Blister Agents (HN T Q L HL)

7/25/2019 Blister Agents (HN T Q L HL)

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JOINT

CTB

CONTACTPOINT

@nd

?ESr

JOINT

ClB

TECHNICAL

DATA

SOUR.CEBOOIf

VOLUME

V.

BLISTER,

BLOOD, AND

CHOKING

AGENTS

PART 4.

AGENTS

HN,

O,T,

L,

AND

HL

october

1ee3

-.,noJit{S

U#O[D

,-4"1$r.ffiffiSnu""*

JOINT

CONTACT

POINT

DIRE,CTORATE

U.

S.

Armg

Dugway Prouing

Ground.

,

utah

4=-

F.

r

;ll}

lV1

Gl.

s"

^u')


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vhich

do

not

ag.es

wnlcn

oo

not

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Inconsistent

page

numbers

are

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omittance of

blank

\

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AD

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PROIECT

NO.

&CO-210{49-2r2

DPCi REPORT

NO.

DPG/JCP.94/OO2

JOINT

CB

TECHNICAL

DATA

SOURCE

BOOK

voLUME

V.

BLISTER, BLOOD,

AND

CHOKING

AGENTS

PART

4.

AGENTS

HN,

Q,

T,

L,

AND

HL

Prepared

by

Don

T.

Parker

Andrew

C.

Parker

ANDRULIS

Research

Corporation

660 South 200

East, Suite

418

salr Lake

city,

uT

84111-3835

October

1993

Project Manager:

Kenneth

S.K. Chinn

Dirtribution

limircd

to

U.S.

Govcrnmcnt

rgencig only

(Octobcr

1993).

Olhcr

rEqucatr

murt

bc rpfcrrpd

to: Commandcr,

U,S.

Army

Dugwey

hoving

Grcund,

ATTN:

STEDP-JCP,

Dugury,

UT

&(n2-5m0

JOhIT'GOtr\ITACT

:PPg1l

;,,I)_EEGTOBA,

E

:,:,,

.

U;s;

aRlvtY

DUcwev,inovntc

Gnoullo:::

::

:


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.

NEUTRAL LANGUAGE

STAIEMEI{T

Thp words

'he,

him,

his, etc.'

ufien

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in the documcot rprsent

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DISCLAIMEN,

STATEMENT

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DO49)

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rd

rocon'ncadetionr

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dosuml

rrc Dot

to

bc construcd

es m officid

poeition

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U.S. Army Dugwey

Proving Ground,

tho

Tcct rnd Evrluation Comnaod,

or tho

Deprrtrcnt

of tho

Army.

TRADE

NAME

STATEMEIYT

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ir this document

doos

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oodorgemt or

rpplovel of the

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or rcftunrp.

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colLEtim ol

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t lw

pa.

rqlcra, imluaiE

tha

tim

td

?.Yiawiie

irtt ucrid.

xrch&

ariilire dttl

louc6,

O.rh.rir{

md m.im.idrE

r:ha d.it

r.d.d, fi

cmCatir

rrrd

rditwiE

tlr

coabsiion

ol hl{madm. Sli CmmJltt

taef,ditE

tt*

brrd.n

-timal.

d

$Y otltr

rp.d

ol

rh.

Hichw.y,

Srir.

12O4,

A.lirlrs, VA 22ZO2atO2,.t

rc ir

Otth. ol MmI.moa

id Eude.(,

Pprwrt

i.dElin

PtC.sr

p7oa.Ol22l,

Wd*ErtL D'C. 20603.

. AgkNcY

Ush oNLY

(L-n

Dank)

lz.

tltfoHl

uAlE

lJ.

rcruxl

IYr ANU 9AIED suvEEu

I

October

1993-

|

fechnical/Current

Joint CB Technical Data

Source

Book,

Volume

V, Blister, Blood,

and Choking

Agents.

Part

4, Agents

HN,

Q,

T, L,

and

HL

ullUINS

NUMECFD

TECOM

8-CO-21

A-049-21

2

Contract DAAD09-87-

D-0008

B.

AUTHOR(SI

Parker,

Don

T.;

Parker, Andrew

C.

Properod

by

Aadrulie

Rcscerch Coqroretioa,

660 South 20O

Etst,

Salt I-rke

City,

UT t4111-3t35

for

U.S.

Army

Dugrvry Proving Ground, ATTN:STEDP-JCP

Dugwey,

UT

84022-5000

,.sR

trSOHIli6TMONrrC'HI[ti[6ENCYI,TAMEISI

AtrD

ADORESS(ESt

O.

SFONSOBING/MONIIOHING

AGENCY REPORT

NUMBER

1.

SUPPLEMENTARY NOTES

Project Manager

for

DPG

is Kenneth

S.K.

Chinn

2.. DIsTRIBUTION/AVAILAEILITY STATEMENT

Distribution limited

to U.s.

Government

agencies

only

(october

19931.

Other

requests for

this document

must

be

relerred to: Commander,

U.S.

Army

Dugway

Proving

Ground,

ATTN:

STEDP-JCP,

UT

84022-5000

2b. DISTFIBUTION

CODE

The

chemical warfare

agents discussed in

this

book were

developed prior

to

World War

ll,

but

none

have been used

in

warfare by or

against

U.S.

military

forces.

Because materials of

greater

toxicity

have

been developed,

thess

agents

have

bssn considered

obsolete.

Defense

capability

remains

a

possible

requirement because

of the

ease

with

which

some

of

these

agents

can be

produced

and the

low

cost

of

production.

These chemical

warfare

agents,

if

used

at

deliverable

rates

in

the

field, would

cause

casualties

with

days

to

weeks

of

incapacitation, but

few

deaths

would result from

such

uss.

All

are

capable of

causing skin blisters,

eye

injuries

and,

at

high exposure

levels,

various

physiological

responses such

as

respiratory

and

intestinal

iniury.

I4. SUBJECT

TERMS

Chemical defease, Chemicel

wrrfare,

Ageot

HN,

Agent

Q,

Agent T,

Agent L,

Aosrt III- Aocnt IfT Nittnoen mrrstrrd, Iqvisitc- Scsouimusterd. Orvocn musterd.

5.

NUMEEF

OF PAGES

54

{crcluding

Distribution)

Vesicetion,

Cerciaogeoicity,

Mechlorethamine,

Physicd

protrction,

Protoctive

"1srhing,

Deconteminstioa, Chemicd ageot

destructioo.

16. PflICE CODE

/.

SEUUiiI

I

Y

ULADJIIIUA IIt,N

OF REFORT

UNCLASSIFIED

I'.

SEUIJhI

I Y UUDJFruA

IIU

OF TH]S PAGE

UNCLASSIFlED

tl. E{;unll

r cllltllrl(ialtun

OF ABTTRACT

UNCLASSIFlED

20. LIMITATION

OF ABSTRACT

PrEib.a

by

Arig

srd.

23e.18

2a&ro2

DPG/JCP-94/002


6/65

DOCUMENT

UNCLASSIFIED

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JCP-|,

DPG

FORSWORI)

The

Joint

Chemicd/Biological

(CB)

Technical Data Source

Book is

organized

as a

series

of volumes,

each addressing an identifiable area of

information related to the andysis of CB

weaponri

and defensive systems. Areas

inelude

chemical/biological

agents,

general

models

weapons

systems, chemical simulants,

biological

nonpathogens, and

knowledge

deficiencies.

This

doorment,

Volume

V,

Part

4

of

the

loint

CB Technical

Data

Source

Book

is

a

discussion-

of

blister

agenti

other than

H,

which

was

published

as

Volume V, Part 1.

This

Source

Book volume was

prepared

by Andrulis Research Corporation

under

contract

No.

DAAD09-t7-D-000E. The

au&ors

would like

to

thank

Kenneth S.K.

Chinn

for his

comprehensive review of

ttris document.


7/65

DOCUMENT

UTVCLASS

IFIED

UPON REPRODUCTION

JCP-|,

DPG

TABLE OF

CONTENTS

FOREWORD

LIST OF TABLES AI{D FIGURES

. . .

.

1.

INTRODUCTION

2.

NITROOEN MUSTARDS

2.1

CHEMICAL COMPOSIIION

AND

PTIYSICAL

PROPERTIES

OF

NITROGEN

MUSTARDS

CHEMICAL

REACTIONS

OF

MTROGEN MUSTARDS

PREPARATION

OF NrIT.OGEN MUSTARD

SYMPTOMATOLOGY

AI{D

PATIIOI.OGY

OF

MTROGEN MUSTARD

POISONINO

MECTIAMSM OF ACTION

OF

MIROGEN

MUSTARDS

TI

TOXICITYOFNIIROGENMUSTARDS....

