 5

B. Carcinogenicity Study in Crl:CD-1(ICR)BR Mice ....................................................... 10

V. TOXICOLOGY .................................................................................................................... 11
A. Metabolism .................................................................................................................... . 11

B. Mutagenicity .................................................................................................................. . 12
C. Structure Activity Relationship ...................................................................................... 14

D. Sub-Chronic and Chronic Toxicity Studies ................................................................... 14

VI. MODE OF ACTION STUDIES ........................................................................................ 17
1. Mode of Action Assessment-Thyroi d Tumors in Male Rats ............................................. 17
2. Data Supporting the Proposed Diethofencarb MOA ......................................................... 17
3. The Key Events for Diethofencarb- Induced Thyroid Tumor MOA .................................. 19 Key Event #1: Increased liver metabolism as seen by increased hepatic UDP-GT (UDG) activity....................................................................................................................... ............ 19 Key Event 2: Increased hepatic metabo lism and biliary excretion of T4 ............................. 22 Key Event 3: Decreased serum T 4 half- life and concentra tion and Increased TSH ............ 24 Key Event #4: Thyroid lesions (hypertrophy and hyperplasia) ........................................... 25 Key Event # 5: Thyroid follicular Adenomas and Carcinomas. ........................................... 26 Summary of Dose-response for Ke y Events and Carcinogenesis ......................................... 26 Summary of Time Concordance for Key Events , Associated events, and Carcinogenesis .. 27
4. Strength, Consistency, and Specificity of Association of Tumor Response with Key

Events ........................................................................................................................ ............... 28
5. Biological Plausibility and Coherence ............................................................................... 28

6. Alternative Modes of Action ............................................................................................. 28

7. Data Limitations, Uncertainties, Inconsistencies ............................................................... 29
8. Human Relevance .............................................................................................................. 30

VII. COMMITTEE’S ASSESSMENT of the WEIGHT OF EVIDENCE ................................ 30

VIII. CLASSIFICATION OF CARCIN OGENIC POTENTIAL ........................................... 31

IX. QUANTIFICATION OF CANCER RISK ........................................................................ 31

X. BIBLIOGRAPHY ................................................................................................................. 32Diethofencarb (PC Code 112102) FINA L

Page 4 of 34 I. EXECUTIVE SUMMARY

On May 20, 2015, the Cancer Assessment Review Committee (CARC) of the Health Effects
Division of the Office of Pe sticide Programs evaluated th e carcinogenic potential of
diethofencarb.

In the carcinogenicity study in rats, diethofencarb was administ ered in the diet at 0, 40, 200, 1000, and 5000 ppm for 104 weeks with interim sacrifices at 52 and 104 weeks. Male rats had statistically signifi cant trends, and significant pai r-wise comparisons of the high dose group (5000ppm, 220.30 mg/kg/ day) with the controls, for thyroid follicular cell
carcinomas and combined adenomas and/or carcinomas. This increased incidence of
carcinomas was outside the histor ical control range. There was also a significant trend for thyroid follicular cell adenomas in male rats. Female rats ha d statistically significant trends, and significant pair-wise comparisons of the high dose group (5000ppm, 288.19 mg/kg/day) with the controls, for thyroid follicular ce ll adenomas and combined adenomas and/or carcinomas. No non-neoplastic lesions were obs erved in males or females. The high dose was considered to be adequate but not exces sive in both sexes based on increased thyroid
follicular tumors seen at this dose. The CARC concluded that thyroid tumors in male
and female rats were treatment-related.

In the carcinogenicity study in mice, diethofencarb was administer ed in the diet at 0, 10, 100, 1000, and 10,000 ppm for 78 weeks with interim sacrifices at 13 and 52 weeks. There were no significant increases in the occurrence of any tumor type in either sex. Dosing was considered to be adequate to assess carcinog enicity since the highest dose tested was the
limit dose and at this dose he patocellular hyperplasi a was observed in males and reduced
survival was seen in females. The CARC concluded there was no evidence of carcinogenicity in males or female mice

.

There was no evidence of mutagenicity in vivo or in vitro

.

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), the CARC determined that there is “Suggestive Evidence of Carcinogenic
Potential” for diethofencarb based on the presence of thyroid tumors in male and female rats. There was no evidence of carcinogenicity in male or female mice at dose levels that were considered adequate to assess carcinog enicity. Additionally, there is no concern for mutagenicity.

Quantification of human cancer risk is not re quired. The chronic Reference Dose (RfD) will adequately account for all chronic toxicit y, including carcinogenicity, which could result from exposure to diethofencarb.Page 5 of 34 II. INTRODUCTION

On May 20, 2015, the Cancer Assessment Review Committee of the Health Effects Division of the Office of Pesticide Programs evaluate d the carcinogenic potenti al of diethofencarb.

III. BACKGROUND INFORMATION

Diethofencarb, [isopropyl 3,4-di ethoxycarbanilate], is a ne w active ingredient (a.i.) fungicide with broad spectrum activity in fruits and vegetables. It is a systemic fungicide with protective and curative action. It is read ily absorbed though the leaves and roots and translocated throughout the plant. It inhibits mitosis in grey mold germ tubes, and has secondary activity against powdery mildews. Th is mode of action has not been established
in mammals.

Technical diethofencarb is a pi nk granular solid with a me lting point of 98.3 – 100.9oC and a specific gravity of 1.19 g/cc. Diethofencarb is slightly soluble in wa ter (27.64 mg/l at 20°C) and significantly more soluble in organic solvents.

IV. EVALUATION OF CARCINOGENICITY STUDIES

Studies available for evaluation included a two- year chronic/oncogenicity study in rats and a 78 week carcinogenicity study in mice.

A. Combined Chronic Toxicity/Carcinoge nicity Study in Sprague-Dawley Rats

Reference: Cox, R. (1989). Combined chronic toxicity and oncogenicity study in rats with S-32165. Hazelton Laboratories America, In c., Vienna, VA. Laboratory Study No. 343-163, April 14, 1989. MRID 49267454. Unpublished.

In the combined chronic/carcinogenicity study, five groups of 80 Crl:CD ® (SD)BR rats/sex/group were administ ered Diethofencarb in the diet at 0, 40, 200, 1000, and 5000 ppm (equivalent to 0, 1.69, 8.42, 42.70, a nd 220.30 mg/kg/day in males; 0, 2.18, 10.90, 54.50, and 288.19 mg/kg/day in females) for 104 weeks with interim sacrifices of 10/sex/group at 52 weeks and 20/sex/group at 104 weeks.

1. Survival Analyses

The survival analyses indicated a statistically significant negative trend and significant negative pair-wise comparisons of the 200 and 5000 ppm dose gr oups with the controls in male rats ( Table 1 ). There were no statistically si gnificant survival disparities among female rats ( Table 2 ).Diethofencarb (PC Code 112102) FINA L

Page 6 of 34 Table 1. Diethofencarb – Crl:CD ® (SD)BR Rat Study (MRID 49267454 ) Male Mortality Rates + and Cox or Generalized K/W Test Results

Weeks

Dose (ppm) 1-26 27-52 53 i 53-78 79-106 f Total

0 0/80 4/80 10/76 14/66 24/52 42/70 (60) **n

40 0/80 0/80 10/80 16/70 24/54 40/70 (57) n

200 1/80 0/79 10/79 6/69 21/63 28/70 (40) **n

1000 0/80 1/80 10/79 9/69 27/60 37/70 (53) n

5000 2/80 1/78 10/77 4/67 17/63 24/70 (34) **n +Number of animals that died during the interval/Number of animals alive at the beginning of the interval.

i Interim sacrifice at week 53.

f Final sacrifice at weeks 105-106.

n Negative trend or negative pair-wis e comparison with the control. ( ) Percent.
Time intervals were selected for display purposes only. Significance of trend denoted at control. Significance of pair-wise comparison with control denoted at dose level.
If * , then p < 0.05. If ** , then p < 0.01.Page 7 of 34 Table 2. Diethofencarb – Crl:CD ® (SD)BR Rat Study (MRID 49267454 ) Female Mortality Rates + and Cox or Generalized K/W Test Results

Weeks

Dose (ppm) 1-26 27-52 53 i 53-78 79-106 f Total

0 1/80 2/78 a 10/76 10/66 30/56 43/69 (62)

40 0/80 2/80 10/78 8/68 27/60 37/70 (53) n

200 0/80 0/78 b 10/78 9/68 29/59 38/68 (56) n

1000 0/80 1/80 10/79 8/69 30/61 39/70 (56) n

5000 0/80 4/80 10/76 9/65 c 28/56 41/69 (59) n
+Number of tumor bearing animals/Number of animals examined, ex cluding those that died or were sacrificed before observation of the
first tumor.

a First adenoma not in an interim sacrifice an imal was observed at week 71, dose 0 ppm.

b First carcinoma observed at week 100, dose 5000 ppm.

c Two animals in the 5000 ppm dose group had both an adenoma and a carcinoma.

d One animal in the interim sacrifice group in both the 1000 and 5000 ppm dose groups
had an adenoma. Interim sacrifice an imals are not included in this analysis. Significance of trend denoted at control. Significance of pair-wise comparison w ith control denoted at dose level.
If * , then p < 0.05. If ** , then p < 0.01.

