170

'C. ; :;:f, i'g:. 4!:*E S 1995; 37 (suppl): s489.IO) *;*lU !i , tittBtjt=, LU. *.Spl *. BFj, @> * F<! @> j: j=0, *. c. :: i!i, E: :*E3 1995; 37: s 8.

ii) iE . Z5, {4, ! 15: :, E15', 9 , **t'-; :, 1!q tts. i ?x ?. iEi, :03g A. 6? * :1CB, ' f3E. 3 1 *1996; 72: 450-454.

12) Nielsen J, Welinder H. Horstinann V. Skerfving S.Allergy to methyltetrahydrophthalic anhydride in epoxyresin workers. Br j Tnd Med L992; 49: 769-775.

13) Welinder H, Nielsen j, Gustavsson C. Bensryd l.Skerfving S. Specific antibodies to methyltetrahydroph.

thalic anhydride in exposed workers. Clin Exp AUergy1990; 20: 639-645,

14) Drexler H, Schaller K, Nielsen j, et o!. Efficacy of mea.sures of hygiene in workers sensitised to acid anhydridesand the inftuence of selection bias on the results. OccupEnviron Med 1999; 56: 202-205.

15) Drexler H. jonsson BAG. Goen T. Nielsen j. LakemeyerM, Welinder H. Exposure assessment and sensitisationin workers exposed to organic acid anhydrides. lnt ArchEnviron Healtb 2000: 73: 228-232.

16) Nielsen J, Welinder H. Skerfving S, Allergic airway dis-ease caused by methyl tetrahydrophthalic anhydride inepoxy resin. Scnad j Work Environ }{ealth L989; 15:154-155.

L7) Kanerva L. Jolanki R, Tupasela O, et @!, lmmediate anddelayed aUergy ft. om epoxy resins based on diglycidylether of bisphenolA. Scand J Work Environ llea!th 1991:17: 208-215.

18) Tarvainen K. Jolanki R. Estlander T. Tupasela O. PfafniP, Kanerva L. linmunologic contact urticaria due to air-borne methylhexahydrophthalic and methyltetrahy.

drophthalic anhydrides. Contact Dermatitis 1995; 32:204-209.

19) Jolanki R. Estiander T. Kanerva L. Occupational contactdermatitis and contact urticaria cause by epoxy resins.Acta Dermtovener 1987; 134: 90-94.

20) Kanerva L, Hyry H, Jolanki R, Hytonen M. Estiander T,Delayed and immediate allergy caused by methylhexa.hydrophrhalic anhydride. Contact Dermatitis 1997; 36:34-38.

21) Yokota K, Yamaguchi K, Takeshita T. Morimoto K. Thesignificance of specific lgG4 antibodies to methylte.trahydrophthalic anhydride in occupationally exposedsubjects. Clin Exp AUergy 1998; 28: 694-701.

i$i3 44 , 2002

N. ?4 '. JL, .2.1 '. U f:>

C51t1gNO[CASs 872-50.4]

iB!1 :: 1ppm. (4 m. g/, 3) (, ,,,

i !jE: {j, ,i< j ;

' 4J i1;{*:C' !. : t 7JV7b lJ ; ' ,.J ; - 24.4t3 i $ , ;: 202t: (760mmHg) 150t:(162mmHg), ; : 1 5 3.40 ( j j ), j O. 29mmHg 20t: t;! D +;i 1E 382ppm, 3F!1<, 93t:, 1*1<, ;; 79t:, gt!}<f : 270t:, t!: 1.027(25t:), i ;fif1;L ;i<*3, k Og; !j 11=j fi\, :i j +: ji

2 . 1s!P9,1 .*s J: LFFg: tlhtl! 1, 'h! 1*'1 0*::j a- .{ >. j ; j, , ,,,,,:11 !! , sJ:0* ;0 E - 1, 1 E' 13:E<i ;{1:i ! , !: Lt*liF t'LtV. . . 1987, FO, E ;,' L U * - iV;; ;iib. lC;k b ; 'j :9 j j;b* .\/>j E !@>*:&51$iL *Lt:i:at>, f :+= !: L'Ci3:7* *'LOOE:). i. *?ib*jsj@>FE j3:*;s J:- . 6,000 } 3, '/ F (1995).3 . @tr! !=*s! . , ! 1tr ;. y } :. v. i !, j!j 3;i1=*sv. C, i a, 1 , *sJ:O'$:*it::b. e, 1!*!1X *'L , '. " . ig:!Dc. *Lt:N. ?c .)v. 2. i, oU l? :,' (NMP) @>: < B5 . 13, i*;i, ,i:' J: b tP. @>3;,, { ;!t ! { 8!;' i'L ;b .E5 t:: . , :. 142 0 { ;!t !, 1t , 5-hydroxy-N-methy1-2-pyrrolidone "C. ;E ;*, 3).45mg/kg O " C. NMP, 'H. NMP. . ' y i. != fi$. li11!9!Cii;* . L i: : C ,, 70% 1* 12 B5:1;,!;!P4!C , 80%1t 24 R Ra!;!1#, 1=*1. 1 .!= Ft l; *Lj:. - 6 R+1 :0 !f i 1 1, :fi+! '@ 2 %, d fi 'C' 3 %, .@D{ 4>RaEt1= , L!: < 53. aiiL'C v*it=. ./:: . , fl: !i' f1!;t (70-75%) 1;t, ,,-methylgamma amino benzoic acid 'c, :io j::4).4 . Etr!1il=.;s! ; .EE '1 i) ii!i , . t:e

v, >X: LD, , 5,130mg/kg" ; y F: LD, , 4320mg/kg')2) ilF;!:, 1 E

'>, 1',!' 100%i i .!t:, Ri, 0 1jgjjE: !.;3'. " . ** ,j A ;g:-j; ;1;*::E U;:: v* 6).

