CHEMICALRESEARCH,

S--DEVELOPMENT GENGINEERING CRDEC-TR-1CENTER

(V)

USE OF METHYL SALICYLATESAS A TRIALING CHEMICAL AGENT SIMULANT

DTICS ELECTE,-JUN2919901

E .. .

Alan T. SeitzingerPaul S. Grasso

William E. White, Ph.D.Arthur K. Stuempfle

Ammon Birenzvige, Ph.D.

RESEARCH DIRECTORATE

May 1990

U.S. ARMY UAARMAMENT

ApFI'wr" C. .HEMICAL. COMMAND

mm I I I II II

Abereen Povirg Omund. Mar1end 21010-B423

90 06; 28 034

Disclaimer

The findings in this report are not to be construed as an officialDepartment of the Army position unless so designated by otherauthorizing documents.

Distribution Statement

Approved for public release; distribution is unlimited.

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4. TMU AND SUUILE L .UN-NG M

Use of Methyl Salicylate as a Trialing Chemical Agent PR-665612Simulant

4. AUTHOS) i

Seitzinger, Alan T.; Grasso, Paul S.; White, William E.,Ph.D.; Stuempfle, Arthur K.; and Birenzvlge, Amnon, Ph.D.

1. PERFORMNG ORGANIZATION NAME() ANO AOORESS(ES7 L PERP00INE OlGAt ZT"ORElPORT "uskmagn

Cdr, CRDEC, AMTN: SMAC-RSP, Aberdeen Proving Ground, MD21010-5423 CRD)EC-TR-178

9. SPONSORING/IMNITOAING AGINC NAME(S) AND AOORISM(S) 10. SON NMONITO<MNG

11. SUPPLEMENTARY NOTES

12a. O1%TPJ8UTION/AVAZLAfItM STATEMENT 2.1SNUI Co

Approved for public release; distribution is unlimited.

13. AlSTRACT Nox-u-la hiS report s objective was to provide a ccmprehensive assess-ment of the use of methyl salicylate (MS) as a trailing chemical agent simulant foroperaticnal testing (0T) for the U.S. Army Armor and Engineering Board. MS has beenused for OT as a simulant for blistering agents in hard/threat analysis, collectiveprotection, decontamination, and detection. It's used because it satisfies mostof the selection criteria used to determine the suitability of any proposed chemicalagent simulant. These criteria involve the medical/safety aspects, envirorinmentalimpact, chemical/physical properties, sampling/detection/analytical methods, agent/simulant correlations, producibility, and transportation/storage/disposal require-ments associated with a simulant. In evaluating MS against previously mentionedcriteria, MS can be an aoceptable OT trailing slimulant for blistering agents in mosttest conditions. However, if spread behavior is of major interest for a given test,neat MS spreads ,ifferently than mustard on most surfaces (i.e., either chemicalagent resis tie coating or alkyd painted surfaces). The addition of thickener toneat MS ay or may not help the given situation, depending on subsequent test char-acteristics of interest. If an odorless simulant is required, MS may not be suit-aba because it has the recognizable and distant odor of wintergreen.

EA-uJECT TERMS' 1is. wi FPAWES

Methyl salicylate, Simulant selection criteria 61Simulant use / Chemical agent simulants . y 1ac. cool

17. SEOJAIT ClASSIFIATION IL. SECURITY CLASSIICATION 119. SECIJRMI O.ASSWICAIn" 20. UMITATFNO SY

Of RIPOAT OF THIS PAGE OF AWSTRACT

NIICLASSIFFlE UNLASSIFIED I USFiu IULNSN 7540--14.SO.5O Stedord Fotm I" (Rev 249)

ý"fto QJ

B1lank

PREFACE

The work described in this report was authorizedunder Project No. 665712, Chemical Agent Moniter. This workwas started in November 1988 and completed May 1989.

The use of trade names or manufacturers' names inthis report does not constitute an official endorsement of anycommercial products. This report may not be cited for purposesof advertisement.

Reproduction of this document in whole or in part isprohibited except with permission of the Commander, U.S. ArmyChemical Research, Development and Engineering Center, ATTN:SMCCR-SPS-T, Aberdeen Proving Ground, Maryland 21010-5423.However, the Defense Technical Information Center and theNational Technical Information Service are authorized to repro-duce the document for U.S. Government purposes.

This report has been approved for release to the

public.

Accession For

NTfS C;RA&IDTIC TA!i

ju,; t i fl; :, 1 on

i. 7 Codes

3/cr

L 15

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CONTENTS

Page

1. INTRCDUCTION ................ . . . . . . .. .. 7

1.1 Purpose ........... ............ . . * * 71.2 Background . . . . . . . . . . . . . . . . . 7

2. METHYL SALICYLATE USAGE AS A TRAILING SIMULANT . 7

2.1 Threat/Hazard ............... . . . ... . 82.2 Collective Protection . . . . . . . . . .. 92.3 Decontamination ........... .............. 92.4 Detection . . . . . . . .......... 9

3. SELECTION/USE CRITERIA FOR METHYL SALICYLATE . . 10

3.1 Medical/Safety......... . . . . . . . . . 103.1.1 Toxicity . . . . . . . . . . . . ... . 10

3.1.2 Dermal Effects .. ................... . 113.1.3 Safety Precautions . . . . . . . . 113.2 Environmental Impact ............. 123.3 Chemical/Physical Properties. . ..... 123.4 Sampling/Detection/Analytical Methods . . 123.5 Application/Dissemination Methods . . ... 133.6 Agent/Simulant Correlations . . . . . ... 133.7 Producibility ............. ............ .. 173.8 Transportation/Storage/Disposal

Information . . ........... . .. 173.9 Chemical Stability/Material Compatibility

Information . . . . . . . . . . . . . . . 17

4. CONCLUSION . . . . . . . . . . . . . . . . . . . 17

LITERATURE CITED . ............... 19

APPENDIXES

A. METHYL SALICYLATE TOXICITY DATAEXTRACTED FROM LITTLE . . . . . .... 21

B. MATERIAL SAFETY DATA SHEETFOR METHYL SALICYLATE . ...... ... 33

C. CHEMICAL/PHYSICAL/ENVIRONMENTALINFORMATION ON METHYL SALICYLATE .... 37

D. ESTIMATION OF THE SPREADOF METHYL SALICYLATE . . . . . . .... 57

E. MATERIAL SAFETY DATA SHEET FOR K125 59

5

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6I

USE OF METHYL SALICYLATE AS A TRIALINGCHEMICAL AGENT SIMULANT

1. INTRODUCTION

1.1 Purpose.

This report provides a comprehensive assessment of theuse of methyl salicylate (MS) as a trialing chemical agent simulantfor operational testing (OT).

1.2 Background.

A simulant is a material which is substituted for achemical agent due to either desired similar chemical or physicalproperties, or due to its ability to simulate chemical/physicalreaction mechanisms of interest for an agent in a givenenvironment. Simulants can be used for training or trialingpurposes. Training refers to the process of learning to useequipment or to perform tasks. Trialing pertains to ascientifically designed and evaluated experiment for the research,development and testing of equipment which evaluates performanceand utilization.

Methyl salicylate has been used as a chemical agentsimulant for blistering (H) agents, such as mustard (HD), in boththe laboratory and out in the field. Its usage is primarily dueto similarities of some of its chemical/physical properties withmustard and its relative safety involving human exposure. Little:stated that MS, in relatively small quantities, has been approvedby the Food and Drug Administration for its use in foods (50-3300ppm) perfumes and anti-Inflammatory ointments as a flavor/odor (oilof wintergreen) additive, and as a topical counterirritant,analgesic and/or anti-inflammatory agent. It was given generallyrecognized as safe (GRAS) status by the Flavor and ExtractManufacturers' Association in 1965.

2. METHYL SALICYLATE USAGE AS A TRIALING SIKULANT

Chemical agent simulants have been used to test theoperation and performance of materiel for many years, but it hasbeen only in the last 5-8 years that efforts to standardize theuse of simulants have been initiated. In the past simulant useinformation obtained by an organization in the process ofconducting a test was usually retained only by that organization.Now, databases are being formed containing simulant use informationfrom the United States and other nations, and access to thisinformation will aid in eliminating the obscure and unnecessary

7

research in testing with simulants. In general, the use ofsimulants to test materiel can be subdivided into seven categories:

a. Threat/Hazard - Simulation of dissemination mechanismsor the hazard created by a munition.

b. Individual Protection - Eye, skin, respiratory systemand other body protection (i.e., mask, overgarments, boots).

c. Collective Protection - Exit/entry procedures and airpurification design impacts for shelters and vehicles.

d. Decontamination - Simulation of the physical andchemical effects for decontamination equipment and solutions.

e. Materiel Protection - Equipment shipment container-ization and cover design.

f. Medical - Prophylaxis and therapy.

g. Detection - Simulation of chemical warfare (CW) agentbehavior in respect to warning, agent identification, contaminationreconnaissance, and monitoring.