2. Tumor Analyses

Statistical analyses of the tumors observed in the male rats were based upon Peto’s
Prevalence Test due to si gnificant survival dispariti es among the dose groups ( Table 3a ). Male rats had significant tre nds at p < 0.01 and significant pa ir-wise comparisons of the 5000 ppm dose group with the controls at p < 0.05 for thyroid gland follicular cell
carcinomas and combined adenomas and/or ca rcinomas. There was also a statistically significant trend for thyroid follicular cell adenomas at p < 0.05.

Female rats had significant trends at p < 0.01 and significan t pair-wise comparisons of the 5000 ppm dose group with the controls at p < 0.05 for thyroid gland follicular cell
adenomas and combined adenomas and/or carc inomas. The statistical analyses of the tumors in the female rats were based upon Fi sher’s Exact Test and the Exact Test for Trend ( Table 4 ).Diethofencarb (PC Code 112102) FINA L

Page 8 of 34 Table 3a. Diethofencarb – Crl:CD ® (SD)BR Rat Study (MRID 49267454 )

Male Thyroid Gland Follicular Cell Tumor Rates + and
Peto’s Prevalence Test Results Dose (ppm) Tumor Type 0 40 200 1000 5000

Adenomas (%)

P = 2 a /62 (3)

0.0105* 1/62 (2)

0.7108 0/65 (0)

0.8371 3 d /62 (5)

0.3467 5 d /64 (8)

0.1047

Carcinomas (%)

p = 1/31 (3)

0.0000** 0/36 (0)

0.8497 1/48 (2)

0.6526 0/37 (0)

0.8612 7 b /49 (14)

0.0460*

Combined
Adenomas/Carcinomas (%)

p = 3/62

(5)

0.0000** 1/62

(2)

0.8445 1/65

(2)

0.8203 3/62

(5)

0.5395 10 c /64

(16)

0.0405*
+Number of animals that died during the interval/Numbe r of animals alive at the beginning of the interval.

i Interim sacrifice at weeks 52-53.

f Final sacrifice at weeks 105-106.

n Negative pair-wise comparison with the control. ( ) Percent.

a One accidental death at week 52, dose 0 ppm.

b Two accidental deaths, both at week 52, dose 200 ppm.

c One accidental death at week 78, dose 5000 ppm. Time intervals were selected for display purposes only. Significance of trend denoted at control. Significance of pair-wise comparison w ith control denoted at dose level.
If * , then p < 0.05. If ** , then p < 0.01.

Table 3b. Historical Control Data of Thyroid Tumors in Sex Tumor type Mean Range (%) Sample Males Adenoma 2.28 0 – 8 7 studies,
448 animals Carcinoma 1.14 0 – 4 Females Adenoma 0.43 0 - 2 7 studies,
443 animals Carcinoma 0.71 0 - 2 Data obtained from MRID 49264955, page 22, Table 3.Page 9 of 34 Table 4. Diethofencarb – Crl:CD ® (SD)BR Rat Study (MRID 49267454 )

Female Thyroid Gland Follicular Cell Tumor Rates + and
Fisher’s Exact Test and Exact Trend Test Results Dose (ppm) Tumor Type 0 40 200 1000 5000

Adenomas (%)

P = 0/66 (0)

0.0026** 1/67 (1)

0.5038 1/68 (1)

0.5075 0/69 (0)

1.0000 5 a /66 (8)

0.0289*

Carcinomas (%)

p = 1/66 (2)

0.3106 2/67 (3)

0.5057 1/68 (1)

0.7593 1/69 (1)

0.7629 2 b /66 (3)

0.5000

Combined (%)

p = 1/66 (2)

0.0068** 3/67 (4)

0.3153 2/68 (3)

0.5113 1/69 (1)

0.7629 7/66 (11)

0.0310*
+Number of tumor bearing animals/Number of animals examined, excluding those that died or were sacrificed before week
54.

a First adenoma observed at week 86, dose 5000 ppm.

b First carcinoma observed at week 72, dose 5000 ppm.

c Two animals in the 5000 ppm dose group had both an adenoma and a carcinoma.

d One animal in the interim sacrifice group in both the 1000 and 5000 ppm dose groups
had an adenoma. Interim sacrifice an imals are not included in this analysis. Significance of trend denoted at control. Significance of pair-wise comparison w ith control denoted at dose level.
If * , then p < 0.05. If ** , then p < 0.01.

3. Non-neoplastic lesions and other findings

There were no remarkable non-neoplastic lesions in the liver or the thyroid. Selected macroscopic and non-neoplastic microscopic fi ndings observed at the week 104 sacrifice
are shown in Table 5 . The occurrence of macroscopi c pituitary lesions (pituitary enlargement, and mottled pituitary) was more frequent in males treated at 1000 and 5000 ppm. Microscopic lesions mo re frequent in males treate d at 1000 and 5000 ppm included angiectasis/sinusoid ectasia in the pituitary. While the incidence of pituitary tumors was not statistically signif icant, pituitary hypert rophy/hyperplasia fit w ith the proposed mode
of action -- increased T4 clearance leadi ng to increased stimulation of pituitary thyrotroph cells. Pituitary hypertrophy/hyperpla sia may be difficult to identify in older rats since there is typically age-related stimulation of gonadotrophs and lactotrophs, which could obscure a treatment effect specifi cally on thyrotrophs.) In this case, there appears to be a significant increase in the incidence of gross pituitary enlargement and mottling and angiectasis/sinusoid ectasia in males, all of which appear to track together. In females, which have higher b ackground incidence of these changes, there is a similar pattern (modestly higher incidence of angiectasis/sinusoi d ectasia, general concordance with enlargement) but no appare nt significant differences between control and high-dose groups.Diethofencarb (PC Code 112102) FINA L

Page 10 of 34 TABLE 5. Selected macroscopic and non-neoplastic microscopic findings at week 104 sacrifice.

Dose (ppm) 0 40 200 1000 5000

Sex M F M F M F M F M F 2-yr dose level (mg/kg/day) 0 0 1.69 2.18 8.42 10.90 42.70 54.50 220 288

Macroscopic findings Pituitary – enlarged 4 14 2 17 4 14 11 13 11 15 Pituitary -- mottled 1 6 1 10 1 6 6 7 8 11 Microscopic non-neoplastic findings Pituitary – angiectasis/sinusoid
ectasia 5 12 2 19 7 17 11 15 18 19

Data obtained from Table B.6.5.1-7, p. 287, DAR Diethofencarb Vol. 3, Annex B6.

4. Adequacy of Dosing for Carcinogenic Potential

The doses tested were determined to be ade quate to assess the car cinogenic potential of
diethofencarb based on the occurrence of t hyroid tumors at the high dose (5000 ppm; 220 mg/kg/day in males and 288 mg/kg/day in fema les), However, the CARC noted that there were no treatment-related effects on body wei ghts, food conversion efficiency, clinical pathology, organ weights or non-neoplastic lesi ons at any dose, including the high dose. For chronic toxicity, the no-obsereved-effect level (NOAEL) was 5000 ppm; a lowestobserved-effect-level (LOA EL) was not established.

B. Carcinogenicity Study in Crl:CD-1(ICR)BR Mice

Reference: Cox, R. (1988). Oncogenicity st udy in mice with S-32165. Hazelton Laboratories America, Inc., Vienna, VA. Laborator y Study No. 343-164, December 2, 1988. MRID 49267453. Unpublished.

In a carcinogenicity study, five groups of 75 Crl:CD-1(ICR)BR mice/sex/group were
administered Diethofencarb in the diet at 0, 10, 100, 1000, and 10,000 ppm (equivalent to 0, 1.63, 16.47, 163.8, and 1682 mg/kg/day in male s; 0, 2.03, 20.53, 202.9, and 2108 mg/kg/day in females) for 78 weeks with interim s acrifices of 10/sex/group at 13 weeks and 15/sex/group at 52 weeks. Mortality, clin ical signs, body weight, and food and water consumption were recorded. Differentia l leukocyte counts and cell morphology were conducted on blood from all surviving animals after 52 and 78 weeks of treatment. Gross necropsies, organ weights, and microscopic examination of tissues were performed on
decedents and on those sacrificed on schedule.

1. Survival analysis:Page 11 of 34 Survival was similar among the treated gr oups of mice in the main study, except for females at 10,000 ppm which had a significantly lower surv ival rate relative to controls at 78 weeks (P<0.05; 16/49 vs. 33/50 in controls).

2. Tumor Analyses:

At the doses tested, there was not a treatme nt-related increase in tumor incidence when compared to controls.

3. Adequacy of Dosing for Carcinogenic Potential

The highest dose tested was the limit dose ( 10,000 ppm) and at this dose hepatocellular hyperplasia was observed in males (1682 mg/kg/ day) and reduced survival was seen in females (2108 mg/kg/day). Therefore, the doses tested were determined to be adequate to assess the carcinogenic potential of diethofencarb in this species.

V. TOXICOLOGY

A. Metabolism

In a series of metabolism st udies (MRIDs 49267467 – 49267471), [Phenyl- 14 C] Diethofencarb was administered to groups of male or female rats at doses of 10 or 300 mg/kg bw as a single or two-day dose. In an addition, male rats were treated with a 10 mg/kg bw/day unlabeled test material for 14 days followed by a single radiolabeled dose
of the test material.