.,....

L4

TIIERAPYANDPROPHYLNilS....

.....,

I7

EMPLOYMENT

..

18

3. SULFURMUSTARDS,TA}iIDA...

2I

3.I

CTIEMICAL COMPOSITION AND PHYSICAL

PROPERTIES

OF

T

AND

Q

2I

3.2

CHEMICAL

REAETIONS

2L

3.3 PREPARATION

OF

T AND

Q

2I

3.4 SYMPTOMATOLOGY, PATHOLOGY,

AND

MECHANISM OF ACTION

PRODUCEDBYTANDA

...

3.5

TOXTCTTY

OFT

AI{D

a

. .

.

3,6

TIIERAPY AND

PROPHYI.AXIS

.

.

.

3.7

EMPLOYMENT

.

.

LEWISITE(L)AT.TDMUSTARD/LEWISTE6L) ......

29

4.I

CIIEMICAL

COMPOSIIION A}iID

PI{YSICAL

PROPERTIES

29

4.2

CTIEIUICAL REACTIONS

OF

LE\I'ISITE

29

4.3

PREPARATION OF

AGEITIT

32

4.4

SYMPTOMATOLOGY, PATHOLOGY,

AND MECHANISM

OF

ACTION

. . . .

13

4.5 TOXTCITY

36

4.6

PROPHYI-AXIS

A .ID

TIIERAPY

3t

4.7

EMPI,OYMEM

..

39

DEFENSE AGAINST CIIEMICAL

AGEITI'TS

4T

5.1 DE]ECTION

4I

5.2

PT{YSICAL

PROTECTION

42

5.3 DECONTAIUINATION

,,.,.. 4

6.

DEMILITARIZATION

OF CHEMICAL

AGEMS A}.ID

MUMTIONS . .

.

6.1

INTRODUCTION

..

6.2

CONSIDERATION

OF DISPOSAL

PROCEDURES

.

. . .

2.2

2.3

2,4

t

v

3

3

9

2.5

2.6

2.7

2.8

25

25

27

27

4.

5.

47

47

47

ul


8/65

DOCUMENT

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IFIED

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JCP.L

DPG

LIST

OF

TABLES

AND FIGURES

Table

l.

Ch-emical

Structure

and

Properties of

HN

2.

Physical Propenies

of

HN

3.

Eruyme

Inactivation

by

Vesicants in

Wtro

4. Penetration

of Human

Forearrn

Skin by Saturated

Vesicant

Vapor

i. li**Ifi

*#fffiffifi;i,,

.

.

. . . . .

'

.

......

. . .

. . .

9.

Toxicity

of

HN-l and

HN-2

Vapor for Man

10.

Toxicity

of

HN-3 for Man

11.

Estimated

Dosages

for Nitrogen

Mustard

and

H to Produce Skin

Damage

on

Human

Forearm

12.

Cutanous

Injury in

Masked

Volunteers

Exposed

to

HN-l

and

HN-3

Vapor

while

Wearing Nonprotective

Clothing

13.

Chemicel

Structure

and

Properties

of

T

and

Q

14.

Physical

Properties

ofT and

Q

15.

Lethal

Dosage

of

H,

T,

and

Q

for

Various Animds

16. Effect

of

Chamber

Airflow

Rate

on

Lettrd

Dosage

for Vesicant

Agents

to

which

Mice Are

Exposed

17. RElative Vesication

Resulting from H, T, or

Q

Deposited on Human

Skin

.

18.

Chemical Structure

and Properties

of

L

and

HL

19. Physical Properties of

L

end

HL.

20.

Sequentid Effect of One Drop of Liquid Lewisite or

Sulfur

Mustard on

the Skin

of

the Human Forearm

21. Toxicity of

L

for Animds when the Entire Body Is

Exposed

to

Agent

Vapor

. .

.

.

22. Toxicity of

L

for

Animals when Exposed

to

Vapor

23. Toxicity to Animds of

Percutenoous Application of

Liquid

L

.

. .

24.

Toxicity of Lewisite

for

Man

Flgure

l. Transformations of Methyl-bis-(p-Chloroethyl)-amine

(IIN-2)

in Water

Page

4

5

t

t2

l4

15

l5

l5

16

l6

16

L7

22

23

26

26

26

30

31

34

36

37

37

37

lv

6


9/65

DOCU

M E

N7

UNCLASS

I

F

ED

UPO N

REPRO

D

UCT

O

N JC

P. I, DPG

SECTION 1.

INIRODUCTION

Chemical compounds

that have

been

included

or considered

for inclusion in

the U.S. arsenal

of

chemical warfare

(CW)

blister

agents

are

the sulfur

mustards,

the nitrogen

mustards,

the arsenicals,

and

certain

mixures

of

these agents.

The

sulfur

mustards

GI,

HD, and THD),

composed of the

active

ingredient [email protected])

sulfide,

were

presented

in

the

lolnt

QumicalBblogical

Technical

Data

Source

Bo,ot

(SB),

Volume

V, Part I

@ef.

t).

This document,

Volume

V,

Part

4

of the Sowce

Book,

contains

infonnation

on other blister-qpe CW agents. Section 2 addresses thenirogen

mustards;

Section

3, sulphur mustards

T

and

Q;

and Section

4,

arsenicals

Lewisite

and

Lewisite/mustard

mixture.

Section

5

addresses

defense againstthese

CW

agents,

and Section 6

discusses

agent

disposal.

The

CW

agents discussed

in

this

doctment

were,

for

the

most

part,

developed

prior

to

the end

of

World

War

II,

though

experimental evaluation

of some

continued

for

several

years

thereafter.

These

agents

were selected

as the most

appropriate

for

use

as

CW

agents

from among a large number

of

compounds

that

were

oraluated. There is no indication

that

any of the CW

agents

discussed wore ever

used

in military

conflict.

With

ttre development of nerve

agents,

which

are

much more toxic ttran

ury

of the

vesicurt

agents,

interest

in

further

development

of

vesicants

declined.

However,

recent employment

of sulfur mustard

(H

or HD) by Iraq

and

Iran

has

renewed

interest in vesicants,

particularly

interest in defense requirements

should

these CW agents

be used against

U.S.

forces in a limited conflict.


10/65

2.1

DOCUMENT

UNCLASSIFIED

UPON

REPRODUCTION

JCP-|,

DPG

SEETION 2. NITROGEN

MUSTABDS

CHEMICAL COMPOSMON

AND

PHYSICAL PROPERTIES OF

NITROGEN

MUSTARDS

2.1.1

Introduction

In lgii

and

1935,

lVard

@ef.

2)

studied

the

propertix

of

chlorinated-*tryl

amines

including the

tertiary amines,

which

he

found to have vesicant

properties. Further

study

establistred the applicability

of

these agents to

military

use.

The

designation

'mustard

agent"

has been

given

to

these

chlorinated

ethyl

amines because

of

their

struchral

relationship

and

similarity

in

physiological

effects

to

sulfur

mustard.

In

U.S.

CW

literature, nitrogen mustards

are

given

the

general

symbol

HN.

Three

of

the

tertiary

chlorinated *tryl

amines were

selected as

CW agents

and

have

been

designated by

the

symbols

HN-l,

HN-2, and

HN-3.

Designations

by

which these agents

may be identified

in various literature sources are

HN-l:

ettryl S,

NH-LOST,

NOR,

nitrogen

mustard-I, and

NSC 10873;

HN-2: dichloren,

N-Methyl-LOST, mustine, nitrogen

mustard.2,

NSC

762,

S,

and

mechloroethamine;

HN-3: nitrogen mustard-3, TO.

2.1.2

Chemical

and

Physicd Propertix

The

chemicd

struc$re

and

properties

of HN-l,

HN-2

and

HN-3

are

listed

in

Table

l. The

physical

properties

of these

agents

are

given

in Table 2.

2.2

CHEMICAL

REACTIONS

OF

NITROGEN MUSTARDS

2.2.1

Reactions in

Storage

The nitrogen

mustards dimerize

in

storage as

a

result of self-dkylation.

Dimerization

is

relatively

independent

of

the

presence

of

metals such

as

steel,

brass,

or solder.

The

HN-3

is

the

most

stable

of the

three

nitrogen mustards,

HN-l

the least

stable.

If

HN-3

i.

dry,

it will

store

for

a

very long time

witltout

excessive

dimerization.

Dimerization

increases

with

the

increase

of storage temperature,

and

is

relatively

rapid

in 0re

presence

of

polar

solvents. Early

evidence

of the

instability of

HN-2

in

storage eliminated

it ftom

further

serious consideration as a

CVf

agent.

