TOXICOLOGY AND APPLIED PEIARMACOLOOY 7, 93-101 (1965) 

Comparative Eye Testing: Man vs. Animal 

JOHN HENRY BECKLEY 

Medical Research Services, Colgate-Palmolice Company, Sew York, New York lOOZ-7 

The title of this paper LLComparative Eye Testing: Man VUS. Animal” should be 

modified to read, ‘Some Observations and Limited Conclusions Which Might Be 

Acceptable, after Review of Data Obtained by Following the Recommended Procedure for Tests for Irritancy of Substances to the Eye Mucosa of Albino Rabbits, and 

a Comparison of the Results with the Same Substances in the Eyes of Dogs, Monkeys, 

and Man.” I shudder to think what the Program Committee’s reaction would have 

been had I sent them this title! 

Because of our concern with making products safe under recommended conditions 

of use and reasonably foreseeable misuse, we are vitally interested in the development of the most meaningful and practical tests of safety, both in vitro and in ZJ~VO, 

that can be devised. We must keep in mind that a product’s physical form, container. 

and labeling also enter into this problem of safety. 

Any discussion of the toxicology of the eye must include reference to W. Morton 

Grant. His book Toxicology of the Eye (1962) is all-inclusive. It is not only one of 

the most informative works in this field, but it is delightful reading. The preface 

states: (‘The purpose of this book is to present a synopsis of what we know about substances which have toxic properties injurious to the eyes, disturbing to vision or 

affecting the eyes in other unwanted ways.” The information which is summarized 

represents what has been published in approximately the last hundred years, plus a 

moderate number of previously unpublished observations. Approximately 1600 substances are covered, with previously unpublished observations on more than 200. 

The preface continues: “Intentionally in this book the weaknesses and deficiencies 

of our knowledge are made quite evident, so that anyone having an opportunity to 

make further observations may easily see where the need is for more complete and 

accurate information. 

“In the same vein, in the interest of research and investigation, attention is called 

to unsolved problems of mechanism of injurious action and to conditions for which 

specific treatments are lacking, yet by scientific methods could conceivably be 

developed.” 

Mechanism of Injurious Action 

When we review the literature of the past several years, it becomes apparent that 

our knowledge of the mechanism of “injurious action” on the eye from direct contact 

with toxic substances is wanting. The annual review of toxicolo,T and pharmacology 

which appears in the Archives of Ophthalmology has not in the past three years made 

any mention of toxic substances accidentally introduced into the eye. (Who is better 

qualified than the ophthalmologist to observe and help explain the mechanism of 

injury caused by substances which enter the eye accidentally or otherwise?) Much 

93 
94 JOHN H. BECKLEY 

work has been done with various species of animals to test products for potential injury 

to the eyes, but little has been written on the relation of such findings to human eyes. 

Are the results obtained in animal eyes truly indicative of what will happen in human 

eyes? Are there significant differences in the anatomy, histology, and physiology of 

rabbit, dog, monkey, and human eyes? The anatomist will say “yes,” and so will the 

histologist and physiologist. But are these differences of a kind and magnitude to 

invalidate results obtained with these animals as predictive of effects in human 

eyes? How do the rabbit, dog, and monkey eyes differ from each other and from the 

human eye? Not as a whole, but in terms of the particular tissues that may be directly 

involved following the introduction of irritant substances into the eye. This will narrow 

our discussion principally to a consideration of the lids, conjunctiva, cornea, and 

lacrimal apparatus and accessory glands. 

There are some interesting facts relating to the eyes of these animals which the 

comparative anatomist has assembled, and which to a few of us may not be known. 

These three animals, for the purpose of classification, are referred to by the zoologists 

as “placentals.” They are all mammals. 

The rabbit is one of the most widely used test animals. It is classified among the 

Lagomorpha, an order of gnawing mammals resembling the Rodentia, but having two 

pair of upper incisors, one behind the other. 

