Document rBd1MMb7jJkp6VdJN62yrYbvv
Ex,-eriment No.: Conducted At: Dates Conducted: --onducted By:
Re%,iewed By:
ID
Acute Ocular Irritation Test -ith T-3421
in Albino Rabbits
0883L--BC286
Safety Evaluation Laboratory Riker Laboratories, Inc. St. Paul, Minnesota
June 21, 1983 to August 1, 1983
L
D. M. Markoe, Jr., BS Toxicologis t Study Director
Date
K. D. O'Malley, BS Senior Toxicologist Acute Toxicology
Date
Ebbens, BS Supervisor, Toxicology
Testing Date
do: @t. T. Case F. D. Griffith
Summary
The results of the acute ocular irritat-icn test conducted from
June 21, 1983 to Au@@ust 1, 1983 at R,-ker Laboratories, inc., St. Paul,
M,@nr,esota indicate that T-3421 is moderately irr,-tat--ing(40.0/110.0) to the ,,@nwashed eye of the fe.-ialeal2ino rabbit. A five second an4 t.@i,-rlsyecond
contact washed eye procedure .,ere also conducted employing a five liter wash.
The irritation ratings for T-3421, using the 1,.cLr-edcontact procedures, were
mildly irritating (15.7/110.0) for the five second and rildly 1-rritat,-ng
(18.3/110.0) for the thirty second contact procedure.
Minimal corneal opaz:ity, iritis and moderate conjurctivitis were produced
dur,-ng the unli.7.itecicontact zrocedure by the one hour evalua-@,,on. '-7@e
irritation subsided to r%inir-ia-c,o-rneal opacity with vasc,,@.la-rization (-@@wo
and slight conjunctivit@-s (three animals) by t-e day seven evaluation.
T-3421, when allowed a five and thirty second contact, produced ir'.tis
and nuld conjunctivitis by the one hour evaluation. All irritaticn subsided
by the day two evaluataon. Of either '@reat-ment group.
Cornea! opaci-ty was not observed in any animal
introduction The objective of t-his study was to assess t-he acute ocular irritation
properties of T-3421 when instilled into the washed and unwashed eye of female albino rabbits. This study was conducted in accordance with the Food and Drug Administration's Good Laboratory Practice Regulation of 1978. The raw data generated by t-he Study Director and the final report are stored in the conducting laboratory's archives.
2
Method and Results
Young albino rabbits of the New Zealand bree--a were used to evaluate
the ocular irritating properties of the test article. b
modeled after that of Draize et al-@--.
Tte rest method was
The test article was instilled into the conjunctival sac of the right
eye of each rabbi-. according to the treatment procedure Dresented in
Table 1 with the left eye of each animal serving as a control. At each
scoring interval, the cornea, iris and palpebral conjunctiva were exataned
and graded for irritation and injury according to a stan(3ard sccring b
systenr . The maxim,= possible score at any one examination and scoring c)eriod 110 points, -which indicates maximal irritation and damage to all
three ocular tissues (cornea, iris, conjunctiva) while a score of zero
indicates no irritation (Table 2). in this scoring system, sr)ecial
emphasis is placed udon irritation or damage to t-he cornea, while less
enz)hasis is pi-aced uz>on danage to the iris and conjunctiva.
After co:7,pletionof the test, the scores were analyzed, and a
descriptive eve irritation rating was assigned to the test article. The
criteria used for assignment of the descriptive rating were the frequency,
the extent and the persistence of irritation or damage which occurred to
the three ocular tissues (Table 3). The individual results are presented
in Tables 4-6.
a Hazleton Dutchland, Inc., Denver, PA Draize: Appraisal of the Safety of Chemicals Cosmetics (1965).
in Foods, Drugs and
3.
The rating is arrived at by selecting the maximum mean irritation score at one hour, one, two or t-l@.redeays after instillat@.on. if the rate of dissipation of injury does nct meet the requirements defined for t-l,.e descriptive rating appropriate for a particular numerical score, t-l,,e descriptive rating is raised by one or more levels. The rat-ing system is ,nresented in Table 3. The protocol, principal personnel involved in the study, composition characterist-ics and 2uality Assurance statement are contained in Appendices I - IV.
'J'ableI Eye Irritation Test - Albino Rabbits
Treatment Procedure
Test Article T-3421
T-3421
T-3421
Number ot Animals
Evaluated
6
Quantity of
@'orill
'I'estArticle
Adniinistere(i---A-(Intinistered
Contact Period (secorids
waxy solid
0.1 gm
unlimited
3
waxy solid
0.1 qm
5 seconds
3
waxy solid
0.1 qm
30 seconds
volume
Fva I
ot Wash
flo.,i
(tal)water)- Aciini
none
1 llo a n(i
none
I lic and
none
1H
and
Table 2
5.
