Toxicolog y an dRis k

Assessment Chemtur aCorporatio n Chemtur a



# REVIE WO FOTHE RSCIENTIFICALL YRELEVAN TINFORMATIO N

FO RTH EEDS PTIE RISUBSTANC E DICHLOBENI L[CA S NO
. 1194-65-6]



## Prepare db y Shail aRao , Ph D Shar i Long , M S Toxicolog y an dRis k

Assessmen t Chemtur aCorporatio n 19 9 Benso nRoa d Middlebury , C T 0674 9



# FINA LREPOR T

Marc h16,201 0

### DICHLOBENI L |CA S No
. 1194-65-6 )

Introductio n I nrespons e t o th e Environmenta l Protectio n Agency' s (EPA ) issuanc e order s fo r dat afro m testin g require di n Tier

1 o f th e Endocrin e Disruptio n Screenin g Program(EDSP)
. arevie w o f th e othe r Scientificall y Relevan t

Informatio n (OSRI ) usin g toxicologica l dat afro mi n viv o an di n vitr o studie s fo r

Dichlobeni l an dit s effect s o n endocrine activit y (estrogenic
. androgenic , an d thyroid ) ar e presented
. Studie s tha t evaluate deffect s o n reproductio n and/o r feta l developmen t tha t coul drepresen t

change s i n endocrin e functio nals o ar e included
. Extensiv e publi c literatur e dat asearc hfo r th e relevan t

EDS Pstudie s returne danumbe r o f records. Thes e studie s wer e utilize di n ou r assessmen t

fo r Dichlobeni l EDS Preview
. Strategie s initiall y focuse dstrictl y o n Tier 1 an drelate dtests . A n overal l assessment o f th e dat a describe di n thi s report , alon g wit hpropose drecommendation s fo r respondin g t o EP A t o addres s th e nee dfo r

additiona l testin g a s describe di n th e EDS PTie r 1 guidelines , i s give n i n th e nex t section
. Evaluatio n o f

th e Availabl e Toxicologica l Dat a Dichlobeni l ha s a n extensiv e databas e o f al l toxicologica l studies
. Dat afro mth e availabl e toxicologica l studie s considere drelevan t fo r EDS Passessmen t

ar e summarize di n th e Tabl e 1 below
. Som e o f

thes e studie s wer e submitte dearlie r t o EP A an dth e availabl e MRI D number s fo r thes e studie s ar e provide dfo r you r reference
. A lis t

o f th e en dpoint s assesse dfo r th e evaluatio n o f E D activit y i s include di n th e tabl e below
.

### Tabl e 1
. Dat aSummary ' fro mDichlobeni l Studie s considere dfo r Potentia l E D Activit y Stud y Type/ Guidelin e Chroni c Toxicit v Two-Year Ra t Feedin g Study Guidelin e Stud y #83- 1 an d83- 2

Combine d Chronic / Carcinogenicit y Stud y Chroni c Hamste r Feedin g Studie s Guidelin e Stud y #83- 2 "Dose s

Teste d

0 , 50 , 400 o r 3,20 0 pp m

0.5 , 26 , 13 2 an d 67 5 pp m Som e o f

th e 

### EDS PAssay En d Point s checke d Orga n weight : testis , epididymides , uterus , ovaries , liver , kidne y an d othe r Histopathology : uterus , ovaries , testis , epididymides , prostat e an dothe r
Organ weight : testis , epididymides , uterus , ovarie s an d othe r Histopathology : uterus , ovaries , testis , epididymides , prostate an dothe r ~ j

• , Results/Comment s '
Dichlobeni l wa s fe dt o mal e an dfemal e Fische r 34 4 rat s fo r

tw o year s a

t dietary concentration s o f

50 , 40 0 o r

3,20 0 ppm . Reduce dsurviva l wa s see ni n mal e rat s an dreduction s i nbody weigh t gai nan d foo dintak e were see

ni nmal e an dfemal e rat s a t th e hig hdosag e level
. Histopathologica l effect s wer e seen i n kidney s i nhig hdos e male s an dfemale s an di nliver s o f

mi dan dhig hdos e females
. There wa s a n increase dincidenc e i n hepatocellular

tumor s a t

th e hig hdos e grou p i nbot

hth e sexes . Tumor s di dno t appea r t o occu r wit hdecrease dlatency
. Th e NOE Lfo r

chroni c toxicit y i nrat s wa s 5 0 pp m(2. 5 mg/kg/day)
. I nthi s stud y dichlobeni l wa s fe dt o mal e an dfemal e hamster s fo r

8 8 an d8 0 weeks , respectively , at

dietar y concentration s o f

5 , 26 , 13 2 an d67 5 ppm . Hamster s i nth e hig hdos e group exhibite dslightl y reduce d bod y weigh t

gain
. Hig hdos e femal e hamster s ha dan increase dincidenc e o f adrena l cortica l hyperplasi aan d hepatocellula r

enlargement
. There wa s n o increas e i ntumo r

incidenc e a s aresul t

o f dichlobeni l administration
. Th e NOE Lfo r chroni c toxicit y i nhamster s wa s 1 3 2 ppm . Reference/ - MRiD #
Chroni c Feedin g Stud y o n Dichlobeni l i nth e Rat
. (1984)
. Lab Projec t

I D # Exp
. No
. 40(010

- 002)
. MRID # 0014743 8

Dichlobeni l - Potentia l Tumorigeni c Effect s i n Prolonge d Dietar y Administratio n t o Hamster s (1991)
. Laborator y Projec t I d#: PDR/47 8 MR1 D # s 41988301 , 4201510 1Stud y Type / Guidelin e Combine d Chronic / Carcinogenicit y Stud y

Chroni c Hamste r Feedin g Studie s
Guidelin e Stud y #83- 2 On e Year Do g Feedin g Stud y Guidelin e Stud y #83- 1 Dose s

Teste d 0
. 675
. 1,500 an d 3,37 5 pp m

0,1, 6 an d3 6 mg/kg / da y Some o f

th e EDS P Assa y En d Point s checke d Orga nweight : testis
. epididymides
. uterus , ovarie s an d othe r Histopathology : uterus , ovaries , testis
. epididymides , vagina , prostate , an dothe r

Orga nweight : testis
. uterus . ovaries , prostat e , thyinus , thyroid s an dothe r Histopathology : uterus , ovaries
. testis , epididymides
. vagina , prostate , jejunum , mammar y glands , thyroid s an dothe r - Results/Comment s

' I nanothe r

study , dichlobeni l wa s fe dt o mal e an dfemal e hamster s fo r 9 1 an d7 8 weeks , respectively , at dietary concentration s o f

675 , 1,50 0 an d3,37 5 ppm . Reduce dbody weigh t gai nwa s seen i nal l treate dmale s an dhig hdos e femal e hamsters
. Microscopi c evidenc e o f liver toxicit y wa s see

n i nmale s an dfemale s give n1 ,50 0 an d3,37 5 ppm . A nincrease d incidenc e o f

live r adenoma s wa s seeni n hig hdos e mal e hamsters , whic hwa s considere dt o b e th e resul t

o f liver toxicity
. Th e NOE Lfo r

chroni c toxicit y i n hamster s wa s les s tha n67 5 ppm .
Dichlobeni l wa s administere di ncapsule s t o mal e an dfemal e Beagl e dog s fo r on e yea r at dosage s o f

