Toxicology and Risk Assessment

Chemtura Corporation

Chemtura

REVIEW OF OTHER SCIENTIFICALLY RELEVANT INFORMATION

FOR THE EDSP TIER I SUBSTANCE

DICHLOBENIL [CAS NO. 1194-65-6]

Prepared by

Shaila Rao, PhD

Shari Long, MS

Toxicology and Risk Assessment

Chemtura Corporation

199 Benson Road

Middlebury, CT 06749

FINAL REPORT

March 16,2010
DICHLOBENIL

|CAS No. 1194-65-6)

Introduction

In response to the Environmental Protection Agency's (EPA) issuance orders for data from

testing required in Tier 1 of the Endocrine Disruption Screening Program (EDSP). a review of

the other Scientifically Relevant Information (OSRI) using toxicological data from in vivo and in

vitro studies for Dichlobenil and its effects on endocrine activity (estrogenic. androgenic, and

thyroid) are presented. Studies that evaluated effects on reproduction and/or fetal development

that could represent changes in endocrine function also are included.

Extensive public literature data search for the relevant EDSP studies returned a number of

records. These studies were utilized in our assessment for Dichlobenil EDSP review.

Strategies initially focused strictly on Tier 1 and related tests. An overall assessment of the data

described in this report, along with proposed recommendations for responding to EPA to address

the need for additional testing as described in the EDSP Tier 1 guidelines, is given in the next

section.

Evaluation of the Available Toxicological Data

Dichlobenil has an extensive database of all toxicological studies. Data from the available

toxicological studies considered relevant for EDSP assessment are summarized in the Table 1

below. Some of these studies were submitted earlier to EPA and the available MRID numbers for

these studies are provided for your reference. A list of the end points assessed for the evaluation

of ED activity is included in the table below.
Table 1. Data Summary' from Dichlobenil Studies considered for Potential ED Activity

Study Type/

Guideline

Chronic

Toxicitv

Two-Year Rat

Feeding Study

Guideline Study

# 83-1 and 83-2

Combined

Chronic/

Carcinogenicity

Study

Chronic Hamster

Feeding Studies

Guideline Study

# 83-2

"Doses

Tested

0, 50,

400 or

3,200

ppm

0.5,

26, 132

and

675

ppm

Some of the

EDSP Assay End

Points checked

Organ weight:

testis,

epididymides,

uterus, ovaries,

liver, kidney and

other

Histopathology:

uterus, ovaries,

testis,

epididymides,

prostate and other

Organ weight:

testis,

epididymides,

uterus, ovaries and

other

Histopathology:

uterus, ovaries,

testis,

epididymides,

prostate and other

~j

• , Results/Comments

'

Dichlobenil was fed to male and female

Fischer 344 rats for two years at dietary

concentrations of 50, 400 or 3,200 ppm.

Reduced survival was seen in male rats

and reductions in body weight gain and

food intake were seen in male and female

rats at the high dosage level.

Histopathological effects were seen in

kidneys in high dose males and females

and in livers of mid and high dose females.

There was an increased incidence in

hepatocellular tumors at the high dose

group in both the sexes. Tumors did not

appear to occur with decreased latency.

The NOEL for chronic toxicity in rats was

50 ppm (2.5 mg/kg/day).

In this study dichlobenil was fed to male

and female hamsters for 88 and 80 weeks,

respectively, at dietary concentrations of 5,

26, 132 and 675 ppm. Hamsters in the

high dose group exhibited slightly reduced

body weight gain. High dose female

hamsters had an increased incidence of

adrenal cortical hyperplasia and

hepatocellular enlargement. There was no

increase in tumor incidence as a result of

dichlobenil administration. The NOEL for

chronic toxicity in hamsters was 1 32 ppm.

Reference/ -

MRiD#

Chronic Feeding

Study on

Dichlobenil in the

Rat. (1984).

Lab Project ID #

Exp. No. 40(010-

002).

MRID#

00147438

Dichlobenil -

Potential

Tumorigenic

Effects in

Prolonged

Dietary

Administration

to Hamsters

(1991).

Laboratory

Project Id # :

PDR/478

MR1D #s

41988301,

42015101
Study Type/

Guideline

Combined

Chronic/

Carcinogenicity

Study

Chronic Hamster

Feeding Studies

Guideline Study

# 83-2

One Year Dog

Feeding Study

Guideline Study

# 83-1

Doses

Tested

0. 675.

1,500

and

3,375

ppm

0,1,6

and 36

mg/kg/

day

Some of the

EDSP Assay End

Points checked

Organ weight:

testis.

epididymides.

uterus, ovaries and

other

Histopathology:

uterus, ovaries,

testis.

epididymides,

vagina, prostate,

and other

Organ weight:

testis. uterus.

ovaries, prostate ,

thyinus, thyroids

and other

Histopathology:

uterus, ovaries.

testis,

epididymides.

vagina, prostate,

jejunum,

mammary glands,

thyroids and other

-

Results/Comments

'

In another study, dichlobenil was fed to

male and female hamsters for 91 and 78

weeks, respectively, at dietary

concentrations of 675, 1,500 and 3,375

ppm. Reduced body weight gain was seen

in all treated males and high dose female

hamsters. Microscopic evidence of liver

toxicity was seen in males and females

given 1 ,500 and 3,375 ppm. An increased

incidence of liver adenomas was seen in

high dose male hamsters, which was

considered to be the result of liver toxicity.

The NOEL for chronic toxicity in

hamsters was less than 675 ppm.

Dichlobenil was administered in capsules

to male and female Beagle dogs for one

year at dosages of 1 , 6 and 36 mg/kg/day.

Body weight gain was reduced in high

dose males. Mid and high dose males had

lower albumin, hemoglobin, packed red

cell volume and red blood cell count.

Males and females in the mid and high

dose groups and low dose males had

elevated serum cholesterol, triglyceride

and phospholipid concentrations in blood.

Mid and high dose males and females and

low dose females had increased liver

weights, while all treated females and high

dose males had increased thyroid weights.

Kidney weights were increased in high

dose males and high dose females had

reduced uterus and ovary weights. High

dose males and females exhibited liver cell

hypertrophy and adrenal cortical

vacuolation. At a dose level of 1

mg/kg/day, the only effects seen were

slightly higher blood triglyceride

concentrations in males and increased liver

and thyroid weight in females. Since there

were no histopathological lesions at 1

mg/kg/day and no evidence of functional

impairment in any organ, the No Observed

Adverse Effect Level (NOAEL) for

chronic toxicity in dogs was considered to

be 1 mg/kg/day.

