Document b8Ew9Ka5Q0OJkOep94O5dDmZ
Experiment No.: Conducted At: Dates Conducted: Conducted By:
Reviewed By:
Acute Ocular Irritation Test with T-3494
in Albino Rabbits
Hm-oyy
0884EB0011
Safety Evaluation Laboratori ;* Riker Laboratories, Ine. St. Paul, Minnesota
January 3, 1984 to January 10, 1984
& CM D. M. Markoe, Jr., 'Bs Toxicologist Study Director
* Date
__ xM m ._
Kk.7 Dd.7 O'Malley/,^VBS g
Date
Senior Toxicologist
Acute Toxicology
de: M. T. Case K. L. Ebbens F. D. Griffith W. C. McCormick
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1. Summary
The results of the acute ocular irritation test conducted from January 3, 1984 to January 10, 1984 at Riker Laboratories, Inc., St. Paul, Minnesota indicate that T-3494 is minimally irritating (3.3/110.0) to the eye of the female albino rabbit. Neither corneal opacity nor iritis were produced during the study. Minimal conjunctivitis was noted at the one hour evaluation and subsided by the two day evaluation.
Introduction The objective of this study was to determine the acute ocular irritation
properties of T-3494 when instilled into the eye of female albino rabbits. This study is not regulated by the Food and Drug Administration's Good Laboratory Practice Regulation of 1978, although the standard operating procedures of this laboratory adhere to the general principles of this regulation. The raw data generated by the Study Director and the final report are stored in the conducting laboratory's archives.
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Method and Results Young albino rabbits of the New Zealand breed-- were used to evaluate
the ocular irritating properties of the test article. The test method was modeled after that of Draize jat al-- .
The test article was instilled into the conjunctival sac of the right eye of each rabbit according to the treatment procedure presented 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 examined and graded for irritation and injury according to a standard scoring system^. The maximum possible score at any one examination and scoring period 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, special emphasis is placed upon irritation or damage to the cornea, while less emphasis is placed upon damage to the iris and conjunctiva.
After completion of the test, the scores were analyzed, and a descriptive eye 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 Table 4.
a Hazleton Dutchland, Inc., Denver, PA
-- Draize: Appraisal of the Safety of Chemicals in Poods, Drugs and Cosmetics (1965).
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The rating is arrived at by selecting the maximum mean irritation score at one hour, one, two or three days after instillation. If the rate of dissipation of injury does not meet the requirements defined for the descriptive rating appropriate for a particular numerical score, the descriptive rating is raised by one or more levels. The rating system is presented in Table 3. The protocol, principal personnel involved in the study, composition characteristics and Quality Assurance statement are contained in Appendices I - IV.
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Table 1 Eye Irritation Test - Albino Rabbits
Treatment Procedure
Test Article
Number of Animals
Evaluated
Form Administered
Quantity of Test Article Administered
Contact Period (seconds)
Volume
Evaluation Time
of Wash
Post Dose
(tap water) Administration
T-3494
6
solid
0.1 gm
unlimited
none
1 Hour, 1, 2, 3 and 7 Days
i
cessoo
t*
Table 2
Eye Irritation Test - Albino Rabbits
Scale of Weighted Scores for Grading the Severity of Ocular Lesions
Ocular
Tissues__________________________ Description________________________
Conjunctiva Redness (A)
Redness (refers to palpebral conjunctiva only).
Vessels definitely injected above normal.
More diffuse, deeper crimson red, individual
vessels not easily discernible.
Diffuse beefy red.
Chemosis (B)
Any swelling above normal (included nictitating membrane).
Obvious swelling with partial eversion of the lids.
Swelling with lids about
half-closed.
Swelling with lids abouthalf-closed tocompletely closed.
Discharge (C)
Any amount different from normal (Does not include small
amount observed in inner canthus of normal animals).
Discharge with moistening of the lids and hairs just
adjacent to the lids.
Discharge with moistening of the lids and hairs and
considerable area around eye.
Draize Grade
i
2
3
1 2 3 4
1
2
3
Score ( A + B + C ) x 2
Total maximum = 20
Cornea
Opacity (A) Opacity - Degree of density (area which is most dense is taken for reading). Scattered or diffuse area, details of iris clearly visible. Easily discernible translucent areas, details of iris slightly obscured. Opalescent areas, no details of iris visible, size of pupil barely discernible. Opaque, iris invisible. Area of Cornea Involved (B) One quarter (or less) but not zero. Greater than one-quarter, but less than one-half. Greater than one-half, but less than three-quarters. Greater than three-quarters, up to whole area.
1 2
3
4
1 2 3 4
Score equals A x B x 5
Total maximum = 80
Iris
Values (A) Folds above normal, congestion, swelling, circumcorneal 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 destruction (any or all of these).
1 2
Score equals A x 5
Total maximum = 1 0
Note: The maximum total score is the sum of all scores obtained for the
3 "i'infitiva.
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Bm w um im
Table 3
Eye irritation Test - Albino Rabbits
Classification of Test Materials Based on Eye Irritation Properties
6
Rating
Non-Irritating
Practically Non-Irri tating Minimally Irritating Mildly Irritating Moderately Irritating
Severely Irritating
Extremely Irritating
Range 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
Definition
To maintain this rating, all scores by the one day reading must be zero; otherwise, increase rating one level.
To maintain this rating, all scores by the one day reading must be zero; otherwise, increase rating one level.
TO maintain this rating, all scores by the three day reading must be zero; otherwise, increase rating one level.
To maintain this rating, all scores by the seven day reading must be zero; otherwise, increase rating one level.
