### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE



# SIDS Initial Assessment Report

For

SIAM 20

Paris, France, 19-22 April 2005

1. Che mical Na me : 4,4 ́

- Methylenedic yclohe xyl diisocya nate

2. CA S Nu mb er: 5124-30-1

3. Spon sor Countr y: Contac t Poin t:

BMU (Bundes minister iu m für U mw elt, Na turschu tz und

Reaktor siche rhei t)

Contac t pe rson:

Prof . Dr . Ulr ich Schlot t mann

Postf ach 12 06 29

D- 53048 Bonn



### 4. Shared Partnership wi th :

-



### 5. Roles/Respon sibilities o f

the Partners: -

• 

### Name of industr y s ponsor

/consortium Ba y er AG, Ger man y

Contac t pe rson:

Dr. Burkhard t Stock

D-51368 Leve rkusen

Gebäude 9115

• 

### Proces s used OECD/ICCA - The BUA Pee r Revi ew Proces s: s ee n ext page



### 6. Spon sorship History

• 

### H ow was the che mica l or

categor y brought into the

OEC D HPV Chemica ls

Programm e ? b y ICCA-In iti ativ e



### 7. Review Process Prior to

the SI AM: l ast li te ratu re s earch (upda te) :

4 Octob er 2004 (Hu man Heal th): dat abases m edline, t oxl ine; sea rch

prof ile CAS- No. and speci al sear ch t er ms

8 Novem ber 2004 (Eco toxico log y ): dat abases CA, bio sis ; se arch

prof ile CAS- No. and speci al sear ch t er ms OECD/ICCA



### 8. Quality check process: IUCLID was used a s a bas is for t he SIDS dossie r. Al l data we re

checked and val idated b y BUA. A f ina l eva luat ion o f t

he hum an

heal th p art has been p erfo r med b y t he Fede ral Ins ti tute for Risk

Assessm ent (BfR) a nd of th e eco toxico logic al p art b y t he Fed era l

Environm ent Agenc y

(UBA).



### 9. Date of

Su bm is sion: Deadlin e fo r c ircu lat ion: 21 J anuar y 2005



### 10. Date of

last Up date: Last l it era ture se arch : IUCLID Chapte rs 1-4 : 2003 -08-13

, Chapt er

3.2 .1 2004 -07-27, Chapte r 5 : 2003-01 -22;

1

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

11. Co m me nt s: OECD/ICCA - The B UA * 

### Peer Review P rocess

Qualified BUA personnel (toxicologists, ecotoxicologists)

perform a qualit y control on the full S IDS do ssier s ubmi tted by

industr y. This qualit y control process follows internal BUA

guidelines/ instruct ions for the OECD/ICCA peer review

process and includes:

• 

### a full (or update) literature search to verify compl eteness of

data provided b y

industr y in the IUCLID/HEDSET

• 

### Review of data and assessment of the qualit y of data

• 

### Review of data evaluation

• 

### Check of adequac y of selection process for key studies for

OEC D endpoints, and, w here relevant, for non-OECD

endpoints b y

checking original reports/publicat ions

• 

### Review of ke y study de scription according robu st

s um ma ries requirem ents; comp let eness and correctness is

checked against original reports/publicat ions

(if original reports are missing: reliabi lit y (4), i.e.

reliabili t y not as signable)

• 

### Review o f validit y of structure- activit y relationships

• 

### Review of full SIDS dos sier (including SIAR, SIA P and

propo sal for conclusion and recom me nda tion for further

w ork)

• 

### In case of data gaps, review of testing plan or rationale for

not testing

* BUA (GDCh- Ber ater gr emium für Altstoffe): Advisor y Com mittee on Ex isting Chemicals of t he Association of

German Chemists (GDCh)

2

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

S I D S I N I T I A L A S S E S S M E N T P R O F I L E

C A S N o. 5124- 30- 1

C h e m i c al N am e 4,4 ́

- M e t hyl e ne di c yc l ohe xyl di i s oc ya na t e

S t r u c t u r al F or m u l a N

C

O N

C

O



### S U M M A R Y C O N C L U S I O N S O F T H E S I A R

H u m an H e al t h

4,4 ́

- M e t hyl e ne di c yc l ohe xyl di i s oc ya na t e i s of l ow or a l a nd de r m a l a c ut e t oxi c i t y w i t h a n or a l L D 50 ( r a t ) of

9900 m g/kg bw a nd a de r m a l L D 50 ( r a bbi t ) > 10,000 m g/kg. T oxi c s ym pt om s a f t e r or a l a dm i ni s t r a t i on i nc l ude d

s e ve r e di a r r he a

, l os s of a ppe t i t e a nd i n c r e a s i ng w e a kne s s

. A s s e s s m e nt of the a c ut e i nha l a t i on t oxi c i t y da t a

i ndi c a t e s t ha t e xpos ur e t o r e s pi r a bl e a e r os ol s of 4,4 ́

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e c onf i ne d pr e dom i na n t l y

t o t he r e s pi r a t or y t r a c t

. C l i ni c a l s i gns ( s a l i va t i on, br a dypne a

, s t r i dor ) i ndi c a t e d r e s pi r a t or y di s t r e s s

. A

ha e m or r ha gi c l ung e de m a w a s c ons i de r e d t o be c a us a t i ve f or m or t a l i t y. A n a ni m a l s t udy a c c or di ng t o

O E C D T G 403 gi ve s a

L C 50 ( 4 h, r a t ) o f

434 m g/ m 3

.

4,4 ́

- M e t hyl e ne di c yc l ohe xyl di i s oc ya na t e i s m ode r a t e l y t o s e ve r e l y i r r i t a nt t o t he s ki n of r a bbi t s ( O E C D T G 404)

. I r r i t a nt e f f e c t s w e r e obs e r ve d a f

t e r i ns t i l l a t i on of 4,4 ́

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e i nt o t he e ye s of r a bbi t s

( O E C D T G 405)

. T he r e pe a t e d dos e s t udi e s i ndi c a t e t ha t 4,4 ́

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e c a us e s

i r r i t a t i on of

t he r e s pi r a t or y t r a c t

.

A ni m a l da t a a r e not uni f or m how e ve r the y f

r e que nt l y pr ovi de e vi de nc e of a s k i n s e ns i t i z i ng pot e nt i a l of 4,4

 ́

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e

. H um a n c a s e r e por t s de s c r i be a l l e r gi c c ont a c t de r m a t i t i s due t o 4,4

 ́

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e e xpos ur e

. A l t hough no va l i da t e d a ni m a l m ode l i s a v a i l a bl e t o a s s e s s t he

pot e nt i a l f

or r e s pi r a t or y s e ns i t i z a t i on or a s t hm a i n hum a ns a ni m a l da t a s uppor t t o s om e e xt e nt the hypot he s i s t ha t

r e s pi r a t or y hype r s e ns i t i vi t y m a y be i nduc e d by 4,4 ́

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e

.

N o r e s ul t s f

r om r e pe a t e d- dos e t oxi c i t y t e s t s a r e a va i l a bl e f or t he or a l a nd de r m a l r out e of e xpos ur e

. A s uba c ut e

i nha l a t i on s t udy ( 1, 6 a nd 36 m g/ m 3 ; 6 hour s / da y on f i ve da ys / w e e k f

or 4 w e e ks ) w i th r a t s ( O E C D T G 412)

i ndi c a t e s t

he r e s pi r a t or y t r a c t t o b e t he t a r ge t or ga n o f r e s pi r a bl e 4,4 ́

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e a e r os ol

. T he r e por t e d N O A E L f

or e f f e c t s gove r ne d by r e s pi r a t or y t r a c t i r r i t a t i on i s 1 m g/ m 3 ; the L O A E L i s 6 m g/ m 3 ( i .e

. hi s t opa t hol ogi c a l c ha nge s i n na s a l pa s s a ge s

, l a r ynx a nd br onc hi )

. T he r e s ul t s of a r e pr oduc t i on/ de ve l opm e nt a l

t oxi c i t y s c r e e ni ng t e s t ( O E C D T G 421) c orr e s ponds t o the r e s ul t s of t he s uba c ut e s t udy.

4,4 ́

- M e t hyl e ne di c yc l ohe xyl di i s oc ya na t e di d not i nduc e ge ne m ut a t i ons i n ba c t e r i a ( O E C D T G 471) a nd

de m ons t r a t e d no po t e nt i a l t o i nduc e c hr om os om e a be r r a t i ons i n C hi ne s e ha m s t e r V 79 c e l l s i n v i t r o

( O E C D T G 473) e i t he r w i th o r w i thout m e t a bol i c a c t i va t i on.

D a t a f r om a n i nha l a t i ve r e pr oduc t i on/ de ve l opm e nt a l t oxi c i t y s c r e e ni ng t e s t a c c or di ng t o O E C D T G 421 w i t h r a t s

( 1, 6 a nd 36 m g/ m 3 ) di d not r e ve a l s ubs t a nc e r e l a t e d i m pa i r m e nt of r e pr o duc t i on up t o a 4,4

 ́

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e c onc e nt r a t i on of 6 m g/ m 3

. A s l i ght l y r e duc e d f e r t i l i t y i nde x w a s obs e r ve d

a t a n e xpos ur e l e ve l ( 36 m g/ m 3 ) tha t w a s a s s oc i a t e d w i t h pa r e nt a l t oxi c i t y. N O A E L s w e r e c ons i de r e d t o be

1 m g/ m 3 i n m a l e s a nd f

e m a l e s f or ge ne r a l t oxi c i t y. N O A E L f or r e pr oduc t i ve t oxi c i t y i s 6 m g/ m 3

.

P r e

- na t a l i nha l a t i on t oxi c i t y t e s t i ng i n r a t s ( O E C D °T G °421) i ndi c a t e s t he a b s e nc e of s e l e c t i ve t oxi c i t y t o t he

de ve l opm e nt a t l e ve l s up t o 36°m g / m 3

. N o f i nd i ngs i ndi c a t e a ny s pe c i f i c de ve l opm e nt a l e f

f e c t s s uc h a s l i ve b i r t h

i nde x, vi a bi l i t y i nde x a nd a ppa r e nt m a l f or m a t i on. T he r e por t e d N O A E L ( de ve l opm e nt a l ) f or 4,4 ́

- m e t hyl e ne di c yc l ohe xyl

di i s oc ya na t e i n a de ve l opm e nt a l t oxi c i t y s t udy a c c or di ng t o O E C D T G 414 ( 1, 6 a nd 36 m g/ m 3 ) i s 6 m g/ m 3 / da y.

A t t he 36 m g/ m 3 l e ve l tha t c a us e d c l e a r m a t e r na l r e s pi r a t or y t r a c t t oxi c i t y ( N O A E L ( m a t e r na l ) = 1 m g/ m 3 ) i nc r e a s e d

3

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

i nc i de nc e s of ve n t r i c ul a r s e pt a l de f e c t s of t he he a r t a nd s l i ght di l a t i on of l a t e r a l br a i n ve nt r i c l e s w e r e obs e r ve d,

w hi c h l a y m a r gi na l l y a bove t he upp e r or w i t hi n t he nor m a l r a nge of s c a t t e r i ng of

t he r a t s t r a i n us e d r e s pe c t i ve l y.

E n v i r o n m e n t

4,4’

- M e t hyl e ne di c yc l ohe xyl d i i s oc ya na t e i s a s l i ght l y ye l l ow i s h, m oi s t ur e / w a t e r s e ns i t i ve l i qu i d w i t h a m e l t i ng

poi nt of 15 °C

. 4,4’

- M e t hyl e ne di c yc l ohe xyl di i s oc ya na t e ha s a r e l a t i ve de ns i t y of 1.07 a t 25 °C

, a boi l i ng poi nt

of 167

- 168 °C ( a t 2 hP a )

, a nd a va por pr e s s ur e of 2.13 x 10

- 5 hP a a t 25 °C [ D i r e c t i ve 92/ 69/ E E C

, A .4]

. A w a t e r

s ol ubi l i t y a nd a l og K O W a r e not de t e r m i na bl e due t o t he i ns t a bi l i t y of 4,4’

- m e thyl e ne di c yc l ohe xyl di i s oc ya na t e i n

w a t e r

. T he f

l a s h poi nt of 4,4’

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e i s 200 °C [ D I N 51758 ]

, the i gni t i on poi nt i s

225 °C a nd t

he v i s c os i t y i s a ppr oxi m a t e l y 30 m P a x s a t 25 °C [ D I N I S O E N 3219/ A .3]

. T he c a l c ul a t e d ha l f

- l i f e

of 4,4’

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e i n a i r due t o i ndi r e c t phot ode gr a da t i on i s a bout 15.0 h.

4,4’

- M e t hyl e ne di c yc l ohe xyl di i s oc ya na t e hydr ol ys e s r a pi dl y i n t he pr e s e nc e of w a t e r

, the m a j or pr oduc t i n t he

a que ous pha s e i s m e t hyl e ne bi s ( 4- c yc l ohe xyl a m i ne )

. I n w a t e r

, a ha l f

- l i f e f or 4,4’

- m e t hyl e ne di c yc l ohe xyl

di i s oc ya na t e of a ppr oxi m a t e l y 2 hour s w a s de t e r m i n e d e xpe r i m e nt a l l y. D ue t o t he r a pi d hydr ol ys i s of

4,4’

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e

, a t r a ns por t of the s ubs t a nc e b e t w e e n e nvi r onm e nt a l c om pa r t m e nt s i s

unl i ke l y. C ons e que nt l y, a c a l c ul a t i on of t h e H e nr y L a w C ons t a nt a nd of t he di s t r i bu t i on be t w e e n t he

e nvi r onm e nt a l c ompa r t m e nt s a c c or di ng t o t he M a c ka y f uga c i t y m ode l l e ve l 1 i s not s u i t a bl e

.

H ow e ve r

, s e ve r a l a qua t i c t oxi c i t y t e s t s ha ve be e n unde r t a ke n w i t h 4,4’

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e a nd

i t s hydr ol ys i s pr oduc t s

. B e c a us e o f the r a pi d hyd r ol ys i s t he a s s e s s m e nt of t he s ubs t a nc e s houl d be ba s e d on t he

hydr ol ys i s pr oduc t s a nd not on 4,4’

- m e thyl e ne di c yc l ohe xyl di i s oc ya na t e

. T he hydr ol ys i s pr oduc t m e t hyl e ne bi s

p- c y c l ohe xyl a m i ne w a s a s s e s s e d by the E U P B T W or ki ng G r oup. T he hydr ol ys i s pr oduc t w a s no t c l a s s i f i e d a s a

P B T s ubs t a nc e

.

4,4’

- M e t hyl e ne di c yc l ohe xyl d i i s oc ya na t e i s not r e a di l y bi ode gr a da bl e

.

D ue t o t he r a pi d hydr ol ys i s 4,4 ’

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e i s ne i t he r pe r s i s t e nt i n t he w a t e r

c om pa r t m e nt nor bi oa c c um ul a t i ve

. T he c a l c ul a t e d K

oc - va l ue i ndi c a t e s tha t 4,4 ’

- m e t hyl e ne di c yc l ohe xyl

di i s oc ya na t e m a y s t

r ongl y a ds or b t o s oi l but due t o i t s r a pi d hydr ol ys i s a ny e m i s s i on t o t he t e r r e s t r i a l

c om pa r t m e nt w oul d be a f f e c t e d by hum i di t y a nd t he r e f or e

, ge oa c c um ul a t i on of 4,4’

- m e t hyl e ne di c yc l ohe xyl

di i s oc ya na t e i s not e xpe c t e d t o oc c ur

. C onc e r ni ng t

he t oxi c i t y of 4,4’

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e a nd i t s hyd r ol ys i s pr oduc t s t ow a r ds a qua t i c

s pe c i e s

, r e l i a bl e e xpe r i m e nt a l r e s ul t s o f t e s t s w i th f i s h, D aphni a

, a nd a l ga e a r e a va i l a bl e ( *

= de t e r m i ne d a s T O C

a nd ba c k- c a l c ul a t e d t o pa r e nt s ubs t a nc e , n = nom i na l c onc e nt r a t i on)

.

D ani o r e r i o ( f i s h) : 96 h- L C 50 > 8.1 m g/ l *, [ D i r e c t i ve 92/ 69/ E E C

, C .1]

D aphni a m agna ( a q. i nve r t e br a t e ) : 48 h- E C 50 > 8.3 m g/ l *, [ D i r e c t i ve 92/ 69/ E E C

, C .2]

Sc e ne de s m us s ubs

pi c at us ( a l ga e ) : 72 h- E

r C 50 > 5 m g/ l *, [ D i r e c t i ve 92/ 69/ E E C

, C .3]

A c t i va t e d s e w a ge s l udge ( ba c t e r i a ) : 3 h- E C 50 = 191 m g/ l ( n)

, [ D i r e c t i ve 88/ 302/ E E C

, P a r t C

( c or r e s ponds t o t he O E C D T G 209) ]

.

I t ha s t o be c ons i de r e d tha t the t oxi c i t y obs e r ve d i n t he r e por t e d a qua t i c s t udi e s w a s c a us e d both by t he

4,4’

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e a s w e l l a s by t he hydr ol ys i s pr oduc t s due t o the i ns t a bi l i t y o f the t e s t

s ubs t a nc e

. B a s e d on t he a c ut e a qua t i c t oxi c i t y da t a on t hr e e t r ophi c l e ve l s ( f

i s h, D aphni a

, a l ga e )

, t he P r e di c t e d N o E f f e c t

C onc e nt r a t i on ( P N E C

a qua ) c a n be c a l c ul a t e d w i t h a n a s s e s s m e nt f a c t or o f 1000 a ppl i e d t o t he l ow e s t a c ut e e f f e c t

c onc e nt r a t i on. T he l ow e s t 72 h- E

r C 50 - va l ue of > 5 m g/ l ob t a i ne d f or the a l ga s pe c i e s Sc e ne de s m us s ubs pi c at us

w a s us e d t o de r i ve a P N E C

a qua of > 5 μ g / l

.

E xp os u r e

C om m e r c i a l 4,4’

- m e t hyl e ne di c yc l ohe xyl d i i s oc ya na t e m a nuf a c t ur i ng s t a r t s w i t h hyd r oge na t e d

m e t hyl e ne di a ni l i ne ( m e thyl e n e bi s

- p- c yc l ohe xyl a m i n) w hi c h i s phos ge na t e d. T he gl ob a l pr oduc t i on c a pa c i t y of

4,4’

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e i s 10 000

- 20 000 t onne s / a

, w i t h m os t of i t i n t he U S A

. I n G e r m a ny,

t he onl y pr oduc e r ha s a m a nuf a c t ur i ng c a pa c i t y of 1000

- 5000 t onne s / a of 4,4’

- m e t hyl e ne di c yc l ohe xyl

di i s oc ya na t e

.

4,4’

- M e t hyl e ne di c yc l ohe xyl di i s oc ya na t e i s a n i nt e r m e di a t e i n t he c he m i c a l i ndus t r y, us e d f o r t he m a nuf

a c t ur e of

bi nde r s or h a r de ne r s f

or c oa t i ng m a t e r i a l s or a dhe s i ve s ( 60 % )

, pr e pol ym e r s ( 20 % )

, a nd f or othe r a ppl i c a t i ons

,

4

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

e .g. f o r t he pr oduc t i on of e l a s t om e r s ( 20 % )

. 4,4’

- M e t hyl e ne di c yc l ohe xyl di i s oc ya na t e i s not u s e d f or “ D o I t

Y our s e l f ” a ppl i c a t i ons or i n ot he r c ons um e r pr oduc t s

. 4,4’

- M e t hyl e ne di c yc l ohe xyl di i s oc ya na t e i s r e gi s t e r e d a s a

c om pone nt i n a ppr oxi m a t e l y 50 i ndus t r i a l pr oduc t s l i s t e d i n t he D a ni s h, F i nni s h, a nd S w e di s h P r oduc t R e gi s t e r s

w i t h a c ons um pt i on o f a bout 30 t onne s / a i n 2000 a nd 2001 ( l a s t ye a r s of r e c or d)

. 4,4’

- M e t hyl e ne di c yc l ohe xyl

di i s oc ya na t e i s c onf

i de nt i a l l y l i s t e d i n t he N or w e gi a n P r oduc t R e g i s t e r

. T he r e i s no r e gi s t r a t i on f or a c ons um e r

pr oduc t

. T he m a i n us e c a t e gor y i s “ non- di s pe r s i ve us e ”

. F o r 4,4’

- m e t hy l e ne di c yc l ohe xyl d i i s oc ya na t e t he S w i s s

P r oduc t R e gi s t e r l i s t s 34 i ndus t r i a l pr oduc t s ( w i th c onc e nt r a t i ons of up t o 100 % 4,4 ’

- m e t hyl e ne di c yc l ohe xyl

di i s oc ya na t e ) , but no c ons um e r p r oduc t

.

B y t he pr oduc e r i n G e r m a ny, 4,4’

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e i s m a nuf a c t ur e d a nd pr oc e s s e d ( i nc l udi ng

f i l l i ng) i n c l os e d s ys t e m s a t the s a m e i ndus t r i a l s i t e

. T o the c us t om e r s m os t of t he 4,4’

- m e t hyl e ne di c yc l ohe xyl

di i s oc ya na t e i s t r a ns por t e d i n I S O c on t a i ne r s , a nd t o a m i nor p a r t , i n dr um s

.

D ur i ng 4,4 ’

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e m a nuf a c t ur i ng a nd pr oc e s s i ng, vi r t ua l l y no

4,4’

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e ( < 25 kg/ a ) i s e m i t t e d i nt o t he a t m os phe r e f r om t he B a ye r

pl a nt s . W a s t e

f r om t he m a nuf

a c t ur i ng a nd pr oc e s s i ng of 4,4’

- m e thyl e ne di c yc l ohe xyl di i s oc ya na t e i s di s pos e d of f i n a n

i nc i ne r a t or f

or ha z a r dous w a s t e s

. D ue t o w a s t e w a t e r

- f r e e m a nuf

a c t ur i ng a nd p r oc e s s i ng, a nd t o r a pi d hydr ol ys i s

,

no e m i s s i ons i nt o the a qua t i c e nvi r onm e nt a r e e xpe c t e d.

S ur ve ys of t

he w or kpl a c e s ha ve be e n pe r f or m e d a l s o a c c or di ng t o G e r m a n T e c hni c a l G ui da nc e T R G S 402,

T R G S 430, a nd T R G S 900 by the pr oduc e r i n G e r m a ny. T o pr ot e c t w or ke r s f r om e xpos ur e

, s e ve r a l

pr e c a ut i ona r y a nd pr ot e c t i ve m e a s ur e s a r e t a ke n, e .g., s a m pl i ng t a ke s pl a c e i n a w i de l y c l os e d s ys t e m

. I n

G e r m a ny f

or oc c upa t i ona l s e t t i ngs

, t he m a xi m um pe r m i s s i bl e c onc e nt r a t i on f or 4,4’

- m e t hyl e ne di c yc l ohe xyl

di i s oc ya na t e i s 0.054 m g/ m 3

. A t t he pr oduc e r i n G e r m a ny, a l l e xpos ur e da t a w e r e be l ow t he m a xi m um

pe r m i s s i bl e c onc e nt r a t i on.

N o e nvi r onm e nt a l m oni t or i ng da t a ha ve be e n i de nt i f i e d. T r a c e s of 4,4’

- m e thyl e ne di c yc l ohe xyl di i s oc ya na t e ( up

t o 2 μ g / m 3 ) w e r e de t e c t e d a s a the r m ol yt i c d e gr a da t i on p r oduc t dur i ng j oi nt w e l di ng of pol yur e t ha ne f l oor

c ove r i ng i n a

s m a l l r oom w i th no ve nt i l a t i on.

T he e xpos ur e of c ons um e r s t o 4,4’

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e i s unl i ke l y t o oc c ur

, b e c a us e no

c ons um e r pr oduc t i s know n t o c ont a i n 4,4’

- m e t hyl e ne di c yc l ohe xyl di i s oc ya na t e

. A n e xpos ur e v i a t he

e nvi r onm e nt i s a l s o unl i ke l y t o oc c ur be c a us e t he r e a r e vi r t ua l l y no e m i s s i ons of 4,4’

- m e t hyl e ne di c yc l ohe xyl

di i s oc ya na t e

, a nd 4,4’

- m e thyl e ne di c yc l ohe xyl di i s oc ya na t e r e l e a s e d t o e nvi r onm e nt w oul d r a pi dl y be de gr a de d

by phot ooxi da nt s a nd w a t e r

.



### R E C O M M E N D A T I O N A N D R A T I O N A L E F O R T H E R E C O M M E N D A T I O N A N D

N A T U R E O F F U R T H E R WO R K R E C O M M E N D E D

H u m an H e al t h : T he c he m i c a l pos s e s s e s pr ope r t i e s i ndi c a t i ng a ha z a r d f or hum a n he a l t h ( s e ve r e i r r i t a t i on of s ki n,

e ye a nd r e s p i r a t or y t

r a c t

, s e ns i t i z a t i on of s ki n a nd pr e di c t e d t o be a r e s pi r a t or y t r a c t s e ns i t i z e r be c a us e i t i s a

di i s oc ya na t e )

. B a s e d on da t a pr e s e nt e d by t he S pons or c oun t r y ( r e l a t i ng t o pr oduc t i on by one pr oduc e r w hi c h

a c c ount s f

o r a ppr oxi m a t e l y 5 % t o 50 % of gl oba l pr oduc t i on a nd r e l a t i ng t o t he us e pa t t e r n i n s e ve r a l O E C D

c ount r i e s )

, oc c upa t i ona l e xpos ur e i s a nt i c i pa t e d t o be l ow a nd t he r e a r e no know n c ons um e r us e s

. T he r e f or e t hi s

c he m i c a l i s c urr e nt l y of l ow pr i or i t y f or f ur t he r w or k. C oun t r i e s m a y de s i r e t o i nve s t i ga t e a ny e xpos ur e s c e na r i os

t ha t w e r e not pr e s e nt e d by t he S pons or c oun t r y.

E n vi r on m e n t : T he c he m i c a l ( i nc l udi ng i t s hydr ol ys i s pr oduc t s ) pos s e s s e s pr ope r t i e s i ndi c a t i ng a ha z a r d f or t he

e nvi r onm e nt

. B a s e d on da t a pr e s e nt e d by t he S pons or c ount r y ( r e l a t i ng t o pr oduc t i on by one pr oduc e r w hi c h

a c c ount s f

o r a ppr oxi m a t e l y 5 % t o 50 % of gl oba l pr oduc t i on a nd r e l a t i ng t o t he us e pa t t e r n i n s e ve r a l O E C D

c ount r i e s )

, e xpos u r e t o t he e nvi r onm e nt i s a nt i c i pa t e d t o be l ow

, a nd the r e f or e t hi s c he m i c a l i s c ur

r e nt l y of l ow

pr i or i t y f or f ur t he r w or k. C ount

r i e s m a y de s i r e t o i nve s t i ga t e a ny e xpos ur e s c e na r i os tha t w e r e not pr e s e nt e d by t he

S pons or c ount r y.

5

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE



# SIDS Initial Assessment Report

1 I DENT ITY

Identi fication o f t he S ubsta nce

CAS N umber : 5124-30-1

Substance name 4,4  ́

- me th y le ne dic y cl oh ex y l diisocy an at e (EINECS name)

IUP AC Name : 1,1  ́- Meth yl en ebis(4- isoc ya na toc y cl oh exan e)

Molecular

Formul a: C 15 

### H 22 

### N 2 

### O 2



### Structural F ormul a:

N

C

O N

C

O



### Molecular

Weight: 262.35 g/mo l

S yn on y ms : C yc loh exane, 1,1’-meth y le ne bis- (4-isoc ya na to)- (CAS name)

Desmodur

W (Product of Bay er MaterialSc ience A G)

H yl ene W

H ydrog enat ed MD I

H 1 2 

### MDI

Meth yl en e bis(4-c yc lo hex y li so c ya na te )

4,4’-Dic yc lo hex y l me th an ediisoc y an at e

4,4’-Diisoc ya

na todic y c lo hex y l m et ha ne

4,4’-Meth yl en ebis(c y cl oh ex y l isocy an at e)

Bis(4-isoc ya

na toc y cl oh ex y l) m et han e

Dic yc lo hex y l me th an e- 4,4'-diisocy an at e

Meth yl en ebis(1,4- c yc lo hex y le ne ) diisoc ya na te

Meth yl en e bis(4-isoc ya

na toc y cl oh exan e)

Meth yl en edi- 1,4-cy cl ohex y l en e isocy an ate

Meth yl en edi- 4-cy cl ohex y l en e diisocy an at e

Purity/I mp urities/Additives

A t yp ic al composit ion of 4,4’-me th yl en ed ic y cl oh ex y l diisocy an at e was specified b y Dieterich and

U hlig (2002) with a purity of 92 % 4,4’-meth y l en e dicy cl oh ex y l diisocy an at e and the corresponding

isomeric composit ion:

• cis

, cis -isomer 14 %

• cis

, tran s -isomer 58 %

• trans

, tran s -isomer 20 %

• others 8 % (2,4 '-me th yl en ed ic y cl oh ex y l diisocy an at e).

The comm er cia l product of 4,4’-meth y l en edi c yc lo hex y l diisoc ya na te also contains

2,4’-me th y le ne dic y cl oh ex y l diisocy an at e (Ba ye r MaterialScien ce AG, 2004a).

6

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

Phy sico- C hem ical properties

Table 1 Summ ar y of ph ys ico- chemi cal properties of 4,4’-meth y l en edi c yc lo hex y l

diisocy an at e

Prope rty Val ue Reference IUCLID

S ubstance t yp e Organic compound Ba ye r MaterialScience

AG, 2004b 1.1.1

P h ys ical s tate S lightly y el lowish liqu id with

s light lachr ym ato r y odour Ba ye r MaterialScience

AG, 2004b 1.1.1

Melt ing point 15 ° C** Dieterich and Uhlig, 2002 2.1

Boiling po int 167

- 168 °C (at 2 hPa) GI AP, 1969 2.2

Relative density 1.07 at 25 ° C NI OSH, 2004 2.3

Vapour pressure 2.13 x 10 -5 hPa at 25 °C Ba ye r AG, 1994a 2.4

Parti tion coefficient noctanol/water

(K

ow ) Calculation i s not suitable due

to hy drol y si s* 2.5

Wa ter solubi lity Hy dr ol ys is* NI OSH, 2004 2.6.1

Flash point 200 ° C Ba ye r AG, 1979 2.7

Ig nition point 225 ° C Zhuravlev, 1976 2.8

Viscosity ca. 30 m Pa x s at 25 °C Ba ye r MaterialScience

AG, 2004b 2.13

* I n w a t e r

, 4

, 4 ’

- m e t

h y l e n e d i cy c l o h e x y l d i i s o c y a n a t e h y d r o ly s e s w i t

h a h a l f -l i f e o f a p p r o x i m a t e l y 2 h

( B aye r A G

, 1 9 9 9 ) * * F o r t h e m i x t u r e r e p o r t e d b y D i e t e r i c h a

n d U h l i g ( 2 0 0 2 ) i n C h a

p t e r 1

. 2

. M e l t i n g p o i n

t m a y

v a ry a c c o r d i n g t o e x a c t i s o m e r i c c o m p o s i t i o n

.



## 2 GENE RAL INFORMAT ION ON EXPOSURE

Production Volume s and U se Pattern

Com me rci al 4,4’-me th y le ne dic y cl oh ex y l diisocy an at e manufactur ing starts with hy drog enated

me th y le ne diani line (4,4’-me th y le ne bis(c y cl oh ex y la m in e), CAS 1761-71-3) w hich is generall y

known as H 12 

### M DA or P ACM. P ACM is a mix ture of three isomers, trans

, tran s -, cis

, tran s -, and

cis

, cis -PAC M which is obtained by catal y t ic h yd rogenat ion of me th y le ne diani line (MD A). P ACM

is phosgenated (Six and Richter, 2003):

NH 2 

### -C 6 

### H 4 

### -CH 2 

### -C 6 

### H 4 

### -NH 2 

### + 2 COCl 2 

### → OCN-C 6 

### H 10 

### -C H 2 

### -C 6 

### H 1 0 

### -NCO + 4 HCl

During pho sgenation h yd rochlor ic acid is stripped and rec yc le d to y ie ld chlorine for the pho sgene production. The isocy an at e is dried and distilled. The reaction product consists of 92 %

4,4’-me th y le ne dic y cl oh ex y l diisocy an at e with 14 % cis

, cis -isomer, 58 % cis

, tran s -isomer, and

20 % tran s

, trans -isomer (Dieterich and U hlig, 2002), the 2,4 ́- isomers accounting for the rema ining

approx. 8 % (Bay er MaterialScien ce A G, 2004a). Since the trans

, tran s -4,4’-me th y le ne dic y cl oh ex y l

diisoc ya na te is solid in the pure state [me lting point 83 °C ( Dieteri ch and Uhlig, 2002)], to obtain a liquid diisoc ya

na te product in the subsequent pho sgenation, the amount of trans

, tran s

4,4’-me th y le ne bis(c y cl oh ex yl a mi ne ) has to be reduced to less than 20 % ( select ive h yd rogena tion

and/or cry st al lisation) (Six and Richter, 2003).

7

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

The global production capacit y of 4,4’-me th y le ne dic y cl oh ex y l diisocy an at e is 10,000

- 20,000

tonnes/a, with most of it in the US A (Ba ye r MaterialScien ce AG, 2004a). In G erm an y, Ba ye r

MaterialSc ience A G (2004a) is the only producer and has a manuf acturing capacit y of 1000

- 5000

tonnes/a of 4,4’-me th yl en ed ic y cl oh ex y l diisocy an at e.

4,4’-Meth yl en edic y c lo hex y l diisocy an at e is used as an interm edia te in several industries, e.g. the

che mica l industr y and coatings industry

. 4,4’-Meth yl en edic y c lo hex y l diisoc ya na te is u sed as a

mono me r and is industriall y processed to pol y me rs with e.g. pol yo ls in the coatings industr y to

produce e. g. binders, prepol y me rs

, and elasto mers. 4,4’-Meth yl en edi c yc lo hex y l diisoc ya na te is

supplied to the che mica ls industr y, ma inl y coatings industr y, but is not distributed to consumers. It

is used for the manufac ture of

• Binders or hardeners for coating ma teria ls or adhesives (60 %)

• Prepol y

me rs (20 %)

• Others, e.g. for the production of elastom ers (20 %) (Ba ye r MaterialScien ce AG, 2004a).

4,4’-Meth yl en edic y c lo hex y l diisoc ya na te is not used for “D o it Y ourself” applications or in other

consumer products (Ba ye r MaterialSci ence AG

, 2004a). Con sistentl y

, 4,4’-meth y l en ed ic y cl oh ex yl

diisoc ya na te is registered a s a component in approxi mate l y 50 industrial products in the Danish,

Finnish, and S wedish Product Registers with a consumption of about 30 me tric tonnes/a in 2000

and 2001 (last ye ars of record). It is used a s an interm edia te for the m anufactur e of rubber and

plastic products, industrial paints, chemic al products, construction and transport equip ment. There

is no registration for a consumer product. It is confidenti all y listed in the N orwegian Product

Register. The main u se categor y is “ non-dispersive use” ( SPIN, 2004).

The Swis s Product Register (2004) lists 34 industrial products (with concentrations of up to 100 %

4,4’-me th y le ne dic y cl oh ex y l diisoc ya na te), but no consumer product containing 4,4’-meth y l en e

dic yc lo hex y l diisoc ya

na te.

Environm en tal Exposure and Fate

When 4,4’-me th y le ne dic y cl oh ex y l diisoc ya na te is released to water, degradation occurs through

h yd rol y si s ( cf. Chapter 2.2.3). A half- life of approxima tel y 2 hours w as deter mined for

4,4’-me th y le ne dic y cl oh ex y l diisoc ya na te (Ba ye r AG, 1999). The hy dro l ys is product

4,4’-me th y le ne bis(c y cl oh ex yl a mi ne ) wa s asses sed by the EU PBT Working G roup (2003). The

h yd rol y si s product wa s not classified as a PBT (persistent, bioaccum ula tive, toxic) s ubstance.

Sources of

Environ me ntal Exposure

Environ ment al infor mat ion from manuf actur ing and processing of 4,4’-meth y le ne dic y c lo hex y l

diisoc ya na te is available for the Ba ye r plants in German y. Both plants are at the same industrial site

(Ba ye r MaterialScien ce AG, 2004a).

Since phosgene (precursor) and 4,4’-m eth y le ne dic y c lo hex y l diisoc ya na te (product) react violentl y

with traces of water, the sy nth esis is performed in a closed, water-free s yst em (Ba ye r

MaterialSc ience A G, 2004a).

The exhausts from manufac turing and processing are connected to a therm al exhaust purification

plant. Amine and isoc ya na te tanks are secured with activated carbon filters. The product is

auto mat ical l y filled into special me tal drums or IS O containers (20 feet containers) u sing s uction

devices and widel y closed s ys tem s ( cf. Chapter 2.3.1). Thus, according to the current Official

8

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

Em ission Declarat ion of the y ea r 2000, Bay er emit ted virtuall y no 4,4’-meth y le ne dic y c lo hex y l

diisoc ya na te (< 25 kg/a) into the atmosphere during manufac turing and processing (Bay er

MaterialSc ience A G, 2004a).

Waste from the m anufactur ing and processing is incinerated in an incinerator for hazardous wastes

(Ba ye r MaterialScien ce AG, 2004a).

Due to the water sen sitivit y of precursors and product, 4,4’-meth y le ne dic y c lo hex y l diisoc ya na te is

manuf actured in closed sy ste m virtuall y free of water. Water is u sed only in the case of ma in

tenance (after the sys tem has been eluted with solvent), to flush the sy ste m to ensure hy dro l ys is of

phosgene. Due to this procedure, the wastewater doe s not contain 4,4’-m eth y le ne dic y c lo hex y l

diisoc ya na te. However, all wastewater from manuf acturing and processing is led into a Ba ye rowned wastewater treatm ent plant (hy dr auli c retention times > 1 d), where 4,4’-m eth y le ne di

c yc lo hex y l diisocy an at e would be hy drol y z ed ( cf. Chapter 2.2.3). N o additiona l inform ation is

availab le from other comp anies (Ba ye r MaterialScien ce AG, 2004a). H owever, there is no doubt

that rules were abided to and regulations are strictl y met in the Spon sor countr y.

Photodegradation

There are no experim ental data on the stabilit y of 4,4’-meth y l en ed ic y cl oh ex yl diisoc y an at e in the

at mosphere. A half- life of about 15 hour s is esti mat ed due to reaction with photochem ical l y pro

duced h yd

rox y l radicals, considering a mean OH concentration of 0.5 x 10 6 

### O H radicals/cm 3 as a

24 h-average (Ba ye r Indu str y Services, 2004a) ( cf. Table 2). Ho wever, the AO PWIN program used

for this estima te does not take into account that 4,4’-me th yl en ed ic y cl oh ex y l diisocy an at e is

sensitive to h yd

rol y si s e.g. in aerosols with aquatic phases.

Table 2 Photodegradation of 4,4’-meth y l en edi c yc lo hex y l diisoc ya na te (IUCLID 3.1.1)

Para me te r Method Result Reference

In dire ct

photodegrad ation

in air Calculation for 24 h- day

,

500,000 OH/cm 3

, Rate constant =

25.8 x 10 -12 cm 3 /(molecule x s) t 1/2 = 15 h Ba ye r Industr y Services, 2004a



### Stability in Water

4,4’-Meth yl en edic y c lo hex y l diisoc ya na te hy dro l yz es rapidl y in the presence of water. A half- life

for 4,4’-me th y le ne dic y cl oh ex y l diisocy an at e h yd rol y si s of approxi mat el y 2 hour s was deter mined

experi men tall y (Bay er AG, 1999).

In this study performed

in accordance with the GLP-requirem ents, 1 g/l 4,4’-m eth y le ne dic y c lo hex y l

diisoc ya na te dissolved in an acetonitri le/wa ter- mix ture was investigated at 23 °C. The decrease of

NCO-content wa s observed in this solution during the study period. For this purpose the

concentrat ion of 4,4’-me th y le ne dic y cl oh ex y l diisocy an at e was deter mined by means of capill ar y gas chrom atograph y u sing flame ionization detection at continuous time intervals ( cf. Table 3).

The rapid h yd

rol y si s m eans that 4,4’-meth y l en edi c yc lo he x yl diisoc ya na te discharged into the

environ ment will be abiotical l y degraded.

A preli mi nar y test according to the OECD TG 111 was carried out with

4,4’-me th y le ne dic y cl oh ex y l diisoc ya na te to deter min e the resulting products from the reaction with

9

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

water. A solution of 2.64 g/l was incubated in deminer ali zed, unbuffered water at 50 °C during

5 da ys under continuous stirring (Bay er Industry Services, 2004b).

In the aqueous pha se the three isomers of 4,4’-meth y l en ebis(c y c lo hex y l a mi ne ) were identifi ed with

GC- and HPLC-M S. Additionall y

, the H PLC-anal y sis s howed to a minor extent traces of a trim eric

dia mine compound ; this w as bound b y urea-groups. Insoluble droplets obtained during hy dro l ys is

testing adhered to the glass wall. The y were anal yz ed with IR spectroscop y and were found to

contain urea componen ts (poly m er ic urea) and encapsulated traces of isoc ya na te- group s (Ba ye r Industry Services, 2004b). This h yd rol ys is product is more or less inert and

- because of its

ma crom ol ecular size - not bioavailabl e. In addition, this s ubstance is formed only in the case of high

isoc ya na te concentration w hich does not correspond to environmen tal conditions ( EU PBT

Working G roup, 2003)

.

Table 3 Hy drolysis o f 4,4’-m et hy lenedicyclohexyl diisocyanate ( IUCL ID 3.1.2)

Test s ubstance Proc edure Result Reference

4,4’-meth yl enedi

cy cl ohex yl

di isoc ya na te 50 % acetonitrile, 50 % water

Determination of

NCO-content

us ing GC anal ys is wi th F ID

detection t 1/2 = 1.97 hours at 23 °C;

Rate constant k obs =

9.78 x 10 -5 1/s Ba y er AG, 1999



### Transport bet we en Environ me ntal Co mp art me nts

In the aquatic environ ment, 4,4’-meth y l en edi c yc lo hex y l diisoc ya na te will undergo hy dro l ys is

(Ba ye r A G, 1999). Due to the rapid hy dro l ys is of 4,4’-meth y le ne di c yc lo hex y l diisoc ya na te, a

transport of the substance between environmen tal compart me nts is unlikel y

.

A calcul ation of the Henry Law Constant and also of the distribution between the environ ment al

comp artm en ts according to the Mackay fugacit y model level 1 is not suitable due to the hy dro l yz in g properties of 4,4’-me th y le ne dic y cl oh ex y l diisocy an at e.

For the hy drol y si s product, 4,4’-me th yl en eb is(c yc lo he x yl a mi ne ), a Henry Law Constant of

0.00046 Pa-m3/ mo le is obtained b y the Bond method and of 0.016 Pa-m3/ mo le by the vapor pressure/water solubilit y equation (U S EPA, 2005). The Mackay results are compil ed in Table 4.

The predom inant environ ment al compar tm en t of the h yd

rol ys is product is water (98 %) (EU PBT

Working G roup, 2003).

10

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

Table 4 Input parame ters and results for 4,4’-me th y le ne bis(c y cl oh ex yl a mi ne ) of the

Mackay Fugacit y Model Level I (I UCLID 3.3.2)

I np ut Param et er s Val ue

Mo lar mass 210.36 g/mol

Temperature 20 ° C

Vapour pressure 0.033 Pa

Wa ter solubi lity 5800 g/m 3

log K

ow 2.03

Melt ing point 320 ° C

Compart me nt Calculated d istributio n

Wa ter 98.256 %

Air 0.041 %

Sedi ment 0.823 %

S oil 0.880 %

Aquatic Biota 0.001 %



### Biodegradation

Based on the available experi ment al biodegradation test result for 4,4’-meth y l en edi c yc lo hex y l

diisoc ya na te, the s ubstance is classified as not readil y biodegradabl e ( cf. Table 5). No test on

inherentbiogradabil it y is available.

In a GL P-stud y w hich w as conducted according to Directive 92/69/EEC C.4-D (Manome tric

Respirom etr y Test), the biodegradation of 4,4’-me th y le ne dic y cl oh ex y l diisocy an at e w as investi

gated with a test substance concentration of 100 mg/ l (no toxicit y to bacteria observed). Within the

test period of 28 day s, a degradation of 0 % wa s determ ined for 4,4’-meth y le ne dic y c lo hex y l

diisoc ya na te (Bay er AG, 2000a).

In a GL P-stud y w hich w as conducted according to OEC D TG 301F, the biodegradation of

4,4’

- me th y le ne dic y cl oh ex y l diisocy an at e was tested at an initial concentration of 12 mg/ l because a preli min ar y test at 100 mg/l indicat ed that the sub stance was toxic to bacteria present in the sewage sludge. This difference of toxicit y between the two tests, both performed with an inoculu m from a

domest ic sewage sludge, is presumabl y due to changes in sludge properties. Within the test period

of 28 da ys

, a degradation of 0 % was determ ined for 4,4’-meth y le ne dic y c lo hex y l diisoc ya na te

(Ba ye r A G, 1992).

Table 5 Biodegradation o f 4,4’-m et hy lenedicyclohexyl diisoc yanate (I UCLI D 3.5)

Inocul um Pro cedure Result Reference

Aerobic predominantly

domest ic sewag e Directive 92/69 /EEC,

C .4- D 0 % degr adation after 28 da ys Ba ye r AG, 2000a

Domestic activated

s ludge OECD TG 301F 0 % degr adation after 28 da ys Ba y er AG, 1992



### The biodegradabili t y of the hy dro l ys is product, 4,4’-m eth y le ne bis(c y cl oh ex y la m in e), wa s

calcula ted with the EPIWIN BIOWIN (v4.02) Program. Four out of six estim ation me thods predict

11

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

fast biodegradation, with an ultim at e biodegradation tim efram e of weeks (US EPA, 2005). The EU

PBT Working Group (2003) as sessed biodegradation tests on the hy drol y si s product

4,4’-me th y le ne bis(c y cl oh ex yl a mi ne ). These tests sho w that 4,4'-meth y le ne bis(c y cl oh ex y la m in e) is

at least inherentl y biodegradable.

Bioaccum ulation

Measured bioconcentrat ion factors (BC F) for 4,4’-m eth y le ne dic y c lo hex y l diisoc y an at e are not

availab le.

4,4’-Meth yl en edic y c lo hex y l diisoc ya na te hy dro l yz es rapidl y in the presence of water with a half

life of approxi mate l y 2 hour s. Therefore a risk estima tion regarding the bioaccumu lat ion potential

of 4,4’-meth y l en edi c yc lo hex y l diisocy an at e on the ba sis of a log K

ow 

### , determ ined b y Q SAR, is

misl eading. A calcul ated theoretic al log K

ow 

### value reflects the undis sociated mo lecul e without

influence of water.

According to the EU Technical Guidance Documen t a s ubstance is regarded as potentiall y

bioaccu mu lativ e if the log K

ow 

### exceeds 3 and the half life ti me in water exceeds 12 hours. This is

not the case for 4,4’-meth y le ne dic y c lo hex y l diisocy an at e. The sub stance is not persistent in water

due to the rapid h yd

rol ys is

. Therefore it is not bio-availab le. Possible h yd rol y z at ion products are

less lipophilous. On the basis of these informa tion it can not be expected that bioaccu mu lat ion of

4,4’-me th y le ne dic y cl oh ex y l diisocy an at e occurs (Bay er Industry Services, 2003).

The hy dro l ys is product, 4,4’-m eth y le ne bis(c y cl oh ex y la m in e) is also not bioaccu mu lat ive (EU PBT

Working Group, 2003). With a m easured log K

ow 

### (OECD 107) of 2.03, and calculated log K

ow 

### values of 2.55 (CLO GP3 program) (EU PBT Working Group, 2003) and 3.26 (EPIWIN BCF

Program (v2.15)) ( US EPA, 2005), log BCF values of 0.863 (BCF

= 7), 1.264 (BCF

= 18), and

1.814 (BCF = 65) were calculat ed, respectivel y

.

Geoaccum ulation

There are no experim ental data on the geoaccu mu lation potential of 4,4’-meth y l en edi c yc lo hex y l

diisoc ya na te, because the substance hy drol y z es rapidl y in aqueous environmen t.

The distribution of 4,4’-me th y le ne dic y cl oh ex y l diisocy an at e between the organic phase of soil or

sedim ents and the porewater wa s calcula ted u sing Q SAR. With the PCK OC program (v 1.66), a

K

oc 

### -value of 3.8 x 10 5 

### wa s calcul ated for 4,4’-meth y l en edi c yc lo hex y l diisoc ya na te (Bay er Industry

Services, 2004a). For the h yd rol y si s product, 4,4’-meth y l en ebis(c y c lo hex y la m in e)

, a K

oc 

### of 672 is

obtained (US EPA, 2005) ( cf. Table 6).

Table 6 Geoaccum ulation properties o f 4,4’-m et hy lenedicyclohexyl diisoc yanate an d

its hy droly sis product ( IUCL ID 3.3.1)

Compound Method Result Reference

4,4’-meth yl enedi c y cl o

he x yl di isoc ya

na te S oil organic carbon- water

di stribution coefficient calculated

with P CKOC W IN, v.1.66 K

oc = 3.762 x 10 5

, log K

oc = 5.575 Ba ye r Industr y Services,

2004a

4,4’-meth yl enebis

(c yc loh exy la mine) S oil organic carbon- water

di stribution coefficient calculated

with P CKOC W IN, v.1.66 K

oc = 672 US E PA, 2005

12

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

According to Litz (1990) 4,4’-me th y le ne dic y cl oh ex y l diisocy an at e s hould be regarded a s a

substance with ver y high geoaccumu lat ion properties. Ho wever, geoaccu mu lation in soil will be

affected by humidit

y due to its rapid h yd

rol y si s.

It is therefore concluded that geoaccu mul ation of 4,4’-meth y l en edi c yc lo hex y l diisocy an at e is

unlikel y to occur. The hy dro l ys is product ha s onl y a small to med ium tendenc y for

geoaccu mul ation.

Environm en tal Monitoring

No data have been identified.

Hum an Exposure

Occupational Exposure

Occupational exposure to 4,4’-m eth y le ne dic y c lo hex y l diisoc ya na te is most likel y to occur through

inhalat ion and derm al routes.

Workplaces

At the Bay er manuf

actur ing site, s ome 4,4’-meth y l en edi c yc lo hex y l diisoc ya na te is also used in the

production of powder coatings. During this processing 4,4’-me th y le ne dic y cl oh ex y l diisocy an at e is

converted into a poly

m er ic resin (Ba ye r MaterialSc ience AG, 2004a). Workplaces where

4,4’

- me th y le ne dic y cl oh ex y l diisocy an at e is m anufactur ed and processed include ( cf. Chapter 2.1)

• the s yn

thesis of phosgene from carbon monoxide and chlorine s upplied via pipelines from other

manuf acturers in the Bay er integrated industrial site and

• the s yn

thesis of 4,4’-me th y le ne dic y cl oh ex y l diisoc ya na te from phosgene and P ACM, and

finall y

• the isolation and filling of 4,4’-meth y le ne di c yc lo hex y l diisoc ya na te , and

• the processing of 4,4’-meth y l en ed ic y cl oh ex y l diisocy an at e.

4,4’-Meth yl en edic y c lo hex y l diisoc ya na te is manufac tured in closed s yst em s ( cf. Chapters 2.1 and

2.2.1).

To the custom ers most of the 4,4’-meth y le ne dic y c lo hex y l diisoc ya na te is transported in IS O

containers, and (a minor

part) in drums (Ba ye r MaterialScien ce AG, 2004a).

Precautionar y measures at the workplace

In accordance with the principles of Respon sible Care and Sustainable Develop ment, a t Ba ye r the

exposure of workers is reduced to the lowest technical l y practicab le level (Bay er MaterialSci ence

AG, 2004a).

