Document ID: EPA-HQ-OPP-2005-0265-0029
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2007-01-11T05:00Z

TXR No.:	0054321

		

MEMORANDUM

								

DATE:		September 5, 2006

			

SUBJECT:	DICLORAN: Report of the Cancer Assessment Review Committee

PC Code: 031301

										

FROM:	Jessica Kidwell, Executive Secretary

		Cancer Assessment Review Committee

		Health Effects Division (7509C)

TO:		Byong-Han Chin, Toxicologist (RRB1)

		Toiya Goodlow, Risk Assessor (RRB1)

		Health Effects Division (7509P)

		Nathan Mottle, Chemical Review Manager

		SRRD (7508P)

			

The Cancer Assessment Review Committee met on June 9, 2005 to evaluate
the carcinogenic potential of Dicloran.  Attached please find the final
Cancer Assessment Document.

cc:	J. Pletcher

	Y. Woo

					

										

						

		



CANCER ASSESSMENT DOCUMENT

EVALUATION OF THE CARCINOGENIC POTENTIAL OF

DICLORAN

PC CODE 031301 

August 29, 2006

FINAL

CANCER ASSESSMENT REVIEW COMMITTEE

HEALTH EFFECTS DIVISION

OFFICE OF PESTICIDE PROGRAMS



DATA PRESENTATION:			_________________________________________

						Byong-Han Chin, Toxicologist

DOCUMENT PREPARATION: 		_________________________________________

						Jessica Kidwell, Executive Secretary

CARC MEMBERS WHO COMMENTED AND VOTED:  

Karl Baetcke					________retired____________________________

William Burnam (Chair) 			_________________________________________

Vicki Dellarco					_________________________________________

Kit Farwell					_________________________________________

Abdallah Khasawinah				_________________________________________

Nancy McCarroll 				_________________________________________

Tim McMahon				_________________________________________

Esther Rinde					_________________________________________

Linda Taylor					_________________________________________

NON-COMMITTEE  MEMBERS IN ATTENDANCE: (Signature indicates concurrence
with the pathology report)

John Pletcher, Consulting Pathologist
_________________________________________

TABLE OF CONTENTS

 TOC \f 

EXECUTIVE SUMMARY 	1

I. INTRODUCTION	4

II.  BACKGROUND INFORMATION	4

III.  EVALUATION OF CARCINOGENICITY STUDIES	5

1. Combined Chronic Toxicity and Carcinogenicity Study with Dicloran in
Wistar Rats	5

2. Carcinogenicity Study in Mice	12

IV.	TOXICOLOGY	15

1. Metabolism	15

2. Mutagenicity	15

3. Structure-Activity Relationship 	15

4. Subchronic and Chronic Toxicity	16

5. Mode of Action Studies	19

V.  COMMITTEE'S ASSESSMENT OF THE WEIGHT-OF-THE-EVIDENCE	20

VI.  CLASSIFICATION OF CARCINOGENIC POTENTIAL	21

VII.  QUANTIFICATION OF CARCINOGENIC POTENTIAL	21

VIII BIBLIOGRAPHY	22

 							

EXECUTIVE SUMMARY  tc \l1 "EXECUTIVE SUMMARY  

The CARC evaluated the carcinogenic potential of dicloran via an
electronic meeting on June 9, 2005.  This is the first time that the
CARC has evaluated the carcinogenic potential of dicloran.

Byong-Han Chin of Reregistration Branch 1 provided information on the
chronic toxicity/carcinogenicity studies in rats and mice.  In a
combined chronic toxicity/carcinogenicity study (MRID 46360701),
dicloran (94.9% a.i.;  batch/lot # 000313) was administered in the diet
to groups of 50 male and 50 female Wistar (HsdCpb:WU) rats at
concentrations of 0, 60, 240 or 1200 ppm for the first 105 days.  The
dietary concentration was raised from 1200 ppm to 1440 ppm on treatment
day 106 because the effects on body weight gains in animals, especially
females was less than expected from the 90-day range finding study. 
Therefore, the calculated time-weighted average dietary concentration
for the high dose main group was 1405 ppm.  The dietary concentrations
were equivalent to 0, 2.8, 11.3, and 71.0 mg/kg/day, respectively, for
males and 0, 3.7, 15.0, and 94.1 mg/kg /day, respectively, for females. 
Additional groups of 10 male and 10 female rats were administered the
same diets for 12 months for interim evaluations.  In a carcinogenicity
study (MRID 40977101), dicloran technical (96.2-97.4% a.i.; Batch No. CR
20642/3) was administered in the diet to Crl:CD-1(ICR)BR mice
(50/sex/dose) at concentrations of 0, 50, 175, or 600 ppm (equivalent to
0/0, 7.4/10.1, 24.5/35.4, and 86.5/118.8 mg/kg/day in males/females) for
up to 18 months. 

The CARC concluded the following:

Carcinogenicity

Rats

nificant increasing trend, at p≤0.01, and a significant difference in
the pair-wise comparison of the 1405 ppm dose group with the control, at
p≤0.05, for benign testicular Leydig cell tumors.  The incidence of
the Leydig cell tumors was outside the historical control range of 0-8%
for the testing laboratory.  Accompanying these tumors was a
statistically significant increase in leydig cell hyperplasia at the
high dose (34%, high dose vs. 8%, control).  The CARC considered the
Leydig cell tumors to be treatment-related at the top dose.	

• In female rats the incidence of malignant uterine endometrial
adenocarcinoma was 3/50 (6%), 7/29 (24%), 7/21 (33%), and 9/50 (18%) in
control, low-, mid-, and high-dose females, respectively.  Although
there were significant differences in the pair-wise comparisons of the
60 ppm dose group, at p≤0.05, and the 240 ppm dose group, at p≤0.01,
with the controls for endometrial adenocarcinomas, not all animals were
examined for endometrial tumors in these dose groups.  Therefore, the
significant findings at 60 and 240 ppm are not considered to be
biologically relevant.  There was no significant increase in the
pair-wise comparison of the high dose group (18%) with the controls (6%)
(p=0.06). In addition, the incidence at the high dose (18%) was within
the historical control range of the testing laboratory (0-22%).  The
incidence of endometrial hyperplasia was increased in high-dose females
(9/50 vs 4/50 for controls, p=0.12) compared with that of controls, but
was not statistically significant.  Therefore, the CARC did not consider
the endometrial adenocarcinomas to be treatment-related.

