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.: NIA 

Petition No.: NIA 

Risk Assessment Type: NA 

TXR No.: 0057298 

MRID No.: NIA 

DP Barcode: NI A 

Registration No.: NIA 

Regulatory Action: NI A 

Case No.: NIA 

CASNo.: NIA 

40 CFR: NIA 

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 Risk Assessment (March, 2005). Attached please 

find the final Cancer Assessment Document. 

Page 1 of34 
Diethofencarb (PC Code 112102) FINAL 

Page 2 of 34

CANCER ASSESSMENT DOCUMENT

 

 

 

 

 

 

 

 

 

 

EVALUATION OF THE CARCINOGENIC POTENTIAL OF 

Diethofencarb 

PC Code: 112102 

 

 

 

 

 

 

 

August 27, 2015 

CANCER ASSESSMENT REVIEW COMMITTEE 

HEALTH EFFECTS DIVISION 

OFFICE OF PESTICIDE PROGRAMS 

 
Page 3 of 34 

Table of Contents 

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

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

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

IV. EVALUATION OF CARCINOGENICITY STUDIES ...................................................... 5

A. Combined Chronic Toxicity/Carcinogenicity 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-Thyroid 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 metabolism and biliary excretion of T4 ............................. 22

Key Event 3: Decreased serum T4 half- life and concentration 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 Key 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 CARCINOGENIC POTENTIAL ........................................... 31

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

X. BIBLIOGRAPHY ................................................................................................................. 32
Diethofencarb (PC Code 112102) FINAL 

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 Pesticide Programs evaluated the carcinogenic potential of 

diethofencarb. 

In the carcinogenicity study in rats, diethofencarb was administered 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 significant trends, and significant pair-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 historical control range. There was also a significant trend for 

thyroid follicular cell adenomas in male rats. Female rats had 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 cell adenomas and combined adenomas and/or 

carcinomas. No non-neoplastic lesions were observed in males or females. The high dose 

was considered to be adequate but not excessive 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 administered 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 carcinogenicity since the highest dose tested was the 

limit dose and at this dose hepatocellular hyperplasia 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 carcinogenicity. Additionally, there is no concern for 

mutagenicity. 

Quantification of human cancer risk is not required. The chronic Reference Dose (RfD) will 

adequately account for all chronic toxicity, 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 evaluated the carcinogenic potential of diethofencarb. 

III. BACKGROUND INFORMATION 

 

Diethofencarb, [isopropyl 3,4-diethoxycarbanilate], is a new 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 readily 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. This mode of action has not been established 

in mammals. 

Technical diethofencarb is a pink granular solid with a melting point of 98.3 – 100.9oC and a 

specific gravity of 1.19 g/cc. Diethofencarb is slightly soluble in water (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/Carcinogenicity Study in Sprague-Dawley Rats 

Reference: Cox, R. (1989). Combined chronic toxicity and oncogenicity study in rats with 

S-32165. Hazelton Laboratories America, Inc., 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 administered Diethofencarb in the diet at 0, 40, 200, 1000, and 5000 

ppm (equivalent to 0, 1.69, 8.42, 42.70, and 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 groups with the controls in 

male rats (Table 1). There were no statistically significant survival disparities among 

female rats (Table 2). 
Diethofencarb (PC Code 112102) FINAL 

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 53i

 53-78 79-106f 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-wise 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 53i

 53-78 79-106f Total 

0 1/80 2/78a 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 0/78b 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 9/65c 28/56 41/69 

(59)n

+Number of tumor bearing animals/Number of animals examined, excluding those that died or were sacrificed before observation of the 

first tumor. 

a

First adenoma not in an interim sacrifice animal 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 animals are not included in this analysis. 

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. 

 2. Tumor Analyses 

Statistical analyses of the tumors observed in the male rats were based upon Peto’s 

Prevalence Test due to significant survival disparities among the dose groups (Table 3a). 