Surve ys of the Bay er workplaces are performed according to German Technical G uidances

TRGS 402 (1997), TRGS 430 (2004), and TRGS 900 (2004). This includes regular s urve ys in the

production plant for an y possible exposure to phosgene, an organic solvent, and

4,4’

- me th y le ne dic y cl oh ex y l diisoc ya na te under all relevant w ork situations, and application of

13

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

appropriate control measures. In the proces sing plant, 4,4’-meth y le ne di c yc lo hex y l diisoc ya na te is

moni tored (Bay er MaterialSci ence A G, 2004a).

To protect w orkers from exposure, several precautionar y and protective measures are taken. E.g.,

sampl ing takes place in a widel y closed s ys tem

. F or filling in ISO containers the workers have to

wear full protective clothing and gas filter masks. Repair and maint enance work is only carried out

on parts of the manufa cturing sy ste m, which have been emp tied. Prior to repair and ma inten ance the

relevant components are flushed with s olvent and water to remov e residual sub stances. Special

written permits are required which include a detailed description of the protective me asures depending on the w ork to be done (e.g., full protective clothing and gas filter masks (classifica tion

ABEK)) (Bay er MaterialSc ience A G, 2004a).

Down stream users of 4,4’-meth y l en edi c yc lo hex y l diisoc ya na te are inform ed b y wa y of a ma teri al

safet y data s heet on the recom me nded safet y measures (see above) (Bay er MaterialSc ience

AG, 2004a).

Potential exposure at the workplace

In German y for occupational settings, the maxi mu m permissible concentration for 4,4’-meth y le ne

dic yc lo hex y l diisoc ya

na te is 0.054 mg/m 3 according to TRGS 900

.

The ma in process to manufa cture 4,4’-me th yl en ed ic y cl oh ex y l diisoc ya na te is by a phosgenation

process. Thus special safety measures are taken to prevent an y risk of exposure

. These measures

include a continuous pho sgene mon itoring coupled with an auto mat ic water/am mo ni a s pra y s yste m

for abate men t. Since 4,4’-meth y l en edi c yc lo he x yl diisoc ya na te is closel y as sociated with phosgene

during manufac turing, these measures are also suited to ensure that neither the environmen t nor the

workers are exposed to 4,4’-meth y l en edi c yc lo he x yl diisocy an at e. In the proces sing area, w here

4,4’-me th y le ne dic y cl oh ex y l diisoc ya na te is used to manuf acture powder coatings, 17

4,4’

- me th y le ne dic y cl oh ex y l diisocy an at e m easurem en ts (8 total shift and 9 s hort term measure

men ts) were made between 1994 and 2001. All results were below the max im um perm issible

concentrat ion (Ba ye r MaterialScien ce AG, 2004a).

Ther mal degradation products form ed during grinding and welding of certain pol yu re thanes were reported to include 4,4’-meth y le ne dic y c lo hex y l diisoc ya na te. Traces of 4,4’-meth y le ne dic y c lo hex y l

diisoc ya na te (up to 2 μg/m 3 

### ) were detected as a ther mol y ti c degradation product during j oint

welding of poly

ur eth ane floor covering in a small room with no ventilat ion in a car repair s hop

(Henriks-Ecker man et al., 2002).

4,4’-Meth yl en edic y c lo hex y l diisoc ya na te ( which was u sed for the manufa cturing of water pipes

equipped with water flow measuring devices), w as not detect able with a li mit of detection of

< 0.0006 mg/sam

pl e (< 0.0022 μg/l) in workplace air of an U S plant (Lewis, 1980).

Con sum er Exposure

4,4’-Meth yl en edic y c lo hex y l diisocy an at e is exclusivel y used as an interm edia te in chemi cal

processes. A direct use of this sub stance is not known (Bay er MaterialSc ience A G, 2004a).

Consistentl y, there is no registration of a consumer product containing 4,4’-me th y le ne dic y cl oh ex y l

diisoc ya na te in the Danish, Finnish, S wedish ( SPIN, 2004), and S wiss P roduct Register (2004).

4,4’-Meth yl en edic y c lo hex y l diisocy an at e is confidenti all y listed in the N orwegian Product Register

(SPI N, 2004), but since the main use categor y is “ non-dispersive use”, it is assumed that the

confidenti al registration is also for industrial use onl y.

14

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

The exposure of consumers to 4,4’-meth y le ne dic y c lo hex y l diisoc ya na te is unlikel y to occur via

consumer products, because no consumer product is kno wn to contain 4,4’-meth y l en ed ic y cl oh ex yl

diisoc ya na te (Bay er MaterialSc ience A G, 2004a)

. A n exposure of consumers to 4,4’

- meth y l en e

dic yc lo hex y l diisocy an at e via the environm ent is also unlikel y to occur because there are virtuall y

no emissions of 4,4’-me th y le ne dic y cl oh ex y l diisoc ya na te

, and 4,4’-meth y l en edi c yc lo hex y l

diisoc ya na te released to environ ment w ould rapidl y be degraded by photooxidants ( cf. Chapter

2.2.2) and w ater

( cf. Chapter

2.2.3)

.



## 3 HUMA N HEALTH HAZARD S

Ef fect s on Hum an Health

Toxicokinet ics, Metabolism an d Distribution

There are no data availab le (With regard to inform ation on the fate of 4,4  ́

- me th y le ne dic y cl oh ex y l

diisoc ya na te in aqueous s ys tem s see chapter 2.2.3).

Acute Toxic ity

Studies in Animals

Inhalation

The acute inhalation toxicit y of 4,4 ́

- meth y l en edi c yc lo hex y l diisoc ya na te (purity > 99.2 %) wa s

studied b y Bay er A G (1995a) b y exposing Wistar rats in seven groups, each containing 5 ma les and

5 fem ales. The method used wa s essentiall y that of OEC D TG 403. Each group was no se only

exposed to concentrations of the aerosol of the test substance. After exposure (4 hours) the ani mals

were observed for two week s. The actual m ean concentrat ions of 4,4 ́

- meth y l en edi c yc lo hex y l

diisoc ya na te were 151, 388, 418, 552, 730, 865 and 1352 mg/ m 3



### . The test sub stance aerosol

exhibited a particle- size indicating that this aerosol was of adequate respirabilit y (90 % of the

particl e mass was ≤ 3 μm ; mass medi an aerod yn am ic diam eter ( MMA D)

≈ 1.4 μm; geometr ic

standard deviation (GS D)

≈ 1.8 μm). Rats exposed to ≥ 151 mg/ m 3 

### experienced signs of re spirator y

tract distress (i.e. salivation, brad yp ne a, stridor). Exposure to concentrat ions of ≥ 388 mg/ m 3 

### caused

mort ali t y, which occurred on the exposure day through po st expo sure day 4. Gro ss necropsy findings (less collapsed lungs including a hemorrhag ic lung edema, red secretions in the nose, pale

liver with lobular pattern, pale spleen and kidne ys ) were ob served only in the rats which died during

the observation period The LC 5 0 

### (4 h) stated in this study (Bay er AG, 1995a) is 434 mg/ m 3 

### with

confidence limi ts (95 %) of 355

- 533 mg/m 3 

### both sexes combin ed.

Another stud y report ( Moba y Chemi cal Corp., 1985) docum ented that the four-hour LC 50 

### of 4,4

 ́

- me th y le ne dic y cl oh ex y l diisoc ya na te (purit y technica l grade, no further data) to ma le rats w as

295 mg/ m 3 

### with 95 % confidence interval of 221 to 380 mg/m 3



### , and to fem ale rats it wa s 307 mg/ m 3



### with 95 % confidence interval of 268 to 327 mg/ m 3



### . The no-observed-effect level was less than

113 mg/ m 3



### . The anim als w ere exposed, by heads onl y, to 4,4  ́

- me th y le ne dic y cl oh ex y l diisoc ya na te

aerosol and observed for two weeks after the exposure. The data on particle size distribution

showed that the mass med ian aerody na m ic dia meter (MM AD) of all concentra tion groups were

≤ 2 μ m but the geome tric standard deviation (GS D) wa s in the range of 2.4 to 5.5. Differences in

the anal y ti ca l me thod for the deter mina tion of the chamber concentrat ion between this study and the

15

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

stud y conducted b y Bay er ten ye ar s after (Bay er A G, 1995a) ma y account for marg inal discrepanc y

of the LC 5 0 

### -values. Due to the analy ti ca l m ethod the airborne concentrat ion measured were probabl y lesser than the actual one because the test substance partl y w ould have been captured by

reaction with filter ma teri al and/or humidi t y. Nevertheless the qualitative data of both studies are in

agree ment. All compound- exposed anim als exhibited nasal and ocular irritat ion during expo sure

and po st- expo sure and the gro ss lesions observed were m ainl y in the no se and lung.

Dermal

In an early acute der mal toxicit y stud y done b y Mon santo Co. (1966) 1 rabbit/dose w as u sed in 6

dose group s with alternating sex. 4,4 ́

- Methy le ned ic y cl oh ex y l diisoc ya na te (purit y not specified)

was applied as 50 % solution in corn oil or undiluted at the do se levels of 1000, 1580, 2510 and

3980 mg/kg b w or 6,310 and 10,000 mg/kg bw throughout a 24-hour exposure period. The test site

was covered. There were no deaths. Transient reduction of activi t y and appetite was observed in

ani mals at the two high dosage levels. No LD 5 0 

### could be obtained from this study

, and it wa s

therefore > 10 g/kg bw.

Oral

An earl y acute oral toxici t y study was conducted on rats with 4,4 ́

- meth y l en edi c yc lo hex y l

diisoc ya na te (purit y not specified) in dose s up to 12,600 mg/kg b w (admin istered as 50 % s olution

in corn oil). Mortalit y occurred at ≥ 7940 mg/kg bw and the LD 5 0 

### wa s determ ined to be

9900 mg/kg b w. Toxic s ym pt om s included severe diarrhea, loss of appetite and increasing

weakness. At autops y

liver discoloration and renal hy pe rem ia were recorded (Mon santo Co., 1966).

Conclusion

4,4  ́

- Meth yl en edic y c lo hex y l diisocy an at e is of low oral and derma l acute toxicit y with an oral LD 50 

### (rat) of 9900 mg/kg bw and a der mal LD 5 0 

### (rabbit) > 10,000 mg/kg. Toxic s ym pt om s after oral

adm inistra tion included severe diarrhea, loss of appetite and increasing weakness

. As sessment of

the acute inhalation toxicit y data indicates that expo sure to respirable aerosols of 4,4  ́

- me th y le ne

dic yc lo hex y l diisoc ya

na te confined predominan tl y to the respirator y tract. Clinica l signs ( salivat ion,

brad yp ne a, stridor) indicat ed respiratory distress. A hemorrhagic lung ede ma wa s considered to be

causative for mortal it y

. A n ani mal study according to OECD TG 403 gives a LC 50 

### (4 h, rat) of

434 mg/ m 3



### .

Irritation

Skin Irritation

Studies in Animals

In two well- conducted (but non-GLP) studies according to OECD TG 404 4,4 ́

- meth y l en e

dic yc lo hex y l diisoc ya

na te (liquid and solid test sample, no data on purity ) was applied under

occlusive dressings for 4 hours to the intact but shaved s kin of a group of 6 male albino Ne w

Zealand rabbits ( Bay er AG, 1981 a, b) ). Skin irritat ion was as sessed after 4, 24, 48, 72 hours and 8

da ys using the D raize s cale. The calculat ion of the primar y irritation index was based on the s cores

of the 24 and 72 hours reading times for ery th em a and ede ma forma tion. In these studies 4,4

 ́

- me th y le ne dic y cl oh ex y l diisocy an at e was considered as moderat el y irrita ting to the skin with an

irritat ion index of 4.2 (liquid sample) and 3.6 (solid sampl e) of max 8.0 (3.1

- 5.0

= mod erate l y

irritat ing). At the end of the po st ob servation period (8 da ys ) surface s kin scaling was observed.

In a study performed according to OEC D TG 404 4,4  ́

- me th y le ne dic y cl oh ex y l diisocy an at e was

considered as severel y irritating to the s kin after 4 hours semi- occlusive exposure (Ba ye r

16

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

AG, 1994b)

. According to the guideline for reasons of ani mal welfare, due to the expected irritant

potenc y of the test substance in the test onl y one anima l was used. The scores according to the

Draize s cale of the 24, 48 and 72 hour s reading ti mes w ere used in calcul ating respective mean

value. The mean value for ery th em a/ eschar formation was 2.7 of max. 4 and the mean value for

ede ma format ion wa s 1.3 of max. 4. After 14 day s the epider mis of the exposed skin area had

beco me partial l y detached.

In 1996 the primar

y dermal irritation /corrosion potentia l of 4,4  ́

- meth y l en edi c yc lo hex y l diiso

c ya na te wa s evaluated when applied to the skin of 3 rabbits under semi- occlusive conditions for

exposure periods of 3-minu tes, 1-hour, and 4-hours (Ba ye r Corporation, 1996). For this purpose the

undiluted test ma teria l was applied to three separate areas on the intact s kin on each ani mal  ́s back.

In this well conducted GLP-stud y no evidence of corrosion was observed at any of the test sites for

an y of the exposure periods. Ba sed on these results, the test mater ial wa s not considered to be a

corrosive ma teri al. Dermal irritat ion wa s evident at all exposure sites and was character ized b y very slight to well- defined er yt he ma (scores of 1 to 2 according to the Draize s cale of max. 4) and very slight to slight ede ma (scores of 1 to 2 according to the Draize scale of max. 4). By da y 21 all signs

of ede ma had s ubsided and only one ani mal wa s noted with ver y slight er yt he ma at all exposure

sites. Ho wever, on day 21, areas of thickened skin were ob served at some or all of the exposure

sites for two anima ls. There w ere no remarkab le signs of clinica l toxicit y and/or ill health noted

during the course of this study

.

E ye Irritation

Studies in Animals

In two studies according to OECD TG 405 4,4 ́

- meth y l en edi c yc lo hex y l diisoc ya na te (liquid and

solid test sampl e) w as instilled into the conjunctival s ac of each ey e of 6 mal e albino New Zealand

rabbits (Bay er AG, 1981 c, d). The right e ye wa s rinsed with saline 30 seconds after instilla tion and

the left ey e remain ed unrinsed. E ye irritation was asses sed using the D raize scale. In these studies

4,4  ́

- me th y le ne dic y cl oh ex y l diisocy an at e was considered to be not irritating to the ey e with an

irritat ion index (24

- 72 hour) of 3.0 (liquid sample, with/without rinsing) and 0.4 ( solid sample,

with rinsing) and 6.3 respectivel y (solid sampl e, without rinsing) (0-10

= not irritating). However,

the individual findings at the various observation times (24, 48, 72 hours) s howed that irritat ion of

the conjunctivae wa s evident for both test samples and both test procedures ( with/without rinsing).

Signs of irritation were character ized b y rednes s and chemosis scored 1 to 2. B y day 8 all signs of

irritat ion had subsided for the ani mals, which have been treated with the s olid s amp le. Slight effects

on the con

junctivae (score 1-2) at the end of the observation period were still ob served in 3/6

rabbits treated with the liquid test mater ial. Corneal opacit y wa s restricted to 3/6 ( solid/liqu id, with

rinsing) and 2/6 (solid, without rinsing) anima ls and was reversible within 72 hours at the latest.

Respirator y Tract Irritation

Studies in Animals

Based on ‘regulator y ’ acute toxicit y studies ( cf. Chapter 3.1.2) no conclusions can be drawn

regarding the respirator y irritating properties of 4,4  ́

- meth y l en edi c yc lo hex y l diisoc ya na te. The s am e applies for the studies that determ ined the 4,4  ́

- me th y le ne dic y cl oh ex y l diisocy an at e concentra tion

causing a 50 % decrease in respirator y rate (R D 50 

### ) for mice (Mobay Chemi cal Corp., 1984; We ye l

and Schaffer, 1985). This test s yst em is restricted to vapors (

= upper tract irritant). It is irrelevant

for aerosols for which the deposit pattern strongl y depends on the generation of the test atmosphere.

For aerosols irritat ion of the respirator y tract is apparentl y more dependent on the specific site

receiving the highest fraction of the do se rather than the total airborne concentration. H owever, the

repeated do se studies ( see 3.1.5 and 3.1.8) do indicate that 4,4 ́

- meth y l en edi c yc lo hex y l diisoc ya na te

causes irritat ion of the respirator y tract.

17

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

Conclusion

4,4  ́

- me th y le ne dic y cl oh ex y l diisoc ya na te is modera tel y to severe irritant to the skin of rabbits

(OECD TG 404). Irritant effects were observed after instillat ion of 4,4  ́

- me th y le ne dic y cl oh ex y l

diisoc ya na te into the ey es of rabbits (OECD TG 405). The repeated dose studies indicat e that 4,4

 ́

- me th y le ne dic y cl oh ex y l diisocy an at e causes irritation of the respirator y tract.

Sensitisation

Studies in Animals

Skin

4,4  ́

- Meth yl en edic y c lo hex y l diisoc ya na te, wa s assessed for sen sitizing properties u sing a modif ied

Guinea pig max im iz ation test of Magnusson and Kligman by Bay er AG (1984). 4,4

 ́

- Meth yl en edic y c lo hex y l diisoc ya na te, 10 % in paraffin oil and Freund’s Complet e Ad juvant were injected intracutaneousl y on day s 0 and 7 in 20 Guinea pigs. D erm al provocation applications of

0.03 and 0.1 % 4,4 ́

- meth y l en edi c yc lo hex y l diisoc ya na te in paraffin oil were made on day 21 (6

hours) and on da y 35 (6 hours). Two negative control groups (one control group for each challenge)

of 10 ani mals were treated with Freund’s Complet e A djuvant and paraffin oil. 4,4 ́

- Methy le ne

dic yc lo hex y l diisoc ya

na te wa s not considered to be a skin sensitizer in this test.

This negative test result was confirmed by the findings of the same laborator y using the G uinea pig

max im iz at ion test of Magnus son and Kligman, which compl y mostl y with OECD TG 406 (Ba ye r

AG, 1985). 4,4 ́

- Methy le ned ic y cl oh ex y l diisoc ya na te, 1 % in paraffin oil and Freund’s Comple te

Ad juvant were injected intracut aneousl y on da y 0 in 20 Guinea pigs. The topical induction was

done on day 7 with 10 % 4,4 ́

- meth y l en edi c yc lo hex y l diisocy an at e for 48 hours. Dermal provo

cation applica tions of 0.001 and 0.01 % 4,4  ́

- me th y le ne dic y cl oh ex y l diisocy an at e in paraffin oil

were made on day 21 (24 hour s, occlusive). A negative control group of 10 ani mals was treated

with F reund’s Compl ete A djuvant and paraffin oil.

The fact that slightl y irritating test concentrat ions were applied for the challenge in both studies

does not invalidate the findings that 4,4  ́

- meth y l en edi c yc lo hex y l diisoc ya na te is not a s kin s ensitizer

in the Guinea pig maxi mi za tion test.

Positive results were reported for 4,4  ́

- me th y le ne dic y cl oh ex y l diisocy an at e in the Buehler As sa y (Ameri can Cy an am id Compan y 1984; Zissu, Binet and Li masset, 1998), mouse ear s welling test

(Stadler and Karol, 1985; Thorne et al., 1987), the local ly mph node assa y ( Dear man, Basketter and

Kimber, 1992; Dearman, Spence and Kimber, 1992).

Stadler and Karol (1984) dealt with the relationship between inhalation of 4,4 ́

- meth y l en e

dic yc lo hex y l diisoc ya

na te and the developmen t of derm al sensitivit y

. F or this purpo se mice and

guinea pigs were exposed to an aerosol (4,4  ́

- meth y l en edi c yc lo hex y l diisocy an at e in acetone) for 2

hours/da y on 3 con secutive day s. Both species exhibited contact sensitivit y upon s ubsequent derma l

challenge whereas caution must be exercised because nose-only exposure s ys tem has an

unavoidable contribution of derm al involve men t.

Respiratory T

ract

In an unpublished report of Bay er AG (1995b), s ensitizat ion of 8 guinea pigs with a single

intrader ma l injection of 4,4 ́

- me th y le ne dic y cl oh ex y l diisoc ya na te (100 μl, 0.13% s olution in olive

oil) followed after four weeks by inhalat ion challenge with the 4,4 ́

- meth y l en edi c yc lo hex y l

diisoc ya na te hapten (30 min, 68 ± 3.6 mg/m 3 

### ) wa s exa mined. N o i mm ed iate- onset responses were

observed. Gros s pathologic al examina tions showed roughly the same incidence of lung changes in

18

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

all G uinea pigs of this study

. The histopathologic al asses smen t of the degree of eosinophilia re

vealed an increased influx of eosinophilic granuloc yt es in ani mals sensitized with 4,4 ́

- meth y l en e

dic yc lo hex y l diisocy an at e. Because eosinophils are known to pla y a critical role in pathogenesis of

asthm a and of other hy pe rresponsive airwa y diseases the study provided evidence that 4,4

 ́

- me th y le ne dic y cl oh ex y l diisocy an at e is a weak respirator y sen sitizer in guinea pigs.

In another set of studies, the Murine Local Ly mph Node As sa y (LLNA) and M ouse IgE Test were

used for the identifica tion of re spirator y allergens, frequentl y as sociated with specific IgE antibod y (Dearm an, Basketter and Kimber, 1992; Dearman, Spence and Kimber, 1992). These data s uggest

that 4,4  ́

- me th y le ne dic y cl oh ex y l diisocy an at e appears not to induce respirator y sensitization. In

another study no pulmonar y sensitivit y wa s detected in any of 12 guinea pigs sensitized b y topical

exposure to 4,4 ́

- meth y l en edi c yc lo hex y l diisoc ya na te (Karol and Magreni, 1982).

Although s ome anim al studies have been published for this endpoint, none are considered as

validat ed assay s to as sess the potential for respirator y sensitizat ion or asthma in humans.

Studies in Humans

Skin

In humans, case reports have demonstrat ed skin effects usually attribu table to occupationa l

exposure to 4,4 ́

- me th y le ne dic y cl oh ex y l diisocy an at e (E mm et t, 1976; Malten, 1977; King, 1980;

Israeli, Smirnov and Sculsky

, 1981; H offman 1982; White, 1982; White, Stewart and

R yc roft, 1983; Thompson and Belisito, 1997; Frick et al., 2003). Some of these cases were subsequentl y determ ined to be cases of derm al sensitizat ion as confirm ed b y patch testing.

Respiratory T

ract

There are no data availab le.

Conclusion

Anima l data are not uniform however they frequentl y provide evidence of a s kin sensitizing

potentia l of 4,4  ́

- me th y le ne dic y cl oh ex y l diisoc ya na te. Human case reports describe allergic contact

derm ati tis due to 4,4  ́

- me th y le ne dic y cl oh ex y l diisoc ya na te exposure. Although no validat ed anima l

mode l is availabl e to a ssess the potentia l for respirator y sensitizat ion or asthm a in humans, ani mal

data support to some extent the h yp oth esis that respiratory h yp ersensit ivit y ma y be induced by 4,4

 ́

- me th y le ne dic y cl oh ex y l diisocy an at e.

Repeated Dose Toxicity

Studies in Animals

No repeated- dose toxicit y studies are available for the oral and derma l route of exposure.

Inhalation

A subacute 4-week inhalation study with 4,4  ́

- me th y le ne dic y cl oh ex y l diisocy an at e according to the

OECD TG 412 wa s perform ed with male and fema le Wistar rats (Ba ye r MaterialScien ce

AG, 2004d). The rats were exposed under d yn am ic directed- flow no se- only expo sure conditions for

6 hour s/da y on 5 day s a week to 0, 1, 6 and 36 mg/ m 3 

### (

= target concentration). The mean actual

exposure concentrations (= anal y ti ca l concentrat ion) were 1.057, 6.022 and 33.83 mg/m 3 

### ).

Throughout the group s the mass median aerody na mi c diame ter (MM AD) was in the range of 1.0-

1.2 μ m (the geom etric Standard deviation

≈ 2) and therefore wa s highly respirable to rats. Mortalit y

did not occur up to the highest concentration tested. N o clinic al effects were recorded for the rats

19

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

exposed to 1 mg/.m 3 

### At 6 mg/m 3 

### in most rats (7/10 mal es and 7/10 fe males) a borderline response,

such as nasal discharge (wet no se), w as observed whilst at 36 mg/ m 3 

### in all rats respirator y tract

irritat ion occurred (brady pn ea, labored breathing patterns, irregular breathing patterns, tach y pn ea,

nasal discharge, stridor, nostrils: red encrustations). The rats of this group experienced a mild

h yp other mi a. No dose dependent effect on body weights wa s observed. There wa s no evidence of

adverse hemato logic al effects. Clinical- chem istr y and urinal y sis were without pathological findings.

There were relativ e to bod y weight significantl y elevated lung weights (app. 12 %) in rats of the

high- level exposure group. No statistical l y significant or conclusive changes of the other absolute or

relativ e organ weights were ob served. Histopathologic al changes were re stricted to the nasal

caviti es, phary

nx, lar yn x, bronchi and lungs, which became unequivocal evident at 36 mg/ m 3 

### and

which occurred at 6 mg/m 3 

### in borderline intensit y. All findings are suggestive of a direct local

irritant me chanis m at the location of initial deposition of aerosol. The lar yn ge al squamous epithelia l

me tapl asia, which w as observed at all exposure concentrations is considered to be a rather ratspecific response and causall y related to adaptive rather than adverse effects. Therefore 1 mg/m 3



### constitutes a no-ob served- adverse-effect- level (N OAEL) for effects governed by respirator y tract

irritat ion (histopathologi cal changes in nasal pas sages, phary nx, bronchi and lung).

4,4  ́

- Meth yl en edic y c lo hex y l diisocy an at e has been exa mined in Wistar rats in a reproduction /

develop men tal Toxicit y Screening Test according to OECD TG 421 (for details and exposure period see Chapter 3.1.8; Ba ye r MaterialScienc e AG, 2004e). The rats were expo sed no se- only

dail y for 6 hour s/da y to nebulized 4,4  ́- me th yl en ed ic y cl oh ex y l diisoc ya na te in concentrat ions of 0,

1, 6 and 36 mg/m 3 

### (= target concentra tions). In all expo sure groups, the aerosol was highly

respirable to rats, i.e., the average mass median aerod yn am ic dia met er ( MMA D) wa s ≈ 1 μ m, the

geom etri c standard deviation ( GSD) was ≈ 2. N o test sub stance- related effects on the appearance,

health or behavior were observed in the F 0 

### parental anima ls up to 36 mg/ m 3 

### except for clear signs of

respirator y tract irritat ion (changes in breathing behavior) at 36 mg/m 3



### . At 6 mg/m 3 

### onl y serous

nasal discharge and red encrusted nostrils were noted in F 0 rats. O ne ma le of the high dose group

was found dead during the prem ating period and one fema le of the high dose group has to be killed

in moribund condition. Bod y w eight gain wa s reduced in both sexes at 36 mg/m 3 

### at some ti me points. Transient reduced food con sump tion was restricted to the mal es of the high do se group. The

absolute and relativ e lung weights were significantl y elevated (14 and 18 %, respectivel y ) at

36 mg/ m 3 

### in male rats. Thus the N OAEL of the subacute study (

= 1 mg/ m 3 

### ) corresponds to these

findings.

Conclusion

No results from repeated- dose toxicit y tests are availabl e for the oral and dermal route of exposure.

A subacute inhalation study (1, 6 and 36 mg/ m 3 

### ; 6 hour s/da y on five da ys /week for 4 weeks) with

rats according to the OEC D TG 412 indicat es the respirator y tract to be the target organ of

respirable 4,4 ́

- meth y l en edi c yc lo hex y l diisocy an at e aerosol. The reported NO AEL for effects

governed by respirator y tract irritation is 1 mg/ m 3 

### ; the LOAEL is 6 mg/m 3 

### (i.e. histopathologi cal

changes in nasal pa ssages, lar yn x and bronchi). The results of the reproduction/dev elopm en tal

toxicit y screening test (OECD TG 421) corresponds to the re sults of the subacute stud y.

Mutagenicity

In vitro Studies

4,4  ́

- Meth yl en edic y c lo hex y l diisocy an at e did not induce gene muta tions in Salmonella typhimurium

strains TA 1535, TA 1537, TA 98, TA 100 and TA 102 in an Ames test under GLP, and according

to OEC D TG 471 (Ba ye r MaterialScien ce AG, 2005). Concentrat ions of up to 50 μg/plate (with S9-

mix) and 16 μg/plate (without S9-mix) w ere u sed. 4,4 ́

- Methy le ned ic y cl oh ex y l diisocy an at e

20

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

showed a strain- s pecific c yt ot oxic it y, starting at 1.6 μg/plate. Appropriate reference mutagens were used as positive controls and sho wed the expected results throughout all tested strains.

A previous Ames test ( DuPont De Nemours, 1977) which does not comp l y with the current

guideline also gave no evidence for a genotoxic potentia l of 4,4  ́

- Methy le ned ic y cl oh ex y l diiso

c ya na te in bacteria. Deficiencies of this Ames test from 1977 comp ared to today  ́ s guideline are the

number and kind of tester strains, the missing independent repeat experim ent and the li mited

docum enta tion.

4,4  ́

- Meth yl en edic y c lo hex y l diisoc ya na te wa s tested in the chromoso me aberration assay with

Chinese hamst er V 79 cells in vitro according to OECD TG 473 (Bay er MaterialScien ce

AG, 2004f). N one of the cultures treated with 4,4 ́

- meth y l en edi c yc lo hex y l diisoc ya na te in the

absence and in the presence of S9 mix up to cy to toxi c concentrat ions (4.5 μg/ml without S 9 mix

and 12 mg/m l with S9 mix) s howed biologica ll y relevant or statistical l y significant increased

numbers of aberrant metaph ases. The positive controls induced clastogenic effects.

In vivo Studies

There are no data availab le.

Conclusion

4,4  ́

- Meth yl en edic y c lo hex y l diisoc ya na te did not induce gene muta tions in bacteri a (OECD TG 471) and demonstra ted no potentia l to induce chromoso me aberrations in Chinese

hamst er V79 cells mam ma li an cells in vitro (OECD TG 473) either with or without met aboli c

activa tion

Carcinogenicity

There are no data availab le.

Toxic ity fo r Reproduction

Studies in Animals

Effec ts on Fertility

In a reproduction/develop me nt al toxicit y screening test according to OEC D TG 421 ( Ba ye r

MaterialSc ience A G, 2004e) Wistar r ats (12 anim als/sex/dose) were exposed to 4,4  ́

- me th y le ne

dic yc lo hex y l diisoc ya

na te aerosol. The rats were exposed nose-onl y dail y for 6 hour s/da y to

concentrat ions of 0, 1, 6 and 36 mg/ m 3 

### (= target concentrations). F 0 

### male and fem ale rats were exposed for 2 weeks (prem ating exposure period), which wa s continued during the approxi mat el y 2

week m ating period. Males were exposed for at least 28 da ys (prior to necropsy ) whereas the

exposure of the F 0 

### femal es continued during the pregnanc y up to day 19 po st coitu m (p.c.).

Exposure of the F 0 

### femal es wa s suspended up to the da y of necrops y on day 4

- 6 p.p. (post partu m),

i.e., the ti me points at which F 1 

### pup s were sacrificed. In all exposure groups, the aerosol was highl y

respirable to rats, i.e., the average mass median aerod yn am ic dia met er ( MMA D) wa s ≈ 1 μ m, the

geom etri c standard deviation (G SD) was ≈ 2. Clinica l signs as changes in breathing behavior and/or

serous nasal discharge were docum ented for F 0 

### anima ls of the 6 and 36 mg/ m 3 

### group s. One ma le of

the high dose group was found dead during the premat ing period and one fem ale of the high do se

group had to be killed in moribund condition. N o effect on body weights gain, food consumption

and necropsy findings, were observed at ≤ 6 mg/ m 3



### . Significant increases of ab solute and relative

21

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

weights of the lungs were detected at 36 mg/m 3 

### in ma le rats. N o effects of 4,4 ́

- meth y l en e

dic yc lo hex y l diisoc ya

na te on reproductive para meters s uch as insem inat ion index, gestation index

and length and the number of impl anta tion sites were described. At 36 mg/ m 3 

### a slightl y reduced

fertili t y index wa s noted ( 0, 1, 6, 36 mg/m 3 

### : fertilit y index: 91.7, 81.8, 83.8, 66.7* % (*= p > 0.05))

. No remark able clinical sign s were s een in an y F 1 

### pub s during the 4 da y lactation period and body

weight gain was comparabl e to the control anim als. In the testes of both group s evaluated (control

and high concentration F 0 

### anima ls) tubular degeneration (main l y mult i/foca l) wa s seen in the

majorit y of anim als. In the epidid y mi de s, spermat ic debris and oligosperm ia occurred in almost all

rats. These histopathologic al findings are concordant with the results of the s perm atolog ical

evaluat ion of all ani mals (no or ver y low sperm mot ili t y and high percentage of abnormal sperms in

control rats and in all concentration groups). Nevertheless the findings seen in the testes are not

substance- related because they were found also in the control ani mals and they are do se in

dependent. Mechanical stress on the epidid y m id es and testes caused by the narrowness of exposure

restrainers seems to be respon sible for the effects seen in all 4,4  ́

- meth y l en edi c yc lo hex y l diiso

c ya na te and air exposed anima ls.

Based on these findings, the N OAEL s w ere considered to be 1 mg/ m 3 

### in males and femal es for

general toxicit y. Due to a slightl y reduced fertilit y index at 36 mg/ m3

, 6 mg/m 3 

### is the N OAEL for

reproductive toxicit y i n rats.

Developmental

T oxicit y

No effects of 4,4 ́

- meth y l en edi c yc lo hex y l diisoc ya na te on developm enta l param eters such as live

birth index and viabilit y index and n o apparent ma lform at ion w ere found in pups of a reproduction/d evelop me nta l toxicit y screening test according to OECD TG 421 in which Wistar

r ats (12 anima ls/sex/dose) have been exposed dail y for 6 hours/da y during two weeks before ma ting

until day 19 of ge station to nebulized 4,4 ́

- me th y le ne dic y cl oh ex y l diisoc ya na te in concentrat ions of

0, 1, 6 and 36 mg/m 3 

### (

= targetconcentra tions; Ba ye r MaterialScien ce AG, 2004e).

The prenatal toxicit y of 4,4 ́

- meth y l en edi c yc lo hex y l diisocy an at e in pregnant Wistar rats was

additiona ll y investigated b y aerosol inhalation according to OECD TG 414 (Ba ye r MaterialSc ience

AG, 2004g). Mated fem ale rats (at least 27/dose) were exposed nose-only to target concentrations

of 0, 1, 6 and 36 mg/m 3 

### for 6 h/day from day 6 to da y 19 p.c.. Particle size determ inat ion of the

aerosol yi el ded M MAD s within the re spirable range (

≈ 1 μ m, the geometr ic standard deviation

(GS D)

≈ 2). Exposure to 4,4 ́

- meth y l en edi c yc lo hex y l diisoc ya na te aerosols caused no premature

death. Clinical signs of respiratory tract irritation (i.e. decreased re spirator y rates, labored breathing,

irregular respiration and sound s consistent with rhinitis) beca me apparent at 36 mg/ m 3



### . Furthermor e, rough fur, serous nasal discharge, reddish encrusted nostrils, occurred in the 36 mg/ m 3



### group. From a pilot inhalation stud y (Ba ye r MaterialScien ce AG, 2004c) it is kno wn that at this

exposure concentration also the lung weights were significantl y increased. At 6 mg/ m 3 

### only single

fem ales evidenced clinical signs of beginning respirator y irritation. Reduction in food consumpt ion

occurred at 36 mg/m 3



### , which was acco mpani ed by a dela y of body weight develop ment during the

treat me nt period (approxim ate l y 24 % below controls) and during gestation (approxim atel y 15 %

below controls). Gro ss-pathologica ll y no treatm ent- related findings in the dams occurred at an y

concentrat ion. The gestation rate, appearance of placent as, placental weights, postimpl anta tion loss,

number of live fetuses, fetal sex distribution, and fetal weights were unaffected by treat men t up to

and including the concentra tion of 36 mg/ m 3



### . With regard to the results on malfor ma ti on a

marg inal l y increased incidence of ventricular septal defects of the heart (three fetuses out of three

litters, 1.2 % of total fetuses) occurred at the 36 mg/ m 3 

### level, which lay onl y margina ll y above the

upper normal range (0.9 % affected fetuses) of scattering of the rat strain used.

The incidence and ty

pe of external or visceral deviations were unaffected by treatm ent at levels up

to and including 6 mg/ m 3



### . A statistica ll y significant l y increased incidence of slight dilation of

22

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

latera l brain ventricles occurred at 36 mg/m 3



### . A treat me nt related effect for this anom al y is unlikel y,

as the incidence is norm all y broadl y scattering between unaffected stud y group s, and because the

value (11.3 % affected fetuses, 56.5 % affected litters) lay within the range of historical control data

and data of different unaffected study groups of the rat strain used (up to 12.7 % affected fetuses, up

to 65.0 % affected

litters).

Nevertheless, a NO AEL of 6 mg/m 3 

### was deter min ed in this stud y with regard to develop men tal

toxicit y

.

Conclusion

Data from an inhalative reproduction/deve lopm en tal toxicit y screening test according to

OECD TG 421 with rats (1, 6 and 36 mg/m 3 

### ) did not reveal s ubstance related i mpair me nt of

reproduction up to a 4,4  ́

- me th y le ne dic y cl oh ex y l diisoc ya na te concentra tion of 6 mg/ m 3



### . A slightl y

reduced fertilit y index was observed at an exposure level (36 mg/m 3 

### ) that wa s as sociated with

parental toxicit y. NO AEL s w ere considered to be 1 mg/m 3 

### in ma les and fem ales for general

toxicit y

. N OAEL for reproductive toxicit y is 6 mg/m 3



### .

Pre-natal inhalat ion toxicit y testing in rats (OECD°TG°421) indicates the absence of selective

toxicit y to the develop men t at levels up to 36 mg/ m 3



### . N o findings indicate an y s pecific

develop men tal effects s uch as live birth index, viabili t y index and apparent ma lform at ion

. The

reported NO AEL (deve lo pm enta l) 

### for 4,4  ́

- me th y le ne dic y cl oh ex y l diisocy an at e in a develop ment al toxicit y

stud y according to OECD TG 414 (1, 6 and 36 mg/m 3 

### ) is 6 mg/ m 3 

### /da y. At the 36 mg/m 3 

### level that

caused clear matern al re spirator y tract toxicit y (N OAEL (materna l) 

### = 1 mg/ m 3 

### ) increased incidences of

ventricul ar septal defects of the heart and slight dilation of lateral brain ventricles were observed,

which lay marg inall y above the upper or within the normal range of scattering of the rat strain used

respectivel y

.

Experi ence wi th hu ma n exposure

Eleven of 15 workers of a plant w hich has in 1981 established a ne w process to prevent glass

bottles from cracking b y coating the bottles with poly ur ethan e (4,4 ́

- me th y le ne dic y cl oh ex y l

diisoc ya na te was u sed as mono me r) suffered from several sign s of an intoxica tion (I sraeli, Smirnov

and Sculsk y, 1981). All worker s dealt for the first ti me with 4,4 ́

- meth y l en edi c yc lo hex y l

diisoc ya na te. The on set of the s ym pt om s wa s observed 4

- 7 da ys after the exposure (no further

details availab le) and all w orkers recovered within 10

- 14 da ys

. With the symp to ms which were

recorded allergic and non-allergic s kin reactions predomin ated (11/11). Six w orkers s uffered from

vertigo with or without headaches and four developed a decrease of the obstructive lung function,

tach y ca rdi a and h yp ot ension (EK G normal). The occupationa l hy gi ene with regard to ventilation

was described as insufficient but no air monitor ing has been done.

Additional informat ion relating to experience with human exposure is presented in Chapters 2.3 and

3.1.4.

Initial A sses sm en t for Hu ma n Health

4,4  ́

- Meth yl en edic y c lo hex y l diisocy an at e is of low oral and derma l acute toxicit y with an oral LD 50 

### (rat) of 9900 mg/kg bw and a der mal LD 5 0 

### (rabbit) > 10,000 mg/kg. Toxic s ym pt om s after oral

adm inistra tion included severe diarrhea, loss of appetite and increasing weakness. A sses smen t of

the acute inhalation toxicit y data indicates that expo sure to respirable aerosols of 4,4  ́

- me th y le ne

dic yc lo hex y l diisoc ya

na te confined predominan tl y to the respirator y tract. Clinica l signs ( salivat ion,

brad yp ne a, stridor) indicat ed respiratory distress. A hemorrhagic lung ede ma wa s considered to be

23

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

causative for mortal it y

. A n ani mal study according to OECD TG 403 gives a LC 50 

### (4 h, rat) of

434 mg/ m 3



### .

4,4  ́

- Meth yl en edic y c lo hex y l diisoc ya na te is moderat el y to severel y irritant to the skin of rabbits

(OECD TG 404). Irritant effects were observed after instillat ion of 4,4  ́

- me th y le ne dic y cl oh ex y l

diisoc ya na te into the ey es of rabbits (OECD TG 405). The repeated dose studies indicat e that 4,4

 ́

- me th y le ne dic y cl oh ex y l diisocy an at e causes irritation of the respirator y tract.

Anima l data are not uniform however they frequentl y provide evidence of a s kin sensitizing

potentia l of 4,4  ́

- me th y le ne dic y cl oh ex y l diisoc ya na te. Human case reports describe allergic contact

derm ati tis due to 4,4  ́

- me th y le ne dic y cl oh ex y l diisoc ya na te exposure. Although no validat ed anima l

mode l is availabl e to a ssess the potentia l for respirator y sensitization or asthma in humans ani mal

data support to some extent the h yp oth esis that respiratory h yp ersensit ivit y ma y be induced by 4,4

 ́

- me th y le ne dic y cl oh ex y l diisocy an at e.

No results from repeated- dose toxicit y tests are availabl e for the oral and dermal route of exposure.

A subacute inhalation study (1, 6 and 36 mg/ m 3 

### ; 6 hour s/da y on five da ys /week for 4 weeks) with

rats ( OECD TG 412) indicat es the respirator y tract to be the target organ of respirable 4,4

 ́

- me th y le ne dic y cl oh ex y l diisocy an at e aerosol. The reported NO AEL for effects governed b y respirator y tractirritat ion is 1 mg/m 3 

### ; the LO AEL is 6 mg/m 3 

### (i.e. histopathologi cal changes in na sal

passages, lar yn x and bronchi). The results of a reproduction/develop me nt al toxicit y screening test

(OECD TG 421) corresponds to the re sults of the subacute stud y.

4,4  ́

- Meth yl en edic y c lo hex y l diisoc ya na te did not induce gene muta tions in bacteri a (OECD TG 471) and demonstra ted no potentia l to induce chromoso me aberrations in Chinese

hamst er V79 cells in vitro ( OECD TG 473) either with or without m etabol ic activation.

Data from an inhalative reproduction/deve lopm en tal toxicit y screening test according to

OECD TG 421 with rats (1, 6 and 36 mg/m 3 

### ) did not reveal s ubstance related i mpair me nt of

reproduction up to a 4,4  ́

- me th y le ne dic y cl oh ex y l diisoc ya na te concentra tion of 6 mg/ m 3



### . A slightl y

reduced fertilit y index was observed at an exposure level (36 mg/m 3 

### ) that wa s as sociated with

parental toxicit y

. NO AELs were considered to be 1 mg/m 3 

### in ma les and fem ales for general

toxicit y

. N OAEL for reproductive toxicit y is 6 mg/m 3



### .

Pre-natal inhalat ion toxicit y testing in rats (OECD°TG°421) indicates the absence of selective

toxicit y to the develop men t at levels up to 36°mg/ m 3



### . N o findings indicate an y s pecific

develop men tal effects s uch as live birth index, viabili t y index and apparent ma lform at ion

. The

reported NO AEL (deve lo pm enta l) 

### for 4,4  ́

- me th y le ne dic y cl oh ex y l diisocy an at e in a develop ment al toxicit y

stud y according to OECD TG 414 (1, 6 and 36 mg/m 3 

### ) is 6 mg/ m 3 

### /da y. At the 36 mg/m 3 

### level that

caused clear matern al re spirator y tract toxicit y (N OAEL (materna l) 

### = 1 mg/ m 3 

### ) increased incidences of

ventricul ar septal defects of the heart and slight dilation of lateral brain ventricles were observed,

which lay marg inall y above the upper or within the normal range of scattering of the rat strain used

respectivel y

.



## 4 HAZARDS TO THE ENVIRONMENT

Aq uatic Ef

fect s

The inherent propert y of 4,4’-meth y le ne dic y c lo hex y l diisocy an at e is to h yd rol y ze in an aquatic

environ ment. In the following the toxicit y of 4,4’-me th yl en ed ic y cl oh ex y l diisocy an at e and its

h yd rol y si s products is reported. Because of the rapid h yd rol y si s the as sessment of the sub stance

24

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

should be ba sed on the h yd rol y si s products and not on 4,4’-me th yl en ed ic y cl oh ex y l diisocy an at e.

Tests w ere conducted according to the GLP requiremen ts and speciall y laid do wn test conditions.

Acute Toxicit y Test Results

Concerning the acute toxicit y of 4,4’-me th y le ne dic y cl oh ex y l diisocy an at e and its h yd rol ys is

products towards aquatic species, experi men tal results for the three trophic levels ( cf. Table 7) are

availab le. QS AR (EcoSar, version 0.99) calcula tions showed s ubstantial l y lower EC/LC

x 

### values for

the main hy dro l ys is product, 4,4’-me th y le ne bis(c y cl oh ex y la m in e).

A static acute test with D anio rerio (formerl y Brachydanio re rio ) was conducted according to the

German U BA-proposal of 1984, which is in most parts equivalent to OEC D TG 203. The test

solutions were treated in w ater with ultra- turrax at 8000 rpm for 60 seconds, before the ani mals

were added. Based on nomin al concentration of 4,4’-meth y l en edi c yc lo he x yl diisocy an at e a 96 hLC 5 0 

### of 1.2 mg/l (nomina l) was obtained (Bay er AG, 1992). H owever, this test has not been taken

into account for the as sessment of 4,4’-meth y le ne di c yc lo hex y l diisoc ya na te. The aquatic half-life of

this isoc ya

na te is approxi mat el y 2 hour s. P ossible aquatic em issions of the substance would enter a

wastewater treat me nt plant with a h yd rauli c retention time of several h yd rol y si s half-lives, which

me ans that virtuall y all isoc ya na te would hy drol y z e before it enters environm enta l waters. Thus, for

asses sm ent, not the isocy an at e, but its h yd rol y si s product have to be tested. The hy dro l ys is product,

4,4’-me th y le ne bis(c y cl oh ex yl a mi ne ), is the predom inant form of the test substance in the following

tests:

Before beginning of the following studies with D anio rerio (formerl y Brachydanio re rio ), Daphnia

magna and Scenedesmus subspicatus pre-treat men ts were performed with 4,4’-me th yl en ed i

c yc lo hex y l diisoc ya

na te according to the recom me ndat ion mention ed in the “ OECD Guidance

Documen t on aquatic toxicit y testing of difficult s ubstances and mixtur es” in order to accelera te the

solution procedure. F or that purpose the solutions of the test substance were prepared at a nomina l

concentrat ion that were 5fold higher than the m axim um water s olubilit y found for

4,4’

- me th y le ne dic y cl oh ex y l diisocy an at e in prelim inar y tests. The solutions were treated in water

with ultra- turrax 60 s/8000 rpm, afterwards stirred for 24 hours on a magn etic stirrer and finall y

filtered. Because of the short half- life of 4,4’-meth y le ne dic y c lo hex y l diisoc ya na te, testing with the

degradation products is required and has been conducted a s seen in this test. Filtration removed

additiona l insoluble h yd

rol ys is products. Substance concentrat ions (m ainl y the soluble h yd rol y si s product 4,4’-me th y le ne bis(c y cl oh ex y la m in e)) were determ ined as TOC and back-calcula ted to the

parent compound.

Acute toxicit y to fish ( D anio re rio ) has been investigated in a limi t test under static conditions

according to Directive 92/69/EEC, C.1. A concentrat ion of 30 mg/l 4,4’-me th y le ne dic y cl oh ex y l

diisoc ya na te was pretreated before start as described above. A 96 h-LC50 of > 8.1 mg/ l (deter min ed

as TOC and back-calcul ated to parent substance) was observed (Ba ye r AG

, 2000b). At this

concentrat ion level 10 % morta lit y was detected, however, in a range finding test no mor tal it y

occurred at the highest concentration tested of 6 mg/l (nomina l).

The hy dro l ys is product, 4,4’-m eth y le ne bis(c y cl oh ex y la m in e), has a low ecotoxici t y (LC

5 0 

### (fish)

= 38 mg/l) and was not classified as a PBT substance (EU P BT Working Group, 2003).

With the invertebrate Daphnia m agna one acute static lim it test in accordance with Directive

92/69/EEC, C.2, is availabl e. For a test period of 48 hour s an EC 0 

### value of ≥ 8.3 mg/l (deter min ed

as TOC and back- calculat ed to parent substance) wa s deter min ed. At this concentra tion no mor tal it y

was observed. A start concentrat ion of 45 mg/l 4,4’

- me th y le ne dic y cl oh ex y l diisoc ya na te was

treated for 24 h in the same wa y as described above (Ba ye r A G, 2000c).

25

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

Concerning the algal toxicit y, a 72-hour test with Scenedesmus subspicatus was performed.

According to Directive 92/69/EEC, C.3, the growth inhibit ion of the alga s pecies was investigated

with test substance concentrations in the range of 0.08 to 5 mg/l. The proceeding for preparation of

the stock solution wa s in the same way as described above (stirring and filtration). A 72 h-E

r 

### C 50 

### of

> 5 mg/l (deter min ed a s TOC and back- calculated to parent s ubstance) was deter min ed. A s the test

concentrat ions for the deter mina tion of the N OEC and LOEC were below the detection li mit of the

TOC determ inat ion (2 mg/l), the test results of the algal toxici t y study refer to nomina l

concentrat ions. The arithm etic means of the TOC deter mina tion of the highest test concentrat ion

(5 mg/ l) exhibited an expected recover y rate (90 %) of the test substance based on organic C (Ba ye r

AG, 2000d).

Because of the short half-live of, testing with the degradation product is required for as sessment.

The results of the aquatic toxicit y testing on fish, D aphnia and algae of virtuall y comp lete l y

h yd rol y ze d 4,4’-me th yl en ed ic y cl oh ex y l diisocy an at e are compi led in Table 7 (all studies compi led

in this Table have a reliabil it y of 1).

Table 7 Acute toxicit y of h yd rol y ze d 4,4’-me th yl en ed ic y cl oh ex y l diisocy an at e to fish,

Daphnia and algae

Species Test type Result Reference IUCLID

Brachydanio rerio

(fish) S tatic, 96 h LC 50 > 8.1 mg/l*

(10 % m ortalit y

rate) Ba y er

AG, 2000b 4.1

Daphnia magna

(crustace an) S tatic, 48 h EC 50 > 8.3 mg/l* Ba y er

AG, 2000c 4.2

Scenedesmus s ubspicatus

(alga e) S tatic, 72 h E

r C 50 > 5 mg/l*

NOEC (cell density ) = 0.31 mg/l (n)

LO EC (cell densi t y) = 0.63 mg/l (n) Ba y er

AG, 2000d 4.3

*determined as TOC and back- calculated to the parent compound

(n) nom inal concentration



### Chronic Toxicit y Test Results

Chronic data for aquatic toxicit y of 4,4’-meth y le ne di c yc lo hex y l diisoc ya na te are not available.