1 , 6 an d3 6 mg/kg/day
. Body weigh t

gai nwa s reduce di nhig h dos e males
. Mi dan dhig hdos e male s ha d lowe r albumin , hemoglobin , packe dre d cel l volum e an dre dbloo dcel l count . Male s an dfemale s i nth e mi dan dhig h dos e group s an dlo w dos e male s ha d elevate dserumcholesterol , triglycerid e an dphospholipi dconcentration s i nblood
. Mi dan dhig hdos e male s an dfemale s an d lo w dos e female s ha dincrease dlive r weights , whil e al l treate dfemale s an dhig h dos e male s ha dincrease dthyroi dweights
. Kidne y weight s were increase di nhigh dos e male s an dhig hdos e female s ha d reduce duteru s an dovary weights
. Hig h dos e male s an dfemale s exhibite dlive r cel l hypertrophy an dadrenal cortica l vacuolation
. A t

ados e leve l o f

1 mg/kg/day , th e onl y effect s see n wer e slightl y highe r

bloo dtriglycerid e concentration s i nmale s an dincrease dlive r an dthyroi dweigh t

i nfemales
. Sinc e ther e were n o histopathologica l lesion s at 1 mg/kg/da y an dn o evidenc e o f functiona l impairmen t

i nan y organ , th e N o Observed Advers e Effec t

Level (NOAEL ) fo r chroni c toxicit

y i n dog s wa s considere dto b e 1 mg/kg/day
. , ,'Reference / " MRID # Diclobeni l - Potentia l Tumorigeni c effect s i n Prolonge d Dietar y Administratio n t o Hamster s (1992 ) Stud y # PDR/51 1 MRI D # s 42221201
. 4256360 1 Dichlobeni l - 5 2 Wee k Oral (Capsule ) Toxicit y Stud y i nth e Beagl e Do g (1995 ) Stud y # 56352/41/9 5 MRID # 4396970 1s

rStud y Type

/ Guidelin e Reproductiv e Toxicit v Ra t Reproductio n Stud y Guidelin e Stud y #83- 4

Teratolog y Rabbi t Teratolog y Stud y Guidelin e Stud y #83- 3

Ra t Teratolog y Stud y Non-guidelin e stud y Dose s

Teste d
0,60 , 35 0 an d 2,00 0 pp m

0,15 , 4 5 an d 13 5 mg/kg / da y

0,20 , 6 0 an d 18 0 mg/kg / da y Som

e o f th e EDS P Assa y En d Point s checke d
Evaluation : Bod y weigh t

gain , matin g performance , pregnanc y rates , fertilit y o r fecundit y o f adults , duratio no f gestatio no r surviva l t o weanin g o f offsprin g
Organ weight : uterus , ovaries
. live r et c Evaluation : uterus , ovaries
. pregnanc y status , corpor alutea , positio n o f implantations , feta l dat aetc . Orga n weight : uterus , ovaries
. placent aan dfeta l weight s et c Evaluation : uterus , ovaries
. pregnanc y status , corpor alutea , positio n o f implantations , fertilit y indices , feta l dat aet c - Results/Comments ' - t *
Dichlobeni l wa s fe dt o tw o generation s o f mal e an dfemal e Spragu e Dawle y rat s a t dietar y concentration s o f

60 , 35 0 an d 2.00 0 ppm . Bod y weigh t

gai n wa s impaire di n Pan dF l male s an dfemale s give n2,00 0 pp man di nF l male s given 35 0 ppm . Mea n pu p weight s wer e reduce dat dosag e level s o f

35 0 an d2,00 0 ppm . N o effect s wer

e see n o n reproductiv e parameters . Th e NOE Lfo r systemi c an ddevelopmenta l toxicit y i n rat s wa s 6 0 pp m( 3 mg/kg/day)
. Th e NOE Lfo r reproductiv e toxicit y wa s greate r tha n2,000 pp m( 1 0 0 mg/kg/day)
. Dichlobeni l wa s administere db y ora l gavag e t o pregnan t

Ne w Zealan dWhit e rabbit s at dosag e level s o f

1 5 , 4 5 an d1 3 5 mg/kg/day
. Materna l toxicity , a s evidence db y reduction s i nfoo dintak e an d bod y weigh t

gai nfro mda y 7 t o 1 3 o f gestation , wa s see

n at 13 5 mg/kg/day
. Litter s o f thre e hig hdose s showe dreduce d feta l weigh t

an da nincrease dincidenc e o f developmenta l malformation s whic hwer e attribute dt o sever

e materna l toxicity
. Th e NOE Lfo r

materna l an ddevelopmenta l toxicit y i nrabbit s wa s 4 5 mg/kg/day
. Dichlobeni l technica l wa s administere dt o pregnan t rat s at dos e level s o f

0 , 20 , 6 0 an d1 8 0 mg/kg/day
. Materna l toxicity , a s evidence db y reduction s i nfoo dintak e an d bod y weigh t

gain , wa s see

n at 6 0 an d1 8 0 mg/kg/day
. N o effect s were seen o n pu p development
. Th e NOE Lfo r materna l toxicit y i nrat s wa s 2 0 mg/kg/da y an dth e NOE Lfo r

developmenta l toxicit y wa s greater tha n1 8 0 mg/kg/day
. ; . Reference/ , MRID #, '

Dichlobenil : 2

- Generatio nOra l (dietar y administration ) Reproductiv e Stud y i nth e Ra t (1989)
. Lab Projec t

ID : 5798-65/1 8 MRI D # s 4 125730 3 an d 4223910 1
Dichlobenil : Ora l (Gavage ) Teratolog y Stud y i nth e Rabbi t (Experimen t

11 ) (1989 ) Lab Projec t

ID : 5626-65/17 B an d5942-65/ 1 9 MRI D # s 4125730 1 an d 4125730 2 Oral Embryotoxicity / Teratogenicit y Stud y wit h Dichlobeni l i n Rat s (1984 ) Projec t #B83

- 104 5 MRID # 0014743 7Stud y Type/. ;

Guidelin e Subchroni c Toxicit v 90-day feedin g stud y Guidelin e Study (no t available )

1 3 -Wee k Dietar y Toxicit y Stud y i n Hamste r Guidelin e Stud y #82- 1 Dose s

Teste d

0 , 100 , 1000 , o r 300 0 pp m (0,5 , 50 , 15 0 mg/kg / day)
.

0,5 , 60 , 300 , 1500 , an d 500 0 mg/kg / da y SAITIPfrf

fli p * k?UlII V \J M IJJ V EDS PAssay En d Point s checke d
Organweight : testis , uterus , ovaries , live r

et c Histopathology : uterus , ovaries
. testis , adrenals , urinar y bladder
. thyroi detc .

Orga nweights : prostate , semina l vesicles , testis , uterus , ovaries , liver , kidne y etc . Histopathology : testis , epididymides , prostate , semina l vesicles , urinar y bladder , uterus . ovaries , vagina
. adrenal , pituitary , thyroi dwit h parathyroi d Results/Comment s

Rat s ( 1 2/sex/dose ) wer e give n dichlobeni l i nth e die t

fo r 1 3 week s a t dose s o f 0 , 100 , 1000 , o r

300 0 pp m(0 , 5 , 50 , 1 5 0 mg/kg/day)
. A nadditiona l grou p o f 6 mal e rat s wa s maintaine do na 10.00 0 pp mdiet
. Compound-relate d effect s include dincrease dabsolut e an d relativ e live r

an dkidne y weight s a t

100 0 pp man dhigher
. Ther e wa s als o hepati c degeneratio nwithou t

significan t

necrosi s a t 300 0 pp man dhigher , an dmortalit y ( 5 ou t o f 6 ) an dhepati c necrosi s a t 1 0,00 0 ppm . Th e NOE Lwa s 5 mg/kg/da y (10 0 ppm)
. Th e LOE Lwa s se t at 5 0 mg/kg/da y (100 0 ppm ) base do n increase dabsolut e an drelativ e live r an d kidne y weights
. I na90-day ora l toxicit y stud y i n hamsters , increase dlive r weight , enlarge dlive r

(wit hroug hsurface) , an d swolle nhepatocyte s wer e observe di n females
. I naddition , decrease dweigh t o f th e prostat e an dmineralizatio no f th e prostat e wer e reporte di nmales
. Tubula r degeneratio ni nth e testi s an ddecrease d number s o f

spermatocyte s i nth e epididymi s wa s seen a t

th e highe r

dos e level
. Uteru s an dsplee nweight s were reduce da t

highe r dos e level
. However , histppatholog y 'examination. , showe d, n o abnormalities
. > .Reference/