To maintain this rating, scores by sever days must be ^ 10 for 60% or more of the animals. Also, mean seven day scor< must be jC 20. If seven day mean score ; <_ 20 but < 60% of animals show scores <10, then no animal among those showin scores > 1 0 can exceed a score of 30 if rating is to be maintained; otherwis raise rating one level.
To maintain this rating, scores by seve days must be ^ 30 for 60% or more of the animals. Also, mean seven day sco: must be j< 40. If seven day mean score _< 40 but < 60% of the animals show scores _< 30, then no animal among thos showing scores > 30 can exceed a score of 60 if rating is to be maintained; otherwise, raise rating one level.
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TABLE 4
EYE IRRITATION TEST - ALBINO RABBITS
with T-3494
Examination
Tissue
Period
Cornea(D-A) 1 Hour
Iris
Conjunctiva (RSD)
Total
Cornea(D-A) 1 Day Iris
Conjunctiva (RSD)
Total
Cornea(D-A) 2 Days
Iris
Conjunctiva (RSD)
Total
Cornea(D-A) 3 Days
Iris
Conjunctiva (RSD)
Total
Cornea(D-A) 7 Days
Iris
Conjunctiva (RSD)
Total
3B2037 0
____________ RESULTS________________ ANIMAL NUMBERS
3B2036
3B2035
3B2040
000
00 0 0
4(2-0-0) 4(2-0-0)
4(2-0-0)
2(1-0-0)
44 4 2
3B2039 0 0 4(2-0-0) 4
3B2038 0 0 2(1-0-0) 2
00 0 0 0 0
00 0 0 0 0
0
2(1-0-0)
2(1-0-0)
0
0
0
02 2 0 0 0
00 0 0 0 0 00 0 0 0 0 00 0 0 0 0
0 0 0 0 0 0
00 0 0 0 0 00 0 0 0 0 00 0 0 0 0 00 0 0 0 0
00 00 00 00
0000 0000 0000 0000
---------- 1------ ----
Means 0.0 0.0 3.3 3.3
1
0.0 0.0 0.7 0.7
0.0 0.0 0.0 0.0
0.0 0.0 0.0 0.0
0.0
0.0
0.0
0.0
------- --
-J
{ BEST COPY AVAILABLE
r-`-c Riker Experiment N o.:__________________
APPENDIX I
PROTOCOL
8._
jE S Y ; Acute Ocular Irritation Test
SPONSOR: 3 M __ --------------------------------------------------------------------------------------------------------------------------------------Divislc
CONDUCTED BY: Safety Evaluation Laboratory, Riker Laboratories, Inc., S t. Paul, M innesota
TEST ARTICLE:___ X;-.fe-?5.--------------------------------------------------------------------------------------------------------------------- !_________
CONTROL ARTICLE: . 1
-------------------------------------------------------------------------------------------------------------------------- --
PROPOSED STARTING/COM PLETION DATE OF TEST:
------! / - - ______________________________
TEST SYSTEM: Female New Zealand White Albino Rabbits
SOURCE: T*' . `r" <
A;r ' ` A < - ' * ' A
O B JE C T IV E :
The objective of this test will be to determine the irritation potential of the test article to the ocular tis (cornea, iris and conjunctiva) o f __:----------albino rabbits. Rabbits were selected as the test syi for their sensitivity to irritants, historical use, ease of handling and general availability.
METHOD:
The animals will be housed in standard wire-mesh cages in temperature and humidity contr
rooms with food and water offered ad libitum. Each animal will be assigned a numbered ee
which will correspond to a card affixed to the outside of the cage. The test article will be instillei
the conjunctival sac of the right eye at a dose of
-------- with the contralateral eye of each a
serving as a control. A t ------------------- :-----------------------hours and . . A ; .....t.--- !...c ../------------------
(additional scoring intervals may be added to further characterize the ocular reactions), the tissui
be examined and graded for irritation and injury according to a standard scoring system of I
ef a/fe. After completion of the test, the scores will be analyzed, and a descriptive eye irritation
assigned to the test article. Eye examinations may be carried out with the aid of sodium fluore
If deemed necessary by th e ^ u d y director, washed eye procedures entailing a 5 and 30 s
contact period with a
**____ L ll___wash over a ___ _____________ period will be conductec
3 animals per procedure. All raw data generated by the study director and the final report
stored in the Riker Laboratories' Archive, St. Paul, Minnesota.
Purina Rabbit Chow, Ralston-Purina, St. Louis, Missouri Draise: Appraisal of the Safety of Chemicals in Foods, Drugs, and Cosmetics (1965)
Published by the Editorial Committee of The Association of Food and Drug Officials of the United States.
Sponsor
Date
Study Director
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APPENDIX II principal participating personnel Involved in the Study
Name D. M. Markoe, Jr., BS K. L. Ebbens, BS K. D. O'Malley, BS G. C. pecore
Function
Toxicologist Study Director
Supervisor Toxicology Testing
Senior Toxicologist Acute Toxicology
Supervisor Animal Laboratory
9
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APPENDIX III Composition Characteristics This study is not regulated by the Good Laboratory Practice Act of 1978 and therefore information pertaining to composition characteristics is not applicable for inclusion in this study.
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11.
APPENDIX IV Quality Assurance Statement This study is not officially regulated by the Good Laboratory Practice Regulation of 1978, and therefore a statement signed and prepared by the Compliance Audit department is not applicable. The standard operating procedures of this laboratory does adhere to the general principles of this regulation. The Compliance Audit department does inspect different significant phases for studies underway in the Acute Toxicology Laboratory on a recurring cycle, and the facilities are examined on a three month schedule. In addition a select number of Research & Development studies are routinely picked at random from the Archives by the Compliance Audit department for review.
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