The dog belongs to a large amorphous order, the Carnivora (flesh eaters) and the 

monkey to the order of Primates. And so the three test animals about which we are 

talking are all ‘Lplacentals.” Th ey are all mammals, but each belongs to a different 

order of mammals. Throughout the many orders of placentals, a considerable range 

of variation in the structure of the eye and adnexa occurs, but through the class the 

similarity is great. For instance, the histological structure of the cornea is built on the 

typical vertebrate plan as seen in man, but most species do not have a Bowman’s 

membrane. Descemet’s membrane, however, is present including its endothelium, which 

is often very substantial (Prince et at., 1961). The thickness and surface area of the 

cornea1 epithelium vary considerably. Most placentals have lacrimal glands, situated 

in the upper outer quadrant, which secrete a watery fluid. However, in other types 

of animals the lacrimal gland is not always associated with the upper lid; for instance, 

in the t.errestrial amphibian it is near the medial canthus associated with the lower 

lid. In birds and reptiles it is near the outer canthus, but still associated with the 

lower lid. In the mouse family the gland is said to be lacking. In the pig its secretion 

is mucoid rather than watery, and in the whale and porpoise it is oily. In addition to the 

lacrimal glands, there are two other glands which are commonly found in placentals: 

(1) Harder’s gland situated on the nasal side of the orbit whose function is to 

lubricate the nictitating membrane, and (2) the nictitan gland situated around the 

cartilage within the nictitating membrane. 

We were unable to find comparative data reIating to the tissues in which we are 

most interested for the purpose of this discussion, namely, the similarity or dissimilarity of the conjunctiva, the cornea, and the lacrimal and accessory glands in 

the rabbit, the dog, and the monkey. All three of these animals have a well-developed 

palpebral and bulbar conjunctiva. The arrangement is very similar to that found in the 

human. There are abundant blood and lymph capillaries, and this explains the 

rapidity with which certain substances are absorbed from the conjunctival sac. I 
COMPARATIVE EYE TESTING 9.5 

have been told that there are compounds, one drop of which when introduced into 

the conjunctival sac of the rabbit, will cause almost instantaneous death. I understand that some organic phosphates will act in this manner when dropped into the 

eye of a rabbit. The mystery story writers should have a field-day with this if they 

,learn about it. It will surely top Shakespeare’s account of the sudden death of Ham 

let’s father by henbane which was dropped into his ear while he was sleeping in the 

orchard. But then this was only a “ghost’s story.” 

Lacrimal and Accessory Glands of the Rabbit, Dog, and Monkey 

How frequently many of us have heard that the reason why the rabbit is not a 

good test animal for determining eye irritancy is that the rabbit does not tear. This 

statement, of course, must be qualified. The rabbit has a well-defined lacrimal gland 

almost completely surrounding the orbital rim. There is a duct which passes into the 

conjunctiva of the upper lid near the lateral canthus. It is reported that there is 

also a very small duct which passes into the lower lid. This gland is a serous gland 

with little vascularization. 

In addition to the lacrimal gland, the rabbit also has a well-developed Harder’s 

gland which secretes lipids, and a nictitan gland which has serous secreting units. 

Both these glands are closely associated with the nictitating membrane. 

The lacrimal drainage takes place through one punctum which lies on the inner 

surface of the lower lid, a short distance from the inner canthus. It drains into the 

nasolacrimal duct (Prince et al., 1961). 

The dog and the monkey both have well-developed lacrimal glands. The dog does 

not have a Harder’s gland but does have a nictitan gland associated with the nictitating 

membrane. These glands produce a serous secretion which passes from the lacrimal 

sac into the nasolacrimal duct. 

NOW! let’s take a look at the cornea in these animals. The references in the literature which I have consulted gave conflicting measurements for the thickness of the 

cornea1 epithelium and for the entire cornea, as well as differences in the superficial 

area of the cornea. These differences in measurement could be accounted for by the 

method that was employed, and whether the measurements were made on eyes which 

had been removed from the animals for a sufficient time to permit a considerable loss 

of moisture. Davcon (1962) reports: “The most recent measurements of the thickness of normal corneas carried out in vivo by various optical methods give the following values,” which I will show below. He also calculated the superficial areas of 

cornea in relation to the total area of the globe (Table I). 

These measurements show differences in the superficial area of the cornea which 

TABLE 1 

CORNEAL THICKNESS AND CORNEAL AREA OF SEVERAL SPECIES OF AND.XAL~ 

Thickness 

Species (mm) 

Man 0.53-0.54 

Rabbit 0.4 

Mouse 0.1 

Rat - 

a As percentage of the total area of the globe. 

Arean 

(k) 

7 

2.5 

50 

“- wl 
96 JOHN H. BECKLEY 

may be meaningful, and differences in the thickness of the cornea. To my knowledge 

in viva measurements by optical methods of the cornea of dogs and monkeys have 

not been published. 