• MRID #

Ninet y da y Feedin g Studie s o f Casoro ni n Rats
. 1965
. MRID # 0010710 6

A 13-Wee k Toxicity Stud y wit hDichlobeni l i nMal e an d Femal e Hamste r followe db y a 4-week Recovery Perio d (1987)
. Lab Projec t

ID : D T 87/0 2 MRID # 4060070 1



# \

### Study Type / Guidelin e 13-Week Dietar y Toxicit y Stud y i n Mic e Guidelin e Study #82- 1

90-da y toxicit y stud y i ndog s Guidelin e Study

- no t specifie d 

### Dose s

Teste d 0,25 , 125 , 625
. o r 312 5 ppm ( 0,4 , 19,95 , o r 47 3 mg/kg / day )

0,50 , 150 , an d 45 0 pp m 

### Some o f

the " ' EDS P Assay En d Point s checke d Orga nweights : prostate , semina l vesicles , testis , uterus , ovaries , liver , kidne y etc . Histopathology : testis , epididymides , prostate , semina l vesicles , urinar y bladder , uterus , ovaries , vagina , adrenal , pituitary , thyroi dwit h parathyroi d Organweights : thyroid , pituitary , adrenal , testi s liver , kidne y etc . Histopathology : thymus , adrenal , testis , epididymides , uterus , ovarie s an d othe r /

i Results/Comment s I na13-week

ora l toxicit y test , mic e wer e give ndichlobeni l i nth e die t a t concentration s o f

0
. 25 , 125 , 625 , o r 312 5 pp m(0 , 4 , 19 , 95 , o r 47 3 mg/kg/day)
. Advers e effect s i n th e live r (specifi c effect s wer e no t

reported ) wer e observe di nfemal e mic e a t th e 9 5 mg/kg/da y level
. Th e absolut e an d relativ e testi s weight s wer e increase da t th e highe r

dos e levels
. However , histopathoibgica l .examinatio ndi d.no t showtah y abnormalities
.

Fou r group s o f

2 mal e an d2 femal e ( 3 an d1 fo r th e 45 0 mg/k g die t

group ) pur e bre dbeagl e dog s wer e fe do nabasa l die t supplemente dwit hdichlobeni l a t level s o f 0 , 50 , 150 , o r

45 0 mg/k g die t

fo r a perio do f 9 0 days
. Macroscopi c an d microscopi c examinatio no f organ s an d tissue s di dno t

revea l an y abnormalit y tha t migh t b e ascribe dt o th e ingestio no f dichlobenil
. Th e no-toxi c effec t leve l wa s foun dt o b e 5 0 ppm . correspondin g wit h 1 .2 5 mg/k g bod y weight/da y 

### Reference/ MRID # A13-Wee k Dietar y Toxicit y Stud y wit h Dichlobeni l i n Mal e an dFemal e Mic e (1987)
. Lab Projec t

ID : D T 87/0 1 N o MRI D #

Short-ter m(90

- day ) toxicit y stud y wit h Dichlobeni l (H I 33 ) i nbeagl e dog s (1967)
. Rapport Nr
. R 236 2 N o MRI D #



### Stud y detail s relate dt o EDS P endpoint s Subchroni c Toxicity I n th e subchroni c toxicit y stud y i n th e hamster s (MRI D #40600701 ) ther e wer e indication s o f reversibl e morphologica l an dfunctiona l effect s o n th e liver
. Followin g th e withdrawa l o f treatmen t i t wa s eviden t

tha t th e live r ha drecovere dnorma l functio nan dmorphology ; th e prostat e showe dadose-relate dweigh t reduction
. Uteru s an dsplee n weights , absolut e an d relative , wer e reduce da t th e 4.64 8 mg/k g die t

leve l o f th e females ; however , histopatholog y examinatio ndi dno t

sho w an y abnormality
. Th e macroscopi c an dmicroscopi c finding s ar e summarize di n th e table s below
.Thirteen-wee k dietar yexposur e o f hamster s t o dichlobeni l Macroscopi c observation s

. Number s examined Orga n Ovar y Peyer s patc h Semina l vesicl e Teste s Thymu s Urinar y bladde r Uteru s Observation s

Cys t Enlarge d Haemorrhagi c are a sligh t Smal l Haemorrhagi c are a sligh t Smal l Clea r are a Fille d wit h-flui d Fille d wit hflui d Thi n Uteru s hor n on e large r tha n othe r Dos e rat e (mg/k g diet. , actual ) Se x i
H . f 0 4 1 | '209 1,28 9 4 .,64 8 Afte r treatmen t period (1 3 weeks ) 2 0 • 2 0 1 0 1 0 

### 1 0 

### 1 0 1 0 1 0 . 9

1 0 0 4,64 8 Afte r 4-wee k recover yperio d 1 0 - 1 0 1 0

1 0 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

* Incidence s yieldin g statistica l significanc e f P<fi
. 10 ) i n atwo-side dles t agains t tren dwithdos e leve l
Thirteen-wee k dietaryexposur e o f hamster s t o dichlobeni l

Microscopi c observation s

Dos e rat e (mg/k

g diet,-actual )
***

Orga n Ovar y Pituitar y

Prostat e

Testi s Thyroi d Vagin a Observatio n

N o abnormalitie s Burs a cys t N o abnormalitie s Par s distali s cys t N o abnormalitie s Mineralizatio n

- margina l

- sligh t

- moderat e Prostatiti s

- margina l

- sligh t

- moderat e N o abnormalitie s Tubule s degenerate d

- margina l

- sligh t

- moderat e

- marke d N o abnormalitie s Cys t a fe w No abnormalitie s Epitheliu mcornifie d Se x
M F Afte r treatmen t perio d (1 3 weeks ) " 0 2 0 2 0 4 1 1 0 1 0 20 9 1 0

. 1 0 1,28 9

1 0 I B 4,648

9 1 0 Afte r recover

y perio d ( 4 weeks) j ' ; 0 

### i e 1 0 4,64

8 - ; . :i0 ; V , 

### '•:i e '•''•' . •'•' •

F F

M

M

M F 1 9 1 1 7 1 1 6 0 0 1 0 2 2 1 8 0 1 0 1 1 8 1 1 0 9 9 0 0 1 0 0 1 6 0 1 2 0 0 2 5 1 3 0 1 2 0 1 0 0 9 0 5 0 2 1 0 1 1 2 * * 2 0 4 1 8 0 4 5

### Tubula r

degeneratio n i n th e testi s an ddecrease dnumber s o f spermatocyte s i n th e epididymi s wa s see n i n th e 4,64 8 mg/k g die t group . Gall-bladde r

calcul i occurre di n bot hsexe s a t th e highes t die t level , thi s effec t

remaine dafte r

th e recovery period
. N o histopathologica l abnormalitie s wer e seen i n uteru s an dsplee n i n th e femal e grou p a t th e 4,64 8 mg/k g die t

level
. Conclusion : I n th e subchroni c studie s i n hamsters , rats , mic e increase dabsolut e an drelativ e orga n weight s wer e seen a t highe r dos e levels , however , histopatholog y examinatio ni n man y o f th e organ s showe dn o abnormalities
. Th e result s di dno t indicat e an y effect s pertainin g t o endocrin e syste mother

tha n orga

n weigh t increas e onl y at

highe r dos e levels
. Chroni c Toxicit y I nth e chroni c feedin g stud y i n rat s (MRI D #00147438 ) result s a t wee k 11 0 fo r th e 3,20 0 pp m dos e grou p ar e reporte dfo r female s only , a s al l male s die dbefor e termina l sacrifice
. N o effect s wer e see n a t

5 0 ppm , wherea s a t

40 0 pp mfollowin g effect s wer e noted ; absolut e an drelativ e live r weigh t increas e fo r

bot hsexes , absolut e an drelativ e kidne y weigh t increas e fo r

males , decreas e o f

absolut e thymu s weigh t

an dincreas e o f

th e relativ e brai n weigh t fo r males
. Th e female s a t

3,20 0 pp mshowe dfollowin g effects ; absolut e an drelativ e live r an dkidne y weigh t increase , absolut e decreas e o f adrena l weigh t

an dthymus
. Th e othe r

effect s wer e considere dt o resul t fro mth e suppressio n o f th e bod y weigh t

gain
. Histopathological dat ao f organ s pertainin g t o endocrin e modulatio n ar e summarize di n th e tabl e below
. Ther e ar e n o majo r concern s wit h regar dt o endocrin e syste mothe r tha n body/orga n weigh t changes
.