,

,'Reference/

" MRID#

Diclobenil -

Potential

Tumorigenic

effects in

Prolonged

Dietary

Administration

to Hamsters

(1992)

Study #

PDR/511

MRID #s

42221201.

42563601

Dichlobenil - 52

Week Oral

(Capsule)

Toxicity Study

in the Beagle

Dog (1995)

Study #

56352/41/95

MRID#

43969701
s

rStudy Type/

Guideline

Reproductive

Toxicitv

Rat

Reproduction

Study

Guideline Study

#83-4

Teratology

Rabbit

Teratology

Study

Guideline Study

#83-3

Rat Teratology

Study

Non-guideline

study

Doses

Tested

0,60,

350

and

2,000

ppm

0,15,

45 and

135

mg/kg/

day

0,20,

60 and

180

mg/kg/

day

Some of the

EDSP Assay End

Points checked

Evaluation:

Body weight gain,

mating

performance,

pregnancy rates,

fertility or

fecundity of

adults, duration of

gestation or

survival to

weaning of

offspring

Organ weight:

uterus, ovaries.

liver etc

Evaluation:

uterus, ovaries.

pregnancy status,

corpora lutea,

position of

implantations,

fetal data etc.

Organ weight:

uterus, ovaries.

placenta and fetal

weights etc

Evaluation:

uterus, ovaries.

pregnancy status,

corpora lutea,

position of

implantations,

fertility indices,

fetal data etc

-

Results/Comments' -t

*

Dichlobenil was fed to two generations of

male and female Sprague Dawley rats at

dietary concentrations of 60, 350 and

2.000 ppm. Body weight gain was

impaired in P and Fl males and females

given 2,000 ppm and in Fl males given

350 ppm. Mean pup weights were

reduced at dosage levels of 350 and 2,000

ppm. No effects were seen on

reproductive parameters. The NOEL for

systemic and developmental toxicity in

rats was 60 ppm (3 mg/kg/day). The

NOEL for reproductive toxicity was

greater than 2,000 ppm ( 1 00 mg/kg/day).

Dichlobenil was administered by oral

gavage to pregnant New Zealand White

rabbits at dosage levels of 1 5, 45 and 1 35

mg/kg/day. Maternal toxicity, as

evidenced by reductions in food intake and

body weight gain from day 7 to 13 of

gestation, was seen at 135 mg/kg/day.

Litters of three high doses showed reduced

fetal weight and an increased incidence of

developmental malformations which were

attributed to severe maternal toxicity. The

NOEL for maternal and developmental

toxicity in rabbits was 45 mg/kg/day.

Dichlobenil technical was administered to

pregnant rats at dose levels of 0, 20, 60

and 1 80 mg/kg/day. Maternal toxicity, as

evidenced by reductions in food intake and

body weight gain, was seen at 60 and 1 80

mg/kg/day. No effects were seen on pup

development. The NOEL for maternal

toxicity in rats was 20 mg/kg/day and the

NOEL for developmental toxicity was

greater than 1 80 mg/kg/day.

;

 . Reference/ ,

MRID# ,'

Dichlobenil: 2-

Generation Oral

(dietary

administration)

Reproductive

Study in the Rat

(1989).

Lab Project ID:

5798-65/18

MRID #s

4 1257303 and

42239101

Dichlobenil:

Oral (Gavage)

Teratology Study

in the Rabbit

(Experiment 11)

(1989)

Lab Project ID:

5626-65/17B

and 5942-65/1 9

MRID #s

41257301 and

41257302

Oral

Embryotoxicity/

Teratogenicity

Study with

Dichlobenil in

Rats (1984)

Project # B83-

1045

MRID#

00147437
Study Type/.;

Guideline

Subchronic

Toxicitv

90-day feeding

study

Guideline Study

(not available)

13 -Week Dietary

Toxicity Study in

Hamster

Guideline Study

#82-1

Doses

Tested

0, 100,

1000,

or

3000

ppm

(0,5,

50,

150

mg/kg/

day).

0,5,

60,

300,

1500,

and

5000

mg/kg/

day

SAITI k?UlIIVP \J frMf fli IJJVp *

EDSP Assay End

Points checked

Organ weight:

testis, uterus,

ovaries, liver etc

Histopathology:

uterus, ovaries.

testis, adrenals,

urinary bladder.

thyroid etc.

Organ weights:

prostate, seminal

vesicles, testis,

uterus, ovaries,

liver, kidney etc.

Histopathology:

testis,

epididymides,

prostate, seminal

vesicles, urinary

bladder, uterus.

ovaries, vagina.

adrenal, pituitary,

thyroid with

parathyroid

Results/Comments

Rats ( 1 2/sex/dose) were given

dichlobenil in the diet for 13 weeks at

doses of 0, 100, 1000, or 3000 ppm (0, 5,

50, 1 50 mg/kg/day). An additional group

of 6 male rats was maintained on a

10.000 ppm diet. Compound-related

effects included increased absolute and

relative liver and kidney weights at 1000

ppm and higher. There was also hepatic

degeneration without significant necrosis

at 3000 ppm and higher, and mortality (5

out of 6) and hepatic necrosis at 1 0,000

ppm. The NOEL was 5 mg/kg/day (100

ppm). The LOEL was set at 50

mg/kg/day (1000 ppm) based on

increased absolute and relative liver and

kidney weights.

In a 90-day oral toxicity study in

hamsters, increased liver weight,

enlarged liver (with rough surface), and

swollen hepatocytes were observed in

females. In addition, decreased weight

of the prostate and mineralization of the

prostate were reported in males. Tubular

degeneration in the testis and decreased

numbers of spermatocytes in the

epididymis was seen at the higher dose

level. Uterus and spleen weights were

reduced at higher dose level. However,

histppathology 'examination., showed , no

abnormalities.

>

.Reference/ •

MRID#

Ninety day

Feeding Studies

of Casoron in

Rats. 1965.

MRID#

00107106

A 13-Week

Toxicity Study

with Dichlobenil

in Male and

Female Hamster

followed by a

4-week

Recovery Period

(1987).

Lab Project ID:

DT 87/02

MRID#

40600701

\
Study Type/

Guideline

13-Week Dietary

Toxicity Study in

Mice

Guideline Study

#82-1

90-day toxicity

study in dogs

Guideline Study

- not specified

Doses

Tested

0,25,

125,

625. or

3125

ppm(

0,4,

19,95,

or 473

mg/kg/

day)

0,50,

150,

and

450

ppm

Some of the "'

EDSP Assay End

Points checked

Organ weights:

prostate, seminal

vesicles, testis,

uterus, ovaries,

liver, kidney etc.