,>*1' 2 Draize test'6 6 0 1 l!'! V. 'C 0.5 mZ OLoo% }lMP .. ::1 Li::!+;j, ;:j = Ltgv* . j* jc ;fti L 24 Bi E8 ,:3 ,1: 0* 72 BE:115t !=\lji3: L i:: : CZ, , iljgt;1:El;t F, 'lc v. 0.5 !: *ny;ijF *, Lt: 6).

3 ) B;!. 1 t!F .t*X LD, ,: 2,310mg/kg" v } LD, ,: 3.050mg/kg'5 . 3E. ; . 1!E , li;Ei) i. i, ;i:El lO l!E75. i;, ;:g . . tl*i!* ,',> X !=, 0 1.000, 2,500,7,500ppm @> i j5E 'C' i!; != t *t; 4 ;a l= ig: b - ; . 7::

,\

., ,

U

t

H

l

H

O

0

0

0

4

4

C

J

J

J

N

0

}

j

*

*

*

*

*

R

R

e

.

@ i;*44 , 2002

7,500 ppm 2: 2,500 ppm 8*'CRg' .$ji. :. - j j j= 2;at> ,

xiLjj;' } U #" U ~1= 4 F@>jx >,$:. tE!c aj>, a p. >:,. '. n -iVOt ilU 'il*1= ab>i: . 7,500 ppm '@1, , 7 iV :b U 7

,1. X 7 7 ' - .1 @>jiE4* 2: :!i iV ,' * A Ojg :!*,$:'t!! 10 ,9\.

3 1;!O 1=; 3!>i::. 1,000 ppm t:'i, , ;i !!-lC J: ,:g tl* g;t)

G, *L * NOAEL l* 1,000 ppm Z::it'. . ,*'Li= ").2) =!;:;' i!!E .}*v. 'C 0.4, 0.8. 1.6 m!/kg O i :1;!:'C 20 B @>* E!:

,ig; jEg= :-j .;:E , jj: 6). 3 !,, *!!: :j, !: i =* . j, 0; ;t:'j!'V*, '0* , ,, xEO . j* 1*j' 7jS ;t> t, *L/:*t

O. 4. 0.8 ml/kg 'G l3 , ,!t. 0E ii* *;b> G, *L::E *,. o i:. .

l. 6 ml/kg\\' C 4 1*' L a3 ;6S El= L t:**, ;j* jpj\ ,t:'!,qj:!C .? '1*. , 7= g, '5:6. 0 *:.

3) ! . 7. :E

y F j= NMP \ @> ,E" Eg *:. fi:!*U j&j;! != ;!t V. *

370 ppm O t :1;!'C'- B i:= b 6 R *ll5, lO B 1;5 !=*?;!: b0 /::75*g9", g:i=i 1 j'$~ !13: gb) i;> *'L, ::7j. 0 /:: ').

- B !ii:= b 6 Et*R5, iB. 5 B , 4 ia!Cb i:: b 4 @> ' y

} !=1! , E*t j : 0, 0.1, 0.5, 1.0 mg/! 'C'!;533: . fT o *: "). 1. Omg/! @>j!*j i' !,, j ; ;, U . 13t, *3 , : LFj j*Bi=

*t gat) g, i, L/=. Bt=i;tj j != L, tiib ;, . gji, j, ,j >,/*

*a @? *S g6b Q, *Li:6* 1 33 : 2 ial5'@1 :1, -

32 E90 v } :. 17 B , 31 B @DIBg3S: ig!:** !\\@>;f 4 8 i=5p'!i' 3; !'t o t: 7).

Dimethylacetaimne (DMA) t: NM P :. 4 6 !=t!E .

L ;, ..;= . *b' l B 3 Rj*1;5, i 6 B j!'o it:. DMA O

SFJ jj ;*E1, : 150 ppm, NMP @>=FJtii9:j*:;d: lOO ppm C:';\,o t::. ,:9t;E : @>t ;!: L'C , : , 3g ', nn. k :,

A. e , n t, ' > , ,\? } :>' U y F , 1 nn. : R, AST, ALT,

7 " :b U 7 * X 7 7 ' - .1 :' til;x: L ;t: . ' 0* , ,,

AST, ALT, 7 )V:b 1) 7 ,i. X 7 7 : ' -*1:1d:, 17 B l lCl, 1;t g86 :;6, 0 i:::6S 31 g tl*;j9 :; . L j. :bS gb> E, j'L ; Et im: : :, '\"E:?" D 1 <' >" , '\7 F ' U y F , 1*1im:6k

;t!C l* 1* g;t> !, *'L;:*6. o t::. : /::ll Eg :, tlCOV. 'Cl*,

,F :, '1 , 1i .@, jin75* .b> E,*Lt:.

