10.14.1. Quy nh i vi tp cht l dung mi tn d (CPMP/ICH/283/95)

 

M u

Mc tiu ca Quy nh ny l ra lng dung mi cho php tn d trong dc phm, nhm bo m s an ton ca ngi bnh. Quy nh khuyn co dng cc dung mi t c v ra nhng gii hn c tnh c th chp nhn c i vi mt s dung mi.

Dung mi tn d trong dc phm l cc cht hu c bay hi, c s dng hoc sinh ra trong qu trnh sn xut cc dc cht, t dc hoc qu trnh bo ch cc dc phm. Cc dung mi ny khng loi b c hon ton trong qu trnh sn xut. S chn lc dung mi thch hp c th nng cao sn lng hoc quyt nh cc c tnh nh dng tinh th, tinh khit, tnh ho tan ca sn phm. V vy, i khi dung mi l yu t quyt nh trong quy trnh tng hp. Quy nh ny khng cp n cc dung mi dng c cn nhc k lng nh mt cht ph gia, hoc n cc solvat. Tuy nhin hm lng dung mi trong cc sn phm loi ny phi c xc nh v chng minh hp l.

V cc dung mi tn d khng c tc dng iu tr, cc dung mi ny phi c loi b n mc ti a t c cc yu cu k thut ca sn phm, vic thc hnh tt sn xut (GMP) hoc cc yu cu cht lng khc. Dc phm phi cha mt mc dung mi tn d khng c cao hn cc d liu an ton. Phi trnh dng mt s dung mi c c tnh khng th chp nhn c (dung mi nhm 1, Bng 10.14.1-1), tr khi li ch ca vic s dng chng c xc nh chc chn. Mt s dung mi c c tnh t nguy him hn (dung mi nhm 2, Bng 10.14.1-2) cng cn phi dng hn ch, bo v ngi bnh khi tc dng c hi. Tt nht phi dng cc dung mi t c (dung mi nhm 3, Bng 10.14.1-3).

 

Phm vi p dng

Cc dung mi tn d trong dc cht, t dc v dc phm thuc phm vi p dng ca quy nh ny. V th phi thc hin php th tm cc dung mi tn d trong qu trnh sn xut hay tinh ch kim sot s hin din ca chng. Ch cn kim tra i vi cc dung mi c s dng hay c sn sinh ra trong qu trnh sn xut hoc tinh ch cc dc cht, t dc hoc dc phm . Mc d cc nh sn xut c th chn phng php xc nh hm lng dung mi tn d trong sn phm, ta vn c th tnh hm lng , i t hm lng dung mi tn d trong cc thnh phn dng sn xut ra sn phm . Nu kt qu tnh ton bng hoc thp hn gii hn cho php c khuyn co trong bn quy nh ny, th khng cn tin hnh th nghim trn sn phm. Tri li, nu kt qu tnh c vt mc gii hn cho php, dc phm phi c th nghim bit chc chn lng tn d dung mi c nm trong phm vi cho php khng. Sn phm cng phi c th nghim nu c dng dung mi trong qu trnh sn xut.

Quy trnh ny khng p dng cho dc cht, t dc hoc sn phm mi ang trong qu trnh nghin cu p dng lm sng v cng khng p dng cho cc dc phm ang c lu hnh trn th trng.

Quy nh ny p dng cho mi dng bo ch v mi cch dng thuc. Trong mt vi trng hp, c th cho php gii hn dung mi tn d cao hn nh khi dng trong thi gian ngn (30 ngy hay t hn), hoc khi dng dng thuc p. Vic chng minh s ng n ca gii hn cao ny phi da trn c s ca tng trng hp mt.

Xem ch thch 2 bit thm thng tin c bn c lin quan ti cc dung mi tn d.

 

Cc nguyn tc c bn

Phn loi dung mi tn d theo mc nguy him

Thut ng liu c th dung np c cho mi ngy (tolerable daily intake, TDI) c Chng trnh quc t v an ton ho cht (IPS) s dng v thut ng liu c th dng mi ngy (acceptable daily intake ADI) c T chc y t th gii, cc Vin v cc c quan qun l sc kho quc gia v quc t khc s dng ch gii hn hm lng cc ho cht c c th dng mi ngy.

