8/11/2019 EHC 62 - 1,2 Dichloroethane (First Edition) http://slidepdf.com/reader/full/ehc-62-12-dichloroethane-first-edition 1/77 INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY ENVIRONMENTAL HEALTH CRITERIA 62 1,2-DICHLOROETHANE This report contains the collective views o an international !ro"p o e#perts an$ $oes not necessaril% represent the $ecisions or the state$ polic% o the &nite$ Nations Environ'ent Pro!ra''e( the International La)o"r Or!anisation( or the *orl$ Health Or!ani+ation, P")lishe$ "n$er the -oint sponsorship o the &nite$ Nations Environ'ent Pro!ra''e( the International La)o"r Or!anisation( an$ the *orl$ Health Or!ani+ation *orl$ Health Or!ni+ation Geneva( ./01 The International Pro!ra''e on Che'ical Saet% 2IPCS3 is a -oint vent"re o the &nite$ Nations Environ'ent Pro!ra''e( the International La)o"r Or!anisation( an$ the *orl$ Health Or!ani+ation, The 'ain o)-ective o the IPCS is to carr% o"t an$ $isse'inate eval"ations o the eects o che'icals on h"'an health an$ the 4"alit% o the environ'ent, S"pportin! activities incl"$e the $evelop'ent o epi$e'iolo!ical( e#peri'ental la)orator%( an$ ris56assess'ent 'etho$s that co"l$ pro$"ce internationall% co'para)le res"lts( an$ the $evelop'ent o 'anpower in the iel$ o to#icolo!%, Other activities carrie$ o"t )% the IPCS incl"$e the $evelop'ent o 5now6how or copin! with che'ical acci$ents( coor$ination o la)orator% testin! an$ epi$e'iolo!ical st"$ies( an$ pro'otion o research on the 'echanis's o the )iolo!ical action o che'icals, IS7N /8 9 .:98;8 9 The *orl$ Health Or!ani+ation welco'es re4"ests or per'ission
This report contains the collective views o an international !ro"po e#perts an$ $oes not necessaril% represent the $ecisions or thestate$ polic% o the &nite$ Nations Environ'ent Pro!ra''e( theInternational La)o"r Or!anisation( or the *orl$ Health Or!ani+ation,
P")lishe$ "n$er the -oint sponsorship o the &nite$ Nations Environ'ent Pro!ra''e( the International La)o"r Or!anisation( an$ the *orl$ Health Or!ani+ation
*orl$ Health Or!ni+ation Geneva( ./01
The International Pro!ra''e on Che'ical Saet% 2IPCS3 is a -oint vent"re o the &nite$ Nations Environ'ent Pro!ra''e( the International La)o"r Or!anisation( an$ the *orl$ Health Or!ani+ation, The 'ain o)-ective o the IPCS is to carr% o"t an$ $isse'inate eval"ations o the eects o che'icals on h"'an health an$ the 4"alit% o the environ'ent, S"pportin! activities incl"$e the $evelop'ent o epi$e'iolo!ical( e#peri'ental la)orator%( an$ ris56assess'ent 'etho$s that co"l$ pro$"ce internationall% co'para)le res"lts( an$ the $evelop'ent o 'anpower in the iel$ o
to#icolo!%, Other activities carrie$ o"t )% the IPCS incl"$e the $evelop'ent o 5now6how or copin! with che'ical acci$ents( coor$ination o la)orator% testin! an$ epi$e'iolo!ical st"$ies( an$ pro'otion o research on the 'echanis's o the )iolo!ical action o che'icals,
IS7N /8 9 .:98;8 9
The *orl$ Health Or!ani+ation welco'es re4"ests or per'ission
to repro$"ce or translate its p")lications( in part or in "ll, Applications an$ en4"iries sho"l$ )e a$$resse$ to the Oice o P")lications( *orl$ Health Or!ani+ation( Geneva( Swit+erlan$( which will )e !la$ to provi$e the latest inor'ation on an% chan!es 'a$e to the te#t( plans or new e$itions( an$ reprints an$ translations alrea$% availa)le,
2c3 *orl$ Health Or!ani+ation ./01
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The 'ention o speciic co'panies or o certain 'an"act"rers< pro$"cts $oes not i'pl% that the% are en$orse$ or reco''en$e$ )% the *orl$ Health Or!ani+ation in preerence to others o a si'ilar nat"re that are not 'entione$, Errors an$ o'issions e#cepte$( the na'es o proprietar% pro$"cts are $istin!"ishe$ )% initial capital letters,
CONTENTS
EN=IRONMENTAL HEALTH CRITERIA FOR .(86>ICHLOROETHANE
., S&MMARY AN> CONCL&SIONS
8, I>ENTITY( PHYSICAL AN> CHEMICAL PROPERTIES( ANALYTICAL METHO>S
0,.,?, Ac"te eects on e%es an$ s5in 0,8, Occ"pational e#pos"re
/, E=AL&ATION OF H&MAN HEALTH RISS AN> EFFECTS ON THE EN=IRONMENT
/,., Eval"ation o h"'an health ris5s /,8, Eval"ation o eects on the environ'ent
/,8,., Air /,8,8, *ater /,8,?, Soil
., RECOMMEN>ATIONS FOR F&RTHER ST&>IES
.., PRE=IO&S E=AL&ATIONS 7Y INTERNATIONAL 7O>IES
REFERENCES
*HO TAS GRO&P ON .(86>ICHLOROETHANE
Me')ers
>r 7, Gil)ert( CO>ETEC( &niversit% Cit%( Ca'pinas( 7ra+ilProessor P, Grasso( Ro)ens Instit"te( &niversit% o S"rre%( G"il$or$( S"rre%( &nite$ in!$o'Mr M, Green)er!( Environ'ental an$ Criteria Assess'ent Oice( &S Environ'ental Protection A!enc% M>6:8( Research Trian!le Par5( North Carolina( &SA 2Rapporte"r3Proessor M, I5e$a( >epart'ent o Environ'ental Health( Toho5" &niversit% School o Me$icine( Sen$ai( Dapan 2Chair'an3>r N,N, Litvinov( A,N, S%sin Instit"te o General an$ Co''"nit% H%!iene( &SSR Aca$e'% o Me$ical Science( Moscow( &SSR 2=ice6Chair'an3>r G,7, Mar"( Carcino!enesis >ivision( Cancer Research Insti6 t"te( Tata Me'orial Center( Parel( 7o')a%( In$iaProessor M, Noweir( Occ"pational Health Research Centre( Hi!h Instit"te o P")lic Health( &niversit% o Ale#an$ria( Ale#an$ria( E!%pt>r E, Ra"c5'an( Carcino!enesis an$ To#icolo!ica Eval"ation 7ranch( National Instit"te o Environ'ental Health Sciences( National To#icolo!% Pro!ra'( Research Trian!le Par5( North Carolina( &SAProessor >,D, Ree$( Environ'ental Health Sciences Center( Ore!on State &niversit%( Corvallis( Ore!on( &SA>r E, Ross5a'p( Instit"te or *ater( Soil an$ Air H%!iene o the Fe$eral Ministr% o Health( 7erlin 2*est3>r S, S"sten( >oc"'ent >evelop'ent 7ranch( >ivision o Stan$ar$s >evelop'ent an$ Technolo!% Transer( National Instit"te or
Swit+erlan$>r T, =er'eire( National Instit"te o P")lic Health an$ Environ'ental H%!iene( 7ilthoven( Netherlan$s 2Te'porar% A$viser3Mr D, *il)o"rn( &nit o Carcino!en I$entiication an$ Eval"ation( International A!enc% or Research on Cancer( L%ons( France
a IPCS Cons"ltant,
NOTE TO REA>ERS OF THE CRITERIA >OC&MENTS
Ever% eort has )een 'a$e to present inor'ation in thecriteria $oc"'ents as acc"ratel% as possi)le witho"t "n$"l%$ela%in! their p")lication, In the interest o all "sers o theenviron'ental health criteria $oc"'ents( rea$ers are 5in$l%re4"este$ to co''"nicate an% errors that 'a% have occ"rre$ to
the Mana!er o the International Pro!ra''e on Che'ical Saet%(*orl$ Health Or!ani+ation( Geneva( Swit+erlan$( in or$er thatthe% 'a% )e incl"$e$ in corri!en$a( which will appear ins")se4"ent vol"'es,
A $etaile$ $ata proile an$ a le!al ile can )e o)taine$ro' the International Re!ister o Potentiall% To#ic Che'icals(Palais $es Nations( .8.. Geneva .( Swit+erlan$ 2Telephone no,/009 6 /0:0:3,
EN=IRONMENTAL HEALTH CRITERIA FOR .(86>ICHLOROETHANE
A *HO Tas5 Gro"p on Environ'ental Health Criteria or.(86>ichloroethane 'et in Geneva ro' 8: to ? A"!"st( ./0;,Proessor F, =alic opene$ the 'eetin! on )ehal o the >irector6General, The Tas5 Gro"p reviewe$ an$ revise$ the $rat criteria$oc"'ent an$ 'a$e an eval"ation o the health ris5s o e#pos"reto .(86$ichloroethane,
The $rats o this $oc"'ent were prepare$ )% >R T, =ERMEIRE
o the National Instit"te o P")lic Health an$ Environ'entalH%!iene( 7ilthoven( the Netherlan$s,
The eorts o all who helpe$ in the preparation an$inali+ation o the $oc"'ent are !rate"ll% ac5nowle$!e$,
Partial inancial s"pport or the p")lication o thiscriteria $oc"'ent was 5in$l% provi$e$ )% the &nite$ States>epart'ent o Health an$ H"'an Services( thro"!h a contract ro'the National Instit"te o Environ'ental Health Sciences(Research Trian!le Par5( North Carolina( &SA 6 a *HOColla)oratin! Centre or Environ'ental Health Eects, The&nite$ in!$o' >epart'ent o Health an$ Social Sec"rit%
!enero"sl% s"pporte$ the costs o printin!,
., S&MMARY AN> CONCL&SIONS
.(86>ichloroethane 2>CE3 is a colo"rless( la''a)le( an$volatile li4"i$ that $eco'poses slowl% in the presence o air('oist"re( an$ li!ht its vapo"r $eco'poses in la'e an$ on hots"races %iel$in! h%$ro!en chlori$e( phos!ene( an$ otherchlorine6containin! co'po"n$s,
Sensitive anal%tical 'etho$s have )een $evelope$ or the$eter'ination o .(86$ichloroethane "sin! !as chro'ato!raph%,>etection li'its are in the ran!e o ,8 6 .,8 !B'? air(
,. 6 . !Blitre water( 8: !Blitre )loo$( an$ 99 6 .!B5! oo$ or tiss"e, Metho$s "se$ or air anal%sisincl"$e $irect "ltraviolet or inrare$ spectroscop% an$ $irectrea$in! colori'etr% t")es,
*orl$ pro$"ction o .(86$ichloroethane in ./0. was esti'ate$to )e a)o"t 8? 5ilotonnes, In ./0?( the che'ical was ran5e$as the .:th hi!hest vol"'e che'ical pro$"ce$ in the &SA, It isprincipall% "se$ in the s%nthesis o vin%l chlori$e, H"'ane#pos"re 'ainl% occ"rs at( an$ in the vicinit% o( pro$"ctionacilities( thro"!h s5in contact an$ inhalation, Al'ost ; othe total e'ission 2a)o"t ,8 o pro$"ction3 is esti'ate$ to )elost to the air( water( an$ soil ro' these in$"stries nearl%one6thir$ o this loss is esti'ate$ to occ"r via $isposal oheav% en$s in vin%l chlori$e pro$"ction 2E>C tars3, H"'ane#pos"re to the vapo"r as a res"lt o $ispersive "ses o .(86$ichloroethane can occ"r when it is "se$ in !asoline or as asolvent or see$ "'i!ant, Losses via $ispersive "ses acco"ntor a)o"t 9 o the total e'ission, E'issions also occ"r ro'conta'inate$ water an$ ro' waste6$isposal sites,
Avera!e concentrations o"n$ in the vicinit% o pro$"ctionacilities have )een )elow 9 !B'?, In the air o cities(avera!e concentrations o )etween ,? an$ ;,: !B'?( with areporte$ 'a#i'"' o ? !B'?( have )een 'eas"re$, Onl% two ol$reports on s'all !ro"ps o occ"pationall%6e#pose$ 'en areavaila)le( in$icatin! e#pos"re levels o 9 6 0 '!B'?,
In air( .(86$ichloroethane is $e!ra$e$ )% s"nli!ht airl%rapi$l% %iel$in! 'ainl% car)on o#i$es an$ h%$ro!en chlori$e,This prevents acc"'"lation in the at'osphere,
E'issions o .(86$ichloroethane enterin! water 'a% a'o"nt toa)o"t ,. o pro$"ction vol"'e in a$$ition( so'e o thee'issions ro' E>C tars will also conta'inate water, However(avera!e levels in $rin5in!6water are !enerall% )elow .!Blitre, The 'ain re'oval process ro' water is
evaporation( since che'ical $e!ra$ation( )io$e!ra$ation( an$)ioconcentration are "nli5el% to occ"r,
LC: val"es or ish e#pose$ or . 6 9 $a%s ran!e$ )etween0: an$ :: '!Blitre water( with )ioacc"'"lation "nli5el%, A no6o)serve$6a$verse6eect level o .. '!Blitre was o"n$ or
Daphnia magna, ollowin! lon!6ter' e#pos"re, .(86>ichloro6ethane $oes not pose a si!nicant ha+ar$ or the a4"aticenviron'ent( e#cept in cases o acci$ent or inappropriate$isposal,
.(86>ichloroethane is rea$il% a)sor)e$ via the $er'al( oral(or inhalation ro"tes,
Ater oral a$'inistration( )loo$ levels pea5 earlier withlow than with hi!h $oses( an$ are : ti'es hi!her with orale#pos"re to $oses o the or$er o .: '!B5! )o$% wei!ht thanwith si'ilar inhalation e#pos"re, Ater inhalation( a$isproportionate increase in )loo$ level occ"rs with increasin!
$ose, At an e#pos"re level o ?8 '!B'?