Eye --rritation Test - A'-tiro RabtitS
Ocular Tissues Conjunctiva
Scale of Weighted Scores for Grad--ng the Severity of -Icular Les,.zns
DescriDI-i-on
Redness (A) Redness (refers to nalpebral ccn-unctiva only).
Vessels definitely in3ected above normal. .More diffuse, deeper crimson red, -:-,dividual
vessels not easily discernible.
Diffuse beefy red.
Cl@emosis (B) Any swelling above nor-mal (included nictitating membrane). Obvious swelling with partial eversion of the lids.
Swelling with 14@ds about half-closed. Swelling with lids about half-close-@ to completely closed.
Discharge (C) A.,iyamount different from nor7,,al(Does not include small amount observed in inner canthus c@@normal animals).
-Discharge with moistening adjacent to the lids. Discharge with moistening
of -@-e li,-4sand hairs -iust of the lids and '-,airsand
considerable area around eye.
Draize @@rac@e
1
2
3
1 2 3 4
I
2
3
Cc)rnea
Score (A + S + C) x 2
Total L-.--xinum= 20
o@,acitv (A)
ODacity - Degree of density (area w-ich is most
dense is taken for read-,@ng).
Scattered or diffuse area, details of iris clearly visible.
I
Easily discernible translucent areas, details of
2
'r,.s sl-,ghtly obscured.
Opalescent areas, no details of iris visible, size of
3
pi-,p:.blarely discernible.
Opaque, iris invisible.
4
Area of Cornea Involved (B)
One quarter (or less) but not zero.
1
Greater than one-quarter, but less than one-half.
2
Greater than one-half, but less t-hantliree-quarters.
3
Greater than three-quarters, up to whole area.
4
Score equals A x B x 5
Total maximum = 80
Iris
Values (A)
Folds above normal, congest-ion, swelling,
1
circumccrneal injection (any or all of these or
combination of any thereof), iris still reacting
to light (sluggish reaction is positive).
No reaction to light, hemorrhage, gross
2
destruction (any or all of these).
Note:
Score equals A x 5
Total maximum = 10
The maximum total score is the sum of all scores obtained for the cornea, iris and con3unctiva.
6.
@@ati-ng No,i-irritating
Practically No,-i-irrita@@ing Minimally irritating Mildly Irritating
Moderately irritating
Severely Irritating
Extremely Irritating
3
EYE IF-R@'TATION -,EST ALB--!,C
Classification of Test Material-S Based on Eye Irritation Properties
@ange 0.0 - 0.5 > 0.5 - 2.5 > 2.5 - 15.0 > 15.0 - 25.0 > 25.0 - 50.0
> 50.0 80.0
> 80.0 110.0
t ion
To maintain this rating, all scores by the one day reading --.ustbe zero; otherwise, increase rating one level.
To ma@-n@,a;-nthis rating, all scores by t--- one day read-*-ngmust be zero; otherwise, increase rating one level.
To maintain this rating, all scores tv the three 4-a@?re=-d@-nc@-,Last'--ezero; otherwise, increase rating one level.
To maintain this rating, all scores bv t-e 7-day reading nust be zero; other-wise, increase rating one level.
To maintain this rating, scores by 7 davs -.iustbe < 10 'Lor 60% or -nore of t"..e animals. Also, mean 7-day score must !De < 20. if 7-day mean score is < 20 but < 60% of animals show scores < 10, then no an4--ialamong those showing scores > 10 can exceed a score of 30 if rating is to be maintained; otherwise, raise rating one level.
To -.ain,@ainthis rating, scores by 7 days must be < 30 for 60% or more of the a-,iimals. Also, mean 7-day score must be < 40. if 7-day mean score is < 40 but < 60% of the animals show scores < 30, then no animal among those showing scores > 30 can exceed a score of 60 if rating is to be maintained; otherwise, raise rating one level.
