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# TRI Box 567 Prepped by Ryan Dugan



## Document

Number: 

# 6DE1-00 3 Docket Number: 

# 40011 9

Printed 7/18/2007

3:35:46 PM Sheet 61 of 126P. 2

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\ U J o UNITE D STATE S ENVIRONMENTA L PROTECTIO N AS^Gt o t WASHINGTON , D.C . 2046 0


# ^ e e K„ *



### OG T 6 

### 199

7 OFFIC E O F

PREVENTION

. PESTICIDE S AN D TOXI C SUBSTANCE S 

### MEMORANDU

M Subject :

From :

To : Revie w o f th e Interactiv e Effect s o f Methy l Ethy l Keton e

(MEK ) wit h Neurotoxi c Solvents : Respons e t o OSHA/NIOS H Comment s Loi s Dicker , Ph.D. , Chief.y^cExistin g Chemical s Assessmen t Branc h Ris k Assessmen t Divisio n (7403 ) Mari a Doa , Ph . Toxi c Releas e Environmenta l D. , Chie f

Inventor yBranc h Assistanc e Divisio n !7408 ) mJ~J c *
1 • \ •3 r*.. « -

— i CA r o r o O T T

" : , •i " - :A

—•M l

•—* > -* • c f — '--' • _ . o r n 

## o °

Pe r you r reques t (memorandumdate d Septembe r 4 , 1997) , RA D ha s reviewe d th e letters , references , an d othe r material s sen t t o EA D b yNIOS H an d OSH Aconcernin g th e interactiv e effect s o f ME K wit h neurotoxi c solvent s (RA D review s attached) . Epidemiologica l dat a involvin g acut e exposure s a t lo w dose s repor t n o advers e effect s relate d t o co-exposur e o f ME K wit h MIBK , toluene , o r acetone . Ther e wer e n o epidemiologica l dat a involvin g chroni c exposures . Anima l studie s indicat e tha t ME K alon e produce s onl y transien t neurologica l effect s a t hig h vapo r concentration s wit h n o evidenc e o f permanen t damag e t o th e nervou s system . However , ME K i n th e presenc e o f othe r neurotoxi c solvent s suc h as , n hexan e an d methyl-n-buty l ketone , appear s t o potentiat e neurotoxicity
. Whil e th e anima l dat a suppor t th e potentiatio n o f th e neurotoxicit yo f othe r solvent s b yMEK , th e dat a ar e inadequat e t o full ycharacteriz e th e mechanis m o f action
. Whil e i t i s pruden t t o conside r th e potentiatio n o f ME K i n th e workplac e settin g a s pointe d ou t b yOSH Aan d NIOSH , RA D doe s no t believ e a n accurat e evaluatio n o f effect s du e t o ME K potentiatio n i s possibl e unde r th e TR I statut e a t thi s time
. Lac k o f informatio n

6398868834 6 Recycled/Recyclabl e Printe d wit h Soy/Canol a In k o n pape r tha t contain s a t leas t 50 % recycle d fibe r

## PT ' P. 3



### concernin g huma n exposur e scenario s an d th e compositio n o f chemica l mixture s a t facilit yfencelines , a s wel l a s lac k o f informatio n o n th e mechanis mo f actio n o f ME K wit h othe r solvent s al l contribut e t o this
. W e v/il l however , i n th e futur e discus s whe n appropriate , th e possibilit yo f synergisti c effect s o f a chemica l i n RA D hazard/ris k assessment s prepare d fo r TR I listing/delistin g requests .

Attachment s (2 )
cc : Vaness a V

u Osca r Hernande z Andre a Pfahles-Hutchen s Debora h Norri s Katherin e Anitol e Da n Bushma n (7408 ) Caro l Christense n (7408 )P. 4

^ e0S * * . UNITE D STATE S ENVIRONMENTA L PROTECTIO N AGENC Y 

### WASHINGTON

, D.C

. 2046 0

OFFIC E O F PREVENTION . PESTICIDE S AN D TOXI C SUBSTANCE S 

### Septembe r

17 , 199 7 MEMORANDU M SUBJECT : Respons e t o OSHA/NIOS H comment s o n ME K FROM : Andre aPfahles-Hutchen s f-^V \ TO : Osca

r Hernande z THRU : Loi s Dicke r

^^• ^ 

### I reviewe dth e packag e o f material s fromMari aDoa , date dSeptembe r 4 , 1997 , o n OSH A an d NIOS H comment s o n ME K toxicity

. Th e followin g ar e th e conclusion s tha t I hav e draw n base d o n th e revie w o f

thi s packag e an dit s reference dmaterial

. Conclusion s 1

. Th e epidemiological dat ao n th e potentiatio n o f neurotoxi c effect s create db y coexposur e o f ME K andothe r

chemical s i s ver

y limited

. However , th e dat athat ar e availabl e repor t

n o advers e effect s relate dt o exposur e o f ME K wit h MIBK , toluene , o r

aceton e afte

r acute , short-duratio n exposure . 2

. Non e ofth e reliabl e epidemiological dat ao n ME K coexposur e an danothe r

substanc e refer

t o chroni c exposures . 3

. Th e occupationa l studie s o n ME K coexposur e describe di

n th e OSH A an dNIOS H letter s involv e workplac e exposure s t o solvent s whic h ma y b e neurotoxin s alone

. 4

. Th e epidemiological studie s eithe r hav e no t bee n performed , ar e inconclusive , o r d o no t support th e "significant " acut e o r "seriou s o r

irreversible " chroni c healt h effect s criteri aneede dt o lis t ME K o n th e TR I List

. 5

. NIOS H an dOSH A ar e involve di n studyin g an dregulatin g th e occupationa l environment , wher e i t seem s mor e appropriat e t o evaluat e toxicity base do n actual exposure s in th e workplac e



# 3 bP. 5



### (an dthu s cumulativ e o r

synergisti c effect s o f

chemicals)

. However , for th e purpose s o f

TRI , i t i s m y opinio n tha

t thi s same approac h canno t b e applie dt o release s t o th e ambient air

. Basi s for conclusion s Th e occupationa l studie s that I reviewe ddi dno t

report neurological effect s associate dwith exposur e t o 20 0 pp mME K o r 100 pp mME K

+ 5 0 pp mMIB K

fo r 4-hour s duratio n (Dick , e t al. , 1992)

. Dic k

e t al

. als o studie dhuma

n subject s fo

r interactio n effect s o f

MEK+toluen e (1984 ) an d MEK+aceton e (1989 ) andreporte dn o neuropotentiatio n effect s relate dt o short-termexposures . Hjelme t al. , (1990 ) examine dth e neurotoxi c effect s o f MIBK+toluen e i

n asmall numbe r

o f huma n subject s bu t

reporte donly sensor

y irritation

. Smit

h andMayer s (1944 ) repor t o n 2 cas e report s that

involv e coexposur e t o aceton e andMEK ; however , i t i s difficul t t o dra w conclusion s fromthes e report s sinc e th e exposure s ar e s o hig h (combine do f almos t 100 0 ppm ) an dit

i s no t clea r whethe r othe r substance s wer e presen t

i n th e workplace

. I didn' t revie w th e studie s o n glu e sniffin g (Altenkirch , e t

al , 1977 , an dothers ) for

several reasons : som e o f

the mwer e no t

i n English , th e constituent s ofth e glu e ar e no t know n an d therefor e th e polyneuropathie s reporte dcanno t b e attribute dt o an

y on e substanc e o r

combinatio n o f specifi c substances , th e exposure s ar e abnormal andcanno t b e measured , th e subject s ar e no t reliabl e sinc e it

i s difficul t t o determin e thei r

othe r exposure s an dlif

e styl e factor s tha t

ma y hav e influence dth e onse t

ofth e neuropathies

. Va n Engelen , e t

al

. (1997 ) reporte di

n atoxicokinetic s stud y i

n human s tha t

ther e i s littl e effec t

o f ME K coexposur e wit

h n-hexan e afte

r short-term , acut e exposur e an dthat interactio n o f

ME K andn-hexan e actuall y le

dt o adecreas e i

n concentratio n o f

2, 5 hexane-dion e (th e neurotoxi c metabolite ) a s compare dt o n-hexan e alone

. Thi s contradict s th e suppose dmechanis mo f actio n tha t ha s bee n describe di

n th e anima

l data

.
Reference s Dic k RB , Krie g EF , Setze r

J , Taylo r B
. (1992)

. Neurobehaviora l effect s fromacut e exposure s t o methy l isobuty l keton e andmethy l ethy l ketone

. Fund Appl Toxicol 19:453-473

. Dic k RB , Setze r

JV , Wai t R , Hayde n MB , Taylo r

BJ , Tolo s B , Putz-Anderso n V
. (1984)

. Effect s o f acut e exposur e o f

toluen e andmethy l ethy l keton e on psychomoto r performance

. Int

Arch Occup Environ Health 54:91-109

. Dic k RB , Setze r

JV , Taylo r

BJ , Shukl aR
. (1989)

. Neurobehaviora l effect s o f shor t duratio n exposure s t o methy l ethy l ketone

. Br J Ind Med 46:111-121

. Hjel mEW , Hagber g M , Iregre n A , Lo f A

. (1990)

. Exposur e t o methy l isobuty l ketone : Toxicokinetic s andoccurrenc e o f irritativ e CN S symptom s i n man . Int

Arch Occup Environ Health 62:19-22

. Smit h AR , Mayer s MR
. (1944)

. Poisonin g an dfir e hazard s o f

butanon e andacetone
. Ind Bull of NY23:S, 174-176

. 

# 4f ^ ! 7i""''- : • * ••'• • 1 : 

## f - •

• - 

### Altenkirc h H , Mage r J , Stoltenbur g G , e

t al

. (1977)

. Toxi c polyneuropathie s after sniffing glu e thinner

. J Neurol 214:137-152

. •> 

### i : 

### . van Engele n JG , Rebel-d e Haa n W , Opda mJJ , Mulde r GJ

. (1997)

. Effec t

o f coexposur e t o methy l ethy l keton e (MEK ) o n n-hexan e toxicokinetic s i n human volunteers

. Toxicol Appl Pharmacol 144:2 , 385-395

.



# SP. 7

•c r M

* 

# X. »

^ t PRO** ° 

# y UNITE D STATE S ENVIRONMENTA L PROTECTIO N AGENC Y WASHINGTON , D.C

. 2046 0



### SE P I 8 .'33 7 OFFIC E O F PREVENTION , PESTICIDE S AN D TOXI C SUBSTANCE S



### MEMORANDU M

SUBJECT : FROM :

THROUGH :

TO : > 6 o



### TR I Delistin g o f Methy l Ethy l Keton e Debora h Norris , Ph.D . Neurotoxicologis t Scienc e Suppor t Branc h Ris k Assessmen t Divisio n (740 3 To m McClintock , Chie f Scienc e Suppor t Branc h Ris k Assessmen t Divisi o Osca r Hernandez , Deput yDivisio n Directo r Ris k Assessmen t Divisio n (7403 ) 

## ««S> - ro* o ..'mJm



### CONCLUSIO N I hav e reviewe d th e memorandu mo f Septembe r 4 , 199 7 fro m Mari a Do a regardin g th e toxicit yo f methy l ethy l keton e (MEK ) an d th e letter s an d reference s attached . Thes e document s suppor t th e conclusio n tha t th e neurotoxicit yo f ME K alon e i s no t a significan t concern . However , exposur e t o ME K a t th e sam e tim e a s othe r solvent s suc h a s n-hexan e ma ycaus e seriou s neurotoxi c effects . Chemica l mixture s ca n produc e fa r differen t neurochemica l effects , wit h differen t potencie s fro mthei r individua l components . Thi s i s th e cas e fo r numerou s chemicals
. I n th e cas e o f solvent s such.a s MEK , n-hexane , acetone , ethanol , methy l iso-buty l keton e (MiBk) , methyl-n-buty l keton e (MnBK ) an d ethyl-n-buty l keton e (EBK) , a metaboli c mechanis mo f potentiatio n i s postulated . 

# u CJmb Recycled/Recyclabl e
" Printe d wit h Soy/Canol a In k o n pape r tha t contain s a t leas t 50 % recycle d fibe rP. 8



### BASI S FO R CONCLUSIO N Accordin g t o th e ATSDR , 10,00 0 pp mME K cause d incoordinatio n an d narcosi s i n guine a pig s acutel yexpose d i n a stud yb yPatt y e t al . (1935) . OSH Asubmitte d tw o report s o n th e neurotoxi c effect s o f MEK . Astud yb yYtakeuch i e t al . (1983 ) showe d sligh t increase s i n moto r nerv e conductio n velocit yan d mixe d nerv e conductio n velocit yan d a decreas e i n dista l moto r latenc yi n rat s expose d t o 20 0 pp mME K fo r 1 2 hours/day, 7 days/week . However , thi s sligh t effec t wa s see n onl ya t 4 week s o f exposur e an d di d no t occu r agai n ove r 2 4 week s o f exposure . Studie s o f huma n occupationa l exposur e submitte d b yOSH Aar e difficul t t o interpret
. I n on e study , peopl e wer e expose d t o a mixtur e o f solvent s includin g MEK . I n anothe r study , peopl e reporte d disablin g dermatose s wit h numbnes s a t exposure s o f 30 0 pp mt o 60 0 ppm . I t i s no t clea r i f th e numbnes s wa s du e t o contac t dermatiti s o r othe r factors . Th e lette r fro mNIOS H concur s wit h th e EP Ahealt h assessmen t tha t "ME K alon e doe s no t caus e periphera l neuropathy . Th e issu e o f concer n i s th e synergis mo f ME K an d othe r solvent s suc h a s n-hexan e an d MnBK . A s state d i n th e ATSD R "th e potentiatio n o f th e neurotoxicit yo f n-hexan e an d methyl-n-buty l keton e by . 2-butanon e (MEK ) i s well-documente d i n animals"
. Evidenc e submitte d b yOSH Aals o indicate s th e potentiall y enhance d toxicit yo f solvent s suc h a s acetone , i n th e presenc e o f MEK , i n humans . I n thi s report , wome n concurrentl yexpose d t o 398-56 1 pp m

ME K an d 330-49 5 pp maceton e suffere d fro mheadache , confusion , los s o f consciousnes s an d convulsion
. ATSD R an d NIOS H propos e a metaboli c mechanis mfo r thes e synergisti c effects . Specifically , i t i s postulate d tha t ME K enhance s th e productio n o f th e activ e metabolit e o f 2,5

- hexanedion e i n solvent s suc h a s n-hexane , ethanol , methyl-n-buty l keton e an d ethyl-n-buty l ketone . 2,5-hexanedion e i s th e mos t poten t neurotoxi c metabolit e o f n-hexan e an d othe r solvents . Thi s i s th e sam e mechanis mpostulate d t o effec t th e enhance d neurotoxi c action s o f mixture s o f MiB k wit h n-hexane , an d MnB K wit h 0-ethy l 0-4-nitropheny l phenylphosphonothioat e (Abou-Donia , 1992) . Whil e stron g evidenc e exist s fo r a metaboli c mechanis mo f potentiation , th e evidenc e i s no t definitiv e tha t metaboli c activatio n i s th e onl ymechanis menhancin g neurotoxicity
.



# 7P. 9



### REFERENC E Abou-Donia , Mohamme d "Principle s an d Method s fo r Evaluatin g Neurotoxicity" , i n Neurotoxicology
. Ed . M . Abou-Donia , CR C Press , Boc a Raton , FL , 1992 .



# ?P.1 0

v> " >^^ % UN I T E D STATE S ENVIRONMENTA L PROTECTIO N AGENC Y WASHINGTON , D.C . 2046 0 i " *.-* \


### SEP r4 199 7

OFFIC E O F PREVENTION

. PESTICIDE S AN D TOXI C SUBSTANCE S 

## MEMORANDU M SUBJECT : Review o

f Toxicit y o f Methyl Ethyl Ketone (MEK ) 

# L FROM : Mari aDoa/Chief V Toxic s Releas e Inventor

y Branch Environmenta

l Assistanc e Division (7408 ) TO : Vaness aVu , Director

Risk Assessmen

t Division (7403 ) Severa l week s ago , Lyn

n Goldma n aske du s t o contac t

OSH A t o se e whethe

r tha t agenc y ha dinformation tha

t coul db e helpfu

l i n ou r consideratio n o

f th e petitio n fo

r removing methy l ethy l keton e (MEK

) fro mth e Toxic s Releas e Inventor y (TRI)

. We requeste dassistanc e fro m bot h OSH A an dNIOS H on the questio n raise db y Lyn n concerning possibl e neurotoxi c effects of ME K andprovide dbot

h agencie s wit

h copie s o f EPA' s healt

h assessment
. A s you wil l not

e fro mth e attachments , bot

h OSH A an dNIOS H toxicologist s expresse d concer n abou t interactiv e effects o

f ME K wit h neurotoxi c solvent s suc

h a s n-hexane andn-methyl buty l keton e (MnBK)

. Information on thi s i s als o foun di n the attache dpage s fromthe ATSDR on MEK
. Th e information receive dindicate s tha t ME K ca n interac t wit h n-hexane andMnB K

to increas e thos e chemicals ' releas e o f 2,5-hexanedione , ametabolit e whic h ha s bee n identifiedwit

h neurotoxi c effects

. I

t wouldsee mtha t the identification o

f thi s mechanis mo

f action ca n b e used to distinguis h betwee

n thi s situatio n an

dasituation wher

e th e caus e o f potentiatio n o

f toxi c effects o f achemica l (o r grou p o f chemicals ) i s not

known

. The letter w e receive dfro

mNIOS H i

n reply to our

reques t fo r review of EPA' s hazar

d assessmen t state s that : ^ A s EP A ha s notedin thi s assessment , researc h ha s documentedtha t ME K alone doe s not caus e periphera

l neuropathy

. However , in combinatio n wit h othe r chemical s tha

t produc e the reactiv e metabolit

e 2,5-hexanedione (2,5-HD) , ME K potentiate s the neuropathi c effects of thi s metabolite , increasin g th e productio n o f 2,5-HD

. Tw o solvent s [MnB K and n-hexane ] hav e demonstrate dthi s effec t wit h MEK....No detaile dmentio n o f thi s potentiatio n appear s i

n the [EP A healt h assessment] othe

r tha n abrief statemen t o n pag e 4 o f the Hazar dAssessmen

t o f MEK, "Prior

concern s wer

e base don enhancemen

t b y ME K o f neurotoxicit

y see n wit h othe r solvents. " I

f neithe r MnB K o r n-hexane ar

e presen t in 

# q Recycled/Recyclabl e . Printe d wit h Vegetabl e Oi l Base d Int e o n 100% Recycle d Pape r(40 % Postconsumer )P.1 1