Deter mina tion of PNEC

aqu a 

### :

Since there are acute test results availabl e for 4,4’-me th yl en ed ic y cl oh ex y l diisoc ya na te and its

h yd rol y si s products from three trophic levels, an as sessment factor of 1000 wa s applied for the

derivation of the PNEC

aqu a 

### according to the EU Technica l Guidance Document. The lowest acute

tested concentration level wa s 5 mg/ l for the alga s pecies Scenedesmus s ubspicatus : 72 h-E

r 

### C 50



### > 5 mg/l (nomina l) (Ba ye r A G, 2000d). This value was u sed to calculat e the

PNE C

aq ua 

### > 5 μg/l

Toxicit y to Microorganis ms

Regarding the toxicit y to microorgan isms, an ox yg en consumption inhibition test according to

Com mission Directive 88/302/EEC, Part C (correspond s to the OEC D TG 209) with activated

sewage sludge during 3 hours was performed and an EC 50 

### of 191 mg/ l (nomina l) w as determ ined

(Ba ye r AG, 2000e). Before testing a pre-treat me nt wa s performed with the test substance according

to the reco mm enda tion mention ed in the OECD G uidance Documen t on aquatic toxicit y testing of

difficult substances and mixtures. 4,4’-Meth yl en edic y c lo hex y l diisoc y an at e wa s directl y weighted

26

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

into water, treated by ultrasound for 3

- 4 hours and stirred overnight. This led to the nearly

comp let e hy drol y si s of 4,4’-meth y le ne dic y c lo hex y l diisocy an at e and to the forma tion of the

h yd rol y si s product, 4,4’-meth y l en ebis(c y c lo hex y l a mi ne ).

The EU PBT Working G roup (2003) reports that the hy dro l ys is product, 4,4’-meth y le ne bis

(c yc lo hex y la m in e), has a low ecotoxici t y ( EC 3 

### (bacteria)

= 80 mg/l)

.

B y an oxy gen consumption inhibition test according to ISO 8192 with activat ed sewage sludge

during 3 hours, an EC 5 0 

### of 19 mg/l (nomin al) was deter mined under conditions w hich were not

relevant for as sessment (Bay er AG, 1992).

Microbial toxicit y of the hy drol y si s products of 4,4’-meth y l en edi c yc lo hex y l diisocy an at e is

presented in Table 8.

Table 8 Toxicity o f h yd rolyzed 4,4’-me th yle nedicyclohexyl diisoc yanate to

m icroorganis ms

Species E nd point Param et

er E ffects Reference IUCLID

Activated s ludge In hibition of

respiration 3 h-EC 50 191 mg/l (n) Ba y er AG, 2000e 4.4

(n) nom inal concentration



### Terrestrial E ff

ects

No data available.

Other Environ me ntal Ef fect s

No data available.

Initial A sses sm en t for t he E nvironm ent

4,4’-Meth yl en edic y c lo hex y l diisocy an at e is a slightl y ye ll owish, moisture/wa ter sen sitive liquid

with a mel ting point of 15 °C. 4,4’-Meth yl en edic y c lo hex y l diisocy an at e has a relative densit y of

1.07 at 25 °C, a boiling point of 167

- 168 °C (at 2 hPa), and a vapor pressure of 2.13 x 10 -5 

### hPa at

25 °C [Directive 92/69/EEC, A.4]. A water solubilit y and a log K OW 

### are not deter minab le due to the

instabili t y of 4,4’-me th yl en ed ic y cl oh ex y l diiso cy an at e in water. The flash point of

4,4’-me th y le ne dic y cl oh ex y l diisoc ya na te is 200 °C [ DIN 51758], the ignition point is 225 °C and

the viscosity is approxi mat el y 30 mPa x s at 25 °C [ DIN ISO EN 3219/A.3]. The calcula ted half- life

of 4,4’-me th y le ne dic y cl oh ex y l diisocy an at e in air due to indirect photodegradat ion is about 15.0 h.

4,4’-Meth yl en edic y c lo hex y l diisoc ya na te hy dro l ys es rapidl y in the pre sence of water, the major

product in aqueous phase is 4,4’-meth y l en eb is(c yc lo hex y l a mi ne ). In water, a half- life for

4,4’

- me th y le ne dic y cl oh ex y l diisoc ya na te of approxim ate l y 2 hour s was deter mined experi men tall y

. Due to the rapidhy dro l ys is of 4,4’-meth y le ne di c yc lo hex y l diisoc ya na te, a transport of the substance

between environmen tal compar tm en ts is unlikel y. Con sequentl y

, a calculat ion of the Henr y Law

Constant and of the distribution between the environ ment al co mpart me nts according to the Macka y fugacit y mod el level 1 is not suitable.

27

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

However, several aquatic toxicit y tests have been undertaken with 4,4’-meth y le ne dic y c lo hex y l

diisoc ya na te and its h yd

rol ys is products. Because of the rapid h yd rol ys is the as sessment of the

substance should be based on the hy dro l ys is products and not on 4,4’-meth y l en ed ic y cl oh ex y l

diisoc ya na te. The hy drol y si s product 4,4’-me th yl en eb is(c yc lo hex y l a mi ne ) was asses sed by the EU

PBT Working G roup. The h yd rol ys is product wa s not classified as a PBT sub stance.

4,4’-Meth yl en edic y c lo hex y l diisoc ya na te is not readil y biodegradable.

Due to the rapid hy dro l ys is 4,4’-me th yl en ed ic y cl oh ex y l diisoc ya na te is neither per sistent in the

water compart

me nt nor bioaccum

ula tive. The calcul ated K

oc 

### -value indicates that 4,4’

- meth y l en edi

c yc lo hex y l diisoc ya

na te ma y strongl y adsorb to s oil but due to its rapid hy dro l ys is an y emission to

the terrestria l compart

me nt would be affected b y humidi t y and therefore, geoaccum ula tion of

4,4’

- me th y le ne dic y cl oh ex y l diisocy an at e is not expected to occur.

Concerning the toxicit y of 4,4’-me th y le ne dic y cl oh ex y l diisocy an at e and its h yd rol ys is products

towards aquatic s pecies, reliable experim enta l results of tests with fish, Daphnia

, and algae are

availab le (*

= determ ined as TOC and back-calcul ated to parent s ubstance, n = nomina l

concentrat ion).

Danio rerio (fish): 96 h-LC

5 0 

### > 8.1 mg/l*, [Directive 92/69/EEC, C.1]

Daphnia magna (aq. invertebrat e): 48 h-EC

5 0 

### > 8.3 mg/l*, [Directive 92/69/EEC, C.2]

Scenedesmus subspicatus (algae): 72 h-E

r 

### C 5 0 

### > 5 mg/l*, [Directive 92/69/EEC, C.3]

Activated se wage sludge (bacteria) : 3 h-EC

5 0 

### = 191 mg/l (n), [Directive 88/302/EEC, Part C

(corresponds to the OEC D TG 209)].

It has to be considered that the toxicit y observed in the reported aquatic studies w as caused both by

the 4,4’-meth y l en edi c yc lo he x yl diisoc ya na te as well a s b y the h yd rol ys is products due to the

instabili t y of the test substance.

Based on the acute aquatic toxicit y data on three trophic levels (fish, D aphnia

, algae), the Predicted

No Effect Concentration (PNEC

aqu a 

### ) can be calculated with an as sessment factor of 1000 applied to

the lowest acute effect concentrat ion. The lowest 72 h-E

r 

### C 50 

### -value of > 5 mg/l obtained for the alga

species Scenedesmus s ubspicatus wa s used to derive a P NEC

aqu a 

### of > 5 μg/l.



## 5 R ECOMMENDATION S

Hum an Health:

The chem ical pos sesses properties indicating a hazard for human health (severe irritation of skin,

e ye and respirator y tract, sensitization of s kin and predicted to be a respirator y tract sensitizer

because it is a diisocy an at e). Based on data presented b y the S ponsor countr y (relating to

production by one producer which accounts for approxi mat el y 5 % to 50 % of global production

and relating to the use pattern in several OECD countries)

, occupationa l exposure is anticipa ted to

be low and there are no known consumer uses. Therefore this chemi cal is currentl y of low priorit y

for further work. Countries ma y desire to investigate an y expo sure scenarios that were not pre sented

b y the Spon sor countr y.

Environm en tal:

The che mic al (including its h yd rol y si s products) po ssesses properties indicat ing a hazard for the

environ ment. Based on data presented by the Sponsor country (relating to production by one producer w hich accounts for approxima tel y 5 % to 50 % of global production and relating to the u se

28

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

pattern in several OECD countries)

, exposure to the environ ment is anticipat ed to be low, and

therefore this chemi cal is currentl y of low priorit y for further work. Countries ma y desire to

investigat e an y exposure scenarios that were not presented b y the S ponsor countr y. The chem ical is

currentl y of low priorit y for further work.

29

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE



## 6 R EFERENCES

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sensitizat ion study in guinea pigs with toluene diisoc ya na te and others with cover letter dated

051592; Auletta, CS and Daly IW. Bio/d yn a mi cs Inc. Pro ject No. 4971-84 Decemb er 20, 1984

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Ba ye r AG (1981a). Bericht ueber die Pruefung von Dic yc loh ex yl m e th an- 4,4-diisocy an at flues sig

auf prima ere Hautreizwirkung. Schreiber G, Fraunhofer In st (FH G) April 02, 1981 and Moba y

Corp (1981). The evaluat ion of liquid dicy cl oh ex yl m et ha ne- 4,4 ́- diisocy an at e for pri mar y skin

irritat ion in rabbits with cover letter dated 072987 NTIS/OTS 515391 Doc I. D. 86-870001232

(1987).

Ba ye r A G (1981b). Bericht ueber die Pruefung von Dic yc lo hex y l me th an- 4,4-diisoc ya na t fest auf

prim aere Hautreizwirkung. Schreiber G

, Fraunhofer In st ( FHG) A pril 02, 1981 and Mobay Corp

(1981). Bericht ueber die P ruefung von Dicy cl ohex y l m et ha n- 4,4-diisoc ya na t fest auf primaere

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auf Schlei mhautr eizwirkung. Schreiber G

, F raunhofer Inst (F HG) A pril 02, 1981 and Mobay Corp.

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Ba ye r A G (1999). Decrease of N CO-Content in Water. Unpublished Report N 99/0049/01 LEV,

1999-05-14.

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31

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Dieterich D, Uhlig K (2002). Poly ur ethan es. Ullm ann's Ency cl op edia of Industrial Chem istr y (electron ic release). Wile y

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Henriks-Ecker man M-L, Vaelim aa J

, Rosenberg C, Peltonen K

, Engstroem K (2002). Expsure to

airborne isoc ya

na tes and other therm al degradation products at poly ur ethan e- processing

workplaces. J . Environ. Monit. 4 , 717-721.

Hoffman TE (1982) Allergic Contact D erm ati tis to new plastic resins. Arch Derma tol 118 , 962.

Israeli R, Smirnov V

, Sculsk y M (1981). Vergiftungserscheinungen bei Dicy cl ohex y l

- me than4,4'-diisocy an at

- Exposition (Intoxication due to dicy cl oh ex yl

- m ethane- 4,4 '-diisoc y an at e exposure).

Int. A rch. O ccu. Environ. Health 48 (2), 179-184.

Karol M H, Magreni C (1982). Extensive s kin s ensitizat ion with mini ma l antibody production in

Guinea pigs as a result of expo sure to dic yc lo hex y l me th an e- 4,4'-diisocy an at e. Toxicol. A ppl.

Pharma col. 65, 291-301 and D ow Chem ical Co. (1992). Initial submission: Sen sitivi t y to

dic yc lo hex y l m et ha ne diisoc ya na te with cover letter dated 050792, NTIS/OTS 537254 D oc I.D. 88-

92002444 (1992).

King CM (1980). Contact sensitivit y to Hy len e W. Cont. Dermat. 6 , 353-354.

Lewis FA (1980). NIOS H Health Hazard Evaluation Deter mina tion Report Number 79-141-711,

Fischer and Porter Compan y

, Warminst er, Pennsy lv ania. U S NIO SH, PB81-167918, 13 pp.

Litz N (1990). Schutz vor weiteren anthropogenen Organika- Einträgen. In: Blume H-P (ed.):

Handbuch des Bodenschutzes. Bodenoekologie und –belastung; V orbeugende und abwehrende

Schutz massnahm en. Ecomed- Verlag Landsberg / Lech. 581.

Malten KE (1977). 4,4 '-Diisod ya na to dicy cl ohex y l methan e ( H yl en e W): a strong contact sensitizer.

Cont. Dermat. 3 , 344-346.

Mobay Chem ical Corp. (1984). Sensory irritation of D esmodur W to mic e. Sangha GK Study

Number 82-341-03 Report N o. 479, Ma y 3, 1984 and Moba y Chemi cal Corp. (1987). Sensory

irritat ion of Desmodur W to mi ce with cover letter dated 072987 NTI S/OTS 515436, Doc I. D. 86-

870001277 (1987).

Mobay Chem ical Corp. (1985). Acute inhalat ion stud y with dicy cl oh ex yl m et ha ne 4,4-diisocy an at e (Desmodur W) in rats. Sangha G K Study Number 82-041-05 Report N o. 642, July 15, 1985 and

Mobay Chem ical Corp. (1985). Acute inhalat ion stud y with dicy cl oh ex yl m et ha ne 4,4-diisocy an at e

32

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

(Desmodur W) in rats with cover letter dated 080687 NTIS/OTS 515395, Doc I.D. 86-870001236

(1987).

Monsanto Co. (1966). Toxicologi cal investigation of: 4,4 ́- diisocy an at o dic yc lo hex y l meth ane.

Younger FM Y ounger Laboratories Mon santo Pro ject N umb er YO -66-107 June 9, 1966 NTIS/OTS

555173, Doc I.D. 88-920008675 (1992).

NIO SH (2004). http://www.cdc.gov/niosh/npg /npgd0412.ht ml (Pocket G uide to Chem ica l

Hazards); U .S.A.

Six C, Richter F (2003). Isocy an at es, Organic, 4. Production. Ullm ann's Enc yc lo ped ia of Industrial

Chem istr y. Electron ic release. Wile y

- VCH Verlag GmbH & Co. KGaA, Weinheim

.

SPI N (2004). Substances in Preparations in Nordic Countries. w ww. spin2000.net/spin.h tm l

.

Stadler J C, Karol M H (1984). Experim ent al dela ye d h yp ersensitv it y following inhalat ion of

Dic yc lo hex y l me th an e- 4,4'-diisocy an at e: a concentration- response relationship. Toxicol A ppl

Pharma col 74 , 244-249.

Stadler J C, Karol M H (1985). U se of do se-response data to compar e the s kin sensitizing abilities of

dic yc lo hex y l m et ha ne- 4,4'-diisoc ya na te and picr yl chloride in two ani mal species. Toxicol. Appl.

Pharma col. 78 , 445-450.

Swis s Product Register

(2004). Per sonal comm

un icat ion to B UA, Juli 2004.

Thompson T, Belisito DV (1997). Allergic contact derma tit is from a diisocy an at e in w ool

processing. Cont. Dermat. 37 , 239.

Thorne P S, Hillebrand J A, Lewis GR, Karol MH (1987). Contact s ensitivit y by diisocy an at es: potencies and cros s-reactivi ties. Toxicol. Appl. Pharmaco l. 87 , 155-165.

TRGS 402 (1997). Technische Regeln für Gefahrstoffe 402: Ermi ttlung und Beurteilung der

Konzentrationen gefaehrlicher Stoffe in der Luft in A rbeitbere ichen http://www.baua.de/prax /

ags/trgs402.pdf

.

TRGS 430 (2004). Isocy an at e –Exposition und Ueberwachung http:/ /www.baua.de/prax/ index.ht m

TRGS 900 (2004). Technische Regeln für Gefahrstoffe 900: Lim it values relating to air in the

workplace, http://www.baua.de/pr ax/ags/trgs900.pdf.

US EP A (US Environm enta l Protection Agency ) (2005). EPIWIN progra m (EPI suite) calculat ion

for 4,4’-me th y le ne bis(c y cl oh ex yl a mi ne ) (C AS 1761-71-3).

http://www.epa.gov/opp tintr /exposure/docs/ episuit edl.ht m (for program do wnload).

We ye l D A, Schaffer RB (1985). P ul monar y and sen sor y irritation of dipheny l me th ane- 4,4'- and

dic yc lo hex y l m et ha ne- 4,4'-diisoc ya na te. Toxicol. Appl. Pharmaco l. 77 , 427-433.

White IR, Stewart J R, Ry crof t R J (1983). Allergic contact derma tit is from an organic di- isocy an ate.

Cont. Dermat. 9 , 300-303

White R (1982). Allergisches Kontakt- Ekzem aufgrund eines organischen Di-isoc ya na ts. Beitrag

zum Kolloquium zu den Orientierungsgrundsaetz en der Forschung im Bereich der Industriellen

Toxikologie, Nancy 27.-29.09.1982: 22-23.

Zhuravlev EZ (1976). Flash and ignition points of certain organic isoc ya na tes. J

. Appl. Che m.

US SR (Engl. Transl.) 49 , 90-94.

33

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

Zissu D

, Binet S, Limasset JC (1998). Cutaneous sensitization to some poly is oc y an at e prepol y me rs

in G uinea pigs. Cont. Derma t. 39 , 248-251.

34

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE



# S I D S

Dossier

Ex isting Chem ica l : ID: 51 24-3 0-1

C AS No. : 5 12 4-30-1

EINECS Name : 4 ,4'-me thylen edicyclohexy l diisocyana te

EC No. : 2 25-8 63-2

Molecu lar W eight : 2 62 .3 5 g/m ol

Molecu lar Formul a : C1 5H22N 2O2

Produc er r elated p art

Company : B ayer A G

Cre ation date : 0 8. 12. 19 94

Substan ce r el ated part

Company : B ayer A G

Cre ation date : 0 8. 12. 19 94

St atus :

Memo :

P rinting date : 0 9. 11. 20 06

Revision date : 1 2. 02. 19 97

Date of la st update : 0 9. 11. 20 06

Number of

p age s : 1 30

Chapter (profile) : Ch apt er: 1 , 2, 3, 4, 5, 6, 7, 8 , 1 0

Re liabi lit y (profile) : Relia bility: without relia bility, 1, 2, 3 , 4

Fl ags (profil e) : Flags: without fl ag, n on con fi de ntial, W G K (DE), TA -Lu ft (DE), Mat erial

S af ety Da tase t, Risk Ass essm ent , Directive 6 7/ 548 /EEC, SIDS

35

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

1. GENERAL INF ORMATIO N I D: 5124-30-1

DATE: 09.11.2006

1 .0 .1 AP PLIC A NT AN D COMP AN Y INFORM AT ION

1 .0 .2 LOCA TION OF PRODUCTION SIT E, IMP ORTER OR FORMUL A TO R

1 .0 .3 ID ENTITY OF RECI PIENTS

1 .0 .4 DETA ILS ON C AT EGORY/TEMPL A TE

1 .1 .0 SUBSTA NC E IDENTIF IC AT ION

IU P AC Na me : 1, 1 ́- m et hylenebis(4-isocyanat ocyclohexane)

S mil es Code : O=C=NC( CCC (C1)CC (CCC (N= C=O)C2)C2) C1

Mole cula r formula : C15 H22 N 2 O2

Mole cula r w ei ght : 26 2. 35 g/ mol

P etrol c la ss :

Rem ark : IUPAC n am e was gen erate d by ICS n am ing system (h ttp: //by- cis.b ayerag.co m: 81/icsweb/n aming/ nami ng_single)

Fl ag : Critical s tudy fo r S IDS e nd poin t

0 2. 01. 20 06 (93)

1 .1 .1 G ENER AL SUBST AN CE INF ORM A TIO N

Pu rit y ty pe : typical fo r m arke ted subs ta nce

Sub stanc e t ype : organic

Physical status : liquid

Pu rit y : 10 0 % w/w

Colour : light yello wish

Odour : slight lachrymat ory o do ur

Rem ark : 10 0 % purity rel ates t o t he us uabl e co mp on ents o f t he pro duct (isomers o f

4, 4'- m et hylene dicyclohex yl diis ocyanat e an d 2 ,4'-me thylen edicyclohexy l

diisocyana te)

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 11. 20 04 (32)

Rem ark : As lo ng as n ot ot herwise st ate d, t he is om ers mixture o f 92 % 4 ,4 ́-isom ers

an d 8 % 2 ,4 ́-isom ers is me an t

Re sult : Th e ap proximat e isom eric co mp osition o f t he pur e ind ustrial pro duc t is:

4, 4'- m et hylene dicyclohex yl diis ocyanat e (in to tal 9 2 %)

- cis,cis- iso mer 1 4 %

- cis,trans-iso mer 5 8 %

- trans ,trans-iso mer 2 0 %

- ot hers 8 % (2, 4'- m et hylene dicyclohex yl diis ocyanat e)

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 4. 12. 20 05 (45)

36

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

1. GENERAL INF ORMATIO N I D: 5124-30-1

DATE: 09.11.2006

1 .1 .2 S PECTR A

1 .2 SYNONYMS AN D TR AD EN A M ES

1 ,1-Methy lenebis(4- i socyanatoc y clohexane)

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 0. 09. 20 04 (4) (45)

4 ,4 '- Di c yclohex ylmethanediisocy anate

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 0. 09. 20 04 (4)

4 ,4 '- Dii socya natodicy clohex ylmethane

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 0. 09. 20 04 (45)

4 ,4 '- Methy lenebis(cy clohexy l iso c yanate)

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 0. 09. 20 04 (4)

Bi s(4- i socyanatoc y clohex yl )methane

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 0. 09. 20 04

Cy clohexane , 1, 1'-methy lenebis(4-iso c yanato)

-

Rem ark : CAS n am e

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 6. 09. 20 04 (4)

De smodur W

Fl ag : Critical s tudy fo r S IDS e nd poin t

(45)

Di c yclohex ylmethane- 4, 4'-diiso c yanate

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 0. 09. 20 04 (4)

H1 2MDI

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 0. 09. 20 04 (84)

Hy drogenated MDI

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 0. 09. 20 04 (4)

Hy lene W

37

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

1. GENERAL INF ORMATIO N I D: 5124-30-1

DATE: 09.11.2006

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 5. 11. 20 04

Methy lene bis(4-iso c yanatoc yclo hexan e)

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 0. 09. 20 04

Methy lenebis(1, 4- cyclohex ylene) dii soc yanate

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 0. 09. 20 04

Methy lenedi- 1 ,4-c yclohexy lene iso c yanate

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 0. 09. 20 04

Methy lenedi- 4-cyclohex ylene dii socya nate

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 0. 09. 20 04 (4)

1 .3 IMPURITI ES

Pu rit y : typical fo r m arke ted subs ta nce

CA S- No :

EC-No :

E INECS-Name :

Mole cula r formula :

V alu e :

Rem ark : no im purities re porte d

2 2. 11. 20 04

1 .4 AD DI TIVES

1 .5 TOTA L QUA NT ITY

Qu antit y : 10 00 - 50 00 to nn es pro duc ed in 20 03

Rem ark : Th e global pr oduc tion cap acity o f 4, 4'-me thylene dicyclohex yl diisocyanat e

is 10 ,0 00-20 ,0 00 t on nes/ a, with mo st o f it in th e US A. I n G erm any, B ayer

MaterialSci ence AG is t he only pro ducer a nd ha s a ma nu fa ct uring c ap acity

of 1, 00 0- 5 ,0 00 t on nes /a o f 4 ,4'-me thylen edicyclohex yl diisocyana te.

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 11. 20 04 (31)

1 .6 .1 LA BE LLING

L abell ing : as i n Directive 6 7/ 548 /EEC

38

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

1. GENERAL INF ORMATIO N I D: 5124-30-1

DATE: 09.11.2006

Sp ec ific l imits : Sym bols : T,

, , Nota :

, , R-Phra se s : (23) T oxic by in hala tion

(36/ 37 /38) Irrita ting t o eyes, respirat ory system a nd skin

(42/ 43) May caus e se nsitization by inh alatio n a nd skin co ntac t

S-Ph ras es : (26) I n cas e o f co nt act with eyes , rinse i mm edia tely with p len ty of water

an d s eek m ed ical advice

(28) A ft er c ont act with skin, wash i mm edia tely with p len ty of water

(38) I n cas e o f

ins uf fi cien t ventilatio n, wear suit able r espiratory eq uipm en t

(45) I n cas e o f

acci den t or i f you fe el unwell, se ek me dical a dvice

im me diately (s how th e la bel where p ossible)

1 .6 .2 CLA SSIFIC A TI ON

Cl ass ified : a s in Directive 67 /54 8/E EC

Cl ass of danger : irritating

R-Phra se s : (3 6/3 7/3 8) Irritating to eyes, res piratory system an d skin

Sp ec ific l imits :

Cl ass ified : a s in Directive 67 /54 8/E EC

Cl ass of danger : s ensitizing

R-Phra se s : (4 2/4 3) May ca use sensitization by in hala tion an d skin c on tact

Sp ec ific l imits :

Cl ass ified : a s in Directive 67 /54 8/E EC

Cl ass of danger : t oxic

R-Phra se s : (2 3) Toxic by inh alatio n
Sp ec ific l imits :

1 .6 .3 PA CK A G ING

1 .7 US E P AT TERN

Ty pe of us e : type

Category : Non disp ersi ve use

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 11. 20 04 (85)

Ty pe of us e : ind ustrial

Category : Che mical in dustry: use d in synt hesis

Rem ark : Used fo r t he m an uf ac tur e o f rub ber a nd plas tic prod ucts, ind ustrial pai nts,

ch emical pr od ucts, c ons truction an d tr ansp ort equip me nt

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 11. 20 04 (85)

39

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

1. GENERAL INF ORMATIO N I D: 5124-30-1

DATE: 09.11.2006

Ty pe of us e : us e Category : In term edia tes

Rem ark : 4, 4'- Me thylene dicyclohex yl diis ocyanat e is registered a s a co mp on ent i n

ap proximat ely 50 ind ustrial pro ducts in th e Da nish, Finnish, an d Swedish

Pro duct R egisters with a c ons um ptio n of ab ou t 30 t on nes/ a in 2 00 0 a nd

20 01 (last years of record). T he re is n o registration f or a c ons um er pro duct

. It is c on fi de ntially listed in th e Norwegian Prod uct Register. T he m ain us e

cat egory is "n on-dis persive us e"

. Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 11. 20 04 (85)

Ty pe of us e : us e Category : In term edia tes

Rem ark : Th e Swiss Pro duct Register lists 3 4 ind ustrial pro ducts (with conc entr ations

of up to 10 0 % 4 ,4'-m et hylenedicyclohexy l diisocyan ate), b ut no co nsu mer

pro duct con taining 4 ,4'-me thylene dicyclohex yl diisocyanat e.

Th e fo llowing ind ustrial pro duc t cat egories were re port ed:

auxiliary m at erial; cle aning agen t; glue, sur fac er, ce me nt; se aling m ass;

har den er; p aints , dyes, lacqu ers; plas tic mol ding

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 11. 20 04 (89)

1 .7 .1 DETA ILED U SE PA TTER N

1 .7 .2 METHODS O F M AN UF A C TU RE

1 .8 RE GUL A TO RY MEA SURES

1 .8 .1 OCCUPA TIO N AL EX POSURE LIMIT V AL UES

Ty pe of li mit : MAK (DE)

Lim it value : .0 54 m g/m 3

Short te rm ex posure limit value

Lim it value :

Tim e s chedul e : 8 h our(s)

Fr equency : tim es

Rem ark : Mea n fo r 8 h shi ft

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 11. 20 04 (32)

1 .8 .2 AC CEPT A B LE RES IDUES LE VELS

1 .8 .3 WA TER POLLUTION

Cl ass ified by : ot her: B ayer A G

L abell ed b y :

40

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

1. GENERAL INF ORMATIO N I D: 5124-30-1

DATE: 09.11.2006

Cl ass of danger : 1 (weakly water p olluti ng)

Rem ark : Id enti fic ation no . 6 72 4.

Class of da nger: acc ording to VwV wS A pp en dix 3

2 1. 12. 20 04 (32)

1 .8 .4 MA

JOR AC CI DENT H AZ A R DS

L egisl ation : St oer fallverordnu ng (DE)

Sub stanc e li sted : yes

No. i n Seveso dir ective :

Rem ark : Rep orted in A pp en dix II Nr. 4 c; I II T eil 2 K at. 2; IV K at . 2

("gif tige S to ff e" )

2 3. 06. 19 98

1 .8 .5 AI R P OLLUTION

Cl ass ified by : ot her: B ayer A G

L abell ed b y :

Number : ot her: T A-L uf t 5. 2. 5 organic s ubst anc es

Cl ass of danger : I

2 2. 11. 20 04 (32)

1 .8 .6 LI STINGS E .G . CHEMIC AL IN VENTORIES

1 .9 .1 DE GR AD A TI ON /TR A NS FORM A T IO N PR ODUCTS

Ty pe : degrad atio n pro duc t in water

CA S- No : 17 61-7 1-3

EC-No : 21 7-16 8-8

E INECS-Name : 4, 4'- m et hylene bis(c yclohexy lamine)

IUCLID Chapter : 3. 1.2

1 6. 09. 20 04 (29)

1 .9 .2 COMPON ENTS

1 .1 0 S OURCE OF E XPO SURE

1 .1 1 AD DI TION AL REM AR KS

1 .1 2 LA ST L ITER AT URE S E AR CH

Ty pe of se ar ch : In tern al an d Extern al

Chapter s covered : 1

41

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

1. GENERAL INF ORMATIO N I D: 5124-30-1

DATE: 09.11.2006

Date of se arch : 13 .0 8.2 00 3

1 6. 09. 20 04

Ty pe of se ar ch : In tern al an d Extern al

Chapter s covered : 2

Date of se arch : 13 .0 8.2 00 3

1 6. 09. 20 04

Ty pe of se ar ch : In tern al an d Extern al

Chapter s covered : 3, 4

Date of se arch : 13 .0 8.2 00 3

Rem ark : La st litera ture s earch f or Ch apt er 3. 2.1 27-JUL-20 04

1 6. 09. 20 04

Ty pe of se ar ch : In tern al an d Extern al

Chapter s covered : 5

Date of se arch : 22 .0 1.2 00 3

Rem ark : Hum an Healt h: las t literat ure se arch J anu ary 22 , 2 00 3: CA S nu mb er

se arch in extern al an d i ntern al da ta bases , e.g. Biosis, E mb as e, T oxline,

Scise arch

1 4. 09. 20 04

1 .1 3 RE VIE WS

42

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

2. PH YSICO C HEMICAL DATA I D: 5124-30-1

DATE: 09.11.2006

2 .1 MELTING POINT

V alu e : 15 °C

Sub limation :

Method : ot her: n o d at a

Year : 20 04

GL P : no da ta

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, p urity: 9 2 %

Re sult : Th e me lting poi nt o f t he is om eric m ixture of 4, 4'- m et hylenedicyclohexy l

diisocyana te (cis, cis-isom er: 14 %; cis, tra ns- iso mer: 58 % a nd trans

, trans-iso mer: 20 %, 8 % 2 ,4-iso mers) is 15 °C.

Th e me lting poi nt o f

4 ,4'-me thylene dicyclohex yl diisocyanat e is 8 3 °C.

Re liabi lit y : (2) valid with restrictions

Dat a fr om p eer-revie wed ha nd bo ok or c ollection of da ta

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 9. 09. 20 04 (45)

V alu e : <

- 1 0 °C

Sub limation :

Method : ot her: n o d at a

Year : 20 04

GL P : no da ta

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, n o p urity sp ecif ied

Rem ark : Freezing po int. No in fo rm atio n su pplied on th e iso meric co mp osition of th e

su bsta nce

Re liabi lit y : (2) valid with restrictions

Dat a fr om h an db ook or collectio n of da ta

1 9. 09. 20 04 (78)

V alu e : 49 .8 °C

Sub limation :

Method : ot her: n o d at a

Year : 19 75

GL P : no

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, p urity no t b elow 9 9. 9 %

Rem ark : A s am ple o f 4 ,4'-me thylen edicyclohex yl diisocyana te h aving a mel ting p oin t

of 49 .8 +/- 0 .2 °C was us ed f or di ff er en t investigations conc erning

physicoch emical pr op erties.

No in fo rm atio n su pplied on th e iso meric co mp osition of th e su bsta nce

Re liabi lit y : (2) valid with restrictions

Basic d at a given

2 2. 11. 20 04 (99)

V alu e : = 78 °C

Sub limation :

Method : ot her: n o d at a

Year : 19 71

GL P : no

T est sub stance : ot her T S: tra ns, tra ns-4, 4'- Me thylenedicyclohexy l diisocyan ate , no purity

sp ecifi ed

Re sult : Th e solidi ficati on p oin t of crystalline tr ans, trans-4, 4'- m et hylene dicyclohex yl

diisocyana te is 7 8 °C

Re liabi lit y : (2) valid with restrictions

43

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

2. PH YSICO C HEMICAL DATA I D: 5124-30-1

DATE: 09.11.2006

Basic d at a given

0 4. 11. 20 05 (4 0) (74)

V alu e : = 80 °C

Sub limation :

Method : ot her: n o d at a

Year : 19 68

GL P : no

T est sub stance : ot her T S: tra ns, tra ns-4, 4'- Diisocyanat odicyclohexy lmeth an e, n o p urity

sp ecifi ed

Rem ark : trans ,trans-4 ,4'-Met hylenedicyclohex yl diisocyana te is pr ep ared by reac ting

a c arbo n di oxide- 4, 4'- m et hylene bis(cyc lohexy lamine)-ad duc t (con tains

95 % w/ w of

th e tra ns,tra ns-isom er) with ph osgen e

Re liabi lit y : (2) valid with restrictions

Basic d at a given

1 0. 05. 20 04 (5) (40)

V alu e : 81 .5 82 °C

Sub limation :

Method : ot her: n o d at a

Year : 19 65

GL P : no

T est sub stance : ot her T S: tra ns, tra ns-4, 4'- Me thylenedicyclohexy l diisocyan ate , purity: 98 %

Re liabi lit y : (2) valid with restrictions

Dat a fr om p eer-revie wed ha nd bo ok or c ollection of da ta

0 4. 11. 20 05 (40)

V alu e : ca. 25 °C

Sub limation :

Method : ot her: n o d at a

Year :

GL P : no da ta

T est sub stance : as pr escribe d by 1 .1

- 1. 4

Rem ark : Poi nt o f solidi fic ation

Re liabi lit y : (4) no t assigna ble

Man uf ac turer da ta without pr oo f

2 3. 11. 20 04 (32)

V alu e : 19 2 3 °C

Sub limation :

Method : ot her: n o d at a

Year : 20 04

GL P : no da ta

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, n o p urity sp ecif ied

Rem ark : No in fo rm atio n gi ven o n iso meric co mp ositio n of mixture

Re liabi lit y : (4) no t assigna ble

Dat a fr om n on pe er- reviewed h an db ook or collectio n o f d at a

1 9. 09. 20 04 (92)

V alu e : 60 7 1 °C

Sub limation :

Method : ot her: n o d at a

Year : 19 77

GL P : no

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, n o p urity sp ecif ied

44

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

2. PH YSICO C HEMICAL DATA I D: 5124-30-1

DATE: 09.11.2006

Rem ark : No in fo rm atio n gi ven o n iso meric co mp ositio n of mixture

Re liabi lit y : (4) no t assigna ble

Man uf ac turer da ta without pr oo f

1 9. 09. 20 04 (6)

2 .2 BOIL ING PO INT

V alu e : 16 7 16 8 °C a t 2 h Pa

De composition :

Method : ot her: n o d at a

Year : 19 69

GL P : no

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, n o p urity sp ecif ied

Rem ark : No in fo rm atio n gi ven o n iso meric co mp ositio n of mixture. T he Britis h pa te nt

1. 17 3.8 90 is t he English (British) version of th e Frenc h p at ent 1 .5 78 .80 8

Re liabi lit y : (2) valid with restrictions

Basic d at a given

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 9. 09. 20 04 (60) (8 1) (88)

De composition :

Method : ot her: n o d at a

Year :

GL P : no da ta

T est sub stance : as pr escribe d by 1 .1

- 1. 4

Rem ark : Not m ea sura ble (d eco mp osition) a t st an dard pr essure

Re liabi lit y : (4) no t assigna ble

Man uf ac turer da ta without pr oo f

0 2. 11. 20 05 (32)

V alu e : 15 5 16 0 °C a t . 67 hP a

De composition :

Method : ot her: n o d at a

Year : 19 65

GL P : no

T est sub stance : ot her T S: tra ns, tra ns-4, 4'- Me thylenedicyclohexy l diisocyan ate , purity: 92 %

Re liabi lit y : (2) valid with restrictions

Basic d at a given

0 4. 11. 20 05 (40)

2 .3 DENS ITY

Ty pe :

V alu e : 1. 07 a t 2 5 °C

Method : ot her: n o d at a

Year : 20 04

GL P : no da ta

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, n o p urity sp ecif ied

Rem ark : No in fo rm atio n su pplied on th e iso meric co mp osition of th e su bsta nce

Re liabi lit y : (2) valid with restrictions

Dat a fr om h an db ook or collectio n of da ta

45

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

2. PH YSICO C HEMICAL DATA I D: 5124-30-1

DATE: 09.11.2006

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 9. 09. 20 04 (78)

Ty pe : de nsity

V alu e : 1. 00 58 g/cm3 a t 5 5 °C

Method : ot her: n o d at a

Year : 19 75

GL P : no

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, p urity no t b elow 9 9. 9 %

Rem ark : Th e me th od of d et ermin atio n of

th e d ensity was d escribe d in a n e arlier

rep ort which is n ot available (Zh uravle va EZ a nd Melen t’eva T I, All-Union

Scie ntif ic an d T ec hnic al Con fe renc e o n t he Che mistry an d T ec hn ology of

Pro ductio n, Pr ocessing, a nd Ap plicatio ns of Polyureth an es an d

In term edia tes f or

th eir Prod uctio n, F ebruary 1 0-13 , 1 97 1, Vl adi mir.

Abs tracts o f

P ap ers [in R ussian] (19 70), p . 1 7).

Re sult : Th e te mp erat ure de pe nd enc e of th e d ensity of 4, 4'- m et hylenedicyclohexy l

diisocyana te was de termi ned : t [°C] de nsity [g/ m3 ]

55 1. 005 8

60 1. 002 4

65 0. 999 0

70 0. 995 4

75 0. 992 0

80 0. 988 4

In th e te mp erat ure ra nge stu died th e d ensity of t he diisocyana te d ecre ases

linearly with increas e of te mp erat ure

Re liabi lit y : (2) valid with restrictions

Basic d at a given

1 9. 09. 20 04 (99)

Ty pe : de nsity

V alu e : ca. 1. 07 g/cm3 a t 2 5 °C

Method : ot her: DIN EN IS O 28 11

Year :

GL P : no da ta

T est sub stance : as pr escribe d by 1 .1

- 1. 4

Re liabi lit y : (4) no t assigna ble

Man uf ac turer da ta without pr oo f

2 3. 11. 20 04 (32)

Ty pe : de nsity

V alu e : 1 .0 29 g/cm3 at 70 °C

Method : ot her: n o d at a

Year : 19 77

GL P : no

T est sub stance : as pr escribe d by 1 .1

- 1. 4

Re liabi lit y : (4) no t assigna ble

Man uf ac turer da ta without pr oo f

2 3. 11. 20 04 (6)

Ty pe : de nsity

V alu e : 1. 07 g/c m3 a t 2 0 °C

Method : ot her: n o d at a

Year : 20 04

GL P : no da ta

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, n o p urity sp ecif ied

46

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

2. PH YSICO C HEMICAL DATA I D: 5124-30-1

DATE: 09.11.2006

Rem ark : No in fo rm atio n su pplied on th e iso meric co mp osition of th e su bsta nce

Re liabi lit y : (4) no t assigna ble

Dat a fr om n on pe er- reviewed h an db ook or collectio n o f d at a

1 9. 09. 20 04 (92)

2 .3 .1 GRA NU LOMETR Y

2 .4 VA POUR PRES SURE

V alu e : .0 00 02 13 hP a a t 2 5 °C

De composition :

Method : Directive 92 /6 9/E EC, A .4

Year : 19 94

GL P : no da ta

T est sub stance : as pr escribe d by 1 .1

- 1. 4

Re sult : Va po ur press ure at dif fe re nt te mp erat ures:

1. 22* 10E-0 5 h Pa at 20 °C,

2. 13* 10E-0 5 h Pa at 25 °C,

3. 00* 10E-0 4 h Pa at 50 °C

Re liabi lit y : (2) valid with restrictions

Non-GL P guid eline st udy

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 3. 11. 20 04 (1 6) (32)

V alu e : .0 01 3 hP a a t 25 °C

De composition :

Method : ot her (m eas ured): n o d at a

Year : 20 04

GL P : no da ta

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, n o p urity sp ecif ied

Rem ark : No in fo rm atio n su pplied on th e iso meric co mp osition of th e su bsta nce

Re liabi lit y : (2) valid with restrictions

Dat a fr om h an db ook or collectio n of da ta

1 9. 09. 20 04 (78)

V alu e : .0 00 43 6 h Pa at 53 .7 °C

De composition :

Method :

Year : 19 75

GL P : no

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, p urity no t b elow 9 9. 9 %

Method : Th e vapour pr essure was me as ured by K nu dse n's ef f us io n m et ho d with t he

aid of d iap hragms h aving ori fices 4 .1 0E-04 a nd 17 .49 E- 0 4 cm 2 in ar ea a nd

Clausing co ef

fi cie nts 0 .8 060 an d 0 .8 956

. Rem ark : No in fo rm atio n su pplied on th e iso meric co mp osition of th e su bsta nce

Re sult : Th e te mp erat ure de pe nd enc e of th e vapo ur press ure o f

4, 4'- m et hylene dicyclohex yl diis ocyanat e was d et ermin ed:

t [°C] vap our pr essure [ hP a]

53 .7 0 .0 00 436

75 .7 0 .0 02 782

85 .9 0 .0 06 158

99 .6 0 .0 16 945

47

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

2. PH YSICO C HEMICAL DATA I D: 5124-30-1

DATE: 09.11.2006

11 0. 6 0 .0 37 43 7

11 4. 3 0 .0 46 51 6

13 0. 1 0 .1 28 88 3

Re liabi lit y : (2) valid with restrictions

Basic d at a given

2 2. 11. 20 04 (99)

V alu e : .4 h Pa at 13 8 °C

De composition :

Method : ot her (m eas ured): n o d at a

Year : 19 77

GL P : no

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, n o p urity sp ecif ied

Rem ark : No in fo rm atio n su pplied on th e iso meric co mp osition of th e su bsta nce

Re sult : Va po ur press ure at dif fe re nt te mp erat ures:

0. 40 0 hP a a t 1 38 °C; 5. 86 6 hP a a t 1 89 °C

0. 53 3 hP a a t 1 40 °C; 1 2. 66 hP a a t 2 10 °C

0. 66 7 hP a a t 1 45 °C; 2 9. 33 hP a a t 2 32 °C

1. 46 7 hP a a t 1 60 °C; 7 1. 99 hP a a t 2 45 °C

3. 33 3 hP a a t 1 78 °C;

Esti mat ed t o b e 1 01 3 h Pa at 36 0 °C

Re liabi lit y : (4) no t assigna ble

Man uf ac turer da ta without pr oo f

1 9. 09. 20 04 (6)

V alu e : .0 01 3 hP a a t °C

De composition :

Method : ot her (m eas ured): n o d at a

Year : 20 04

GL P : no da ta

T est sub stance : ot her T S: 4, 4'- Me thylenedicyclohexy l diis ocyanate , no p urity sp ecifi ed

Rem ark : No in fo rm atio n su pplied on th e iso meric co mp osition of th e su bsta nce

Re liabi lit y : (4) no t assigna ble

Dat a fr om n on pe er- reviewed h an db ook or collectio n o f d at a

3 1. 10. 20 05 (92)

V alu e : .0 00 58 .0 01 72 h Pa at 25 °C

De composition :

Method : ot her (calcul ate d): EP I W I N MPBP W IN v1.4 1

Year : 20 05

GL P : no

T est sub stance : ot her T S: 4, 4'-Methylene bis(cyc lohexy lamin e)

Re sult : Va por pr essure e sti matio ns usi ng a bo iling p oint of 32 0.0 0 °C (us er

en tere d):

0. 00 043 8 m m Hg = 0. 00 05 8 hP a (A ntoi ne Me tho d)

0. 00 067 1 m m Hg (Modi fie d Grai n Met hod)

0. 00 129 mm Hg = 0. 001 72 (Mackay Met ho d)

Sel ecte d vapor pr essure 0 .0 00 67 1 mm Hg = 0. 00 089 hP a (Modi fie d Grai n

Meth od)

Re liabi lit y : (2) valid with restrictions

Acce pt ed c alculatio n m et ho d

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (94)

48

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

2. PH YSICO C HEMICAL DATA I D: 5124-30-1

DATE: 09.11.2006

2 .5 PA RTITION COEFFICIENT

P artition co efficient : oct an ol- water

Log po w : at °C

pH value :

Method : ot her (calcul ate d): Fragme nt

Year : 20 04

GL P :

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e

Method : Th is e nd poin t ca n no t b e d et ermin ed exp erime ntally du e t o ra pid

hydrolysis.

Fragme nt m et ho d calc ulatio n

TY PE | NUM | FRA GMENT | COEFF | V ALUE

Frag | 9 |

- CH2- | 0 .4 911 | 4 .4 19 9

Frag | 4 |

- CH | 0 .3 61 4 | 1. 44 56

Frag | 2 |

- N=C=O | 0 .0 100 **| 0 .0 200

Co nst | | | | 0. 229 0

log Kow = 6. 11 45

**A n es tima ted co ef

fi cien t was u se d

Rem ark : Th e calcula tion of l og K ow f or 4, 4'- m et hylenedicyclohexy l diis ocyanate is

un suita ble. A calc ulate d t he oretical log Kow value re flec ts th e

un dissocia ted mol ecule without in fl ue nce o f water.

4, 4'- Me thylene dicyclohex yl diis ocyanat e hydrolyzes ra pidly in t he

pres ence of water

with a h al f life of

ap proximat ely 2 h ours (cf . Ch apt er

3. 1.2 , st ability in water)

Re sult : Log K ow (version 1. 66 e stim ate): 6. 11

NOT E: I socyana tes hydrolyze....estim at e questio na ble!

In water, 4, 4'- m et hylenedicyclohexy l diis ocyanate hydroly zes with a h alf -lif e

of ap proximately 2 h

. Re liabi lit y : (2) valid with restrictions

Acce pt ed c alculatio n m et ho d

Fl ag : Critical s tudy fo r S IDS e nd poin t

3 1. 10. 20 05 (93)

P artition co efficient : oct an ol- water

Log po w : 2. 03 2. 55 at °C

pH value :

Method : ot her (calcul ate d)

Year : 20 03

GL P : no da ta

T est sub stance : ot her T S: 4, 4'-Methylene bis(cyc lohexy lamin e)

Re sult : For 4, 4'-me thylene bis(cyc lohexy lamin e) a m ea sure d log Kow (O ECD 1 07)

of 2. 03 a nd calcul ate d log Kow (QSAR) = 2. 55 were de ter mine d

Re liabi lit y : (2) valid with restrictions

Basic d at a given

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (58)

P artition co efficient : oct an ol- water

Log po w : 3. 26 a t 2 5 °C

pH value :

Method : ot her (calcul ate d): EP I W I N KO W W I N Program (v1.6 7)

Year : 20 05

GL P : no

T est sub stance : ot her T S: 4, 4'-Methylene bis(cyc lohexy lamin e)

49

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

2. PH YSICO C HEMICAL DATA I D: 5124-30-1

DATE: 09.11.2006

T est condition : LO GKO W Fragm ent m et ho d:

9 -CH2- [alip ha tic carbo n] (0 .4 911) 4 .4 19 9

4 -CH [alip hatic c arbo n] (0 .36 14) 1 .4 45 6

2 -NH2 [ aliph atic at tac h] (- 1 .4 14 8)

- 2 .8 29 6

Equa tion c onst an t 0. 22 90 log Kow = 3. 264 9

Re liabi lit y : (2) valid with restrictions

Acce pt ed c alculatio n m et ho d

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (94)

2 .6 .1 S OLUBILITY IN DIFF ERENT MEDI A

So lubility in : W a t e r

V alu e : at °C

pH value :

c oncentration : a t °C

T emperatur e effects :

E xam ine differ ent pol. :

pKa : at 25 °C

De scr iption :

St able :
Deg . product :

Method : ot her: n o d at a

Year : 20 04

GL P : no da ta

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, n o p urity sp ecif ied

Rem ark : No in fo rm atio n su pplied on th e iso meric co mp osition of th e su bsta nce

Re sult : 4, 4'- Me thylene dicyclohex yl diis ocyanat e hydroly zes in water with a h alf

live

of 2 h ours (c f. Cha pt er

3 .1 .2 o f t his IUCLID)

Re liabi lit y : (2) valid with restrictions

Dat a fr om h an db ook or collectio n of da ta

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 9. 09. 20 04 (78)

So lubility in : W a t e r

V alu e : at °C

pH value :

c oncentration : a t °C

T emperatur e effects :

E xam ine differ ent pol. :

pKa : at 25 °C

De scr iption :

St able :
Deg . product :

Method : ot her: n o d at a

Year :

GL P : no da ta

T est sub stance : as pr escribe d by 1 .1

- 1. 4

Re sult : 4, 4'- Me thylene dicyclohex yl diis ocyanat e is insol uble i n water. It hydroly zes

in c ont act with water

a nd fo rm s car bon dioxide

Re liabi lit y : (4) no t assigna ble

Man uf ac turer da ta without pr oo f

2 3. 11. 20 04 (32)

So lubility in : W a t e r

V alu e : at °C

50

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

2. PH YSICO C HEMICAL DATA I D: 5124-30-1

DATE: 09.11.2006

pH value :

c oncentration : a t °C

T emperatur e effects :

E xam ine differ ent pol. :

pKa : at 25 °C

De scr iption :

St able :
Deg . product :

Method : ot her: n o d at a

Year : 20 04

GL P : no da ta

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, n o p urity sp ecif ied

Rem ark : No in fo rm atio n su pplied on th e iso meric co mp osition of th e su bsta nce

Re sult : 4, 4'- Me thylene dicyclohex yl diis ocyanat e is insol uble/re active in water

Re liabi lit y : (4) no t assigna ble

Dat a fr om n on pe er- reviewed h an db ook or collectio n o f d at a

3 1. 10. 20 05 (4 1) (92)

So lubility in : W a t e r

V alu e : 5 5. 8 g/l at 20 °C

pH value : 11 .5

c oncentration : 5 g/l a t 20 °C

T emperatur e effects :

E xam ine differ ent pol. :

pKa : at 25 °C

De scr iption :

St able :
Deg . product :

Method : ot her: n o d at a

Year : 20 00

GL P : no da ta

T est sub stance : ot her T S: 4, 4'-Methylene bis(cyc lohexy lamin e), no purity report ed

Re sult : Dat a fr om IUCLID

Sour ce : Dat a fr om B ayer A G an d H uels A G

Re liabi lit y : (2) valid with restrictions

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (58)

So lubility in : W a t e r

V alu e : 11 46 mg /l at 25 °C

pH value :

c oncentration : a t °C

T emperatur e effects :

E xam ine differ ent pol. :

pKa : at 25 °C

De scr iption :

St able :
Deg . product :

Method : ot her: c alculat ed: EP I W I N W S K O W v1.41

Year : 20 05

GL P : no

T est sub stance : ot her T S: 4, 4'-Methylene bis(cyc lohexy lamin e)

Rem ark : 4, 4'- Me thylene bis(c yclohexy lamine) is exp ecte d no t t o hydrolyse i n

aqua eo us solu tion du e t o lack o f hydrolyzable grou ps (expert judge me nt)

Re sult : W i t h th e W S K O W Program (v1.4 1), a water s olubility of 11 46 mg/l is

calcula te d.