These studies have shown that there is quick and extensive absorp tion of diethofencarb, limited distribution in tissues, extensive metabolism into sulfate and glucuronide metabolites, and quick and extensive excreti on with no bioaccumulation. In a standard series of ADME tests with single and multip le gavage dosing at various dose levels,
metabolism of diethofencarb in rats was found to be independent of sex, dose level and pre-treatment. Oral absorption is quick a nd extensive (> 87% of administered dose or AD by day 2). Organ/tissue radioactivity de creased rapidly and was mainly found in liver, adrenals, blood/blood cells, kidney and skin. T max was 0.5 to 1.0 hr in blood and tissue. A plasma T 1/2 value was not included in the repor t. Diethofencarb was extensively biotransformed into several metabolites, ma inly sulphate and gl ucuronide conjugates. Excretion was extensive and quick (> 93% of AD by day 2) and occurred in urine (> 61% of AD), expired air (> 21% of AD) and f eces (> 13% of AD). This resulted in organ/tissue depuration t 1/2 values of <35 hours based on da ta up to 72 hr pose-dose and a low retained fraction (<2% of AD on day 7), a nd the deduction that th ere is no significant entero-hepatic recirculation. The quick and extensive excretion, as well as the rapid organ/tissue decrease in radioactivity suggested there is no bioaccumulation.Diethofencarb (PC Code 112102) FINA L

Page 12 of 34 Figure 2. Proposed metabolic pathways for Diethofenc arb in rats including the route to 4-OH-5-TLA DFC

Figure taken from MRID 49267470, page 5.

B. Mutagenicity

Diethofencarb has been eval uated in a battery of genot oxicity assays comprising in vitro bacterial and mammalian gene mutation, in vitro and in vivo mammalian chromosomal aberrations, and an in vitro Unscheduled DNA Synthesis (UDS ) assay. All assays were OCSPP and/or OECD guideline studies, and were considered to be valid assays based on appropriate background counts and sensitivit y of each test system to known positive
control substances

. The Mutagenicity battery is consid ered complete and Acceptable. There is no mutagenicity concern for diethofencarb.

Gene Mutations

In an in vitro bacterial reverse mutation assay (MRID 49267456), diethofencarb dissolved in dimethylsulfoxide (DMSO) did not indu ce an increase in mutant colonies over background in S. typhimurium strains TA98, TA100, TA1535, and TA1537, TA1538 andPage 13 of 34 E. coli strain WP2 uvr A at concentrations up to 1000 μg/p late with and without S9 mix) using the pre-incubation method and duplicate plating.

In an in vitro bacterial reverse mutation assay (M RID 49267457), diethofencarb (dissolved in DMSO) did not induce an increase in mutant colonies over background in S. typhimurium strains TA98, TA100, TA1535, and TA1537, TA1538 and E. coli strain WP2

uvr A at concentrations up to 2000 μg/plate with and without S9 mix, using the preincubation method and duplicate plating.

In a mammalian cell gene mutation assay at the hypoxanthine-gua nine phosphoribosyl transferase (HGPRT) locus (MRID 49267458), Ch inese hamster lung V79 cells cultured

in vitro were exposed to technical diethofencar b dissolved in DMSO for 5 hours at concentrations of 0, 20, 50, 100, or 200 μg/mL in three independent experiments in the
absence of metabolic activati on and in two independent expe riments in the presence of
metabolic activation. There was no evidence of induced mutant colonies over background.

Chromosome Aberrations

In an in vitro mammalian cell chromosome aberration assay (MRID 49267459), Chinese hamster ovary cells were exposed to di ethofencarb without S9 at 13.37, 26.73, 53.46 and 133.66 μg/mL for 24 and 48 hr with no recovery period. In the presence of S9 activation, the concentrations were 26.73, 53.46, 133.66 and 267.32 μg/mL for 6 hr with an 18 hr recovery period. There was no evidence of chromosome aberrations induced over background.

In an in vivo ICR mouse bone marrow micronucle us assay (MRID 49267460), 6 male mice/group were each given a single intraperit oneal (i.p.) injection of diethofencarb in corn oil (females were excluded from this study without justificat ion). Two independent studies were conducted: a time-course study a nd a dose-response study. In the time-course study, three groups of mice received a dose of 5000 mg/kg (guideline limit dose is 2000 mg/kg). Six animals were sacrificed at 24, 48 and 72 hr after treatment. Two additional groups of 6 mice apiece were treated with th e vehicle only (20 mL/kg) as a negative control, or with cyclophosphamide as a pos itive control (80 mg/kg bw). In the doseresponse study, three groups of mice were tr eated with diethofencar b at dose-levels of 1250, 2500 or 5000 mg/kg. Two additional groups of 6 mice apiece were treated with the vehicle only (20 mL/kg) as a negative contro l, or with 9,10-dimethyl-1,2-benzanthracene (DMBA) at a dose of 50 mg/kg bw. All animal s were sacrificed 48 h after treatment. In the dose-response study, the test article produced small, but statistically significant, decreases in the polychromatic erythrocytes ( PCEs), which were also dose-related. The
time-course studies at 48 a nd 72 h also showed reductions in the PCEs. This was an
indication that these treatments cause d moderate bone marrow cell toxicity. Administration of the positive control chemical s in both studies resulted in significantly higher numbers of micronucleated-PCEs co mpared with the corresponding vehicle controls, demonstrating the va lidity of the assay. At th e doses tested, there were noDiethofencarb (PC Code 112102) FINA L

Page 14 of 34 significant increases in the frequencies of mi cronucleated polychromatic erythrocytes in bone marrow after any treatment time or dose level.

C. Structure Activity Relationship

Diethofencarb is an N-phenyl isopropyl car bamate. Carbamates have been extensively
studied in the 1980s with uret hane (ethyl carbamate) as be ing the most well-known lung and skin carcinogen. An overview of SAR of carcinogenic carbamates has been published (Woo, 1983). In general, carbamates are very sens itive to change in the size of the alkyl group of the ester group (which serve as an al kylating agent) but can tolerate substitution at the amino group.

Carcinogenic activity has been detected in ca rbamates with only one to three carbons on the ester group. Iso-propyl carbamate has been shown to induce lung tumors in Strain A mice in a medium-term assay with 12 thrice -weekly i.p. injection and 20-week observation (Shimkin et al., 1969, cited in Woo, 1983). Howeve r, its activity was substantially lower than that of urethane. In skin painting st udy isopropyl carbamate was inactive. Overall, there is only marginal SAR support for Diethofencarb as a thyroid carcinogen.

D. Sub-Chronic and Chronic Toxicity Studies

Rats

28-day Oral Subchronic study (MRID 49297440) Groups of Sprague Dawley rats (10/sex/group ) were administered diethofencarb (97.4% a.i., Batch PK 84042) in the diet at concentrations of 0, 100, 1000, 3000, or 10,000 ppm (corresponding to 9.02, 89.1, 276, or 878 mg/kg bw/day in males and to 9.94, 98.9, 300, or 1009 mg/kg bw/day in females) for 4 weeks.

Both sexes at the 10,000 ppm dose level had higher blood cholesterol concentrations (increases of 43% and 22% in males and females, respectively), and swelling of centrilobular hepatocytes in all animals. Males only at 10,000 ppm dose level had lower food intake (a reduction of 11%), higher abso lute liver weight (i ncrease of 14%), and higher relative liver weight (increase of 25 %). These increases in cholesterol and liver weights are considered adaptive responses that are not adverse. No treatment-related
adverse effects were observe d at 10 or 1000 ppm dose levels in either sex. The NOAEL was 3000 ppm (300 mg/kg bw/day) in fema les and 1000 ppm (89.1 mg/kg bw/day) in
males

. The target organ was identified as th e liver, based on swe lling of centrilobular hepatocytes and increased blood cholesterol c oncentration.

90-day subchronic study (MRID 49267444) Diethofencarb at dietary concentrations of 300, 1000, 3000 or 10,000 ppm, for a period of 90 days (corresponding to 21.3, 78.2, 232 or 752 mg/kg/day in males, and 27.2, 90.8, 275 or 824 mg/kg/day in females).Page 15 of 34 At 10,000 a small (-4% in males,) decrease in body weights in both sexes was observed, as well as lower food consumption and water intake in females. Increases in absolute and relative liver weights were observed, acco mpanied by centrilobular hepatocellular hypertrophy as well as hypertrophy of endopl asmic reticulum in males at 3000 ppm and both sexes at 10,000 ppm (see table 3a). These li ver effects were cons idered as adaptive responses to S-32165-induced toxicity. Th e LOAEL is 824 mg/kg bw/day based on decreased body weight in females. The female NOAEL was 275 mg/kg bw/day. No significant toxicity was observed in males so the NOAEL is 752 mg/kg bw/day and the
LOAEL is not established.

2-year chronic/oncogenic ity study (MRID 49267454) Five groups of 80 Crl:CD ® (SD)BR rats/sex/group were administered Diethofencarb in the diet at 0, 40, 200, 1000, or 5000 ppm (equivalent to 0, 1.69, 8.42, 42.70, or 220.30 mg/kg/day in males; 0, 2.18, 10.90, 54.50, or 288.19 mg/kg/day in females) for 104 weeks with interim sacrifices of 10/sex/group at 52 weeks and 20/sex/group at 104 weeks. Mortality, clinical signs, body weight, and food and water co nsumption were recorded. Samples of blood and urine were collected for clinical pathology evaluation, including
cholinesterase activities in plasma and red blood cells, at weeks 13, 26, 52, 78, and 104.
Brain tissue for cholinesterase determinati on was collected at weeks 52 and 104. Gross necropsies, organ weights, and microscopic examination of tissues were performed on
decedents and on those sacrificed on schedule.

