-------
                                  DISCLAIMER

    This report  1s  an external  draft  for  review purposes only  and  does not
constitute  Agency  policy.   Mention of  trade  names  or  commercial  products
does not constitute endorsement or recommendation for use.
                                      11

-------
                                    PREFACE
    Health and  Environmental  Effects Documents (HEEOs) are  prepared  for the
Office of  Solid  Waste  and Emergency Response  (OSWER).  This document series
1s Intended to support  listings  under  the  Resource Conservation and Recovery
Act  (RCRA)  as  well as  to provide health-related  limits and goals  for emer-
gency  and  remedial actions  under the Comprehensive  Environmental  Response,
Compensation  and  Liability  Act  (CERCLA).   Both  published literature  and
Information obtained from Agency  Program Office files are  evaluated  as  they
pertain to potential human health, aquatic  life  and environmental  effects of
hazardous  waste  constituents.   The  literature searched for  In  this document
and  the  dates  searched  are  Included In  "Appendix:  Literature  Searched."
Literature search  material  1s  current up  to 8 months previous  to  the final
draft  date listed  on  the front  cover.   Final  draft document  dates  (front
cover) reflect the date the document 1s sent to the Program Officer (OSWER).

    Several quantitative  estimates  are  presented  provided  sufficient  data
are available.   For systemic toxicants,  these  Include Reference doses (RfOs)
for  chronic   and  subchronlc  exposures  for  both  the Inhalation  and  oral
exposures.  The  subchronlc  or  partial  lifetime  RfD, 1s  an estimate of an
exposure  level   that would  not  be  expected  to  cause adverse  effects  when
exposure occurs  during  a  limited time  Interval,  for  example,  one  that  does
not constitute a significant portion  of  the  Hfespan.  This type of exposure
estimate has  not been  extensively  used, or  rigorously  defined as previous
risk   assessment   efforts  have  focused  primarily   on   lifetime  exposure
scenarios.   Animal data   used  for  subchronlc  estimates   generally  reflect
exposure  durations  of   30-90  days.   The  general  methodology  for  estimating
subchronlc RfDs  1s  the  same  as  traditionally  employed for  chronic  estimates,
except that subchronlc  data are utilized  when available.

    In  the  case  of   suspected   carcinogens,  RfDs   are  not  estimated.   A
carcinogenic  potency   factor,   or   q-|*   (U.S.   EPA,  1980a),   1s  provided
Instead.  These  potency estimates are  derived for  both  oral  and   Inhalation
exposures  where  possible.   In addition,  unit  risk  estimates  for  air  and.
drinking water are presented based on Inhalation and oral  data, respectively.

    Reportable quantities  (RQs)  based on both chronic toxlclty and cardno-
genlclty are derived.   The RQ  1s used to determine the quantity, of a hazar-
dous  substance for  which  notification Is required  1n the  event of a release
as specified under  the  CERCLA.  These  two  RQs  (chronic toxlclty and carclno-
genlclty)  represent twa of six'Scores,;, developed, tthe rewaVtitngi four reflect
IgnltablTtt'y,. reactivity, aquatic toxtclty;  and  acute mammalla'n-  toxlclty).
Chemical-specific RQs.'reflect  the lowest of  these six primary criteria.   The
methodology for  chronic  toxic Hy and  cancer-based  RQs are  defined  1n  U...S..
EPA, 1983a and 1986a» respectively,.

-------
                               EXECUTIVE  SUMMARY

    Haloethers  are  compounds  that  contain  an   ether  moiety   (R-O-R)  and
halogen  substHuents  1n  the  carbon  framework.     With   the  exception  of
b1s(2-ch1oroethoxy)methane,   all   the  other  haloethers  with  known  water
solubility  characteristics  are  either  slightly   soluble  or  Insoluble  In
water, although  some of  the  haloethers decompose  1n water (see Table 1-2).
The  haloethers  are  also  soluble  1n  a wide  variety  of  organic  solvents
(Hawley, 1981; Weast,  1985;  Wlndholz, 1983).  Of  the 27 selected haloethers,
at  least  nine were  produced  1n quantities  >0.1 million  pounds  1n 1977 (see
Table  1-3).   Currently,  only five companies manufacture  unknown amounts  of
four  haloethers  In  the  United  States  (SRI,  1986).   The haloethers  are
generally  used  as  chemical   Intermediates, particularly  for  polymers  and
resins,  and  as  solvents  (Hawley,  1981; IARC,  1974, 1975,  1977;  Wlndholz,
1983; V1al, 1979;  Ellersteln  and Bertozzl, 1982).
    The  selected  haloethers  are  not  expected to  be persistent  atmospheric
contaminants.   In  the  atmosphere,  the  haloethers  will  react  relatively
rapidly 1n the  vapor  phase with hydroxyl radicals  at half-lives  ranging from
1.61  hours  to  1.54  days  (U.S.  EPA,  1987).  In  water,  the  a-chloroalkyl
ethers  have  extremely short  hydrolytlc half-lives  and  are not  expected  to
persist for  extended periods  of  time (U.S.  EPA,  1980b).   Hydrolysis Is.no.t,
envl.tfortmenitaiVTy}  tmpartaitt,,  hawftxefv  far.', the! B-chloroalkyl,  ethers .or, the
aromatic ttaToe-tfters(UvS.  EPA,  T980b,-cr Mabeyi el *T>, T98;T; Oa/Hahan et al.,;.
1979);>-  Based on  tftefr. relatively• ftlgh Tog-If"-,  valuesi  £>4$»;  the apoma,Uc:;
haloethers may  have  a  tendency to. bftacofucentrate' fit* aquatic'organisms and •.
adsorb to  sediment and suspended  soTftfsMn water- ' Vx»TatAUza:1S,Yonfromswater &
may be  an  Important  transport  process for  haloethers  such as b1s(2-chloro-
                                      1v

-------
ethyl)  ether,  2-chloroethyl vinyl  ether,  b1s(2-chloro-l-methylethyl) ether,
4-chlorophenyl   phenyl   ether  and   2,3-d1chlorotetrahydrofuran;  however,
volatilization will  not  be Important for 2,4,4'-tr1chloro-2'-hydroxyd1phenyl
ether,  l,2-b1s(2-chloroethoxy)  ethane  or 1,2-b1s(2-chloroethoxy)methane (see
Table 2-3).   2-Chloroethyl  vinyl  ether,  the  only selected haloether contain-
ing  a  double  bond,  1s  susceptible  to  oxidation  using the  singlet oxygen
concentration  In sunlit  natural   water.   (Mabey  et  al.,  1981)  and  has  an
estimated  half-life of 69  hours.  The alky!  haloethers are  not  expected  td
undergo  significant  direct photolysis 1n the  ambient  environment (Durkln  et
al.,  1975; Callahan  et  al.,  1979).  The  aqueous  photolysis  half-lives  of
2- and  4-chlorophenyl phenyl  ether at  the  surface  of  water under  summer
sunlight  conditions  at   40° N were  estimated  to be -36  and  200  days,
respectively  (Dulln et  al.,  1986).   Sufficient data  are  not available  to
estimate   the   relative    significance   of   m1crob1al   degradation   of  the
haloethers.  Several  of  the haloethers  have  been  found  to  be biodegradable
under  specific  testing  conditions,  while  others  have  been found  to  be
resistant  to  degradation  (Tabak  et al.. 1981;  Ludzack and  Ettlnger, 1963;
Dojlldo,  1979;  Voets  et  al., 1976).   In  soil,  the   a-chloroalkyl  ethers
will  hydrolyze In  the presence of moisture.   Based on estimated K   values
(see  Table  2-4),  the aromatic haloethers will  generally be Immobile  1n soil
and  are  not  expected  to, leach, significantly.   With  the .exception  of
octachfKororflc-ff-p^opiyT ether',  the alky!  haToeth'ers  have a^  medium  to rttghv
degree  of  soil mobility, which  suggests  thai  these compounds are, susceptible
to leaching to groundwater  In the absence of degradation processes.' .
    Chloroalky,!  ethers, do. not occur  as  such  Vn. nature; their, occurrence 1s
entrreTy  anthropogeitfc   (Ui.Sv.   EPAw  Haflavtr^ at  c)'.    Discharges1 from
Industrial  and manufacturing processes represent  the major  sources of these
                                       v

-------
organic  pollutants  In  the aquatic   environment.   Various  haloethers  have
been  detected  1n  drinking  water,  river  water,  groundwater  and  effluent
wastewater {see Table  3-1).   Human exposure to haloethers by  Inhalation may
be  confined  to occupational  settings  (U.S.  EPA,  1980a,b,  or c);  however,
l,2-b1s(2-chloroethoxy) ethane has been  detected  1n an Incinerator waste gas
effluent  (James et  al.,  1984).  Sufficient data were  not  located  to estimate
dally human exposure to these compounds.
    Data  concerning  toxldty  of  haloethers  to  aquatic  biota are  limited.
Studies  by  U.S.  EPA (1978) using  bluegllls and  Daphnla  maqna  Indicate that
2-chloroethyl  vinyl  ether and  b1s(2-chloroethyl) ether  have  nearly equiva-
lent  acute  toxldty  In  these  two species.   D.  maqna appeared  to  be more
sensitive  to  these compounds  than bluegllls.   The  lowest  reported acutely
toxic  concentration   was   184   mg/l   b1s(2-chloroethyl)   ether,   a  96-hour
LC5Q for fathead minnows (Dow Chemical Co., 1984a).
    Pharmacoklnetlc  da\.a  are  available  for  l4C-b1s(2-chloroethyl)  ether
and  l'*€-bTs(Z^hloro>t-methylethyl)   ether  (Smith et  al.,   1977;  L1ngg  et
al.,  1982).   Radioactivity associated with  these compounds Is  rapidly and
nearly  completely  absorbed and  widely distributed throughout  the body.  No
tissue appears to have a  tendency  to  retain radioactivity that Is associated
with  either   of  these compounds,  with  the exception  of the  liver  of the
monkey,  which  appeared   to  retain  14C  associated  with ll4C-b1s(2-chloro-
1 -raethylethyV};; ether tSmVftf et  at.. V97*E,  Th#od1gfycp«r ar~fdS Is the major•
urtnary  metabaltte  oft bte(2-onloroethyT)  ether^  and urtB'ary'raetabo-TTtes of-
bts.(2.-clKlar,o-l'-niethyTethy1).   ether:    include,:    2-T2-chloro-l-me:thyTeti»oxy)-
propanolc  acid and  N-acetyl-^(2,-hydr,o*ypropyl)-L-cys:;telne  (Lfngg  efc al.,.
1982).   Carbon  dioxide   1s  an  important^  metabolite'  of   both  df Jtltes:e!,
haloethers 1n  rats  (Llngg et al., 1982).  Degradation of  14C-haloethers to
single   carbon  units   that   are  Incorporated'  readily   Into   endogenous

                                      vf

-------
substances   may  account   for   the   retention   of  detectable   levels  of
radioactivity  In  the  tissues 7 days after  single  doses to rats and monkeys.
Excretion  Is  primarily  through  the  urine and  expired  air.   The  time  to
excrete  one/half  of  the  dose  of  radioactivity 1n  rats  through  urine and
expired  air  was  12  hours   for  ll4C-b1s(2-chloroethyl) ether  and  19   hours
for ll4C-b1s(2-ch1oro-l- methylethyl) ether (Llngg et al., 1982).
    Rats  exposed  to 1 or  10 (3 or 33 mg/m3)  chloromethyl methyl  ether, 6-7
hours/day  for  up  to  30 days,  and  rats  and  hamsters  exposed  to 1  ppm  (5
mg/m3)  bls(chloromethyl)  ether, 6  hours/day  for  up  to 30  days...  experienced
mortality  and  hlstopathologlcal   alterations  of  the   respiratory  tract.
Lifetime  exposure  of  rats  and hamsters   to  1  ppm  (3 mg/m3)  chloromethyl
methyl ether,  6 hours/day,  5 days/week produced hlstologlcal  changes In the
respiratory  tract  (Laskln  et  al.,  1975).    Survival   was  not  affected.
Inhalation  exposure  to  20  or 70  ppm  (140  or  490 mg/m3)  b1s(2-chloro-l-
                                                           • •           * •
methylethyl) ether,  6 hours/day,  5 days/week  for 4  weeks did  not produce
altered blood or  urine Indices, or  tissue  histology;  however,  reduced weight
gain occurred at 70 ppm (Gage, 1970).
    Dally, oral  exposure to  b1s(2-chloro-l-methylethyl)  ether  for  13  weeks
produced  reduced  body weight 1n rats at'250 mg/kg but  not at lower doses (no
hlstologlcal effects at any  doses)  (NCI,  1979),  and focal pneumonHls at >50
mg/kg  In  mice  (N.TP.,19821.  Subcbrontc'aral  exposure. to<  \Q» mg- bAsll-chToro-r
T-methyTe.ttfyl J etWer?  (22: dtfse*  fnv3T days-):" produced1" decreased growth":1tr rat*
(Dow  Chemical,  rud..);• Increased-  relative  liver,  kidney  and  spleen weights
occurred  at  200   mg/kg;.    Ora-T exposure   to  2;,4,4'-tr1chloro-2r-d1hydroxy--
dlp.henyl.  ether on  6  days/week for 4.  weeks  caused, reduced weight gain and
mortality  In rats at  1000  mg/kg  but  not  at  lower doses (Lyman  and furtay
1969).  Nasal  tumors  developed  1n  rats  and possibly lung  tumors developed In
mice  that were exposed to  b1s(chloromethyl)  ether by  .Inhalation  at concen-

-------
tratlons  of  100  ppb   (5  vg/m3).  &  hours/day,  5  days/week  for  6  months
with  lifetime observation  (Leong  et al.,  1981} and  nasal  tumors  In  rats
exposed  to 0.1  ppm  (0.5  mg/m3)  for 6  hours/day,  5 days/week, for  40-100
exposures with lifetime observation  (Kuschner et  al.,  1975).
    Another study  Indicated  that  treament-related  respiratory  tumors of  an
unspecified  type  developed   1n  rats  exposed  to 0.1  ppm  (0.5  mg/m3)  b1s-
(chloromethyl) ether  vapor,  6 hours/day,  5 days/week  for 30 exposures  with
lifetime observation  (Dulak  and  Snyder,  1980).   b1s(Chloromethyl) ether  also
produced an  Increased  Incidence and frequency of  lung adenomas In  strain A
mice  exposed   to  1  ppm  (5   mg/m3),  6  hours/day  for  82  days   In  27  weeks
(Leong et al., 1971).
    Commercial   grade   chloromethyl   methyl  ether  vapor   did   not   produce
significantly  Increased Incidences  of  respiratory  system tumors 1n rats  or
hamsters  exposed  to  1  ppm  (3  mg/m3)  for  6  hours/day,  5  days/week,  but
there  were Increased Incidences  of  squamous  metaplasia  of  the trachea  and
bronchial  hyperplasla  1n  the  rats   (Laskln  et  al.,  1975).  Strain  A  mice
exposed  to 2  ppm  chloromethyl  methyl ether  vapor,  6 hours/day, 5  days/week
for  10.1  days  In 21  weeks  also  developed  lung  tumors,,  but the  results; were  .
judged  Inconclusive because  the  test material  was  contaminated  with  bls-
(chloromethyl) ether  (Leong  et  al.,  1971).  Epidemic!ogle  studies of workers
exposed  to b1s(cb,loromethy."l) ether  and  cpoBtercAal ct>loroinett»y_V tnethyV ethers
Nave  rfemcrrsitrited4,:; exTW^ofe-re^fetf. occutfmteei  of"  Turfg "^umorsv;  prerfonrf^
nanUiy smaliT  ceW-undlfiferenttated or;  oat-ce*Tl   capctnoraas  (>see   Section'
6v2r.Tr.JL);;.,   Because;  frtdustrlaj  grade;  chtoronietttyrF methyl', ether;  contatns.
carcinogenic ,b:i»sf(chloroniethylj  etherr as-a, contaminant',, and because  therev Vsi
Vnsufvffclterct?^'epttfemlologfc\ev1dence'-,to  separate the carcinogenic effects  of
these  compounds,  there  Is  sufficient  evidence  to conclude  that  b1s(chloro-
                                     v11V

-------
methyl)  ether  and  Industrial  grade  chloromethyl  methyl  ether  are  human
carcinogens (IARC, 1979; U.S. EPA, 1980b).
    Dally  Intubation  with  commercial  grade b1s(2-chloroethyl)  ether  at  a
dose  of  100 mg/kg  on days  7-28  of life  followed by  administration  In the
diet  at  a concentration of  300  ppm for the next  76  weeks produced signifi-
cantly Increased  Incidences  of  hepatomas In male  and female B6C3F1 mice and
male  B6AKF1  mice  (BRL,  1968;  Innes  et  al.,  1969);  the  TWA dose was  41.3
mg/kg/day.   Twice  weekly  administration  of   100%  pure  b1s(2-chloroethyl)
ether  by gavage  at  doses  of 25  or  50  mg/kg  for  78 weeks, followed  by a
26-week  observation  period,  was  not  carcinogenic  1n Charles River  CD  rats
but caused  reduced  weight  gain at both  doses and  mortality at the high dose
(Helsburger et al., 1981).
    Cardnogenldty bloassays of  technical  grade b1s(2-chloro-l-methylethyl)
ether were conducted  1n  which groups  of 50 F344 rats  of each sex (NCI, 1979)
and 50 B6C3F1  mice of each  sex  (NTP,  1982) were  treated  by gavage at doses
of 100 or  200 mg/kg, 5  days/week  for  103 weeks.   The technical  grade chemi-
cal was  -70X  pure,  containing -28.5X 2-chloro-l-methylethyl-(2-chloropropyl)
ether, and  2% ^b1s(2-chloro-n-propyl) ether.  The  rats were  observed  for 1-2
weeks following  treatment.   Increased  Incidence  of tumors  did  not occur  In
the rats  but  there were  nonneoplastlc  effects  that  Included reduced weight
gain  and decte&sed. survival .(both doses),  centrllobular necrosis {high dose)
and e*ophragea?T hyptertfeTattt^s^ (ffr;fgft%KfCfS^.  Tlfe  mfcr were: observed  for T-7^
weeks  following  treatment  and  developed s,1gn1f leant Ty  Increased•  Incidences
of  alveolar/bronchlolar  adenomas  (both  sexes.),   hepatocellular   carcinomas
(.males),..and- low,  Incidences, of iquamous  ce;Yl pap.1.llomas, or carcinomas in the-
stomach'or  forestomach  (high-dose females)'.  Nonneop'Tastlc effects'occurred
In the male mice,  Including  fatty metamorphosis and  chronic Inflammation  of
                                      1x

-------
the nasal  cavity  and  nasolacMmal  duct.   High purity (98.5%) b1s(2-chloro-l-
methylethyl) ether was  not  carcinogenic  to SPF-ICR mice when administered  In
the diet   to  groups  of  56  mice/sex  at  concentrations  of 80,  400,  2000  or
10,000 ppm for  durations  as long as 104 weeks (M1tsumor1  et al., 1979).  The
average dally   Intake  of  chemical  by  the 10,000  ppm group was  higher  (961
mg/kg/day  by males; 927  gm/kg/day  by females) than that given to^the mice  In
the NTP   (1982)  bloassay.   Toxic  effects  Included  mild  anemia,  Increased
polychromatic  erythrocytes  and  splenic  hemosldeMn  deposition  at  the  high
dose  1n  both  sexes  primarily during  the  first  half of  the study.  Similar
effects also occurred  at 2000 ppm  1n  the  females  and only at  13 weeks at  80
and 400 ppm In  the males.
    The  cardnogenlcHy  of  numerous  chloroethers  has  been   evaluated  1n
dermal application,  dermal  Initiation-promotion,  subcutaneous  Injection and
Intraperltoneal Injection  studies.   Host  of  these  studies were  connected  by
Van Duuren et  al.  (1968,  1969,  1971, 1972, 1974, 1975), who administered the
compounds   thrice  weekly (dermal studies)  or  once  weekly  (Injection studies)
to  mice  for  life.   b1s(Chloromethyl)  ether was  tumorlgenlc  In all  of the
aforementioned  types  of studies. Including  mouse  skin  assays" In-wh-fch  bis1-
(chloromethyl)  ether   was  active   as  an  Initiator  or  promoter.   1,2-bls-
(chloromethoxy)ethane  and  1,2,3-tr1s(chloromethoxy)propane  were tumorlgenlc
in vtfermaft; •atfp'Tfea'tfl.tfriv;.  subtetttaftedus , fnfec&fow?: Srttfl, trttraper^fionea'T   trf|ee-
tlon  studies*.   Chloromethyl  methyl  ether,  bits(a'-chToroethyl)'   ether  and
T,2v3-trVs(chiToromethoxy')R'*opan»j were tutmmtgerrl'c by  subcutaneous Injection.
    Positive   responses;,  have 'been  produced1  by  bts(chloromethyl)   ether,
b;1Tsi2-Cih^aroe;thyl%:;:e*herAand b*s(2-chloto;-1-meth'y.Tethyl)  eth'er;  Vn^la^vl^rg;;
assays with  various  strains  of  S.  typhlmurlum.  B.  subtnis.  E..  coll   and  S.
cerevlslae  without  metabolic  activation  (Shlrasu  et  al., 1975;  Simmon  et

-------
al.,  1977a,b,  1978;  Anderson and  Styles,  1978), which  Indicated that  these
chloroethers  may be  direct-acting mutagens.  b1s(2-Chloroethyl)  ether also
produced  chromosome  aberrations  and  slster-chromatld exchanges  In cultured
Chinese  hamster  ovary  cells  (NTP,  1982).   bls(Chloromethyl)  ether  did not
produce  chromosome  aberrations  In  the  bone marrow cells  of  mice exposed by
Inhalation  (Leong  et al.,  1981).   2,2,4'-Tr1chloro-2'-hydroxyd1phenyl  ether
was  negative In  the j_n vivo  spot test with  mice (Russell  and Montgomery,
1980).
    Pertinent  data   regarding  the  teratogenldty  of  the  chloroethers  could
not  be  located  In the  available  literature as  cited 1n Appendix A.   Intra-
perltoneal  Injection of  2,4,4'-tr1chloro-2'-hydroxyd1phenyl ether to mice on
postconceptlon  day   10.25  caused  reduced   Utter  sizes  because  of maternal
toxldty  at  25 mg/kg and  reduced postnatal survival  at 3-25 mg/kg (Russell
and Montgomery,  1980).
    A  carcinogenic   potency  (q,*)  of  59.5  (mg/kg/day)'1  was  estimated for
oral  and  Inhalation  exposure  to  bls(chloromethyl)  ether,  based   on the
Induction  of nasal   esthesloneuroepUhellomas  In rats  exposed by  Inhalation
(Leong et  al.,  1981).   A cancer-based RQ  of 1  was estimated  for b1s(chloro-
methyl)  ether  from  the  same  data.  b1s(Chloromethyl)ether  was  assigned to
EPA Group A.
    ChToTometffyT methy/T; eth'eit was  ass.1gn.ett to  EPA. Group'; AV  on: the»:' Kafst'r- af4'
ep1dem1olog1cal  (occupational) evidence, of human carclnogenldty.  Data were.
Insufficient for estimation  of  carcinogenic potencies:.  A" .cancer-based  :RQ of-
T was  based on the  assignment of.  chloromethyl  me.thyl ether  to Potency  Group
2...   A toxlc1ty;-based-. RQ; of.: TQff  was* derfved^ fifcornvdata on. h;l;stop4too^ojg1;caCK
alteration  of  the   tracheal  and  bronchial epithelium  In  rats  exposed  by
Inhalation for life  (Laskln et al., 1975).
                                      x1

-------
    b1s(2-Chloroethyl)  ether  Is  an  EPA  Group  B2  carcinogen,  which   Is
associated with the  Induction  of  hepatomas  In orally exposed male mice (BRL,
1968;  Innes  et   al.,  1969).   A  q^  of  2.46  (mg/kg/dayr1  was  estimated
for  oral  exposure  and  a  q,*   of  1.23   (mg/kg/day)"1  was   estimated   for
Inhalation  exposure  to b1s(2-chloroethyl)  ether  based  on the  data  1n mice.
A  cancer-based  RQ of  10  also  was derived  from  the  data  regarding hepatomas
In  male  mice.   A  tox1dty-based RQ  of 100 was  based  on  mortality  1n a
chronic oral study In  rats (Helsburger et al., 1981).
    b1s(2-Chloro-l-methylethyl) ether,  technical grade, was  assigned to  EPA
Group C,  predominantly because the technical  grade material  1s ~70% pure  and
1s contaminated with  other chloroethers that may  contribute  to Us cardno-
genldty.   An  NTP (1982)  gavage  bloassay  associated  technical grade b1s(2-
chloro-1-methylethyl)  ether  with   Induction of  hepatocellular  carcinomas  and
adenomas  In  mala  mice.   From   these  data  a  q *  of  6.97xlO~2   (mg/kg/
day)'1  for  oral   exposure   and  a  q  *   of  3.49xlO~2   (mg/kg/day)'1   for
Inhalation  exposure  have  been  estimated.  A  cancer-based  RQ  of 100 was also
derived from.the.se data.   A  tox1c1ty-based  RQ of 1000 was .based on mortality
1n rats In a negative  2-year cancer study (NCI,  1979).
    Few data were located for 2,4,4'-tr1chloro-2'-hydroxyd1phenyl  ether.  A
subchronlc  oral RfD.-of .-200 mg/,day,was based  on  a NOEL of. .429,  mg/kg/day In a
4i-weefe- ora-TV study us:i:n& r«tii' (fcynair .antf fitr#av. fS6&)|.  WortaTtty,; aiwti reduced
body weight gain  were observed at 
-------
                              TABLE OF  CONTENTS
1.  INTRODUCTION ...........................   1-1

    1.1.   STRUCTURE AND  CAS  REGISTRY NUMBER .............   1-1
    1.2.   PHYSICAL AND CHEMICAL  PROPERTIES .............   1-1
    1.3.   PRODUCTION  DATA ......................   1-1
    1.4.   USE DATA .........................   1-1
    1.5.   SUMMARY ..........................   1-12

2.  ENVIRONMENTAL  FATE AND  TRANSPORT .................   2-1

    2.1.   AIR ............................   2-1

           2.1.1.   Reaction  with Hydroxyl Radicals .........   2-1

    2.2.   WATER ...........................   2-3

           2.2.1.   Hydrolysis ....................   2-3
           2.2.2.   Oxidation ....................   2-3
           2.2.3.   Photolysis ....................   2-3
           2.2.4.   Mlcroblal  Degradation ..............   2-5
           2.2.5.   Volatilization ..................   2-6
           2.2.6.   Adsorption  to Sediment ..............   2-7
           2.2.7.   B1oconcentrat1on .................   2-7
                             .                          • •           " •
    2.3.   SOIL  ................. .......... _2-9

           2.3.1.   Mlcroblal  Degradation ..............   2-9
           2.3.2.   Chemical  Degradation ...............   2-9
           2.3.3.   Adsorption ..............  ......   2-9

    2.4.   SUMMARY. .  ........... .............   2-10

3.  EXPOSURE .............................   3-1

    3.1.   WATER ...........................   3-1
    3.2.   FOOD  .... ....... ........  ........   3-1  :
                   ......  . .. .. . .. . .. . ...... ...., ........ ... ......  3-5
    3.5'.   SUMMARY.  .  ....  . . ....... ...... .  . ..  . ...  .  . ... .   3-5

4..  AQUATIC TOXICITY.  .  .  .! >.;..,. > .. ., ., ..,. ....... .....  . , ..... ,...—. ..  4-1

    4.1.   ACUTE • TOXICITY  ........ ----- . .  ....... .......  .  .  .   4-1
    4.2..   CHRONIC; EFFE-CTS...  .. .. . ..... . .. . „  ......  ..  .  .. ..  .. ..  4-1
    4;3v   FLAW?- EWECTSr;  ....... .. .- . , . .  . .  . ...... . ..  .  «  4--T-
    *;.«r..-   SUMMARY.  .  .  .  ..... ., ------- . ., ..  . , ______ .  . ,. . ..  « .
                                     X111

-------
                          TABLE  OF  CONTENTS (cont.)