W i t h th e EC OSAR Pr ogram (v0.99 h), a water s olubility o f

20 7. 6 mg/l is

51

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

2. PH YSICO C HEMICAL DATA I D: 5124-30-1

DATE: 09.11.2006

calcula te d.

W i t h th e W a t er

Sol Proga m (v1.01), a water solu bility o f 1 60 55 mg/l is

ob tain ed

T est condition : Equa tion u se d to ma ke water s olubility es tim ate:

Log S (m ol/l) = 0 .6 93-0. 96 l og K ow- 0 .0 09 2(T m-25)-0. 00 31 4 M W +

Correction (Ami ne, a liph atic 0. 83 8)

log Kow u se d by water s olubility es tima te: 3. 26

Melting Pt ( Tm) = 1 5. 00 °C (T m = 25 °C us ed fo r all liquids)

Re liabi lit y : (2) valid with restrictions

Acce pt ed c alculatio n m et ho d

2 2. 12. 20 05 (94)

2 .6 .2 SURFA CE TENS ION

2 .7 FLA SH P OINT

V alu e : 20 0 °C

Ty pe :

Method : ot her: DIN 5 17 58

Year : 19 79

GL P : no

T est sub stance : as pr escribe d by 1 .1

- 1. 4

Re liabi lit y : (2) valid with restrictions

Basic d at a given

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 3. 11. 20 04 (7)

V alu e : > 20 1.7 °C

Ty pe :

Method : ot her: n o d at a

Year : 20 04

GL P : no da ta

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, n o p urity sp ecif ied

Rem ark : No in fo rm atio n su pplied on th e iso meric co mp osition of th e su bsta nce

Re liabi lit y : (2) valid with restrictions

Dat a fr om h an db ook or collectio n of da ta

1 9. 09. 20 04 (78)

V alu e : 19 9 °C

Ty pe :

Method : ot her: n o d at a

Year : 19 76

GL P : no

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, p urity no t b elow 9 9. 9 %

Rem ark : Th e experime nt al tec hnique a nd th e m et ho d us ed f or t he c alculati on were

de scribed i n an earlier re port which is no t availabl e (Monak hov VT

, Meth ods fo r I nvestigating t he Fire H azards o f S ubs ta nces [i n Russia n], Izd.

"K himiya", Moscow (1 972)).

No in fo rm atio n su pplied on th e iso meric co mp osition of th e su bsta nce

Re sult : Th e experime nt ally d et ermin ed f la sh p oin t of 4, 4'-me thylene dicyclohex yl

diisocyana te was 19 9 °C a nd th e calc ulate d f las h p oint was 2 23 °C. Th e

results o f t he de ter minati ons were red uced to nor mal a tm osp heric press ure

T est condition : Th e tes t was p erf or me d in a n o pe n cruci ble.

52

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

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DATE: 09.11.2006

Re liabi lit y : (2) valid with restrictions

Basic d at a given

2 2. 11. 20 04 (98)

V alu e : ca. 20 0 °C

Ty pe :

Method : ot her: DIN EN 22 71 9

Year :

GL P : no da ta

T est sub stance : as pr escribe d by 1 .1

- 1. 4

Re liabi lit y : (4) no t assigna ble

Man uf ac turer da ta without pr oo f

2 3. 11. 20 04 (32)

V alu e : 21 0 °C

Ty pe :

Method : ot her: n o d at a

Year : 19 77

GL P : no

T est sub stance : as pr escribe d by 1 .1

- 1. 4

Re liabi lit y : (4) no t assigna ble

Man uf ac turer da ta without pr oo f

2 3. 11. 20 04 (6)

V alu e : 20 1. 7 °C

Ty pe :

Method : ot her: n o d at a

Year : 20 04

GL P : no da ta

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, n o p urity sp ecif ied

Rem ark : No in fo rm atio n su pplied on th e iso meric co mp osition of th e su bsta nce

Re liabi lit y : (4) no t assigna ble

Dat a fr om n on pe er- reviewed h an db ook or collectio n o f d at a

2 2. 12. 20 05 (41)

V alu e : > 11 0 °C

Ty pe :

Method : ot her: n o d at a

Year : 20 04

GL P : no da ta

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, n o p urity sp ecif ied

Rem ark : No in fo rm atio n su pplied on th e iso meric co mp osition of th e su bsta nce

Re liabi lit y : (4) no t assigna ble

Dat a fr om n on pe er- reviewed h an db ook or collectio n o f d at a

2 2. 12. 20 05 (92)

2 .8 AU TO FLA MM A BI LI TY

V alu e : 22 5 °C a t

Method : ot her: n o d at a

Year : 19 76

GL P : no

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, p urity no t b elow 9 9. 9 %

53

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

2. PH YSICO C HEMICAL DATA I D: 5124-30-1

DATE: 09.11.2006

Rem ark : Th e experime nt al tec hnique a nd th e m et ho d us ed f or t he c alculati on were

de scribed i n an earlier re port which is no t availabl e (Monak hov VT

, Meth ods fo r I nvestigating t he Fire H azards o f S ubs ta nces [i n Russia n], Izd.

"K himiya", Moscow (1 972)).

No in fo rm atio n su pplied on th e iso meric co mp osition of th e su bsta nce

Re sult : Th e experime nt ally d et ermin ed ignitio n poi nt o f 4 ,4'-me thylen edicyclohexy l

diisocyana te was 22 5 °C a nd th e calc ulate d ignition p oin t was 2 26 °C. T he

results o f t he de ter minati ons were red uced to nor mal a tm osp heric

press ure.

T est condition : Th e tes t was p erf or me d in a n o pe n cruci ble

Re liabi lit y : (2) valid with restrictions

Basic d at a given

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 11. 20 04 (3 9) (98)

2 .9 FLA MM A BI LI TY

2 .1 0 E XPLO SIV E PRO PERTIES

2 .1 1 O XIDIZING P ROPERTI ES

2 .1 2 DI SSOCIA TION CONSTA NT

2 .1 3 V ISCOS ITY

V alu e : ca. 30

- mP a s (dynamic) a t 25 °C

Re sult :

Method : ot her: DIN I SO E N 32 19 /A. 3

Year :

GL P : no da ta

T est sub stance : as pr escribe d by 1 .1

- 1. 4

Re liabi lit y : (4) no t assigna ble

Man uf ac turer da ta without pr oo f

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 3. 11. 20 04 (32)

V alu e : 12 .6 58

- mP a s (dynamic) at 55 °C

Re sult :

Method : ot her: n o d at a

Year : 19 75

GL P : no

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, p urity no t b elow 9 9. 9 %

Rem ark : Th e me th od of d et ermin atio n of

th e viscosity was d escribe d in a n e arlier

rep ort which is n ot available (Zh uravle va EZ a nd Melen t’eva T I, All-Union

Scie ntif ic an d T ec hnic al Con fe renc e o n t he Che mistry an d T ec hn ology of

Pro ductio n, Pr ocessing, a nd Ap plicatio ns of Polyureth an es an d

In term edia tes f or

th eir Prod uctio n, F ebruary 1 0-13 , 1 97 1, Vl adi mir.

Abs tracts o f

P ap ers [in R ussian] (19 70), p . 1 7).

No in fo rm atio n su pplied on th e iso meric co mp osition of th e su bsta nce

Re sult : Th e te mp erat ure de pe nd enc e of th e viscosity of 4, 4'- m et hylenedicyclohexy l

54

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

2. PH YSICO C HEMICAL DATA I D: 5124-30-1

DATE: 09.11.2006

diisocyana te was de termi ned : t [°C] viscosity [m Paxs]

55 1 2. 658

60 1 0. 452

65 8 .6 74

70 7 .2 20

75 6 .0 05

80 4 .8 90

Re liabi lit y : (2) valid with restrictions

Basic d at a given

1 9. 09. 20 04 (99)

V alu e : 6. 3 - m m2 /s (static) at 70 °C

Re sult :

Method : ot her: m ea sure d n ot s peci fie d

Year : 19 77

GL P : no

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, n o p urity sp ecif ied

Re sult : At 70 °C: 6. 3 m m2 /s

At 80 °C: 5. 1 m m2 /s

At 90 °C: 4. 1 m m2 /s

Re liabi lit y : (4) no t assigna ble

Man uf ac turer da ta without pr oo f

1 9. 09. 20 04 (6)

2 .1 4 AD DI TION AL REM AR KS

55

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

3. ENVIRO NMENTAL FATE AN D PATHWA YS I D: 5124-30-1

DATE: 09.11.2006

3 .1 .1 PH OTODEGRA D A T IO N

Ty pe : air

Light sour ce :
Light sp ectrum : n m

Re lative inten sit y : b ase d o n in tensity of sunlight

Conc. of substan ce : a t 2 5 °C

INDIRECT PH OTOLYSIS

S ens itizer : OH

Conc. of sen sitizer : 50 00 00 m olec ule/c m3

Rate constant : .0 00 000 00 00 26 c m3/(m olecule*s ec)

Degr adation : 50 % af te r 1 5 h our(s)

Deg . product :

Method : ot her (calcul ate d): EP I W I N AOP W I N v1.9 1, 2 00 0

Year : 20 04

GL P :

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e

Rem ark : Th e EP I W I N A OP W IN v1.9 1 progra m do es n ot tak e int o a ccou nt t ha t

4, 4'- m et hylene dicyclohex yl diis ocyanat e is se nsitive t o hydrolysis e.g. in

aer osols with aq uatic p ha ses

Re sult : A h alf -lif e o f a bo ut 1 5. 0 h ba sed on a 2 4-ho ur d ay is e stim ate d du e t o

reacti on with ph ot oche mically pr oduc ed hydroxyl ra dicals (OH

co ncen tratio n: 0 .5E+6 radicals/c m3)

Re liabi lit y : (2) valid with restrictions

Acce pt ed c alculatio n m et ho d

Fl ag : Critical s tudy fo r S IDS e nd poin t

0 4. 11. 20 05 (28)

3 .1 .2 STA BILIT Y IN WA TER

Ty pe : abi otic

t1 /2 pH4 : a t °C

t1 /2 pH7 : a t °C

t1 /2 pH9 : a t °C

Deg . product :

Method : ot her: D ecrease of NCO- Co nte nt in W a t e r, f ol lowed by GC- a nalysis

Year : 19 99

GL P : yes

T est sub stance : as pr escribe d by 1 .1

- 1. 4

Method : 1 g o f th e t est s ubs tanc e was d issolved in a cet onitrile a nd fille d u p t o 1 00

ml. 10 ml o f

t his sol ution were pi pet ted , 40 ml of ace to nitrile a dd ed (see

rem ark) a nd fi lled up with water to 10 0 m l. T his s olutio n was inject ed in to

th e gas c hrom atograp hy system every 2 0 m in.

Rem ark : Th e pre parati ons with a lower con ten t of ac eto nitrile were clo udy d ue to th e

low water solu bility o f

t he tes t su bsta nce. Th e de termi natio n o f t he

co ncen tratio n ch ange in such an inh om ogeno us s olutio n gi ves wrong

results. For this reas on t he lowest c onc entra tion o f a cet onitrile required to

ob tain a cle ar solu tion was ch ose n. T he sol ution of th e te st s ubst ance in

ac eto nitrile was st able over m ea sure me nt ti me.

Re sult : Th e hal f-ti me of t he tes t su bsta nce in water was d et ermin ed t o b e

ap proximat ely 2 h ours a t 2 3 °C (t 1/2 = 1 .9 7 h ours). T he ra te c onst ant kobs

was 9 .7 8E-05 1/s

. T est condition : Th e co nte nt o f t est s ubst anc e was d et ermin ed by me an s o f ca pillary gas

chro ma tography an d f la me ionis ation de tecti on (GC-FID) u nd er th e

56

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

3. ENVIRO NMENTAL FATE AN D PATHWA YS I D: 5124-30-1

DATE: 09.11.2006

fo llowing co nditio ns:

Chrom at ographic col um n: f us ed silica ca pillary, length: 30

m, int ernal di am et er: 0. 32 m m, f il m thick ness: 0. 25 μ m;

St atio nary ph as e: HP 1 ; Carrier gas: h elium ; Split: 30 ml/ min ; Press ure: 0 .6 bar;

Te mp er ature program m:

T em p [°C] Ti me [m in] Ram p [ K/ min]

18 0 0 1 0

26 0 1

- Det ector t em pera ture: 25 0 °C;

Sa mpl e injec tion: split injec tion;

Inj ection volume : 2 μ l;

Qu anti fic ation was p erf orm ed by ar ea com pariso n

Re liabi lit y : (2) valid with restrictions

St udy m ee ts ge nerally acc ept ed sci enti fic pri nciples

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 3. 11. 20 04 (20)

Ty pe : abi otic

t1 /2 pH4 : a t °C

t1 /2 pH7 : a t °C

t1 /2 pH9 : a t °C

Degr adation : 10 0 % a ft er 5 d ay(s) at pH a nd °C

Deg . product : yes

Method : OECD G uide-line 11 1 "Hydrolysis as a Fu nction of pH"

Year : 20 04

GL P : yes

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e, > 9 9. 5 % p urity

Deg . products : 17 61-7 1-3 21 7-16 8-8 4 ,4'-me thylen ebis(cyclohex ylamine)

Rem ark : Th e aim of this s tudy was t o d et ermine th e d egradati on pr od ucts f or me d

when 4, 4'-me thylene dicyclohex yl diisocyanat e re acts with water.

Re sult :

- Th e aque ous p ha se c ont aine d 3 isom ers of 4, 4 ́- m et hylenedicyclohexy l

diisocyana te; t hey were id en tifi ed by GC a nd HPLC (CAS 17 61-71-3 ).

- Ad dition ally, HPLC s howed trac es of a trimeric di amin e. T he m on om ers

were c onn ect ed by ure a- grou ps.

- Th e insolu ble dr ople ts ad her ed t o t he glass wall were an alysed with IRSp ectrosc opy. Th ey con tain ed ur ea c om po ne nts (p olyurea) a s well as

traces of isocyanat e- grou ps. T he p olymeric urea co mp oun ds e nca psula ted

isocyanat e groups which slows d own th e co mpl ete hydrolys is o f t he

isocyanat e groups

. T est condition :

- Prelimin ary tes t only per fo rm ed in de min eralized water

- 2. 64 g o f

th e t est s ubs tanc e were dissolved in 1 0 m l a cet onitrile. 1 ml o f

this s olutio n was d ilute d t o 1 00 ml with de min eralized water. T he f in al

solu tion was th us 0 .0 1 mo l/l (2. 64 g/l). In cub atio n was a t 5 0 °C d uring 5

days un der c onti nuo us stirring.

- W a t e r was no t bu f

fe re d f or t he pr elimin ary test

.

- Th e soluti on was extracte d with m et hylene c hloride a ft er adj usting th e

solu tion a t pH 11 an d t he n a nalysed with GC- MS, HPLC-MS an d IRsp ectrosco py.

Re liabi lit y : (2) valid with restrictions

Gui deline stu dy with a cce pta ble restrictio ns

Fl ag : Critical s tudy fo r S IDS e nd poin t

0 4. 11. 20 05 (29)

3 .1 .3 STA BILIT Y IN S OIL

57

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

3. ENVIRO NMENTAL FATE AN D PATHWA YS I D: 5124-30-1

DATE: 09.11.2006

3 .2 .1 MONITORING D AT A

Ty pe of me asur ement : co ncen tratio n at co nta mina te d site

Medi a : air

Conc entration :

Method : LC/UV

Method : Th e th erm al degrad atio n pro ducts of polyureth an es (PURs) a nd exposure

to isocyanat es were s tu died by st atio nary an d p erso nal m ea sure me nts in 5

dif fe re nt occ upa tion al environm en ts (car rep air s ho p, m ac hining of PUR

co ating, injecti on m ou lding, welding o f dis trict h ea ting pip es, a nd

inst allation of

P UR fl oor c overing) f ro m Se pte mb er 19 99 un til Novemb er

20 00

Rem ark : During grinding an d welding th ermal d egrad ation pro ducts o f c ertain

polyureth an es were r eport ed t o incl ude 4, 4'- m et hylene dicyclohex yl

diisocyana te. I n t he air sa mples tak en d uring joint welding of PUR fl oor

covering a nd sam ples t ak en in th e bre at hing zon e of a f lo or c overing layer

who was welding f lo or covering o n his kn ees in a s mall ro om with no

ventilatio n sm all am ou nts o f 4 ,4'-m et hylenedicyclohexy l diisocyan ate were

de tect able (limit of de tecti on <0 .6 mg /m 3).

Re sult : Tr aces o f 4 ,4'-me thylen edicyclohexy l diisocyana te (u p t o 2 μg/m 3) were

de tect ed as a th erm olytic degrad atio n pro duc t during join t welding o f

polyureth an e fl oor covering in a s mall roo m withou t ventilatio n in a car

rep air s ho p

T est condition :

- Isocyan ates were collec ted on glass fi ber f ilt ers impr egnate d with 1-(2-

me th ox yphe nyl )piperazine (2MP) an d via th e n-di butylamin e i mpinger

me th od

- Derivati ves a nalyzed by LC with UV (2 50 n m) a nd elec troch emical

de tecti on

- Limit of quan tific atio n < 0. 02-0 .1 μg p er s am ple d ep en ding o n isocyanat e (not indica te d which is valid fo r 4, 4 ́- me thylen edicyclohexy l diisocyana te)

T est sub stance : 4, 4'- Me thylene dicyclohex yl diis ocyanat e, p urity 10 0 % , fr om T okyo K asei

Organic Che micals, To kyo, us ed a s extern al sta ndar d fo r qu anti fica tion

Re liabi lit y : (2) valid with restrictions

Basic d at a given

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 11. 20 04 (62)

Ty pe of me asur ement : co ncen tratio n at co nta mina te d site

Medi a : air

Conc entration : < .0 022 μg/l

Method : HPLC

Re sult : 4, 4'- Me thylene dicyclohex yl diis ocyanat e was n ot de tect able

T est condition :

- US pl ant m an uf ac turi ng water pi pes with equip me nt t o me as ure f low rate

- Asb estos type ins ulatio n co ate d t he i nside o f a signific ant part of th e pla nt

buildi ngs

- Several ch emic als were h an dled in th e pl an t, e .g.

4, 4'- m et hylene dicyclohex yl diis ocyanat e, h aloorganics, an d e pichloro hydrin

- 3 s am ples t ake n in S ep te mb er an d Oc tob er, 1 97 9

- Isocyan ate a bs orbe d in ni tro re agent in im pinger, air fl ow ra te 1 l/mi n

- An alysis by NIO SH me th od N42 0 (m odi fie d), via HP LC,

- Limit of de tecti on: 0 .0 00 6 mg/s am ple (<0. 002 2 μg/l)

Re liabi lit y : (2) valid with restrictions

Basic d at a given

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 6. 11. 20 04 (71)

Ty pe of me asur ement : co ncen tratio n at co nta mina te d site

58

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

3. ENVIRO NMENTAL FATE AN D PATHWA YS I D: 5124-30-1

DATE: 09.11.2006

Medi a : air

Conc entration : < .0 2 . 03 μg /l

Method : GC

Rem ark : Au th or s tat es t hat it is no t cle ar whether t he me as urem ents are valid

be caus e re actions of 4, 4'- m et hylenedicyclohexy l diisocyan ate may have

occ ured in th e sa mpling s olutio n be fo re me as urem ents

No s ensitizing ef

fe ct s o f 4 ,4'-me thylen edicyclohexy l diisocyana te were

fo un d in a ppr oximately 2 00 workers of this US ma nu fa ct uring p lan t

Re sult : 4, 4'- Me thylene dicyclohex yl diis ocyanat e was n ot de tect able

T est condition :

- US pl ant m an uf ac turi ng d at a proc essing an d c ontrol eq uipm en t was

mo nit ored

- Several ch emic als were h an dled in th e pl an t, e .g.

4, 4'- m et hylene dicyclohex yl diis ocyanat e, h aloorganics, cyanide, an d nitric

acid

- 5 s am ples t ake n on May 7 , 1 97 5 (NIOSH s urve y)

- Air sa mpling volume of 29 4- 4 75 l/sa mpl e

- Isocyan ate a bs orbe d in u ns pecif ie d solu tion

- GC

- Limit of de tecti on: 0 .0 1 mg /sam ple ( equals to a li mit of de tecti on o f 0 .0 2-

0. 03 m g/m 3)

Re liabi lit y : (4) no t assigna ble

Docu me nta tion insu ff ici ent f or ass esm en t

2 2. 11. 20 04 (82)

3 .2 .2 FI ELD STUDIES

3 .3 .1 TRA NSPOR T BET WEEN E NVIRONMENT AL COMPA RT MENTS

Ty pe : ad sorptio n

Medi a : water - s oil

Ai r : % (Fugacity Mod el Level I)

W ater : % (Fugacity Mod el Level I)

So il : % (Fugacity Mod el Level I)

Biota : % (Fugacity Mod el Level II /III)

So il : % (Fugacity Mod el Level II /III)

Method : ot her: c alculat ed with PCK OC W IN v1.6 6, 2 00 0

Year : 20 04

Rem ark : Calculati on is n ot suita ble d ue to hydrolysis. In water,

4, 4'- m et hylene dicyclohex yl diis ocyanat e hydroly zes with a h alf -lif e o f

ap proximat ely 2 h

Re sult : Koc = 3. 762 E+05

log Koc = 5 .5 75

T est sub stance : 4, 4'- Me thylene dicyclohex yl diis ocyanat e

Re liabi lit y : (2) valid with restrictions

Acce pt ed c alculatio n m et ho d

Fl ag : Critical s tudy fo r S IDS e nd poin t

0 3. 11. 20 05 (28)

Ty pe : ad sorptio n

Medi a : water - s oil

Ai r : % (Fugacity Mod el Level I)

W ater : % (Fugacity Mod el Level I)

So il : % (Fugacity Mod el Level I)

Biota : % (Fugacity Mod el Level II /III)

So il : % (Fugacity Mod el Level II /III)

59

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

3. ENVIRO NMENTAL FATE AN D PATHWA YS I D: 5124-30-1

DATE: 09.11.2006

Method : ot her: c alculat ed with PCK OC W IN v1.6 6, 2 00 0

Year : 20 05

Re sult : Koc (estim at ed): 6 72

T est sub stance : 4, 4'- Me thylene bis(c yclohexy lamine)

Re liabi lit y : (2) valid with restrictions

Acce pt ed c alculatio n m et ho d

Fl ag : Critical s tudy fo r S IDS e nd poin t

3 1. 10. 20 05 (94)

3 .3 .2 DI STRIBUTION

Medi a : water - a ir

Method : ot her (calcul ation): EPI W I N HENRY (v3.1 0) Program

Year : 20 05

Re sult : HENRYs LA W CON ST ANT at 25 °C:

- Bo nd e sti mat e: 4 .5 4E-00 9 a tm-m 3/ mo le = 1 .8 6E-00 7 u nitless = 0 .0 004 6

Pa-m 3/ mol e

Bo nd esti matio n:

22 Hydrogen to c arbo n (aliph atic) bo nds

- 2 .6 32 9

4 Hydrogen t o nitr ogen b on ds 5 .1 34 1

14 C- C f rag men ts 1. 62 83

2 C-N fr agm ents 2. 602 0

To tal 6. 73 1

- Grou p es tim ation : In com plet e

- Esti matio n f ro m vap or pressur e/water solu bility eq uatio n usi ng a vapor

press ure of

0. 00 06 71 m m Hg a nd a water s olubility of 11 46 mg/l: 1 .6 21 E00 7 a tm-m 3/ mol e = 0. 01 6 P a- m 3/ mo le

T est sub stance : 4, 4'- Me thylene bis(c yclohexy lamine)

Re liabi lit y : (2) valid with restrictions

Acce pt ed c alculatio n m et ho d

Fl ag : Critical s tudy fo r S IDS e nd poin t

0 3. 11. 20 05 (94)

Medi a : air - bio ta - s edim ent(s) - soil - water

Method : Calculati on a ccording Mack ay, L evel I

Year : 20 00

Re sult : Distributio n on co mp artm ents :

Air: 0 .0 41 %

Soil: 0 .8 80 %

W a t e r: 9 8. 256 %

Se dim ent : 0. 82 3 %

Biot a: 0 .0 01 %

Sour ce : Huels A G, Marl (calcul ation in IUCLID)

T est condition : In put par am eters:

Molar ma ss: 21 0. 36 g/ mol

log Kow: 2 .0 3

Va po ur press ure: 0. 03 3 Pa

W a t e r s olubility: 5. 8 g/l at 2 0 °C

- --- --- --- --- --- --- --- --- --- --- --- - Equa tions u se d fo r a ddi tion al da ta:

log Koc = 0 .9 89 log K ow - 0 .3 46

- --- --- --- --- --- --- --- --- --- --- --- - Vol um es us ed ( m3):

Air: 6 00 0 0 00 00 0

Soil: 45 0 00

60

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

3. ENVIRO NMENTAL FATE AN D PATHWA YS I D: 5124-30-1

DATE: 09.11.2006

W a t e r: 7 00 0 0 00

Se dim ent : 2 1 0 00

Sus pe nd ed S edi me nt: 3 5

Biot a: 7

T est sub stance : 4, 4'- Me thylene bis(c yclohexy lamine)

Re liabi lit y : (2) valid with restrictions

Acce pt ed c alculatio n m et ho d

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (58)

Medi a : air - bio ta - s edim ent(s) - soil - water

Method : Calculati on a ccording Mack ay, L evel I

Year : 20 05

Rem ark : Result is dif fe re nt fr om th e res ult of th e EU PB T W o r ki ng Gro up b ec ause

dif fe re nt (m ostly calcul ate d) inp ut p aram et ers were u sed

Re sult : Com part me nt

W a t e r 3 7. 70 %

Air 0. 15 5 %

Se dim ent 1. 35 0 %

Soil 6 0. 75 %

Sus pe nd ed s edim en t 0. 04 2 %

Aer osol <0.0 01 %

Aqua tic biot a 0 .0 033 %

T est condition : In put par am eters:

Te mp er ature 25 °C

Va po ur press ure 0. 08 9 Pa

W a t e r s olubility 1 14 6 mg/l

log Kow 3. 26

Melting poi nt 3 20 °C

T est sub stance : 4, 4'- Me thylene bis(c yclohexy lamine)

Re liabi lit y : (2) valid with restrictions

Acce pt ed c alculatio n m et ho d

0 4. 11. 20 05 (30)

3 .4 MODE O F DEGRA D A T IO N IN A CT U A L USE

3 .5 BIOD EGR AD A TI ON

Ty pe : aer obic

Ino culum : activate d sludge , do me stic, n on-a da pte d

Conc entration : 10 0 mg /l r elate d t o Te st subs tanc e

relat ed t o

Contact tim e :
Degr adation : 0 (±) % a ft er 2 8 d ay(s)

Re sult : ot her: n ot rea dily b iod egrada ble

Control sub stance : Be nzoic a cid, s odiu m s alt

Kin etic : 14 day(s) 8 7 %

%

Deg . product :

Method : Directive 92 /6 9/E EC, C.4-D

Year : 20 00

GL P : yes

T est sub stance : as pr escribe d by 1 .1

- 1. 4

Rem ark : Th e us ed c once ntrati on o f t he test su bsta nce di d n ot s how t oxic ef f ec ts to

ba cteria (t oxicit y con trol)

61

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

3. ENVIRO NMENTAL FATE AN D PATHWA YS I D: 5124-30-1

DATE: 09.11.2006

T est condition :

- Activated sludge c onc entra tion i n te st f lasks : 30 mg ss /l.

- Te st t em per ature : 20 +/- 1 °C.

Re liabi lit y : (1) valid withou t restriction

GL P guidelin e st udy

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 3. 11. 20 04 (21)

Ty pe : aer obic

Ino culum : activate d sludge , do me stic

Conc entration : 12 mg/l relat ed to T es t su bst ance

relat ed t o

Contact tim e :
Degr adation : 0 (±) % a ft er 2 8 d ay(s)

Re sult : ot her: n ot rea dily b iod egrada ble

Control sub stance : Anilin e

Kin etic : 28 day(s) 8 3 %

%

Deg . product :

Method : OECD G uide-line 30 1 F "R ea dy Bio degrad ability: Ma nom etric

Respiro metry T es t"

Year : 19 92

GL P : yes

T est sub stance : as pr escribe d by 1 .1

- 1. 4

Rem ark : In a f irst r espirom et er t est per for me d with a t est s ubs tanc e co nce ntratio n o f

10 0 mg /l, th e t est s ubst anc e sh owed toxic e f fe ct s t o ba cteria . Th er eup on a

Closed Bo ttle T es t s houl d be co nd ucte d with l ower tes t su bsta nce

co ncen tratio ns. B ut a t las t this test was n ot f ea si ble b eca use n eit her a

stock soluti on c ould be pre pared nor a direc t weighing o f t est subs tanc e

was p ossible . Th er ef ore th e respiro me ter te st was per for me d with a t est

su bsta nce c onc entra tion o f 1 2 mg /l.

T est condition :

- Activated sludge was tak en fr om lab orat ory wastewater tre at me nt system

, sludge c onc entra tion: 30 mg dry weight/l

- Te st t em per ature 20 +/- 1 °C

Re liabi lit y : (2) valid with restrictions

Gui deline stu dy with a cce pta ble restrictio ns (conc entr ation tes ted was

lower th an th e required by t he O ECD TG 3 01 of 10 0 mg/l, as t he toxicity

thres hold towards ba cteria availa ble a t th e ti me was lower t ha n t he c urrent

available p eer-revie wed toxicity)

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 3. 11. 20 04 (14)

Ty pe : aer obic

Ino culum :

Contact tim e :
Degr adation : (±) % af te r

Re sult : ot her: 4 o ut o f 6 es tima tion me th ods pr edict fa st bio degrada tion , with a n

ulti mat e bio degrad ation tim ef ra me o f weeks

Deg . product :

Method : ot her: (calc ulate d) EP I W I N BIO W IN pr ogram

Year : 20 05

GL P : no

T est sub stance : ot her T S: 4, 4'-Methylene bis(cyc lohexy lamin e)

Rem ark : Alth ough E PI W IN is a n a ccep te d calcul ation me th od f or m any physical

par am eters, its reliability fo r esti matio n o f bi odegrad atio n is no t cle arly

pro of ed

Re sult : Biowin1 (Line ar Mod el Pre diction): Bi od egrades f as t

Biowin2 (Non-Lin ear Mo del Pre diction): Biod egrades f as t

Biowin3 (Ultimat e Bio degrad ation Ti me fr am e): W e e ks

62

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

3. ENVIRO NMENTAL FATE AN D PATHWA YS I D: 5124-30-1

DATE: 09.11.2006

Biowin4 (Primary B iod egradati on T im ef ra me): Days- W e e ks

Biowin5 (MIT I Lin ear Mo del Pre diction): Does n ot bio degrad e fa st

Biowin6 (MIT I Non-Li near Mo del Pr edictio n): Does no t bi odegrad e f as t

Re liabi lit y : (4) no t assigna ble

Docu me nta tion insu ff ici ent f or ass esm en t

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (94)

Ty pe : aer obic

Ino culum :

Contact tim e :
Degr adation : 20 (±) % af te r 28 day(s)

Re sult : ot her: 4 ,4'-Met hylenebis(cyclohex ylamine) is at leas t in heren tly

bio degrada ble

Deg . product :

Method : ot her: Z ah n- W e ll en s

Year : 20 00

GL P : no da ta

T est sub stance : ot her T S: 4, 4'-Methylene bis(cyc lohexy lamin e)

Rem ark : Only s hort d oc um ent atio n available

Re sult : Bio degrada tion t ests on 4, 4'- m et hylene bis(c yclohexy lamine) s how t hat th e

su bsta nce is a t le ast in here ntly bi odegrad able

Re liabi lit y : (2) valid with restrictions

Reliable sourc e

Fl ag : Critical s tudy fo r S IDS e nd poin t

0 2. 01. 20 06 (58)

3 .6 BOD5 , COD OR BOD5 /COD R AT IO

0 1. 04. 20 04

3 .7 BIOA CC UM UL A TI ON

E limin ation :

Method :

Year : 20 03

GL P :

T est sub stance : ot her T S: 4, 4'-Methylene dicyclohex yl d iisocyanat e

Rem ark : 4, 4'- Me thylene dicyclohex yl diis ocyanat e hydroly zes ra pidly in t he prese nce

of water with a h al f life of

ap proximat ely 2 h ours . Th er ef ore a risk

esti mati on regarding t he b ioacc um ulati on p ot enti al of

4, 4'm ethylene dicyclohex yl diisocyanat e o n t he basis o f a log Kow,

de ter mine d by Q SAR, is misle ading. A calcula te d th eore tical log Kow value

ref lects th e u ndissoci ate d mo lec ule without inf lu ence of water.

Accor ding t o t he EU Te ch nical G uid ance Docu me nt a su bsta nce is

regarde d as p ot en tially bio accum ulative if t he l og K ow excee ds 3 an d t he

hal f lif e ti me in water exceeds 12 ho urs. T his is n ot th e c ase f or

4, 4'm ethylene dicyclohex yl diisocyanat e. T he s ubst anc e is no t p ersiste nt in

water d ue to th e ra pid hydrolysis. T her ef or e it is n ot b io-available. Possibl e

hydroly zation pro ducts are l ess lipo philous . On th e b asis of th ese

inf or ma tion it can no t b e expec ted th at bi oacc um ulatio n o f

4, 4'm ethylene dicyclohex yl diisocyanat e o ccurs

Re liabi lit y : (2) valid with restrictions

63

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

3. ENVIRO NMENTAL FATE AN D PATHWA YS I D: 5124-30-1

DATE: 09.11.2006

Acce pt ed c alculatio n m et ho d

Fl ag : Critical s tudy fo r S IDS e nd poin t

0 4. 11. 20 05 (27)

Sp ec ies :

E xposur e per iod : a t 2 5 °C

Conc entration :

BCF : 7 18

E limin ation :

Method : ot her: (calc ulate d) BCF- eq uati on f ro m E PI W IN BCF Pr ogram (v2.15)

Year : 20 05

GL P : no

T est sub stance : ot her T S: 4, 4'-Methylene bis(cyc lohexy lamin e)

Re sult : Equa tion u se d to ma ke BCF esti ma te:

log BCF = 0. 77 l og K ow - 0. 70

log Kow u se d by B CF esti mat es:

me as ured l og K ow (OECD 10 7) o f 2 .0 3

log BCF values o f

0. 86 3 (BCF = 7)

calcula te d log Kow (CLO GP3 program) = 2 .5 5

Esti mat ed l og BCF = 1 .2 64 (BCF = 1 8).

Conclusi on: Not bi oacc um ulative accordi ng t o EU TGD

Re liabi lit y : (2) valid with restrictions

Acce pt ed c alculatio n m et ho d

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (58)

Sp ec ies :

E xposur e per iod : a t 2 5 °C

Conc entration :

BCF : 65

E limin ation :

Method : ot her: (calc ulate d) EP I W I N BCF Program (v2.15)

Year : 20 05

GL P : no

T est sub stance : ot her T S: 4, 4'-Methylene bis(cyc lohexy lamin e)

Re sult : Equa tion u se d to ma ke BCF esti ma te:

log BCF = 0. 77 l og K ow - 0. 70

log Kow u se d by B CF esti mat es: 3 .2 6

Esti mat ed l og BCF = 1 .8 14 (BCF = 6 5. 16).

Conclusi on: Not bi oacc um ulative accordi ng t o EU TGD

Re liabi lit y : (2) valid with restrictions

Acce pt ed c alculatio n m et ho d

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (94)

3 .8 AD DI TION AL REM AR KS

64

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

4. ECOTOXICITY I D: 5124-30-1

DATE: 09.11.2006

4 .1 AC UT E/PROLONGED TOX ICITY TO F ISH

Ty pe : sta tic

Sp ec ies : Brac hydanio rerio (Fish, fr esh water)

E xposur e per iod : 96 ho ur(s)

Unit : mg/l

LC0 : >= 8 .1

Lim it test : yes

An al yt ical monitoring : yes

Method : Directive 92 /6 9/E EC, C.1

Year : 20 00

GL P : yes

T est sub stance : ot her T S: Des mo dur W

, purity: 99 .5 % (2 1.1 % tra ns,tra ns4, 4'- m et hylene dicyclohex yl diis ocyanat e, 5 0. 2 % tra ns,cis4, 4'- m et hylene dicyclohex yl diis ocyanat e, a nd 28 .2 % cis,cis4, 4'- m et hylene dicyclohex yl diis ocyanat e

Rem ark : Be fo re b eginning o f t he s tudy a pr etre atm en t was p erf or me d with t he tes t

su bsta nce a ccording t o th e rec om me nd atio n me nti on ed in th e O ECD

Gui danc e Doc um ent on aqua tic toxicity t esting o f di ff ic ult su bst ances an d

mixtures in order t o a ccelera te t he soluti on pr oce dure. For th at p urp ose a

five f ol d a mo un t (3 0 mg/l) o f th e m aximu m water solu bility of th e te st

su bsta nce in th e pr eliminary t est (6 mg/l) was weighed int o water, tre ate d

fo r 6 0 s eco nds a t 8 00 0 rp m with an ultra-turrax, af te rwards stirred fo r 2 4

ho urs on a mag netic stirrer an d f in ally fi ltere d.

An alysis of th e only tes t su bsta nce c onc entra tion an d t he c ontr ol was

per fo rm ed d aily by me ans of TO C de ter minati on.

Th e tes t result LC0 >= 8. 1 mg /l (10 % mor tality rat e) ref ers t o a

co ncen tratio n of th e t est s ubst anc e which was calcul ate d directly f ro m

an alyticall y de ter mine d TO C values (arit hm etic me an) . Acc ording to

relevant pr od uct in fo rm atio n, 1 mg/l T OC equ als to 1. 5 mg/l o f t he tes t

su bsta nce (struc tural f or mul a C15H 22N2O 2, m ol ecular weight 2 62 .4

g/mol).

Deviating f ro m t he prelimi nary te st, a mo rtality ra te o f 1 0 % was d et ecte d in

th e m ain test at th e limit t est ed c onc entra tion o f 6 mg/l. Th e validit y criteria

of th e te st guid eline p ermit a m aximu m m ortality o f 1 0 % in t he con trol.

Re sult : LC0 >= 8. 1 mg /l (10% m ort ality rat e)

T est condition :

- Th e tes t was c ond uct ed in a ventila ted vessel ( 300 x 13 5 x 20 0 m m) f ille d

with 5 l tes t me di um

.

- Synthe tic fr esh water

(in accord anc e with I SO) was use d f or dilutio n. T he

water h ard ness was 14 .1 °dH.

- 20 fi sh es were u se d fo r t he tes t (10 fi shes fo r t he tes t vessel an d 1 0 f or

th e co ntrol). L ength : 2. 9-3. 5 c m. Fres h weight o f 1 0 f is hes: 4 .4 1 g (con trol)

an d 4 .0 2 g (test vessel).

- Th e tes t was p erf or me d at th e n omi nal limit test co ncen tratio n of 6 mg /l.

- Ph oto perio d: 1 6 h ours light/ 8 ho urs dark

.

- Te st t em per ature in t he t est vessel d uring th e st udy p erio d was 2 1. 3 to

21 .8 °C, pH-value was 7 .8 to 8 .0 an d oxygen c once ntrati on varied b etween

8. 1 a nd 8. 6 mg/l (oxy gen sat uratio n: 9 3. 8 t o 99 .5 %).

Re liabi lit y : (1) valid withou t restriction

GL P guidelin e st udy

Fl ag : Critical s tudy fo r S IDS e nd poin t

0 4. 11. 20 05 (22)

Ty pe : sta tic

Sp ec ies : Brac hydanio rerio (Fish, fr esh water)

E xposur e per iod : 96 ho ur(s)

65

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

4. ECOTOXICITY I D: 5124-30-1

DATE: 09.11.2006

Unit : mg/l

LC0 : .6 9

LC5 0 : 1. 2

LC1 00 : 2. 76

Lim it test : no

An al yt ical monitoring : no

Method :

Year : 19 92

GL P : yes

T est sub stance : ot her T S: Des mo dur W

, purity: 91 .6 % (2 4.3 8 % tr ans,tr ans4, 4'- m et hylene dicyclohex yl diis ocyanat e, 4 3. 00 % trans ,cis4, 4'- m et hylene dicyclohex yl diis ocyanat e, a nd 24 .20 % cis,cis4, 4'- m et hylene dicyclohex yl diis ocyanat e

Method : Ger ma n UBA-Pro pos al "L et ale W i r ku ng b ei m Ze brab aerbling Brac hydanio

rerio" (LC 0 , L C 50 , LC 10 0; 4 8-96 St un de n), May 1 98 4 (this pr op osal is in

mo st p arts eq uivalent to OECD T G 2 03)

. Rem ark : Bec aus e of th e high r eactivity o f

t he t est subs ta nce in water a nd th e low

water s olubilty, resp ectivel y, n o d et ermin atio n of th e t est s ubst anc e

co ncen tratio ns in t he test vessels was per fo rm ed during th e t est.

Th is t est h as n ot be en tak en in to a cco unt fo r t he a ssess me nt o f

4, 4'- m et hylene dicyclohex yl diis ocyanat e. 4 ,4'-Methylene dicyclohex yl

diisocyana te is n ot a c onsu mer p rod uct a nd may o nly be rele ase d int o th e

aqua tic environm ent fr om ma nu fa ct uring or pr ocessing. T he aqu atic ha lflif e o f t his isocyanat e is a pproximat ely 2 ho urs. Po ssible aq uatic e missio ns

would en ter a wastewater tr eat me nt p lan t with a hydraulic ret enti on ti me of

several hydrolysis h alf -lives, which me an s th at vi rtually all isocyana te

would hydroly ze t o th e c orrespo nding am in e duri ng wastewater tre atm en t

be fo re it en ters e nvironme ntal waters. T he hydrolysis pr oduc t,

4, 4'- m et hylene bis(c yclohexy lamine), is vi rtually th e o nly fo rm o f t he t est

su bsta nce in th e aqu atic environ me nt. T hu s, fo r a ssessm en t, n ot th e

isocyanat e, b ut its hydrolysis prod uct h as t o b e t est ed.

In th e te st a t issu e, t he t est subs ta nce was use d i mm ediat ely af te r c ont act

with water, a nd significa nt c onc entra tions o f t he un hydroly zed isocyan ate

were pr ese nt a t th e s tart o f inc uba tion . Th us , t hes e tes t co nditio ns d o n ot

ref lect environm en tal co nditio ns, a nd were n ot use d f or ass essm ent

T est condition :

- Th e tes t was c ond uct ed in ventilate d vessels (30 0 x 1 35 x 20 0 m m) ea ch

fill ed with 5 l t est me diu m.

- Synthe tic fr esh water

(in accord anc e with I SO) was use d f or dilutio n. T he

water h ard ness was 12 .8 °dH.

- 80 fi sh es were u se d fo r t he tes t (10 fi shes fo r e ac h of th e seven test

vessels an d 1 0 f or th e co ntrol). L ength : 2. 5-3. 5 c m. Fres h weight o f 1 0

fi sh es: 2 .1 6 g (c ontrol) an d 2 .1 7 t o 3 .5 0 g (test vessels).

- To pr ep are th e st ock s olutio n an am ou nt of th e te st s ubst ance was

weighed into water

a nd tre ate d with a n u ltra-turrax f or 60 sec on ds at 80 00

rpm

.

- Th e fo llowing no min al co nce ntratio ns were t est ed: 0. 08, 0. 17, 0. 35, 0. 69,

1. 38, 2. 76 a nd 5. 53 mg/l.

- Te st t em per ature in t he t est vessels d uring th e st udy p erio d was b etween

20 .7 a nd 21 .6 °C, pH-value was b etwee n 7. 5 a nd 8. 1, a nd oxy gen

co ncen tratio n varied be tween 8 .3 a nd 9. 4 mg /l (ox ygen s atura tion: 96 .0 t o

10 8. 0%)

Re liabi lit y : (2) valid with restrictions

Com para ble t o guid eline st udy with acc ept able restrictions

2 2. 12. 20 05 (14)

4 .2 AC UT E TOX ICITY TO A QU A T IC IN VERTEBR AT ES

66

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

4. ECOTOXICITY I D: 5124-30-1

DATE: 09.11.2006

Ty pe : sta tic

Sp ec ies : Dap hnia magn a (Crustac ea)

E xposur e per iod : 48 ho ur(s)

Unit : mg/l

EC 0 : >= 8 .3

Lim it Test : yes

An al yt ical monitoring : yes

Method : Directive 92 /6 9/E EC, C.2

Year : 20 00

GL P : yes

T est sub stance : ot her T S: Des mo dur W

, purity: 99 .5 % (2 1.1 % tra ns,tra ns4, 4'- m et hylene dicyclohex yl diis ocyanat e, 5 0. 2 % tra ns,cis4, 4'- m et hylene dicyclohex yl diis ocyanat e, a nd 28 .2 % cis,cis4, 4'- m et hylene dicyclohex yl diis ocyanat e

Rem ark : Be fo re b eginning o f t he s tudy a pr etre atm en t was p erf or me d with t he tes t

su bsta nce a ccording t o th e rec om me nd atio n me nti on ed in th e O ECD

Gui danc e Doc um ent on aqua tic toxicity t esting o f di ff ic ult su bst ances an d

mixtures in order t o a ccelera te t he soluti on pr oce dure. For th at p urp ose a

five f ol d a mo un t (4 5 mg/l) o f th e m aximu m water solu bility of th e te st

su bsta nce in th e pr eliminary t est (9 mg/l) was weighed int o water, tre ate d

fo r 6 0 s eco nds a t 8 00 0 rp m with an ultra-turrax, af te rwards stirred fo r 2 4

ho urs on a mag netic stirrer an d f in ally fi ltere d.

An alysis of th e only tes t su bsta nce c onc entra tion an d t he c ontr ol was

per fo rm ed a t t he start o f

t he tes t an d a ft er 48 ho urs of exposure by m ea ns

of TO C de ter minati on.

Th e tes t result EC0 >= 8. 3 mg/l r ef ers t o a co ncen tratio n of th e t est

su bsta nce which was c alculat ed d irectly fr om a nalytically d et ermin ed T OC

values (arith metic m ea n).

Accor ding t o rel evant pro duct inf or ma tion, 1 mg /l TO C equals t o 1 .5 mg/l o f

th e t est s ubst anc e (structur al fo rm ula C 15H2 2N2O2 , mo lec ular wei ght

26 2. 4 g/m ol).

T est condition :

- Th e tes t was c ond uct ed in a n ot ventilate d cylindrical t est vessel

(diam et er: 4. 0 c m, h eight: 6. 5 cm) f ille d with 2 0 ml t est m ed iu m.

- M4- Me diu m acc ording to Ele ndt a nd BG A (1 992) was us ed f or diluti on.

Th e water

h ard ness was 14 .2 °dH.

- 20 da ph nids, 0 -24 ho urs old , were u se d fo r t he tes t (10 da ph nids f or th e

tes t vessel an d 1 0 f or

th e c ontrol).

- Th e tes t was p erf or me d at th e n omi nal limit test co ncen tratio n of 9 mg /l.

- Ph oto perio d: 1 6 h ours light/ 8 ho urs dark

.

- Te st t em per ature in t he t est vessel a ft er 48 ho urs was 2 0. 2 °C, p H- value

was 7 .9 a nd oxy gen co nce ntratio n was 8 .5 mg/l.

Re liabi lit y : (1) valid withou t restriction

GL P guidelin e st udy

Fl ag : Critical s tudy fo r S IDS e nd poin t

0 4. 11. 20 05 (23)

4 .3 TO XICITY T O A QU A T IC PL AN TS E. G. AL G A E

Sp ec ies : Sce ne des mus s ubs picat us (Algae)

Endpoint : gro wth rat e

E xposur e per iod : 72 ho ur(s)

Unit : mg/l

EC 50 : > 5

Lim it test : no

An al yt ical monitoring : yes

Method : Directive 92 /6 9/E EC, C.3

Year : 20 00

67

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

4. ECOTOXICITY I D: 5124-30-1

DATE: 09.11.2006

GL P : yes

T est sub stance : ot her T S: Des mo dur W

, purity: 99 .5 % (2 1.1 % tra ns,tra ns4, 4'- m et hylene dicyclohex yl diis ocyanat e, 5 0. 2 % tra ns,cis4, 4'- m et hylene dicyclohex yl diis ocyanat e, a nd 28 .2 % cis,cis4, 4'- m et hylene dicyclohex yl diis ocyanat e

Rem ark : Results of a nalytical mo nit oring (t est s ubst ance co ncen tratio n):

- Contr ol at s tart o f

inc ub ation < 2 mg /l, af te r 7 2 h 4 m g/l

- Inc ub ation soluti on (n omi nal 5 mg/l) at start o f i ncub atio n 4 mg/l, a ft er 7 2

h 6 mg/l

- Inc ub ation soluti on withou t algae ( nomi nal 5 mg/l) at start of incu batio n 4

mg/l, a ft er 72 h 3 mg/l

As t he tes t co ncen tratio ns fo r t he de ter minati on o f t he NOEC an d L OEC

were b elow t he de tectio n limit of t he TO C de ter mina tion ( 2 mg/l) th e t est

results r ef er t o n omi nal c once ntrati ons. T he a rithm etic m ea ns o f t he TO C

de ter minati on o f

t he h ighest t est conc entr ation (5 mg/l) exhibite d a n

expect ed rec over y rat e o f t he t est subs tanc e b ase d o n organic C ( 4.5 m g/l

= 90 % recovery)

Re sult : Cell nu mb er/ml (x10E3)

2 4h 48 h 72 h

Con trol: 41 .1 14 0 30 4

0. 08: 4 8. 9 1 57 3 07

0. 16: 5 0. 0 1 58 4 50

0. 31: 4 6. 7 1 66 3 61

0. 63: 3 6. 7 1 42 1 97

1. 3: 2 7. 8 1 43 1 65

2. 5: 2 2. 2 1 53 2 11

5. 0: 2 2. 2 1 50 1 80

Growth an d growth ra tes a t s everal c once ntrati ons:

Con trol: 0 an d 0

0. 08:

- 8 .4 * an d 0

0. 16:

- 3 2. 5* a nd

- 1 8. *

0. 31:

- 1 9. 5* a nd

- 9 .1 *

0. 63: 18 .2 a nd 9. 1

1. 3: 2 6. 0 a nd 18 .2

2. 5: 1 6. 9 a nd 9. 1

5: 23 .1 a nd 9. 1

*increas e

Toxicities:

En dp oint growth: EbC5 0 > 5 mg/l,

En dp oint growth rate : ErC5 0 > 5 mg/l,

NOEC (cell de nsity a ft er 72 h): 0 .3 1 mg/l,

LO EC (cell de nsity a ft er 7 2 h) : 0. 63 mg/l

T est condition :

- Prep aratio n o f st ock solu tion accordi ng t o t he reco mm en datio n m en tion ed

in t he O ECD Gui danc e Doc um ent on aqua tic toxicity t esting o f di ff ic ult

su bsta nces a nd mixtures: A 5 fo ld co ncen tratio n of (37 .5 mg /l) o f

t he

maxim um water

s olubility o f

th e t est s ubs tanc e in p relimin ary tes t (7. 5 mg/l)

was weighed int o water an d tr eat ed f or 60 sec on ds at 80 00 rpm in a n ul tra

turrax. Th e susp esion was stirred by a mag netic s tirrer f or 24 h.