Dimerization

of

HN-3

yields,

as a

first

product,

an

N.N.N'.N'-terakis-

(2-chloroethyl)-pipera-

mnium

dichloride.

Other

products

result

from

storage

in the

presence

of

solvents

or

acids

(Ref.

4).

3


11/65

D O C U M

E N

7

UNCrA

SS

tF t

E

D U

p

O N

R

E

p

R O D

u c

T Oy,J_q

?:1_

c

Table

l. Chemicd Structure

and

Properties

of HN.

HN-3

It2clt2c,

lllrCHzCl

Chqnical

Formule

cJ{,rc?rN

Moleuler

lfleiqht

170.08

Rete of HvdrolYsis

Vcry

slow

Pnoducts of Hvdrolysis

Chenricel

Neme

Bie{2-chlorocthyl)

o6yluinc

Bie-2(chlorocthyl)

mcthylaoiac

Tri{2+hlorocthyl)

rmine

(Rcf.

3)

(Rcf.

3)

@cf.

3)

Ethylbis(2-chlorocthyl)

rnine

2,2'dic.hloro-N-rethyl

diethyl-

Tri(2+hlorocthyleminc

(Rcf.

3)

rmino

(Rcf.

3)

(Rd.3)

Ethyltie{p.oNoroc6yl)

mino

N,N-bis(2-chlorocthyl)

ncthyl-

2,2',2'-trichloto-tricthyl

Gef

a.)

rmina

(Rcf.

3)

rmino

(Rcf.

3,

5)

Chenrical Stnrcture

Cblonmino

(Rcf.

3) Tris(p.chlotoethyl)

enino

@cf.

a)

Morhyl-bis

(p


12/65

DOCUMENT

U'VCLASS'FIED'JPON

REPROOUCTION

JCP.I,

OPG

Table

2. Physical Properties

of HN..

HN-I

HN-2

HN.3

Phvsicel

Stetc et Room Ternperaturd

Uquid

Dercitv &iquid

ft/mf)

1.09 et 25oC

Dcnsitv

(Veoor

-

es Conoamd to Air)

-.

5.9

5.4

Boilins

Point

194cC

(cdculetod)

75cC

et

15

mm Hg.

Dccomposcs

bclow

boiliag at Dccomposes

below boiliry

et

stmofphcnc

pressurE

ilmotphefic

prcssulla

Dccom

oosition TclrrDcraturc

Freczinq Tenrperature

-34cC

Ilash Foint

Hish

Viscositv

Latnt Heat

of

Vanorizstion

77

cdlg

VaDor kessure

(mm

Hg)

0.24 rrt25oC

Solubilitl in Weter

Sparingly

Solubilitv in Solvenb

Freoly solublo

in ecolone

rnd

othcr organic

rolvcnts

Volebilitv

(ng/n)

127

tt

-lOoC

308

rt OcC

1,52$.t

2OoC

3,1O0

rt

30"C

{O

to

{5oC

High

78.8 cal/g

0.29 at 20oC

1.25

et 40oC

lZ

glt

rt 2'C

@ef.

7)

Soluble

in

acstouo

and other

orgrnic

solvcnts

3,5E0

rt

25oC

5,100

rt

30oC

10,q)O

rt 40oC

oily

Liquid

1.24 art25oC

._

?.r

2566C

(crlculstGd)

Po"orp"Cgs

bclow

boiling at

ttEotphcnc

prcssurc

150'C

(Rcf.

5)

-3.7"C

-4"C

(rclting)

(Ref.

5)

High

5.9 cSt

rt

25"C

(Rcf.

5)

74

ctllg

0.0109

rt

25oC

Liquid

1.15 et

20"C

0.0110 et 25"C

(Rcf.

0.0009

et

OoC

@cf.

0.0Cr26

et

10oC

(Rcf.

0.0069

et

20cC

(Rcf.

0.0106

rt

25'C

@cf.

0.0164

rt

30"C

(Rcf.

0.00E

g/100g

(Ref.

5)

O.5

gll

et 20oC

(Rcf.

7)

Solublc in

moct

orgeaic oolvcnis:

cthers, bcnzcoc,

rcclong, nrlfur

Euslrrd, e.hloropicrin

(Rcf.

5)

13

et

OoC

l?l.t?5"C

ItO * 300c

390.t

40oC

120 rt

25oC

(Ref.

5)

'Drtr

rcfcrred to ero

l-rom

RcllIunfess othffise

dcslgnsted.

s)

7)

7)

1)

't)

7)

5


13/65

DOCUMENT

UIVCLASSIFIED

UPON

REPRODUCTION

JCP-|,

DPG

2.2.2 Hydrolysis

The

nitrogen mustards

ue

slightly soluble in water

and are

very slowly hydrolped;

HN-3 is the

least

soluble. However, in

water

adjusted

to

pH

t

with

bicarbonate,

HN-l

and

HN-2

are

rapidly

soluble,

HN-3

somewhat less

so.

The hydrolysis

products

of HN-2

are

shown

in

Figrre

I

(Ref.

4).

The imonium

form and

ehtorohydrin

are soluble

in water and

are toxic. Only

the

product

of the

final

stage of

hydrolysis, metryldiehanolamine,

is

nontoxic.

MI-2

cH,N/

cH2ol2cl

cll

---r--_-

-l

+Ncl2crr2ct

ll

-

*t'cxp'

l--

T,

T,

,ll

I

o(

i",

r.mcrhyr.t{p


14/65

DOCUMENT UruCLASS IFIED

IJPON

REPRODUCTION

JCP-|,

DPG

derivatives

will

predominate

as the dimerization

products.

Hydrolysis

of HN-l and

HN-3

is

closely allied

to ttrat shown

for HN-2.

However, HN-l

is less susceptible

to

dimerization;

HN-3

yields

three

imonium

ions as compared

to two

with

HN-l

and

HN-2

(Ref.

4).

In unbuffered

water containing

a small

percenege

of

niEogen

mustard,

the

nitrogen musBrd

and

the

hydrolys-is

products

can be

found in solution

concrrrently

after

48

to

72 hours and

presumably

will

remain

in

such

a state

indefinitely.

Water

treated

with

t

percent

HN-2

and allowed to

stand at

room

temperature

for

48 hours

or

longer

had

a

neurotoxic

effect on

laboratory animals.

The

solubility

and

toxicity of

the

hydrolysis

products

in

water

are conducive

to

the

poisoning

of

food and water by

thxe

CW

agents.

-'

2.2.3

Reactions

with Acids

The

reaction of

principal

interest

is that of

HN-3 and

hydrochloric

acid

to

yield

tris-(2-chloro-

ethyl)-ammonium

chloride,

a

stable,

water

soluble

compound

that

has the

same

toxicity

as

HN-3 and can

be stored

indefinitely.

As

stated

in

paragraph

2.2,2,this

makes

it

an

effective

poison

for

food

and

water.

A

yellow

crystalline

picrate

is formed

when HN-3

reacts with

picric

acid.

This

reaction

is used to

quantitatively

identify HN-3 in

solutions.

Reaction

with

picrylsulfonic

acid

yields

a

more

precise

quantitative

assessment

of

dilute

solutions

(Ref.

a).

The

HN-3

reacts

with

a

number

of

other mineral

acids

to

yield

toxic sals.

2,.2.4

Oxidation

and

Chlorination

Reactions

The

nitrogen mustards

are not

readily oxidized,

and only

powerful

oxidizers

are

effective

in

oxidizing

these

agens.

Potassium

pennanganate,

dissolved

in dilute

hydrochloric acid, slowly

oxidizes

HN-3. Fuming

nitric

acid and

chromosulfuric

acid

quickly react

with HN-3 to

form

a

number

of

unidentified

oxidation

products. At

elevated

temperaturss

the

oxide

of

HN-3 is obtained through

oxidation

by

hydrogen

peroxide

(Ref.

7).

Chloride of lime

and

the chloramide.s

commonly

used

as

decontaminants

for sulfur

mustards either

do not

oxidize

or

ineffectively oxidize

the

nitrogen mustards.

However, several

chloramides

do

react

effectively

with

nitrogen mustards,

as

does calcium

hypochlorite.

An

excess of the

reacting chlorine

compound

is required to completely

inactivate

nitrogen

mustard agents.

2.2.5

Reaction

of

the

Nitrogen Mustards and

Functional

Groups

The nitrogen

mustards

react

with

a

great

number

of

chemical functional

groups.

However,

the

reaction appears

not

to

occur

until

thp tertiary

amine

has been transformed

to the cyclic

imonium form,

as

occurs in the

process

of

hydrolysis.

The nitrogen

mustards

react with

the amino

group

of almost

all

amino acids

and

with

organophosphate

and sulftrydryl

groups.