### th e atmospher

e wit h MEK, the

n the periphera

l neurotoxi c potentia

l o f ME K i s minimal

. W e wouldappreciat

e RAD' s review o

f th e letter s (including reference s an dothe r materials ) sen

t to u s b y NIOS H an

dOSH A an drevisio n o

f the ME K healt h assessmen

t a s appropriat e i n ligh t o f the comment s mad

e b y thos e agencies

. Pleas e let m e know whe

n you r staf f will hav e their

review andpossibl e revision s completed , a s w e ar e tryin g t o issu e adenia

l o f thi s petitio n a s soon a s possible

. Also , I believ e tha t yo u indicate da

t the ME K briefing tha

t yo u wouldprovide information on MEK' s neurotoxicit y to Dr
. Goldman , pleas e forwar dacop y o f wha t eve r you provide to Dr
. Goldma n to Da n Bushma n of m y staff

. Thanks

. Attachment s (3 )
cc: , Da n Bushma n -^Caro l Christensen Myr aKarstad t Fre dMet z (7406 ) Katherine Anitol e (7403 )



# /oP.1 2



# 2-BUTANON E

U.S . DEPARTMEN T O F HEALT H & HUMA N SERVICE S Publi c Health Servic e Agenc y fo rToxi c Substance

s an d Diseas e Registr y

F«dtf d Recyclin g Progr» m ] i Print * o n R*cyd« d Pip w_BJ 3

3 4 2 . HEALT H EFFECT S

Hepati c Effects . N o studie s wer e locate d regardin g hepati c effect s i n • humfffT T afte r inhalation , oral , o r derma l exposur e t o 2-butahone . Anima l dac a indicat e tha t hepati c effect s afte r high-leve l exposur e t o 2-butanon e woul d b e minima l i n humans . Live r congestio n wa s foun d i n guine a pig s expose d acutel y b yinhalatio n t o 10,00 0 ppmo r mor e (Patt ye t al . 1935) . Seru mconcentration s o f hepati c enzyme s wer e no t change d i n rat s afte r 2-butanon e exposure s o f 300-5,00 0 pp

mfo r 1-1 2 week s (Cavende r e t al . 1983 ; L i e t al . 1986 ; Schwet z e t al . 1974) . N o lesion s tha t coul d b e linke d t o 2-butanon e exposur e wer e foun d following histologica l examination , althoug h a sligh t increas e i n absolut e an

d relativ e live r weigh t wa s note d (Cavender * e t al . 1983) . Afte r exposur e o f rat s t o 80 0 pp m2-butanon e fo r 5 weeks , n o change s wer e observe d i n th e conten t o f hepati c cytochrom e P-45 0 o r i n th e cytochrom e P-45 0 isozyme profil e (Toftgar d e t al . 1981) . 2-Butanone , however , .altere d th e metabolis m o f androscenedion e b yincreasin g th e formatio n o f tw o metabolite s an d decreasin g th e formatio n o f tw o othe r metabolites
. Furthermore , live r weigh c wa s increase d i n the 2-butanone-expose d rat s (Toftgar d e t al . 1981) . Whil e n o inductio n o f microsoma l enzyme s wa s foun d i n rat s expose d t o 2-butanon e b y inhalation , severa l studie s hav e show n tha t 2-butanon e ha s th e abilit yc o induc e microsoma l live r enzyme s i n rat s afte r acut e ora l exposur e (Brad ye c al . 1989 ; Rauni o e c al . 1990 ; Robertso n e t al . 1989 ; Traige r e t al . 1989) . Thes e scudie s als o suggeste d tha t 2-butanon e potentiate s th e toxicit yo f oche r chemicals , suc h as , carbo n tetrachloride , n-hexane , m-xylene , an d chloroform , b yincreasing thei r metabolis mt o toxi c metabolites
. Whil e enzvm e inductio n b yicsel f represent s a norma l physiologica l respons e t o a xenobioti c rathe r rhii n n n n l i i , i i ff i i r . th

r p^yi)* ? inductio n b y2-bUCanon 6 tia

n b e viewe d as " a n .advers e effec t i f coexposur e t o othe r chemical s to r whic h 2-bUCanOri e potentiate s toxicit yb ythi s mechanis moccurs . Tneretore , human s workin g o r 1'ivin g nfifi r ri-iTpr*

- *" 1 "
- "•"••'•'•

* ni mwher e thes e chemical s ar e presen t alon g wit h 2-butanon e ma

yb e a c greate r ris k o f advers e hepatic * e~tfeces , Rena l Effects . Rena l effect s o f 2-butanon e exposur e i n human s woul d probabl yb e minima l base d o n anima l data . Kidne ycongestio n wa s found ir t guine a pig s expose d acutel ybyinhalatio n t o 10,00 0 pp mo r mor e (Patt ye c al . 1935) . Cavende r e t al . (1983 ) assesse d kidne yfunctio n wit h measurement s o f bloo d ure a nitrogen , urin e volume , urin e specifi c gravity , an d p H afte r a 90-da yexposur e c o 5,000'pp m2-butanone . Al l value s wer e withi n norma l ranges , an

d n o histopathologica l lesion s attributabl e to . 2-butanon e exposur e wer e found . Ora l exposur e o f rat s t p 1,08 0 mg 2-butanone/k g cause d mil d rena l tubul e necrosi s bu t ha d n o effec t o n rena l organi c io n transpor t o r plasm a creacinine ; therefore , i n spit e o f mil d necrosis , norma l kidne yfunction s wer e no t impaired
. Exposur e o f human s t o 2-butanon e a t hazardou s wast e sice s is , therefore , no t likel yt o resul t i n sever e kidne yeffects . _ Neurologica l Effects . Th e mai n neurologica l complaint s o f human s expose d occupationall yt o 2-butanon e ar e headaches , dizziness ! nausea , and fatigu e (Le e an d Frederic k 1981 ; Le e and Parkinso n 1982) . However , ches e symptom s wer e no c reporce d i n severa l inhalacio n studie s i n whic h human s wer e expose d t o 20 0 pp

mo f 2-butanon e fo r 4 hour s (Dic k e t al . 1984 , 1988 , 1989 ; Liir a



# 19-

### 3 5 HEALT H EFFECT S

e c al . 1988a , 1988b) . I n the occupationa l exposure s cited , 2-butanon e wa s combine d wit h severa l othe r solvents ; therefore , a neurologica l effec t exclusiv e t o 2-butanon e canno t b e inferred
. Dic k e t al . (1984 , 1988 , 1989 ) foun d tha t exposur e t o 2-butanon e ha d n o effec t o n an yneurobehaviora l measurement . Nevertheless , earl ysign s o f narcosi s an d incoordinatio n base d o n a batteryo f neurobehaviora l test s wer e describe d i n juvenil e baboon s afte r continuou s exposur e t o 10 0 ppm2-butanon e fo r 7 day s (Gelle r e t al . 1979) . I t i s als o possibl e tha t the baboon s wer e distracte d durin g testin g b yth e irritan t effect s o f 2-butanon e o n the respirator ytrac t an d wer e not , a s the investigator s concluded , i n a stat e o f narcosis
. Narcosi s an

d incoordinatio n wer e als o observe d i n guine a pig s expose d t o 10,00 0 pp

mo r mor e 2-butanon e i n ai r fo r a fe w hour s (Patt ye t al . 1935) . 2-Butanon e wa s no t neurotoxi c a t lowe r concentration s i n longe r duratio n studie s i n animals
. Rat s continuousl yexpose d t o 1,12 5 ppmfo r 5 month s showe d n o sign s o f periphera l neuropath yo n histologica l examinatio n (Saida e t al . 1976) . Altenkirc h e t al . (1978a ) observe d n o clinica l sign s o f neuropath

yi n rat s expose d fo r 7 week s t o 6,00 0 ppm . N o neurologica l effect s wer e observe d i n rat s expose d b yinhalatio n t o 5,00 0 ppmfo r 9 0 day s (Cavende r e t al . 1983). . Alteration s i n nerv e conductio n velocit ywer e see n i n rat s expose d b

yinhalatio n fo r 4 week s t o 20 0 ppm2-butanon e (Takeuch i e t al . 1983) . Th e toxicologica l significanc e o f thi s observatio n i s questionabl e becaus e norma l nerv e conductio n velocitie s wer e observe d a t al l time point s beyond 4 weeks . N o neurologica l effect s wer e observe d i n rat s afte r ora l exposur e t o 1,72 5 mg/k g fo r 9 0 day s (Ralsto n e t al . 1985) . Therefore , exposur e o f human s t o 2-butanon e alon e i n th e workplac e o r a t hazardou s wast e sice s i s no t likel yt o resul t i n seriou s neurologica l effects . e - Although exposur e t o 2-butanon e appear s relativel yinnocuous , thi s keton e i s veryhazaraou s i n comoxnatio n wit h othe r solvents . 2-Butanon e markedl y •potenciaces

- the neurotoxicit yo f qthanol . n-hexane . methyl-n-buty l ketone^an d ethyl-n-buty l kecon e (Altenkirc h e t al . 1977 ; Cunningha me t al . 1989 ; Kin g • • e c al . 1985 ; Ralsto n e t al
. 1985 ; Robertso n e t al . 1989 ; Valla t e t al . 1981) . Glu e formulation s containin g bot h 2-butanon e an d n-hexan e caused."glu e sniffers ' neuropathy " (Altenkirc h e c al . 1977 ; Kin g e t al . 1985 ; Valla t e t al . 1981) . Thi s neuropath yi s characterize d b ymoto r nerv e dysfunction , paresis , paralysis , muscula r atrophy , and neura l tissu e morpholog ychange s includin g paranoda l axo n swelling ! neurofilamentou s hyperplasia , an d demyelinatio n (se e Sectio n 2.6) . Therefore, , human s workin g o r livin g nea r hazardou s wast e sices
. wher e methyl-n-buty l ketone , eChyl-n-buty L ketone . o r n-hexane~i s presen c o r wh o Ittfqufei,Uly_us

e alcoho l mayb e a r grsat-o r r i cW fr>

r npurn l ng i a.\ effect s "i f 2-Sutanpn e i s als o presenc . Developmenta l Effects . N o studie s wer e locate d regardin g developmenta l effece s i n human s followin g inhalation , oral , o r derma l exposur e t o 2-butanone . Inhalatio n exposur e o f rat s an d mic e t o 3,00 0 ppmdurin g gestatio n resulte d i n fetotoxi c effects , suc h a s reduce d feta l weight , skeleta l variations , an d delaye d ossificatio n (Deaco n e t al . -1981 ; Mas t e t al ; 

# <rm '!

I'll . Ili :
ii i 7 M



# / JP.1 5

4 0 2 . HEALT H EFFECT S

identifie d tha t woul d be usefu l a s biomarker s t o characteriz e effect s o f 2-butanone . 2. 6 INTERACTION S WIT H OTHER CHEMICAL S Th e neurologica l an

d hepati c effect s o f 2-butanone alon e ar e minimal . Fo r certai n applications , 2-butanon e i s combined wit hothe r chemical s tha t hav e seriou s neurotoxi c o r hepatotoxi c effects . Clinica l report s an d anima l studie s hav

e clearl y

show n tha t 2-butanon

e potentiate s bot hth e neurotoxicity o f ethanol , n-hexane , an d methyl-n-buty l ketone and.the hepatotoxicity o f carbo n tetrachloride an d chloroform . Altenkirc h e t al . (1977 ) investigated a larg e outbrea k o f toxi c polyneuropathie s i n a grou p o f Wes t Berli n "glu e sniffers. " Th

e developmen t o f neuropathie s (muscular atrophy , paresthesia , paresis , quadriplegia ) coincide d wit h a chang e i n th e compositio

n o f a glu e tha t wa s popula r fo r sniffing
. Unti l th e fal l o f 1975 , th e majo r constituent s o f th e glu e wer e n-hexane , toluene , ethy l acetate , an d benzene. . A t this , time , 2-butanon e wa s adde d t o the mixtur e an d th e sudde n appearanc e o f th e toxi c neuropathie s began . A39-year-ol d woma n wh o ha d worked for severa l year s gluin g shoe s develope d polyneuropath yafte r a fe

w week s o f wor k i n a poorl y ventilate d sho p (Valla t e t al . 1981) . Th e glu e sh e wa s usin

g containe d 20 X 2-butanon e an d 8% * n-hexane . "Glu e sniffin g neuropathy " wa s als o described i n a clinica l cas e repor t o f thre e me n wh

o had simila r symptom s (Kin g e t al . 1985) . Al l had bee n sniffin g the same bran d o f glu

e containin

g light , volatil e hydrocarbon s (C 6 -C 8 ) , toluene , an d 2-butanone ; 2-Butanon e ha d recentl y

bee n adde

d t o th e glu e formulation , an d th e author s suggeste

d tha t thi s ma

y hav e increase d the neurotoxicity
. A

chang e i n th

e formulatio

n o f a solven t compound als o precipitate d a sudden outbreak o f periphera l neuropath y in a coate d fabric s plan t (Alle

n e t al . 1975 ; Billmaie r e t al . 1974) . Methyl-n-buty l keton e introduce d int o a solven t used at th e plan t wa s implicate d a s th

e causativ

e agent ; however , th

e solven t als o contained hig hconcentration s o f 2-butanone . Combine d exposur e to 2-butanon e an d methyl-n-buty l keton e ha s no t bee n studie d epidemiologicall y

i n humans ; therefore , whethe r 2-butanone potentiate s methyl-n-buty l ketone neurotoxicity i n human s i s no t know n (Kat z 1985) . Th e potentiation o f th e neurotoxicity

o f n-hexane an

d methyl-n-buty l keton e b

y2-butanon

e i s well-documented i hanimal s (Altenkirche t al . 1978a , * j 1978b , 1982a , 1982b ; Said a e t al . 1976 ; Takeuch i e t al . 1983) . Altenkirc h e t al . (1978a ) exposed rat s t o eithe r 10,00 0 pp

m n-hexane or a combinatio n o f 1,00 0 ppm2-butanon e and 9,00 0 pp m n-hexane . A

summar y o f three experiment s under' thes e condition s showe d tha t rat s exposed t o th e combinatio

n o f n-hexan e an d 2-butanon e develope d paresi s mor e rapidl y an d i n greate r number s tha n rat s expose d t o n-hexane only . I n th e sam e study , rat s expose d t o 6,00 0 pp

m 

# 14

### 4 1 HEALT H EFFECT S

2-butanon

e onl y showe d no sign s o f neurotoxicit y u p t o 7 weeks , whe n al l th e rat s in thi s grou

p died suddenl y

o f bronchopneumonia . Thes e result s wer e confirmed i n a secon d study ; mixture s o f 50 0 pp m n-hexan e an

d 2-butanon

e (4: 1 o r 3:2 ) o

r 70 0 pp

m (5:2 ) cause d clinica l sign s o f neuropath y 1- 5 week s earlie r tha n 50 0 pp

m n-hexane alone (Altenkirche t al . 1982a) . Histologica l examinatio

n reveale

d morphologica l change s i n th e rat s simila r t o thos e foun d i n youth s sufferin

g fro** * glue sniffin

g neuropathy , includin g paranoda l axo

n swelling , accumulatio n o f neurofilament s i n th e cytoplasm , an

d demyelination . Takeuch i e t al . (1983 ) observe d a significan t decreas e i n moto r nerve conductio

n velocit y

i n rat s expose d to 30 0 pp m n-hexane:2-butanon e (1:2) . I n thi s study , moto r nerv e conduction velocit y increased i n rat s exposed t o 20 0 pp m 2-butanon

e alone an

d di d no t chang e i n rat s expose d t o 10 0 pp m n-hexan e alone . Mal e Wista r rat s exposed to n-hexane o r a coipbinatio n o f n-hexane an

d 2-butanone develope d ultrastructura l change s i n th e intrapulmonar

y nerve s characteristi c o f hexacarbon neurotoxicit y (Schmidt e t al . 1984) . Concomitan t exposur e to n-hexane an d 2-butanone decreased th e onse t o f observabl e neuropatholpgica l changes . Said a e t al . (1976 ) reporte d a marked potentiation o f periphera l neurotoxicity

whe n rat s wer e exposed*t o methyl-n-buty l ketone*,2-butanon e (225:1,12 5 ppm) . Rat s expose d t o methyl-n-buty l ketone-only-developed- ' paralysi s b

y 6 6 days . The combinatio n caused paralysi s i n 2 5 days , whil e 2-butanon

e alon e ha d n o effec t u

p to 5 months . Histologica l examinatio n o f neuron s reveale

d morphologica l change s simila r t o thos e reporte d b y Altenkirch et al . (1982a) , whic hincluded paranoda l axo n swelling , accumulation o f neurofilaments , an

d demyelination . Subcutaneou s injection.o f methyl- r n-butyl keton e wit ho

r withou t 2-butanone increase d dista l moto r latenc y an d decrease

d motor fiber conduction velocit y i n mal e Donry

u strai n rat s (Misura i an d Nagan o 1985) . Th

e combinatio

n o f the . tw

o ketone s enhance d thes e effects . I n vitr o studie s suppor t th e hypothesi s tha t 2-butanone potentiate s n-hexan e an d methyl-n-buty l keton e neurotoxicity . Verones i e t al . (1984) - observe d that , in tissue s cultured fro m feta l mous e spina l cord, , dorsal ' roo t ganglia , an

d muscle , th

e combination o f 2-butanon e an d n-hexan e produced gian t axona l swelling s mor e rapidl y than culture s treate d wit hn-hexane alone . Furthermore , culture s expose d t k nontoxi c concentration s o f n-hexane als o develope

d gian t axo'na

l swelling s whe n 2-butanon e wa s administered concomitantly . •_

_Biotransformatio n o f bot hn-hexan

e an d methyl-n-buty l ketone ca n produc e "~2,5-hexanedione (Cour i e t al . 1978 ; DiVincenz o e t al . ly/b ; "Robertso n e t ai. " l'uxm i Thi c r*-.tr 1 pr.i i md

_i s th e mos t poten t neurotoxi c metabolit e o f n-hexan e and . ,-methyl-n-butyl ketone " know n (Kat z 1985 ~ ?-5utanon e ma v potentiat e n-hexane ^ an d methyl-n-b-iify

l keton e neurotoxicit y b y enhancin

g thei r metaboli c conversio

n to 2^j-hexanedione . Combine d administratio

n o f metnyT^nPbuty l £ —kettmS~"and 2-butanon e produce d mnr* ? 7

,5-hrirnnrr

H nn r fhn n irlmin i --rratio

n o f ^---ffigttty

i -n-buty l ketone alone (Cour i e t al . 1978) . The concentration s o f th e n-hexan e metabolite s 2,5-nexanedione an d 2,5-dimethylfura n wer e significantl y 