Thut ng mi liu phi nhim c php mi ngy (permitted daily exposure, PDE) c nu trong Quy nh ny l mt lng dung mi tn d c th a vo c th, trnh nhm vi liu ADI ca cng dung mi.

Cc dung mi tn d ghi trong Quy nh ny c lit k theo tn thng thng. Chng c phn lm 3 nhm, tu thuc kh nng gy c i vi sc kho con ngi, nh sau:

Nhm 1: Cc dung mi cn trnh dng

Cc cht gy ung th cho ngi hay c kh nng gy ung th cho ngi r rt. Cc cht nhim c mi trng.

Nhm 2: Cc dung mi cn hn ch dng

Cc cht gy ung th trn ng vt khng c cho gen hoc cc tc nhn c th gy c khng hi phc nh c tnh trn thn kinh hoc gy qui thai. Cc dung mi nghi c c tnh quan trng, nhng hi phc c.

Nhm 3: Cc dung mi c tnh thp

3.1. Cc dung mi c c tnh thp trn ngi: Khng cn xc nh liu gy tc hi cho sc kho.

Cc dung mi nhm 3 c liu phi nhim c php mi ngy (PDE) bng hoc ln hn 50 mg/ngy.

3.2. Phng php xc nh gii hn phi nhim

Phng php dng xc nh liu phi nhim c php mi ngy ca cc dung mi tn d c gii thiu trong ch thch 3. Tm tt cc d liu v c tnh dng thit lp liu phi nhim c php mi ngy c cng b trong Pharmeuropa Vol 1, No 1, Supplement April/1997.

3.3. Cch xc nh gii hn dung mi nhm 2

C hai cch c th p dng xc nh gii hn cho cc dung mi nhm 2.

Cch 1:

C th dng hm lng (nng ) gii hn tnh theo phn triu (ppm) ghi trong Bng 10.14.1-2. Cc nng ny c tnh theo cng thc (1) vi lng ch phm dng mi ngy cho l 10 g.

1000 x PDE

Nng (phn triu) = (1)

10

Vi PDE: liu phi nhim c php mi ngy tnh theo mg/ngy,

10: s ly lm lng ch phm dng trong mi ngy v tnh theo g/ngy.

Gii hn ny p dng cho mi dc cht, t dc hoc dc phm. Cch mt c th p dng nu liu dng hng ngy khng c bit hoc khng c quy nh c th. Khi mi t dc, dc cht c trong cng thc bo ch p ng vi gii hn cho bi cch 1, cc thnh phn ca ch phm c th dng theo bt k t l no. Khng cn tnh ton g thm, nu liu dng mi ngy khng qu 10 g. Ch phm c liu dng ln hn 10 g mi ngy phi tnh theo cch 2.

Cch 2:

Khng nht thit mi thnh phn ca dc phm u phi p ng gii hn a ra trong cch 1. C th dng liu phi nhim c php mi ngy (PDE) tnh theo mg/ngy ghi trong bng 10.14.2, cng vi liu ti a mi ngy v cng thc (1) xc nh hm lng dung mi tn d cho php trong dc phm. Cc gii hn ny c chp nhn min l chng minh c rng dung mi tn d c gim n lng thc t ti thiu. Cc gii hn ny phi thc t c lin quan n chnh xc ca php phn tch, iu kin sn xut, cc thay i hp l ca qu trnh sn xut v cc gii hn phi thc hin cc tiu chun cng ngh ng thi.

C th p dng cch 2 bng cch cng cc lng dung mi tn d trong mi thnh phn ca ch phm. Tng lng dung mi dng trong ngy phi thp hn liu phi nhim c php mi ngy (PDE).