4) ,;al ;!g! .5 a*E v } ;6. Q, g:. , DMA, }lMP, DMA + NMP* :

. ,:s J: Ot3 ' ! , . i;g v. ( - 5 P9 '3' 0 ) DMAl, ooO mg/kg, NMP l, OOO mg/kg. DMA+NMP ( -!jg,3

Z: !, 500 mg/kg) 'E:' l B ~1 1 4 B E5fi*:, *!* :. uj:: 7). ..O* ; , . t: L V. f* @>*xjU O 1$1::C gab E, *L,

DMA+NMP ;i;p -g3'Ci;t AST, ALT @?**jjn !. gb i:=i:s!jt

4!jtx -8 t;lJ: b>;**. o i=,

6 . , i:E::g1!x

IO !* 0 . *'L **'Lt!E i!*'7 ,> X i= 0 1,000, 2,500,

7,500 ppm @D NMP *:' \!;1= t! . 1, 3 - . JE O lt j: - U *: .

* *1 RB' iiEld: 2,500, 7.500 ppm 'C' a3b ,*L, 1 1B :

!=fi{: :"0>* ;bn, s J: cl* i:i. p, C. /j*:;E@>fiB:/>76*!1gt*j j lc Z

j '

'0

{\ 6

&b G, *L it: 1,000 ppm 'C' 1, g E {E ! 2. bb :> *'L ";*

l. OOO ppm i5tNOAEL p::iE'.; . !, *Li: ").L, '- E," )V;1= 11i*tE!C NMP \:. 25, 79, 250 mg/kg/d 13 i8

!c j$: b ; : . U j:= lO) . -@) x , j*: :@>j 4> !: nn. ,j* :Ot ilD*' 250 mg/kg/d 'C''!*; U, j j : !=im. j* =z L-. 7:.

. .n - iPOig: *:6S a, t) !, *Li::.

O , 800, 2*000, 5,000 ppm @? 1{MP ,*! 'tr 1; pt . 4 \

o :t y 1* != (-3 25 PO, il*t ) 90 B .; ../::. '@>* ip,;*j!, *lj'. L. Of 'g!1 '1* Z;b E,*L :i6,0 7=:b*, - < @> :

'C e: < **B!:@, t' **' :":@?* U*' 86) , *L, i 'C l, . 0>

pH !: tb :6*g! {1: U, im. ti;' GPT 1;* 5,000 ppm '6:1iiiirr L*jt: . J;!, b. *, 1;> , NOAEL 13 2,000 ppm Z: :iE' . G, *, L/: 6),

4 ** ( -8* 60 pO) :6* g, ,g:. 7, >x ;E!ji; v. t 90 B @?, t;E

jpg*;j*j *?*L7=. '@>* , E 1aZgftOi >*'t\'Cld:: i i E'C', il*'Cid: 1,000, 2.000 ppm 'C 2;bt> ,*'Lt:. t

!$a@Dj ,!>, t;p -!=3S;!E';'.E';! :} 1, :3 g6) g, *'L5,*. o j= 6) .7 '1! t!E 5E**A, j gx

. 83 120 1!9@>il t*@); v } !. v*: 3: ; ! 33 :. 4 oi::. 1!;g3 iE;i;!!* 0, 40 (10 ppm) , 400 mg/m' (lOOppm)'c, 6 ,j,j;6/B , ;g;:jj:: b 5 B , 2 >Fj pj 'o i= "'

6 , 13, 18 6. . )E t:'ji!jl!E IO p*.;'0 ,!: -E!! Lit:. 2 ,j=f !C

13:;;3 b O y } 't" <'C' 'i '3O L/::. , @>j 4>, S J: 0*

3E!7b*A, 1!;El, a6t) i;, *'L;:* ;6. 0 7::. 400 mg/m' 'c'i, , j:$:

Oj ,!>75t Z;t> *,*'Lit:, NOAEL 1;*, 40 mg/m' (lO ppm). C'35 0 i=.

8 . E*;; *:3 J: OS**j ,,,,,

*;E* : v } lC 6 Bp'lla/B IC 150 ppm O NMP ' G7-G20

'C'!!:, 3 L i:: ""' . :*: f3x :'1* Lb=:i ;@, 1x,\0 i :.

j 'Li::t:it>, f3 : *,\@>' '1 *S < j Ol 1 OEi=: lC: l

@>,!*v. jEp; :. ;:StiELt:. RE$L t !,, 1 3* 'cj* g@>j

T, '1*:gg' '@>j .*L76* Z&!) Q, *Li:. **i j 1 Fl !C

ov*tl*, ,, jj ti;* @9 E*j j=oV*tl, : . jj;'13: &:)

,*L; .:6*0 /::. !ati*tyi;giS!t (Rotarod) , Open field ,

$.*iLt:., t \ :;b !=. ov. ci* i* ;t, e, *'L, ::*. o i::. L, 6.

L, Morris water maze ,:3 J: 0'Skinner boxes 'C'a;!'3S;\\

** i;0 'C V./=.

!;Ei Fl. G4-G20 : 'C' 165 ppm @> NMF !C 6 E / B !;!'3g: L 21 B l !Cjx @> ;,#i i3 .@?jj . ; \:. j' 0 *: 12). , ,,,

@?': 13:1, : &!) p,*'L, *:*. 0 *=. L76" L, 'fi i i @? ROEx

Ot ;brr!:'B'{bOi .*L7b*;Z;b E, *Lt=.

25 1Z9 0 !;E !!* 'i y } :' 6 ,E, ft5 / B 'C' G6-G15 : 't?