Undissolved p articles were rem oved by fil tratio n thr ough a fo ld ed fil ter of

th e p ore size of 7-12 μm

- Th e cultivation o f

st ock c ultures, precult ures a nd tes t cult ures was

per fo rm ed in a light c ha mb er a t 2 3 +/- 2 °C an d with a qu ant um fl ux which

equals 1 20 μE /m 2 x s

- Th e tes t was c ond uct ed in Erlen meyer fl asks (3 00 m l) with st op pers, e ac h

fill ed with 10 0 m l of

tes t me di um . Th e tes t fl asks were p ut i n a light

ch am ber with s hak er

- Deionis ed water was u se d fo r d ilutio n

- In oculu m: a lgal s usp ensio n ta ken fr om an expo ne ntially gro wing

68

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

4. ECOTOXICITY I D: 5124-30-1

DATE: 09.11.2006

prec ulture which serves to adj ust a n initi al cell de nsity o f 1 0, 000 cells per

ml

- Th e fo llowing no min al co nce ntratio ns were t est ed: 0. 08, 0. 16, 0. 31, 0. 63,

1. 3, 2 .5 an d 5 mg/l

- Th e pH- value in t he t est vessels was 8. 1 a t t he b eginning o f t he t est an d

be tween 9 .3 a nd 10 .4 af te r 72 ho urs o f

expos ure

- An alytical mo nit oring by T OC m ea sure me nt (limit o f d et ectio n 2 m g C/l).

An alysis of th e highes t tes t co nce ntratio n a nd th e co ntrol was p erf or me d a t

th e st art of

th e t est a nd af

te r 7 2 h of exposure . Ad ditio nally an alysis of th e

highest conc en tration without algal in oculu m was per fo rm ed a t t he sam e

tim e int ervals

Re liabi lit y : (1) valid withou t restriction

GL P guidelin e st udy

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 8. 01. 20 06 (24)

4 .4 TO XICITY T O MICROORG AN ISMS E .G. BA CT ERI A

Ty pe : aqua tic

Sp ec ies : activate d sludge of a pr edo min antly d om es tic sewage

E xposur e per iod : 3 h our(s)

Unit : mg/l

EC 50 : = 19 1

An al yt ical monitoring : no

Method :

Year : 20 00

GL P : yes

T est sub stance : ot her T S: Des mo dur W

, purity: 99 .5 % (2 1.1 % tra ns,tra ns4, 4'- m et hylene dicyclohex yl diis ocyanat e, 5 0. 2 % tra ns,cis4, 4'- m et hylene dicyclohex yl diis ocyanat e, a nd 28 .2 % cis,cis4, 4'- m et hylene dicyclohex yl diis ocyanat e

Method : Com missio n Directive 8 8/ 302 /EEC, Of fi cial J ourn al of

t he EC L 13 3, P art C:

Bio degrada bility: Te st fo r in hibitio n of oxy gen cons um ptio n (corresp on ds to

th e O ECD T G 20 9).

Rem ark : Th e de scribed m et ho d f or th e pr ep aration of tes t solu tion will lea d to th e

ne arly co mple te hydrolysis of 4, 4'- m et hylene dicyclohex yl d iisocyanat e an d

to th e fo rm ati on o f

t he hydrolysis pr od uct, 4 ,4'-m et hylenebis

(cyclohex ylamine)

T est condition :

- Be fo re t he incu bati on a pre treat me nt was per fo rm ed with th e t est

su bsta nce a ccording t o th e rec om me nd atio n me nti on ed in th e O ECD

Gui danc e Doc um ent on aqua tic toxicity t esting o f di ff ic ult su bst ances an d

mixtures. T he t est subs tanc e was ad de d to ab ou t 13 0 m l d eio nised water,

trea te d 3-4 h by ultras ou nd a nd stirred overnight b ef or e t esting

(equilibration p ha se)

- Th e fo llowing no min al co nce ntratio ns were t est ed: 56 , 1 00 , 18 0, 32 0 a nd

56 0 mg /l

- Th e tes t co ncen tratio n of activate d slu dge was 3 20 mg/l

- Th e pH- value of th e sus pe nsion b ef or e a pplica tion was 6. 7

- Inc ub ation tim e: 3 ho urs with p erm an en t aer atio n.

- Th e tes t te mp erat ure was 2 0 +/- 2 °C

Re liabi lit y : (1) valid withou t restriction

GL P guidelin e st udy

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (25)

Ty pe : aqua tic

Sp ec ies :

69

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

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DATE: 09.11.2006

E xposur e per iod :

Unit : mg/l

EC 3 : 80

Method :

Year : 20 03

GL P :

T est sub stance : ot her T S: Met hylene bis(4-cyclohex yldiamine)

Re sult : Th e hydrolysis pr od uct, 4 ,4'-m et hylenebis(cyclohex ylamine), h as a low

ec otoxicity

Re liabi lit y : (2) valid with restrictions

Reliable sourc e

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (58)

Ty pe : aqua tic

Sp ec ies : activate d sludge of a pr edo min antly d om es tic sewage

E xposur e per iod : 3 h our(s)

Unit : mg/l

EC 50 : = 19

An al yt ical monitoring : no

Method : IS O 81 92 "T es t f or inhibiti on o f oxygen co nsu mp tion by a ctivated slu dge"

Year : 19 92

GL P : yes

T est sub stance : ot her T S: Des mo dur W

, purity: 91 .6 % (2 4.3 8 % tr ans,tr ans4, 4'- m et hylene dicyclohex yl diis ocyanat e, 4 3. 00 % trans ,cis4, 4'- m et hylene dicyclohex yl diis ocyanat e, a nd 24 .20 % cis,cis4, 4'- m et hylene dicyclohex yl diis ocyanat e

Rem ark : Th e tes t su bsta nce was no t c om plet ely solu ble in water a t

all te ste d co nce ntratio n levels.

Th is t est h as n ot be en tak en in to a cco unt fo r t he a ssess me nt o f

4, 4'- m et hylene dicyclohex yl diis ocyanat e. 4 ,4'-Methylene dicyclohex yl

diisocyana te is n ot a c onsu mer p rod uct a nd may o nly be rele ase d int o th e

aqua tic environm ent fr om ma nu fa ct uring or pr ocessing. T he aqu atic ha lflif e o f t his isocyanat e is a pproximat ely 2 ho urs. Po ssible aq uatic e missio ns

would en ter a wastewater tr eat me nt p lan t with a hydraulic ret enti on ti me of

several hydrolysis h alf -lives, which me an s th at vi rtually all isocyana te

would hydroly ze t o th e c orrespo nding am in e duri ng wastewater tre atm en t

be fo re it en ters e nvironme ntal waters. T he hydrolysis pr oduc t,

4, 4'- m et hylene bis(c yclohexy lamine), is vi rtually th e o nly fo rm o f t he t est

su bsta nce in th e aqu atic environ me nt. T hu s, fo r a ssessm en t, n ot th e

isocyanat e, b ut its hydrolysis prod uct h as t o b e t est ed.

In th e te st a t issu e, t he t est subs ta nce was use d i mm ediat ely af te r c ont act

with water, a nd significa nt c onc entra tions o f t he un hydroly zed isocyan ate

were pr ese nt a t th e s tart o f inc uba tion . Th us , t hes e tes t co nditio ns d o n ot

ref lect environm en tal co nditio ns, a nd were n ot use d f or ass essm ent

Re sult : Te st conc entr ation* res perati on ra te In hibitio n (mg/l)

(mg/l h) (%)

0 2 2. 2 0

5 .6 19 .5 12 .2

10 16 .0 27 .9

18 10 .8 51 .4

32 7. 0 6 8. 5

56 4. 0 8 2. 0

* n omi nal

T est condition :

- Th e fo llowing no min al co nce ntratio ns were t est ed: 5. 6, 1 0, 18 , 32 a nd 56

mg/l

- Type of ap plicatio n: T es t su bsta nce s tock e mu lsion was pre pare d by

70

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

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DATE: 09.11.2006

ad ditio n of 1 g/l o f

te st s ubst ance int o water an d tre at me nt with u ltra-turrax

at 80 00 rpm fo r 6 0 s econ ds. T he e mu lsion was us ed f or pre para tion o f

t est

solu tions by dilu tion o f

a liquots

- Th e conc en tration of inoc ulum was 6 g/l t est subs ta nce

Re liabi lit y : (2) valid with restrictions

Com para ble t o guid eline st udy with acc ept able restrictions

1 8. 01. 20 06 (14)

4 .5 .1 CHRONIC TOXICITY TO F ISH

4 .5 .2 CHRONIC TOXICITY TO AQ U A TI C INV ERTEBR A TES

4 .6 .1 TO XICITY T O SED IMENT D WELLING OR G AN ISMS

4 .6 .2 TO XICITY T O TERRESTRIA L PLA NTS

4 .6 .3 TO XICITY T O SO IL DW ELLING ORGA NIS MS

4 .6 .4 TO X. TO OTHER NON M AM M. TERR. S PECI ES

4 .7 BIOL OGICA L EFFECTS MONITORING

4 .8 BIOTRA NS FORM A TI ON A ND KINETIC S

4 .9 AD DI TION AL REM AR KS

71

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DATE: 09.11.2006

5 .0 TO XICOKINETICS , MET AB OLISM A ND DI STRIBUTION

5 .1 .1 AC UT E OR AL TOX ICITY

Ty pe : LD5 0

V alu e : = 99 00 mg/kg bw

Sp ec ies : rat

Str ain : Spr ague- D awle y

S ex :

Number of

a nim als : 5

V ehi cle : ot her: c orn oil

Dos es : 63 10 , 79 40 , 1 00 00, 12 60 0 mg/kg

Method : ot her: s ee T es t Co nditio n

Year : 19 66

GL P : no

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : MORT ALI TY:

Num ber o f

d ea ths a t e ac h do se: 63 10 m g/kg: 0/ 5, 7 94 0 mg /kg: 1 /5 , 1 00 00

mg/kg: 3/ 5, 12 60 0 mg/kg: 4 /5

SURVIV AL T IM E:

On e t o fo ur

days

CLINICA L SI GNS:

severe diarrh ea, loss of ap pe tite a nd incre asing weakn ess

NECROPSY:

Liver disc oloratio n a nd ren al hyperemi a

T est condition : ADMINIS TRA TION: th e t est m at erial was a dmi nistere d by st om ach t ub e

as 5 0% soluti on-susp ensio n in corn oil

sex: 5 a nim als per do se with alter nat e sex (e.g. 3 f em al es an d 2 ma les or 2

fe ma le s an d 3 m ales)

po st o bservation p erio d: n o d at a

EXAMINAT IONS: mor tality, clinical signs a nd ne cropsy o f t he ani mals t ha t

succ um bed

CALCULA TI ON OF LD 50 :

Accor ding t o a mo di fic ation of th e me th od of E.J . de Be er

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n, n o d at a o n p urity o f te st s ubst ance

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (77)

Ty pe : ot her: A LD

V alu e : > 11 00 0 mg /kg bw

Sp ec ies : rat

Str ain : ot her: C hR- CD

S ex : ma le

Number of

a nim als :

V ehi cle : pe an ut oil

Dos es : 67 0, 2 25 0, 34 00 , 50 00 , 75 00 , 1 10 00 m g/kg

Method : ot her: n o d at a

Year : 19 63

GL P : no

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , no d at a on purity

Rem ark : ALD = A ppr oximate le th al dos e

Re sult : MORT ALI TY: n o m ort ality

CLINICA L SI GNS: I nitial weight l oss; di arrhea, perin eal disc oloratio n,

72

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

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DATE: 09.11.2006

disco mf or

t at levels o f

2 25 0 mg/kg a nd ab ove NECROPSY: Slight t o m od erat e c ha nges in kid ney a nd brain at all do ses;

injury to st om ach a nd sm all intes tine at 1 10 00 mg/kg

T est condition : No. o f A nim als: n o d at a

ADMINIS TRA TION: th e t est m at erial was a dmi nistere d by st om ach t ub e

as s usp ensio n in p ea nu t oil in si ngle d os es

po st o bservation p erio d: 1 4d

EXAMINAT IONS: mor tality, clinical signs a nd ne cropsy

Re liabi lit y : (3) invalid

Th e do cum en tati on o f

t he s tu dy is insu ff ici ent , i.e . th e n um ber o f a nim als is

no t m en tion ed

2 1. 10. 20 04 (46)

5 .1 .2 AC UT E INH AL A T IO N TOXICITY

Ty pe : LC5 0

V alu e : = 43 4 mg/m3

Sp ec ies : rat

Str ain : W i s ta r

S ex : ma le/ fe ma le

Number of

a nim als : 5

V ehi cle : ot her: n o

Dos es : 15 1, 3 88 , 4 18 , 55 2, 73 0, 8 65 , 1 ,3 52 mg /m3

E xposur e time : 4 h our(s)

Method : OECD G uide-line 40 3 " Acu te I nh alatio n Toxicity"

Year : 19 85

GL P : yes

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , purity > 99 .2 %

Re sult : VA LUE:

LC5 0 (m ale): 4 56 mg/m 3 (9 5% co nf id enc e int erval of 31 3 t o 6 67 mg/m 3)

LC5 0 (f em al e): 43 1 mg /m 3 (95% co nf ide nce i nterval o f 3 63 to 51 3 mg /m 3)

LC5 0 (m ale/ fe ma le): 4 34 mg/ m3 (9 5% c on fid enc e int erval of 35 5 t o 5 33

mg/ m3)

MORT ALI TY:

Num ber o f

d ea ths a t e ac h do se (ti me o f d ea th), m al e rats: 15 1 mg/ m3 : 0 /5;

38 8 mg /m 3: 2 /5 ( 1d-2d); 41 8 mg/ m3 : 2 /5 (1 d-2d); 55 2 mg/ m3 : 5/ 5 (1 d- 4 d);

73 0 mg /m 3: 4 /5 ( 1d-3d); 86 5 mg/ m3 : 2 /5 (1 d-2d); 1, 352 mg/ m3: 5/ 5 (0d-1 d)

Num ber o f

d ea ths a t e ac h do se (ti me o f d ea th), f em al e r ats: 1 51 mg/ m3:

0/ 5; 3 88 mg/ m3: 2/ 5 (1 d); 41 8 mg /m 3: 2 /5 ( 1d); 5 52 mg/m 3: 4/ 5 (1d-2 d);

73 0 mg /m 3: 5 /5 ( 1d); 8 65 mg/m 3: 5/ 5 (1d-3 d); 1 ,3 52 mg /m 3: 5 /5 ( 0d-1d)

CLINICA L SI GNS:

Num ber o f

a nim als with clinical signs, m al e rats : >= 1 51 mg/ m3: 5/ 5 (du e t o

early d ea th a t 1 ,3 52 m g/m 3 clinical signs were only f or 4/ 5 a nim als

record ed) sh owed during t he exp osure a nd up to 12 d a ft er th e expos ure

bra dypnea , dyspne a, l abo ured brea thing, rales , irregular br ea thing pa tt ern,

ungroo me d c oat , pilo erection , mo tility re duce d, tr em or, hu nc hed pos ture,

highlegged gait, st aggered gait, sluggish, cyanosis, vocalization,

em acia tion, sero us disch arge fr om no se, red dish rhin arium, wheezing,

no se with red e ncrus tatio ns, n os e- Muzzle/red e ncrus tatio ns, pr ostrati on (ly ing on b elly); at t he en d o f t he pos t ob servation p eriod all surviv ing

ani mals were without symp to ms

Num ber o f

a nim als with clinical signs, f em al e rats: >= 15 1 mg /m 3: 5 /5 (du e

to early d ea th a t 1 ,3 52 mg /m 3 clinical signs were o nly f or 4/ 5 a nim als

record ed) sh owed during t he exp osure a nd up to 9d af te r t he exposure

bra dypnea , dyspne a, l abo ured brea thing, rales , irregular br ea thing pa tt ern,

ungroo me d c oat , pilo erection , mo tiltiy re duce d, tr em or, hu nc hed pos ture,

highlegged gait, st aggered gait, sluggish, cyanosis, vocalization,

73

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

em acia tion, sero us disch arge fr om no se, red dish rhin arium, wheezing,

no se with red e ncrus tatio ns, n os e- Muzzle/red e ncrus tatio ns, pr ostrati on (ly ing on b elly); at t he en d o f t he pos t ob servation p eriod all surviv ing

ani mals were without symp to ms

BODY W E I G HT :

>= 1 51 mg/m 3: bo dy weight re tard ation

RECT AL T EM PERA TURE:

co ncen tratio n de pe nd ent decr ease

REFLEX EXAMINA TION:

no su bsta nce i nduc ed e f fe ct s

NECROPSY:

rats di ed during th e p ost obs ervation peri od:

pal e liver, spl een an d kid neys, lob ular pa tt ern of th e liver, d uo de nu m was

fill ed with a re d m uc ous m ass , trac hea was f illed with a mu co us ma ss, less

collaps ed lungs with re d fo ci , pul mo nary e de ma an d hydro thorax; lu ngs

were re d up t o he pa toid ch anges, re d secr etions in t he n os e

rats s acrific ed a t t he e nd of th e p ost obs ervation peri od:

>= 1 51 mg/m 3 n o s peci fic c once ntrati on d ep en de nt organ ch anges

T est condition : ADMINIS TRA TION:

vapour in hala tion un der dyna mic h ea d- n os e only exposure co nditio ns

po st o bservation p erio d: 2 weeks

no min al co ncen tratio ns: 6 67 , 1, 16 7, 1 ,3 33, 1, 66 7, 2 ,5 00, 3, 333 , 6, 66 7

mg/ m3

ch am ber co nce ntratio n:

An alysis of th e te st a tm osp here:

th e ch am ber s am ples were tak en i n th e vicinity o f t he bre athing zone an d

th e t est-subs ta nce c once ntrati on was de ter mine d by H PLC (tes t ma terial

was c ollecte d in a glass tu be f ille d with m in eral wool which was

im pregnat ed with a ni troco mp ou nd t o re act in situ with th e diisocyan ate)

an d by gravimetric a nalysis ( filter: Gl ass Fibre-Filter)

th e a nalytical values de ter mine d by H PLC < th e a nalytical values

de ter mine d gravimetricall y

th e a nalytical values were 2 0 t o 3 3% o f t he no min al co ncen tratio n;

particle size distrib utio n:

90 % of th e p article m ass with an aer odyna mic dia me ter <= 3 μ m

ma ss m edi an a ero dynamic di am et er (MMAD) » 1 .4 μ m; geo me tric

sta nd ard deviatio n (GSD) » 1. 8 μm

EXAMINAT IONS:

mor tality; clinical signs; bo dy weight; rectal t em per ature , ref lex, ne cropsy

CALCULA TI ON OF LC 50 :

acc ording t o A .P . Rosiello e t al ., J. Tox. a nd Environ. He alth 3 , 7 97-8 09

(19 77) an d m od if ie d by J . Pa ulu hn; Bayer Rep ort No. 11 84 5 (19 83)

Re liabi lit y : (1) valid withou t restriction

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 4. 01. 20 05 (18)

Ty pe : LC5 0

V alu e : 29 5 30 7 mg /m3

Sp ec ies : rat

Str ain : Spr ague- D awle y

S ex : ma le/ fe ma le

Number of

a nim als : 10

V ehi cle : ot her: n o

Dos es : 19 1, 1 13 , 3 07 , 28 8, 34 0, 6 08 mg/ m3

E xposur e time : 4 h our(s)

Method : ot her: s ee T es t Co nditio n

Year : 19 85

GL P : yes

T est sub stance : ot her T S: se e Te st su bsta nce

74

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

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DATE: 09.11.2006

Re sult : VA LUE:

LC5 0 (m ale): 2 95 mg/m 3 (9 5% co nf id enc e int erval of 22 1 t o 3 80 mg/m 3)

LC5 0 (f em al e): 30 7 mg /m 3 (95% co nf ide nce i nterval o f 2 68 to 32 7 mg /m 3)

NOEL : < 11 3 mg /m 3

th e res ult fo r 1 91 mg/ m3 was no t u se d in c alculating t he L C50

MORT ALI TY:

Num ber o f

d ea ths a t e ac h do se (ti me o f d ea th), m al e rat: 11 3 mg/ m3 : 1 /1 0

(1d), 1 91 mg/ m3 : 0/ 10 , 28 8 mg /m 3: 5 /1 0 (1d), 30 7 mg/ m3 : 3 /1 0 (0-1d), 34 0

mg/ m3: 7/ 10 (1-2 d), 6 08 mg/m 3: 10 /10 (0- 1 d)

Num ber o f

d ea ths a t e ac h do se (ti me o f d ea th), f em al e r at: 1 13 mg/ m3:

0/ 10, 19 1 mg /m 3: 0 /1 0, 2 88 mg/m 3: 3/ 10 (1-3 d), 3 07 mg/m 3: 4 /1 0 (1 d), 34 0

mg/ m3: 9/ 10 (1-2 d), 6 08 mg/m 3: 10 /10 (0- 1 d)

CLINICA L SI GNS:

nu mb er of

ani mals with clinical signs (m ale/ fe ma le): 1 0/ 10 >= 11 3 mg /m 3

na sal an d o cular irritatio n duri ng exp osure a nd

po st- exp osure. So me of th e a nim als expose d t o 30 7, 34 0 a nd 60 8 mg /m 3

air sh owed s alivation, lacrim atio n, d ecreas ed activity, o ccasio nal tr em ors

an d c orne al op acity. T he clinical signs las ted up to te n d ays in bo th m al e

an d f em al e a nim als. Di ff iculty in br eat hing was als o ob served in a nim als

when th ey were tak en ou t of th e t ub es. Most of th e surviv ing ani mals

exhibite d alo pecia of var ying d egree i n are as t hat were in con tact with th e

co mp oun d d uring t he exposur e. T he al opeci a was n otic ed o n d ay 2 or 3

an d las ted un til th e en d o f t he stu dy. Neck ed em a o bserved in ani mals was

relat ed t o t he mo de of exposure an d n ot t o t he co mp oun d.

BODY W E I G HT :

Th e group m ea n b ody weights o f m ale ani mals exp osed to test ma terial

were signi fican tly lower th an th ose o f

t he con trol group o n d ays 2, 3 a nd 4

at conc en trations 11 3 a nd 28 8 mg /m 3 air, o n d ays 2 t hrough 7 at

co ncen tratio n 34 0 mg /m 3 air a nd on days 2 t hro ugh 14 at conc en tration

30 7 mg /m 3 air.

Th e group m ea n b ody weights o f c om pou nd-expos ed f em al es were significa ntly lower

o n d ay 2 a t expos ure c once ntrati on 1 91 mg/ m3 a ir, an d

on days 2 thro ugh 4 a t c onc entra tions 2 88 , 3 07 an d 3 40 mg/ m3 a ir.

NECROPSY an d HI ST OPA THO LOGY:

Com po un d- rel ate d gross lesions obs erved in m ost of th e ani mals sacrific ed

at ter m inclu ded alo pecia of t he ear an d h ea d skin (t he ar eas directly

expose d t o te st m at erial) a nd occ asion al crusty zon es. T he gross lesio ns

ob served in t he a ni mals t hat die d duri ng 0 1: af te r co mp ou nd exp osure

were ago nal c ha nges an d inclu de d lacrim ation , dark pink or red lungs,

yello w or re d n asal d ischarge, re dd en ed t urbin ates a nd gas- f ille d

int estines . Ot her gross lesio ns ob served in c ontrol a nd co mp ou nd-expose d

ani mals were incid ent al an d dis tribut ed ra nd omly in bo th grou ps.

Microscopic exa minati on o f t he e ar a nd skin lesio ns s howed th at t he

severity o f

e ar lesio ns was conc entr ation-rela ted (P<O.O5). Th e lesions

co nsisted of aca nth osis, c hronic or c hronic-active inf la mm ati on a nd

La ngha n's giant c ells with ph agocyti zed h air an d f oa my cytoplas m. T he se

lesions occ urred in t he ears a nd skin o f s everal s acrifice d a nim als at all bu t

th e lowest co nce ntratio n level an d pr oba bly repres ent a f or eign bo dy

reacti on initi ate d by de bris con ta mina ting t he der mis thr ough overlyin g

ulcers. Exp osed ani mals t ha t di ed d uring th e st udy h ad no ear or skin

lesions which m ight re fl ect a sh orter exposur e tim e t o t he c om po un d.

Le sions o f

lu ng, liver, an d ki dney were lesio ns were toxicologically

no nsignific ant since t hey were s ee n in b ot h co ntrols a nd expose d an im als

(sacrific ed a nd fo un d de ad) or were s ee n only in c ontrol a nim als.

T est condition : ADMINIS TRA TION:

Te st ma terial was genera ted as a liquid aer osol by an ap par atus t ha t

co nsisted of two c once ntric nozzles. T he t est m at erial was c on duct ed i nto a

fi ne inn er nozzle by an inf usi on p um p at a c onst ant rate . Ani mals were

expose d u nd er dynamic con ditions in a 60-liter cylindrical c ha mb er. In th e

mi ddle p ortio n of

th e c ha mb er

were two rows of te n tu bes ea ch, which

75

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

were a tt ache d ra dially t o t he ch am ber. T he a nim als were i ndividually

po sition ed in th ese t ub es s o th at o nly t heir he ad s were exp osed to th e te st

ma terial while th eir

b odi es re main ed within p erf ora ted tu bes.

po st o bservation p erio d: 1 4 d ays

no min al co ncen tratio ns:

50 0, 7 50 , 1 ,0 00, 1, 24 0, 1 ,5 00 a nd 1, 75 0 mg/ m3

ch am ber co nce ntratio n:

An alysis of th e te st a tm osp here:

An alytical co nce ntratio n o f t he c ha mb er at mos ph ere was d et ermin ed by

taki ng s am ples n ear t he ani mal br eat hing zone; 1 .5 to 3-liter sa mpl es were

tak en a t 1 5 m in ute intervals; sa mples were dr awn t hrough Millipore FH

(pore size 0. 5 u m) f ilt ers at a ra te o f 1 .5 l/ min ; th e c ont ents of t he fi lter were

de ter mine d by H PLC.

Th e an alytical values were 23 to 38 % o f no mi nal co nce ntratio n, exce pt f or

on e value ( 113 mg/m 3) which was on ly 15 %.

particle size distrib utio n:

50 % of th e p article m ass h ad ma ss m edi an aero dynamic d iam et er (MMAD)

bel ow 2 μ m; ab ou t 9 0% o f t he particle m as s ha d MMAD less t ha n 6 .6 μ m

EXAMINAT IONS:

mor tality, clinical signs a ppr oximately (thr ee t o f ou r ti mes p os t- expos ure (on d ay of

exp osure) a nd th en twice daily u p t o 1 4 d ays), b ody weights

(prior to exp osure a nd on d ays 2 , 3 , 4, 7 an d 1 4 a ft er exp osure), n ecro psy,

hist opa thol ogy (lu ngs, liver, kidn eys fr om a nim als expose d t o 11 3, 11 9, 2 88

an d 3 40 mg/ m3).

CALCULA TI ON OF LC 50 :

Th e LC5 0 values with 95 % co nf ide nce limits were c alculat ed by pr obit

an alysis. During sa mpling. higher rec overies (3 0.7 %) were se en a t 3 07

mg/ m3 a ir

c onc entra tion (no minal 1 ,0 00 m g/m 3 air) an d l ower recoveries

(23. 2%) at 28 8 mg /m 3 air (n omin al 1, 24 0 mg/ m3 air. Th is re fl ecte d high er

mor tality a t t he l ow conc entr ation an d lower m ort ality at th e high

co ncen tratio n, which ma de it di ff ic ult t o calc ulate th e LC 50. Th ere fo re, th e

co ncen tratio ns of 28 8 a nd 30 7 mg /m 3 air an d t heir c orrespo nding

mor talities were averaged in calcula ting L C50 values.

T est sub stance : 4, 4 ́- Met hylenedicyclohexy l diisocyan ate , tec hnical grad e, n o f ur th er da ta

Re liabi lit y : (2) valid with restrictions

Due to t he me th od ap plied f or t he a nalysis o f

t he tes t at mo sph ere t he

values fo r th e an alytical c onc entra tions u nd eresti mat e t he a ct ual expos ure

co ncen tratio n be caus e t he t est sa mple partly would h ave be en ca pture d by

reacti on with th e f ilter m at erial an d/ or hu midity; no re plicate o f t he

de ter minati on u sing a no th er de tecti on m et ho d (e.g. gravimetric an alysis)

was p erf orm ed

Fl ag : Critical s tudy fo r S IDS e nd poin t

0 6. 11. 20 06 (76)

Ty pe : ot her

V alu e : Sp ec ies : rat

Str ain : ot her: C hR- CD

S ex : ma le

Number of

a nim als : 4

V ehi cle : ot her: n o

Dos es :

E xposur e time : 4 h our(s)

Method : ot her: s ee T es t Co nditio n

Year : 19 63

GL P : no

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : MORT ALI TY RAT IO :

76

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

0/ 4 (2 00 °C); 2 /4 (25 0 °C); 2/ 4 (3 00 °C)

OB SERVA TI ONS:

At th e 25 0 a nd 30 0 °C l evel th e ra ts exhibite d gasping, la bore d res piration,

ruf fl ed f ur , extrem ely red extremities, eye irritation a nd lacrima tion . In

ad ditio n to CO, white f um es were obs erved in th e exp osure c ha mb er.

At th e 20 0 °C l evel th e a nim als sh owed slightl y d ee p res piration , red

extremities , eye irritation a nd lacrim ation . Neit her CO n or fu me s were

de tect able in t he exp osure c ha mb er at 20 0 °C.

T est condition : ap prox. 20 grams o f ma teri al was pl aced in a fl ask a nd he at ed t o a nd

ma int aine d at th e required te mp eratur e (20 0, 2 50 , 30 0 °C) in a h ea ting

ma ntl e. A dry air stre am pa ssed thro ugh th e f la sk to a 8-liter bell jar

co ntaini ng t he rats; s urvi vors killed 14 days lat er;

no min al co ncen tratio n:

12 ,1 m g/m 3 (3 00 °C); 1 1, 1 mg/ m3 (25 0 °C); 10 ,4 m g/m 3 (2 00 °C)

(com pu ted fr om weight loss of s am ple a nd air fl ow)

Re liabi lit y : (3) invalid

Due to t he high t em pera ture d ec om positio n of th e t est m at erial ca nn ot b e

exclude d; n omi nal expos ure was no t verifie d an alyticall y; whole b ody

exposure

1 4. 01. 20 05 (46)

Ty pe : ot her

V alu e : Sp ec ies : rat

Str ain : ot her: C hR- CD

S ex :

Number of

a nim als : 4

V ehi cle : ot her: b utyl a ce tat e

Dos es :

E xposur e time : 1 h our(s)

Method : ot her: s ee T es t Co nditio n

Year : 19 68

GL P : no

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : During exp osure n o clinic al signs o f res piratory irritatio n were s ee n;

im me diate red deni ng o f t he rat e ars fo llowed over a 14-d ay p eriod by

swellin g o f

t he e ars, sl uf

fi ng of th e o ut er ear ski n an d its regenera tion. Th is

was a ccom pa nied by m icrosco pically ide ntif iabl e ed em s a nd congesti on o f

th e e ar skin layers which was still m idly evide nt 1 4 d ays a ft er exposure , th e

tes t ma terial c aus ed tr ach eitis an d brinc hitis which was he aling 7 d ays a ft er

exposure an d h ad he ale d 14 days af te r expos ure

no min al isocyanat e c once ntrati on: 2 ,8 5 mg /m 3

T est condition : Th e tes t ma terial was dissolved in co mm ercial bu tyl ac eta te , th e t est

solu tion was sprayed a t t he sa me u nif or m ra te in to t he exposure cha mb er

thro ugho ut t he exp osure, th e sol utions were s prayed with st ainless s teel

pai nt s pray nozzle u sing h ou se a ir. Con trol rats were similary expos ed t o

bu tyl ac eta te o nly. Dro plet size distribu tion was me as ured with Mo nsan to

casc ade imp act or; 2 ra ts were s acrifi ed f or gross an d his top at hologic

examin atio n at ea ch o f 7 an d 1 4 d ays pos t- exp osure; tissue examin ed

were lu ng, liver, brain , spl een , kidn ey, t est es, st om ach , thym us, t hyroid,

adr enal, ear a nd bo ne ma rrow.

Re liabi lit y : (3) invalid

Due to l ack of

stu dy d ocu me nt ation an d st udy d esign a nd unr eliable

exposure an alysis

1 4. 01. 20 05 (47)

Ty pe : ot her: Class B P oison Te st

V alu e : Sp ec ies : rat

77

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

Str ain : ot her: C hR- CD

S ex : ma le

Number of

a nim als : 10

V ehi cle : ot her: n o

Dos es :

E xposur e time :

Method : ot her: s ee T es t Co nditio n

Year : 19 72

GL P : no

T est sub stance : ot her T S: Hylene W

, no d at a on purity

Re sult : Th e tes t ma terial is n ot a Class B P oiso n by i nhal ation as

de fi ne d by th e De part men t of Tr ans porta tion

T est condition : Exposure No. 1 :

ap prox. 10 0 grams o f

t he tes t ma terial was ma int aine d a t roo m

te mp erat ure in a ro und-b ott om ed fl ask. Dry h ous eline a ir was pa sse d over

th e m at erial an d in to a 20-lit er exp osure c ha mb er co ntaini ng t he rats.

Sa mpl es of

th e c ha mb er

a tm os pher e were t ake n a t le ast t hree ti me s during

exposure an d a nalyzed u sing a c olorime tric m et ho d. Neit her gross nor

hist opa thol ogic exa minati on was per for me d o n a ny a nim als t este d

Exposure No. 2 :

Proc edure sa me a s a bove with o ne mo di fic ation : ho us eline air was pa ssed

int o th e f la sk thr ough a stai nless st eel n ob ulizer to ge nerat e a erosol a nd

tes t ma terial was he at ed a t 6 2-75 °C

Re liabi lit y : (3) invalid

Meth od ological d ef icie ncies, an alytical de tec tion me th od a nd /or t he

genera tion of

t he tes t at mo sp here ar e u nrealia ble b eca use t he an alytical

co ncen tratio ns range d fr om 0 .0 05 -0. 51 4 mg/l f or several expos ures which

were c ond uct ed u nd er ide ntical c onditi ons

2 2. 10. 20 04 (50)

Ty pe : ot her: i nhal ation hazard t est

V alu e : Sp ec ies : rat

Str ain : no da ta

S ex : ma le

Number of

a nim als : 4

V ehi cle : ot her: n o

Dos es : no da ta

E xposur e time : 6 h our(s)

Method : ot her: s ee T es t Co nditio n

Year : 19 66

GL P : no

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : MORT ALI TY:

All ani mals s urvi ved t he exposure as well a s th e f oll owing o bs ervation

perio d

CLINICA L SI GNS:

red uced activity a nd occ asion al ch anges in b rea thing rat e were t he only

ou tward evide nce o f

t oxicit y. Nas al an d o cular m uc osa e were n ot

inf la mm ed an d t here was n o weakn ess; ac tivit y an d a pp eara nce were

nor mal in 24 ho urs. No co mplicatio ns d evelope d d uring t he te n d ay

ob servation p eriod

T est condition : Th e ani mals (whole b ody exposure) were expose d t o a conc en trate d

at mos ph ere o f

vapors pr oduc ed by p assing a strea m o f air t hrough 1 00 ml

of th e co mp ou nd c ont aine d in a 2 50 ml Erl enm eyer f la sk, vap ors f ro m th e

fl ask p ass ed in to a o ne liter bo ttle t o re move dr oplets an d t he n int o t he

ch am ber

Average te mp erat ure insid e th e c ha mb er: 75 oF

78

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

Average relative hu midity i nside t he ch am ber: 6 3%

po st o bservation p erio d: 1 0 d ays

Re liabi lit y : (3) invalid

Due to l ack of

stu dy d ocu me nt ation an d expos ure a nalysis; whole b ody

exposure

2 2. 10. 20 04 (77)

Ty pe : ot her: RD5 0 (sens ory irritation)

V alu e : = 27 mg/ m3

Sp ec ies : mo us e

Str ain : CD- 1

S ex : ma le

Number of

a nim als : 4

V ehi cle : ot her: a cet on e

Dos es : 8, 8, 18 , 20 , 1 9, 36 , 48 , 7 2, 93 mg/m3

E xposur e time : 3 h our(s)

Method : ot her: s ee T es t Co nditio n

Year : 19 84

GL P : yes

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , co mm ercial grade , no

fu rt her d at a

Re sult : VA LUE:

RD50 = 2 7 mg /m 3 (95% co nf ide nce li mits: 1 8 t o 3 6 mg /m 3)

MORT ALI TY: 1⁄4 at 20 , 4 8 a nd 93 mg/ m3

CLINICA L SI GNS:

Num ber o f

a nim als with clinical signs (d uratio n of sympt oms): 8 mg/ m3 :

0/ 4, 8 mg/ m3 : 0/ 4, 1 8 mg/m 3: 2 /4 (during exposur e up to 3d) , 20 mg/ m3 : 1⁄4

(during exposure up to 1d), 19 mg/ m3: 1⁄4 (during exposure up to 1d), 36

mg/ m3: 4/ 4 (during expos ure up t o 1d) , 48 mg/ m3 : 3⁄4 (during exposur e up

to 3d), 72 mg/ m3: 4/ 4 (during expos ure up t o 1d) , 93 mg/ m3 : 4/ 4 (d uring

exposure up to 7d)

Th e signs of

t oxicit y were conc en tration-rela ted an d incl ude d di ff ic ulty in

bre athing, d ecre ase d activity, tre mors a nd at axia a nd laste d f ro m o ne to

thre e d ays excep t at 93 mg/ m3 where on e m ou se s howed lab ored

bre athing o n d ays 6 an d 7 a nd was f ou nd d ea d prior t o n ecro psy.

BODY W E I G HT : n o c om po und relat ed e f fe ct

RESP IRAT ORY RA TE :

Th e tim e- r espo nse r elatio nships s how a n incr ease in t he res piratory ra te in

th e b eginning of exposure fo llowed by a d ecre ase i n th e res piratory rat e

reac hing m aximu m d ecre ase by th e e nd of th e t hree-ho ur expos ure. T his

pa tter n of resp onse was m ore clear a t th e lower conc entr ation (8 mg/ m3)

where only a n increas e in t he respirat ory rate was ob served. A n incre ase in

th e res piratory rat e is in dicative o f d ee p lu ng irritatio n (p ulmo nary irritation),

whereas a de crease in res piration rate indica tes irritatio n of th e u pp er

respirat ory tract (s ensory irritatio n). Th e ani mal r espo nses t o t he tes t

ma terial exhibit ed irritatio n of bo th th e up per an d lower res piratory tr act.

NECROPSY:

No c om pou nd-relat ed gross lesi ons were ob served in a ny o f t he ani mals. A

ran do m lesio n no te d was gas an d f lui d fi lled intes tines i n on e a nim al

expose d t o 20 mg/ m3

. T est condition : ADMINIS TRA TION:

Te st ma terial was genera ted as liquid a erosol. Desired c onc entra tions o f

aer osol a tm osp here were gen erate d by using 0. 3 t o 4 .8 5% (w/ w) s olutio n

of Desm od ur W i n ac eto ne, he ad-o nly expos ure ch am bers were use d; n o

co ncurrent ace to ne or air con trol groups were us ed d uring th e st udy. Th e

ac eto ne a nd air co ntrol d at a us ed is f ro m a si milars tu dy using t he s am e

strain o f m ice. Th e da ta s how t ha t no signific ant ef f ec t o n th e respirat ory

rate of ani mals was ob served du e t o t he u se of a ce ton e as th e solvent or to

th e m et ho d of

exposur e (air con trol).

79

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

po st- o bs ervation peri od: 7 d ays

no min al co ncen tratio ns: 2 3, 3 7, 51 , 7 5, 9 0, 10 0, 16 0, 2 45 , 3 88 mg/m 3

EXAMINAT IONS:

mor tality, clinical signs, bo dy weight, bo dy pl ethysmograp hy, n ecro psy

Re liabi lit y : (3) invalid

Unsuit able test fo r a eros ols bec aus e th e ge neratio n o f t he t est at mos ph ere (- > par ticle size dis tributio n) de termi nes t he pa ttern of th e te st m at erial

de posit in t he res piratory tr act a nd th us th e res po nse, th eref ore no reliable

co nclusion is possi ble; t est (RD50 de termi natio n) is restricte d to vapours (up per trac t irritant)

1 4. 01. 20 05 (75)

Ty pe : ot her: RD5 0 (sens ory irritation)

V alu e : = 4 mg/ m3

Sp ec ies : mo us e

Str ain : Swiss W e b s te r

S ex : ma le

Number of

a nim als : 4

V ehi cle : ot her: a cet on e

Dos es : 16 .7, 28 8 , 37 9, 5 05 , 6 69 mg/ m3

E xposur e time : 4 h our(s)

Method : ot her: s ee T es t Co nditio n

Year : 19 85

GL P : no da ta

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , purity 99 .3 % mi nimu m

Rem ark : To c on firm th e p ulm on ary irritatio n pr operties mic e were exp osed via

trach eal c an nula (4 14 mg/m 3) which will elimin at e se nsory irritation an d

pul mo nary irritation ca n be st udie d alo ne. A d ecre ase in respirat ory

fr eque ncy was o bs erved, indica ting t ha t t he t est ma terial a cts as pul mo nary

irritant.

Re sult : VA LUE:

RD50 = 4 0 mg /m 3

RESP IRAT ORY RA TE : d ecline de pe nde nce on bo th t he dur ation of

exposure an d t he exposure conc entr ation

LUNG W E I GH T: increas e with exp osure c onc entra tion

T est condition : ADMINIS TRA TION:

Th e tes t ma terial was gen erate d as liquid a eros ol. Desired conc en trations

of aer osol at mo sp here were gener ate d by using 0. 25 to 1 .5 % solu tion of

tes t ma terial i n ac eto ne; th e ch am ber c onc entra tions were de ter mine d

grav imetrically

po st- o bs ervation peri od: a ll ani mals were killed 2 4 hr pos texposure

EXAMINAT IONS:

bo dy pl ethysm ography, l ung wei ght

Re liabi lit y : (3) invalid

Limi ted doc um en tatio n; t est system u nsuit able fo r a eros ols bec aus e th e

genera tion of

t he tes t at mo sp here (-> p article size distribu tion) a f fe ct s t he

pa tter n of tes t sa mpl e de posit in t he r espiratory tr act a nd th us t he

resp onse ; th ere for e n o relia ble co nclusio n is po ssible; test (RD50

de ter minati on) is restricte d to vapo urs ( upp er tract irritants)

1 4. 01. 20 05 (95)

Ty pe : LC5 0

V alu e : 51 mg/m3

Sp ec ies : guine a pig

Str ain : ot her: E nglish sm oot h-haire d

S ex : ma le/ fe ma le

Number of

a nim als : 5

V ehi cle : ot her: n o

Dos es : 0, 17 , 44 , 5 5, 90 mg/ m3

80

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

E xposur e time : 1 h our(s)

Method : ot her: s ee T es t Co nditio n

Year : 19 82

GL P : no

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : VA LUE:

LC5 0 (m ale/ fe ma le): 5 1 mg /m 3 (95 % co nf ide nce interval = 3 6 t o 7 2

mg/ m3)

MORT ALI TY:

Num ber o f

d ea ths a t e ac h do se (ti me o f d ea th), m al e rats: 17 mg/ m3: 0/ 5,

44 mg/ m3: 0/ 5, 5 5 mg /m 3: 3 /5 (2- 3 d), 9 0 m g/m 3: 5 /5 (1- 3 d)

Num ber o f

d ea ths a t e ac h do se (ti me o f d ea th), f em al e r ats: 1 7 mg /m 3: 1 /5

(4d), 4 4 m g/m 3: 1 /5 (2d), 5 5 m g/m 3: 2 /5 (3d), 9 0 m g/m 3: 4 /5 (1- 2 d)

CLINICA L SI GNS:

Th e mo st f requ en t clinical signs, ob served duri ng t he firs t thr ee d ays o f t he

stu dy, c onsist ed o f

p allor of th e skin o r cyanosis, res piratory dis tress,

weakness or let hargy, an d n asal disc harge (n o inf or ma tion o n nu mb er of

ani mals with clinical signs per c onc entra tion an d sex)

BODY W E I G HT :

bo dy weight l osses o ccurred in all tre at ed grou ps except fo r m ales expose d

to th e lowest co ncen tratio n. B ody wei ght losses were m ad e go od by th e

en d o f t he f irst week o f

t he ob servation p eriod

ANT IB ODY ANA LYSIS: n o inf or mati on availabl e

NECROPSY:

mark ed gross c ha nges in t he l ungs such as ru bb ery texture, swell ing a nd

red deni ng were ob served in t he ani mals t ha t die d.

T est condition : ADMINIS TRA TION:

Th e tes t ma terial was gen erate d as a liquid a erosol by usi ng a co nce ntric

jet glass a to mizer

su pplie d with pr edried co mpress ed a ir. Th e ani mals were

po sition ed in plexiglas whole- b ody exposure ch am bers.

po st o bservation p erio d: 1 4 d ays

no min al co ncen tratio ns (calcula ted fr om th e weight l oss fr om t he ge nerat or

an d t he tot al air

flow t hrough t he ch am ber duri ng t he 1-ho ur expos ure

perio d): 70 , 9 0, 14 0, 2 40 mg/ m3

EXAMINAT IONS:

mor tality, clinical signs, bo dy weights, an tibo dy an alysis, n ecropsy

CALCULA TI ON OF LC 50 :

Th e LC5 0 value a nd th e 9 5% c on fid enc e int erval were c alculat ed u sing th e

me th od of

L itch fi eld a nd W i lc ox on, J ourn al of Ph aram acol ogy &

Experime ntal T he ra pe utics, 1 94 9, 9 6 (2), 99-1 13

. Re liabi lit y : (3) invalid

Signific ant me th od ological d ef icie ncies (i.e . whole bo dy exp osure) a nd

limite d do cu me nta tion

1 4. 01. 20 05 (3)

5 .1 .3 AC UT E DERM AL T OXICITY

Ty pe : ot her: ski n ab sorpti on MLD

V alu e : > 10 00 0 mg /kg bw

Sp ec ies : rab bit

Str ain : New Ze alan d white

S ex : ma le/ fe ma le

Number of

a nim als : 1

V ehi cle : ot her: c orn oil

Dos es : 10 00 , 15 80 , 2 51 0, 3 98 0, 6 ,3 10 , 10 00 0 mg/kg

Method : ot her: s ee T es t Co nditio n

Year : 19 66

81

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

GL P : no

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : no mo rtality u p t o 1 00 00 mg/kg; activity a nd ap pe tite were re duce d f or

several days af

te r 61 30 an d 1 00 00 mg/kg, th ere was mo der ate weakness

bu t n o p aralysis

T est condition : Th e un dilut ed s am ple (6 130 an d 1 00 00 mg/kg) a nd dilut ed s am ple (5 0%

solu tion/s usp ensio n in c orn oil) was a pplie d t o t he cl osely clipp ed i ntact

skin o f a ma le or fe ma le rab bit. T he tre at ed ar eas were covered with plas tic

strips a nd th e ani mals plac ed in wooden stocks fo r 2 4 h ours; ob servations

were m ad e f or

toxic sympto ms a nd since th ere were no de at hs, n o

au to psies were per

for me d

po st o bservation p erio d: n o d at a

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n, o nly o ne ani mal p er d ose with alt erna te s ex, n o

da ta o n purity o f

t est s ubst anc e

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 10. 20 04 (77)

Ty pe : ot her: Class B P oison Te st

V alu e : Sp ec ies : rab bit

Str ain : no da ta

S ex : ma le

Number of

a nim als : 6

V ehi cle : ot her: n o

Dos es : 20 0 mg /kg

Method : ot her: s ee T es t Co nditio n

Year : 19 72

GL P : no

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : Af te r a 24-h our expos ure o f 2 00 mg/kg b.w. 0/ 6 ani mals die d; n o clinical

signs were o bserved

T est condition : Th e tes t ma terial was ap plied to th e in tact clippe d dors al skin. Th e rabbits

trunks were t he n wrapped with a layer o f S aran wrap, s tretch gauze

ba nd age an d e lastic a dh esive t ap e. A ft er 2 4-ho ur expos ure p eriod, th e

wrapping were rem oved an d t he skin was washed with water a nd drie d.

Th e ani mals were ob served fo r a f ur th er 4 8 ho urs.

Re liabi lit y : (3) invalid

Limi ted doc um en tatio n a nd only o ne do se grou p t este d

2 2. 10. 20 04 (49)

5 .1 .4 AC UT E TOX ICITY, O THER ROUTES

5 .2 .1 SK IN IRRIT AT ION

Sp ec ies : rab bit

Conc entration : 50 0 ot her: u l

E xposur e : Occlusive

E xposur e time : 4 h our(s)

Number of

a nim als : 6

V ehi cle : ot her: n o

PD II :

Re sult : mo der ately irritating

Cl ass ification :

Method : OECD G uide-line 40 4 " Acu te Der mal Irritati on/Corrosio n"

82

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

Year : 19 81

GL P : no

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate liquid s am ple, no da ta

on purity

Re sult : A pri mary irritation value of 4. 2 was calcula ted (3.1

- 5. 0 = mo der ately

irritating);

retrogression a ft er 8d to th e level of a slight irritation (surf ace , parc hm en tlike skin sc aling)

T est condition : tes t su bsta nce was ap plied on th e f la nk skin on bo th si des o f t he bo dy o f

ea ch a nim al; t he d et ermin atio n of fi ndi ngs fo llowed im me diat ely af te r

rem oval o f

t he cloths an d washing ( water) of th e ap plicatio n sit e (4 h

value), th en af

te r 24 , 4 8 a nd 72 h an d a ft er 8 d. Th e 24 an d 7 2 h values a re

th e b asis fo r t he irritancy in dex; t he 24 an d 7 2 h levels of erythem a a nd

ed em a f or ma tio n in b ot h te st ar eas were averaged f or th e t est a nim als; t he

eight average values were divided by f ou r, t o yield th e pri mary skin irritatio n

ind ex

Re liabi lit y : (2) valid with restrictions

No d at a on purity of tes t su bsta nce

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 0. 11. 20 04 (8)

Sp ec ies : rab bit

Conc entration : 50 0 ot her: mg

E xposur e : Occlusive

E xposur e time : 4 h our(s)

Number of

a nim als : 6

V ehi cle :

PD II :

Re sult : mo der ately irritating

Cl ass ification :

Method : OECD G uide-line 40 4 " Acu te Der mal Irritati on/Corrosio n"

Year : 19 81

GL P : no

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , solid sam ple, no da ta

on purity

Re sult : A pri mary irritation value of 3. 6 was calcula ted (3.1

- 5. 0 = mo der ately

irritating);

retrogression a ft er 8d to th e level of a slight irritation (surf ace skin sc aling)

T est condition : tes t su bsta nce ( moist ene d in oil) was ap plied on th e f la nk skin on bo th

sides of t he bo dy o f

e ach ani mal; th e de ter mina tion o f f in dings f oll owed

im me diately a ft er rem oval o f t he cloths an d washing ( water) of te h

ap plicatio n site (4 h value), th en af te r 24 , 4 8 a nd 72 h a nd af te r 8 d. Th e 24

an d 7 2 h values ar e th e b asis f or th e irritancy in dex; th e 2 4 a nd 72 h l evels

of erythem a a nd ed em a f or ma tion in b ot h te st ar eas were averaged f or th e

tes t ani mals ; th e eight average values were d ivided by f ou r, to yield t he

prim ary skin irritation ind ex

Re liabi lit y : (2) valid with restrictions

No d at a on purity of tes t su bsta nce

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 0. 11. 20 04 (9)

Sp ec ies : rab bit

Conc entration : 50 0 ot her: u l

E xposur e : Se miocclusive

E xposur e time : 4 h our(s)

Number of

a nim als : 1

V ehi cle :

PD II :

83

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

Re sult :

Cl ass ification :

Method : OECD G uide-line 40 4 " Acu te Der mal Irritati on/Corrosio n"

Year : 19 94

GL P : yes

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , purity > 99 .2 %

Re sult : RESUL T: "s everel y irritating to th e skin " On th e expos ed ski n stro ng

erythem at ous a nd exsuda tive re actions were o bserved. Fro m d ay 7 o n a

white to yellowish squa mo us co at (o n d ay 1 4 t he coa t was white) an d

esc har fo rm ati on were se en. On day 14 on th e expos ed ski n are a t he

epi dermis was par tly rem oved.