Histopathology:

testis,

epididymides,

prostate, seminal

vesicles, urinary

bladder, uterus,

ovaries, vagina,

adrenal, pituitary,

thyroid with

parathyroid

Organ weights:

thyroid, pituitary,

adrenal, testis

liver, kidney etc.

Histopathology:

thymus, adrenal,

testis,

epididymides,

uterus, ovaries and

other

/ i

Results/Comments

In a 13-week oral toxicity test, mice were

given dichlobenil in the diet at

concentrations of 0. 25, 125,

625, or 3125 ppm (0, 4, 19, 95, or 473

mg/kg/day). Adverse effects in the liver

(specific effects were not reported) were

observed in female mice at the 95

mg/kg/day level. The absolute and

relative testis weights were increased at

the higher dose levels. However,

histopathoibgical .examination did .not

showtahy abnormalities.

Four groups of 2 male and 2 female (3

and 1 for the 450 mg/kg diet group) pure

bred beagle dogs were fed on a basal diet

supplemented with dichlobenil at levels

of 0, 50, 150, or 450 mg/kg diet for a

period of 90 days. Macroscopic and

microscopic examination of organs and

tissues did not reveal any abnormality

that might be ascribed to the ingestion of

dichlobenil. The no-toxic effect level was

found to be 50 ppm. corresponding with

1 .25 mg/kg body weight/day

Reference/

MRID#

A 13-Week

Dietary Toxicity

Study with

Dichlobenil in

Male and Female

Mice (1987).

Lab Project ID:

DT 87/01

No MRID #

Short-term (90-

day) toxicity

study with

Dichlobenil

(HI 33) in beagle

dogs (1967).

Rapport Nr. R

2362

No MRID #

Study details related to EDSP endpoints

Subchronic Toxicity

In the subchronic toxicity study in the hamsters (MRID # 40600701) there were indications of

reversible morphological and functional effects on the liver. Following the withdrawal of

treatment it was evident that the liver had recovered normal function and morphology; the

prostate showed a dose-related weight reduction. Uterus and spleen weights, absolute and

relative, were reduced at the 4.648 mg/kg diet level of the females; however, histopathology

examination did not show any abnormality.

The macroscopic and microscopic findings are summarized in the tables below.
Thirteen-week dietary exposure of hamsters to dichlobenil

Macroscopic observations

.

Numbers examined

Organ

Ovary

Peyers patch

Seminal

vesicle

Testes

Thymus

Urinary

bladder

Uterus

Observations

Cyst

Enlarged

Haemorrhagic area slight

Small

Haemorrhagic area slight

Small

Clear area

Filled with -fluid

Filled with fluid

Thin

Uterus horn one larger

than other

Dose rate (mg/kg diet., actual)

Sex i

H.

f

0 41 | '209 1,289 4 .,648

After treatment period (13 weeks)

20 •

20

10

10

10

10

10

10

.9

10

0 4,648

After 4-week

recovery period

10 -

10

10

10

f

r

M

M

M

M

F

F

2

0

0

0

0

0

0

1

1

0

0

2

1

0

0

0

0

0

0

0

0

1

1

2

0

0

0

0

0

1

1

0

0

1

1

0

0

0

0

1

2

0

1

2

1

1

1

I

1

3*

0

0

0

0

I

1 0

* Incidences yielding statistical significance f P<fi. 10) in a two-sided lest against trend with dose level

Thirteen-week dietary exposure of hamsters to dichlobenil

Microscopic observations

Dose rate (mg/kg diet,-actual)

***

Organ

Ovary

Pituitary

Prostate

Testis

Thyroid

Vagina

Observation

No abnormalities

Bursa cyst

No abnormalities

Pars distalis cyst

No abnormalities

Mineralization

- marginal

- slight

- moderate

Prostatitis

- marginal

- slight

- moderate

No abnormalities

Tubules degenerated

- marginal

- slight

- moderate

- marked

No abnormalities

Cyst a few

No abnormalities

Epithelium cornified

Sex

M

F

After treatment period (13 weeks)"

0

20

20

41

10

10

209

10

. 10

1,289

10

IB

4,648

9

10

After recovery

period

(4 weeks)j ' ;

0

ie

10

4,648 -

;. :i0; V,

'•:ie '•''•'. •'•'•

F

F

M

M

M

F

19

1

17

1

16

0

0

1

0

2

2

18

0

1

0

1

18

1

10

9

9

0

0

1

0

0

1

6

0

1

2

0

0

2

5

1

3

0

1

2

0

10

0

9

0

5

0

2

1

0

1

1

2

**

2

0

4

1

8

0

4

5
Tubular degeneration in the testis and decreased numbers of spermatocytes in the epididymis

was seen in the 4,648 mg/kg diet group. Gall-bladder calculi occurred in both sexes at the highest

diet level, this effect remained after the recovery period. No histopathological abnormalities were

seen in uterus and spleen in the female group at the 4,648 mg/kg diet level.

Conclusion: In the subchronic studies in hamsters, rats, mice increased absolute and relative

organ weights were seen at higher dose levels, however, histopathology examination in many of

the organs showed no abnormalities. The results did not indicate any effects pertaining to

endocrine system other than organ weight increase only at higher dose levels.

Chronic Toxicity

In the chronic feeding study in rats (MRID # 00147438) results at week 110 for the 3,200 ppm

dose group are reported for females only, as all males died before terminal sacrifice. No effects

were seen at 50 ppm, whereas at 400 ppm following effects were noted; absolute and relative

liver weight increase for both sexes, absolute and relative kidney weight increase for males,

decrease of absolute thymus weight and increase of the relative brain weight for males. The

females at 3,200 ppm showed following effects; absolute and relative liver and kidney weight

increase, absolute decrease of adrenal weight and thymus. The other effects were considered to

result from the suppression of the body weight gain. Histopathological data of organs pertaining

to endocrine modulation are summarized in the table below. There are no major concerns with

regard to endocrine system other than body/organ weight changes.