4 EYE li@l@l'I'ATION 'I'LSI'- AI,131NO f@AI-if3lI'S
with T-3421
'I'issue 'uzriect(D-A)
EXalninatioii ileriod
1 flour
iris CL)11)unctiva
(RSD)
Coriica(D-A) iris Conjunctiva
(RSD)
Cornea(D-A)
Total 1 Day
Total 2 Days
iris
Conjunctiva (RSD)
Total
Coriiea(D-A) 3 Days
Iris
Colijuiictiva (kSD)
Total
k-'uL-iica (I)-A)
7 Days
iris
Conjunctiva (RSD)
Total
3B988 lo(I-2)
5 16(2-3-3) 31 20(1-4)
5 18(3-3-3) 43
-0-@-1- 4 5 12(2-2-2) 37
--31398@l 15 (1-3)
AN I MAI, NIJMIIF:l@@;
3BI012 --@- -3111-014-------@
5(1-1)
5(1-1)
3B.995 lo(I-2)
0 10(2-1-2)
5 14(2-2-3)
0 14(2-2-3)
5 10(2-1-2)
25
24
19
25
20(1-4)
20(1-4)
20(1-4)
20(1-4)
5
5
5
5
12(2-2-2)
16(3-2-3) 12(2-2-2)
18(3-3-3)
37
41
37
43
2C)(1-4)
5 12(2-2-2)
5 14(2-2-3)
5 10(2-1-2)
12(2-2-2)
37
39
35
37
20(1-4) 5
33 lo(I-2)V
0 B(2-1-1) JB
20(1-4) 5
33 10(1-2)V
0 8(2-1-1) in
20(1-4)
20(1-4)
5
5
l@__(2-27:21
37
33
-
0
2 (1-0-0-.)--0-----
2
0
20(1-4) 5 8
33 0
0 0
Key:
Cornea: D=Density A=Area
Conjurictiva: R=Re(illess S=Swelling D=Discliarge
V=Vascularization
3B9 5 0 14( 19 20(
14( 39
12( 27 10(
5 -B
23 0 0 0 0
TAilt,E 5
EYE IRRII'ATION TEST - AI,BINO RADDITS with T-3421 (5 Second Contact)
JAESUI,TS
Examination
ANl?4AI, NUMBERS
MEJ
Tissue
Period
3BI1()l-
3BI164
3Bll48
Cornea(D-A) 1 Hc)ur
0
0
0
0.
Iris
5
5
5
Conjunctiva
12(2-2-2)
12(2-2-2)
8(2-1-1)
(RBD)
Total 17
17
13
15.
Cornea(D-A) 1 Day 0 0 0 0.
Iris
5
5
5
Conjunctiva
8(2-1-1)
6(1-1-1)
(no)
Total
13
11
11
:ornea(D-A) 2 Days
0
0
0
0.
Iris
0
0
0
0.
Conjunctiva
0
0
0.
(R&D)
Total
0
0
0
0.
Cornes(D-A) 3 lays 0 0 0 0.
Iris
0
0
0
0
Conjunctiva
0
0
(RrsD)
Tota
0
0
Cornea(D-A) 7 Days
0
0
0
0
Iris
0
0
0
0
Conjunctiva
0
0
L@RSD)
Total
0
0
Key:
Cornea:
D = Density A = Area
Corijtinctiva-- l@ = R(-Idiiess S = Swelling D = Discharge
TABLE 6
EYE IltRITATION TEST - ALBINO RABBITS wityi T-3421 (30 Second Contact)
RESUT,TS
Examination
ANIRAL NUMBERS
ME
Tissue Period 3lill7O 3BI162 3D0II65 0
Cornea(D-A) 1 flour
0
0
Iris
5
5
5
5
12(2-2-2)
16(3-3-2)
12(2-2-2)
13
Conjunctiva
Total
17
21
17
IB
Cornea(D-A) 1 Day
0
0
0
0
Iris
5
5
5
5
njunctiva
8(2-1-1)
10(2-2-1)
10(2-2-1)
1)
(R&D)
Total
13
15
15
14
r
Cornea(DA) 2 Days 0 0 0 0
0
0
0
0
Iris
t(C
0
0
0
Conjunctiva
(RW)
Total
0
0
0
Cornea(D-A) 3 Days
0
0
0
Iris
0
0
0
0
Conjunctiva 0 0 0
(RSD)
Tota
0
0
0
0
A) 77 Days
0
0
0
0
Cornta(D-A)
70
0
0
0
Iris
0
0
0
0
onjun ctiva
(RSD)
Tota
0
0
0
0
Key:
Cornea:
D = Density A = Area
Conjunctivd:
l@ = Re(Iriess s = swellitig D = Discharge
APPE',IMIX 1
PROTOCOL
Riker Experiment No-:
TEST:
Acute Ocular IrritatioTnest
SPONSOR: 3M CONDUCT ED BY: Safety Evaluation Laboratory, Riker Laboratories,Inc.,St.Paul, Minnesota
TEST ARTICLE:
CONTROL ARTICLE:
PROPOSED STARTING;COMPLETION
DATE OF TEST:
TEST SYSTEM: Female New Zealand White Albino Rabbits
SOURCE:
10. Divlsion
OBJECTIVE: METHOD:
The objectiveof thistestwillbe to de termine the irritatipoontentialof the testarticleto the c>culartissues (cornea,irisand conjunctiva)of - '' - albinorabbits.Rabbits were selected as the testsystem fortheirsensitivittyo irritantsh,istoricaulse, ease of handling and general availability.