25 ppm, 90 ppm @> NMP !1! ,, g: L 7:: "). 1g @>- 1;**Egt 1 ! !:Z< ,;!1: 1 1 ' Ui:. { 'i 1 ; 9=C'

:t* 5. i @?f Dl;* a6, !, *Lt*6. o i=.

, } :! j;g v. it= 2 '1 { :j *'4 ' *? *'L t v. , , ls).

Reproductive toxicity phase 't:' !, P, f!tf 1, , 0 10,51, 116 ppm O NMF . 6 B$,R, / B , 7 B /iaO C; ,; 3 . 34 B ii$7i. *, 4 ' 0 ?:: . t!E1*1! 3S IOO B : 7:', i 1**E

. i 3

$ ij! t: )

171

.V

\

A

*

*

*

t

t

*

X

O

O

O

O

O

O

O

O

O

O

O

O

O

p

O

O

O

O

O

O

O

O

O

O

O

O

0

00

0

0

0

0

0

0

0

0

OO

O

O

O

O

b

N

C

C

C

CC

C

C

C

C

C

C

C

i

i

*

*

*

*

6

6

6

6

6

6

6

6

6

6

6

6

6

6

6

6

6

6

b

b

b

b

b

bb

b

b

O

O

F

*

*

*

*

*

E

E

E

E

Z

Z

Z

Z

Z

Z

L

L

L

g

g

b

bb

b

b

b

6

6

6

6

6

*

j

R

R

*

t

t

G

=

b

'

*

*

*

#

;

*

::

:

:

172

$L;!B@D 143 B :~C11 3\ .*U: E L7=. F, 1b:{ 1t, 70 B e\@ F, ll tt; E:' 3:5BE ' .!t"i'-p;'i!t 7::. 1L6 ppm3\7: 1t, ~O{ !=. 8g'3i$ Oil* :. F , 330itEt$!= ' .3 . j

i::- P0 3:3 J: 0*Fi !: j>11 3S. != J: , Ll*ZE;b@Dl Tl a;t> ,*'L'j*, ;iL. *s ,k Ci'9R!i @> iE:@> :{b j> *:*'0 *:. L** L. , '1=*t"S'-*,! ! :'1:E1d P, 0 116 pPm li 3S:3*t:'1*, i;,;fy*!={ T LTV.7::, F, 'C'1t 10ppm 'C'tl*,E. Ri:lC{}'@>*1' ;!3*l=E1:i!3 L, :$'j : : : :j 4> s ;&> Q.*t*:7j* 5ippm '@i*:;jg j: j coj >j *. < ': . 4 E$@Di >1*i **}: t>! E3; *'L7:: 116 ppmE*'C' a3t, b> i'L?:=. L, *" U, -;6'*S, E$ *L , V* ;'!t;jg:g:5:. j;j,!*!* a i6 *L;:,*, o t:. : :@)i$'"'!t\E$LB ' : t:'*1E : Lt:** ' @>j 1 . U *:.NOAEL i , 5ippm !:, '; . i;, *L7t:. F, of\ R!,:, tfl t 2 B !. i :Li:=. *li { @>1 s. g :, !!= :a*3, i $L: ,l:EtbO* ;'C, ;jc+F5 p !1t:j tB: *L;**. o i . f .

" '"'> &b *,*L; *. 0 t:.Developmenta! toxicity phase@> *g:;* 'C' !* O

L16ppm @>iR;1; @> NMP 01!j33; . 34 B* ib. Q, ltt E@? ' ?} != 12; 03:* i!8, ;*5 B i, 21 B @> Ei il rt. (1 O ,.) 1=1! ES; L. ?::. G2i !c!1g :

.!$.; 3L, , i{\.@>t : t . t oi::. bE: ;, 'i , j tb, ! C; !,'@1 g!Cf\5 g a!!*i 'tt! ?'L;*:;6.0 ;*:;b*, ff ,1 @D{*. :1* 116ppm lS!E$ -@;g' :!=1! jv*.75, 237, 750mg/kg@? NMP :' !;;:6*!C- 25PE@)!B;* :Z v F l=, G6-G15 :'C'; :!*- L G20 B jcjp- :ui= 14). ' @>*$ , 750 mg/kg Z:'1 0, j;: j ,!>*S g&b , t'Li::. :i , , :B:1 ; ti9{= . ., ! n@>$*j ** , b ,*Li=.750 mg/kg 'C'i;*, ft 1 1t1 !: A, ;:' ;$:: LC$!5 6'$', fi :{3'O@>! .!DL!= . 0 . 7i* a. b> Q,*Lt:7i* , Ro: , 1 1= J: , t>O !: :p'; , 11, i'Lit= . 75 ,:S ,!: U'237 mg/kg 'C id:, fijil'E.\@> !j3: Ztsb *,, *'L;:t v..9 " " " """

Ames Test (TA-1535. TA-1537. TA~1538, TA-98,TA. LOO) 'C'ld:, S9 (+) :1,. Ziv. !t S9 (- ) '6 j> : . J;:\j:it &!i 4, *'L;5, :6'. 0 ;t: 15).