Food conversion efficiency was lower in both sexes at the high dose and water consumption was also lower for females. Pl atelet counts and chol esterol levels were elevated in high dose females. However, the el evated platelet counts were within the range
of historical control and are not considered adverse; the elevated cholesterol was not
considered adverse in the absence of corroborat ing effects such as changes in liver weight or liver histopathology.

There was a significantly higher incidence of thyroid follicular tumors in both sexes at 5000 ppm relative to controls. (220.3 mg/ kg/day and 288.19 mg/kg/day in males and females, respectively, as evidenced by a treatment-related increase in thyroid follicular cell tumor incidence (carcinomas in males, aden omas in females). Dosing was considered adequate based on evidence of the thyroid tumors at 5000ppm, however, a LOAEL have not been established for this study because there were insufficient indicators of nonneoplastic toxicity at the dose levels tested.

Mice

28-day Oral Subchronic study (MRID 49267442) Groups of CD-1 (ICR) BR mice (10/sex/group) were administered diethofencarb (97.2% a.i., Batch PKG 84093) in the diet at the dietary concentrations of 0, 100, 3000, 10,000 or 30,000 ppm for 28 days. No analyses of dietary admixtures were performed to investigateDiethofencarb (PC Code 112102) FINA L

Page 16 of 34 the homogeneity, stability, and achieved concentr ations of the test substance. Mortality, clinical signs, body weight, and food consum ption were recorded. Samples of blood and were collected for clinical pathology evalua tion at the end of treatment. All surviving animals in all groups were then sacrificed and subjected to gross necropsy. Selected organs were weighed, and, in the control and 30,000 ppm groups, a standard range of organs and tissues was removed, fixed, and ex amined microscopically. Livers, kidneys, and urinary bladders of mice in all groups were examined microscopically. The 100, 3000, 10,000 and 30,000 ppm dietary levels correspond ed to nominal dose-levels of 18.7, 563, 1852, and 6169 mg/kg bw/day in males and to 24.4, 720, 2337, and 8450 mg/kg bw/day in females for the 28 days of feeding.

No mortality occurred. Both sexes at th e 30,000 ppm diet had hi gher platelet counts (increases of 16% and 24% in males a nd females, respectively), higher albumin concentrations (increases of 13% and 20% in males and females, respectively), higher protein concentrations (incr eases of 15% and 17% in males and females, respectively), higher total cholesterol concentrations in blood (increases of 74% and 66% in males and females, respectively), higher alanine aminotra nsferase (ALT) activitie s (increases of 88% and 79% in males and females, respectively), hi gher absolute liver we ights (increases of 34% and 53% in males and females, respectivel y), higher relative liver weights (increases of 63% and 61% in males and females, respec tively), dark livers in 6/10 males and in all 10 females, as well as foci of necrosis in livers, hepatocellular hype rtrophy, proteinaceous casts and regenerative epithelium in kidneys , and submucosal lymphoid hyperplasia in urinary bladders in both sexes. Males onl y at the 30,000 ppm diet showed a reduction in body weight gain, which amounted to 49%. Th e LOAEL in CD-1 (ICR) BR mice of both sexes was the 10,000 ppm diet (corresponding to nominal dose levels of 1852 and 2337 mg/kg bw/day in males and females, resp ectively) based on hi gher platelet counts (increases of 10% and 17% in males and fema les, respectively), higher total cholesterol concentrations in blood (increases of 26% in both sexes), higher ab solute liver weights (increases of 14% and 23% in males and fe males, respectively), higher relative liver weights (increases of 17% and 20% in males a nd females, respectively), as well as foci of
necrosis in livers. Males onl y at the 10,000 ppm dietary le vel had submucosal lymphoid hyperplasia in urinary bladders and hepatocellular hypertrophy.

No treatment-related adverse effects were obs erved at the 100 or 3000 ppm dietary levels
in either sex. The NOAEL in both sexes was the 3000 ppm diet (corre sponding to nominal doses of 563 and 720 mg/ kg bw/day in males and females, respectively ). The target organs were identified as the li ver, kidneys, and urinary bladder.

78-week Carcinogenicity Study (MRID 49267453) Five groups of 75 Crl:CD-1(I CR)BR mice/sex/group were admi nistered Diethofencarb in the diet at 0, 10, 100, 1000, or 10,000 pp m (equivalent to 0, 1.63, 16.47, 163.8, or 1682 mg/kg/day in males; 0, 2.03, 20.53, 202.9, or 2108 mg/kg/day in females) for 78 weeks with interim sacrifices of 10/sex/group at 13 weeks and 15/sex/group at 52 weeks. Mortality, clinical signs, body weight, and food and water co nsumption were recorded.Page 17 of 34 Differential leukocyte counts and cell morphology were c onducted on blood from all surviving animals after 52 and 78 weeks of treatment. Gross necropsies, organ weights, and microscopic examination of tissues were performed on decedents and on those
sacrificed on schedule.

Females at 10,000 ppm had a signif icantly lower survival rate relative to controls at 78
weeks. The incidence of he patocellular hyperplasia in high dose males was significantly higher (p<0.05) relative to controls, and th e incidence of hepatocel lular hyperplasia in males at 1000 ppm was consid ered treatment-related.

Under the conditions of this study, the system ic LOAEL for Diethofencarb in CD-1 mice was 10000 ppm in the diet in males (1682 mg/ kg/day) based on increased incidence of hepatocellular hyperplasia, a nd 10000 ppm in females (2108 mg /kg/day) based on reduced survival. The NOAEL was 1000 ppm in ma les and females (163.8 and 202.9 mg/kg/day, respectively).

VI. MODE OF ACTION STUDIES

1. Mode of Action Assessment-T hyroid Tumors in Male Rats

The hypothesized MOA for diethofencarb-induced thyroid follicular-cell adenomas involves an extrathyroidal mechanism mediated by th e induction of hepatic enzymes, including uridine diphosphate glucuronyl transferase ( UDP-GT or UGT). Subsequently, the increased liver UGT activity leads to increased metabo lism of T4 by glucuronidation and increased biliary excretion of the T4 conjugate, thereby causing a decrease in serum T4 half-life and concentration. In response to decreased seru m T4 levels, the HPT axis is activated, and
blood concentrations of TSH fr om the pituitary in crease. With continued metabolism and clearance of T4, TSH elevations are prolonged in order to stimul ate thyroid follicular cells to synthesize and release more thyroid hormones to reestablish homeostasis. The follicular cells initially undergo hypertrophy to addre ss the need for increased thyroid hormone biosynthesis, but with sustained TSH stimul ation, follicular cells undergo hyperplasia to meet thyroid hormone demand. TSH-stimulated follicular cell hyperpla sia can progress to neoplasia, resulting in follicular cell adenomas. The

The Registrant submitted mode of ac tion (MOA) studies (MRIDs 49267473, 49267474) for thyroid tumors which are discussed in detail below. The postulated MOA for diethofencarbinduced rat thyroid tumors is altered home ostasis of the hypothalamic-pituitary thyroid (HPT) axis.

2. Data Supporting the Proposed Diethofencarb MOA

The relevant experimental data used to eval uate the proposed thyroi d follicular cell tumor MOA include guideline repeated-dose toxicity studies (for executive summaries see Section IV) in rats (diethofencarb exposures for 2- , 4- and 13weeks, and 24-month time points), asDiethofencarb (PC Code 112102) FINA L

Page 18 of 34 well as two mechanistic studies (discussed below) designed to examine effect of diethofencarb on the HPT axis (MRIDs 49267473, 49267474).

14- Day Mechanistic Study (MRID 49267473)

In this study, diethofencarb was administered to groups of 10 male Sprague Dawley rats 7-, 37-, and 66-weeks of age at concentra tions of 0, 5000 or 20,000 ppm for 2 weeks to determine effects on thyroid hormone concen tration; to groups of ten 31-week male Sprague Dawley rats at concentrations of 20,000 ppm for 7 and 14 days to determine tissue distribution; and to groups of two to four 7- and 37-week male Sprague Dawley
rats at concentrations of 0 and 20,000 ppm for 14 days for biliary excretion and
metabolism studies.

Rats in the biliary excretion/metabolism study received an i.v. injection of 2 μg/kg bw

125 I-thyroxin in 0.5 mL saline at the end of feeding period to determine radiolabeled
excretion. The estimated doses to anim als in the two-week feeding study were approximately 0, 430, and 1720 mg/kg bw/day for 7-week animals, and 0, 345, and 1380 mg/kg bw/day for 37- and 66-week animals, respectively. For th e tissue distribution study, the rats received an estimated dose of approximately 1380 mg/kg bw/day. Finally,
the estimated doses for rats treated with th e test material were approximately 430 and 1380 mg/kg bw/day for 7-week and 37-week ra ts treated with 20,000 ppm, respectively. Since body weights were not reported except terminal body weights in the 2-week study, these were not included in the assumptions for bioaccumulation and biliary excretion studies.). Summary data from these st udies indicate treatm ent with 20,000 ppm Diethofencarb for up to two weeks decreased se rum T4 concentrations and induced slight
increases in TSH concentrations with no effect on T3 concentrations. In the bioaccumulation study, the kidney had the highest 14 C concentrations followed by the liver, skin and hair following both 7- and 14-days of treatment. No indication of
bioaccumulation of radiolabel was found in th e thyroid. The data also suggested that
increased T4 excretion in the bile arose th rough metabolic processes related to hepatic
UDP-GT induction. Females were not used in this study, and dose levels below the tumorigenic dose (5000 ppm) were not investigated.