In an effort to prove out an item, more than just one ofthese simulant use categories is usually required, and to date nosingle chemical agent simulant has been developed to satisfy therequirements associated with each of the seven categories. Methylsalicylate is no exception, but compared with the other chemicalagent simulants available it is one of the most used.

2.1 Threat/Hazard.

Methyl salicylate used at temperatures above -8.625 °C(its melting point) will be in liquid form. Test conditions areusually well above the melting point of MS, so its liquid formoffers many mechanisms for it to be disseminated. U.S. ArmyChemical Research, Development and Engineering Center (CRDEC),Human Use Protocol', utilized a hand-held garden sprayer to applythe simulant in a fine mist (droplet size 3 mm in diameter) tosimulate the contamination likely to occur from a chemical agentbomb, missile, or other munition exploded or discharged in the airabove a target area. Field tests with the Chemical Agent Monitor(CAM) have been conducted using 9- x 12- x 2-in. glass baking pansfilled with MS as large vapor sources to simulate groundcontamination. CAM performance testing also utilized 500 mLsyringes with calibrated dispensers (Hamilton, Model PB 600) tocontaminate small items and personnel with standard-size drops ofa known concentration of MS. Vapor hazard studies have beenperformed with MS inside a M113 armored personnel carrier (APC)involving the desorption of MS vapor from contaminated patches ofbutyl rubber and overgarment material placed inside the vehicle.(Tytus, Cooper and Wasel') A computer model predicting the vapor

8

concentration of MS within enclosures was also developed from theM113 APC research. (Tytus, Wasel and Cooper') In addition to thiscomputer model, other computer models have been developed toestimate the vapor hazard associated with indoor and outdoor spills(i.e., the D2PC Spill Model) of many c!iemicals including MS.Methyl salicylate can also be aerosolized, and studies arecurrently being conducted with MS investigating this latest threat.

2.2 Collective Protection.

Methyl salicylate has been used in exit/entry tests forboth shelters and vehicles. (Blewett'; Blewett, Stickel, Arca,Hill'; Blewett, Stickel'; Blewett') Specifically, using thepreviously referenced protocol, MS thickened withpolymethylmethacrylate and mixed with a fluorescent tracer (TinopalSWN) was applied to both vegetation and personnel in missionoriented protective posture (MOPP) IV gear. An area of vegetationwas contaminated by the MS solution, and personnel travelledthrough in MOPP IV gear. The now contaminated personnel proceededto enter the test shelter or vehicle according to the latestdoctrine. An ultra-violet light was used to trace contaminationbrought into the shelter through subsequent contact (liquidtransfer) by test personnel.

2.3 Decontamination.

Methyl salicylate has been used in studies (Long,Wallace') investigating the effectiveness of variousdecontamination (decon) systems (i.e., hot air and hot water jetdecon) in removing the simulant from various surfaces. Methylsalicylate was applied to a surface on a test substrate at a knownuniform concentration. Decontamination of the test substrate wasperformed, and analysis of the test surface and/or the spent deconsolution for MS determined how much MS remained on the test surfacefollowing decontamination. Test substrates were made from varioussteel and aluminum alloys and were painted or coated to investigatethe effect the surface condition would have on the efficiency ofdecontaminating the surface. Some surfaces, for example, werecoated with a polyurethane paint (CARC) and for comparison, othersurfaces would be coatel with an alkyd paint. Dirt or mud effectson a test surface have also been investigated. (Tytus, Wasel andCooper"0 )

2.4 Detection,

One of the most extensive areas of MS simulant usage wasin the area of testing chemical agent detection equipment. TheU.S. Army Armor and Engineering (AA&E) Board requested CRDECsupport in designing their follow-on operational test andevaluation (FOT&E) for the CAM using MS as a simulant. The typesof problems to be tested with the CAM are sorting contaminatedpersonnel, and large/small equipment from clean personnel and

9

equipment (assuming a hasty decontamination situation); sheltercontamination monitoring; f eld survey for key terrain, and fieldsurvey for limits of contamination (reconnaissance). The supportrole of CRDEC was to design contamination technology and monitoringmethods to accomplish the goals of the FOT&E. These test goalswere as follows:

a. CAM operational verification,b. Test the man/machine interface,c. Test the CAM use doctrine.

The test conditions and information gained allowed theAA&E Board to identify that test failure sources of error(equipment, man/machine interface, and doctrine) were random andensured that simulant was present when required in the test matrix.It was also desired that a real-time record of contaminationrelease be kept and that different levels of simulant "hazard"(concentration) be produced.

Investigation of the CAM's response to MS revealed thatit was possible to produce predictable bar (hazard) response levelsto the simulant for a given CAM, but not between CAMs. Also, real-time monitoring of MS using the MIRAN-lA infrared gas analyzer tosupport the CAM's bar readings would not be possible for all testsconducted. The lower limit of the MIRAN's ability to detect MSapproaches the upper limit of the CAM before it becomes saturated.Due to this limitation, it was decided to use referee CAMs tobackup the test CAM response of the soldier in the field. Anotherfield test limitation taken into consideration was the control ofMS concentration in space and time. It is likely that two CAMssamplings at slightly different times or locations will see verydifferent concentrations due to shifts in the simulant vapor plumeseven under relatively stable wind conditions. In addition to theCAM, M8 and M9 chemical agent detection papers respond to MS asthey would to mustard.

3. SELECTION/USE CRITERIA FOR METHYL SALICYLATE

3.1 Medical/Safety.

The toxicity, dermal effects, and safety precautionsassociated ith MS and its exposure to personnel in using thesimulant werce investigated in this report and are evaluated in thefollowing paragraphs.

3.1.1 Toxicity.

Methyl salicylate in small concentrations for use as aflavoring agent (50-3300 ppm) in food is safe, but it has beenfound that MS taken in small but concentrated amounts can beacutely toxic. A dose of 30 mL of concentrated MS (approximately

10

0.5 g/kg) may be fatal to adults, while a dose as small as 4-10 mL

may be fatal to children or infants. (See Appendix A)

3.1.2 Dermal Effect5.

Methyl salicylate is considered a strong dermal andmucous membrane irritant and can be absorbed through the skin.Precautions must be taken to avoid MS from being applied to theeyes or any mucous membrane due to the likelihood of severeirritation. Caution should also be exercised to avoid applying MSto already-irritated skin, wounds, and large areas of the bodybecause of the toxicity of the MS that can be absorbed through theskin.

3.1.3 Safety Precautions.

While using MS as a trialing simulant, it is highlylikely that test personnel will be both directly and indirectlyexposed to chemical simulant. To minimize the amount of ZIS taKeninto the body by any route (i.e., oral, inhalaZicn or skinabsorption) the following precautions should be taken:

a. Wear protective/impermeable rubber gloves (i.e., M4rubber gloves), a chemical apron and either chemical goggles or aface shield when handling liquid MS. The simulant will softenregtlar surgical gloves rendering them useless, so elbow-lengthprotective rubber gloves (i.e., impermeable, M4, protective glovesconforming to MIL-G-12223G) offer the best protection from it beingabsorbed through the skin on your hands. Depending on the quantityof liquid simulant involved, a chemical protectivegloves/apron/face shield or eye goggles combination should be wornwhen handling quantities of 10 mL or less, or a gloves/apron/faceshield/shoe or boot covers combination for greater quantitiesshould be worn to protect the eyes, face and rest of the body fromsimulant splatter from spills. Once liquid MS gets into leatheror any regular clothing it is very difficult to remove even aftermultiple washing.

b. Wear a pressurized air hood, self-contained breathingapparatus, or a face mask (w/vapor filters) in conjunction with thesuggested protective clothing when exposed to MS vaporconcentrations greater than 600 mg/m'.

c. Have some rags, kitty litter, or some other absorbentmaterial readily available to soak up any MS accidentally spilledin handling.