• Dosing was considered adequate and not excessive for evaluating the
carcinogenic potential of dicloran based on decreased body weight,
decreased body weight gain, and histopathologic lesions in the brain and
spinal cord of both sexes, optic nerve in females and Leydig cell
hyperplasia in the testes in males.

Mice

• No treatment-related tumors were seen in male or female mice.

• Dosing is considered adequate to assess the carcinogenic potential
of dicloran in mice based upon histopathologic changes in organs (liver
and uterus) and increased liver and kidney weights seen at 600 ppm (86.5
mg/kg/day for males, 118.8 mg/kg/day for females).

Mutagenicity 

Dicloran was a confirmed positive in the Ames assay, and was negative up
to precipitating concentrations (10-20 ug/ml) in both the in vitro
chromosome aberration assay in human lymphocytes and primary rat
hepatocyte unscheduled DNA synthesis assay.   The CARC recommended a
confirmation study of gene mutations in mammalian cells.

Structure Activity Relationship 

The metabolite DCPD (4-amino-2,6-dichloroaniline) is not a rat
metabolite but it is found in the plant residues.  DCPD was tested by
the NTP (1982, TR-219).  It was negative in rats but was positive for
combined liver adenomas and carcinomas in mice of both sexes when tested
at doses of 1000 or 3000 ppm in the diet for 103 weeks.		

Classification and Quantification

In accordance with the EPA Final Guidelines for Carcinogen Risk
Assessment (March 29, 2005), the CARC classified Dicloran as
“Suggestive Evidence of Carcinogenic Potential” based on benign
testicular Leydig cell tumors in male rats (1 sex, 1 species) at the
high dose, which was considered adequate but not excessive, as well as a
positive Ames test.  In addition, there is some evidence that a plant
metabolite, but not an animal  metabolite, had some carcinogenic
activity.  No evidence of carcinogenicity was seen in mice at doses that
were considered to be adequate for the assessment of carcinogenicity of
dicloran.  Quantification is not required.

I. INTRODUCTION tc \l1 "I. INTRODUCTION 

The CARC evaluated the carcinogenic potential of dicloran via an
electronic meeting on June 9, 2005.   The data on dicloran was sent out
by email to the members on June 9, 2005 and the email voting ended on
June 16, 2005.  This was the first time that the CARC evaluated the
carcinogenic potential of dicloran.

II.  BACKGROUND INFORMATION tc \l1 "II.  BACKGROUND INFORMATION 

The major commercial use of dicloran (2,6-dichloro-4-nitroaniline
(DCNA)) is as a fungicide and as an intermediate in manufacture of dye. 
The fungicide is registered for treatment of many crops.  It delays
germination and causes a severe check to hyphal growth.  It is suggested
that dicloran is a structurally non-specific toxicant exerting its
effect by disorganizing cell growth and division in particular plant
pathogens.  Dicloran has low acute toxicity.  The target organs include
the liver, kidney, spleen and hematopoietic system (anemia) particularly
destruction of red blood cells.  

The metabolite DCPD (4-amino-2,6-dichloroaniline) is not a rat
metabolite but it is found in the plant residues.  DCPD was tested by
the NTP (1982).  		

III.  EVALUATION OF CARCINOGENICITY STUDIES tc \l1 "III.  EVALUATION OF
CARCINOGENICITY STUDIES 

1. Combined Chronic Toxicity and Carcinogenicity Study with Dicloran in
Wistar Rats tc \l2 "1. Combined Chronic Toxicity and Carcinogenicity
Study with Dichloran in Wistar Rats 

Reference:  Ramesh, E.  2004.  Combined chronic toxicity and
carcinogenicity study with dicloran in Wistar rats.  Toxicology
Department, Rallis Research Centre, Rallis India Ltd., Peenya II Phase,
Bangalore - 560 058, India,  Laboratory project ID 3080/00, August 10,
2004.  MRID 46360701.  Unpublished.

A. Experimental Design

Dicloran (94.9% a.i.; batch/lot # 000313) was administered in the diet
to groups of 50 male and 50 female Wistar (HsdCpb:WU) rats at
concentrations of 0, 60, 240 or 1200 ppm for the first 105 days.  The
dietary concentration was raised from 1200 ppm to 1440 ppm on treatment
day 106 because the effects on body weight gains in animals, especially
females was less than expected from the 90-day range finding study. 
Therefore, the calculated time-weighted average dietary concentration
for the high dose main group was 1405 ppm.  The dietary concentrations
were equivalent to 0, 2.8, 11.3, and 71.0 mg/kg/day, respectively, for
males and 0, 3.7, 15.0, and 94.1 mg/kg /day, respectively, for females. 
Additional groups of 10 male and 10 female rats were administered the
same diets for 12 months for interim evaluations.

B. Discussion of Survival and Tumor Data

Survival

Survival was not affected by treatment with the test material.

Table 1.  Survival (%) at terminal sacrifice in rats treated with
dicloran in the diet for up to 

2 years

Parameter	

Dose (ppm) ADVANCE \d4 

	

 ADVANCE \d4 

0	

 ADVANCE \d4 

60	

 ADVANCE \d4 

240	

 ADVANCE \d4 

1405

 ADVANCE \d4 

Males, Terminal Sacrifice	

 ADVANCE \d4 

72	

 ADVANCE \d4 

66	

 ADVANCE \d4 

74	

 ADVANCE \d4 

88

 ADVANCE \d4 

Females, Terminal Sacrifice	

 ADVANCE \d4 

78	

 ADVANCE \d4 

66	

 ADVANCE \d4 

70	

 ADVANCE \d4 

74 

Data taken from survival table in DER.