( a stea$% )loo$ levelis achieve$ ater 8 6 ? h, Ater oral $osin!( .(86$ichloro6ethane showe$ a preerence or a$ipose tiss"e an$ liver,Followin! inhalation( acc"'"lation was 'ainl% o)serve$ ina$ipose tiss"e( )"t not in the liver, At hi!her levels oe#pos"re( relativel% 'ore .(86$ichloroethane acc"'"late$,
.(86>ichloroethane was o"n$ in etal tiss"es an$ in theplacenta( when pre!nant rats were e#pose$ )% inhalation to theco'po"n$ at . '!B'? or ? $a%s,
*hen a$'inistere$ orall%( parenterall%( or )% inhalation torats an$ 'ice( it is e#tensivel% )iotransor'e$ to "rinar%'eta)olites 2:: 6 /3, Relativel% 'ore is 'eta)oli+e$ at lower$oses, Meta)olis' 'a% occ"r via two 5nown pathwa%sJ one viac%tochro'e P69:6'e$iate$ o#i$ation an$ the other via!l"tathione con-"!ation, The or'er pathwa% involves theor'ation o 86chloroacetal$eh%$e an$ 86chloroethanol, Altho"!hthis pathwa% appears to )e i'portant in vitro in pro$"cin!inter'e$iates capa)le o interactin! with >NA( it $oes notappear to )e i'portant in vivo. Reactive inter'e$iates areor'e$ when .(86$ichloroethane is 'eta)oli+e$ via !l"tathionecon- "!ation, The i$entit% o these inter'e$iates has not )eenconir'e$( tho"!h so'e evi$ence s"!!ests the or'ation o S6286chloroeth%l3 !l"tathione an$ its al5%latin! epis"loni"' ion(which( )% reaction with >NA( %iel$ an in$icate$ a$$"ct( S6K862N16!"an%l36eth%l !l"tathione,
E#cretion o .(86$ichloroethane or its 'eta)olites ro'ro$ents is rapi$, At least 0/ o the )o$% )"r$en was e#crete$via the l"n!s or "rine within 89 h in intraperitoneall%6in-ecte$'ice an$ within 90 h in orall%6$ose$ 'ice,
The oral L>: was o"n$ to )e 9.? 6 90/ '!B5! )o$% wei!ht inthe 'o"se( ;0 6 0: '!B5! )o$% wei!ht in the rat( an$ 8:'!B5! )o$% wei!ht in the $o!, The ;6h LC: was esti'ate$ to )e.; '!B'? in the 'o"se an$ :. 6 ;;; '!B'? in the rat,
>eaths occ"rre$ within a narrow ran!e o concentrations,
In an e#pos"re6response inhalation st"$% on rats( no a$verseeects were o)serve$ in a 16h e#pos"re to .8 '!B'?, At thene#t hi!her e#pos"re level 289 '!B'?3( $epression o the
central nervo"s s%ste' 2CNS3 was o)serve$( an$ so'e o the rats
$ie$ ater 1 h, As the e#pos"re levels increase$( $epression othe CNS )eca'e 'ore severe( an$ $eaths occ"rre$ aterpro!ressivel% shorter e#pos"re perio$s, At the hi!hestconcentration 20. '!B'?3( rats )eca'e co'atose an$ so'e $ie$within ,? h, Liver an$ 5i$ne% $a'a!e was o"n$ in 'ost o theani'als that $ie$,
Ater sin!le oral $oses o ;.: 6 11 '!B5! )o$% wei!ht(liver $a'a!e was o)serve$ histolo!icall% in rats, M%ocar$ialoe$e'a an$ $a'a!e to coronar% vessels were o)serve$,
In ? short6ter' inhalation st"$ies( vario"s species weree#pose$ to concentrations o )etween 9: an$ ?/ '! .(86
$ichloroethaneB'?
air( ; or 1 h per $a%( or : $a%sBwee5, Micean$ rats appeare$ to )e 'ore sensitive than !"inea6pi!s(ra))its( 'on5e%s( $o!s( an$ cats, The overall no6o)serve$6a$verse6eect level or e#pos"re perio$s ran!in! ro' 9 to /'onhts in the rat was a)o"t 9 '!B'?, Si!ns o into#ication(incl"$in! central nervo"s s%ste' $epression an$ $eath( wereo)serve$ in all species e#pose$ to the hi!her concentrations o)etween .;8 an$ ?/ '!B'?, For rats( liver $a'a!e( 'ainl%consistin! o att% chan!es( was o)serve$ ater e#pos"re to .:9'!B'? or "p to .8 wee5s( .;8 '!B'? or "p to 0 wee5s( an$ ./'!B'? or "p to . wee5, In rats( !"inea6pi!s( an$ 'ice( anincrease$ 'ortalit% rate was o)serve$ at concentrations o 1?'!B'? or 'ore, In ra))its( there was an increase in the'ortalit% rate ro' .:9 '!B'? an$( in 'on5e%s( ro' .;8 '!B'?,>o!s an$ cats onl% showe$ increase$ 'ortalit% at ?/ '!B'?,
Repeate$ oral a$'inistration o .(86$ichloroethane at a $oseo ? '!B5! )o$% wei!ht was lethal or rats ater : $oses an$pro$"ce$ necrosis an$ att% chan!es in the liver, No eectswere o)serve$ when the che'ical was !iven orall% to rats at .'!B5! )o$% wei!ht $ail% or / $a%s or at .: '!B5!( : ti'es perwee5( or 8 wee5s,
.(86>ichloroethane is wea5l% '"ta!enic in Sal'onellat%phi'"ri"' TA .:?:( )oth in the a)sence o( an$ in the presenceo( a 'icroso'al activation s%ste', However( in the presence oc%tosolic !l"tathione6S6transerase( a stron!er positive
response was o)taine$, Ne!ative res"lts were o)taine$ withstrains TA .:?1( TA .:?0( an$ TA /0, M"ta!enicit% occ"rs in"n!i( Drosophila, an$ 'a''alian cells in vitro. In two h"'ancell lines e#pose$ to .(86$ichloroethane( the inci$ence o !ene'"tations was o"n$ to increase with increasin! levels o!l"tathione6S6transerase, Micron"clei or $o'inant lethals werenot in$"ce$( an$ a wea5 '"ta!enic eect was reporte$ in a spottest on 'ice, >NA $a'a!e has )een o)serve$ in )acteria('a''alian cells in vitro, an$ in 'a''als in vivo. .(86>ichloroethane $i$ not in$"ce cell transor'ation in one o two
assa%s( an$ enhance$ vir"s6in$"ce$ cell transor'ation in theother,
.(86>ichloroethane is carcino!enic in 7;C?F. 'ice an$Os)orne6Men$el rats ollowin! a$'inistration o $oses o : 6? '!B5! )o$% wei!ht( !iven )% !ava!e( in oil, In 'ale rats(s4"a'o"s cell carcino'as o the oresto'ach( s")c"taneo"s
i)ro'as( an$ hae'an!iosarco'as in several or!ans 2'ainl% thespleen3 were pro$"ce$ ollowin! !ava!e in e'ale rats( 'a''ar%!lan$ i)ro'as an$ 'a''ar% a$enocarcino'as were increase$, In'ice( increase$ inci$ences o hepatocell"lar carcino'as in 'alesan$ 'a''ar% !lan$ a$enocarcino'as in e'ales( an$ l"n! a$eno'asin )oth se#es were o)serve$, No increase in t"'o"r inci$encewas reporte$ in inhalation st"$ies on Swiss 'ice an$ Spra!"e>awle% rats e#pose$ to concentrations o "p to ;1 '!B'?,
A prolon!ation o the estr"s c%cle( an increase in e')r%onal'ortalit%( pre6i'plantation losses( an$ hae'ato'as were o"n$when e'ale rats were e#pose$ to .: '!B'?( 9 h per $a%( ;$a%sBwee5( or 9 'onths prior to 'atin! an$ $"rin! pre!nanc%,
*hile the etal to#icit% o .(86$ichloroethane was not conir'e$at hi!her e#pos"re levels( severe to#ic eects on rats wereo)serve$ an$ all i'plantation sites resor)e$, No etala)nor'alities were o)serve$ in the ra))it, Oral a$'instrationto 'ale an$ e'ale rats o "p to ?: '! .(86$ichloroethaneB5!)o$% wei!ht per $a%( via the oo$( or "p to 8 %ears( $i$ notaect repro$"ction, No eects on ertilit% or !estationin$e#( an$ no teratolo!ical eects were o)serve$ in a 86!eneration st"$% on 'ice treate$ with : 6 : '! .(86$ichloroethaneB5! )o$% wei!ht per $a%( via $rin5in!6water( or"p to 8: wee5s,
.(86>ichloroethane 'a% ca"se severe corneal $a'a!e inani'als( )"t no !ross s5in reactions occ"rre$ in a .86h occl"$e$patch test on !"inea6pi!s, Corneal opacit% was o)serve$ in$o!s( ollowin! s")c"taneo"s in-ection,
In 'an( i''ersion o the han$s or 9 h at inter'ittentintervals ca"se$ severe $er'atitis, Con-"nctivitis has )eenreporte$ ro' e#pos"re to vapo"r( an$ corneal opacit% ro'acci$ental in!estion,
Two earl% reports $escri)e h"'an eects ro' occ"pationale#pos"re( an$ a n"')er o atal case histories thro"!hacci$ental oral in!estion, Co'plaints reerra)le to the CNS(liver( an$ !astrointestinal tract were reporte$ in wor5ersocc"pationall% e#pose$ to concentrations o .(86$ichloroethane
o 8: 6 0 '!B'?, Si'ilar co'plaints were reporte$ lessre4"entl% )% wor5ers e#pose$ to concentrations o 9 6 .:'!B'?, Liver an$ )ile6$"ct $isor$ers( ne"rotic con$itions(a"tono'o"s $%stonia( ne"ro'%al!ia( an$ h%perth%roi$is' have )eenreporte$ in wor5ers e#pose$ to : 6 .: '! .(86$ichlorethaneB'?,
Acci$ental in!estion o . 6 8: ! .(86$ichloroethaneres"lte$ in $eath in all instances, Hae'orrha!e at vario"ssites( $epression o the CNS( liver an$ 5i$ne% $a'a!e( an$p"l'onar% oe$e'a occ"rre$,
Ma5in! an overall eval"ation( in the a)sence o h"'an $ata(an$ ta5in! into acco"nt thatJ 2a3 .(86$ichloroethane pro$"ces areactive inter'e$iate that al5%lates >NA( 2)3 it is positive ina n"')er o '"ta!enicit% tests in vitro, tho"!h wea5l% so( an$2c3 )oth rare an$ co''on t"'o"rs are pro$"ce$ in rats an$ 'ice(it wo"l$ )e pr"$ent to consi$er .(86$ichloroethane as a possi)le
h"'an carcino!en, Th"s( it sho"l$ )e re!ar$e$( or practicalp"rposes( as i it presente$ a carcino!enic ris5 or 'an, Ineval"atin! repro$"ction ha+ar$s an$ terato!enicit%( it isnecessar% to rel% on the li'ite$ $ata availa)le ro' la)orator%investi!ations since there are no h"'an $ata, The wei!ht oevi$ence $oes not s"!!est that e#pos"re to prevailin!environ'ental levels poses a repro$"ctive or terato!enicha+ar$,
>e!ra$ation processes are rapi$ eno"!h to prevent acc"'"6lation o .(86$ichloroethane in the at'osphere, E#cept in thecase o acci$ents or inappropriate $isposal( .(86$ichloroethane$oes not present a si!niicant ha+ar$ or the a4"atic
environ'ent, Availa)le $ata are not s"icient to eval"ate itseects on soil,
F"rther st"$ies are nee$e$ onJ 2a3 >NA al5%lation 2a$$"cti$entiication3 2)3 s")6chronic to#icit% )% vario"s ro"tes oe#pos"re 2c3 assess'ent o the e#tent to which E>C tarscontri)"te to conta'ination o !ro"n$water )% .(86$ichloro6ethane an$ 2$3 $ose6response on sensitive( co''erciall%i'portant ish species 2partic"larl% st"$ies relevant to E>C tarspills3,
8, I>ENTITY( PHYSICAL AN> CHEMICAL PROPERTIES( ANALYTICAL METHO>S
Conversion actorJ . pp' 9,: '!B'? air at 8: C an$ ..,? 5Pa 21; ''H!3
8,8 Ph%sical an$ Che'ical Properties
.(86>ichloroethane is a la''a)le co'po"n$ that )"rns with as'o5% la'e, *hen $r%( .(86$ichloroethane is sta)le at or$inar%te'perat"res, In the presence o air( 'oist"re( an$ li!ht( theli4"i$ $eco'poses slowl%( %iel$in! h%$ro!en chlori$e an$ othercorrosive pro$"cts, =apo"r6air 'i#t"res are rea$il% i!nite$,In a la'e( or at a hot s"race( .(86$ichloroethane $eco'poses(%iel$in! h%$ro!en chlori$e( phos!ene( an$ other chlorine6containin! co'po"n$s, So'e ph%sical characteristics o .(86$ichloroethane are !iven in Ta)le .,
8,? Anal%tical Metho$s
A s"''ar% o relevant 'etho$s o sa'plin! an$ anal%sis ispresente$ in Ta)le 8,
Ta)le ., So'e ph%sical characteristics o .(86$ichloroethane6666666666666666666666666666666666666666666666666666666666666
Ph%sical state li4"i$
Colo"r colo"rless
Taste sweet
O$o"r chloroor'6li5e
O$o"r threshol$ 8: 6 9: '!B'?( or perception .;8 6 1: '!B'? or reco!nitiona
The a)ove pro$"ction processes an$ the pro$"ction o en$6pro$"cts( 'ainl% vin%l chlori$e( are i'portant so"rces o
e'ission o .(86$ichloroethane into the environ'ent, In ./1/(in the &SA( al'ost ; o the total e'ission o .8 5ilotonneswas lost )% these in$"stries to the air( water( an$ soil an$a)o"t 9 via $ispersive "ses as a solvent 2Se"ert et al,(./03, In the &SA( in ./11( appro#i'atel% ?: o the e'issionso .(86$ichloroethane associate$ with the pro$"ction o theco'po"n$ itsel an$ en$6pro$"cts were esti'ate$ to occ"r via$isposal o heav% en$s( the so6calle$ E>C tars( a 'i#t"re olow6 an$ hi!h6)oilin! chlorinate$ h%$rocar)ons 2Gol$( ./03,
?,8,.,? >isposal o wastes
Lar!e a'o"nts o western E"ropean tars "se$ to )e $"'pe$ in
the North Sea( )"t incineration at sea see's to )e the presentpractice 2Densen et al,( ./1:3, In the &SA( $isposal o E>Ctars is "s"all% )% )"rial in a lan$ill or incineration 2>r"r% Ha''ons( ./1/ Gol$( ./03,
?,8,.,9 &ses
The 'a-or in$"strial "se o the co'po"n$ is in the s%nthesiso vin%l chlori$e 2appro#i'atel% / o the total pro$"ction inDapan an$ appro#i'atel% 0: o total pro$"ction in the &SA32IARC( ./1/3, Other che'icals pro$"ce$ ro' .(86$ichloroethaneare .(.(.6trichloroethane( eth%lenea'ines( vin%li$ene chlori$e(trichloroeth%lene( an$ tetrachloroeth%lene, In ./11( 8 6 9 othe total pro$"ction o .(86$ichloroethane in the &SA was "se$or the s%nthesis o each o these che'icals, Another 8 was"se$ in the &SA as a lea$ scaven!er in !asoline, Thisapplication will $ecline in i'portance with the worl$6wi$econversion to "nlea$e$ "el, A s'all raction o the totalpro$"ction( appro#i'atel% ,. in the &SA in ./11( was "se$ orsolvent an$ "'i!ant applications 2Gol$( ./03, *hen "se$ as a"'i!ant( .(86$ichloroethane is "s"all% 'i#e$ with car)ontetrachlori$e to re$"ce the ire ha+ar$( an$ s'all portions oother "'i!ants 'a% )e a$$e$ 2*HO( ./183,
?,? Transport an$ Fate in the Environ'ent
O"t o the total pro$"ction o .(86$ichloroethane in the &SA
in ./1/( appro#i'atel% ,8 was esti'ate$ to )e lost to theat'osphere( 9 o this $"rin! $ispersive "se as a solvent or"'i!ant 2Se"ert et al,( ./03, Evaporation ro' $isposalsites also occ"rs, In ./11( losses to the at'osphere wereesti'ate$ to )e hi!her 2. o total pro$"ction3, Mini'alesti'ates or e'issions enterin! water an$ or e'issions viaE>C tars in ./11 were ,. an$ ,: o total pro$"ction(respectivel% 2Gol$( ./03,
Evaporation appears to )e the 'a-or pathwa% )% which .(86
$ichloroethane is lost ro' water, In a controlle$ o"t$oore#peri'ent( the hal6lie or the $isappearance ro' r"nnin!river water was o"n$ to )e .,9 h 2Scher)( ./103, This a!reeswell with la)orator% in$in!s 2>illin! et al,( ./1:3, Loss )%che'ical reaction with water is insi!niicant 2Ra$$in! et al,(./113,
