ABSTRACT
PDGHLQWKHYDOLGDWLRQRIDOWHUQDWLYHWHVWVIRUGHUPDOWR[LFLW\ PDU\RI UHFHQWSURJUHVV LVSURYLGHGIRU WKHYDOLGDWLRQRI WHVWV VLRQLUULWDWLRQVHQVLWL]DWLRQDQGSKRWRWR[LFLW\&XUUHQWHIIRUWV RSHUFXWDQHRXVDEVRUSWLRQPHWKRGDUHGLVFXVVHG
SKIN CORROSION
YHUHFHQWO\EHHQYDOLGDWHGIRUWKHPHDVXUHPHQWRIVNLQFRUUR HDQ &HQWUH IRU 9DOLGDWLRQ RI $OWHUQDWLYH 0HWKRGV (&9$0 %RWKWKHWUDQVFXWDQHRXVHOHFWULFDOUHVLVWDQFHDVVD\7(52OLYHU DQGWKH(SLVNLQŠWHVWZHUHIRXQGWREHDFFHSWDEOHIRUDZLGH ODVVHV 7KH\ PHW DOO RI WKH FULWHULD RI XQGHUSUHGLFWLRQ DQG
RYHUSUHGLFWLRQDQGV LELOLW\&RUURVLWH[ŠZ RIWKHWHVWFKHPLFDOV
$ SURSRVHG2(& XVLQJWKH WHVWUHVXOWV DO7KHDXWK QRQFRUURVLYHE\ WKH DFWLYLW\ UHODWLRQVKLS DERYHYDOLGDWHGPHW WHVWQHHGVWREHFRQ ,Q 9LWUR ,QWHUQDW
9DOLGDWLRQ RI$OWHUQ URVLWH[Š IRU VNLQFR FOXGHG WKDW LQ FHUWD &RUURVLWH[ŠFRXOGEH XVHGDVSDUWRIDWLH
$OWKRXJKDQXPE DQGVNLQPHPEUDQHS DQG WKH UHVXOWLQJ LQÁ LUULWDWLRQLVOLNHO\WR FRUURVLYLW\ UHVSRQVH KXPDQ VNLQ HTXLYDOH VWXGLHV %RWKDPHW D QRF\WHFXOWXUHVDUHQ LVLPSRUWDQWLQWKHLU
$Q (&9$0VSR 7KHVWXG\FRP (SLVNLQŠ3UHGLVNLQŠ
IXQFWLRQWHVW6,)7 ZHOOHQRXJKWRDGYD SKDVH,,,GLGQRWPH UHPDLQVWREHHYDOXD
7KH ORFDO O\PSK YDOLGDWHGE\,&&9$ DORQHDOWHUQDWLYHIRU VSHFLÀFVWHSVDVRXW WKHXVHRIPLFHIHZ WKHPLFHKDYHOHVVGL
KRZHGDFFHSWDEOHLQWUDODERUDWRU\DQGLQWHUODERUDWRU\UHSURGXF DVDOVRHYDOXDWHGLQWKHVWXG\EXWZDVQRWXVDEOHIRUDERXW 7KLVWHVWGLGQRWPHHWDOOWKHFULWHULD IRUDFFHSWDELOLW\ ' WHVWLQJ VWUDWHJ\ IRU FRUURVLYH FKHPLFDOVZDV HYDOXDWHG E\ IRU WKHFKHPLFDOV LQ WKHDERYHYDOLGDWLRQVWXG\:RUWKHW RUVFRQFOXGHG WKDWFKHPLFDOVFDQEHFODVVLÀHGDVFRUURVLYHRU VHTXHQWLDODSSOLFDWLRQRI WKUHHDOWHUQDWLYHPHWKRGV VWUXFWXUH V ZKHUH DYDLODEOH S+PHDVXUHPHQWV DQG HLWKHU RQH RI WKH KRGV7(5RU(SLVNLQŠ$ÀQGLQJRIQRQFRUURVLYLW\LQWKHWLHU ÀUPHGZLWKDUDEELWWHVW LRQDO DVNHG WKH ,QWHUDJHQF\ &RRUGLQDWLQJ &RPPLWWHH RQ WKH DWLYH0HWKRGV ,&&9$0 WR HYDOXDWH WKH XVHIXOQHVV RI &RU UURVLYLW\PHDVXUHPHQWV7KH ,&&9$0SHHUUHYLHZSDQHO FRQ LQ FLUFXPVWDQFHV XVH IRU86'HSDUWPHQW RI7UDQVSRUWDWLRQ XVHGDVDVWDQGDORQHDVVD\,QRWKHUFDVHVWKHDVVD\FRXOGEH UHGDVVHVVPHQWVWUDWHJ\