# 15

### ill .

4 2 ' 2 . HEALT H EFFECT S
highe r i n the bloo d and-sciati c nerv e o f rat s pretreate d b y gavag e wit h 2-butanon e followe d b y inhalatio n exposur e t o n-hexan e compare d wit hrat s expose d t o n-hexan e alon e (Robertso n e t al . 1989) . I n addition , concomitan t ora l administratio n o f 2-butanon e an d 2,5-hexanedion e i n rat s reduce d bloo d 2,5-hexanedion e clearanc e (Ralsto n e t al . 1985) . Ethyl-n-buty l keton e i s a wea k neurotoxi n (O'Dohoghu e e t al . 1984) . Ora l administratio n i n rat s fo r severa l week s cause d th e paranoda l axo n swellin g an d neurofilamentou s hyperplasi a characteristi c o f n-hexan e an d methyl-n-buty l keton e neurotoxicity . Biotransformatio n o f ethyl-n-buty l keton e produce d tw o neurotoxi c metabolites , 2,5-hexanedion e an d 2,5-heptanedione . 2,5-Hepcanedion e ca n b e furthe r metabolize d t o 2,5-hexanedione . Concomitan t inhalatio n exposur e t o 70 0 pp m ethyl-n-buty l keton e and 70 0 pp m 2-butanon e fo r 4 consecutiv e day s cause d a 2.6-fol d increas e i n th e serum ' concentratio n o f 2,5-heptanedione . Qral-adm-intstratio n o f 2-butanon e potentiate d th e developmen t o f p/

l i,n*•*•'* * 1 anr i h. cr-plnf-Hr-a

l gift-ri g o f ethyl-n-buty l neurotoxicity,*^—* " 2-Butanone - ha s als o hear t found t o potentiat e th a neurotoxicit y o f ethano l (Cunningha

m e t al . 1989).Mic e pretreate d intraperitoneall y wit n i- butanone followe d b y

intraperitonea l injectio n o f ethano l 3 0 minute s late r showe d prolonge d los s o f rightin g refle xinduce d b y ethanol . 2-Butanon e als o decrease d th e rat e o f ethano l eliminatio n i n mic e i n viv o and inhibite d th e i n -vitro activit y

o f alcoho l dehydrogenase , th e mai n mechanis m fo r ethano l elimination . Thes e result s sugges t tha t 2-butanon e potentiate d the • neurotoxicit y

o f ethano l by

inhibitin g it s metabolis m by - alcoho l . dehydrogenase . 2-Butanon e i s no t a universa l potentiato r o f hydrocarbon - and aliphati c ketone-induce d neuropathie s (O'Donoghu e et.al . 1982) . Concomitant , ora l administratio n o f 2-butanon e and 5-nonanon e di d no t potentiat e the . neurotoxicit y

o f 5-nonanone» - '.. [^Butanon

e alon e i s minimall y neurotoxi c (Altenkirc hetal . 1978a ; Said a e t al . 1976) . This , compound , however , i s frequentl y mixe d wit hn-hexan e and methyl-n-buty l ketone-fo r variou s commercia l and industria l applications . Th e previou s discussio n emphasize s th e publi c healt hhazar d o f mixe d solven t exposur e t o 2-butanone . Exposur e t o a mixe d solven t i s mor e likel y t o occu r i n a n occupationa l settin g o r a t a hazardou s wast e site , tha n exposur e t o 2-butanon e alone . 2-Butanon e alon e i s no t highl y hepatotoxi c (se e th e discussio n o f Heggti c Effect s i n Sectio n 2.2.1.2 ) bu t ha s a well-documente d rol e i n potentiatin g haloalkane-Induce d hepatotoxicit y (Brow n and Hewit t 1984 ; Diet z and Tralge r 1979 ; HeVlL L e i al . 1963 , 1986 , 19&7 ; , Tani i e t al . 1986) . Intraperitonea l injectio n o f chloroform (0. 5 mL/kg ) cause d a nine-fol d increas e i n ra t SGP T activit y (Brow n an d Hewit t 1984) . I n contrast , chloroform injectio n cause d a 195-fol d increas e i n ra t SGP T activit y i f administere d 1 8 hour s afte r ora l administracio n o f 2-butanone . Similarly , intraperitonea l injectio n o f 

# <e J I,P.1 8



### 4 3 2 . HEALT H EFFECT S

chlorofor

m increased ra t plasm a ornithine carbamy l transferas e activity 215-fol d i f given 1 8 hour s afte r ora l administration o f 2-butanone (Hewit t e t al . 1983) . I n additio n t o th e dose s administered , th e lengt ho f tim

e between administratio n o f 2-butanon

e an d th e chlorofor

m injectio

n determined th e severity

o f hepatotoxicit y

(Hewit t e t al . 1987) . Measurement s o f SGP T an d plasm a ornithine carbamy l transferas e revealed tha t 2-butanone i s mos t efficaciou s fo

r potentiation o f chloroform-induce d hepatotoxicit y i f administered 1 8 hour s befor e chloroform . 2-Butanon

e als o potentiate s carbon tetrachloride-induced'hepatotoxicit y (Diet z an

d Traige r 1979 ; Traige r e t al . 1989) . Measuremen t o f SGP T activity an d hepati c triglyceride conten t showe d tha t administration o f 2-butanon e 1 6 hour s befor e intraperitonea l injectio n o f carbo n tetrachloride significantl y

enhance d live r damage . The mechanis m o f 2-butanone potentiatio n o f chlorofor

m an d carbon tetrachloride hepatotoxicit y ma y b e related t o biotransformation o f th e keton e to it s metabolite , 2,3-butanediol . Carbo n tetrachloride increased ra t SGP T 164-fol d whe n injected 1 6 hour s afte r ora l administratio

n of . 2,3-butanediol . Replacemen t o f 2,3-butanedio l with, . ... . 2-butanon

e increased th

e transaminas e 66-fold . Hepati c triglyceride content wa s potentiate d to a simila r degre e b y bot h2-butanone an d 2,3-butanediol . However , th

e maxima l potentiation o f carbon tetrachloride-induce d hepati c injur y b y pretreatmen t wit h2-butanon e coincide d wit hincreased microsoma l enzym e activit y

withi n th

e sam e tim e fram e followin

g exposur e to 2-butanone , alon e (Traige r e t al . 1.989) . Thi s strongl y suggest s tha t 2-butanon e potentiate s th

e hepatotoxicit y

o f carbo

n tetrachlorid e b

y enhancin

g it s metabolis

m to toxi c intermediates . Th e mechanism

o f 2-butanon

e potentiation , o f chloroform-induce d hepatotoxicit y apparentl y

doe s no t involve , biotransformation o f chlorofor m t o a reactiv

e intermediate , an alteratio n o f th e cytochrom

e P-45 0 system , o

r depletio

n o f live r glutathione (Hewit t etal . 1987) . I t i s possibl e tha t 2,3-butanedio l als o contribute s to th e toxicit

y o f chloroform . Pretreatmen t o f dd Y mic e wit hcarbo

n tetrachloride 2 4 hour s befor e ora l administratio

n o f 2-butanone reduced th e 2-butanone LD 5 0 abou t 20X (Tani i e t al . 1986) . Th e mechanism o f thi s effec t wa s no t investigated . Exposur e o f pregnan t rat s continuousl y t o n-hexane alon

e (1,000-1,50 0 ppm ) o r n-hexane an d 2-butanon

e (1,20 0 pp

m n-hexane , 30 0 pp

m 2-butanone ) throughou t gestatio n and/or durin

g th e postnata l perio

d resulte

d i n reduced birt hweigh t o f pups , an d weigh t gai n reduction persisted durin g th e postnata l exposur e period (Stoltenburg-Didinge r e t al . 1990) . Th e effec t wa s mor e pronounce d wit hth e mixtur e o f solvents . I n addition , hindlim b weaknes s in . one da m durin g th e gestationa l exposur e period progressin g t o quadriplegi a i n al l dam s durin g th e postpartu

m exposur e perio

d wa s fo

r th e solvent mixture , whil e onl y hindlim

bweaknes s wa s observed i n th e dam s exposed t o n-hexan

e alone . 

# )7P.1 9

4 4 2 . HEALT H EFFECT S

Coexposur e o f ? , cerevisia e t o 2-butanone , ethy l acetate , an d propionitril e enhanced th

e inductio

n o f chromosom

e los s caused b

y 2-butanone (Zimmermah n e t al . 1989) . Coexposur e o f S . cerevisia e t o 2-butanone an d nocodazol e enhanced th e inductio

n o f aneuploid

y cause d b

y 2-butanone alon

e (Maye r an

d Goi n 1987) . 2. 7 POPULATION S THA T AR E UNUSUALLY SUSCEPTIBL E N o studie s wer e locate d tha t identified population s tha t ar e unusuall y susceptibl e to advers e healt heffect s afte r exposur e t o 2-butanone . Th e ver y youn g an d th e ver y ol d ar e typicall y mor e susceptibl e t o chemica L toxicit y tha n are older children , adolescents , an d health

y adults . Individual s tha t ar e alcoholic s an d thos e wit hexistin

g live r diseas e woul d b e expected t o metaboliz e 2-butanon e differentl y

tha n th e genera l population . Person s wit hexisting.neuropathie s ma y als o be mor e susceptible . Exposur e t o bot h2-butanon e an d n-hexan e o r methyl-n-buty l ketone i s possibl e i n occupationa l setting s an d a t hazardou s wast e sites ; thus , neurologica l effect s o f n-hexane an d methyl-n-buty l keton e ma y b e greate r wit hcoexposur e t o 2-butanone . Likewise , occupationa l exposur e o r exposur e at hazardou s wast e site s t o a combination o f 2-butanone an d th e haloalkanes , carbo n tetrachloride , o r chloroform , present s a greate r ris k fo r live r damage . 2. 8 MITIGATIO

N O P EFFECT S Thi s section wil l describe clinica l practic e an d researc hconcernin g method s fo

r reducin g toxi c effect s o f exposur e to 2-butanone . Thi s section i s intende d t o infor m th e publi c o f existin g clinica l practic e an d th e statu s o f researc h concernin

g suc hmethods . However , becaus e som e o f the treatment s discussed ma y be experimenta l an

d unproven , thi s section shoul d no t b e use d a s a guide fo r treatment o f exposure s t

o 2-butanone . Whe n specifi c exposure s have occurred , poison contro l center s an

d medica l toxicologist s shoul d b e consulted for medica l advice . 2-Butanone ha s a lo w orde r o f systemi c toxicity . Th e main.effect s i n human s ar e irritatio

n o f respirator

y tissue s an

d eye s an

d nonspecifi c neurologica l effects , suc ha s headache , dizziness , nausea , an d fatigue . Sucheffect s ar e characteristi c o f solven t exposur e an d ar e mitigate d primaril y b y removin

g affected individuals , fro m exposur e condition s an d decontaminating exposed area s (Bronstei n "and : Curranc e 1988 ; Stut z an

d Janus z 1988) . > Fo r example P ,contaminate d clothing i s remove d an d ski n washed . I f th e eye s wer e exposed , the y ar e flushed wit hwater . For ingestio n o f 2-butanone , there , i s controvers y a s t o whethe r o

r no t to administe r emetics . Th e controvers y

center s aroun

d th e ris k o f aspiration o f vomitu s int o th e lung s durin

g emesis . Administratio n o f activate d charcoa l ha s bee n suggeste d to reduc e gastrointestina l absorption . Pleas e refe r t o Bronstei n an

d Curranc e (1988 ) an d Stut z an

d Janus z (1988 ) for mor e complet e information . — \ . A T thoug h2 butauuu " "•»"«• • j g nr»r. highl y neurotoxi c or hepatotoxic , i t potentiate s i__Eh e neurotoxicit y

o f n-hexane an

d methyT-n-buty i ketone , an d th e hepatotoxicit y

of ~ chlorofor

m an d carbo n tetrachlorid e (se e Section z.bj . Exposur e t o 2-butanon e wit h othe r solvent s isjftr p lik^ y

rha n exposur e t

o 2-butanone alon e i n occupationa l and ^ environmenta l settings . Sinc e bot hn-hexane art d in-aLliylMi-tJuEy

l ketone ca

n be 

# It4 5 HEALT H EFFECT S P.2 0

metabolized to 2,5-hexanedione (Cour i e t al . 1978 ; DiVincenz o e t a l 1976) , a poten t neurotoxi c agen t (Kat z 1985) , 2-butanone ma y potentiat e th

e neurotoxicit y

o f th e othe r chemical s b

y enhancin

g th e biotransformatio n o f n-hexane an d methyl-n-buty l keton e t o 2,5-hexanedione b y inducin

g microsoma l enzymes . Th e potentiation o f th e hepatotoxicit y

o f carbo n tetrachlorid e an d chlorofor

m b y 2-butanone ma

y b e relate

d t o th e biotransformation o f 2-butanone t o 2,3-butanediol , a metabolit e tha t potentiate s th

e hepatotoxicit y

o f carbo n tetrachlorid e to a greate r exten t tha n doe s 2-butanone (Diet z an d Traige r 1979) . Alternatively , th e induction o f microsoma l enzyme s b

y 2-butanon

e ma y enhanc e th

e biotransformatio n o f chlorofor m and-carbo

n " tetrachloride to toxi c intermediate s (Brad y e t al . 1989 ; Traige r e t al . 1989) . If . carbon tetrachloride or chlorofor m shif t metaboli c pathway s o f 2-butanone i n favor o f greate r formatio n o f 2,3-butanediol , administration o f an agen t tha t block s thi s shif t coul d mitigat e th e potentiation . 2-Butanone i s reduced t o 2-butano l an d oxidize d t o 3-hydroxy-2-butanone , whic hi s furthe r reduced to 2,3-butanedio l (DiVincenz o e t al . 1976) . However , th e enzym e system

s involved i n th

e biotransformation o f 2-butanone hav e no t bee n characterized . Similarly , i f 2-butanone enhance s th e metabolism

o f chlorofor

m an d carbon tetrachlorid e b y inducin g microsoma l enzymes , agent s tha t bloc k thi s inductio n coul d mitigat e thi s potentiation . 

### 2. 9 ADEQUAC

Y OF TH E DATABAS E Section 104(i)(5 ) o f CERCL A a s amende d direct s th e Administrato r o f ATSD R (i n consultation wit hth e Administrato r o f EP A an d agencie s an

d programs o f th

e Publi c Healt hService ) t o asses s whethe r adequat e information on th e healt heffect s o f 2-butanone i s available . Wher e adequat e information i s no t available , ATSDR , i n conjunction wit hth e Nationa l Toxicolog y Progra m (NTP) , i s required to assur e th e initiatio

n o f a progra

m o f researc hdesigne d to determine th e healt heffect s (an d technique s fo

r developin

g method s t o determin e suc hhealt heffects ) o f 2-butanone .

. Th e followin

g categorie s o f possibl e dat a need s have bee n identified b y a join t tea m o f scientist s fro m ATSDR , NTP , an

d EPA . They

ar e defined a s substance-specifi c informationa l need s that , i f met , woul d reduc e o r eliminat e th e uncertaintie s o f huma n healt hassessment . I n th e future , th

e identified dat a need s wil l be evaluate d an d prioritized , an

d a substance-specifi c researc hagenda , wil l b e proposed . . . 2.9. 1 Existin

g Informatio

n o n Healt hEffect s o f 2-Butanon e The existin

g dat a on healt heffect s o f inhalation , oral , an d derma l exposur e o f human s an

d animal s to 2-butanone ar e summarized i n Figur e 2-4 . The purpos e o f thi s figur e i s t

o illustrat e th

e existing information concernin g th e healt heffect s o f 2-butanone . Eac hdo t i n th e figur e indicate s tha t one o r mor e studie s provid e information associated wit htha t particula r effect . Th e do t doe s no t imply anythin

g abou t th

e quality

o f th e stud y o r studies . Gap s in , thi s figur e shoul d no t b e . interpreted a s "dat a needs " information . Studie s regardin

g th e advers e healt heffect s o f exposur e t o 2-butanon e i n human s i s limited (Figur e 2-4) . No report s exis t regardin g deat hi n human s 

# nP.2 1

4 6 2 . HEALT

H EFFECT S


## ^IGUR E 2-4 . Existin g Informatio n o n Healt h Effects o f 2-Butanon e

Inhalatio n Ora l Derma l HUMAN

3JPHEALT H EFFECT S

followin g exposur e t o 2-butanon e b yan yroute . Existin g informatio n regardin g . systemi c effect s o f 2-butanon e exposur e hav e com e primaril yfromtw o clinica l report s involvin g accidenta l poisoning : on e b yora l exposur e an d on e by inhalatio n (Ber g 1971 ; Kopelma n an d Kalfaya n 1983) . Aclinica l stud yreporte d contac t urticari a triggere d byderma l exposur e t o 2-butanon e i n a 48-year-ol d mal e painte r (Varigo s an d Nurs e 1986) . Intermediat e derma l exposur e t o 2-butanon e ha d n o effec t o n human s (Wahlber g 1984) . Acut e inhalatio n studie s i n human s showe d n o advers e neurologica l effect s (Dic k e t al . 1984 , 1988 , 1989) . However , 2-butanon e produce d nose , throat , an d ey e irritatio n i n human s (Nelso n e t al . 1943) . Epidemiologica l studie s showe d n o clea r relationshi p betwee n occupationa l exposur e t o 2-butanon e an d th e developmen t o f neoplasm s (Alderso n an d Ratta n 1980 ; We n e t al . 1985) . Anima l studie s regardin g deat h afte r acut e an d intermediat e exposur e t o 2-butanon e b yinhalation , oral , dermal , an d othe r route s ar e available
. Severa l studie s ar e als o availabl e tha t sho w tha t acut e an d intermediat e inhalatio n exposure s hav e minima l o r n o systemic.effects
. Minima l effect s wer e limite d t o smal l increase s i n orga n weigh t (Cavende r e t al . 1983 ; Toftgar d e t al . 1981) . Inhalation , oral , an d derma l studie s showe d tha t 2-butanon e i s minimall yneurotoxi c i n mos t species
. Guine a pig s expose d acutel yt o hig h concentration s (10,00 0 ppm ) develope d incoordinatio n an d narcosi s (Patt ye t al . 1935) . Juvenil e baboon s expose d t o 10 0 ppm2-butanon e als o appeare d t o sho w earl ysign s o f incoordinatio n an d narcosi s i n a comple x discriminan t neurobehaviora l tes t (Gelle r e t al . 1979) . Histologica l examinatio n o f reproductiv e organ s o f mal e an d femal e rat s expose d by inhalatio n t o 5,00 0 pp mreveale d n o effect s (Cavende r and Case y1981 ; Cavende r e t al . 1983) . Studie s o f acut e ora l exposur e showe d tha t 2-butanon e cause d rena l tubula r necrosi s (Brow n an d Hewit t 1984 ; Hewit t e t al . 1983 ) an d induce d hepati c microsoma l enzyme s (Brad ye t al . 1989 ; Rauni o e t al . 199.0 , Robertso n e t al . 1989 ; Traige r e t al . 1989) . On e intermediat e ora l exposur e showe d tha t 2-butanon e wa s no t neurotoxi c (Ralsto n e t al . 1985) . Acut e an d intermediat e derma l exposure s t o 2-butanon e wer e mildl yirritatin g t o th e ski n o f rabbits , rats , an d guine a pig s (Hazleto n Laboratorie s 1963a ; Wahlber g 1984) . N o report s o f systemi c toxicit yar e availabl e fo r derma l exposure . Severa l studie s demonstratin g tha t 2-butanon e i s moderatel yirritatin g t o th e eye s o f rabbit s ar e available
. 2-Butanon e wa s fetotoxic , causin g delaye d developmen t i n fetuse s o f rat s (Deaco n e t al . 1981 ; Schwet z e t al . 1974 ) an d mic e (Mas t e t al . 1989 ) expose d byinhalation
. Severa l studie s ar e availabl e regardin g 2-butanon e potentiatio n o f n-hexan e an d methyl-n-buty l keton e neurotoxicit yan d 2-butanon e potentiatio n o f haloalkan e hepatotoxicity
. 2.9. 2 Dat a Need s Acute-Duratio n Exposure . Severa l studie s ar e availabl e tha t repor t th e result s o f acut e duratio n exposur e t o 2-butanon e byinhalation , oral , an d derma l route s i n bot h human s an d animals
. I n acut e inhalatio n studies , a n