Hy xt mt v d p dng cch 1 v cch 2 cho dung mi acetonitril trong mt dc phm. Liu phi nhim c php mi ngy ca (PDE) acetonitril l 4,1 mg/ngy. Nh vy, gii hn tnh theo cch 1 l 410 phn triu (410 ppm). Lng dng ti a mi ngy ca dc phm l 5,0g; dc phm cha 2 t dc. Thnh phn dc phm v hm lng ti a ca acetonitril tn d th hin trong bng sau y:

 

Thnh phn

Lng trong cng thc ch

Hm lng acetonitril

Lng phi nhim mi ngy

Dc cht

0,3 g

800 ppm

0,24 mg

T dc 1

0,9 g

400 ppm

0,36 mg

T dc 2

3,8 g

800 ppm

3,04 mg

Dc phm

5,0 g

728 ppm

3,64 mg

T dc 1 p ng gii hn tnh theo cch 1.

T dc 2, dc cht v dc phm khng p ng gii hn tnh theo cch 1.

Tuy th, dc phm tnh theo cch 2 p ng gii hn 4,1 mg/ngy, v nh vy ph hp vi yu cu ca quy nh ny.

Hy xt mt v d khc, coi acetonitril l dung mi tn d. Lng dng ti a mi ngy ca mt dc phm l 5,0 g, dc phm c cha 2 t dc. Thnh phn dc phm v hm lng ti a ca acetonitril tn d th hin trong bng sau:

 

Thnh phn

Lng trong cng thc ch

Hm lng acetonitril

Lng phi nhim mi ngy

Dc cht

0,3 g

800 ppm

0,24 mg

T dc 1

0,9 g

2000 ppm

1,08 mg

T dc 2

3,8 g

800 ppm

3,04 mg

Dc phm

5,0 g

1016 ppm

5,08 mg

 

Trong v d ny, dc phm khng p ng gii hn tnh theo cch 1 v c cch 2 bng cch cng. Nh sn xut phi th nghim dc phm xem qu trnh bo ch c lm gim mc tn d ca acetonitril khng. Nu sut qu trnh bo ch, mc acetonitril khng gim ti gii hn cho php, khi nh sn xut phi tin hnh cc bc lm gim lng acetonitril trong dc phm. Nu tt c cc bc ny khng lm gim c mc tn d ca acetonitril, trong trng hp c bit, nh sn xut c th cung cp bn tm tt nhng c gng gim lng dung mi tn d, nhm t quy nh ny, v a ra l l phn tch nguy c/li ch khi dng ch phm c cha dung mi tn d mc cao ny.

3.4. Qu trnh phn tch dung mi tn d

Phng php phn tch dung mi tn d thng thng l dng k thut sc k nh sc k kh. Nu thch hp, dng phng php xc nh dung mi tn d m t trong dc in. Ngoi ra, nh sn xut c th t do chn la mt quy trnh phn tch c hiu lc thch hp nht p dng ring. Nu ch hin din dung mi nhm 3 thi, c th dng mt phng php khng c hiu nh phng php gim khi lng do sy kh (Ph lc 9.6).

Thm nh cc phng php xc nh dung mi tn d phi tun th cc quy nh ca ICH (Hi ngh quc t bn vic hi ho cc yu cu k thut ng k cc thuc dng cho ngi) ghi trong Vn bn thm nh quy trnh phn tch (Text on validation of analytical procedures) v M rng vn bn thm nh quy trnh phn tch (Extension of the ICH Text on validation of analytical procedures).

3.5. Bo co mc dung mi tn d

Nh sn xut dc phm cn nm chc thng tin v nng dung mi tn d trong dc cht v t dc dc phm sn xut ra t c mc ca Quy nh ny.

Sau y l cc v d v cc thng tin m nh cung cp t dc hay dc cht c th cung cp cho nh sn xut dc phm. Nh cung cp c th chn mt trng hp thch hp trong s cc trng hp sau y:

- Ch c cc dung mi nhm 3 hin din. Gim khi lng do sy kh khng dng qu 0,5%.