                                                                          Page

5.  PHARMACOKINETCS	5-1

    5.1.   ABSORPTION	5-1
    5.2.   DISTRIBUTION	5-1
    5.3.   METABOLISM	5-3
    5.4.   EXCRETION	5-4
    5.5.   SUMMARY	5-5

6.  EFFECTS	6-1

    6.1.   SYSTEMIC  TOXICITY	6-1

           6.1.1.    Inhalation Exposures	_^6-l
           6.1.2.    Oral Exposures	6-4
           6.1.3.    Other Relevant Information	6-10

    6.2.   CARCINOGENICITY	6-10

           6.2.1.    Inhalation	6-10
           6.2.2.    Oral	6-21
           6.2.3.    Other Relevant Information	6-26

    6.3.  .MUTAGENICITY	6-35
    6.4.   TERATOGENICITY	........   6-35
    6.5.   OTHER  REPRODUCTIVE EFFECTS  	   6-40
    6.6.   SUMMARY	6.-40

7.  EXISTING GUIDELINES AND STANDARDS  	   7-1

    7.1.   HUMAN.,	=....',.	,7-1
    7.2.   AQUATIC	-1-2

8.  RISK ASSESSMENT	8-1

    8.1.   CARCINOGENICITY	8-1

          ' 8.T*T'.«   InteTa;t1on.iV «.«„„„ *•„.., «•.««,«.« . ,«;... ... —,  8>I'.';'
           8'a-.'?.:   Or'al. . . .*'-'•..  . ....  . .,., ..  .  .  ..,..., .. ... ., ~ .  . -.-  842  .
           8.K3-.    Other Router.  .	   8-3
           B.T.4?.    Weight of Evidence-	,	^.8-4;
           8.1^5?.    Quantitative Risk;  Assessment.  .;	..8-5

    8.2.:   SYSTEMIC  TOXICITY. .	 .,	«	 ., .  .,  8-11
           S??:!'. *• rrih-aiTa-td'an; Efxpo'swre;-^. . ,...,:•... ., .	, ., .,  ....  . ..,  8;-1il
           8.2.2.    OraT E-xp'osiine  .  4 -	 .........  .-,,. ... „.,  .  •*
                                      x1v

-------
                           TABLE  OF  CONTENTS  (cont.)
 9.  REPORTABLE QUANTITIES	_9-l

     9.1.   BASED ON SYSTEMIC TOXICITY 	   9-1
     9.2.   BASED ON CARCINOGENICITY	   9-11

10.  REFERENCES	10-1

APPENDIX A: LITERATURE SEARCHED	A-l
APPENDIX B: CANCER DATA SHEETS FOR DERIVATION OF q^s	B-l
APPENDIX C: SUMMARY TABLES FOR HALOETHERS	C-l
                                      xv

-------
                               LIST OF TABLES
No.                               Title                                 Page
1-1     Synomyns, CAS Numbers, Empirical  Formulas  and Structures
        of Selected Haloethers ....................  1-2
1-2     Physical Properties of the Haloethers  ............  1-6
1-3     1977 U.S. Production  Data for  the Haloethers .........  1-8
1-4     Use Data for Haloethers  ...................  1-11
2-1     Haloether Reaction Rates with  Atmospheric  Hydroxyl
        Radicals ...........................  2-2
2-2     Hydrolysis Rates of Haloethers  In Water  ...........  2-4
2-3     Volatilization of Haloethers  from Water  ...........  2-8
2-4     Estimated Koc of Selected Haloethers .............  2-11
3-1     Occurrence of Haloethers  In Various  Types  of  Waters
        1n the United States .....................  3-2
3-2     Levels of Haloethers  In  U.S.  Waters  Computed  from
        STORET Data Base .......................  3-4
6-1     Acute Oral and Inhalation Toxldty of  Chloroalkyl Ethers. .  .  6-11
6-2-     Incidences of Tumors  In  Male  Sprague-Dawley SPF Rats               :
        (Spartan Substraln) and  Hale  Ha/ICR  Mice Exposed to
        bls(Chloromethyl) Ether  by Inhalation  for  6 Hours/Day,
        5 Days/Week for 6 Months with  Lifetime Observation ......  6-13
6-3     Incidence of Respiratory Tract  Tumors  1n Hale Sprague-
        Dawley Rats Exposed to 0.1 ppm bls(Chloromethyl) Ether
        for 6 Hours/Day, 5 Days/Week  for  10-100  Exposures with
        Lifetime Observation .....................  6-16
fc-C-    L'ung Career Mortality :1nf Workers  Exposed to bVs(ChlORa-»;:.
        methyl)" Ether 'artd? Techrtfcal -Grades Chloromethyt MethyT <•.
        Ether (Selected Ep1demto.logxtcal Studies)-.  ----------- ..... . .... fr-22
S-i£    Incidence of Hepatomas 1n Two  Stra.Jnsi of Hleenfffiyen Oral   V  '
        Oases jaf b1s(2-Chloroethy;l:)/ fcther u .  .  .  ,.'•.; _,.;^ ... ~  .. ,,  .„ 6*2$
6-6 i   Incidence of, .Tumors;, In, B&C3F1  Mice Treated with .Technical
        Grade b.1s(2-Ch)lorlo:-T^me;tWylethy;l?) -PtKer  In Corn 011s by
        Savage'V S-vDay^/Week foH vaa.Weetesf .„ *.>„• - ------- . . . -~r ., .  .  fr.-27.sf
6-7     Dermal Tumor1gen1c1ty  of  Haloethers  1n Female Mice ......  6-29
                                     xv1

-------
                           LIST OF  TABLES (cont.)
No.                               Title                                Page
6-8     House Skin Tumor-Initiating and Tumor -Promo ting  Activity
        of Chloroethers .......................   6-30
6-9     Subcutaneous Injection CardnogenlcHy Studies of
        Haloethers ..........................   6-33
6-10    IntraperHoneal Injection CardnogenlcHy  Studies
        of Haloethers with Mice ...................   6-36
6-11    Mutagenldty and Other Short-Term Genotoxldty Assays
        of Haloethers ...........  .............   6-37
9-1     Toxldty Summary for Chloroethers ..............   9-2
9-2     bls(Chloromethyl)  Ether: Minimum Effective Dose  (MED)
        and Reportable Quantity (RQ) .................   9-4
9-3     Composite Scores for Chloroethers ..............   9-6
9-4     Chloromethyl Methyl Ether:  Minimum Effective Dose  (MED)
        and Reportable Quantity (RQ) .................   9-7
9-5 ..  b1s(2-Chloroethyl.) Ether: Minimum Effective  Dose (MED)
        and Reportable Quantity (RQ) .....  ............   9-8
9-6     b1s(2-Chloro-l-methylethyl) Ether: Minimum Effective
        Dose (MED) and Reportable Quantity (RQ) ...........   9-10
9-7     2,4,4'-Tr1chloro-2'-hydroxyphenyl) Ether:  Minimum
        Effective Dose(MED) and Reportable Quantity  (RQ) .......   9-12r
9-8     Derivation of Potency Factor (F) for bls(Chloromethyl)
        Ether ............................   9-13
9-9     Derivation of Potency Factor (F) for b1s(2-Chloromethyl)
        Ether ... ..••... . ...„,., ..... . .. „• ,. ., . ,..., *. . .....,- .......  $-15?'
i-JOV   Oen-Dvfft-ron: of Potency; Factor (iFf forr
        methyTethyl) Ether (CommerdaT Grade)  .  .  .  .  .  ..... ...   9-T8
                                    xv11

-------
                             LIST OF  ABBREVIATIONS

B(a)P                   Benzo(a)pyrene
BCF                     Bloconcentratlon
bw                      Body weight
CAS                     Chemical Abstract Service
EC,.                    Concentration effective to 50% of recipients
GOT                     Glutamlc oxaloacetlc transamlnase
GPT                     Glutamlc pyruvlc transamlnase
KQW                     Octanol/water partition coefficient
LC5Q                    Concentration lethal to 50% of recipients
LC.                      Lowest lethal concentration
  Lo
LD5Q                    Dose lethal to 50% of recipients
LOAEL                   Lowest-observed-adverse-effect level
MTO                     Maximum  tolerated dose
NOAEL                   No-observed-adverse-effect level
NOEC                    No-observed-effect concentration
PEL                     Permissible exposure level
PMA                     Phorbol  myMstate acetate
ppb                     Parts per bill loft
ppm                     Parts per mtlllon.
RfD                     Reference dose
RQ                      Reportable quantity
RV.                     Dose-rating value
RV                      Effect-rating value
  e
STEL                    Short-term effect level
TLV                     Threshold, leve,! value
TPA                     T2-Q-n-te.tratfecan0y 1 pttor p4b'o;fl--T3 -acetate;
TWA*                     Tlme-wetghted average"
UV                      Ultraviolet-
                                     xv1)1

-------
                               1.  INTRODUCTION
1.1.   STRUCTURE AND CAS REGISTRY NUMBER
    Haloethers  are  compounds  that   contain  an   ether   moiety   (R-O-R)  and
halogen  substltuent(s)  In  the  carbon  frameworks.   The  structures,  CAS
Registry numbers,  synonyms  and  empirical  formulas of the selected haloethers
are presented In Table 1-1.
    In  an  ether,  the  numbering or  lettering of  the  carbons begins  at the
carbon  next  to  the oxygen.   Additionally,  an a-haloalkyl  ether  1s  the same
as 1-haloalkyl ether.
1.2.   PHYSICAL AND CHEMICAL PROPERTIES
    The  available  physical  properties   of  the  selected  haloethers  are
presented 1n Table 1-2.
1.3.   PRODUCTION DATA
    Production  data  available  for  1977  are  presented   In  Table 1-3.   SRI
(1986) lists current U.S. production of the  following haloethers:

    b1s(2-Chloro-l-methylethyl)  ether     Dow Chem., Freeport, TX
    a,a-D1chloromethyl methyl ether       Aldrlch Chem.,  Milwaukee, HI
    b1s(.2-Chloroethyl) ether              Buckman Labs, Memphis, TN
    l,2-b1s(2-Chloroethoxy:)ethane         Eastman Kodak,  Batesvllle, AR
                                          Koch Ind., Whitehall, MI

B1s(2-chloroethoxy)methane  1s  produced  as.  an  on-slte Intermediate .for the,
product-Ton;  of paTysuTftde/po!Tymef$  fCllersteTnl  arid; Bftrttozrt.  T982J;,  poTy*
sulflde polymers are currently  manufactured'by Morton1 Thtoko'l tn Moss Point,
MSr (SRI, 1986).
1.4.   USE. DATA
    U"s,e data' for selected haloethers are: g,fyefr !n Table: 1-4.
0037d                               1-1                               07/07/87

-------
o
o
Oi
                                                                             TABLE  1-1

                                          Synonyms,  CAS Numbers,  Empirical  Formulas and Structures of Selected Haloethers
                      Compound
              Synonyms
CAS Number
                                                                                                Empirical
                                                                                                Formula
Structure
 i
rsj
         1,2-bls(2-Chloroethoxyjethane
         bts(2-Chloroethoxy)methane
          '''"
         bls(2-Chloroethyl) ether
bts(a-Chloroethyl) ether


 • <      v              ' r:


1,4-bls(Chloromethoxy)butane

1.2-bls(Ch1oromethpxy)ethane




1,6-bls(Chloromethoxy)hexane,

bls(Chloromethyl) ether
trlethylene glycol dlchlorlde.
trtglycol dlchlorlde,
l,2-bls(chloroethoxy)ethylene.
2-J2-chloroethoxy) -ethyl
2'-chloroethyl ether

ethane, l,l'-[methylene-
t)lsjo»y)]bls-l2-chloro-,
bisi^-chloroethyl) formal.
dl|2-chloroethoxy)methane,
d||2-chloroethoxy) formal.
djchjbrodlethyl formal.
2,2-dtchloroethyl formal.
jiis(B-chloroethyl) formal
 ' '' "-/'^ ^
ethane, 1,1' -oxybls[2-chloro-,
B.B'-dlchloroethyl ether,
jjich)ort>ethyl ether,
dichloroethyl oxide,
sym'-dlchloroethyl ether, DCEE. BCEE
• ": "• '',^5,
ethanf, l,l'-oxybls[l-chloro-,
blsjlrthloroethyl) ether,
dl-l-chloroethyl ether,
i.l'-dlchlorodlethyl ether
7 , ~

biitan'e, l,4-bls(chloromethoxy)-

bls-i,|-(chloromethoxy (ethane,
ethylene glycol bls(chloro-
        ether
o
en
     '*
b*$-|,|-(chlororoethoxy)hexane
    " * )'.
methane, oxyblsjchloro-,
BCHE, J-(dlchloroinethyl) ether.
chlprodlmethyl ether,
dlmejihyl-1 ,1-dlchloro ether
                                                                                  112-26-5
                              C1-CH2-CH2-0-CH2-CH2-0-CH2CH2-C1
  111-91-1     CsHioCl202     C1-CH2-CH2-0-CH2-0-CH2-CH2-C1
  111-44-4     C4HBC120       C1-CH2-CH2-0-CH2-CH2-C1
                                                                                          6986-48-7     C4H8C120
                              CH3-CH-0-CH-CH3
                                  I     I
                                  Cl    Cl
                                                                                         13483-19-7     C6"l2c12°2      C1-CH2-0-CH2-CH2-CH2-CH2-0-CH2-C1

                                                                                         13483-18-6     C4H8C12°2       C1-CH2-0-CH2-CH2-0-CH2-C1



                                                                                         56894-92-9     C8H16C1202      C1-CH2-0-(CH2)6-0-CH2-C1

                                                                                           542-88-1     C2H4C120        C1-CH2-0-CH2-C1
CD
ca

-------
                                                                         TABLE  1-1  (cont.)
                      Compound
              Synonyms
CAS Number     Empirical
                Formula
                           Structure
         2, ?'-Oxyb1s(2-chloropropane)
         bts(4-Chlorophenyl)  ether
         2-Bromophenyl phenyl ether
         3-Bromophenyl phenyl ether
b|$|?-chloro-2-methylethyl) ether.
i>jf (2-chlorotsopropyl Jether,
dl(2-ch1orolsopropyl) ether
beniene, l.l'oxybls(4-chloro-.
tltt(p-chlorophenyl)] ether.
4.V-d1chlorodlphenyl ether.
 ?,ja'-d!chlorodlphenyl ether
 ,*"..           <.
ttenpene, l-bromo-2-phenoxy-.
p'-i»fonophenyl phenyl ether
beniene. l-bromo-3-phenoxy-.
p-6rpmpheny1 phenyl ether,
pi'-j>iienoxyphenyl bromide
39638-32-9     C6H1?C120
 2444-89-5
 702S-06-1     C12H9BrO
 6876-00-2     C12H9BrO
                             Cl  C1

                         CH3-{-0-i-CH3

                             ^H3 CH3
co       2-Chloroethyl methyl  ether
         2-Chloroethyl vinyl  ether
         Chloromethyl methyl  ether
         2-Chlorophenyl  phenyl ether
         3-Chlorophenyl phenyl ether
ethane, l-chloro-2-methoxy,
2-nethoxyethyl chloride

ethene. (2-chloroethoxy)-,
O^chjoroethyl vinyl ether
2-yjjnyloxyethyl chloride

methane, chloromethoxy-. CHHE
methyl chloromethylether.
              chloride
beniene, l-chloro-?-phenoxy-
ij-cljlorophenyl phenyl ether
2-cljlorodlphenyl ether
beniene. 1-chloro-3-phenoxy-
ni-ehlorophenyl phenyl ether
3-chlorodlphenyl ether
  627-42-9


  110-75-8



  107-30-2



 2689-07-8
C3H7C10


C4H7C10



C2H5C10



C,2H9C10
 6452 49-9     Cj2H9C10
CH3-0-CH?-CH2-C1


C1-CH2-CH2-0-CH=CH2



C1-CH2-0-CH3
 oa
         4-Chlorophenyl phenyl ether
beniene, 1-chloro ^-phenoxy-.
p-cMorophenyl phenyl ether
4-chjorodlphenyl ether
 7005-72-3     C12H9C10

-------
o
Gi
                                                                      TABLE  1-1  (cont.)
                    Compound
              Synonyms
CAS Number
Empirical
 Formula
Structure
       2,3-Dlchloro-p-dloxane
1.4-dtoxane, 2.3-dlchloro-.
p-dioxane, 2.3-dlcnloro-
   95-59-0     C4H6C1202
       trans-2.3-Olchloro-p-dtoxane
1.4-dtoxane, 2,3-dlchloro-, trans-
 3883-43-0

       a.a-Dlchloroaiethyl methyl
       ether    >:  -,
       2,3-Dlchlorotetrahydrofuran
       trans-2.3-Olchlorotetrahydrofuran
•ethane, dlcMoronethoxy-
dlchlqronethyl "ethyl ether
•ethyl'dtchlorooethyl ether
|,l-dlchiprp«ethyl *ethyl ether
none
               none
 4885-02-3     CZH4C120
 3511-19-1     C4H6C120
13129-90-3     C4H6C120
                         C1-CH-0-CH3

                            Cl
                             1,
                          p-p
 o.
 •j
 v.
 CD
       Octachloro-dl-n-propyl ether
       bls(2-Chloro-l-oethylethy1)  ether
propane, ),}|-oxybls(2.3.3.3-tetra-
chlbrqpctachlorodlpropyl) ether.
bit(2.3.3,3-tetrachloropropyl)  ether
rjonsantp 1^226
bls(2-chlorolsopropyl) ether.
dlchlQroispprqpyl ether. DCIP,
2.2J-oxyblsjV-chloropropane),
propy)ene'ch|prohydrln ether
D.P:-dtch)6r«Viopropyl ether. BC1E
  127-90-2     C6H6ClflO
  108-60-1     C6H|2C120
                                                                                                                                 J,
                  Cl                Cl
                  I                 I
               C1-C-CH-CH2-0-CH2-CH-C-C1
                  II               II
                  C1C1              C1C1

               C1-CH2-CH-0-CH-CM2-C1
                      I    I
                      CH3  CH3

-------
o
o
to
                                                                        TABLE 1-1 (conl.)
                     Conpound
Synonyms
                                         CAS Number
Empirical
 Formula
                                                                                   Structure
         2.4.4'-Tr|ch1oro-2'-hydro)cy-
         dtphenyl ether
         1.2.3-trts(Ch1oromethoxy)propane
phenol. 5-chloro-2-(2.4-d1chloro-         3380-34-5
  eenoxy)-, Cloxlfenol. Irgasan,
  xql 300, trtclosan. TCC, 1HOP.
2-hydroxy-?'.4.4'-trIchlorodl-
phenyl ether. 2.3>-oxybts(1'5-dt-
chlprophehyl-5-chlorophenol).
S-ch1oro-2-(2,4-dlch1orophenoxy)-
pheriol, 3-ch1oro-6-(2.4-d»chloro-
phenoiyjpnenol

trls-1.2.3-(ch1oronethoxy)propane        38571-73-2
glycerlp trls(chloromethyl) ether
glycerol trl(chlorooethyl) ether
 i
 en
                                                         C1-CH2-0-CH2-CH-CH2-0-CH2-C1

                                                                      0
                                                                      I
                                                                      CH2

                                                                      Cl
 o
 -j
 o
 «J

 00

-------
              TABLIE 1-2
Physical Properties of the Haloethers
0
0
CO
-J
o.









t
1












tr»
\
t\J
ox
CO •
-o

Haloether
1.2-bls(2-Chloroethoxy)ethane'
bls(2-Chloroethoxy)me thane
••'-• -'„._ -rf '
bls(2-Chloroethyl) ether
-. . "-'•--. • y. '-
bls(o,-Chloroethyl) ether
1 ,4-bli(Chloromethoxy)butan9
l,2-bls(Chloromethoxy)ethane
'"•'•" -
-------
                                                                         TABU 1-2 (cont.)
O
o
 O
 en
 cx>
Haloether
trans -2. 3-01 chloro-p-dloxanc
o.a-Olchloromethyl piethyl ether
2.3-Olchlorotetrahydrofuran
trans-2.3-Dlchlorotetrahydrgfuran
Octachloro-dl-n-propyl ether
bls(2-chloro-l-inethylethy) ether
2.4.4'-Trlchloro-2'-hydroxy-
dlphenyl ether ~:' " '
1, 2, 3-Tr1s(chloromethoxy (propane
Molecular
Weight
Ifl.Ol
JJ4.97
141.01
ML 01
3*1 •"
M?-08
289.53
231.53
Melting
Point
NA
NA
NA
NA
NA
-97C
54-57*
NA
Boiling
Point
NA
84. 5d
NA
NA
NA
189C
NA
(at 19 inn)
Density
(20"C)
(g/cro3)
NA
1.27d
NA
NA
NA
1.113d
NA
1.3575*
(17.5°C)
Mater
Solubility
(mg/l)
NA
NA
NA
NA
NA
1700° (room
temperature)
51
decomposes^
Vapor Pressure
(run Hg)
NA
NA
NA
NA
NA
0.85 (20°C)C
0.000004 (20°C)k
NA
Log Kow
•1>
1.1 38b
1.522b
1.522b
5.472b
1.614b
5.001b
1.560b
allawley. 1981


bU.S. EPA (1987) calculated value


cCaltahan et al., 1979


dOurkln et al.. 1975
•:- '  ' '.           -«i'-'

eHansch and teo. I,g85


flARC, 1974. 1977


QWeast. 1985


"Verschueren, 1983


'Mabey et al.. 1981


^Branson. 1977


kUlndholz. 1983


Elites and Lopez-Ay I la, 1980


NA = Hot available

-------
o
o
CO
                  TABLE  1-3

1977 U.S.  Production Data  for  the Haloethers*
                 Haloeth.er
               Company/Location
Manufacturer/
   Importer
Production Range
    (pounds)
  l,2-b1s(2-Chlbroethoxy)ethane
7* bjs(2-Chloroethoxy)methane
CD
  b1s(2-Chloroe.thyllethejr
o
in
00

CD
              3 M Co
                St. Paul, HN
              Muskegan Chem.
                Whitehall, HI
              Rohm and Haas
                Philadelphia, PA
              E.T. Horn Co.
                LaHlrada, CA

              Thlokol Chem.
                Moss Point, MS

              Dow Chem.
                Freeport,.TX
              Muskegon Chem.
                Whitehall, HI
              Buckman Labs
                Memphis, TN
                Cadet, HO
              E.T. Horn
                LaHlrada. CA
              Fallek Chem
                New York, NY
              Alcolac
                Baltimore, HD
              Unlroyal
                Naugatuck, CN
              confidential
manufacturer

manufacturer

manufacturer
 and Importer
Importer


manufacturer
(site-limited)

manufacturer

manufacturer


manufacturer
manufacturer
Importer

Importer

Importer

Importer

confidential
<1000

0.1-1.0 million

confidential
0.1-1.0 million
0.1-1.0 million


10-50 million


1-10 million

confidential


10-100 thousand
confidential
1-10 million

0.1-1 million

0.1-1 million

0.1-1 million

0.1-1 million

-------
                                                TABLE 1-3 (cont.)
o
o
Gi
—4
Q.
                 Haloether
 Company/Location
Manufacturer/
   Importer
Production Range
    (pounds)
  l,2-b1s(Chloromethoxy)ethane
  bls(Chloromethyl) ether
  2,2'-Oxybls(2-chloropropane)
  2-Chloroethyl methyl ether
  2-Chloroethyl ylnyl ether
  Chlqrpmethyl methyl ether
   4-Chlorophenyl phenyl e|her
Kodak
  Rochester. NY

Tennessee Eastman
  Ktngsport, TN

Dow Chem
  Freeport, TX

Clba-Gelgy
  Cranston. RI

Alcolac
  Baltimore. HD

Dow Chem.
  Midland. HI
lonac Chem.
  Birmingham, NJ
Rohm and Haas
  Philadelphia. PA
Columbia Organlcs
  Columbia. SC

Dow Chem.
  Midland. HI
manufacturer
(site limited)

manufacturer
manufacturer
manufacturer
(site-limited)

manufacturer
manufacturer

manufacturer

manufacturer

manufacturer


manufacturer
confidential


0.1-1.0 million


1-10 million


none


confidential


10-50 million

0.1-1.0 million

confidential

<1000


0.1-1.0 million
o
en
ro
CD
09

-------
o
o
                                                TABLE 1-3 (cont.)
                  Haloether,
  Company/Location
Manufacturer/
   Importer
Production Range
    (pounds)
   2,3-Dlchloro-p-iilgxane
  a,a-Dlchloromethyl methyl  ethep
   bls(2-chloro-l-methylejthyl) ether
   2,4,4'-Tr1ch1orp-j2'hydroxyd1phenyl ether
 Hercules
   Hattlesburg. MS
 Kodak
...  Rochester, NY

 Kodak
   Rochester, NY

 Olln Corp.
   Brandenburg, KY
 Jefferson Chem.
   Port neches, TX

 Clba-Gelgy
   Cranston, RI
 Henkel Inc.
   Teaneck, NJ
 manufacturer
(site-limited)
 manufacturer
manufacturer


manufacturer

manufacturer


manufacturer

Importer
   *Source: U.S. EPA,  J977
confidential

none


<1000


1-10 million

confidential


0.1-1.0 million

<1000
o
U1
09

-------
o
o
co
                                                         TABLE 1-4

                                                  Use  Data  for  Haloethers*
                Haloether
                                                          Use
                                                                Reference
o
in
CD
><•
CO
       1,2-81 s (2-ch Jorpethoxy)
       ethane

       bt s(2-Chloroethoxy)methane
b1s(2-Chloroethyl) ether



l,2-b1s(Ch1orQmethoxy)ethane



bls(Chloromethyl) ether

2-Chloroethyl vinyl ether

Chloromethyl methyl ether

bls(2-Chloro-l-methylethyl)
ether        :       •  ..... i.

2f4,4'-Tr1chlor72!-hydrp:xy-
(hphenyl ether
";  "•*•,.       .••.&

1,2,3-Tr1s(chloi:omethoxy)-
propane
                                solvent for hydrocarbons, oils, etc.; extractant; Inter
                                mediate for resins and Insecticides; organic synthesis

                                Intermediate for polysulflde rubber; solvent
soil fumlgant. Insecticide, acarldde; solvent for fats,
waxes, greases; textile scouring agent; In paints,
varnishes, lacquers; In paint removers; Intermediate

does not appear to have been used commercially, but has
potential uses In synthesis of Ion-exchange resins and
light-sensitive polymers

Intermediate for Ion-exchange resins

polymer production

Intermediate, particularly for Ion-exchange resins

solvent for fats, waxes, greases; extractant; paint and
varnish removers; spotting agents and cleaning solutions

|>acter1ostat and preservative for cosmetic and
detergent preparations

does not appear to have been used commercially, but has
{potential use In resin production
                                                            Hawley.  1981
Ellersteln and
Bertozzt. 1982;
Hawley, 1981

IARC, 1975
                                                                                                    IARC,  1977



                                                                                                    Hawley,  1981

                                                                                                    Vial,  1979

                                                                                                    IARC,  1974

                                                                                                    Hawley.  1981


                                                                                                    Wlndholz, 1983


                                                                                                    IARC,  1977
        *Commerc1a1  use  data were not  located  for  the other haloethers.