SCORE:

Erythem a (o bservation ti me): 2 (1 h, 7 2h , 7d)); 3 (2 4h, 48 h, 1 4d)

Ed em a (o bservation ti me): 2 (1 h, 2 4h); 1 (4 8h, 72 h, 7 d), 0 (1 4d)

me an value " erythem a" : 2. 7

me an value " ed em a" : 1. 3

T est condition : For reas ons of a ni mal welf are, d ue to th e expec ted irritant p ot ency o f t he

tes t su bsta nce o n th e skin, in th e t est o nly o ne ani mal was us ed.

Th e scores a t t he rea ding ti me s 24 , 4 8, 7 2 ho urs fo r a n e f fe ct were us ed in

calcula ting respec tive m ea n values

. Re liabi lit y : (1) valid withou t restriction

Fl ag : Critical s tudy fo r S IDS e nd poin t

0 6. 11. 20 06 (17)

Sp ec ies : rab bit

Conc entration : 50 0 ot her: u l

E xposur e : Se miocclusive

E xposur e time :

Number of

a nim als : 3

V ehi cle :

PD II :

Re sult : irritating

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 19 96

GL P : yes

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , purity: 99 .8 9%

Re sult : Th er e was n o evide nce o f c orrosion o bs erved a t a ny o f t he test sites f or any of th e expos ure p eriods (3-m inu tes, 1 -ho ur, a nd 4-ho urs).

Derm al irritation was obs erved spor adically fr om t he 4 -ho ur ob servations

(f or th e 4-h our exposure sites) thr ough t he 7 2-ho ur o bservations an d a t

mo st exp osure sit es fr om t he 96-h our o bservations thro ugh th e Day 14

ob servations. T his der mal irritatio n was c haract erized by very slight t o wellde fi ne d erythe ma (scores of l to 2) a nd ver y slight to slight ed em a (scores

of 1 t o 2) . On Day 2 1, a ll signs o f e de ma ha d s ubsid ed an d o nly on e a nim al

was n ot ed with ver y slight erythe ma a t all exp osure sit es. H owe ver, o n D ay

21 , ar eas o f

t hicken ed ski n were o bs erved a t t he exposure sites f or two

ani mals (all expos ure sit es fo r A nim al No. 40 22 an d t he 3 -min ute exposure

site f or Ani mal No. 4 02 3).

Th er e were n o re mark able signs o f clinical t oxicit y an d/ or ill h eal th n ot ed

during t he c ourse of

t his st udy. All ani mals gain ed wei ght over th e co urse

of th e st udy.

T est condition : TE ST A NIMAL S:

strain: New Ze alan d W h i t e albin o

sex: mal e

EXPOSURE T IM E: 3 mi nut e, 1-h our a nd 4-ho urs

ADMINIS TRA TION/ EXPOSURE:

Th e un dilut ed t est m at erial was a ppli ed t o t hree sep arat e tes t are as o n t he

84

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

int act skin o n eac h a nim al's back . Ea ch ar ea of a pplic ation was c overed

with a 2. 5-cm x 2. 5- c m ga uze p atc h sec ured with P ap er

ta pe, loos ely over

wrappe d with Gr an W r a p, an d s ecure d with E last oplast

ta pe t o pr ovide a s emi occlusive dr essing. Th e wrappings a pplie d t o e ach

tes t site were in dep en de nt o f th e o th er sites. Eac h a nim al was expos ed t o

th e t est m at erial fo r 3-m in ute , 1

- h our, an d 4-h our p eriods of tim e. A t t he

en d o f t he 3 -min ute , 1

- h our, or 4-h our exp osure p eriods , th e p atc hes were

rem oved an d t he tes t sites were washe d using t ap water. T he t est ma terial

was re moved f ro m th e te st sit es as t hor oughly as possi ble without irritating

th e skin.

EXAMINAT IONS:

At th e en d o f

t he 3-mi nut e, 1

- h our , or 4-h our exp osure p erio ds, o ne pa tch

fr om ea ch a ni mal was rem oved an d t he trea ted are a was exa mine d f or

evidenc e of corrosion . Corrosion is ch aracterized by irreversible alter ations

at th e site of con tact which m ay i nclud e ulcer ation an d n ecrosis; c ha nges

suc h as e de ma , erythe ma , slo ughing o f t he epi dermis, an d tissuring al one

do no t c onstit ute corrosion . Af te r th e initi al corrosion examin atio n, t he

residu al tes t ma teri al was re moved u sing t ap water to p revent f ur th er tes t

ma terial exp osure. Af

ter rem oval o f

t he pa tches , ea ch a pplic ation site was

examin ed f or

erythe ma an d e de ma reacti ons a ccording to th e Draize

tec hnique (rec orde d as t he 3-mi nut e, 1 -ho ur, or 4-h our Score).

Su bsequ ent exa min ations were m ad e a t 2 4, 48, 72, an d 9 6 h ours a nd days

7, 14 , an d 2 1. Ea ch sit e per ani mal (3-mi nu te, 1 -ho ur, an d 4 -ho ur exposure sites) was sc ored ind epe nd ently a t t hes e ti me points . Th e un trea te d skin o f

ea ch a nim al was u se d fo r c om pariso n. P hot ographs were ta ken of all

exposure sites f or

ea ch a ni mal a nd all exposur e tim es f or ea ch a nim al, a nd

a s am ple o f

u ntre ate d skin , were pr eserved fo r fu tu re p ossible microsc opic

evaluati on.

Ani mals were also obs erved fo r signs o f clinical t oxicit y an d/ or ill h ealt h at

ea ch in terval o f

d erm al irritation sc oring; t hes e o bservations were rec orded

by exce ption

. Re liabi lit y : (1) valid withou t restriction

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 10. 20 04 (26)

Sp ec ies : rab bit

Conc entration : 50 0 ot her: u l

E xposur e : Se miocclusive

E xposur e time : 4 h our(s)

Number of

a nim als : 6

V ehi cle :

PD II :

Re sult : corrosive

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 19 73

GL P : no

T est sub stance : ot her T S: Hylene W

, no d at a on purity

Re sult : Accor ding t o t he regulatio n of th e De part men t of Tr ans porta tion

(Depart me nt o f

T ra nsport atio n, Hazardo us Mat erials R egulations Bo ard,

Docke t No. HM-57 , Fe deral Register, V ol. 3 8, no .2 8, sec tion 17 3.2 40

, Febr uary 12 , 1 97 3) Hylene W is consi dere d a c orrosive m at erial

4/ 6 ra bbits with corrosion (no f ur th er inf or ma tion)

T est condition : th e t est m at erial was a pplie d t o int act skin of 6 a nim als; a ft er 4 h ours t he

wrapping a nd gauze pa ds were rem oved an d a ny ski n reac tions were

evaluat ed; th e t est sit es were washe d, re adings were again m ad e 2 4 a nd

48 ho urs af

te r initi al ap plicatio n

Re liabi lit y : (4) no t assigna ble

In dividual ani mal d at a are no t re porte d, n o d at a o n pri mary skin irritatio n

85

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

indices , expos ure sites were o nly ob served at 24 an d 4 8 ho urs

2 2. 10. 20 04 (51)

Sp ec ies : guine a pig

Conc entration :

E xposur e :

E xposur e time : 24 ho ur(s)

Number of

a nim als : 10

V ehi cle : ot her: yes

PD II :

Re sult :

Cl ass ification :

Method : ot her: t he tes t ma terial was ap plied to intac t skin o f 1 0 a nim als as a

solu tion i n ac eto n: di oxane (1 :1) co ntai ning 1 3% guinea pig fa t (f .a .d.)

Year : 19 63

GL P : no

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : 24-h our re actio n: str ong erythem a a nd ed em a (5%),

strong erythe ma (0,5%), no irritation (0 ,05 %)

Re liabi lit y : (3) invalid

Unsuit able test system

2 5. 10. 20 04 (46)

Sp ec ies : guine a pig

Conc entration : 50 ot her: u l

E xposur e :

E xposur e time : 24 ho ur(s)

Number of

a nim als : 3

V ehi cle : ot her: a cet on e

PD II :

Re sult :

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 19 77

GL P : no

T est sub stance : ot her T S: Hylene W

, no d at a on purity

Re sult : 24 ho ur reac tion : mo der ate irritation (5 0%, 2 5%) a nd mild

irritation (1 0%, 5 %)

T est condition : TE ST A NIMAL S:

strain: albin o

sex: mal e

ADMINIS TRA TION/ EXPOSURE:

On e dr op (= 0. 05 m l) ea ch o f a 50 %, 2 5%, 10 % an d 5 % a cet one solu tion

was a pplie d an d lightly ru bbe d int o t he s haved i ntact ba ck skin.

EXAMINAT IONS:

Rea dings were m ad e 2 4 h ours a ft er th e t opical a pplica tions

. Re liabi lit y : (3) invalid

Unsuit able test system

2 5. 10. 20 04 (55)

Sp ec ies : guine a pig

Conc entration : 50 ot her: u l

E xposur e : no da ta

E xposur e time :

Number of

a nim als : 10

V ehi cle : ot her: a cet on e

PD II :

Re sult :

86

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 19 77

GL P : no

T est sub stance : ot her T S: Hylene W

, no d at a on purity

Rem ark : A ra nge- f in ding st udy was do ne on 3 a nim als with 5 0% , 25 %, 1 0% a nd 5 %

tes tm aterial in ace to ne, a ft er 24 ho urs 3/ 3 a nim als sh owed mild ( 5% an d

10 %) or mo der at e (25% an d 5 0%) erythe ma

Re sult : 24 an d 4 8 h our reactio n: slight (8 /10 an d 6 /1 0) to n o reactio n (0, 5%), n o irritation (0 ,05 %)

T est condition : TE ST A NIMAL S:

strain: albin o

sex: mal e

ADMINIS TRA TION/ EXPOSURE:

On e dr op (= 0. 05 m l) ea ch o f a 0. 5% a nd 0. 05% soluti on o f t est m at erial in

ac eto ne was ap plied an d lightly rub bed into th e sh aved int act s ho ulder

skin.

EXAMINAT IONS:

Rea dings were m ad e 2 4 a nd 48 ho ur(s) a ft er ap plicatio n

Re liabi lit y : (3) invalid

Unsuit able test system

2 5. 10. 20 04 (54)

Sp ec ies : rab bit

Conc entration : un dilut ed

E xposur e : Occlusive

E xposur e time : 24 ho ur(s)

Number of

a nim als : 3

V ehi cle :

PD II :

Re sult : mo der ately irritating

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 19 66

GL P : no

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : Th e co mp oun d was classe d as a m od erat e irritant; th e average m aximum

score was 4. 3 o ut of

a p ossible 8 in 24 ho urs, within 7 d ays e de ma

disa pp eared bu t mil d red ness r em aine d.

T est condition : TE ST A NIMAL S:

strain: albin o

sex: 1 m al e, 2 fe ma le s

ADMINIS TRA TION/ EXPOSURE:

Th e un dilut ed c om po und was a pplie d to th e clipp ed , int act skin an d

rem oved af

te r 2 4 h ours. Th e ap plicatio n was c overed with p lastic strips

EXAMINAT ION:

ob servations were ma de at th e e nd of 1 h our, 24 , 48 , 7 2, 12 0 a nd 16 8

ho urs; t he d at a were score d acc ording to th e me th od of Draize.

Re liabi lit y : (4) no t assigna ble

Limi ted doc um en tatio n, e .g. no d at a on ap plicat ed volu me, no individual

scores a re re porte d

2 5. 10. 20 04 (77)

5 .2 .2 EYE IRRITA TION

Sp ec ies : rab bit

87

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

Conc entration : un dilut ed

Dos e : 10 0 ot her: u l

E xposur e time :

Comment : ot her: rins ed a ft er 30 sec. /no t rinse d

Number of

a nim als : 6

V ehi cle :

Re sult : irritating

Cl ass ification :

Method : OECD G uide-line 40 5 " Acu te Eye Irritati on/Corrosio n"

Year : 19 81

GL P : no

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate liquid s am ple, no da ta

on purity

Re sult : A pri mary irritation value of 3. 0 was calcula ted (0 - 10 = no t irritating); with

regard to th e res ults th e t est m at erial was cl assifi ed " no t irritating", however

th ere were slight e f

fe ct s o n t he co njunctivae (grade 1 -2) in 3 /6 ani mals a t

th e e nd of

t he ob servation p eriod ; th ere was no dif fe re nc e be tween "with

rinsing" an d "witho ut rinsing"

INDIVUDUAL SC ORES, with rinsing (1, 2 4, 48 , 72 h, 8d /a nimal)

- C ornea : 0, 1, 0, 1, 1, 0; 0 (all fu rt her ti me poin ts)

- Iris : 1 , 0, 0, 0, 0, 0; 0 (all f ur ther ti me poin ts)

- Conju nctivae (redn ess): 3 , 2, 2, 2, 2, 2;

1 , 0 , 1 , 0, 1, 1;

1 , 0 , 1 , 0, 1, 1;

1 , 0 , 1 , 0, 0, 1;

1 , 0 , 2 , 0, 0, 1;

- Conju nctivae (che mosis): 2 , 2 , 2 , 1 , 3 , 1;

0 , 2 , 1 , 0 , 1 , 1 ;

0 , 2 , 1 , 0 , 1 , 1 ;

1 , 1 , 1 , 0 , 1 , 1 ;

1 , 0 , 2 , 0 , 0 , 1 ;

INDIVUDUAL SC ORES, without rinsing (1, 2 4, 48 , 72 h, 8d /a nimal)

- C ornea : 0 (all ti me poi nts evalua te d)

- Iris : 1 , 0, 0, 0, 0, 0; 0 (all f ur ther ti me poin ts)

- Conju nctivae (redn ess): 2 , 2, 2, 2, 3, 2;

2 , 0 , 1 , 0, 1, 1;

1 , 0 , 1 , 0, 1, 1;

0 , 0 , 1 , 0, 0, 1;

0 , 0 , 2 , 0, 0, 1;

- Conju nctivae (che mosis): 2 , 2 , 2 , 1 , 3 , 1;

1 , 2 , 1 , 0 , 1 , 1 ;

1 , 2 , 1 , 0 , 1 , 1 ;

0 , 1 , 1 , 0 , 0 , 1 ;

0 , 1 , 2 , 0 , 0 , 1 ;

T est condition : TE ST A NIMAL S:

strain: New Ze alan d W i g ht

sex: mal e

ADMINIS TRA TION/ EXPOSURE:

th e t est m at erial was a pplie d int o t he c onju nctival s ac of th e lower

lid of

bo th eyes ; th e lids were gently h eld toget her f or on e s econ d. T he right eye

was f lu she d 3 0 s a ft er th e ap plicati on (p hysiol. s aline s olutio n; 3 mi n.) th e

lef t was n ot f lu sh ed

EXAMINAT ION:

Th e fi ndi ngs were de ter mine d 1 (only f or th e f lus he d eyes), 24 , 4 8 a nd 72

ho urs an d 8 d a ft er ap plicatio n.

EV ALUA TI ON:

Th e scoring system o f

Draize was ap plied to calcula te t he irritation in dex;

th e 2 4, 4 8 a nd 72 h ours values a re t he basis f or th e irritatio n ind ex; t he

88

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

levels o f d am age t o c ornea (0- 8 0), iris (0-10) a nd co njunc tiva (0-20),

toget her 0-1 10 , ar e ad de d f or all six ani mals af te r 24 , 4 8 a nd 72 ho urs. t he

to tal is divided by 1 8, a nd yields th e level o f pri mary irritatio n to th e eye.

Re liabi lit y : (2) valid with restrictions

Th e text of

th e s um mary a nd th e in dividual sc ores ar e co ntradict ory, t he

reas ons why th e e ff ec ts on th e c onju nctivae at th e e nd of t he ob servation

perio d h ave no biological relevance are n ot gi ven

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 0. 11. 20 04 (10)

Sp ec ies : rab bit

Conc entration : un dilut ed

Dos e : 10 0 ot her: u l

E xposur e time :

Comment : ot her: rins ed a ft er 30 sec/ not rinsed

Number of

a nim als : 6

V ehi cle :

Re sult : irritating

Cl ass ification :

Method : OECD G uide-line 40 5 " Acu te Eye Irritati on/Corrosio n"

Year : 19 81

GL P : no

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate solid s am ple, n o da ta

on purity

Re sult : A pri mary irritation value of 0. 4 was calcula ted fo r t he fl ush ed eyes (0 - 10

= no t irritating); a pri mary irritation value of 6, 3 was c alculat ed f or t he

un fl ush ed eyes (0 - 10 = no t irritating); th e slight irritation o f t he conj unctiva

(score 1-2 fo r r edn ess a nd che mosis) h as al mos t su bside d a ft er 2 4 h ours

with rinsing, a nd af

te r 72 ho urs without rinsing; t ot al recovery was

do cum en te d af

te r 7 2 h ours (with rinsing) an d 8 days (without rinsing);

corn eal o pacity was restricte d t o 3/ 6 (with rinsing) an d 2 /6 ( without rinsing)

ani mals, resp ectivil y a nd it was r eversible within 24 (with rinsing) a nd 72

ho urs (without rinsing), resp ectivil y.

INDIVUDUAL SC ORES, with rinsing (1, 2 4, 48 , 72 h, 8d /a nimal)

- C ornea : 1, 1, 0, 0, 0, 1; 0 (all fu rt her ti me poin ts)

- Iris : 0 (all tim epoi nts)

- Conju nctivae (redn ess): 2 , 2, 2, 1, 1, 2;

0 , 1 , 1 , 0, 0, 0;

0 , 1 , 1 , 0, 0, 0;

0 , 0 , 0 , 0, 0, 0;

0 , 0 , 0 , 0, 0, 0;

- Conju nctivae (che mosis): 1 , 1 , 1 , 1 , 0 , 1;

0 , 0 , 0 , 0 , 0 , 0 ;

0 , 0 , 0 , 0 , 0 , 0 ;

0 , 0 , 0 , 0 , 0 , 0 ;

0 , 0 , 0 , 0 , 0 , 0 ;

INDIVUDUAL SC ORES, without rinsing (1, 2 4, 48 , 72 h, 8d /a nimal)

- C ornea : 1 h was no t evalua te d

4, 0, 0, 0, 0, 1

1, 0, 0, 0, 0, 0

0, 0, 0, 0, 0, 0

0, 0, 0, 0, 0, 0

- Iris : 0 (all tim epoi nts)

- Conju nctivae (redn ess): 2 , 2, 2, 1, 2, 2;

2 , 1 , 1 , 1, 2, 2;

2 , 1 , 1 , 1, 1, 2;

2 , 0 , 0 , 1, 0, 0;

0 , 0 , 0 , 0, 0, 0;

- Conju nctivae (che mosis): 2 , 1 , 2 , 2 , 1 , 2;

89

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

2 , 0 , 0 , 0 , 1 , 1 ;

2 , 0 , 0 , 0 , 1 , 1 ;

0 , 0 , 0 , 0 , 0 , 0 ;

0 , 0 , 0 , 0 , 0 , 0 ;

T est condition : TE ST A NIMAL S:

strain: New Ze alan d W i g ht

sex: mal e

ADMINIS TRA TION/ EXPOSURE:

th e t est m at erial was a pplie d int o t he c onju nctival s ac of th e lower

lid of

bo th eyes ; th e lids were gently h eld toget her f or on e s econ d. T he right eye

was f lu she d 3 0 s a ft er th e ap plicati on (p hysiol. s aline s olutio n; 3 mi n.) th e

lef t was n ot f lu sh ed

EXAMINAT ION:

Th e fi ndi ngs were de ter mine d 1 (only f or th e f lus he d eyes), 24 , 4 8 a nd 72

ho urs an d 8 d a ft er ap plicatio n. T he 2 4, 48 an d 7 2 h ours values are t he

ba sis fo r t he irritatio n in dex; th e levels o f d am age t o c orne a (0-80), iris (0-

10) a nd co njunc tiva (0-20) , toge ther 0-1 10 , ar e ad de d f or all six an im als

af te r 24 , 4 8 a nd 72 ho urs. t he to tal is divided by 1 8, a nd yields th e level o f

prim ary irritation t o t he eye.

Re liabi lit y : (2) valid with restrictions

No d at a on purity of tes t su bsta nce

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 0. 11. 20 04 (11)

Sp ec ies : rab bit

Conc entration : un dilut ed

Dos e : 10 0 ot her: u l

E xposur e time : 24 ho ur(s)

Comment : rinsed af te r (see exposure tim e)

Number of

a nim als : 3

V ehi cle :

Re sult :

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 19 66

GL P : no

T est sub stance : ot her T S: 4, 4 ́- m et hylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : Th e co mp oun d was classe d as a s evere eye irritan t; t he average m aximu m

score was 63 .3 ou t of

a possi ble 11 0 i n 24 ho urs; n o r eversibilit y within 1 68

ho urs
Copio us disc harge, p artial eversion o f t he lids, m od erat ely severe

erythem a, a nd mo de rat e corn eal clo udin ess pr oduc ed a n average score o f

44 .3 i n on e h our . Th e lids were cl osed ovenight a nd swell ing exte nde d f or

a c onsid erable dist ance aro und th e eye. T he iris was visible a nd co ntin ued

to react to light. In dividual vessels o f t he conj unctivae were no t ea sily

discerni ble. Gr adu al im proveme nt f oll owed

irri gation. Th e lida were still ne arly cl osed af te r five days bu t cor neal cl arity

ha d i mproved m arke dly lea ding to th e co nclusion th at eyesight would n ot

be per ma ne ntly da mag ed.

T est condition : TE ST A NIMAL S:

strain: albin o

sex: 1 m al e, 2 fe ma le s

ADMINIS TRA TION/ EXPOSURE:

Th e un dilut ed c om po und was pl aced in t he c onju nctival s ac of th e right

eye; t he eyes were rinse d with iso to nic saline soluti on a ft er 2 4 ho urs

EXAMINAT ION:

ob servations were ma de at th e e nd of 1 h our, 24 , 48 , 7 2, 12 0 a nd 16 8

ho urs; t he d at a were score d acc ording to th e me th od of Draize.

Re liabi lit y : (4) no t assigna ble

90

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

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DATE: 09.11.2006

No in dividual sc ores ar e rep orte d

2 5. 10. 20 04 (77)

Sp ec ies : rab bit

Conc entration : un dilut ed

Dos e : 10 0 ot her: u l

E xposur e time :

Comment : ot her: rins ed a ft er 20 sec (6 rab bits), no t rinse d (2 ra bbits)

Number of

a nim als :

V ehi cle :

Re sult :

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 19 79

GL P : no

T est sub stance : ot her T S: Hylene W (com positio n: 9 9. 3%)

Rem ark : Th is t est was do ne to d et ermin e t he m os t e ff ec tive eye wash fo r rem oval o f

Isocyanic a cid, Me thylenebis-(4-cyclohex yl) e ster f ro m eyes

Re sult : Th e two ra bbits , which s erved as p ositive c on trols (dos ed with Hylene W

an d n ot washed) sh owed mild c onju nctivitis an d irritatio n of th e o ut er lids

(hair loss a nd occ asion al necr otic sp ots); n o c orneal o r iritic e f fe ct s occ ured

an d t he eyes were n orm al at 15 days except th e hair l oss on th e o ut er lids

which was retur ning t o n orm al at 28 days

T est condition : TE ST A NIMAL S:

strain: no da ta

sex: no da ta

ADMINIS TRA TION/ EXPOSURE:

Th e un dilut ed c om po und was pl aced in t he c onju nctival s ac of th e right

eye; t he tr eat ed eye of

2 a nim als was n ot washed; a ft er 20 sec onds th e

trea te d eyes o f

t he o th er rab bits were washe d a s fo llows:

- 2 eyes washe d 1 mi nut e with t ap e water

- 2 eyes washe d 1 5 m inu tes with ta pe water

- 2 eyes washe d 1 mi nut e with 2 5% aq ue ous pr opylene glycol with 0 .0 1%

thi meros al

EXAMINAT ION:

ob servations o f

t he c orne a, iris an d c onju nctiva were ma de with a ha nd-slit

lam p a t 1 an d 4 ho urs, 1 , 2 , 3 , 7 , 1 4 or 1 5, an d 2 8 d ays

Re liabi lit y : (3) invalid

Unsuit able test system ( for fu rt her explan atio n se e "re mark ")

2 5. 10. 20 04 (56)

5 .3 S ENSITIZA TION

Ty pe : ot her: Mo dif ied Gui nea pig m aximization t est

Sp ec ies : guine a pig

Number of

a nim als : 20

V ehi cle : ot her: p ara ff in oil

Re sult : no t se nsitizing

Cl ass ification :

Method : ot her: m od if ied OECD T G 4 06

Year : 19 84

GL P : no

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate (liquid), mixed isom ers,

no fu rt her d at a

Rem ark : In a pil ot st udy with 4 ani mals t he skin irritation was exami ned fo r t he

ch allenge with 0 .0 3, 0 .1 , 0. 3% a nd 1% (24 h ours , occlusive); th e a nim als

91

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

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DATE: 09.11.2006

were tr eat ed with FCA an d p ara ff in oil like th e co ntrol a nim als

0. 03% : 3 o f

4 a nim als sh owed m ild or mo der ate e rythem a;

>= 0 .1% : all an im als showed m ild u p t o pr ono unc ed signs o f irritation which

were still eviden t af

te r 7 2 h ours.

Re sult : 1/ 20 tr eat ed ani mals di ed a ft er th e sec on d in ductio n, b ec ause no ne of t he

rem aining ani mals showed clinic signs th e d ea th s ee me d t o be n ot

su bsta nce rel ate d.

1. challe nge:

0. 01% : 0/ 19 (2/1 0 in t he co ntrol group) with a p ositive r eactio n

0. 03% : 0/ 19 (6/1 0 in c ontr ol group) with a po sitive re action

2. challe nge:

0. 01% : 0/ 19 (5/1 0 in t he co ntrol group) with a p ositive r eactio n

0. 03% : 1/ 19 (6/1 0 in c ontr ol group) with a po sitive re action

Th e reas on why th ere were mor e p ositive res po nses in th e co ntrol grou ps

with b ot h co nce ntratio ns is no t e ntirely u nd ersto od b ut local irritant ef f ec ts

se em ed t o b e involved.

T est condition : Ani mals ar e accli matise d t o t he l abora tory co nditio ns f or ap prox. 1 week

prior to th e t est.

Be fo re t he tes t, a nim als are ran domis ed a nd assigne d t o th e tr eat me nt

groups; Num ber o f

a nim als: 20 t est a nd 2 x 10 co ntrol guine a pigs have

be en use d; re moval of

hair is by sh aving an d c he mical de pilatio n (challe nge). Th e ani mals ar e weighed be fo re th e te st c om me nces a nd

every week d uring th e st udy. All skin re actions an d a ny u nus ual f in dings,

includi ng syste mic reacti ons were ob served twice a day an d rec orde d.

In ducti on: Intr ader mal I njectio ns

Day 0

- trea te d group

Th re e pairs o f

in trad ermal inj ections of 0. 1 ml volume are given in th e

sh ould er r egion which is s haved.

Inj ection 1: a 1 :1 mixture (v/ v) Freu nds Co mpl ete Adj uvans (FCA)/ water

Inj ection 2: th e te st su bst ance in p araf fi n oil

Inj ection 3: th e te st su bst ance fo rm ulat ed in FCA

Day 0

- co ntrol groups

Th re e pairs o f

in trad ermal inj ections of 0. 1 ml volume are given in th e s am e

sites a s in t he tre ate d ani mals

. Inj ection 1: a 1 :1 mixture (v/ v) FCA/water

Inj ection 2: para ff in o il

Inj ection 3: FCA

In ducti on: Intr ader mal injec tions

Day 7

- trea te d group

Th re e pairs o f

in trad ermal inj ections of 0. 02 5 ml volu me o f t he un dilute d

tes t ma terial a re given i n th e s am e sites as in th e in ductio n.

Day 7

- co ntrol groups

no tre atm en t

Challe nge: To pic al Ap plicatio n

Day 2 1 - tre at ed a nd firs t co ntrol group

A p atc h with t he tes t su bsta nce is ap plied t o t he op pos ed f la nks o f t he

ani mals. Th e pa tch es are hel d in c ont act by an occl usive dressi ng f or 6

ho urs.

Day 3 5 - tre at ed a nd sec ond con trol group

A p atc h with t he tes t su bsta nce is ap plied t o t he op pos ed f la nks o f t he

ani mals. Th e pa tch es are hel d in c ont act by an occl usive dressi ng f or 6

92

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

ho urs.

Obs ervations - tre ate d an d c on trol groups

Af te r rem oving th e p atc h (1 h our b ef or e t he firs t evaluati on) th e c hallenge

are a is clea ne d an d

de pilat ed t o f ac ilitate th e evalua tion o f t he skin re action ;

- ap proximately 8 h ours f ro m th e st art of th e ch allenge

ap plicatio n th e skin reacti on is o bs erved a nd record ed a ccordi ng t o

MAGNUSSON AND K LI GMAN GRADING SC ALE FOR TH E

EV ALUA TI ON OF CHAL LENGE PA TCH TE ST REAC TIONS

0 = n o visible cha nge

1 = discre te or pa tchy e rythem a

2 = m od erat e a nd con fl ue nt erythe ma

3 = in tens e erythe ma an d swelling

- ap proximately 1 6 ho urs af te r this obs ervation a sec ond obs ervation (2 4

ho urs), a t hird (4 8 ho urs) an d f ou rt h (72 ho urs) is ma de an d o nce again

record ed.

Skin r eactio ns which are o bs erved a t two ob servation ti mes are evalu at ed

"p ositive". A n a nim al is evalua ted as s ensitized if t he trea ted ani mal

sh owes a positive resp ons e without a ny evide nce of irritatio n.

1st : In duc tion ( day 0) : 10 % intra der mal

2n d: I nd uctio n (d ay 7): u ndil ute d intra der mal

3rd: Challe nge (day 2 1 an d 3 5): 0 .0 1 an d 0 .0 3% o cclusive (6 h ours);

Re liabi lit y : (2) valid with restrictions

Restrictions : no st and ard pr otoc ol; n o ra nge fi ndi ng f or th e in duc tion;

slightly irritating co nce ntratio n fo r th e ch allenge

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (12)

Ty pe : Gui nea pig m aximization t est

Sp ec ies : guine a pig

Number of

a nim als : 20

V ehi cle : ot her: p ara ff in oil

Re sult : no t se nsitizing

Cl ass ification :

Method : ot her: si milar to OECD TG 4 06

Year : 19 85

GL P : yes

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate (liquid), mixed isom ers,

no fu rt her d at a

Rem ark : In a pil ot st udy f or t he c halle nge th e skin irritatio n was exa mine d with 4

ani mals with 0. 01 , 0. 03 , 0. 1 a nd 0. 3% (2 4 ho urs, o cclusive); t he a ni mals

were tr eat ed with FCA an d p ara ff in oil like th e co ntrol a nim als; o nly on e

ani mal s howed skin irritatio n with a ll ap plied c onc entra tion an d a t every

examin atio n tim e (4 8 an d 7 2 ho urs af te r ap plicati on)

Re sult : 0. 00 1%: 1 /2 0 (1/ 10 i n th e c ontrol grou p) with a positive reac tion

0. 01% : 1/ 20 (5/1 0 in c ontr ol group) with a po sitive re action

Th e reas on why hal f

of th e co ntrol a nim als sh owed a p ositive r eactio n

towards 0. 01% is no t e ntirely un ders too d b ut l ocal irritant e f fe ct s s ee me d to

be involved.

T est condition : Ani mals ar e accli matise d t o t he l abora tory co nditio ns f or ap prox. 1 week

prior to th e t est.

Be fo re t he tes t, a nim als are ran domis ed a nd assigne d t o th e tr eat me nt

groups; Num ber o f

a nim als: 20 t est a nd 10 co ntrol guine a pigs have b ee n

us ed; r em oval o f

ha ir is by s having an d c he mical de pilati on (ch allenge).

93

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

Th e ani mals ar e weighed be fo re th e t est c om me nces an d every week

during t he s tudy. All skin r eactio ns a nd any un usu al fi ndi ngs, includi ng

systemic re actions were o bserved twice a d ay a nd record ed.

In ducti on: Intr ader mal I njectio ns

Day 0

- trea te d group

Th re e pairs o f

in trad ermal inj ections of 0. 1 ml volume are given in th e

sh ould er r egion which is s haved.

Inj ection 1: a 1 :1 mixture (v/ v) Freu nds Co mpl ete Adj uvans (FCA)/ water

Inj ection 2: th e te st su bst ance in p araf fi n oil

Inj ection 3: th e te st su bst ance fo rm ulat ed in par af fi n oil/FCA (1 :1)

Day 0

- co ntrol group

Th re e pairs o f

in trad ermal inj ections of 0. 1 ml volume are given in th e s am e

sites a s in t he trea ted ani mals.

Inj ection 1: a 1 :1 mixture (v/ v) FCA/water

Inj ection 2: para ff in o il

Inj ection 3: para ff in o il in a 1: 1 mixture (v/v ) FCA/water

In ducti on: To pical A pplic ation

Day 7

- trea te d group

A a dh esive t ap e (2. 5 x 2 .5 cm) is f ully- lo ad ed with tes t

su bsta nce in par af

fi n oil an d a pplie d t o th e t est a rea an d h eld i n co ntac t by

an occlusive dressing f or 48 ho urs.

Day 7

- co ntrol group

Par af fi n o il only is a ppli ed in a si milar ma nn er to th e

tes t are a a nd hel d in c ont act by an occl usive dressi ng f or 48 ho urs.

Challe nge: To pic al Ap plicatio n

Day 2 1 - tre at ed a nd co ntrol groups

A p atc h with t he tes t su bsta nce is ap plied t o t he op pos ed f la nks o f t he

ani mals. Th e pa tch es are hel d in c ont act by an occl usive dressi ng f or 24

ho urs.

Obs ervations - tre ate d an d c on trol groups

Af te r rem oving th e p atc h th e c hallenge area is clea ne d an d

de pilat ed t o f ac ilitate th e evalua tion o f t he skin re action ;

- ap proximately 4 8 ho urs fr om th e s tart o f t he c halle nge

ap plicatio n th e skin reacti on is o bs erved a nd record ed a ccordi ng t o

MAGNUSSON AND K LI GMAN GRADING SC ALE FOR TH E

EV ALUA TI ON OF CHAL LENGE PA TCH TE ST REAC TIONS

0 = n o visible cha nge

1 = discre te or pa tchy e rythem a

2 = m od erat e a nd con fl ue nt erythe ma

3 = in tens e erythe ma an d swelling

- ap proximately 2 4 ho urs af te r this obs ervation a sec ond obs ervation (7 2

ho urs) an d t hird (96 ho urs) is m ad e

an d o nce again rec orde d.

An ani mal is evalu ate d a s se nsitized i f th e tre ate d a nim al sh owes a skin

reacti on grad ed >=1 without any evidenc e of irritation a t 2 ob servation

tim es.

CONCENTRA TI ON:

94

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

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1st : In duc tion ( day 0) : 1% intrad erm al

2n d: I nd uctio n (d ay 7): 1 0% to pical (occlusive; 48 ho urs)

3rd: Challe nge (day 2 1): 0 .0 01 an d 0 .0 1% to pical (occlusive ; 2 4 h ours)

Re liabi lit y : (2) valid with restrictions

No ra nge fi ndi ng f or

th e in duc tion. Slightly irritating t est c onc entra tions f or

th e ch allenge

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (13)

Ty pe : Bu ehler T es t

Sp ec ies : guine a pig

Conc entration : 1 st : I nd uctio n 2 %

2 nd : Ch allenge . 5 %

3 rd :

Number of

a nim als : 20

V ehi cle : pe trolat um

Re sult : se nsitizin g

Cl ass ification :

Method : Directive 96 /5 4/EC, B. 6

Year : 19 98

GL P : no da ta

T est sub stance : ot her T S: Des mo dur W

, purity: > 99 .5%

Re sult : 19 /2 0 sh owed a p ositive r eactio n

T est condition : Strai n: Du nkin- H artley

Sex: fe ma le

Dose : 0. 5 m l fo r i nduc tion a nd ch allenge

Histop ath ological examin ation was c arried ou t t o clari fy d ou btf ul reacti ons,

an d t he results were int erprete d a s po sitive o nly if t hey were co nf irm ed a s

se nsitization reac tions o f exp erimen tal e czema; th e se nsitivit y an d

realia bility o f

t he test were a ssesse d by th e u se o f re fe renc e su bst ance (ne omycin sul fa te)

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n

Fl ag : Critical s tudy fo r S IDS e nd poin t

0 5. 11. 20 04 (1 00)

Ty pe : Bu ehler T es t

Sp ec ies : guine a pig

Number of

a nim als : 15

V ehi cle : ot her: o live oil a nd an hydrous ac et one (1 : 1 )

Re sult :

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 19 84

GL P : yes

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate , no d at a on purity

Rem ark : An irritation ra nge- f in ding st udy was per fo rm ed in ord er to s elect a vehicle

an d d oses fo r t he ind uction an d c hallenge a pplic ations

. Six a nim als were tr eat ed t opic ally with 1. 0, 0 .3 , 0. 1, 0 .0 3, 0 .0 1 a nd 0. 00 3

Molar of th e t est m at erial in 1 00 % olive o il or in a 1 : 1 mixture o f olive oil

an d a nhydrous ace to ne u nd er occlusive co nditio ns. T he p atc hes were lef t

in pl ace f or

6 ho urs. O bservations f or irritation were ma de 2 4 a nd 48 ho urs

af te r ap plicati on a nd again a t d ay 4 , 5 or 6

. Re sult : Au th or ́s c onclusio n: Un der c onditi ons o f t his stu dy 4 ,4

 ́- m et hylenedicyclohexy l diisocyan ate exhibit ed th e po te ntial t o pr oduc e

der mal s ensitization i n guine a pigs.

Conc entra tions select ed f or in ductio n were only n on-irritating fo r all low95

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

an d m id-do se a nim als 24 ho urs a ft er t he firs t ind uctio n expos ure;

su bseque ntly al most all ani mals d evelop ed ski n reac tions; fo r t he high

do se grou p th e in ducti on c once ntrati on was irritating u po n initi al

ad ministra tion ; resp ons es gener ally incr ease d in i ncide nce a nd severity

af te r su bseque nt i nduc tion exp osures; this type of resp onse to repe at ed

exposures may re presen t a cu mula tive irritant e f fe ct a nd /or m ay b e

indica tive o f

se nsitization.

W i t h th e high challe nge co ncen tratio n (60 milliMolar = m id-do se f or

ind uctio n) 9 // 15 a ni mals o f t he l ow dos e f or ind uction ; 13 /1 5 a nim als of th e

mi d- d ose fo r in duc tion a nd 15 /1 5 a nim als of th e high d ose fo r in duc tion

sh owed sc ores great er th an 0

. W i t h th e m id-high ch allenge c onc entra tion (2 0 m illiMolar = low- d os e fo r

ind uctio n) 1 /1 5 a nim als of th e low d os e fo r i nduc tion; 5/ 15 a ni mals o f t he

mi d- d ose fo r in duc tion a nd 5/ 15 ani mals o f t he high do se f or

ind uctio n

sh owed sc ores great er th an 0

. W i t h th e o th er ch allenge co nce ntratio ns (0. 06-6 milliMolar) n o skin

reacti ons were ob served in a ny a nim al of do se grou ps fo r ind uction

. 2/ 6 irritation con trols ad high d ose ha d m inim al scrores a t 4 8 h ours o nly.

cross- r eactivity t o struc turally relat ed ma terials (e.g. T DI , MDI, IPD I) was

less pr ono unc ed.

T est condition : Num ber o f a nim als: 1 5/c once ntrati on; 6 c ontrol a nim als (did no t receive

ind uctio n exposur es)

Dose levels

ind uctio n exposur e: 2 0, 6 0, 20 0 m illiMolar

ch allenge expos ure: 6 0, 20 , 6, 0. 6, 0 .0 6 m illiMolar/dose l evel

In ducti on: To pical a pplic ation

Tr eat ed grou p:

On e f la nk is cle ared o f

h air (closely- clippe d). Th e te st m at erial was

adi minist ered in a volu me o f 5 0 m icroliters be ne at h an ad he sive- b ack ed

gauze pa tch. Th e tes t pa tch was covered by ovela pping, i mper me able

plas tic an d f irmly s ecure d by an elas tic ad hesive ba nd age wound a rou nd

th e t orso o f

th e a nim al. T he p atc h was h eld in co nt act with t he skin f or 6

ho urs af te r which it was re moved . T his was rep eat ed at t he sa me site

on ce weekly fo r 3 weeks, f or a t ot al of 3 a pplica tions

.

co ntrol group: no t us ed

Challe nge

Tr eat ed grou ps:

Fourt ee n days af

te r t he last in ducti on exp osure t he un treat ed fl ank of

trea te d ani mals is cl eare d of hair (closely- clipp ed). Five dif fe re nt

co ncen tratio ns (25 microliters) were a dm inistere d a s de scribed fo r t he

ind uctio n. T he p atc h was h eld i n co ntac t fo r 6 h ours. In o rder t o

dif fe re nti ate possi ble d erm al reacti ons pr od uced by irritatio n fr om t hos e

pro duce d by se nsitization, 6 ad ditio nal a nim als (= c ontrol grou p) were

su bjecte d t o t he sam e c hallenge proce dure

Cross- Ch allenge

Single co nce ntratio ns o f 4 dif fe re nt ma terials were ap plied to th e high d ose

tes t ani mals up on r ecovery f ro m challe nge (7 d ays a ft er c halle nge). Crossch allenge co ntrol a nim als were als o tre at ed with th ese m at erials an d

co ncen tratio ns.

Obs ervations - tre ate d an d c on trol groups

96

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

In ducti on sit es: prior t o d osing an d a ppr oximately 2 4 h ours af te r ea ch

ind uctio n ap plicatio n

Challe nge sites: prior to do sing a nd ap proximat ely 24 an d 4 8 h ours af te r

ch allenge ap plicati on

GRADING SC ALE FOR TH E E VA LUAT ION OF CHA LLENG E P ATCH

TE ST R EACT IONS

0 = n o visible cha nge

1 = discre te or pa tchy e rythem a

2 = m od erat e a nd con fl ue nt erythe ma

3 = in tens e erythe ma an d swelling

Re liabi lit y : (2) valid with restrictions

Only 1 5 a ni mals/ dose group, n o con trol ani mals d uring ind uctio n exposur e;

pro nou nce d skin re actio n duri ng in duc tion exp osure, slightl y irritating tes t

co ncen tratio ns fo r t he ch allenge

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (2)

Ty pe : Mous e ear swellin g t est

Sp ec ies : mo us e

Number of

a nim als :

V ehi cle : ot her: a cet on e

Re sult : se nsitizin g

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 19 87

GL P : no da ta

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate , purity > 99 .3%

Re sult : Th e do se res po nse c urve ha s a ne arly vertical direc tion (single d at a were

no t re porte d); this suggests th at t his co mp ou nd m ay ef f ec t thres hold

resp onse rath er th an a d ose-d ep en den t on e; th e st ee p do se-resp onse

curve s uggested a t hresh old-type resp ons e occ uring a t 0 .2 4 mg/kg;

Crossreactio n was obs erved to HDI a nd MDI

T est condition : NUMBER OF ANIMA LS: groups 4

- 5 a nim als were use d p er do se with

ma ny r eplicat e de ter minati ons (n o f ur ther d at a).

Mice were s ensitized an d c halle nged u sing t he me th od describ ed by

St adler a nd Kar ol (T oxicol. Ap pl. P har am acol. 7 8, 44 5-45 0, 1 98 5) ad ap te d

fr om th at of

A sh erson a nd Pt ak (I mm un ology 1 5, 40 5-41 0, 1 96 8). 1 00 uI

ac eto ne c ont aining th e s pecif ie d am ou nt of diisocyanat e (n o fu rt her

inf or ma tion availa ble) was a pplie d to th e s haved a nd de pilate d a bd om en o f

th e t est a nim als. A ft er 4 days t he m ice were ch allenged on th e right ear

with a cet one an d o n t he lef t ear with ac eto ne c ont aining a n onirritati ng

do se isocyan ate .Challenge dos es were de termi ned in se para te

experime nts i n which grou ps of mic e were a dm inist ered 4 0, 10 0, 2 00 , 4 00

ug isocyanat e t o t he e ar a nd me as urem ents of ear t hickn ess were t ake n a t

24 h. A d os e bel ow th at which ca use d an incre ase in ear t hickn ess was

selec ted . Ba sed on th ese tests , 40 ug 4 ,4 ́-me thylene dicyclohex yl

diisocyana te were us ed f or ch allenge.

Cross- re activit y st udies were per fo rm ed with di phe nylmeth an e- 4 ,4

 ́- diisocyan ate (MDI), t olue ne d iisocyanat e (TDI) a nd hexa met hylene

diisocyana te (HDI); th e d ose fo r s ensitization was 0. 75 m g 4, 4

 ́- m et hylenedicyclohexy l diisocyan at/kg

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (91)

97

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

Ty pe : Mous e local lymp hn ode assay
Sp ec ies : mo us e

Number of

a nim als :

V ehi cle :

Re sult :

Cl ass ification :

Method : ot her: a n a ltern ative e nd poi nt (pro ducti on o f in terleukin 6) was m ea sure d

(in vi vo a nd in vitro exp erime nts)

Year :

GL P : no da ta

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate , no d at a on purity

Rem ark : Th e obj ective o f t he stu dies p ublish ed i n th e cit ed p ap ers was t o evalu ate

th e p ot ential o f

a mo lec ular (IL-6 pr od uctio n), rath er th an a c ellular

(lymphocyte proli fer atio n), en dp oint f or d et erming th e exte nt o f lymph n od e

activation ind uced by t opic al exposure to a c he mical allergen; fo r t his

sp ecial pur pose th e experim ents were d on e with che micals k nown t o c aus e

co ntact se nsitization

Re sult : 3 d ays a ft er initiatio n o f expos ure t he t est ma terial

ind uce d at all lymph n od e c ells ( LNC) co nce ntratio ns

vi gorous pr olif erative r espo nse a nd signific ant levels o f

IL-6 pro ductio n

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n

2 2. 12. 20 05 (43) (6 3) (65)

Ty pe : Mous e local lymp hn ode assay
Sp ec ies : mo us e

Number of

a nim als :

V ehi cle : ot her: a cet on e : o live oil (4 : 1)

Re sult :

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 19 92

GL P : no da ta

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate , no d at a on purity

Rem ark : Th e obj ective o f t he stu dies p ublish ed i n th e cit ed p ap ers was t o evalu ate

th e p ot ential o f

a mo lec ular (IL-6 pr od uctio n), rath er th an a c ellular

(lymphocyte proli fer atio n), en dp oint f or d et erming th e exte nt o f lymph n od e

activation ind uced by t opic al exposure to a c he mical allergen; fo r t his

sp ecial pur pose th e experim ents were d on e with che micals k nown t o c aus e

co ntact se nsitization

Re sult : W h i le a lymphocyte pr olif erative respo nse in lymph n od es dr aining was

ob served, th e t est m at erial di d no t in duc e a cha nge in s erum IgE

co ncen tratio n. W i t h regard to t he au th or ́s o pinio n t his result is consist ent

with t he d if

fe re ntial i mm un e res pons e f or con tact an d res piratory se nsitizer.

Th e tes t ma terial a pp ears n ot to ca use res piratory allergy bu t c auses

co ntact se nsitization.

T est condition : A c om bina tion o f l ocal lymph n od e a ssay (Gro ups of m ice (n = 4) rec eived

25 ul o f various co nce ntratio ns (0. 1 - 5 %) o f t he tes t ma terial o r an equ al

volume of vehicle alo ne o n t he dors um o f b ot h e ars. T hr ee d ays la ter all

mic e received [ 3H]m et hylth ymidine iv via t he t ail vein. Mice were kille d 5 h r

lat er a nd drai ning a uricular lymph no des isolat ed a nd po ole d fo r e ac h

experime nt al group.) a nd me asur em ent of s erum IgE c once ntrati on in mice

(n= 10) which recieved t he tes t ma terial (5 0 ul , 2 o r 1%) o n e ac h sh aved

fl an k an d s even days lat er th e sa me tes t ma terial ( 25 ul of a 1 :1 dilutio n)

was a pplie d to th e d orsu m o f bo th ears.

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n

98

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (4 2) (44)

Ty pe : ot her

Sp ec ies : ot her: m ou se an d guine a pig

Number of

a nim als :

V ehi cle : ot her: m et hylethyl ke ton e

Re sult :

Cl ass ification :

Method : ot her: S ee Te st Con dition

Year : 19 85

GL P : no da ta

T est sub stance : ot her T S: Des mo dur W

, no d at a on purity

Re sult : Ap plicatio n of high d oses of

e ac h ch emic al result ed in extensive erythem a

an d a large pro portio n of ani mals b ec am e se nsitzed. L ower d oses

pro duce d less sensitivity. In mice , as well a s in guinea pigs, a d os eresp onse relatio nship was a pp arent be tween t he s ensitizing do se a nd bo th

severity o f

res po nse a nd nu mb er o f a nim als resp ondi ng. For mic e,

co mp arison o f

t he d os e of

ch emical r equired to se nsitize 5 0% o f t he

ani mals (SD 5O) yielded 0 .4 0 mg/kg fo r P iCl a nd ap proximat ely 0. 20 mg /kg

fo r 4 ,4 ́-Methylene dicyclohex yl diisocyanat e (using pr obit a nalysis).

T est condition : Th e stu dy was u nd ertak en to d et ermin e i f t he do se-resp onse relatio nship

co uld be us ed to a ssess th e se nsitizing p ot encies . Picryl chloride (PiCl)

was s electe d b eca use t he extensive literat ure de scribing its ability t o c ause

del ayed der mal s ensitivity.

Grou ps (4-8) o f

B AL B/cBy m ice a nd English s mo oth-h aired guin ea pigs (8)

were expos ed to 4 ,4 ́-Met hylenedicyclohexy l diisocyana te or PiCl by t opical

exposure . Mice were challe nged 5 days lat er using an e ar swelling a ssay (20 u l 0. 5% PiCl, 0 .1 % 4, 4 ́- Me thylenedicyclohexy l diisocyan ate) a nd th e

thick ness o f

e ach ear was me as ured 6 , 2 4 a nd 48 h ours p ostc hallenge

. Gui nea pigs were ch allenged 7 d ays l ater by pa tch testi ng (2 5 ul o f 0 .5 %

PiCl or 0. 1% 4 ,4 ́-Methylene dicyclohex yl diisocyanat e) an d res po nses

graded at 1, 2, 4 , 6 , 8 ,2 4 a nd 48 hr po stch allenge.

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n

Fl ag : Critical s tudy fo r S IDS e nd poin t

0 9. 11. 20 06 (87)

Ty pe : ot her

Sp ec ies : guine a pig

Number of

a nim als :

V ehi cle :

Re sult :

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 19 82

GL P : no da ta

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate , purity: 99 ,3 %

Rem ark : Th e stu dy u tili ze a rec ently d evelop ed a nim al m od el (Karol e t a l., T oxicol.

Ap pl. P har macol. 53 , 2 60-27 0 ( 198 0) an d 5 8, 22 1- 2 30 (19 81)) to evaluat e

4, 4 ́- m et hylenedicyclohexy l diisocyan ate as a se nsitizing ag ent a nd to

co mp are its res piratory a nd der mal s ensitizing abilities with th at o f T DI.