Male rats had significant trends at p < 0.01 and significant pair-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 carcinomas. 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 significant 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 carcinomas. The statistical analyses of the 

tumors in the female rats were based upon Fisher’s Exact Test and the Exact Test for 

Trend (Table 4). 
Diethofencarb (PC Code 112102) FINAL 

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 = 

2a/62 

(3) 

0.0105* 

1/62 

(2) 

0.7108 

0/65 

(0) 

0.8371 

3d/62 

(5) 

0.3467 

5d/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 

7b/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 

10c/64 

(16) 

0.0405* 

+Number of animals that died during the interval/Number 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 with 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, 

 Carcinoma 1.14 0 – 4 448 animals 

Females Adenoma 0.43 0 - 2 7 studies, 

Carcinoma 0.71 0 - 2 443 animals 

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 

5a/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 

2b/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 animals are not included in this analysis. 

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. 

 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 findings observed at the week 104 sacrifice 

are shown in Table 5. The occurrence of macroscopic pituitary lesions (pituitary 

enlargement, and mottled pituitary) was more frequent in males treated at 1000 and 5000 

ppm. Microscopic lesions more frequent in males treated at 1000 and 5000 ppm included 

angiectasis/sinusoid ectasia in the pituitary. While the incidence of pituitary tumors was 

not statistically significant, pituitary hypertrophy/hyperplasia fit with the proposed mode 

of action -- increased T4 clearance leading to increased stimulation of pituitary 

thyrotroph cells. Pituitary hypertrophy/hyperplasia 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 specifically 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 background incidence of these changes, there is 

a similar pattern (modestly higher incidence of angiectasis/sinusoid ectasia, general 

concordance with enlargement) but no apparent significant differences between control 

and high-dose groups. 
Diethofencarb (PC Code 112102) FINAL 

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 adequate to assess the carcinogenic potential of 

diethofencarb based on the occurrence of thyroid tumors at the high dose (5000 ppm; 220 

mg/kg/day in males and 288 mg/kg/day in females), However, the CARC noted that there 

were no treatment-related effects on body weights, food conversion efficiency, clinical 

pathology, organ weights or non-neoplastic lesions at any dose, including the high dose. 

For chronic toxicity, the no-obsereved-effect level (NOAEL) was 5000 ppm; a lowestobserved-effect-level (LOAEL) was not established. 

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

Reference: Cox, R. (1988). Oncogenicity study in mice with S-32165. Hazelton Laboratories 

America, Inc., Vienna, VA. Laboratory 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 males; 0, 2.03, 20.53, 202.9, and 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 

consumption were recorded. Differential 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 groups of mice in the main study, except for 

females at 10,000 ppm which had a significantly lower survival 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 treatment-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 studies (MRIDs 49267467 – 49267471), [Phenyl-14C] 

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 absorption of diethofencarb, 

limited distribution in tissues, extensive metabolism into sulfate and glucuronide 

metabolites, and quick and extensive excretion with no bioaccumulation. In a standard 

series of ADME tests with single and multiple 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 and extensive (> 87% of administered dose or 

AD by day 2). Organ/tissue radioactivity decreased rapidly and was mainly found in 

liver, adrenals, blood/blood cells, kidney and skin. Tmax was 0.5 to 1.0 hr in blood and 

tissue. A plasma T1/2 value was not included in the report. Diethofencarb was extensively 

biotransformed into several metabolites, mainly sulphate and glucuronide 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 feces (> 13% of AD). This resulted in 

organ/tissue depuration t1/2 values of <35 hours based on data up to 72 hr pose-dose and a 

low retained fraction (<2% of AD on day 7), and the deduction that there 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) FINAL 

Page 12 of 34

Figure 2. Proposed metabolic pathways for Diethofencarb in rats including the route to 4-OH-5-TLA DFC 

Figure taken from MRID 49267470, page 5.

B. Mutagenicity 

Diethofencarb has been evaluated in a battery of genotoxicity 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 sensitivity of each test system to known positive 

control substances. The Mutagenicity battery is considered 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 induce an increase in mutant colonies over 

background in S. typhimurium strains TA98, TA100, TA1535, and TA1537, TA1538 and
Page 13 of 34 

E. coli strain WP2 uvrA at concentrations up to 1000 μg/plate with and without S9 mix) 

using the pre-incubation method and duplicate plating. 