The animals willbe housed in standard wire-mesh cages in temperature and humidity controlled
rooms with fooda-and water offeredad libitum.Each animal willbe assigned a numbered ear tag
which willcorrespond to a card affixedto the outsideof the cage. The testarticlewillbe instilleidnto
the conjunctivalsac of the righteye at a dose of
withthe contralateraelye of each animal
serving as a control.At
hours and
days
(additionalscoring intervalsmay be added to furthercharacterizethe c>cularreactions),the tissues will
be examined and graded for irritatioand injuryaccording to a standard scoring system of Draize
et alt. Aftercompletion of the test,the scores willbe analyzed, and a descriptiveeye irhtabonrating
assigned to the test articleE.ye examinations may be carded out with the aid of sodium fluorescein.
Ifdeemed necessary by the study director,washed eye procedures entailinga 5 and 30 second contact pe@@ with a TI 1 1 '-4- wash over a @ @-i- - periodwillt>econducted using 3 animals per procedure. Allraw data generated by the study directorand the finalreportwillbe
stored in the Riker Laboratories'Archive,St. Paul, Minnesota.
C. Sponsor
2 Purina Rabbit Chow, Ralston-PuHna, St.Louis,Missouri Draise: Appraisalof the Safety of Chemicals inFoods, Drugs, and Cosmetics (1965 Published by the EditoriaClommittee of The Associationof Food an6'DiG6-o-ffcii,als--,IT7F of the United States.
--,-,,3 Date
ID-k-@
Study Director
JEUTNYN 13 19833 j UALUAIJON
SASALFE,TY E1V3AL1U9A8IION
@L
@t 7
0883EB0286
.%;,oE,4Drx r (--ortclu@!ed) oeviationc And/or A=enjrents to protocol The source for the test animals is wazelton-C,-ltchland Labs., Denver, PA.
z-t,,:dDyirector
6/21/83 Date
2.
3.
olrector 4.
study Director
Ca t a
Study Directoc
cats
12.
APPR-NCIX 11
Principal ParticL@ating Personnel Involved in tfte Study
Nazie D. M. Markoe, Jr., BS K. L. Ebbens, BS
K. D. O'Malley, BS G. C. Pecore
Fu.,itcion
T'OX-'LCologist
Study Director
supervisor
Toxicology Test-ing
Senior Toxicologist Acute Toxicology
Supervisor Animal Laboratory
13. Test and/or Control Article Characteri-zat,@on
1. The identity strength, unifor-mity, composition, pur@.,,yor other pertinent ch&racterizations of the test and/or control s,-L@-,sta:-.]c@:aevse,_, been deter-mined and doc-,Lmented as of -1
2. The method of synthesis or origin of the test and contr--l including their a.,,iounatnd the mer-liodof bioassay (:.faz-@,licat'-e)is docL,.,nented. yes @@ no
3. -.he stat-ility of the test and/'or cdn,.rol S,,L'-Sta.-Ic@eisa*.*1e:@-endeter-
r'l,nedor will be deterr-.inedas of
T,
The a@)ove infor-.7ationand docu.-rentationare located in t@@e
re-
cords.
Sponsor
Date
1983
14.
APPV-NDIX IV
QUAL:TY A-ZSUR-KNCE STATE,4-7NT
Acute Toxicology Laboratory
Study No.:
0883EB0286
Stud4-es
T'nis short term study was audited by Compl4-ance Audi-. and the
final report exam4-ned against the raw data on August 29, 1983
-.he results of t@@ieaudit ,@?erereported
management on August 30, 1983
to the study d@-rector and to
in addition to t-ne data audit, d,-tferent s@-gn@-fican-.phases for
s-@ud--,@esunde--way @-.it-fteAcute Toxicology Laboratory are i-nsE->ecl@ed
weekly on a recurr@-,,igcycle, and tne
are examined by
Compli.ance Aud4-t on a -Z:-hreemonth sclieclule.
'@)
15Z:@7-7@
e--C'-ompliance Aud-it
August 30, 1983
Da te