-------
1.5.   SUMMARY
    Haloethers  are  compounds   that  contain  an  ether  moiety  (R-O-R)   and
halogen  substHuents  1n   the   carbon  framework.    With  the  exception  of
b1s(2-chloroethoxy)methane,  all  the  other  haloethers  with   known  water
solubility  characteristics  are  either  slightly  soluble  or  Insoluble  1n
water, although some  of  the   haloethers  decompose 1n water  (see Table 1-2).
The  haloethers are   also  soluble  1n  a  wide  variety  of  organic  solvents
(Hawley, 1981; Weast, 1985; Wlndholz, 1983).  Of  the  27  selected haloethers,
at  least  nine were produced 1n  quantities  >0.1 million pounds 1n  1977  (see
Table  1-3).   Currently,  only five  companies  manufacture unknown  amounts  of
four  haloethers  1n   the  United  States   (SRI,   1986).   The  haloethers   are
generally  used as  chemical  Intermediates,  particularly  for  polymers   and
resins,  and  as solvents  (Hawley, 1981;  IARC,   1974,  1975,  1977;  Wlndholz,
1983; V1al, 1979;  Ellersteln and Bertozzl,  1982).
0037d                               T-72 '                            05/28/87'

-------
                     2.  ENVIRONMENTAL FATE AND TRANSPORT

    Six  of  the selected haloethers  have been classified  as  priority  pollu-
tants  by the  U.S.  EPA  (Callahan et  al.,  1979).   These  haloethers  Include
bls(chloromethyl)   ether,   b1s(2-chloroethyl)  ether,   2-chloroethyl   vinyl
ether,  4-chlorophenyl   phenyl  ether,  b1s(2-chloroethoxy)methane  and  b1s(2-
chloro-1-methylethyl)  ether.   The majority  of  the  available  experimental
data  useful  1n assessing environmental  fate  and  transport processes  pertain
to these compounds.
2.1.   AIR
    Based on  the  limited available vapor pressure  data (see Table  1-2),  the
selected  haloethers can  generally  be  expected  to  exist  primarily  1n  the
vapor  phase  In the  ambient atmosphere;  E1senre1ch et  al.  (1981)  Indicated
that  organlcs  having  vapor  pressures  >0.0001   mm Hg  should  exist  almost
entirely  1n  the vapor  phase 1n the atmosphere.   2,4,4'-Tr1chloro-2'-hydroxy-
dlphenyl  ether may  exist  partly sorbed  to  partlculate  matter  1n the  air
since Its vapor pressure 1s <0.0001 mm Hg.
Z'.T.T.   Reaction  with  Hydroxyl   Radicals.   When  released  to  the  ambient
atmosphere 1n  the vapor  phase,  the selected haloethers are expected to react
relatively   fast  with  photochemically  produced  hydroxyl  radicals.    The
reaction;  rate; .con$tafttsv ai«t ftalfwitve* of  tlfe- Najoetherst are: presented? Vtir
Table  2-T.    The  rate  const-ants:  TVsted' Vn- Table- 2-T  are  estimated, values,
based,  on hydrogen  abstraction  reactions  (U.S. •>EPA,,  1987).   The  estimated
half-lives  tndtcatr that  this" reaction  wVTl  be  the•dominant  environmental •
fate, process1  1n ilre atmosphere.  Although: other  process'es< such  as  hydroTyits
1n moist  air  may  be  significant  for  a  few  compounds Including  blsfchloro-
methyl)  ether  and 1,2-b1s(chloromethoxy)ethane  (IARC,  1974,  1977),  hydroly-
sis will be considerably slower 1n aAr tha.n 1n aqueous, solutVon  (IARC,. 1914.),..

0038d                               2-1                               05/28/87

-------
                                   TABLE  2-1

         Haloether Reaction Rates with Atmospheric Hydroxyl Radicals3
Haloether Rate Constant at 25°C
(cm3/molecule-secxl012
1 ,2-b1s(2-Chloroethoxy)ethane
b1s(2-Chloroethoxy)methane
b1s(2-Chloroethyl) ether
bls(a-Chloroethyl) ether
1 ,4-b1s(chloromethoxy)butane
1 ,2-b1s(Chloromethoxy)ethane
bls(Chloromethyl) ether
b1s(4-Chlorophenyl) ether
3-Bromophenyl phenyl ether
2-Chloroethyl methyl ether
2-Chloroethyl vinyl ether
2-Chlorophenyl phenyl ether
2,3-D1chloro;-p-d1oxane
a,a-01chloromethyl methyl ether
2,3-Olchlorotetrahydrofuran
bl.sffZXhT^o^T-meth'yl^^B; «Httr»..
2,4, 4:1 -Tr 1 cbiToro-2 ' -hydr oxy-
ilRhenyl etlien
F, 2;, T-Trl s,f chrTorotnet'hoxyJ'proparre
34.9
149.8
17.9
32.5
25.5
24.6
7.38
10.2
. 22.1 .
10.7
17.0
6.5
49.5
8.3
26.5;
7M
ltt.2,
65% 5-
Half-L1feb
) (hours)
6.90
1.61
13.44
7.41
9.43
9.79
1.36
23.59
.10.89
22.47
9.00C
,1.54. ,
4:86
1.20
a.oai,
31 T2;
23.6
3.67
aSouriC«i; U.S. EPA, 1987   £

 Assumes atmospheric hydroxyl radical concentr'at'lon  of  8x10"  molecules/cm3.

clncludes reaction with ozone at an atmospheric  concentration of  6-OxlO11
 molecules/cm3 (rate constant = 1.3xlO~17 cm3/molecule-sec).   The rates  of
 this, reaction are negligible with otherrreactarTtS;V  *


0038d                               2-2                               05/28/87

-------
    CupHt  (1980)  reported  that  the  anticipated  atmospheric  degradation
products  of  bls(chloromethyl) ether  that  result from  reaction  with hydroxy
radicals  Include H_CO, HC1, chloromethylformate and C1HCO.
2.2.   WATER
2.2.1.   Hydrolysis.   In  general,  the a-chloroalkyl  ethers  have  extremely
short  hydrolytlc  half-lives   In  aqueous  solutions  and  are therefore  not
expected  to  persist  for  any  extended period  of  time  1n water  (U.S.  EPA,
1980b).   The B-chloroalkyl  ethers,  however,  are much  more stable to aqueous
hydrolysis. The  available  experimental  hydrolysis  data have been reviewed by
several authors  (Durkln  et al.,  1975;  Callahan et al.,  1979;  Habey et al.,
1981).   Much   of the  available  data   have  been  generated  using  different
solvent   systems  (e.g.,   water:d1oxane  or   water:d1methylformam1de)   and
variable  temperatures.   Table 2-2  lists  rate constants  and  half-lives that
have been reported for 100X water at ambient temperatures.
    The halogenated  aromatic  ethers  (chlorophenyl  phenyl  ethers and bromo-
phenyl phenyl  ethers)  are  not expected  to hydrolyze  In water (Habey et al.,
1981; Callahan et al., 1979).
2.2.2.   Oxidation.   With  the   exception   of   2-chloroethyl  vinyl  ether,
oxidation of the haloethers 1n natural water 1s not expected  to be Important.
2-Chloroethyl   vinyl  ether  may  be  susceptible  to  oxidation  because  of  the
presence  of  the caPboit-carbon  doutle bond..  Rabey; e£  a TV (T98T), estimated
the rate;  constant For  the/'reaction-i'ofv- 2-ch,loroethyl vinyl ether - with; sing-let
oxygen  In rrajtural  water,  to  be  IxTO1^ H-hour:.   Assuming that  the • singlet
oxygen concentration  In  sunlit  natural wafer  Is.  -lxlO~" H' (Habey 'el' al.,
1981),, the half-life can; be calculated to; be;—6.9; hours.
2.2.3.   Photolysis.  The  alky!  haloethers do  not  strongly  absorb  UV 'light
and are  not  expected to react  by means of direct  photolysis In the ambient
environment (Durk,1n et/al., 1975;/Callahan et al<, 19,7.9.)...
0038d                               2-3                               07/07/87

-------
                                                        TABLE  2-2
0
0
co
CD
Q.
Haloether
bls(Chloromethyl) ether
"*'£ '
b1s(2-Chloroethyl) ether
2-Chloroethyl yjnyl ei\\ef
4-Chlorophenyl phenyl ether
ro - . .•£•,.-•
l :::
bl s ( 2-Chloroethoxy )me thane
Chloromethyl methyl ether
a,a-D1chloromethyl methyl
ether «*!';"' * '
bls(a-Chloroethyl) ether
Hydrolysis Rates
" '* -
Rate Constant
j).018 second"1
4.6x10"* hour"1
(estimated)
$.6x10"* hour"1
(estimated)
•";'- •- - )
4.6x10"* hour"1
(estimated)
*
-T*^ * '
<$>••
of Haloethers In
Half-Life
38 seconds
-20 years
-20 years
hydrolysis not
significant
-20 years
<1 second
<2 minutes
<2 minutes
Water
Conditions
20°C, pH 7
25°C. pH 7
25°C, pH 7
all environmental
conditions
25°C, pH 7
25°C
0°C
0°C

Reference
Callahan
et al., 1979
Habey et al. ,
1981
Habey et al. ,
1981
Habey et al..
1981
Habey et al..
1981
Durkln et al.,
1975
Durkln et al.,
1975
Durkln et al.,
                                                                                                       1975
o
en
ro
00
co -'

-------
    Choudhry  et   al.   (1977)   subjected   methanollc   solutions  of  2- and
4-chlorophenyl  phenyl  ether and b1s(4-chlorophenyl)  ether  to Irradiation at
wavelengths >290 nm by a  merry-go-round  apparatus  for 8 hours and found that
1.3-1.954 of the  Initial concentration  had  reacted  at the end of the exposure
period.
    Dulln et  al.  (1986)  measured the  quantum  yields  and photolysis rates of
2- and 4-chlorophenyl phenyl  ether  In  water.   Under winter  sunlight at 40° N
latitude, the measured photolysis  half-lives  of 2- and 4-chlorophenyl phenyl
ether  were  240 and  >400  days,  respectively.   Under  summer  conditions,  the
photolysis half-life of  2-chlorophenyl phenyl ether was  estimated to be 3.6
days;  however,  this  estimate was based  on  a  calculated rate constant, which
was  subsequently  determined  to  be 10  times  greater  than  the  measured rate
constant.  Therefore,  under  summer conditions,  the half-life  of 2-chloro-
phenyl  phenyl  ether   Is  actually  closer   to 36  days.   The  half-life  for
4-chlorophenyl  phenyl  ether under  summer conditions was. estimated to be 200
days.   All   of   these  half-lives  pertain  to  photolysis  at  surface water
conditions and  are, therefore, maximum rates.   As  the water  depth Increases,
the photolysis rate will  decrease.
2.2.4.   Mlcroblal  Degradation.    Tabak et al.   (1981)  examined  the  b1o-
degradabllUy of  the  organic priority pollutants  In  an attempt to determine
the,  potential -'and  condVttons  for  ralcrobAaTdegradation  of?  these com-
pounds. ., The b;iodegrada;tVon test  method:  Involved a,  siatfc.-cuT.ture  flaikr
screening procedure  us1ng:  a 7-day stat;.1c  Incubation  followed by Incubation
Vn 3'weekly  subcultures   ("28 total  tnfcubatTon days).   The  concentrations of
the.  tes't compound: were; 5/ and TO; ppmv and'•  •&  settleddomsstfc was:tewa,ter was
used  as  the  mlcroblal  Inoculum.   b1s(2-Chloroethyl)  ether,   2-chToroethyT
vinyl  ether   and  b1s(2-chloro-l-methylethyl)   ether were  all  found  to have


0038d                               2-5                               07/07/87

-------
significant  degradation  with rapid  adaptation.  4-Chlorophenyl  phenyl  ether
and  b1s(2-chloroethoxy)methane  did  not  degrade significantly  under  the test
conditions.
     Ludzack  and  Ettlnger  (1963)  studied the breakdown  of  b1s(2-chloroethyl)
ether  to  CO- 1n  Ohio  River water  that  was supplemented with  settled sewage
(1%  by  volume was added  weekly).  The authors  found  extensive degradation of
the  chloroether  after a 25- to  30-day  lag period;  ~85% of  the theoretical
C0_  was  recovered  after  65  days  of   Incubation.   Upon  redoslng  the  test
medium  with  the  chemical,   CO-  evolution occurred at  rates  several-fold
higher  than  the  first time  (Indicating  the necessity for  acclimation of the
microorganisms  to  the  haloether).   DojUdo   (1979) Investigated  the  b1o-
degradablHty  of  b1s(2-chloroethyl)   ether   by  three   methods   (Sapromat
resplrometer,  river  die-away  and  activated  sludge   unit)   and  found  the
compound  was biologically Inert  under  all  three  tests.  The  river  die-away
test  was   conducted  only  for  18 days;  as noted  above 1n  the  Ludzack  and
Ettlnger  (1963)  study,  a  lag period of  25-30  days  has  been  observed before
Initiation of m1crob1al  decomposition.                                      *'
     Voets  et'al.  (1976)  examined the blodegradatlon of 2,4,4'-tr1chloro-2'- '"
hydroxydlphenyl  ether  using  flask  Incubation  methods under both aerobic and
anaerobic  conditions.  No degradation was  observed over a  3-week period when
av sat* extract  wasr used? as* the^rolcfQbAai? litiaeuJwB^  Use?; oft at  &#itta&¥c
sewage  '• Inoculum1:  resulted  1n[ .50% de'gr.ada'l.to.n,  af£e/f;:/3I: weeM  under  ,b,o'th  the",
aerobtc;and  anaerobic conditions-.,,
2.2F.5.    Volatilization".   Volatilization 1s* n'ot  expected to ber an  Important.;
fate: ,p,r,Qce.ssf, far-  the7ia-chlo'rioa?l?kyl ue;the,ri?s^ sintiei- they  hyd'rpiTyie nap-Ydly; t;n?
water;  T,2,3"-Tfts(chloromethoxy)propane also decomposes In* water.-
0038d               "                 2-6    '                         05728/87 J

-------
    Table 2-3  lists  estimated Henry's Law  constants  and estimated volatili-
zation  half-lives  of  various   non-a-chloroalkyl   ethers.   For  2,4,4'-tr1-
chloro-2'-hydroxyd1phenyl   ether;    1 ,2-b1s(2-chloroethoxy)ethane;   b1s(2-
chloroethoxy)methane  and   possibly   2,3-d1chloro-p-d1oxane,  volatilization
from water will  not  be  environmentally  significant.  Volatilization may have
some  Importance  for   the  other  haloethers.   4-Chlorophenyl  phenyl  ether has
an  estimated  log K    of 4.08  (see  Table  1-2),  which  Indicates  a tendency
to  adsorb  to  sediment  1n water,  which  may significantly  reduce  Us  rate of
volatilization.
2.2.6.   Adsorption  to  Sediment.   Based  on  their  log  K  s  (see  Table
1-2), the haloalkyl  ethers  are  not expected  to  partition  significantly from
the  water  column  to  sediment.   The   only   exception  among  the  selected
haloethers Is  octachloro-d1-n-propyl  ether,  which  has  an  estimated  log K
of 5.472.
    The  aromatic haloethers  have estimated   log  K  s  >4.0,  which suggests
that  these compounds  may  partition  significantly  to organic  partlculate
matter and sediment In natural water.
2.2.7.   Bloconcentratlon.  Based on  their log  K   s  (see  Table  1-2),  the
haloalkyl ethers  are  not  expected to  bloconcentrate significantly  In aquatic
organisms.  Velth et  al.  (1980) measured a BCF  of  11 for b1s(2-chloroethyl)
ether I* Wueg^lT sunf tshL Lepomt sy roacrochtFOSV for; arc;  exposure perVod olf 28t
days.   Sasaki  (1978);  also  found; that  b1s{2-chloroethyl.)  ether does  not
accumulate  In   f1sh.;   The.  only  haloaT;kyl  ether,   that;  to; expected,  to
bloaccumulate  Is octachloro-dl-n-propyl ether  which  has  an  estimated; Tog
It    of 5. 472.   The BCF  of: an  oirg^trl'c'. cherotca'? caw tie :  estimate* Frum  the/
 OW it'
following regression equation  (Lyman et al. , 1982):
                         log BCF = 0.76 log K   - 0.23                   (2-1)
                           3                 ow
0038d                                2-7                               07/07/87

-------
                                                    TABLE 2-3
g Volatll
CO
CD
O.
Haloether
b,1s(2-Chloroethyll ether
2-Chloroethyl vinyl ether
4-Chlorophenyl phenyl ether
b1sJ2-Chloro-l-methylethyl) ether
Z^jA'-Trlchloro-^'-hydroxydlphgpyl ether
a> l,2-b1s(2-Chloroe£hoxy)ethane
b1s(2-Chloroeihoxy)methane
2,3-blchloro-p-dloxane
2,3-Dlchlorotetrahydrofuran
Ization of Haloethers from Water
Estimated Henry's Law Constant
' (atm-mVmol)
1.3xlO~sb
2.5xlO--b
2.2xlO"«b
l.lxlO--b
3.1xlO~'b
9.8xlO"8C
<2.8xlO~'b
2.3xlO'6d
1.8xlO~4d

Estimated Volatilization
Half-Life*
3.4 days
6.6 hours
9.8 hours
13.8 hours
200 days
500 days
>168 days
19.7 days
9.3 hours
rvj
00
CD
  aAssumes  a  river  1  m deep,  floy/lng  at a  speed of  1  m/sec  with a  wind velocity  of  3 m/sec;  estimation
   method outlined  In  Lyman  et  al.  (1982).

  ^Calculated from  wa.ter  solubility and  vapor  pressure data In Table 1-2.
  ->-    ,       \'^- '","-•'•
  ^Average of bond,  and group estimation  methods  of Hlne and Mookerjee (1975)

  dBond estimation  method of Hlne fnd Mookerjee  (1975)

-------
For octachloro-d1-n-propyl  ether,  the  BCF  value calculated from Equation  2-1
1s -8500, which Indicates the possibility of significant bloaccumulatlon.
    The  log  KQWS  of  the  aromatic  haloethers  range  from  4.08-5.876   (see
Table  1-2).   Using Equation  2-1,  the  estimated  BCF values  of the aromatic
haloethers will  range from 740-17,200.   Therefore,  significant bloaccumula-
tlon of aromatic haloethers In aquatic organisms 1s possible.
2.3.   SOIL
2.3.1.   M1crob1al Degradation.  Sufficient  data  are not  available to esti-
mate the relative  significance  of  mlcroblal  degradation of the haloethers  1n
soils.  As noted  1n  Section 2.2.4., several of  the  haloethers were found  to
be  biodegradable  under  specific  testing  conditions  while others  have  been
found to be resistant to degradation.
2.3.2.   Chemical   Degradation.    Since   the   a-chloroalkyl   ethers    are
susceptible to  rapid  hydrolysis 1n aqueous media  (see  Section 2.2.1.),  they
can be expected to hydrolyze  rapidly  1n moist  soils.  There  are no available
data  to  Indicate  that  the aromatic  haloethers  will  degrade  chemically  )n
soil.
    Wilson and  Noonan  (1984)  examined  the degradation of  2-chloroethyl vinyl;
ether  In  subsurface  soil  using microcosm tests.   Comparison  of  autoclaved
vs.  nonautoclaved  samples  Indicated   that  2-chloroethyl  vinyl   ether   was
degraded, by an.abiotic process  in  sail; however, the, degradation,• process was/
not; de.ter.nr1 ned.  As  noted1.n: Section  2-2.2'..,. ?-ch;l'oroethyl'. vinyl ether Vs.
susceptible  to  oxidation  In  water.   It may  be  possible  that the chemical
degradation process Involves:a free radical- oxYdatVon tnechanVsm.
2.3U3.   Adsorption.   Leaching?  wtTT  not  be-  Important,  for  the  a-chlorov
aTkyT ethers since-they;are expected' to  hydro^Tyze rapMly  fn  moist;
0038d                               2-9                               05/28/87

-------
    Table  2-4  lists  estimated  KQC  values  of  selected  haloethers.    The
K    values  for   the  aromatic  haloethers are  high  and  Indicate  that  they
will  generally  be Immobile  1n  soil; therefore,  significant leaching 1s  not
likely  to  occur.   With  the  exception of  the  highly chlorinated  octachloro-
d1-n-propyl  ether, the  alkyl  haloethers  have a medium to  high  degree of  soil
mobility,  which suggests  potential  leaching to groundwater  In  the  absence of
degradation  processes.
    Wilson   et  al.   (1981)   reported  that  b1s(2-chloroethyl)  ether moved
readily  through  a  sandy  soil  column.    This  agrees with  the prediction  of
high  soil  mobility from Table 2-4.
2.4.   SUMMARY
    The  selected  haloethers  are not  expected  to  be persistent  atmospheric
contaminants.   In  the  atmosphere,  the  haloethers  will  react  relatively
rapidly  In  the  vapor  phase with hydroxyl.radicals at half-lives  ranging  from
'1.61  hours  to  1.54  days  (U.S. EPA,  1987).    In water,  the" a-chloroalkyl
ethers  have extremely  short  hydrolytlc  half-lives  and are not  expected  to
persist  for extended periods of time (U.S. EPA,  1980b).    Hydrolysis  Is  not
environmentally   Important,  however,  for  the  B-chloroalkyl   ethers  or   the
aromatic haloethers  (U.S.  EPA,  1980b,c;  Mabey et al., 1981;  Callahan et  al.,
1979).   Based on  their relatively  high  log  K   values  (>4), the  aromatic
haloethers  may  have  a  tendency to  bloconcentrate  In  aquatic organisms  and
adsorb? fa-  sediment"and  suspended soWds   In water.  VolatlTlzat-Von  f-rom'water
may, be'4tf  tnpartarrt  transpwrt  process for  haiToetttePs: such a$ bts:C2>:  ether,? 2vcfcloroethy.l  vinyl  ether,: b-ts-tZi-chtaroi-Ti-methylethy.!):' etherv
4-chTioropherryT;;   Rhenyl  .; ether?  and:  2,3l^di1chlorotetraitTyd1raf!ura:n;   howeve.r..
volatilization wtll  rrof treV frnportaW fBfr^^^^^^p^cWor^^'Miydrcwydlpherfyr
ether, 1,2-b1s(2-chloroethoxy)  ethane or 1,2-b1s(2-chloroethoxy)methane  (see
0038d                                2-10                              07/07/87

-------
                                                     TABLE  2.4
o
a
01
g
Haloether
b1s(2-Chlor9ethyl) ether
bJs(2-Chloroethoxy)methan^
l,2-b1s(Chlprpmethoxy)ethane
b1s(4-Chlorophenyl) ether
Bromophenyl phenyl ether
i
=i 2-Chloroethyl vinyl ether
4r-Chloropheriyl phenyl ether.
2,3-D1chlorpTp-d1oxane
2,3-Dlchlorotetrahydrofuran
.(-, J I? ' \ • i • t - - . $:•
Octachloro-dl-p-propyl ether
b1s(2-Chlorp-)-methylethyl ethej)
2,4,4l-Trlchlo.rp-2'-hydroxyd1phenyl
Estimated Koc of Selected Haloethers
Koc Estimated from
Water Solubility3
27
9
ND
ND
ND

22
2263
ND
ND
ND
73
ether 1800

Koc Estimated
from Log KQ^
120
61
95
37,500
17,000

03
9,760
275
160
22,600
180
12,500

Soil
Mobility0
high
high
high
Immobile
Immobile

high
Immobile
medium
medium
Immobile
medium
Immobile
°  Vpg
           =  3.64  -
log S ()n ppm) (Lyman et al.,  1982);
for S from Table 1-2
  f*lpg K
00 • ' '    OC

mCSwann  et  a),,  1983


  NO = Not determined
            =  Q..5IH Io9 K   * i-377 (Lyman et  al.,  1982);  values for K   from Table  1-2
              ~~~ ' . ,'    -   .,»*" , '  "i*.1"' .                                     viw

-------
Table 2-3).  2-Chloroethyl vinyl ether,  the  only  selected haloether contain-
ing  a  double  bond,   Is  susceptible  to  oxidation  using  the  singlet  oxygen
concentration  1n  sunlit  natural  water  (Mabey  et al.,  1981)  and  has  an
estimated  half-life  of 69  hours.  The alkyl  haloethers are  not  expected  to
undergo  significant  direct  photolysis 1n the ambient  environment (Durkln  et
al.,  1975; Callahan  et al.,  1979).  The  aqueous  photolysis  half-lives  of
2- and  4-chlorophenyl phenyl  ether  at  the  surface  of  water under  summer
sunlight conditions at 40° N  latitude were  estimated  to be -36 and 200 days,
respectively  (Dulln   et al.,  1986).   Sufficient  data  are not available  to
estimate   the   relative  significance   of   microblal  degradation  of  the
haloethers.  Several  of  the  haloethers  have been  found  to  be biodegradable
under  specific  testing  conditions,  while  others  have  been found   to  be
resistant  to  degradation  {Tabak  et al., 1981;  Ludzack and  Ettlnger,  1963;
Dojlldo,  1979;  Voets et  al.,   1976).   In  soil,  the a-chloroalkyl  ethers
will hydrolyze In the presence  of moisture.  Based  on estimated K   values
(see Table 2-4);,; the aromatic haloethers will  generally  be  Immobile In soil
and  are   not  expected  to   leach  significantly.   With  the  exception  of
octachlorod1-n-propyl  ether,  the  alkyl  haloethers  have a  medium  to high
degree of  soil mobility, which  suggests  that these compounds are susceptible
to leaching to groundwater In the absence of degradation processes.
0038d*                               2-12                             07/07/87

-------
                                 3.  EXPOSURE
3.1.   WATER
    Chloroalkyl ethers  do  not occur naturally; their  occurrence  Is entirely
anthropogenic  (U.S.  EPA, 1980b).   Discharges  from Industrial  and manufactur-
ing  processes  represent the  major  sources  of these  organic  pollutants  1n
water.
    Table 3-1  lists  the selected  haloethers  found 1n  various  types of waters
In  the  United  States.   Haloethers  have  been  detected  In  drinking  water,
river water, groundwater and effluent wastewater.
    The U.S.  EPA  conducted the National  Organlcs Monitoring Survey  of U.S.
drinking water  1n  three  phases  between  March 1976  and January  1977  (U.S.
EPA, 1980b).   In  phase  II, the drinking water  of 13/113 cities was found to
contain  b1s(2-chloroethyl)  ether  at  a  mean  concentration  of  0.1   ppb.
b1s(2-Chloro-l-methylethyl) ether was  detected  In  8/113  waters  at a mean
concentration of 0.17'ppb.  In  phase' III,  8/110 cities had detectable  levels
of  b1s(2-chloroethyl)  ether   {mean  concentration 0.024  ppb)  while  7/110
cities  had  detectable   levels  of  b1s(2-chloro-l-methylethyl)  ether  (mean
concentration 0.11 ppb).
    Staples et  al.  (1985)  examined  the  U.S.  EPA  STORET'Data Base to  assess
the  occurrence of  priority  pollutants  1n U.S.  waterways.   The  results  of
this examination  for selected haloethers  are  presented  Vn Table  3-2.   Cole
et  a,T..  (1984) reported the preT-fmlrtary. resuTfs:  of the* U.S. EPA-. Nationwide
Urban  Runoff   Program  to  assess'  the  occurrence   of  priority .pollutants  In
urban  stormwater  runoff.   None  of^ the  haloethers were detected  In  runoff
waters from 15 cities that were monitored.
3.2.   FOOD
    Pertinent  data  regarding  the exposure  to  haloethers  by food Ingestlon
could not be located 1n the available literature as cited In  Appendix A.  ,

0039d                               3-1                              07/07/87

-------
                       TABLE  3-1



Occurrence of Haloethers tn Waters of the United States
o
o
CO
vO
Q.