In an in vitro bacterial reverse mutation assay (MRID 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 

uvrA 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-guanine phosphoribosyl 

transferase (HGPRT) locus (MRID 49267458), Chinese hamster lung V79 cells cultured 

in vitro were exposed to technical diethofencarb 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 activation and in two independent experiments 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 diethofencarb 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 micronucleus assay (MRID 49267460), 6 male 

mice/group were each given a single intraperitoneal (i.p.) injection of diethofencarb in 

corn oil (females were excluded from this study without justification). Two independent 

studies were conducted: a time-course study and 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 the vehicle only (20 mL/kg) as a negative 

control, or with cyclophosphamide as a positive control (80 mg/kg bw). In the doseresponse study, three groups of mice were treated with diethofencarb 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 control, or with 9,10-dimethyl-1,2-benzanthracene 

(DMBA) at a dose of 50 mg/kg bw. All animals 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 and 72 h also showed reductions in the PCEs. This was an 

indication that these treatments caused moderate bone marrow cell toxicity. 

Administration of the positive control chemicals in both studies resulted in significantly 

higher numbers of micronucleated-PCEs compared with the corresponding vehicle 

controls, demonstrating the validity of the assay. At the doses tested, there were no 
Diethofencarb (PC Code 112102) FINAL 

Page 14 of 34

significant increases in the frequencies of micronucleated polychromatic erythrocytes in 

bone marrow after any treatment time or dose level. 

C. Structure Activity Relationship 

Diethofencarb is an N-phenyl isopropyl carbamate. Carbamates have been extensively 

studied in the 1980s with urethane (ethyl carbamate) as being 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 sensitive to change in the size of the alkyl 

group of the ester group (which serve as an alkylating agent) but can tolerate substitution 

at the amino group. 

Carcinogenic activity has been detected in carbamates 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). However, its activity was substantially lower 

than that of urethane. In skin painting study 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 absolute liver weight (increase 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 observed at 10 or 1000 ppm dose levels in either sex. The NOAEL 

was 3000 ppm (300 mg/kg bw/day) in females and 1000 ppm (89.1 mg/kg bw/day) in 

males. The target organ was identified as the liver, based on swelling of centrilobular 

hepatocytes and increased blood cholesterol concentration. 

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, accompanied by centrilobular hepatocellular 

hypertrophy as well as hypertrophy of endoplasmic reticulum in males at 3000 ppm and 

both sexes at 10,000 ppm (see table 3a). These liver effects were considered as adaptive 

responses to S-32165-induced toxicity. The 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/oncogenicity 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 consumption 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 determination 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. Platelet counts and cholesterol levels were 

elevated in high dose females. However, the elevated 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 corroborating 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, adenomas 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 investigate 
Diethofencarb (PC Code 112102) FINAL 

Page 16 of 34

the homogeneity, stability, and achieved concentrations of the test substance. Mortality, 

clinical signs, body weight, and food consumption were recorded. Samples of blood and 

were collected for clinical pathology evaluation 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 examined 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 corresponded 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 the 30,000 ppm diet had higher platelet counts 

(increases of 16% and 24% in males and females, respectively), higher albumin 

concentrations (increases of 13% and 20% in males and females, respectively), higher 

protein concentrations (increases 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 aminotransferase (ALT) activities (increases of 88% 

and 79% in males and females, respectively), higher absolute liver weights (increases of 

34% and 53% in males and females, respectively), higher relative liver weights (increases 

of 63% and 61% in males and females, respectively), dark livers in 6/10 males and in all 

10 females, as well as foci of necrosis in livers, hepatocellular hypertrophy, proteinaceous 

casts and regenerative epithelium in kidneys, and submucosal lymphoid hyperplasia in 

urinary bladders in both sexes. Males only at the 30,000 ppm diet showed a reduction in 

body weight gain, which amounted to 49%. The 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, respectively) based on higher platelet counts 

(increases of 10% and 17% in males and females, respectively), higher total cholesterol 

concentrations in blood (increases of 26% in both sexes), higher absolute liver weights 

(increases of 14% and 23% in males and females, respectively), higher relative liver 

weights (increases of 17% and 20% in males and females, respectively), as well as foci of 

necrosis in livers. Males only at the 10,000 ppm dietary level had submucosal lymphoid 

hyperplasia in urinary bladders and hepatocellular hypertrophy. 

