Document O15zvKG40JyQRQ0rO437ywjLv
AR226-2904
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EVALUATION OF OCULAR IRRITANCY POTENTIAL: SOURCES OF INTRALABORATORY VARIABILITY AND EFFECT OF DOSAGE VOLUME
-1 Company SanWzedL Does not contain T SC A CBI
Haskell Laboratory Report No. 85-81
October 6 , 1981
EVALUATION OF OCULAR IRRITANCY POTENTIAL: SOURCES OF INTRALABORATORY VARIABILITY AND EFFECT OF DOSAGE VOLUME
Study Performed by:
J^Ladn S. Ford Technician
Technician
Report Priapared by:
seephn J. Williams Research Toxicologist
Study Director
Apjproved by: ____ -___________ --OAJor. ^ Gerald L. Kennedy, Jn, i
Chief, Acute Toxicology
SJW: ic:WP:3,,4
;
Stud) nltlated/Compie ted: 2/7/81-4/8/81
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H ask ell Laboratory Report No. 485-81
October 6 , 1981
EVALUATION OP OCULAR IRRITANCY POTENTIAL: SOURCES OF INTRALABORATORY VARIjABILITY AND EFFECT OF DOSAGE VOLUME
ACKNOWLEDGEMENTS
!. The author would like to acknowledge the excellent technical asslstence of John E. .Henry and Lynn S. Fordjand thank G. Jay Graepel for consultation on the design of these studies anq for statistical analysis of the data.
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Haskell Laboratory Report No. 485-81
October 6, 1981
t5!^LUATI0N 0F
IRRITANCY POTENTIAL: SOURCES OP
IBTKALABORATORY VARIABILITY AND EFFECT OF DOSAGE^VOLUMB
INTRODUCTION
Current standard methods or assessing chemicals have been the subject of
^, .. ocular irritancy potential of
The best documented criticism ils a study m whl^ h ^ nUmber f dlrectlons* degree of Intralaboratory and <nt-v.fov * hl h demonstrated the high
such tests using a 'standardized' ^ f u j a^ry variability of results from
criticized based on T ^ 3 3 L ^ 2 S ^ -
te8t 1188 also bee"
scores obtained from three separate o e u S ^ f 7 f 8ddln 8emi-quantitative
suggested that a dosage volume^ of 0 l
Moreover* ic has been
extremely high relative to the s u r f ^ e ^ e a VOlUne U8ed* 18
together with known ohvsiolovll
? f the ratbic e^e` This fact,
risk (2). The most recent criticism
PURPOSE
I' |
C
* Ero.0,
,b" n d'eisDei "
i-m. rabble . / c a r
23- S ^ 1'.1VltT " *
'1TM * . . o . l ..a 0,o . of Che teat n.lng reduce doa.
PROCEDURE
H a a b f i r L b ^ r f J*;!!."" " .*.t.*J B) > " o l F ta.tad oalag at.nd.rd
the heal, of being llgoida eeaf n . . S
cPnnda "*r* "looted on
i-S-SS:
cob. Odd Elvon a letter
TM rL
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U
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-sssjss
- ? <72 * " . * .
corneal surface of the right eye of 1 of 7 m fif' i f * app^fed directly to the
was untreated and served as Che m n r L i 7J1 albil M bits. The le f t eve
was not washed or manipulated in any way C b m l l ^ d V " ' 'laaa"d and the eye similar manner into the right eve of a ^ kkff p0?M,d G fcd8 instilled in a
used. Compound G served as the I n t e J L f bblta* but a volume of 0.10 mL was
provided the data base foi
CBt" 1 * flnd eyes dosed with it
rfligi?1 ?c 1 and * hours and at 1, 2 3 7Cef/ vfrffbflity* Eyes were then
O H P b y 2 independent and experienced
.and 21 daF8 (Haskell SOP, f k m f t
'"vowsrvations of the cornea ri* ..a ^ers (J, E. Henry and L. S. Ford
ophthalmoscope. Fluor-i-strin* etainfn^UnCtiVa Were made with an
*
were recorded separately. To characteiize^hi' corneal and i r l tic changes
or the indices (total corneal1 o re S i f L i B?"rce# of v a ria b ility , each
independently using analysis of v a r i S c ^ m C g "nctvaf ' TM > as analyzed
the variab ility change over time, each of the MBecausa of the agnitude of
independently.
. aCn of the time periods was analyzed
RESULTS
to elucidate*theSource S ^ j S S S i * ^ 0'1 "t* M r eii os lntemol controls
scots. f ,, conjuoctlv. . J c o TM e . 0" i.7.t" ' ' I S " " " " ''
*ot"
since this compound did not have any iritie Iff t~ * deterluations,
data is given in Appendices Clrad
Thf* effect. The analysis of variance
rabbit differences are the greatest',,r reaults demonstrate that rabbit to
At o. t i ,, st. ths test group, s'aource^f f l`H ? illCT *C " V *-- tlo.
group results re consi.fen^lj S S S f o
euSestln8 that test
significant reader variabilltfluaa --
reproducible. The only
apparent for both corneal M d ^ o n j u " ^ * ! / hUf? P8t doslnS* This is
attributed to an artifact of th
, scores. This difference might be
that 1 reader consistently read before***
8tudy director was not aware
th. offsets, is ,, s t c . . ,, , " 2 S s e h i . 0tb.=t- At 4 1>" post trestnent
rapidly. Consequently, the difference L ma*iB|un and may be changing
effect, not reade variability^.
served is probably due to a time
Animal strain: New Zealand White Rabbits Supplier : B & H Rabbitry, Rockville, MD
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Dose-effect Relationship
f o r i S S S cS . L . i 2 2 2 3 f f i 'T S 2 . " 2 . ! ; cor" * 1 r * " j 1'' *
purpose, the f i r s t ..b it do2 3 ' ?