Table: Histophatological findings at week 110 in Chronic feeding study in Rats

Dose level

Sex i

Organ Finding

Number of animals examined

Adrenal Pigmentation

Vacuolic change

Telangieclasis

Hemorrhage

+ Pheochromocytoma

Autolysis

Hyperplasia

Metastasis

Cyst

Chronic inflammation

Acute inflammation

Dysplasia

Hyperplasia

Hemorrhage

Atrophy

Metastasis

0

M / F ,

47/47

1 T / 46'

IV/39 '

10V39'

0 / 0

6

r

/ r

0/4 '

2'.' 1"

o/ r

o/ r

r / o

o / r

0/2 '

0 / 0

0 / 0

T i r

0 / 0

50

•M/ F

47/46

2'/45'

I8V39'

I4'/2I '

r / o

6'/ T

r/3 '

0/0

r /o

0 / 0

r / o

0/0

0 / 0

0 / 0

r / o

0/0

0 / 0

400

M / F

47/47

3'/45'

I2'/3S '

I7' / \T

0 / 0

6VO

r/3 '

r/2'

i • / r

0 / 0

r / o

0 / 0

o / r

0 / 0

0 / 0

r / o

0 / 1 '

3,200

"M/ F

50/47

3'/46'

T 1 W

9V 5'

20' /O

0/0

3V 3'

2

r

/ 0

T i r

0 / 0

0 / 0

0/0

o/ r

r / o

o.-o

0 / 0

0 / 0
Dos

e level

Sex

Organ Findin

g

Vacuolic change

Number of animals examined

Thryoid

C-cell hyperplasia

Hyperplasia

Parathyroid hyperplasia

Aulolysis

+ C-cell adenoma

•+ Adenoma

Pigmentalion

Squainous metaplasia

Cyst

* Adenocarcinoma

Number of animals examined

Teslis

Hypospennia

+ Interstitial cell tumor

Hyperplasia interstitial cells

Atrophy

Aulolysis

Calcification

Pigmentation

Number of animals examined

Epididymis

* Mesothelioma

Pigmentation

Number of animals examined

Sem. V.

Atrophy

Hyperplasia

Number of animals examined

Mammary

Hyperplasia

Atrophy

+ Fibroadenoma

* Adenocarcinoma

Fibrocystic disease

Aulolysis

Calcification

* Adenoacamhoma

Fibrosis

Pigmentation

Other

Acute inflammation

Chronic inflammation

Granulomatous inflammation

Hyperplastic nodule

+ Fibroma

* Carcinosarcoma

0

M /F

0 /0

44/47

12' / 16' 2V IT

3'/0

IV 5'

IV5 ' 4V 0

0/3'

0 /0

r /o

0 /0

47/0

44' /Q

38VO

6 VO

2 VO

0 /0

2'/0

r /o

2/0

r /o

0 /0

37/0

34" /O

0/0

24/44

6V 4'

0 /0

0/3'

0/2 ' vi v

0/0

0 /0

0 /0

0 /0

r /o

r /o

o/ r

r /o

0 /0

o /r

r /o

o/ r

50

M /F

0/0

45/47

8V22'.5"

18',l"/3' 9V 4'

0/4 ' 5V 2'

r /o

2'/0

r /o

0/0

0 /0

47/0

40' /O

33' /O

8'/0

3'/0

0 /0

0 /0

0 /0

I /O

r /o

0 /0

40/0

40' /O

r /o

23/44

3'/ 10'

0 /0

0/5 ' o / r

0 /0

o /r

0 /0

r /o

0 /0

0 /0

0 /0

0 /0

0 /0

0 /0

0 /0

0 /0

0 /0

400

M /F

0 1

46/47

12'/26'.4"

34V7'

16'/T

I'/ 3"

3v r

o /r

o/ r

o /r

0 /0

0 /0

47/0

44' /Q

43VO

3'/0

3'/0

r /o

0/0

0/0

2/0

r /o

0 /0

41/0

40' /O

r /o

30/4/5

2V 10'

r /o

0/7 '

r /o

o /r

o /r

0 /0

o /r

0 /0

0/0

0 /0

0 /0

0 /0

0 /0

0 /0

0 /0

0 /0

3,200

M /F

0/0

48/46

O/ 11 '.I"

4'.l"/2 '

37-/17 '

0/5 '

0/2 ' 2V 1'

0 /0

0/2 '

r /o

o /r

50/0

47' /O

35' /O

I7VO

2'/0

r /o

0 /0

0 /0

I /O

r /o

r /o

3V /«

39' /O

0 /0

33/47

0/5'

26' /O

0/3' 0 / 0

0 /0

0 /0

iv r

0 /0

r /o

0 /0

0 /0

0 /0

0 /0

r /o

0 /0

0 /0

0 /0
Dose level

• :

 ;; •• " Sex

Organ Finding

Number of animals examined

Pituitary

Telangicciasis

Pigmentation

Hypcrplasia

-

1

- Adenoma

Cyst

Autolysis

* Adenocarcinoma

Atrophy

Necrosis

Metastasis

Crystals

Number of animals examined

Prostate

Atrophy

Chronic inflammation

Hypcrplasia

Autolysis

* Squamous cell carcinoma

Number of animals examined

Ovary

Pigmentation

Atrophy

Autolysis

Metastasis

Cyst

Hemorrhage

+ Luleoma

Number of animals examined

Uterus

Pigmentation

Cystic cndometrial

hyperplasia

Aulolysis

+ Polyp

Hydrometra

Metastasis

* Fihrosarcoma

Calcification

Necrosis

* Fibromyxoma

Atrophy

+ Leiomyoma

* Adenocarcinoma

Peritonitis

Hemorrhage

Number of animals examined

Vagina * UndifTerenliated sarcoma

0

M / F

47/47

I4';23 "

ir/34 '

8'/2 '

11' ,' 14'

0.' 10'

0/3'

0/5 '

r / o

0 / 0

0 / 0

0/0

47/1)

22' /O

3'/ 0

2'/ 0

0 / 0

1 ' / 0

0/47

0/43'

0 / 1 T

0/2 '

0 / 1 '

0/3 '

0 / 0

0 / 1 '

0/47

0/39'

0/7 '

0/3 '

0/2 '

0/4 '

0 / 0

O / r

0 / 0

0 / 0

o /r

O / r

0 / 0

0 / 0

o / r

0 / 0

0/0

0 / 0

'50

M /F ^

.

46 /4ft

I8'/20'

9'/2l '

20V 9'

4'/ IT

r/4 '

0/3 '

O / r

0 / 0

1 • / 0

0 / 0

0 / 0

47/0

24' /O

0 / 0

0 / 0

0 / 0

0 / 0

0/47

0/42'

0/6'

0/3'

0/3'

0 / 0

0 / 0

0 / 0

0/47

0 / 40'

O/ 12'

0/4 '

0/3'

0/ 0

0/2 '

0 / 0

0/2 '

0/2 '

o /r

0 / 0

o /r

0/ 0

0 / 0

0 / 0

0/0

0 / 0

400

M / F

47/46

I2V21 '

3'/21 '

10V9'

T ! 10'

0/2 '

V IT

o/ r

o / r

0 / 0

0 / 0

o/r

47/0

33'/0

0 / 0

0 / 0

r / o

0 / 0

0/47

0/42'

0/3'

0/3'

0/4 '

0/2 '

o /r

0 / 0

0/46

0/40'