The material safety data sheet (MSDS) for MS containsmore specific information concerning precautions and otherimportant MS safety data (i.e., chemical/physical properties,transportation, storage and hazard information).(See Appendix B)

11

3.2 Environmental Impact.

The U.S. Department of Transportation (DOT) does not listMS as a hazardous substance and MS is not listed as a hazardouswaste according to the Resource Conservation and Recovery Act(RCRA). The environmental fate data (See Appendix C) on MScontains detailed information on its behavior in soil, water, andair when MS is released into the environment. When released insoil it will probably hydrolyze with moisture in the soil orbiodegrade, and its reaction products eventually leach into thewater table. Due to its low vapor pressure, very little MS willevaporate (volatilize) from the contaminated soil. If released inwater it will probably hydrolyze at alkaline pH and biodegrade, butit will neither evaporate readily nor adsorb appreciably intosediments. It is also not likely that MS will bioconcentrate inaquatic organisms. Unfortunately, no atmospheric fate data hasbeen reported for MS, but it was expected that MS would be oxidizedby hydroxyl radicals with an estimated half-life of 5.7 days.

3.3 chemical/Physical Properties.

See Appendixes B and C.

3.4 Sampling/Detection/Analytical Methods.

There are many methodologies for monitoring, sampling,and detecting MS as a vapcr and liquid. The vapor can be detectedwith the MIRAN 1A, a 20 m optical path length infrared detector(minimum detectable limit approximately 1 ppm or 6.25 mg/mi').Another method of analysis is the collection of MS vapor in sorbenttubes (filled with a given sorbent material), followed by thermaldesorption into a gas chromatograph (GC) with a flame ionizationdetector (FID) or photoionization detector (PID). For exampledesorption tubes, filled with tenax having undergone a thermaldesorption at 250 "C for 20 min, have yielded MS vapor recoveryefficiencies of 95% with a minimum detectable limit of 0.2micrograms. Ion chromatography, colorimetry, and fluorometry havealso been used in a study to analyze the amount of MS desorbed fromvarious sorbent materials to assist in developing a chemical agentand simulant dosimeter. (Dillon, RoE.e, Davis") Another passivesampling technique developed for MS uses patches of latex rubberas adsorptive samplers. The MS vapor sampling rate is controlledby its rate of diffusion into the rubber, and the resultant MSconcentration is determined through back calculations using adiffusion equation from the total mass of MS adsorbed into therubber patch. The mass of MS adsorbed into the rubber isdetermined by extracting the MS from the patch with a 0.5 normalsodium hydroxide solution and analyzing the resultscolorimetrically. This technique produced a minimum detectablelimit of either 1 microgram or 0.1 mg/m' for a 10 min sampling

12

period with a 2 - in. diameter patch. The CAM has been used todetect MS vapor in the concentration range of 0.1748 - 4.39 mg/m'for a 2-6 bar response for a given test CAM.

Liquid MS can be analyzed by extracting the simulant fromthe test surface using a suitable solvent, one in which MS issoluble, and then analyzing by either GC or a previously mentionedspectrophotometric method. For example, liquid MS has been sprayedon personnel in MOPP IV protective gear, and then they underwenta hasty decontamination (decon) procedure. The protectiveovergarment was then placed in an ultrasonic bath of hexane whichextracted the residual MS remaining in the clothing item.Subsequent GC analysis yielded a minimum detectable level of I ppmfor the residual liquid MS retained by the protective overgarmentafter hasty decon. MS has also been applied to other clothingmaterials and painted surfaces and then extracted with ethanol andanalyzed spectroscopically at 308 nanometers.

3.5 Application/Dissemination Methods.

Fortunately, MS both neat and thickened will be in liquidform when used in most test conditions, so this createb flexibilityin how the simulant can be applied and disswminated. It can bepoured into most containers opened to the atmosphere, thus creatinga vapor source. The more vapor sources, or the greater t'he surfacearea of simulant exposed to the air, the greater the concentrationof MS vapor generated downwind. Increasing the temperature of thesimulant contained in the vapor source (when possible) will alsoincrease the downwind concentration of MS vapor to a certaindegree, because the evaporation rate of MS increases withtemperature. A downwind MS vapor concentration can be determinedby using any one of the analytical/detection procedures previouslydescribed in paragraph 3.4 for vaporized MS (i.e., MIRAN 1A orCAM).

Liquid MS can be brushed on or sprayed directly tocontaminate a given area or item of interest. The desired area ofcontamination, surface condition, simulant disseminationuniformity, and surface contamination concentration are allimportant test parameters that will make one application ordissemination technique more practical than another. As with thavapor contamination, it is extremely important to determine theinitial and final surface contamination concentrations during atest, and the analytical procedures for liquid MS in paragraph 3.4can be employed. A 250 jAL or smaller syringe can be used tocontaminate small items directly with s known quantity of liquidsimulant.

3.6 Agent/Simulant Correlations.

Methyl salicylate is used as a trialing simulant for HDor 2,2 - Dichicrodiethyl sulfide. Depending on the test subject

13

of interest involving either the vapor hazard or contact hazard ofHD, it is desirable that the chemical agent simulant used wouldhave similar physical characteristir3 in those properties whichinfluence the chemical/physical mechtnism(s) associated with thehazard's) under investigation. For example, molecular weight,melting print, boiling point, vapor density, and vapor pressurewould be properties of particular interest for a simulant wheninvestigating the vapor hazard of HD. In studying the liquidcontact hazard or transfer characteristics of HD, the surfacetension, spread factors, viscosity, and diffusion coefficient ofthe simulant would be properties of greater interest in comparisonto those mentioned for a vapor hazard. The table below comparessome of the physical properties between MD and MS.

Table 1. Comparison of Some Physical Properties Between MS andHD. (Long, Wallace')

Description ef Property MS HD

Molecular Weight (g/mol) 152 159molecular Volume (cmn/mol) 129 125Melting Point ('C) 1 14Boiling Point ('C) 223 217Flash Point (°C) - Closed Cup 101 105Saturation Concentration at 20 *C 7.57 x 101 6.09 x 102(mg/mr)Vapor Pressure at 20 OC (mmHg) 0.091 0.070Liquid Density at 25 "C (g/mL) 1.18 1.27Viscosity at 20 "C (cs) 8.26 4.50Heat of Vaporization at 25 *C 89.4 90.8(cal/g)Surface Tension at 25 °C (dynes/cm) 39.8 42.1Solubility in Watcr (g/100 mL) 0.07 @30 "C 0.09 @22 "CSolubility Parameters:1. Hildebrand (cal/cm') 10.6 10.02. H-bond (cal/cm2 ) 6.0 4.0

Contact Angle on Dry Surface (degrees)1. Teflon 54 632. Silicone 44 573. Paraffin 47 504. Polyethylene 28 435. Lucite 20 156. Glossy White Polyurethane Paint 11 177. Matt Olive Polyurethane Paint 8 158. Rust Alkyd Undercoat Paint 33 25

14

The area spread or covered by a drop is determined bythe drop volume and initial area contacted or wetted by the drop(measurable by the contact angle *, see Figure 1). The contactangle is a function of the liquid density, liquid surface tensionand the acceleration of gravity (See Appendix D for more detailedinformation for estimating the spread of a liquid). It can be seenfrom the data in the table that MS does not spread the same way asHD does for most substances. MS spreads quite differently on apolyurethane painted surface when compared to an alkyd paintedsurface. Figure 2 shows this spread difference for MS on an alkydpainted surface and a chemical agent resistant-coated (apolyurethane painted) surface. MS can be thickened by adding PolyMethylmethacrylate (K125) to modify some of its properties tobetter approximate the spread of HD on some surfaces and othercontact or liquid transfer characteristics (See Appendix E for theMSDS on K125).

Evaporation

Adsorption

SurfaceFilm

Substrate

Figure 1 - Definition of a Contact Angle Formed By a Drop on a

Surface

15

P 0

4gs 0

-ooCC 0 C600

C.4.

0 V)

00 0 c

*Z3 033O)VW

16.

3.7 Producibility.

Methyl salicylate is commercially available in industrialand analytical grades. It is manufactured by various chemicalcompanies such as Monsanto Company located in St. Louis, Missouriand Bayer U.S.A., Inc./Mobay Corporation located in Pittsburgh,Pennsylvania.

3.8 Transportation/Storage/Disposal Information.

See Appendix B.

3.9 Chemical Stability/Material compatibility Information.

See Appendixes B and C.