Re sult : an tibo dy res pons e:

with t he d ou ble-di ff us io n ass ay, n o a nti bodi es were d et ecte d in sera t est ed

of any HMDI tr eat ed a ni mal; f ew ser a de mo nstra te d an tibo dies when

ap plying th e mo re s ensitive passive cut an eo us an ap hylax is t ech nique, b ut

an tibo dy tit ers were extre mely low.

cut an eous reacti ons:

99

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

- co ntac t se nsitivit y was o bserved in th e ani mals expose d by to pical

ap plicatio n (12 /1 2) a nd to ep ad inoc ulatio n

- der mal s ensitivity was ob served in t he a ni mals expos ed by t opical

ap plicatio n (9/ 12) a nd i.p. i njectio n (3/ 4)

- pul mo nary se nsitivit y was o nly elicite d with HMDI in ace to ne in 2/ 11

ani mals which have b ee n s ensitized with t oe pa d in oculati on o f t est m at erial

in Fre und ́s c om plet e adj uvant; c halle nge with HMDI- G SA d id n ot prod uce

any pul mo nary res po nse in th ese a nim als. No pul mo nary s ensitivit y usi ng

HMDI- GS A was d et ect ed in any of 12 guine a pigs sensitized by to pical

exposure

. T est condition : Gui nea pigs were expos ed by to pical a pplica tion, intra derm al an d

intra perito neal i njectio n, as well as t oe pa d inoc ulatio n o f t est m at erial in

Freu nd ́s co mpl ete a djuvan t; su bsequ ent t he ani mals were exami ned fo r

an tibo dy b ody respo nse (sera ta ken on days 15 an d 2 2), c on tact s ensitivity

(0,1 % tes t ma teri al on to cle an de pilate d d orsal are a), d erm al sensitivity

(intrad ermal i njectio n of 0. 1% HMDI- G SA) a nd pul mo nary se nsitivit y (bronc hial provocati on c hallenge with 0. 1% HMDI in a ce ton e a nd HMDI

- G SA)

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (67)

Ty pe : ot her

Sp ec ies : ot her: m ou se an d guine a pig

Number of

a nim als :

V ehi cle : ot her: a cet on e

Re sult :

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 19 84

GL P : no da ta

T est sub stance : ot her T S: Des mo dur W

, no d at a on purity

Re sult : Gui nea pig: skin s ensitivit y fo ll owin g in hala tion o f

> 3 ug/l, no sensitization af te r 1, 25 ug/l;

mic e: co nt act se nsitivit y was d et ecte d f oll owing in hala tion

of > 1 7 ug/l, no reac tion af te r < 7 ug/l;

der mal c ont act o f

t he he ad, as would o ccur d uring i nhal ation exposures

, also resulte d in con tact sensitization

T est condition : INDUCTION:

guine a pig: inh alatio n f or 2h /d ay on 3 cons ecu tive days; h ea d o nly

exposure to an aer osol (1, 3, 17 , 32 , 4 4, 53 mg/m 3); 4

ani mals/c onc entra tion

mic e: expos ure was si miliar t o t ha t de scribed fo r guin ea p igs, h owever

mic e were exp oed nos e o nyl expos ed

mic e: direc t ap plicatio n t o th e n os es of mic e to cover a n area co mp arable

to th at which exten de d int o th e " no se-only" in halati on c ha mb er; th e

ap plicatio n was p erf or me d over a p eriod of 2h on 3 c ons ecutive days

CHALL ENGE:

7 d ays f ol lowing th e initial in hala tion exposure guinea pigs were ch allenged

by t opic al ap plicatio n (25 ul, 0 .1% = no nirritating c onc entra tion) o nt o th e

fl an k are a an d a ll mice (inhal ation an d d erm al ap plicatio n) by a pplica tion

(20 u l, 0 .1% = n onirritati ng c once ntrati on) to ea ch si de o f t he right e ar (ear

swellin g t est)

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 4. 01. 20 05 (86)

100

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

Ty pe : ot her: l ung sensitization fo llowing intra der mal in ductio n
Sp ec ies : guine a pig

Number of

a nim als : 8

V ehi cle :

Re sult :

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 19 95

GL P : yes

T est sub stance : ot her T S: Des mo dur W ; purity: > 99 .2 %

Re sult : Following ind uction , slight skin re actions at th e injec tion sit es occ urred.

During or fo llowing te st m at erial- ch allenges, th e incid ence of im me diateon set r espiratory re actio ns was ro ughly th e sa me in vehicle c ontrols a nd

tes t su bsta nce-ind uce d an im als. No d ea ths o r an ap hylactic re actio ns were

ob served during ch allenge, an d n o clinical signs or s peci fic a bn orm alities

were o bserved a t n ecropsy. Th e hist op ath ological evalu atio n of lungs

revealed a m arke d in fl ux of eo sino phils in t est m at erial- s ensitized guine apigs, a c harac teristic fe at ur e of ast hm a a nd airwa y hyperse nsitivit y.

Th e stu dy pr ovides evide nce t ha t t he t ests ubt anc e is weak respirat ory

se nsitizer in guine a pigs.

T est condition : ADMINIS TRA TION:

Grou ps o f

eight fe ma le guine a- pigs were intrad erm ally i nduc ed o nc e on day 0 (injec tion volume: 10 0 ul /, 0 .1 3 % s olutio n in olive oil). Eight f em al e

co ntrols received vehicle al on e un der o th erwise ide ntical c onditi ons.

Following a rec over y p eriod o f a ppr oximately f ou r weeks (starting o n d ay 28) a t est m at erial- h ap te n ch allenge (m ea n co nce ntratio n: 6 8 ± 3. 6 mg/ m3

air) was per

fo rm ed (c hallenge d ura tion: 30 mi n). Th e tec hnical exp osure

criteria sp ecifi ed in OECD T G 40 3 were fu lf illed inso fa r as th ese ar e

ap plicable to this s tudy. Th e aer osolized tes t ma teri al proved t o b e o f

ad equat e res pirability.

EXAMINAT IONS:

During a nd af

te r c hallenge exp osures with th e h ap ten , im me diat e- o ns et

respirat ory reacti ons were evaluat ed by m ea sure me nt o f res piratory rat e,

tid al volume, respirat ory min ut e volume , ins piratory an d expirat ory tim es,

an d p eak expiratory fl ow ra te. Ad dition al par am eters were derived

ma th em atically. D uring sacri fice th e trac hea , lu ng, a nd lu ng a ssociat ed

lymph n od es were fixed an d s ubject ed to h istological evalua tion

. Re liabi lit y : (1) valid withou t restriction

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 4. 01. 20 05 (19)

Ty pe : Pa tch-Te st

Sp ec ies : hu ma n

Number of

a nim als :

V ehi cle : pe trolat um

Re sult :

Cl ass ification :

Method : ot her: n o f ur th er da ta

Year : 19 76

GL P : no da ta

T est sub stance : ot her T S: Pre polymers co nsisting of 4 ,4 ́-me thylen edicyclohexy l

diisocyana te (n o fu rt her in fo ma ti on availabl e)

Re sult : 2/ 2 co nt act d erm atitis pa tie nts sh owed a p ositive reacti on in a p atc h t est

with pr epolymers c onsisting of 4, 4 ́m ethylene dicyclohex yl d iisocyanat e

T est condition : 8/ 12 e mp loyees o f a sm all polyureth an e mo ul ding p lan t who worked as

plas tic mol ders d evelope d co nt act d erm atitis; t he c ase history o f 3 pa tie nts

is de scribed i n de tails; p atc h t esting was p erf or me d with 2 of th ese 3

101

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

pa tien ts with n onirritating c once ntrati ons (1%) a nd 4 h eal thy volun teers

served as con trol

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (57)

Ty pe : Pa tch-Te st

Sp ec ies : hu ma n

Number of

a nim als :

V ehi cle : ot her: t olu ene

Re sult :

Cl ass ification :

Method : ot her: n o f ur th er da ta

Year : 19 80

GL P : no da ta

T est sub stance : ot her T S: Hylene W

, no d at a on purity

Re sult : A c ase re port a bo ut a s tud ent with c ont act s ensitivit y develo pe d duri ng a

projec t on ma nu fa ct ure of p olyureth ane fo am ; th e s tud ent sh owed a

po sitive reac tion when pa tch test ed with 1% Hylene W ; co ntrol pa tch tes ts

were p erf or me d on a me mb er o f st af f who s howed no resp ons e

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 5. 11. 20 04 (70)

Ty pe : Pa tch-Te st

Sp ec ies : hu ma n

Number of

a nim als :

V ehi cle : pe trolat um

Re sult :

Cl ass ification :

Method : ot her: n o f ur th er da ta

Year : 19 77

GL P : no da ta

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : A c ase re port a bo ut a c he mical engin eer who beg an investigative work with

various polyester a nd isocyanat es su ff er d fr om itchy polymorp hic

der ma titis; he was p atc h t este d with t he su bsta nces o f t he inter natio nal

sta nd ard tray an d with 3 2 subs tanc es h e h as u se d in his rese arch; t he o nly

su bsta nce t o which he clearly re act ed was 4, 4 ́diisocyanat odicyclohexy l

me th an e (1%).

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (73)

Ty pe : Pa tch-Te st

Sp ec ies : hu ma n

Number of

a nim als :

V ehi cle : pe trolat um

Re sult :

Cl ass ification :

Method : ot her: n o f ur th er da ta

Year : 19 97

GL P : no da ta

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate , no d at a on purity

102

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

Re sult : A c ase re port a bo ut a t extile worker with pruritic, p ap ulovesicular eru ptio n

on th e d orsu m of

her ha nds , fo re arms , axillae, ster num an d a nt erior neck

. Pa tch t esting t o work rela ted ch emicals reveale d stro ng positive reac tions

to 4, 4 ́- m et hylenedicyclohexy l diisocyan ate ( 0.5, 0. 1 a nd 0. 05%) a nd

triethylene tetra min e.

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (90)

Ty pe : Pa tch-Te st

Sp ec ies : hu ma n

Number of

a nim als :

V ehi cle : pe trolat um

Re sult :

Cl ass ification :

Method : ot her: n o f ur th er da ta

Year :

GL P : no da ta

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : In a f ac tory where 4 ,4 ́-me thylen edicyclohexy l diisocynat e was u se d to

fo rm a sur

fac e- c oa ting p olyureth ane 7 f em al es o per atives s uf fe re d fr om

co ntact der ma titis, 2/ 7sh owed a p ositive r eactio n in t he pa tch with 4, 4

 ́- m et hylenedicyclohexy l diisocyan ate ( 1%); no reac tion was ob served fo r

th e 5 0 c ontrol p ati ents.

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (9 6) (97)

Ty pe : Pa tch-Te st

Sp ec ies : hu ma n

Number of

a nim als :

V ehi cle : pe trolat um

Re sult :

Cl ass ification :

Method : ot her: n o f ur th er da ta

Year : 19 82

GL P :

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : A wom an woma n who beg an working with 4 ,4 ́-me thylen edicyclohex yl

diisocyana te a nd a p oly- type ca talyst s uf fe re d f ro m pruritic, erythe ma tous

der ma titis af

te r on e week. P atc h t esting were p erf or me d with t he

diisocyana te (1%), th e polyet her glycol b len d, a pr eviousl y u sed ep ox y

resin a nd har den er an d t o t he sta ndar d Am erican Aca de my o f Der mat ology

tray o f p atc h te st s ubst ances ; th ere was a r eactio n (3+) to 4, 4

 ́- m et hylenedicyclohexy l diisocyan ate; all ot her p atc h t ests were nega tive

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (64)

Ty pe : Pa tch-Te st

Sp ec ies : hu ma n

Number of

a nim als :

V ehi cle : pe trolat um

Re sult :

Cl ass ification :

103

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

Method : ot her: s ee T es t Co nditio n

Year : 20 03

GL P : no da ta

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : 13 /1 7 co ntac t der ma titis pa tien ts working at a f ac tory m an uf ac turing

me dical eq uipm en t sh owed a p ositive re actio n with 4 ,4

 ́- m et hylenedicyclohexy l diisocyan ate ( 0.1 a nd 1%) a nd th e isocyan ate

glue, while no ne r eact ed t o t he ot her

co nstitu ent , TD I. 5 pa tie nts sh owed sim ultan eo us reac tions t o 4 ,4

 ́- m et hylenedicyclohexy l diisocyan ate a nd 4, 4 ́- m et hylene bis

(cyclohex ylamine). In several cas es, t he p ati ents also s howed m ultipl e

reacti ons t o 1 or m ore

pre parati ons o f

t he is ocyanat e series. 9 p atie nts a lso re acte d t o 1. 6-

hexa met hylenediisocyana te (HDI), 4 t o is oph oron ediisocyana te (IPDI), 1 t o

isop horo ne di ami ne (I PDA) an d 5 to MDA.

5/ 12 s howed p ositive re actio n with 0 .0 1% 4 ,4 ́-me thylene dicyclohex yl

diisocyana te.

T est condition : Pa tch t esting was per for me d u sing t he Finn C ha mb er o n Sca np or

t ap e

tec hnique lixed with S ca npor or Medip ore t ap e. P atc h tes ts were r em oved

af te r 2 days by t he pa tien t an d re ad af te r 1 d ay, acc ording to I nt erna tion al

Con tact D erma titis Rese arch Gro up criteria . In 7 c ases, a 2 nd rea ding was

do ne 7 d ays a ft er th e initial a pplica tion of

pa tch es.

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (59)

Ty pe : Gui nea pig m aximization t est

Sp ec ies : guine a pig

Number of

a nim als : 20

V ehi cle : ot her: o live oil a nd ace to ne/ olive oil (2. challe nge)

Re sult :

Cl ass ification :

Method : OECD G uide-line 40 6 " Skin S ensitization "

Year : 19 93

GL P : no

T est sub stance : ot her T S: Des mo dur W

, pur tiy: 99 .2 %

Rem ark : A pil ot st udy f or t he i nduc tion (in trader mal: 1 , 2 , 2 .5 an d 5 %; t opical: 12 , 25

, 50 an d 1 00 %) was per

fo rm ed

. In a pil ot st udy with 5 ani mals t he skin irritation was exami ned fo r t he

ch allenge with 0 .2 5, 0 .5 , 1 an d 3 % (24 ho urs, occl usive); th e a nim als were

trea te d with FCA a nd olive oil like th e c ontrol a nim als;

skin e f fe ct s were n otic ed i n

2/ 5 a nim als >= 0 .2 5%

3/ 5 a nim als >= 0 .5%

4/ 5 a nim als with 1 %

Re sult : Und er th ese t esting c onditi ons it c an no t be exclude d t hat

th e t estsu bsta nce has a s ensitizing po te ntial

1. challe nge:

0. 25% : 20 /2 0 (10 /1 0 in t he con trol group) with a p ositive re actio n

1%: 20 /2 0 (7/ 10 in co ntrol group) with a p ositive r eactio n

2. challe nge:

0. 25% : 17 /2 0 (8/ 10 i n th e c ontrol grou p) with a positive reac tion

1%: 20 /2 0 (9/ 10 in co ntrol group) with a p ositive r eactio n

T est condition : CONCENTRA TI ON:

1st : In duc tion ( day 0) : 5% intrad erm al

2n d: I nd uctio n (d ay 7): 3 % o cclusive (4 8 ho urs)

104

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

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DATE: 09.11.2006

3rd: Challe nges (day 2 1 an d 3 5): 0 .2 5 an d 1 % se miocclusive (24 ho urs);

vehicle: ac eto ne /olive oil (1 :1)

Re liabi lit y : (3) invalid

Clearly irritating c onc entra tion f or th e two ch allenges; irritating vehicle

2 7. 10. 20 04 (15)

Ty pe : In tracut an eus t est

Sp ec ies : guine a pig

Number of

a nim als : 10

V ehi cle :

Re sult : se nsitizin g

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 19 77

GL P : no

T est sub stance : ot her T S: Hylene W

, no d at a on purity

Re sult : On e a nim al die d fr om n onc om po un d relat ed c aus es.

1. challe nge (by error o nly 5 of th e 9 tes t ani mals were tre ate d):

po sitive resp ons e in 5 /5 ani mals with 0. 5% s olutio n;

po sitive resp ons e in 2 /5 with 0 .1% soluti on; n o respo nse

with 0 .0 5% an d 0 .0 1% s olutio n

2. challe nge:

po sitive resp ons e in 5 /9 with 0 .1% an d 1 /9 with 0. 05% soluti on

T est condition : A s eries of fo ur sacral in trad ermal inj ections was given, on e e ach week

over a t hree week p eriod , which consist ed o f 0 .1 ml o f

a 1% solu tion o f

t est

ma terial in dim et hyl ph th alate ; fo llowing a 2 weeks res t perio d, t he tes t

ani mals were ch allenged by a pplying a nd lightl y ru bbing in, 0. 05 m l of a

0. 5%, 0 .1 %, 0 .0 5% an d 0 .0 1% s olutio n of tes t ma teri al in ac eto ne on th e

sh aved intac t sh ould er skin. Agroup of p reviously un exposed ani mals

received similar a pplica tions at t he tim e o f ch allenge. Af

ter a two week rest

perio d t he t est ani mals were rech allenged by a pplying an d lightly ru bbing in

on e dr op o f

a 0. 1% a nd 0. 05% solu tion i n ac eto ne. A n ew group of te n

previously un expose d an im als were tre at ed in th e sa me fa sh ion

. Re liabi lit y : (3) invalid

Unsuit able test system

2 7. 10. 20 04 (54)

Ty pe : ot her

Sp ec ies :

Number of

a nim als :

V ehi cle :

Re sult : se nsitizin g

Cl ass ification :

Method : ot her: m ou se ear swelling tes t (pu blishe d elsewhere a nd local lymp h no de

ass ay, u np ublishe d)

Year : 19 94

GL P : no da ta

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate , no d at a on purity

Rem ark : In this ar ticle th e d evelopm en t an d validati on o f t he murin e loc al lymph

no de assay are d escrib ed a nd co mp arisons with guinea pig p redictive tes t

me th ods discuss ed. I n a ddi tion we exami ne t he advant ages an d li mitatio ns

of th e me th od an d c onsid er new o pp ortu nities a nd ap plicatio ns o f th e

ass ay in t he con text of

t he toxicological evalu atio n of se nsitizin g p ot enti al.

Re sult : bo th t est results ar e cit ed a s po sitive in this review a rticle

Re liabi lit y : (4) no t assigna ble

Sec on dary litera ture

2 2. 12. 20 05 (69)

105

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

Ty pe : ot her

Sp ec ies : guine a pig

Number of

a nim als : 6

V ehi cle :

Re sult :

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 19 74

GL P : no

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : During s ensitization p erio d a s mall b ut sta tistically

significa nt i ncrease in airway resist anc e; in th e recovery

perio d a nim als retur ned to within b aselin e level af te r a s hort p erio d of tim e;

af te r ch allenge expos ure n o incr ease in airway resist anc e

T est condition : Ani mals were expose d (whole bo dy) to an average of 6. 70 ug/l 4 h ours /day

fo 5 d ays; 2 weeks a ft er t he last exp osure t he ani mals rec eived a si ngle

ch allenge expos ure of

1. 6 ug/l f or

4 ho urs;

isocyanat e a erosol was ob tain ed by h ea ting at 7 5-12 0 °C i n an ap par atus

an d dry ho use-air ears pa ssed thro ugh;

3 a nim als were sacrific ed i mm edi ately a ft er t he ch allenge expos ure a nd

an ot her 3 were killed s even days lat er fo r p at hological exa minati on, b loo d

was c ollecte d fr om t he h ear t at th e ti me o f

t he sacri fice in order t o o bt ain

an ti- isocyan ate imm un e s erum ; lungs were fixed an d pr epar ed f or

miscrosc opic slides

Re liabi lit y : (3) invalid

Unsuit able test system

2 2. 12. 20 05 (52)

Ty pe : ot her

Sp ec ies : mo us e

Conc entration : 1 st : 2 %

2 nd :

3 rd :

Number of

a nim als :

V ehi cle :

Re sult :

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 20 04

GL P : no da ta

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : th ere were no ch ange in t ot al or di ff er en tial c ell c ou nts a t any ti me; significa nt hyp errespo nsiveness at 2 weeks; th ese di ff er en ces were great er

at 4 weeks

T est condition : BA LB/c mice received 5 der mal exp osure over a perio d o f 2 weeks; mic e

were t he n ch allenged with incre asing dos es o f me th ac holine an d

resp onsiveness was ass essed using whole bo dy p let hysmorgraphy; h alf o f

th e group was killed a nd seru m, bronc ho alveolar l avage f lui d an d lymp h

no des were c ollecte d fo r t ot al IgE, c ell c ou nts a nd cytokine pr of iling; t he

rem aining mic e were exp ose d fo r a ddi tion al 2 weeks a nd reass essed

Re liabi lit y : (4) no t assigna ble

Abs tract

2 2. 12. 20 05 (83)

Ty pe : ot her

Sp ec ies : mo us e

Number of

a nim als :

V ehi cle :

106

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

Re sult :

Cl ass ification :

Method : ot her: s ee T es t Co nditio n

Year : 20 02

GL P : no da ta

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : ind uctio n of cytokines which are charac teristic of a T h2 T c ell r espo nse

T est condition : Previous st udies h ave sh own t ha t RNA me ssage l evels f or th e Th 2T cell

cytokines I L4 , IL 10 an d I L 13 ar e elevate d in respo nse to r espiratory

se nsitizer trimellitic an hydride a nd th ese incr eases may be d et ecte d by

ribon ucleas e pr otecti on a ssay (RPA).

Fe male BA LB/c m ice were t opically expos ed t o t he tes t ma terial a nd to tal

mRNA was isolat ed fr om draini ng lymp h no des 14 days po st c hallenge.

Re liabi lit y : (4) no t assigna ble

Abs tract

2 2. 12. 20 05 (80)

Ty pe : ot her

Sp ec ies : guine a pig

Number of

a nim als : 6

V ehi cle :

Re sult :

Cl ass ification :

Method : ot her: s ee T es t Co nditit on

Year : 19 71

GL P : no

T est sub stance : ot her T S: Hylene W

, no d at a on purity

Re sult : 1/ 6 elicite d se nsitization res pons e, n o cr oss- s ensitization with TD I an d MDI

(polymer)

T est condition : Ani mals were expose d t o t he a eros ol mist (0.2 2 p pm x 4 ho us x 3 d ays),

fo llowing a on e- week res t peri od, t he ani mals were ch allenged via t he ski n

rout e (0. 5% a nd 0. 1% Hylene W in 1 3% guinea pig f at in a 1: 1 sol ution of

ac eto ne a nd dioxan e)

Re liabi lit y : (3) invalid

Unsuit able test system

2 9. 10. 20 04 (48)

5 .4 RE PE AT ED DOS E TOX ICITY

Ty pe : Su b-acu te

Sp ec ies : rat

S ex : ma le/ fe ma le

Str ain : W i s ta r

Route of adm in. : inh alatio n: a eros ol

E xposur e per iod : 5 d ays

Fr equency of treatm. : 6 h /d ay o n 5 co nsec utive d ays

Po st ex posure period : 2 d ays

Dos es : 0, 1, 6, 3 6 mg/m3 (t arget co ncen tratio n)

- 1 .7 , 5 .8 6, 3 4. 18 mg /m3 (act ual

co ncen tratio n)

Control group : ot her: c on dition ed air

Method : ot her: p ilot d ose-ra nge fi ndi ng s tudy acc ording O ECD Gui de-line 4 12

Year : 20 02

GL P : yes

T est sub stance : ot her T S: Des mo dur W

, purity 99 .3%

Rem ark : pilot dos e- r ange f in ding stu dy (m ain st udy: Bayer Mat erialScienc e AG ;

107

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

Rep ort No. AT 01 05 7 (2 00 4))

Re sult : Mortality: n on e

Rats exp osed to 1 a nd 6 m g/m 3 di d no t el ab orate any tes t su bsta nceind uce d clinical signs, ne urological e ff ec ts , c hanges i n rect al te mp erat ures

or ch anges o n b ody

weights. Ra ts expos ed t o 3 6 mg /m 3 an d a bove exp erience d a mild a nd

transi ent decre ase in bo dy weights an d signs o f respira tory tract irritation

(salivation, br adypne a, strid or).

At 36 mg/m 3 t he lung (m=1 2%;f =1 4%) an d h eart (m=17% ; f= 3%) weights

were signi fican tly increas ed.

Gross n ecro psy fi ndi ngs (less collaps ed l ungs with re d fo ci an d re d

secreti ons in th e n ose) were ob served only at t his expos ure level.

T est condition : TE ST OR GANISMS

- Age: 2 mo nt h

- Num ber o f

a nim als: 5 /d ose/s ex

ADMINIS TRA TION / EXPO SURE

- Type of exposure : no se-only exposure

- Particle size: MMAD range: 0. 94 7- 1 .0 2μ m (geo metric s ta ndard

deviatio n: a pprox. 2)

CLINICA L OB SERV AT IONS AND FRE QUENCY:

- Clinical signs: twice da ily (exposure d ays)

- Mortality: twice daily

- Bo dy weight: days 0, 4, 7

- Rectal T em pe ra ture: days 0 a nd 4

ORGANS EXAMINED AT NECROP SY (MACROSCOP IC AND

MICROSCOPIC):

- Gross P at hology

- Organ W e ig ht s: Br ain, H eart, K idn eys, Liver, L ungs,

S ple en,

- Microscopic: n on e

ST AT IS TI CAL METH ODS: Du nn ett T es t, A djus ted W e l ch T es t, Kr uskalW a l li s T es t

Conclu sion : Au th or c onclu de d: T aki ng a ll fi ndi ngs in to a cco unt 6 mg/ m3 co nstitu tes a

no-o bserved a dverse ef f ec t-level.

Re liabi lit y : (2) valid with restrictions

A pil ot d ose-ra nge fi ndi ng s tudy

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 4. 01. 20 05 (33)

Ty pe : Su b-acu te

Sp ec ies : rat

S ex : ma le/ fe ma le

Str ain : W i s ta r

Route of adm in. : inh alatio n: a eros ol

E xposur e per iod : 4 weeks

Fr equency of treatm. : 6 h ours per d ay (5 days/week)

Po st ex posure period : no ne

Dos es : 0, 1, 6, 3 6 mg/m3 (t arget co ncen tratio n); 1. 06 , 6. 02 , 33 .8 mg/m3 ( actu al

co ncen tratio n)

Control group : ot her: c on dition ed air

NOA EL : = 1 mg/ m3

Method : OECD G uide-line 41 2 "R ep eat ed Dos e I nh alatio n Toxicity: 2 8-day or 1 4-

day St udy"

Year : 20 03

GL P : yes

T est sub stance : ot her T S: Des mo dur W

, purity 99 .3%

108

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

Re sult : Mortality: n on e

Clinical signs:

Grou p 1 an d 2 (con trols an d 1 mg/ m3):

all rats t olera ted th e expos ures without any clinical signs.

Grou p 3 (6 mg/ m3): 7/ 10 m al e an d 7 /1 0 f em al e a nim als with signs a ft er

exposure ; e.g. nas al disch arge (mos t rats rec overed d uring t he exposurefr ee weeken ds).

Grou p 4 (36 mg/m 3):

Bra dypnea, lab ored b rea thing pa tt erns, irregular bre athing p att erns, s tridor,

tac hypnea , na sal disc harge, n ostrils: red en crusta tions.

A ge nder-sp ecific susce ptibility co uld n ot be ascert aine d. Mos t signs

suggestive o f

respira tory tract irritation were ob served fr om t he s eco nd

exposure week onwards.

Nasal disc harge a nd redd en ed n ostrils were o bs erved t hro ughout th e st udy

perio d.

Rect al te mp eratur e:

In co mp arison t o th e c ontrol grou p, t here th e b ody (rectal) te mp erat ures of

rats o f t he 36 mg/m 3 grou p were m ildly, al tho ugh signific antly d ecre ase d

on days 0 (bot h sexes) an d 2 1 ( males).

Bo dy weights:

no toxicologically c onsiste nt e f fe ct o n b ody weights up t o an d i ncluding t he

36 mg/ m3 grou p.

1 mg /m 3:

no signific ant d if

fe re nt bo dy weights c om pare d to co ntrol a nim als (except

an increas e o n d ay 1 4 i n fe ma le s)

6 mg /m 3:

significa nt i ncrease on days 4, 11 , 1 4, 1 8, 21 , 2 5, 2 8 in fe ma le s,

36 mg/ m3:

no signific ant d if

fe re nt bo dy weights c om pare d to co ntrol a nim als (except

an increas e o n d ay 1 1 i n fe ma le s)

Hem at ology a nd Clinical Pa th ology:

no ef f ec ts consi dere d to be of pa th odiagnos tic relevance

Op hth alm ology: no ch anges

Gross P at hology:

Abs olut e Organ W e ig ht s:

1 mg /m 3:

ma le: n o cha nges

fe ma le : el evated s plee n a nd thymus wei ghts

6 mg /m 3:

ma le: n o cha nges

fe ma le : el evated s plee n a nd liver weights

36 mg/ m3:

ma le: n o cha nges

fe ma le : el evated l ung weights (ap prox. 1 2%)

Relative Organ W e ig ht s (vs. b ody weights):

1 mg /m 3:

ma le: n o cha nges

fe ma le : d ecreas ed brain a nd kid ney weights

6 mg /m 3:

ma le: n o cha nges

109

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

5. TOXICITY I D: 5124-30-1

DATE: 09.11.2006

fe ma le : d ecreas ed brain weights

36 mg/ m3:

ma le: e levate d lung weights (a pprox. 12 %)

fe ma le : el evated l ung weights (ap prox. 1 2%) a nd de creas ed liver weights

Relative Organ W e ig ht s (vs. br ain weights):

1 mg /m 3:

ma le: n o cha nges

fe ma le : el evated s plee n a nd thymus wei ghts

6 mg /m 3:

ma le: n o cha nges

fe ma le : el evated s plee n weights

36 mg/ m3:

ma le: n o cha nges

fe ma le : el evated l ung weights (ap prox. 1 2%)

During n ecro psy, n o f in dings were s ee n which have t o be ass esse d as

trea tm ent-rela ted

.

Histop ath ological fi ndi ngs:

NASA L CA VITY:

In th e an terior level of th e n asal c avit y (nas al loca tion 1) squa mo us

epi thelial m et apl asia occ urred in all high c once ntrati on (3 6 mg/ m3) m al es

an d f em al es, in m ost rats t ogeth er with m uc us an d/ or cells in lu me n (1 0/1 0

ma les; 8 /1 0 f em al es), with inf la mm at ory inf iltrat es (8/ 10 m ales , 7/ 10

fe ma le s) an d so me ma les (3 /10) i n co mbin atio n with f oc al e pit helial

ne crosis.In th ese a nim als, in th e na sal loc atio ns 2 to 4 (p osterior level)

epi thelial c ha nges were d et ecta ble in som e ra ts (m ax. 2-4 ani mals per s ex)

indica ting beginni ng m et apl asia.

In mid do se (6 mg/m 3) ani mals epit helial c hanges were on ly se en in th e

an terior level of

t he na sal cavity in s om e rats ( 3/1 0 ma les, 3/ 10 f em al es).

In low do se (1 mg/m 3) an im als no epi thelial c ha nges were s een in t he

na sal cavity.

PHARYNX:

In th e ph arynx, epi thelial m et apl asia o ccurred i n alm ost all high

co ncen tratio n (36 mg/m 3) ma les (9 /1 0) a nd fe ma le s (9/ 10) a nd in o nly on e

mi d co ncen tratio n ma le.

LARYNX

In th e larynx, all te st su bst ance expose d an im als showed e pit helial

me ta plasia ( 30/ 30 m al es an d 3 0/ 30 f em al es) t ogeth er with incre ase d

inf la mm at ory inf iltrat es. Foc al inf la mm at ory inf iltrat es were a lso d et ecta ble

in c ontrol a nim als.

Focal i nf la mm atory i nf iltrates :

co ntrols:

10 /1 0 ma les with grade 1 ; 9 /1 0 f em al es with grade 1

1 mg /m 3:

2/ 10 m al es with grad e 1 an d 8 /1 0 ma les with grade 2 ;

5/ 10 f em al es with grade 1 a nd 5/ 10 fe ma les with grade 2

6 mg /m 3:

10 /1 0 ma les with grade 2 ; 1 0/ 10 f em al es with grade 2

36 mg/ m3:

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10 /1 0 ma les with grade 2 ; 1 0/ 10 f em al es with grade 2

Epit helial m et apl asia:

co ntrols:

0/ 10 m al es an d 0 /1 0 f em al es

1 mg /m 3:

10 /1 0 ma les with grade 2

2/ 10 f em al es with grade 1 a nd 8/ 10 fe ma les with grade 2

6 mg /m 3:

5/ 10 m al es with grad e 3 an d 5 /1 0 ma les with grade 4

5/ 10 f em al es with grade 3 a nd 5/ 10 fe ma les with grade 4

36 mg/ m3:

3/ 10 m al es with grad e 3 an d 7 /1 0 ma les with grade 4

1/ 10 f em al es with grade 3 a nd 9/ 10 fe ma les with grade 4

TR ACHEA:

In th e trac he a, e pith elial cha nges in dicating begin ning e pit helial m et aplasi a

were s een in a bo ut h alf o f t he high co nce ntratio n (36 mg/ m3) m ales (6/1 0)

an d f em al es (5 /1 0) a nd in e ac h on e l ow an d mi d c once ntrati on m ale

, resp ectivel y.

LUNG:

In th e lu ngs, i nf la mm atory l esions i n th e br onchi olo- a lveolar region

occ urred in t he ma

jority of high co nce ntratio n m ales (8/1 0) an d f em al es (9/1 0). T he se i nf la mm atory l esions c onsist ed o f a n incr ease d cellul arity i n

th e t ermin al bro nchioles an d alveolar d ucts with mo re alveolar

ma crop hages a nd a f oc ally incre ase d se ptal t hicke ning.

Furth erm ore, in traalveolar ma crop hages, m ai nly enl arged an d with a f oa my

cytoplasm , were obvious in alm ost a ll high co nce ntratio n rats (10/ 10 m al es,

9/ 10 f em al es) a nd in s om e an im als fr om th e o th er groups (6 mg/m 3: 4 /1 0

ma les, 3 /1 0 f em al es; 1 mg /m 3: 2 /1 0 in b ot h s exes; c on trol ani mals: 0/ 10

ma les, 1 /1 0 f em al es)).

Com para ble t o t he epit helial c hanges i n th e u pp er airwa ys, si milar lesions

indica ting beginni ng m et apl asia occ urred in th e bro nchi (3 6 mg/ m3 : 10 /1 0

ma les, 9 /1 0 f em al es; 6 mg /m 3: 5 /1 0 ma les, 4/ 10 f em al es ; 1 mg/m 3 a nd

co ntrol ani mals of

b ot h s exes: no cha nges), pre do mina ntly a t t he m ai n

airwa y bi furc atio ns.

In th e ot her orga ns/tissu es evalua te d, n o f in dings co uld b e d et ecte d which

have t o b e a ssesse d a s tre atm en t relat ed. All th e o th er f in dings were

kn own fr om c ontrols o f

pr evious stu dies t o b e o f sp on tan eo us na ture

. T est condition : TE ST OR GANISMS

- Age: 2 mo nt h

- Num ber o f

a nim als: 1 0/ dose /sex

ADMINIS TRA TION / EXPO SURE

- Type of exposure : dyna mic direct ed-fl ow n ose-o nly expos ure

- Doses:

me an ac tual a nalytical co ncen tratio ns of 1. 05 7, 6 .0 22, 33 .8 3 mg/ m3;

no min al co ncen tratio n of 4. 8, 1 9. 8 a nd 11 8. 9 mg/ m3

- Particle size: MMAD range: 1. 0- 1 .2 μm (geom etric sta nd ard deviatio n

ap prox. 2); highly res pirable t o ra ts

CLINICA L OB SERV AT IONS AND FRE QUENCY:

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- Clinical signs: twice da ily (exposure d ays)

- Mortality: twice daily

- Bo dy weight: twice weekly

- Rectal T em pe ra ture: days 0 a nd 21

- Ref lexes: d ays 3 an d 2 1

- Op hth alm oscopic exa min ation : prior t he f irst exposure

, towards th e e nd

of th e expos ure peri od

CLINICA L PA THO LOGY at th e e nd of stu dy

- Hae ma tology

- Bioc hemis try

- Urinalysis

ORGANS EXAMINED AT NECROP SY (MACROSCOP IC AND

MICROSCOPIC):

- Gross P at hology:

Fixed o rgans: A dre nals, a orta , brai n (cerebru m, cere bellum , p onsl me dulla),

epi didymides, eso ph agus, eyes, eyelids, extraorbital lac hrymal glands,

fe mu r, har derian glan ds, h ea d (with n as al an d p aran asal c avities), h eart,

int estine (du ode nu m, j ejun um, ileu m, c ecu m, c olon, rectu m a nd rem aining

int estine), kidn eys, larynx, liver, lymph n od es ( man dibul ar, bro nchial/ hilus,

an d m es ent eric), l ung, ma mm a, o ptical n erves, ovaries, oviducts

, pa ncreas , ph arynx, pit uitary, pr osta te, salivar y glands, sciatic n erve,

se minal vesicles (incl. co agulating glands), skelet al mu scle (t high), ski n (ma mm ary a nd muzzle), spi nal cor d (cervical, th oracic, l u,m bar), s plee n,

stern um , st om ach ( for est om ach a nd gland ular sto mac h), t estes , thym us, thyroids (including p arat hyroid glan ds), to ngue, trach ea, uret er, ur ethra

, urinary bl ad der, u terus with u terine cervix

, vagina, Zymbal’s glan ds an d all

organs or tissues with m acrosc opic f in dings.

Organ W e ig ht s: A dre nals, br ain, he art, kid neys, Liver, L ungs, Ovaries,

Spl een , Te st es, T hym us

- Microscopic: Fro m t he r espiratory tr act (n asal c avit y, p harynx, larynx,

trach ea , lungs a nd lung ass ociate d lymph no des) slid es fr om all a nim als

were evalu ate d. Fro m t he o th er organs/ tissues assigned fo r

hist opa thol ogical

evaluati on, slid es were prep ared fr om th e f irst f ive a nim als of all groups

an d evalu ate d fr om t he con trol an d t he high co ncen tratio n group.

ST AT IS TI CAL METH ODS: Du nn ett T es t, A djus ted W e l ch T es t, Kr uskalW a l li s T es t

Conclu sion : Th e tes t su bsta nce was tol erate d without any systemic a dverse ef f ec ts a t

all expos ure levels ( 1, 6 , 36 mg/ m3). At 3 6 mg/m 3, evide nce of r espiratory

irritation existe d which a lso o ccurred a t 6 mg/ m3 in b orderline int ensity.

W i t h regard t o his top ath ological cha nges, all c ha nges ob served were

relat ed t o p ortal-of -e ntry, l ocal irritant e f fe ct s (n asal p assages, laryn x,

airwa ys an d a lveoli), i. e, ch anges t ha t occ urred a t a na to mical struct ures, t o

so me ext ent r at sp ecif ic, f avoring fo ca l de positi on o f irritant partic ulates . No

ch anges o f

pa th odiagn ostic relevant e occ urred a t 1 mg/ m3, except t he

laryngeal f in dings. T he laryngeal squam ous epit helial m et apl asia is

co nsidere d to be a rath er rat-speci fic r espo nse. In th e rat , th e layout of th e

up per res piratory str uctures is ta nde m s uch t ha t t he a ir c ould travel i n

ne arly linear f as hi on f ro m t he no se t o t he bif urca tion of t he trac hea . Th e

linear arr angem en t of th e u pp er airwa ys allows t he laryn x o f rats to lie

close to t he po sterior e dge of th e or al an d n asal c avities. In t he co nditio n,

th e e piglottis lies agains t th e s of t p ala te. T he a pp ositio n of th e e piglottis to

th e so ft p alat e in th e resting co nditio n isola tes t he oral c avit y fr om t he

respirat ory airwa ys an d m ak es t he r at a n o bligatory no se br ea ther (virtuall y

no oro ph aryn x). Th us , t he d irection of fl ow in r ats is al mos t line ar where as

in h um ans it is rect angular ( for m ore de tails se e De Sesso , Qu ality

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ass urance Go od Pr actice , Regulatio n, a nd Law 2, 21 3- 2 31 ,1 99 3). Ap art

fr om th ese do sime tric issu es a co ncen tratio n de pe nd ent increas e in t he

extent of cell inf iltratio n in th e larynx, as in direct evide nce o f loc al irritation,

did no t occ ur. Th er ef ore , th e m et apl astic ch anges o bserved a t t his loca tion

are c onsid ered to be caus ally relat ed t o a da ptive ( dif fe re ntiati on o f

c ells t o

be com e m ore resista nt) rat her th an adverse e f fe ct s.

Ta king all f in dings int o acc oun t, 1 mg/ m3 cons titut es a no-o bservedadverse-ef

f ec t-level (NOAEL) f or

ef f ec ts governed by respirat ory tract

irritation.

Re liabi lit y : (1) valid withou t restriction

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 4. 01. 20 05 (34)

Ty pe : Su b-acu te

Sp ec ies : rat

S ex : ma le/ fe ma le

Str ain : W i s ta r

Route of adm in. : inh alatio n: a eros ol

E xposur e per iod : two weeks b ef or e m ati ng u ntil d ay 1 9 o f gest ation

Fr equency of treatm. : 7 x 6 h ours/week

Po st ex posure period : 4-6 d ays (f em ales)

Dos es : 0, 1, 6, 3 6 mg/m3 (t arget co ncen tratio n)

Control group : ot her: c on dition ed air

Method : ot her: s ee T es t Co nditio n

Year : 20 04

GL P : yes

T est sub stance : ot her T S: purity 99 .5%

Rem ark : For th e res ults o n Re prod uction /Developm en tal T oxicity s ee c ha pter 5 .8 .3

Re sult : MORT ALI TY:

<= 6 mg/ m3: no de at hs

36 mg/ m3: 2/ 24 d ea ths ; on e m al e was f ou nd d ea d d uring pre ma ting p eriod

an d o ne fe ma le ha s to be killed in mori bun d c onditi on.

CLINICA L SI GNS:

at 6 mg /m 3: s erous n as al disch arge; nos trils with red e ncrust atio n

at 36 mg/ m3 br ea thing sympt oms a nd /or s erous n as al disc harge an d

no strils with red e ncrus tatio n

BODY W E I G HT :

at 36 mg/ m3 b ody weight ret arda tion i n bo th sexes

FOOD CONSUMP TION:

at 36 mg/ m3 tr ansie nt re ducti on in mal es

ORGAN W E I GH T:

at 36 mg/ m3 i ncrease d lu ng (a bsolu te/rel ative) weights in ma les

(14% /18%).

T est condition : Accor ding t o O ECD Guid eline N o. 4 21

ADMINIS TRA TION/ EXPOSURE:

Type of exposure : no se-only exposure

An alytical co nce ntratio ns: 0 .0 01 06, 0. 00 595 , 0. 03 40 4 mg/l

Nomi nal c once ntrati ons: 0 .0 05 , 0. 02 0, 0 .1 19 m g/l

Particle size: m ass me dia n aer odyna mic dia me ter: a ppr ox 1 u m (geom etric

sta nd ard deviatio n: a ppr ox. 2)

Re liabi lit y : (2) valid with restrictions

A s tudy accor ding t o O ECD TG 4 21 primarily exami nes t he ef fe ct s o n

repro ducti on a nd develo pm ent

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (35)

Ty pe : Su b-acu te

113

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Sp ec ies : rat

S ex : no da ta

Str ain : no da ta

Route of adm in. : inh alatio n

E xposur e per iod : 4 h ours /day

Fr equency of treatm. : 5 d ays/week d uring 2 weeks

Po st ex posure period : no da ta

Dos es : 12 0 mg /l an d 4 0 mg/ m3

Control group : ot her: n o d at a

Method : ot her: n o d at a

Year :

GL P : no da ta

T est sub stance : no da ta

Re sult : Clinical signs o f m arke d res piratory irritation an d

de crease d growth ra tes were ob served in ra ts expose d t o 1 20 mg/m 3. A t

40 mg/ m3 o nly a n i nitial weight loss was ob served

Re liabi lit y : (4) no t assigna ble

Onyl a n a bs tract available

1 4. 01. 20 05 (61)

5 .5 G ENETIC TO XICITY ‘ IN VITRO ‘

Ty pe : Bac terial gen e mu ta tion ass ay System of testing : S. typhimuriu m T A 15 35 , TA 1 53 7, TA 9 8, TA 1 00 , T A 10 2

T est con centration : up to 50 μg/pla te

Cy cotoxic conc entr. : 1. 6 μg/ plate

Metabol ic a ctivation : with a nd without

Re sult : nega tive

Method : OECD G uide-line 47 1

Year : 20 05

GL P : yes

T est sub stance : ot her T S: Des mo dur W ; purity 99 .5%

Rem ark : Ap propriat e re fe renc e m ut agens (so dium azid, nitro fu ra ntoin , 4-nit o-1, 2-

ph enylene dia mine , mi to mycin C, c um en e hydrop eroxide an d 2-

am ino ant hrace ne) were use d a s po sitive co ntrols a nd sh owed t he

expect ed res ults.

Re sult : GENO TOXIC EFF ECT S:

Evidence of mu tage nic activity was no t se en . No bi ologically rel evant

increas e in t he mu ta nt c ou nt, i n co mp arison with th e n egative c ontr ols, was

ob served.

CYTOT OXIC CONCENTRA TI ON:

Doses up to an d inclu ding 0. 5 μg/pl ate did n ot ca use a ny b act eriotoxic

ef f ec ts . To ta l ba cteria c ou nts re main ed unc ha nged a nd no inhibiti on in

gro wth was o bs erved. At h igher do ses, t he su bsta nce h ad a strain-sp ecific

ba cteriot oxic ef

f ec t. Nevertheless this ra nge co uld p artially be us ed u p t o

50 μg/pla te f or

ass essm en t pur pos es.

T est condition : SYST EM OF T ES TI NG:

1. experime nt: Plat e inc orporati on a ssay

2. experime nt (= ind ep end en t rep eat): preinc uba tion test

Meta bolic ac tivation system : S9 liver micros om al fr actio n o f ma le S pragu e

Dawle y rats which rec eived a single i. p. injec tion of Ar oclor 12 54

ADMINIS TRA TION:

co ncen tratio n tes te d:

114

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1. an d 2 . experim ent

without S 9 m ix:0.05 , 0. 16 , 0. 5, 1 .6 , 5 .0, 16 .0 μg/ plat e

with S 9 m ix: 0 .1 6, 0 .5, 1. 6, 5 .0 , 16 .0 , 50 μg/pl ate

SO LVEN T:

et hylene glycol dim et hylether (EDGE) fo r th e te st su bst ance an d t he

po sitive co ntrols

dei onized water fo r m ito mycin C

Re liabi lit y : (1) valid withou t restriction

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (38)

Ty pe : Am es t est

System of testing : S. typhimuriu m T A 15 35 , TA 1 53 7, TA 1 53 6, T A 98 , T A 10 0

T est con centration : up to 25 0 ug/ plat e Cy cotoxic conc entr. : Pret est res ults ar e no t re porte d

Metabol ic a ctivation : with a nd without

Re sult : nega tive

Method : ot her: s ee T es t Co nditio n

Year : 19 77

GL P : no

T est sub stance : ot her T S: 4, 4 ́- Me thylenedicyclohexy l diis ocyanate , no d at a on purity

Re sult : GENO TOXIC EFF ECT S:

- without m et ab olic a ctivation: no significa nt i ncrease of revertants i n any strain (in dividual t est results s peci fie d)

- with m et ab olic a ctivation: no significa nt incr ease of revertants in any strain (in dividual t est results s peci fie d)

PRECIP IT AT ION CONCEN TRAT ION: no da ta

CYTOT OXIC CONCENTRA TI ON: "Pri or to t esti ng f or mu tage nicity, t he

co mp oun d was test ed fo r t oxicit y to th e t ester s trains. " (no f ur th er

inf or ma tion availa ble)

T est condition : SYST EM OF T ES TI NG:

Plat e inc orpora tion a ssay

Meta bolic ac tivation system : S9 liver micros om al fr actio n o f rats

On e experim ent with o ne tes t pla te (n o re plicates)

ADMINIS TRA TION:

co ncen tratio ns tes te d:

without S 9 m ix: 0 .1, 0. 2, 0 .4 , 0. 6, 0 .8 an d 1 ug/pl ate ;

with S 9 m ix: 5 0, 1 00 , 1 50 , 20 0 a nd 25 0 ug/ plat e;

SO LVEN T: ace ton

- Positive an d n egative con trol groups a nd tre atm en t

nega tive co ntrol: s olvent

po sitive co ntrol: withou t me ta bolic a ctivation

TA 15 35 , T A1 00 : N-Methyl- N- ni tro- N-nitros oguanidi ne

TA 15 37 : 9-A min oacridin e

TA 15 38 , T A9 8: 2-Nitrof luor ene

with m et ab olic a ctivation

fo r T A1 00 : 2-A mi noa nthr acen e (5 ug/ plat e)

TA 98 , T A1 53 8, TA 15 35 : 2-A min oa nthrac en e (10 ug/pla te

TA 15 37 : 2-A min oa nthrac en e (10 0 ug/ plate)

Re liabi lit y : (2) valid with restrictions

Th e tes t de sign do es n ot c om ply with t he current guideline with regard t o

th e n um ber a nd kind of ap plied s trains; n o i nde pe nd end rep eat exp erime nt

was p erf orm ed , limit ed d ocu me na tion (i. e. n o d at a on S9-m ix pr epara tion

,

no de tails o f

th e pr etes t on t oxicit y to th e te ster str ains)

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 12. 20 05 (53)

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Ty pe : Chrom oso mal ab erration tes t

System of testing : Chines e Ha mst er V7 9 Cells

T est con centration : 1. 5, 3 , 4 .5 , 6, 8 a nd 7. 5 μg/ ml without S 9 m ix a nd 6, 12 , 20 , 2 4 a nd 28

μg/ml with S9 mix (see als o f re et ext T C)

Cy cotoxic conc entr. : 4. 5 μg/ ml without S 9 m ix an d 1 2 μg/ml with S9 mix (se e als o fr ee text RS)

Metabol ic a ctivation : with a nd without

Re sult : nega tive

Method : OECD G uide-line 47 3

Year : 20 04

GL P : yes

T est sub stance : ot her T S: Des mo dur W

, no d at a on purity

Rem ark : Th e po sitive co ntrols m ito mycin C a nd cyclophos pha mid e in duce d

clast ogenic ef

f ec ts an d d em ons trate d t he s ensitivity o f t he test system a nd

th e ac tivit y of th e us ed S 9 m ix.

Re sult : W i t h ou t S 9 mix cytotoxic e ff ec ts were o bs erved a t 4 .5 μg/ml a nd ab ove

af te r 4 ho urs tre atm en t an d a t 8 μg/ml an d a bove a ft er 1 8 h ours trea tm ent

. W i t h S9 mix cytotoxic ef f ec ts

were o bserved a t 1 2 μg/ ml an d a bove. Precipit ation in t he m ed iu m was n ot

ob served.

Th er ef ore , co ncen tratio ns of 4. 5, 6 a nd 7. 5 μg/ml tes t su bsta nce (4 ho urs

trea tm ent) a nd 2. 5, 5 a nd 8 μg/ ml (1 8 ho urs tre atm en t) were c hose n f or

rea ding i n th e a bse nce of S 9

mix. In th e pres enc e of S9 mix 6 , 1 2 a nd 20 μg/ ml of tes t su bsta nce were

em ployed. All of th ese c ultures harveste d 18 ho urs a ft er t he begin ning o f

th e tre at me nt were includ ed. In ad dition , cult ures tre ate d in th e ab se nce o f

S9 mix with 7. 5 μg/ ml an d h arvested 30 ho urs af te r t he b eginning o f

t he

trea tm ent were u sed . Th e sa me was tru e f or cult ures tre ate d in t he

pres ence of S9 mix with 20 μg/ml

. Non e of th e c ultures tr eat ed with te st su bst ance in t he a bs ence an d in th e

pres ence of S9 mix s howed bi ologicall y relevant or st atistically signific ant

increas ed n um bers of ab errant me ta ph ases.

T est condition : MET AB OLIC AC TI VA TI ON:

S9 mix - f ro m liver

h om oge nat es of

with Ar oclor 12 54 ind uced ma le

Sp argue Dawley ra ts. T he S 9 m ix co ntai ned 40 % S9 fr acti on.