0 /T

o/r

0 / 0

o /r

0/2'

o /r

0/ 0

0 / 0

o/ r

0 / 0

0 / 0

o /r

0 / 0

o /r

0/0

0 / 0

3,200 -

M / F

-/y/46

5'/ 12'

0 / 1 1 '

. S'/T

0 /T

o/ r

o/ r

0 / 0

0 / 0

0 / 0

r/o

0/0

50/0

40' /O

0 / 0

0 / 0

0 / 0

0 / 0

0/47

0/40'

0/5 '

0/4'

0/2'

0 / 0

0 / 0

0 / 0

0/47

0/40'

0/7'

0/5 '

0 / 0

0 / 0

0 / 0

0/2 '

o/ r

o /r

0 / 0

0 / 0

0 / 0

0 / 0

0 / 0

0 / 0

0/1

o /r

Grade of findings:

-normal, '=slighl. ' '^moderate.'' '^marked

* = neoplaslic lumor

+ = non-neoplasiic lumor
In both chronic dog toxicity studies, as well as in the combined chronic toxicity/carcinogenicity

study (MRID # 00147438) in the rat increased liver weights and hepatic enzymes, as well as

liver histopathology, were observed. In addition to the liver, the nose is considered a target

organ for dichlobenil. Delayed maturity of the uterus was observed in all high-dose females

tested in the chronic oral (capsule) toxicity study in the dog (MRID # 43969701). A marked

decrease in mean uterine weight at the high dose confirmed this finding. Ovarian weights were

also decreased in high-dose females, but ho Alterations ^Iwj

Conclusion: In the chronic toxicity studies treatment related changes were primarily confined to

the high dosage level. Although there were no pathological findings of clear toxicological

importance, the changes in the liver and kidney are noted in many of the studies. The

ovarian/uterine weights were also decreased in high dose females, but no changes were observed

in microscopic and macroscopic findings. Chemtura is well aware of the changes attributed to

various organs interested in the endocrine evaluation but would like to emphasize that the

microscopic findings did not show any concern. We would request EPA to consider the chronic

toxicity studies in their evaluation.

Reproductive/Teratology Studies

In the reproductive toxicity study (MRID #s 41257303 and 42239101) no treatment-related

effects were observed on fertility index, fecundity index, gestation index, or mean gestation

length in either P or FI females. Mean pup weights at 2000 ppm and 350 ppm were lower in the

litters for both generations. No treatment-related effects were observed on live birth index,

viability index, lactation index, or sex ratio in either FI or p2 offspring. In addition, the mean

number of pups bom live/litter was unaffected in FI offspring but decreased (P<0.001) at 2000

ppm in F? offspring (1 1 .0 vs. 1 3.7 in controls). This was likely due to the decreased number of

implantations/F| dam at 2000 ppm. At > 350 ppm, the mean pup body weight of F] offspring

was decreased by 16-23% (P<0.05) from postnatal day (PND) 4 (precull)-21. The effect was

dose-dependent. In ¥2 offspring, mean pup body weight was also dose-dependently decreased by

19-22% (P<0.05) from PND 14-21. There are no major organ weight changes of concern at

lower dose levels indicating an alteration in the sexual hormonal level.

In rabbit teratology study (MRID #s 41257301 and 41257302) the number of corpora lutea and

implantations were comparable in all groups. There is no increase in the number of

preimplantation losses. This indicates that the damage to the fertility of these animals is not seen

as there is no variation in the morphology and/or motility of these organs.

Fetal weight was lower than controls in the high dose group. There was no adverse effect on fetal

weight in the low and intermediate dose groups. The incidence of litters containing fetuses

showing major defects was significantly higher than controls in the high dose group. The

increase was mainly attributed to litters 66, 71, and 72 suggesting that these were mediated by

maternal toxicity.
t

In the rat teratology study (MR1D # 00147437) the fertility indices ranged from 84.0 to 92.0 and

are within the range calculated from the historical control groups. The number of corpora lutea

and implantation sites was comparable in all groups. Empty uterus weight was significantly

lower in the mid-dose group only. Ovary weight, gravid uterus weight, placenta and fetus

weights as well as fetus lengths were similar in all groups. Although the total incidence of minor

visceral anomalies and visceral variants was somewhat higher in the treated groups than the

controls, there was never a dose-response relationship.

Conclusion: Overall there was no evidence of increased susceptibility to offspring following prenatal exposure to rats or rabbits in developmental/teratology toxicity studies. Evidence of

increased pre-/post-natal susceptibility was observed in the two-generation reproduction study in

rats and body weight changes are noted in all studies. However, the degree of concern for the

endocrine effects is considerably low. These studies did not indicate any potential to interact

with the estrogen, androgen, or thyroid hormone systems. We request EPA to consider our

argument along with the available higher tier studies in lieu of conducting the EDSP tier 1

testing.

Toxicity Assessment of the Metabolite-BAM: Toxicity studies for the dichlobenil metabolite,

BAM are evaluated in detail. Based on the results from these studies, the toxicity of BAM is

considered not greater than that of its parent compound, dichlobenil. These results indicate no

concern to the mechanism of endocrine system with respect to the metabolite and the parent

dichlobenil.

Overall Conclusion: Though there are body weight changes in all the litters examined at higher

dose groups, the macroscopic and microscopic concerns pertaining to estrogenicity,

androgenicity, thyroidal effects related to endocrine mechanism are of no concern in these

studies. Chemtura would request EPA to consider these arguments put forth from the above

chronic, reproductive, teratology and subchronic toxicity studies in lieu of the testing requested

for EDSP assays.

Ecotoxicological Evaluation

Dichlobenil has many acute toxicity studies in Rainbow trout, Fathead Minnow, Bluegill

Sunfish, Sheepshead minnow, Eastern oyster, mysid shrimp and daphnia. The acute toxicity test

results indicate that dichlobenil is low to moderately toxic. The metabolite, BAM of dichlobenil

is practically non-toxic to aquatic organisms. EPA in its review concluded that dichlobenil has

adequate data to assess the acute and chronic hazards of dichlobenil to non target aquatic

animals. The early life stage toxicity study in Rainbow trout is discussed in detail below.

The Early Life Stage Toxicity of Dichlobenil to Rainbow Trout (Salmo Giardneri) in a FlowThrough System was conducted according to the guideline # 72-4. This study has been reviewed

by EPA and assigned an MR1D # 40825101. This study was conducted to estimate the Maximum

Acceptable Toxicant Concentration (MATC) limits. The mean measured concentrations of

dichlobenil were 0.33, 0.66, 1.20, 2.40 and 5.1 mg/L. These values ranged from 96 to 110 % of

the nominal test concentrations. Viability of the newly fertilized eggs (day 11) used averaged

96% for the controls. Hatchability of the rainbow trout eggs after 41 days, survival at day 34 and
day 60 post-hatch, and rainbow trout growth were significantly reduced at higher test

concentration when compared to control data. However, the growth effects were transient at

lower concentrations as the reduction in the length does not appear in the two lowest

concentrations. Based on this data the MATC was considered to be 0.79 mg/L.

