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THIS DOCUMENT CONTAINS 15 PAGES, COPY NO. 1 OFCOPIES.

AS A VEHICLE FOR INCAPACITATING ACENTS

Prepared by:

24 December 1971

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This report has been prepared by 1 as a part of a Government Contract. The viewa expressed are those of personnel and not necessarily those of the United States Government.

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TABLE OF CONTENTS

Page
Protocol Statement . i
List of Figures and Tables . iii
Problem. , . 1
Discussion. 1
I. Potential Applications . 1
II. 1. 3
II. Physiological Considarations. . 4
A. Introduction -- Nature of the Skin. 4
B. Theories of Penetration. 5
C. Substances "Carried" 5
D. Penetration Studies . . 6
I. Stratum Corneum. 6
2. To the Bloodstream. 8
E. Fate and Metabolism 11
F. Local Reactions and Toxicity. 12
G. Physiological Conclusions. . 14
IV. Other System Factors. 16
V. Recommendations. 18
References.. 19

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LJST OF FIGURES -

Figure 1 Section Through the Skin of the Human Shoulder. . . . . 4

LIST OF TABLES

Table I Dermal Penetration Rates of Various 1 }Mixtures. . ..

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AS A VEHICLE

FOR INCAPACITATING AGENTS

PROBLEM

To evaluate, especially from the physiologic point of view.
as a vehicle for personnel incapacitating agents.

DISCUSSION

I. Potential Applications For Incapacitation

lis a chemical with the rather extraordinary property of penetrating skin rapidly. Ihe skin, long thought uf as a virtually im-. penetrable barrier or as an only slightly, slowly permeable one, is easily, quickly, and reversibly breached Furthermore, many chemicals, when dissolved can cross the barrier along with

Such a proper-y lends to consideration as a possible means of delivering an incapacitating chernical agent via the skin. Those drugs which interfere with a person's state of consciousness - inducing lcss of consciousness, panic, disorientation or hallucination -- could conceivably be administered, as well as drugs which incapacitate by causing motor dysfunction or muscular paraiysis, or those which incapacitate by producing somatic preoccupation such as itching or burning. Since many incapacitating drugs requirefairly critical dosage, the usefulness of a lincapacitating agent rnixture would

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probably be limited to individuals, where the dosage could be more carefully controlled as to quantity and site of application. In a crowd situation, uniform dosage wouid be quite hard to obtain.

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本 The lowest temperature at which vapors will ignite in air.

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A. Intruduction -- Nature of the Skin.

A primary function of the skin is protection of the body. One way in which it does this is by serving as a barrier to penetration of chemicals -- harmful or oiherwise -- into the hody through its surface. It is a forridable barrier to such pcnetration. For example, the epidermis retards the diffusion of low moiecular weight, water soluble nonelectrolytes (among the most diffusible of susstances) by a factor of over one thousand tires.

To get from the surface of the skin to the circulatory system, a substance. must first penetrate the atratum corneum, or horny layer of the epidermis. This is a thin layer of dead, keratinized epithelial cells approximately 10μ thick. Once this is passed, the stratum Malpighii, or living part of the epidermis (100μ or so thick), then the papillary part of the dermis (100 - 200μ thick in most places) must be traversed before the capillaries in the dermal papillae are reached. The stratum corneum constitutes by far the major part of the skin barrier insofar as resistance to diffusion is concerned. 7 If it can be breached, drugs can gain entrance to the body via

III. Physiological Considerations

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the skin -- elininating the need to administer them orally, by injection, r hy other routes.

B. Theories of Penctration.

The actual mechanism of penetration of the human skin lis largely uaknown, although several th:ories have been advanced. There is little or no cvidence in support of any of the theories, however. According to the most widely held hypothesis, the molecules replace molecules of bound water in the straturn corneum. \bonds are less tight than HOH - HOH bonds and, therefore, temporary dissociation, allowing to ailow other substances to penetrate the stratum corneurm, saturation of the intermolecular spaces may be necessary. As says, "It is almost as if the penetrant is conducted through the horny-layer barrier by remaining which occupies interdissolved in a continuous channel
molecular spaces." This "openingup" of a pathway through the stratumn corneum occurs for a limited time only; leaves the stratum corneum open to penetration by other chemicals for l-1/2 to 3 hours oniy.,  It is suggested that by the end of this time the saturating quantity of /nas either diffused away from the stratum corneum or beer absorbed into the circulation.