No treatment-related adverse effects were observed at the 100 or 3000 ppm dietary levels 

in either sex. The NOAEL in both sexes was the 3000 ppm diet (corresponding to nominal 

doses of 563 and 720 mg/ kg bw/day in males and females, respectively). The target 

organs were identified as the liver, kidneys, and urinary bladder.

78-week Carcinogenicity Study (MRID 49267453) 

Five groups of 75 Crl:CD-1(ICR)BR mice/sex/group were administered Diethofencarb in 

the diet at 0, 10, 100, 1000, or 10,000 ppm (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 consumption were recorded. 
Page 17 of 34 

Differential 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. 

Females at 10,000 ppm had a significantly lower survival rate relative to controls at 78 

weeks. The incidence of hepatocellular hyperplasia in high dose males was significantly 

higher (p<0.05) relative to controls, and the incidence of hepatocellular hyperplasia in 

males at 1000 ppm was considered treatment-related. 

Under the conditions of this study, the systemic 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, and 10000 ppm in females (2108 mg/kg/day) based on reduced 

survival. The NOAEL was 1000 ppm in males and females (163.8 and 202.9 mg/kg/day, 

respectively). 

 

VI. MODE OF ACTION STUDIES 

 

1. Mode of Action Assessment-Thyroid Tumors in Male Rats 

The hypothesized MOA for diethofencarb-induced thyroid follicular-cell adenomas involves 

an extrathyroidal mechanism mediated by the induction of hepatic enzymes, including 

uridine diphosphate glucuronyl transferase (UDP-GT or UGT). Subsequently, the increased 

liver UGT activity leads to increased metabolism 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 serum T4 levels, the HPT axis is activated, and 

blood concentrations of TSH from the pituitary increase. With continued metabolism and 

clearance of T4, TSH elevations are prolonged in order to stimulate thyroid follicular cells to 

synthesize and release more thyroid hormones to reestablish homeostasis. The follicular 

cells initially undergo hypertrophy to address the need for increased thyroid hormone 

biosynthesis, but with sustained TSH stimulation, follicular cells undergo hyperplasia to 

meet thyroid hormone demand. TSH-stimulated follicular cell hyperplasia can progress to 

neoplasia, resulting in follicular cell adenomas. The 

The Registrant submitted mode of action (MOA) studies (MRIDs 49267473, 49267474) for 

thyroid tumors which are discussed in detail below. The postulated MOA for diethofencarbinduced rat thyroid tumors is altered homeostasis of the hypothalamic-pituitary thyroid 

(HPT) axis. 

2. Data Supporting the Proposed Diethofencarb MOA 

 

The relevant experimental data used to evaluate the proposed thyroid 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), as 
Diethofencarb (PC Code 112102) FINAL 

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 concentrations of 0, 5000 or 20,000 ppm for 2 weeks to 

determine effects on thyroid hormone concentration; 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 

125I-thyroxin in 0.5 mL saline at the end of feeding period to determine radiolabeled 

excretion. The estimated doses to animals 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 the tissue distribution 

study, the rats received an estimated dose of approximately 1380 mg/kg bw/day. Finally, 

the estimated doses for rats treated with the test material were approximately 430 and 

1380 mg/kg bw/day for 7-week and 37-week rats 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 studies indicate treatment with 20,000 ppm 

Diethofencarb for up to two weeks decreased serum T4 concentrations and induced slight 

increases in TSH concentrations with no effect on T3 concentrations. In the 

bioaccumulation study, the kidney had the highest 14C 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 the thyroid. The data also suggested that 

increased T4 excretion in the bile arose through 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 each group were given a 

single IP injection of 125I to determine uptake. Histological examinations were limited to 

the thyroid of rats not treated with 125I. 