They

dso

react with inorganic

phosphates,

sulfides,

polysulfides,

and

bisulfides

(Ref.

7).

Reactions

occur

more

effectively at

an alkaline

pH.

The mustard

agents inactivate or

paftially

inactivate

a

number

of enzymu.

The

chloroethyl

group

is

the active

alkylating

component of

both

the

sulfur

and

nitrogen

mustard

molecules.

Consequently,

the

action of nitrogen

mustard

should be

expected

to be similar

to

that of sulfur

mustard.

A

degree

of

similarity

is demonstrated

in the effect on enjzymes,

as

shown

in Table

3.


15/65

DOCUMENT

UruCLASSIFIED

UPON REPRODUCTION

JCP.L

DPG

Table

3. Enzyme Inactivation

by

Vesicans

iz

Yirro.

.ffiffiffiiA-

Etzyr.

Adcoylic rcid

dsrminrro

Adcoylpymphoqhrtrro

Adcoylpyrophoephrtrsc

(myosin)

Acrobic

phoaphorylrse

Alcofol dchydr4coreo

d-Amino

rcid oxidrso

Bctriac

ddohl&

oxidesc

Crboryhsc

Crtbcpsitr

Cholincstcnsc

(scrum)

Cholincdcnsc

Gnin)

Cbolinsstcnso

(hdncy)

Cholinatcmr

(cyc)

Choliac

oxi&gc

Chymprprin

Chymtrypin

Crcrtino

pborpbokinasc

Cytochrom oxi&ec

Dcutcrohcxokiorss

Glucoec

dchydrqcorsc

Glutrmic

rcid oridesc

Glyccrolphoryho,kinrsc

alycorophoapbetc

dchydrogcnrso

Glyordrsc

Hsxokinrsc

Histrninaso

Loucinc

dc.Einrso

Mdic rcid

dchydrogcoesc

Prprin

PGpsi

Pcpsimsc

(swinc

kidncy)

Pcpsiaogen

Popti&sc

(conrm,

plrsmr,

skin, lung)

Phcayldrninc

dcroineso

Phospbrtrrc

(rid

rnd

dkrlirc)

Pbospborylrsc

Pyrophospbrtrso

Pyruvrtc phoryho&inasc

Pyrwic

oridrc

Srccinodchydrogmrsc

Srcrrsc

Ttymnrrclcodcpolymnse

Trioccphocphrto

dchydrogmese

Tryprin

Uricrsc

VdiDe

dcrnirrsc

AA

2t40

2t{o

up to

l)

up

to

Z)

0

up to 20

0

el-lod

up o

20

up to

2O

91-100

0

2140

up

to 20

2140

0

0

9l-100

61-90

0

21{0

up

to 90

2140

2t40

91-100

0

2140

61-90

2140

0

up

to

20

2t{o

2t{o

up o 20

zr{o

up

to

20

91-r00

up

to

20

2r{o

61-90

up o 20

up

to 20

91-100

61-90

0

2t-60

2140

::

2140

:

up

to 20

.rt1:

91-100

up

to

20

ttp

to 20

up

to 20

6r-90

21.60

6140

2t-60

0

2t40

2140

up to

20

0

9l-100

up

o

20

2t40

91-100

91-100

o

ztio

;

up o

20

up to 20

up to 20

up to 20

21{o

u, a

r?,

61-90

2140

::

2140

up o 20

6

0

o

'D&

( -Ctrlorcatryl) rulfrdc

rMahyl-Dir

(P+hbroc*hyl)

rminc

'rris

(F-Chlorocthyl)

rminc

ho dete

NOTE: Studrrd brrtmcnt L

conridcrcd

to bc incubrtion

with 3 millirnolcr of

H

or cqually

rctivc

rmounr of

othcr

n9rtcnt

for onc.halfto

ons hour,


16/65

DOCUMENT

UA'CLASSIFIED

UPON REPRODUCTION

JCP.I,

DPG

2.3

PREPARATTON OF NITROGEN MUSTARD

Ward

(Ref.

2) reported

pr@aration

of

the

primary

and secondary

chloroahyl

aglines

(preparation

of both

had

been

previously

reported)

and

the

tertiary

chloro*hyl

amines

(preparation

had

not

been

previously

reportd).

He reported

the

tertiary chloroahyl

amines

to

have

caused edema

followed by

blisters

on

his hands, which required many weeks

to fully

heal.

Tho

primary

and

secondary

chloroethyl

amines

are not

vesicants.

IIe

prepared

ttre

chloro*hyl

amines

by

the

reaction

of

thionylchloride in

chloroform

on the

corresponding

ethanolamine.

Essentially the same

procedure

was used for

plant production

of HN,

partioilarly

HN-3,

the

compound of choice as

a CIV agent.

For HN-3,

the reaction

is:

N(CfiI2CII,OiO.

+

3S0C|,'JV(CII2CIILC}T'

HCI

+

350,

+

2IICI

fire

chloroethylamine occurs

in

the reaction as a

hydroctrloride

sdt,

which is

converted

to the free base

by

aqueous sodium

hydroxide.

Ettranolanine

is

prepared

by conversion of *hylene oxide

with

ammonia

by

excess

hydrogen

chloride.

Other

procedures

have been

prolnsed

@ef.

4).

The

indusnial

IIN-3

is

ordinarily

a dark brown color and

will

contain

95

to

97

percent

tris-(2-chloroethyllamine

(Ref.

7).

2.4

SYMPTOMATOLOGY AND PATHOLOGY OF

NTTROGEN

MUSTARD

POISONING

The nitrogen mustards

are

vesicants

urd

produce

erythema

of

the skin, followed by development

of

skin

lesions.

The

skin

rash is violet

in

color

(Ref.

7). The

comparative

vesicurcy

of ttre

three

nitrogen mustards and H are

H > HN-3 >

HN-2

>

HN-l. This

order

of

vesicancy

and

lesion

production

applies

both to

vapor

and

liquid exposure

@ef.

4).

The

lesions caused by HN are reported

to be less

deep and to

heal

more readily than those

causod

by H, but they

are more

painful.

A

rash

may

appear

within

an

hour following

exposure

to

a

high concentration

of

agent,

but

with

exposure

to

what

may

be mnsidued a

field

concentation the rash may

not

appear

for 6

o

8

hours.

Large

lesions

indicative

of exposure

to a subsuntial

concenuation

are

accompanied

by

a

deterioration in

health

and loss

of

weight.

The

upper

and lower respiratory

tracts are affected by

respiratory

exposure

to

HN

vCIor

or

aerosol. Mild

intoxication causes catarrh in the larynx

and other air

passages.

More

severe exposure

can

damage

lung tissue,

and the

pulse

and

respiratory rate may increase. Muscle

sparnu

may

accompany

injury

to

the

central

newous

system,

and the

gastrointestind

tract

may

be damaged

(Ref.

7).

No systemic

injuries

in

individuals

exposed in chamber trials to

low dosages

of

HN-l

and HN-3 have been

manifesr

(Ref.

4).

The

characteristics of niEogen mustard intoxication

in

animals,

for

each

of

the three

niuogen

mustards,

ue

briefly

presented

in

the

following

puagraphs.

9


17/65

DOCUMENT

UNCTASSIFIED UPON REPRODUCTION

JCP.I,

OPG

2.4.L Symptomaology

and

Pathology Produced by

HN-l

in Animals

Intravenous

or subcutaneous

injection

of

HN-l

in

mice caused

netrvous system

disturbances

raoging

from

poor

coordinationto tremors

and conwlsions.

In rabbits,

intravenous

iujection first

caused

centrd neryous

system

stimulation

followed

by

dqression

urd

rapid

death.

Anorexia, emaciation,

lancopenia,

aod diarrtea

occurred with applicuion

of HN- ,

to

the

skin

of

rabbits.

Dogs

receiving

cuuncous ctrdlenges

showed symptoms

of shock. Ras

given inravenous injection

of

HN-l

showed no

early overt symplosa, but

nzurological

injury

was wident

after

3 or

4 days,

followed

by death.

Internal

manifestations.in

rats

receiving

an

LD,

dose

of

HN-l by

four

routes-of

invasion

(intravenous,

subcutanous, cutaneDus,

and

vapor

exposure)

were

mild

to moddate

in regards o

total systemic

injury,

lymphoid

atrophy, myeloid

injury, leucopenia,

and

enteritis.

With

intravenous and

cuUneous

sf,posure,

weight loss

was

severe

(Ref.

4).

Observed effects

were not deemod

respottsible

for

the deaths

of

the

animals.