Jligh concentrations are needed for effective penetration. 7 This may be a resalt of the l:2 or 1:3 associational complex formed with water. A 75% or greater has space remaining available for association with tissue water molecules -- they can be removed from the stratum corneum and replaced 1

C. Substances "Carried" 1 Various investigators nave conducted experiments jin conjunction

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with a wide variety of chemicals in hopes of getting them through the skin barrier. As a general rule, low molecular weight, nonionized chemicals pass through the moat quickly, thoac which are ionized and/or of higher molecular weight paas through more slowly, if at ail, and substances of high molecular weight such as insulin and ragweed aliergen do not pass through at all.

Some substances which have been tried and which do penetrate the stratum corneum

It should be strested that neaxly all of these studies measured penetratioa only through the stratum corneam or into the skin. They do not inpiy penetration into the bloodstrearn. Indeed, many of these subatances, including have been found to penetrate only through the stratum corneum into tr.e epidermis and dermis, where they may form a reservoir. Some, such as /may remain in the stratum corneurn for the most part.

D. Penetration Studies.

1. Stratum Corneum.

There are two main fastors to consider in the penetration {through the skin barrier -- the speed of penetration and the quantitative amount of penetration. Neither has been established with any degree of precision, but some figures are available.

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fourd that 1.5%

|penetrated

(as established by serial stripping of the skin's horny layer with cellophane tape) to the base of the horny layer in one minute. The liquid was applied as a "pool" by means of glass cylinders taped to the back of male Negrocs. He alsc found that in a glass cup produced whealing as early as two minutes after application. For whealing to occur (most probably due to histamine liberation from the mast cells) penetration below the stratum corneum muot have occurred. These results were ottained with 1 present in depth above the area treated, hcwzver -- rot with it spread over the skin or aoplied in small quantities.

[on the back and spread it with a glass rod. They noted signs of reaction (whealing, e-pecially around the hair follicles) in 5 to 15 minutes. The differences in whealing times between work may indicate that tt≥ absorption time is a function of the amount enabling quicker penetration than thin layex.

ohtained anesthesia of the eardrum (which has a stratum corneum
just like any otaer skin area) sufficient to allow painlass myringotomy (cut
ting of the eardrum) within one minute after wiping the eardrum with 1

In another atudy. Ipenetrated to the base of the horny layer \_n 20 minutes. In the time was 55 niinutes, and in 1z0 minutes was the time for peretraticn. These results emphasize the need to use high concentrations [tor rapid, maximun. ponetration.

Published studies on the quantitative penetration have been almost nil. in gel form on the elbow and let it stand for 30 minutes. By then wiping off and weighing what remaineri at lhe

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had been abend of ihat fime, they.calculated that 25-40% of sorbed. This was obviously a rough determination only.

"i eight hours after dermal application, that 20% of the applied dose was still in the epidermis. He did not menticn where or how the remaining 80% was distributed.

These two studies demostrate that dermal application lis no
assurance that all of the compound will penetrate the skin. Furthermore, of
that portion which does penetxate, some may remain in the epidernis for a alone; chemicals
considerable length of time. These studies were may or may not behave in like manner. At present, it
"carried"
would e almost impossible to predict what the behavior of a given chemical
ayent lwould be with regard to percent absc.ption or penetration rate
without actuaily running tests on that particular chemical. .. nriabic which has been little investigated is the location of the skin to nurated. It is known that, with regard to such thirgs as water diffusibility. rin areaa of the body are considerably more permeable than others. For 7 smpic, scrotal skin is considerably more permeable than abdominal skin. .ze are several variables which may be at wozk. The skin itself (epidermis lurmis) varies in thickness, and the stratum corneum itseif may vary .: ither thic'cness or structure. Other than on the soles of the feet and the .ns oi the hands, where the stratum corneum is considerably thicker, but ..s a higher liffusivity, the stratum corneum varies Little in thickness. It y vary in nature, however, as in the forehead, where there is a less orderly. There may also be some difference ti thickness and composition of the stratum corneur among various
peoples -- lor example, Negroes vis-a-vis Caucasians.