 

Body weight changes were small, -4% to -6%, by the end of the study. Slight doserelated statistical decreases in circulating free T4 and increases in TSH (thyroid 

stimulating hormone) were found in 20,000 ppm rats at study end; however, total T4 was 
Page 19 of 34 

not statistically different from control rats, though decreased 16%. No significant effects 

were found on total or free T3 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 125I thyroid uptake, and no microscopic 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 statistically 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 was 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 significant increase in absolute 

liver weight was found. These results suggest that Diethofencarb 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 T4 concentrations that likely triggered the 

feedback mechanism of the pituitary gland, 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 weight gain, decreased serum free T4, 

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 induction 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 and biliary excretion of T3/T4; 

 Key Event #3: Decreased T3/T4 serum half-life/concentration 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) FINAL 

Page 20 of 34

respectively, per gram liver, and 164% and 275%, respectively, per whole liver (Table 6). 

Measurements of UGT activity were not reported in the two week mechanistic study 

(MRID 49267473). 

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

Study1

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: increased liver weight, hepatic cell Proliferation 

and hypertrophy 

In the 90-day rat study discussed above, there was a dose-related increase 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 statistically 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 increased 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 Study1

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 concurrent control at p<0.01. 

 

Diethofencarb-induced increases in liver weight and/or hepatocellular hypertrophy have 

been reported in two repeated-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 increases were small at 3000ppm (8 

- 12%), but were statistically 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 Relationship in Diethofencarb-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) FINAL 

Page 22 of 34

Table 8. Concordance in Dose and Temporal Relationship in Diethofencarb-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) that increased liver enzyme activity was 

demonstrated by increased liver weight with 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 levels 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 metabolism and biliary excretion of T4 

 

Hepatic Metabolism 

The induction of UDP-GT activity in males at 5000 and 20000 ppm in the study (MRID 

49167474, Table 6) discussed in Key event #1 implies an increase in the hepatic 

metabolism of T3/T4 hormones through conjugation, 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 studied 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 125I-thyroxine excretion. 
Page 23 of 34 

Figure 3. Cumulative biliary 125I excretion after intravenous injection of 125I-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-treated rats are 

the means ± SD of 2 animals. 

From page 38 of MRID 49267473 

T4 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 the data to some extent, at and above the 

tumorigenic dose of 5000ppm by induction of UDPGT, as seen by statistically increased 

activity of UDPGT (measured by per mg protein). Increased T4 excretion (measured by 

125I clearance) occurred only above the tumorigenic dose in males, and females were not 

tested, so dose-concordance is not established. Temporal concordance has been 

established in males in that increased hepatic metabolism occurred at the tumorigenic 
Diethofencarb (PC Code 112102) FINAL 

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 T4 half- life and concentration and Increased TSH 

Serum thyroid hormone levels were measured 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 T4 levels were statistically 

decreased (-23%, p<0.05) at 20000 ppm. In the 90-day study, free T4 levels were 

decreased (-17%, p<0.01) at 20000 ppm, T3 levels were generally unchanged. No 

changes in T4 or T3 levels were noted at the tumorigenic 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. The most marked effects were 

seen in the 37-week rats, as presented in Table 10. T4 levels were statistically decreased 

at 20000ppm and TSH levels were statistically increased at this level. Effects at 5000pm 

were less marked and not statically significant in any of the groups. As seen above in 

Table 9, these effects on T4 and TSH in the two-week study 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 

T4b

(μg/dl) Free T4c

 (μg/dl) T3b

(μg/dl) 

Free T3c

(μg/dl) 

TSH 

(μg/dl) 

14 daysa

0 

(n=10) 3.62±0.095 2.45±0.46 0.84±0.12 1.55±0.33 3.40d±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 the 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<0.01 
Page 25 of 34 

Table 10. Serum thyroid hormone concentrations of male rats treated with Diethofencarb for 14 days 

a seven, 37 and 66 weeks of age. 