In the troposphere( rain6o"t an$ a$sorption on at'osphericaerosols are "nli5el% )eca"se o the hi!h vapo"r press"re an$the low sol")ilit% o the co'po"n$ 2C"pitt( ./03, The 'a-orpart o the .(86$ichloroethane is re'ove$ ro' the at'ospherevia o#i$ation )% h%$ro#%l ra$icals, On the )asis o e#peri6'entall%6$erive$ rate constants( an$ h%$ro#%l ra$ical concen6trations o 9,0 # .; an$ ., # .; ra$icalsB'l( respectivel%(hal6lives or this reaction have )een calc"late$ o . $a%s
2Ra$$in! et al,( ./113 an$ ?; $a%s 2Howar$ Evenson( ./1;3, Alieti'e o :? $a%s was pre$icte$( which wo"l$ precl"$eacc"'"lation in the troposphere an$ transport to the strato6sphere 2Howar$ Evenson( ./1;3, The reporte$ $e!ra$ation
pro$"cts are or'%l chlori$e( h%$ro!en chlori$e( car)on $io#i$e(car)on 'ono#i$e( an$ 'onochloroacet%l chlori$e 2Pearson McConnell( ./1: Spence Hanst( ./103, Since .(86$ichloro6ethane a)sor)s li!ht within the solar spectral re!ion( photo6l%tic transor'ation is possi)le 2C"pitt( ./03, However( thee#tent o this reaction has not )een veriie$ e#peri'entall%,
Slow )io$e!ra$ation o .(86$ichloroethane was o)serve$ inresh water( see$e$ )% settle$ $o'estic waste water, Non6accli'ate$ c"lt"res ca"se$ a )iolo!ical $e'an$ o .; o thetheoretical o#%!en $e'an$ or the co'po"n$ in . $a%s 2Price etal,( ./193, .(86>ichloroethane was )io$e!ra$e$ in a4"eo"s 'e$ia)% accli'ate$ aero)ic 'i#e$ c"lt"res ro' soil or sewa!e sa'ples2St"c5i et al,( ./0. Ta)a5 et al,( ./0.3, An aero)ic )acteri"'G.( a Pseudomonas strain( that was a)le to "se .(86$ichloro6ethane as a sole so"rce o car)on an$ ener!% or !rowth( wasisolate$ ro' sa'ples containin! a 'i#t"re o activate$ sl"$!ean$ soil sa'ples 2Danssen et al,( ./093, In a$$ition( slowanaero)ic )io$e!ra$ation( 'ainl% to car)on $io#i$e( was o)serve$in an a4"eo"s 'e$i"' with a 'i#e$ 'ethano!enic c"lt"re( !rown onwaste activate$ sl"$!e with so$i"' acetate as a pri'ar%s")strate 27o"wer McCart%( ./0?3,
In soil( .(86$ichloroethane a$sor)s aselectivel% to)entonite cla% an$ peat 'oss( )"t not to $olo'itic li'estone an$silica 2>illin! et al,( ./1:3,
9, EN=IRONMENTAL LE=ELS AN> H&MAN E@POS&RE
9,. Environ'ental Levels
9,.,. *ater
Concentrations o .(86$ichloroethane 'eas"re$ at $ierentlocations are s"''ari+e$ in Ta)le ?, It will )e note$ thatS%'ons et al, 2./1:3 o)serve$ 'ore positive sa'ples in inishe$water than in "ntreate$ water, This s"!!ests treat'ent6relate$
Concentrations o .(86$ichloroethane 'eas"re$ in air atvario"s locations are s"''ari+e$ in Ta)le 9,
9,.,? Foo$
Reports on .(86$ichloroethane in oo$ are scarce, 7a"er2./0.3 o"n$ that levels were !enerall% low in the Fe$eralRep")lic o Ger'an%, Mil5 pro$"cts with a$$e$ r"its containe$an avera!e o ,0 !B5!, In Cana$a( .: o"t o ?9 sa'ples ospice oleoresins containe$ )etween 8 an$ ?9 '! o .(86$ichloroethane( "se$ as an e#tractant( per 5! 2Pa!e enne$%(./1:3,
In resi$"e st"$ies( vario"s a'o"nts o .(86$ichloroethanewere o"n$ to re'ain in "'i!ate$ !rain( $epen$in! on the t%peo !rain an$ "'i!ation 'i#t"re( e#pos"re con$itions( an$ the
e#tent o s")se4"ent ventilation 27erc5( ./;:( ./193, *heat waso"n$ to contain the hi!hest resi$"e levels( var%in! ro' .; to8.? '!B5!( ollowin! co''on "'i!ation practices, Processin!re$"ces resi$"e levels or e#a'ple( . 6 . '!B5! were recovere$in !ro"n$ wheat lo"r less than 8 '!B5! was present in )rea$2L%nn =orhes( ./:1 *it et al,( ./;/3, In the &nite$ in!$o'(. o"t o 80. sa'ples o wheat containe$ .(86$ichloroethane at alevel o 8/ '!B5! in the re'ainin! sa'ples( the concentrationwas )elow the $etection li'it o 9, '!B5! 27aile% et al,(./083, .(86>ichloroethane at a level o :. '!B5! in "'i!ate$so%)eans was co'pletel% e#tracte$ )% he#ane( $"rin! thepro$"ction o oil )% solvent e#traction 2Store% et al,( ./183,
9,.,9 In$"strial wastes
E>C tar ori!inatin! ro' vin%l chlori$e pro$"ction in ./1929 tonnes on a !lo)al )asis3 containe$ "p to ?: .(86$ichloroethane to!ether with other co'ponents( seven o whichhave )een i$entiie$,
Ta)le ?, Environ'ental levels in water66666666666666666666666666666666666666666666666666666666666666666666666666666666666666T%pe o water Location >etection Levels o)serve$a Reerence li'it 2"!Blitre3
Ger'an%( Fe$eral Rep6 ., n$7a"er 2./0.3 ")lic o . cities66666666666666666666666666666666666666666666666666666666666666666666666666666666666666a n$ not $etecte$,
9,8 General Pop"lation E#pos"re
>ail% inta5e ro' "r)an air in the &SA has )een esti'ate$ to)e )etween 0 an$ .9 ! per $a% 2Sin!h et al,( ./0?3, In theNetherlan$s( the i!"re is 8;,: ! per $a% 2G"icherit
Sch"ltin!( ./0:3,
More speciicall%( people can )e e#pose$ via air at( ornear( sites o pro$"ction an$ $ispersive "se( nota)l% in anti65noc5 a!ents in !asoline, At .8 locations near pro$"ctionacilities in each o ? areas in the &SA( avera!e airconcentrations !ra$"all% $ecrease$ ro' ;. !B'? to 8 !B'? at$istances o . 5' an$ ? 6 9 5'( respectivel%, Th"s( nearpro$"ction acilities( appro#i'atel% .8,: 'illion people in the&SA were esti'ate$ to )e e#pose$ to avera!e ann"al concentra6
tions o "p to 9 !B'? 2Elers( ./1/ ella' >"set+ina(./03,
The ann"al avera!e pop"lation e#pos"re to .(86$ichloroethanero' !asoline( in the &SA( has )een esti'ate$ to re'ain )elow,.8 !B'? 2ella' >"set+ina( ./03,
9,? Occ"pational E#pos"re
No $ata were availa)le to the Tas5 Gro"p concernin! e#pos"relevels in the .(86$ichloroethane6 an$ vin%l chlori$e6s%nthesi+in! in$"stries, Poisonin! inci$ents ollowin!inhalation or s5in e#pos"re have )een reporte$ re4"entl% orplaces o wor5 where .(86$ichloroethane is "se$ as a solvent or"'i!ant( )"t $ata concernin! e#pos"re levels are scarce2Ha$en!"e Martin( ./:? Paparopoli Cali( ./:; S"veev 7a)ichen5o( ./;/3,
.(86>ichloroethane levels o "p to .: '!B'? 2o+i5( ./:13an$ ran!in! ro' 9 to 0 '!B'? 2Cetnarowic+( ./:/3 were
$etecte$ in in$"strial plants "sin! the che'ical as a solvent,
Ti'e6wei!hte$ avera!es o ,. an$ . '!B'?( respectivel%(have )een reporte$ or 8 $ierent -o)s in an anti65noc5 a!ent)len$in! plant in the &SA, The 'a#i'"' e#pos"re level 'eas"re$was 0,/ '!B'? 2Daco)s( ./03,
Ta)le 9, Environ'ental levels in air666666666666666666666666666666666666666666666666666666666666666666666666666666T%pe o site Location >etection Avera!e Reerence li'it levels
E#ha"st !ases &nite$ in!$o' ?0 6 ?8:a Tsani67a+aca2cars3 et al,2./0.3
Airport vicinit% &SA n$ Tsani67a+aca
et al,2./083
Motorwa% &nite$ in!$o' ,0 Clar5 etal,
2./09a3666666666666666666666666666666666666666666666666666666666666666666666666666666a Ran!e o val"es 2not avera!e3,) Man% sites with "n$etecta)le levels o .(86$ichloroethane were not
consi$ere$ in the avera!e,n$ not $etecte$,
:, INETICS AN> META7OLISM
:,. A)sorption
.(86>ichloroethane can )e o"n$ in the )loo$ o ro$ents(al'ost i''e$iatel% ater $er'al( oral( or inhalation e#pos"re,
>"rin! a .86h $er'al e#pos"re o !"inea6pi!s to "n$il"te$.(86$ichloroethane( )loo$ concentrations o .(86$ichloroethaneincrease$ rapi$l% $"rin! the irst hal ho"r an$ then 'oreslowl%( "p to the en$ o e#pos"re 2Da5o)son et al,( ./083, In'ice( a $er'al a)sorption rate o 91 !Bc'8 per 'in was'eas"re$ over the irst .: 'in ollowin! application o"n$il"te$ .(86$ichloroethane 2Ts"r"ta( ./1:3,
Oral e#pos"re o rats to 8: or 8: '! E>CB5! )o$% wei!ht incorn oil pro$"ce$ pea5 )loo$ levels within / an$ / 'in(respectivel%, 7loo$ levels appeare$ to increase linearl% withe#pos"re ro' .? '!Blitre at 8: '!B5! "p to levels o )etween ?
an$ 1 '!Blitre at .: an$ 8: '!B5!, S'all 4"antities o'eta)olites( )"t no $etecta)le a'o"nts o .(86$ichloroethane(were recovere$ in aeces 2Sopi5ov Gorsh"nova( ./1/ Reit+ etal,( ./083,
>"rin! inhalation at concentrations o "p to ?8 '!B'?(stea$%6state )loo$ levels o the che'ical in rats were reache$within 8 6 ? h, The )loo$ levels increase$ $isproportionall%with e#pos"re ro' .,9 '!Blitre at 88 '!B'? to 0,? '!Blitre at;1 '!B'? an$ :; '!Blitre at ?8 '!B'?, These $ata s"!!est
sat"ration o the 'eta)olic capacit% at a )loo$ level oappro#i'atel% : '!Blitre, Pea5 )loo$ levels o .(86$ichloro6ethane were al'ost : ti'es hi!her ollowin! oral e#pos"re to.: '!B5! )o$% wei!ht than ater inhalation e#pos"re to;1 '!B'?( which appeare$ e4"ivalent to ..? '!B5! )o$% wei!ht2Sopi5ov Gorsh"nova( ./1/ Spreaico et al,( ./0 Reit+ etal,( ./083, These e#pos"re concentrations were the hi!h $ose
levels or the NCI 2./103 oral st"$% an$ the Maltoni et al,2./03 inhalation st"$%,
:,8 >istri)"tion
The $istri)"tion o .(86$ichloroethane in tiss"e has 'ainl%)een investi!ate$ $"rin! e#pos"re o la)orator% ani'als, How6ever( one report( has )een i$entiie$ that !ives an in$icationo the relative $istri)"tion o .(86$ichloroethane in h"'antiss"es 2L"+ni5ov et al,( ./0:3, As shown in Ta)le :( .(86$ichloroethane concentrations were 'eas"re$ in ten )iolo!icalco'part'ents ollowin! ac"te oral poisonin!, 86Chloroacet6al$eh%$e( a 'eta)olite o .(86$ichloroacetal$eh%$e( was not
$etecte$, In a$$ition to .(86$ichloroethane( $etecta)le4"antities o 86chloroethanol an$ 'onochloroacetic aci$ werereporte$, In this report( the o'ent"' an$ sto'ach containe$si'ilar hi!h levels o .(86$ichloroethane liver an$ 5i$ne%contents were co'para)le( )"t appro#i'atel% . ti'es less, The$etecta)le a'o"nts o 'eta)olites were too low to 'a5eco'parisons,
Ta)le :, Levels o .(86$ichloroethane an$ its 'eta)olites $eter'ine$ )%!as chro'ato!raph% in ca$averic or!ans an$ tiss"es o .: h"'an )ein!swho $ie$ ater ac"te oral poisonin!a
66666a Fro'J L"+ni5ov et al, 2./0:3,n$ not $etecte$,
NoteJ The anal%tical $etection li'it or .(86$ichloroethane an$ all'eta6 )olites e#cept 'onochloroacetic aci$ was . !Blitre or .!B5! tiss"e or 'onochloroacetic aci$( the li'it was . !Blitreor . !B5! tiss"e, Ater oral e#pos"re o rats to 8:( :( or .: '! .(86$ichloroethaneB5!( in corn oil( pea5 levels o the parent
co'po"n$ in a$ipose tiss"e at 9: 6 ; 'in e#cee$e$ those in)loo$ )% ?,/ 6 0,? ti'es, Pea5 levels in the liver( . 'inater e#pos"re( e#cee$e$ those in )loo$ )% .,? 6 8,8 ti'es,This acc"'"lation was lower than e#pecte$ at the 8 hi!here#pos"re levels( in$icatin! sat"ration o the tiss"es at hi!her$oses, >"rin! inhalation( stea$%6state levels in rat tiss"eswere reache$ within 8 6 ? h an$ increase$ 86 to ?6ol$ whenthe e#pos"re increase$ ro' 88 to ..8 '!B'?( s"!!estin! asat"ra)le 'eta)olic capacit% 2section :,?3, Levels in a$iposetiss"e( at stea$%6state( were 1 6 0 ti'es hi!her than those in
)loo$( while levels in the liver were 8 )elow those in )loo$,At co'para)le )loo$ levels( the 'a#i'"' concentration o .(86$ichloroethane ater inhalation was lower in the liver an$hi!her in l"n! an$ a$ipose tiss"e than ater oral e#pos"re,Levels in the spleen( )rain( an$ 5i$ne% were si'ilar to those inthe )loo$( irrespective o the ro"te o a$'inistration2Spreaico et al,( ./03,
Fort%6ei!ht h ater in!estion o .: '!B5! )o$% wei!ht orinhalation e#pos"re to a concentration o ;1 '!B'?( ? 6 9 othe )o$% )"r$en o la)elle$ .(86$ichloroethane was recovere$ inthe carcass o rats, Most ra$ioactivit% was o"n$ in the liveran$ 5i$ne%s, Resi$"al ra$ioactivit% in selecte$ tiss"es was . 68 ti'es hi!her ater oral e#pos"re than ater inhalation,Another $ierence )etween oral an$ inhalation e#pos"re was thehi!her resi$"al activit% in the oresto'ach( well ater the oral
e#pos"re, A si'ilar $istri)"tion pattern e'er!e$ or 'acro6'olec"lar )in$in!( as $eter'ine$ 9 h ater oral in!estion or$irectl% ater inhalation, At these ti'es( oral e#pos"re pro6$"ce$ lower levels o total 'acro'olec"lar )in$in!( )"t hi!herlevels o >NA al5%lation than inhalation e#pos"re, The a)sol"televels o >NA al5%lation 28 6 .9 'ol e4"ivalents o .(86$ichloroethane per 'ol >NA at . ''olB5! )o$% wei!ht3 wereconsi$ere$ low 2Reit+ et al,( ./083,
In another st"$%( rats an$ 'ice were co'pare$ with respect
.(86>ichloroethane 'eta)olis' involves the or'ation os"l"r6containin! 'eta)olites( which appear in the "rine, Twopropose$ pathwa%s o 'eta)olis' o .(86$ichloroethane are$epicte$ in Fi!, . one pathwa% )e!ins with c%tochro'e P69:6'e$iate$ o#i$ation( an$ the other )e!ins with !l"tathionecon-"!ation, There is a lac5 o evi$ence that $oses o .(86$ichloroethane( either )% !ava!e or inhalation( have an% eectson the $istri)"tion o its 'eta)olites )etween these pathwa%s,C%tochro'e P69: en+%'es catal%se an o#i$ative transor'ation o.(86$ichloroethane to or' reactive inter'e$iates( which res"ltin the or'ation o 86chloroacetal$eh%$e an$ 86chloroethanol2G"en!erich et al,( ./03 2Fi!, .3, Dohnson 2./;:( ./;;( ./;13has shown that 86chloroacetal$eh%$e reacts )oth en+%'aticall%an$ non6en+%'aticall% with !l"tathione 2GSH3,
Rann"! et al, 2./103 irst reporte$ that '"ta!enic co'po"n$sco"l$ )e or'e$ )% the reaction o GSH with .(86$ihaloal5anes inthe presence o c%tosolic !l"tathione6S6transerases, Thiso)servation le$ wor5ers to investi!ate in !reater $etail the