Tumor Data

At the doses tested, the incidence of benign Leydig cell tumors was
0/50, 1/50, 1/50, and 5/50 in control, low-, mid-, and high-dose males
rats, respectively.  All Leydig tumors were found in animals sacrificed
at study termination.  There was a significant increasing trend, at
p≤0.01, and a significant difference in the pair-wise comparison of
the 1405 ppm dose group with the control, at p≤0.05, for testicular
benign Leydig cell tumors (Table 2).  High-dose male rats also had a
significantly increased incidence (34%) of Leydig cell hyperplasia
compared with that of controls (8%).  The historical control incidences
for leydig cell tumors are listed in Table 4.

Table 2. Dicloran - Wistar Rat Study (MRID 46360701 )

Male Testicular Leydig Cell Tumor Rates and ad hoca Fisher’s Exact
Test and Trend Tests and Non-Neoplastic Findings

Tissue and observation	

Dietary concentration (ppm)

	

 ADVANCE \d4 0	

 ADVANCE \d4 60	

 ADVANCE \d4 240	

 ADVANCE \d4 1405

Benign Testicular Leydig cell tumor

(%)

p =	

0/50

(0)

0.004543**	

1/50

(2)

0.50000	

1/50

(2)

0.500000	

5/50

(10)

0.02814*

Leydig cell hyperplasia

(%)

	

4/50

(8) 

	

 ADVANCE \d4 5/50

(10)

	

 ADVANCE \d4 5/50

(10)

	

17/50**

(34)

 ADVANCE \d4 ** = p≤0.01; * = p≤0.05

aad hoc statistical analysis performed by L. Brunsman, 6/1/05, from data
taken from Table 58, MRID 46360701.	

 ADVANCE \d4 b2/5 rats (Nos. 5112 and 5116) had both Leydig cell tumor
and Leydig cell hyperplasia. Three other rats with Leydig cell tumor did
not have Leydig cell hyperplasia.

The incidence of malignant endometrial adenocarcinoma was 3/50, 7/29,
7/21, and 9/50 (p=0.061) in control, low-, mid-, and high-dose females,
respectively.  Although there were significant differences in the
pair-wise comparisons of the 60 ppm dose group, at p≤0.05, and the 240
ppm dose group, at p≤0.01, with the controls for endometrial
adenocarcinomas, not all animals were examined for endometrial tumors in
these dose groups (Table 3).  Therefore, the significant findings at 60
and 240 ppm are not considered to be biologically relevant.  The
incidence of endometrial hyperplasia was increased in high-dose females
(9/50 vs 4/50 for controls, p=0.12) compared with that of controls.  The
historical control incidences for endometrial adenocarcinomas is listed
in Table 4. 

Table 3. Dicloran - Wistar Rat Study (MRID 46360701 )

Female Endometrial Tumor Rates and ad hoca Fisher’s Exact Test and
Trend Tests and Non-Neoplastic Findings

Tissue Observation	

Dietary Concentration (ppm)

	

0	

60b	

240b	

1405

Adenocarcinoma

(%)

p =	

3/50

(6)

0.3298	

7/29

(24)

0.02524*	

7/21

(33)

0.00551**	

9/50

(18)

0.06062

Endometrial hyperplasia

(%)

p=	

4/50

(8)	

2/29

(7)	

1/21

(5)	

9/50

(18)

0.12

aad hoc statistical analysis performed by L. Brunsman, 6/1/05, from data
taken from Table 58, MRID 46360701.

bNot all animals were examined in these dose groups.

≤0.05; ** = p≤0.01

Table 4. The Ranges for the Historical controls of Leydig cell tumor
(Benign) and 

Endometrial adenocarcinoma (Malignant)

Tissue and observation

	

 ADVANCE \d4 Rallis Research Center (the testing laboratory; n=11)	

 ADVANCE \d4 Bomhard and Rinke,

1994a	

 ADVANCE \d4 Charles River Laboratories, 

2003b	

 ADVANCE \d4 MRID 46360701 Highest dose tested

Testes

Leydig cell tumor (Benign)	

 ADVANCE \d4 0-8%

(average =1.7%)	

 ADVANCE \d4 2.1-16.3%

(average =7%)	

 ADVANCE \d4 1.67-10.91% (average= 2.16%)	

 ADVANCE \d4 10%

 ADVANCE \d4 Uterus Endometrial adenocarcinoma (Malignant) 	

 ADVANCE \d4 0-22%

 (average =10%)	

 ADVANCE \d4 0-16.3%

(average =7.8%)	

 ADVANCE \d4 1.67-5.45%

(average =2.3%)	

 ADVANCE \d4 18%

 ADVANCE \d4 aBomhard, E. and Rinke M. 1994. Frequency of spontaneous
tumours in Wistar rats in 2-year studies.  Exp Toxic Pathol 46
(1994):17-29

bGiknis, M and Clifford, C. 2003. Spontaneous Neoplasms and Survival in
Wistar Han Rats:Compilation of Control Group Data. Charles River
Laboratories, March 2004.

C. Non-Neoplastic Lesions

The incidences of microscopic non-neoplastic lesions are summarized in
Table 5a and 5b.  At interim sacrifice (12 months), treatment-related
microscopic lesions were observed in the liver (males only), spleen,
brain, and spinal cord of high-dose male and female rats.  The
incidences of hepatocellular hypertrophy was increased in mid- and
high-dose males and the incidence of increased hemosiderosis in the
spleen was increased in mid- and high-dose males and at all doses in
females.  The incidence of vacuolation in the three regions of brain and
spinal cord were increased in high-dose males and females.  One male rat
in the mid-dose group had vacuolation in the cerebral cortex. Cerebral
vacuolation occurred bilaterally in the corpus callosum, cerebral
peduncles, substantia nigra and the anterior commissures with minimal to
moderate severity in males and mild to moderate severity in females. 
Cerebellar vacuolation was minimal to mild in both sexes, and
medullar/pons vacuolation was minimal to moderate in both sexes.  Spinal
cord vacuolation was minimal to moderate.

≤0.05-0.01) of males at all doses compared with only 18% in the
control group and in 80% (p≤0.01) of high-dose females compared with
36% in the control group.  The incidence of vacuolation in the three
regions of the brain and spinal cord ranged from 62-96% and 56-86%,
respectively, of high-dose males and 84-98% and 46-86%, respectively, of
high-dose females compared with no more than 4% of male controls and 2%
of female controls.  High-dose females also had a marginally significant
increased incidence of vacuolar changes in the optic nerve (8% vs 0% for
controls).  Vacuolation in the optic chiasma was observed in 28% of
high-dose males and 34% of high-dose females.  The severity was minimal
to severe in the cerebral cortex and medulla/pons, minimal to moderate
in the cerebellum, and minimal to severe in the spinal cord. 