Table : Histophatologica l finding s a t wee k 11 0 i nChroni c feedin g stud y i nRat s
Dos e leve l Sex i Orga n Findin g Numbe r o f animal s examine d Adrena l Pigmentatio n

Vacuoli c chang e Telangieclasi s Hemorrhag e + Pheochromocytom a Autolysi s Hyperplasi a Metastasi s Cys t Chroni c inflammatio n Acut e inflammatio n Dysplasi a Hyperplasi a Hemorrhag e Atroph y Metastasi s 0 M / F, 47/4 7 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 5 0

•M/ F 47/4 6 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 40 0

M / F 47/4 7 3'/45 ' I2'/3S ' I7' / \ T 0 / 0 6V O 

### r/3 ' r/2 ' i• / r 0 / 0 

### r / o 0 / 0 

### o / r 0 / 0 0 / 0 

### r / o 0 / 1 ' 3,20 0 "M/ F 50/4 7 3'/46 ' T 1 W 9 V 5 ' 20 ' / O 0/ 0 3 V 3 ' 2 r / 0 

### T i r 0 / 0 0 / 0 0/ 0 

### o / r r / o 

### o.- o 0 / 0 0 / 0Dos e leve l Se x Orga n Findin g

Vacuoli c chang e Numbe r o f animal s examine d

Thryoi d C-cel l hyperplasi a

Hyperplasi a Parathyroi dhyperplasi a Aulolysi s + C-cel l adenom a
• + Adenom a Pigmentalio n Squainou s metaplasi a Cys t * Adenocarcinom a Numbe r o f animal s examine d

Tesli s Hypospenni a

+ Interstitia l cel l tumo r Hyperplasi ainterstitia l cell s Atroph y Aulolysi s Calcificatio n Pigmentatio n Numbe r o f animal s examine d Epididymi s * Mesotheliom a

Pigmentatio n Numbe r o f animal s examine d Sem
. V
. Atroph y

Hyperplasi a Numbe r o f animal s examine d

Mammar y Hyperplasi a Atroph y + Fibroadenom a * Adenocarcinom a Fibrocysti c diseas e Aulolysi s Calcificatio n * Adenoacamhom a Fibrosi s Pigmentatio n Othe r Acut e inflammatio n Chroni c inflammatio n Granulomatou s inflammatio n Hyperplasti c nodul e + Fibrom a * Carcinosarcom a 0 M / F 0 / 0 44/4 7 12 ' / 16 ' 2 V I T 3'/ 0 I V 5 ' IV5 ' 4 V 0 0/3 ' 0 / 0 

### r / o 0 / 0 47/ 0 44 ' / Q 38V O 6 V O 2 V O 0 / 0 2'/ 0 

### r / o 2/ 0 

### r / o 0 / 0 37/ 0 34 " / O 0/ 0 24/4 4 6 V 4 ' 0 / 0 0/3 ' 0/2 ' 

### v i 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 5 0

M / F 0/ 0 45/4 7 8V22'.5 " 18',l"/3 ' 9 V 4 ' 0/4 ' 5 V 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 23/4 4 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 46/4 7 12'/26'.4 " 34V7 ' 16'/ T I' / 3 " 

### 3 v r o / r o / r o / r 0 / 0 0 / 0 47/ 0 44 ' / Q 43V O 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 2 V 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 3,20 0 M / F 0/ 0 48/4 6 O / 1 1 '.I " 4'.l"/2 ' 37-/17 ' 0/5 ' 0/2 ' 2 V 1 ' 0 / 0 0/2 ' 

### r / o o / r 50/ 0 47 ' / O 35 ' / O I7V O 2'/ 0 

### r / o 0 / 0 0 / 0 I / O 

### r / o r / o 3 V / « 39 ' / O 0 / 0 33/4 7 0/5 ' 26 ' / O 0/3 ' 0 / 0 0 / 0 0 / 0 

### i v r 0 / 0 

### r / o 0 / 0 0 / 0 0 / 0 0 / 0 

### r / o 0 / 0 0 / 0 0 / 0Dos e leve l
•: ; ; • • " Se x Orga n Findin g Numbe r o f animal s examine d

Pituitar y Telangicciasi s

Pigmentatio n Hypcrplasi a

- 1

- Adenom a Cys t Autolysi s * Adenocarcinom a Atroph y Necrosi s Metastasi s Crystal s Numbe r o f animal s examine d

Prostat e Atroph y

Chroni c inflammatio n Hypcrplasi a Autolysi s * Squamou s cel l carcinom a Numbe r o f animal s examine d

Ovar y Pigmentatio n

Atroph y Autolysi s Metastasi s Cys t Hemorrhag e + Luleom a Numbe r o f animal s examine d

Uteru s Pigmentatio n

Cysti c cndometria l hyperplasi a Aulolysi s + Poly p Hydrometr a Metastasi s * Fihrosarcom a Calcificatio n Necrosi s * Fibromyxom a Atroph y + Leiomyom a * Adenocarcinom a Peritoniti s Hemorrhag e Numbe r o f animal s examine d Vagin a * UndifTerenliate dsarcom a 0 M / F 47/4 7 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 0/4 7 0/43 ' 0 / 1 T 0/2 ' 0 / 1 ' 0/3 ' 0 / 0 0 / 1 ' 0/4 7 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 '5 0

M / F^

. 4 6 /4f t I8'/20 ' 9'/2l ' 20 V 9 ' 4' / I T 

### 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 0/4 7 0/42 ' 0/6 ' 0/3 ' 0/3 ' 0 / 0 0 / 0 0 / 0 0/4 7 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 47/4 6 I2V21 ' 3'/21 ' 10V9 ' T ! 10 ' 0/2 ' V I T 

### o / r o / r 0 / 0 0 / 0 

### o/ r 47/ 0 33'/ 0 0 / 0 0 / 0 

### r / o 0 / 0 0/4 7 0/42 ' 0/3 ' 0/3 ' 0/4 ' 0/2 ' 

### o / r 0 / 0 0/4 6 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 3,20 0 - M / F -/y/4 6 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 0/4 7 0/40 ' 0/5 ' 0/4 ' 0/2 ' 0 / 0 0 / 0 0 / 0 0/4 7 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.' ' '^marke d

* = neoplasli c lumo r + = non-neoplasii c lumo r

### I nbot hchroni c do g toxicit y studies , a s wel l a s i nth e combine dchroni c toxicity/carcinogenicit y

stud y (MRI D #00147438 ) i n th e ra t increase dlive r

weight s an dhepati c enzymes , a s wel l a s live r histopathology , wer e observed
. I n additio nt o th e liver , th e nos e i s considere datarge t organ fo r dichlobenil
. Delaye dmaturit y o f th e uteru s wa s observe di nal l high-dos e female s teste di n th e chroni c ora l (capsule ) toxicit y stud y i n th e do g (MRI D #43969701)
. A marke d decreas e i nmea n uterin e weigh t a t th e hig hdos e confirme dthi s finding
. Ovaria n weight s wer e als o decrease di nhigh-dos e females , bu t h o Alteration s ^Iw j Conclusion : I nth e chroni c toxicit y studie s treatmen t relate dchange s wer e primaril y confine dt o th e hig hdosag e level
. Althoug hther e wer e n o pathologica l finding s o f clear toxicologica l importance , th e change s i n th e live r an dkidne y ar e note di n man y o f th e studies
. Th e ovarian/uterin e weight s were als o decrease di n hig hdos e females , bu t n o change s wer e observe d i nmicroscopi c an dmacroscopi c findings
. Chemtur ai s wel l awar e o f th e change s attribute dt o variou s organ s intereste di n th e endocrin e evaluatio n bu t woul dlik e t o emphasiz e tha t th e microscopi c finding s di dno t sho w an y concern . W e woul dreques t EP A t o conside r

th e chroni c toxicit y studie s i nthei r

evaluation
. Reproductive/Teratolog y Studie s I nth e reproductiv e toxicit y stud y (MRI D # s 4125730 3 an d42239101 ) n o treatment-relate d effect s wer e observe do n fertilit y index , fecundit y index , gestatio n index , o r mea n gestatio n lengt hi neithe r