# £ '

### 4 8 HEALT H EFFECT S

LC 5 0 valu e i n rat s (LaBell e an d Briege r 1955 ) an d othe r exposure s tha t cause d deat h i n rat s (Klemisc h 1988 ; Smyt h e t al . 1962) , mic e (LaBell e an d Briege r 1955), . an

d guine a pig s (Patt ye t al . 1935 ) wer e identified
. Th e targe t organ s identifie d i n guine a pig s afte r acut e inhalatio n exposur e t o hig h concentration s o f 2-butanon e ar e th e respiratorysystem , liver , kidney , eye , an d centra l nervou s syste mPatt ye t al . 1935 . Sligh t neurotoxicit ywa s als o see n i n mic e an d baboon s expose d t o lo w concentration s (DeCeaurri z e t al . 1983 ; Gelle r e t al . 1979) . Narcosi s and incoordinatio n wer e observed , i n guine a pig s expose d acutel yt o hig h concentration s o f 2-butanon e (Pattye t al . 1935) . A n acute-duratio n inhalatio n MR L wa s no t derived'becaus e targe t organ s o f rat s and mic e hav e no t bee n sufficientl yinvestigated
. Althoug h targe t organ s o f acut e inhalatio n exposur e o f rat s and mic e hav e no t bee n sufficientl yinvestigated , intermediat e duratio n studie s indicat e tha t effect s o n th e liver , kidney , respirator ysystem , an d nervou s syste mo f rat s ar e minimal
. I n acut e ora l studies , LD S 0 value s fo r rat s (Kimur a e t al . 1971 ; Smyt h e t al . 1962 ) an d mic e (Tani i e t al . 1986 ) wer e available , an d the kidne y wa s identifie d a s a targe t (Brow n and Hewit t 1984) . N o acut e ora l MR L wa s derive d becaus e targe t organ s hav e no t bee n sufficientl yinvestigated
. Furthermore , inhalatio n studie s indicat e tha t 2-butanon e i s a developmenta l toxicant , bu t developmenta l effect s afte r ora l exposur e wer e no t studied
. Acut e derma l studie s hav e shown tha t 2-butanon e i s a ski n an d ey e irritan t i n rabbit s (Hazleto n Laboratorie s 1963a , 1963b ) and guine a pig s (Anderso n e t al . 1986 ; Wahlber g 1984) , bu t th e systemi c toxicit yo f acut e derma l exposur e ha s no t bee n investigated
. Th e availabl e pharmacokineti c dat a ar e no t sufficien t t o predic t whethe r targe t organ s woul d b e simila r byth e variou s route s o f exposure . Acut e exposur e o f human s nea r a toxi c wast e sit e t o 2-butanon e alon e woul d probabl yno t hav e seriou s clinica l consequences . 2-Butanon e i s detectabl e b

yhuman s a t concentration s fa r belo w it s OSH Aan d NIOS H permissibl e level s becaus e o f it s odor . Furthe r acut e exposur e studie s wit h 2-butanon e alon e woul d probabl yno t b e useful . I n contrast , furthe r acut e exposur e studie s byoral , inhalation , an d derma l route s o f 2-butanon e combine d wit h suc h hepatotoxin s a s chloroforman d carbo n tetrachloride , o r wit h suc h neurotoxin s a s n-hexan e an d methyl-n-buty l keton e woul d yiel d valuabl e informatio n o n th e potentiatio n o f th e hepatotoxicit yan d neurotoxicity , respectively , o f th e othe r chemical s b y2-butanone . Thes e chemical s ar e ofte n found togethe r i n formulation s use d occupationall yan d they'migh t b e store d togethe r a t toxi c wast e sites
. Therefore , worker s an d population s surrounding hazardou s wast e site s migh t b e expose d t o thes e substance s fo r acut e durations ; Intermediate-Duratio n Exposure . Acomprehensiv e 90-dayinhalatio n stud y i n rat s showe d tha t 2-butanon e di d no t hav e advers e effect s i h th e respiratory , cardiovascular , gastrointestinal , musculoskeletal , hematological , hepatic , renal , o r dermal/ocula r system s (Cavende r an d Case y1981 ; Cavende r e t al . 1983) . Th e mos t seriou s effec t wa s slightl yincrease d live r weigh t a t the highes t concentratio n tested , 5,00 0 ppm . Occupationa l exposure s t o concentration s thi s hig h ar e unlikel ysinc e human s find * 35 0 pp m2-butanon e intolerabl e (Nelso n e t al . 1943) . N o sign s o f neurotoxicity , eithe r clinica l

msA— *J*

### 4 9 HEALT H EFFECT S

o r histological , wer e observe d i n severa l studie s o f intermediat e exposure s t o hig h concentration s o f 2-butanon e up t o 6,00 0 pp m(Altenkirc h e t al . 1978a , 1978b ; Cavende r and Case y1981 ; Cavende r e t al . 1983) . Therefore , mos t organ s an d tissue s i n human s probabl ywoul d no t b e adversel yaffecte d b yintermediat e 2-butanon e exposure s eithe r occupationall yo r nea r toxi c wast e sites
. A n intermediat e duratio n inhalatio n MR L wa s no t derive d becaus e nos e and throa t irritatio n occurre d i n human s a t acut e inhalatio n exposur e level s lowe r tha n th e NOAE L value s fo r intermediat e duratio n inhalatio n exposur e i n animals
. No . intermediat e ora l o r derma l studie s investigate d the systemi c toxicit yo f 2-butanon e bythes e routes , an d th e availabl e pharmacokineti c dat a ar e no t sufficien t t o predic t whethe r targe t organ s woul d b e simila r byth e variou s route s o f exposure . 2-Butanon e ha s bee n detecte d i n air, , water , food , an d soi l (se e Sectio n 5.4) ; therefore , exposure s b yth e inhalation , oral, , an d derma l route s ar e possible
. Fro ma publi c healt h perspective , exposur e t o solven t mixture s i s mor e likel ytha n exposur e t o a singl e pur e chemical
. Therefore , intermediat e exposur e studie s o f 2-butanon e mixe d wit h othe r solvent s (hexacarbon s an d haloalkanes) , th e toxicit yo f whic h i s potentiate d by2-butanone , woul d provid e valuabl e informatio n o n neurotoxicit yan d systemi c toxicity
. Thi s informatio n i s importan t sinc e thes e chemical s ar e ofte n foun d togethe r i n solvent s use d occupationally , an d the ymigh t b e store d togethe r a t hazardou s wast e site s wher e surroundin g population s coul d b e expose d fo r intermediat e durations
. Chronic-Duratio n Exposur e an d Cancer . flo studie s wer e \qrftt-i-i. r^^arding

, th e healt h effect s o f chronic , exposur e t o 2-butanon e byan yrout e i n human s -t£r<^""" " animals , bu t acut e an d intermediat e dura*-*" " '• |, ^ i

- 1 af , ',u_

" viudle s indicate d tha t ^ ~ ^-by—ttSelf , 2-butanon e i s minimall ytoxic
. Pharmacokineti c dat a ar e ' " insurticien t t o predic t Lli e uusbibl ytarge t organ s o f chroni c exposur e b yan y route . Sinc e 2-butanon e ha s bee n detecte d i n air , water , food , and soi l (se e Sectio n 5.4) , exposure s b yth e inhalation , oral , and derma l route s ar e possible
. 2-Butanon e i s ofte n found i n formulation s wit h othe r chemicals , suc h a s chloroform , carbo n tetrachloride , n-hexane , and methyl-n-buty l ketone , th e toxicitie s o f whic h 2-butanon e potentiates
. Thes e chemical s ma yb e store d togethe r a t hazardou s wast e sites
. Chroni c inhalation , oral, , an d derma l studie s i n whic h animal s ar e administere d thes e chemical s i n combinatio n wit h 2-butanon e ma yprovid e dose-respons e informatio n fo r th e potentiatio n o f the neurotoxicit yan d hepatotoxicit yo f thes e chemical s b y2-butanone . Thi s informatio n i s importan t becaus e ther e ar e population s surroundin g hazardou s wast e site s tha t migh t byexpose d t Q thes e chemical s fo r simila r durations
. Althoug h n o cance r bioassay s wer e available , preliminar yepidemiologica l —^..i _. , studie s sugges c tha c occupationa l exposur e t o 2-butanon e doe s no t increas e the developmen t o f neoplasms . Furthermore , 2-butanon e wa s no t genotoxic , eithe r wit h o r withou t metaboli c activation , i n severa l microorganism s an d culture d mammalia n cell s (O'Donoghu e e t al . 1988 ; Thorp e 1982) . Furthermore , n o inductio n o f micronucle i wa s found i n th e erythrocyte s o f hamster s (Basle r 1986 ) o r mic e (O'Donoghu e e t al . 1988 ) afte r intraperitonea l injectio n wit h • j



# 2. 3

_

### 5 0 HEALT H EFFECT S

2-butanone . O n th e basi s o f thi s information , 2-butanon e doe s no t appea r t o b e carcinogenic
. Genotoxicity
. N o inductio n o f micronucle i wa s found i n th e erythrocyte s o f hamster s (Basle r 1986 ) o r mic e (O'Donoghu e e t al . 1988 ) afte r intraperitonea l injectio n wit h 2-butanone . Acomprehensiv e batter yo f i n vitro , test s showe d tha t 2-butanon e wa s no t mutageni c i n tw o prokaryoti c organism s an d tw o eukaryoti c organisms , di d no t transformmammalia n cell s i n culture , an d di d no t induc e unschedule d DN Asynthesi s i n ra t primary hepatocyte s (O'Donoghu e e t al . 1988 ; Thorp e 1982) . 2-Butanon e di d no t caus e gen e mutation s i n S . cerevisia e (Thorp e 1982) , bu t cause d mitoti c chromosom e los s (Whittake r e t al . 1990 ; Zimmerraan n e t al . 1989 ) an d aneuploid yi n S , cerevisia e (Maye r an d Goi n 1987 ) a t hig h concentrations
. Th e positiv e inductio n o f chromosom e los s i n th e yeas t cell s wa s enhance d bycoexposur e t o 2-butanone , ethy l acetate , an d propionitril e (Zimmermann e t al . 1989) . Th e positiv e inductio n o f aneuploid ywa s enhance d bycoexposur e t o 2-butanon e an d nocodazol e (Maye r an d Goi n 1987). . Althoug h 2-butanon e contain s a n electrophili c cente r a t th e carbony l carbon , furthe r testin g fo r genotoxicit y doe s no t see mwarranted , excep t i n combinatio n wit h othe r solvents . Reproductiv e Toxicity
. N o studie s wer e locate d regardin g effect s o n reproductiv e capacit yo r reproductiv e organ s an d tissue s i n human s followin g exposur e t o 2-butanone . Th e author s o f a healt h hazar d evaluatio n repor t fo r NIOS H conclude d tha t a perceive d increas e i n th e numbe r o f spontaneou s abortion s amon g femal e worker s believe d t o resul t fromexposur e t o 2-butanon e an d severa l othe r volatil e chemical s a t a sho e factorywa s no t relate d t o exposur e (Thar r e t al . 1982) . N o histopathologica l lesion s wer e foun d i n mal e o r femal e reproductiv e organ s o f rat s expose d t o 5,00 0 pp m2-butanon e fo r 9 0 day s (Cavende r an d Case y1981 ; Cavende r e t al . 1983) , bu t reproductiv e functio n wa s no t assessed . Furthe r studie s o f th e reproductiv e functio n o f 2-butanon e b yal l duration s an d route s woul d provid e valuabl e informatio n particularl yi f th e studie s includ e histologica l examinatio n o f the organ s an d tissue s o f th e reproductiv e system . I f reproductiv e organ s wer e identifie d a s target s o f 2-butanon e toxicity,'singl e o r multigeneratio n reproductiv e studie s probabl ywoul d b e warranted . Sinc e 2-butanon e potentiate s the neurotoxicit y o r hepatotoxicit yo f certai n chemicals , i t woul d b e valuabl e t o investigat e th e reproductiv e effect s o f mixe d solven t exposure s tha t includ e 2-butanone . Thi s investigatio n woul d b e usefu l becaus e 2-butanon e i s ofte n foun d i n mixture s o f othe r solvent s i n occupationa l settings , an d thes e mixture s mayb e found togethe r a t o r nea r hazardou s wast e sites
. Developmenta l Toxicity
. Informatio n regardin g developmenta l toxicit yo f 2-butanon e i n human s wa s no t located . 2-Butanon e wa s slightl yfetotoxi c i n rat s (Deaco n e t al . 1981 ; Schwet z e t al . 1979 ) an d mic e (Mas t e t al . 1989 ) followin g inhalatio n exposur e o f pregnan t rat s an d mic e t o 3,00 0 ppm . Th e fetotoxicit ywa s relate d t o delaye d development . Furthermore , fiv e o f eigh t pregnan t rat s expose d continuousl yt o 80 0 ppmthroughou t gestatio n faile d t o delive r litter s (Stoltenburg-Didinge r e t al . 1990) . I n addition ,



# ab•

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# FA X COVE

RSHEE T
DIRECTORATE O

E HEALTH STANDARD S PROGRAMS OCCUPATIONAL SAFET Y AN D HEALTH ADMINISTRATIO N ROOMN-371 8 20 0 CONSTITUTION AVENUE , N W WASHINGTO

N D C 2021 0

Augus t19,199 7 Pagelofl7„ , 

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# =2 5—• P? 7 OJ/19/9 7 TU E 16:2 0 FA l 20 2 21 9 712 5 GSH.V-K3 P • UL , .
U S DeoartmOfl t O f Labo r Occupationa l Safet yan d Healt h Administratio n

KWashington , O.C

. 2021 0 Repl yt o th e Attentio n of*

.



### MyraKarstadt , Ph.D

. Office o f Prevention , Pesticide s & Toxi c Substance s 

### U.S

. EP A Washington , D.C

. 2046 0
Dea r Dr
. Karstadt :
Thi s i s i n referenc e t o your letter date dAugus t

1 t o Dr
. Finkel

. I n tha

t letter you ^ aske dust b " " review th e Environmenta

l Protectio n Agency' s (EPA ) report o n asstssnier^6. f

th ejiealth effects...

. o f methy l ethy l keton e (MEK)

. Youspecificall y wante du i to'Joaisits cpmmer&Q& : : 

### .;-?-:

- neurotoxicity

. I woul dlik

e t o thankyo u for

givin g u s thi s opportunit

y tOHpreseifrourjyiewott-P p thismatter v / --•-••.-•*.