7.4.2 Symptomatology and

Pathology Produccd

by

HN-2 in

Animals

When

HN-2

was administered

to

laboratory animds by

parenterd

i4jection,

a

cholinergic action

similar

to

Orat

produced

by

acetylcholine

was

observed;

however, inactivation

of

ctrolinesterase

is

apparently not

involved. The

agent is

responsible

for a

pardytic

action

in

animals,

affecting

first

the

head

and neck and then the extremities and

tho thorax. Cessation

of

respiration

follows.

Ras receiving HN-2

vapor or

intravenous

injertion

demonstrated

narologic

injury,

but

cutaneous

or subcutaneous

adminisuation

of

IIN-2

did

not

cause

neurologic symptoms.

In rats, a

reaction

related

to

the alarm

reastion

was

observed.

In dogs,

the

agent

frequently

caused

vomiting, diarrhea,

intestinal bleeding,

reduction in or loss of control of body

temperaEre,

anorexia,

dSilitation,

and

eventud

respiratory

failure,

perhaps

associated

with

circulatory

intribition.

Direct injury to the

heart

has not

been indicated.

Events

associated

with administration

of

an LD,

dose

of

HN-2 consisted

of

a symptomatic

latent

period

of

I

to

2

days;

however,

during ttris

time,

adverse

respome

and

injury to

various

internal organs

was

occurring,

followed by anorexia,

weight

loss, diarrhea,

prostration,

ard death.

Animds that survived

the

LDr,

for

the

most

paf,t,

did

recover

from

dl

effects.

Observations

on the effect

of

HN-2

on

hematopoiesis

indicates early leucocytosis,

followed

after

a day

or rwo by

leucopenia.

This effect

has

been observed

with

agent

H.

Sensitization

to HN-2

has been

shown

to

develop

in

the

animal body

as

a result

of

repeated

exposure

to

smdl

liquid doses

of the agent. Also,

tolerance

has

been

demonstrated

following

repeated

exposure

to a series of small

doses

of agent

administered

over

several

months.

2.4.3

Symptomatology urd

Pa0rology Produced

by

HN-3

in Animals

High subcutanous

doses of

HN-3 result

in

conwlsive action

in

various animals. Death is

attributed

to

respiratory

failure

presumably

associated

with

restricted respiratory

exchanges.

WiOr

doses below the immediate conrnrlsive

level, a

progressive

development

of

muscular

weakness,

diarrhea,

mldness, hyperexcitability,

and

retropulsive

movements

and

tremors

culminated

in

prostration

and

death

from respiratory

failure.

The

general pathological

course is

lymphoid atrophy,

bone

10


18/65

DOCIJMENT

UNCLASSIFIED UPON

REPRODUCTION

JCP.L

DPG

manow

deterioration,

and

failure in

blood cell

generation;

thus leucopenia, enteritis, and

weight

loss were

observed. As

with

the

other nitrogen muserds

and

with

agent

H, some

variation,

though

less

so

with

agent

H, was

obsewed for the different

routes

of

agent

entry

into

the urimal body.

2.4.4

Sympomaology

and

Pathology Produced

by

HN

in

Man

Six

human subjects, each at a

termind

stage

of

an incurable

disease, responded

to

daily

small

intravenous

doses

(0.1

mg/kg)

of

HN-3.HC|

wittr

nausea,

vomiting,

headache, malaise, drowsiness, and

marked reduction

in

blood

cdls. In

normd

volurteers,

a single dose

of

0.1

mg/kg

of

HN-3'HCf

caused

headactre

and

nausee

8ftr

t

hours.

Dizziness and

weakness

dso

occurred

in

some,

and

all volunteers

developed

ttrrombophlebitis. No vomiting or

anorexia

occured.

Ingestion

of 2

to

6

mg

of

HN-2.HC

in

tap

wuer

resulted in

anorexia,

resurrent

nausea

and

vomiting,

tenseness,

gassiness,

and mild diarrhea dong with depression.

lngestion

of

I

mg

produced

very

mild to

zero

symptoms and

pathological

murifestations. Severity increasod

with inreased dosages.

Recovery was

within

48 hours.

Inadvertent exposure

o

HN-l

and subsequent

intoxisation

in

man

caused

laryngitis, bronchitis,

hoarseness,

coughing,

elevatod tmperafire,

nsusea, and

vomiting.

Inadvertent exposure

to

minute

emounts

of

HN-l

vapor

caused

conjunctivitis,

asthrnafioid

bronchitis, but

m effect

on

temperature or

blood

properties

(Ref.

4).

Two of six

humans

exposed acciden0y to HN-2

vapor

complained

of

nausea

5

hours

following

exposure, and one

vomited

until

12

hours after exposure.

Two

showed

a

decline in

leucocyte

count, but soon recovered

(Ref.

a).

Persons accidently

exposed

to

HN-3

vapor

suffered eye

and upper

respiratory

tract

irritation, headache,

and

vomiting

(Ref.

a).

2.4.5

Symptomatology and

Pathology

of

HN

Transformation Products

Each

of

the three

nitrogen

mustards

hydrolyzes

to

yield

hydrolytic

products,

particularly

the

imoniums and chlorohydrins as shown

in

Figure

l.

These are

readily

formed in

water and in other

aqueous-based

solutions.

They

have been examined

as

to

toxicity,

symptomatology,

and

pathology. In

general,

they

are

equal

in toxicity to

the

basic nirogen

mustard

compound

and, with

slight

vuiation,

elicit

the

same

symptoms

and

pathology

as

the corresponding

niuogen

mustard

Eef.

a).

2.5 MECHANISM

OF

ACTION

OF

NITROGEN

MUSTARDS

2.5.1

Physiological Action

The

action

of

vesicants

involves

penetration

of

at

least

the

upper skin surface. Peneuation

of

the

skin by the

mustard

agents

has

been suggested to be

related

to

fieir

solubilities

in lipids,

a

property

of

both

the sulfur and nitrogen

mustards,

which

facilitate

penetmtion

through

oil

secretions

around

hair

follicles.

However, penetration

of

skin ueas

devoid

of

pors

or hair follicles

has been

demonstrated

(Ref

4).

The rates

of

penetration

of

HN-l,

HN-3,

and

H

are

given

in

Table 4.

1l


19/65

DOCUM

ENI

UNCTASS

IFIED UPON REPROD

UCTION JCP.I,

DPG

Table

4.

Penetration

of Human Forearm

Skin

by

Saturated

Vesicant Vapor

in

Exposure Cup

(Ref.

a).

Room

TGDPdrturE

Agcnt

('F)

Rolrtivo

HuEidity

(r)

Numbor of

Erperimmts

Voletilitf

(ne/f)

Pcoctrrtion

Rsto

fuglcm2/min)

H

HN.I

HN-3

7t-72

,

t5-87

72-73

t5

5GS2

4749

45-48

474E

60

49

6

56

t5

36

u4

4t-49

70:73

E7

0.74

t.$

l.t

3:3

0.10

0.18

0.

l8

o.29

1.4

2.7

2.t

5.1

'Cdcuhud

on

thc

maraption rlut

lha

tor?cnurr of drc

poeutioo

eup

ru

thrt

of

tha mom.

The nitrogen

mustards, like H, react

immediately

with animd tissue constituents,

and their

action

on the tissue is rapidly irreversible.

The

view

regarding

the mechanism of action of

niuogen mustard has evolved to the

present

from

the

era

of

lYorld War

l,

when the furmation

of

hydrochloric

acid

by

mustard

vapor

entering the

body

was

assumed

to

be

responsible for

toxicity.

Little

research

was

conducted

between the hro

world wars,

but

during World War

II

extensive

research

demonstrated that alkylation

of

animal tissue constituents

war

the action

of

the chloroatryl

grcups

of

the mustsrd molecules.

It was also

observed

that dkylation

required

the

transformation of

the

nitrogen or

sulfur

molecule to

the

cyclic

ettrylenimonium or the

ethylenesulfonium

cations

of

nitrogen

or sulfur

mustard,

respectively. It was

recognized

that

ttrese cations

produced

a

qpe

of

action on cells

unlike

any

other chemical agent, but not

unlike

the action

of

radiation

Eef.

t).

It

has

been

proposed

(Ref.

9) that

sulfur

mustard

forms the cyclic

imonium

ion, which reacts

with

and

dkylates

electron-rich molecular

structures such

as

sulftydryl and

amino

groups.

Upon

entering the

skin,

the

irnonium

ion

dkylates

the

purine

bases,

quinine and

adenine

of

deoxyribonucleic acid

@NA),

forming

apurinic

sites.

These

are acted on

by apurinic

endonucleases,

leading

to removal of

the

dkylated

bases

and breaks in

the

DNA.