Po r F I females
. Mea n pu p weight s a t 200 0 pp man d35 0 pp mwer e lowe r i nth e litter s fo r bot hgenerations
. N o treatment-relate deffect s wer e observe do n liv e birt hindex , viabilit y index , lactatio n index , o r se x rati o i neithe r

F I o r p 2 offspring
. I naddition , th e mea n numbe r o f pup s bo mlive/litte r

wa s unaffecte di nF I offsprin g bu t decrease d(P<0.001 ) a t

200 0 pp mi nF ? offsprin g ( 1 1
. 0 vs . 1 3. 7 i ncontrols)
. Thi s wa s likel y du e t o th e decrease dnumbe r o f implantations/F | da ma t

200 0 ppm . A t

> 35 0 ppm , th e mea n pu p bod y weigh t o f F ] offsprin g wa s decrease db y 16-23 % (P<0.05 ) fro mpostnata l da y (PND ) 4 (precull)-21
. Th e effec t wa s dose-dependent
. I n¥ 2 offspring , mea n pu p bod y weigh t wa s als o dose-dependentl y decrease db y 19-22 % (P<0.05 ) fro mPN D 14-21
. There ar e n o majo r orga n weigh t

change s o f

concern a t lowe r dos e level s indicatin g a nalteratio n i nth e sexua l hormona l level
. I nrabbi t teratolog y stud y (MRI D # s 4125730 1 an d41257302 ) th e numbe r o f corpor alute aan d implantation s wer e comparabl e i n al l groups . There i s n o increas e i n th e numbe r o f preimplantatio n losses
. Thi s indicate s tha t th e damag e t o th e fertilit y o f thes e animal s i s no t

see n a s ther e i s n o variatio n i n th e morpholog y and/o r motilit y o f

thes e organs . Feta l weigh t

wa s lowe r

tha n control s i n th e hig hdos e group . There wa s n o advers e effec t o n feta l weigh t i n th e lo w an dintermediat e dos e groups . Th e incidenc e o f litter s containin g fetuse s showin g majo r

defect s wa s significantl y highe r tha n control s i n th e hig hdos e group . Th e increas e wa s mainl y attribute dt o litter s 66 , 71 , an d7 2 suggestin g tha t thes e wer e mediate db y materna l toxicity
.

# t I nth e ra t teratolog y stud y (MR1 D #00147437 ) th e fertilit y indice s range dfro m84. 0 t o 92. 0 an d ar e withi n th e rang e calculate dfro mth e historica l contro l groups . Th e numbe r o f corpor alute a an dimplantatio n site s wa s comparabl e i n al l groups . Empt y uteru s weigh t wa s significantl y lowe r i n th e mid-dos e grou p only
. Ovar y weight , gravi duteru s weight , placent aan dfetu s weight s a s wel l a s fetu s length s wer e simila r i n al l groups . Althoug hth e tota l incidenc e o f mino r viscera l anomalie s an dviscera l variant s wa s somewha t highe r i n th e treate dgroup s tha n th e controls , ther e wa s neve r adose-respons e relationship
. Conclusion : Overal l ther e wa s n o evidenc e o f increase dsusceptibilit y t o offsprin g followin g pre nata l exposur e t o rat s o r rabbit s i n developmental/teratolog y toxicit y studies
. Evidenc e o f increase dpre-/post-nata l susceptibilit y wa s observe di n th e two-generatio n reproductio n stud y i n rat s an dbod y weigh t

change s ar e note di n al l studies
. However , th e degre e o f concern fo r

th e endocrin e effect s i s considerabl y low
. Thes e studie s di dno t indicat e an y potentia l t o interac t wit hth e estrogen , androgen , o r thyroi dhormon e systems . W e reques t EP A t o conside r

ou r argumen t alon g wit hth e availabl e highe r tie r studie s i n lie u o f

conductin g th e EDS Ptie r 1 testing
. Toxicit y Assessmen t

o f th e Metabolite-BAM : Toxicit y studie s fo r th e dichlobeni l metabolite , BA M ar e evaluate di n detail
. Base do n th e result s fro mthes e studies , th e toxicit y o f BA M i s considere dno t

greater tha n tha t

o f it s paren t

compound , dichlobenil
. Thes e result s indicat e n o concern t o th e mechanis mo f endocrin e syste mwit hrespec t t o th e metabolit e an dth e paren t dichlobenil
. Overal l Conclusion : Thoug hther e ar e bod y weigh t change s i n al l th e litter s examine da t highe r dos e groups , th e macroscopi c an dmicroscopi c concern s pertainin g t o estrogenicity , androgenicity , thyroida l effect s relate dt o endocrin e mechanis mar e o f n o concern i n thes e studies
. Chemtur awoul dreques t EP A t o conside r

thes e argument s pu t

fort hfro mth e abov e chronic , reproductive , teratolog y an dsubchroni c toxicit y studie s i n lie u o f th e testin g requeste d fo r EDS Passays . Ecotoxicologica l Evaluatio n Dichlobeni l ha s man y acut e toxicit y studie s i n Rainbo w trout , Fathea dMinnow , Bluegil l Sunfish , Sheepshea

dminnow , Eastern oyster , mysi dshrimp an ddaphnia
. Th e acut e toxicit y tes t result s indicat e tha t

dichlobeni l i s lo w t o moderatel y toxic
. Th e metabolite , BA M o f dichlobeni l i s practicall y non-toxi c t o aquati c organisms
. EP A i n it s revie w conclude dtha t dichlobeni l ha s adequat e dat at o asses s th e acut e an dchroni c hazard s o f dichlobeni l t o no n targe t aquati c animals
. Th e earl y life stag e toxicit y stud y i n Rainbo w trou t i s discusse di n detai l below
. Th e Earl y Life Stag e Toxicit y o f Dichlobeni l t o Rainbo w Trou t (Salmo Giardneri ) i n aFlow

Throug hSyste mwa s conducte daccordin g t o th e guidelin e #72-4
. Thi s stud y ha s bee n reviewe d b y EP A an dassigne da n MR1 D #40825101
. Thi s stud y wa s conducte dt o estimat e th e Maximu m Acceptabl e Toxican t

Concentratio n (MATC ) limits
. Th e mea n measure dconcentration s o f dichlobeni l wer e 0.33 , 0.66 , 1.20 , 2.4 0 an d5. 1 mg/L
. Thes e value s range dfro m9 6 t o 11 0 % o f th e nomina l tes t

concentrations
. Viabilit y o f th e newl y fertilize degg s (da y 11 ) use daverage d 96 % fo r th e controls
. Hatchabilit y o f th e rainbo w trou t

egg s afte r

4 1 days , surviva l a t

da y 3 4 an d

### da y 6 0 post-hatch , an drainbo w trou t growt hwer e significantl y reduce da t highe r tes t concentratio nwhe ncompare dt o contro l data
. However , th e growt heffect s wer e transien t a t lowe r concentration s a s th e reductio ni n th e lengthdoe s no t appear i n th e tw o lowes t concentrations
. Base do n thi s dat ath e MAT C wa s considere dt o b e 0.7 9 mg/L
. Conclusion : I nth e rainbo w trou t toxicit y stud y ther e ar e indication s o f toxicit y a t

highe r tes t concentrations
. I nthei r

assessmen t

EP A mentione dtha t

ther e ar e n o concern s fo r aquati c toxicity
. W e woul dreques t EP A t o conside r

th e rainbo w trou t

stud y an dth e lo w toxicit y value s a t variou s othe r

dos e level s alon g wit hth e EPA" s assessmen t tha t ther e i s adequat e dat aavailabl e fo r ris k assessmen t