High-dose male rats also had a significantly increased incidence (34%)
of Leydig cell hyperplasia compared with that of controls (8%) (Table
5b).   SEQ CHAPTER \h \r 1 The incidence of endometrial hyperplasia was
increased in high-dose females (9/50 vs 4/50 for controls, p=0.12)
compared with that of controls, and the incidence of thyroid c-cell
hyperplasia was increased in high-dose males (11/50 vs 5/50 for
controls, p=0.086) (not listed in Table 5).  

TABLE 5a.  Histopathological findings in male and female 

Organ/Lesion	

Dietary concentration (ppm)

	

0	

60	

240	

1405	

0	

60	

240	

1405

	

Males - 12 month interim group	

Females - 12 month interim group

Liver [# animals examined]

Hepatocellular hypertrophy	

[10]

0	

[10]

0	

[10]

4	

[10]

6	

[10]

3	

[10]

5	

[10]

6	

[10]

7

Spleen [# animals examined]

Increased hemosiderosis	

[10]

2	

[10]

3	

[10]

8	

[10]

7	

[10]

2	

[10]

7	

[10]

7	

[10]

9

Brain [# animals examined]

             Cerebral cortex, vacuolation                Cerebellar
cortex, vacuolation              Medulla/pons, vacuolation	

[10]

0

0

0	

[10]

0

0

0	

[10]

1

0

0	

[10]

10

2

9	

[10]

0

0

0	

[10]

0

0

0	

[10]

0

0

0	

[10]

10

8

10

 Spinal cord [# examined]

Cervical, vacuolation

Thoracic, vacuolation

Lumbar, vacuolation	

[10]

0

0

0	

[0]	

[0]	

[10]

2

2

0	

[10]

0

0

0	

[0]	

[0]	

[10]

9

6

3

	

Males - main group	

Females - main group

Liver [# animals examined]

Eosinophilic focus(i)

Hepatocellular hypertrophy

Necrobiotic focus(I) 	

[50]

5 (10)

3 (6)

10	

[50]

4

7

2	

[50]

12* (24)b

15** (30)

10	

[50]

15** (30)

38** (76)

18	

[50]

5

28

5	

[50]

1

27

5	

[50]

3

35

7	

[50]

6

36

15**

Spleen [# animals examined]

Increased hemosiderosis	

[50]

9 (18)	

[50]

23* (46)	

[50]

35** (70)	

[50]

42** (84)	

[50]

18 (36)	

[50]

21	

[50]

26	

[50]

40** (80)

Testes [# animals examined]

Leydig cell hyperplasia	

[50]

4	

[50]

5	

[50]

5	

[50]

17**	

NA	

NA	

NA	

NA



Brain [# animals examined]

         Cerebral cortex, vacuolation 

         Optic chiasma, vacuolation 

         Cerebellar cortex, vacuolation

         Medulla/pons, vacuolation	

[50]

1

0

2

1	

[50]

0

0

0

0	

[50]

1

0

0

0	

[50]

48** (96)

14** (28)

31** (62)

48** (96)	

[50]

0

0

1

0	

[50]

0

0

0

0	

[50]

0

0

0

0	

[50]

49** (98)

17** (34)

42** (84)

46** (92)

Spinal cord [# examined]

Cervical, vacuolation

Thoracic, vacuolation

Lumbar, vacuolation	

[50]

0

0

0	

[50]

0

0

0	

[50]

0

0

0	

[50]

43** (86)

42** (84)

28** (56)	

[50]

0

1

0	

[50]

0

0

0	

[50]

0

0

0	

[50]

43** (86)

40** (80)

23** (46)

Eyes, optic nerve [# examined]

Vacuolar changes	

[50]

0	

[24]

0	

[16]

0	

[50]

1	

[50]

0	

[17]

0	

[17]

0	

[50]

4

Data taken from Table 51 (pages 259-274) and 58 (pages 379-432) MRID
46360701. 

bNumbers in parentheses are percent of control calculated by the
reviewer.

≤0.05, **p≤0.01, statistically significant, treated group compared
with the control group, calculated by the reviewer using Fisher’s
exact test.

  SEQ CHAPTER \h \r 1 Table 5b.  Summary of Histopathological
(Non-neoplastic and Neoplastic) Findings of Combined Fates

Tissue and observation	Dietary  concentration (ppm)

	0	60	240	1405

Testes [# animals examined]

    Leydig cell tumor (Benign)	50

0 (0) a	50

1 (2)	50

1 (2)	50

5 (10) b

    Leydig cell hyperplasia	50

4 (8) 	50

5 (10)	50

5 (10)	50

17 (34)

Uterus [# animals examined]

    Endometrial adenocarcinoma (Malignant)	50

3 (6)	29

7 (24)	21

7 (33)	50

9 (18)

    Endometrial hyperplasia	50

4 (8)	29

2 (7)	21

1 (5)	50

9 (18)

Data taken from Table 58, MRID 46360701. 

a Numbers in parentheses: Percentage value

 b 2 rats (Nos. 5112 and 5116) had both Leydig cell tumor and Leydig
cell hyperplasia.  Three other rats with Leydig cell tumor did not have
Leydig cell hyperplasia.

D. Adequacy of the Dosing for Assessment of Carcinogenicity

Dosing was considered adequate and not excessive for evaluating the
carcinogenic potential of dicloran based on decreased body weight,
decreased body weight gain, and histopathologic lesions in the brain and
spinal cord of both sexes, optic nerve in females and Leydig cell
hyperplasia in the testes in males.

2. Carcinogenicity Study in Mice tc \l2 "2. Carcinogenicity Study in
Mice 

Reference: Mallyon, B.A. and L.P. Markham (1989) T104 Technical
Dicloran: oncogenicity study in the mouse (final report) part 1. 
Schering Agrochemicals Limited, Essex, England.  Laboratory Project Id.:
Tox/86006, January 6, 1989.  MRID 40977101.  Unpublished.