90-Day Mechanistic study (MRID 49267474)

In this study, diethofencarb was administered to 20 male SD rats/sex/dose in the diet at levels of 0, 5000, or 20,000 ppm (equivalent to 0, 307.9, or 1277.9 mg/kg bw/day). Twenty-four hours before scheduled sacrifice, half the rats in e ach group were given a single IP injection of 125 I to determine uptake. Histologi cal examinations were limited to the thyroid of rats not treated with 125 I.

Body weight changes were small, -4% to -6 %, by the end of the study. Slight doserelated statistical decreases in circulating free T 4 and increases in TSH (thyroid stimulating hormone) were found in 20,000 pp m rats at study end; however, total T 4 wasPage 19 of 34 not statistically different from control rats, though decreased 16%. No significant effects
were found on total or free T 3 in rats treated with 20,000 ppm. There was a 16% increase in relative to body thyroid weight of 20,000 male rats, but no effects were found on absolute thyroid weight or 125 I thyroid uptake, and no micr oscopic effects were found. Statistically significant increases in liver UDP-GT (UDP-glucuronyltransferase) activities were found in 20,000 ppm rats with activity/kg bw (3.7 fold), activity/g liver weight (2.6 fold), and activity/mg protein (1.9 fold). Slight increases were also found in 5000 ppm rats for the same parameters, but were not st atistically increased ( 1.3 fold for activity/kg bw, 1.4 fold for activity/g liver weight, and 1.4 fold for activity/mg protein). The absolute liver weight of 20,000 ppm rats wa s statistically increased 25%, while the liver relative to body weight was increased 42%. The liver weight relative to body weight was statistically increased 13% in 5000 ppm rats, while no signifi cant increase in absolute liver weight was found. These re sults suggest that Diethofenca rb had no direct effect on the thyroid, but the effects were due to accelerated excretion of thyroid hormones from the liver as evidenced by the increase in liver UDP-GT activity.

This resulted in a decrease in serum free T 4 concentrations that likely triggered the feedback mechanism of the pituitary gl and, and promotion of TSH release. The LOAEL
for Diethofencarb in male SD rats was 20,000 ppm (equivalent to 1277.9 mg/kg bw/day) based on decreased body weight and body we ight gain, decreased serum free T 4 , increased TSH, and increased liver UDP-GT activities. The NOAEL was 5000 ppm (307.9 mg/kg bw/day). Females were not used in this study, and dose levels below the tumorigenic dose (5000 ppm) were not investigated.

3. The Key Events for Diethofencarb-Induced Thyroid Tumor MOA

The postulated key events in the i nduction of thyroid tumors are:

 Key Event #1 : Increased liver metabolism as seen by increased hepatic UDP-GT (UDG) activity;

 Key Event #2 : Increased hepatic metabolism a nd biliary excretion of T3/T4;

 Key Event #3 : Decreased T3/T4 serum half-life/c oncentration resulting in increase in TSH concentrations;

 Key Event #4 : Increased incidence of cellular thyroid hypertrophy and follicular cell hyperplasia ;

 Key Event #5 : Thyroid follicular cell adenomas and carcinomas

Key Event #1: Increased liver metabolism as seen by increased hepatic UDP-GT (UDG) activity

In the 90 day mechanistic study (MRID 49267474) discussed above at doses at and above the tumorigenic dose (5000ppm), UGT activity was increased 33% and 94%, respectively compared to control levels when expressed as per mg microsomal protein, 43% and 160%,Diethofencarb (PC Code 112102) FINA L

Page 20 of 34 respectively, per gram liver, and 164% and 275%, respectively, per whole liver ( Table 6 ). Measurements of UGT activity were not re ported in the two w eek mechanistic study (MRID 49267473).

Table 6. Hepatic UGT Activity with 125 I-Thyroxine in the Thyroid Tumor MOA Study 1

Dose (ppm) Activity (pmol/min)

per mg Protein per gram Liver per kg body weight

Mean

n=8 % Change Mean
n=8 % Change Mean
n=8 % Change

0 0.087
±0.0488 NA 2.11
±1.287 NA 68.83
±40.362 NA

5000 0.116**
±0.0401 +33 3.02
±1.077 +43 112.50
±42.256 +64

20000 0.169**
±0.0710 +94 5.48**
±2.788 +160 257.03**
±134.111 +275

1 Data derived from MRID No. 49267474 NA= Not applicable. **Statistically significant from concurrent control at p<0.01

.
Data supporting other associated events: increa sed liver weight, hepat ic cell Proliferation and hypertrophy

In the 90-day rat study discussed above, there was a dose-related incr ease in both absolute and relative liver weights at 5000 ppm (the tumorigenic dose) and 20000 ppm, with all except the increase in absolute liver weight at 5000ppm being stat istically significant, when measured at the termination of the study ( Table 7 ). At 5000 and 200000 ppm, absolute liver weights were increased by 6% and 25%, respectively. Similarly, relative liver weights were significantly in creased by 13% and 43%, respectively.Page 21 of 34 Table 7. Male Rat Liver Weight Increases with 13 weeks of Dietary Diethofencarb Treatment in the Thyroid Tumor MOA Study 1

Dose (ppm) Dose (mg/kg/day) Absolute Liver Weight (g) Relative Liver Weight (g/100 g body wt)

Mean % Change Mean % Change

0 0 16.30 NA 3.26 NA

5000 308 17.19 +6 3.70** +13

20000 1278 20.41** +25 4.65** +43

1 Data derived from MRID No. 49267474 NA= Not applicable. * Statistically significant from concurrent control at p<0.05. **Statistically significant from c oncurrent control at p<0.01.

Diethofencarb-induced increases in liver weight and/or he patocellular hypertrophy have been reported in two rep eated-dose toxicity studies in rats (summarized in Table 8 ). In these studies, there was an increased magnitude and incidence of liver effects at higher doses, but not with significantly increased magnitude with longer duration exposure to diethofencarb. Relative (to body weight) liver weight increa ses were small at 3000ppm (8 - 12%), but were sta tistically significant (p <0.05) and demonstrated dose-response with the higher dose of 10000, suggesting a significant liver weight increase at the tumorigenic dose of 5000ppm.

Table 8. Concordance in Dose and Temporal Rela tionship in Diethofencar b-Induced Liver Weight Changes and Histopathological changes in Two Repeat-Dose Toxicity Studies a Dose, ppm 0 300 1000 3000 10000
Sex M F M F M F M F M F
4 weeks

Absolute Liver weight, g 16.05 9.7 15.8 9.32 16.11 9.91 17.05 (+6%) 9.54 (-2%) 18.31* (+14%) 9.75 (+1%)

Relative Liver Weight, g/100g 4.228 4.061 4.247 4.238 4.359 4.262 4.716* (+12%) 4.389 (+8%) 5.295 (+25%) 4.928* (+21%)

Centrilobular hepatocellular hypertrophy 0/10 0/10 0/10 0/10 0/10 0/10 3/10 (30%) 0/10 10/10 (100%) 10/10 (100%)

Hypertrophy
of smooth endoplasmic
reticulum NR NR NR NR NR NR NR NR NR NR

13 weeks

Absolute Liver weight, g 17.87 8.734 19.16 9.180 18.86 8.342 18.18 (+2%) 8.73 (+0%) 21.07** (+18%) 9.41 (+28%)

Relative Liver weight g/100g 3.195 2.977 3.303 3.224 3.325 3.063 3.444* (+8%) 3.186 (+7%) 3.936** (+23%) 3.810 (+28%)

Centrilobular hepatocellular hypertrophy 0/15 0/15 0/15 0/15 0/15 0/15 4/15 (27%) 0/15 15/15 (100%) 10/15 (67%)Diethofencarb (PC Code 112102) FINA L

Page 22 of 34 Table 8. Concordance in Dose and Temporal Rela tionship in Diethofencar b-Induced Liver Weight Changes and Histopathological changes in Two Repeat-Dose Toxicity Studies a Dose, ppm 0 300 1000 3000 10000
Sex M F M F M F M F M F Hypertrophy
of smooth endoplasmic
reticulum 0/15 0/15 0/15 0/15 0/15 0/15 0/15 0/15 2/5 4/5

a Data derived from MRIDs 49297440 and 49267444 “+”= Increased; M= male; F= female; NR = not reported The number in parentheses indicates the percentage change relative to controls

.

Conclusion

There is some evidence (based on data at 3000ppm and 10000ppm, dose levels below and above the tumorigenic dose of 5000ppm) th at increased liver enzyme activity was demonstrated by increased liver weight w ith hypertrophy at the tumorigenic dose with
dose-concordance in males and females. UGT activity changes were seen after 90 days at dose levels at and above the tumorigenic dose in males (Table 6). The mechanistic
studies were not conducted in both sexes at le vels below, at and above the tumorigenic dose, so the conditions of this key event have not been met in terms of dose concordance. Temporal concordance was demonstrated in males because these effects were noted before the occurrence of tumorigenic events at two years. Temporal concordance is
established in males and females with liver enzyme activity, liver weight changes and hypertrophy as they relate to thyroid tumors because they occur before the tumorigenic events reported in the two-year study.