(fro mEP A RED ) i nlie u o f conductin g th e fis hshort ter mreproductiv e assay . Majo r

rout e o f dissipatio nfo r

dichlobeni l i s volatilization
. Ther e i s lo w potentia l fo r bioaccumulatio ni nfish
. Chemtur aha s no t

conducte dan y amphibia n studie s bu t ther e ar e literatur e article s available
. Thes e studie s examine dth e effect s o f herbicide s i n aquati c system . There i s on e stud y whic h evaluate dth e effect s o f

th e herbicide s o n amphibian s an dinclude ddichlobeni l a s on e o f th e herbicides
. Thi s stud y i s discusse di n detai l below
. I nth e stud y "Effect s o f

Fiel dApplication s o f

th e Herbicide s Diqua t

an dDichlobeni l o n Amphibians" 1 

### th e effect s o nth e cage dfro g Ran atemporari aan dtoa dBuf o buf o tadpole s an do n free-livin g population s o f smoothnewt s Trituru s vulgari s hav e bee n studies
. There were n o significan t

difference s betwee ntreatmen t group s an dcontro l group s i n th e activit y level
. Herbicid e treatmen t

ha dn o effec t

o n developmen t

rate . I n th e pond s treate dwit hdichlobenil , weight s were greater

tha nthos e o f

th e contro l tadpole s o f

bot hspecie s o n day s 1 8 an d32
. There wer e n o marke ddifference s i n developmen t rate s betwee n treatments . Intestine s o f tadpole s fro m dichlobeni l treate dpond s usuall y containe dsimila r number s o f

unicellula r

algae , filamentou s alga e fragment s an ddiatom s a s thos e o f contro l tadpoles
. Dat ao n intestina l content s ar e summarize di n tabl e below
. Table : Intestina l Content s o f Tadpole s

Fro g - Ran a remporai'i a Da v 4 Dav 1 8 Dav3 2 Toad- Buf

o buf o Da v 4 Da v 1 8 Da v 3 2 Contro l

Dichlobeni l Contro l Dichlobeni l Contro l Dichlobeni l
Contro l Dichlobeni l Contro l Dichlobeni l Contro l Dichlobeni l Numbe r o f tadpole s examine d

4 4 2 2 2 2
4 4 2 2 2 2 Mea ngu t content s (thousands ) Filamentou s alga e 0.3 4 1. 2 2. 5 6. 2 0.5 9 1. 3
0.3 7 0.5 7 I . I 0.8 4 0.9 1 0.8 3 Unicellula r

alga e 0.2 5 0.2 6 1. 9 0.7 4 1. 6 1. 2
0.1 0 0.0 7 1. 5 0.1 3 0.6 3 0.4 2 Diatom s

0.8 3 2. 1 3. 3 1 3 3. 3 3. 1
0.3 9 0.3 7 1. 4 2. 7 3. 0 2. 5

1 Cooke.A.S
. "Effect s o f

Fiel dApplication s o f

th e Herbicide s Diqua t

an dDibhlobeni l o nAmphibians " Environ.Pollut
. (12)(1977)pp43-5 0

### Despit e havin g simila r quantitie s o f

alga e an ddiatom s i n thei r intestine s t o contro l tadpoles , th e dichlobeni l treate dtadpole s showe dincrease dgrowt hrate s o n da y 1 8 an d32
. Ther e ar e studie s whic hsho w arelationshi p betwee n growtho f alga e an dgrowtho f

tadpole s i n th e field , an di t seem s reasonabl e t o sugges t tha t th e overal l increas e i n growthrat e wa s du e t o th e dichlobeni l treatmen t causin g th e proliferatio n o f certai n highly-acceptabl e algae
. I n conclusion , herbicid e treatmen t produce dn o marke ddetrimenta l changes
. O n th e contrary , b y indirectl y stimulatin g tadpol e growth , th e herbicid e ha dabeneficia l effect , tadpole s mor e rapidl y attainin g asiz e a t whic hthe y woul dhav e bee n relativel y saf e fro mpredators
. Conclusion : I n thi s amphibia n stud y dichlobeni l neithe r cause dan y mortalit y amon g th e tadpole s no r change ddevelopmen t

rat e o r leve l o f activity
. W e reques t

EP A t o conside r

th e argumen t

an d th e literatur e stud y i n lie u o f conductin g th e amphibia n toxicit y testing
. Dat aSummar y an dRecommendatio n Ther e i s evidenc e tha t

dichlobeni l exhibit s som e concern s o f E D activity ; th e stronges t evidenc e wa s reporte di n mos t

o f th e studie s wit hbody/orga n weigh t changes
. Ther e ar e som e endocrin e relate dconcern s wit hrespec t t o specifi c organs/organ weigh t change s i n th e mechanis m reproductiv e an dtumorogeni c studies
. Ther e wa s n o evidenc e o f estroge n recepto r

(ER ) bindin g an dtha t dichlobeni l ma y interfer e wit hthyroi dhormon e homeostasi s als o wa s no t o f aconcern . Studie s conducte dwit hmal e an dfemal e rat s demonstrate dtha t ora l administratio n o f

dichlobeni l induce dsignifican t

irregularitie s i n reproductiv e tissue s bu t there were n o concern s wit hregard t o estrogen/androge n an dthyroi dhormon e systems . Chemtur awoul dreques t EP A t o conside r

ou r argumen t

alon g wit hth e availabl e robus t lexicologica l studie s i n lie u o f conductin g EDS Ptie r

1 assays .

### Bibliograph y o f Cite dDichlobeni l Studie s Order/DCI #EDSP-027401-12 0

0010710 6 Hodge , H. ; Maynard , E. : Downs , W. : e t al
. (1961 ) Ninet y Da y Feedin g Studie s o f

Casoro n i n Rats
. (Unpublishe dstud y receive dAp r 26 , 196 5 unde r unknow n admin
. No. ; prepare db y Univ
. o f Rocheste r

Schoo l o f

Medicin e an d Dentistry , Dept
. o f

Pharmacology , submitte db y Thompson-Haywar dChemica l Co. , Kansa s City , KS ; CDL:108430-A ) 0014743 7 Koeter , H
. (1984 ) Oral Embryotoxicity/Teratogenicit y Stud y wit hDichlobeni l i n Rats : Fina l Report : Repor t No
. V84.026/231045
. Unpublishe dstud y prepare d b y Netherland s Organizatio n fo r Applie dScientifi c Research
. 10 9 p . 0014743 8 Inoue , H
. (1983 ) Chroni c Feedin g Stud y o n Casoro n i n th e Rat : Repor t No.314 ; Duphar

Report No
. 56645/41/84
. Unpublishe dstud y prepare db y Biosafet y Researc hCenter , Foods , Drug s an dPesticides
. 272 8 p . 4060070 1 Kemp , A. ; d e Haan , M
. ; Jager , F
. (1987 ) A 13-wee k Toxicit y Stud y wit h Dichlobeni l i n Mal e an dFemal e Hamste r Followe db y a4-wee k

Recover y Perio d: Laborator y Projec t I D D T 87/0 2 : Doc
. No
. 56645/04/87
. Unpublishe d stud y prepare db y Dupha r B.V
. 20 2 p . 4082510 1 McAllister , W
. (1988 ) Earl y Life Stage Toxicit y o f Dichlobeni l t o Rainbo w Trou t

(Salm o gairdneri ) i n aFlow-throug hSystem : Fina l Report #36182
. Unpublishe dstud y prepare db y Analytica l Bio-Chemistr y Laboratories , Inc
. 3 7 p . 4125730 1 Barker , L
. (1989 ) Dichlobenil : Ora l (Gavage ) Teratolog y Stud y i n th e Rabbit s (Experimen t

II) : Dupha r

Report No
. 56645/85/87 : Laborator y Projec t I D 5626

- 65/775
. Unpublishe dstud y prepare db y Hazleto n UK
. 13 9 p . 4125730 2 Barker , L
. (1989 ) Dichlobenil : Ora l (Gavage ) Teratolog y Stud y i n th e Rabbi t (Experimen t

II) : Repeat

Study : Laborator y Projec t I D 5942-65/19 : Dupha r Report No
. 56645/21/89
. Unpublishe dstud y prepare db y Hazleto n UK
. 14 3 p . 4125730 3 Leeming , N
. (1989 ) Dichlobenil : 2 Generatio n Ora l (Dietar y Aministration ) Reproductio n Stud y i n th e Rat : Laborator y Projec t I D 5798-65/18
. Unpublishe d stud y prepare db y Hazelto n UK
. 33 7 p . 4198830 1 Hooks , W. ; Gary , R. ; Colman , K. ; e t al
. (1991 ) Dichlobenil : Potentia l Tumorigeni c Effect s i n prolonge dDietar y Administratio n t o Hamsters : La b Project Number : PDR/478 : 56645/85/90
. Unpublishe dstud y prepare db y Huntingto n Researc hCentr e Ltd
. 161 0 p .