role o !l"tathione6S6transerases in the 'eta)olis' an$ )io6activation o )oth $i)ro'oethane 2>7E3 an$ .(86$ichloroethane2Rann"!( ./0 S"n$hei'er et al,( ./08 O+awa G"en!erich(./0? Ins5eep G"en!erich( ./093, This pathwa% 2Fi!, .3involves the $irect reaction o GSH with .(86$ichloroethane toor' S6286chloroeth%l3 !l"tathione( which is a hal '"star$ witha hal6lie o ;/ 'in at 8 C 2Schasteen Ree$( ./0?3 an$ lessthan .: 'in at ?1 C 2Fo"re'an Ree$( ./0:3, Non6en+%'icconversion o the hal '"star$ to the correspon$in! epis"loni"'ion !ives a p"tative al5%latin! a!ent 2epis"loni"' ion3 that
has several ates 2Fi!, .3, Reaction can occ"r with water toor' S6286h%$ro#%eth%l3 !l"tathione or reaction with thiols s"chas GSH to or' ethene )is6!l"tathione or with >NA to or'a$$"cts, *ith the e#ception o >NA a$$"cts( the reaction pro6$"cts are consi$ere$ non6to#ic an$ "n$er!o "rther 'eta)olis',These reactions an$ s")se4"ent 'eta)olis' o the pro$"cts canacco"nt or all o the 5nown s"l"r6containin! 'eta)olites o"n$
in the "rine o .(86$ichloroethane6treate$ ani'als,
Altho"!h '"ch evi$ence has )een reporte$ that s"pports theP69: 'e$iate$ 'eta)olis' o .(86$ihaloethanes( this )ranch othe pathwa% 2Fi!, .3 $oes not appear relevant to >NA a$$"ctor'ation )% .(86$ichloroethane 2o!a et al,( ./0;3, G"en!erichet al, 2./03 propose$ the possi)ilit% o chloroso o#i$ationpro$"cts o .(86$ichloroethane in >NA a$$"ct or'ation 2Fi!, .3,
However( the% o)serve$ that the apparent sti'"lation o P69:6$irecte$ >NA a$$"ct or'ation )% GSH was a res"lt o inco'pletere'oval o GSH con-"!ates $"rin! anal%sis 2o!a et al,( ./0;3,In a$$ition( the% concl"$e$ that 8H an$ .0O st"$ies on the
or'ation o 86haloethanols an$ 86haloacetal$eh%$es ro' .(86$ihaloethanes are inconsistent with a 'a-or role o s"ch a'echanis' or >NA $a'a!e 2G"en!erich et al,( ./0; o!a et al,(./0;3,
It sho"l$ )e pointe$ o"t that the P69: $irecte$ pathwa% canpres"'a)l% or' consi$era)le 4"antities o 86haloacetal$eh%$es(which rea$il% )in$ to protein an$ non6protein thiols( as shownor vin%l )ro'i$e an$ vin%l chlori$e 2G"en!erich et al,( ./0.3an$ $i)ro'oethane 2>7E3 2van 7la$eren et al,( ./0.3,
Altho"!h so'e >NA $a'a!e can )e pro$"ce$ via the P69: path6wa% "n$er in vitro con$itions 2Hill et al,( ./10 7aner-ee etal,( ./0 G"en!erich et al,( ./0 Lin et al,( ./0:3( severallines o evi$ence s"!!est that the GSH con-"!ation pathwa% ispro)a)l% o !reater si!niicance than the P69: pathwa% as the'a-or in vivo ro"te or >NA $a'a!e 2G"en!erich et al,( ./0Rann"!( ./0 S"n$hei'er et al,( ./08 Ins5eep et al,( ./0;3,
It has )een possi)le to correlate the .(86$ichloroethane6in$"ce$ '"tation re4"enc% o two h"'an cell lines with the$ierence in levels o !l"tathione6S6transerase activities,AHH6. cell line '"tation re4"enc% was 8: ti'es that in the T;cell line in the presence o .(86$ichloroethane, The $ierencewas attri)"te$ to the act that the AHH6. cell line possesses :ti'es 'ore !l"tathione6S6transerase activit% than the T; cellline 2Crespi et al,( ./0:3,
Male 7;C?F. 'ice( pretreate$ with piperon%l )"to#i$e 2PI73(were e#a'ine$ or the e#tent o hepatic >NA $a'a!e pro$"ce$ 9 hater .(86$ichloroethane a$'inistration 2Storer Conoll%(./0:3, PI7 is a P69: inhi)itor, Hepatic >NA $a'a!e( as'eas"re$ )% the al5aline >NA "nwin$in! assa% or sin!le6stran$)rea5s an$ al5ali6la)ile lesions( was potentiate$ )% PI7,Treat'ent o 'ice with hi!h $oses o 86chloroethanol aile$ topro$"ce >NA $a'a!e( as 'eas"re$ )% this assa%, >ieth%l'aleate(a GSH $epletor( potentiate$ the hepatoto#icit% o 86chloro6
E#cretion o .(86$ichloroethane ro' ro$ents is rapi$,Appro#i'atel% 0/ or 'ore o the )o$% )"r$en o the co'po"n$ wase#crete$ within 89 h in ip6in-ecte$ 'ice 2Yllner( ./1.3( within
90 h in orall% e#pose$ 'ice 2Mito'a et al,( ./0:3( an$ within90 h in rats e#pose$ orall% or via inhalation 2Reit+ et al,(./08 Mito'a et al,( ./0:3, In the ? st"$ies cite$ a)ove(
e#cretion o .(86$ichloroethane or its 'eta)olites 'ainl%occ"rre$ in e#hale$ air via the l"n!s an$ in "rine via the5i$ne%s, In )oth species( an$ at vario"s e#pos"re levels( 1 6.0 o the 'eta)oli+e$ .(86$ichloroethane was e#crete$ as car)on$io#i$e 2CO83 an$ appro#i'atel% 0 6 0: as non6volatile'eta)olites 2Ta)le ;3, The 'eta)olis' o .(86$ichloroethane in'ice an$ rats is $ose6$epen$ent, For e#a'ple( in 'ice( .. an$9: o the )o$% )"r$ens o .(86$ichloroethane( res"ltin! ro' ipe#pos"re to : an$ .1 '!B5! )o$% wei!ht( respectivel%( weree#crete$ "nchan!e$ via the l"n!s within 18 h 2Yllner( ./1.3, In
rats( .,0( ..,:( an$ 8/ o the )o$% )"r$ens were e#crete$"nchan!e$ via the l"n!s within 90 h ollowin!J an inhalatione#pos"re at ;1 '!B'? or ; h 2e4"ivalent to a $ose o ..? '!B5!)o$% wei!ht3 2Reit+ et al,( ./083( an oral $ose o . '!B5!)o$% wei!ht 2Mito'a et al,( ./0:3( an$ an oral $ose o .: '!B5!)o$% wei!ht 2Reit+ et al,( ./083( respectivel%,
The rate o eli'ination ro' )loo$ an$ tiss"es appears to$epen$ on the e#pos"re level the hi!her the e#pos"re level( the
slower the eli'ination rate o .(86$ichloroethane( ater )othoral an$ inhalation e#pos"re, Hal6lives in the )loo$ o rats(e#pose$ orall%( increase$ ro' 8: 'in at 8: '!B5! )o$% wei!ht to:1 'in at .: '!B5! )o$% wei!ht, *ith inhalation e#pos"re(hal6lives increase$ ro' .? 'in at 88 '!B'? to 88 'in at ..8'!B'?( ater a ;6h inhalation e#pos"re 2Spreaico et al,( ./03,In a$$ition( ater oral e#pos"re o rats to .: '!B5! )o$%
wei!ht( an initial hal6lie o / 'in in )loo$ $ecrease$ to8 6 ? 'in( when )loo$ levels ell )elow : 6 . '!Blitre ater? h 2Reit+ et al,( ./083, Eli'ination o .(86$ichloroethanero' )loo$( a$ipose tiss"e( l"n!( liver( )rain( 5i$ne%s( an$spleen was co'para)le ater oral e#pos"res o "p to .: '!B5!)o$% wei!ht, Eli'ination ro' the liver was reporte$ to )e)iphasic with a hi!her eli'ination rate -"st ater reachin! pea5levels o .(86$ichloroethane, Eli'ination ro' other or!ans was'onophasic, Followin! inhalation( eli'ination was the slowestin a$ipose tiss"e an$ the 'ost rapi$ in the l"n!( "p to ane#pos"re level o ..8 '!B'? 2Spreaico et al,( ./03, *ithe% Collins 2./03 also reporte$ that the eli'ination o .(86$ichloroethane was $ose6$epen$ent, Ater iv a$'inistration o
ro' ? to .: '!B5! )o$% wei!ht to 'ale *istar rats( the a"thorso"n$ that the eli'ination itte$ a two6co'part'ent 'o$el at alow6$ose level an$ a three6co'part'ent 'o$el at hi!h6$oselevels,
;, EFFECTS ON ORGANISMS IN THE EN=IRONMENT
;,. A4"atic Or!anis's
;,.,. Ac"te to#icit%
The ac"te to#icit% o .(86$ichloroethane or a4"aticor!anis's is s"''ari+e$ in Ta)le 1, The concentration o .(86$ichloroethane was 'eas"re$ in o"r o the st"$ies cite$ 2seeootnotea in Ta)le 13 the concentrations reporte$ in theother st"$ies were no'inal, It sho"l$ )e note$ that( in opens%ste's( the to#ic eects o)serve$ '"st have occ"rre$ atconcentrations lower than the no'inal ones reporte$ in latterst"$ies( $"e to the anticipate$ evaporation o .(86$ichloro6ethane in the a4"atic 'e$ia,
The species 'ost sensitive to .(86$ichloroethane were'e')ers o the class Cr"stacea, A no6o)serve$6a$verse6eectlevel )elow ;0 '!Blitre was o"n$ or Daphnia magna 2Le 7lanc(./03, The shri'p Cran!on cran!on showe$ a /;6h LC: o0: '!Blitre in sea water( 'eas"re$ )% the low6thro"!h 'etho$
2A$e'a( ./1;3, *hen the )rine shri'p Artemia salina was e#pose$to .(86$ichloroethane at levels ran!in! ro' ,8: to8: '!Blitre( !rowth inhi)ition was note$ 89 h ater c%st wettin!2erster Schaeer( ./0?3,
E>C tar is '"ch 'ore to#ic or 'arine species than .(86$ichloroethane( the heav% ractions o the tar )ein! responsi)leor the hi!h to#icit% o)serve$ 2Dernelv et al,( ./18 Rosen6)er!( ./18 Densen et al,( ./1: Rosen)er! et al,( ./1:3,
*hen )l"e al!ae Mycrocystis aerigunosa an$ !reen al!ae Scenedesmus quadricauda were e#pose$ in close$ containers to.(86$ichloroethane at .: an$ 1. '!Blitre( respectivel%( or 0$a%s( cell '"ltiplication starte$ to )e inhi)ite$ 27rin!'ann Uhn( ./103, G"ppies (Poecilia reticulata) were e#pose$ or 1
$a%s in a static test( an$ an LC: o .; '!Blitre was o"n$,Sol"tions were renewe$ $ail%( )"t no water anal%sis $ata werereporte$ 2ne'ann( ./0.3, Finall%( an earl% lie sta!e low6thro"!h test was $one, Fathea$ 'innows (Pimephales promelas)
were e#pose$ to concentrations o )etween 9 an$ :; '!Blitre)e!innin! ro' 8 to : $a%s ater spawnin! an$ contin"in!thro"!ho"t the s")se4"ent e')r%onal( larval( an$ -"venile sta!es"p to 80 $a%s ater hatchin!, *ater was anal%se$ or .(86$ichloroethane, 7o$% wei!ht was re$"ce$ at :/ '!Blitre, Thes"rvival o -"veniles( the percenta!e o nor'al larvae at hatch(an$ the hatcha)ilit% o e')r%os were not aecte$ 27enoit etal,( ./083,
a *ater anal%sis or .(86$ichloroethane was reporte$,) Flow6thro"!h or static 'etho$ open or close$ s%ste',c MIC 'ini'"' inhi)itor% concentration or cell '"ltipication, EC:an$ LC: concentration(
ca"sin! an eect an$ $eath( respectivel%( in : o the pop"lation,$ Fleas "ne$, Eect was co'plete i''o)ili+ation,
e Fleas e$, Eect was co'plete i''o)ili+ation, Eect was !rowth inhi)ition( 'eas"re$ )%9C "pta5e $"rin!photos%nthesis,! *hen the concentration was !ra$"all% )"ilt "p $"rin! the irst ho"r(the /;6h LC: was
/ '!Blitre( an$ the percenta!e o hatche$ e!!s( lai$ within .:$a%s( was $ecrease$ )% / at
9 '!Blitre, The latter was not note$ at 8 '!Blitre,h Concentration was !ra$"all% )"ilt "p $"rin! the irst ho"r,
;,.,? Lon!6ter' e#pos"re
No6o)serve$6a$verse6eect an$ eect concentrations were$eter'ine$ on the )asis o repro$"ction or len!th or Daphnia
'a!na in a 806$a% test( in stoppere$ las5s, The test sol"tionwas anal%se$ )% !as chro'ato!raph%, The lowest o)serve$ a$verseeect concentrations were 8. '!Blitre( on the )asis o repro6$"ction( an$ 18 '!Blitre( on the )asis o len!th, The no6o)serve$6a$verse6eect concentrations were .. '!Blitre( on the
)asis o repro$"ction an$ 98 '!Blitre( on the )asis o len!th2Richter et al,( ./0?3,
;,.,9 7ioconcentration
7ioconcentration o .(86$ichloroethane in a4"atic species is"nli5el% in view o its ph%sical an$ che'ical properties, In atracer st"$%( a )ioconcentration actor o 8 was o"n$ or)l"e!ill s"nish (Lepomis macrochirus) in lowin! water, Thehal6lie or the eli'ination o .(86$ichloroethane ro' tiss"eswas . 6 8 $a%s 27arrows et al,( ./03,
*hen tiss"es o several a4"atic species( collecte$ ro' nearthe $ischar!e +one o a wastewater treat'ent plant( were ana6l%se$ or .(86$ichloroethane( the concentration o the co'po"n$was less than ,: !B5! wet wei!ht in all cases( while theavera!e el"ent concentration was 9. !Blitre an$ the avera!ese$i'ent concentration was less than ,: !B5! $r% wei!ht2Gossett et al,( ./0?3,
;,8 Microor!anis's
.(86>ichloroethane at an inl"ent concentration o8:0 '!Blitre $i$ not aect the treat'ent eicienc% o a )ench6scale activate$ sl"$!e s%ste', The co'po"n$ itsel wasvirt"all% co'pletel% re'ove$ )% strippin! )"t not )% )io$e!ra6$ation 2Stover incannon( ./0?3, In a )atch anaero)ic
to#icit% assa%( .(86$ichloroethane was sli!htl% to#ic to theanaero)ic $i!estion process ro' a concentration o8,: '!Blitre( tho"!h accli'ation was o)serve$ ater several$a%s, A concentration o 8 '!Blitre ca"se$ 'ore severeretar$ation( while accli'ation was slow, In se'i6contin"o"sassa%s( stress )eca'e evi$ent at .(86$ichloroethane concentra6tions o )etween : an$ 1,: '!Blitre 2St"c5e% et al,( ./03,
>eaths occ"r within a narrow ran!e o concentrations, Inrats( the $ierence )etween the ;6h LC. an$ ;6h LC/ wasappro#i'atel% 80 '!B'? 27onnet et al,( ./03, No $eaths wereo)serve$ in rats ater ; h o e#pos"re to 8 '!B'? 2Spencer etal,( ./:.3, In 'ice( an e#tre'el% narrow ran!e o a)o"t: '!B'? was o)serve$ )etween the ;6h LC. an$ the ;6h LC/2Gra$is5i et al,( ./103,
E#pos"re o rats to sin!le hi!h $oses o .(86$ichloroethaneres"lte$ in a$verse eects on the CNS( liver( 5i$ne%s(a$renals( an$ l"n!s 2Spencer et al,( ./:.3, Gro"ps o . 6 :8*istar rats were e#pose$ to 0. ( 90 ;( .8 .( ;.( 9(?8( 89( or .8 '! .(86$ichloroethaneB'? or vario"s len!thso ti'e, At the hi!hest concentration 20. '!B'?3( $eathswere o)serve$ in ani'als e#pose$ or ,? h or lon!er, >eathswere o)serve$ at all e#cept the lowest o the other concentra6tions with e#pos"re perio$s o ,9( ,1( ?,( 9,( 1,( an$1, h( respectivel%, No $eaths were o)serve$ in rats e#pose$ tothe lowest concentration or 1 h,
Severe $epression o the central nervo"s s%ste' res"ltin! inco'a was o)serve$ in rats e#pose$ to the hi!hest concentration,At lower concentrations( this $epressant action e#presse$ itselas vario"s levels o $r"n5eness, In this investi!ation(Spencer et al, 2./:.3 $i$ not speci% the se# o the rats,
In the sa'e p")lication( the a"thors reporte$ another st"$%in which !ro"ps o 9 6 ; e'ale rats were e#pose$ to 90 ;(.8 .( 9( .8( or 0 '!B'?, A$verse eects 2not$escri)e$ )% the a"thors3 were o)serve$ at the 9 hi!hest levels
in rats e#pose$ or ,8( ,:( ?,( an$ :,: h( respectivel%, Noa$verse eects were o)serve$ in e'ale rats e#pose$ to thelowest concentration( or 1 h,
E#a'ination o internal or!ans in !ro"ps o rats 5ille$(either when 'ori)"n$ or 89 h ater the last e#pos"re( showe$that( ater e#pos"re to .(86$ichloroethane levels o 89 '!B'?