- Ch c cc dung mi nhm 2 (X, Y...) hin din. Tt c phi thp hn gii hn tnh theo cch 1 ( y, nh cung cp ch r tn cc dung mi nhm 2; X, Y...).

- Ch c cc dung mi nhm 2 (X, Y...) v cc dung mi nhm 3 hin din. Cc dung mi nhm 2 tn d di mc gii hn tnh theo cch 1 v cc dung mi nhm 3 tn d khng qu 0,5%.

Nu chc chn c hin din cc dung mi nhm 1 th phi nh tnh v nh lng chng. Dung mi chc chn c hin din l nhng dung mi c dng trong giai on cui ca quy trnh sn xut v cc dung mi khc c dng trc m khng c loi b hon ton bng cc bin php hu hiu.

Nu dung mi hin din mc ln hn gii hn cho php tnh theo cch 1 (nhm 2) hay ln hn 0,5% (nhm 3) th chng phi c nh tnh v nh lng.

 

Gii hn dung mi tn d

4.1. Dung mi phi trnh s dng

Khng c s dng cc dung mi nhm 1 trong cc x nghip sn xut dc cht, t dc v dc phm. Chng c c tnh khng th chp nhn c, hoc c tc hi n mi trng. Khi buc phi s dng chng trong quy trnh sn xut mt dc phm c tc dng tr liu tin trin, phi tun th gii hn ghi trong bng 10.14.1. Dung mi 1,1,1-tricloroethan c trong Bng 10.14.1-1 v l mt tc nhn nguy hi cho mi trng. Gii hn 1.500 phn triu da trn c s mt thng tin v d liu an ton.

4.2. Dung mi phi hn ch s dng

Cc dung mi trong Bng 10.14.1-2 phi c quy nh mc gii hn c trong dc phm v c tnh vn c ca chng. Liu phi nhim c php mi ngy (PDE) gn 0,1 mg/ngy. Hm lng tn d trong dc phm cho php gn 10 phn triu.

4.3. Dung mi c c tnh thp

Cc dung mi nhm 3 (c trong Bng 10.14.1-3) c th coi nh t c v c nguy c thp i vi sc kho con ngi. Nhm 3 bao gm cc dung mi khng nguy him i vi sc kho con ngi hm lng thng c chp nhn trong dc phm. Tuy nhin cha c cc nghin cu v c tnh trng din v v kh nng gy ung th ca nhiu dung mi thuc nhm ny. Cc d liu hin c cho thy cc dung mi ny t ra t c trong cc cuc nghin cu cp din hoc ngn hn v cho kt qu m tnh vi nhng th nghim c tnh trn di truyn. Do , coi nh c php dng cc dung mi ny vi lng 50 mg mi ngy hoc thp hn (tng ng vi hm lng 5000 ppm hoc 0,5% tnh theo cch 1) m khng cn phi thuyt minh. C th dng mc cao hn, min l thc t c lin quan n kh nng sn xut v thc hnh sn xut tt.

4.4. Dung mi cha c thng tin v c tnh

Cc dung mi trong Bng 10.14.1-4 c th cng c cc nh sn xut dc cht, t dc hoc dc phm quan tm. Tuy nhin, cha c cc d liu y v c tnh ca chng lm c s cho vic xc nh liu phi nhim c php mi ngy (PDE). Khi s dng cc dung mi ny trong sn xut, nh sn xut phi gii trnh r rng s tn d ca cc dung mi ny trong sn phm ca mnh.

Bng 10.14.1-1: Nhm 1 cc dung mi trong dc phm

 

Dung mi

Nng gii hn (ppm)

c tnh

Benzen

2

Gy ung th

Carbon tetraclorid

4

c v nguy hi cho mi trng

1,2- Dicloroethan

5

c

1,1- Dicloroethen

8

c

1,1,1- Tricloroethan

1500

Nguy hi cho mi trng

 

Bng 10.14.1-2: Nhm 2 cc dung mi trong dc phm

 

Dung mi

Liu phi nhim c php mi ngy (PDE) mg/ngy

Nng c gii hn (ppm)