'W - _
Tta ;lth chejr,bhle * d eech
ofl^^HAl
S e h M h h f i T T " f 08f grc?ups was nade eing the M a n n -W h itn ^ ^ ^ W ) J was assigned the mean score for the 2 readers at eacS time ita
? H d fr C0nparl8on were
score and time to recovery for the
22 222 2 " 1" 1 80111 2 2s i i J S l n d *significantly different at the jp< 0.05 level.
iod.r
y
I Lcj-volume Eye Teat
The median scores for corneal and conjunctival effects are Binp p ^
x p s r 1 : i t .m e s S s S S S . --
JStSZ/ZZi
s ? u - ~ " 5 1
S S s ' . ' S i ' S ~upuctiv.co.ps2d
o
E rS rf
23 31.S
as--
inalJ'y . since a Clear Hnfie-affact relationship has been
~
coJ2l2T22c2i
<fP""u tested ld ee.or.ble cornee! sod
SUMMARY
!
22 2 2 2 2-- S K L ^ ^ i i S ? ' , <*.,,Jieye test is used routinely at Haskell onlv for Pf f
,, ,W e V r ' the
Jtof ocular irritancy potential 'Therofnro7 effect/no effecu determination
222 22223S22^S? - - -
"
When tested at a dosage voliume of 0.01 er n in ri , , ,, __
relationship was discernible
1 * a dose-errect
maximal effect as endpoints. I P * ] "81"8 either tme to recovery or
G
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e - i s ;iva*ii.^s:d#":vss;y
,
b.Hd'on : * " l : ^ k S " i;,ci i r i f " s i " p0i" n;ec,t'i ln thi* j y *i
f * v i u L a .ppiiS . c . " TM
T ii.bc*^ " "'" l y 1
chemicals fj>r eye irritancy potential at Haskell
I
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Material TeBted
Haskell No.
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c< Q
O
mum
13,895 13,896
1 13,897
13,611
APPENDIX A - TEST COMPOUNDS
Date Received
Letter Code
Othe: Codes Used In
and Names
Study ; Material Submitted By
I M12/10/80
T ^12/12/80
h
TI
H C
Textile Fibers Dept.
Chemicals & Pigments Dept. Jackson Lab
Chemicals & Pigments Dept. Jackson Lab
Chemicals & Pigments Dept. Jackson Lab
nemicala & Pigments Dept. Jackson Lab
Central Research & Development Dept. Haskell Laboratory
Chemicals & Pigments Dept. Jackson Lab
APPENDIX B CHARACTERISTICS OF TEST COMPOUNDS Composicin: f Contaminants: Composition: Purity: Composition: Contaminants: Purity:
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Time Post-Dosing
1 Hr. 4 Hr. 1 Day 2 Day 3 Day 7 Day 14 Day 21 Day
appendix C
analysis op vaptamTM
C0|iKOL CORNEAL SCORES1
Reader NSC 0.25 NS NS
NS NS NS NS
-- Variance Group Rabbit NS 0.91 NS 0.25 NS 0.33 NS 0.30 NS : 3.03 NS 1.71 NS 1.73 NS 1.75
Residual 1.10 0.67 0.54 0.86
0.62 0.93 0.38 0.05
Due To Rabbits 45.1 21.4
38.1
25.8 83.1 65.1
81.8 97.2
.
rabbits. ValUe iS baSCd UPn Cl|e total corneal score obtained from 36
rabbits/week lor"? c) Not significant
aB8eS8ed on the basis of 6
i j 1
c
i
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Tine Post-Dosing
1 Hr. 4 Hr. 1 Day 2 Day 3 Day 7 Day 14 Day 21 Day
Reader NSC 0.99 NS NS NS NS NS
NS
appendix d
ANALYSIS OP VAb t Ann? CONTROL CONJUNCTIVAL SCORES*
Variance
Group Rabbits Residual
NS
1.60
0.95
NS
0.75
0.53
NS
1.43
0.73
NS
3.00
0.62
NS , 3.01
0.48
NS ; 1.45
0.39
NS 0.64
0.19
NS : 0.04
0.05
X Of Variance Due To Rabbits
61.1 33.0 66.2 82.9 86.0 78.8 77.1 30.8
36 rabbits31"6 ^ b M e d UPn th* tOCal con-1u<*ivaI core obtained iron
f T T C frouP differences were assessed on the basis of 6
rabbits/week for 6 weeks
:
c) not significant
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APPENDIX E
Corneal Scores - Dose-Effect Relationship
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APPENDIX F
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APPENDIX G
SCORE
-A-wootMTt a.e-jwn x-c-xvra 0--MOW*ATI +-D-MILB 0f-WH.C VIM|IU>
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APPENDIX H
MEDIAN CONJUNCTIVAL SCORES
"
a-A-UODOUIt AaC-SCVOK X*t IVtU OB-U00DUTt +aD-UIU> Oaf-MILD 9.M-UIID
TIME IN DAYS
,
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APPENDIX I
Literature Cited
(1) Well, C. S. and Scala, R. (1971). "Study of Intra-and Inter-
IrritaMny
/ I th Rsulta of Rabbit Eye and Skin
Irritation Tests . Toxicol, Appl. Pharmacol._ 19:276-360.
(2'
A (198o/`
' 'i *' ??UCe* R* Dr 8eer' P * J" Bannan E*
Aihinn BaKKi ,,D08"**8*}* Studies with Chemical Irritants in the
Ei! HS Basi s or Selecting Optimum Testing
(3) Snedecor, G. W. and Cochrai^, W. G., (1980) Statistical Methods, The Iowa State Dniversity Pres4, Ames, Iowa.
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