A. Experimental Design

Dicloran technical (96.2-97.4% a.i.; Batch No. CR 20642/3) was
administered in the diet to Crl:CD-1(ICR)BR mice (50/sex/dose) at
concentrations of 0, 50, 175, or 600 ppm (equivalent to 0/0, 7.4/10.1,
24.5/35.4, and 86.5/118.8 mg/kg/day in males/females) for up to 18
months. 

B. Discussion of Tumor Data

No treatment-related increase in tumor incidence was reported. 

C. Non-Neoplastic Lesions

≤0.05) in the incidence of focal necrosis with dose was observed, and
the incidence of minimal to moderate focal necrosis was increased
(p>0.05) in the 600 ppm males (10/50) vs minimal to slight in controls
(4/50).  Increased (p≤0.05-0.01) incidences (# affected/50) in the
following hepatic lesions were also observed in the 600 ppm males: (i)
minimal to moderate single cell necrosis in treated (6) vs moderate in
controls (1); (ii) slight to severe centrilobular hepatocyte enlargement
in treated (26) vs minimal to moderate in controls (8); (iii) minimal to
slight acute inflammatory infiltration in treated (9) vs minimal to
slight in controls (2); and (iv) centrilobular hemosiderocytes present
in treated (12) vs controls (1). 

 

≤0.05) incidence of minimal to severe vacuolation of centrilobular
hepatocytes was observed in the 600 ppm females (12/50) vs slight to
moderate in controls (4/50).  Minimal to severe cystic endometrial
hyperplasia in the uterus was increased (p≤0.05) at ≥175 ppm
(24-31/50) vs minimal to severe in controls (17/50).  A positive trend
(p≤0.01) in the incidence of each lesion (vacuolation and hyperplasia)
with dose was found.  The incidence of all other lesions in the treated
groups were similar to the controls.

Table 6.  Incidence (# affected/50) of selected non-neoplastic
microscopic lesions in mice treated with Dicloran in the diet for up to
80 weeks. a

Microscopic lesion	

Dose (ppm)

	

0	

50	

175	

600

Males

Liver 	             Focal necrosis (total)	

4*	

2	

5	

10

Minimal	

3	

0	

3	

4

Slight	

1	

2	

1	

5

Moderate	

0	

0	

0	

1

Severe	

0	

0	

1	

0

Single cell necrosis (total)	

1**	

1	

0	

6*

Minimal	

0	

0	

0	

1

Slight	

0	

1	

0	

4

Moderate	

1	

0	

0	

1

Centrilobular hepatocyte enlargement (total)	

8***	

8	

7	

26***

Minimal	

1	

2	

0	

0

Slight	

5	

5	

5	

10

Moderate	

2	

1	

1	

15

Severe	

0	

0	

1	

1

Acute inflammatory infiltration (total)	

2*	

4	

9	

9*

Minimal	

1	

2	

4	

3

Slight	

1	

1	

3	

6

Moderate	

0	

1	

1	

0

Severe	

0	

0	

1	

0

Centrilobular hemosiderocytes present	

1***	

2	

4	

12**

Females

Liver	Vacuolation of centrilobular hepatocytes (total)	

4***	

3	

3	

12*

Minimal	

0	

0	

0	

1

Slight	

3	

2	

2	

8

Moderate	

1	

1	

1	

2

Severe	

0	

0	

0	

1

Uterus 	Cystic endometrial hyperplasia	

17**	

21	

24	

31*

Minimal	

5	

5	

1	

1

Slight	

9	

9	

13	

15

Moderate	

2	

7	

7	

12

Severe	

1	

0	

3	

3

a	Data were obtained from Table 11 on pages 95, 121, and 132 and
Appendix VIII on pages 1073-1080 of MRID 40977101.

≤0.05

**	Treatment group significantly differs from controls or a positive
trend of response with dose; p≤0.01

**	Treatment group significantly differs from controls or a positive
trend of response with dose; p≤0.001

D. Adequacy of the Dosing for Assessment of Carcinogenicity

Dosing is considered adequate to assess the carcinogenic potential of
dicloran in mice based upon histopathologic changes in organs (liver and
uterus) and increased liver and kidney weights seen at 600 ppm (86.5
mg/kg/day for males, 118.8 mg/kg/day for females).

IV.	TOXICOLOGY tc \l1 "IV.	TOXICOLOGY 

1. Metabolism tc \l2 "1. Metabolism  

Dicloran is rapidly absorbed and metabolized in rats following oral
administration (MRID 44061001).  Approximately 96% of the administered
dose was excreted in 24 hours. The urine was the major route of
excretion (86.3% of the administered dose), and smaller amounts in feces
(8.7% of the administered dose).  Dicloran does not appear to accumulate
in tissues. The major urine metabolites were DCHA-sulfate (
4-amino-3,5-diclorophenol), and DCHA-glucuronide which accounted for
45.5% to 79% of the total dose.  Other metabolites detected were DCHA
(3.3 to 22.8%), DCAP (4, amino-2,6-diclorophenol, 0.3% to 8.5%), and
DCNAP (3,5-dichloro-4- hydroxyacetanilide, <0.1% to 1.0%).  A small
amount of dicloran was detected in feces.

2. Mutagenicity tc \l2 "2. Mutagenicity 

Dicloran was a confirmed positive in the Ames assay (40508801), and was
negative up to precipitating concentrations (10-20 ug/ml) in both the in
vitro chromosome aberration assay in human lymphocytes (40508802) and
primary rat hepatocyte unscheduled DNA synthesis assay (40619001). 	

There is reproducible evidence of a positive response both in the
presence and the absence of S9 activation in Salmonella typhimurium
TA1538 and TA98 at 500, 1500 and 5000 ug/plate +/-S9.  The response
appears to be slightly greater in the presence of S9 (TA1538 - 5.1X at
5000 ug/plate+S9  vs 3 X at 5000 ug/plate -S9; TA98 - 3.7X  at 5000
ug/plate+S9 vs 2.2 X at 5000 ug/plate -S9).  The response is valid
because: 1) the effect was reproducible and 2) the findings with strain
TA1538 were confirmed by TA98 (almost always, + with strain TA1538 is
followed by a + with TA98, that's why TA1538 is no longer necessary in a
guideline Ames test).  There is also some residual activity with TA100. 