Key Event 2: Increased hepatic metabo lism and biliary excretion of T4

Hepatic Metabolism

The induction of UDP-GT activity in ma les at 5000 and 20000 ppm in the study (MRID 49167474, Table 6 ) discussed in Key event #1 implie s an increase in the hepatic metabolism of T3/T4 hormones through conjuga tion, which would facilitate the biliary excretion of the conjugated thyroid hormones leading to a decrease in circulating serum T3 and T4 levels (Dellarco et al. 2006).

Biliary Excretion

T4 biliary excretion and metabolism were st udied in males in the two-week study (MRID 49267473). As seen in Figure 3 , 20000 ppm diethofencarb in the diet for 14 days resulted in an approximately 2-fold increase in biliary 125 I-thyroxine excretion.Page 23 of 34 Figure 3. Cumulative biliary 125 I excretion after intravenous injection of 125 I-thyroxine
to 37-week-old rats fed basal diet or 20,000 ppm of Diethofencarb for 14 days.

Data points of clean (basal) diet-treated rats are the means ± SD of 3 animals. Data points of 20,000 ppm Diethofencarb-treate d rats are
the means ± SD of 2 animals. From page 38 of MRID 49267473

T 4 biliary excretion was not measured in the other special mechanistic study (MRID 49267474) or in any other studies in the database.

Conclusion

Increased hepatic metabolism was inferred by th e data to some extent, at and above the tumorigenic dose of 5000ppm by induction of UDP GT, as seen by sta tistically increased activity of UDPGT (measured by per mg protein). Increased T 4 excretion (measured by

125 I clearance) occurred only above the tumorige nic dose in males, and females were not tested, so dose-concordance is not established. Temporal concordance has been
established in males in that increased he patic metabolism occurred at the tumorigenicDiethofencarb (PC Code 112102) FINA L

Page 24 of 34 dose in advance of the appearance of tumors . Temporal concordance was not established in females, which were not tested.

Key Event 3: Decreased serum T 4 half- life and concentr ation and Increased TSH

Serum thyroid hormone levels were measur ed in males after two-week and 13-week exposures to diethofencarb. As seen in Table 9 actual serum hormone measurements are
available for diethofencarb. In the 14 day study, protein-bound T 4 levels were statistically decreased (-23%, p<0.05) at 20000 pp m. In the 90-day study, free T 4 levels were decreased (-17%, p<0.01) at 20000 ppm, T3 levels were generally unchanged. No changes in T 4 or T 3 levels were noted at the tumorige nic dose of 5000ppm. In addition,
these measurements were taken in animals of different ages: 7, 37 and 66 weeks, to determine the effects of age on the two-week exposure. Th e most marked effects were seen in the 37-week rats, as presented in Table 10 . T 4 levels were statistically decreased at 20000ppm and TSH levels were st atistically increased at this level. Effects at 5000pm were less marked and not statically significan t in any of the groups. As seen above in
Table 9 , these effects on T 4 and TSH in the two-week st udy were seen in the 90-day study as well, with the degree of change reaching statistical significance only at 20000ppm and not at the tumorigenic dose.

Table 9. Serum thyroid hormone concentrations of male rats treated with Diethofencarb for 14 or 90 days. Dose,

ppm T4 b (μg/dl) Free T4 c (μg/dl) T3 b (μg/dl) Free T3 c (μg/dl) TSH (μg/dl) 14 days a
0 (n=10) 3.62±0.095 2.45±0.46 0.84±0.12 1.55±0.33 3.40 d ±1.71

5000 (n=10) 4.15±0.83 2.73±0.34 0.87±0.13 1.6±0.49 4.04±2.04
+19%

20000 (n=10) 2.79 * ±0.38
-23% 2.13±0.31
-13% 0.76±0.16
-10% 1.33±0.15
-14% 4.07±2.04
+20% 90 days

0 (n=10) 4.7±0.63 2.61±0.318 0.7±0.09 1.2±0.26 2.69±1.695

5000 (n=10) 4.4±0.30 2.56±0.386 0.8±0.13 1.3±0.33 5.42±6.133
+101%

20000 (n=10) 4.0±0.70
-15% 2.16 ** ±0.328
-17% 0.8±0.12
+14% 1.2±0.12
0% 5.91±6.536 *
+119%
Data taken from MRID 49267473 DER page 12, and MRID 49267474 DER page 7.

a animals were seven weeks old at the beginning of the 14-day study, and five weeks old at th e beginning of the 90 day study.

b T3 or T4 bound to serum protein

c T3 or T4, free form

d N=8
* Statistically different from concurrent control, p<0.05

* Statistically different from concurrent control, p< 0.01Page 25 of 34 Table 10. Serum thyroid hormone concentrations of ma le rats treated with Diethofencarb for 14 days a seven, 37 and 66 weeks of age.

Dose, ppm T4 b (μg/dl) Free T4 c (μg/dl) T3 b (μg/dl) Free T3 c (μg/dl) TSH (μg/dl)

7 weeks

0 (n=10) 3.62±0.095 2.45±0.46 0.84±0.12 1.55±0.33 3.40 d ±1.71

5000 (n=10) 4.15±0.83 2.73±0.34 0.87±0.13 1.6±0.49 4.04±2.04
+19%

20000 (n=10) 2.79 * ±0.38
-23% 2.13±0.31
-13% 0.76±0.16
-10% 1.33±0.15
-14% 4.07±2.04
+20%

37 weeks

0 (n=10) 2.74±0.36 2.21±0.22 0.69±0.18 1.07±0.64 2.92 d ±1.54

5000 (n=10) 2.97±0.49 2.32±0.29 0.60±0.08 0.82±0.16 3.36±1.87
+15%

20000 (n=10) 1.88 ** ±0.41
-31% 1.70 ** ±0.22
-23% 0.76±0.11 0.82±0.20 4.48 * ±2.93
+53%

66 weeks

0 (n=10) 2.77±0.65 1.91±0.35 0.69±0.12 0.96±0.27 2.13±1.18

5000 (n=10) 2.53±0.79 1.72±0.37 0.71±0.15 0.92±0.19 2.64±1.64
+23%

20000 (n=10) 2.04**±0.41
-26% 1.45**±0.28
-24% 0.67±0.12 0.87±0.11 2.55±2.14
+20%
Data taken from MRID 49267473 DER pages 12 & 13.

b T3 or T4 bound to serum protein

c T3 or T4, free form

d n=8
* Statistically different from concurrent control, p<0.05
* Statistically different from concurrent control, p<0.01

Conclusion

Decreased serum T 4 levels in males were seen only above the tumorigenic dose; TSH
concentration was increased in both a dose-re sponse relationship, and with time from the 14-day study to the 90 day study ( Table 9 ). However, the increases were observed at doses above the tumorigenic dose. Treatment-re lated adverse effects was observed in the pituitary in in the chronic rat study, as disc ussed in Section III.A.3 as they related to increased TSH concentrations. These effects, gross pituitary enlargement and mottling and angiectasis/sinusoid ectasia at 1000 ppm and 5000 ppm, app eared to be biologically
relevant in males but not females. Dose concordance for this key event has not be demonstrated in males and females, at dose levels below, at and above the tumorigenic
dose. Time concordance has not been established in males and females.

. Key Event #4: Thyroid lesions (hypertrophy and hyperplasia)

No thyroid lesions were obser ved in the subchronic or ch ronic toxicity/carcinogenicity studies or special mechanistic studies.Diethofencarb (PC Code 112102) FINA L

Page 26 of 34 Key Event # 5: Thyroid follicul ar Adenomas and Carcinomas.

In the rat chronic toxicity/carcinoge nicity study (MRID 49267454) an increased
incidence of carcinomas and adenomas + carcinomas combined was observed at 5000ppm in males (Table 2 ), and an increased incidence of adenomas and adenomas + carcinomas combined was observed at 5000ppm in females (Table 4). These observations were statistically significant (p < 0.05) and outside historical control ranges (Table 3b). Male rats had significant tr ends at p < 0.01 and si gnificant pair-wise comparisons of the 5000 ppm dose group with th e controls at p < 0.05 for thyroid gland
follicular cell carcinomas and combined adenomas and/or carcinomas. There was also a statistically significant trend for thyroid follic ular cell adenomas at p < 0.05. Female rats had significant trends at p < 0.01 and signi ficant pair-wise compar isons of the 5000 ppm dose group with the controls at p < 0.05 for thyroid gland follicular cell adenomas and
combined adenomas and/or carcinomas.

Summary of Dose-response for Key Events and Carcinogenesis

Table 11. Summary of Key Events Dose Response and Dose Concordance for Diethofencarb-induced Rat Thyroid Tumors.