or 'ore( the 'ost severe $a'a!e occ"rre$ in the 5i$ne% an$consiste$ o hae'orrha!e an$ t")"lar necrosis, The liver showe$att% chan!es an$ hepatocell"lar necrosis with hae'orrha!e( an$a$renal !lan$s were hae'orrha!ic, L"n! oe$e'a was o)serve$ atconcentrations a)ove .8 . '!B'?, The in-"r% to or!ans in thisst"$% was acco'panie$ )% hi!h )loo$6"rea levels( a $ecrease inser"'6phosphatase activit%( an$ increase$ lipi$ concentration inthe liver 2Spencer et al,( ./:.3,
>epression o the central nervo"s s%ste' was note$ $"rin!e#pos"re o rats to .(86$ichloroethane concentrations e#cee$in!.8 '!B'? 27onnet et al,( ./03, Fro' an e#pos"re level o9 '!B'?( or 9 h( rats showe$ altere$ )ehavio"r, A narcotic
eect was o)serve$ at /. '!B'?
2*ol et al,( ./1/3,
Al)ino rats( !iven a sin!le oral $ose o ;.: '!B5! )o$%wei!ht( showe$ con!este$ livers with clo"$% swellin! an$ att%$e!eneration, The '%ocar$i"' showe$ oe$e'a an$ hae'orrha!in! in
the walls o the coronar% vessels( stasis( an$ thro')i in thevessels, These chan!es were associate$ with an increase$activit% o alanine6 an$ aspartate a'inotranserase in the ser"'an$ $ecrease$ tiss"e levels o nicotina'i$e coen+%'es 2Nats%"5 Che5'an( ./1:3, A sin!le a$'inistration o 0;. '!B5!( )%!ava!e( was reporte$ to partiall% "nco"ple o#i$ative phosphor%6lation 'eas"re$ in vitro in al)ino rat livers( .( ?( or ; $a%sater e#pos"re 2Nats%"5 et al,( ./193, In rat liver 'icroso'es(c%tochro'e P69: levels were sli!htl% $ecrease$ ater an oral$ose o ;8: '!B5! 2Moo$% et al,( ./0.3, Ater a sin!le oral$ose o .(86$ichloroethane in corn oil at 11 '!B5! )o$% wei!htin rats( $%stroph% in the c%toplas' an$ h%perchro'atosis in then"clei o hepatoc%tes were o)serve$, A $ecrease in proteins%nthesis an$ l%soso'al en+%'e activit% was also reporte$, Thesa'e chan!es too5 place in renal nephrons 27oi5ova ravtsova(./083, A sin!le $ose o 0: '!B5! in al)ino rats res"lte$ in a$ecrease in R7C co"nt( hae'atocrit( an$ other hae'atolo!icalchan!es 2Larionov o5arovtseva( ./1;3, Oral a$'inistration o.(86$ichloroethane 2;.: '!B5!3 to ra))its in$"ce$ prono"nce$'orpholo!ical chan!es in the liver in a)o"t 89 h 2Na+i5hi S5ri+hins5%( ./1?3, Eects on i)rinol%tic activit% in the
)loo$ o ra))its a$'inistere$ .(86$ichloroethane at .91; '!B5!have )een reporte$ )% a!ra'anov a+ieva 2./183, Electro6car$io!raphic chan!es in al)ino rats associate$ with $oses o .(.,:( an$ 8 '!B5! have )een reporte$ 2Saitanov Arsenieva(./;/3,
1,.,8 S5in an$ e%e irritation
*hen "n$il"te$ .(86$ichloroethane was applie$ $irectl% onthe clippe$ s5in o !"inea6pi!s or "p to .8 h in occl"$e$ patch
tests( no !ross s5in reactions were visi)le 2Da5o)son et al,(./083, Microscopic chan!es appeare$ 9 h ater application(co'prisin! 5ar%op%5nosis( perin"clear oe$e'a( spon!iosis( an$-"nctional separation 2ronevi et al,( ./0.3, In si'ilar testson ra))its( 'o$erate er%the'a an$ oe$e'a were o)serve$( 89 hater application, Microscop% on the thir$ $a% reveale$necrosis an$ other lesions s"ch as "lcerations an$ acanthosis,
The severit% o the chan!es was not in$icate$ 2>"prat et al,(./1;3,
Instillation o ,. 'l o "n$il"te$ .(86$ichloroethane intothe con-"nctival sac o the e%e o ra))its !enerate$ reversi)le('il$ irritation characteri+e$ )% con-"nctivitis an$ epitheliala)rasion, Epithelial 5eratitis( $escri)e$ as )ein! in a stateo repair( was o)serve$ 'icroscopicall%( 1 $a%s aterapplication 2>"prat et al,( ./1;3, Reversi)le clo"$in! o thecornea was o)serve$ in $o!s within . h o s")c"taneo"sa$'inistration o "n$il"te$ .(86$ichloroethane at ,/B5! )o$%wei!ht, The clo"$in! contin"e$ "p to 90 h( )"t the corneasappeare$ clear ater : $a%s, The histolo!ical chan!es(
incl"$in! necrosis o the corneal en$otheli"'( partiall% $en"$e$>esce'et<s 'e')rane( or'ation o e#cess )ase'ent 'e')rane( an$swellin! o the corneal stro'a( were also o)serve$ in $o!s(cats( an$ ra))its ater oc"lar in-ection o .,0 '! .(86$ichloroethane 2,.: 'l o a . sol"tion3 into the anteriorcha')er 2"wa)ara et al,( ./;03,
1,8 Short6Ter' E#pos"res
1,8,. Inhalation e#pos"re
The eects o repeate$ e#pos"re to .(86$ichloroethane have)een st"$ie$ in 'ice( rats( !"inea6pi!s( ra))its( cats( $o!s(an$ 'on5e%s 2Heppel et al,( ./9; Spencer et al,( ./:. Ho'annet al,( ./1.3,
Heppel et al, 2./9;3 e#pose$ rats o the *istar an$ Os)orne6Men$el strains to .(86$ichloroethane concentrations o 98( 1?(.:9( or ?/ '!B'? in air( 1 h $ail%( : $a%sBwee5( or severalwee5s, The $"ration varie$ with each e#pos"re level, No losso wei!ht an$ no $eaths occ"rre$ in rats o either straine#pose$ to 98 '!B'? or "p to 9 'onths 219 e#pos"res3, Seveno"t o .8 *istar rats e#pose$ to 1? '!B'? $ie$ within .: wee5s2ater . 6 1? e#pos"res3 an$ 0B.8 si'ilarl% treate$ rats o theOs)orne6Men$el strain $ie$ ater . 6 ; e#pos"res, Nine o"t o
.; rats 2strain "nspeciie$3 $ie$ within .8 wee5s ater 8 6 ;e#pos"res to .:9 '!B'? 8B8; 2strain "nspeciie$3 $ie$ within? wee5s ater ? 6 .: e#pos"res to ?/ '!B'?, G"inea6pi!s weree#pose$ to the sa'e concentrations o .(86$ichloroethane as therats, Several $eaths( which occ"rre$ in the lowest e#pos"re!ro"p 298 '!B'?3 an$ in controls( were attri)"te$ to aninterc"rrent $isease, At hi!her $ose levels( 'ortalit% wasrelate$ to .(86$ichloroethane e#pos"re, Five o"t o .9 !"inea6pi!s $ie$ ater : 6 ..: e#pos"res to 1? '!B'? within 8? wee5s,Fo"rteen o"t o 8 !"inea6pi!s $ie$ ater 0 6 ;: e#pos"res to
.(86$ichloroethane at .:9 '!B'? within .? wee5s, All !"inea6pi!s e#pose$ to ?/ '!B'? ha$ $ie$ )% the 9th $a% o thest"$%,
Ra))its were e#pose$ to the three hi!her concentrations o.(86$ichloroethane onl%, No $eaths were o)serve$ when ra))itswere e#pose$ to 1? '!B'? or 8: wee5s, All : ra))its e#pose$
to .:9 '!B'? $ie$( one ater one e#pos"re an$ the rest ater0/ 6 /1 e#pos"res within ./ wee5s, Five o"t o ; ra))itse#pose$ to ?/ '!B'? $ie$ ater 8 6 9? e#pos"res within /wee5s,
A !ro"p o ./ 'ice s"rvive$ or 9 wee5s when e#pose$ to 98'!B'?( )"t .0B8 'ice $ie$ within . $a%s )% the en$ o 1e#pos"res to 1? '!B'?, In other species( a !ro"p o ; e'ale$o!s s"rvive$ "p to ?: wee5s o e#pos"re to .:9 '!B'?, Two o"to ; $o!s e#pose$ to ?/ '!B'? $ie$ ater ? an$ 9? e#pos"res(respectivel%, Two o"t o si# cats e#pose$ to ?/ '!B'? $ie$ater 9? e#pos"res, Cats were not e#pose$ to lowerconcentrations, Two 'on5e%s $ie$ ater 8 an$ ?8 e#pos"res(
respectivel%( to ?/ '!B'?
( )"t 8 others e#pose$ to 1? '!B'?