Acetonitril

4,1

410

Clorobenzen

3,6

360

Cloroform

0,6

60

Cyclohexan

38,8

3880

1,2- Dicloroethen

18,7

1870

Dicloromethan

6,0

600

1,2- Dimethoxyethan

1,0

100

N,N- Dimethylacetamid

10,9

1090

N,N- Dimethylformamid

8,8

880

1.4- Dioxan

3,8

380

2- Ethoxyethanol

1,6

160

Ethylenglycol

6,2

620

Formamid

2,2

220

Hexan

2,9

290

Methanol

30,0

3000

2- Methoxyethanol

0,5

50

Methylbutylketon

0,5

50

Methylcyclohexan

11,8

1180

N- Methylpyrrolidon

48,4

4840

Nitromethan

0,5

50

Pyridin

2,0

200

Sulfolan

1,6

160

Tetralin

1,0

100

Toluen

8,9

890

1,1,2- Tricloroethen

0,8

80

Xylen*

21,7

2170

* Thng dng hn hp gm m-xylen 60%. p-xylen 14%. o-xylen 9% v ethyl benzen 17%.

Bng 10.14.1-3: Cc dung mi nhm 3, phi c gii hn v GMP hoc v cc yu cu cht lng khc

 

Acid acetic

Heptan

Aceton

Isobutyl acetat

Anisol

Isopropyl acetat

1- Butanol

Methyl acetat

2- Butanol

3- Methyl-1-butanol

Butyl acetat

Methylethylketon

Tert Butylmethyl ether

Methylisobutylketon

Cumen

2- Methyl-1-propanol

Dimethylsulfoxid

Pentan

Ethanol

1- Pentanol

Ethyl acetat

1- Propanol

Ethyl ether

2- Propanol

Ethyl format

Propyl acetat

Acid formic

Tetrahydrofuran

Bng 10.14.1-4: Cc dung mi cha c thng tin v c tnh

 

1,1- Diethoxypropan

Methylisopropylketon

1,1- Dimethoxymethan

Methyltetrahydrofuran

2,2- Dimethoxypropan

Petroleum

Isooctan

Acid tricloracetic

Isopropyl ether

Acid trifluoroacetic

 

* Ch thch 1: Thut ng

Genotoxic carcinogens: Tc nhn gy ung th do tc ng ln gen hay chromosome

LOEL: Vit tt ca t lowest-observed effect level.

Lowest observed effect level: Liu thp nht dng trong mt th nghim hay nhm cc th nghim gy s gia tng c ngha sinh hc v tn s hoc v mc nghim trng ca bt k cc tc dng no trn ngi hay ng vt b phi nhim.

Modifying factor (Thng s hiu chnh): Mt thng s c chuyn gia c cht hc xc nh v p dng cho cc d liu nh lng sinh hc th hin cc d liu an ton cho ngi.

Neurotoxicity: Nhim c thn kinh

NOEL: Vit tt ca t no-observed effect level

No-observed effect level: Liu cao nht ca cht dng m khng gy s gia tng c ngha sinh hc v tn s hoc v mc nghim trng ca bt k cc tc dng no trn ngi hay ng vt b phi nhim.

PDE: vit tt ca t Permitted daily exposure

Permitted daily exposure: Lng cao nht c th dng trong mt ngy ca dung mi tn d trong dc phm.

Reversible toxicity: c tnh phc hi c, tc l s mt i sau khi kt thc phi nhim.

Strongly suspected human carcinogen: (tc nhn nghi ng gy ung th trn ngi):

Mt cht khng c du hiu dch t hc l c kh nng gy ung th nhng li cho kt qu dng tnh v c tnh trn gen v cc du hiu r rng v kh nng gy ung th trn loi gm nhm.

Teratogenicity (c tnh gy qui thai): S c gy d tt v cu trc trong qu trnh pht trin thai nhi khi s dng mt cht trong thi k mang thai.