4. CONCLUSION

Methyl salicylate (MS) is a good overall mustard (HD)trialing simulant, especially in the investigation of the vaporhazards associated with MD. It has proven to be an excellentchemical agent simulant for HD in the use categories ofhazard/threat, individual and collective protection,decontamination, and detection. In addition, MS is relatively safeto the environment and those personnel handling the liquid. Thedisposal of MS is also less costly and restrictive when comparedto other simulants, because it is not considered a RCRA waste ora hazardous material. However, experimental measurements have beenconducted on the spread of MS and HD on various coated surfaces,and it was noted that MS does not simulate the spread of HD on mostsurfaces. In particular, HD does not spread appreciatively onalkyd painted surfaces while MS spreads extensively. on chemicalagent resistive coated (CARC) surfaces, both liquids spread, butMS spreads more slowly on a CARC surface than on an alkyd paintsurface. So, this behavior would suggest that neat MS would notbe an acceptable HD simulant where spreading and its relatedphysical processes are critical. The evaporation of MS from paintswill be unlike the evaporation of HD, because the area covered(spread) will be different even though their vapor pressures andevaporation rates are similar. Thickened MS approximates thespreading of HD much better than neat MS. In addition, MS has astrong wintergreen odor and depending on the manufacturer, it maybe either clear, light yellow, or pink. Test personnel in MOPP IVgear should not smell the MS vapor if their masks are properlysealed, but if test personnel are not wearing a mask they will beable to smell MS in the area. The odor or color of MS may or maynot make MS a suitable chemical agent simulant depending on thespecific test requirements.

17

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LITERATURE CITED

1. Little, A.D., Development of Candidate Simulant List: TheEvaluation of Candidate Chemical Simulants Which May Be Used inChemically Hazardous operations, AFAMRL-TR-82-87, Arthur D. Little,Inc., Acorn Park, Cambridge, MA, December 1982, UNCLASSIFIEDReport.

2. Blewett, W.K., Exit/Entry Tests for Collective ProtectionNBC Shelters Using Human Volunteers and the Simulant MethMSalicylate With Tinopal SWN and Polymethylmethacrylate, Human UseProtocol, U.S. Army Chemical Research, Development and EngineeringCenter, Aberdeen Proving Ground, MD, October 1986, UNCLASSIFIEDReport.

3. Tytus, R.P., Cooper, W.A., azA¢ Wasel, W.D., Exit/Entry:M113 Interior Vapor Hazard Studies, ARCSL-TR-82032, U.S. ArmyChemlcal Systems Laboratory, Abirda'nD Proving Ground, MD, August1982, UNCLASSIFIED Report.

4. Tytus, R.P., Wasel, W.D., and Cooper, W.A., Evaluation ofModel for Predicting Vapor Concentration In an M113 APC Containing•Luid Contamination, ARCSL-TR-82053, U.S. Army Chemical Systems

boatory, Aberdeen Proving Ground, MD, June 1983, UNCLASSIFIEDReport.

5. Blewett, W.K. Testing of Entry/Exit Procedures for Vansand Vehicle - Muien'ceu c' 1-' i ters in an NBC Environment, ARCSL-TR-82082, U.S. -7-i•r1ica Systems Laboratory, Aberdeen ProvingGrounds, MD, Fi'c-iar 1963, UNCLASSIFIED Report.

6. Blewctt, w.K., .tickel, G.A., Arca, V., and Hill, T.,Field Testing of ;o(.edures for Employing the M20 CollectiveProtection Equipment as a Tactiical Operat ons Center, CRDEC-TR-88001, U.S. Army Chemical Research, Development and EngineeringCenter, Aberdeen Proving Ground, MD, October 1987, UNCLASSIFIEDReport.

7. Blewett, V.K., and Stickel, G.A., Use of the ChemicalAgent Monitor (CAM* With the M20 Simpliiied NBC CollectiveProtection £guipment, "RDEC-TR-87057, U.S. Army Chemical Research,Development and Engine-eting Center, Aberdeen Proving Ground, MD,June 1987, UNCLASSIFIED Report.

8. Blewett, W.K., Testinr: c1f Enty/Exit Procedures for theXM20 Simplified Collective Protection Equipment iSCPE), CRDC-TR-85008, U.S. Army Chemical Research and Development Center, AberdeinProving Ground, MD, August 1985, UNCLASSIFIED Report.

19

9. Long, D., and Wallace, V., Some Considerations forChoosing Decontamination Simulants, T-180-A, U.S. Army DugwayProving Ground, Dugway, UT, September 1981, UNCLASSIFIED Report.

10. Tytus, R.P., Wasel, W.D., Cooper, W.A., Field ExpedientRemoval of Liquid Contamination from the Overgarment and ButylRubber Material Using Dirt and Sand, ARCSL-TR-83065, U.S. ArmyChemical System Laboratory, Aberdeen Proving Ground, MD, June 1983,UNCLASSIFIED Report.

11. Dillon, K.H., Ph.D., Rose, V.E., D.P.H., and Davis, K.S.,M.S.P.H., Chemical Agent and Simulant Dosimeter, USAFSAM-TR-86-22,University of Alabama at Birmingham, school of Public He4lth,Department of Environmental Health Sciences, University Station,Birmingham, AL, prepared for: USAF School of Aerospace Medicine,Aerospace Medical Division, Brooks AFE, TX, December 1986,UNCLASSIFIED Report.

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APPENDIX A

METHYL SA.LICYLATE TOXICITY DATA EXTRACTED FROM LITTLE'

21

IIETIIYL SAI.ICYLATE

Methyl salicylate has the characteristic odor and tas'e of wintergreen.It is widely used in the perfume and food industries, ar -ell as medicinallyin the form of local analgesic nr anti.-rnflaIammatorv Mv't.ýnts o- liniments(Collins et al., 1971). It was given GPAS ria'us 'tn Flavor and ExtracttlanufacturF-r- Association (1965). The Food and Drug Administration proposedtolerances for methyl salicylate of 100 ppm in bakery goods, 300 ppm incandy. 70 p~n in carbonated beverages, 3300 ppm in chewing gum and 50 ppm inice cream (Food Chemical News Guide, 1982). Methyl salicylate is alsocleared for use in adhesives and as an. antioxidant and stabilizer forsemirigid and rigid acrylic and modified acrylic plastics (Food Chemical NewsGuide, 1982). Furia and Bellanca (1975) reported uses of 54 ppri in bakerygoods. S40 ppm in candy, 59 ppm in non-alcoholic beverages, 8400 ppm inchewing gum, 27 ppm in ice cream and 200 ppm in synrps. The Eleventh Reportof the Joint FAO/WHO Expert Committee on Food Additives (1968) reported anestimated acceptable daily Intake for man of up to 500 pg/kg body weight.

Potential Health Effects

Humnan Data

0 Acute Toxicity

Although methyl salicylate is considered safe for use as a flavoringagent in various foods when added in low concentrations, it has been found tobe acutely toxic when ingested in relatively small but concentrated amounts.A dose of 30 ml concentrated methyl salicylate (-0.5 g/kg) may be fatal toadults, while as little as 4-10 ml may be fatal to infants or children,depending on the size and condition of the child (Stecher, 1968; Adams etal., 1957; Cann and Verhulst, 1958; Canselmo, 1948; Deichmanr, and Gerarde-,T969; wade, 191?).

Symptoms of methyl salicylate poisoning are similar to those caused byother salicylates (i.e., sodium salicylate. acetylsalicylic acid) And mayinclude nausea, vomiting, perspiration, marked thirst and dehydration,occasional diarrhea, acidosis, pulmonary edema, pneumonia, hyperpyrexia,hyperpnea, high blood pressure, increased heart rate, dimness of vision andexcitation of the central nervous system. In severe cases, generalizedconvuisions and coria are followed by cardiovascular collapse and respiratoryinsufficioercy leading to death within 12-36 hours after exposure (Adams etal., 1957; Stecher, 1968; Deichmann 3nd Gerarde, 19691. In general, symp^omso- salicylate roisoning become apparent with blood sdlicylate lrvfls ofzpproximazely 25 rq/•i0 ml, severe intoxication in inofviduals with lowerblood salicylate levels, however, is not uncommon (Cann ana Verhulst, 1958;Deichmann and Gerarde, 1969).