SKIN IRRITATION
HURIPHWKRGVIRUVNLQLUULWDWLRQKDYHEHHQHYDOXDWHGLQFHOOFXOWXUH UHSDUDWLRQVQRPHWKRGVKDYHDV\HWEHHQYDOLGDWHG6NLQLUULWDWLRQ DPPDWRU\ UHVSRQVH LV D FRPSOH[ SURFHVV 6LPXODWLRQ RI VNLQ EHPRUHGLIÀFXOWLQDQ LQYLWURV\VWHPWKDQLVVLPXODWLRQRIWKH 7KH (&9$0 VNLQ LUULWDWLRQ WDVN IRUFH UHSRUW FRQFOXGHG WKDW QW PRGHOV VKRXOG JHW KLJK SULRULW\ IRU (&9$0 SUHYDOLGDWLRQ O )XUWKHUPRUH WKH UHSRUW VWDWHV WKDWPRQROD\HUNHUDWL RWVXLWHGIRUURXWLQHWHVWLQJRIFKHPLFDOVEHFDXVHVNLQSHUPHDWLRQ ULWDWLRQSURFHVVDQGFDQQRWEHHYDOXDWHGLQFHOOFXOWXUHV QVRUHG SUHYDOLGDWLRQ VWXG\ ZDV FRQGXFWHG GXULQJ DQG SDUHGWKHSUHGLFWLYHFDSDELOLWLHVRIÀYHWHVWPHWKRGV(SLGHUPŠ WKHQRQSHUIXVHGSLJHDUPRGHODQGWKHPRXVHVNLQLQWHJULW\ 1HLWKHU3UHGLVNLQQRUWKHQRQSHUIXVHGSLJHDUPRGHOSHUIRUPHG QFHWRSKDVH,,,7KHSHUIRUPDQFHRI(SLGHUPDQG(SLVNLQ LQ HW WKHFULWHULDVHWIRUDIRUPDOYDOLGDWLRQVWXG\7KH6,)7WHVW WHGLQSKDVH,,,)HQWHPHWDO
SKIN SENSITIZATION
QRGH DVVD\ //1$ UHFHQWO\ EHFDPH WKH ÀUVW WHVW PHWKRG
07KHSHHUUHYLHZSDQHOUHFRPPHQGHGWKH//1$DVDVWDQG FRQWDFWVHQVLWL]DWLRQSURYLGHGWKDWWKHSURWRFROFRQWDLQHGFHUWDLQ OLQHGLQWKHUHSRUW$QRQ$OWKRXJKWKH//1$UHTXLUHV HUDQLPDOVDUHQHHGHGWKDQZLWKDQLQYLYRVWXG\)XUWKHUPRUH VFRPIRUWVLQFHWKHDVVD\RQO\LQYROYHVLQGXFWLRQRIVHQVLWL]DWLRQ
7KH(XURSHDQ8Q LQWKDWHYDOXDWH SKRWRKHPRO\VLV WHVW 6NLQ7HVWVNLQDQG 7158WHVWZDVI YDOLGDWLRQRIWKH7 FKHPLFDOVLQO ZLWKLQYLYRGDWD6S PLWWHHDQGWKH(XURS YDOLGDWHGDQGUHDG\ 6FLHQWLÀF&RPPLWWH WKDW WKH7158P FRVPHWLFLQJUHGLHQWV
,Q YLWUR VNLQ DEV KD]DUGRXVWRSLFDOO\D FRQFHUQLQWKHH[SRVX EHPRVWUHOHYDQWEXW WRREWDLQKXPDQVNLQ FROOHFWHG EXW WKH SU $QLPDODEVRUSWLRQG KXPDQVNLQ,IPHWD IURPKXPDQVNLQZR ,QYLWURVNLQDEVR