- ;.--•- - -y ,w :; 

### -,., p , P: : 

### > '-•'.- -^,.A : - Afte r reviewin g th e documen

t sferi f t o u s b y you , w e foun di t

diffi ^ .' , th e origina

l article s wer

e submitte dwit

h th e report
. Th e EPApr6vided~H$ own.summarie^.e f P

- variou s document s i t

ha duse dii i it s regulator

y process . These : summ&ie s bynhemselves"(withou t th e original articles ) are inadequat e t o mak e an y indqpenden

t judgemei^ld^etr^i t

ftbii wfia l th^.7 ; EP A ha dconcluded

. "''' " -" I 

### ' t



### -- J : 

### '-•-••

- y- •••• >••"• --'

- •'-'- Occupationa

l Safety.andHeahhAdihrms^ ^ describe s tfi

e neurotoxicit

y of MEK alone

. Durin g th e las t

proposed * rale making proces s o n June"

- 12,1992 , OSHA..considered2 studiesJhat dealt wiAjieuiotoxiceilect^MEK^-Wtaie^ : 

### - presentin g th e conchmo n o f tl* ^ ~ - In on e ofth e studies,jrat^expose dt p a200-pp mconcentratio n o f 2-butanone fo

r 1 2 hours/days , 7 days/wee k fo r 2 4 wetfcj^jK^e dslight

an dreversibl e neurologica

l effects afte

r 4 week s of exposur e (Takeuchi e t

aT ; 1985) t



### A slight increas e i n motor

nerv e conductio n velocit

y andmixe d nerv e conductio n velocit

y andadecreas e i n dista

l motor latency.wa s observe dat

4 week s o f exposure . However , n o differenc e wa s observe dafte r 4 weeks

. I t

i s not jpossibl e t o determin e the l significanc e o f

thi s increase?ui ; motor

nerv e conductio n velocity

. In anothe r studies , worker s expose dt o 2-butanone vi ainhalatio n andski n contac t hav e bee n reporte dt o experienc e dermatiti s andnumbnes s ofth e extremitie s (STmit h andMayers , 1944)

. Also , tw o youn g women expose dconcurrently t o 2-butanone a t concentration s of

29 8 t o 56 0 ppmand„t o acetoniea

t concentiations^ f

3J O t o 49 5 pp mexhibitedsignsefsever e intoxication, - 

### includin g convulsion s andlos s o f Consciousnes s (Smith ; 1944),, ;

### Thi s stud y only dealt

wit h acute* : effects

. :,\r'3*10-9 7 H E 16 : .1 0 FA- L '~'0~ -l afl--" * vjon.i

. M I P.2 8



### Base do n th e EPA' s summarie s ofth e literature , I agree ma t ther e i s n o convincin g evidenc e that

. ME K i s neurotoxi c in eithe

r experimenta

l animal s or

humans

. However , there i s als o no eyidenc e presente dby th e EP A tha t rule s out th e MEK' s neurotoxicity

. W e agree wit

h th e EP A tha t n o periphera

l neuropath

y o f sciati c nerv e andintrinsi c foo t muscle s wa s observe din rat s continuously expose dt o ME K (112 5 ppm) fo

r 16-5 5 day s i n astud

y b y Saidae t al

. (1976)

. Thi s stud

y demonstrate dtha

t ME K exposur e u p t o 504 1 pp mdi dno t produc e an

y neuro-histopathologica

l changes

. Also , n o evidenc e of periphera l neurohistopathologica

l change s wa s see

n i n rat s continuousl

y exposedt o 1125 ppmME K fo r u p t o 5 months

. Othe

r studie s hav e foun

dn o treatment-relate dcentra l or periphera l neurohistopatholog y i n rat s expose dfo r 9 0 day s ( 6 h/days , 5 d/wk

) t o ME K concentration s up t o 504 1 ppm(Toxigenics , 1981 ; Cavende r etal. , 1983)

. ? However , I disagre e wit

h the report' s conclusio n o n th e significanc e o f th e stud y b y Gelle r et al ^ (1979 ) Gelle

r et al

. conducte dOperan

t conditioning s behavior

tes t i n baboon s durin g exposur e t o 10 0 pp mME K

continuously fo

r 7 day s andcomparedi t

pre-exposur

e tes t scores . The operan

t behavior selecte dwa s amatch-to-sampl e discriminatio n tas k an dexperimenta

l protoco l allowed th e performanc e b f

eac h baboo n durin g exposur e to b e comparedtil ^ durin g a.: . • clea n air exposur e i n th e sam e chambe

r immediatel

y prio r tt > eac h exposure . A decreas e i n mea n respons e tim e an drespons e durin g delay

. But n o significant^ectwa s observe do n accuracy . ' W e agre e wit

h author s tha

t thi s coul db e a

n earl y manifestatio n o f

incooVtinatiO

T an*f rtait^sis v 

### ^ ' However , thi s conclusio n i s cloude db y th e fac t thes e animal s wer

e p^rtbusly!expose dfoother chemicals

. Thi s stud

y ma y no t b e a s inconclusiv e a s the EP A has * stated;-W e agree tha t i t i s not
clea r whethe r th e observed.effect

wa s produce db y ME

K alon e or b y MEK*sinteractio n with-- * othe r chemical

. However , i t

i s clea r that MEK' s hadasigmfieaBfrrbt e i n maiuiestationO f

thi s '•'• effec t eithe r alon e or b y exacerbatio n ofth e effectso f othe r chemical s since&e;te$ t

score s wer e compared.wit

h preexposur

e tes t scores . I t is^urpris^thaitfii s study , wa s no t repeate dwith

v • MEK alon e t o ascertai n th e effect * o f MEK»~
. ••;-"-_ ; •-.-.•*•*. ' :*•. : ••• - y-•••-•••. A.A A simila r stud y wa s conducte di n male^ta ^ et"i|F.;:1988)

. These P volunteer s wer

e expose dt o 18 6 ppmfo

r ^ Kburs

. No

* statisticall y sigmfi^ t

chafe s in , *,.

. neurobehaviora

l performanc e wer

e observed

. Sm^Uii s was'only aotA e exposur e study- ; i t .ianofc

- • possibl e t o extrapolatet o situation s where^orkersma y b e chronically expose dt o MEK
. ^ • • P
•*•*•;-c?r > ZK

- 

### The tim e weighte dav^g e concentratio n of ME K i n agrou p o f :C*6rker S i n aprinting , factor

y has-"

- been reporte dt o ra$g e Jron i 1.4 3 t o 223. 7 ppjri , wit

h amea n concentra.tion,Q

f 47;. 6 ppm " v

* -.-. . :.. . (Yoshikaw ae t

al v i995) i : Iathis'sttidy , persona l exposur e jgr^toring^wasricarriedout ^*J , 

### ft K .•im

passiv e sampler s durin g th e wor k shift*.

- Althoughthi s is aJa^anese^studyv-simila r America n workers.i s quit

e poissible sinc e OSHA' s PE L i s 20 0 pprn : An'aftefe

doperant^' ; conditionin g behavior

tes t i n baboon s at

10 0 ppmi n astud y by.Gelfe

T et'al.(W*9 ) mse^ncerns.r
. a t OSH A about worker s healt

h sinc e this-i s fa

r belo w th e currehtPEL

. ^r--:-;.- ; • 

# 21J8/19/9 7 TU E 16:2 0 FA l 20 2 21 9 712 5 Ciu,
.



### Th e rol e o f

ME K i n potentiatin g periphera

l neuropathie s cause db y potent neurotoxin s suc h as . hexane an dmethyl-n-butylketohe i s wel l documented

. ME K b y itsel f ma y o r ma y no t hav e an y neurotoxi c effect, bu t

it s potentiatin g effects o n othe r neurotoxi n are unquestionable

. Va n Engelen e t

al

. (1997 ) exposedvolunteer s t o n-hexane (6 0 ppm) wit h o r withou t simultaneou s inhalator

y coexposur

e t o ME K (20 0 or 30 0 ppm) fo

r 15. 5 minutes

. N o effec

t o f MEK wa s observe do n th e concentration-tim e cours e o f

exhale dn-hexane

. The conentration-tim e cours e ofth e neurotoxi c metabolite , 2,5-hexanedione , reveale dadecreas e i n th e rat e o f formatio n o f 2,5-hexanedione (about

threefold) afte

r coexposur

e t o ME K indicatin g that

interactio n o f

n hexane an dME K

lead s t o adecrease dconcentratio n ofth e neurotoxi c metabolite

. Furthermore , th e time t o reac h th e pea

k concentratio n wa s increase dfro m1 8 t o 3 0 minute s afte

r th e star t o f exposure . ..*•„

. ' Yasu i e t a l (1995 ) injecte drat s subcutaneousl y wit h 2,5-hexanedione (2,5-HD 2. 6 mmol/kg ) alone or.wit

h methy l ethy l keton e (2. 6 o r 13. 0 mmol/kg ) anddtferminedth e concentratio n o f 2,5-H D i n seruman di n th e sciati c nerv e 0.5,1,2,4, 8 an d1 6 h afte r administration

. The

y found tha t th e concentratio n o f

2,5-HD inth e serum , th e sciati c nerve , andth e urin e wa s increase d significantl

y i n adose-relate dmanne

r i n th e co-administere dgroups : Also , til e clearanc e of 2,5

- H D frombot

h serumandth e sciati c nerv e wa s delaye di n th e co-administration

. Th e stud y b y Va n Engelen e t

al

. (1985 ) observe dtha

t MEK reduce dth e productio n o f

aneurotoxi c metabolit

e whic h woul dsugges t

adecreas e i n n-haxene toxicit y i n th e presenc e o f

MEK
. However , astud

y by Yasu i e t

al

. (1995 ) demonstrate dtha t th e MEK increase s th e availabilit

y o f aneurotoxi c metabolit e a t th e target site(s)

. Sinc e w e know tha t ME K increas e n-hexane induce d neurotoxicity , later

ma y b e mor e critica l step s i n interactio n between MEK an dn-hexane

. Unde r man y occupationa

l settings , n-hexane andME K i s likely t o b e present

i n asam e mixture

. Therefore , i t

woul db e mor

e appropriat

e to conside

r th e toxicit y o f n-hexane andME

K i n a mixtur e tha n eithe r o f thes e chemical s individually

. Than k yo u agai n fo

r givin g u s th e opportunit

y t o provide comments
. I f

you hav e an

y additiona

l questions , pleas e fee

l free t o cal l me at

(202 ) 219-7157

.

Sincerely 

## t~<9^-r^rt-< * s\>v« * 

### Surende r Ahir , PhD Office o f Ris k Assessent enclosure s 

# 3-1

## Copyrighted page/s removed. Please contact the EPA Docket Center, Public Reading Room to view this document. Address: 1301 Constitution Ave, NW Room 3334 Washington, DC 20004 Telephone: 202-566-1744 Fax: 202-566- 9744 Email: docket-customerservice@epa.gov'0$ . 19 . 9 7 TIE 16:2 3 FM 20 2 Hi Ti .

welding fum e fum e dens e t o th

i •Jo n o f 3 0 mg . m il y accepte d max * din g fum e Wh e limit , visibility ' utio n no tpresentl y jlaint j fro m work nitfo rtota l fur

n uard s from nn e rata oxide , oao n j . I tis , therefor e :neve rdens e <*<l

d 

### la r rtecentl y d e fien. mistin g o f

a .. '•de r(Fig . 2 ) um e lade n ai r Th e size o f

pvun j \ s o chose n tha t
• produce d b y o n ion o f fum e i s 3 ( i n rncasureme

n mtc ' - -rna l lineH > h

'* Space s meets i n th e pr o velopmento f

su p lifferfrom ai rH

m uire th e workme i -i d mouth . Ai ri nets eithe rarou n : d downwards ; ; wards , o ri n fro n cithe rtoward s th i face . I n ai l ty ; mospher e o f fres l c e with th e exc.es o ai d i n \cx. Thes e suppli e i n confined sp a uar d i s know n itothe rform s preventin g m ' P wun ,

'•* continu*** ! 

### INDUSTRIA L HYGIEN E DIVISIO N O F INDUSTRIA L HYGIENE , NE W YOR KSTAT E DEPARTMEN T O F LABO R LEONAR D GREENHJRG. M

. O . EXECUTIV

E pmtCTO E Aaprfeifa d Jrom Thm Industrial Ouilrin UJIM-

J uoch month oe Altai * by tho Industrial

Commissionerof

tha State of

Sow York. Vol. 23 ; Wo

. 3; May, IUi BONIN G AN

D FIR E HAZARD

S O F BUT.VMON

E AN D ACETONE " A0U.AIO C ROS

S SMITH , MO. . aa * MA Y K . MAYtU . M.O . utaoonc , o rmeJiy i ethy l keton e (CH - C O C-H.) , u effectiv e solven t[o rcertai n gum s an d resins , al^ o cellulos e acetate . A s suc h i thaa foun d consider . e us e i n industry , very ofte n a s a substitute to. - n toxi c solvent s suc h as benzol . Animal expert nt s wit h butanone , conducte d b y Patty , Schrenk . i Yam 1 , showe d tha tits actio n is as a narcoti c mucou s membran e irritant , an d tha ti c ha s a tuivel y lo w degre e o f

toxicity . The y foun d that concentratio n o tI pe rcen tby volum e i n ai r ,00 0 P.P.M. ) coul d b e tolerate d fo rseveral hou n experimental animal s withou tseriou s disturbance , t-mone m changes , i n animal s afte rexposur e t o concentration s wer e foun d t o be : Marke d con tio n o f th e brain , systemi c organ s an d lungs , itatio n of

th e eye s an d nasa l passage s wa s promi tamon g th e note d effects . N o repon s hav e bee n Id e o f an y harmfu l effect s o f butanon e o n humans . ^fUttooe , o rdimethy l keton e (CH.COCH.) , als o "efficien tsolven tfo rman y organi c compounds , ha s eive d considerabl y mor e stud y tha n butanone- . It , ha s a narcoti c actio n i n hig h concentration s an d a n irritan tt o mucou s membrane s o f th e ey e an d pirator y tract , bu tn o acut e case s of poisonin g hav e reported' fro m industria l exposure . A fewcase s hav e bee n described , characterize d b y ey e an d throa tirritatio n with coughing , erat e depressio n o

f th e centra l nervou s system headache . * Plan tI—Exposur e i n Raincoa tManufaaur e Recentl y a situatio n i n whic h ther e wa s exposur e both o f thes e solvent s simultaneousl y withou tex is tventilatio n of

an y kin d wa s investigate d b y Divisio n o f

Industria l Hygiene . Tw o case s o f ite intoxicatio n ha d develope d unde rthes e circum aces . Since , s o fa ra s i s known , acut e industrial oxicatio n du e t o thes e solvent s ha s no tbee n re tted , i tseem s worthwhil e t o describ e thes e case s a contributio n t o knowledg e o f di e toxi c potenuali o f tw o commonl y use d solvent s whic h ar c gen y considere d t o b e relativel y harmless , rh e exposur e referre d t o occurre d i n th e proces s waterproofin g th e seam s o f raincoat s fo rth e Army , iterial s use d fo rth e purpos e wer e tw o vinylit e on e dissolve d i n butanon e an d th e othe ri n ^in* . tone . I*h e compound s wer e applie d wit h a brus h t o al l i n a n operatio n know n as brushing , - Each , receive d thre e brushing ? a tinterval * o f two ,

. I n th e tin ttwo , aceton e wa s the'solvent* , i n

_third , butanone . . _ _ The roo m i n whic h th e operatio n o f brushin g was ' rrie d o n wa s approximatel y 30'x85 ' wit h a 12 ' fit aaaWit a u d chtauca

l ie»u ' *••)• * atati * > y wiltUi a >wkt . Mtato*vitt . »i%r

l $ . Tri*** n

f *H . Divi.tA * n l TMiMfrit tHt^itn c „f . A . P»uv , o i fidtlir * »« 4 U-MUiliy ta»w«K tUITIMI A

; • ' • * ceiling . I twa s don e a ttable s 10 " lon g with on e o r tw o brushe n a teac h uble . Eac h brusherha d befor e he ra n ope n eight-ounc e ja rcontainin g th e compoun d sh e wa s using . Ther e were 5 9 tabl e i a th e roo m altogether , an d 8 2 operator! . Afte rbrushing , th e coats were hun g u p t o dr y o n clothe s rack

s locate d betwee n th e tables . Tw o thousan d coats were ordi narily i n th e roo m a ton e time . Althoug h there wer e window s o n thre e side s o f th e room , i n coo i weathe ronl y a fe w wer e opened . Ai r tests disclose d concentrations ' of butanon e rangin g from 39 8 t o 56 1 P.P.M . an d fo raceton e fro m 33 0 t o 49 5 P.P.M . Since - vapo n o f bot h solvent

s wer e presen ti n th e ai ra tth e sam e tim e th e accumulate d concentratio n o f

bot h togethe rwa s i n th e vicinity o f 1,00 0 P.P.M . Evidenc e o f th e toxi c effecto f

suc h concentration s was , see n i n th e tw o acut e episode s herewit h reported . Tw o Case s o f

Acut e Poisonin g Cas e 1—I . H. , a gir

tbrusher , 1 8 yea n o f

age , complaine d o f

gastri c distres s on e ninrnin g i a January whil e a twork . He rtablemate als o notice d tha the r eye s wer e watering . I n th e afternoo n sh e fd twon e an d wen tt o th e res troo m where, sh e wa s foun d unconsciou s a shor ttim e later . A n ambulanc e wa s calle d an d sh e wa s take n t o a nearb y hospita l abou t4:3 0 r . M . Sh e was admitte d i n com a wit h a stron g odo ro f aceton e 6 a th e breath . Thi s cause d th e admittin g physician t o suspec tdia beta , bu tth e urin e wa s negative . Physica l exaaina * tio n was als o negativ e excep tforoccasional twitchin g o f th e fac e an d extremitie s an d hyperactiv e reflexes . Puls e 112 . Temperatur e 98° . B.P . 128/70 . Spina l u p showe d fluid unde rpressure—19 0 nun . mg . Sh e wa s give n a 6c c o f conmi n intravenousl y withi n a n hou rof

admissio n an d responde d immedi ately . He ronl y complain tthereafte rwa s sever e headache . O n th e day afteradmissio n there wer e n o objectiv e signs . Th e headach e subsided . Sh e wa s discharge d tw o day s later . Cas e 2—M . M. , likewis e a girl brusher , age d 1 9 years , fainte d whil e a twor k th e da y followin g the . episod e describe d above . Th e faintin g wa s followe d b y a convulsion , afte rwhic h sh e regaine d consciousness . Sh e was take n t o th e same , hospita l wher e th e admittin g physicia n foun d he rmentally confuse d an d complainin g o

f headache . N o evidenc e wa s foun d i n eithe rhistor

y o rphysical examinatio n o f an y pre-existin g conditio n whic h migh thav e bee n responsibl e fo rth e convulsion . Afte ra n hour' s ob servation , sh e wa s allowe d t o g o hom e an d tw o diy s " : T*teFsheijreturne

d t o work . '?'. * • Fir e Hazar d On e canno tomi tmentio n o f th e serious fir

e hazar d ' which"H . associate d with thi s typ e o f wor k sinc e thes e divan s arc highl y iiiAammAblc . *



# \l

•c ' k

i->

i 

# I

* * 

# v l \i

, •P.3 6

'08-19/9 7 Tl' E 16:2 4 FM 20 J Hi '12 3 'Jirt A Hi P

1



# r . I n th e plan tunde rdiscussion , thousand s o l coata ,

wer e foun d hun g u p t o dr y al l ove rth e mom—ai l dos e together ; an d al l givin g of f solven tvapon . Th e workroo m wa s als o crowde d with small table s o n which , th e solven twa s applie d t o th e raincoats . An y spark fro m a cigarett e coul d hav e starte d a catastrophi c fire i n thi s room ; and , onc e started , th e fir e woul d hav e swep trapidl y fro m coa tt o coat . An y attemp to n th e par tof th e worker

s t o flee th e fir e woul d hav e cause d larg e number s o f th e rain coat s t o dro p of

f thei rhangar s o n to p of them . Th e stag e wa s perfec tfo ra seriou s pani c an d grea tlos s o f life , despit e th e presenc e of fir e exits a tboth end s o f th e room . Discussio n Sinc e vapor s o f

bot h butanon e an d aceton e wer e freel y presen ti n th e ai ro f th e workroom , i ti s of coun e impossibl e t o ascrib e th e abov e effect s solel y t o th e actio n of

on e o rth e other . I tmustlogicall y b e assume d tha tthe y wer e th e resul to f th e cooabina tio n o f both . Bot h solvent s ac ta s narcotics , an d bot h case s reporte d wer e characterize d by centra l nervou s syste m Involvement . Thi s inciden tbring s u p th e questio n o f permissabl e concentration s o f

butanon e an d aceton e vapors i n th e ai ro

f workrooms . N o standard s fo rbutanon e hav e a s ye tbee n published . Whethe ro rno ti ti s more , toxi c tha n aceton e canno tb e detennine d with ou tfurthe rexperience , bu to n th e basi s of i s chemi . ca l similarit y t o aceton e (butanon e bein g methy l ethy l keton e whil e aceton e i s dimethy l ketone ) i tseem s likel y tha tth e tw o ar e of approximatel y th e sam e orde ro f toxicit y an d dia tth e sam e permissabl e limi a fo rai rconcentratio n woul d b e suitabl e fo rboth. . Investigatio n b f

suggeste d standard s fo rsaf e con centration s fo raceton e i n thi s country reveal s a surprisingl y wid e variation , on e whic h ranges fro m 20 0 t o 1,50 0 part s pe rmillion . I f w e assume tha t • butanon e an d aceton e ar e of th e sam e orde ro f toxicity , th e experienc e indicate s tha tconcentrate s o f eithe ri n th e neighborhoo d of 1,00 0 P.P.M . ar e too-high . I tmay , o

f course , b e tha tth e combinatio n of th e tw o differen tvapo n produce s a synergisti c effec t whic h make s th e tw o togethe rmor e toxi c tha n eithe r on e alon e i n equa l concentrations . Th e possibilit y mus tb e take n int o consideratio n whereve rther e i s exposur e t o tw o o rmor e potentiall y ton e substance s a tth e sam e tune . Plan tII—Exposur e t o Butanon e i n th e Manufactur e

o f Raincoa tMateria l I n th e manufactur e o f th e waterproof

material fro m whic h thes e raincoat s ar e made , there ma y b e exposur e t o hig h concentration s o f butanon e (methy l ethy l ketone ) unles s prope rprecaution s ar e observed . Thi s proces s involve s machin e spreading , o n a fabri c base , o f a jelly-lik e resin dissolve d i n thi s solvent . I n th e preparatio n o f

th e jelly , an d i n th e spreadin g operations , worker s ar e expose d t o varyin g amount s o f th e solvent , whic h i s highl y volatil e an d permeate s th e ai ro f

th e workroom . Worker s als o ten d t

o was h thei rhands , i n th e solvent . The y als o di p a wipin g clot h int o i twit h whic h the y clea n th e spreadin g blade s o f

thei rmachines . Thes e practice s gread y increas e thei rexposure—i n term s of direc tskin con tac tan d a n opportunit y t o inhal e hig h concentration s o f th e vapor* . 