 

Ch thch 2:

2.1. Quy ch bo v mi trng i vi cc dung mi hu c bay hi

Mt s dung mi thng dng trong sn xut dc phm c lit k nh cc ho cht c trong cc chuyn lun Cc tiu chun trong sch mi trng (EHC = Environmental Health Criteria) v v H thng cnh bo nguy c tim tng (IRIS = Integrated Risk Information System). Trong cc mc tiu ca cc t chc nh Chng trnh th gii v an ton ho cht (IPCS = International Programme on Chemical Safety), C quan bo v mi trng M (USEPA = United States Environmental Protection Agency) v T chc qun l thc phm v dc phm M (USFDA = United States Food and Drug Administration) c vic xc nh cc mc phi nhim c th chp nhn c. Mc ch l bo v sc kho con ngi v gi gn s trong sch vn ton ca mi trng, chng li cc tc dng c th c hi ca cc ho cht do phi nhim lu di ti mi trng. Cc phng php dng xc nh mc ti a phi nhim an ton thng c cn c trn cc th nghim di hn. Khi dng c cc d liu t nhng th nghim di hn, c th dng d liu t cc th nghim ngn hn vi vic ci tin cch tip cn nh vic s dng cc yu t thng s an ton ln hn. Cch tip cn ni trn y ch yu lin quan ti cc phi nhim di hn hay sut i, i vi cc cng ng dn c, trong mi trng xung quanh nh khng kh, thc n, nc ung v cc iu kin mi trng khc.

2.2. Dung mi tn d trong thuc

Cc gii hn phi nhim trong quy cch ny c thit lp cn c vo cc phng php hc v cc d liu v c tnh m t trong cc tiu chun trong sch mi trng (EHC) v trong cc chuyn lun ca H thng cnh bo nguy c tim tng (IRIS). Tuy nhin, mt s gi nh c bit v dung mi tn d trong vic tng hp v bo ch cc dc phm phi c tnh n khi thit lp cc gii hn phi nhim. l:

1/ Nhng ngi bnh (khng phi ton th cng ng) phi s dng thuc phng hoc cha bnh.

2/ Vic gi nh l a s cc dc phm gy phi nhim sut i cho ngi bnh l khng cn thit, song c th thch hp nh mt gi thit lm vic, nhm gim nguy c n sc kho con ngi.

3/ Cc dung mi tn d l nhng thnh phn khng th trnh c trong sn xut dc phm v cn thng l mt phn ca thuc.

4/ Cc dung mi tn d phi khng c vt qu cc mc khuyn co, tr nhng trng hp c bit.

5/ Cc d liu t cc nghin cu c cht hc dng xc nh cc mc chp nhn c cho cc dung mi tn d phi c thit lp bng cch s dng cc quy trnh thch hp, chng hn cc quy trnh do OECD m t v s dng cun sch ca T chc qun l thc phm v dc phm ca M (FDA Red book).

 

Ch thch 3: Phng php thit lp cc gii hn phi nhim

Phng php nh gi nguy c ca Gaylor - Kodell (Xem: Gaylor, D.W. v Kodell, R. L. - Thut ton ni suy tuyn tnh nh gi liu thp ca cc cht c. J. Environ Pathology, 4, 305, 1980) thch hp vi cc dung mi gy ung th thuc nhm 1. Ch trong cc trng hp c cc d liu ng tin cy v tnh gy ung th th phi p dng ngoi suy bng cch dng cc m hnh ton hc thit lp cc gii hn phi nhim. Cc gii hn phi nhim ca cc dung mi nhm 1 c th c xc nh vi vic s dng mt thng s an ton ln (t 10 000 n 100 000) i vi mc khng pht hin c gy hi (NOEL). Vic pht hin v nh lng cc dung mi ny phi c thc hin bng cc k thut phn tch tin tin hin thi.