Methyl salicylote poisoning is apparently due to the salicylate moiety,and not the methyl alcohol produced by hydrolysis of the ester in thestoniach. Most clinical signs of methyl salicylate poisoning are attributableto changes in the acid-base balance and electrolyte structure of the plasma.Salicylate stimulation of the respiratory center produces hyperpnea andresults in a CO2 deficit in blood, decreased carbonic acid content and a rise

APPENDIX A 22

in blood pH (i.e., respiratory alkalosis). Renal compensation by increaselibicarbonate excretion facilitates the development of acidosis. Anothercontributing factor tu acidosis is a salicylate-induced chaoige incarbohydrate metabolisr which causes an abnormal production and accumulationof organic acids. TI-e refreval of these abnormal metabolic end-productsresults in :he excr.e.ion of fixed base. Salicylates have been shown toinhibit the first two steps in the Kreb's tricarboxylic cycle, resulting inketosis which may contribute to the acidosis. The diaphoresis and hyperpneaproduced by the salicylate moiety cause water loss from the body, which isincreased by coincident vomiting and diarrhea. This leads to body waterdeficit with impaired renal function and decreased salicylate excretion.Salicylate poisoning may also cause hypoprothrembitnemia, leading todepression of plasma fibrinogen and widespread capillary damaqe (Cant andVerhulst, 1958; Adams et al., 1957). Hyperlamtatemia and hyperkalemia wereobserved in patients wi si-ubsequently died from myocardial failure followingaccidental ingestion of -30-90 ml of methyl salicylate. Autopsy revealedmyofibrillar necrosis which was mast marked in the subendocardlal region ofthe left ventricle (0.iambo, 1971b).

* Demval Effects

Methyl salicylate is a strong dermal and mucous membrane irritant and isreadily absorbed through the skin. Although it is considered to be tooirritating for internal use, methyl salicylate has been frequently employedas a topical counterirritant, analgesic and/or anti-inflammatory agent. Itis used both undiluted or in various ointments, liniments and lotions forrelief of pain, stiffness and inflammation of sciatica and rheumaticconditions (Wade, 1977; Tilley, 1980; Delchmann and Gerarde, 1969; Oav 4 son etal., 1961). When applied to the skin, the resulting irritation r,portedlyTnterferes with the transmission of impulses from local pain fibers. Tilley(1980) urged that caution should be taken to avoid application to the eyes ormucous membranes because of potential severe irritation and to avoidapplication to irritated skin, wounds or large areas of the body because ofpotential toxicity resulting from systemic absorption.

Although Morgan (1968) reported sensitivity to methyl salicylateconfirmed by patch tests in 2 patients, Epstein (1973) reported no irritationand no sensitization after application of methyl salicylate (8% inpetrolatum) for 48 hours with occlusion.

. Hemolytic Effects In Vitro

Two studies reported significant hemolysis in human red blood cellsincubated with methyl salicylate at concentrations as low as 0.004 ml (in 5ml solution). The hemolytic effect was concentration- and time-dependentwith maximum effects seen with 60 minutes exposure to 0.01 -;l. Methylsalicylate appears to cause henhlysis, even at very low co, rtrations, byreducing the surface tension, resulting in damage to the erythrocytemembrane (Muragesh, 1981a). This was further substantiated by the effectiveand significant antagonism of the methyl salicylate-lnduced hemolysis byaddition of a variety of drogs to the cell suspension; these includedurethane, histamine acid phosphate, procaine hydrochloride, acetazolamide and

APPENDIX A 23

tetracycline hydrochloride. Hemolysis was decreased approximately 7O0 by thesimultaneous addition of 1 x 10-3 H antagonist and I x 10-3 1 methylsalicylate to the red blood cells or by the initial incubation of cells andantagonist, prior to addition of methyl salicylate. Although the exaccmechanism of this protective effect Is not known, it was suggested thatcomplexes or interactions between the methyl salicylate and the drugs led toinactivation of the methyl saltcylate, thus preventing the lowering of thesurface tension and the resulting membrane damage (tHuragesh, 1981b).

0 Cytotoxicity

At concentrations of 1, 10 or 100 pg/ml, methyl salicylate was notcytotoxic to HeLa cell cultures (Silyanovska et al., 1968).

Animal Studies

* Acute and Subchronic Toxicity

LDon values for a number of different species have been reported(Opdyke, 1978b; Stecher, 1968; Sax, 1979; RTECS, 1980) as follows:

SOral LOa (mg/lkg) Dermal LOo (mg/kg)

mouse 1100rat 887, 1250guinea pig 700, 1060rabbit 1300, 2800 >5000dog 2100

Administration of 0.5 ml methyl salicylate by oavaoe caused slight rednessand irritation of the stomach mucosa of rats (Strom and Jun, 1974). Inanother study, however, methyl salicylate was found t^ have markedly lessacute gastric ulcerogenic activity compared to salicylic acid whenadministered orally to rats. Groups of 4-6 animals were given a 1 mlsuspension of methyl salicylate in water, or the same dose of salicylic acid,followed by a brief exposure to the cold (1-15%C for 45 minutes) as astress-sensitizing procedure. The number of gistric lesions was reduced from4.8 t 1.9 with salicylic acid to zero with methyl salicylate. This reductionin ulcerogenic activity was apparently not accompanied by any anti-inflamnqa.tory activity. In the same study, oral administration of methyl salicylatewas also notably more effective than salicylic aci(r'in significantly reducingfever Induced in rats by subcutaneous injection of 2. g/kg dried Brewer'syeast in saline (Rainsford and Whitehouse, 1980; Whitehouse and Rainsforcl,1980).

Administration of 0.6-4.7 g/kg methyl salicylate by intubation into thestomach and duodenum of 4 dogs caused nausea, vomiting, diarrhea, intensehyperpnea, excitation of the central nervous system and death in two animalsat 8 and 18 hours, respectively. An increase in respiratory amplitude but nochange in arterial pressure were noted when anesthetized dogs were given0.6-5 g/kg methyl salicylate (Lacroix and Ferragne, 1964).

APPENDIX A 24

Ojiambo (1974), howeve-, reported a drop in blood pressure and cardiacoutput and a slight increase in heart rate within 5 hours. after intragastricadministration of 0.7 9/kg methyl salicylate to dogs. Methyl salicylate-Induced changes in various metabolic parameters were thought to beresponsible for resulting myocardial failure and skeletal (hind Iat) musclenecrosis; these included increased levels of creVtit. phosrpokinase (CPI) incoronary effluent and skeletal muscle bed, a maM.d nrt efflux of both K andlactate from the muscle bed, and a steady rise in oxygen consumption. It wasconcluded that hyperkalemia was produced by a methyl salicylate-induceduncoupling of oxidative phosphorylation, which caused a reduction in thelevel of high energy phosphate necessary to maintainthe normal muscle cellmembrane potential, thus altering the transport of K . The exact mechanismand site of uncoupling was not determined (Ojiambo, 1971b,d). Ojiambo(1971a) also suggested that increased arterial levels of catccholamines(epinephrine and norepinephrine) in dogs intoxicated by methyl salicylate mayhave been a factor in the skeletal and cardiac cell damage. -

In a subchronic feeding study, Webb and Hansen (1963) observed growthretardation but no gross or microscopic abnormalities in 20 rats fed 10,000ppm methyl salicylate in the diet (1%) for '17 weeks. No effects wereobserved in rats fed 1,000 ppm (0.1%). Harrison et al. (1963) reported anincrease in cancellous (i.e., spongy) bone in theiTeirs and tibias of ratsfed 20,000 or 11,250 ppm methyl salicylate in the diet for 10 weeks, while noeffects were observed with levels of 2,000 3,W60, 6,330 or 9,000 ppm.

Weight loss and death within a month were observed in pairs of dogsgiven daily capsules of SOU, 800 or 1200 mg/kg methyl salicylate 6 days/week.At the two highest dosage levels, moderate to marked amounts of fattymetamorphosis were noted in the liver. No adverse effects were noted in 8dogs given daily capsules of 50, 100 or 250 -.g/kg, 6 days/week for up to 59days ?Webb and Hansen, 1963).

Anorexia, weight loss, depression and death in 6-28 days occurred in 3rabbits after application to the clipped back with 4 ml/kg/day methylsalicylace, 5 days/week. In one case, microscopic examination of tissueshowed several distinct lesions indicative of kidney damag( Applications of2, 1 or 0.5 mllkg/day, 5 days/week for up to 96 days resulted in a slight tovery slight dermatitis and an increased incidence of spontaneous nephritisand mild hep4tit;s. Two of 3 rabbits treated with 2 ml/kg/day showed aslight sloughing of the epidermal scales (Webb and Hansen, 1%3).

Gage (1970) reported no signs of toxicity or organ abnormalities in ratsafter twenty 7-hour exposures to saturated methyl salicylate vapor (120 ppm,70U mg/m3).

e Chrunic Toxicity

In a 2-year feeding study, growth vetardation, rough coats and deathwithin 49 weeks were observed in 50 rats fed 20,000 ppm methyl salicylate inthe diet (2%). Pneumonia was the only obvious gross lesion, occurring in29/50 (58%) of the treated inimals; this condition was more acute andresulted in more lung abscesses in the treated rats compared tc contrcl rats.Although no other gross lesions were apparent, it must be noted that all thetreated rats died before the usual age at whic" spent-aneous lesions develop.