CO
1




05/28/8'

(location/Source of Water
Philadelphia. PA
Philadelphia, PA
Delaware River
Chemical plant effluent
Delaware River (downstream)
Cleveland. OH •;,
Kanawha River, WV
Chemical plant discharge
(to Ohio River)
Ohio River (Evansvllle, IN)
fvansvllle. IN
New Orleans, LA
Chemical plant discharge
River (downstream)
•-.,- •- —

Type o,l, W4tera
finished ,
drinking water
finished
drinking water
river water
wastewa.ter
river,, water
finished
drinking water
river water r
rlyer water "...
wastewatef
river water
finished
drinking water
finished
drinking w|ter
wastewatef
river wa|er
•J * ~ """"•• ' •-

Haloether Identified11
b1s(2-chloroethyl)ether
l,2-bls(2-chlor'oethoxy)ethane
bls(2-chloroethy1)ether
1 ,2-bts(2-chloroethoxy (ethane
bls{2-chloroelhyl)ether
1.2-bls(2-chloroethoxy)ethane
1.2-bls(2-chloroethoxy)ethane
1.2-bls(2-chloroethoxy)ethane
bls(2-chloro-l-methylethyl)
ether
bls(2-chloroethyl)ether
bls(2-chloro-l-melhylethyl)
ether
bls(2-chloro-l-methy1ethyl)
ether
b1s(2-ch1oro-l-methylethyl)
ethef
bls(2-chloro-l-roethylethyl)
ether
b1s(2-chloro-l~methylethyl)
ether
b1s(2-chloroethyl) ether
!'•' V
2.4,4'-trlchloro-2'-hydroxy-
dlphenyl ether
2,4.4' -tr lchloro-2' -hydroxy-
dlphenyl ether


Concentration*-
(ppb)
0.5
0.03
NO
NO
NO to trace
NO to 15
100
1
NO
NO
NO
500-35,000
0.5-5.0
0.8
0.03-0.51
0.04-0.44
6000-14,000
12-300


Comment
also not detected In
drinking water of four
other cities
2-year sampling period
(1975-1977)
August. 1976 to March,
1977 sampling
August, 1977 sampling;
suggested plant effluents
eventually reach Phila-
delphia finished drinking
water
NC
NC
NC
NC
NC
August, 1974 sampling
NC
NC


Reference
U.S. EPA. 1975
Suffet et al..
1980
Sheldon and
Hltes. 1978
Sheldon and
Hltes. 1979
SanJIvamurthy,
1978
Rosen et al. ,
1963
Kleopfer and
Falrless. 1972
Kleopfer and
Falrless. 1972
Kleopfer and
Falrless. 1972
Keith et al..
1976
Jungclaus
et al.. 1978
Jungclaus
et al.. 1978


-------
                                                                             TABLE 3-1 (coot.)
O
O
co
10
o.
Location/Source of Hater
River sediment
love Canal
Wilmington. DE
Calvert City. K»
Louisville. KY.
Louisville. KV
Type of Mater3
sedlmenl
sed lmen| -water -
soil .complex
grpundwater
wastewater
wastewater
waslewa»er
Haloether Identified"
2.4,4'-trlchloro-2'-hydroxy-
dlphehyl ether
bls(2-chloroethyl)ether
bts(2-chloro-l-methylelhy1)
ether
4-chlorophenyl phenyl ether
bts(2-chloroethyl)ether
bls(4-chlorophenyl (ether
b1s(4-chlorophenyl)ether
2-chloroethyl vinyl ether
Concentration11
(ppb)
1200-5000
NQ
NQ
MQ
0.1-12.400
NQ
NQ
NQ
Comment
NC
NC
the values reflect con-
centrations of landfill
leachate (maximum) and
artesian well water
(minimum) downslope from
contaminated site
chemical plant effluents
Reference
Jungclaus
et al.. 197B
Hauser and
Bromberg. 1982
Dewalle and
Chlan. 19B1
Shackelford
and Keith.
1976
co
          NQ = Not quantified,; NO  =  not detected; JJC = no  comment
 O
 tn
 ^.
 to
 CO
 ><,
 CO

-------
o
o
CO
VD
Q.
                                                                              TABLE  3-2


                                                levels  of  Haloethers  In U.S.  Waters Computed from STORET Data Base*

co
•*»



Haloether
bls(Chloromethyl) ether
bls(2-Chloroethyl) ether
2-Chloroethyl vinyl ether
4-Chlorophenyl phenyl ether
bts(2-Chloroethoxy)methane
b1s(2-Chloro-l-methylethyl) ether

Median
Concentration
(PPb)
<1.0
<10.0
<5.d
<10.0
<10.0
<10.0
Effluents
Number of
Reporting
Stations
977
1241
1291
1333
1243
1243
Ambient Water
Percent
Detectable
1.4
1.6
1.0
1.1
1.0
1.6
Median
Concentration
(PPb)
<10.0
<10.0
<10.0
<10.0
<10.0
<10.0
Number of
Reporting
Stations
317
808
929
837
834
834
Percent
Detectable
0.0
0.4
0.8
0.2
0.1
0.1
          •Source:  Staples et al.,  1985
en
ISJ
oo

-------
3.3.   INHALATION
    No  ambient atmospheric  monitoring data  were  located  for  the  selected
haloethers.  Human exposure  to  these  compounds  by  Inhalation  may be confined
to   occupational   settings   (U.S.   EPA,   1980b).    James   et   al.   (1984)
qualitatively  detected  1,2-b1s(2-chloroethoxy)ethane  as  a combustion product
1n  an  Incinerator waste  gas effluent, which  suggests  that  Incineration  of
various types of refuse may release haloethers to the atmosphere.
3.4.   DERMAL
    Pertinent  data  regarding  dermal  exposure  to  haloethers  could not  be
located 1n the available literature as cited 1n Appendix A.
3.5.   SUMMARY
    Chloroalkyl ethers  do  not occur  as  such  In nature;  their  occurrence  Is
entirely  anthropogenic  (U.S. EPA,  1980b).   Discharges  from  Industrial  and
manufacturing  processes  represent  the major sources  of  these  organic pollu-
tants  In  the  aquatic environment.   Various hdloethers have been detected  In
drinking  water,  rlverwater,  groundwater  and  effluent wastewater  (see  Table
3-1).  Human  exposure to haloethers  by  Inhalation may be  confined  to  occu-
pational  settings  (U.S.  EPA, 1980b);  however,  1,2-b1s(2-chloroethoxy) ethane
has been  detected  1n  an  Incinerator  waste gas  effluent  (James et al., 1984).
Sufficient data were not located  to  estimate dally  human  exposure  to  these
compounds.
OC39d                               3-5                              07/07/87

-------
                             4.  AQUATIC TOXICITY
4.1.   ACUTE TOXICITY
    Relatively  little  Information was  available concerning  toxlclty of  the
subject  haloethers  to  aquatic  organisms.   U.S.  EPA  (1978)  reported  the
following  96-hour  LC5_  values  for  bluegllls,  Lepomls  macrochlrus:   354
mg/a  2-chloroethyl  vinyl   ether  and  >600  mg/a b1s-(2-chloroethyl) ether.
In  these  studies,  96-hour  NOECs were  <101  mg/i 2-chloroethyl  vinyl  ether
and  <220   mg/8,  b1s-(2-chloroethyl )  ether.    Buccafusco   et  al.  (1981)
reported  96-hour  LC5Q  values  of  350  mg/a  2-chloroethyl  vinyl  ether  and
600  mg/8,   b1s-(2-chloroethyl)  ether  for   bluegllls.    Dow  Chemical   Co.
(1984a)  reported a  96-hour LC5Q  of 184  mg/a  b1s-(2-chloroethoxy)  methane
for  fathead  minnows,   Plmephales  promelas.   Konemann  (1981)  calculated  a
7- to  14-day  LC,..  of  54.4  mg/a.  bis   (2-chloroethyl  ether)  for  gupples,
PoedHa retlculata.
    The only available toxlclty  data  for  freshwater Invertebrates  applies  to
Daphnla maqna.   U.S.  EPA   (1978) reported a  48-hour  EC™  of 238' mg/a  and
a  NOEC of  <7.8 mg/i  b1s-(2-chloroethyl)  ether.   Oow  Chemical  Co.  (1984b)
reported a 48-hour LC5Q  of  201  mg/a. b1s-(2-chloroethoxy) methane.
4.2.   CHRONIC EFFECTS
    In  the  only available  chronic  studies,  no  adverse effects  occurred  at
concentrations  up  to  19   mg/a.  b1s-(2-chloroethyl)  ether  In  the  fathead
                   promeTas'., erabniyowTairv*T tes-f  tUVff.
4*3..   PLANT EFFECTS
    Pert1nen;t  data  regardfng effects:;. of harToethers;  on  aquatic pTants;  couM,
no,t be located 1;n- the a.va1'labtei.T1;terature- as c1ted/1n- Appendix. A.
0040d                               4-T                               05728/8T

-------
4.4.   SUMMARY
    Data  concerning  toxIcHy  of  haloethers  to aquatic  biota are  limited.
Studies by  U.S.  EPA  (1978) using  bluegllls  and Daphnla magna  Indicate  that
2-chloroethyl vinyl  ether  and b1s-(2-chloroethyl) ether have  nearly  equiva-
lent  acute  toxldty  In  these two  species.   J).  magna appeared  to be  more
sensitive to  these  compounds  than bluegllls.   The  lowest reported  acutely
toxic  concentration  was   184  mg/8,   b1s(2-chloroethyl)   ether,   a  96-hour
LC-Q for fathead minnows (Dow Chemical Co., 1984a).
0040d ^                             4-2                              05/28/87

-------
                             5.  PHARMACOKINETICS
5.1.   ABSORPTION
    Groups  of  three  female Charles  River  CD  rats  were  given  single  oral
doses  of  0.2   vg/kg  or   3,   30  or  300  mg/kg  14C-bis-(2-chloro-l-methyl-
ethyl) ether In  corn oil  or  Emulphor EL620-ethanol-water  (1:1:8)  (Smith et
al., 1977).  The  U.S.  EPA (1980b) established  that  the  compound was labeled
with  14C   at   the  o- position.    There  was  evidence   of   saturation  of
absorption mechanisms at  the highest  dose,  but  peak concentrations of radio-
activity In the blood occurred  2-4  hours  after  treatment at the lower doses.
Radioactivity  was  detected  1n  the  blood  after  15  minutes,   the  earliest
sampling time.  Two rhesus monkeys  that  were given  single oral  doses  of 30
mg/kg  of  the   same  14C-labeled  compound  had  maximum  concentrations  of
radioactivity  In  the blood after 2  hours (Smith et  al.,  1977).   These  data
Indicate  that  gastrointestinal   absorption  of  b1s-(2-chloro-l-methylethyl)
ether  was  rapid.   Lingg  et  al.   (1982)   administered   single  doses  of
1  laC bis (2-chloroethyl)   ether    (40    mg/kg)   and   l-14C-b1s(2-chloro-l-
methylethyl) ether  (90 mg/kg)  In  corn oil by gavage to groups of seven adult
male - Sprague-Dawley rats  and  measured  the  radioactivity  1n  expired  air,:
ur'mc,  feces,  carcass and  cage  wash 48 hours  after treatment.   Total  f4C
recovery was  80.9^16.9X  of  the  administered  bis-(2-chloroethyl)  ether  and
73.3*1.7%  of  the  administered  bisC2.-cbloro-l-inethylethylJ  ethers .  F:eca,r
excretion  accounted- for?  21.4% of, the-dose,  of'.bis (2-chloroethyl)'. ether and
3:8% of  the dose  of bVs(2-chloro-1-methylethyl)  ether,  which suggested tthat
gastrointestinaT'absorption-was nearly" complete^
5.2.   DISTRIBUTION
    DTsappearaftce  of radioact'ivtfy  frVwirc-the PToods-of two monk'eys^fdHowIng
administration   of  single  oral  30  mg/kg  doses  of  l-l4C-b1s(2-chloro-l-
mcthylcthyl) ether  (see  Section  -5.1.)  was  biphasic, with half -lives -.of -5

0041d          .                      5-1                              07/07/87

-------
hours  for  the a or distribution  phase  and >2 days  for  the  3 or elimination
phase  (Smith  et al., 1977).   Identical  treatment of  three  CD rats showed a
monophaslc decline  1n  blood radioactivity, with  a  half-life of 2 days;  that
suggests that  metabolism plays a more significant  role  than distribution  1n
the  disposition of b1s(2-chloro-l-methylethyl)  ether  than  1n  the  rat.  The
radioactivity  die-away curves  of  the  data from monkeys and  rats were  similar
after 24 hours.
    In   another  study,   rats   were   administered  single   oral   doses   of
14C-labeled  b1s(2-chloroethyl)  ether (40  mg/kg)  or  b1s(2-chloro-l-methyl-
ethyl)  ether   (90 mg/kg)  as detailed In  Section 5.1. (L1ngg  et al.,  1982).
Radioactivity   determinations  48  hours  after   dosing  showed  that   blood,
muscle,  liver and  kidney  were the only  tissues that had  i4C levels- >0.05%
of  the administered doses.   The highest  amounts of  radioactivity from the
b1s(2-chloroethyl)  ether, expressed as  percent of administered dose,  were  In
the  muscle  (0.96%),   kidney  (0.56%)  and  blood  (0.49%),  and  the   highest
concentrations  of  radioactivity  from the  b1s(2-chloro-l-methylethy-l)  ether
were 1n  the liver (0.55%), muscle (0.50%) and  blood  (0.36%).
    Smith  et   al.  (1977) determined  tissue distribution  of radioactivity 7
days  after single  30  mg/kg  Injections  of l-l4C-b1s(2-chloro-l-methylethyl)
ether  In  three  female  CD  rats   (1ntraper1toneal  Injection)  and  one  monkey
(Intravenous   Injection).    Distribution  was  widespread  with  the   highest
amounts^ expressed  as percentages  ,ofadmin^s-teredl ratifaact^lv.Vty^ occurrfhg-,
In-  the  mustTe (2.8%),  Itver tT.SXJ,  fat  (-0.8%! and  bTood  (0.7%)   In" the-
monkey,.  and , IB the fat (.2.Q?t)V muscle  (:T.2%J;r. blood  (ff.8%.y,. skin  (0.7%, .
kidneys  £0.7%) and  liver (0.4%1  In the  rats.   The highest  tissue,  concentra-
tions  «Tn  rats£ p.;2^5L7  u9/
-------
found  In  the  liver  (28.8 pg/g),  followed  by the  adrenals,  kidneys,  spleen
and  pancreas  (3.8-6.6  yg/g).    With  the  exception  of  the  liver   In  the
monkey,  no  tissue  appeared  to  have  a  markedly  greater  tendency  than  any
other to retain radioactivity.
5.3.   METABOLISM
    Th1od1glycol1c  add  was  the  major  urinary  metabolite  of  l-l4C-b1s(2-
chloroethyl)  ether  1n  rats,  accounting  for -48%  of  a single  40  mg/kg oral
dose  and  7554  of  the  total  48-hour  urinary  14C  (L1ngg  et  al.,  1982).
Lesser metabolites  Included 2-chloroethoxyacetlc  add  (-3.2% of the dose and
-5%   of    the  urinary   14C)   and   N-acetyl-S-[2-(2-chloroethoxy)ethyl]-L-
cystelne (-4.5%  of  the  dose  and -7% of  the urinary 14C).   An  earlier study
of  the  same  design qualitatively  Identified  2-chloroethyl-B-D-glucopyrano-
slduronlc  add as  another urinary  metabolite  of b1s(2-chloroethyl)  ether
(L1ngg et  al.,  1979),  but  this  1s  not considered  to be a  major  product
(L1ngg et  al., 1982).   Thlodlglycollc add  and  S-(carboxymethyl)-L-cyste1ne
were Identified   1n  the  urine  of  rats  following  a   single  IntraperVtoneal
Injection of  100  mg/kg b1s(2-chloroethyl)  ether   (Mueller  et  al.,  1979),  but
the latter metabolite  appeared  to be an Intermediate  In  the. .pathway leadings
to th1od1glyco!1c add  (L1ngg et al., 1982).
    Urinary  metabolites  of  single   90  mg/kg  oral   doses   of  l-l4C-b1s(2-
chloro-l-methylethyl)  ether  In   rats  Included.  ZrC^chloro-t-^Bethyjlethaxx)-
pro.pana.fc .aclid; and M-^aceiy,T>S!-(!Z-hydrox;yprapy;T)-L-cystfr.t'ne (LLlnggt et  al..v,
1982).   These metabolites  accounted  for  8.9- and 17%  of  the administered
dose,  respectively,  and -36  and  19%  of.  the  totals urinary  ,14C,  .respec-;
         l.-Chloro.-2-propano;T  (tt.,1-1.0%? aft the administered dose.)>; propy/Iene'
     c  [rot- quartfltatedj' and-2-(;Z^chToro:.T-«iethyTethoxyypropai»otc  add (not
quantHated)  were Identified  as  urinary  metabolites In  rats  treated with 30
mg/kg b1s.(Z-chloro-l-methylethyl) ether by gavage,. (Smith,, etal., .19.7:7),.
0041d                               5-3                              07/07/87

-------
    Carbon dioxide  Is another  Important  metabolite  of  at least  some halo-
ethers.   Llngg  et al.  (1982)  administered  single  oral  doses  of l-l4C-b1s-
(2-chloroethyl)   ether   (40  mg/kg)   and  l-14C-b1s(2-chloro-l-methylethyl)
ether  (90  mg/kg)  to  groups   of  seven   rats  and   recovered  11.5*_5.6  and
20.3*9.4%  of  the doses  of  radioactivity,  respectively,  as  14C02  within
48 hours.
    Pertinent  data  regarding  the metabolism of  the other  haloethers could
not be located 1n the available literature as cited 1n Appendix A.
5.4.   EXCRETION
    Elimination  of  14C  was examined  for 48 hours  following administration
of  single  oral  doses  of   l-14C-b1s(2-chloroethyl)  ether   (40   mg/kg)  and
l_i*C-b1s(2-chloro-l-methylethyl)  ether   (90 mg/kg)  to  groups  of seven rats
(Llngg et  al.,  1982).  Most  of the radioactivity was excreted  In the urine
and  expired   as   C0».   The  percentages   of  administered  radioactivity that
were  eliminated  1n  the urine,   feces,  expired  C02  and  remained   1n  the
carcass  after  48  hours were  64.7*_14.8,   2.4.*1.3,  11.5*5.6  and  2.3*1.2,
respectively,  for b1s(2-chloroethyl)  ether.  The  respective percentages for
b1s(2-chloro-l-methylethyl)  ether  were   47.5*8.1,   3.8*0.3,  20.3*9.4  and
1.7^0.5.   The time  to  excrete one-half  of the  dose through urine  and C0_
was determined  to be 12 hours  for  b1s(2-chloroethyl) ether  and 19 hours for
b1s(2-chloro-l-methylethyl) ether.
    Urinary*  excr&Ktom.of   radioactivity  was esseat 1 ally  complete^/?4t" flours
fo&Totffng? tntripecftone&T;, tthree. rats! «r intravenous: tone monkey); tnj;ecttotr
of;-. ..*•  single,  3ffi; mg/kg:'  dase;  of?"C^tttr(;2;-cttToi^T>methylethyl,)v  ether.
although, the.  ratsv excreted  approximately, tw^ce; as.mucft as the, monkey  (55 vs.
25X of'the administered5 dose) ;|Sm1th iet  ail^  19^7).^ Approximately 1 .aad'. 6%5
of  the  administered  radioactivity was eliminated  by  the monkey  and rats,
respectively, 1n  the feces  by 7 days> ,

0041d y                             5-4     ?                        07/07/87"

-------
5.5.   SUMMARY
    Pharmacok1net1c  data  are  available  for  l4C-b1s(2-chloroethyl)   ether
and  l4C-b1s(2-chloro-l-methylethyl)  ether  (Smith  et  al.,  1977;  L1ngg  et
al.,  1982).   Radioactivity associated  with  these  compounds  Is rapidly  and
nearly completely  absorbed and widely  distributed  throughout  the body.   No
tissue appears  to have  a  tendency to  retain radioactivity associated  with
either of  these compounds, with  the  exception of  the  liver  of the monkey,
which  appeared  to   retain   14C   associated  with   l-l4C-b1s(2-chloro-l-
methyl-ethyl) ether (Smith et  al.,  1977).   Th1od1glycol1c add Is the  major
urinary metabolite  of  b1s(2-chloroethyl) ether,  and  urinary metabolites  of
b1s(2-chloro-l-methylethyl)   ether    Include   2-(2-chloro-l-methylethoxy)-
propanolc  acid  and  N-acetyl-S-(2-hydroxypropyl)-L-cyste1ne (Llngg  et  al.,
1982).   Carbon  dioxide   Is  an   Important   metabolite   of  both  of   these
haloethers 1n rats  (Llngg  et al.,  1982).   Degradation  of  14C-haloethers  to
single carbon units that are  Incorporated readily  Into  endogenous  substances
may account  for the retention of  detectable  levels of radioactivity  1n  the
tissues 7 days  after single parenteral  doses  to  rats  and  monkeys.  Excretion
1s  primarily  through   the urine  and  expired  air.   The  time  to. excrete
one-half  of  the dose of radioactivity  In rats through  urine and expired  air
was   12   hours    for   l-l4C-b1s(2-chloroethyl)  ether  and  19  hours   for
l-l*C-bU(2,-ctaoro^l-aethv. lethal) ether lUngg.;et,aU,. T9.a2)u,
004Td                               5-5                              07/07/87

-------
                                  6.  EFFECTS
6.1.   SYSTEMIC TOXICITY
6.1.1.   Inhalation Exposures.
    6.1.1.1.   SUBCHRONIC — Groups   of  25   elght-week-old  male   Sprague-
Oawley  rats  were exposed  to  1   or  10  ppm  (3  or  33  mg/m3)  chloromethyl
methyl ether  vapor,  probably for  6 or  7  hours/day for 30 days  (Drew et  al.,
1975).   Two of the  rats at  1  ppm died  during the  exposure period;  5  were
sacrificed  at the  end of  the exposure  period;  5  were  sacrificed 2  weeks
following  the end of  the exposure periods;  and  the  13  remaining  rats  were
maintained  for  life.    H1stolog1cal  examination of  the  lungs  (other  tissues
not examined)  showed   that  one  of the  rats  killed after  30 exposures had  a
slight bilateral  hemorrhage.   H1n1mal  mucosal  effects  occurred In  the  rats
that  were  observed for  their  llfespans  (two  with regenerative  hyperplasla,
one with squamous metaplasia of  the  bronchial  epithelium, one  with trachea!
squamous  metaplasia).   The  significance  of   these  effects   Is   uncertain
because control data were  not  reported.  Weight change In  the  1  ppm rats was
not significantly  different  from  that of an unspecified control  group.  Rats
that,  were  exposed to  10  ppm (3.3 mg/m3)  chloromethyl  methyl ether  had  high.
mortality (22/25  by exposure day  30).
    Rats  or  hamsters' that  were exposed  to  1  ppm  (5  mg/m3)  b1s(chloro-
methyV) etherv &  houns/daiy, for  up to 3,0 days, also had high, mortality,, tmedlan
TTfesparfc ,af<  Z3, and:  42; days-,.  respecttveTy^  ftfeew; et- a,!',,.  HTSjL   ftTghV
Incidences  of  pulmonary-  effectsv.  Including-, bronc-hlal Vhyperplas1a   In  the
chloromethyl  methy.T ether-expo.sed-rats* trachea!".and bronchial- hyperplasla j
and: metaplasia  w
-------
    Groups  of  four  male  and four  female  Alderly Park  SPF  rats  (average
weight  200 g)  were  exposed  to   20  ppm  (HO mg/m3)  b1s(2-chloro-l-methyl-
ethyl) ether, 6 hours/day,  5  days/week  for  4 weeks (Gage, 1970).  Effects on
clinical  signs, body weight  (measured  dally),  urlnalysls Indices at termina-
tion  (specific gravity,  pH,  reducing sugars, blUrubln,  protein), hematology
Indices  at  termination  (hemoglobin,  packed cell  volume,  mean corpuscular
hemoglobin content, total  white  and  differential  cell  count, platelet count,
clotting  function, urea, sodium  and  potassium),  gross  pathology or histology
(lungs,  liver, kidney,  spleen and adrenals) were  not  observed.  Exposure to
70  ppm  (490 mg/m3)  (same  groupings  of  animals and   treatment  schedule)
produced  lethargy and  reduced  body  weight gain  (not  quantified)   but  no
alterations  of  the blood  or  urine  Indices  or pathological  effects.   Eight
5-hour  exposures  to  350 ppm  (2450 mg/m3) produced an unspecified Incidence
of  lethargy,  respiratory  difficulty,  retarded body  weight  gain  and hlsto-
Iog1 al  congestion of  the  liver  and kidneys  1n a  group  of four rats of each
sex.   It  1s  Implied  that  the eight  350  ppm dally exposures were not contin-
uous  (I.e., apparently 5/week).
    6.1.1.2.   .CHRONIC --  Groups  of  120 male  SPF  Sprague-Dawley  (Spartan
substraln) rats and 144-157 male Ha/ICR  m"1ce were exposed to ff, 1, TO or  TOO
ppb  (0,  5,  47  or  470  vg/m3)   of  bls(chloromethyl)   ether   vapor,  6 hours/
day,  5 days/week  for 6  months .an^  obseryetf for  Ufe tUeong,. et al.-., 19SH*
«dd1tvtaita1:^nf(yrfla;tfofrt iregaffd'fngv:the^,«lestgm of  this./study  ;1s presented- tm
Section  6.2.1.    Treatment-related,  effects' on  body  weight, gain were-  not;
observed1.   Mortality war   Increase* W  ttfe- h^gh-do^e*paitsv bittr  this   was
attributed, to tumor, development.  Absolute  and  r elat.tve; organ  weight  theart,
brain,  liver, kidneys  and  te*te's), determined 1n  four rats'/group af^fife-end
of  the 6-month exposure  period,  did  not  significantly differ  between  the