Cc mc phi nhim chp thun c ca cc dung mi nhm 2 ghi trong quy nh ny c thit lp bng cch tnh cc gi tr PDE theo cc quy trnh xc nh gii hn phi nhim ca cc thuc (xem Pharmacopeial Forum 11-12/1989) v theo phng php c Chng trnh th gii v an ton ho cht (IPCS) tha nhn nhm nh gi nguy c i vi sc kho con ngi do ho cht (xem Environmental Health Criteria 170, WHO, 1994). Cc phng php ny tng t nh cc phng php ca c quan bo v mi trng M (USEPA) v ca t chc qun l thc phm v dc phm M (USFDA) v cc t chc khc na. Phng php c gii thiu s lc y nhm cung cp mt hiu bit tt hn ngun gc ca cc liu phi nhim c php mi ngy (PDE). Khng nht thit phi thc hin cc php tnh ton ny m s dng ngay cc gi tr PDE ghi trong cc bng trnh by mc 4 ca quy nh ny.

Gii hn PDE c tnh t Mc khng pht hin gy hi (NOEL) hoc t mc pht hin gy hi thp nht (LOEL trong th nghim trn sc vt nh sau:

 

 

NOEL x th trng quy c

PDE =

F1 x F2 x F3 x F4 x F5

 

Vi:

Th trng quy c = trng lng c th ngi trng thnh, khng phn bit gii tnh, c quy c tnh y l 50 kg.

F: Cc thng s hiu chnh

PDE thng c tnh t NOEL. Khi khng thit lp c NOEL, c th dng LOEL. Cc thng s hiu chnh ra y chuyn i cc d liu th nghim trn sc vt sang cho ngi, cng tng t nh cc thng s khng chc chn (Uncertainty factors) dng trong Tiu chun trong sch ca mi trng (EHC) (Xem Environmental Health Criteria 170, WHO, Geneva, 1994) v thng s hiu chnh (modifying factors) hay thng s an ton (Safety factors) dng trong Pharmacopeial Forum.

Cc thng s hiu chnh

F1 l thng s ngoi suy gia cc loi

F1 = 2, khi ngoi suy t th nghim trn ch sang ngi

F1 = 2,5, khi ngoi suy t th nghim trn th sang ngi

F1 = 3, khi ngoi suy t th nghim trn kh sang ngi

F1 = 5, khi ngoi suy t th nghim trn chut trng ln (rat) sang ngi

F1 = 10, khi ngoi suy t th nghim trn cc loi ng vt khc sang ngi

F1 = 12, khi ngoi suy t th nghim trn chut nht sang ngi.

F1 tnh c khi so snh t l gia din tch b mt vi trng lng c th ca loi vt tham gia th nghim v ca ngi. Din tch b mt (S) c tnh nh nhau:

 

 

Vi:

M: Trng lng c th (trng lng c th ca sinh vt tham gia th nghim, dng trong cng thc trn, c lit k trong bng 3-1).

k = 10

F2 l thng s ch s khc bit gia cc c th

F2 = 10, thng dng cho tt c cc dung mi hu c v dng thng nht trong quy nh ny.

F3 l mt thng s khng hng nh, dng trong cc th nghim phi nhim ngn hn.

F3 = 1, cho cc th nghim ko di t nht bng 1/2 i sng ca vt th nghim (1 nm i vi loi gm nhm hoc th, 7 nm i vi ch, mo hoc kh).

F3 = 1, cho cc th nghim v sinh sn, ko di trong sut thi gian hnh thnh cc c quan ph tng.

F3 = 2, cho cc th nghim ko di 6 thng, trn loi gm nhm hoc 3,5 nm trn cc th khng thuc loi gm nhm.

F3 = 5, cho cc th nghim ko di 3 thng, trn loi gm nhm, hoc 2 nm trn th khng thuc gm nhm.

F3 = 10, cho cc th nghim ngn hn hn.

Trong mi trng hp, khi th nghim ko di trong khong thi gian nm gia 2 mc thi gian quy nh trn, th ta cho F3 gi tr cao, ng vi mc thi gian th nghim ngn. V d: F3 = 2 trong th nghim ko di 9 thng trn loi gm nhm (v 9 thng nm trong mc 1 nm v 6 thng, do ly F3 bng F3 ca mc 6 thng).