NMP '*:' 3,800 mg/kg :'C' (LD, , 0 80 %!C*B !!) -1 jt : :- Ut= zt, E: 16 j;d, 24 R*i;6, 48 " iBdj; 'Ci , ',> x

'C@>:p ml: /i ; $ 1t1 1 : *= Chinese llamster O' Ei*;i\ :t:'3 . @>t*i , . . ' . gb); *. o j= 16).9 . i, j. jc*:st*. , S$jjj j .:.+?!iL, j* @> b!c 6 -L'Cv ,{ -@>*!b{ '7b3: . *'L'C v* . , "). C @>{ ;j$*!1'C'1t, D-methylac-etamide (DMA) :N-methylpyrrolidone ! 4 6 !=t; , . 1, i::;j$jS;; : lilcDiai'Ct:1 . 1, i:=i :1= 1 . :. j iU7:0 , 31 J=tf'*; 200 :.e:St { ! . 4 =v*p* ! ;@>.:c ?. ?! ),-*pj -j i . .200t::"U; :E;j 't DMA, }lMP l;ti$*, 7, .!C ;-3$L, t;b3t:i 7j<+ji.'e- 3{F t q, != jtB L t:. 1 3$i :ft,

" " """"0

ntno-diphenylether !. lO %@? J, .

,b, C. @>illj j 13: .@>3507:= ' i '0! :0i $5 ': :g!LtV. . j' g' 13:4>i9:V*!:*g ' '13:jp; LCV. ).;$'t;;* ' . i 110{ !: L'CNMP . :i {F !j={ j* Lt v. 2 T;!!g-j=o v. .c*R -*s;i,.*, " ). -0-0oT; ,;d:, L, ,7>C f z; 'C fl j : . jU. :Q)i=ib@? tr : *: Lt V >,>< bj*ji . 1 >j=?p@>j;5!=*?7= b NMPt .

a!: i . L'CV. ;t:. C@?. *3. Z!'@> 4 : @>{ '1=0v*'C 5

B i=*?7:: b fla/\1 ,gi gE !98 :1, i:2: C Z, , E R5jjn 5p;b it:' 0. L4-0.69 ppm 't'z15 0 it:. :?t: C @?:E;;! t' 5 @?t1lf '** lq :1= hD Lt:!: C ,{ : C@>! ESi&g513:O. 24-0.32 ppm '@ ;i, o i::. : t:, i 5 -0 @>:E;;g'C lt ,?$' . E ,'*tg ; :LC33 b , g i iOj i != v.Cv. t:. .@>:E:! 'Ci;t 8 :*i@>f ' ' 5 B 1=*?7: b l A1 33i ' 1:i L t: : C Z, 0,04-0.59 ppm !=53';fti L'CV. i:=. iil :E;; !: > tiMP@> ;1, ,\0i i ; ld:** *u : 0 *:.C *'L , 0 { j;j 1= ti6 :'S' . , fi:j!: : ' :R lt , nn. i ; ;

l. . l

DMA :b* lO ppm, NMP l3 '*'L!;\T !:tt,iii*i;$ *L. . C. @>{ - :jc !b:. ' f' j;: :p'91'b'. 10 : (22 -40 i*t) E:. 2 ,j=ft5g .&j; Li=. 4ip :1 1;t3a :pa*6B , 't?, 1-9>Ft 0 t=.C @>{j=j;!' 'C13, ifu. rP llb, WBC O*ji U;bt ab, G, *'Lt:.l t9! 1 : (GOT, GPT @>*glin) j> a&> ,*'Li:=.$3p' , : . *; ' ,.T*$0 ,* :3az; C, i < $c ;;j. 0t -EE !=OV. 'C @>!1: j*R j'jj*,:: *Ltv. .; 17).C O ft=; ! '!t i;i '. 1 ; t;'@ 0 1i @>: fE "@ negativephotoresist . 1{MP 'C; !:j$i. Lj ;$\ *;'. tV.i::. :>'U >';Bio NMP !>b ; A l=i5.1**i5 L, - B ?:: b ** lL@>NMP ; . tle\ L, 7. !z } :.,, ?! 3,' / -? jcjlg . Ll;*) L'C v*i::. !iEt;;20iEl :'C' NMP !=! ES: L 31 ;$'C'-E .3B lc 07t:. 1 t@>{ ; . t 0'Cv 6,{ @>- :F1@, @>fF E;t i* 1: . t:'ld:, 0.05 ppm ti'35 0 i::. L, *. L,

:1:F@>. ,E. !;! :!={F :E: @> *$ :{F b * @) : -:j*fj*?*Lt:t:

. l

(RBC, WBC. Hb, Ht) ,E. {1, !;@;t$:51: (AST, ALT, y -GTP,*3:a 1, .::< .5" n -iL. , HDL, TG), ECG, fi 1 j;X-p ; . t*;, . 1*tV.i::;5*V. 't'*L@>jp: :'C > ., j , ld:;gab ,*'L*:*'o *:. L-. ;,';C- lf T*9 1=;*sv. 'C, i @?{ 3jb ! . lc. *sv*'c! j*'\0; !iC ,k b ! j*: 0 Et$*g3 , b ,*Lt:.f - tit. $$'c t f :{=t: Utv. ,6fF; , @>; ' :. 1*: @>; 1*t1 1-z*$g, ' . :3g :L*: :*R . *t'C V. " '. C O. 'CO C *L 6, Of ;*b': '13 , ;;S,t;t !NMP != iO !, i, tl*i$! b .Ll*';;*o i:: NMP .* '6; ; !.

{F; ! :. L'cv. ?=. c. *'LG, {F:j: . oi#q l ilt:, *31 @> $ 'iit! ., ft ', *!:!C; L, C, s b , 'A - ld:1:ablt L'Cv.