Conclusion: In the rainbow trout toxicity study there are indications of toxicity at higher test

concentrations. In their assessment EPA mentioned that there are no concerns for aquatic

toxicity. We would request EPA to consider the rainbow trout study and the low toxicity values

at various other dose levels along with the EPA"s assessment that there is adequate data available

for risk assessment (from EPA RED) in lieu of conducting the fish short term reproductive

assay. Major route of dissipation for dichlobenil is volatilization. There is low potential for

bioaccumulation in fish.

Chemtura has not conducted any amphibian studies but there are literature articles available.

These studies examined the effects of herbicides in aquatic system. There is one study which

evaluated the effects of the herbicides on amphibians and included dichlobenil as one of the

herbicides. This study is discussed in detail below.

In the study "Effects of Field Applications of the Herbicides Diquat and Dichlobenil on

Amphibians"1 the effects on the caged frog Rana temporaria and toad Bufo bufo tadpoles and on

free-living populations of smooth newts Triturus vulgaris have been studies. There were no

significant differences between treatment groups and control groups in the activity level.

Herbicide treatment had no effect on development rate. In the ponds treated with dichlobenil,

weights were greater than those of the control tadpoles of both species on days 18 and 32. There

were no marked differences in development rates between treatments. Intestines of tadpoles from

dichlobenil treated ponds usually contained similar numbers of unicellular algae, filamentous

algae fragments and diatoms as those of control tadpoles. Data on intestinal contents are

summarized in table below.

Table: Intestinal Contents of Tadpoles

Frog - Rana

remporai'ia

Dav 4

Dav 18

Dav32

Toad - Bufo

bufo

Dav 4

Dav 18

Dav 32

Control

Dichlobenil

Control

Dichlobenil

Control

Dichlobenil

Control

Dichlobenil

Control

Dichlobenil

Control

Dichlobenil

Number of

tadpoles

examined

4

4

2

2

2

2

4

4

2

2

2

2

Mean gut contents (thousands)

Filamentous

algae

0.34

1.2

2.5

6.2

0.59

1.3

0.37

0.57

I .I

0.84

0.91

0.83

Unicellular

algae

0.25

0.26

1.9

0.74

1.6

1.2

0.10

0.07

1.5

0.13

0.63

0.42

Diatoms

0.83

2.1

3.3

13

3.3

3.1

0.39

0.37

1.4

2.7

3.0

2.5

1

 Cooke.A.S. "Effects of Field Applications of the Herbicides Diquat and Dibhlobenil on Amphibians"

Environ.Pollut. (12)(1977)pp43-50
Despite having similar quantities of algae and diatoms in their intestines to control tadpoles, the

dichlobenil treated tadpoles showed increased growth rates on day 18 and 32. There are studies

which show a relationship between growth of algae and growth of tadpoles in the field, and it

seems reasonable to suggest that the overall increase in growth rate was due to the dichlobenil

treatment causing the proliferation of certain highly-acceptable algae. In conclusion, herbicide

treatment produced no marked detrimental changes. On the contrary, by indirectly stimulating

tadpole growth, the herbicide had a beneficial effect, tadpoles more rapidly attaining a size at

which they would have been relatively safe from predators.

Conclusion: In this amphibian study dichlobenil neither caused any mortality among the tadpoles

nor changed development rate or level of activity. We request EPA to consider the argument and

the literature study in lieu of conducting the amphibian toxicity testing.

Data Summary and Recommendation

There is evidence that dichlobenil exhibits some concerns of ED activity; the strongest evidence

was reported in most of the studies with body/organ weight changes. There are some endocrine

related concerns with respect to specific organs/organ weight changes in the mechanism

reproductive and tumorogenic studies. There was no evidence of estrogen receptor (ER) binding

and that dichlobenil may interfere with thyroid hormone homeostasis also was not of a concern.

Studies conducted with male and female rats demonstrated that oral administration of dichlobenil

induced significant irregularities in reproductive tissues but there were no concerns with regard

to estrogen/androgen and thyroid hormone systems.

Chemtura would request EPA to consider our argument along with the available robust

lexicological studies in lieu of conducting EDSP tier 1 assays.
Bibliography of Cited Dichlobenil Studies

Order/DCI# EDSP-027401-120

00107106 Hodge, H.; Maynard, E.: Downs, W.: et al. (1961) Ninety Day Feeding

Studies of Casoron in Rats. (Unpublished study received Apr 26, 1965 under

unknown admin. No.; prepared by Univ. of Rochester School of Medicine and

Dentistry, Dept. of Pharmacology, submitted by Thompson-Hayward Chemical

Co., Kansas City, KS; CDL:108430-A)

00147437 Koeter, H. (1984) Oral Embryotoxicity/Teratogenicity Study with Dichlobenil

in Rats: Final Report: Report No. V84.026/231045. Unpublished study prepared

by Netherlands Organization for Applied Scientific Research. 109 p.

00147438 Inoue, H. (1983) Chronic Feeding Study on Casoron in the Rat: Report

No.314; Duphar Report No. 56645/41/84. Unpublished study prepared by

Biosafety Research Center, Foods, Drugs and Pesticides. 2728 p.

40600701 Kemp, A.; de Haan, M. ; Jager, F. (1987) A 13-week Toxicity Study with

Dichlobenil in Male and Female Hamster Followed by a 4-week Recovery

Period : Laboratory Project ID DT 87/02 : Doc. No. 56645/04/87. Unpublished

study prepared by Duphar B.V. 202 p.

40825101 McAllister, W. (1988) Early Life Stage Toxicity of Dichlobenil to

Rainbow Trout (Salmo gairdneri) in a Flow-through System: Final

Report #36182. Unpublished study prepared by Analytical Bio-Chemistry

Laboratories, Inc. 37 p.

41257301 Barker, L. (1989) Dichlobenil: Oral (Gavage) Teratology Study in the Rabbits

(Experiment II): Duphar Report No. 56645/85/87: Laboratory Project ID 5626-

65/775. Unpublished study prepared by Hazleton UK. 139 p.

41257302 Barker, L. (1989) Dichlobenil: Oral (Gavage) Teratology Study in the Rabbit

(Experiment II): Repeat Study: Laboratory Project ID 5942-65/19: Duphar Report

No. 56645/21/89. Unpublished study prepared by Hazleton UK. 143 p.