The CARC recommended a confirmation study of gene mutations in mammalian
cells.

No mutagenicity studies were found in the open literature. 

 			

3. Structure-Activity Relationship  tc \l2 "3. Structure-Activity
Relationship  

The metabolite DCPD (4-amino-2,6-dichloroaniline) is not a rat
metabolite but it is found in the plant residues.  DCPD was tested by
the NTP (1982, TR-219).  It was negative in rats but was positive for
combined liver adenomas and carcinomas in mice of both sexes when tested
at doses of 1000 or 3000 ppm in the diet for 103 weeks.

4.  Subchronic and Chronic Toxicity tc \l2 "4.  Subchronic and Chronic
Toxicity 

a) Subchronic Toxicity

EXECUTIVE SUMMARY: In a 90-day ranging-finding study (MRID 46360702),
dicloran (94.6% a.i.;  batch/lot # 000313) was administered in the diet
to groups of 10 male and 10 female Wistar (HsdCpb:WU) rats at
concentrations of 0, 300, 1000, 2000, or 4000 ppm for 90 days.  The
dietary concentrations were equivalent to 0, 19.4, 61.5, 121.2, and
246.8 mg/kg/day, respectively, for males and 0, 25.4, 72.4, 133.6, and
264.6 mg/kg/day, respectively, for females.  The following parameters
were examined: clinical signs, body weight, food consumption, clinical
pathology (hematological and clinical chemistry parameters), gross
lesions, selected organ weights, and histopathology of selected tissues
and organs.

All animals survived to study termination and no treatment-related
clinical signs of toxicity were observed at any time during treatment. 
Body weight, weight gain, and food consumption were significantly
(p≤0.05) decreased throughout the study in males and females at 2000
and 4000 ppm.  At 2000 and 4000 ppm, males weighed 10-14% and 19-29%
less  than controls, respectively, and females weighed 6-13% and 8-19%
less  than controls,  respectively.  Males and females in the 2000- and
4000-ppm groups lost weight during the first week of the study.  The
males gained 29% and 56% less weight, respectively, and the females
gained 29% and 44% less weight, respectively, over the entire study. 

≤0.05) less and gained 55% less weight than controls after the first
week.  However, over the entire study, the 1000 ppm group gained 11%
(N.S.) less weight than controls.  Females in the 1000-ppm group weighed
up to 7% (p≤0.05) less than controls from weeks 9-13 and gained 24%
(p≤0.05) less weight over the entire study.  Females in the 1000-ppm
group had weekly weight gains similar to the controls after week 1;
therefore, the cumulative weight gain is not indicative of an adverse
effect.  Body weight and weight gain were not affected at 300 ppm. 
Weekly food consumption was markedly reduced by 42% and 71% in 2000- and
4000-ppm male groups, respectively, during week 1 and was reduced by
10-19% and 15-36% (p≤0.05) less food than controls for the remaining
weeks.  Males in the 1000-ppm group consumed 7-16% (p≤0.05) less food
than controls.  Females in the 1000-,  2000-, and 4000-ppm groups
consumed 24%, 54%, and 66% less food than controls during week 1 and
16-21%, 20-28%, and 21-37% (p≤0.05) less food than controls for the
remaining weeks of the study.

In male and female rats at 2000 and 4000 ppm, the RBC counts were lower
and MCV and MCH were higher than controls.  Blood urea nitrogen (BUN)
was elevated in males and females at 2000 and 4000 ppm, total protein
and albumin levels were elevated in males at 4000 ppm, and total
cholesterol was elevated in females at 2000 and 4000 ppm.  Except for
hepatocyte hypertrophy (see below), which may be associated with
increased protein and BUN, clinical chemistry findings were not
associated with pathologic findings.

At necropsy, terminal body weight was significantly decreased in males
at 2000 and 4000 ppm and absolute epididymis weight was significantly
decreased at 4000 ppm.  Organ:body weight ratios of the adrenals,
testes, kidneys, liver, brain, and spleen were increased at 4000 ppm,
kidney, liver and brain at 2000 ppm, and liver at 1000 ppm.  Terminal
body weight and absolute adrenal weight were significantly decreased and
liver weight was significantly increased in females at 2000 and 4000
ppm; spleen weight was significantly increased in females at 4000 ppm. 
Organ:body weight ratios of liver and kidneys were significantly
increased at 1000-4000 ppm, and the ratios of brain and spleen weights
were significantly increased in females at 4000 ppm.  Except for
increased liver weight, changes in absolute organ weights and organ:body
weight ratios were due primarily to decreases in terminal body weight. 
No treatment-related gross lesions were observed in male or female rats.
 Microscopic examination showed significantly increased incidences of
hepatocellular hypertrophy in males at 2000 and males and females at
4000 ppm, increased hemosiderosis in the spleen of males at 2000 and
4000 ppm and in females at all doses, and hyaline droplets in the renal
tubular epithelium of males at 2000 and 4000 ppm.  Hepatocellular
hypertrophy and hemosiderosis in the spleen are not considered adverse
effects and hyaline droplet formation in the kidney tubules is not
relevant to humans.

Based on the range-finding study, the high dose selected for the
24-month study was 1200 ppm.

The LOAEL for dicloran in the 90-day feeding study in the rat is 2000
ppm (121.2 mg/kg bw/day for males and 133.6 mg/kg/day for females) based
on decreased body weight, weight gain, and food consumption.  The
corresponding NOAEL is 1000 ppm (61.5 mg/kg bw/day for males and 72.4
mg/kg bw/day for females).

b) Chronic Toxicity

Rat

EXECUTIVE SUMMARY: In a combined chronic toxicity/carcinogenicity study
(MRID 46360701), dicloran (94.9% a.i.;  batch/lot # 000313) was
administered in the diet to groups of 50 male and 50 female Wistar
(HsdCpb:WU) rats at concentrations of 0, 60, 240 or 1200 ppm for the
first 105 days.  The dietary concentration was raised from 1200 ppm to
1440 ppm on treatment day 106 because the effects on body weight gains
in animals, especially females was less than expected from the 90-day
range finding study.  Therefore, the calculated time-weighted average
dietary concentration for the high dose main group was 1405 ppm.  The
dietary concentrations were equivalent to 0, 2.8, 11.3, and 71.0
mg/kg/day, respectively, for males and 0, 3.7, 15.0, and 94.1 mg/kg
/day, respectively, for females.  Additional groups of 10 male and 10
female rats were administered the same diets for 12 months for interim
evaluations.