VWXGLHV UHSRUWLQJ JR YLWURVNLQPRGHOLVS WKHVNLQVWUXFWXUHLV D VLPLODUPDQQHU LQ PRUH FORVHO\ VLPXOD RQPHWDEROLVPGXULQ WRFROIRUFRQGXFWLQJ VNLQ %URQDXJK DQG QRWEH DGGHG WR WKH LQWR WKH UHFHSWRU ÁX DQGVNLQFRQWHQWVDW DEVRUSWLRQYDOXHVE\ WKHSURWRFRO VSHFLÀH ZKHQVNLQPHWDEROLV EHVKRZQWREH LQWD WKH(XURSHDQ&HQWHU WKH (XURSHD
SKIN PHOTOTOXICITY
LRQ(8DQG&ROLSDVSRQVRUHGDSUHYDOLGDWLRQVWXG\EHJLQQLQJ GWKHDFFXUDF\RIVHYHQPHWKRGVLQPHDVXULQJSKRWRWR[LFLW\ KLVWLGLQH R[LGDWLRQ WHVW &DQGLGD DOELFDQV WHVW 6RODWH[ 3, WKH7PRXVHÀEUREODVW WHVWQHXWUDOUHGXSWDNH1587KH RXQGWRJLYHWKHEHVWFRUUHODWLRQZLWKLQYLYRGDWD7KHIRUPDO 158WHVWZDVFRQGXFWHGLQ²E\(8&2/,3$XVLQJ DERUDWRULHV7KHUHVXOWVZHUHUHSURGXFLEOHDQGFRUUHODWHGZHOO LHOPDQQHWDO7KH(&9$06FLHQWLÀF$GYLVRU\&RP HDQ&RPPLVVLRQ(&FRQFOXGHGWKDWWKH7158WHVWZDV WREHFRQVLGHUHG IRU UHJXODWRU\DFFHSWDQFH7KH(&6&&1)3 HIRU&RVPHWLFVDQG1RQ)RRG3URGXFWVKDVUHFHQWO\SURSRVHG HWKRGEH WKHVWDQGDUGPHWKRGIRU WHVWLQJ89OLJKWDEVRUELQJ IRUSKRWRWR[LFSRWHQWLDO
PERCUTANEOUS ABSORPTION
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ÁXLG WRSURPRWHSDUWLWLRQLQJRI WKH WHVW FRPSRXQG LG$EVRUSWLRQZDV GHÀQHG DV WKH VXPRI WKH UHFHSWRU ÁXLG WKHHQGRIWKHVWXG\6SOLWWKLFNQHVVKXPDQVNLQJDYHSUHIHUUHG PLQLPL]LQJUHWHQWLRQRIDEVRUEHGPDWHULDOLQVNLQ$OWKRXJK
V WKHXVHRIYLDEOH VNLQQRQYLDEOH VNLQVKRXOGEHVXIÀFLHQW PLVQRWDQLVVXH+RZHYHUWKHEDUULHUSURSHUWLHVRIVNLQPXVW FW3URWRFROVKDYHDOVREHHQSURSRVHGUHFHQWO\ LQ(XURSHE\ IRU(FRWR[LFRORJ\DQG7R[LFRORJ\RI&KHPLFDOV(&(72& Q &RVPHWLF 7RLOHWU\ DQG 3HUIXPHU\ $VVRFLDWLRQ &2/,3$
0DFPLOODQ 0HWKRGV(&9$0
0DMRUDUHDVRIG SUHSDUHGE\WKHDER
$GUDIW2(&'S LVFXUUHQWO\LQWKHDS
DQG WKH (XURSHDQ &HQWUH IRU WKH 9DOLGDWLRQ RI $OWHUQDWLYH +RZHVHWDO LVDJUHHPHQWH[LVWEHWZHHQRXUSURWRFRODQGVRPHRUDOORIWKRVH YH(XURSHDQRUJDQL]DWLRQV7KHLVVXHVDUHOLVWHGEHORZ
URWRFRODQGJXLGDQFHGRFXPHQWKDVDGGUHVVHGWKHVHLVVXHVDQG SURYDOSURFHVV
REFERENCES