The DNA repair requirement actiyates

poly(ADP-ribose)

polymerase,

which

rapidly

depletes

cellular

nicotinamide

adenine

nucleotide

(NAD).

This

depl*ion, which

begins

within

ur

hour

of

exposure to the

chloroahyl

imonium ion

and reaches

a

marimum in

about

4

hours,

inttibits

glycolysis

and

releases cell

proteases,

which results in

cell

necrosis

(Ref.

9).

CIher

mechanisms

of

the

action

of sulfur

mustard

on

animal tissue have

been

postulated

(Ref.

10),

based on some

experimental

support.

Because

the alkylating

moiety

of the nitrogen mustards is the

same

as in

sulfur

mustard

(i.e,

the

chloroahyl

group),

it may

be

expected

that

ttre nitrogen and

sulfur

mustards have the

same mechurism of action.

In

some research,

differences

between the action

of

sulfur and

nitrogen mustards have been

observed. It was

repofied

in

1952

that

HN-2 reacted with

adenine,

quinine,

thymine,

and

uracil ln

vitro

(R,ef.

I l).

A

subsequent

report, which

discussed the

action

of

a

npre

monofunctional sulfur

mustard on

Tl bacteriophage,

indicated that

the sulfur mustard reacted

with

quinine

and adenine bases

of

the

virus

t?


20/65

DOCU MENT

UNCTASS

IFIED UPON REPRODUCT

ION

JCP.I,

DPG

DNA,

whereas

the

niuogen mustard reacted

only with the

quinine

base.

The

sulfur musurd inactivated

the

vinrs,

whereas the nitrogen mustard

did

not

Eef.

12).

Depression of

glycolysis

resulting

from

exposure

of

tissue to

HN-2 has

besn

observed

and

associated wi$

a

depl*ion

of nicotinamide

adenine

dinuclotide

(Ref.

9).

The connrlsant

action of

HN-2

may

be ascribed to

iB

effect

on acetylcholinesterase and other choline compounds, attributed

to

the

similuity

of

choline to

the ethylene

imonium

compounds.

This

does

not occur wittr

the

sulfur

mustards,

presumably

because

of

the

instability

of

the

ethylenesulfoniums

of

the

sulfur mustards

(Ref.

10).

The

HN-2 has

been shown to desrease membrane fluidity and membrane

protein-activity.

Membrane

proteins

of

human

erythrocytes were

preferentially

alkylaed

by

HN-3, most

significantly,

spectrin.

The

HN-3 reacted

extensively

with various hepaocpe membrane

proteins.

2.5.2

Chernotheraputic Action

Because

the

physiological

effect

of

the mustards on

tissue involved

whole cells having relatively

high

rates

of

grounh

and

multiplication,

the

possible

adverse action of

mumrd on

cancer cells

was

investigated.

Tho action

on

cells was

a

result

of

the

formation

of

the

cyclic

imonium

ion.

The

ethylenimonium ion

of

nitrogen

mustard

is less

reactive

and, thus,

more

stable

than

the short-lived

*hylenesulfonium

ion

of sulfur mustard.

The

hydroclloride salt of

the

cation

can

bo diluted

in

saline

to

yield

any desired

concentration suitable for

adminisuation.

For

this

reason,

the

nitrogen

mustards,

particularly

HN-2,

have

been employed as

therapeutic agents

(Ref.

8).

The first

Orerapantic

work reported

was

with

uansplanted lymphosarcoma

in

mice. The

tumor

was

quickly

eliminated

in

response

to a

near-toxic

dose of HN-2, but

subsequently

reappeared.

In

medical literanre,

HN-2

is

sometimes

refefred

to

as mechloroethaurine,

or

simply nitrogen

mustard.

Nitrogen

mustard has

been

most

effectively employed in

the treetment

of Hodgkin's

disease

and

has been

successfully used

in treating various

other

forms

of

cancer

(Ref.

l3).

It frequently

reduces

the

cancerous

tumor

by

induced

cell

apoplosis

followed

by

removal

of

the

dead

cells

by

phagocytosis

(Ref.

14). Although

complete remission associated with

early

treatment has

been

reported for

a

number

of

types of

cancer

(Ref.

13),

the

remission

associated

with HN-2

treatBrent

is

frequently

of

short

duration.

The recurrent

cancer

may

respond to subsequent

treatment,

but

the

cancer cells ultimately

become refractive.

Many

mmpounds

conaining the

two

chloro*hyl

alkylating

$oups

essential

to

tbe

effective

antitumor activity

related

to

HN-2

have

been

formulatcd.

The

first

clinically

effective ctremtherapeutic

agent

was

HN-2

(Ref.

l5),

and

HN-2

and

its

derivatives

such as

phenylamine

mustard

(melpholan),

cyclophosphamide,

and chlorambucil remain among

the

rnost

effective

chemotherapeutic agents

(Ref.

16).

2.5.3

Carcinogenicity urd

CIher

Actions

Aside

ftom the

uses

of

low

doses

of

HN-2

in

treating

human

cancer, extensive

exposure of

humans

to

nitrogen

mustard has not

been reported,

and

a

basis

for

evaluating

the

carcinogenicity of

nitrogen

mustard is

absent. The

lesser

reactivity

of

nitrogen

mus&ud, as

compared

to

sulfur

mustard,

13


21/65

DOCUMENT

UNCTASSIFIED

UPON REPRODUCTION

JCP.I,

DPG

may indicate

a

lower likelihood of

a

long-term effect.

Invxtigations

that

have assessed the

relationship

of

cancer incidence

to exposure to mustard,

presumably

sulfur musurd

(Ref.

l),

indicate

that

short-term

exposure

o relatively high

concemations of sulfur mustard

do

not

eppear to be

responsible

for

an

increased

incidence,

at

least

not

a

suilisticaily significant

increased incidence

of cancer.

In

a

population

of

factory workers

exposed

to

very low levels

of sulfur

mustard

over a

period

of

several

yearc,

a definite

link

betryeen mustard

exposure

and

various cancers,

as

well

as other ailments,

was indicated

Eef.

l).

An

attempt

was

made in

a

rcccnt

publication

(Ref.

17)

to

litrk

canc,er

and

serreral other

ailmens

to

exposure

o

possibly

high, though sublethal,

doses

of

mustard over a

perid

of

a

few

days. The

assumptions made

in that

publication

regarding carcinogenicity

of

mustard

are

questionable,

Subsequent

to

exposure

to mustard, studied

populations

have had

years

of

variod lifestyles,

environmeotal

exposures,

dias, and

ocqrpstiorn

as

well

as

difrerent

heteditary

characteristics

@ef.

l0). These

populations

are

not easily

amenable to ury

definitive

evduation that would

support the

conclusions of

the referenced study

Eef.

l7).

A

more

realistic

and

supportable evaluation

was

prcsented

in

recoguizing

that

bronchitis

arising ftom

prolonged

exposure

to

mustard

may

predispose

a

person

to

have respiratory

problems

including

cancer

of

the respiratory system.

However,

an

increase in

the

incidonce

of

cancer

associated

with exposure

to

mustsrd

at doseges

to

which

populations

have

been exposed

experimemally

or

in

combat

has

not

been

subst8ntiated

as being statistically

significant

and must

be

viewed

as

negligible

(Ref.

l0).

2.6 TOXICITY

OF MTROGEN

MUSTARDS

For

tho nitrogen mustards, most toxicity or dose

response data for

man

and animds

were

obtained

during World

War II,

a

period

when an active search

for

effective CIV agents was

pursued.

All

of

the

data obtained were

ftom

laboraory work which

was

summarized

in 1946

(Ref.

4).

Values

given

in more

recent

publications

dmost

always

correspond to 0rose

published

in

1946.

Howwer,

rmre

recent

data

for

HN-3

toxicity

for

laboratory

animals have been included

@ef.

5).

The

toxicity

of

the three

nitrogen

mustards

for laboratory

animals

is

given

in

Tables

5

through

E.

Estimates

of toxicity

for man are

in

Tables

9 through 12.

Table

5. Toxicity

of

HN-l

for

Laboratory

Animals

(Ref.

4, 7).

Animrl

Rouia

of

Intoxication

Cutrnoous

Subcutrncou Intrrvenou

Iutreperiloncd

Orel

(Modira

Lcthd

Dosc,

E8/kg)

Mousc

R8t

Rlbbit

l3

t7

l5

1.0

-

1.45

1.0 0.5

2.0

r.05

2.5


22/65

DOCU

MENT

UNCTASS I

F

IED

UPON

REPRODUCTION

JCP-|,

DPG

Table

6.

Toxicity of HN-2

for Laboratory

Animals

(Ref.