### 4201510 1 Hooks , W. ; Gary , R. ; Colman , K. ; e t al
. (1991 ) Dichlobenil : Potentia l Tumorigeni c Effect s i n Prolonge dDietary Administratio n t o Hamsters : La b Projec t Number : PDR/478
. Unpublishe dstud y prepare db y Huntingdo n Researc hCentre , Ltd
. 28 5 p . 4222120 1 Chambers , P. ; Hornby , B. : Gibson , W. : e t al
. (1992 ) DichJobenil : Potentia l Tumorigeni c Effect s i n Prolonge dDietar y Administratio n t o Hamsters : La b Projec t Number : PDR/511
. Unpublishe dstud y prepare db y Huntingdo n Researc h Centr e Ltd
. 41 9 p . 4223910 1 Barker , L
. (1992 ) Dichlobenil : 2 Generatio n Ora l (Dietar y Administration ) Reproductio n Stud y i n th e Rat : Addendu m1 - Patholog y Report : La b Projec t Number : 5798-65/18,A-1
. Unpublishe dstud y prepare db y Hazelton , Harrogat e 

### (UK)
. 1 8 p . 4256360 1 Chambers , P. ; Brown , R. ; Gibson , W. ; e t al
. (1992)
. Backgroun dTumou r Incidenc e i n Hamsters : La b Projec t Number : PDR/540
. Unpublishe dstud y prepare db y Huntingdo n Researc hCentr e Ltd
. 41 9 p . 4396970 1 Pickersgill , N
. (1995 ) Dichlobeni l - 5 2 Wee k Ora l (Capsule ) Toxicit y Stud y i nth e beagl e Dog : Lab Projec t Number : 65/510:43593D
. Unpublishe dstud y prepare db y Pharmako n Europe
. 464p
. Studie s Submitte dwit hth e Dichlobeni l Endocrin e Disrupte r Respons e Til , H.P. , VJ
. Fero n an dA.P
. d e Groo t (Marc h1968)
. Short-term(90-day ) Toxicit y Stud y wit hDichlobeni l (HI33 ) i n Beagl e Dogs
. Stud y conducte db y Centraa l Instituu t Voo r Voedingsonderzoe k

fo r Philips-Dupha r

N.V
. Weesp , Th e Netherlands , Repor t

No
. R2362
. 3 5 p . Kemp , A. , M
. D e Haan , R..L.F
. Dawe s (Apri l 1987)
. A 13-Wee k (Dietary ) Toxicit y Stud y wit hDichlobeni l i n Mal e an dFemal e Mice
. Stud y conducte db y Dupha r B.V. , Weesp , Th e Netherlands , Projec t I D D T 87/01 , 16 8 p . Cooke , A.S
. (1977)
. Effect s o f Fiel dApplication s o f

th e Herbicide s Diqua t

an d Dichlobeni l o n Amphibians
. Publishe di n Environ
. Pollut
. (12 ) 1977 , p.43

- 50
.M 

### . o o \ o7lO k

DA Y FEEDIN G STUDIE S O

F CASORQ H I K RAT S
Repor t by : Toxicology :
Urin e Analyses i Hematology : Methemoglobi n Determinations : Pathology : Anima l Care : Graphs : Typing : Harold C . Hodge , Ph.D . Harol d C . Hodge , Ph.D . Elliot t A . Maynard , Ph.D . Willia mL , Downs j M.S . Joh n G . Cop e Stuar t Hulnick LUlia n Salem o Sant o Coc o ' Dougla s W . Smith , M.D . Raymon d Keae l Raymon d Ros e Alic e Millar

d Doroth yWeige l

Fro mth e Departmen

t o f Pharmacolog

y Univerait yo f Rochester Schoo l o f Medicin e an d Dentistr

y Rochester , Ne

wYor k

Signe

d Dat eUo
. 0 0 1^- 7 4-3* 7

^^^ ^



### civo Institute s tn o 

# fo-2055
netherfand s organizatio n fo rapplie d scientifi c researc h

dMilon to rnutritio n an d

tn o p.o . bo x360 370 0 A J zeist netheriand s Repor t No . V

84.026/23104 5 Interna l Documen t Ho . 56645/26/8 4
ORAL EMBRYOTOXICITY/TERATOCESICIT Y STUD Y WITH DICHLQBEHI L I NHAT S (Fina l report )

Autho r
A t th e reques t o f
Projec t numbe r : Ot a H.B.H.M . Koe'te r

: Dupha r B.V . Weesp , Retherland s

: B83-104 5 Star t o f the stud

y: Septembe r 19 , 198 3 Termination o f the stud y: Octobe r 25 . 198 3 Approve d b

y Dat e : D r V.J . Feron

: January > 198 4

Tota l o rpartia l publicatio n o f thi s repor t withou t writte n asaan t i s no t allowed
. 23a-10.000-016 1fO o . o o

RB.V
. Ccci p Prof : se t

ipf t Divisio n Dept
. Sog
. Oocv ? < ?ro>
. Man , 'S'"GtaV83.aad , Hollan d int
. 0pc , so. : issue d

P af c arequ j r:eroen t i 83- 1 an d83- 2 4 0 Ci « § 158,13 3

li
.

os : tJuri s 22:
. 198 2

, Drug s an dpesticide s 58?- 2 arahaiaa , shloshihtieu
. !?ukuae-eho Iwata-gun > Shizuok aPcet:
. 437

- ; 1 2

f
. 212 1 3776f t0at a

St u ¥ A
. 4- ;

A , K H , d e Haa n 

### W o
.

, th e Ne t or.-;: . oil ' Toxicolog y In-t:.: : t>oe . Ro
. .566*5/04/8 ? issue dMarc h Pag e 1 o £20. 2

r - B.V

t o f Toxicolog y {J:,.J, J va « : Routen : laati
. : '{ 6

sp , Th e f^etherlami s
,87/O XSPONSO R DUPHAR B.V . Attn : Ir . R . H . J . Ever s

P.O . Bo x 4 124 3 Z G 's-Gravelan d Hollan d Int . Doc . No. : 56635/23/8 8

STUDY TITL E Earl yLif e Stag e Toxlcit yo f Dichlobeni l t o Rainbo w Trou t (Salm

o gairdneri ) i n a Flow-Throug h Syste m

DAT AREQUIREMEN T U.S . EPA-FIFRA , 4 0 CFR , Sectio n 158.14 5

Guidelin e 72- 4
AUTHO R WilliamA . McAlliste r Aquati c Biologis t II I
FINAL REPOR T DAT E Apri l 26 , 198 8
PERFORMIN

G LABORATORY Analytica l Bio-Chemistr yLaboratories , Inc .