2.To the Bloodstrear

Most of the previously discussed studies of time and rate of penetration considcred the stratum corneum and epidermis only. If the site of

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action of the "carried" drug is the epidermis -- fine, all of the major.
factors have been consiiered. But drugs which have the brain or body organs
other than the skin as sites of action must go pot only through the stratum
corneun, but also through the remainder of the epidermis and then a portion
of the dermis before they rcach the bloodstream. which can transport them.
This is where may fall down. studied the influence on dermal clearance (the time re
quired for the circulation to remove injected substances from the dermis).
Fluoresccin, a fluorescent dye, was injected intradermally- 0. 1 ml in
saline, and in 25%, 50% and 75% solutions. The clearance time for
the control (in saline) was 1.8 hours and the times for the
solutions were 3, 5.5 and 18 hours, respectively. 1

The effects on dermal permeability were studied by measuring the penetration rate of l% aqueous fluorescein through abdorninal skin which had been stripped of its epidermis.  The results are summarized in the : table below.

TABLEI DERMAL PENETRATION RATES OF VARIOUS

In the case of
the dermis. iseems to inhibit or retard passage through offers no theory or hypothesis to account for this, stat
preased ing simply that "the diffusivity of connective tissue was probably being de-{ One qualification, however, is
applied to the intact skin would probably not attain such high concentrations 1
in the dermis as were used in these experiments, so that dermal clearance

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and permeability probably wouid not be rctarded as much in normal use as was observed under the experimental conditions.

For incapacitating agents which act on the brain, the most important consideration is not how fast penetrates the horny layer, but how quickly\_it, or a drug adninistered reaches the bloodstream. using tagged Jgiven dermally, found traces of radioactivity in blood drawn as early as five minutes was applied, but the level did not reach a maximum until 4-6 hours later, reaching a plateau where it remained for some time.

One other published experiment, which gives times and blood concentrations for humans, showed one hour after administration, but the peak level (approximately twice the one hour level) was not attained until four to eight hours after administration.

These two experiments It can be seen that a measurable may penetrate to the bloodstream in as little as five minutes, Whether or not chemicats "carried" by can enter as rapidly would have to be determined experimentally. Other substances may or may not reach the bloodstream this quickly, depending on several factors such as molecular weight, configuration, solubility in tissue water and lipids, and reactivity to tissue components. The jin blood keeps building up to a peak which is only reached after several hours; such behavior would not be acceptable for most brain-active incapacitating agents, for a dose powerful enough to incapacitate in five minutes would continue to increase for several hours, with serious and quite possibly fatal results. Unless the therapeutic ratio \* of the drug is quite high, safety could not be insured. This, however,

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Ratio between the lethal dose and an effective dose.

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assumes tha: the chemical agent would behave the same way wiich may not de the case. There is a possibility, bat only a slight one, :hat a peak concentration of an incapacitating agent could be reached quickly. In this case, maximum effect of the drug would appear soon after administration and a lower, safer dose could be used; the initial incapacitating dose would be the maximum dose received.

One report,

showed apparent worthwhile re-

sults in feeding through the skin
things as glucose, carotene (vitamin A), vitamin ${ \mathfrak { s } } _ { 1 2 } \cdot$ and some amino acids were absorbed in fairly significant amounts, as signified by blood levels and weight gain. The blood glucose level was 165% of the initial value within 30 minutes Japplication. The net elevation at that time, which does not account for any glucose which may have already entered the bloodstream and then been metabolized, accounted for about 3% of the dose administered to the skin.

E. Fate and Metabolism

The metabolic pathways takes in the body are still relatively unknown: Gas chromatographic and radioactive tagging techniques /show that it is excreted as unchanged and as two metabolic byproducts -- dimethyl lare excreted

in the urine; teaves the body via the lungs. Fecal elimination is negligible. Urinary excretion accounts for most of the removal as the lungs eliminate only l-3%. 1

Most subjects Iby the dermal or any other route have a characteristic 'bad breath" said to resemble This is caused by the presence of the which appears in the

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breath soon after administration or so.

land continues for 24 hours

F.Local Reactions and Toxicity. F. Local Reecuons a

concentration typically applied dermally in the is accompanied by transient burning, itching, and erythema (reddening). -7 Its exothermic reaction with water causes an increase in skin temperature. may cause whealing. This is In a siguificant number of cases, A study of over 1000 assumed to be a result of histamine liberation. dermally for a 15- Cierman patients who were given 1 minute perioc per application yielded the following data on skin reactions:

6 - 8% showed no local reaction;

33% had a slight reaction (warmth, itching ard erythem);

56% had the "typical" reaction (burning, itching, erythema for 3 - 4 houxs, aud occasional local urticaria);

2 - S% had a more severe reaction (dermatitis, urticaria, and occasional vesiculation).