Endpoint Dose Level Study Duration 1000 3000 5000 10000 20000 Key event 1: Increased liver metabolism as seen by increased hepatic UDP-GT (UDG) activity

Increase in UDP-GT activity NA NA ++ ¶ NA ++ ¶ 90 days

Key Event 2: Increased hepatic meta bolism and biliary excretion of T4

Increase in Liver Weight (absolute) -- -- -- ++ ++ ¶ 28 days 90 days 90 days 2 years

Increase in Liver Weight (relative) -- ++ ++ ¶ ++ ++ ¶ 28 days 90 days 90 days 2 years Hepatocellular Hypertrophy -- -- -- ++ -- 28 days 90 days Increased Biliary
Excretion of 125 T NA NA ++ ¶ NA ++ ¶ 14 days

Key Event 3: Decreased serum T 4 half- life and concentration and Increased TSH

T3 decrease NA NA -- NA -- 14 days 90 days

T4 decrease NA NA

-- NA ++ ¶ 14 days 90 days

TSH increase NA NA

-- NA ++ ¶ 14 days 90 days Key Event 4: Non-neoplastic thyroid lesions Increased thyroid weight (absolute) NA NA -- NA -- 90 daysPage 27 of 34 Table 11. Summary of Key Events Dose Response and Dose Concordance for Diethofencarb-induced Rat Thyroid Tumors.

Endpoint Dose Level Study Duration 1000 3000 5000 10000 20000 Increased thyroid weight (relative) NA NA -- NA ++ ¶ 90 days

Follicular cell hypertrophy -- -- NA ++ NA 28 days 90 days

Follicular cell Hyperplasia NA NA NA NA NA none

Key Event 5: Adenomas and Carcinomas

Adenomas and
Carcinomas in
males and females -- NA ++ NA NA 2 years

++ A statistically significant effect was seen in the data base at this dose level -- A statistically significant effect was NOT seen in the data base at this dose level NA Not Applicable since testing wa s not conducted at this does level ¶ Males rats only, females not tested

As seen in Table 11 above, the available data do not show dose concordance (below, at and above the tumorigenic dose) for both males and females for any of the key events. Therefore, this element of the IPCS fr amework has not been demonstrated.. .

Summary of Time Concordance for K ey Events, Associated events, and Carcinogenesis

As demonstrated in Table 11 , key events necessary to support the UDP-GT induced thyroid tumors took place in time periods be fore the appearance of thyroid neoplasms in males. Multiple exposure time data were available at 14 days, 28 days, 13 weeks, and 2 years in which diethofencarb was fed in the di et to male SD rats. Increased hepatic UDPGT activity was only measured at 90 days and a statistical increase was demonstrated at 5000 ppm and 20000ppm in males. Liver weight s were increased at 28 days, 90 days (3000 5000, 10000, 20000 ppm) and two years (5 000ppm) in both sexes, but the increases at two years (were not greater than in the shorter time periods) Biliary excretion of T4/T3 was measured only at 14 days in males; however, serum T4 and T3 levels were reduced at two weeks and 90 days at 20000 ppm. Increased TSH levels in the serum were seen at 14 days and 90 days at 20000ppm in males. Increased thyr oid weight (relative only) was seen at only 90 days in ma les (20000ppm), not at 2 years (5000ppm). Thyroid histopathology was not re ported in any of the studi es. Thyroid hyperplasia was not reported in any of the studies. Thyroid fo llicular cell tumors were observed in males at 5000 ppm in the two-year study. Theref ore, time concordance has not been demonstrated in two species a ccording to the IPCS frameworkDiethofencarb (PC Code 112102) FINA L

Page 28 of 34 4. Strength, Consistency, and Specificity of Association of Tumor Response with Key
Events

The key events for diethofencarb-induced rat t hyroid tumors were defined as: 1) induction of UDP-GT activity, 2) increased hepatic metabolism and biliary excretion of T3/T4, 3)
decreased T3/T4 serum half-lif e/concentration resulting in in creased TSH concentrations, 4) increased incidence of ce llular thyroid hypertrophy and folli cular cell hyperplasia, and 5) the occurrence of thyroid follicular cell adenomas and carcinomas. None of these key events were successfully identified and char acterized in terms of both dose and temporal response. In addition, not all expected key ev ents took place, such as increased absolute thyroid weights and an increased incidence of follicular cell hyperplasia. Reversibility
was not evaluated in the available studies.

5. Biological Plausibility and Coherence

Considerable data exist from laboratory studi es in rats demonstrating the relationship between sustained perturbation of the hypot halamic-pituitary-thyroid axis, prolonged stimulation of the thyroid gland by TSH, and the progression of thyroi d follicular cells to hyperplasia, and eventually neoplasia (McClain 1995; Hard 1998; Hurley et al . 1998; Capen et al . 1999; IARC 2001; [as cited in WHO 2007]). Therefore, the proposed MOA for thyroid follicular cell neoplasms is plausible for diethofencarb.

6. Alternative Modes of Action

The following alternative MOAs were cons idered for thyroid tumor formation:

(i) DNA reactivity

Based on the available genotoxicity data, diethof encarb tested negative in all genotoxicity

assays

(ii) Inhibition of the active transpor t of inorganic iodide into the follicular cell (iodide pump). (iii)Inhibition of thyroid peroxidase which converts inorganic iodide into organic iodide and couples iodinated tyrosy l moieties into thyroid hormone. (iv) Inhibition of thyroid horm one release into the blood.

Alternative MOAs #2, #3, and #4 are direct th yroid gland effects and are not supported by the available data on diethofencarb.

(v) Damage to thyroid follicular cells

Not supported by the available data as histop athology data on the thyroid gland do not show overt cytotoxicity. The 90-day mechanistic study (MRID 49267474) showedPage 29 of 34 diethofencarb did not produce any e ffects on thyroid absolute weight, 125 I uptake or thyroid histopathology after 90 da ys of treatment at 20000 ppm.

(vi) Inhibition of the conversion of T4 to T3 by 5'-monodeiodinase at various sites in the body

Unlikely because T3 levels remained unchanged at all dose levels comp ared with controls in the 14-day and 90-day mechanistic studies (MRIDs 49267473, 49267474), even when T4 levels were decreased, which would not be expected with this alternative MOA.

7. Data Limitations, Uncertainties, Inconsistencies

Dose Selection for Mechanistic Studies. The two submitted mechanistic studies (MRIDs 49267473, 49267474) used dose levels at the tu morigenic level (5000ppm) and above (20000ppm) However, no studies were conducted at levels below the tumorigenic level in these two reports in order to provide a more complete do se-concordance profile of the events reported in the studies . In addition, certain parameters such as UDP-GT activity and Biliary Excretion of T4 were measured in one or the other study, not both, preventing
the establishment of time-concordance of events.

UDP-GT Measurements. Increases in UDP-GT were de monstrated after 90 days treatment with diethofencarb ( 185%) with statistical signifi cance at 10800 ppm. Increases in UDP-GT (133%) were demonstrated at 5000 pp m, but without statis tical significance. Changes in thyroid hormone levels were dem onstrated at 2 weeks and 13 weeks, but UDPGT was measured only at 13 weeks. The lack of measurements of UDP-GT at 2 weeks
and the lack of statistical significance in UDP-GT levels at 13 weeks at 5000 ppm do not
affect the overall mechanism of action. The UDP-GT levels are clearly increased at 13
weeks at 5000 ppm to a biologically relevant level (133%) and the changes in the thyroid hormone levels at 2 weeks support th e increase in UDP-GT at 2 weeks.

Lack of Positive Control Data. The two submitted mechanistic studies (MRIDs 49267473, 49267474) did not included data on th e effects of an agent such as pentobarbital, as a positive control. Despite this deficiency, the expected positive results were achieved by diethofencarb. A positive control is not necessary to interpret the positive results of diethofencarb in the assay.

Data Reporting Deficiencies. The 14-day mechanistic study (MRID 49267473) had several data reporting defici encies, such as: lack of animal housing data; lack of individual animal data pertaining to su rvival, body weights, food cons umption, analytical results (total and free T4, total and free T3, TSH, orga n weights, enzyme activities, bile flow and patency, tissue accumulation of radiolabel, etc. ; concentration, homogeneity, and stability data; total amount of radiolab el administered and percent recovered in the studies; historical laboratory data for total and free T 4, total and free T3, TS H, measured enzyme activities; and others. However, since this study provided results that were consistent withDiethofencarb (PC Code 112102) FINA L

Page 30 of 34 the 90-day study, it was considered useful fo r the purpose for which it was conducted and
the data were used in this assessment.

Reversibility of Effects. The submitted data did not eval uate reversibility of effects following treatment cessation during the early stag es of disruption of the thyroid-pituitary axis, which would have demonstrated whether permanent, self-perpetuating processes had
been set in to motion.

8. Human Relevance

CARC considers the established MOA of diethofencarb for follicular thyroid carcinogenesis in animals is qualitatively plausible in humans. However, it is quantitatively implausible based on differen ces in thyroid physiol ogy between rats and humans. Although the postulated MOA could th eoretically operate in humans, marked quantitative differences in the inherent sus ceptibility for neoplasia to thyroid hormones
imbalance in rats allows for the conclusion th at diethofencarb may not pose a carcinogenic risk to humans. “Quantitatively, if humans develop cancer thr ough thyroid-pituitary disruption, it appears that huma ns are less sensitive to the carcinogenic effects than are rodents. Rodents show significant increases in cancer and thyroid- pituitary disruption; humans show little, if any” (USEPA 1998).