The ophthalmologist, when commenting on the possible ‘Lmechanism of injurious 

action” to the human eye following the accidental introduction of various substances, 

often refers to experiments conducted on rabbit eyes. Clinically, he has observed 

differences in the reaction of the cornea to substances accidentally introduced into 

the eye which may be related to their physical character. He is aware, on the basis 

of published reports, that differences in pH may alter the speed and degree of penetration of the cornea1 epithelium and conjunctiva. The experimental work conducted 

in this regard has been done principally on normal rabbit eyes with intact cornea1 

epithelium and on eyes from which the cornea1 epithelium has been removed. When 

the cornea1 epithelium is not intact, there are considerable differences in the character 

of the injury to the eye. In all the reports I have seen on this type of experimentally 

induced eye injury on rabbits, with or without cornea1 epithelium, single compounds 

were employed in various concentrations, and there was a wide range in the duration 

of contact with the eye. We, however, are principally concerned with products which 

are mixtures of substances, and not with single compounds. 

What have the published reports of the last two years revealed on experience with 

the Draize (1959) method, or modifications, as a “test of irritancy of substances to 

the eye mucosa”? Russell and Hoch (1962)) concerned with the reproducibility of 

the method, recommended two important modifications: (1) a standardization of 

procedure for instillation of substances into the rabbit eye, and (2) the development 

of a standard substance which could be used by any testing laboratory to determine 

whether it is scoring at a “standard” level. 

Olson et al. (1962), in testing several surfactants, elected to screen the rabbits for 

possible cornea1 injury by instilling fluorescein into the eyes 24 hours prior to use. 

Fluorescein was also employed as an aid in assessing cornea1 injury. The type and 

intensity of reactions were rated from 1 to 6, from no effect to very severe. Their 

system of evaluating type and intensity of reaction included not only objective 

observations of the eyes, but observation also of how the animals reacted. They 

referred to the latter as a “pain evaluation.” In this study it was interesting and 

maybe significant that the severity of conjunctival irritation did not necessarily 

correlate with cornea1 and iridial involvement. 

Kay and Calandra (1962) published their “Descriptive Eye Irritation Ratings,” 

which is so much more meaningful than the straight numerical scoring. In discussing 

the range of eye irritation typical of some general types of cosmetic products, the 

authors say: “It is worth observing that the test we have been discussing is not to be 

thought of as one whose results are necessarily the exact equivalent of those which 

might be expected following accidental contact of the test agent with the human eye. 

The basic test we have discussed is, comparatively speaking, a very stringent one and 

eye irritation following human ocular contact may be considerably reduced in intensity depending upon the particular circumstances involved. In a sense, we are 

attempting, via this rather rigorous rabbit test, to assess the maximum ocular irritation which might be produced in man.” 

Rieger and Battista (1964) state: “There is very little correlation, if any, between 
COMPARATIVE EYE TESTING 97 

the results obtained from animal tests and actual use of the product by the consumer. 

The Draize rabbit eye test has been widely used as a test of safety for products used 

in, on, around and above the eyes. Information has been presented indicating that 

different laboratories, presumably using the same techniques, have obtained conflicting results with the same product. This might indicate that the results of the rabbit 

test depend either on the conduct of the test, method of interpreting the results, or 

perhaps even on the particular group of rabbits used.” The authors suggest: “Human 

eye instillation tests should be conducted after rabbit eye tests to ascertain safety.” 

I must refer very briefly to Gaunt and Harper’s paper (1964)-a well-presented 

paper followed by a discussion that was most spirited. The authors state: “The major 

problem in all animal screening tests . . . is the subsequent interpretation of the 

recorded data in terms of the anticipated response in man. Obviously man himself 

must be considered the final test. Until it is established, however, that the product 

is safe, then as a precautionary measure it must be assumed that the human eye will 

not be less sensitive than that of the animal used in the test.” During the discussion, 

one of the authors, in describing the immediate reaction in one of the rabbits, said: 

“The eye was closed and there was slight lacrimation.” This is the first time I have 

seen any reference to a rabbit’s eye lacrimating. Dr. Levenstein, in his rather lengthy 

and most informative discussion of this paper, said: “It must be remembered that 

the rabbit eye is very unlike the human eye. It has tissues present which are not 

present in the human eye, and therefore everything that is found in the rabbit’s eye 

cannot be applied to the human.” 