s"rvive$ or 8: wee5s,
i$ne% an$ liver $a'a!e( consistin! o att% chan!es an$necrosis in )oth or!ans( was o"n$ in ani'als that $ie$ ro'e#pos"re to the hi!hest $ose level 2?/ '!B'?3, In a$$ition(the rats showe$ p"l'onar% con!estion an$ hae'orrha!e one 'on5e%
that $ie$ ater ?8 e#pos"res an$ one $o! showe$ a ocal'%ocar$itis, Appro#i'atel% hal o the ani'als that $ie$ atere#pos"re to .:9 '!B'? showe$ si'ilar histolo!ical chan!es inthe liver an$ 5i$ne%s( )"t no s"ch chan!es were o)serve$ in ratsthat $ie$ ro' e#pos"re to lower levels, Hepatic att% chan!eswere o)serve$ in !"inea6pi!s e#pose$ to 1? '!B'?, Histolo!icale#a'inations were not carrie$ o"t on 'ice,
Spencer et al, 2./:.3 e#pose$ rats( !"inea6pi!s( 'on5e%s(an$ ra))its to .(86$ichloroethane at concentrations o .;8(0.( or 9: '!B'?( 1 h per $a%( : $a%sBwee5( or vario"s len!thso ti'e, In a !ro"p o .: 'ale an$ .: e'ale rats( e#pose$ tothe hi!hest level( no ani'als s"rvive$ or 'ore than 0 wee5s(an$ ; 'ortalit% occ"rre$ in a secon$ !ro"p e#pose$ to the sa'ere!i'e ater 8 or ? e#pos"res, Mortalit% was also hi!h in a!ro"p o 0 'ale an$ 0 e'ale !"inea6pi!s e#pose$ to .;8 '!B'?,All 'ales ha$ $ie$ )% the secon$ wee5 an$ all e'ales )%appro#i'atel% the :th wee5, Two 'ale 'on5e%s e#perience$ rapi$an$ severe into#ication, 7oth were 5ille$ when 'ori)"n$ ater
. 6 .8 e#pos"res, On the other han$( 8 'ale an$ . e'alera))its tolerate$ ?? wee5s e#pos"re with no evi$ence o a$verseeects, No 'ortalit% was o)serve$ when !ro"ps o .: 'ale an$.: e'ale rats an$ 0 'ale an$ 0 e'ale !"inea6pi!s were e#pose$to 0. '!B'? or a)o"t ? wee5s 2.:. e#pos"res3 or ?; wee5s2.0 e#pos"res3( respectivel%, Si'ilarl%( no clinical eectswere o)serve$ in !ro"ps o .: 'ale an$ e'ale rats( 0 'ale ore'ale !"inea6pi!s( 8 'ale an$ . e'ale ra))its( an$ . 'ale an$. e'ale 'on5e% e#pose$ or appro#i'atel% ? 6 ?; wee5s to 9:'!B'?,
Histolo!ical e#a'ination was carrie$ o"t on ani'als e#pose$to the three $ose levels, In )oth !"inea6pi!s an$ rats e#pose$to the hi!hest $ose level( liver chan!es consistin! o clo"$%swellin! an$ att% chan!es were o)serve$, None o the otheror!ans were aecte$, Si'ilar )"t less 'ar5e$ chan!es wereo)serve$ in the 'on5e%s( while no a$verse chan!es were o"n$ in
the ra))its, In rats e#pose$ to 0. '!B'?( there were noa$verse chan!es in the liver or other or!ans( )"t re$"ce$ !rowthan$ so'e att% chan!es were o"n$ in the liver o !"inea6pi!s,No a$verse chan!es were o"n$ in ani'als e#pose$ to the lowest$ose level 29: '!B'?3,
Ho'ann et al, 2./1.3 e#pose$ cats( ra))its( !"inea6pi!s(an$ rats to .(86$ichloroethane at ./0 '!B'? or 9: '!B'? or; hB$a%( : $a%sBwee5( or "p to .1 wee5s, At the hi!herconcentration( rats )eca'e $%spnoeic an$ !"inea6pi!s apathetic,Three o"t o 9 ra))its $ie$ ater . 6 .1 e#pos"res( an$ /B.!"inea6pi!s $ie$ ater 9 6 .9 e#pos"res, Rats were 'oresensitive( $%in! ater onl% . 6 : e#pos"res, All cats s"rvive$
? e#pos"res, Histolo!icall%( rats showe$ p"l'onar% h%perae'iaan$ oe$e'a( att% liver( an$ a$renal an$ '%ocar$ial necrosis,Cats an$ ra))its e#hi)ite$ a heart lesion an$ !"inea6pi!s( att%chan!es in the '%ocar$i"'( liver( an$ a$renals an$ necrosis inthe '%ocar$i"' an$ liver, At the lower concentration 29:'!B'?3( rats( !"inea6pi!s( ra))its( an$ cats e#pose$ or .1wee5s $i$ not show an% clinical or histolo!ical chan!es,
O the species st"$ie$( 'ice an$ rats appear to )e 'oresensitive than other species to the a$verse eects o .(86$ichloroethane, The no6o)serve$6a$verse6eect level or short6ter' e#pos"res 29 6 / 'onths3 in rats st"$ie$ in the ?investi!ations is a)o"t 9 '!B'?,
Si!ns o central nervo"s s%ste' $epression o)serve$ in thea)ove st"$ies were apath% in !"inea6pi!s at ./0 '!B'? 2Ho'annet al,( ./1.3 an$ ?/ '!B'? 2Heppel et al,( ./9;3( an$ co'a in$o!s an$ 'on5e%s at ?/ '!B'? 2Heppel et al,( ./9;3, *hen ratswere e#pose$ contin"o"sl% or ?,: 'onths to : '!B'?( chan!es inEEG were o)serve$ 2>'itrieva "leshova( ./1.3, However( thesi!niicance o these in$in!s is not 5nown,
1,8,8 Oral e#pos"re
The liver appeare$ to )e the principal tar!et or!anollowin! oral e#pos"re, Rats( treate$ )% !ava!e with .(86$ichloroethane in corn oil or 8 wee5s( : ti'es per wee5( at
$oses o .: '!B5! )o$% wei!ht or less $i$ not show an%treat'ent6relate$ a)nor'alities in or!an or )o$% wei!hts(histolo!%( clinical che'istr%( or hae'atolo!% 2=an Esch et al,(./11 Reit+ et al,( ./083,
Rats were also e#pose$ or / $a%s( : ti'es per wee5( to (.( ?( or / '!B5! )o$% wei!ht 2=an Esch et al,( ./113, At the8 hi!hest e#pos"re levels( a ten$enc% to $ecrease$ wei!ht !ainwas o)serve$, At / '!B5!( rats o )oth se#es showe$ anincrease in the relative wei!ht o 5i$ne%s( )"t onl% the e'ales
Gro"ps o ..6wee56ol$ Swiss 'ice an$ .86wee56ol$ Spra!"e>awle% rats( co'prisin! / ani'als o each se#( were e#pose$ to8( 9( 88( an$ ..8 '! .(86$ichloroethaneB'? air 2:( .( :(
an$ 8: pp'3 or 10 wee5s( 1 h per $a%( : $a%s per wee5( an$o)serve$ or a lieti'e, P"rit% was reporte$ to )e !reater than//, The hi!hest e#pos"re was re$"ce$ to ;1 '!B'? 2.: pp'3ater a ew wee5s )eca"se o hi!h 'ortalit%, Control !ro"pscontaine$ ..: 'ale 'ice( .?9 e'ale 'ice( or .0 rats o eachse#, Percenta!e s"rvival in 'ale an$ e'ale 'ice( :8 wee5sater the )e!innin! o treat'ent( was( respectivel%( ;? an$ 09in the controls 91 an$ /? at 8 '!B'? ;; an$ 0 at 9 '!B'?:. an$ 0. at 88 '!B'? an$ 9? an$ ;9 at ;1 '!B'?, The last'o"se $ie$ a)o"t . wee5s ater initiation o treat'ent, In'ale an$ e'ale rats( s"rvival at :8 wee5s was( respectivel%( ;1an$ 1? in the controls 1: an$ 0: at 8 '!B'? 1 an$ 0. at9 '!B'? 1 an$ 09 at 88 '!B'? an$ ;1 an$ 1/ at ;1 '!B'?,
Most rats ha$ $ie$ )% a)o"t .9 wee5s ater the start otreat'ent, No speciic t%pes o t"'o"rs or chan!es in theinci$ence o t"'o"rs were o"n$ in either species( with thee#ception o an increase$ inci$ence 2not $ose6relate$3 oi)ro'as an$ i)roa$eno'as o the 'a''ar% !lan$s o e'ale rats
at 8( 88( an$ ;1 '!B'?, The avera!e latenc% ti'e or theset"'o"rs was 0? wee5s in control rats an$ in rats e#pose$ at8 '!B'?( an$ 1/ wee5s at the 8 hi!hest e#pos"res, The a"thorsascri)e the $ierences in the inci$ence o 'a''ar% t"'o"rs)etween the !ro"ps to the $ierent s"rvival rates in the !ro"ps2Maltoni et al,( ./03,
1,9,8 Oral e#pos"re
Gro"ps o : Os)orne6Men$el rats o each se# were e#pose$ toavera!e $oses o .(86$ichloroethane 2technical !ra$e withreporte$ p"rit% W /3a in corn oil o 91 or /: '!B5! )o$%wei!ht or 10 wee5s 2NCI( ./103, Treat'ent was "s"all% !iven :ti'es per wee5( an$ the ani'als were o)serve$ or another .: 6?8 wee5s ater the en$ o treat'ent, Control !ro"ps consiste$o 8 'atche$ controls o each se# treate$ with corn oil an$ ;poole$ control6treate$ rats o each se#, Eleven 'inorconta'inants were $etecte$ in the test co'po"n$, The rats wereho"se$ in the sa'e roo' as rats int")ate$ with other halo!enate$h%$rocar)ons or car)on $is"li$e, 7o$% wei!hts were notaecte$ )% the e#pos"res, A $ose6relate$ increase was o"n$ in
'ortalit% rate( which was .( 81 wee5s ater cessation oe#pos"re to /: '!B5! )o$% wei!ht, As shown in Ta)le /( 'alerats ha$ a $ose6relate$ increase$ inci$ence o s")c"taneo"si)ro'as( an$ oresto'ach s4"a'o"s cell carcino'as wereo)serve$, In treate$ e'ales( the sto'ach showe$ h%perplasticlesions, The inci$ence o hae'an!iosarco'as 2in vario"s or!ans('ainl% the spleen3 was increase$ in a $ose6relate$ 'anner in)oth se#es( )"t the increase was statisticall% si!niicant in'ales onl%, In e'ales( an increase was o"n$ in the inci$enceo a$enocarcino'as o the 'a''ar% !lan$ 2NCI( ./103,
2NS3 2P ,?3) 666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666a A$apte$ ro'J NCI 2./103,) Statistical anal%ses shown are in co'parison with the poole$'atche$ controls,c Statistical anal%ses shown are in co'parison with the 'atche$vehicle controls, In the sa'e set o st"$ies( 7;C?F. 'ice were e#pose$ in asi'ilar ashion to avera!e $oses o ( /1( or ./: '! technical!ra$e co'po"n$B5! )o$% wei!ht or 'ales an$ ( .9/( or 8// '!B5!)o$% wei!ht or e'ales, The% were ho"se$ in the sa'e roo'where several other h%$rocar)ons or other s")stances wereteste$, Ater e#pos"re( the% were o)serve$ or another .8 6 .?wee5s, In e'ales( )o$% wei!hts were $epresse$ at the hi!hest$oses ro' wee5 .: onwar$s( while the s"rvival rate $ecrease$ ina $ose6relate$ 'anner, Mean s"rvival e#cee$e$ ;: wee5s in all!ro"ps, Man% treate$ 'ice s"ere$ ro' )ronchopne"'onia, As
shown in Ta)le /( $ose6relate$ increase$ inci$ences o alveolaror )ronchiolar a$eno'as were o"n$ in )oth se#es, In 'ales( a$ose6relate$ increase$ inci$ence o hepatocell"lar carcino'aswas o)serve$, Fe'ale 'ice showe$ sli!ht( $ose6relate$ increasesin the inci$ence o s4"a'o"s cell carcino'as o the oresto'ach()"t this was not statisticall% si!niicant, In 'ale 'ice(h%perplastic chan!es were o"n$ at this site, The inci$ence oa$enocarcino'as o the 'a''ar% !lan$ was si!niicantl% increase$in e'ales at )oth $oses 2NCI( ./103,
Gro"ps o ? e'ale HaJICR Swiss 'ice were treate$ with 98or .8; '! .(86$ichloroethane in acetone on the shaven $orsals5in( ? ti'es per wee5 or 99 6 :/9 $a%s, In a thir$ !ro"p(each e'ale receive$ one application o .8; '! o the testco'po"n$ ollowe$ 8 wee5s later )% phor)ol '%ristate acetate( a
pro'otor( in acetone ? ti'es per wee5 or 980 6 :1; $a%s, Therewere ? control !ro"ps( a positive control( one or the pro'otor(an$ one or no treat'ent, .(86>ichloroethane $i$ not initiates5in t"'o"rs, There was an elevate$ inci$ence o l"n!papillo'as at the hi!hest $ose co'pare$ with controls 2=an>""ren et al,( ./1/3,
1,: M"ta!enicit% an$ Relate$ En$6Points
1,:,. M"tations
Inor'ation in this section is s"''ari+e$ in Ta)le .,
1,:,.,. 7acteria
Several investi!ators have o)serve$ a wea5 or no eect o.(86$ichloroethane in Salmonella typhimurium TA.:?: or TA . inspot tests or stan$ar$ plate incorporation assa%s with orwitho"t rat liver S/ raction or p"re 'icroso'es 27re' et al,(./19 McCann et al,( ./1: in! et al,( ./1/ G"en!erich et al,(./0 Principe et al,( ./0.3, A wea5 '"ta!enic eect waso)serve$ in .(86$ichoroethane vapo"r6e#pose$ S. typhimurium TA.:?: an$ TA .( which $i$ not increase "rther )% the a$$itiono a 'eta)olic activation s%ste' 27ar)er et al,( ./0.3, However(a stron!er positive response was o)serve$ )% others 2Rann"! etal,( ./10 Rann"! 7ei-e( ./1/ Principe et al,( ./0.3 in TA.:?: in the presence o rat liver 'eta)olic activation s%ste',
It has )een esta)lishe$ that this eect has )een ca"se$ )%c%tosolic !l"tathione6S6transerases 2Rann"! et al,( ./10 G"en6!erich et al,( ./0 Reit+ et al,( ./083( an$ si'ilar res"ltshave also )een o)taine$ in TA . 2van 7la$eren et al,( ./0.)3, "n vitro Salmonella tests "sin! the )ile o 'ice or ratse#pose$ to .(86$ichloroethane( pro)a)l% containin! active con6-"!ates( have conir'e$ these res"lts 2Rann"! 7ei-e( ./1/3,
No '"ta!enic eects were o)serve$ in orwar$ '"tation testswith #scherichia coli 2in! et al,( ./1/3,
'icron"cle"s test 'ice NMRIBpol%chro'atic NA6 in! et al, 2./1/32ip or !ava!e e#pos"re3 er%throc%tes
'icron"cle"s test 'ice C7ABpol%chro'atic NA
6 Denssen Ra'el2ip e#pos"re3 er%throc%tes2./03
$o'inant lethal 'ice ICR SwissB!er' cells NA6 Lane et al, 2./0832ip e#pos"re3
al5aline >NA 'ice 7;C?F.Bliver in vivoB NAX Storer Conoll%"nwin$in! in vitro2./0?3
al5aline >NA 'ice 7;C?F.Bliver in vivoB NAX Storer et al, 2./093"nwin$in! in vitro
"nsche$"le$ >NA h"'an l%'phoc%tes in vitro NAX Perocco Pro$is%nthesis 2e#pos"re )%2./0.3a$$ition in the 'e$i"'3
Cell transor'ation
cell transor'ation S%rian e')r%o cells in vitro AXc Hatch et al, 2./0?32!asBvapo"r e#pos"re3 !ol$en ha'ster
cell transor'ation 'ice 7AL7Bc6?T? in vitro A6 T" et al, 2./0:32e#pos"re )% a$$itionin the 'e$i"'3666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666a P"re 'icroso'es,) C%tosol,c Enhance$ viral in$"ce$ transor'ation,NA not applica)le,1,:,.,8 F"n!i
Forwar$ '"tation tests con$"cte$ with Streptomyces coeli$
color an$ Aspergillus nidulans were ne!ative in plate incor6poration assa%s an$ spot tests 2Principe et al,( ./0.3, In A. nidulans, .(86$ichoroethane in$"ce$ non6$is-"nction an$haploi$i+ation 2Cre)elli et al,( ./093, .(86>ichloroethane waso"n$ to )e a wea5 in$"cer o 'itotic crossin! overin Saccharomyces cerevisiae 2Si''on( ./03,