CONTRO LS:

Ve hicle: DMSO

po sitive co ntrols: m ito mycin C (0.1 an d 0 .0 3 μg/ml); cycloph osp ha mide (2

μg/ml)

Initi ally Chi nese ha mst er V7 9 c ells were expos ed in th e ab se nce o f S 9 m ix

fo r 4 ho urs t o co nce ntratio ns o f 1 .5, 3, 4. 5, 8 an d 7 .5 μg/ml o f t est

su bsta nce. Cultures o f

a ll conc entr ations were h arvested 1 8 h ours af te r th e

begin ning o f

t he trea tm ent . In ad ditio n, c ells tr eat ed with 4. 5, 6 a nd 7. 5

μg/ml were harvest ed 3 0 h ours a ft er th e b eginning

of th e tre atm en t. I n t he p rese nce o f S 9 m ix cells were expose d f or to

co ncen tratio ns of 6, 12 , 20 , 2 4 a nd 28 μg/ ml of tes t su bsta nce. Cultures of

all co nce ntratio ns were h arvested 18 ho urs af te r t he beginni ng o f

t he

trea tm ent . In ad ditio n, c ells tr eat ed with 20 , 2 4 a nd 28 μg/ml were

harveste d 30 h ours a ft er t he begin ning o f t he trea tm ent . W i t h ou t S 9 m ix an

ad ditio nal experim ent was p erf orm ed using co ntin uous trea tm ent fo r 1 8

ho urs, h arvest at t he sa me tim e, a nd tes t su bsta nce-co ncen tratio ns of 2. 5,

5, 8, 1O a nd 12 μg/ ml.

Bas ed on th eir

cytot oxicit y, which was als o de ter mine d 8 ho urs af te r th e

begin ning o f

t he trea tm ent , co nce ntratio ns were s elect ed f or rea ding of

me ta ph ases. 10 0 m et ap has es were sc ored fo r struc tural c hrom oso me

ab erratio ns.

Conclu sion : Bas ed on this t est, th e t est s ubst anc e is co nsidere d no t t o b e clas togenic

fo r m am ma lian cells in vitro.

Re liabi lit y : (1) valid withou t restriction

Gui deline St udy

116

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1 3. 01. 20 05 (36)

5 .6 G ENETIC TO XICITY ‘ IN VI VO‘

5 .7 CA RC INOGENICITY

5 .8 .1 TO XICITY T O FERTILITY

5 .8 .2 DE VELOPMENTA L TO XICITY/TER AT OGENICITY

Sp ec ies : rat

S ex : fe ma le

Str ain : W i s ta r

Route of adm in. : ot her: n os e only inh alatio n: a eros ol

E xposur e per iod : 6 h ours

Fr equency of treatm. : daily

Duration of te st : fr om day 6 up to day 19 p. c.

Dos es : 0, 1, 6, 3 6 mg/m3 (t arget co ncen tratio n)

Control group : ot her: c on dition ed air

NOA EL m aterna l tox. : = 1 mg/ m3

NOA EL t eratogen. : = 6 mg/ m3

Method : OECD G uide-line 41 4 " Te rat ogenicity"

Year : 20 03

GL P : yes

T est sub stance : ot her T S: Des mo dur W

, purity 99 .5%

Re sult : MAT ERNAL D AT A:

Ap pe aranc e, b eh avior, a nd mor tality o f th e f em al es were un af f ec te d a t t he

1 mg /m 3 level, while incre ase d or d ecre ased respirat ory rates , lab ored

bre athing, irregular

respiratio n, a nd so un ds co nsisten t with rhi nitis occurre d ea ch b ef or e a nd

af te r in halati on a t t he 3 6 mg/m 3 level. Furt herm ore, r ough f ur , pilo erectio n (on e fe ma le

,

on e d ay o nly), ser ous n asal d ischarge, a nd red dish e ncrust ed nos trils e ach

be fo re an d a ft er in hala tion , an d re ddish encr uste d no se (o ne fe ma le , on e day only) o ccurred in th e 3 6 mg /m 3 group

. La bore d br eat hing af

te r inh alatio n, pil oerecti on b ef or e a nd af te r inh alatio n,

pal en ess be fo re an d a ft er i nhal ation an d a nd red dish en crust ed n ostrils

af te r in halati on o ccurred i n single fe ma le s a t th e 6 mg/ m3 level; s everal

fe ma le s ha d s erous nas al disch arge be fo re (9 fe ma le s) an d a ft er in hala tion

(17 f em al es) a t t his do se l evel.

Decreas ed f ee d in take (days 6 -9 p .c.: ap prox. 2 2% ; days 9-1 2 p .c.: ap prox. 8%), s tatistically signi fican t tra nsient bo dy weight l oss (ap prox. 5 %) af te r

start of tr eat me nt ( days 6-7 p. c.), res ulting i n a d ecre ase d bo dy weight gain

during t he tr eat me nt p eriod (days 6 -19 p.c ., a pprox. 24 %) an d d uring

gestati on (d ays 0-2 0 p .c., ap prox. 1 5%) o ccurred at t he 36 mg/ m3 level.

Mea n correct ed b ody weight gain was also marginally d ecreas ed (appr ox.

14 %) at t his d ose level.

No tre at me nt rela ted gross p at hol ogical f in dings occ urred a t levels up to

an d incl uding 36 mg/ m3

.

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Th e gestati on ra te, ap pe aranc e of plac ent as, pl ace ntal weights,

po stim plant atio n loss, nu mb er of live fe tu se s, f et al sex dis tributio n, a nd

fe ta l weights were un af f ec te d by tre atm en t with t he tes t ma terial u p to a nd

includi ng t he dos e level of 36 mg/ m3.

GENERA L RE PRODUCTION DA TA

Th e me an nu mb er o f

im plan tati on sit es were l ower at 36 mg/m 3, an d a

slight increas ed pr eim plant atio n loss o ccure d in t his group , whereas t he

me an nu mb er o f

cor poralut ea did n ot dif fe r to me ani ngf ul exten t, in dicating

a h om oge neo us distrib utio n regarding this p ara me ter. T he values i n th e 3 6

mg/ m3 d os e group were co mp arabl e to th e n orm al range o f sc attering fo r

th e rat strain u se d, a nd sta tistical significa nce was no t evide nt f or th ese

fi ndi ngs, so t ha t tre atm en t relat ed u no bs erved e arly po stim plan tatio n loss

(which would no t b e d et ect able by st aining th e u terus, an d would a pp ear a s

prei mpla nta tion l oss) is u nlikely.

Dose mg/m 3: 0/ 1/ 6/ 3 6

Fe males with im plan tatio ns in % of th ose inse mina ted : - 7 7. 8 / 96 .3/ 74 .1 /

71 .9

me an values p er fe ma le with i mpla nt ation sites

- corp ora lut ea: 15 .0 / 14 .4 / 1 4. 1 / 1 4. 7

- prei mpla ntati on loss : 1. 8 / 1. 4 / 1. 7 / 2 .8

- impl ant atio ns: 1 3. 2 / 1 3. 0 / 12 .4 / 11 .8

FET AL DAT A

Dose mg/m 3: 0/ 1/ 6/ 3 6

Mea ns per fe ma le

- pos t im plan tatio n loss : 0. 7 / 0. 8 / 1 .3 / 1 .0

- Num ber o f

live f et us es: 12 .6 / 12 .2 / 1 1. 2 / 1 0. 8

- fe ta l weights g: 3 .5 1 / 3 .5 3 / 3. 40 / 3. 55

- sex o f live f et us es (% m al es): 55 .3 / 5 1. 8 / 5 0. 5 / 51 .8

FET AL MALFORMA TI ONS

A tr eat me nt rel ate d ef

f ec t ca nno t co mpl etely b e exclud ed f or th e m arginally

increas ed i ncide nce (1 .2% versus 0 .9% in hist orical con trols) i n of

ventricular se ptal d ef ec ts o f t he h ear t (com mo n f in ding) at th e

level o f 3 6 mg /m 3, d espit e o f

a lower overall nu mb er of

fe tu se s with

ma lf orm atio ns a t this dos e level, as this d os e sh owed cl ear ma ter nal

toxicity.

Dose mg/m 3: 0/ 1/ 6/ 3 6

- Num ber o f

f et us es p er group: 26 4 / 31 7 / 22 4 / 24 8

- Num ber o f

f et us es with mal fo rm atio ns: 9 / 5 / 5 / 4

- mal fo rm ed fe tu ses per grou p (%): 3. 4 / 1. 6 / 2 .2 / 1 .6

- Num ber o f

litt ers p er grou p: 2 1 / 26 / 2 0 / 23

- Num ber o f

litt ers with ma lf

or mati ons: 6 / 4 /

5 / 4

- mal fo rm ed litters per group (%): 2 8. 6 / 1 5. 4 / 25 .0 / 17 .4

- ventricular sep tal d ef ec t o f t he h ear t: 1 / 1 / 1 / 3

- nu mb er of

litters a f fe ct ed by t his m alf or ma tion:

1 / 1 / 1 / 3

FET AL EXT ERNAL AND V ISCERA L DE VIA TI ONS

Mea ningf ul external o r visceral d eviations o f f et us es were no t ass um ed a t

do se levels up to an d incl uding 6 mg/m 3. A tre at me nt rela ted ef f ec t f or t he

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significa ntly incre ase d incid ence of slight d ilatio n of lat eral brain ventricle(s)

(11. 3% a f

fe ct ed fe tu se s, 5 6. 5% af f ec te d litters) at th e 36 mg/ m3 level is

unlikely, as t he value lay within th e ra nge of hist orical c on trol da ta a nd da ta

of dif fe re nt un af

fe ct ed st udy groups u sed (up t o 1 2. 7% a f fe ct ed fe tu se s, u p

to 65 .5% a f

fe ct ed litt ers).

Dose mg/m 3: 0/ 1/ 6/ 3 6

- Num ber o f

f et us es p er group: 26 4 / 31 7 / 22 4 / 24 8

- Num ber o f

f et us es with deviations : 59 / 6 0 / 4 8 / 53

- fe tu ses with d eviations p er group (%): 2 2. 3 / 18 .9 / 21 .4 / 2 1. 4

- Num ber o f

litt ers p er grou p: 2 1 / 26 / 2 0 / 23

- Num ber o f

litt ers with deviatio ns: 1 8 / 20 / 1 8 / 20

- litters with d eviations p er grou p (%): 85 .7 / 76 .9 / 9 0. 0 / 8 7. 0

- slight d ilatio n of

lat eral brain ventricle (s):

11 / 1 4 / 17 / 2 8

- nu mb er of

litters a f fe ct ed by t his d eviation:

5 / 7 / 8 / 1 3

T est condition : TE ST SYS TEM :

inse min ate d W i s ta r

rats

age: 1 3

- 1 5 weeks

bo dy weight by st udy i nitiatio n: 2 01

- 24 5 g

no . o f an im als: 27 / d os e (dos e group 36 mg/ m3 3 2 fe ma ls were tre ate d)

CHARACT ERIZAT ION OF TE ST A TM OSPHERE :

Particle size de ter mina tion o f t he aer osol yielded MMADs within th e

respirabl e range ( » 1 m m, t he geom etric st and ard d eviation (GSD) » 2)

PARAME TER S A SSE SSED DURING S TUDY:

- Clinical o bs ervations: d aily

- Bo dy weights: day 0 p .c., daily (d ay 6-2 0 p .c.)

EXAMINED AT NECROP SY (MACROSCOP IC AND MICROSCOPIC):

- gross p at hological exa minati on a t t he ti me of

ces arean secti on o n d ay 2 0 p .c. without k nowledge o f tr eat me nt grou ps.

Investigations at Cesare an S ecti on:

- Num ber o f

c orpora l ute a

- Num ber o f

i mpla ntati ons

- Uterine wei ghts

- Num ber o f

e arly resorpti ons

- late resorp tions

- de ad fe tu ses

- Num ber o f

live f et us es

- Sex of live fe tu ses

- In dividual weights of live fe tu se s

- External m alf or ma tions

- Visceral m al for ma tions

- Skel etal m al for ma tions

- External a nd visceral deviatio ns

ST AT IS TI CAL METH ODS:

Dun net t- T es t with a variance an alysis; Fisher’s exact CHI-SQUARE

(positive ANOV A pro ba bility t est with a significa nce levels o f

al pha=5 %)

Re liabi lit y : (1) valid withou t restriction

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 4. 01. 20 05 (37)

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5 .8 .3 TO XICITY T O REPRODUCTION, OTHER S TUDIES

Ty pe : ot her: R eprod uctio n/Develop me ntal T oxicity Scree ning

In vi tro/in vi vo : In vi vo
Sp ec ies : rat

S ex : ma le/ fe ma le

Str ain : W i s ta r

Route of adm in. : inh alatio n

E xposur e per iod : two weeks b ef or e m ati ng u ntil d ay 1 9 o f gest ation

Fr equency of treatm. : 7 x 6 h ours / week

Duration of te st : 9 weeks

Dos es : 0, 1, 6 , 3 6 mg /m 3 (= t arget c once ntrati ons)

Control group : yes, conc urrent no trea tm ent

Re sult : NOAE L - Ge ner al Toxicity: 1 mg/ m3

NOAE L - Re produc tion /Developm ent al Toxicity: 6 mg/ m3

Method : ot her: a ccording O ECD guid e-line 4 21

Year : 20 03

GL P : yes

T est sub stance : ot her T S: Des mo dur W

, p urity 99 .5 %

Re sult : At 36 mg/m 3 c ha nges in br eat hing b eh avior a nd /or ser ous n asal d ischarge

(nostrils with re d e ncrust ation) were no te d in t he ma jority of F0 r ats. A t 3 6

mg/ m3 i n single ani mals a lso signs o f p oor gen eral co nditio ns occ urred a nd

slightly incr ease d (2 o f

2 4 ra ts) mor tality was o bs erved. On e m ale of t he

high do se grou p was f ou nd de ad during th e pr em ating peri od a nd on e

fe ma le of

th e high d os e group h as to b e killed in m orib und co nditio n. A t 6

mg/ m3 o nly s erous n as al disch arge a nd red encr uste d no strils were n ot ed

in F0 rats.

No t oxic ef

f ec t was se en on bo dy weights o f F 0 rats u p to 6 mg/ m3 . A t 36

mg/ m3 re duc ed b ody weight gain was no te d at so me tim e po ints i n bo th

sexes (m ales: week 5-6 : 2 .8g vs. 9 .8g in c on trols, week 4-5: 10 .2g vs.

- 1 .2g in con trols; fe ma le s: week 1-2 : -11 .2g vs -4. 7g in c ontrols).

Th e fo od i ntak e of

36 mg/ m3 F0 m ales was tra nsien tly red uced

. Th e ab solut e (1 4%) an d rela tive (18 %) weights of th e lu ngs were increas ed

in 3 6 mg /m 3 F0 m al e rats

.

PARAME TER S OF R EPRODUCTI ON

At 36 mg/m 3 a slightly reduc ed fe rtility ind ex was no ted

. No o th er repro ductio n p aram et er was a ff ec te d.

Dose mg/m 3: 0 / 1 / 6 / 3 6

Ins emi natio n in dex % : 10 0. 0/ 9 1. 7/ 1 00 .0 / 10 0. 0

Fertility ind ex %: 91 .7/ 81 .8/ 83 .8/ 66 .7 (p > 0 .0 5)

Ges tatio n in dex % : 90 .9 / 10 0. 0/ 1 00 .0 / 10 0. 0

Ges tatio n le ngth Days: 22 .1 1/ 2 2. 25/ 22 .22 / 22 .0 0

Co-ho use d fe ma le s n : 12 / 1 2/ 12 / 12

Num ber o f

i mpla nta tion sit es (p er litt er): 10 .8 / 10 .5 6 / 11 .5 0 / 9 .8 8

Litt ers alive n : 1 0/ 9/ 1 0/ 8

Live birth in dex %: 9 8. 57 / 99 .0 7 / 9 7. 22 / 9 6. 36

Via bility i ndex %: 9 9. 00 / 10 0. 0 / 92 .17 / 9 8. 96

SP ERM AN ALYSIS

Results of

s per m an alysis were exclud ed f ro m th e st udy evalu atio n,

be caus e m ec hanic al stress o n t he epi didymides a nd tes tes c aus ed by th e

narrowness o f

expos ure restrai ners ha d i nduc ed un typical a nd tes t120

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

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co mp oun d in de pen de nt low s perm mo tility ( bel ow 30 %) an d incre ase i n

sp erm a bn orm alities ( higher th an 50 %) in all groups which c orrobora te

with t esticular a nd epi didymal ch anges s ee n hist ologicall y.

Dose mg/m 3: 0 / 1 /

6 / 36

Sp erm m ot ility, (first min) % : 21 / 7 / 26 / 1 6

Sp erm m ot ility (fi ft h m in) %: 18 / 6 / 2 5 / 1 5

Ab nor mal sp erms % : 5 9. 4 / 8 7. 4 / 60 .9 / 66 .4

Mea n nu mb er o f

sp erm atids p er mg t estis:

52 77 3 / 41 76 7 / 4 19 89 / 4 97 07

Mea n nu mb er o f

sp erms p er mg epi didymis:

49 00 37 / 13 81 94 / 3 47 91 3 / 3 23 04 2

HIS TO PAT HOLO GY

No t est c om po und-rela ted ef f ec ts were se en in th e t est es an d e pidi dymides

of F0 ra ts.

In th e te stes of

b ot h grou ps evaluat ed (control a nd high d ose) t ub ular

dege nera tion ( mainly m ulti/ fo cal) was see n in t he ma jority of ani mals :

do se mg /m 3: 0 ; 3 6

Focal t ub ular d egen eration : 5/ 12 ; 8 /1 2

Dif . tu bul ar dege nerati on: 2 /1 2 ; 0/ 12

In th e ep ididymides , sp erma tic de bris an d oligosp ermia o ccurred in al mos t

all rats.

do se mg /m 3: 0 ; 3 6

Sp erm atic de bris: 1 2/ 12 ; 11 /1 2

Oligospermi a: 1 1/ 12 ; 10 /1 2

Th e mor ph ology of

t he ovaries of F0 f em al es was no t a f fe ct ed

.

Dat a On PUPS (F1):

do se mg /m 3: 0 / 1 / 6 / 36

- Live b irth in dex % : 9 8. 57 / 99 .0 7 / 9 7. 22 / 9 6. 36

- Via bility in dex %: 9 9. 00 / 10 0. 0 / 9 2. 17 / 9 8. 96

- Males %: 54 .3 1 / 5 0. 56 / 4 9. 23 / 53 .90

No re marka ble clinical signs were obs erved during th e f ou r d ay l actati on

perio d u p t o 3 6 mg/ m3 . No e f fe ct o n b ody weights a nd no ma crosco pical

alt erations were n ot ed a t p up ne cropsies up to 36 mg/m 3.

T est condition : ANIMAL S:

12 ma le a nd 12 ma le W i st ar ra ts /d ose an d c ontrol grou p

ADMINIS TRA TION / EXPO SURE

Type of exposure : no se-only exposure of an aer osol

An alytical co nce ntratio ns: 1 .0 6, 5 .9 5, 3 4. 04 mg/m 3

Nomi nal c once ntrati ons: 5 , 2 0, 11 9 mg /m 3

Particle size: m ass me die n aer odyna mic dia me ter: a ppr ox 1 u m (geom etric

sta nd ard deviatio n: a ppr ox. 2)

121

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- Tr eat me nt: Th e test su bsta nce was ad minist ered to p are ntal (F0) a nim als

two weeks prior t o a nd during t heir ma ting, d uring th e result an t pregn ancy

up day 19 p. c. Males were d ose d 2 8 d ays a t a mi nimu m. For te chnic al

reas ons (t o avoid withdrawal fr om t heir pu ps) f em al es were no t tre at ed

during lact atio n.

MAT ING PROC EDURES: Th e F0 ani mals were pretr eat ed with th e

co mp oun d f or 2 weeks u p t o t he coh abit ation perio d. During th e f oll owing

ma ting peri od t he first F0 m al e was c oho use d

with t he f irst fe ma le F0 a nim al within th e group an d so on over night a t a

maxim um of

1 2 tim es duri ng t he two- week m at ing perio d. A s a r ule

inse min ate d fe ma le s were no t fu rt her c o- h ou sed . In semi nati on was

est ablish ed by investigating vaginal sm ears pr ep ared in th e m orning.

PARAME TER S A SSE SSED DURING S TUDY F 0:

- Clinical o bs ervations: d aily, de taile d rec ordering at l east onc e weekly

- Bo dy weights: weekl y; f em al es ad dition ally on day 0 a nd 4 af te r birth of

th eir p up s

- Sp erm exa mina tion : mo tility an d viability, sp erm atozoa d en sity per mg

epi didymis, no of

sp erma tid h ea ds per mg t estis

ORGANS EXAMINED AT NECROP SY (MACROSCOP IC AND

MICROSCOPIC):

- Organ weights F 0: lu ngs with trac hea , le ft epi didymis an d t estes

- Histop ath ology F0: t est es, e pididymid es an d ovaries o f c ontrols a nd high

do se

OT HER EXAMINAT IONS :

- In dices:

inse min ation , fe rtility, ges tatio n, live b irth, viability

PARAME TER AS SES SED ON F 1:

- Num ber o f

live a nd de ad pu ps

- Sex of th e pu ps

- bo dy weights

- clinical signs

- ap pare nt m al for ma tions

were d et ermin ed s hortly a ft er birt h a nd on day 4 p .p

..

ST AT IS TI CAL METH ODS:

Dun net t- T es t with a variance an alysis; Fisher’s exact CHI-SQUARE

(positive ANOV A pro ba bility t est with a significa nce levels o f

al pha=5 %)

Re liabi lit y : (1) valid withou t restriction

Fl ag : Critical s tudy fo r S IDS e nd poin t

1 2. 01. 20 05 (35)

5 .9 S PECIFIC IN VEST IG AT IONS

5 .1 0 E XPO SURE EX PERI ENCE

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Rem ark : For in for ma tion on hu ma n exp erience s ee also c ha pter 5 .3

Fl ag : Critical s tudy fo r S IDS e nd poin t

2 2. 11. 20 04

Rem ark : Th er e is a s eco nd re fe re nce o n t he sa me s ubjec t: S mirnov V, Sculsky M,

Israeli R (1 98 1) A cut e in toxication by organic iso cyanat es. Hare fu ah 1 00

(11): 5 20-5 22 , 5 51 . It is pu blishe d in He brew (stu dy no t availabl e).

Re sult : To pr event glass injuries a mo ng on su mers glass b ottl es were c oat ed with

polyureth an e. 4 ,4 ́-Methylene dicyclohex yl diisocyanat e was p olymerized to

polyureth an e fo r this p urp ose. 1 1/ 15 workers who were f irst exp osed to 4, 4

 ́- Met hylenedicyclohexy l diisocyan ate ( no airb orne conc en tration

de ter mine d bu t ins uf

fi cie nt ventilatio n was ad mitt ed) sh owed allergic a nd

no n-allergic skin r eactio n. 6 su ff er ed f ro m vertigo with an d withou t

he ad ach es an d 4 d evelope d a decr ease of th e ob structive lung fu nc tio n,

tac hycardia an d hypo te nsion (E KG n orm aly); th e sympt oms ap pe ared 4-7

days af te r t he exp osure a nd were reversible within 10-1 4 d ays

T est sub stance : 4, 4 ́- Met hylenedicyclohexy l diisocyan ate , no da ta on purity

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n

Fl ag : Critical s tudy fo r S IDS e nd poin t

0 6. 11. 20 06 (66)

5 .1 1 AD DI TION AL REM AR KS

Rem ark : An overall p ersp ective o f t he sensitization po te ntial o f Met hylene bis(4-

cyclohex ylisoc yanat e) is given

Re liabi lit y : (2) valid with restrictions

Dat a fr om a collectio n o f d at a which was revie wed by an expert p an el

2 3. 11. 20 04 (68)

Rem ark : An overall p ersp ective o f a cut e a nim al an d h um an stu dies with Methylene

bis(4-cyclohex ylisoc yanate) is given

Re liabi lit y : (2) valid with restrictions

Dat a fr om a collectio n o f d at a which was revie wed by an expert p an el

2 3. 11. 20 04 (1)

Rem ark : An retros pective an alysis of acu te in hala tion stu dies which shows f or 4 ,4

 ́- m et hylenedicyclohexy l diisocyan ate a mo ng e ach ot her th at fo r irritant

aer osols b ot h th e c once ntrati on a nd th e p article size ar e equ ally imp orta nt

fo r t he ou tco me o f

t he tes t, in de pen de nt o f wheth er th e en dp oint ch osen is

let hality or t he prot ein in bro ncho alveolar l avage f lui d (BA L- pr ot ein).

Re liabi lit y : (2) valid with restrictions

Limi ted doc um en tatio n; 4 ,4 ́-me thylen edicyclohex yl diisocyana te is o ne of

a n um ber of dif

fe re nt diisocyanat es f or which a retros pective an alysis is

per fo rm ed

0 9. 09. 20 04 (79)

Rem ark : A s hort d escriptio n o f th e res ults f ro m s everal t oxicological stu dies (ac ute

oral, r epe ate d or al, skin/ eye irritatio n, skin sensitization) withou t any

inf or ma tion o n d et ails of stu dy per fo rm anc e (incl. d osage).

Re liabi lit y : (4) no t assigna ble

no stu dy d et ails ar e re porte d

0 6. 11. 20 06 (72)

123

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124

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

6. REFERENCES I D: 5124-30-1

DATE: 09.11.2006

(1) A merica n Co nf ere nce of G overme ntal I nd ustrial Hyg ienists (ACGIH) (20 01).

Doc um en tatio n o f

th e T hr esh old Li mit V alues an d Bi ological Exp osure I ndic es, 7 th e ditio n. (2) A merica n Cyana mid Co mp any (198 4). I nitial su bmissio n: A close d- p at ch re pe ate d insult

d erm al se nsitization st udy in guinea pigs with tol ue ne diis ocyanat e an d o th ers with c over

le tter d at ed 0 51 59 2; A ule tta, CS a nd Daly I W

. Bi o/dyna mics Inc . Projec t No. 49 71-84

Dec em ber 2 0, 19 84 N TI S/O TS 53 95 13, Doc I .D. 88-9 20 00 27 54 (1 99 2).

(3) A merica n Cyana mid I nc. (1 98 2). Ini tial su bmissio n: T he ac ut e toxicity o f i nhal ed Des-W in

t he Guin ea p ig ( fin al rep ort) with at tac hm ents an d c over let ter da te d 1 1/ 12/ 91; Collins CJ,

Br eckenridge CB , Broxup B R, Os born e BE , Proc ter B G. Bi o- Res earch La bora tories L TD.

Pr oject No . 81 19 3 J uly 5, 19 82 NTI S/O TS 53 47 36 , Doc I .D. 88-9 20 00 02 87 ( 199 1).

(4) Ariel R esearch (20 04). Regula tory su mm ary o f re fer enc es fo un d in N A da ta bas e fo r CA S

RN(s): 51 24-30-1

. h tt ps://websight.arielrese arch.c om /desk top mo dul es/d ata bas es/DBDSS umR p. (5) B ASF (1 96 8). Ver fa hre n zur

T re nn ung von Ge misch en von stere oisom eren

Dia mino dicyclohex ylalkanen. Pa ten t Ger ma ny 1 81 09 24.

(6) B ayer

A G (1 977). 4, 4'- Diisocyanat o-dicyclohex yl- m et ha n, S to ffw erte. May 1 97 7.

(7) B ayer

A G (1 979). Desm od ur W

, Flam mp unk t. Un pu blished Rep ort 79 /0 219 (51 106 7),

1 97 9-12-0 1.

(8) B ayer

A G (1 981 a). B ericht u eb er die Prue fu ng von Dicyclohex ylmeth an-4, 4- d iisocyanat

f lu essig a uf

prim aere H autreizw irkung. Sc hreiber G Frau nh of er I nst (FHG) April 02 , 1 98 1.

Mo bay C orp (19 81). T he evalu atio n of liquid dicyclohex ylmeth ane-4 ,4 ́-diisocyanat e f or

pri mary skin irritatio n in r abbits with cover lett er da te d 07 29 87 NT IS/O TS 51 53 91 Doc I .D.

8 6-87 00 01 232 (19 87).

(9) B ayer

A G (1 981 b). B ericht u eb er die Prue fu ng von Dicyclohex ylmeth an-4, 4- d iisocyanat

f es t a uf prim aere H autreizw irkung. Sc hreiber G Frau nho fe r I nst. (FHG) April 0 2, 1 98 1.

Mo bay C orp (19 81). B ericht u eb er di e Pru ef ung von Dicyc lohexy lmet han-4 ,4-diisocyana t

f es t a uf prim aere H autreizw irkung (HMDI) with c over let ter da te d 0 72 98 7 NT IS/ OT S

5 15 39 3 Doc I .D. 8 6-87 00 01 234 (19 87).

(1 0) B ayer

A G (1 981c). Bericht ue ber di e Pr uef ung von Dicyclohex ylmetha n- 4 ,4-diisocyan at

f lu essig a uf

Sc hleim hau treiz wi rkung. S chreib er G, Fra un ho fer Ins t. (FHG) April 02 , 1 98 1.

Mo bay C orp. (1 981). Bericht ue ber di e Pr uef ung von Dicyclohex ylmetha n- 4 ,4-diisocyan at

f lu essig a uf

Sc hleim hau treiz wi rkung with cover le tter d at ed 0 72 98 7 N TIS /OT S 5 15 39 0 Doc

I .D. 86-8 70 00 12 31 ( 198 7).

(1 1) B ayer

A G (1 981 d). B ericht u eb er die Prue fu ng von Dicyclohex ylmeth an-4, 4- d iisocyanat

f es t a uf Schl eimh au treiz wi rkung. S chreib er G, Fra un ho fer Ins t. (FHG) April 02 , 1 98 1.

Mo bay C orp. (1 981). Th e evaluatio n o f solid dicyclohex ylmeth an e- 4 ,4 ́-diisocyanat e f or

m uc ous m em br ane irritation in rab bits with c over let ter d at ed 0 72 98 7 NT IS/ OT S 5 15 39 2

Doc I.D. 8 6-87 00 01 23 3 (19 87).

(1 2) B ayer

A G (1 984). Sch midt W M 4 ,4-Diisocyanat o- dicyclohexylmetha n (H- MDI),

Un tersuc hunge n zur

s ensibilisieren den W i rk un g a n d er Meersc hweinchen hau t (m odi f.

Maximierungstes t mi t nur intrak uta ner In duk tion). R eport No. 1 30 39 , Novem ber 15 , 1 98 4.

(1 3) B ayer

A G (1 985). Sch midt W M 4 ,4-Diisocyanat o- dicyclohexylmetha n (H- MDI), Pru ef ung

a uf sensi bilisierende W i rk un g a n d er Meerschweinch enh au t (Maximierungstest n ach

Magn usson /Klingma n). Re port No . 13 78 7, A ugust 2 9, 19 85

. (1 4) B ayer

A G (1 992). Deter mina tion o n th e ec ological b eh aviour of Desm od ur W

. Unp ublishe d

Re port 2 18 A/ 90 , 19 92-0 5-29

. (1 5) B ayer

A G (1 993). Vo hr H W

. Untersuc hu ngen a uf ha utse nsibilisierend e W i r ku ng bei m

Me erschweinchen (Maximierungstest n ach Magnusso n un d K lingma n). Rep ort No. 22 61 6,

Oc to ber 20 , 1 99 3.

(1 6) B ayer

A G (1 994 a). Des mo dur W

, A bschluß bericht Dam pf dr uck. Un publish ed R eport

9 4/ 12 1 A, 19 94-10-1 1.

(1 7) B ayer

A G (1 994 b). Kro etlinger F. Des mo dur W

, S tu dy fo r skin irritation /corrosion in rab bits.

Re port N o. 2 28 68, Febru ary 2, 19 94

. (1 8) B ayer

A G (1 995 a). P aulu hn J . Unt ersuch ungen zur ak ute n I nh alatio nstoxiz itaet a n d er

Ra tte nac h O ECD- No. 4 03 . Re port N o. 2 44 90, Novemb er 20 , 19 95

. (1 9) B ayer

A G (1 995 b). P aulu hn J . Des mo dur W

, Pilo t stu dy f or lung se nsitization in G uin eapigs f oll owin g in trad ermal in duc tion. Rep ort No. 24 19 9, J uly 26 , 19 95

. (2 0) B ayer

A G (1 999). Decreas e of NCO- Co nt ent i n W a t e r. Unp ublishe d Re port N 9 9/ 00 49/ 01

L EV , 19 99-0 5-14

.

125

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

6. REFERENCES I D: 5124-30-1

DATE: 09.11.2006

(2 1) B ayer

A G (2 000 a). MR- T es t. Un pu blished Rep ort 85 8 A /9 9 R, 2 00 0-01-1 0.

(2 2) B ayer

A G (2 000 b). Fish t est

. Unp ublishe d Re port 8 58 A/ 99 F , 20 00-0 1-07

. (2 3) B ayer

A G (2 000c). Dap hnia t est . Unp ublish ed Re port 8 58 A/ 99 D, 20 00-0 1-06

. (2 4) B ayer

A G (2 000 d). Algal te st. U npu blishe d Rep ort 85 8 A /9 9 Al, 20 00-0 1-06

. (2 5) B ayer

A G (2 000 e). T oxicity t o b act eria. Un pu blished Rep ort 85 8 A /9 9 B, 20 00-0 1-17

. (2 6) B ayer

Cor poratio n (1 996). Acu te d erm al irritation c orrosive st udy i n rab bits in D esm odur W

. W a k e fi le d A

Corning Hazleto n (CHV) CHV S tu dy No. 17 56 8, J uly 17 , 19 96

. (2 7) B ayer

I nd ustry Services (20 03). Des mo dur W / 4, 4'm ethylene dicyclohex yl diisocyanat e

CA S: 5 12 4- 3 0-1, Reques t of Delisting. 20 03-0 1-24

. (2 8) B ayer

I nd ustry Services (20 04 a). Desm od ur W

. Calcula tion o f

- I ndirect Ph oto degrad ation with A OP W I N v1.91 , 20 00

. - S oil Ads orptio n Co ef

fi cien t with PC KOC W I N v1.66, 20 00.

(2 9) B ayer

I nd ustry Services (20 04 b). Hydrol ysis as a f un cti on o f pH an d t em pera ture o f

Des mo dur W

. Res ults o f pr eliminary t est. Unp ublishe d Re port A 04 /0 044 /01 LE V, 2 00 4-09-

2 3.

(3 0) B ayer

I nd ustry Services (20 05). 4 ,4'-Met hylenebis(cyclohex ylamine). Calc ulatio n of Mackay

f ug acity mo de l level 1 . U npu blishe d.

(3 1) B ayer

Ma terialScie nce A G (2 004 a). Des mo dur W

- In tern al Data on Pro ductio n,

Pr ocessing, Use Pa ttern , an d W o rk pl ac e Expos ure (u npu blishe d).

(3 2) B ayer

Ma terialScie nce A G (2 004 b). Sa fe ty Dat a Sh ee t Des mo dur W

. No . 02 89 79 /08 , 20 04-

0 3-10

. (3 3) B ayer

Ma terialScie nce A G (2 004c). Pa uluh n J Pilo t- s ub acut e in halati on t oxicit y on rats

. Re port N o. A T0 03 92 , May 0 2, 20 04, un pu blishe d.

(3 4) B ayer

Ma terialScie nce A G (2 004 d). Pa ulu hn J . Su bac ut e inh alatio n t oxicit y on rats. Rep ort

No . AT 01 05 7, March 0 8, 2 00 4, un pu blished

. (3 5) B ayer

Ma terialScie nce A G (2 004 e). Eib en R, Rose nbruc h M. Des mo dur W

, Re prod uctio n/Developm en tal T oxicity S cree ning Te st i n rats. Rep ort No. AT 01 09 6, Marc h

1 9, 20 04, un pu blishe d.

(3 6) B ayer

Ma terialScie nce A G (2 004 f) . Herbol d B. Desm od ur W

, in vitro chro mos om e

a berrati on t est with chin ese ha mst er V7 9 cells. Re port N o. A T0 11 32 , April 0 8, 2 00 4,

u np ublish ed.

(3 7) B ayer

Ma terialScie nce A G (2 004g). La ngewische F W

. Developm en tal t oxicit y stu dy in r ats

a ft er i nhal ation

. Rep ort No. AT 01 21 8, May 24 , 2 00 4, u np ublish ed.

(3 8) B ayer

Ma terialScie nce A G (2 005). W i rn itzer U. Desm od ur W S alm on ella/Microsom e T es t

Pl ate Inc op oration an d Pr eincu ba tion Me th od Re port N o. A T0 17 57 ; Ja nu ary 13 , 20 05

,

u np ublish ed.

(3 9) B eilstein (200 3). Ha ndb ook Register N um ber: 2 21 78 00, La st Up dat e: 2 00 3-12-0 8.

(4 0) B eilstein (200 3). Ha ndb ook Register N um ber: 2 94 36 66, La st Up dat e: 2 00 3-12-0 8.

(4 1) Ch em fi nd er (20 04). I nter net d at ab ase: ht tp: //ch em fi nd er/cam bridgeso ft .co m. (4 2) De arm an RJ, B ask ett er D A, Ki mb er I (1 992). Varia ble e f fe ct s of ch emic al allergens o n

s erum IgE co nce ntratio n in m ice. Prelimin ary evaluati on o f a novel a ppro ach to t he

in de ntif icatio n o f

res piratory se nsitizers. J. Ap pl. T oxicol. 12 , 3 17-3 23

. (4 3) De arm an RJ, H ope JC, Ho pkins SJ , Debicki RJ, Ki mb er I (1 99 3). In terleukin 6 (I L- 6)

pr od uction by lymp h no de cells: a n al tern ative e nd poin t fo r th e Murine l ocal lymph no de

a ssay. Toxicol. M eth ods 3 , 2 68-2 78

. (4 4) De arm an RJ, S pe nce LM, Ki mb er I (1 99 2). Charac terization o f mu rine imm un e res pons es

t o allergenic d iisocyanat es. T oxicol. Ap pl. P har mac ol. 11 2, 19 0-19 7.

ICI Am ericas I nc. (1 99 1). Char acterization o f m urine im mu ne res po nses t o allergenic

diis ocyanates with a ttac hm en ts an d c over le tter d at ed 1 00 89 1. N TIS /OT S5 33 62 1 Doc I .D.

8 6-92 00 00 055 (19 91).

(4 5) Diet erich D, Uhlig K (2 002). Polyureth anes

. Ullman n's E ncyclopedia of In dustrial Ch emistry

(elec tronic rele ase). W i le y- VCH V erlag Gm bH & Co. K Ga A, W e i nh ei m.

126

### OECD SI DS 4,4’-METH YLENEDICYCLOHEXYL DIIS OCYA NATE

6. REFERENCES I D: 5124-30-1

DATE: 09.11.2006

(4 6) Du Po nt De N em ours & Co (1 963). La bora tory Rep ort o n Met hylene-Bis(4-

Cyclohexy lisoc yanat e) with Cover Le tter (S anitized) Sh erm an H Hask ell La bora tory Rep ort

No . 15 5-63 Dec em ber 2 7, 1 96 3; NT IS/O TS 53 01 82 , Doc I .D. 8 6-91 00 004 2S ( 199 0).

Du Po nt De N em ours & Co (1 963). Acu te or al tes ting with ma le ra ts Sh erm an H Haskell

L ab orat ory Rep ort No. 1 55-6 3 D ecem ber 2 7, 19 63 NT IS/O TS 51 49 59 , Doc I .D. 8 6-

8 70 00 10 57 (1 98 8).

Du Po nt De N em ours & Co (1 963). Acu te or al tes ting o n mal e rats with Met hylene- B is(4-

Cyclohexy lisoc yanat e) Sh erm an H Hask ell La bora tory Re port No . 15 5-63 Dece mb er 27

, 1 96 3 N TIS /OT S 5 14 90 4, D oc I.D. 86-9 10 00 100 2 (1 988).

(4 7) Du Po nt De N em ours & Co (1 968). Acu te in hala tion t oxicit y in rats. W a ri tz RS Haskell

L ab orat ory Rep ort No. 1 81-6 8 A ugust 9 , 1 96 8; NTI S/O TS 51 60 30 , Doc I .D. 86-8 70 00 11 27

(1 98 8).

(4 8) Du Po nt De N em ours & Co (1 971). Prod uctio n of skin s ensitization by in halati on o f

Is ocyanat es. McDo nnell ME H askell La bora tory Re port 1 61-7 1 May 20 , 19 71 NT IS O TS /

3 03 Doc I .D. 58 4-03 03 SU (19 84) a nd NTI S/O TS 51 48 95 , Doc I .D. 86-8 70 00 09 93(1 98 8)

a nd NT IS/O TS 51 49 62 Doc I .D. 86-8 70 00 10 59 (1 98 8).

Du Po nt De N em ours & Co (1 971). La bora tory rep ort on f ou r isocyana tes with cover lett er (sa nitized). McDo nn ell ME Haskell La bor atory Re port 1 61-7 1 May 20 , 1 97 1; N TIS /OT S

5 30 19 4 Doc I .D. 8 6-91 00 00 436 S (19 90).

Du Po nt De N em ours & Co (1 971). Initial s ub mission: Pro ductio n o f skin s ensitization by

in hala tion o f

is ocyanates in guin ea pigs with c over le tter 1 0/ 15/ 92. McDonn ell ME Haskell

L ab orat ory Rep ort 16 1-71 May 2 0, 1 97 1; NTI S/O TS 55 58 95 Doc I.D. 88-9 20 01 06 26

(1 99 2).

(4 9) Du Po nt De N em ours & Co (1 972). Class B p oiso n te sting on rab bit skin. M.B McDon nell

Hask ell La borytory R eport No. 1 59-7 2 May 4, 19 72; NT IS/O TS 51 60 35 , Doc I .D. 8 6-

8 70 00 11 32 (1 98 8).

(5 0) Du Po nt De N em ours & Co (1 972). In halati on class B p oiso n te sting in rats . Brown RhM

Hask ell La bora tory Rep ort No. 38 1-72 Oct ober 2 , 1 97 2; N TI S/O TS 51 49 69, Doc I .D. 86-

8 70 00 10 66 (1 98 8).

(5 1) Du Po nt De N em ours & Co (1 973). Dep artm ent o f tr ans porta tion ski n corrosio n tes ting on

ra bbit ski n. McAlack J W Hask ell La bora tory Re port No . 43 3-73 July 1 3, 19 73; NT IS/O TS

5 14 97 0, Doc I.D. 8 6-87 00 01 06 7 (19 88).

Du Po nt De N em ours & Co (1 973). La bora tory rep ort on Hylene W with c over let ter

(sa nitized) McAlack J W H askell La bor atory Re port No . 43 3-73 July 1 3, 19 73 ; NT IS/ OT S

5 30 19 2 Doc I .D. 8 6-91 00 00 434 S (19 90).

(5 2) Du Po nt De N em ours & Co (1 974). Im mu no pat hological f ea tur es o f Is ocyanat e co mp ou nds

Hask ell La bora tory rep ort April 1 6, 1 97 4; NT IS/O TS 30 3 D oc I.D. FYI- OT S-05 84-0 30 3SU

(1 98 4).

Du Po nt De N em ours & Co (1 974). Im mu no pat hological f ea tur es o f Is ocyanat e co mp ou nds

with at tach me nts. Le e K P Hask ell L ab orat ory Rep ort No. 24 9- 7 4 April 16 , 1 97 4; N TIS /OT S

5 14 89 3, Doc I.D. 8 6-87 00 00 99 1 (19 88).

Du Po nt De N em ours & Co (1 974). Im mu no pat hological f ea tur es o f Is ocyanat e co mp ou nds.

L ee KP Haskell La bor atory Re port N o. 2 49-7 4 A pril 1 6, 19 74 , NT IS/ OT S 5 16 02 2 Doc I .D.

8 6-87 00 01 119 (19 88).

Du Po nt De N em ours & Co (1 974). Im mu no pat hological f ea tur es o f Is ocyanat e co mp ou nds

with cover

l etter (sa nitized). Le e K P Hask ell L ab orat ory Rep ort No. 24 9- 7 4 April 16 , 1 97 4,

N TIS /OT S 5 30 18 4 Doc I.D. 8 6-91 00 00 42 6S (1 99 0).

(5 3) Du Po nt De N em ours & Co (1 977). Mutage nic activity o f Is ocyanic acid, Methylene bis- (4-

cyclohexy l) es ter in t he Sal mo nella/Microso me a ssay. Russell JF Hask ell La bora tory

Re port N o. 4 28-77 Ju ne 10 , 19 77 ; N TIS /OT S 5 16 97 1, Doc I.D. 8 6-87 00 01 06 8 (19 88).

(5 4) Du Po nt De N em ours & Co (1 977). Primary skin irritation a nd se nsitization te sting on

G uine a pigs. T aylor JD Haskell La bor atory Re port N o. 9 16-7 7 Novem ber 1 1, 1 97 7;

N TIS /OT S 5 16 03 3, D oc I.D. 86-8 70 00 113 0 (1 988).

Du Po nt De N em ours & Co (1 977). La bora tory Rep ort o n I mlock 5 69 98-0 01-5 an d isocyanic

a cid, m et hylenebis-(4-cyclohex yl)ester with c over

le tter (sa nitized) T aylor JD Haskell

L ab orat ory Rep ort No. 9 16-7 7 N ovember 1 1, 19 77 ; NT IS/ OT S5 30 191 Doc I .D. 86-

9 10 00 04 33S (199 0).

127

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6. REFERENCES I D: 5124-30-1

DATE: 09.11.2006

(5 5) Du Po nt De N em ours & Co (1 977). Range f in ding skin irritatio n te sting on Gui nea pigs.

T aylor JD Haskell La bor atory Re port N o. 7 34-7 7 S ep tem ber 1 6, 19 77 ; NT IS/ OT S 5 16 03 2,

Doc I.D. 8 6-87 00 01 12 9 (19 88).

Du Po nt De N em ours & Co (1 977). La bora tory Rep ort o n isocyanic a cid, m et hylenebis-(4-

cyclohexy l)ester an d I mlock 5 69 97-0 01-5 with c over let ter (sanitized) Taylor JD H askell

L ab orat ory Rep ort No. 7 34-7 7 S ep te mb er 16 , 19 77 , N TIS /OT S 5 30 19 0, D oc I.D. 86-

9 10 00 43 2S (1 990).

(5 6) Du Po nt De N em ours & Co (1 979). La bora tory Rep ort o n isocyanic a cid, m et hylenebis-(4-

cyclohexy l) es ter with c over let ter (sa nitized) E dwards DF Hask ell La bora tory Rep ort No.

2 93-7 9 J une 22 , 1 97 9; N TIS /OT S 5 30 18 8, D oc I.D. 86-9 10 00 043 S (1 990).

Du Po nt De N em ours & Co (1 979). Rab bit eye te st f or mo st e f fe ct ive eye wash t o re move

isocyanic a cid, m et hylenebis-(4-cyclohex yl est er) (Hylene) Edwards DF Haskell L ab orat ory

Re port N o. 2 93-79 Ju ne 22 , 19 79 ; N TIS /OT S 5 16 03 4, Doc I.D. 8 6-87 00 01 13 1.

(5 7) E mm et t E A (19 76). A llergic co ntac t der ma titis in P olyuretha ne pl astic m oul ders. J. Occu p.

Me d. 1 8, 80 2- 8 04

. (5 8) EU PB T W o r ki ng Gro up (2 00 3). Eur ope an Che micals Bur ea u PB T list no . 2 0.

4 ,4'-me thylen e- dicyclohexyl d iisocyanat e (includi ng EU ECB IUCL ID of Feb . 11 , 2 00 0).

P aris.

(5 9) Frick M, Bjo erkner B , Ha mn erius N, Zim erson E (2 00 3). Allergic co nt act d erm atitis fr om

dicyclohexylmetha ne- 4 ,4'-diisocyana te. Co nt. Derma t. 4 8, 30 5- 3 09

. (6 0) G IAP (Sta te S cienti fic-Rese arch a nd Design Ins titut e of th e Nitrogen I nd ustry, US SR)

(1 96 9). Proc édé de pré parati on d 'isocyanat es organiques. Pa te nt Franc e 1 .5 78. 80 8.

(6 1) Hask ell La bora tory (19 77). U npu blishe d da ta MR- 06 52-00 3; cite d in

E .I. Dup ont D e Ne mo urs & Co ( 197 7) int ernal d at a da te d Ju ne 2 2, 19 77

. (6 2) He nriks- Eck erma n M- L , V aeli maa J, Ros en berg C, Pelt on en K , E ngstroe m K (200 2).

Expsure to airborn e isocyana tes a nd ot her t her mal d egrada tion pr od ucts a t p olyuretha nepr ocessing workplaces. J. Environ. Mo nit. 4 , 7 17-7 21

. (6 3) Hilto n J, De arm an RJ, Debicki RJ, Ra mdi n LS P, Ki mb er I (1 99 4). In terleukin 6 pr od uctio n in

vitro: an alt ernative rea d- o ut fo r t he local lymp h no de ass ay. T oxic. in Vi tro 8, 71 1-71 3.

(6 4) Ho ff m an TE (1 982). Allergic Co ntact Derm atitis to new plastic r esins. Arc h. Der mat ol. 11 8,

9 62

. (6 5) Ho pe JC, Dear man RJ, Ki mb er I , Ho pkins S J (19 94). T he kin etics o f cytokine prodc tion by

dr aining lymph n od e c ells f oll owing p rimary exp osure o f m ice t o c he mical allergens.

I mm un ology 83 , 2 50-2 55

. (6 6) Isr aeli R, Sm irnov V , S culsky M (19 81). V ergif tungsersch einu ngen b ei Dicyclohex yl

m et ha n- 4 ,4'-diisocyan at-Exposition (Int oxication du e t o dicyclohexyl

- me th an e4 ,4'-diisocyana te exp osure). I nt. Arch. Occu. Environ. He alth 4 8 (2), 17 9-18 4.

(6 7) K arol MH, Magreni C (19 82). Exte nsive skin se nsitization with m inim al an tib ody pr od uction

in Guin ea pigs a s a result o f exp osure t o dicyclohexylmetha ne-4, 4'-diisocyanat e. T oxicol.

A ppl. Ph arm acol. 6 5, 29 1- 3 01

. Dow C hemic al Co. ( 199 2). Ini tial su bmissio n: S ensitivity t o dicyclohexylmetha ne

diis ocyanate with c over let ter da te d 0 50 79 2, N TIS /OT S 5 37 25 4 Doc I .D. 8 8-92 00 24 44

(1 99 2).

(6 8) K ayser

D, Schle de E (2 001). Che mikalien un d K on takt allergie - Ein e b ewertend e

Z usam me nst ellung. V erlag Urb an & Vogel Me dien un d Me dizin Verlagsgesellscha ft m bH &

Co . KG ., Mu enc hen

. (6 9) Ki mb er I, D earm an RJ, Sch oles E W

, Bask ett er DA (1 994). Th e local lymh n od e a ssay:

d evelop me nts a nd ap plicatio ns. T oxicology 93 , 13-3 1.

(7 0) Ki ng CM (1 980). Cont act s ensitivity t o Hylene W

. Co nt. Der mat . 6, 35 3-35 4.

(7 1) L ewis FA (1 98 0). NIOSH H ealth Hazard Evaluatio n Det ermin atio n Rep ort Nu mb er 79-1 41-

7 11 , Fischer a nd Por ter Co mp any, W a r mi ns ter , Pe nnsylvania. US NIO SH, PB 81-1 67 91 8,

1 3 p p. (7 2) L om on ova GV, Sivko v G V, Pisk arev YU G , Osi pova TV , Arzyaeva E YA, Feklina T YU,

Kli mova EI , Sh al ́nova VA(19 91) T oxicological a sssess me nt o f 4 ,4 ́Dicyclohex ylmetha ne

diis ocyanate . Gig. Tr ud . Pro f. Za bol 1 : 3 7

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