Referring to the 1964 pamphlet, Principles and Procedures for Evaluating the 

Toxicity of Household Substances,l prepared by the Committee on Toxicology of the 

National Academy of Sciences, National Research Council, the recommended procedure for testing compounds to determine potential eye irritation in part says: 

“Albino rabbits are ideally suited for the study of compounds which may produce 

mild to severe eye irritation. The relatively large size of the eye, the consequent ease 

of instillation of test material, and the ease of the evaluation of results, commend 

the rabbit over other species for eye irritation tests.” The Committee goes on to 

suggest: “Since the rabbit eyes may frequently show evidence of injury sustained 

in the course of living, it is important that the eyes be examined before application 

of the test substance.” They suggest instillation of fluorescein, and preliminary examination to screen the animals prior to use. This type of screening procedure, as you 

will recall, was used by Olson et al. (1962). The Committee further recommended 

that, for the purposes of the Federal Hazardous Substances Labeling Act, a dose of 

0.1 ml of liquid or 10 mg of fine, dry powder be instilled into the conjunctival sac 

of six rabbits. The lids are to be held open for 20-30 seconds, and the animals are 

then returned to their cages. This procedure differs in several important respects 

from the current test for eye irritants prescribed in the regulations” to the Act. 

This brings us to our experience with a liquid product which was tested in the 

eyes of several animal species, including man. 

We use a number of well-established and, in our opinion, competent consulting 

laboratories for conducting animal tests on our products. We often run screening tests 

1 Publication 1138, National Academy of Sciences, National Research Council, Washington, D, C, 

2 21 CFR 191.12. 
98 JOHN H. BECKLEY 

for eye irritation using three or four rabbits and have run as many as 80-100 such 

screening tests on variations of the same product, before using groups of six rabbits 

on selected formulations. We will report on a formulation which, in the rabbit eye, 

produced cornea1 and iridial involvement. The same product instilled into the eye 

of the dog produced less overall reaction, and in the monkey still less (Table 2, 

Laboratory A; Table 3, Laboratory B). It is not dermally toxic or a primary dermal 

irritant on rabbits. Human skin testing did not produce primary irritation or sensitivity. 

The test material was a light-duty liquid detergent, consisting of water, SOY,, ethyl 

alcohol, lZ%, and the rest an alkylbenzene sulfonate plus conventional organic foam 

builder and solubilizer. It contained no inorganic salts, other than a small amount of 

the sodium sulfate usually present in industrial alkylbenzene sulfonates. Its pH was 6.3. 

Human Findings 

The human eye testing was under the direct supervision of physicians, including 

an ophthalmologist. 

There were three separate human eye studies using this formulation by three 

different investigators. Fifteen male subjects were used in each study. 

Study A. One-tenth milliliter of a series of increasing concentrations beginning 

with 10% was instilled into the lower conjunctival sac of one eye. The eye was not 

washed out. When it was found that the diluted solutions could be tolerated, 0.1 ml 

of the undiluted solution was instilled into the conjunctival sac daily for 7 consecutive days. 

There was no immediate visible reaction to any of the diluted solutions, or to the 

single instillation of undiluted solution. However, with the higher concentrations there 

was immediate burning sensation which lasted about 20 minutes; during this time 

there developed a slight injection of the conjunctival vessels which abated within 1 

or 2 hours, and no sign of irritation was evidenced the next day. 

Readings were made immediately and during the first 2-3 hours, and at the end 

of each 24 hours. Ten of the subjects completed the study without evidence of eye 

damage. Five of the subjects began to develop a conjunctivitis after 3 or 4 days, and 

further instillations were stopped. The conjunctivitis promptly disappeared. In no 

instance was there cornea1 or iris involvement. 

Study B. This study differed from Study A in that 0.1 ml of the undiluted solutions 

were instilled on alternate days into the right and then the left conjunctival sac in 

gradually increasing concentrations until 100% concentration was achieved. In every 

instance the 0.1 ml of fluid flooded the conjunctival sac. The solution was held in 

place by a gauze square for 2 minutes. Ten minutes after the removal of the gauze, 

the eyes were washed with water. After the twentieth day, 0.1 ml of the 1005% solution was applied to the same conjunctival sac for a period of 8 consecutive days. 