0042d                               6-2                         .     05/29787

-------
treated  and control  groups.   Comprehensive hlstologlcal  examinations using
rats  and  limited  hlstologlcal  examinations  using  mice  (nasal  turblnates,
gross liver and  lung  lesions)  did not reveal treatment-related nonneoplastlc
alterations.   Hematologlcal  evaluations, conducted  on  10 rats  from each of
the 0  and 100 ppb  exposure  groups at  the  12th exposure week  and  on 4 rats
from  each of  the  0,  1,  10  and 100  ppb groups  at the termination  of  the
6-month  exposure period, were unremarkable;  determinations  Included packed
call volume,  hemoglobin  concentration, total red  blood  cell  count  and total
and differential white cell counts.
    Seventy-four male  Sprague-Oawley  rats and  90 male Syrian golden hamsters
were exposed  to  commercial  grade chloromethyl methyl ether  by Inhalation at
a  concentration of  1  ppm  (3  mg/m3),  6  hours/day, 5  days/week  for  life
(Laskln et  a!.,  1975).  Groups  of 74  rats  and 88 hamsters  served as chamber
controls.  Hlstologlcal examinations  of  the respiratory  tract and lungs were
conducted on  at  least  54 of the  treated  rats,  on  at least  7'1 of the exposed
hamsters and on  similar numbers  of controls (numbers of  animals .examined not
specifically  stated).   There  were  no  treatment-related  effects  on weight
gain, survival  or  occurrence  of  respiratory  system  tumors  (Section 6.2.1.).
Squamous  metaplasia  of the trachea  occurred 1n 10% of  the  treated rats and
3% of the controls, but  the  Incidence of trachea! hyperplasla was similar In
the treated (3054) and  control  (2954)  rats.  Bronchla.l hyperplasla occurred 1n
5954 ;ofr  the  treated  anrfV35%" of th'e. contnosT  rats; but- We  occurrence of
bronchiaV squaraous metaplasia  was: the. same. In  both  treated and control rats
(13%);.   Bronchoalveolar   metaplasia  was,  noted  1n  9 exposed ,hamsters,  and:
atypical  appearance. o.f. the. nucle.1, of  alveolar: "cells, was noted. In 10 exposed
hamsters;* atypical  alveolar; cell nuclei were,  observed  Vn .only  oite> canitraT
hamster.  Presumably,  bronchoalveolar  metaplasia was not observed In control
hamsters.(,

0042d                               6-3                               07/07/87

-------
6.1.2.   Oral Exposures.
    6.1.2.1.   SUBCHRONIC -- Groups  of  10 F344  rats  of each sex were  admin-
istered  dally gavage  doses of  0,  10,  25,  50, 100  or  250 mg/kg  technical
grade  b1s(2-chloro-l-methylethyl)  ether  1n  corn  oil,  7  days/week   for  13
weeks  1n  a range-finding study  for a  carclnogenlclty bloassay  (NCI,  1979).
The  technical grade  compound was  -70%  pure as detailed In  Section  6.2.2.
Body weight measurements  conducted at the end of the  study showed  that there
was  an adverse  effect  1n  the  high-dose males  (mean  weight  was 80%  of  the
control  value).   Occasional  urine stains  and  a hunched  or thin  appearance
were  observed occasionally during  weeks  4-7   1n  the  high-dose males,  but
treatment  had no effect  on  survival or gross or hlstologlcal  findings at any
dose  In either  sex.   The  extent  of  the  pathological examinations  was  not
specified.
    Groups of  10 B6C3F1  mice of  each sex were  given  once dally gavage doses
of  0,  10, 25,  50,  100  or  250  mg/kg technical  grade b1s(2-chloro-l-methyl-
ethyl)  ether  In  corn  oil  for 13 weeks  1n  a  range-finding  study for  another
carclnogenlclty  bloassay   (NTP,   1982).    The   compound  was  -70%  pure  as
detailed   in  Section  6.2.2.   There  were  no  compound-related  effects  on
terminal  mean   body  weight  or  survival.   Comprehensive  hlstopathologlcal
examinations  revealed that  focal  pneumonHls was  the only  alteration;  this
effect  occurred   at  50  mg/kg;.  (3/10 males,  1/1,0, females),  100, mg/ltg (2/\&;
matfesv  3/W^ fetoafesfc-arrd 250i mg/kgj.f8y!Ttt; males?,, 4/T.O?-feraaftes.^;but,- peesum^
ab'Ty, not  1* oont ro 1 s.. -
    In  a^ How*-CheittVca>T. fn.d^F s^wfthi. na£*< gs^r'a^iv and? number  noi.-specified)
werr-e  sdnriftts-fcered; 22 doses of,-.. b-Vs-(-2i-c-h-Toro:-T-fliett.lty^ethyT )•; .either In. aH-ver-.
ol'Ttfy  gavage 1rn 31 days4.   The? Tdwes£ antfHighest dosages  were O.OT anrf 0.27
g/kg,  but  the number  and  magnitude of  Intermediate  dosage levels were not

0042d.          -v -.                  6-4                               05/29*87)

-------
Indicated.   Controls  were  used  but  details  were not  specified.   Decreased
growth rate  and  Increased  relative  liver,  kidney and spleen weights occurred
at the highest dose.   The  Intermediate and low doses produced only decreased
growth rate.   Hematologlcal  Indices  were  normal  at all doses.   It  was not
Indicated If pathological examinations were conducted.
    2,4,4'-Tr1chloro-2'-hydroxyd1phenyl  ether  (purity  >97%)  In  gum  arable
was administered by gavage  to groups  of five male and five female white rats
(strain  not  specified) at  doses  of  0,  50,   100,  200,  500 or  1000  mg/kg,  6
days/week for  4 weeks  (Lyman and  Furla,  1969).   Effects were  noted  In the
high-dose group  and  Included mortality (2/10)  and  slightly  reduced  weight
gain.   Hlstopathologlcal   examinations  and   blood  and  urine  analyses  were
unremarkable  In  all treatment groups, but  the  extent of  these evaluations
was not Indicated.  Additional Information was not reported.
    6.1.2.2.   CHRONIC — Groups  of  26 male  and  26  female Charles  River  CD
rats were treated  with b1s(2-chloroethyl)  ether of  100% purity by gavage at
doses of  25 or  50  mg/kg,  twice  weekly  for  78 weeks, followed  by a 26-week
observation  period (Welsburger et  al., 1981).   Matched and  pooled control
groups were  Included   In the  study, but the  sizes of these  groups  were not
reported.  Mean  body weights,  determined weekly  during the Initial month and
biweekly thereafter,  were  lower  1n  the treated females  and  high-dose males
than  In  the  corresponding, controls,.   Quantitative  data were  not reported,
but  tire  effect am trotfy;, wetfgttt; f.n:  the: females; was,  Indicated  to be; subs.tan-;
t!Va:T.  Treatment-related increased  Incidence of  mortal 1 ty, occurred  In the
high-dose females,  but data  were  not, adequately  reported.  Survival at' 52"
weeks, was 6.5X In. the high-dose females, 9&-100% In the other: tneated groups/
and-97-99%  1n 'pooled controls"fromithefJenffre1 stttdyiri wttfcfc frtctfudw£ corttrtfF
groups from tests with  b1s(2-chloroethyl) ether  as well  as  numerous other


0042*                               6-5                   .           07/07/87

-------
compounds.   Data  for  survival  beyond  52  weeks  were  not reported  for  the
b1s(2-chloroethyl)  ether-treated rats.   Comprehensive  pathological examina-
tions  were conducted  (Section  6.2.2.)  but  nonneoplastlc effects  were  not
reported.
    Technical  grade  b1s(2-chloro-l-methylethyl)  ether  was  administered  by
gavage  1n  corn  oil  to groups  of 50 male and  50 female F344 rats at doses  of
0, 100  or  200 mg/kg,  5 days/week for 103-105 weeks, followed  by  1-2 weeks  of
observation  (NCI,  1979).   Purity  was  -70%  as  detailed  In  Section   6.2.2.
Tox1c1ty  endpolnts  were  the  same as  those  routinely  assessed  In  NCI/NTP
cardnogenlcHy  bloassays.   Effects  Included  dose-related   decreased  mean
body  weight  1n  both   dose  groups  and  sexes   throughout  most  of  the  study.
Treatment-related decreased survival occurred In  the  high-dose males  after
week 45 and  1n  the  low- and high-dose females after weeks 60  and 30,  respec-
tively.   Survival  at  week  78  1n  the  vehicle control,  low- and   high-dose
groups  was 44/50 (88%),  46/50  (92%) and  28/50 (56%)  1n  the males,-respec-
tively., and 48/50 (96%),  44/50 (88%)  and 25/50 (50%)  In the  females,  respec-
tively.   An  Increased  Incidence of esophageal hyperkeratosls  occurred  1n the
high-dose  males  and   females;  Incidences   In  the  vehicle  control, low-, and
high-dose  groups  were  9/50, 10/50 and  40/49  1n the males, respectively, and
13/50,  10/49  and  31/48  1n the  females,   respectively.   A  small  number  of
high-dose  females also had  esophageal acanthosAs (1/50, 0/49  and 5/48. Vn the ,
vehWfe1- contrcrtv Tow- and? tffgh-dose? groupsv, respec^tveTy;)-.;;  CjeatrtlbtxtfTari
nscfosts  of-i tlte>ttver  was -twcrea'sed;  In  the h4gh-4o?re-males :. arwf  females, but
there;was; no; teftec'ence  to;,Ui.ts.'effect"fir;  secXtans of the: report-ather "than-
an apperrdftd, data summary.   Occurrence? of- other  rvonneaplastlc lesions  wer&
not remarkable.     '  -
0042d               <  •              6-fc                               05/29/87

-------
    Technical  grade  b1s-(2-ch1oro-l-methylethyl)  ether  was  administered  by
gavage  to  groups  of 50 male  and  50 female B6C3F1 mice  In  a carclnogenldty
bloassay (NTP, 1982).  The  compound  was  given  1n corn oil at doses of 0, 100
or  200  mg/kg,  5 days/week  for  103 weeks, followed by 1-7  weeks  of observa-
tion  In  the males and 2-7  weeks  of observation  In the  females.   Purity was
~70%  as  detailed   In  Section  6.2.2.   Clinical  signs,  mean  body  weights
(determined  weekly  for   the  first  13  weeks   and monthly   thereafter)  and
survival were  comparable  between  the treated and control  groups of each sex.
Survival until  termination  of  the  study In the  control,  low-  and high-dose
groups  was  41/50  (82%),  44/50  (88%)  and 37/50  (74%), respectively,  In the
males,  and  31/50  (62%),  34/50  (68%)  and 28/50  (56%), respectively,  1n the
females.   Treatment-related nonneoplastlc  pathological  effects  of exposure
occurred only  In  the males  and Included  fatty  metamorphosis (2/50, control;
16/50,  low dose;  15/50,  high  dose) and  chronic Inflammation  of  the nasal
cavity (0/50/0/50, 30/50) and nasolacMmal duct  (0/50, 0/50, 28/50).
    Unpublished results of  a  mouse  study  (NCI,  1978), which appears to have
been conducted with  the  NCI (1979)  rat  bloassay, are summarized  In U.S. EPA
(1980b).  An  unspecified  number of  mice of unspecified  strain were treated
with  0,  10  or 25 mg/kg  of  b1s(2-chloro-l-methylethyl)  ether  by  gavage,  5
days/week  for  728  days.   The  primary  systemic  effect was  centrllobular
necrosis of  the liver,, which occurred \n veh.j£le control,  the low-dose and
the'hlglf-dosegrouprs at  Incidence*of  2, 27  and 0%, respectTveTy,  1n the
male  mice,  and  0,  19 and  6%, respectively,   1n  the female mice.   The In-
creased  Incidence  of centrllobular  necrosis,  In  the  Tow-dose groups  was not
explained..   Incidences  of  pulmonary, hemorrhage  (&,,  2,   14%)  and  esophageal
VnfTammatloTi -(&„ Z>;  5%)  were  slightly   Trtcreasech tnr ttref  tftgfl-dotfe males.•,
0042d                               6-7                              07/07/87

-------
Additional Information  regarding  the design or  results  of  this study  (e.g.,
chemical composition, survival data)  were  not  reported.   It appears that  the
Inexplicable  lack  of centMlobular  necrosis  1n the high-dose  groups  may be
the  reason  for exclusion  of  this study from  the NCI (1979)  report and  the
basis for apparent retestlng by the NTP (1982).
    MHsumoM  et  al.  (1979)  administered  b1s(2-chloro-l-methylethyl)  ether
of  high  purity (98.5%) to  groups of 56 male  and 56  female SPF-ICR mice In
the  diet  at  concentrations  of  0,  80,   400,  2000  or  10,000  ppm.    Seven
mice/dose/sex were sacrificed at  weeks  13, 26  and 52, six mice/dose/sex were
sacrificed at  week 78, and  the  remaining  surviving  mice were sacrificed at
week 104.  Body weight  and food  consumption were measured monthly  throughout
the  study, and  comprehensive  hematologlcal, blood biochemical  and  urlnalysls
determinations were  performed at  the Interim and terminal sacrifices,  and on
mice,  sacrificed   .when .moribund.    Comprehensive   gross   and   hlstologlcal
examinations  were  conducted on all  animals at  th'e  scheduled  sacrifices  and
on those that were moribund or died.'
    Markedly  decreased mean  body  weight, food  consumption and  food  effi-
ciency,   and   Increased  mortality,  which   was  due to  consequent  starvation^
occurred  at   10,000   ppm   in  both  sexes   (MHsumorl  et  al.,  1979).    Water
consumption also was  decreased  In the 10,000 ppm females.   The hematologlcal
and  hlstologlcal examinations revealed  effects. Indicative of anemia, at weeks.
13ri  26,atvd- 52r 1n th«>TO,.000  ppm,matesr amfc females.;, ttres'efncladed.^.decreased'.
erv;thro>c-y.te.   count,,   hema.tocrTt  and  hemo.glob1n,r  Increased, polychromatic
er-y;throcytesv    spTertte1    hemosftJerlrT    deposition    and:   extra-medullary
hematopqlesTs  of.  the  sp/leem (latter ,.effect  only  1n  males  at  week Tl^
Splenic  hemosiidefln; deposltiYatf; was?,tKe;{ oalya  one? .of  these*; effects that  was?
evident   at  104 weeks,  occurring  1n  34/112 treated  mice of  both  sexes  vs.
3/112 controls.   Similar, but  less ..pronounced effects,  (slight. reduction 1n ,
0042dv  .                             6-8    £                         07/07^875

-------
mean  body  weight,  mild  decreased  In  erythrocyte  count  and  hemoglobin
concentration and  Increased  polychromatic  erythrocytes)  occurred at 2000  ppm
In the  females.   Effects consistent with anemia  also  occurred at 80 and  400
ppm  but only  In  males  at  13  weeks.   These  Included  decreased erythrocyte
count,  hematocrU  and  hemoglobin,  but  there  were no  splenic histologlcal
alterations.   The  hematologlcal  examinations  also  revealed  mild leukopenla
(reflecting    decreased    lymphocytes   and    Increased   polymorphonuclear
neutrophlls) during  the  first  half  of  the study,  primarily  in the 2000  and
10,000  ppm  groups,  but  this  was  attributed  to  malnutrition.   Treatment-
related  effects  Including   Increased  plasma  GOT  and  GPT,   Increased urea
nitrogen,   Increased   alkaline   phosphatase,   decreased   total  protein   and
decreased  blood  glucose, occurred  In  the  10,000 ppm  male  and female  groups
at weeks  13,  26  and  52.   The  urlnalyses  were  unremarkable.   Absolute  and
relative  organ weight  measurements  at  week  104 were  unremarkable;   slight
decreases  occurred  In  the weights  of  various organs, but  they corresponded
to the  decreased  body weight.   Treatment-related nonneoplastlc pathological
effects other than the splenic alterations discussed above were not observed.
    Although the effects  described above primarily occurred during the  first-
half  of the study  and  were  mild  In  degree,  the  hematologlcal  and   histo-
loglcal evidence was  concluded to  be  Indicative  of treatment-related  eryth-
rocyte  destruction  (MUsuraorl et  al... (.ia794.   The, anenla  was corisAdereA to-
bev toxIcoTogicaTTyi  yTgrrfffcawt a"t<- TO',;000:V ppnr frr both sexes  and' at* 2000  ppm
In  the  females,, and:, maximum, na-effeet  levels  (actuaTTy, NOAEls)  were, con-
cluded  to  be 2000 ppm  (198  mg/kg: bw/day;, determined byT,Investigators)'in  the:
male mice and 400 ppm,  13.5..8. mg/kg^ bw/day). 1:n the  female, mice,..
0042d                               6-9                               07/07/87

-------
6.1.3.   Other   Relevant   Information.   The   acute  oral   and   Inhalation
toxldty of  various  chloroalkyl ethers  are summarized  1n  Table 6-1.  These
data  Indicate  that  the  a-chloroalkyl  ethers  [bls(chloromethyl)  ether   and
chloromethyl  methyl  ether]  are more acutely  toxic  than  the  B-chloroalkyl
ethers  [b1s(2-chloroethyl)  ether  and b1s(2-chloro-l-methylethyl)  ether]  by
Inhalation exposure but not  by oral  exposure.   This appears  to  be  related to
reduced  toxic  potential  resulting  from  extremely  short  lifetimes  of   the
a-chloroalkyl ethers 1n aqueous solution  (U.S.  EPA,  1980b).
    The  primary acute  toxic  effect  of  Inhaled  bls(chloromethyl)  ether  Is
Irritation  of the respiratory passages  and  lungs  (U.S.  EPA,   1980b).   This
appears  to  be  attributable  to  decomposition  Into  hydrogen  chloride   and
formaldehyde  In  the presence of water.
6.2.   CARCINOGENICITY
6.2.1.   Inhalation.   Groups  of  120  male  SPF  Sprague-Oawley   (Spartan  sub-
strain)  rats- and 144-157 male Ha/ICR mice were'exposed to  0,  1,  10  or  100
p,pb.  (0,  5,  47:. or  470  yg/m3) of  bls(chloromethyl)  ether  vapor,  6; hours/
day,  5  days/week for 6 months and observed for  the duration of their life-
span  (Leong  et  al.,  1981).   Body  weights were determined once  a week  for the
Initial  3  months of  the  study and  monthly thereafter.  Gross  necropsies  and
comprehensive  hlstologlcal   examinations were  conducted on  four  rats/group
that  were   sacrificed  for  pulmonary  exfollatlve  cytologlcal  evaluation  on,
post,erxp,o.sure  period/day  1,  on  f,ttur< ratsVgroup that.'were :,sacrtfIced?on* potst-
expasune; period day.  i for cytogenetlc evaluation  {Section 6*3,.),:  and .on. all
rats-,:th£t dited  spontaneously  or-  werfr  satr^f^cedi"wh'en - moirstbiwd^ during  rth"e.
observation:  period.   Necropsies .also were; conducted on. all  mice, that  died
during/ theT exposure  or  observation.:  pentads.; or.4'were" s,acr?,ifVced .whewmoribund
during the  observation  period, but  complete  histology  was not  performed on


0042d                                6-10   '  -   '                      07/07/87

-------
1  I\J
                                                                                TABLE 6-1
                                                        Acute Oral and Inhalation Toxlclty of Chloroalkyl Ethers3
                         Compound
Species
                                                                   Route
       tethal Dose or Concentration
                                                         Reference
             Chlofomethyl methyl ether
             btsJChloromethyl) ether
             bls(2-Chloroethyl) ether
             Transr2,3-dlchloro-p-dloxane
rat

hamster
ra|"
haasier
ra|
             bls(2-Chloro-l-methyJethyl| ether       rat
             2-Chloroethyl vinyl ether
ral
oral
Inhalation
Inhalation
oral
Inhalation
Inhalation
Inhalation
oral
Inhalation

Inhalation
oral
Inhalation
oral
Inhalation
oral
1050 - 817 ng/kg
LCso = 55 ppn (181 mg/m*) for 7 hours
LC$o - 65 ppra (214 mg/ra») for 7 hours
LD50 = 0.21 ml/kgb
LCjo = 7 ppra (33 rog/m*) for 7 hours
LCjo = ?*> n>g/n>* for 6 hours
       7 ppn (33 mg/ra*) for 7 hours
       75 ng/kg
       1000 ppm (S.8 g/ra») for 45 minutes
       ppm (1460 rag/ro1) for 4 hours
     •= 105 ppm (614 mg/m1) for 250 minutes
LOjo * 240 rog/kg
LC^Q = 700 ppm (490 mg/m') for 5 hours
LD$o = 250 mg/kg
LC^o -= 250 ppm (1090 mg/m*) for 4 hours
LOSO =1.41 ml/kgc
1050
LC|.o =
or 250
N10SH. 1974
Drew et al.. 1975
Drew et al.. 1975
Smyth et al.. 1969
Drew et al.. 1975
Leong et al.. 1971
Drew et al.. 1975
Smyth and Carpenter. 1948
Smyth and Carpenter, 1948;
Carpenter et al.. 1949
Schrenk et al.. 1933
Smyth et al.. 1951
Gage. 1970
Smyth et al.. 1949
Carpenter et al., 1949
Smyth et al.. 1969
             'Source: U.S. EPA.19800
             Equivalent to 278 mg/kg (U.S. EPA.  1980b)
             'Equivalent dosage expressed as rog/kg cannot be estimated because density of compound was not available (see Table 1-2).
  CO

-------
all  mice,  because   an   ascending  urinary  tract  Infection  caused  early
mortality.  H1stolog1cal  examinations  using the mice were limited to grossly
recognized liver and  lung lesions,  which suggests a tumorous process, and  on
nasal turblnates from 208 mice.
    There  were  no significant  differences  1n  body weight  gain  between the
control  and  treated  rats,   but  tumor-related  mortality  was  significantly
Increased  In  the  high-dose  rats  after  the  seventh  experimental  month  (1
month postexposure)  (Leong  et al.,  1981).   Atypical or neoplastlc cells  were
not  detected  by the pulmonary  exfollatlve cytology examinations, but 96/111
(86.5%)  of  the  rats  exposed  to  100  ppb  developed  nasal   esthesloneuro-
epHhellomas) (Table  6-2).   These  tumors arose from the olfactory epithelium
and  some  had  metastases.   During  months 7-12  and  13-18  of the  study, 67/76
and  27/31  moribund  or dead  rats,  respectively, that had been  exposed to 100
ppb  had  gross and microscopic  evidence  of the esthes1oneuroep1thel1oma  for-
mation.   Pulmonary adenomas  occurred 1n 4/111  (3.6%)  of the 100 ppb exposed
rats,  an   Incidence  that  Is almost  statistically slgnflcant (p=0.059).  The
majority  of  rats exposed  to 10,  1 or 0 ppb bls(chloromethyl)  ether died  of
spontaneous or  age-related diseases after  the 16th experimental month;,  some
survived as long as 28 months.
    Mean  body weights  of the  treated  groups  of mice  were comparable  with
those  of  the .contrail  mice? throughout ther expje^tiwititi: lU«»ng; ,e# a;L ,/138&l;.  ;
MoctarTitty; that  was. due, .to, an, ascteitd'Tng;.urinary  tract fnfecttan occurred?., fnv,
the majority:  of  the  treated and control mice but may.have  bee^ aggravated  by
treatment "as,  onset-'.was.- earlier  fat the treated ffllte ~f~T ;montfy, of  exposure vs.
3 months1  Vn? thecontrols).   The' ftrcildenee oTrpuT'irojiary; tumors ^adeyiomas, and  ;•
adenocardnomas) was  Increased In 'the ^high-dose mTce,  but  the  Increase was  <•
statistically significant only when mice  that  survived  beyond  the  Initial
6-month exposure period were  considered  (see Table  6-2). -                      5

0042d                               6-12                             07/07/87^

-------
o
o
                                        TABLE 6-2



Tumor Incidences In Male Sprague-Dawley SPF Rats (Spartan Substraln) and Hale Ha/ICR Mice

 Exposed  to  b1s(Chlop:pmethyl)  Ether  by Inhalation  6  Hours/Day,  5  Days/Week  for  6 Months

          .  ,     ,              with  Lifetime  Observation3
OJ
Species Concentration
(ppm)
Rat 100
10
t
P
100
10
]
0
Mouse 100
10
Tj
0
100
IP
1
0
Duration
$f Study** Target Tumor Type
(months) Organ •
19C nose esthesloneuroeplthelloma
28
28
28
19C lung adenoma
28
28
28
25 lungs adenomas or adenocarclnomas
25
25
25
25 lungs adenomas or adenocarclnomas
25
25
25
Tumor Incidence
(p Value)
96/111 (p<0.005)d'e
0/111
0/113
0/112
4/111 (p=0.059)d
0/111
0/113
0/112
10/144f (p>0.05)d
3/143f
7/138f
10/157f
8/279 (p<0.05)d
3/379
5/459
9/869
cb

-------
o
o
ro
o.
                                              TABLE 6-2  (cont.)
                                               QUALITY OF EVIDENCE

                        The compound was administered by  a  natural route  of  exposure to large  groups  of two
                        species at  three  dose levels.  The animals were  observed for  life  and comprehensive
                        hlstologjcal examinations were conducted on the rats.
Strengths of study:
  Weaknesses of study:  The exppsure duration was relatively short and females were not tested.  Comprehensive
                        h)stolpg1caj examinations of  the mice were  precluded by early mortality  because of a
                        urinary Infection  that was  not treatment-related.   Animal ages  and  compound  purity
                        were not Deported;  animals were ambient rather than sham-exposed.
  Overall adequacy:
                      Adequate
         :  Leong et al., 1981

        from survival curves

  cNasal tumor development caused e^rly mortality.

  dF1sher Exact tes|

  eHetastas1s of esthesloneuroeplthelloma to regional  lymph nodes occurred In 5/111 rats (p<0.05)
                   ^  !; fiw i; ,1.1 s,      '£.?'• J_

  fIncidences of tumors  In all mjce In the study.

  ^Incidences of tumors  In mice tha,| survived past  the 6-month exposure period.
o
~j
\
o
-J

3

-------
    In  an  earlier  study,  groups  of  20-50  male  Sprague-Dawley  rats  were
exposed  to  0.1  ppm (0.5  mg/m3)  bls(chloromethyl) ether vapor,  6  hours/day,
5 days/week  for  10, 20,  40,  60,  80 or  100  exposures and  observed  for  life
(Kuschner  et  al.,  1975).   As detailed  1n Table 6-3, nasal  esthesloneuro-
epHhellomas  and  lung  squamous  cell carcinomas  were  Induced  by the  expo-
sures.   Determination  of statistical significances  of the  tumor  Incidences
reported  In Table  6-3  1s  precluded by  a lack  of  Incidence  data   for  the
control  group,  which  consisted  of  240  unspecified  animals  that appear  to
have  been  used   only   for   llfespan  comparisons.   The  cardnogenlcHy  of
b1s(chloromethyl)ether  Is demonstrated clearly, however, by the total number
of  treated  rats  with malignant nasal  tumors  (26/200,  Including  17/200  with
esthesloneuroepHhellomas)  and  lung  tumors   (14/220,  Including 13/220  with
squamous  cell  carcinomas)   and   a  slgmoldal  exposure-response  curve  for
combined  tumors  1n survivors  beyond 210  days that  was  linear  upon problt
transformation.    Compound   purity   was  not   specified,   however,   and  the
respiratory system  was the  only  site  subjected  to  pathologic  examinations.
Preliminary results of this  study were reported by Laskln et al. (1971).
    Dulak and Snyder (1980)  reported that  respiratory tract tumors  developed
1n -35%  of  an  unspecified number of male  Sprague-Dawley rats  exposed to 0.1
ppm  (0.5 mg/m8)  bls(chloromethyl)  ether  vapor, 6  hours/day, 5  days/week
foe 3.Q exposures.  The  rats  were  observed  for life and, the first tumors were
observed- after  350 days; the types of  tumors  were not spec/If led an* addi-
tion* 1 1nf orraa11on was not reported.
    A group of 50 male  Strain A/Heston mice  were  exposed to' fndustrtal grade
b1:s(ch^oromethy.l)   ether   vapor   at  a.   concentration  of  0.005,   mg/iv  (.5,
mg/rn*),1  6 htwrs/
-------
                                                     TABLE  6-3
o
o
               incidence of Respiratory Tract Tumors In Hale Sprague-Dawley Rats Exposed to 0.1 ppm
         bls(Ch)or.pmethyl)  itiiejf,  6 Hours/Day.  5 Days/Week  for  10-100 Exposures  with Lifetime Observation3
Number of
Exposures
Hedjaq
LVfespan
(weeks)
Target Organ
Tumor Type
Tumor Incidence
      100
       80
       60
       40
       20
5ft
43
nose
lung
respiratory tract

nose
lung
respiratory tract

nose
lung
respiratory tract

nose
lung
respiratory tract

nose
lung
respiratory tract
esthesloneuroeplthelloma
squamous cell carcinoma
total malignant tumors

esthesloneuroeplthelloma
squamous cell carcinoma
total malignant tumors

esthesloneuroeplthelloma
squamous cell carcinoma
total malignant tumors

esthesloneuroeplthelloma
squamous cell carcinoma
total malignant tumors

esthesloneuroeplthelloma
squamous cell carcinoma
total malignant tumors
 3/30
 8/30
12/20b

 9/50c
 3/5QC
15/34b

 2/20
 2/20
 4/18b

 2/20
 0/20
 4/18b

 1/50
 0/50
 3/46b
o
01
10
\
CO

-------
                                                 TABLE 6-3 (cont.)
§
Median
Number of Ltfespan
Exposures (weeks)
10 69
0 66

Target Organ
nose
lung
respiratory tract
NR

Tumor Type
esthes loneuroepHhel Ionia
squamous cell carcinoma
total malignant tumors
NR

Tumor Incidence
0/50
0/50
l/41b
NR
   a§purce:  Kuschner et al.,  1375


   bAnimals surviving beyond  21Q  days


^ cTwenty of the rats  Included In  this  tabulation  were  exposed  In  an  earlier  experiment.