7=7b', 'Ot :$t: @9i::, t) .; '!: 0 ! 'C'1 0 t=t:3t>, i5. ig> ,., E ,;:, 3$ , ; ., ;; ijt 0gSf, ll. :Ui!=. {,= , Pil:j 1 !$j! ti:1=j 1 :b< . C, 3 ; 1 t !C . 1*@?;;b29:;6S'1" til ; .;t:2:: L, t, .. . 2 i @> il*, { d' *tOE!E1* ;}:13:; < :b. , .!: Zi, @>1 E ' 'Ai! :\! . j :fjiUCv. i!:i= , 7i* .*? i 3 B !=. b C,

i*i3:44 , 2002

t,

V

V

0

0

0

0

0

0

0

00

0

0

0

0

0

0

0

0

0

0

0o

O

O

O

OO

O

0

0

0

0

o

O

O

0

0

o

o

O

O

7

Q

N

t

t

Z

Z Z

t

t

@

C

6

? J

c

t

t

*

*

*

*

*

*

*

*

*

*

*

*

*

*

6

6

E

Q

G

G

G

U

L

LL

b

b

b

b

b

T

R

L

A

B

F

F

i j$i' 44 , 2002

j j g 2:! j&:;:Z; *G, j jj 0! j*b : 7j*3 b> G, *Li=. C. @?

ft:;t; '1, :E=. ; ! . j : ;> C O{ ' * 1, 'i:.

C 0> 2 b 1!;\:9'FIC, lO: j@>{ ;i::g'@> 1. < i5*{t:;;;Ba*ti

1-2 B j 1= 1 !ia;@>!;:N;!Fti< 0 . . 4 0 7=. 10 : q.8 P;iibt{ t!;Bat6f : 6 ;!at !. 5 $ ,$!. !ii::. .@?* &:, 8 :*i

.i-,<t@>{j= '*<{iar1G7b'OlF:1* : '; Ltv*i:, ,

*;:t t, :i !1* 22 @>{j:;; : 'C'; , ty { : : 2 B El l=i

o* 'lC 1@?iEi1=3E i !:;*: . .{\5 ,Ffi . g;b <} . j L, CV*i::. '@>4 ;i; ;13; !!: D* ,@> t ., ! lri .IO. t: } 'C@?{ i*s J:0$t i "t ;

NMPIOO mg ' 'i . 1=*E - Ljji @>{ j' ! oo* j

F!:j *s J: 0';iF:E:{b L i:: f3;:7b**&i ' *Ltv. 6, 20). i*.

O { ;!* ld: NMP. 5-hydroxy \7. methy1-2-pyrroli-

done (5HNMP), N-methylsuccinimide (MS1), 2-hydroxy-N-methylsuccinimide (2HMS1) 7b*iiFit, !=; ab, E,*'Lit:.

it. **'L@>5j. il,, NMP 76*0.8%, 5}11iMP i *44%, MSl *g

O*4%, 2HMS175S 20%'C'B:, o it: . ;j -ft0 1/3 fd:E . rt, 1=

l ll!!. *L:: i5.0 7::. 5HNMP, MST, 2HMSl @>,F!j*i, j B eje

i ;!al, '*'L **'L, 4 , 8 , 17 R ,1!a'C;E,O i::-

6 i@>tE' ', i<.:> >.'i . 7 i= J: ;Z, iiElS! :0*& '*S, *LC v. .i, "''. 6 : jOtF3; ; 'i,, 4 B Og ;:* .,, B IC O10, 25, 50 mg/m' O NMP IC1!;!"3 i$ *'Lf::. 1! 3g:jjtr, F*,:s ,: tlSj !=nn. ! i4. $:s J: OSiibil. @> NMP , . 1:i L i::. : 7:

; ,\@) ! ,! : .6, t:, 6 !c . : j. b: F; t * ! 15 L,

i=. '@D * E::, j&jjg:j; !C. *sv. 'C >1 g&!= J: b E , L. \

; @?:4<' ! ;1*b!@ 1:'t*, ., ;f, :3 ,: 0'$:b iKliE:t:' ;> t: (;

O! ;it '' 1F;tl != .k & ild:; ! *L5: . 0 *:. mL , P

O NMP 02j5i i411, 4 Bt*R6C?;*, b . ,,t1d 4.5 1 R5 '@;t> 0 *:. ! "ES;rP 8 B ; 5*;s J: 0'* -T4 44 R Ea l= rP lcj

U*' i'Li:: NMP l;,, f$;:L. 1 .!,! i'L7= 11MP @> 2 %'C;

o t:. 1! E$:*g-Tj l R 5f @>nn. :rp NMP tggE : -T

2 ,E*j!5 E5 . .@> NMP Ot&! !: !;t, !V. *apq7b*z;) 0 /= :L'Cv. .i,.

:E*E{ : '!=, 3 1,ti, NMP Ol:&1, ,!ttri*;@>*R ';6tt *Lt v* .i, 18), t, , ;,. >C. r: !$, e*+ j;6 i. .*Ej=tiE . ~.i, { ;g:*".!:3 J: Z 5 iO :i : ' >," " 7 'C'3:, b One-compartinent

model Zi'fi\FjLtV. , ,. '0* , :Ft ll :O j&EElg,

O, 04-0.69 ppm 7:'t > b } ;. rh O NMP t :j*: :. Y (ng/mg :?'L, .7 .= 7) 2: {,, nn. t;:rt, i 1t ,$: X (ng/m!) !:'*';5, !=,

Y=0.747X-1.88 (p<0.01) @> 1;81; :.*;. v*1 Lt v* 6 .