Readings were made immediately after removal of the gauze square, and 4 and 5 

hours later, and at the end of each 24-hour period. There was transient burning, 

discomfort, and conjunctival erythema in all subjects. These symptoms were immediate and lasted for a few minutes to a few hours. In most cases, the symptoms were 

more prolonged in the early stages of the study when low concentrations of the substance were used. Near the completion of the test, when higher concentrations were 
COMPARATIVE EYE TESTING 99 

TABLE 2 

SCORES OF OCULAR LESIONS PRODUCED BY INSTILLATION OF A LIoum DETERGENT INTO 

RABBIT EYES (LABORATORY A) 

Time of Eyes Eyes 

reading Tissue unflusheda flushedh 

24 hours Cornea 20.0 20.0 

Iris 2.5 3.3 

Conjunctiva 8.7 9.3 

48 hours Cornea 16.7 13.3 

Iris 3.3 3.3 

Conjunctiva 6.3 9.3 

72 hours Cornea 20.0 13.3 

Iris 2.5 3.3 

Conjunctiva 6.7 5.3 

4 days Cornea 20.0 13.3 

Iris 25 3.3 

Conjunctiva 13.0 2.0 

7 days Cornea 21.7 0 

Iris 2.5 0 

Conjunctiva 10.3 0 

a The numbers in this column are the mean Draize (1959) scores of six animals. 

b The numbers in this column are the mean Draize (1959) scores of three animals. The eyes 

were flushed 4 seconds after instillation of the sample. 

TABLE 3 

SCORES OF OCULAR LESIONS PRODUCED BY INSTILLATION OF .4 LIQUID DETERGENT INTO THE EYES 

OF SEVERAL SPECIES OF ANIMALS (LABORATORY B) 

Time of 

reading Tissue 

Eyes unflusheda Eyes flushed0 

Rabbit Dog Monkey Rabbit Dois Monkey 

1 hour 

24 hours 

48 hours 

72 hours 

4 days 

7 days 

Cornea 

Iris 

Conjunctiva 

Cornea 

Iris 

Conjunctiva 

Cornea 

Iris 

Conjunctiva 

Cornea 

Iris 

Conjunctiva 

Cornea 

Iris 

Conjunctiva 

Cornea 

Iris 

Conjunctiva 

33.3 40.0 20.0 lS.0 

10.0 s .o 2.S 10.0 

12.0 4.0 1.0 10.0 

33.3 45.0 10.0 13..3 

10.0 5 .O 0 10.0 

12.0 4.0 0 10.0 

26.7 30.0 5.0 6.7 

10.0 s .o 0 10.0 

10.0 4.0 0 8.7 

21.7 30.0 0 5.0 

10.0 5.0 0 8.3 

9.3 0 0 7.3 

10.0 10.0 0 1.7 

10.0 5.0 0 6.7 

10.0 0 0 4.7 

6.7 0 0 1.7 

8.3 0 0 3.3 

6.7 0 0 2.7 

40.0 0 

0 0 

0 0 

20.0 0 

0 0 

0 0 

20.0 0 

0 0 

0 0 

20.0 0 

0 0 

0 0 

10.0 0 

0 0 

0 0 

0 0 

0 0 

0 0 

a The numbers in these columns are the mean Draize (1959) scores of six rabbits, six dogs, and 

four monkeys. 

b The numbers in these columns are the mean Draize (1959) scores of three animals of each 

species. The eyes were flushed 4 seconds after instillation of the sample in the case of rabbits and 

dogs; 2 seconds in the case of monkeys. 
100 JOHN H. BECKLEY 

employed, reactions were minimal except in three subjects. One subject developed a 

conjunctival erythema which lasted one day following the instillation of the 60% 

concentration but tolerated the higher concentrations. Two subjects developed similar 

reactions, one on days 8, 9, and 16, the other on days 8, 12, and 18. In the latter 

there was a localized collection of purulent material on the lower conjunctiva on 

day 18. The erythema in this subject was still present on day 19, and the instillation 

was placed in the other eye. Because the irritation seen in these two subjects might 

be due to superimposed bacterial infection, conjunctival cultures were obtained. NO 

pathogenic organisms were isolated. The ophthalmologist who took part in this study 

noted that the subjects who developed more pronounced reactions later in the study 

gave histories of low-grade pustular conjunctivitis which occasionally flared up. He 

felt that the symptoms and signs observed were due to fluctuations in susceptibility 

in these subjects. During the entire study it was observed that neither cornea nor iris 

was affected. None of the subjects developed chronic conjunctivitis. There was no 

evidence of sensitization. 