## •* 5 l a on e such plant , wher e ai ranalyse s concentration s o

f methy ethy

l keton e rantin c 30 0 P.P.M . t o 60 0 P.P.M. , worker s develope d ablin g dermatoses an d severa l worker s compl . of numbnes s o

f th e fingers an d arms . On e v . describe d on e shoulde ra s feelin g "a

s thoug h i t mad e o f dough , an d di d no tbelon g t o him " s o h e coul d no tli e o n i tatnight . Anothe r* « complaine d o

f numbnes s i n th e leg s an d a te n fo rthe m t

o suddenl y giv e wa

y unde rhim . _• me n wh o merely worke d in th e room s where 3^ ? solven twa s presenti n th e air , butha d n o occa i go t o touc h it , develope d a dermatiti s whic h origin * *)f* * o n th e fac e an d was confine d t o tha tarea : <• » - 5 Discussio n Bpera t Th e experienc e i n thi s plant , wher e th e expo* ^b^°. wa s t o butanon e alon e i n concentration s ranging fi * w '' f ' 30 0 t o 60 0 P.P.M . whe n considere d i n th e ligh i tom * t * Plan tI , woul d see

m t o indicate ver

y definitel y i . * n< i thes e concentration s are to o high . Th e complaint s o

f numbnes s whic h might , ot l ' . wis e hav e been , difficulto f interpretatio n woul d » M*» . t o acquir e significanc e i n th e ligh tof . th e n U L sever e poisonin g i n th e girl s i n Plant . I . I n k ^ Instances , th e nervou s system was primarily invoh i Dermatiti s venenata developin g i n worker s f i , ' handlin g butanon e i s no tuncommon . I ti s . IEFFT alway s necessary , however , fora worke rt o act u . - j ; wor k wit h an d touc h a volatil e solven twit h hi s h a t i n orde rt o develop * a dermatitis . A s i n di e cas t- th e tw o worker

s abov e mentioned , a dermatiti s o f ' fac e o rothe rexpose d surface s o f th e ski n ma y de n Venti l solel y a s a resultof

expoaur e o f th e ski n tb vap pde n o rfinely atomize d droplets i n th e air . Her e ves tjaibtc tio n provide s di e solutio n t o th e dermatiti s prob l itilat k

Contro l Measure s * [j j J j Ventilation—Adequat e loca l exhaus tventilatsc - ^ p ( a basi c safet

y measur e i n exposure t o thes e solv e 4 ya( J I n considerin g maximum allowabl e concentrati . n th e occurrenc e o

f periodi c surge s i n whic h ther e 1 . } p a o b e brief exposures a tspecifi c point s i n th e worki tj 4 ^ c a t o muc h highe rconcentration s tha n ar e t o b e f 0 1 ^y- , i n th e room a

s a whol e mustb e take n int o acco*

_* t Th e maintenanc e o

f solven tvapo n i n th e ai rbe 4^ ' 0 _ toxi c limits , automaticall y prevent s concentrat

i -^ whic h are explosive . , ope r Attentio n t o stoppag e o f leaks from raachinn, < • jr . mf . in g rooms , an d th e like , is extremely important ; 1 ; m • a als o th e disseminatio n o f vapo n int o the workr

c p o f L fro m uncovere d barrel s o rothe rsolven tcontai n _c c whethe rful l o rempty . m m Th e importanc e o

f ventilatio n i n th e control ^ng C C dermatiti s has already bee n discussed . . *^ n . Ski n Protection—Asid e fro m cleanlines s o f

th e s x ^ protectiv e measures includ e the us e o f (1 ) glove s ^ ^^ sleeves ; (2 ) protectiv e water-solubl e cream a app j £-»,

„ i n advanc e o f

exposure an d re-applied periodi c jf ort u durin g th e day ; (3 ) soothin g creams an d lotio n ^j ^ b e appUed afte rwashin g atth e en d of th e da y • „ * replac e th e fatt

y elements i n th e skin removed by [ y *„ , solvent s i n th e cours e o

f th e day' s work ; (4 ) dis c t j wj tinuanc e of

th e practic e o

f immersin g uncovc ^ ^ hand s i n th e solven tfo ran y purpos e whatever , inc ! • era j_ in g it s us e a

s a cleansin g agen tfo rth e skin . TK*- — importan tno tmerely a s a means o

f protectin g CP. * skin , bu tals o a

s a IHM W of

p-dunn* ; inhibito r^

_ 

# 3 5 1?

5 / > :•)%• 19-9 7 TI E 16 : FAI.2 0 2

naiyse * h e ranging i develope d ke n eomp l -s . On e thoug h i t t o him " s o t atvapon .

wil l Soca e workers , onc e the y hav e becom e

__ , neve ragai n b e abl e t o work wit h chemicals ; othe n ma

y becom e "hardened " b y mous exposure . Summar y an d Condusion s
, w >u

_—i_Evidenc e i s presente d o f a n acutel y toxi c effect Anothe rwo tm 4 combinatio n o f aceton e an d butanon e vapo n

- s an d a tend e ^y i et hy l ketone ) whic h togethe rreache d ap * J w: - T oatimatel

y 1,00 0 P.P.M . w.

5 2—Evidenc e i s als o presente d o f lo w grad e intoxi ha d n o occa s ,jo n m d dermatiti s fro m exposur e t o butanon e whic h origin a i0t

m concentration s ranging fro m 300-60 0 P.P.M . • 3—Th e inflammabilit y of thes e solvents a troom nperatur e suggests extrem e cautio n i n thei ruse. . ^ ^ 4—Concentration s of thes e solven tvapors , suffi her e th e expo s ^ , o w t o prowc t^ e healt h o f workers , wil l ^ ^ itomatically provid e saf e concentration s from th e e an d explosio n standpoint . tions rangin g t d i n th e ligh t i erf definitel y -hic h migh t©t

i aaraumca s •tatio n woul d s

« •?" • F v * s^*" 1 " - JJ * *•< *** Y *"« * wI* 1 A*** 1 ! ' ' • • HUO n , W B r " * " M> * Mr * t o tpe n <*H

»• « ov * coMmraa l •rt w itrh to f th e m m . !•»••»•• . th* . *»»«•• . a.** , w i , i m PI n tI I n b * mi * m ' AUc * : u<, » u W T«n«oto*|*f . Hupn , IS<H

. primaril y invol v , 0 . i i n worke n f

r mmon . I ti s EFFECTIV E CONTROL S O F HAZARD S worke rt o act a I N WELDING , FLAM E CUTTIN G ven twit h hi s h a AN D METALLIZING * A s i n th e cas e , •»,.„ . '
, a dermatiti s o f

» T Arthu rC Ste m h e ski n ma y dev e Ventilatio n o f confine d space s requires specia l th e ski n t o va p uideration . Respirator y protectio n of th e type s ! *ir . Here * ven tBribe d i s th e bes tmetho d o f control . General uatiti s prob h ablatio n o f

space s unde r5,00 0 cubi c foo tshoul d tb e lef tt b natura l ventilation , eve n i n part , bu t ^ .. . jul d hav e th e entir e ventilation loa d handle d b y xhaus tventilano i ^ Fo r^ ^ jpac o ^ {o r^ mtex \ orof tan k s « t o thes e solv e a^ veru iiatio n o f th e orde ro f

fro m 75 0 t o 1,50 0 abl e concentrati ' n ^ wdde r^p^ent , goo d practice . Th e smalle r v n whic h ther e B E jpaCftdi e gn^cx i s th e hazar d fro m fum e an d nt s i n th e *TM**° s accumulation . Notwithstandin g an y minimizin g ha n ar e t o b e to tvoidin g hazard s tha tma y see m apparen ti n thi s take n int o acco v _ ^ i tmm t- ^ j^d ^ d m gase s suc h a s nitrou s o n u s th e ai rb e [ ^ otCM u d c^jto n monoxid e whic h offerlittl e -ent s concentra u ^ d « di e lo w dilution s encountere d i n wor k i n , . e ope n room ma y becom e highl y concentrate d an d fro m machines , a ,,0 ^ dangerou s t o a ma n weldin g insid e a tan k aely important ; a ; M

^ ima | 1 > improperl y ventilate d room. 1 tnt o th e workr o Fo T ^ ventilatio n o f enclose d o rsmal l space s i n :t solven tcontai n j p construction- work , several specia l fans an d • . , . swe n hav e appeare d o n th e market . The y ar e Qn TM * e "Otro l ^^ d wit h multipl e inle to routle tconnection s u f se ^; . , . , rthree , four , si x o ran y numbe ro f flexibl e hoses . cleanlines s o f

th e s l l e mump-dots i s tha tth e variou s welde n wil l US e O f (I ) glOVe S S r

K* m n » . h* . ~ —fl^rrW- k« » fn r KM * wntiliMnr i (I ) glove s s ch «tang e hi s ow n flexible hos e fo rbes tventilatio n olubl e crcam a app l d thu s a numbe ro f workme n ma y b c protected , re-applie d periodi c ,f or tunatel y eac h welde ran d forema n i s no ta cream s an d lotton** ! n ,y»tio n enginee rs o tha tth e usua l resul tU tha t h e en d o f

the^da y tui wWc n W M originall y overrated , become s woe i e ski n remove d b y ^ ma dequat c a s addition s an d bend s ar e adde d ay' s work ; (4 ) dis c d « hose , kink s an d leak s develop , an d section s o f unmenin g uncov e K

^ m cnuhe d an d otherwis e obstructed . I n ipos e whatever , mc l ^ di e mean s o f ventilation shoul d eithe rb e i tth e skin . Th i > .« . j f protectin g C»»«ta«*** fro a p*« « l«a . Ap*

U IS M ina * o

f Tur n Imam* , reducin g inhalatio n J"""

* * 17 6 properl y engineere d an d permanentl y installe d or , itpermanen tinstallatio n i s impossible , fo r-f* k temporary setup , th e choic e o f fan , nuinbe ro f hose s pex fan , hos e diamete ran d length , an d typ e an d placemen tof

hoo d shoul d b e delegate d t o th e car e of a traine d ventilatio n man . Thi s ma n shoul d b e supplie d with sufficientaccurat e da u abou teac h fan , hoo d an d siz e o f

hos e employe d s o tha th e ca n make aecurrate on-the-spo testimate s o f th e per formanc e o f

each suc h temporary setup . Workme n shoul d no tb e allowe d t o star twor k unti l th e ventilat in g ma n complete s hi s setu p an d give s th e go-ahea d signal t o th e welders . Shipyar d experienc e point s : o th e valu e o f

usin g bot h suppl y so d exhaus tai r t o double-botton a an d simila rspace s rathertha n exhaus talone . Th e suppl y ai rshould , of course , b e take n fro m out-of-dctors , rathertha n fro m som e othe rpa n of

th e ship , and , wher e possible , semi , permanen tsoli d metal suppl y duct s shoul d b e ex tende d tb plenu m chambe n strategicall y locate d abou tth e ship , from , whic h loca l suppl y ma y b e take n a s needed .

Ventilatio n i a Factorie s Fo rordinar

y factor y wor k exhaus talon e wil l suffice , sinc e windows , doo n an d kxtvere d wil l opening s ca n supply sufficien tmake-u p ai rwithou t excessiv e pressur

e drop . Wher e exhaus tonl y i s used , i tmay tak e th e for m o f eithe rbea l exhaust , a s nea ra s possibl e th e poin to f weld , o ro f

genera l roo m ventilation . Loca l exhaus tn generall y feasibl e onl y whe n weldin g i s don e o n a productio n baa s o a bencha . I ti s sometime s attempte d o o productio a wor k o f more extensiv e character , b y having * th e welde rmov e th e exhaus thoo d a s h e mov a about . th e work , but . thi s i s no tusuall y ver y satisfactor y insofa ra s th e welde ri s pron e t o wel d to o fa r fro m hi s hoo d befor e movin g it , o rt o neglec tt o mov e i ta ta L Table s hav e bee n prepare d and , even , incorporate d i n code s specifyin g th e relation betwee n ai rquantity t o b e exhauste d an d distanc e from hoo d t o weld . However , fo rth e reasons abov e noted , i ti s preferabl e t o bas e al l loca l exhaus tfo r weldin g o n th e more fundamenta l bas u o f th e main tenanc e o f

an ai rvelocit y a tth e poin to f wel d o f 10 0 linea l fee tpe rminut e awa y fro m th e breathin g ton e o f th e welde ran d toward s th e hood , boot h o r enclosure provided . Standard s forgeneral room ventilatio n ar e ver y difficul tt o formulate i n th e abstract . On e reason abl e criterio n i s t o requir e no tles s tha n fou rai r change s pe rhour , supplie d eithe rb y natura l ventila tion , mechanical venulatio n o rboth . Th e recentl y issue d Ne w Jerse

y Departmen tof

Labo rWeldin g Protectio n Standard s als o recommen d tha tweldin g bay s shoul d no tb e structurall y blocke d thereb y obstructin g cros s ventilatio n an d tha tther e shoul d b e provide d eithe ra space , allowanc e of 15,00 0 cubi c fee tpe rweldero rventilatio n o f a tleas t35 0 cf

m pe rwelder . Th e genera

l conclusion s concernin g weldin g haz ards an d thei rcontro l are , therefore , tha tb y wearin g of orope rprotectiv e clothing , goggle s an d helmet s an d providin g adequate ventilation , welding , cuttin g an d metallizin g ca n b e undertake n i n industry with ou thazar d to th e workme n involved . >-•*— « ^ * ^ 

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documen t http*.'/se«rc h theaM>^»ie.c 0ra/cgij, jt vaf.totrnut.cgi



### | leS H Headin g (Major ) Alcohol , Ethylj*BL ; Alcohols , Butyl|* ; Carcinogensl* ; Chromatography , Gas|*MT/S T leS H Headin g Butanones ; Forensi c Medicine ; Human ; PostmortemChange s

I 'ublicatio n Typ e JOURNA L ARTICL

E SSN ' 0379-073 8 Countr y o f Publicatio n IRELAN D CAS Registry/E C Numbe r 0 (Alcohols,'Butyl) ; 0 (Butanones) ; 0 (Carcinogens) ; 64-17- 5 (Alcohol , Ethyl) ; 75-65- 0 (tert-buty l alcohol) ; 78-93- 3 (methylethyl ketone )

Record3 fro

mdatabase : MEDLIN E Orde r ful l text for thi s documen

t Titl e Biologica

l monitoring of

occupationa

l exposur e t o methy l ethy l keton e i n Japanes e workers

. Autho r Yoshikaw aM ; Kawamot

o T ; MurataK ; Arashidan

i K ; Katoh T ; Kodam

aY Addres s Divisio n o f Occupationa

l Hygiene , Schoo l pf

Nursing an

dMedica l Technology , Universit

y of Occupationa

l andEnvironmenta

l Health , Kitakyushu , Japan
. Sourc e Arc h Enviro n Conta

mToxico l 1995 Ju

L 29:1 , 135- 9 Abstrac t The relationshi

p between occupationa

l exposur e t o methy l ethy l keton e (MEK

) an dit s concentratio n i n urine an dbloo dwa s studie di

n agrou p o f 7 2 worker s i

n aprintingjactory

. Persona l exposur e monitoring wa s carrie dou t

wit h passive samplers durin

g the"workshifts

. The tim

e weightedaverag e (TWA) concentratio n o f

ME K range dfrom1. 3 t o 223. 7 ppm-, wit h amea n concentratio n of

47. 6 ppm . I n additio n t o MEK, toluene , xylene , isopropyl alcohol , an dethyUcetatewer e detecte da s th e maSnTcontaroinant

s in al l samples

. A

t th e endofth e workshift, urin e sample s wer

e collecte dt o ,. determine th e urinar

y MEK, hippuri c aci

d(HA) , an dcreatinine , an

dbloo dsample s wer

e als o collecte dat

th e sam e tim e fo r determination of

MEK
. The concentration s o f urinar y ME K ranged fro m0 2 0 t o 8.0 8 mg/

L wit h amea n of 1.1 9 mg/ L an dsignificantl

y correlate dwit

h TW A concentration s o f

ME K i n th e ai r wit h acorrelatio n coefficien

t o f 0.88 9 fo r uncorrecte durine samples

. The concentratio n o f MEK in th e bloo dwa s als o significantl y correlate dwit

h th e TW A concentratio n of

MEK wit h acorrelatio n coefficien

t o f 0.820

. Fro mthes e relationships , ME K concentration s in urine andbloo dcorresponding t o th e threshol dlimi t value-TW A (20 0 ppm ; 