F4 l mt thng s p dng trong cc trng hp c tnh nghim trng nh: Gy ung th khng c cho gen, c tnh thn kinh, c tnh gy qui thai. Trong cc th nghim v c tnh sinh sn, thng s ny c dng nh sau:

F4 = 1, khi gy c trn bo thai cng vi gy c trn m.

F4 = 5, khi gy c trn bo thai, nhng khng gy c trn m.

F4 = 5, khi gy qui thai cng vi gy c trn m

F4 = 10, khi gy qui thai trn bo thai, nhng khng gy c trn m

F5 l mt thng s khng hng nh, p dng khi khng thit lp c mc khng pht hin gy hi (NOEL). Khi ch c th xc nh c mc gy hi thp nht (LOEL), c th cho F5 gi tr cao, c th ti F5 = 10, tu thuc vo mc nghim trng ca c tnh.

Trng lng c th quy c cho ngi trng thnh, khng phn bit gii tnh y l 50 kg. Trng lng ny tng i thp hn trng lng chun mc (60 70 kg) thng p dng trong cc tnh ton cng loi (tnh liu dng thuc) l nhm mc ch an ton.

Mt s ngi bnh c trng lng nh hn 50 kg, nhng ngi bnh ny phi c xem xt iu chnh bng cch dng thng s an ton xc nh PDE.

Nu dung mi c trong mt cng thc dc phm chuyn dng cho khoa Nhi, ta phi iu chnh thch hp, v trng lng c th ca tr thp.

Th d p dng cng thc tnh PDE:

Hy xt mt th nghim c tnh ca acetonitril trn chut nht, th nghim ny c tm tt trong Pharmaeuropa Vol 9, No1, Supplement April 1997 page S 24 mc khng pht hin gy hi (NOEL) l 50,7 mg/kg/ngy. PDE ca Acetonitril trong th nghim ny c tnh nh sau:

 

 

Vi:

F1 = 12: Thng s ngoi suy t th nghim trn chut nht sang ngi

F2 = 10: Thng s khc bit gia cc c th (thng nht quy nh l F2 = 10).

F3 = 5: Thi gian th nghim ch c 13 tun (> 3 thng)

F4 = 1: Khng thy c tnh nghim trng no.

F5 = 1: mc khng pht hin gy c hi (NOEL) c xc nh.

Phng trnh dng cho kh l tng PV = nRT c p dng chuyn hm lng cht kh trong th nghim dng phng php xng (inhalation studies) t n v phn triu thnh n v mg/l hay mg/m3.

Hy xt th nghim c tnh sinh sn trn chut trng bng cch xng kh carbon tetraclorid (khi lng phn t 153,84) c tm tt trong Pharmaeuropa Vol 9. No1. Supplement April 1997, p.S9:

 

 

Dng cng thc 1000 lt = 1m3 suy ra hm lng mg/m3

 

 

 

 

 

Bng 10.14.1-5. Cc gi tr dng tnh ton trong ti liu ny

 

Trng lng chut trng (Rat)

425 g

Trng lng chut trng c thai (Pregnant rat)

330 g

Trng lng chut nht (Mouse)

28 g

Trng lng chut nht c thai (Pregnant mouse)

30 g

Trng lng chut lang (Guinea pig)

500 g

Trng lng kh n (Rhesus monkey)

25 kg

Trng lng th (c thai hoc khng c thai)

4 kg

Trng lng ch sn nh (Beagle dog)

11,5 kg

Dung lng h hp ca chut trng (Rat respiratory volume)

290 l/ngy

Dung lng h hp ca chut nht

431 l/ngy

Dung lng h hp ca th

1440 l/ngy

Dung lng h hp ca chut lang

4301 l/ngy

Dung lng h hp ca ngi

28800 l/ngy

Dung lng h hp ca ch

9000 l/ngy

Dung lng h hp ca kh

1150 l/ngy

Lng nc chut nht dng

5 ml/ngy

Lng nc chut trng dng

30 ml/ngy

Lng thc n chut trng dng

30 g/ngy