≤0.05) less than that of controls.  Mean body weight of high-dose
males remained 8-13% (p≤0.05) less than that of controls for the
remainder of the study, and mean body weight of high-dose females was
10-14% (p≤0.05) less than that of controls during the second year of
the study.  High-dose males and females gained 13% (p≤0.05) and 20%
(p≤0.05) less weight, respectively, than controls for the entire
study.  High-dose rats consumed significantly less food than controls
during the first 17 weeks (males) and 73 weeks (females); total food
consumption was not affected and food efficiency for the entire study
was similar for high-dose and control rats.  Body weight, weight gain,
and food consumption were not significantly and adversely affected in
low- and mid-dose rats of either sex.

Analysis of hematological parameters showed very mild transient changes
in red blood cell (RBC) count, mean cell volume, and mean cell
hemoglobin in high-dose male and female rats and was indicative of a
mild hyperchromatic macrocytic anemia.  These changes are not considered
adverse.  Other hematological changes (total white blood cell (WBC),
neutrophil, and lymphocyte counts in male and female rats and
prothrombin time and platelet count in females) were not considered
treatment-related.  Significant changes in clinical chemistry parameters
in high-dose rats were  transient and were not correlated with
histopathologic findings.

Statistically significant changes in absolute organ weights and
organ:body weight ratios were due to decreased terminal body weight. 
Postmortem examination showed no treatment-related gross findings in
male or female rats receiving any dose of the test material.  The
primary target for 

microscopic lesions appeared to be the brain and spinal cord. 
Vacuolation was observed in the cerebral cortex including the optic
chiasma, cerebellar cortex, and medulla/pons regions of the brain and in
the cervical, thoracic, and lumbar segments of the spinal cord of
high-dose males and females at 12 and 24 months.  In the main group,
vacuolation was observed in the brain of 62-96% of males and 84-98% of
females and in the spinal cord of 56-86% of males and 46-86% of females
compared with 0-4% of male controls and 0-2% of female controls.  In
addition, vacuolation in the optic chiasma in the cerebral cortex
occurred in 28% of high-dose males and 34% of high-dose females compared
with none of the controls.  Vacuolar changes in the optic nerve were
observed in 8% (p=0.059) of high-dose females compared with none of the
controls, and the incidence of Leydig cell hyperplasia in the testes was
34% (p≤0.05) in high-dose males compared with 8% of controls.  

The lowest-observed-adverse-effect level (LOAEL) for dicloran in rats
is 1405 ppm (71.0 and 94.1 mg/kg bw/day for males and females,
respectively) based on reduced body weight, reduced body weight gain,
and histopathologic lesions in the brain and spinal cord of both sexes,
optic nerve in females and testes in males.  In addition,
treatment-related increase in the relative weights in the liver, brain
and testes in males and relative liver weight in females were observed. 
 The no-observed-adverse-effect level (NOAEL) is 240 ppm (M//F:11.3/15.0
mg/kg bw/day.

Mouse

EXECUTIVE SUMMARY:  In a carcinogenicity study (MRID 40977101), dicloran
technical (96.2-97.4% a.i.; Batch No. CR 20642/3) was administered in
the diet to Crl:CD-1(ICR)BR mice (50/sex/dose) at concentrations of 0,
50, 175, or 600 ppm (equivalent to 0/0, 7.4/10.1, 24.5/35.4, and
86.5/118.8 mg/kg/day in males/females) for up to 18 months. 

No treatment-related effects were observed on mortality, clinical signs,
body weights, body weight gains, food consumption, food conversion
ratios, or differential leukocyte counts.

Hepatotoxicity was indicated in the 600 ppm males due to increased
incidences (# affected/50; p≤0.05-0.01) in the following findings: (i)
minimal to moderate focal necrosis in treated (10) vs minimal to slight
in controls (4); (ii) minimal to moderate single cell necrosis in
treated (6) vs moderate in controls (1); (iii) slight to severe
centrilobular hepatocyte enlargement in treated (26) vs minimal to
moderate in controls (8); (iv) minimal to slight acute inflammatory
infiltration in treated (9) vs minimal to slight in controls (2); and
(vi) centrilobular hemosiderocytes present in treated (12) vs controls
(1). 

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 treated, each lesion vs 2-3/50 controls).  Minimal to severe cystic
endometrial hyperplasia in the uterus was increased (p≤0.05) at ≥175
ppm (24-31/50) vs minimal to severe controls (17/50).  As there were no
further effects observed at 175 ppm, the endometrial hyperplasia at this
dose was not considered adverse.

No effects were observed at the lower doses.

The LOAEL is 600 ppm (equivalent to 86.5/118.8 mg/kg/day in
males/females), based on an increased incidence of microscopic hepatic
lesions in males, centrilobular hepatocyte vacuolation in females, and
distended, enlarged uterus with cystic endometrial hyperplasia.  The
NOAEL is 175 ppm (24.5/35.4 mg/kg/day in males/females).

5. Mode of Action Studies tc \l2 "5. Mode of Action Studies 

No mode of action data were submitted.

V.  COMMITTEE’S ASSESSMENT OF THE WEIGHT-OF-THE-EVIDENCE tc \l1 "V. 
COMMITTEES ASSESSMENT OF THE WEIGHT-OF-THE-EVIDENCE  

1. Carcinogenicity

Rats

•  In male rats the incidence of benign testicular leydig cell tumors
was 0/50, 1/50 (2%), 1/50 (2%), and 5/50 (10%) for the control, 60, 240,
and 1405 ppm dose groups, respectively.  There was a significant
increasing trend, at p<0.01, and a significant difference in the
pair-wise comparison of the 1405 ppm dose group with the control, at
p<0.05, for  benign testicular Leydig cell tumors.  The incidence of the
Leydig cell tumors was outside the historical control range of 0-8% for
the testing laboratory. Accompanying these tumors was a statistically
significant increase in leydig cell hyperplasia at the high dose (34%,
high dose vs. 8%, control).  The CARC considered the Leydig cell tumors
to be treatment-related at the top dose.	