   NR = Not reported
Q
th
INJ
US
CO

-------
examination of the lungs  at  conclusion of exposure showed that  26/47  surviv-
ing mice  had  lung tumors, with an  average of 2.9 tumors/mouse.   Lung tumors
were  found  In  20/49  untreated  chamber  control  mice observed  for 130  days
(average   0.9  tumors/mouse)   and   46/49   positive  controls    (500   mg/m3
urethane, 6 hours/day  for 130 days  1n 28 weeks)  (average  54.2  tumors/mouse).
Bls(chloromethyl)  ether  was  considered to be  a tumorlgen  1n  this assay  on
the basis of  the  Increased mean number  of  tumors/mouse In  the treated  group.
    Kuschner  et  al.   (1975)  exposed 100  male Syrian golden hamsters  to  0.1
ppm  (0.5  mg/m3)  bls(chloromethyl)  ether  by  Inhalation,   6   hours/day,  5
days/week  for life.   A   single  undlfferentlated carcinoma  of  the lung  was
observed  1n  one  hamster  that  died   on  day  501  after  334  exposures.   A
survival  curve  Indicated  that there was significant mortality  In  the  treated
hamsters  after  20 weeks,  with 100% mortality after -75 weeks.   This  survival
curve  1s  similar to  curves  for  data  In  rats  exposed to 0.1 ppm  b1s(chloro-
methyl)  ether,  which  reflected  mortality  from  respiratory'  system  tumor
development   (Kuschner et al.,  1975).   The  mortality   In  the   hamsters  Is
difficult  to  evaluate,  however, as  no cause  was Indicated, sites other than
the   respiratory   system  were  not   subjected  to  gross  or   hlstologlcalv
examinations  and  because  colony  controls  rather than sham-exposed  controls
were used.
    Laskln  et al.  (1975) exposed  74  male Sprague-Dawley  rats and,  90 male
SyrTani golden  hamsitersr:'  ta   commercial igrade  c.lKlo.raime.thyfE: methylt -either: by;:
f nh&U&f on--*t a  concertlratlorv  of  7 ppm  i3'rug/m*);.  & hours/day,.  5 days/week
foe:  T.1«feL,  Group* of 74  nat:s and.  88 hamsters  served* as?  chamber/controls^
HTs'toTogical  evaluations,- of v the- respiratory vferactC-ainxk Tungs: werer conducted-
on at  least  54 "of t he! v treatedvratsv ort  atn'teas^B loCvthe^expcsetf hamsters:
and  on similar numbers  of  controls  (exact numbers  of  animals examined  not


0042d                                6-18                              07/07/87

-------
specified).   Although not  stated  specifically,  the  results  of  this  study
Indicate  that  hlstologlcal   examinations  of  gross  abnormalities  In  other
tissues were  also conducted.  Mortality  and  weight gain  were  similar  among
the rat and hamster  treatment and control  groups.   Tumors of the  respiratory
tract, found  In  two  of the  treated  rats,  Included  a squamous cell carcinoma
of  the  lung  that  metastaslzed  to  the  kidneys,  and  an  esthesloneuro-
epHhelloma that  originated  1n   the  olfactory  epithelium.   Another  exposed
rat  had  an undlfferentlated pituitary  tumor.   One  treated hamster had an
adenocarclnoma  of the  lung  and  another  had  a  squamous  papllloma of  the
trachea.    Although  the  Incidences  of  these   tumors  are not  statistically
significant, the  authors speculated  that  the  tumors might be attributable to
bls(chloromethyl)  ether,  which  could have  been present In  the  commercial
grade chloromethyl methyl ether tested 1n this experiment.
    A group of 50 male Strain A/Heston mice  were exposed to Industrial-grade
chloromethyl  methyl   ether   vapor  at  a  concentration  of  0.006  mg/s.  (6
mg/m3), 6  hours/day, 5  days/week for 101  days 1n  21  weeks  (Leong  et al.,
1971).  Gross examination of  the  lungs after  exposure showed that 25/50 mice
had  lung  tumors,  with an  average  of 1.5  tumors/mouse.  Lung  tumors were
found 1n 20/49 untreated chamber  control  mice  observed for 130 days (average
0.9  tumors/mouse)  and  46/49  positive  controls   (500  mg/m3  urethane,   6
hours/day, ,5; days/week  for  .130  days In  28   weeks),  (average  S4..2 tumors/
mouse:).   The  results-  of  th-ls. pulmonary; tumor assay, were  considered  to be.
Inconclusive  as   bls(chloromethyl)  ether occurred  as  a contaminant  In  .the
test  material at concentrations  that  Increased   from  0.3-2.6X  during, the-
experlmenta,! period.
    U;.S>.  EPA;  fT980b)   concluded  that   unequivocal  evidence * exists   that
bls(chloromethyl)  ether  and, for  practical  purposes,   chloromethyl   methyl


0042d                               6-T9                             07/07/87

-------
ether,  are  human  respiratory  carcinogens.   The  conclusion  regarding the
cardnogenlcHy  of chloromethyl  methyl  ether   Is  based  on  the  facts  that
commercial    grade    chloromethyl    methyl    ether    typically   contains
bls(chloromethyl)  ether as  an  Impurity,  generally  1-8%  (IARC,  1979), and
Insufficient  ep1dem1olog1cal  evidence Is available  to separate the carcino-
genic  effects  of these  two  compounds.   IARC (1979)  has also concluded  that
bls(chloromethyl)  ether and  technical  grade  chloromethyl methyl  ether are
carcinogenic for  humans.
    Respiratory  cancers  have  been  Identified 1n workers that were exposed  to
commercial  grade chloromethyl methyl ether  In  a Philadelphia chemical  plant
where  1t  was used  as  an alkylatlng agent (Flgueroa  et a!.,  1973; Weiss and
Boucot,  1975;  Weiss,  1976;  Weiss  and  Flgueroa,  1976; OeFonso  and  Kelton,
1976;  Weiss  et  al., 1979; Albert et  al.,  1975; Pasternack et al., 1977);  to
bls(chloromethyl)   ether  when  used  as  a  contaminant   In  a  California
an1on-exchang«.-  resin"  manufacturing  plant'  (Lemen  et  al.,  1976);   to  b1s-
(chloromethyl)  ether  In a Japanese dyestuff factory  (Sakabe,  1973);   and  to
bls(chloromethyl)  ether In  the  testing laboratory  and production operation
of  a  German  chemical   plant  (Thless  et al.,  1973).   Heavy -exposures =~to-
bls(chloromethyl)  ether and  chloromethyl  methyl ether  have been Identified
as  the  cause  of  lung  adenocardnomas   In  two   German   research  chemists
(Bettendorf,  1976;  Reznlk  et al.,  1977)..  Two  studies ^have  shown a
association  betVeeff abnorma-T puTmorvary; cytolo'gy and} Vxpp sure' to
mefthy-T)  ether,  which  was \ not  related  to  cigarette  smoking  (Frost  e;t; asl«,
1973;"  Lemen  :et~:a:ir, TaTtff.   Irr tataTc, Attf appears;  that, at leasit 4;Z cases  of1
lump  cancer have, been  associated  wtt ft exposure to  bTs(.chloromethyT};: ether
and  oommercitai;  ch
-------
predominant  hlstologlcal  type  has  been  small  cell-undlfferentlated  or  oat
cell carcinomas.  Several of  the  studies  demonstrated  that  the occurrence of
lung cancer was related to the Intensity and duration of exposure.
    The  ep1dem1olog1cal  studies  of  bls(chloromethyl)  ether  or  chloromethyl
methyl ether-exposed workers  cannot  be  used  as  a  basis for  quantitative risk
estimation  for  either  of these compounds because  quantitative exposure data
were  not  reported  and  because  exposures  cannot  be   attributed solely  to
either compound.   Also,  since  U.S.   EPA  (1980b)   considered  the  studies  to
provide  unequivocal  evidence  of  human  cardnogenldty (U.S.   EPA,  1980b;
IARC,  1979),  they will  not  be reviewed or  evaluated  comprehensively.   An
overview of several of  the more extensive studies  1s presented 1n Table 6-4.
6.2.2.   Oral.  Commercial  grade b1s(2-chloroethyl)  ether  was  administered
orally to  groups  of  18 male  and  18  female  B6C3F1  and  18 male and 18 female
B6AKF1 mice  (BRL,  1968; Innes  et   a!.,  1969).   These  hybrid  strains  were
designated  (C57BL/6xC3H/Anf )F]   and   (C57BL/6xAKR)F1,  respectively.   In  the
Innes et al.  (1969)  report.   The oral  treatment  schedule consisted  of dally
Intubation of 100 mg/kg  of  the  compound In  distilled water  from days 7-28 of
life, followed  by administration In  the  diet at  a  concentration of 300 ppm
until 80'weeks  of age.   The  gavage  dose represented  the MTD (determined 1n
preliminary  subchronlc  studies),  and  was  not  adjusted   to changing  body
weight during  the 3 weeks,  of treatment..  The  diet  coAceatratloB WAS ca,\cu-.
Tatetf to? prwfde1 approx^matfeTy>;: thff sai&rl^:'.vs-fn$--\ttieiwif4W^' the*,TWA dosage for  the  entire* study^s; 4^^
mg/kg/day.    Negative control  groups  consisted  of four  untreated groups and


Q0*2d:                               6-2T                             07/07/87

-------
                                                                               TABLE  6-4
             Lung Cancer Mortality |n Workers fxppsed to Unspecified Concentrations of bts(Ch)oromethyl)  Ether  and Technical  Grade Chloromethyl Methyl Ether
IVJ
o
—I
o
~J
•s.
00
Exposed
Population
669 Philadelphia
chemical plant
workers3
1446 Philadelphia
chemical plant
workers3 * • :.
(465 exposed)
721 Chemical
plant workers6
136 California
anlon-exchange
plant workers?
Control
Population
1616 unexposed
workers from the
same plant ' r'
general . -
population
(Philadelphia)
1815 unexposed
workers^ from the
same plant ;
general
population
(Connecticut)
Duration of Exposure
<1 year,1? (n=398)
1 to <5 years'* (n=170)
>5 years6 (n=101)
«12 year.;!*
m *e3n
£5 years
Type of Lung Cancer
(predominant)
NR
small cell carcinoma
NR
small cell carcinoma
(undifferenttated) '.
Number of Number of
Observed Expected
Cancer Deaths Cancer Deaths
19 5.0
39 18.1
23 4.5
5 0.54
Increased Risk
[ Obser ved/E xpec t ed ]
(p value)
3.8' (p<0.01)
2.15c'd (p<0.001)
5. 1C (p<0.05)
9.24 (p<0.01)
Reference
DeFonso and
Kelton, 1976
Weiss
et al.. 1979
Pasternack
et al., 1977f
Lemen
et al.. 1976
3Chloromethyl methyl ether was  used as an aljcylatlng agent In the manufacture of organic  compounds.   This plant was the subject  of  eplderolologlcal studies
 by flgueroa et al. (1973).  Weiss and Boucot  (1975).  Weiss  (1976), Weiss and Ftgueroa  (1976). DeFonso and Kelton  (1976)  and  Weiss et al.  (1979).
DA qualitative exposure rating system was used to approximate relative exposure concentrations and duration times.
'Increased risk was shown to be dependent on  the duration and Intensity of exposure.
dstgntfIcantly  Increased  risk  occurred only, among workers  with  moderate  and heavy exposure.   The  Increased risk was  6.9  In 97 moderately  exposed workers
 (9 observed cases vs.  1.3f expected) and 30 In heavily exposed workers (9 observed cases vs. 0.3 expected).
eThls appears to be the same plant that was studied by DeFonso and Kelton (1976) and Weiss  et al. (1979).
^Preliminaryresults were reported by Albert  et al. (1975)  and Nelson (1976).
9bls(Chlorpfnethyl) ether was a contaminant In a manufacturing process that produced anlon-exchange resins.
NR = Not reported                  '-.«           .#,.

-------
one group  that was  treated  with 0.5% gelatin; each of these groups consisted
of  18  mice/strain/sex.  Following  the treatment period,  all  surviving mice
were  dissected  and grossly  examined,  and   tissue  samples  from  the  chest
contents,  liver,  spleen, kidneys,  adrenals,  stomach,  Intestines and genitals
were microscopically  examined.   Moribund mice  were  sacrificed and subjected
to  gross  pathological  examinations,  but  hlstologlcal  examinations  were
performed  only   when   deemed   appropriate   (criteria  not  specified).   As
detailed 1n  Table 6-5, the Incidences of hepatomas  In  males of both strains
and  females   of   one  strain were  statistically  higher   than  In  the  pooled
control  group.   All  unmetastaslzlng hepatic-cell  tumors were  diagnosed  as
"hepatomas."
    b1s(2-Chloroethyl)  ether of 100% purity was  administered  1n SSV vehicle
to groups  of  26  Charles River  CD rats of both sexes by gavage at doses of 25
or  50  mg/kg, twice weekly  for  78  weeks,  followed by a  26-week observation
period  (Welsburger  et  a!.,  1981).   These doses  were Intended  to represent
the MTD  and  one-half   the HTD  as determined  1n  a subchronlc study.  Matched
and pooled control  groups  were  used but the sizes of these groups were not
reported.  Necropsies  that  Included  comprehensive  hlstologlcal examinations
were conducted  on  all  rats  (Including  those that were  moribund  during the
study)  that  developed  palpable  tissue masses  during the study  and  on five
rats of;" each sex* tit the telgtr-dose' group, at  the end, of: the 18:-week.( treatment
period.    The authorr.  concluded:  that   b1s(2-chToroethyl)   ether; was  not
carcinogenic,,, but  the  results  of  the  pathological •  examination were  not;
specifically  reported.  Compound-reTated decreased  body  weight  occurred In'
th'e  treated!  females   and  h1gh;-dose  mal;es,v  and. survival was/Tower.  In; the
high-dose  females'  (see Section  6.1.2.7.).    The authors1 suggested ;an; fff'e -;
basis  of  the survival  data  that the doses  for  the males may not have been
sufficient to eHcH a  carcinogenic  response.

0042d                                6-23                             07/07/87

-------
                                   TABLE 6-5
              Incidence of Hepatpmas 1n Two Strains of Mice Given
                   Oral Doses of b1s{2-Chloroethyl) Ether3.b
Strain
B6C3F1

B6AKF1

Sex
M
F
M
F
Dosec
(mg/kg/day)
0
41.3
0
41.3
0
41.3
0
41.3
Hepatoma Incidence
(p value)
8/79d
14/16 (p<0.01
0/87d
4/18 (p<0.01
5/90d (p<0.01
9/17
l/82d (NS)
0/18
)e
)e
)e

                              QUALITY OF EVIDENCE
Strengths of study:   Both  sexes of  two  strain  of  mice  were  exposed by  a
                      natural  route for  a significant  portion  of  the  life-
                      span.
Weaknesses of study:  Multiple  species  and doses  were not  tested  and group
                      sizes  were relatively  small.   Extensive  histologlcal
                      examinations  were  not conducted.
Overall adequacy:     /Adequate

aSource:  BRL, 1968; Innes et al.,  1969
bCommercJa,l grade, test chemical
CTWA dose; reflect-Trfg- TOO mg/Kg/xta-y -gava.ge  treatment "for  ^ week*antf 300'ppm
 diet treatment  for the  next 76iweeks*.   A-da1:ly dose was  calculated from the
 300 ppm diet, concentration  by assuming  that mouse food,consumption 1s equiv-
 alents' to l;3%£o£.body :weifgh|t/
-------
    Groups of  50  F344  rats  of each sex were treated by gavage with technical
grade  b1s(2-chloro-l-methylethyl)  ether In corn  oil  at doses  of  0 (vehicle
control), 100  or  200 mg/kg,  5 days/week for 103 weeks, and maintained for an
additional 1-2 weeks (NCI,  1979).   The technical  grade compound was obtained
from  three  different  sources and  contained -2% b1s(2-chloro-n-propyl) ether
and   28.5%   2-chloro-l-methylethyl(2-chloropropyl)   ether.    Dose-related
decreased  mean body  weight  occurred   1n  both  sexes,  and  treatment-related
decreased  survival  occurred  In the high-dose  males  and  high- and low-dose
females  (see Section 6.1.2.2.).  Almost all of  the high-dose group rats died
by  the  end  of the  bloassay.   Comprehensive gross  and hlstologlcal examina-
tions  that  were  conducted  on dead, moribund  and  surviving  animals   (47-50/
group  examined)   did  not  reveal   treatment-related  Increased  Incidences  of
tumors  1n either  sex.   Expression  of  tumoMgenlcHy,  however,  may have been
complicated  by the  low  survival  1n  the   high-dose  group,  as  Insufficient
            • •           * •
numbers  of  high-dose  rats of  each sex were considered at  risk for develop-
ment of  late-developing tumors.
    Technical  grade  b1s(2-chloro-l-methylethyl)  ether  In  corn  oil was also
administered by  gavage to groups  of 50 B6C3F1  mice of each  sex at doses of
0,-~100  or 200-mg/kg/day,  5  days/week for 103 weeks, followed by 1-7 weeks-of
observation  (NTP,  1982).   The  technical grade product  was  -70%  pure,  con-
talnWf- -26-28.5%; 2-chloFo-4-(Bethylethyl (2,-chloropjrapKU *U«r  aM 2.1-2.;6Jfc;
b-1s (-2-chloropropyl)  e-ther.   Ra-ts   a-Tso- were-  treated,  but; tnTs  study. was
aborted  when a dosing  error after 7T  weeks; caused (;a. Targe number of  deaths;;,
details;, were not  reported.   There-were no compound-related; effects-on body
we;Vgh*sr- or-  survival;   ksee  Sectlonv  6..T..&2.;}:;,-.  Treatment  was;  carcinogenic,/
however,   Inducing ' stattsffca-TTy  significant"   Increased ? Incidences "• of
alveolar/bronchlolar adenomas  1n  both  sexes  and  hepatocellular   carcinomas


0042d                                6-25                             07/07/87

-------
with lung metastases  In  the males (Table 6-6).  A  low  Incidence  of squamous
cell papHlomas or  carcinomas  occurred  In the stomach  or  forestomach  of the
female mice.   Since  these  stomach tumors are  rare  In  B6C3F1  mice,  1t  was
concluded that the occurrence was probably treatment-related.
    b1s(2-Chloro-l-methylethyl)  ether  of  high  purity  (98.5%)  was  adminis-
tered  to groups  of  56  male  and  56  female  SPF-ICR  mice  In  the diet  at
concentrations of  0,  80, 400, 2000  or  10,000 ppm  (MHsumorl et  al.,  1979).
Comprehensive  gross  and hlstologlcal  examinations were  conducted on  seven
mice/dose/sex  after  13,  26 and  52 weeks of  treatment,  on  six  mice/dose/sex
after 78 weeks of  treatment,  on  remaining surviving  mice  after  104 weeks of
treatment,   as  well  as   on   moribund   and   dead   mice.   Treatment-related
neoplastlc   lesions  were  not observed.   Expression of  tumor1gen1dty  1n the
high-dose group,  however,   may have been  complicated  by  low survival  (see
Section  6.1.2.2.).   Average dally Intake  In  the  10,000 ppm  dose groups was
reported to be 961 mg/kg/day 1n the males and 927  mg/kg/day In the females.
6.2.3.   Other  Relevant  Information.   The  cutaneous  cardnogenldty  of
various  chloroethers  was evaluated 1n mice  (Van  Duuren et al.,  1968, 1969,
1974,  197-5;  Lyman  and  Furla,  1969).   These Devaluations  Included long-term
thrice weekly dermal  application studies  and Initiation-promotion  studies
(Tables  6-7 and  6-8).   The skin  application  studies  showed  that  b1s(chloro-
•ethyH? 'ftther;*.1 T.Z^M st^ftw^t^^ha^.aml;  poistfcJx , tcU^a^cltforo;-
methoxy.)propane- were  active  as  complete   carcl-nogem,.    Bre1n1t1at1on-
pr.amrt.Von itudles* which teste4var.tou5? chJapoe.thelrs as tiatii Initiators ar\4;
promotensv  showed," that: fctsfchlororaethyl)  ether  was- actVv#  as  *  tumor
promo:ter; Fonilowtng;- Initiation  with " stinger dosesr  of B;fa"pL   fftlter; situdi^es-T
                 v>
showed that  bls(chloromethyl)  ether was active also  as a mouse sktn burner
Initiator  when  TPA  was  used  as  the  promoter   (Zajdela  et  al.,  1980).


0042d                               6-26                             07/07/87

-------
a

2
rvi
ex
                                            TABLE 6-6



Incidence of Tumors In B6C3F1 Nice Treated with Technical Grade b1s(2-Chloro-l-methylethyl)  Ether

                       "In Corn Oil by Gavage, 5 Days/Week for 103 Weeks3
09
Sex Dose
(pig/kg)
» 0
100
200
P
100
200
0
100
?oo
0
100
200
0
100
200
f 0
100
£00
0
100
200
Duration
of Study
(weeks)
104-110
104rllO
104-110
104-110
104-110
105.110
105-JlO
Target Organ
lung
lung
liver
liver
stomach or
forestomach
lung
lung
Tumor Type
alveolar /bronchlolar
adenoma or carcinoma
alveolar/bronchlolar
adenoma
hepatocellular adenomas
and carcinomas?
hepatocellular carcinoma
squamous cell papllloma
alveolar/bronchlolar
adenoma or carcinoma
alveolar/bronchlolar
adenoma
Tumor Incidence
(p value)b
6/50 (p>0.05)c»d
15/50 (p=0.02)c-d
13/50 (p>0.05)c»d
5/50 (p>0.05)C.d
13/50 (p=0.03)c»d
11/50 (p>0.05)e.f
13/50 (p<0.01)c»d
23/50 (p=0.03)d'e
27/50 (p<0.01)c'd
5/50 (p<0.01)c»d
13/50 (p=0.03)d»e
17/50 (p<0.01)c.d
0/49 (p>0.05)e.f
1/50 {p>0.05)e'f.h
1/50 (p>0.05)e'f."
1/50 (p<0.01)c'd
4/50 (p>0.05)e.f
10/50 (p<0.01)c«d
1/50 (p=0.01)c'd
4/50 (p>0.05)e«f
8/50 (p=0.02)c-d

-------
                                                 TABLE  6-6  (cqnt.)
Sex
f
Dose
(mg/kg)
0
100
200
Duration
of Study
(weeks)
105-1J0..
Target Organ
stomach or
forestomach
Tumor Type
squamous cell papllloma
or carcinoma
Tumor Incidence
(p value)*5
0/50 (p>0.05)e»f
0/49 (P>0.05)e»f
3/49 (p>0.05)e«f'n
er>
&
CD
   Strengths of study:
                                                QUALITY  OF  EVIDENCE

                         Adequate numbers  of  animals of both  sexes were  exposed  by a  natural  route at  two
                         doses for  the  majority of  their  llfespan.  Adequate numbers  of animals survived  to
                         be  at  risk  for  late-developing  tumors  and comprehensive  hlstologlcal examinations
                         were.conducted.
   Weaknesses of study:  Jechnlcal grade  compound  of 70%  purity  was tested.   Although only one  species was
      '         "  '"  '    Jested^ the  results  of rats tested  with essentially the  same protocol and the  same
   Overall adequacy:
                         batches of chemicals were reported earlier (NCI, 1979)

                         Adequat^
o
in
oo
    Source: NTP, 1902
        p  value for the  CochrjnTArm1tage  test for linear  trend  Is  shown next  to  the control Incidence;  the
    yalue for the Fisher Exact test Is shown next to the Incidences In the treated groups.

   cp<0.05 In j|fe table analysis

    p<0.05 In Incidental tumor test
    ": ' .        /  *, *" .J            *• - r
   ep>0.05 1n Ijfs table analysis
   c •''<•-       *•''.""•'            .,*••*.
r3   p>0.05 In Incidental tumor test

     etastases |o the lung occurred In 1/50 control, 4/50 low dose and 3/50 high dose male mice.

       was concluded  that these tumors were probably  related  to treatment since  they are rarely observed In
    vehicle control and untreated control B6C3F1 mice.

-------
                                                                         	 TABLE 6-7


                                                           Dermal lumorlgenlclty of Haloethers In Female Nice
rv»
a.
Chemical
Chloromethyl methyl ether

bls(Chloromethyl) ether

a.a-Dtchloromethyl
methyl ether
 Octachloro-dt-n-propyl
^ ether
2,3-Dlchloro-p'dloxano
l,2-bls(Chloromethoxy|
ethane' ' '
1.4-b1s(Chloromethoxy)
butane • '•-, ,
1 .6-bts(Chlorornethoxy^
hexane %. '•
1 ,2.3-Tr Is(Chloromethoxy)
propane ; .*•;''
2.4.4'-TMchloro-2'-
hydroxydtphenyl ether
o
^ aVehtcle control data given
Strain
ICR/IU
Swiss
ICR/Ha
Swiss
ICR/Ha
ICR/Ha
Swiss
Swiss-
Hlllerton
Swiss-
Hi! ler ton
ICR/Ha
Swiss
ICR/Ha
Swiss
ICR/Ha
Swiss
ICR/Ha
Swiss
ICR/Ha
Swiss
Charles
River
Swiss
In parentheses
Pose
(vehicle)
(benzene)
28 mg
(benzene)
2.Q mg
(benzene)
2.0 mg
jjjenzene
(benzene)
\.0 mg
(benzene)
0,5 mg
'(acetone)
J:P ""a
(cyclohexane)
(cyclohexane)
1.0 mg
(cyclohexane)
1.0 mg
(cyclohexane)
Q.I rot of O.S
or l.OX acetone
solution
Application
3 times/week
3 times/week
for 325 days
3 times/week
3 times/week
3 times/week
3 times/week
3 times/week
3 times/week
3 times/week
3 times/week
3 times/week
3 times/week
, Statistical evaluations conducted
Duration
329 days
540 days
329 days
325 days
450 days
450 days
580 days
502 days
503 days
503 days
502 days
19 months
Median
Survival
llmea
(days)
NR
>540 (>540)
313 (NR)
313 (>540)
>450 (>450)
>450 (>450)
478 (543)
>502 (>504)
473 (>504)
484 |>504)
493 (>504)
NR
only on carcinoma Incidences
Incidence of
Papllloroas3
0/20 (0/20)
0/20 (0/20)
13/20 (0/20)
13/20 (0/20)
0/20 (0/20)
0/20 (0/20)
2/50 (0/50)
4/50 (0/50)
1/50 (0/50)
0/50 (0/50)
6/50 (0/50)
NRd
In the Van Duuren
Incidence of
Carcinomas'1
0/20 (0/20)
0/20 (0/20)
12/20 (0/20)
12/20 (0/20)
0/20 (0/20)
0/20 (0/20)
0/50 (0/50)
4/50b (0/50)
1/50C (0/50)
0/50 (0/50)
3/50c (0/50)
NRd
et al. (1975) study
Reference
Van Duuren
et al.. 1968
Van Duuren
et al.. 1969
Van Duuren
et al.. 1968
Van Duuren
et al.. 1969
Van Duuren
et al.. 1969
Van Duuren
et al.. 1969
Van Duuren
et al.. 1974
Van Duuren
et al.. 1975
Van Duuren
et al.. 1975
Van Duuren
et al.. 1975
Van Duuren
et al.. 1975
Lyman and
Furla, 1969
.
f\J •  h
us   b
     , p<0.05

S   Vo.qs
      Tumor Incidences not reported but were similar In treated and control groups.