Dose, ppm T4b (μg/dl) Free T4c (μg/dl) T3b (μg/dl) Free T3c (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 3.40d±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 2.92d±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 T4 levels in males were seen only above the tumorigenic dose; TSH 

concentration was increased in both a dose-response 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-related adverse effects was observed in the 

pituitary in in the chronic rat study, as discussed 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, appeared 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 observed in the subchronic or chronic toxicity/carcinogenicity 

studies or special mechanistic studies. 

 
Diethofencarb (PC Code 112102) FINAL 

Page 26 of 34

Key Event # 5: Thyroid follicular Adenomas and Carcinomas. 

In the rat chronic toxicity/carcinogenicity 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 trends at p < 0.01 and significant pair-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 carcinomas. 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 significant 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 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 metabolism 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 125T NA NA ++¶ NA ++¶ 14 days 

Key Event 3: Decreased serum T4 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 days 
Page 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 was 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 framework has not been demonstrated.. . 

 

Summary of Time Concordance for Key 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 before 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 diet 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 weights were increased at 28 days, 90 days 

(3000 5000, 10000, 20000 ppm) and two years (5000ppm) 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 thyroid weight (relative 

only) was seen at only 90 days in males (20000ppm), not at 2 years (5000ppm). 

Thyroid histopathology was not reported in any of the studies. Thyroid hyperplasia was 

not reported in any of the studies. Thyroid follicular cell tumors were observed in males 

at 5000 ppm in the two-year study. Therefore, time concordance has not been 

demonstrated in two species according to the IPCS framework 
Diethofencarb (PC Code 112102) FINAL 

Page 28 of 34

4. Strength, Consistency, and Specificity of Association of Tumor Response with Key 

Events 

The key events for diethofencarb-induced rat thyroid 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-life/concentration resulting in increased TSH concentrations, 

4) increased incidence of cellular thyroid hypertrophy and follicular cell hyperplasia, and 

5) the occurrence of thyroid follicular cell adenomas and carcinomas. None of these key 

events were successfully identified and characterized in terms of both dose and temporal 

response. In addition, not all expected key events 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 studies in rats demonstrating the relationship 

between sustained perturbation of the hypothalamic-pituitary-thyroid axis, prolonged 

stimulation of the thyroid gland by TSH, and the progression of thyroid 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 considered for thyroid tumor formation: 

(i) DNA reactivity 

Based on the available genotoxicity data, diethofencarb tested negative in all genotoxicity 

assays 

(ii) Inhibition of the active transport of inorganic iodide into the follicular cell (iodide 

pump). 

(iii)Inhibition of thyroid peroxidase which converts inorganic iodide into organic 

iodide and couples iodinated tyrosyl moieties into thyroid hormone. 

(iv)Inhibition of thyroid hormone release into the blood. 

Alternative MOAs #2, #3, and #4 are direct thyroid 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 histopathology data on the thyroid gland do not 

show overt cytotoxicity. The 90-day mechanistic study (MRID 49267474) showed 
Page 29 of 34 

diethofencarb did not produce any effects on thyroid absolute weight, 125I uptake or 

thyroid histopathology after 90 days 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 compared 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 tumorigenic 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 dose-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 demonstrated after 90 days 

treatment with diethofencarb (185%) with statistical significance at 10800 ppm. Increases 

in UDP-GT (133%) were demonstrated at 5000 ppm, but without statistical significance. 

Changes in thyroid hormone levels were demonstrated 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 the 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 the 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 deficiencies, such as: lack of animal housing data; lack of individual 

animal data pertaining to survival, body weights, food consumption, analytical results 

(total and free T4, total and free T3, TSH, organ weights, enzyme activities, bile flow and 

patency, tissue accumulation of radiolabel, etc.; concentration, homogeneity, and stability 

data; total amount of radiolabel administered and percent recovered in the studies; 

historical laboratory data for total and free T4, total and free T3, TSH, measured enzyme 

activities; and others. However, since this study provided results that were consistent with 
Diethofencarb (PC Code 112102) FINAL 

Page 30 of 34

the 90-day study, it was considered useful for the purpose for which it was conducted and 

the data were used in this assessment. 