APPENDIX A 25

Hematclogical analyses were negative, while microscopic examination revealedan excess of cancellous tissue in the bone. Addition of 10,000 ppm methylsalicylate to the diet (!t) for 2 years caused growth retardation and roughcoats. Both 10,000 ppm (31) and 5000 ppm (0.5%) in the diet caused a slightexcess in cancellous tissue in the bone. No gross or microscopic effectshere noLed with a.dit.;v, oT 1,000 ppm (0.1%) (Webb and Hansen, 1963).

In the same study, weight loss and growth retardation were noted in 7dogs given daily capsules of methyl salicylate (150 or 350 mg/kg/day), 6days/week for 2 years. Gross examination revealed enlarged livers, an"microscopic examination showed enlarged hepatic cells, b.jt no excess fattymetamorphosis. iNo effects were noted in 4 dogs dosed with 50 mg/kg/day for 2years (Webb ar, Hansen, 1963).

* Skin Irritation/Sersitization

A number of studies have reported various dermal effects of methylsalicylate applied to rabbit, rat or guinea pig skin. Mloreno (1973) foundmethyl salicylate to be a moderate irritant to intact or abraded rabbit skinwhen applied full strength for 24 hours under occlusion. Similarly, Yankell(1972) noteO mild to moderate irritation following application of 1,3 or 61methyl salicylate in several different vehicles to intact rabbit skin (shavedand depilated) for 24-72 huurs with occlusion (Saranz wrap). Results were asfollows:

Irritation Index*methyl salicylate concentration

Vehicle is 31 61

H 0 suspension 0.83 (mild) 1.83 mod.PRG 400 0.33 (mild) 0.50 (mild) 0.50 (mild)70% ethanol 1.17 (mild) 4.17 (mod.) 4.00 (mod.)70% ethanol with emollients 2.17 (mod.) 3.00 mod 3.00 (mod.)

'`ccording to the Draize Miethod

Slight erythema and edema were noted after 24 hours with 1% methyl salicylatein 70% ethanol, while necrosis was observed with the 3% and 6% formulations.hecrosis and intradernal and subcutaneous hemorrhage were produced with allthree concentrations of methyl salicylate in 70% ethanol with emollients.Polyethylene glycol (PEG) reportedly inhibits the penetration of methylsalicylate into the skin and/or decreases its release from solution.Similarly, the addition of emollients has been reported to cause rlPA-. ofonly a part of the total amount of methyl salicylate from an ethanolsolution.

In a skin sensitization test, methyl salicylate caused no significantallergic reactions in guinea pigs. Twenty animals received oneintracutaneous injection of 0.1% methyl salicylatc in Freund's adjuvant andsaline every other day for 3 weeks for a total of 10 applications. Fourteendays after the last injection, a challerge dose of 1 ml of 0.1% methylsalicylate was administered by intradermal injection. Positive allergic

APPENDIX A 26

reactions were noted in 2/20 (10%) treated animals coqmared to 0/20 incontrols (P>0.01). A second challenge dose ot methyl salicylate,administered 10 days later by the epidermal route, consisted of a maximalsubirritant concentration (10%) applied in soft white petrolatum underocclusive dressings for 24 hours. No allergic reactions wero ""mberved in anyof the 20 treated animals (Haurer et al., 1980).

* Hematological Effects

Salicylates have been known to interfere with the synthesis of vitaminK -dependent clotting factors VII, IX and X, and also to prolong prothrombintime in vitamin K -deficient rats and rabbits. Park and Leek (1981) observedsignificant decrelses in prothrumbin complex activity (PCA) and in levels ofvitamin K1-dependent clotting factors II, VII and X (but not V) in rabbitsfollowing intramuscular injection of I g/kg methyl sa.Ilcate in .a splitdose). Despite this high dose, recovery of normal plasma PCA.Accurred afterabout 30 hours, or within 2 hours if 2 mg/kg vitamin K1 was administeredintravenously. The reappearance of PCA was directly ýelated t( plasmasalicylate levels, with total suppression of the synthesis.of PCA (Indicat'complete inhibition of clotting factor synthesis) occurring at a minim=salicylate level of 355 : 12 pg/ml. The data indicated that methylsalicylate elicited its effect on the vitamin K -epoxide cycle at the epoxidereductase step, thus preventing regeneration ;V vitamin K and causing areduction In clotting factor synthesis. Although salicylales are not knownto produce hypothrombinemia at normal therapeutic doses, ther authorssuggested that such an effect could occur with an overdose or with a normaldose taken simul aneously with another drug which affected vitamin K1concentrations in the liver.

, Reproductive Effects/Teratogenicity

A number of studies have reported increased incidences of teratogeniceffects in rats and hamsters following induction of methyl salicylatepoisoning in pregnant dams during the early stages of embryonic development.To our knowledge, however, congenital malformations attributable to methylsalicylate or salicylate intake by the mother have not been recorded in ran.

Single subcutaneous injection of 0.1 ml methyl salicylate to pregnantrats on day 10 or 11 of gestation resulted in incidences of fetil resorptionof 27.3 and 32.7%, respectively, and fetal abnormalities in 31.4 and 18.2%,respectively, of the live births. Most abnormalities involved thecardiovascular, urcgenital and/or skeletal systems. -Retarded fetal growth,abnormalities of the branchial arch arterial 4,erivatives. cleft lip, cleftpalate and hydroureter were commonly seen; "club-foot" And phocomelia of thehind-limbs were frequently seen after injection on day 11. Hydronephrosis,ectoplc kidneys, and exencephaly were occasionally observed. Greater fre-quencies of resorption and fetal abnrmalities were apparent when administra-tion of methyl salicylate was combined with hypoxia for 6 hourt (25,000 feetaltitude equivalent). It was suggested that hypoxia aggravat!ci the increasedutilization of oxygen by the tissues which was induced by the methyl salicy-iate (Bertone and Monie, 1965).

Warkany and Takacs (1968) observed even higher incidences ofabnormalities in rats following single subcutaneous injections of 0.1-0.5 ml

APPENDIX A 27

methyl salicylate to 116 pregnant dams on days 9, 10 or 11 of gestation.Results of treatment included 26 maternal deaths (22.4%), 47 resorptions(40.5%) and 120 fetal abnormalities among 298 live births (40.3%). No fetalabnormalities were noted in 484 live births from S9 untr!ated controls.Congenital malformations included 4 cases of exenceDhaly, 4 cases ofhydrocephalus and 9 cases of harelip, oblique 'aci*.ti Llfti and/or cleftpalate. Some anomalies of the vertebrae and ribs werD noted, while in only 2cases were the bones of the extremities grossly deformed. Of special note inth!s study was the occurrence of 12 cases of craniorachischisis, a congenitalfissure of the skull ,and spinal column; S of these 12 also had gastroschisiswith protrusion of the stomach, liver and Intestine. This condition wasthought to be comparable to early stages of craniorachischisls in humans(Warkany and Takacs, 1968).

In an extension of the above study, using the same methods, Takacs andWarkany (1968) observed induction of cardiovascular malformations In 36/159(18.9%) fetuses removed on day 21 of gestation from methyl salicylate-treateddams. The most common abnormality was transposition of the aorta to theright, with displacement ranging in degree from "overriding aorta* tocomplete transposition. In addition, there were 2 cases of isolatedventrictilar septal defects and two dextrocardias.

Similarly, Woo and Hoar (1971, 1972) found that intraperitonealinjection of O.OS or 0.1 ml methyl salicylate to pre3nant rats on days 10 or11 of gestation caused a retardation in renal development, particularlygrowth of renal papilla. During the normal pattern of renal development inthe rat fetus the renal papilla increase slowly and steadily in length, whiletho renal parenchyma increases rapidly and almost exponentially in weight,resulting in an abnormally large renal pelvis and Oapparent hydronephrosis"late in gestition. This apparent abnormality decreases by steady lengtheningof the renal papilla with advancing fetal anw postnatal age, and generallydisappears shortly after birth. Treatment uf pregnant females with methylsalicylate appeared to inhibit the lengthening of the renal papilla andcaused reduced kidney weights through come effect on renal growth. Thisresulted in an increased number of kidneys with an apparently enlarged renalpelvis. In addition, a higher frequency of fetuses f.vm treated dams hadkidneys with no papilla at all. Some re~covery from meth.yl salicylate-inducedeffects was apparent, with kidney weights and renal papillary lengths nearlynormal by postnatal day 6. However, gross dilation of the renal pelvis,reduction of renal parenchyma, and papilla of narrower circumference(although of norml length) were noted in 11/138 (8%) of the treated fetusesat weaning., This persistent condition, suggestive, of hydronephrosis orhypoplasia, was not noted in control fetuses.