4,

7)

Rouio of Intoxication

Animal

Cuteneous Subcutraoous

Intrrvenous Orsl

(Mcdim

Lcthel Doae,

mS/kS)

Mouso

Rrt

Rsbbit

Guince

Pig

Do8

Gort

Mootcy

29-35

t+an

L2-t7

>E

a

20


23/65

DOCTJMENT UIVCLASS

IFIED UPON

REPRODUCTION

JCP.I,

DPG

Table 9.

Toxicity of

HN-l and

IIN-2

Vapor

for

Man

(Ref'

3' 5)

Route

of Intoxicrtioo

Inhelation

Pcrcutrnous

HN.I

L(Ctb

(rng'urin/d)

I(Ct),

(mg'min/mt)

I

2N

1,500

20,(no

9,000

I{Ct)o

(mg'min/m)

HN-2

(ct)e (mg'nin/m3)

-t

100

,,:

2,5q)-9,0O0

'No

detr.

Table

10.

Toxicity

of

HN-3

for Man

(Ref.

3,

5)

*.uorroo"o

,r"

**"rroo

ffi

'3S*

L(CQ5CF

(mg'min/mr)

LDse

(mg&c)

I(C$str

(mg'min/n)

E(Ct)sd

(mg.min/m)

-a

200

,,:*

42

10,000

0;

2,500

(meskd)

1,500

'Mcdirn

lc*hrl

douge.

DMcdirn

lcthrl

dorc.

'Mcdirn

incrpeciteting

dongc.

Table

11.

70

pg

(to

produce

'It{cdien

doragc

or dorc

to

hitirl

lymPtomr.

'No

dete.

Estimated

Dosages

for

Nitrogen

Mustard

and

H

to Produce

Skin

Damage

on

Human

Forearm

(Ref. a).

Vapor

Train

Ervtheme

Blistcr

-CuP.

Tcst

Agcot

VesicancY

(mg'min/m )

H

HN-I

HN.2

HN.3

21,000

5,800

1,800

3,500

18,(n0

3,7N

TrIo

dete.

16


24/65

DOCU MENT UIVCLASS

IFIED

UPON

REPRODUCTIO

N

JCP-|,

DPG

Table 12.

Cutaneous

Injury

in

Masked

Volunteers Exposed

to

HN-l

and

HN-3

Vapof while

Wearing Nonprotective

Clothing

Vrpor

Number

of

Conccotration

Atoot

Volunters

(14.nin/6)

Sovcrity

of

Injurf

RGst of Body

0.3

t.2

t.7

0.3

--

0.6

0.6

HN.I

1.3

1.4

3.3

1.9

1.8

2.2

1.2

1.4

4.6

0.6

1.5

4.0

100

2@

300

300

450

760

l0

l0

10

8

4

6

HN.3

o.2

0.8

1.8

0.2

o.7

0.E

1.7

I

8

E

8

6

6

8

50

100

150

150

r50

?50

350

1.8

3.0

4.0

2.0

1.5

2.5

4.9

o.5

1.9

4.0

0.0

0.3

1.5

?.6

2.7

'

Exporcd to HN-1 rnd HN-3

Vepor

for @ minuta

in r chambcr

at

90'F

rnd

65 Pcrccnt Rcletivc

Humidity

t

Scvcrity

of Injury

is:

0

-

No

rcaction;

I

:

Mild

crythcma;

2

=

Modcratc

cr;nhcma;

3

=

lntcorc crythcma;

4

=

Erythema

with cdcma;

5

=

Vcriclc

THERAPY

AND

PROPHYLAXIS

In

general,

therapy

for

intoxication

by

nitrogen

mustard

will

be essentially the

same as

for

sulfur

mustard

intoxication.

Protective measures, first

aid,

and

therapy

are described

in

U.S.

Army Field

Manual

8-285

@ef.

l8).

The vesicant

agent

protective

ointment

M5,

containing

chloramide

5-330,

is

applied

for

sulfur mustard

exposure

and

should

be used

for

eryrcsure in the field when identification

of

the agent is not made

immediately- However,

chloramide 5-330

is relatively

ineffective

against

the

nitrogen

mustards.

First

aid decontamination

involves removal

of

evident droplas of liquid

agent

on

skin

or

clothing

by

lifting

or blotting,

followed

by application

of

decontaminant

pads

urd

powder.

Treatment

of

skin

intoxication

involves

management

of blistered

areas.

Blisters should

be

drained and areas

protected

against

infection.

Infected

areas

may

be

treated

wittr

appropriate

antibiotics.

Dressings

should

be

changed

every

two

to three

days.

Liquid

contamination in

the eyes must

be

removed

immediately,

within

seconds,

by irrigating

the

eyes

with

water

from

a canteen

or

other

clean water

supply.

In

a

contaminated area,

this should

be

done

while

holding

the breath

between

doffrng ard donning

of the mask. Eye intoxication

is treated with

eye

ointments. Pain

is alleviated

witlr

morphine

or

other systemic medication, AEopine

drops

may

be

applied.

A

drop 0rree

times

daily

witl

aid

in

alleviating

pain

associated with

swere

photophobia

and

blepharospasm.

Sulfacgamide

may be

applied

to

control

infection.

17


25/65

D O C

U M

E

NT

U/VCLASS

IF

ED U PO N

REP

RO D

U

CT O

N

J

CP.I,

DPG

R

espiraory

involvement, in

mild

eases,

is

treated

symptomatically

o

relieve cough

and

mild

pain.

Antibiotic

treatment

is required

if bron&opnaunonia dwelops. SubctUneous

atropine

injection may be

administered

to

relieve

gastrointestinal

distress caused

by

mustard

intoxiceion. In

sevcre

gases,

shock

therapy and

administruion

of electrolytes

may

be

required.

Atropine

administration to allwiate the

conwlsions

utd

paralytic

effects of nitogen mustard has

been

only slig[0y beneficid.

If

exposure

to

mustard has

been

light,

as widenced

by mild

symploms

usually limited

to

conjunctivitis

and

erythema, trestment may

be

limited

to suppoftive

serc.

In

such

cias6,

recovery

will

be uneventful

cnd complete

in

tsr,o

to

three

weeks.

Experience

witlt

more

severe

cases

of

sulfur

mustard intoxicuion has been obtained from

treatment

of

hospitdized

Iran-Iraq

war

patients

(Ref.

19,

20,21,22,23).

In

general,

the

treatment

of

skin

lesions

was as for thermal

burn

victims;

blisters

were

drained and

moist

occlusive bandages applied,

or the skin

surface

was left

uncovered.

Sulfadiazine and furacine were

applied

and,

in

swere

cases,

cofticosteroid

ointment

was

applied.

Severe conjunctivitis

was

treatod

with

hydrocortisone

ointment.

Extreme

cases of @rnea injury were

corrected

by

cornea

fansplans.

Systemic

sy-trrptoms

required

trestment with

electrolyte

therapy

and

parenteral

fluids

and

blood ransfusion. Respiratory

symptoms

are

0te

most life-threatening

and

have, in

some

cases, required tracheotomy. Therapetrtic

bronchoscopy

was

administered

to

clear

air

passages

of some

patients,

and oxygen

inhalation was required by some. There

is

essentially no

experience

with

treatment

of cases of

nitrogen mustard

intoxication.

Some

prophylactic

research

on the toxic effects of

HN-2

has been stimulated by its use in the

treatment

of

cancer.

Early experimental work

(Ref.

4)

demonstrated

the

beneficial

effects

of

administering

thiosulfate to

animals

coincident with

exposure

to

nitrogen

mustard. Later work

(Ref.

2a)

showed

a suppression

of

the oxic action

of

HN-2

and indicated ttrat

Ore suppression was accomplished

by

degradation

of

the HN-2

in

the

extracellular

spase.

Precursors

of

thiosulf*0,

which

promotes

generationof

thiosulfate

within

animal cells, were

administered to animals

exposed to

HN-2.

Suppression

of the

toxie

effect of

HN-2 wes not

as

great

with

these

precursors

as with

sodium thiosulfate.

The

adminisration

of

seroonin

and

histamine

antagoniss

(Ref.

6,

?s}suppressed

the

oxic effect

of

IIN-2

in

mice.

The

HN-2

was administered

to

mice

as

a single inuaperitoneal

dose

of

5

mg/kg,

which

was

lethal

to

greater

than 85

percent

of

the nonantagonist-treated

controls.

Antihistamine

administered

intraperitoneally

4 hours

prior

o

HN-2

injection, and

4,

E and

24 hours following HN-2

injection

had

a

pronounced

effect on

survival

rate

of

mice.

olre

antihistamine

preparation

was

slightty effective

in

increasing

survival rate when

administered

48

hours following injection

of

HN-2. The

serotonin and

histamine

anugonists

did not interfere with

the suppressive effect

of

HN-2

on canoer

growth

in mice.

other compaitive

scavengers of

nitrogen

mustard,

in

addition

to thiosulfate

and

is

derivatives,

are

cysteine,

glutathione,

and

cystamine

and its

derivatives

(Ref.