VII. COMMITTEE’S ASSESSMENT of the WEIGHT OF EVIDENCE

Rat

Thyroid Follicular Cell Tumors:

The CARC determined that the thyroid follicul ar cell tumors observed in male and female rats are treatment-related. In males, the in cidence of carcinomas and combined adenomas and/or carcinomas at the high dose (5000 ppm) was significantly (p <0.05) increased when compared to controls. In females, the inci dences of adenomas and combined adenomas and/or carcinomas at the high dose (5000 ppm) were significantly (p <0.05) increased when compared to controls.

Adequacy of Dosing:

It was concluded that the dose levels tested were adequate in both sexes to assess the carcinogenicity of diethofencarb based on the pres ence of thyroid tumors. No pre-neoplastic lesions or biologically significant sy stemic toxicity were observed.

Mouse

There was no evidence of carcinogenicity in ma le or female mice when tested at the limit dose (1000 mg/kg/day).Page 31 of 34 Adequacy of Dosing:

It was concluded that the dose levels tested were adequate in both sexes to assess the carcinogenicity of diethofencarb based the ab sence of the neoplastic lesions at 1682 / 2108 mg/kg/day in males and females, respectiv ely. Hepatocellular hyperplasia was observed above the limit dose in males, but even at these high dose levels did not progress to neoplasms. Decreased survival in females was also seen at these levels.

Mutagenicity:

Based on the results from the battery of guide line genetic toxicity studies, there is no concern for mutagenicity for diethofencarb.

Structure Activity Relationship (SAR):

Carbamates with 1-3 carbons on the ester group may be carcinogenic, urethane (ethyl carbamate) being a well-known example. Isopr opyl carbamate has been shown to induce lung tumors in Strain A mice in a medium-ter m assay with 12 thrice-weekly i.p. injection and 20-week observation (Shimkin et al., 1969, cited in Woo, 1983). However, its activity was substantially lower than that of urethane . Overall, there is only marginal SAR support
for diethofencarb as a thyroid carcinogen.

VIII. CLASSIFICATION OF CARCINOGENIC POTENTIAL

In accordance with the EPA’s Final Guidelines for Carcinogen Risk Assessment (March, 2005), the CARC determined that there is “Sugge stive Evidence of Carc inogenic Potential” for diethofencarb based on the presence of follicular cell tumors of the thyroid glands in
male and female rats. There was no evidence of carcinogenicity in male or female mice.
There is also no concer n for mutagenicity.

IX. QUANTIFICATION OF CANCER RISK

Not required. The CARC recommended using a non-linear approach (i.e., reference dose (RfD) that will adequately account for all chro nic toxicity, including carcinogenicity, that could result from exposure to diethofencarb.Diethofencarb (PC Code 112102) FINA L

Page 32 of 34 X. BIBLIOGRAPHY

Capen CC, Dybing E, Rice JM, Wilbourn JD, ed s. (1999) Species differences in thyroid, kidney and urinary bladder carcinogenesis. L yon, International Agency for Research on Cancer (IARC
Scientific Publications N o. 147). As cited in WHO 2007

. Dellarco, V. L., McGregor, D., Berry, S. C., C ohen, S. M., Boobis, A. R. (2006) Thiazopyr and Thyroid Disruption: Case -Study within the Context of the IPCS Framework for Analysing the Relevance of a Cancer Mode of Action For Humans. As cited in WHO 2007

Hard GC. (1998) Recent developments in the in vestigation of thyroid regulation and thyroid carcinogenesis. Environmental Health Pers pectives, 106(8): 1-21. As cited in WHO 2007.

Hurley PM, Hill RN, Whiting RJ. (1998) Mode of carcinogenic action of pesticides inducing thyroid follicular-cell tumors in rodents. Environmental Health Perspectives, 106(8):437—
445. As cited in WHO 2007.

IARC (2001) IARC Monographs on the Evaluati on of Carcinogenic Risk to Humans. Volume 79. Some thyrotropic Agents. Lyon, Inte rnational Agency for Research on Cancer, 763 pp. 2001

McClain RM. (1995) Mechanistic considerations for the relevance of animal data on thyroid neoplasia to human risk assessment. Mutati on Research, 333(1-2): 131-142. As cited in
WHO
2007.

Woo, J. (1983) Carcinogenicity, mutagenic ity and teratogenicity of carbamates, thiocarbamates and related compounds: an overv iew of structure-activ ity relationships and
environmental concerns. E nviron. Sci. Health, C1, 97-133.

World Health Organization (W HO). (2007) Harmonization Proj ect Document No. 4. PART
1:
IPCS FRAMEWORK FOR ANALYSING THE RELEVANCE OF A CANCER MODE OF
ACTION FOR HUMANS AND CASE-STUDIES . PART 2: IPCS FRAMEWORK FOR
ANALYSING THE RELEVANCE OF A N ON-CANCER MODE OF ACTION FOR
HUMANS. Published under the joint sponsorship of the Wo rld Health Organization, the International Labour Organization, and the United Nations Environment Programme, and produced within the framework of the In ter-Organization Progr amme for the Sound Management of Chemicals. WHO Press, World Health Organization. 2007.Page 33 of 34 TXR and MRID Numbers:

TXR 0057126. Diethofencarb Qualitative Risk Assessment based on Crl:CD (SD)BBR Rat Dietary Study. From Anna P. Shah, Health Effects Division to Myron S. Ottley, Health Effects Division. March 24, 2015.

MRID 49267440. Wolfe, G. (1986) Four-Week Feeding Study in Rats S-32165: Final Report. Project Number: 343/159, HHT/61/0030. Unpublished study prepared by Sumitomo Chemical Company, Ltd. 278p.

MRID 49267442. Wolfe, G.W. (1986). F our-Week Feeding Study in Rats—S-32165— Final Report. Hazleton Laboratories Ameri ca, Inc., 9200 Leesburg Turnpike, Vienna, Virginia. Report ID No.: HHT-61-0031. Labor atory Project ID No. 343-162, January 22, 1986. Unpublished.

MRID 49267444. Yamada, T. (1986) Three-Month Subacute Toxicity Study of S-32165 in Rats. Project Number: HHT/60/0033. Unpublishe d study prepared by Sumitomo Chemical Company, Ltd. 391p.

MRID 49267451. Morseth, S. (1988) Two-Gene ration Reproduction Study of S-32165 in Rats: Final Report. Project Number: 343/ 169, HHT/81/0068. Unpublished study prepared by Hazleton Laboratories America, Inc. 892p.

MRID 49267453. Cox, R. (1988). Oncogenicity study in mice with S-32165. Hazelton Laboratories America, Inc., Vienna, VA. Laboratory Study No. 343-164, December 2, 1988. Unpublished.

MRID 49267454. Cox, R. (1989) Combined Chroni c Toxicity and Oncogenicity Study in Rats with S-32165. Project Number: 343/163. Unpublished study prepared by Hazleton Laboratories America, Inc. 4177p.

MRID 49267456. Yoshitake, A., Kogiso, S., Hara, M, Kawaguchi, H., and Miyamoto, J. (1984). Bacterial Mutagenicity Test of S-32165. Laboratory of Biochemistry and Toxicology, Takarazuka Research Center , Sumitomo Chemical Co., Ltd., 4-2-1, Takatsukasa, Takarazuka, Hyogo, Japan. Re port ID No.: HHT- 40-0036. Laboratory Study No. M84-31, December 14, 1984, Unpublished.

MRID 49267457. Kogiso, S. (1988). Reverse Mutation Test of S-1605 in Bacterial Systems. Biochemistry and Toxicology Labor atory, Sumitomo Chemical Co., Ltd., 1-98, 3- Chome, Kasugade-naka, Konohana-ku, Os aka, Japan. Report ID No.: HHT-0070. Laboratory Study No. 1613, December 26, 1988, Unpublished.

MRID 49267458. Kogiso, S. (1989). In Vitro Gene Mutation Test of S-32165 in V79 Chinese Hamster Lung Cells in Culture. Biochemistry and Toxicology Laboratory,Diethofencarb (PC Code 112102) FINA L

Page 34 of 34 Sumitomo Chemical Co., Ltd., 1-98, 3-Chom e, Kasugade-naka, Konohana-ku, Osaka, Japan. Report ID No.: HHT-90-0073. La boratory Study No. 1529, January 10, 1989. Unpublished.

MRID 49267459. Kogiso, S. (1986) In Vitro Chromosomal Aberration Test of S-32165 in Chinese Hamster Ovary Cells (CHO-K1), La boratory of Biochemistry and Toxicology, Takarazuka Research Center, Sumitomo Ch emical Co., Ltd., Hyogo, Japan. Report ID No.: HHT-60-0032, Study ID: MUT84048, March 20, 1986. Unpublished.

MRID 49267460. Kogiso, S. (1987) Micronucleus Test of S-32165 in Mouse Bone Marrow Cells, Laboratory of Biochemistry and Toxico logy, Takarazuka Research Center, Sumitomo Chemical Co., Ltd., Hyogo, Japan. Report ID No.: HHT-70-0060, Study ID: 525, March 20,
1987

. Unpublished.

MRID 49267473. Saito, K. (1989) Biochemical Study of Effects of Diethofencarb on Thyroid Hormones in Rats. Unpublished study prepared by Sumitomo Chemical Company, Ltd. 38p.

MRID 49267474. Nakamura, J. (1989) 3-month S ubacute Toxicity Study of Diethofencarb in Male Rats (Effects on the Thyroid). Pr oject Number: S0023. Unpublished study prepared by Sumitomo Chemical Company, Ltd. 61p.