G, !c j&j j :j; o lg: g$; g; 0 j , j= t !* ,b "1', i3.5ppm X 8 B ;R5@>,;g33;ii!; : Z: 1d, {' 'fi* U*'3a&> 1G *L.$*;*:. e ,*iv :. j v*'C . rP*3 J: CFim. ;FFPt FE > 'ib1' C ,b: L'CV. .ii, C O, E. 7" )b :.!* v*, 0-13.5 ppm x 8 RE: 1!

:1=*:s li'6{ -T Onn :rP3s J: 0* . F*oj&j - - j

L, 7:: : =. z, , NMP iR;1tEldi* , B ib. G, B;3 B lc;b'. ij'fj=: F !=*E n " .i, 6* {,::; * -Tt Oi&i;El,!E , B *. i;, '!;3 B

!=;6.1j'* ". '. , 0 1, 3 %* j;Et:':*, b , NMP o*g:Pj*S )

o C > ! 33 -Tt @> . fF *lF&@>ig1 != 1d:* !7j3 . v*!:.j;-jRI L t v. .i).

NMP l, E l. 0!;::j* 3:. jjj v* i:: in ,, it"o o>j t'!= J: b171 59 (g/m'. h) :j&iv. j ::nO ; ; . ; * iE F; *LtV> .*j 22).

NMP !d:, =t' A E:,*; . &!>i . @>** 0 =,:*i '; i L

ii !:Ell! B3 ,F: ZE l: . , C :;bSi:U Q, *'Lt *3 b , neoprene 3 O

*=,:*F*S '*b'C ) , ;: *Ltv. .6 .

ii. ;E*'}1*!@?Ff! '1

MAK: 19 ppm (80 mg/m') (H) ii, 2 23)12. &ti{ 't

NMP 13:, . t;E$:s J: US ., , tj jg;1=*:sv. 'c4*;!=;;:

l, .: 1:E!,: 83t> 4, *'L,5:v*. g*i *A, *s J: Uti { +: j ,, 1 ;

q *L~!*, , j! , , ;i*g; t? , j!&j ! , 1 jg: gab G, *Lt:v. 9),

'1t*' " i:F i 3;i'Cld, lOOppm O> i: OiF >@?*,.*'1;*i:Ei7i

.!: L'C 8b> G, *'L, L, lOAEL ld lO ppm !: * ;iE, *L. ii "'.NMP 13:, 2 '1 { iE3E:z:', Z!a;j *s , k C F- ; . 1 !=*sv. C

NOAEL j, 51 ppm !: :i .; . G, *'L;b, " '. j!t: jjj;?j E it ;ijc*!5l*. , NOABL 1d 90 ppm" != ;ig'. _ G, j'L. ,.

t: F IC3:31i. , fE ! ! *? :',*,*Rj '7b3;:i ' *LCi, *. ** NMP @>1 gPj :7b* <g 'C ,6, C !:t . 1 E*'C i

C : , {1 @);i$***- j*1 >:*< . e;*, 6, " i:: > :Fj 1*1 1a*t:'z!5 .*,. C *'LIC*j' L, 1= } !=$;31* .,,{ ; : '@,'j*E!Z&tgi!C*t

L. t , UE!!5 " .:Fi i 0.69 ppm 'C!t*a;!*E ** ;2**t> , *L

;: *. o t: !: *& - *. Lc v* t*, " '. :;<+fj::;i !g. jc*:s v. t .

3E 0 j:6**&f ' *tCV. ,i,6gC @:)f '@?1 , Si 1

i3:, 4; :!= !ii& Lt::, 1 1it$@>{ i;:!= 6 - ';5, f .@> j: IE; 0.05 ppm J: b 6 ;fy'!= V* > @> !:t ; :iS *'Ltv*.i, '7).

!E. jj, 6*i;>@?1 .! 7j* gg *Ltv. 6 *:abi . . Cl*,

i; t,*, :5: . J E*!: ' . Q,*L;6. : i=! n O j7j***f ' *Lt*;3 b ! :j* iljgj:j:E , gFv* 18, 22).

i;!L*' G, , i' i !$F : L tE *lia U 'FiElli !: L C

ippm, !E:!E;iDc@> ,.i, C != 6. 1;, (!E:) :.{t!i. .6 c }: E:.

: " .i,. i:=t: L, ! &"01 3*!=0v*t@?. g ij=o

v*tld:: :;tE@>*n*F,'C1d+5FC' v* $6F j: ; . .

:*: i, *l) Midgley T, }{ood AJ, Chasseaud LF. Brindley Cj.

Baughman S. Allan G. Percutaneous absorption of co-administered N-methy1-2-[" C] pyrrolidinone and 2{" C]pyrrolidinone in the rat. Food Chem Toxic01. 1992; 30

57-64.

2) Ravn-Jonsen A, Edelfors S. Hass U, Lund SP: The kinet-

ic of N-methy1-2-pyrrolidone in pregnant rats and their

foestuses compared with non-pregnant rats. Toxicol Lett

1992: Supple: 136.

3) Wells DA. Digenis GA. Disposition and metabolism of

doub!e-labeled ['H and " C] N. methy1-2-pyrrolidinone inthe rat. Drug Metab Dispos 1988; 16: 243-249.