In cnly about 3. 5% was it necessary to discontinue therapy. This was due to
the local skin reactions wbich disappeared upon discontinuation of the treat
ment. There were sometimes complaints of transient nausea and headache but no serious complicatioss. The "bad breath"
among those
was noticed in most subjects, and 50% or so reported they could "taste" the 400 individual

Inall of the studies done on humans (includimg over tvuv muluu in one of the studies) no serious side effects have been noted. The temporary effec:s were those noted above, and no permanent changes or damage have been reported.

tested sensitivity of the conjunctiva \* to drops of 1 Two drops caused only temporary stinging and burning, and, in some cases,

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The membrane covering the anterior eye and the irner surface of the eyelids.

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mild injecticn (congestion) of the conjunctival vessels. These effects soon disappeared.

if dropped onto the eardrum, may be painful, but will 1 cause no long-lasting or permanent damage.

(was withdrawn as a clinical drug in the United States in 1965 by the Food and Drug Administration because of reported lens changes in dogs which had been given up to 5 graris per kilogram

The FDA has subeequently allowed resumption of clinical testing.
There was fairly extensive lin humnans in this country before the
FDA ban, jhas been available as a prescription drug 1 No evidence of any human eye toxicity due to

lhas been observed . leven in the highest experimental doses given (1 g/kg per day íor 12 weeks in one study. 130 g per day for up to 21 months per kg orally or 1, 3, or 9 ml/kg dermally daily for periods of up to 18 months and no toxicologic or pathologic changes have been seen, other than skin reactions.Monkeys have been given intravenous dos  as high as 4g/kg with no deatas.

No estimates of an LD50 \* have been made for monkey or man, but in view of the high experimental doses that have been given already, the LD50 would be far higher than any dose which would be given for puzposes of "carrying" an incapacitant.

Substances given in combination however, may result in an altered toxicity. reported an interaction between alcohol in 1967. He claims to have found increased rates of mortality in rats given

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本 The dose lethal to 50% of those to whom it is administered.

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high doses after previously having been injected with alcohol. Ile also said he found more psychomotor impairment in humans given alcohol (oral-y) and (v'a the skin) than would be expected from alcohol alone. This interac'ion should be investigated further lis to bo considered for usc in incnpacitation since there could be complications if the were used on drunken subjects.

Interactions between various drugs other than alcohol should also be investigated further. One group of investigators found that lip creased the toxicity (as reflected by a change in the $\mathfrak { L D } _ { 5 0 } )$

administered orally to rats by a factor of up to six times.

Thus, there is a possibility could facilitate the body's absorption of drugs from. such sites as the gastrointestinal tract. Such facilitated absorption could conceivably cause an otherwise safe dose oi a drug to become a serious or possibly fatal dose when given

It can be seen, on the basis of the fairly extensive wozk which has been done,'

applied exterrally in small quantities can be expected to have temporary, local effects causing some annoyance and discomfort, but no long-term or permanent damage. Whether or not this would be true of

mixed with a given cherical agent would depend upon the nature of the chemical and how it acts in conjunction Such knowledge would have to be established by experimentation, using the specific chemical agents to be considezed. It would be quite desirable to have further data on the interaction of alcohol as well as any other drugs which potential subjects might take before or /administration.

G. Physiological Conclusions.

F'or use as a "carrying" agent for incapacitants, would have to be used in fairly high concentrations, probably To assure useful speed pf penetration and to ensure penetration it would have to be applied in volume, ì perhaps one ml or more, as shown by various investigators.

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can (airly well be ruied out as a means of quiek delivery for psychotropic agents, or any other agent with thc internal organs as a target. The chances are very good that any agent deliveredì would not reach peak blood levels for several hours. For a drug to be effective quickly (say, reaching the blood in significant amouzts in five minutcs) it would have to be administered as quite a large dose. This is because, so far as is krown, only a small percentage of the administered dose will reach the circulation in that initial five minute pexiod.