41257303 Leeming, N. (1989) Dichlobenil: 2 Generation Oral (Dietary Aministration)

Reproduction Study in the Rat: Laboratory Project ID 5798-65/18. Unpublished

study prepared by Hazelton UK. 337 p.

41988301 Hooks, W.; Gary, R.; Colman, K.; et al. (1991) Dichlobenil: Potential

Tumorigenic Effects in prolonged Dietary Administration to Hamsters: Lab

Project Number: PDR/478: 56645/85/90. Unpublished study prepared by

Huntington Research Centre Ltd. 1610 p.
42015101 Hooks, W.; Gary, R.; Colman, K.; et al. (1991) Dichlobenil: Potential

Tumorigenic Effects in Prolonged Dietary Administration to Hamsters: Lab

Project Number: PDR/478. Unpublished study prepared by Huntingdon

Research Centre, Ltd. 285 p.

42221201 Chambers, P.; Hornby, B.: Gibson, W.: et al. (1992) DichJobenil: Potential

Tumorigenic Effects in Prolonged Dietary Administration to Hamsters: Lab

Project Number: PDR/511. Unpublished study prepared by Huntingdon Research

Centre Ltd. 419 p.

42239101 Barker, L. (1992) Dichlobenil: 2 Generation Oral (Dietary Administration)

Reproduction Study in the Rat: Addendum 1 - Pathology Report: Lab Project

Number: 5798-65/18,A-1. Unpublished study prepared by Hazelton, Harrogate

(UK). 18 p.

42563601 Chambers, P.; Brown, R.; Gibson, W.; et al. (1992). Background Tumour

Incidence in Hamsters: Lab Project Number: PDR/540. Unpublished study

prepared by Huntingdon Research Centre Ltd. 419 p.

43969701 Pickersgill, N. (1995) Dichlobenil - 52 Week Oral (Capsule) Toxicity Study

in the beagle Dog: Lab Project Number: 65/510:43593D. Unpublished study

prepared by Pharmakon Europe. 464p.

Studies Submitted with the Dichlobenil Endocrine Disrupter Response

Til, H.P., VJ. Feron and A.P. de Groot (March 1968). Short-term (90-day) Toxicity

Study with Dichlobenil (HI33) in Beagle Dogs. Study conducted by Centraal

Instituut Voor Voedingsonderzoek for Philips-Duphar N.V. Weesp, The

Netherlands, Report No. R2362. 35 p.

Kemp, A., M. De Haan, R..L.F. Dawes (April 1987). A 13-Week (Dietary) Toxicity

Study with Dichlobenil in Male and Female Mice. Study conducted by Duphar

B.V., Weesp, The Netherlands, Project ID DT 87/01, 168 p.

Cooke, A.S. (1977). Effects of Field Applications of the Herbicides Diquat and

Dichlobenil on Amphibians. Published in Environ. Pollut. (12) 1977, p.43- 50.
M . oo \ o7lOk

DAY FEEDING STUDIES OF

CASORQH IK RATS

Report by:

Toxicology:

Urine Analysesi

Hematology:

Methemoglobin Determinations:

Pathology:

Animal Care:

Graphs:

Typing:

Harold C. Hodge, Ph.D.

Harold C. Hodge, Ph.D.

Elliott A. Maynard, Ph.D.

William L, Downsj M.S.

John G. Cope

Stuart Hulnick

LUlian Salemo

Santo Coco '

Douglas W. Smith, M.D.

Raymond Keael

Raymond Rose

Alice Millard

Dorothy Weigel

From the

Department of Pharmacology

Univeraity of Rochester School of Medicine and Dentistry

Rochester, New York

Signed

Date
Uo. 00 1^-7 4-3*7

^^^^

civo Institutes tno

fo-2055

netherfands organization

for applied scientific

research

dMilon tor nutrition and

tno

p.o. box 360

3700 AJ zeist

netheriands

Report No. V 84.026/231045

Internal Document Ho. 56645/26/84

ORAL EMBRYOTOXICITY/TERATOCESICITY

STUDY WITH DICHLQBEHIL IN HATS

(Final report)

Author

At the request of

Project number

: Ota H.B.H.M. Koe'ter

: Duphar B.V.

Weesp, Retherlands

: B83-1045

Start of the study : September 19, 1983

Termination of the study : October 25. 1983

Approved by

Date

: Dr V.J. Feron

: January> 1984

Total or partial publication of this report without written asaant is not allowed. 23a-10.000-0161
fOo . oo

R B.V.

Cccip Prof: set ipft Division

Dept. Sog. Oocv ?< ?ro>. Man,

'S'"GtaV83.aad, Holland

int. 0pc, so.:

issued

Pa fc a requj r:eroent i 83-1 and 83-2 40 Ci« § 158,133

li.

os: tJuris 22:. 1982

, Drugs and pesticides

58?-2 arahaiaa, shloshihtieu. !?ukuae-eho

Iwata-gun> Shizuoka Pcet:. 437-

 ;12

f. 2121 3776ft
0ata

Stu

¥ A. 4-;

A, K

H, de Haan

W o .

, the Net

or.-;:. oil' Toxicology

In-t:.::t>oe. Ro. .566*5/04/8?

issued March

Page 1 o£ 20.2

r- B.Vt of Toxicology

{J:,.J,J va«

 :Routen:

laati.

 :'{6

sp, The f^etherlamis

,87/OX
SPONSOR

DUPHAR B.V.

Attn: Ir. R. H. J. Evers

P.O. Box 4

1243 ZG 's-Graveland

Holland

Int. Doc. No.: 56635/23/88

STUDY TITLE

Early Life Stage Toxlcity of Dichlobenil to Rainbow

Trout (Salmo gairdneri) in a Flow-Through System

DATA REQUIREMENT

U.S. EPA-FIFRA, 40 CFR, Section 158.145

Guideline 72-4

AUTHOR

William A. McAllister

Aquatic Biologist III

FINAL REPORT DATE

April 26, 1988

PERFORMING LABORATORY

Analytical Bio-Chemistry Laboratories, Inc.

Aquatic Toxicology Division

7200 East ABC Lane

P. 0. Box 1097

Columbia, Missouri 65205

ABC LABORATORY PROJECT ID

Final Report #36182

Page 1 of 37
Otley Bosd, -Herrogats

;:Norsh Yorkshire HG3 SP

CONFIDENTIAL

ORAL (GAVAGE); TggATOl.O(^_S7lJJ)Y

REPORT; MO... 566457S5/37

Oata recalrement: Sideline 83-^3

Author: L. Barker, 8.Sc.,« :

&.. Hclfvcyre. a.sc,,

Study completeil en;: ;2? April 1987

Performing laboratory: iHaailetor. UK,.