Se#6lin5e$ recessive lethal '"tations were in$"ce$in Drosophila melanogaster )% .(86$ichloroethane 2Rapoport(./; Sha5arnis( ./1 in! et al,( ./1/3, Non6$%s-"nction waso)serve$ inconsistentl% 2Sha5arnis( ./;/( ./13( while there4"enc% o so'atic '"tations or e%e pi!'entation increase$2N%lan$er et al,( ./103,
1,:,.,9 Ma''alsB'a''alian cells
A spot test "sin! 'ice provi$e$ wea5 evi$ence that .(86$ichloroethane can in$"ce so'atic '"tations 2Goc5e et al,(./0?3,
In Chinese ha'ster ovar% cells( .(86$ichloroethane in$"ce$'"tations at the HGPRT6loc"s 2Tan Hsie( ./0. a'ora et al,(./0?3, Meta)olic activation increase$ the '"tation re4"enc% inthe presence o NA>PH 2Tan Hsie( ./0.3, .(86>ichloroethanealso in$"ce$ a $ose6relate$ increase in the re4"enc% o'"tations at the HGPRT6loc"s in two h"'an l%'pho)lastoi$ cell
lines( AHH6. an$ T;, The '"tation re4"enc% in the AHH6. cellline was 8: ti'es that in the T; cell line, The $ierence insensitivit% was attri)"te$ to the $ierence in the levels o!l"tathione6S6transerase 2EC 8,:,.,.03 activit%, The activit%o this en+%'e in the AHH6. cell line was : ti'es that in theT; cell line 2Crespi et al,( ./0:3,
1,:,8 Chro'oso'e $a'a!eB>NA $a'a!e
In in vivo st"$ies( no eects were o)serve$ in $o'inantlethal assa%s in 8 !enerations o ICR Swiss 'ice 2Lane et al,(./083 an$ in the 'icron"cle"s test with C7A an$ NMRI 'ice 2in!et al,( ./1/ Denssen Ra'el( ./03,
.(86>ichloroethane was a wea5 in$"cer o "nsche$"le$ >NAs%nthesis in c"lt"re$ h"'an l%'phoc%tes 2Perocco Pro$i(./0.3,
>NA al5%lation in Salmonella )% activate$ .(86$ichloroethanewas $irectl% relate$ to the '"tation re4"enc%( )"t a)sol"televels o >NA al5%lation in Salmonella were consi$ere$ low2Reit+ et al,( ./083,
.(86>ichloroethane wea5l% inhi)ite$ !rowth o >NA pol%'erase$eicient #. coli 27re' et al,( ./19 Rosen5ran+( ./113,
A$'inistration o .(86$ichloroethane to 'ice an$ rats
res"lte$ in covalent )in$in! to 'acro'olec"les 2Reit+ et al,(./08 Arellini et al,( ./09 Ins5eep et al,( ./0;3, A)sol"televels o >NA al5%lation in rats( either )% !ava!e orinhalation( were consi$ere$ low 2Reit+ et al,( ./083,
Hepatic >NA $a'a!e was $e'onstrate$ "sin! the al5aline >NA"nwin$in! assa% in 'ale 7;C?F. 'ice ater a sin!le intraperi6toneal or oral $ose o .(86$ichloroethane that aile$ to in$"ceto#ic eects in the liver, It was also shown that( ater oneinhalation e#pos"re( hepatic >NA $a'a!e onl% occ"rre$ at
eects an$ the ertilit% in$e# an$ !estation perio$ werenor'al, In the p"ps( no eects were o"n$ on se# ratio(s"rvival in$ices( or!an wei!hts( or histolo!%, A s'all $ecreasewas note$ in the n"')er o p"ps in the irst litters at?9 '!B'? 2Rao et al,( ./03,
A terato!enicit% st"$% was "rther peror'e$ with !ro"ps o
./03, These !ro"ps were e#pose$ thro"!h inhalation to ( 9:(or .8.: '! .(86$ichloroethaneB'? air( or 1 h per $a%( ro' the;th $a% o pre!nanc% onwar$s 2rats "p to the .:th $a% an$ra))its "p to the .0th $a% o !estation3, E#pos"res at )othlevels were to#ic or ra))it $a's, The hi!her e#pos"re levelwas severel% to#ic or the rat $a's onl% . o the ew s"rvivin!e'ales was pre!nant( an$ all the i'plantation sites wereresor)e$, No a$verse eects on repro$"ction were o)serve$a'on! rats e#pose$ at 9: '!B'? an$ ra))its e#pose$ at 9: or.8.: '!B'?, The onl% !ross chan!e o)serve$ in rat et"ses was a$ecrease$ inci$ence o )ilo)e$ thoracic centra, There were nosi!niicant alterations in ra))it et"ses,
1,;,8 Oral e#pos"re
Gro"ps o .0 e'ale rats that ha$ receive$ ( .. 6 .1( or8? 6 ?: '! .(86$ichloroethaneB5! )o$% wei!ht per $a% via theee$( or "p to 8 %ears( were 'ate$ with "ntreate$ 'ales, Thep"rit% o the s")stance was not reporte$, No eects onrepro$"ction were o)serve$ 2Al"'ot et al,( ./1;a3,
Lane et al, 2./083 reporte$ a 86!eneration repro$"ctionst"$% on !ro"ps o . 'ale an$ ? e'ale ICR Swiss 'icereceivin! no'inall% :( .:( or : '! .(86$ichloroethaneB5! )o$%wei!ht per $a% via the $rin5in!6water( or "p to 8: wee5s,Control !ro"ps containe$ 8 'ale an$ ; e'ale 'ice, Ater :wee5s o treat'ent( the 'ice were 'ate$ to pro$"ce F.A( F.7( an$F.C litters, Ater weanin! an$ .. wee5s o treat'ent( the F.7'ice were 'ate$ to pro$"ce F8A an$ F87 litters, Re'atin! alwa%socc"rre$ 8 wee5s ater weanin!, In the F.C an$ F87 'atin!s(e'ales were co6ho"se$ with "ntreate$ 'ales or teratolo!%screenin!, The parents $i$ not show an% to#ic eects an$ertilit% an$ !estation in$e#es were nor'al, There were noeects on s"rvival( litter si+e( postnatal )o$% wei!ht( an$!ross patholo!% o p"ps, No con!enital 'alor'ations were
$etecte$, In the F.C an$ F87 litters( no e#pos"re6relate$repro$"ctive eects were o"n$, In the F87 litters( there wasno increase in the inci$ence o etal visceral or s5eletal
ano'alies, F.C litters were not e#a'ine$ or s5eletalano'alies,
1,1 I''"noto#icit%
*hen ra))its were e#pose$ or 1,: 6 0 'onths to .(86$ichloroethane vapo"r o "nspeciie$ p"rit% at a level o. '!B'?( or ? h per $a%( ; h per wee5( an 0 re$"ction inthe pro$"ction o anti)o$ies a!ainst t%phoi$ vaccine waso)serve$, Conco'itantl%( there was a 86ol$ increase in Fors'an
I''"nos"ppression was also note$ in a later oral st"$%( inwhich !ro"ps o ?8 'ale C>6. 'ice were e#pose$ to ?( 89( or.0/ '! .(86$ichloroethaneB5! )o$% wei!ht 2p"rit% "n5nown3 viathe $rin5in!6water or / $a%s, In a$$ition( !ro"ps o . 'aleC>6. 'ice were e#pose$( once a $a%( to 9,/ or 9/ '!B5! )o$%
wei!ht )% water !ava!e or .9 $a%s, Control !ro"ps co'prise$ 90'ice in the /6$a% st"$% an$ .8 'ice in the .96$a% st"$%, Apartro' a ? re$"ction in the le"5oc%te co"nt ater .9 $a%s oe#pos"re to 9/ '!B5! )o$% wei!ht( no eects were o"n$ on otherhae'atolo!ical para'eters an$ relative or!an wei!hts, Ater the/6$a% e#pos"re( $ecreases in )o$% wei!ht an$ l"i$ cons"'ptionwere note$, There was a ten$enc% towar$s a re$"ction ini''"no!lo)"lin spleen anti)o$%6or'in! cells an$ in the ser"'6anti)o$% level ater sheep er%throc%te i''"ni+ation( while noeects were o)serve$ in the response to the 76cell 'ito!enlipopol%sacchari$e S, Ater the .96$a% e#pos"re( 8: an$ 9s"ppression o anti)o$%6or'in! cells were 'eas"re$ at 9,/ an$9/ '!B5! )o$% wei!ht( respectivel%, Ater the /6$a% e#pos"re(
no eects were seen on the cell6'e$iate$ i''"nit%( assesse$ )%'eas"rin! the $ela%e$ h%persensitivit% response to sheeper%throc%tes an$ the spleen cell response to the T6cell 'ito!enConcanavalin A, Ater the .96$a% e#pos"re( a sli!ht s"ppressiono the $ela%e$ h%persensitivit% response was o"n$( which wasnot $ose6$epen$ent 2M"nson et al,( ./083,
0, EFFECTS ON MAN
Li'ite$ $ata are availa)le on the eects on 'an o .(86$ichloroethane, There are no a$e4"ate controlle$ st"$ies( norecent occ"pational st"$ies( an$ no 'ortalit% st"$ies, However(case st"$ies o acci$ental e#pos"res have )een reporte$,
0,. Acci$ental E#pos"res
0,.,. Inhalation e#pos"re
Man% reports are concerne$ with 'i#e$ e#pos"res, However(in this p")lication( onl% case st"$ies are consi$ere$ in whichthe e#pos"re was reporte$ to )e to .(86$ichloroethane alone,Accor$in! to a review )% NIOSH 2./1;3( no $ata on e#pos"relevels an$ $"ration o e#pos"re were reporte$,
wea5ness( c%anosis( '"sc"lar spas's( h%potonia( vo'itin!( an$"nconscio"sness, >eath oten ollows, The respirator% tractcan )e irritate$ an$ inla'e$ with s"ch s%'pto's as co"!h an$rales over the chest, C%anosis 'a% occ"r either as the res"lto respirator% ins"icienc% $"e to $epression o the centralnervo"s s%ste' or )% )ronchial o)str"ction $"e to inla''ation,Epi!astric or visceral pains an$ $iarrhoea have )een o)serve$,A"tops% reports re4"entl% 'ention $a'a!e to the l"n!s( liver(an$ 5i$ne%s 2*irtschater Schwart+( ./?/ Ha$en!"e Martin(./:? Menschic5( ./:1 Troisi Cavalla++i( ./;. S"veev
The eects o ac"te oral e#pos"re are ver% si'ilar to thoseo"n$ ater inhalation( )"t the% are 'ore prono"nce$, A s"''ar%o ac"te oral into#ications was prepare$ )% &S NIOSH in ./1;,The lethal eects o .(86$ichloroethane associate$ with orale#pos"re are presente$ in Ta)le .., Oral $oses o 8 6 : 'l.(86$ichloroethane have )een i$entiie$ as )ein! lethal 2IRPTC(./093, Several 'a-or s%n$ro'es can )e i$entiie$ incl"$in!central nervo"s s%ste' $epression( !astroenteritis( an$$isor$ers o the liver an$ 5i$ne%s, Fre4"entl%6o)serve$
car$iovasc"lar ins"icienc% an$ hae'orrha!ic $iathesis 'a% )erelate$ to chan!es in o#%!enation an$ eects on the liver2*eiss( ./:1 Moro+ov( ./:0 Hin5el( ./;: 7o!o%avlens5i et al,(./;0 Martin et al,( ./;0 Schn)orn et al,( ./1 Yo$ai5en 7a)coc5( ./1? >orn$or et al,( ./1: An$ri"5in( ./1/3,
Ta)le .., Eects associate$ with ac"te lethal oral $oses o .(86$ichloroethane in h"'an )ein!sa
;? $eath in ? 6 9 h liver $a'a!eSecchi et al, 2./;03c
;? $eath at .1 h c%anosis( $iarrhoea i'paire$Schon)orn et al, 2./13 )loo$ coa!"lation
: $eath at 89 h hae'orrha!e at vario"s sitesMartin et al, 2./;03 si!ns o car$iac $a'a!e666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666666
a St"$ies in which $oses co"l$ not )e esti'ate$ have not )eencite$, The rea$er is reerre$ to
NIOSH 2./1;3 or a $escription o these case reports,) &nless otherwise state$( $eath reers to sin!le 'ale in$ivi$"als,c The rea$er is reerre$ to NIOSH 2./1;3 or a 'ore co'plete$escription o s%'pto'olo!%,
S%'pto's o central nervo"s s%ste' $epression co''onl%appear within . h( re4"entl% with c%anosis( na"sea( vo'itin!($iarrhoea( epi!astric an$ a)$o'inal pains( an$ irritation o the'"co"s 'e')ranes, Irreversi)le )rain $a'a!e has )een reporte$in one case( an$ )rain $a'a!e has )een o"n$ in several atalcases 2Roh'ann et al,( ./;/ >orn$or et al,( ./1:3, In so'e othe cases( an interval relativel% ree o s%'pto's ollowe$
in!estion 2Hin5el( ./;: Martin et al,( ./;0 o'arov et al,(./1? >orn$or et al,( ./1:3, In the ne#t phase( $ecreasin!conscio"sness an$ circ"lator% an$ respirator% ail"re 'a% occ"r(oten lea$in! to $eath so'e ho"rs to so'e $a%s ater e#pos"re,>"rin! the into#ication( heart rh%th' $ist"r)ances can lea$ tocar$iac arrest 2Moro+ov( ./:0 Martin et al,( ./;0 Yo$ai5en 7a)coc5( ./1? An$ri"5in( ./1/3, A"tops% reports have reveale$$a'a!e to the '"cosae o the !astrointestinal tract( liver(5i$ne%( l"n!( heart( an$ )rain, Livers can )e enlar!e$, Liveran$ 5i$ne% epitheli"' can show att% $e!eneration an$ necrosis,Renal ins"icienc% has )een reporte$ to ollow $evelop'ent ohepatic ins"icienc% an$ has )een 5nown to pro!ress to "rae'icco'a 2Nats%"5 M"$rits5%( ./193, L"n! oe$e'a is re4"entl%
o"n$, H%perae'ia an$ hae'orrha!ic lesions are o"n$ in so'eor!ans, Accor$in! to so'e a"thors 2Martin et al,( ./;0Schn)orn et al,( ./1 Yo$ai5en 7a)coc5( ./1?3( it appeare$that the )loo$ coa!"lation ti'e was increase$ )eca"se o a$ecrease in )loo$ clottin! actors an$ thro')oc%tes, Theseeects appear secon$ar% to liver cell necrosis co'plicate$"rther )% intravasc"lar coa!"lation, 7ioche'icall%( liver$a'a!e is ill"strate$ )% increase$ ser"' levels o )ilir")in(transa'inases( an$ lactate $eh%$ro!enase 2Martin et al,( ./;0Yo$ai5en 7a)coc5( ./1? >orn$or et al,( ./1: An$ri"5in(./1/3, i$ne% $a'a!e is e#presse$ )% an"ria or oli!"ria2Moro+ov( ./:0 7o!o%avlens5i et al,( ./;0 Yo$ai5en 7a)coc5(./1?3 an$ al)"'in( le"5oc%tes( an$ epitheli"' cells in the"rine, To!ether with the histopatholo!%( this points to ac"tenecrosis o the 5i$ne% t")"le( possi)l% as a res"lt o the livercell necrosis an$ the chan!es in circ"lation 2Moro+ov( ./:0Hin5el( ./;: Yo$ai5en 7a)coc5( ./1?3, Hae'atolo!ical chan!esincl"$e $ecreases in the er%throc%te co"nt an$ hae'o!lo)incontent 2Moro+ov( ./:0 >orn$or et al,( ./1:3,
0,.,? Ac"te eects on e%es an$ s5in
>%s"nction o the central nervo"s s%ste'( which co"l$ )eca"se$ )% )rain oe$e'a( can lea$ to eects on the e%es s"ch as$ilation or constriction o the p"pils an$ i'pair'ent o e%erele#es 2*eiss( ./:1 Troisi Cavalla++i( ./;.3, *eiss 2./:13reporte$ a clo"$% cornea in 8 cases o oral e#pos"re this has
also )een reporte$ in $o!s 2section 1,.,83, Con-"nctivitis waso"n$ in 8 o"t o 9 patients( who ha$ )een e#pose$ to .(86$ichloroethane vapo"r 2Menschic5( ./:13, Ater inter'ittenti''ersion o the han$s o ? 'en in .(86$ichloroethane or 9 h(severe $er'atitis $evelope$ 2*irtschater Schwart+( ./?/3,
0,8 Occ"pational E#pos"re
Onl% 8 reports are availa)le( an$ these $ate ro' )eore
./;, In the irst st"$% 2Cetnarowic+( ./:/3( .; 'ale wor5ersro' an oil reiner%( e#pose$ or 8 6 0 'onths( were selecte$or close e#a'ination, A !ro"p o ; wor5ers was e#pose$ toconcentrations o )etween 9 an$ .: '! .(86$ichloroethaneB'?