There are too many variables to be certain of the fraction of the delivered dose which is likely to xeach the target organ. This is especially critical for dosages of the psychotropic drugs. Whether all the material lands on the skin, huw much remains in contact with the skin, how calloused or "tender" the subjeet's skin may be -- all may afiec: dosage and absorption. Such possible factors as individual variation "penetrability" and possible inseusitivity to the "carried" agent also enter in. All these factors would tend to eliminate most 'brain-active" agents from consideration because of their relatively low therapeutic ratio.

Incapacitation by somatic preoccupation is a major remaining area. Intense itching or burning can be quite incapacitating. Applied in the conventional manner, skin irritants such as itching powder san be removed by washing-

could cause the skin irritant to penetrate inte the skin, where a reservoir could be formed. Once within the skin, washing and rinsing could not remove them and might actually increase the ixritation. Several hours of intense Ltching or other irritation could ensue. Quite possibly agents could be found waich would penetrate the stratum corneum and go no further, eliminating the danger of overdosage which is such a distinct possiblity when psychotropic agents are used.

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IV. Other System Factors

One factor to be considered is the relatively 1 For use at cool temperatures, this would either have to be changed to a lower value by some means or would have to be heated prior to use.

Delivery could be made fairly simple. Used gainst individuals at close range. the could be delivered by a simple water pistol type device. For longer ranges, the mixture could be loaded into capsules that woulc break on contact after being thrown or fired from a gun.

(would be aware The person who receives of it. litsell has a noticeable odor, which could be masked with perfumes, but probably not removed. Soon after administration

local reactiong would appear -- burning, itching, and the like. Finally, subjects would be aware of having seen sprayed or squirted with a liquid. For these reasons, it is highly douutful could be administcred suxreptitiously. i

Ordinarily, when an individual is squirted or sprayed with a liquid, the usual reaction Ls to wipe it off his skin. Since the |takes a finite time to penetrate -- several minutes at least -- much of the administered mazerial would probably be removed well before it had any time to penetrate. This is a fairly strong argument agairst applying

ito exposed skin areas, although wiping may have some effect of "rubbing it in" and spreading it.

These objections can be overcome by applying the to the clothing. The person receiving this solution on his clothing would be aware of it, but clothing removal would normally be too drastic an evasive measure to take, unless the nature of the liguid and the consequences of non-removal were known to the subject. If the liguid were applied to the

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panis (or skirt), ciothing removal would be especially unlikcly, for psychological reasons. wetting the clothing would be in contact with the skin, possibly for a long enough period of time to allow penetration or partial penetration before the reaction to the burning and itching would be strong enough Lo motivate clothing emoval. By then, such evasive tactics could be too late.

}were sprayed on the ciothing, the genital area would be an ideal target, since the scrotal and genital skin is likely to he more "permeeble" to than skin in most other areas of the bośy. Various psychological factors would erter in here also.

[to the clothing would probably not work in
situations where the clothing was already wet, as by rain, by firehcses, etc.
This could be a potential countermeasure -- hosing oneself down. Use of
rain gear could also serve to protect the subjects 1 1

The problems of storage and shelflife could be important; these factors would have to be investigated for the various incapacitating agents both individually and in conjunction í

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V. Recommendations

A. The "carry" psychotropic or other incapacitants which depend on the bloodstream to carry them to their taxget organs can, in all probability, be ruled out if quick incapacitalion is desired. There is a chance that an effective agent could be found which would penetrate the stratum corneum and then go into the bloodstream faster than but such a chance seems remote.

B. should be considered as a possible vehicle for "implantation" of skin irritants. Studies should be made with various irritants, checking for absorption time, duration of action and effectiveness.

C. comes into active consideration as a vehicle for skin irritants, sevexal other operational characteristics should be cetermined by direct investigation.

1. Studies absorption through different types of clothing should be undertaken. Various materials-- cotton, leather, synthetics -- should be checked, as well as the effects of several layers of clothing, loose ys.tightfitting garmnente, etc.

2. Investigaton of the suspected interaction 1 alcohol should be carried out, Also to be considered are possible interactions. jand other drugs which a subject may have taken prior to or subseguent jadministration.

3. Storage and shelflife and various agents should be investigated.

1B.