;o.tVay Road*

iii arrogate,

^•OPtK

 :Yor'kshire»

Lab.orat-sry Project IB: iS626-iS57176-

Date: : August 1989

page .1 ..6:f

 :na
I 1

HAZLETON UK

Oiley Road. Harrog^ c

M

OICHIOBENIL: ORAL (GAVAG£) TEfiATOLOGY

STUDY IK THE RABBIT (EXPERIMENT II)

REPEAT STUJY

AHtttDHEHT TO FIKfiL Rt?ORT

Dupnar Report No. 56645/21/8S

Duphar Study No. C.201.40.022

Data recjireoent: EPA Guldeline 83-3

OCCO Guideline

Prepared by: L. Barker. B.Sc.tHons.). C.Blol.. M.I.Btol.

Study Director

StuCy corpleted on: 6 May 1988

Performing Nazleion UK.

Otley Road.

Harrogete.

Worth Yorkshire.

tKGlANO.

1PY.

Laboratory Project 10; S942-6S/19

Date: August 1989

Page 1 of 3
ID Jo . 4- la :T

CONFIDENTIAL

.B'.V. ,:

Tpxicoldgy

£.*^;. Van .Hpii'ten'i.aen 36,

138'i GP

HOLLMQ...

Int. Coc. No.. 30645/^7/

ed AUQiiSt. X9S9,

gH}.QB^iL: 2 ^£N£RAIION ;QRAL

:! AOKINl'^TRATiOM) REF'SQEUCriON. STUiPy

IN. J1£.;RAT

Odta reaulr&mentv -Guideline B3:-4

21 April :1.98»;

OtTey R

Harrogate,

Yorkshi re,.
PDR 478/90177

(Duphar Int. Doc. No. 56645/85/90)

No.

DICHLOBENIL

POTENTIAL TUMORIGENIC EFFECTS

IN PROLONGED DIETARY ADMINISTRATION

TO HAMSTERS

Final report (Weeks 1 to 88)

VOLUME I of IX

Study completed: 3 May 1991

Data requirement: EPA FIFRA Subdivision F

paragraph

Report issued: 3 May 1991

Principal authors:

William N. Hooks.

Richard J. Cary,

Karyn Colman,

William A. Gibson,

Chirukandath Gopinath,

I. Suzanne Dawe.

Performing Laboratory:

Huntingdon Research Centre Ltd.

P.O. Box 2,

Huntingdon,

Cambridgeshire,

PE18 6ES,

ENGLAND.

Laboratory Project

Id. no.: PDR/478

Page 1 of 1610
FDR 478/91486

(Duphar Int. Doc. No. 56645/160/90)

DICHLOBENIL

POTENTIAL TUMORIGENIC EFFECTS

IN PROLONGED DIETARY ADMINISTRATION

TO HAMSTERS

(Supplemental Data)

VOLUME I OF II

Study completed: 27 June 1991.

Data requirement: EPA FIFRA Subdivision F

Paragraph 83-2

Principal authors:

William N. Hooks,

Richard J. Gary,

Karyn Colman,

Chirukandath Gopinath.

Performing Laboratory,

Huntingdon Research Centre Ltd.,

P.O. Box 2,

Huntingdon,

Cambridgeshire,

PE18 6ES,

ENGLAND.

Laboratory Project i.d. no.: PDR/478

Page 1 of 285

€
FDR 511/9176

(Duphar Int. Doc. Ho. 566A5/52/91)

DICHUOBEM1L

PCTDITIAL T3KDRIGENIC EFFECTS

IV PPDLOHCEL D1ETASY ADHZKISTItATIOK

TO HAMSTERS

VDUKE I OF IX

Study coexisted: 10 February 1992

D*t& requireswnt: EPA FIFRA, 5ubdivi»icn F paragraph 83-2

Authors:

Paul S. Chambers.

Mman B. Hornby.

William A. Gibson.

Chirujrandatb Copinath,

Sosan Bar ling.

I. Sozanmi Dave.

s

Ftrforoing laboratcry:

Departsent of Rodent Toxicology,

Huntingdon Kesearch Centre Ltd. ,

Huntingdon,

Casbridfieihire,

'F5IB 6ES.

EKGLAKD.

Report i«»««dt 10 February. 1992 _". \ ' ;)lal»aratery project I.D. no.i PBS/5 11

Page 1" of 1737
^>)HAZLETOr\ UK

Ottey Rota. HanooaiB

Norm tortsnae H63 tPY England

Solvey Duphar B.V..

Toxicology Department.

C.J. Van Ko-Jtcnlaan 36.

1331 cp tfeesp.

Tne Netherlands.

Addendirs to

Int. Doc. No. 55W5/87/88.

Issued August 19B9

DICHLOBEKIl: 2 GtHERAlION ORAL

CDIPftRY ADHINISTRATIDN) RtFRaPUtTIQN STUDY

IN THE RAT

ADDENDUM 1 - PATHOLOGY REPORT

Data reaulreciert: Guioelinc 63-4

Prepared by: L Barker BScCHons) CBIol HlSiol

Study Director

Pathology conpleted: January J992

Perfonning Laboratory: Kuleton UK.

Otley Road.

Harrogate.

North Yorkshire.

ENGLAND.

KG3 1PY.

Laboratory Project ID: 5793-65/18

Page 1 of 18
FDR 540/920472

(Duphtr InL Doc. No. 56645/5^92)

BACKGROUND TUMOUR INCIDENCE

IN HAMSTERS

(BACKGROUND DATA STUDY)

VOLUME I OF ID

Study completed:

Dzla rcquircmecLReport issued: 29 September 1992

29 September 1992

EPA FIFRA. Subdivision F

paragraph 83 - 2

Principal Aobors:

PaulR. Chamber*.

Rjchard Bro«D.

Wmiaa A. Gibson.

Cbimkaodztb Goptnxtb,

Sue Harltn;.

Performing Ubontoryt

Humingdon Research Centre Ltd..

P.O. Box 2,

Humingdon.

Cambridgeshire.

PE18 6ES.

"•''• ENGLAND.

>.- Laboraoo' Project ID No.: PDR/540

... ...

P««e.lof419 -
INT, DOC. N0, : 56352/4i/95.

UNORdYAr; CHEMICAL Go.lKC.

; BENSON ROAD

BURY,-eT 06749

U.S.A

CO-SPONSOR:.

PBl-GOKDON CORP;

1217 Vinath Street

cnX^t) '64loi,.

.u:s.-A,

- 32 week oral (capsule) toxidly stxsdy irvthfe Beagle dog.

;U.S.EPA-FM=

NUMBER ::

DATE: 20 December 1&>S-