10).

2.8

EMPLOYMENT

The

nitrogen mustards were

developed

as

replacements

for H

under

specific

conditions.

Because

IIN-2 is

unstable,

it

is no

longer

considered

to

be

a

suitable

CIV agent.

However, its

use

in

the

treatment

of some

types

of culcer

has resulted

in

continued investigation

of

its

properties.

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DOC

U M E

N7

U'VCLASS I F

I

ED

U

PO

N R

EP

RO

D

U CT

O N JCP.

I,

DPG

During

World War II,

the Germans socked

HN-3

as

the chemicd

component

of

high

explosive

dremical

artillery

shells.

Based

on

research

during

World

\[ar

II,

both

HN-3

and

HN-l were viewed

as

useful CW agents.

These

agenrc

freeze

at

a much lower temperature &an

H. Agent HN-l is more

volatile,

while HN-3

is

much

less

volatile than

H.

Agent HN-3

can be slored

indefinitely without

appreciable

loss of effectiveness,

it

is

stable

when

disseminated

by high explosive

munitions,

and

is a

potcntial

barrier agent.

Of

the vesicant mustard

agents,

HN-3

is

the rnost toxic.

In field

trids

conducted

to

investigate the effectiveness

of

HN-l

and

HN-3,

af,ea

coverage

dosage

Ievels

attained.were

somewhat

less than

those

for

agent

H. Early tests

indicated that

the

chloramide-

impregnated

U.S.

&emical clothing,

presumably

impregnated

with

the

chloramide 5-330, did

not

protect

tr@ps from

the

vapor

of

these

CIY

agents.

These

findings enhanced the expectation

of

their

value as CW

agents. Subsequent testing showed that trro

layers

of

clothing

impreguated

with

another

chloramide

designatcd

CC-2 did

protect

against

HN-3

but

not

HN-I. Charcod-impregnatod

clothing

did

provide

protection

against

boft

nitrogen

mustards.

Agent

IIN-I

is

rolatively

ineffective

as a

vesicant,

and

was

superceded

by

other materials.

In

1946,

as a

result of field

trials

and

known

proprties

of HN-3, an effective use

was

proposed

(Ref,

4):

"It

is

believed that

in high

explosive bombardments an occasional

high

explosive chemical

shell

charged with HN-3

and indistinguishable upon

detonation from ordinary high-

explosive

would

have been

used.

HN-3

possesses

&e

stability

to

withstand

destnrction

during

the explosion of the

shell

and

the lack

of odor to escape

ready

detection except by

chemical

methods.

It

is

believed that the

potential

harassing

and casualty-producing

effects

of

the

vapor

slowly

evolved

from

the

contaminated

terrain

might

exceod those of

the initid

cloud.

The

duration of

danger from

the

vapor,

the

time

inte,rvals

required for

the

ovolution of casualty-producing dosages,

and

the

areas

over

which

effests would

be

produced

would

depend on

meteorologicd

conditions.

As

an

example

of

the

order

of

magnitude

of

the

hazafi

-

in

warm weather,

explosion

of a single M47A2 bomb

(containing

67 pounds

of HN3)

resulted

within

4

hours in the attaining

of

a dosago

of

100

mg'min/m3

of

vapor

over

approximately

one-half

of

an

artillery

square, and

of

250

mg'min/mt

over about one-fuurth

of

an

artillery square. A

dosage

of 250 mg.min/m3

should more

than suffrce

to

produce

totd disability

of

severd days'

duration due to eye

injuries,

and

possibly

severe

respiraory

injury

as

well.'

With

0re

development

of

the more

oxic

and

persistent

agent VX, the

military vdue

of

HN-3

was

overshadowed.

But

the favorable

properties

of

HN-3,

as stated above,

and

the

ease of

its

preparation

may

still

make

HN-3

a CW

agent useful to a nation seeking

an

unsophisticatod

CW

capability.

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27/65

DOC

U M E

N7

UIVCLASS

I

F

I

ED U

PO

N

R

EPROD

U CT IO

N

J

C

P.

I, DPG

SECTION

3.

STJLFUN, MUSTARDS.

T

AND

O

3.1 CHEMTCAL

COMPOSmON

AND

PHYSTCAL PROPERTIES

OF

T AND

Q

3.1.1

lntroduction

The

sulfur mustard

compound

designated

as

Q

was

described

in

1921

afr 1922

(Ref.

26)

as

synthesized

by

the action

of

thionylchloride on the

hydroxy

compound corresponding

to

1,2 bis-(B-

chloroethylthio)ahane

(Q).

In

1931,

it

was reported

(Ref.

27)

that the

incompl*e

chlorination of

thiodiglycol,

induced

by modification

of

the

thiodiglycol

process

for

the

preparation

of

H, resulted in

the

production

of a mixnre

of

H

and T along with a

smdl

anount of

Q

and some

impurities.

Interest in T

and

Q

was

a consequence ofthe fact that ttreir toxicities are

higher

and their

persistencies

are

greater

than

those

of H.

Agent

T may

be designated

oxygen

mustard. Agent

Q

is

referred

to

as

sesquimustard

or

sesquiyperite.

3.1.2 Chemicd

and

Physical Properties

The

chemical

structur and

properties

of

T

and

Q

are

listed in Table

13.

The

physical properties

of these

agents are

given

in Table 14.

3.2

CHEMICAL

REACTIONS

Agent

Q

is

a

solid

at

most

atmospheric

temperatures.

If

disseminated

by

high

explosive

shell, the

heat

of

the

explosion

results

in

the

decomposition

of

some

of

the

Q,

and

the

principal

decomposition

product

is

H,

some

of which

will

appear

as

a

vapor in

the

resultant

toxic cloud.

If

flashing

occurs

on

dissemination

of

Q,

the

principal

decomposition

product

will

be hydrogen

chloride

(Ref.

30).

Agent

T

reacts with

various

chemicals

somewhat

similarly

to

H;

however,

unlike

H

it

does not

react

with

alkyl

iodides,

chloramine-T,

mercuric

chloride or

iodide,

iodine, or bromine, it is not

oxidized

by hydrogen

chloride

at

l(X)"C,

but at higher temperatures

is

decomposed

to

H and

water

@ef.

31).

3.3

PREPARATTON

OF

T

AND

Q

3.3.1

Preparation

of

T

Agent

T,

or

oxygen

mustard,

was fust

prepared

as

a

result

of

partial

ctrlorination

in the

thiodiglycol

method

of

preparuion

of

H.

This

modification

was

carried

out

by

preheating

the thiodiglycol

to

60oC,

then mixing

it with

conoentreted

hydrochloric

acid,

during

which,

over

the

period

of

an

hour,

the

temperature

rises

to

110

to

lls'C.

Variations

in

conditions,

principally

temperaturs,

varies

the

proportion

of H

produced.

The

normal

product

ratio is

60

percent

H and 40

pereent

T

(Ref.

a).

2l


28/65

DoctJMENruNct:Asslr_EpuPgtyE ,- tc,P 9r o-ry_ ct- ,.?r9

Table

13.

Chemical

Structure and

Properties of T

and

Q.

a

Chenricel Nrme

Bist42{hlotgthylthio)cthy[

othcr

(R.f.

3,

t

2-2'Bi{2-chlorocthylthio)dio6yl

othcr

(Rtf.

7)

Bidf

-chlorccthylthioothyl)cthcr (Rof.

4)

2:2'

-Di\24loroertylthio)dierhyl

othor

(Rcf.

7)

Ctrcmicd

Stnrtrre

Chemical

Formuh

qH'PrPs,

Moleculer Weiqht

%3.3

(Rcf.

3)

263.2

(R:et.29)

Hvdrolysis

Insolublc

-

no hydrolysie

1,2-Bis{hloroG6ylthio)+thuc

(Rof.

7)

1,2-Bir(p-c.hlorocthylfio)c6re

(Rcf.

4)

I

:2-Di{2+hloroothylthio)cthrnc

@cf.

28)

Ethyleoc

bir

p-chlorocthyl

nrlphidc

(Rcf.

26)

c#r2s2cr2

219.2

(Ref.

7)

Hydrolyscs

rolrtively slow

(Ref.

7)

A

procedure

for

preparation

of

pure

T

was reported

in

1948

(Ref.

3l)

in

which T

was produced

by

Blister Agents (HN T Q L HL)

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Transcript of Blister Agents (HN T Q L HL)