Aquati c ToxicologyDivisio n 720 0 Eas t AB C Lan e P . 0 . Bo

x 109 7 Columbia , Missour i 6520 5
AB C LABORATOR Y PROJEC T I D Fina l Repor t #3618 2 Pag e 1 o f 3 7Otle yBosd , -Herrogat s

;:Nors h Yorkshire HG 3 S P 

## CONFIDENTIA L

ORA L(GAVAGE) ; TggATOl.O(^_S7lJJ) Y
REPORT ; MO..
. 566457S5/3 7



### Oat arecalrement : Sidelin e 83-^ 3

Author : L
. Barker , 8.Sc., « :



## &.
. Hclfvcyre
. a.sc, , Stud ycompletei l en; : ;2 ? Apri l 1987 

### Performin g laboratory : iHaailetor
. UK,
.

;o.tVay Road * ii iarrogate , ^•OPt K : 

### Yor'kshire »
Lab.orat-sr y Projec t

IB : iS626-iS57176

- Date : : Augus t 198 9 pag e . 1 ..6: f

: 

### na

# I 1 

# HAZLETO

NU K Oiley Road
. Harrog ^ c 

### M

OICHIOBENIL : ORA L (GAVAG£ ) TEfiATOLOG Y STUDY I K TH E RABBI T (EXPERIMEN T II ) REPEAT STUJ

Y AHtttDHEH T T O FIKfi L Rt?ORT Dupna r Repor t No . 56645/21/8 S Dupha r Stud

yNo . C.201.40.02 2

Dat a recjireoent : EP AGuldelin e 83- 3 OCC O Guidelin e Prepare d by : L . Barker . B.Sc.tHons.) . C.Blol. . M.I.Btol . Stud yDirecto r

StuCycorplete d on : 

### 6 Ma y

### 198 8
Performin g Nazleio n UK . OtleyRoad . Harrogete . Wort h Yorkshire . tKGlANO . 

### 1PY .


### Laborator yProjec t 10 ; S942-6S/1 9


## Date : Augus t 198 9 Pag e 1 o f 3

## I D J o 

## . 4
- l a : T 

## CONFIDENTIA L .B'.V
. , : 

### Tpxicoldg y £.*^;
. Va n.Hpii'ten'i.ae n36 , 

### 138' i G P HOLLMQ..
. Int
. Coc
. No.
. 30645/^7 / e dAUQiiSt
. X9S9 , gH}.QB^iL : 2 ^£N£RAIIO N;QRA L : ! AOKINl'^TRATiOM ) REF'SQEUCriON
. STUiP y IN
. J1£.;RAT

Odt areaulr&ment v -Guidelin e B3:- 4



## 2 1 Apri l :1.98» ;

OtTe yR Harrogate , Yorksh i re, .PDR 478/9017 7 (Dupha r Int . Doc . No . 56645/85/90 )



### No .

DICHLOBENI L POTENTIA

L TUMORIGENI C EFFECT S I NPROLONGE D DIETAR Y ADMINISTRATIO N

T O HAMSTER S Fina l repor t (Weeks 1 t o 88 )
VOLUM E I o f I X

Stud ycompleted : 3 May199 1 Dat a requirement : EP AFIFRASubdivisio n F paragrap h

Repor t issued : 3 Ma y199 1 Principa l authors : Willia mN . Hooks . Richar d J . Cary , Kary n Colman , Willia mA . Gibson , Chirukandat h Gopinath , I . Suzanne Dawe . Performing Laboratory : Huntingdo n Researc h Centr e Ltd . P.O . Box 2 , Huntingdon , Cambridgeshire , PE1 8 6ES , ENGLAND . Laborator yProjec t Id . no. : PDR/47 8 Pag e 1 o f 161 0FD R 478/9148 6 (Dupha r Int . Doc . No . 56645/160/90 )

DICHLOBENI L POTENTIA

L TUMORIGENI C EFFECTS I NPROLONGE D DIETAR Y ADMINISTRATIO

N T O HAMSTER S (Supplementa l Data ) VOLUM E I O F I I

Stud ycompleted : 2 7 Jun e 1991 . Dat a requirement : EP AFIFR ASubdivisio

n F Paragraph 83- 2

Principa l authors : Willia mN . Hooks , Richard J . Gary , Kary n Colman , Chirukandat h Gopinath . Performin

g Laboratory , Huntingdon Researc h Centr e Ltd. , P.O . Bo x 2 , Huntingdon , Cambridgeshire , PE1 8 6ES , ENGLAND . 

### Laborator

yProjec t i.d . no. : PDR/47 8 Pag e 1 o f 28 5 

# €FD R 511/917 6 (Dupha r Int . Doc . Ho . 566A5/52/91 )

DICHUOBEM1 L PCTDITIA L T3KDRIGENI C EFFECT

S I V PPDLOHCE L D1ETAS

Y ADHZKISTItATIO

K T O HAMSTERS

VDUK E I O F I X

Stud ycoexisted : 1 0 Februar y199 2 D*t & requireswnt : EP

AFIFRA , 5ubdivi»icn F paragrap h 83- 2
Authors : Pau l S . Chambers . Mma n B . Hornby . WilliamA . Gibson . Chirujrandat

b Copinath , Sosa n Ba r ling . I . Sozanm

i Dave . s Ftrforoin

g laboratcry : Departsen

t o f Rodent Toxicology , Huntingdo

n Kesearc

h Centre Ltd . , Huntingdon , Casbridfieihire , 'F5I B 6ES . EKGLAKD . Repor t i«»««d t 1 0 February . 199 2 _" . \ ' ;) lal»arater yprojec t I.D . no. i PBS/ 5 1 1 Pag e 1 " o f 173 7

# ^>)HAZLETOr \ U K Ottey Rota
. HanooaiB Normtortsnae H6 3 tP Y Englan d 

## Solve yDupha r B.V. . Toxicolog yDepartment . C.J . Va n Ko-Jtcnlaa n 36 . 

## 133 1 cp 

## tfeesp . Tn e Netherlands . Addendir s t o Int . Doc . No . 55W5/87/88 . Issue d Augus t 19B 9

DICHLOBEKIl : 2 GtHERAlIO NORA L CDIPftRY ADHINISTRATIDN ) RtFRaPUtTIQNSTUD Y I N

### TH E RA

T 

### ADDENDU M 1 - PATHOLOG

Y REPOR T



## Dat a reaulreciert : 

## Guioelin c 63- 4 Prepared by : L Barke r BScCHons ) CBIo l HlSio l Stud yDirecto r 

## Patholog yconpleted : Januar yJ99 2 Perfonnin g Laboratory : Kuleto n UK .

OtleyRoad . Harrogate . Nort hYorkshire . ENGLAND . 

### KG 3 

### 1PY . Laborator yProjec t ID : 5793-65/1 8



## Pag e 1 o f 1 8FDR540/92047 2 (Dupht r In L Doc
. No
. 56645/5^92

)

BACKGROUN D TUMOU RINCIDENC E I N HAMSTERS (BACKGROUND DAT A STUDY ) VOLUMEI O FID 

### Stud y completed : Dzl arcquircmecL

Repor t issued : 29 Septembe

r 199 2 29 Septembe r 1992 EPAFIFRA
. Subdivisio nF paragrap h8 3 - 2

Principa l Aobors : PaulR
. Chamber*
. RjchardBro«D
. Wmia aA
. Gibson
. Cbimkaodzt

b Goptnxtb , Su e Harltn;
. Performin g Ubontoryt Humingdo n Researc

hCentr e Ltd.
. P.O
. Bo x 2 , Humingdon
. Cambridgeshire
. PE1 8 6ES
. "•'' • ENGLAND
. 

### >. - Laboraoo ' Project

I D No. : PDR/540

.. . .. . P««e.lof41 9 -INT , DOC
. N0 , : 56352/4i/95
. UNORdYAr ; CHEMICA

LGo.lKC
. ; BENSO N ROA D BURY,-e T 0674 9 U.S. A
CO-SPONSOR:
. PBl-GOKDO N CORP ; 1217 Vinat hStreet 

## cnX^t ) '64loi,
. .u:s.-A ,

- 3 2 wee k ora l (capsule ) toxidl y stxsd y irvthfeBeagle dog
. ;U.S.EPA-FM =
NUMBE R: :
DATE : 2 0 December

1&>S

-