4) WeUS DA. Hawi AA. Digenis GA. lsolation and identifi-

oi:,

173

"

\

r

v

v

t

t

e

H

E

00

0

O

O

O

O

O

O

O

O

O

O

O

O

0

0

0

0

0

0

0

0

0

0

0

o

0

0

0

0

0

0

O

O

O

O

O

O

o

o

o

6

6

6

6

6

6

6

N

t

t

C

0

0

Z

C

C

N

6

6

6

6

6

6

6

6

6

6

6

t

J

J

0

0

rr

*

*

*

*

*

**

G

G

k

L

L

L

L

b

b

*

*

*

*

*

*

*

*

b

b

j

R

5

5

'

,

,

,

,

*

*

*

*

174

cation of the major urinary metabolite of N-methylpyrro-

lidinone in the rat Drug Metab Dispos 20; 124-126,

5) U. S. Environmental Protection Agency: TSCA section

8 (e) Submission on N-methylpyrrolidone (Submitted byCIBA-GBIGY Corp. : EPA Document Contro! 1.1umber

8EHQ-1087-0695. Washington, D. C. , US Environmental

Protection Agency, 1987

6) GAF Corpration. N-metbylpyrrolidone (M-pyrol)

Summary of toxicity information. GAF Corp. , Wayene

NJ 07470.7) 'BB :, nt' 1:. 8. J:*?! J, ,#!* : ; @? ' 'EE 6

lEf 3 2: < 1= N-dimethylacetamide *s J: Ci' N-

methylpyrrolidone O j t!El= O V, 'C . iiti! 1 *;: 1980;

31: 327-338.

8) Mellert W, Deckardt K. Gembardt C. Hildebraad B. N.

methylpyrolidone -subchronic oral toxicity study in

B6C3Fl mice. Administration in the diet for 3 months

(BASF Project N0. 60C0225/93053. 1995. Departinent of

BASF, Aktiengeselischft D-67056. Ludwigshafen/Rhein,

Germany.9) Lee KP, Chromey NC. Culik R. Barnes jR. Schneider

PW. Toxicity of N-methy1-2-pyrrolidone (blMP): terato-

genic, subclironic. and two-year inhalation studies.

Fundam Appl Toxicol L987; 9: 222-235,

IO) Becci PJ. Gephart LA. Koschier Fj, Johnson WD,

Burnette LW. 1: Subchronic feeding study in beagle dogs

of N. methylpyrrotidone. j Appl Toxic01 1983; 3: 83-86

ll) llass U, Lund SP, Elsner j. Effects of prenatal exposure

to N-methylpyrro!idone on postnatal development andbehavior in rats. Neurotoxicol Terat01 }994; 16: 241-249*

12) Hass U. jakobsen BM. Lund SP. Developmental toxicity

of inhaled N-methylpyrrolidone in the rat. Pharmacol

Toxic01 1995; 76: 406-409*

13) Solomon HM, Burgess BA, Kennedy GL jr. Staples RE.

l-Methy!-2-pyrrolidone OIMP): reproductive and devel.

opmental toxicity study by inhalation in the rat Drug

Chem Toxic01 1995: 18: 271-293.

14) Becci Pj. Knickerbocker Mj, Reagan EL, Parent RA,

Burnette LW. Teratogenicity study of N-methylpyrroli-

done after dermal application to Sprague-Dawley

rats. Fundam Appl Toxic01 1982; 2: 73-76.

15) Maron D. Katzenellenbogen j. Ames BN, Compatibility

of organic solvents with the SalmoneMa/microsome test

Mutat Res 1981; 88: 343-350.

16) Engelhardt G. Fleig H. 1-Methy1-2-pyrrohdinone (NMF)does not induce structura! and numerical cliromosomal

aberrations in vivo. Mutat Res 1993; 298: 149-155.

17) Solomon GM. Morse EP. Garbo MJ. Milton DK. StiUbirth

after occupationat exposure to N-methy!-2-pyrrolidone. A

case report and review of the literature. J Occup Environ

Med 1996; 38: 705-713.

18) E. Xiaofei, Wada Y. Nozaki j. et @1. A linear pliramaco-

kinetic model predicts usefulness of N-methy1-2-pyrroli-

done (NMP) in plasma or urine as a .biomarker for bio.

!ogical monitoring for NMP exposure. j Occup Med 2000;

42: 321-327.

<,

19) Leira llL. Tiltnes A. Svendsen K. Vetlesen L. lrritantcutaneous reactions to N-metby!. 2-pyrrolidone jNMP).

Contact Dermatitis L992; 27: 148-150.

20) Akesson B. jonsson BA, Major metabolic pathway for

N'-methy1-2-pyrrolido, ie in humans. Drug Metab Dispos.

1997; 25: 267-269.

21) Akesson B, Paulsson K. Experimental exposure of male

volunteers to N-methy1-2-pyrrolidone (NMP); acute effects

and pharmacokinetics of NMP in plasma and urine.

Occup Environ Med 1997; 54: 236-240.22) Ursin C, llansen CM. Van Dyk JW. Jensen PO,

Christensen U. Ebbehoej j. Permeabi!ity of commercial

solvents through living human skin. Am lnd Hyg Assoc

J 1995: 56: 651-660.

23) Deutsche Forschungsgemeinschaft List of MAK and

BAT values 2000, Wiley-VCH GmbH D-69469 Weinheim

FRG.

5i$i3 S44 . 2002

t!lCO

,

r

a

a

a

t

t

H

H

l

l

l

l

a

-

-

.