-------
o
o
ro
o.
Chemical
Chloromethyl methyl
ether


i
CJ
o
bls(Chloromethyl) ether




o
o
\ a.-ci-Dlchloromethyl
3 methyl ether"
TABLE 6-8
House Skin Tumor-Inlt latlng and Tumor -Promo ting Activity of Chloroethers3
Strain
'*»««)
ICR/Ha
Swiss |F)
ICR/Ha
$*'« (F)
ICR/Ha.
Swiss (F)
ICR/Ha
Swiss (F)
Charles
River
CDI (F)
ICR/Ha
Swiss (F)
ICR/Ha
Swiss (f)
XVIlnc/Z
K
ICR/Ha
Swiss (F|
ICfl/Ha
Swiss (fj
Charles
CDI (F)
Swiss-
Nil ler ton
(f) •.-.
Initiation/ Promotion (3 times
.Single Dose weekly beginning 14
l01^ days after primary
" treatment)11
1.0 0.025 rag croton
resin
1.0 0.025 mg phorbol
ester
0-15 B(a)P 2.0 mg
0.15 B|a)P 2.0 mg
10.1 0.2 ml of 0.25X
'' :• croton olle
1.0 0.025 ng croton
resin
1.0 0.025 mg phorbol
ester
1.0 2.0 ng TPA
0.15 fl(a)P 2.0 mg .
0.15 B(a)P 2.0 mg
2.1 0.2 ml of 0.25X
croton oil6
l.Q 0.025 ng phorbol
ester
Median Survival
Treatment Time
or Study (days)d
Duration0
329 days NR
540 days 468 (>450)
329 days NR
325 days >540 (540)
30 weeks NR
329 days NR
540 days 474 (NR)
590 days NR
325 days NR
325 days 315 (540)
30 weeks NR
450 days >450 (>450)
Incidence of
Pap111omasd
3/20 (2/20)
5/20 (2/20)
0/20 (0/20)
1/20 (0/20)
NRf
4/20 (2/20)
5/20 (0/20)
12/289 (4/28)9
12/20 (0/20)
13/20 (0/20)
NRn
3/20 (2/20)
Incidence of
Carcinomas''
0/20 (0/20)
1/20 (0/20)
0/20 (0/20)
0/20 (0/20)
NR
0/20 (0/20)
2/20 (0/20)
3/28 (0/28)
11/20 (0/20)
12/20 (0/20)
NR
1/20 (0/20)
Reference
Van Duuren
et al.. 1968
Van Duuren
et al.. 1969
Van Duuren
et al.. 1968
Van Duuren
et al.. 1969
Slaga
et al.. 1973
Van Duuren
et al.. 1968
Van Duuren
et al.. 1969
Zajdela
et al.. 1980
Van Duuren
et al.. 1968
Van Duuren
et al.. 1969
Slaga
et al.. 1973
Van Duuren
el al.. 1969

-------
                                                                            1ABLE  6-8 (cont.)
Chemical
o.o-Dtchloromethyl
methyl ether'

bts(a-Chloroethyl)
ether ,
bls(2-Chloroethyl)
ether
Octachloro-dl-n-propyl
ether ;




2,3-Dlchloro-p-dloxane
: . •"• '
Initiation/ Promotion (3 tiroes Median Survival
Strain Single Dose weekly beginning 14 Treatment Time Incidence of
(sex) (mg) day$ after primary or Study (days)d Paplllomasd
:"- : treatment)" Duration0
Swiss- 0.15 BlaJP 1.0 mg 450 days >450 (>450) 0/20 (0/20)
HUlerton
in "'
ICR/Ha 1.0 2.5 ng PHA 590 days 414(485) 7/20 (2/20)
Swiss (F)
JCR/Ha 1.0 2.5 ng/PHA 590 days 459(485) 3/20 (2/20)
Swiss (F|
Swiss- 1.0 0.025 mg phorbol 450 days >450 (>450) 3/20 (2/20)
filler ton ' ester
}n
Swiss- 0.15 Q(a)P 1.0 mg 450 days >450 (>450) 1/20 (0/20)
HUlerton : -
(n »-.-
ICR/Ha 0.5 2.5 Mg/PHA 385 days 385 (NR) 8/30 (3/30)
Swiss |f)
Incidence of Reference
Carclnomasd
0/20 (0/20) Van Duuren
et al., 1969

0/20 (0/20) Van Duuren
et al.. 1972
0/20 (0/20) Van Duuren
et al.. 1972
1/20 (0/20) Van Duuren
et al.. 1969

0/20 (0/20) Van Duuren
et al.. 1969

2/30 (0/30) Van Duuren
et al.. 1974
     alf more than one dose was (tested In a particular study, data are given for the highest dose If Inactive and for the lowest dose If active.
                             ••""-•   "     "      .  .  '*" •

     bProfiwtlon for duration of study In the Van Ouuren,et al. (1968, 1969. 1972, 1974) studies.  Promotion for 42 weeks In the Zajdela et al.  (1980) study.


     cDuratlon from beginning of promotion phase


     •^Vehicle  (benzene)  control data  In parenlhesetj untreated  and positive control data  reported  but not  presented In this  table.   Acetone was  used as  the
      vehicle for 2,3-dlchlord-p-dloxane.  '      '•'".

          • . -,  •    ,         ..v '       • '•"   ••   . •
     eTwlce weekly applications for 29 weeks beginning 1  week after Initiation.


     fThere were 0.2 paplllomas/treated mouse vs. 0/qouse In controls (26 treated and 29 controls tested).


     QTotal Incidence of paptllqmas;  Incidences of persistent paplllomas were 4/28 tn treated and 1/28 In controls.


     "There were 0.6 paplllomas/lreated mouse vs. O/qtpufe In controls (28 treated and 30 controls tested).
o
tn

-------
2,3-D1chloro-p-d1oxane  showed  possible activity  as  an Initiating agent  with
PMA as the promoter (Van Duuren et al., 1972).
    The  cardnogenlcHy of various  chloroethers was  also  evaluated 1n  mice
and  rats  that  were   treated  by  weekly  subcutaneous  Injections  for  life
(Gargus  et al.,  1969;  Van  Ouuren  et al.,  1969,  1971,  1972,  1974,   1975;
Zajdela  et al., 1980).   These studies,  which  are  summarized  1n Table  6-9,
Indicate  that  chloromethyl methyl  ether,  b1s(2-chloroethyl)  ether, 2,3-d1-
chloro-p-d1oxane,   1,2-b1s(chloromethoxy)ethane,  1,2,3-tr1s(chloromethoxy)-
propane   and   possibly   bls(a-chloroethyl)  ether   Induced   Injection-site
sarcomas  In  mice.   Hlstologlcal  examination  of abnormally appearing tissues
did not reveal treatment-related  distant  tumors  1n these  studies.
    Groups of  48-51 male and  female newborn ICR  Swiss mice were  given  single
subcutaneous   Injections   of   predetermined   MTDs   of   Industrial    grade
bls(chloromethyl)  ether  (12.5  yl/kg)  or  chloromethyl  methyl   ether  (125
vl/kg)  In  peanut  oil  and  observed  for  6  months  (Gargus  et  al.,   1969).
Growth  and survival  of  these mice  were  comparable  with  those of vehicle
controls.   Dissecting  microscopic  examination  of  the  lungs  showed  that
45/100  mice  treated  with  bls(chloromethyl)  ether  and 17/99  treated  wtth
chloromethyl  methyl  ether  developed  adenomas;  the mean  numbers of tumors/
treated mice were  0.64 and  0.21,  respectively.    Seven of 50  vehicle controls
(30 males, 20  females)  had  lung tumors (0.14 tumors/mouse).  These  data were.
Interpreted- a&  Indtcatfng  a   s:Vgn1:f 1 caret-tumor4"gen^Vc: effect;  afr b;1.s;(chToro-;
me:tlry:Tj  ether:  tri  this,  assay, sy/stemv;   Iti  was  suggested  that  the/sraaTT
tncreaiie  1w tumors \m the ohlorometby.tvn«,tiiy:Yether? group may be attributed;
to. b1;s/(ichToromethy''l'); ether,vWhtch: occurred asKa;0;.3% contaminant.!';
    Weekly  1ntraper1toneal  Injections  of; b;1'S(ch'Tonometh;yl)K,fttheF> T,:2-b,ils->
(chloromethoxy)ethane  and  1.2,3-tr1s(chloromethoxy)propane for life produced
significantly  Increased  Incidences,  of   1nject1on-s.1te  sarcomas  In   female:
0042d      -                         6-32                             07/07/87 *

-------
                       •  TABLE 6-9



Subcutaneous Injection Carctnoijenlclty Studies of Haloethers
Q.
Chemical
Chloromethyl methyl ether


-
bls(Chloromethyl) ether
i
CO



bls(a-Chloroethyl) ether
bls(2-Chloroethyl) ether
2,3-01chloro-p-dloxane
o -"•* '""•-
tfl
•^ • 2.3-Olchlorotetrahydrofuran
ift.
Species/Strain
rat/Sprague-
Dawley -..
mouse/ICR/Ha
Swiss
roouse/ICR/Ha
Swiss ;
mouse/ICR Swiss
(newborn)
rat/Spraque-
Dawlev. '
piouse/ICR/Ha
Swiss '•"••'.
mouse/»y|lnc/Z
mouse/KVIlnc/Z
mouse/|CR/Swlss
(newborn)
mouse/ICR/Ha
Swiss * -
mouse/|CR/Ha
Swiss '•'"•''•'•''•••'•
mouse/ICR/Ha
Swiss !;•',.
mouse/|CR/Ha
Swiss ~ V
Sex
F
F
F
H.F
F
F
H
F
M.F
F
F
F
F
Dose and Schedule
3 nig/ Inject I on/weekb
0.3 rag/Injection week
for 26 weeksb
0.3 mg/lnjectlon/weekb
125 nt/kg (132.6 mg/kg).
single Injection
3 mg/ Inject Ion/week for
first 114 daysb;
subsequently 1 mg/
Injection/week1*
0.3 mg/lnject1on/weekb
0.3 rag/Inject lonb, 32
Injections in 42 weeks
0.3 mg/1nject1onb, 32
Injections In 42 weeks
125 yl/kg (132.6 rog/kg).
single Injection
0.3 mg/1nject1on/weekb
1 mg/1njectlon/weekb
0.5 mg/ Inject! on/week6
0.3 mg/lnjectlon weekb
Hedlan
Duration Survival
Time
(days)a
515 days 478 (496)
644 days 497 (497)
life 496 (643)
6 months NR
515 days 325 (496)
371 days 260 (443)
549 days NR
549 days NR
6 months NR
life 649 (643)
life 656 (643)
580 days 444 (523)
life >685 (643)
Injection-Site
Sarcomas8
1/20
5/30
10/30
0/99C
5/20
21/50d
12/27d
10/24d
1/100C
4/30
2/30
17/50d-f
1/30
(0/20)
(0/30)
(0/30)
(NR)
(0/20)
(1/50)
(0/30)
(NR)
(NR)
(0/30)
(0/30)
(0/50)
(0/30)
Reference
Van Duuren
et al.. 1969
Van Duuren
et al.. 1971
Van Duuren
et al.. 1972
Gargus
et al.. 1969
Van Duuren
et al.. 1969
Van Duuren
et al.. 1975
Zajdela
et al.. 1980
Zajdela
et al., 1980
Gargus
et al., 1969
Van Duuren
et al.. 1972
Van Duuren
et al.. 1972
Van Duuren
et al.. 1974
Van Duuren
et al.. 1972

-------
                                                                         TABLE 69 (cont.)
o
o
CJ

Chemical

),2-b1s(Chloromethoxy)ethane
1.4-b1s(Chloromethpxy)butane
1.6-b1s(Chloromethoxy)hexane
,?•;"'_" '. •:••:•!
1.2,3-tr1s(Chloromethoxy]|
propane
'\
Species/Strain

•»• '-.-, •-•?,,.
mouse/ICR/Ha
SyM>'
muuse/ICR/Ha
*W.*:
mouse/ICR/Ha
s-JsiS-;
nibuse/lCR/Ha
•SMiSr^"-
'. '. J i* ' ' •

Sex Dose and Schedule

* •" .
F 0.3 rag/ Injection/week0
F 0.3 mg/1njecllon/weekc
F 0.3 ing/Inject lon/weekc
F 0.3 mg/1njecilon/weekc

Duration

S69 days
569 days
S69 days
569 days
Hedlan
Survival
Time
(days)*
362 (436)
443 (436)
440 (436)
349 (436)

InJectlon-Stte
Sarcomas3

9/50d (0/50)
0/50 (0/50)
1/50 (0/50)
10/50d-9 (0/50)

Reference

Van Duuren
et al.. 1975
Van Duuren
et al., 1975
Van Duuren
et al.. 1975
Van Duuren
et al.. 1975
aVehlcle control data  given In parentheses.  Statistical  evaluation  conducted only  In  the  Van Duuren et al.  (1975)  and Zajdela et al.  (19BO)
 studies.                          ''^r-s^.



bNujo1 vehicle


'Pulmonary tumors jvlso occurred In treaied rats.


?jp<0.01                  i-iv'"
 ' •"'•li.                   "                   .

fJr.lcapryltn vehicle


'Total local malignant tumors; Includes ^4 sarcomas. 1 squamous cell carcinoma and 2  adenocarclnomas


9Two additional animals had carcinomas s'
oo

-------
ICR/Ha  Swiss  mice (Van Ouuren  et  a!.,  1975)  (Table  6-10).   Necropsies that
Included  hlstologlcal  examinations of  abnormally  appearing  tissues  did not
reveal  treatment-related  distant  tumors.   Thrice  weekly  Intraperltoneal
Injections of  b1s(2-chloroethyl)  ether  at  doses  of 8-40 mg/kg for  up to 24
Injections did not  produce  treatment-related  Increased  Incidences  of lung
adenomas  In Strain A mice (Thless et al., 1977).
6.3.   MUTAGENICITY
    Hutagenlclty  and  genotoxldty data  for the chloroethers  are summarized
In  Table  6-11.   Ijn  vitro  assays  with  various strains of  Salmonella typhl-
murlum.  Bacillus   subtnis.  Escherlchla  coll  and  Saccharomyces  cerevlslae
have  yielded  positive  responses   In   b1s(2-chloroethyl)  ether  and  b1s(2-
chloro-1-methylethyl)  ether  without metabolic  activation  preparation, which
Indicates   that   these   chloroethers    may   be   direct-acting   mutagens.
b1s(2-Chloro-l-methylethyl)  ether  also  produced  chromosome  aberrations  and
slsterchromatld  exchanges   In   cultured  Chinese  hamster   ovary   cells  (NTP,
1982).  Dally  gavage administration for  8 weeks of  b1s-(2-chloroethyl) ether
and b1s(2-chloro-l-methylethyl)  ether  at  three unspecified  dose levels did
not , produce   a, detectable  Increase  In   heritable   translocatlons   In  mice
(Jorgenson et  al., 1977, 1978)  (see Section 6.3.).   However, the sample size
used was  so  small that only an Increase of 100 times  the spontaneous level
of  translacafcton* could, have? teea detected;.,-  2.»4,4'-Tr\chlor.o^l-^ydFoxx-
dfptfenyT  ether did.not ^produce somatic mutation* (for, color alterations^ ft*
the offspring  of  mice treated  by  Intraperltoneal Injection  during gestation
(spot test) (Russell and Montgomery, 1980).,. Although the available data are
Indicative of  mu.tagen1c.tty. of  b1s(:2:-ch:loroethy,l);: ether and bis.  (-2-ch;Torff-l>
methylethyl)   ether'  In -Yn  vitro  mfcrobfal- assays,  much*' of 
-------
                                                                            TABLE 6-10


                                            Inlraper Honeal Injection Carctnogentclty Studies of  llaloethers with  Hlcea
Chemical
bls(Chloromethyl) ether

2,3-Dlchloro-p-dloxane

1.2-b1s(Chloromethoxy)ethane

t,4-b1s(Chloromethoxy)butane
. •••''".'*'.*
1 ,6-bls(Chloromethoxy)hexane

1 .2,3-tr1s(Chloromethoxy)propane
-""*•• •:—1-"
Bose and Schedule
p. 02 rag/ Injection/week0

(M rag/ Inject Ion/week*1

0,3 mg/lnjectlon/weekd

0.) »g/ Injection/week*1

0.3 i«g/ Injection/week11
i
0.9 ng/lnject Ion/week*1

Exposure
Duration
(days)
424

450

546

567

567

532

Median
Survival lime
(days)"1
287 (441)

NR

481 (513)

478 (513)

472 (513)

428 (513)

Injection-Site
Sarcomas'1
4/30c (0/30)

0/30e (1/30)

2/30M (0/30)

0/30 (0/30)

0/30 (0/30)

5/30h (0/30)

Incidence of
Papillary Tumors
of Lungs'1
NR

12/30 (10/30)

NR

NR

NR

NR

Reference
Van Duuren
et al.. 1975
Van Duuren
et al.. 1974
Van Duuren
et al., 1975
Van Duuren
et al., 1975
Van Duuren
et al., 1975
Van Duuren
et al., 1975
         "Female ICR/Ha Swiss mice'                  '


         ''Vehicle control dala given In parenthesg$.


         cNuJol vehicle


         dTr1capry!1n vehicle


         eOne treated mouse had a local undlfJe.renHated malignant tumor.






         9jwo additional mice had local undlfftjrenjfated malignant tumors.


         ,".p<0.02                                   ^
o
in
\
TO
ip

CD

-------
                             TABLE 6-11



Hiitagenlclty and Other Short-Term Gcnotoxlclty  Assays  of HaToethers
, >-..'.
Chemical
bls(Chlorqmethyl) ether
*• \ i

o> b1s(2-Chloroethy1) ether,
CJ
-^i





0
«j
*^
o •
-J
*^ '•
00
~J
Assay
reverse mutation
chromosome
aberration
rey.erse mutation
reverse mutation
reverse mutation
reverse mutation
reverse mutation
reverse mutation
reverse mutation
reverse mutatlpn
Indicator
Organism
Salmonella
typhlrourluni
TA1S35
TA1S38
TA9B
TA100
Sprague-Dauley
Spartan rat
bone marrow
cells
S. typhlmurlum
(strains NR)
S. typhlmurlum
TA100
TAT 535
S. typhlmurlma
(strain NR)
S. typhlmurlmi
TA100
TA1535
TA1538
TA98
S. typjilmurlum
TA100
S. typhlmurluni
(strains NR)
S. typhlmurlum
(unspecified
TR strains)
Escherlchla
coll HP2
Application
plate Incorporation
vapor exposure
hi vivo; evaluation
conducted 5 days
postexposure
plate Incorporation
suspension
suspension
vapor exposure
(desiccator)
vapor exposure
(desiccator)
host -mediated
(unspecified species)
NR
plate Incorporation
Concentration
or Dose
NR
NR
NR
20 pg/plate
1-100 ppb,
(5-470 ng/m»)
6 hours/day,
5 days/week
for 6 months
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
NR
Activating Response
System
*
f
»
t +
NA
NR
NR +
NR f
¥
NR »
NR f
NR » (weak)
NR t (weak)
t-
NA
*a
NR
Reference
Anderson and
Styles, 1976
Leong
et al.. 1981
Simmon et
al.. 1977a
Simmon et
al., 1977a
Simmon et
al.. 1977b
Simmon et
al.. 1977a
Simmon et
al.. 1977b
Simmon et
al.. T977a
Shlrasu
et al.. 1975
Simmon et
al.. 1977a

-------
(ABLE  6-11  (cunt.)
g Chemical i ' Assay -'•
bls(2-Chloroethyl) ether reverse mutation
reverse mutation
rec-assay ,;
NR
heritable
trarislocatlon
bls(?-Chloro-l-methylethyl) reverse muta)}on
0, ethei- .-"•••;'••• --^ - ":;-:' -'*^~
reverse mytgiton
'.' ' - ; !• ' "y. F
.-T-; : ••".
reverse mu;tat)on
reverse mutation
'•. •' . • *' «v'*V' .
-: *3 • ** ^ *
C3 NO
tn ^.M,
* '• " "• °"f\. ^'":->
CO
Indicator ' Application
Organism .
E. coll NR
WP? B/rhcr*.
WP? hcr-
Baclllus NR
subtllls
GSY 1035
B. subtllls NR
(strain NR)
Saccharomyces suspension
cerevlslae D3
mouse dally gavage for 8
(strain NR) weeks *
S. typhlmur lum plate Incorporation
TA100
TA1535
S. typhlmur lum suspension
TA100
TA1535
S. typhlrourluni vapor (desiccator)
TA100
TA1535
E. coll WP? plate Incorporation
'''-•• vapor desiccator
S. cerevlslae suspension
D3

Concentration Activating Response
or Dose System
NR - •*
NR - fa
NR - *a
NR NR t
NR NA
(three dose
levels)
NR -
> f (weak)
NR
f » (weak)
NR *
NR - +
NR - * (weak)
f »
NR - » (weak)
NR
^
NR
t f (weak)
NR NR i

Reference
Shlrasu
et al.. 1975
Shlrasu
et al.. 1975
Shlrasu
et al.. 1975
Simmon et
al.. 1977a
Jorgenson et
al.. 1977.
1978
Simmon
et al.. 1978
Simmon et
al.. 1978^

Simmon et
al.. 1978b
Simmon
et al.. 1978
Simmon
et al.. 1978


-------
                                                                           TABLE 6-11 (cent.)
o :
o Chemical
r\>
Q.
b1s(2-CMoro-l-methylethyl)
ether ' '


2.4.V-Tr1chloro-2'-hydroxy-
dlphenyl ether
"*•»
heritable
trans location
chromosome
aberration
sister -chroroat Id
exchange
spot test
(raelanbcytes)
Indicator
Organism
mouse
(strain NR)
Chinese hamster
ovary cells
Chinese hamster
ovary cells
offspring of
Inbred C57BL/E
female mice with
multiple reces-
sive T-stock
males
Application
dally gavage for 8
weeks
unspecified In vitro
unspecified In vitro

Intraper Itoneal In-
jection on post-
conception days 9.25
or 10,25
Concentration
or Dose
NR
(3 dose
levels)
NR
NR
1-25 rag/kg
Activating Response
System
NA
NR *
NR f
NA
Reference
Jorgenson et
al.. 1977.
1978
NTP. 1982C
NTP. 1982C
Russell and
Montgomery.
1980
     'Although not stated specifically, positive responses In all four assay systems by these Investigators Is Implied.



to   bSome of these results also reported by Simmon et al. (1977b)
• rt         - .             i' •  • i >   *,.•"-"'•.'*'
vO
     cUnpubl1shed results


     NR =. Nqt reported; NA. = not applicable
o
en
10
S;

00

-------
6.4.   TERATOGENICITY
    Pertinent  data  regarding the  teratogenldty of  the  haloethers that are
the subject  of this  report could  not  be  located In the available  literature
as cited 1n Appendix A.
6.5.   OTHER REPRODUCTIVE EFFECTS
    Inbred  C57B1/E   female  mice  that  had  been  bred  to  multiple  recessive
T-stock males  were  treated by 1ntraper1toneal Injection of 2,4,4'-tr1chloro-
2'-hydroxyd1phenyl  ether at  doses of  -3,  8  or 25  mg/kg on postconceptlon
days 9.25  or  10.25  (Russell and Montgomery,  1980).   This test 1s  an  \n_ vivo
somatic mutation  assay  (spot test)  (see  Section 6.3.)  and the compound was
99.7%  pure  and  administered  In  methanol.    Reduced  prenatal  survival,  as
Indicated  by  reduced  litter  size,  occurred at  25  mg/kg In  both  treated
groups; this  effect  was  attributed to maternal  toxlclty.   Postnatal  survival
(between birth and  12 days)  was  significantly  reduced at 8  and 25 mg/kg  In
the day  9.25  treatment  group and  at  all doses 1n  the  day  10.25  treatment
group.
6.6.   SUMMARY
    Rats exposed  to 1 or  10 (3 or 33 mg/m3)  chloromethyl methyl  ether, 6-7  ?•
hours/day  for up  to 30  days,  and  rats  and  hamsters exposed  to  1  ppm  (5
mg/m3) b1s{chloromethyl) ether,  6 hours/day  for  up  to  30 days  experienced
mortality  and  hlstopathologlcal   alterations  of  the   respiratory   tract.
L|fe^ftnief'' exposure  of .-> ratsfc aadl  twns^eirs to  1 ^Bpmpia* - mg/n»»%, :ch^^cowethyf
mettty-T ether,  6: hours/day,,. 5 dayr/week .produced.".hr-TTtaTogtcan changes:: In the'
respiratory*; tract". iLasklnC et? aT.i,  IStffff.    Stfrv1vaT=  was  flat  atffekrtetf.
Inhalation  exposure", to  20  or  70 ppm  (140  or 490  mg/m3.)   b1s(2-chloro-T-
methyl-et'hyiT)'. ether,  W tfours/daVi* S;  days/week  for  4"weeks  did no.t  protiuce
altered blood  or  urine  Indices,  or tissue histology;  however, reduced weight
gain was rated at 70 ppm (Gage, 1970).