air( an$ a !ro"p o . wor5ers was e#pose$ to concentrations)etween 8: an$ 0 '!B'?, The wor5ers were also e#pose$ to)en+ene at levels )etween . an$ 8: '!B'?( which was consi$ere$
not si!niicant )% the a"thors, A !eneral re$"ction in )o$%wei!ht was o)serve$, Co'plaints ca'e 'ainl% ro' the !ro"p withthe hi!her e#pos"re an$ incl"$e$ a )"rnin! sensation o thee%es( lachr%'ation( $i++iness( lassit"$e( sleepiness( na"sea(vo'itin!( constipation( poor appetite( epi!astric pain( an$wei!ht loss, There was no control !ro"p( )"t s%'pto's repor6te$l% $isappeare$ when wor5ers were re'ove$ ro' e#pos"res%'pto's ret"rne$ "pon re6e#pos"re, Most( )"t not all( a)nor'6alities were o"n$ in the !ro"p with hi!her e#pos"re an$involve$ the liver 20 wor5ers3( central nervo"s s%ste' 2?wor5ers3( !astrointestinal tract 21 wor5ers3( an$ hae'atolo!icalpara'eters 2. 6 1 wor5ers3, No lesions were o"n$ in the e%e(respirator% tract( l"n!( or heart,
The secon$ st"$% 2o+i5( ./:13( was con$"cte$ on wor5erse'plo%e$ in an aircrat actor% "sin! a !"' $issolve$ in .(86$ichloroethane, No $ata were !iven on the co'position o the!l"e or on the e'plo%'ent stat"s o the wor5ers, Air concentra6tions o .(86$ichloroethane varie$ consi$era)l%( the level )ein!: '!B'? or less $"rin! 1 6 1: o the wor5in! ti'e( an$ 0 6.: '!B'? $"rin! 8: 6 ? o the wor5in! ti'e, The 'or)i$it% othe wor5ers in this $epart'ent $"rin! the whole perio$ "n$erst"$% 2./:.6::3 was increase$ or all $isease cate!ories inco'parison with that in wor5ers in the entire actor%, A !ro"po 0? wor5ers was e#a'ine$ "rther( in the a)sence o controls,There were ./ wor5ers with $iseases o the liver an$ )ile $"ct(.? wor5ers with ne"rotic con$itions( .. wor5ers with a"tono'o"s$%stonia( an$ . wor5ers with h%perth%roi$is' an$ !oitre,
These reports are $iic"lt to eval"ate( )eca"se noin$ication is !iven o the prevalence in "ne#pose$ wor5ers othe s%'pto's an$ si!ns $escri)e$ in the case st"$ies,
/, E=AL&ATION OF H&MAN HEALTH RISS AN> EFFECTS ON THE EN=IRONMENT
/,. Eval"ation o H"'an Health Ris5s
In spite o the hi!h vol"'e o pro$"ction o .(86$ichloro6ethane( there are no 4"antitative e#pos"re6eect $ata on h"'an
)ein!s, Fre4"entl%( .(86$ichloroethane is not the onl% che'icalinvolve$ in an e#pos"re an$ th"s( ca"se6eect relationships are$iic"lt to $erive, No epi$e'iolo!ical or 'ortalit% st"$iesare availa)le, There are onl% two ol$ reports on s'all !ro"pso occ"pationall%6e#pose$ 'en 2section 0,83, These $ata in$i6cate that repeate$ inhalation e#pos"res in the ran!e o appro#6i'atel% 9 6 0 '!B'? 'a% lea$ to central nervo"s s%ste'$epression an$ !astrointestinal an$ liver a)nor'alities, As'i!ht )e e#pecte$( s"ch s%'pto's were 'ore prevalent in in$ivi6$"als e#pose$ to hi!h levels, The onl% availa)le $ata re!ar$in!
oral e#pos"re are those involvin! atal into#ications 2Ta)le ..(section 0,.3,
7eca"se o the li'itations o the h"'an $ata )ase( it isnecessar% to rel% on the availa)le e#peri'ental ani'al $ata to$erive a no6o)serve$6a$verse6eect level or h"'an )ein!s,This is possi)le )eca"se o the si'ilarit% in the spectr"' o
a$verse eects in 'an an$ la)orator% ani'als( which incl"$ecentral nervo"s s%ste' $epression( liver an$ possi)l% 5i$ne%a)nor'alties( l"n! oe$e'a( an$ car$iovasc"lar $isor$ers, The$ose6response $ata ro' ani'al st"$ies incl"$e a no6o)serve$6a$verse6eect level or the rat o a)o"t 9 '! .(86$ichloro6ethaneB'? air 2section 1,8,.3( e4"ivalent to an inta5e o a)o"t?: '!B5! )o$% wei!ht per $a% 2ass"'in! inhalation o 98 litresover 1 h or a :6! rat an$ . a)sorption3, The hi!hestre!istere$ air e#pos"re level o the !eneral pop"lation is;: !B'? 2Ta)le 9( section 9,.,83, This level lea$s to acalc"late$ inta5e o .,? '! per person per $a% 28 '?B$a% #;: !B'?3, A co'para)le inta5e ro' $rin5in!6water containin!the hi!hest level recor$e$ 2; !Blitre3 2Ta)le ?( section
9,.,.3 wo"l$ a'o"nt to a $ail% inta5e o .8 ! 2; !BlitrelitreB$a%3, Th"s( a co')ine$ air an$ water e#pos"re( in theconte#t o a worst6case scenario or the !eneral pop"lation(when co'pare$ with the no6o)serve$6a$verse6eect level orani'als( is lower )% a actor o well over ., Conse4"entl%(or the )iolo!ical en$6points consi$ere$ so ar( it can )econcl"$e$ that .(86$ichloroethane is "nli5el% to present a to#icha+ar$ or the !eneral pop"lation( "n$er prevailin! e#pos"recon$itions,
In an oral a$'inistration st"$%( .(86$ichloroethane pro$"ce$a statisticall%6si!niicant increase in s4"a'o"s cell carcino'ao the oresto'ach( hae'an!iosarco'a( an$ 'a''ar% a$enocarcino'ain rats( an$ 'a''ar% a$enocarcino'a an$ hepatocell"lar carcino'ain 'ice 2section 1,9,83, In one carcino!enicit% st"$%( inhala6tion e#pos"re $i$ not res"lt in an increase in t"'o"r inci$ence2section 1,9,.3, The nat"ral occ"rrence o oresto'ach s4"a'o"scell carcino'as in rats an$ hae'an!iosarco'as in la)orator%ro$ents is "n"s"al, Ta5in! into consi$eration that cancer has
)een pro$"ce$ in two species o e#peri'ental ani'als an$ inseveral tar!et or!ans( it can )e concl"$e$ that .(86$ichloro6ethane is carcino!enic or rats an$ 'ice( when a$'inistere$ )%!ava!e,
In the a)sence o h"'an $ata( an$ ta5in! into acco"nt theact that .(86$ichloroethane pro$"ces a reactive inter'e$iate
that al5%lates >NA( that it is positive in a n"')er o in vitro'"ta!enicit% tests( tho"!h wea5l% so 2section 1,:3( an$ that itres"lts in the pro$"ction o )oth rare an$ co''on t"'o"rs inrats an$ 'ice( it wo"l$ )e pr"$ent to consi$er .(86$ichloro6ethane as a possi)le h"'an carcino!en, Thereore( .(86$ichloro6ethane sho"l$ )e re!ar$e$( or practical p"rposes( as i itpresente$ a carcino!enic ris5 or 'an, Th"s( levels in theenviron'ent sho"l$ )e 5ept as low as easi)le,
Since there are no h"'an $ata( it is necessar% to rel% on
the li'ite$ $ata availa)le ro' e#peri'ental ani'al st"$ies ineval"atin! repro$"ction ha+ar$s an$ terato!enicit%, The wei!hto evi$ence 2section 1,;3 $oes not s"!!est that e#pos"re toprevailin! environ'ental levels wo"l$ pose a h"'an repro$"ctiveor terato!enic ha+ar$,
/,8 Eval"ation o Eects on the Environ'ent
/,8,. Air
E'issions o .(86$ichloroethane into the air 'ainl% occ"r inprocess in$"stries, Other e'issions occ"r $"rin! its "se as a"'i!ant( solvent( an$ lea$ scaven!er( an$ via evaporation ro'conta'inate$ water an$ ro' waste $isposal sites, Total e'is6sions are esti'ate$ to a'o"nt to ,8 o the pro$"ction vol"'e,Photoche'ical $e!ra$ation via o#i$ation )% h%$ro#%l ra$icals isthe 'ost i'portant ro"te o eli'ination ro' air, Raino"t an$a$sorption on at'ospheric particles are "nli5el% to )e i'portantprocesses o eli'ination, Photol%sis is theoreticall% a possi)6ilit%( )"t no evi$ence o this is availa)le, The pro$"cts o
the photoche'ical $e!ra$ation are car)on 'ono#i$e( car)on$io#i$e( h%$ro!en chlori$e( or'%l chlori$e( an$ chloroacet%l6chlori$e, The two last co'po"n$s will $e!ra$e "rther, Theprocess is rapi$ eno"!h to prevent acc"'"lation o the co'po"n$in the at'osphere 2section ?,?3,
/,8,8 *ater
E'issions o .(86$ichloroethane into water 'a% a'o"nt to,. o the pro$"ction vol"'e, So'e o the e'issions ro' E>Ctars( which total a)o"t ,: o the pro$"ction vol"'e( willconta'inate water, The 'ain process o re'oval o .(86$ichloro6ethane ro' water is evaporation, Che'ical $e!ra$ation is note#pecte$( nor is )io$e!ra$ation ast eno"!h to )e o an% si!ni6icance 2section ?,.3, 7ioconcentration in a4"atic species is"nli5el% in view o the rather low octanolBwater partitioncoeicient, This concl"sion is s"pporte$ )% a low )ioconcen6tration actor o"n$ e#peri'entall% 2section ;,.,93,
The co'po"n$ was onl% sli!htl% to#ic or a4"atic speciesteste$, A no6o)serve$6a$verse6eect concentration or Daphnia
'a!na in a lon!6ter' test was .. '!Blitre 2section ;,.,?3, Thelowest LC: val"e 20: '!Blitre3 was o"n$ or the shri'p %rangon
cran!on 2section ;,.,.3, Avera!e environ'ental levels o theco'po"n$ in s"race water are !enerall% )elow . !Blitre( )"t(in heavil% poll"te$ s"race water( avera!e levels o :,;!Blitre have )een 'eas"re$ with a 'a#i'"' o / !Blitre
2Ta)le ?( section 9,.,.3,
On the )asis o the a)ove $ata( it can )e concl"$e$ that(e#cept in case o acci$ents an$ inappropriate $isposal( .(86$ichloroethane $oes not pose a si!niicant ha+ar$ or thea4"atic environ'ent, However( it sho"l$ )e note$ that E>C tarsare '"ch 'ore to#ic than .(86$ichloroethane 2section ;,.,.3,
>ata are not s"icient to eval"ate the eects o .(86$ichloroethane in soil,
., RECOMMEN>ATIONS FOR F&RTHER ST&>IES
., >NA al5%lation 2a$$"ct i$entiication3,
8, St"$ies on s")6chronic to#icit% "sin! vario"s ro"tes o e#pos"re,
?, Assess'ent o the e#tent to which E>C tars contri)"te to conta'ination o !ro"n$water )% .(86$ichloroethane,
9, >ose6response st"$ies on sensitive( co''erciall% i'portant ish species 2partic"larl% st"$ies relevant to E>C tar spills3,
.., PRE=IO&S E=AL&ATIONS 7Y INTERNATIONAL 7O>IES
.(86>ichloroethane was eval"ate$ )% IARC in ./1/ 2=ol"'e 8o the IARC Mono!raphs3, It was concl"$e$ thatJ
There is s"icient evi$ence that .(86$ichloroethane iscarcino!enic in 'ice an$ rats, In the a)sence o a$e4"ate $atain h"'ans( it is reasona)le( or practical p"rposes( to re!ar$.(86$ichloroethane as i it presente$ a carcino!enic ris5 toh"'ans,
7AR7ER( R,>,( >ONISH( *,H,( M&ELLER( ,R, 2./0.3 A proce$"reor the 4"antitative 'eas"re'ent o the '"ta!enicit% o volatileli4"i$s in the A'es Salmonella3microsome assay. Mutat. Res.(90J ?.690,
7OELLI( D,*, E77E&S( 7,7, 2./083 A st"$% o so'earo'atic an$ halocar)on vapors in the a')ient at'osphere o NewDerse%, 1. environ. Sci. 4ealth, A17J ;/?61..,
7REM( H,( STEIN( A,7,( ROSENRAN( H,S, 2./193 The '"ta6!enicit% an$ >NA6'o$i%in! eect o haloal5anes, %ancer Res.(34J 8:1;68:1/,
(Diplocystis) aeruginosa and Scenedesmus quadricauda. Mitt.
"nt. erein Limnol.( 21J 81:6809,
7RINGMANN( G, &HN( R, 2./03 Co'parison o the to#icit%threshol$s o water poll"tants to )acteria( al!ae( an$ proto+oain the cell '"ltiplication inhi)ition test, 9ater Res.( 14J8?.689.,
7RINGMANN( G, &HN( R, 2./0.3 KCo'parison o the eect oha+ar$o"s s")stances on la!ellate$ an$ ciliate$( respectivel%(holo+oic )activoro"s an$ sapro+oic proto+oa, @9 9asser$
A)wasser( 122J ?06?.? 2in Ger'an3,
7RINGMANN( G, &HN( R, 2./083 K>ata on the to#icit% o waterpoll"tants to Daphnia magna in an i'prove$ stan$ar$ test, ;.
CAS*ELL( G,H, CLIFFOR>( H,T, 2./:03 The eect o eth%lene$ichlori$e an$ car)on tetrachlori$e on the !er'ination an$ earl%!rowth o 'ai+e, #mp. 1. e'p. Agric.( 26J ?;:6?18,
CETNARO*IC( D, 2./:/3 E#peri'ental an$ clinical investi!a6tions on the action o $ichloroethane, olia Med. %racov.( 1J.;/6./8,
CLAR( A,I,( MCINTYRE( A,E,( LESTER( D,N,( PERRY( R, 2./09a3A')ient air 'eas"re'ent o aro'atic an$ halo!enate$ h%$rocar)onsat "r)an( r"ral( an$ 'otorwa% locations, Sci. total #nviron.(39J 8;:681/,
CRE7ELLI( R,( CONTI( G,( CONTI( L,( CARERE( A, 2./093In$"ction o so'atic se!re!ation )% halo!enate$ aliphatich%$rocar)ons in Aspergillus nidulans. Mutat. Res.( 1382.3J ??6?0,
CRESPI( C,L,( SEI@AS( G,M,( T&RNER( T,R,( RYAN( C,G,( PENMAN(7,*, 2./0:3 M"ta!enicit% o .(86$ichloroethane an$ .(86$i)ro'oethane in two h"'an l%'pho)lastoi$ cell lines, Mutat.
Res.( 142J .??6.9,
C&PITT( L,T, 2./03 ate o to'ic and haardous materials in
the air environment, Research Trian!le Par5( North Carolina( &SEnviron'ental Protection A!enc%( Environ'ental SciencesLa)orator%( Oice o Research an$ >evelop'ent 2EPA ;B?60609( P7 88./903,
>A*SON( G,*,( DENNINGS( A,L,( >ROS>O*SI( >,( RI>ER( E,2./113 The ac"te to#icit% o 91 in$"strial che'icals to reshan$ saltwater ish, 1. haard. Mater.( 1J ??6?.0,
>MITRIE=A( N,=, &LESHO=( E,=, 2./1.3 KChan!es in thecere)ral )ioelectric activit% an$ electric con$"ctivit% in ratsin chronic into#ications with certain chlorinate$ h%$rocar)ons, @ig. i Sanit.( 36J 868: 2in R"ssian3,
ELFERS( L,A, 2./1/3 Monitoring o am!ient levels o #D% in the
vicinity o #D% production and user acilities, ResearchTrian!le Par5( North Carolina( &S Environ'ental ProtectionA!enc%( Environ'ental Monitorin! an$ S"pport La)orator% 2EPA;B961/68/( P7 8/0??3,
EN=IRONMENT AGENCY( DAPAN 2./0?3 #nvironmental monitoring o
chemicals environmental survey report o iscal years 57> and
FLO*TO*( E, 2./:83 Poisonin! $"e to chlorinate$ h%$rocar)onco'po"n$s( partic"larl% .(86$ichloroethane, %hem. /ech.
(Leipig), 6J 8:?68:9,
FO&REMAN( G,L, REE>( >,D, 2./0:3 Evi$ence or a non6epis"loni"' ion inter'e$iate $"rin! al5%lation )% S6286chloroeth%l3 c%steine )"t not )% S6286chloroeth%l3 !l"tathione, ed. Proc. ed. Am. #'p. :iol.( 44J :.1,
F&DII( T, 2./113 >irect a4"eo"s in-ection !as chro'ato6!raph%6'ass spectro'etr% or anal%sis o or!anohali$es in waterat concentrations )elow the parts per )illion level, 1.
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