Monie (1970) noted occurrences of hydronephrosls and hydroureter infetuses from similarly treated rats. In some casts these abnormalities wereassociated with an obstruction or structural aberration in the urinary tract,while in some, the urinary tract was unobstructed and terminated normally.In the latter cases, the dilatation may have been a result of neuronuscularimbalance. In all cases, there was a reduction In the number of glomeruliand retarded development of the renal tubules; usually the collecting tubuleswere dilated and shortened.

APPENDIX A 28

A variety of repr-tuctive effects were noted when groups of 20 rats werefed 500, 1,500, 3,000 or 5,000 ppm methyl salicylate in the diet for 3generations. Although no significant decrease was observed in the fertilityindex at any dosage level or generation, notahle decreases were observed inaverage litter size, iveraqe rumber of liveborn progeny, viability Index, thenumber of progeny su'o,.ving 4 days and the number surviving to weaning atdose levels of 3,0M and 5,000 ppm methyl salicylate. These decreases weremost significant in the second gereration. Combined results from all 3generations indicated an apparent dose-related response, starting at 1500ppm, in the average litter size, number of liveborn pro.beny and the number ofday 4 survivors. No grossly visible abnormalities were abserved in externalexaminations of newborns or weanlings from any generation; autopsies andhistological examinations of. third generation weanlings revealed noabnormalities or evidence of toxicity (Collins et al., 1971).

Both topical and oral administration of methyl salicylate to pregnanthamsters on day 7 of gestation reportedly resulted in failure 'f neural tubeclosure in nearly 75% of the embryos recovered at day 9. However, in orderfor topical administration to result in blood salicylate levels equal tothose caused by oral administration, a topical dose more than 8 times largerthan the oral dose was necessary (l' g/kg compared to 1.75 g/kg methylsalicylate). Also, the level of salicylates in the blood increased much moregradually following topical application compared to oral administration, withmaximum levels occurring at 5-6 hours and 2 hours, respectively. The authurssuggested that although absorption of methyl salicylate through the hamsterskin could Induce teratogenic effects similar to those obtained after oraltreatment, the response r...quired very large topicAl doses (Overman• 1979;Overman And Mihte, 1978).

White (1978) reported that variations in the teratogenic response inhamsters to methyl salicylate was affected by differences in fetal age whichapparently correspond to different intrauterine positions. When pregnanthamsters were given oral doses of 175-225 mg methyl salicylate per 100 g bodyweight at sp cific times during the period of gestation from day 7 hour 9 today 7 hour 22, the frequency of cranium bitfida in embryos at day 9 rangedfrom 1U-73%, compared to 11% in controls. The critical importance of timingwas indicated by the fact that treatment at hour 21 resulted in a significantfrequency of defects, while treatment just one hour later, at hour 22,induced a frequency of defects not statistically different from the controlvalue.

Szabo et al. (1971) reported that methyl salicylate was embryotoxic andteritogenic'-n-'Toth mice and rabbits when administered during pregnancy(doses, route and time of administ.,ation not stated). 'Malformations includedcleft palate, exencephaly, hydrocephalus, amphalocele, open eyelid a-d spinabiflda.

It should be noted that the doses of methyvl salicylate which inducedteratogenic effects in these studies were close to dose levels which arelethai to the embryo and toxic to the dam, thereby decreasing the expectedyield of offspring. Also these doses were, cn a weight basis, far greaterthan therapeutic human doses. Takacs and Warkany (1968) estimated that an

APPENDIX A 29

equivalent dose in humans to that inducing a teratogenic response in ratswould require intake of approximately 30 g of salicylates ingested by a 60 kgfemale during early gestation.

0 Carcinogenicity

No increase in the incidence of lung tumors was noted in strain A micegiven 24 intraperitoneal injections of a maxiwm. tolerated dose of methylsalicylate or 20% of this dose over an 8 week period. the actual dosesadministered were not stated (Stoner et al., 1973).

Mletabol ic Characteristics

kummn Data

Methyl salicylate is rapidly absorbed through intact hfimn skWn orlbyingestion. It is hydrolyzed In the stomach to methyl alcohol, and salicylicacid which is converted to sc.dium salicylate in the intestine and absorbed.Although largely hydrolyzed, it is also absorbed, at least in part, as theintact ester. Methyl alcohl is seldom produced in sufficient quantities tobe a factor In intoxication; approximately 75% of the sethyl salicylate isavailable as salicylate (Gasselin et al., 1976; Adams et &1., 1957).

' Salicylate Is rapid'y distributed throughout all body fluids and can bedetected in synovial, s'tinal and peritcneal fluid, saliva, hile and milk.The intact ester is also hydrolyzed in the plasma and tissues to salicylica•id and its metabolit'js. Approximately 70-80M of the salicylate in humanplasma is bound to nen-diffusible components, presumably plesma protein.Salicyiates are excreted in the urine in the form of salicylates or theirmetabolites. Small amounts of unhydrolyzed ester my also be excreted,giving the urine a slight odor of wintergreen (Adams et &I., 1957).

Karuta and cowirkers (1977) observed peak serum concentrations of freesalicylic acid (4 ug/ml) and total salicylates (12.5 pg/ml) 8 and 12 hours,respectively, after initiation of a single 12-hour application to the backsof humar volunteers of 10 plasters, each containing 350 mg methyl saltcylateand covered with plastic film. Levels of salicylates were negligible at 24and 48 hours after application. Urinary excretion of total salicylatesreached a plateau of approximately 37 percent 24 hours after application.with 16ttle to no free or total salicylates measured in the urine by 36-48hours. Following repeated 12-hour applications, each 12 hours apart, for 6days, only trace to no free salicylic acid or total salicylates were detected12 hours after removal of the Zrd, 4th or 6th plaster •nd no salicylates weredetected 36 hour; after the last (6th) application. Thms, salicylates didnot appear to accumulate in the human body at this dose level, even withreperted application.

Several studies have itidicated th;t hydrolysis of methyl salicylate inhumans is slower and of lower magnitude than that seen in dogs or rats. Anapprcciable amount of unhydrolyzed methyl salicylate was measured In plasma15 minutes (39%) and 90 minutes (21%) after ingestion of 0.42 ml methylsalicylate in ginger ale. Total plasma salicylate concentrations weresignificantly less than those obtaited after similar administration ofacetylsalicyl'c acid. In tests with dogs, negligible amounts of methyl

APPENDIX A 30

salicylate were measured In the total plasm salicylates within 60 minutesafter oral administration of a much higher dose than that administered tohumans (equivalent to -300-500 mg/kg salicylic acid compared to -7 mg/kg).Other reports have also indicated that lethal concentrations of totalcirculating plasm salicylates in man were 2-3 times higiser than those indogs at the time of death. It has been. suggested that ;arg2 oaases of methylsalicylate administered to humans could overwhelm an apparently inadequatedetoxification mechanism, resulting in even less hydrolysis, greater uptakeof the highly lipid-so1'.1e tondissociated ester by such tissues as the brain,and a consequent increase in toxicity. In 3 cases of accidental ingestion of-30-90 el of methyl salicylate, about 21% of the dose wes still circulatingin the plasma at the time of ryocardial failure (0jiamo, 1971c; Davison etal., 1961).

Aunimal Studies

Absorption of topically applied methyl salicylate was shown to be quiterapid In mice and rabbits. High levels of radioactivity were measured in theskin of hairless mice at the exposure site within 1 hour after p-rcutaneousapplication of a plaster containing 127 mg/kg [("CI-labelled ,ethylsalicylate for 1, 2, 4, 8, 12, 24 or 48 hours. Levels of activity peaked at4 hours, then gradually decreased until virtually no activity was measured at48 hours. Only slight radioactivity was detected In the skin adjacent to theapplication site at 2 and 4 hours. Serum levels of radioactivity peaked(equivalent to 15 pg/ml salicylates) 2 hours after application, thendecreased gradually. Cumulative urinary excretion of radioactivity was 33.5and 39,3% of the dose in mice treateA, for 24 and 48 hours, respectively. Itappeared that the methyl salicylate was absorbed rapidly from the plaster andwas localized at a high concentration in the skin at the application site(Haruta et al., 1977).