Reversibility of Effects. The submitted data did not evaluate reversibility of effects 

following treatment cessation during the early stages 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 differences in thyroid physiology between rats and 

humans. Although the postulated MOA could theoretically operate in humans, marked 

quantitative differences in the inherent susceptibility for neoplasia to thyroid hormones 

imbalance in rats allows for the conclusion that diethofencarb may not pose a carcinogenic 

risk to humans. “Quantitatively, if humans develop cancer through thyroid-pituitary 

disruption, it appears that humans 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 follicular cell tumors observed in male and female 

rats are treatment-related. In males, the incidence 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 incidences 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 presence of thyroid tumors. No pre-neoplastic 

lesions or biologically significant systemic toxicity were observed. 

Mouse 

There was no evidence of carcinogenicity in male 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 absence of the neoplastic lesions at 1682 / 2108 

mg/kg/day in males and females, respectively. 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 guideline 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. Isopropyl 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). 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 “Suggestive Evidence of Carcinogenic 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 concern 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 chronic toxicity, including carcinogenicity, that 

could result from exposure to diethofencarb. 

 
Diethofencarb (PC Code 112102) FINAL 

Page 32 of 34

X. BIBLIOGRAPHY 

Capen CC, Dybing E, Rice JM, Wilbourn JD, eds. (1999) Species differences in thyroid, 

kidney and urinary bladder carcinogenesis. Lyon, International Agency for Research on 

Cancer (IARC 

Scientific Publications No. 147). As cited in WHO 2007 

. 

Dellarco, V. L., McGregor, D., Berry, S. C., Cohen, 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 investigation of thyroid regulation and thyroid 

carcinogenesis. Environmental Health Perspectives, 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 Evaluation of Carcinogenic Risk to Humans. 

Volume 79. Some thyrotropic Agents. Lyon, International 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. Mutation Research, 333(1-2): 131-142. As cited in 

WHO 

2007. 

Woo, J. (1983) Carcinogenicity, mutagenicity and teratogenicity of carbamates, 

thiocarbamates and related compounds: an overview of structure-activity relationships and 

environmental concerns. Environ. Sci. Health, C1, 97-133. 

World Health Organization (WHO). (2007) Harmonization Project 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 NON-CANCER MODE OF ACTION FOR 

HUMANS. Published under the joint sponsorship of the World Health Organization, the 

International Labour Organization, and the United Nations Environment Programme, and 

produced within the framework of the Inter-Organization Programme 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). Four-Week Feeding Study in Rats—S-32165—

Final Report. Hazleton Laboratories America, Inc., 9200 Leesburg Turnpike, Vienna, 

Virginia. Report ID No.: HHT-61-0031. Laboratory 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. Unpublished study prepared by Sumitomo Chemical 

Company, Ltd. 391p. 

MRID 49267451. Morseth, S. (1988) Two-Generation 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 Chronic 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. Report 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 Laboratory, Sumitomo Chemical Co., Ltd., 1-98, 3-

Chome, Kasugade-naka, Konohana-ku, Osaka, 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) FINAL 

Page 34 of 34

Sumitomo Chemical Co., Ltd., 1-98, 3-Chome, Kasugade-naka, Konohana-ku, Osaka, 

Japan. Report ID No.: HHT-90-0073. Laboratory 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), Laboratory of Biochemistry and Toxicology, 

Takarazuka Research Center, Sumitomo Chemical 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 Toxicology, 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 Subacute Toxicity Study of Diethofencarb 

in Male Rats (Effects on the Thyroid). Project Number: S0023. Unpublished study prepared 

by Sumitomo Chemical Company, Ltd. 61p.