# 3 7 8/7'9 7 2:3 3 P Mp 3 0

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. ; Z~b~. — 

## ~+A \ .Documenthttp://searchl.healthg»te.com/cgi-*in/'4-formdt.e'j i 

### ACGI H 1992 ) wer e calculate d t o b e 5. 1 mg/ L an d 3. 8 mg/ L a s a biologica l exposur e inde x (BEI) , respectively . Althoug h th e BE I fo rurinar y MEKobtained from th e presentstudy wa s highertha n tha to f previou s report

s an d ACGEHT

s recommendation (2. 0 mg/L) , the BE I agreed wel l with a previou s study i n Japaa(ABSTRAC T TRUNCATE D A T 25 0 WORDS ) Languag e o f

Publicatio n Englis h Uniqu e Identifie r 9S3143S 2 

### Orde rful l tex tforthis document

MeS H Headin g (Major ) Butanones! * AE/AN ; Environmenta l Monitoringl* ; Occupationa l Exposure| * MeS H Headin g Adult ; Aged ; CreatininelUR ; Female ; Hippurates|UR ; Human ; Japan ; Male ; Middl e Age;'Reference Standards ; Solvents|AN/M E

Publicatio n Typ e JOURNA L ARTICL E ISS N .0090-434 1 Countr y o f

Publicatio n UNITE D STATE S CA S Registry/E C Numbe r 0 (Butanones) ; 0 (Hippurates) ; 0 (Solvents) ; 495-69- 2 (hippuric acid) ; 60-27- 5 (Creatinine) ; 78-93- 3 (methylethyl ketone )

Record 4 from database : MEDLIN E Orde rlul l tex tforthi s document' Titl e Effecto f

coexposur e t o methy

l ethy l keton e (MEK) o n n-hexane toxicokinetic s i n huma n volunteers . Autho r va n Engele n JG ; Rebel-d e Haa n W ; Opda

m JJ ; Mulde

rG J Addres s Divisio n o f

Huma n Toxicology , Universit

y o f Amsterdam , Academi c Medical Centre , The Netherlands . Sourc e Toxico l App l Pharmacol , 199 7 Jun , 144:2 , 385-9 5 Abstrac t I n ordert o study th e effects o f methy l ethy l keton e (MEK) o n th e toxicokinetic s o f n-hexan e and, i n particular , th e fonnatio n o f

2,5-hexanedion e from n-hexane in humans , volunteers wer e expose d t o



# 3$ 8/7/9 7 2:3 3 P MoS < 1-

9 -'97 TU E 1

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ocumen t http^/searchl.hettHh l jait.coBvc S i^in/q.t'onn*t.c5 i 

### n-hexan e (approx , 6 0 ppm , 2. 4 micro M i n th e inhale

dair ) wit h o r without simultaneou s inhalator

y coexposur e t o ME K fo r 15. 5 min

. The concentration-tim e cours e of

n-hexan e (i n exhaledalveola

r air ) an dit s neurotoxi c metabolite , 2,5-hexanedion e (in serum) , wer

e studied

. The concentration-tim e course s obtaine dafte

r exposur e t o n-hexan

e alone wer

e comparedwit

h thos e obtainedafte

r coexposur e t o 20 0 o r

30 0 pp mMEK in th e sam e voluntee r o n th e sam

e day

. N o effec

t o f ME K wa s observedo n th e concentration-tim e cours e of

exhale dn-hexane

. The concentration-tim e cours e o f the metabolite , i.ii-hexanedione , revealedadecreas e i n therat e of

formation o f

2,5-hexanedione (about three-fold) afte

r coexposur

e t o MEK
. Furthermore , the time t o reach th e pea k concentratio n waMncreasedfro

m18 * to~3^Tmmafte

r th e star t o f exposure . Thes e change s i

n th e concentration-tim

e cours e of 2,5-hexanedione cause db

y MEK ar e most likel y th e result

o f inhibitio n ofth e biotransformatio n o f

on e ofth e mtermediat

e step s i n th e conversion of

n-hexane t o 2,5-hexanedione

. Thes e result s indicat

e tha t th e interactio n of

n-hexan e an dME K lead s t o adecrease dconcentratio n ofth e neurotoxi c metabolit

e 2,5-hexanedion

e (afte r short-term , acut

e exposure)

. anguag e o f Publicatio n ' Englis h niqu e Identifie r •9733772 9 ' 

### Orde r ful l tex t fo r thi s documen

t

vleS H Headin g (Major ) Butanones|AD/*PD;Hexanes|AD/*PK/*T O VleS H Readin g Administration , Inhalation ; Adult ; Biotransformation|DE ; Bloo dChemica l Analysis ; Breat

h Tests ; Dru g Interactions' ; Female ; Human ; Male ; Maximu mPermissible Exposur

e Level ; Models , Biologica l

c-ublication Typ e JOURNA L ARTICL

E iSSN 0041-008 X
. Country o f Publicatio n UNITE D STATE S CA S Registry/E C Numbe r 0 (Butanones) ; 0 (Hexanes) ; 110-54- 3 (n-hexane) ; 78-93- 3 (methylethy l ketone )

Recor d5 fromdatabase : MEDLIN E Orde r ful l text fo r thi s documen

t Titl e 

### Influence o

f differen t dose s o f methy l ethy l ketone on 2,5-hexanedion

e concentration s i

n the sciatic nerve , serum , an

durin e o f rats
. 

# 3 9 8/7/9 7 2:3 3 P t08-'19-9 7 TI E 16:2 6 FA X 20 2 21 9 "12 5 OSHA-iiS F *~. " ~ £AL 

## t 

## ' ? Jocymen thn P ;/ ^ se «cKI.hcslth'jate.com/egi.bin/>torm*it.cg i 

### atho r Yasui T ; Zha

o W ; Misum

i J ; Aoki K ; Sbimaok

a A ; Kud o M ddres s Departmen

to f Public Healt

h an d Hygiene , Oit

a Medica l University , Japan

. )urc e Sangyo Eiseigak

u Zasshi , 199 5 Jan, 37:1 , 19-2 4 bstrac t Rat s were injected subcutaneousl y wit h 2,5-hexanedione (2,5-H D 2. 6 m mol/kg ) alone (H D group ) o rwith 2,5-H D an

d methy l ethy l keton e (MEK) (2. 6 i n mol/kg o f each agent, HD&ME

Kgroup ) o r wit h 2,5-H D 2. 6 m mol/k g an d 5 time s tha

tdos e (13. 0 m mol/kg ) o f ME K(HD&5ME Kgroup) . Th e concentration o f

2,5-H D i n seru

m an d inth e sciatic nerv

e wa s determine

d 0.5 , I , 2 , 4 , 8 , an

d 1 6 h afte radministration. Urinar

y 2,5-H D concentration wa s detennined from the beginning o f " administratio

n u p to * 1 6 h afterward. 1 ) Th e concentration o f 2.5-HP . i n the.serunL.the. sciati c nerve , an d th e urin e wa s increased significantl y ( p < 0.05 ) inth e co-administered groups ; the highe rth e MEjtjfose s were^thcjieate rwa s th e increase . 2 ) Th e clearanc e o f 2,5-H D from bot

h th e seru m an d the sciati c nerv

e wa s delayed in th e cn-administere d groups . Th e highes tconcentration in seru m an d the sciati c nerv

e appeare d a tI an d 2 h respectively . Afte

radministration, th e biological halflif e (tl/2 ) o f 2,5-H D from 1 t o 8 h i n seru m wa s 6.5 , 5. 8 an

d 12. 0 h forth e HD , HD&MEK , an d HD& 5 ME

K group s respectively . Fro

m 8 t o 1 6 h, th e tl/ 2 i n seru m wa s 1.2 , 3. 2 an

d 16. 6 h fo rth e HD , HD&MEK

, an d HD&SMEKgroups , respectively . I n nerve tissue , th e prolongatio n o f clearanc e in th e co-administered group s wa s greatertha n tha ti n serum, th e tl/ 2 from 2 t o 8 hbein g 5.2 , 9. 6 an d 19. 9 h forth e HD , HD&MEK, an d HD&5MEKgroups , respectively.(ABSTRAC T TRUNCATED A T 25 0 WORDS ) Languag e o f

Publicatio n Englis h Uniqu e Identifie r 9529999 4 

### Orde rful l tex tforthis documen

t

vleS H Headin g (Major ) Butanones|*AD ; Glycols|*AN/BL/UR ; Sciati c Nerve|*C H VleS H Headin g Animal ; Half-Life ; Male ; Rats ; Rats , Wistar ; Support , Non-U.S . Gov' t

Publicatio n Typ e JOURNAL ARTICLE ISS N 1341-072 5 Country o f

Publicatio n JAPA N CA S Registry/E C Numbe r 0 (Butanones) ; 0 (Glycols) ; 2935-44- 6 (2,5-hexanediol) ; 78-93- 3 (methylethy l ketone ) 

# 4° 8/7/9 7 23 3 PM: —. P.4 2 03.19-'9' 7 TL' E 16:2 6 FM 20 2 21 9 712 5 OSHA-HS P

_^01 7

, - Documen t^• //M,ucl * , - 1,ca Jthgate.com/c*ji-bi*Vq-fonnatet5 i 

### English Unique Identifier 3632338 9 

### Orde r ful l text fo r thi s documen

t

MeS H Heading (Major) Gases|*PD ; Ion Transport|*PH ; Tigh t Junctions|*PH ; Trachea|*ME MeSH Heading Alcohol , Ethyl|ME ; Animal ; Calcium|ME ; Diffusion ; Dogs ; Female ; Magnesium|ME ; Male ; Support , U.S

. Gov't , P.H.S

.
Publicatio n Typ e JOURNA L ARTICL

E ISSN 8750-7587 Countr y o f Publicatio n UNITE D STATE S CA S Registry/E C Numbe r 0 (Gases) ; 64-17- 5 (Alcohol , Ethyl) ; 7439-95- 4 (Magnesium) ; 7440-70- 2 (Calcium )

Recor d1 0 fromdatabase

. MEDLIN E Orde r ful l text fo r thi s documen

t Titl e Reversible myoclonus , tremor , an dataxi ai n apatien t exposedt o methy

l ethyl ketone

. Author Orti-Parej aM ; Jimenez-Jimenez FJ ; Mique l J ; Monter

o E ; Cabrera-Valdivi aF ; Benit o A ; Garcia-Albe aE ' Address Departmen

t o f Neurology , Hospita

l Universitari o Princip e de Asturias , Madrid , Spain

. Source

. Neurology , 199 6 Jan , 46:1 , 27 2 Abstract Abstrac t unavailable online

. Language o

f Publicatio n English Uniqu e Identifie r 9614321 2 

### Orde r ful l text fo r thi s documen

t 

# 4i (t/7/9 7 2:3 3 P MP.4 3



## C 0 V E R

SHEE T To : Dr

. Myr a Karstad t Fax# : 202/401-814 2 Subject : NIOSH comment s o n ME Kassessmen

t Date rAugus

t21,199 7 Pages : 6 , includin

g this cove rshee t COMMENTS:-*-". - ' : 

### /•-T.b^':"';' Fro m Davi d Votaw. 

# FA

X

i



# 4^ Fro m th o deal t of.. . Dian * Mannin g Docke t Offic e Manage r

NIOS H 467 S Columbi a Partwa y Cincinnati . O H 4622 6 913/533-845 0 Fax:513/533-a2B%

_P.4 4

«"*•. * DEPARTMEN T O F HEALT H AN D HUMA N SERVICE S - Publi c Healt h Servic e
Nationa l Institut e fo r Occupationa l Safet y an d Healt h Rober t A . Taf t Laboratorle a 467 6 Columbi a Parkwa y Cincinnat i O H 45226- 1 BB S 

### August 21,199 7
Myr a Karstadt , Ph.D . U.S . Environmenta l Protectio n ' Agenc y OPPT/EAD/TRI B Mailsto p 740 8 40 1 M Street , S.W . Washington , DC . 2046 0 Dea r Dr . Karstad t Th e Nationa l Institute fo r Occupationa l Safety an d Healt h (NIOSH ) ha s reviewe d th e U.S . Environmenta l Protectio n Agency' s (EPA ) Hazar d an d Ris k Assessmen t o

f Methy l Ethy l Keton e (MEK) , focusin g o n th e neurotoxi c effect s o f MEK . Wit h regar d t o you r principa l questio n a s t o whethe r NIOS H ha s identifie d an y dat a that ascrib e neurotoxi c effect s t o ME Kalon e rathe r tha n t o ME Ka s par t o f a mixture , w e hav e no t NIOS H is , however , providin g th e two additiona l comments note d belo wfro m ou r revie

wo f EPA' s ME Kdocuments . A s EP A ha s note d i n thi s assessment , researc h ha s documente d that ME K alon e doe s no t caus e periphera l neuropathy . However , i n combinatio n wit h othe r chemical s tha t produc e th e reactive metabolit e 2,5-hexanedion e (2,5-HD) , ME Kpotentiate s th e neuropathi c effect s o

f thi s metabolite , increasin g th e productio n o f 2,5-HD . Tw o solvents , methy l norma l buty l keton e (MnBK ) an d n-hexane , have demonstrate d thi s effec t wit h ME K[Abdel-Rahma n e t al . 1976 ; Cour i e t al . 1977 ; Spence r e t al . 1980] . N o detaile d mentio n o f thi s potentiatio n appear s i n th e documents reviewe d othe r tha n a brief statemen t o n pag e 4 o f th e Hazar d Assessmen t o f MEK , "Prio r concern s wer e base d o n enhancemen t b y ME Ko f neurotoxicit

y see n wit h othe r solvents. " I f neithe r MnB Ko r n-hexan e ar e presen t i n th e atmospher e wit h MEK , the n th e periphera l neurotoxi c potentia l o

f ME Ki s minimal . Documentatio n i n thi s assessmen t i s wea k regardin g th e acut e toxi c effect s o f exposure s t o ME Ki n humans , especiall y th e dose-respons e ranges fo r occurrence o f effects . EP A ha s describe d anima l studies that use d dos e response range s that coul d no t b e tolerate d b

y humans . Th e Hazar d Assessmen t state s o n pag e 2 , "I n humans , Inhalatio n o

f hig h dose s produces irritatio n ofth e eye s an d uppe r an d lowe r respirator y system , effect s characteristi c o f solven t exposure. " Researc h conducted b y NIOS H [Dic k e t al . 1992 ] indicate s that sensor y an d irritan t effect s were presen t i n huma nP.4 5

Pag e 2 - Myr a Karstad t volunteer s a t 20 0 ppm , no t a hig h dos e whe n compare d t o th e dos e range s cite d i n th e anima l studie s (>300 0 ppm) . Additionally , th e primar y basi s fo r th e Occupationa l Safet y an d Healt h Administratio n (OSHA ) Permissibl e Exposur e Limi t (PEL ) o f 20 0 pp m fo r ME KI s th e preventio n of sensor y Irritatio n [5 4 Federa l Registe r 2452 , Januar y 19 , 1989] . Th e discussio n issu e regardin g sensor y o r Irritan t effects , i

f deeme d a n importan t nervou s syste m effect b y EPA , shoul d b e th e potentia l fo r th e releas e o f ME K int o th e atmosphere a t concentration s that coul d produc e sensor y an d irritan t effect s i n humans . Judgin g b

y th e dat a presente d i n Tabl e 4 , pag e 8 ofth e Hazar d Assessmen t th e stac k

releas e exposure condition s woul d no t produc e suc h exposures . Onl y fugitiv e release s unde r th e maximu m condition s migh t have th e potentia l t o caus e som e debilitatin g Bensor

y an d irritan t effect s i n humans . Than k yo u fo r th e opportunit

y t o revie

wEPA' s Hazar d an d Ris k Assessmen t o

f MEK . I f yo u hav e an y question s regardin g thes e comments , pleas e cal l m e a t (513 ) 533-8327 . Sincerel y yours , 

# IbuVi Davi d M . vota w Toxicologis

t Educatio n an d Informatio n Divisio n Enclosure



# 44P.4 6



### REFERENCES 1 . Abdel-Rahma n MS , Hetlan d LB , Cour i D [1976] . Toxicit y an d metabolis m o

f methy l n-buty l ketone . A m In d Hyg Asso c J 37:95-102 . 2 . Cour i D , Hetlan d LB , Abdel-Rahma n MS , Weis s H [1077] . Th e influence o f Inhale d keton e solven t vapors o n hepati c microsoma l biotransformatio n activities . Toxico l App l Pharmaco l 41:285-289 . 3 . Dic k RB , Krie g EF , Setze r J , Taylo r B [1992] . Neurobehaviora l effect s fro m acut e exposure s t o methy l Isobuty l keton e an d methy l ethy l ketone . Fun d App l Toxico l 18:453-473 . 4 . Spence r P , Schaumber g HH , Sabr i M , Verones i B [1980] . Th e enlargin g viewof hexacarbo n neurotoxicity . CR C Cri t Rev Toxico l 7:279-356 . 5 . 5 4 Fed . Reg . 245 3 [1989] . Occupationa l Safety an d Healt h Administration : ai r contaminants ; fina l rule .