• In female rats the incidence of malignant uterine endometrial
adenocarcinoma was 3/50 (6%), 7/29 (24%), 7/21 (33%), and 9/50 (18%) in
control, low-, mid-, and high-dose females, respectively.  Although
there were significant differences in the pair-wise comparisons of the
60 ppm dose group, at p≤0.05, and the 240 ppm dose group, at p≤0.01,
with the controls for endometrial adenocarcinomas, not all animals were
examined for endometrial tumors in these dose groups.  Therefore, the
significant findings at 60 and 240 ppm are not considered to be
biologically relevant.  There was no significant increase in the
pair-wise comparison of the high dose group (18%) with the controls (6%)
(p=0.06). In addition, the incidence at the high dose (18%) was within
the historical control range of the testing laboratory (0-22%).  The
incidence of endometrial hyperplasia was increased in high-dose females
(9/50 vs 4/50 for controls, p=0.12) compared with that of controls, but
was not statistically significant.  Therefore, the CARC did not consider
the endometrial adenocarcinomas to be treatment-related.

•  Dosing was considered adequate and not excessive for evaluating the
carcinogenic potential of dicloran based on decreased body weight,
decreased body weight gain, and histopathologic lesions in the brain and
spinal cord of both sexes, optic nerve in females and Leydig cell
hyperplasia in the testes in males.

Mice

•  No treatment-related tumors were seen in male or female mice.

• Dosing is considered adequate to assess the carcinogenic potential
of dicloran in mice based upon histopathologic changes in organs (liver
and uterus) and increased liver and kidney weights seen at 600 ppm.

2.  Mutagenicity 

Dicloran was a confirmed positive in the Ames assay, and was negative up
to precipitating concentrations (10-20 ug/ml) in both the in vitro
chromosome aberration assay in human lymphocytes and primary rat
hepatocyte unscheduled DNA synthesis assay.  The CARC recommended a
confirmation study of gene mutations in mammalian cells.

3.  Structure Activity Relationship 

The metabolite DCPD (4-amino-2,6-dichloroaniline) is not a rat
metabolite but it is found in the plant residues.  DCPD was tested by
the NTP (1982, TR-219).  It was negative in rats but was positive for
combined liver adenomas and carcinomas in mice of both sexes when tested
at doses of 1000 or 3000 ppm in the diet for 103 weeks.	

4. Mode of Action

No mode of action data were submitted.

VI.  CLASSIFICATION OF CARCINOGENIC POTENTIAL tc \l1 "VI. 
CLASSIFICATION OF CARCINOGENIC POTENTIAL 

In accordance with the EPA Final Guidelines for Carcinogen Risk
Assessment (March 29, 2005), the CARC classified Dicloran as
“Suggestive Evidence of Carcinogenic Potential” based on benign
testicular Leydig cell tumors in male rats (1 sex, 1 species) at the
high dose, which was considered adequate but not excessive, as well as a
positive Ames test. In addition, there is some evidence that a plant
metabolite, but not an animal  metabolite, had some carcinogenic
activity. No evidence of carcinogenicity was seen in mice at doses that
were considered to be adequate for the assessment of carcinogenicity of
dicloran.

VII.  QUANTIFICATION OF CARCINOGENIC POTENTIAL tc \l1 "VII. 
QUANTIFICATION OF CARCINOGENIC POTENTIAL 

Quantification is not required.

VIII  	BIBLIOGRAPHY tc \l1 "VIII BIBLIOGRAPHY 

MRID		CITATION

40508801	Jones, E.; Fenner, L. (1987) T103 Technical Dicloran: Ames
Bacterial Mutagenicity Test: Project ID: TOX/87/199-85. Unpublished
study prepared by Schering Agrochemicals Ltd. 20 p. 

40508802	Allen, J. (1988) T105 Technical Dicloran: Metaphase Chromosome
Analysis of Human Lymphocytes Cultured in vitro: Project ID: TOX
87/199-188.  Unpublished study prepared by Huntingdon Research Centre. 
23 p.

40619001	Jackson, C. (1988) T108 Technical Dicloran: Assessment of
Unscheduled DNA Synthesis Using Rat Hepatocyte Cultures: Laboratory
Project ID TOX 87224. Unpublished study prepared by Schering
Agrochemicals Ltd. 107 p.	

40977101	Mallyon, B.A. and L.P. Markham (1989) T104 Technical Dicloran:
oncogenicity study in the mouse (final report) part 1.  Schering
Agrochemicals Limited, Essex, England.  Laboratory Project Id.:
Tox/86006, January 6, 1989.   Unpublished.

44061001	Cheng, T. (1996) Metabolism of (carbon-14)-Dicloran (Botran
Technical) in Rats: Final Report: Lab Project Number: HWI 6564-108. 
Unpublished study prepared by Hazleton Wisconsin, Inc.  123 p.

46360701	Ramesh, E.  2004.  Combined chronic toxicity and
carcinogenicity study with dicloran in Wistar rats.  Toxicology
Department, Rallis Research Centre, Rallis India Ltd., Peenya II Phase,
Bangalore - 560 058, India,  Laboratory project ID 3080/00, August 10,
2004.  Unpublished.

46360702	Ramesh, E.  2001.  Dicloran: 90-day dietary dose range finding
study in Wistar rats.  Toxicology Department, Rallis Research Centre,
Rallis India Ltd., Peenya II Phase, Bangalore - 560 058, India, 
Laboratory project ID 3080/00, December 10, 2001.  Unpublished.			

------------ 	NTP. 1982.  Carcinogenesis Bioassay of
2,6-Dichloro-p-Phenylenediamine (CAS No. 609-20-1) in F344 Rats and
B6C3F1 Mice (Feed Study) TR-219. National Toxicology Program.

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DICLORAN 		      CANCER ASSESSMENT DODUMENT		    FINAL

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