Study C. A third study with 15 male subjects was conducted. The procedure was 

essentially the same as that of the previous two studies except that 3 drops of the 

test material were instilled into the eye each day for 3 days. All the subjects experienced immediate burning and smarting, and hyperemia was noted in about 15 minutes. All subjects were normal at the 24-hour reading. One subject developed a more 

persistent conjunctivitis. This subject gave a history of surgical removal of a chalazion 

several weeks before. This subject was eliminated from the group. None of the subjects developed a chronic conjunctivitis, and in no case was there involvement of the 

iris or cornea. 

The reports which we have given show a difference in the results obtained in the 

rabbit, dog, monkey, and man. 

Osler is reported to have said: “May I be delivered from the doctor who draws 

conclusions based on one case history.” We will not be so bold or foolish. We cannot 

say why human cornea and iris were not involved here. We could say it can be 

accounted for by structural differences in the corneas, or by species difference in 

reaction to this particular formulation. We don’t know. 

The structural differences in the rabbit, the dog, the monkey, and the human eye 

may be sufficient to make it imperative that comparative studies be made using these 

species and perhaps others. To help explain why these species often react differently 

to the same substance, we must have more precise comparative knowledge of the 

anatomy, histology, and physiology of their eyes, particularly the cornea, iris, conjunctiva, and lacrimal and accessory glands. 

What do we know about the “mechanism of injurious action” from substances 

introduced into the eyes of the rabbit, the dog, the monkey, or man? Very little. 

Of course, we would all condemn deliberately placing substances into the human eye 

without first knowing how they react to animal eye tissue, as we would condemn the 

use of any new formulation on or in the human body exclusive of the eye, without 

knowledge of its reaction on or in various animal species. 

John Draize and his associates made one of the great contributions by &v&ping 

a method, the first standardized method, for establishing the safety of products to 

be used in the eyes and to estimate the potential injury that may occur if certain 
COMPARATIVE EYE TESTING 101 

products are accidentally introduced into the eye. It is still the most widely used 

method the world over. Its shortcomings have been discussed again and again. There 

have been modifications. One of the modifications has become official under the Federal Hazardous Substances Labeling Act. We recommend that we quit finding fault 

with the prescribed method of using rabbits as the test animal and come up with a 

better method and a more suitable animal, if we can. This could begin by reporting 

our experiences with other species of animals than the rabbit and with man. The 

question we should seek to answer is not only whether a product is potentially dangerous to the human eye, but why? And what is the “mechanism of injurious action”? 

REFERENCES 

DAVSON, H. (1962). The Eye. Vol. I, liegetative Physiology atid Biochemistry. Academic Press, 

New York. 

DRAIZE, J. H. (1959). Dermal toxicity. In: Appraisal of the Safety of Chemicals in Foods, Drugs 

and Cosmetics. Assoc. Food Drug Officials U.S., .4ustin, Texas. 

DUKE-ELDER, S. (1961). System of Ophthalmology. Kempton, London. 

GAUNT, I. F., and HARPER, K. H. (1964). The potential irritancy to the rabbit eye mucosa of 

certain commercially available shampoos. J. Sot. Cosmetic Chemists 15, 209-230. 

GRANT, W. M. (1962). Toxicology of the Eye. Thomas, Springfield, Illinois. 

KAY, J. H., and CALANDRA, J, C. (1962). Interpretation of eye irritation tests. J. Sac. Cosmetic 

Chemists 13, 281-289. 

OLSON, K. J., DUPREE, R. W., PLOMER, E. T., and ROWE, V. K. (1962). Toxicological properties of several commercially available surfactants. J. Sot. Cosmetic Chemists 13, 469-476. 

PRINCE, J. H., DIESEM, C. D., EGLITIS, I., and RUSKELL, G. L. (1961). Anatomy and Histology 

of the Eye and Orbit in Domestic Animals. Thomas, Springfield, Illinois. 

RIEGER, M. M., and BATTISTA, G. W. (1964). Some experiences in the safety testing of cosmetics. 

J. SOL. Cosmetic Chemists l.5, 161-172. 

RUSSELL, K. L., and HOCH, S. G. (1962). Product development and rabbit eye irritation. proc, 

Sci. Sect. Toilet Goods Assoc. 37, 27-32.