# 45245 2 Federa l Registe r/ Vol . 54 , No . 1 2 /

Thursday , Januar y 19 , 19& 9 / Rule s an d Regulation s

n • ' stud y group . Accordin g t o Dr. Smith , whan lh a dat a ar e reanalyze d using arithmeti c meant , the observe d healt h effects woul d b e associate d wit h 9xpoa\irea to muc

h higherdustlevel s tha n thos e presente d i

n th e repor t{Ex . 3-744 . Attachment3 . p . 13) . Becaus e th e ra

w exposure dat

a fro m the stud y war

e no tavailabl e t

o Or . Smith , h e base d hi s reanalysi s o f lha exposur e dat

a o n a n assumptio n tha

tall individual s I

n a job categor

y ha d exposure s equa

l t o the mea n exposure leve l fo rthe lo b categor

y a s a whole . Fo

r example , accordin g t

o Dr . Smith , I f "fou r laborers I n the fusing building had averag e exposure s o

f 49.2 mg/m ' * * " [i twa s assumed ] tha

tall fou rha d the som a exposure " (Ex . 3-744 . Attachment 3 . p . 8) . OSH

A believe s tha

tOr . Smith' s approach provide s les s informatio n aboutthe actua

l exposure s o

f the members o

f th a cohor ttha n doea Dr . Garabraiit' s becaus e Dr

. Garabran

ttoo k tw o factor s (representativ e dat a b y Jo b category a

a wel l a s subjectiv e self

reporting o

f exposur e level s b y employees ) into accoun twhil e Dr . Smit h onl y considere d a singl e facto r (jo b category) . Tha

tle . Dr . Smit h assume s tha

tal l workers I

n a job

. category hav e th e sam e exposure , whil e Dr . Garabranf

s approac h recognize s the impacto f such factors a s Individua l difference s i n wor

k practices , difference s i n control effectivenes s at . differentworkstations , etc , o n th e exposure s o f

individual s i

n th e sam e job category . OSH

A i s therefor

e unparsuade d b y Dr

. Smith' s reanalysis : th e Agenc y find s Dr

. Garabrant' a analysi s convincin g and believe s tha tit mor e accuratel y reflects the tru e exposure s o

f member s o f thi s cohort. Largel y becaus e o

f question s raise d concernin g th e dose-respons e relationshi p fortetraborates . U.S . Bora x ha s bee n conductin g a large epidemiologi c Stud

y al it s facility . Thi s study , deecribe d a

tthe informa

l hearing b y Mr . Mlddleto n (Tr

. pp . 9-11 4 t

o 9-115 , Ex . 120) , wil l spair a three - t o foiir-yea r perio d an d wil l obtai n abou t40 0 measurements o

f workplac e tetraborat

e dust . Th e tes tprotocol s hav e bee n reviewe d by representative s o f OSHA . th e U.S . Burea

u o f Mines . NIOSH. th

e ACGI H TL V Committee , and the Min e Safet y and Healt

h Administration . Th

e Hna l repor tI s expecte d t

o b a release d i

n mld-1988 . A tthe hearing . Mr . Middleton state d the positio n o

f U.S . Borax : Baia d o n th e fea ttha i th e prsaen tdat a doe s oo i suppor tlh a establiih'mcnt

) o f PEL' S fo rthes e compound

a sn d tha tU.S . Bora x I* . presentl y collectin g dal a tha i coul d b a meaningfu l i n establishin

g PEL'S , w e reques t tha tOSH A dela y actio n n n thes e compound

s unti l -has* dat a ar e availabl e an d ca n b a analyzed b

y OSH A an d MSH A (Tr . pp . & - 113). ' OSH A commend s U.S . Bora

x fo r. undertaking thi s effor

tt o stud y the relationshi p betwee n exposur e t o tetraborate s and respirator y effects . OSH A believe s tha

tsuc h del s are essentia l t

o Infor m employee s properl

y ebouthazard s presenti

n their workplace s and to guid e employer s I n th e developmen to

f effectiv e occupational healt

h programs . However . OSH A doea no tagree tha

tthe evidenc e currentl y availabl e I

s Inadequat

e t o oerv e a s a basi s fo

restablishin g a PE

L fo rthe tetraborate s a

tthe presen ttime . Th e study b y Carabren

ta tal . (1985) doe s demonstrat

e e dose-respons e relationshi p fo rrespirator y symptom s an d exposur e t

o sodiu m borates . OSH

A finds tha temployee s shoul d b e protecte d fro

m experiencin g th

a symptom s tha

thav e bee n reported . Thes e symptoms , whic

h hav a bee n reported l n the mor

e recen tGarabran

te t al . (1065 ) and NIOSH (1978© ; 1960b ) studies , a s wel l a

a i n th e olde rliterature . Include nosebleeds , upperrespirator y trac tirritation , dermatitis , an d dyapnat . OSH A believe s the tthia evidenc e clearl y Indicate s tha

tth a tetraborate ! - ac ta a primar y respirator

y an d aki n irritants , and tha

ta 10-mg/m'PE L I

s clearl y warranted . I

n ligh to f the research currently bein g conducte d b y U.S . Borax , however . OSH A note s tha

t th e Agency wil l conside rnaw evidenc e a a i tbecome s availabl e and wil l revis e it s limits i f suc h actio n appears t o b e appropriate . OSH A agree s wit

h U.S . Bora

x tha tat thi s time , ther

e ar e insufficientdat

a upo n which l o establis h differen tPEL s fo rthe differen

thydrated form

s o f tetraborate . OSH

A believe s tha

tcurran t samplin g and analytical procedure s canno tdistinguis h among the variou s hydrated form* n

f tetraborat

e (Ex. 3-744 , Attachment3 , pp . 4-5 ) and therefor e ths tseparate standard s o f 5 mg/m 1 end 1 mg/m ' ar

e notfeasibl e a l thi s time . OSH A conclude s tha

ta n 8-hou rTW A o f 1 0 mg/m 5 i s appropriat

e fo rthe tetraborates , an

d the fina l rul e establishe s thi s limit. OSH A find s that

, in the absenc e o

f an y limito h exposure , employee s ar

e a tsignificantris k o

f experiencin g antl e aye , skin , an d respirator y irritation effects , and thete 10-mg/m * PE

L wil l substantiall y reduce thes e risks . The Agenc

y consider s the eye . skin , and uppe

rrespirator

y trac t Irritatio n cause d by exposur e t

o all form s o f sodiu m tetraborate s t

o b e materia l impairment

s o f health . BROMIN E CAS: 772B-9S-0 : Choniica

l Formula : Bi* » H.S . No . 10* 2 OSHA' s previou s exposur e limi tfo r bromine wa s 0, 1 pp

m a s a n 8-hou rTWA . OSH A propose d t

o supplementthi s TW A limitwit

h a STE L o f 0. 3 ppm . the sam e limitrecommended by the ACGIH . and NIOSH (Ex . 8-47 . Tabl e Nl ) concurred wit

h thi s proposal . I

n th a fina l rule , th e Agency I

s establishin g a 0.1 - pp m TW A limitand a 0.3-pp

m STE L fo r bromine . Bromin

e i s a.derk, reddish brown , noncombustible , diatomi c liquid tha tha s irritating vapors . Earl y studie s o f

bromin e exposur e indicate d tha

tworkers expose d to 0.7

5 pp m fo r8 hours exhibite d n o symptom s (Flur y an d Zemi k 193ia , a s cite d in ACC1 H 1988/Ex . 1-3 . p . 65) . Late r studie s reported physiological response s t o difforan tconcentration s o

f bromine an d use d thes e findings t

o mak e th e followin g recommendations : The maximu m allowabl e concentratio n fo r prolonge d exposure s shoul d b e 0. 1 to 0.1 5 ppm . and th e maximu m allowabl e concentratio n fo rshort-ter m exposure s (i.e . 3 0 minute s t o on e hour ) shoul d b t4 pp m (Henderso n an

d Haggar d 1843b , a a cila d t n ACGI H 1968/Ex . 1-3 , p . 85) . Thes e investigator s foun

d level s o f 4 0 t o 8 0 pp m dangerou s forshort-ter m exposures , and a leve l o

f 1000 pp m prove d rapidly fata

l eve n durin

g shor t exposures . Thes e author

s reported the

t the effects o f

exposur e t o bromine includ e respirator

y irritation and lun

g edema . Elkln

a (1859a/Ex . 1106

) reported tha tworksr s expose d to 1 pp m in a plan thandlin g liqui d bromine foun d thi s leve l excessivel y irritating . OSH A received n o comments o n it s propose d STE

L fo rbromine , othe rtha

n the NIOS H concurrence statemen tThe Agency find s tha

tbot h th e TW A and th e short-ter m limit s ar

e necessar y to substantiall y reduce the risk o f respirator y irritation and lung damage tha tcoul d occu rfollowin g short-ter m exposure s to concentration s o f bromin e tha twoul d b e permitted b y the b hou r TW A limitalone . OSH

A consider s the effects relate d to bromin

e exposure m a teria l impairment

s o f health . Therefore , OSH

A i s revisin g the limitfo

r bromine to 0. 1 pp

m a a a n 8-hou rTW A an d 0.3 pp m a s a 15-minut

e STEL 2-DUTANON

E (METHY

L ETHY L KETONE

) CAS : 79-93-3 ; Chamira

l formula : CH.COCH1CH

, —•« - U. S No . 104 8 OSHA' s forme

rexposur e limitfo

r2- b u tanon e wa s 20

0 pp m TWA . OSH

A propose d t o supplementthi s limi twit h a STE L o f 30 0 ppm . base d o n th

a ACGI H ' (1988/Ex . 1-3 ) recommendation . NIOS H [Ex. 8-»7 . Tabl e Nl ) concurre d wtih thi a proposal . Th

e fina l rul e establishe s a 200-pp m TW A limi tan d a SOO-pp

m 5TEI * 

# 4 6 A•i 

### Federa l Registe r/ Vol , 54 , No
. 1 2 /

Thursday , Januar y 19

. 198 9 / Rule s an dRegulation s 245 3 

# 1

,. : 

### 2-butanone

. 2-Butanon e i t

a jolorless . flammabl e liqui d with a n objectionabl e odor . 2-8utanon e i s a n ocula rand uppe r respirator y trac tirritant. One stud y kelson . Enge . Ros s etal . 1943/E x 1-68 ) Sporte d tha

texposure s l o 20

0 pp m for3 t o 8 minute s cause d mil d ey e Irritatio n I D tom e subject s an d tha

tother s experience d sligh tnos e an d throa t Irritatio n a tconcentration s o

f 10 0 ppm . Exposur e to 35 0 pp

m cause d ey e and nass l Irritatio

n l n a majorit

y o f subject s tested . Studie s condude d i n th e 1940s note d low-grad e intoxicatio n resultin g fro m exposur e t

o 30 0 t o 60 0 pp m (Smit h an d Mayers 1044 . a

a cite d l n ACGI

H 1986/Ex.i-3 . p . 395) , Laterstudie s hav e shown tha

tapproximatel y 6 0 percen tof . traine d panelist s experienced.ey e an d nos e Irritation a

t20 0 pp m (e s reporte d i n ACGI H 1986/Ex . 1-3 . p . 305) : l n the pceambl e discussio n o n 2 - butanone . OSHA note d tha ta numbero l studiee indicat e tha i th e propose d limits ma y no tb e sufficien tl o full y protec t worker s from th e irritanteffect s p f thi s substanc e (ACGIH 1986/Ex . 1-3 ; kelson , Enge . Ros s ata

L 1943/Ex . 1-68) . th a ACGI H als o cite d a manufacturer' s "*, " publicatio n thatstate d thd r200 PPt| l wa s ihe highes tconcentratio n judged b y "* ' huma n subject s t o b a "satlsfdctpry " fo r eigh thours . I n addition , anothe rstud y cited b y th e ACGI

H (1986/EX . 1-3 } -;Ai reported thatexpoaure ' t o ZO O ppm Wa

* v . associate d wit h a 50-percentresponse7 > rate forey e an d nasa l irriutio n (the* . 

### 300-pp m15-minul e STE

Lfo r 2-hutanon c t o protee l employee s fro

m the significantris

k o f sensor y irritation : OSH A consider s the irritatio n cause d by 2-butenon e t

o b e a materia

l impairmen

t o f healt h d rfunctiona

l capacity . n-BUTYLACETAT

B CA S No.'123-88-4 : Chemlee

l Formula : CHiCOO(CU,).CH

. H.S.No.101 7 The previou s OSH

A exposur e limi tfor n-buty l acetat e waa 15 0 ppm , measure d a s a n 8-hou rTWA . OSH

A propose d th e adoptio n o

f a 15-minut

e STE L o f 200 pp m t o supplementthe TW A limit , NIOS H (Ex . &-47

. Tabl e Nl ) concurre d with thi s proposal . Th e fina l rule establishe s limits o f

15 0 pp m a s a n 8 - hou rTW A and 200 pp

m a s a 15-minut

e STE L forthi s substance ; thes e are tha sam e limits a s thos e recommended b y th e ACGI H (1986/Ex . 1-3) . n-Buty

l acetat e i s a colorlas a liqui d with a fruity odor . ' n-Buty l acetat e la a n Irritan

tt o th e ayes . akin , an d respirator y system , i n a stud y involvin g cat s expose d fo rsi x hours to OlOOppm

, sligh tnarcoti c effect s wer e note d (Fair

y and Wirt

h 1883 . a a cite d in : ACGI

H 1568/Ex . 1-9, p . 72) . Whe n expose d t o 420 0 pp m n-butyl aceut e forsi x day s a tsi x hour s pe rday , dat a experience d alightirritatio n p f th e respirator y passage : a

t3100 ppm , // , change s ftp bloo d cal l morphology yiew e •. . recorded . A texposure s o f 160 0 ppicu.«.. . ;.! : thejke ;cats. t^xhi^ d sligh tIrritation o f degree o f Irritation wa a Wo

tBpet^fled

k > • * e ^ e » f n d tB^tueAukn^mm.^ OSHA-ipetlflcnUyteqaestad W* ii-jtfr*!* * *«*• » W^ae-tlMi i n AtJO^UfliaB/**. ; commen toa^\to.U9*MpWWfr&&*'* P^ZkAi/cdmwntreMona ^ e y fo r2-butsttioft

e wer e *ufflctent)y v1 ' 'J i ^ P* . W.00

0 ppm;&-btity

l acetat e prove d f

a la)** » protective . Th e Ne w Jerse y bepiHnjSntV-^ ! t o rat a afte teigh thours ; fourhour s o f c A o f PnbU c Heah h '(Exa-,144,144AfiiJ^t^r"'V^ ,nK'»ur»atrfh e eam e leve l produce d n o - OSH A to se tIt

s limit s fo r2-but*hoi « v v• • ; datfli * (Smyt

h 18M/Ex . 1-759) . A paper., . base d o n EPA' s IRJ

S data ; Th e us e of** ' ' b y Sayew , Schrenk , an d Patty (1868/Ex . '• suc h a n approach I

s discusse d ii) ' ' " 1-802 ) reporte d tha i guine a pig s Sectio n V1;

A o f th e preamble . Th e AFL-i ' demonstrate d ey e lrritetlo n effect s a t " --•-* • 3300 ppm , becam e unconsciou s afte r hin thour s o f exposur e to 700 0 ppm . an d die d afterfou

rhours o f exposur e to 14,000 ppm. • Huma n volunteer s complaine d tha t throa tIrritation, whic h began a ta n exposur e leve l o

f 20 0 pp m n-butyl ' acetate , worsene d and becam e quit e sever e a l 300 pp

m (Nelson . Enge , Ros s e l al . 1943/Ex . 1-66) . NIOSH wa s th e onl y commente rt

o the recor

d ln respons e l o OSHA' S propose d STE

L fo rn-buty l acetate . OSH A finds tha

tworkers ar

e a l significantris

k o f experiencin g sever e eye , skin , an d respiratory irritation . I n additio n t o narcoti c offects , tha

tare associate d wit

h short-ter

m exposure s t o thi s aubstenc e al level s abov e the 8-hou r limit. Th e Agency consider s the Irritant . and narcoti c effoct

s resultin g fro

m CI O (Ex. 194) supporte d the establishmen to

f a STE L forbutanone . * OSH A ha s determine d tha

tIt s : previous 8-hourTW A limi tof20 0 pp m was notsufficien tt o protectworkers- - fro m experiencin g th e Significant . . irritatio n and narcoti c effect s tha tar e associate d wit

h short-ter

m exposure s to ' hig h concentration s o

f 2-butanone . After reviewin g the availabl e report s describing huma

n sensor y response* * to short-ter m exposure s t o 2-butanone . th e Agenc y conclude s tha

ta 300-pp m STEI. • l a Als o necessar y to reduc e the

. significan

tris k o f sensor y irritation : exposur e t o 35 0 pp

m fo rthree to fiv e • • minute s waa reporte d t o caus e eye , - nose , en d throa

tIrritation I

n a mejoril y o f subjects (Nelson . Engo , Ros s e tal . 1843/Bx . 1-66) . Accordingly . OSH A i s establishin g o 2uO-pp

m TW A limitand a 

### exposur e to n-buty l acetat e t o b e maleria l impairment

s o f healt h and functiona l capacity . OSH

A conclude s tha ta STE L I s necessar y t

o reduc e thi s risk , and the Agency i s therefor e revisin g It

s limi tfo rn-buty l acetat e to 150 pp m a s a n 8-hou rTW A lan d 200 pp m a s a 15-minut

e STE L n-BUTY L LACTAT

E CAS : 136-22-? ; Chemica

l Formula : C,H H Q i H.S. No . 105 3 OSH A previousl y ha d n o limi tforftbutyl lactat e bu

tpropose d a 5-pp

m 8 - hou rTW A limit, base d o n the ACGI H recommendation . NIOSH * (Ex. 8-47 , Tabl e Nl ) concurred wit

h tli e propose d 5-pp m TW A limit, an d thi

a limi tI s establishe d i n the final rule . Buty l lactat e Is a colorles s liqui d este ro f lacti c acid . l n humans , prolonge d exposure s t o n butyl lactat e a

tapproximatel y 7 ppm , wit h brie f pea k excursion s t o l l ppm , cause d headache . Irritallon o f th e pharyngea

l and laryngeal mucosa , an d coughin g l n al l workers , en d occasiona l nausea , vprnitlng. an d sleeplness h in som e (Zutdem

e and Pel 1968 . a s cite d i n ACGI H 1986/E x 1-3 , p . 82) . Headache , coughing , an d irritatio n o f th a pharynx wer e someUmes relate d Von-buty l lactat e concentrationsip f 4 ppm : "however, n o advers e effects * wer e , observe d ata concentj-ftlonif^. 4 pjr*m. . Studiesemployin g impWf d san^pn g •, . an d analyti c method * J«v e subeequenll y cdnclude d that. ilffioiinJheJJdoY.A I •&*.',' ; bflty l lactat e I s dlei*«niltiJ#«l th e y-ppm, 7 leve l thi s concentraKohidoae oot.7.' • •'••„ .,• ' produc e objectionabl e ot

Injurious- - «•

. effect s (Tuinpriqn/a a cite d i n ACGI H .* • *1886/Ex.vi-3,p.82) P ;*. * . .. . I n the preamble'discussio n o f th e propose d limitforthi s substance , OSHA . riote d tha tsom e studie s reported acut e advers e affect

s associate d wit

h exposur e levei s belo w the propose d 5 - pp m TW A limit. Thi s wa s als o pointe d outb y Or . Grac e Zlem . a n independen t physicia n (Ex. 46) . Base d o n the stud y b y Turne r(1972 . a a cite d i n ACGI

H 1986/Ex , 1-3 , p . 82) . which ' employed . Improve d sampling and analytica l technique s a s compared to earlie r studies , OSH

A judges tha

tpromulgation o f e 5-pp m 8-liou rTW A limitWil

l effectivel y protec

tworkers fro

m the significantrisk s o

f irritation , headache , and nause a cause d b y exposur e t o higherconentration s o

f n-butyl lactate . OSH A consider s thes e advers e effect s . t o representmateria

l impairment

s o f health . Therefore . OSH

A I s establishin g a 5-pp m 8-hou rTW A limitfo rn-buty l lactate . -*-| ,



# bi<•'.. / cn

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