Kitagawa and coworkers (1979b) noted an even higher rate of cbsorptior.of radiolabeled methyl salicylate when applied to rabbit skin. Radioactivitywas detected in the blood 15 minutes after application and peaked at 2 hoursafter administration. Distribution of methyl salicylate was widespread, withradioactivity ooserved in nearly all organs and "issues. Excretion was alsorapid, with total radioactivity (32.88% of the dose) eliminated In the urineat 94 hours; no radioactivity was found in the feces.

Kida (1978) found that percutaneous absorption of methyl salicylate fromthe back of rabbits, pigs and humans could be increased by raising thetemperatu're of the methyl salicylate-containing poultice.

Several studies have indicated that more extensive hydrolysis of methylsalicylate occurs In the intestine after oral administration compared toother routes of administration. Williams (1959) reported that only 0.2-0.5%of an oral dose of 0.2 g/kg appeart. ichanged in the urine of dogs, while141 of the dose appeared unchanged in the urine after intramuscularinjection. Similarly. Davison et al. (1961) noted from plasma analysesthat hydrolysis was about 95% €mpTete at I and 4 hours in dogs givercapsules (orally) of 300 mg/kg methyl salicylate. Ojiambo (1971a) observedan initial I hour delay in the absorption of methyl salicylate. followed by asteady linear rise in plasma salicylate levels up to 3 or 4 hours afterIntragastric administration of 700 mg/kg nethyl salicylate to dogs. No

APPENDIX A 31

further significant increase In blood salicylate levels was observed after 3hours in dogs surviving the treatment or after 4 hours in dogs dying withinthe study period. The data indicated a higher rate of absorption and/or aslower rate of elimination ia the dogs that died within S hour* of treatment(3 of which had recetved to additional 100 mg/kg methyl salicylate 2 hoursafter the first dosc). 7%.i initial delay in appearance of salicylate in theblood was att-ibutew tu a d.elay in passage of methyl salicylate into thesmall intestine from the stomach, po.s.ibly due to spasm of the pylorus causedby gastric irritation. Once absorption was initiated, hydrolytic anddetoxification mechanisms converted the methyl salicylate to its metabolites.OJiaubo (1971c) also indicated that the level of total plasma salicylateswhich resulted in death of female dogs was lower than that of male dogs.

In a similar study, plasma and brain tissue analyses from ratsdemonstrated negligible amounts of methyl salicylate 20 and 60 minutes afteradministration by oral catheter cf a dose equivalent to 500 rg/kg salicylicacid. Thus, hydrolysis of this near lethal dose was almost complete in aslittle as 20 minutes (Davison et al., 1961).

Monitoring and Detection

Methyl salicylate would be rapidly converted by esterases to salicylicacid (o-hydroxybenzoic acid). The metabolites of salicylic acid includesalicyluric acid (glycine conjugate), the acyl and phenolic glucuronides,gentisic acid and gentisuric acid. Salicyluric acid would be the majormetabolite (-60%) in urine. Sali:ylic and salicyluric acids my be readilyanalyzed in either plasm or urine samples by high performance liquidchromatography (Sadee and Beelen, 1980). The assay is sensitive to 0.5 tg/alfor both cowoounds. A gas chromatographic procedure is reported for theanalysis of methyl salicylatc in either plasma or urine; however, the methodis based on ?0 og of compound/ml plasma (Pentz and Schutt, 1978). Thisconcentration is much higher than can be expected under simulant trainingconditions. Acetylsalicylic acid (aspirin) would give the same metabolicproducts as the salicylate esters. Therefore, unless the salicylate esterscan be detected in plasma, urine or saliva, military personnel would have toforego use of aspirin as a pain reliever prior to any military exercise.

Possible qualitative tests for the uetection of salicylete esters oneither clothing or equipment include ultraviolet light and 5% aqueous ferricchloride spray (greenish-blue color) (Walash and Hassan, 1978).

APPENIDIX A 32

APPENDIX B

MATERIAL SAFETY DATA SHEET FOR METHYL SALICYLATE

33

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APPENDIX B 35

Blank

36

APPENDIX C

CHEMICAL/PHYSICAL/ENVIRONMENTAL INFORMATION ON METHYL SALICYLATE*

*Environmental Fate and Effects: Methyl Salicylate, CRDEC Data Management System,U.S. Army Chemical Research, Development and Engineering Center, Aberdeen ProvingGround, MD, 1987, UNCLASSIFIED Data Report.

37

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APPENDIX D

ESTIMATION OF THE SPREAD OF METHYL SALICYLATE

The volume of a liquid drop and the area which wets thesurface determines the area spread upon and covered by the drop.(Long, Wallace') This area eventually covered is directlyporportional to the force of impact of the drop and its subsequentsplatter or breakup. The radius (r) of the contact circle from theresultant drop can be estimated from the contact angle (9) usingthe following equation: r(cm)

4xV E + E'/8 + E5/192 + E'/9216 + E'/737280tan e = --- x ------------------------------------------- - 1)

r' E + E'/12 + E5/384 + EV/23040 + E'/2211840

where:

V = Drop Volume (cm')

I- d x g I 1/2E=rx --------- I

t

d liquid density (g/cm3 )

g = acceleration of gravity = 980 cm/s'

t liquid surface (dynes/cm)

This equation is reported accurate to within 10% for values of 0up to 30 degrees.

57

Blank

58

APPENDIX E

MATERIAL SAFETY DATA SHEET FOR K125

59

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MUS Ppim - UAS DEPARTMENT OF LASOR Pl

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SbURbulI& W 9**d k f~ptng 2 CFR 1915. 1016, 1917)

ResallarSECTION I

SECTION 11 -'HAZARDOUS INGREDIENTS

0PMUTS PSUUAYATIVW S UOLVS T LV ygMTLICOINSTLV

"Dau~ms NONE 41Ait INITAL NI/A

cATAuYsV NONE ALLOYS X/A

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SECT9V0ION iI .PHSCA DT

S@LUUL06TY IN WATtUN I

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SECTION IV.- FIRE AND EXPLOSION HAZARD DATAOfkss" IPMIMiIpsOC)P00 PL^AMAs*La LIMITS La u

PA;TYmEI TAIPPAWAI'f TE DEC010SMTON TD4PERALTIRE WO REL'-ASE VAPOR~SSM"COAL OF0IN lEl~ F@VFg@ PNcWIJNE THAT WILL RURN1.

ABC DRY POWDER, COpWATER

PAGE (13 APPENDIX E (Continued on' rvewY s ide) 60 Form OSHA-20

1692666 BUEHLER LTD 840 000o 0 CH

SECTION V - HEALTH HAZARD DATA1ONOR9514MA. Urn? WA~a W/A5IFITGTS OF 10EDrx SU W X/A

vt inn =A, wk aTc n

_ ,. K AIIDIED W. A VAT TRAT _CREATFS 1)~

Cond0 om,. OPEUATOR SROUI' MAR APOVED DUST R.E•PMO...

SECTION VI - REACTIVITY DATA

UftSTAI. CWopeo~l'"0 To AVOIDSrAi. N/A

W~~jA500p4ssso5 LCh@UloN *@um-wOaz•Aaoousr Irnmdsaw•.ecue -- coovo. t " "S"

W @ L~'MuA gZAeOU° " A Vo *O.W.L "?O@CCUR :U I NIA

SECTION VII S SPILL OR LEAK PROCEDURES09JOSTO W TAOAW M CA" amAT5*A- IS fti.KASD 00 SAsIAbO

SWEV UP AND DISPOSE IN APPROED• LANDFILL - WON IAZARDOUS

WAIT OI0@A~ ~ INC1h'ERTIO1I, LIL M)FILI1

"SECTION Vill • SPECIAL PROTECTION INFORMATIONaUW,UIATOY PUOTBCTOQN Iqp'/I, S1y ".. ...

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IMCC84ANICAL. lje4000 OTHI[ a

01101 PeNONE RVOTCCTOv( 01- DED

SECTION IX - SPECIAL PRECAUTIONSP49CAUTeOPO1 TO BC TA•KI.ft 4 .AOLNo AMO $TO3Os*C NONE

01 iA PA4CAUTIONS ONE

PAGE 121Fan" OSMA-20PAGE { The data and information as stated was furnished by the sew. OA.ZO

manufacturer and supplier of this product. BUEHLER, LTD.cannot warrant the accuracy of this Information, and shall notbe responaible or liable for any damage that: ay result, should

,PPENDIX E any of the Informaticon hp arro-eous. 61