0042*                               fr-40i                             08/26/87

-------
    Dally  oral  exposure  to  b1s(2-chloro-l-methylethyl)  ether  for  13 weeks
produced reduced body weight  In  rats  at  250 mg/kg but not at lower doses (no
hlstologlcal effects at any doses)  (NCI,  1979),  and focal pneumonHls at >50
mg/kg  1n mice  (NTP,  1982).  Subchronlc oral  exposure  to 10 mg b1s(2-chloro-
1-methylethyl) ether (22  doses  1n  31  days)  produced decreased growth  In rats
(Dow Chemical, n.d.) and  Increased  relative liver,  kidney and spleen weights
at  200  mg/kg.   Oral  exposure  to 2,4,4'-tr1chloro-2'-d1hydroxyd1phenyl ether
on  6 days/week  for  4 weeks caused  reduced  weight gain and mortality  In rats
at  1000 mg/kg  but  not  at  lower  doses  (Lyman  and Furla,  1969).   Nasal tumors
developed  1n  rats  and  possibly  lung  tumors  developed  In  mice  that  were
exposed  to bls(chloromethyl)   ether  by  Inhalation  at concentrations  of  100
ppb  (5  vg/m3),  6  hours/day,  5  days/week  for  6  months  with  lifetime
observation (Leong et a!., 1981) and  nasal  tumors In rats exposed to 0.1 ppm
(0.5  mg/m3)  for  6  hours/day,   5   days/week   for  40-100  exposures  with
lifetime observation (Kuschner et al., 1975).
    Another  study  Indicated  that  treament-related  respiratory  tumors of an
unspecified  type  developed  1n  rats  exposed to  0.1  ppm (0.5  mg/m3)  b1s-
(chloromethyl) ether vapor,  6 hours/day,  5 days/week for  30 exposures, with,
lifetime observation (Dulak and  Snyder,  1980).   bls(Chloromethyl) ether also
produced an  Increased  Incidence and  frequency  of  lung  adenomas  1n strain A
mice,  exposed  to  1  ppm,.  (£ ng/aH*. ft  hour's/day  for  82 days  im  2J weeks
(Leong, et-aT., 1311)... .
    Commercial  grade ;ch-loromethy.V.  methy,7;  ether   vapor  did  not   produce
significantly  Increased  Incidences "of respiratory  system1tumors  In rats;, or
hamsters'  exposed  to? 1.  ppnr• .|3 mq/m'-f  for  &',  hmirs/tfffyv 5?< da.y,s'/we;ek». but
there  were Increased Incidences  of squamous metaplasia of "the  trachea and
bronchial  hyperplasla  In  the  rats  (Laskln  et   al.,  1975).   Strain  A  mice


0042d                               6-41                              08/26/87

-------
exposed to  2  ppm (6 mg/m3)  chloromethyl methyl ether  vapor,  6 hours/day, 5
days/week  for  101  days  In  21  weeks  also  developed  lung tumors,  but  the
results were  Judged Inconclusive because the  test  material was contaminated
with bls(chloromethyl)  ether (Leong et  al.,  1971).  Ep1dem1olog1cal studies
of  workers  exposed  to  b1s(chloromethyl)  ether and  commercial chloromethyl
methyl  ether  have  demonstrated  exposure-related occurrence  of lung tumors,
predominantly  small   cell-undlfferentlated   or   oat-cell   carcinomas   (see
Section  6.2.1.1.)-   Because  Industrial  grade  chloromethyl  methyl   ether
contains carcinogenic  bls(chloromethyl)  ether  as  a contaminant,  and because
there  1s  Insufficient  ep1dem1olog1cal evidence to separate the carcinogenic
effects of  these compounds,  there  Is  sufficient  evidence  to  conclude  that
bls(chloromethyl)  ether  and  Industrial  grade  chloromethyl  methyl  ether  are
human carcinogens (IARC, 1979; U.S.  EPA, 1980b).
    Dally  Intubation- with  commercial  grade  b1s(2-chloroethyl)  ether  at a
dose  of 100 mg/kg  on  days .7-28 of  life  followed by  administration  In  the
diet at a  concentration of "300  ppm for the  next  76  weeks produced  signifi-
cantly  Increased  Incidences  of hepatomas In  male  and female B6C3F1  mice  and
male  B6AKF1  mice  (BRL.  1968;  Innes et  al.,  1969);  the TWA  dose was  41.3
mg/kg/day.   Twice  weekly  administration  of  100%  pure  b1s(2-chloroethyl)
ether  by  gavage  at doses  of 25  or 50  mg/kg  for  78 weeks,  followed by a
26-week observation period,  was  not carcinogenic  In Charles.  River CO  rats;
but caused* reduced weight gain at  both  doses and  mortality fft the; fctgtp dose
(.We1 sburger, e-t? afU* 19&EK
    Carcfrragerttettfy bfoassays of! tecnntfcat;grade ftfsf2-cltTor.a-T:-methyTethyT)
ether were conducted Irr wfrtch groups: .of. 50- F!344: ratsTof.'  each' .sex-  (NCT, T'9'79)
and 50  B6C3F1  mice of  each  sex  (NTP, 1982) were  treated by gavage  at doses
of 100  or  200 mg/kg, 5 days/week  for  103 weeks.  The technical grade  chemi-
cal was -70% pure,  containing -28.5% 2-chloro-l-methylethyl(2^chloroprQpyl)

0042d                                6-42                              08/26/87

-------
ether  and  2% b1s(2-chloro-n-propyl) ether.   The rats were  observed  for 1-2
weeks  following  treatment.   Increased  Incidence  of  tumors  did  not  occur In
the  rats but  there were nonneoplastlc  effects  Including  reduced weight gain
and  decreased  survival  (both doses), centrllobular  necrosis (high dose) and
esophageal  hyperkeratosls (high dose).   The  mice were observed for 1-7 weeks
following  treatment  and  developed  significantly  Increased   Incidences  of
alveolar/bronchlolar   adenomas    (both   sexes),   hepatocellular   carcinomas
(males) and  low  Incidences  of squamous  cell  paplllomas  or carcinomas 1n the
stomach or  forestomach  (high-dose females).   Nonneoplastlc  effects  occurred
In the male  mice,  Including fatty metamorphosis  and chronic Inflammation of
the  nasal cavity and  nasoYacrlmal  duct.  High purity (98.5%) b1s(2-chloro-l-
methylethyl) ether  was  not  carcinogenic to  SPF-ICR  mice  when concentrations
of 80, 400, 2000 or 10,000  ppm  were administered In the diet to groups of 56
ro1ce/sex at  for durations  as long  as  104  weeks  (MHsumorl et  al.,  1979).
The average dally  Intake of  chemical  by the  10,000 ppm group was higher (961
mg/kg/day by males; 927 mg/kg/day  by  females) than that given to the mice In
the  NTP  (1982)  bloassay.   Toxic  effects   Included  mild anemia.  Increased
polychromatic  erythrocytes  and splenic hemoslderln  deposition: at  the: high
dose  In  both sexes primarily during the  first half of  the study.   Similar
effects also occurred  at  2000 ppm In the females  and  only at  13 weeks at 80
and 4^0 ppm In the males....
    The  cardrtogenlcity*  of'numerous;  chToroethers   h'as   been  evaluated  In
dermal application,  dermal  Initiation-promotion,  subcutaneous  Injection and
IntraperttoneaT Insertion  stutffes.   Most of these  studies were conducted' by
Van Quurerv efc. a'*.  (1968^  W&S:,,. T;9^i;.r, TS72* T$£*> T9.75){r. wna a'dnrtnVster-ed; the-
compounds thrice weekly (dermal studies') or once weekly   (tnjectton studies)
to mice  for life.   bls(Chloromethyl)  ether was  tumorlgenlc  In  all  of the


0042d                               6-43                             08/26/87

-------
aforementioned  types  of  studies,  Including  mouse  skin   assays   In  which
bls(chloromethyl)  ether  was  active as  an  Initiator  or  promoter.   l,2-b1s-
(Chloromethoxy) ethane and 1,2,3-tr1s(ch1oromethoxy)propane were tumoMgenlc
In  dermal  application,   subcutaneous  Injection  and  Intraperltoneal   Injec-
tion  studies.   Chloromethyl  methyl  ether,  bls(a-chloroethyl)  ether  and
1,2,3-tr1s(chloromethoxy)propane were tumorlgenlc by subcutaneous Injection.
    Positive   responses   have  been  produced  by  bls(chloromethyl)   ether,
b1s(2-chloroethyl)  ether  and  b1s(2-chloro-l-methylethyl)  ether  1n  In vitro
assays  with various strains  of  S. typhlmurlum. B_.  subtnis.  £.  coll  and S.
cerevlslae  without  metabolic  activation  (Shlrasu   et  al., 1975;  Simmon et
a!.,  1977a,b,  1978; Anderson  and  Styles, 1978), which  Indicates that these
chloroethers  may  be  direct-acting mutagens.   b1s(2-Chloroethyl)  ether  also
produced  chromosome aberrations  and slster-chromatld  exchanges  In cultured
.Chinese  hamster ovary  cells  (NTP,  1982).   bls(Chloromethyl)  ether did not
produce  chromosome  aberrations In  the  bone marrow  cells  of mice exposed by
Inhalation  (Leong  et al., 1981).   2,2,4'-Tr1chloro-2'-hydroxyd1phenyl ether
was^  negative- In  the In  vivo  spot  test  with mice  (Russell and Montgomery,
1980).
    Pertinent  data  regarding  the  teratogenldty  of  the  chloroethers could
not  be  located 1n  the  available  literature  as  cited  1n Appendix A.   Intra-
per 1 toneal  tnjectVaa of  2,4,4' -tr 1 chlono-2,' -hydroxyd 1 phenyl e.ther to'jftVcft,;ore'
po.s,tcQnce,pMotfc. day  T0:.25. .caused^ r,editce&  Hfcter  sires:, largely-:b«cause: of-
maternal  to*totty  at 25  mg/Kg and retfucetiyp0$trtaf«r? stirv^va^rat; 3-25Vmg/kgK
CiRusseTT and:Montgomery,  T98Q).;
0042d                               6-44                              08/26/87

-------
                     7.   EXISTING GUIDELINES AND STANDARDS
7.1.   HUNAN
    bls(Chloromethyl) ether  and chloromethyl  methyl  ether  are  regulated as
carcinogens by  OSHA  without  PELs (OSHA, 1985).  The  ACGIH (1986) recognizes
bls(chloromethyl)  ether  as   a   human  carcinogen  and  recommends a  TLV-TWA
concentration  for  a normal  8-hour  workday  and a  40-hour workweek  of 0.001
ppm  (0.005 mg/m3).  Chloromethyl  methyl  ether 1s  listed as an Industrial
substance  suspect. of carcinogenic potential  for  man by  ACGIH  (1986)  and Is
not  assigned  a  TLV.   An  ambient water  quality  criterion  was  derived  for
bls(chloromethyl) ether by the  U.S.  EPA  (1980b) on the basis of  Induction of
malignant  respiratory tumors  In male rats  (Kuschner  et  al., 1975).   A water
concentration of  0.038  ng/8.  was  calculated to keep  the  Individual  lifetime
cancer  risk  <10~5.   The  rapid  hydrolysis  of bis(chloromethyl)  ether  In
water  precludes  a realistic  estimation  of  exposure  and  that  the  criterion
was calculated 1n the event that levels are monitored In water.
    ACGIH  (1986)  recommended a  TLV-TWA  of  5  ppm  (30 mg/m') and a  TLV-STEL
of  10 ppm (60 mg/ma)  for  dlchloroethyl  ether [b1s(2-chloroethyl)  ether],
and noted  that  skin  exposure  may contribute to overall exposure.  'An ambient
water  quality  criterion  of  0.3   yg/l   was   based  on  the  Induction  of
hepatomas  1n  male  mice  (Innes et al., 1969)  to keep the Individual  lifetime
cancer rtsk of &Vs!*^MaroetnyT)r ether XKT5 (.U.:S» EPA> ISMfel..
    Ant  InterTm  toxlcity-based  ambient  water  quality  cr1ter-Ton  of  34-.7
vg/t  for  bis(2-chloro-T-methylethyl);ether  was  derived  from  the  LOAEL
for, centrllobular  necrosis  in. mtce  of. 10: mg/kg/day  (NCI:, 1S78}. by: the U.S.
EPA friasOtoU  IkSv EPA  (BBQb:)  tncorxect% named; Ms,t2-ch1;oro^-me(thyl^thy;Tr
ether  bts(2-chToro1sopropyT)  ether  and  vused  the  abbreviation BCIEV   The
00*30*                               7-1                              07/07/87

-------
criterion  of  34.7  vq/i  was  considered  an  Interim  criterion  because  the
quality  of  data was  Inadequate; positive  carc1nogen1dty  data  (NTP,  1982}
were available subsequent to preparation of the U.S.  EPA (1980b)  document.
7.2.   AQUATIC
    U.S.  EPA  (1980c)  summarized  the available  data concerning  toxlclty  of
haloethers to  aquatic biota and  concluded  that  acute and  chronic  toxldty  to
freshwater  biota  occurred  at  concentrations  as  low as  0.360  and  0.122
mg/a,  respectively,  and  would  occur at  lower  concentrations among  species
that  are more  sensitive than  those tested.   U.S.   EPA  (1980b)  noted  that
acute  toxlclty of  chloroalkyl  ethers to freshwater  aquatic life  occurred  at
concentrations as  low as 238  mg/a,  and  would occur  at lower  concentrations
among species more sensitive than those  tested.
OM3
-------
                              8.   RISK ASSESSMENT
8.1.   CARCINOGENICITY
8.1.1.   Inhalation.   Inhalation  cardnogenldty  data  are  available  for
bls(chloromethyl) ether and chloromethyl methyl ether.  As detailed 1n
 ctlon 6.2.1., bls(chloromethyl) ether Induced nasal olfactory epthellum tumo
rs  (esthes1oneuroep1thel1omas) and  possibly  pulmonary tumors 1n rats exposed
to  100  ppb   (5  yg/m3),   6   hours/day,   5   days/week  for  6  months  with
lifetime observation  (Leong et al.,  1981)  and nasal  tumors  at  0.1  ppm (0.5
mg/m3), 6  hours/day,  5 days/week  for 40-100 exposures with lifetime obser-
vation  (Kuschner  et  al.,   1975).   Another  study  Indicated  that  treatment-
related respiratory tumors  of an unspecified type  developed In rats exposed
to  0.1  ppm bls(chloromethyl)  ether vapor,  6  hours/day,  5  days/week  for  30
exposures with lifetime observation  (Dulak and  Snyder, 1980).  At 100 ppb (5
vg/m3)  b1s(chloromethyl)   ether,   5   days/week  for  6  months with  lifetime
observation, an  Increase was  observed 1n the  Incidence of  lung adenomas and
carcinomas  1n mice  {Leong  et  al.,  1981).   bls(Chloromethyl)  ether  also
produced an Increased  frequency  of lung adenomas  1n  strain A mice that were
exposed- to  1   ppm  (S^mg/m3),  6  hours/day  on 82 days In  27  weeks (Leong  et*
al., 1971).
    Commercial or  Industrial   grade  chloromethyl  methyl ether  vapor  did not
produce; iVgnlBcaatl^ I'ncrea&eif/ trifcVdeiice*  or respiratortf system; tumors, fir
rats  or  hamsters  exposed  t"o  1 ppm  (3;mg/m*)," £ hours/day,  5  days/week! for;.
life  (Laskln  et  al.,  1975), or In  strain:A  mice exposed, to  2" ppm (6.; mg/m3);^
&  hours/day,  5  days/week  for 'TOT days; In  21 weeds' (Leeng-et  »T.. 197T£.
EpTdem1oTogfca.T  studies? of worker's exposed;  to'. bts;('chTor,oroe£hyl| ether, and"
chloromethyl  methyl  ether   have  demonstrated exposure-related  occurrence  ofv
lung  tumors,  predominantly  small  cell undlfferentlated or oat-cell carcinoma


0044d                               8-1                              07'/08/87"

-------
 (see  Section  6.2.1.1.)-   Because  Industrial  grade  chloromethyl  methyl ether
 contains  carcinogenic  bls(chloromethyl)  ether as a  contaminant,  and because
 there  1s  Insufficient  ep1dem1olog1cal evidence  to  separate the carcinogenic
 effects  of  these compounds,  there 1s sufficient  evidence to  conclude that
 bls(chloromethyl) ether  and  technical  grade  chloromethyl  methyl  ether  are
 human carcinogens (IARC, 1979; U.S. EPA,  1980b).
 8.1.2.   Oral.    The  cardnogenlcHy   of   b1s(2-chloroethyl)   ether   and
 b1s(2-chloro-l-methylethyl) ether  has been evaluated  1n  oral administration
 studies.
    Dally  Intubation  with  commercial grade   b1s(2-chloroethyl)  ether at  a
 dose  of  100 mg/kg on  days  7-28 of  life,  followed  by administration  1n  the
 diet  at  a concentration of 300  ppm for  the  next 76  weeks  produced signifi-
 cantly Increased  Incidences of  hepatomas In  male and  female  B6C3F1 mice  and
 male  B6AKF1 mice (BRL, 1968; Innes  et.al.,  1969)  (see  Section  6.2.2.);  the
 TWA  dose  Is   41.3  mg/kg/day.   Twice weekly administration of   100X  pure
 b1s(2-chloroethyl) ether by gavage at doses  of  25  or  50  mg/kg for 78 weeks,
 followed  by  a 26-week  observation period, was  not carcinogenic  In  male or
 female Charles RIverCD rats (Welsburger  et a*.,  1981).
    CardnogenlcHy bloassays of  technical  grade b1s(2-chloro-l-methylethyl)
 ether were conducted  In  which groups of 50 F344 rats/sex (NCI,  1979) and 50
 B6C3F1 mice/sex  (NTP,  1982), were  treated by^ gavag*  at  doses of> 1!(H£ w  200T
     . S rfay.s/week  for  103:  weeks.   The,VtechnrYcal  grade  chemical  was -70X
                       %, Z^TTfZ^hlorQpr,o,p,y:l) e.yier  and 2%
                       ethef.  The-rat?were; observed for^T-2-weeks follow-
 ing treatment.   Increased ; Incidences iof. tumors  did /no.t'occur xln  any;,of- the
 treatment  groups;   the   low   survival  rate significantly   decreased  the
 Incidence of male and  female  high-dose rats  at  risk  for  development of late

0044d                               8-2                              07/08/87

-------
appearing  tumors.   The  mice,  observed for  1-7 weeks  following  treatment,
developed   significantly   Increased   Incidences   of   alveolar/bronchlolar
adenomas   (both  sexes)  and  hepatocellular  carcinomas  (males)  {see  Table
6-5).    A   low  nonstatlstlcally  significant  Incidence  of   squamous   cell
paplllomas  or  carcinomas  In  the stomach  or  forestomach  of  the  high-dose
female  mice was  also observed.   Stomach   tumors  In B6C3F1  mice were  rare;
therefore,  occurrence  of  tumors  was  probably  treatment-related.   Dietary
administration  of  high purity  (98.554)  b1s(2-chloro-l-methylethyl)  ether  was
not  carcinogenic  to SPF-ICR  mice  (MltsumoM  et  al.,  1979).   In  this  study,
groups  of  56  mice/sex  were   treated  at dietary  levels  of 80,  400, 2000  or
10,000  ppm for durations  as   long  as  104 weeks.  The average dally  Intake  of
chemical  by the  10,000  ppm  group was  higher  (961  mg/kg/day  by males,  927
mg/kg/day  by females) than that given to the mice In the NTP  (1982)  bloassay.
8.1.3.   Other  Routes.  The  cardnogenlclty  of  numerous   chloroethers  has
been  evaluated  In  dermal  application,  dermal  Initiation-promotion,   sub-
cutaneous  Injection and  1ntraper1toneal  Injection  studies.    Most  of  these
studies  were  conducted by Van  Duuren et al.  (1968,  1969,  1971,  1972,  1974,
1975), who administered the compounds thrice  weekly (dermal studies) or  once
weekly  (Injection  studies)  to mice for  life.   As detailed 1n  Section 6.2.3.
and  Tables 6-7 to  6-10,  bls(chloromethyl) ether was  tumorlgenk In all  of
the  aforementioned types of  studies.  Including  mouse  skin  assays In  which
b;t's;fchToromethyT)  ether; was"  active   as; an Initiator or  promoter.   T,2-bTs>
(ChToromethoxy)ethane' and  1,2,3-tr1s(;cnloromethoxy.)pr;opane: were  tumorlgenlc
In? dermal   application,  subcutaneous.  Injection-  and'.Intraperltorteal  Inrjec-
tl'on,  studies1..   ChTorcmiethyiT  methyl;  ether,   K1is:;(:a-cMoroeth-y,T)y  ether  aredr
1,2,3-trVs {chloromethoxyyproparre^werev tumorIgerrtcvby subcutaneous ffffeetlorr.
                                    8-3                               07/08/87

-------
8.1.4.   Weight  of   Evidence.    Inhalation  exposure  to  bls(chloromethyl)
ether  and  commercial  chloromethyl  methyl  ether  Is  associated  with  the
Induction  of  lung tumors  In  humans (see  Section  6.2.1.), and  Inhalation  of
bls(chloromethyl)  ether  has  produced nasal and  lung  tumors 1n  rats and  mice
(Leong et  al.,  1981; Kuschner et  al.,  1975;  Dulak and Snyder,  1980).   Since
IARC  (1979) and  U.S.  EPA (1980b) have concluded that  bls(chloromethyl)  ether
and  technical grade  chloromethyl  methyl   ether  are  human carcinogens  (see
Section  8.1.1.). the appropriate  U.S.  EPA  (1986b)  classification  for  these
chemicals  1s Group A  - human carcinogen.
    Commercial grade b1s(2-chloroethyl) ether  produced Increased  Incidences
of  hepatomas  1n  two strains  of mice  when administered  orally (BRL,  1968;
Innes  et  al.,  1969),  but  100%  pure   b1s(2-chloroethyl)   ether  was   not
carcinogenic  1n  rats  when administered by gavage  (Welsburger  et al.,  1981).
Although  hepatomas  In mice  often  occur  spontaneously and  are  difficult  to
classify,  the  high   Incidences  and  occurrence   1n  two  strains  and  sexes
Indicate  that the hepatomas  1n  the  BRL (1968)  and  Innes  et  al.   (1969)
studies  were   treatment-related  and  the.  animal   data  constitute  sufficient
evidence  for  carc1nogen1c1ty.   On  the basis :of  these  data  supplemented  by
predominantly  positive  responses  In mutagenldty assays  and because  human
data  are  lacking,  b1s(2-chloroethyl) ether 1s  most appropriately  classified
1n EPA Group 82  - probable human carcinogen.  ;,
    Ch'ronte,gavtfge?arimltotfstratfait of, coraraericVal  grade" £-TOX$;  BtfsfZ^-ehToro-
               ethfer was- not  tumoriTgwfcl In' F:3$4". rafti; af either  sex  (NCL;
               ^Q
-------
Chronic  dietary   administration   of   high  purity  (98.5%)  b1s(2-chloro-l-
methylethyl)  ether  was not  tumorlgenlc  to  SPF-ICR  mice (MHsumorl  et  al.,
1979).  Although  there Is evidence of  carc1nogen1dty 1n  B6C3F1  mice (NTP,
1982),  the   effect   cannot   be  attributed  definitely  to  b1s(2-chloro-l-
methylethyl)  ether because  1t cannot  be determined  If  H  1s  due to compound
Impurity or  mouse strain  sensitivity.   The evidence  for  carc1nogen1c1ty 1n
animals  Is   best  considered  limited.   Since  there  are  no  human  data,
b1s(2-chloro-l-methylethyl)  ether  1s   classified  1n EPA  Group C  - possible
human carcinogen.
    The other chloroethers  that  are   the  subject of  this  report  should be
classified  1n EPA Group  D  -  not  classifiable as to  human cardnogenlclty.
Although  1,2-b1s(chloromethoxy)ethane,   1,2,3-tr1s(chloromethoxy)propane  and
bls(a-chloroethyl)  ether  were   tumorlgenlc  1n   dermal,   subcutaneous   and
IntraperHoneal administration  1n  mice,  overall  evidence for  carclnogenldty
of these compounds  1n animals 1s best considered  Inadequate.   Other chloro-
ethers yielded negative  results  In these specialized  tests and still others
have not been tested.
8.1.5.   Quantitative Risk Estimates.
    8.1.5.1.   INHALATION — b1s(Chloromethyl) ether  and commercial  chloro-
methyl  methyl ether  are recognized  as human  respiratory carcinogens,  but
data  suitable for, quantitative risk  estimation  are  available  only, for  bis-
(chloromethy.T):' ether  {:see Section 6.2..K)/.  * The; most  appropriate  basts for
derivation of a  q,*  for  Inhalation  exposure  Is  the  study by  Leong e,t al.
fcl 9.8.1. U: 1n  which, exposure1 to  100. ppb  (,4?& jtg/mai bistchloronethyl} ethers
vapovr,  6-  hours/day.,  5, days/weeK for  &  months produced; nose es.thestoneuro-
epHheTlomas  1n  96/T1T  rats  (see Tab'Te  .6-2)'. t, Respiratory  .tract :tumorsv
Including esthesloneuroeplthellomas and  lung carcinomas, also were  produced


00440*                               8-5                            .   07/08/87'

-------
1n  Sprague-Oawley  rats  exposed  to  0.1  ppm  (0.5 mg/m3)  bls(chloromethyl)
ether, 6  hours/day,  5 days/week for  10-100  exposure  (Kuschner  et al., 1975)
(see  Table  6-3).   This study  provides  a less adequate basis  than  the Leong
et  al.   (1981)  study  for  calculation  of  a  q,*  because  treatment  duration
was  variable and  shorter  (20  weeks  maximum), a  single exposure  level  was
used,  tumor  Incidences  were  lower   (particularly  when  not  pooled),  and
control  group  Incidences  were  not  reported.  Respiratory tract  tumors  also
were  Induced  In  Sprague-Dawley  rats  exposed  to 0.1  ppm,  6 hours/day,  5
days/week  for  30  exposures   (Dulak  and Snyder,  1980), but  this  report  Is
limited by  Inadequate  reporting and most of  the  deficiencies  associated with
the Kuschner et al. (1975) study.
    To derive  the  Inhalation  q * from  the  Leong et  al.  (1981) study,  the
exposure  concentrations  of 0,  1,  10 and  100 ppb (0,  5,  47 and 470  yg/m3)
are  adjusted to continuous concentrations  by multiplying by  the proportion
of  dally  exposure  (6  hours/24 hours)  and  weekly exposure (5  days/7  days).
The  contlauous  concentrations are   transformed  to   mg/kg/day doses  of  0,
0.0002,  0.0023  and. 0.0345  by  multiplying  by the  reference  rat  Inhalation
rate  (0.223 mVday),  dividing by  reference rat body  weight  (0.35 kg)  and
adjusting for average  dally dose  over the  experimental  period by multiplying
by  the  ratio  of  treatment   duration  to  experiment   duration  (6  months/28
months  except  6  months/19   months.  1n the high-dose  group).  .Using  the
transformed; s doses;  wlit'nJ  the,  corresponding- 'esthesVoneurdepftheXfamSr-' tumor:
incidence*'  and the  comp,u.ter1z,«l muTtt stage model ^eyeTop-edfby Howe and1 Crump:
          the*  aaadi'ttstwt  <>  I*. cafcutete* SOK, He  KQAa<; fog/kg/day T1
(Appendix  BT)v   The  human  qw=*y  which ~1sr c&TouJated^btf  multiplying,
unadjusted  q^  by the cutfe  root aft; ttfe>: ratttr oft assumed"' human1 body ^weight  '
(70  kg)  to assumed  rat  body  weight  (0.35 kg),  Is  59.5  (mg/kg/day)'1.   If
It  Is  assumed  that  humans  we-lgh  70 kg and  Inhale. 20 m3/day;of  a1r,.the;
0044d   .                            8-6        x                     07/08/87

-------
concentrations of  bls(chloromethyl)  ether  1n  air associated  with  Increased
lifetime  risk  of  cancer  at  risk   levels  of  10~5,   10~6  and  10~7  are
5.9xlO~7, 5.9xlO~8 and 5.9xlO~9 mg/m3,  respectively.
    A  q *  for  Inhalation  exposure  to  b1s(2-chloroethyl)  ether  can  be
calculated  from  the oral  q  *  (Section 8.1.5.2.)  by  assuming equal  potency
by both  routes.   Since  appropriate  pharmacoklnetlc  data are  not  available,
1t can  be assumed  that  absorption by  the  Inhalation and  oral routes  1s  50
and   10054,   respectively.    Multiplication  of   the  oral   q  *  of   2.46
(mg/kg/dayr1,  derived  from  the   BRL   (1968)   and  Innes   et   al.   (1969)
studies,  by  the  ratio of  the  percentage  absorption by  the  Inhalation  route
to the  percentage absorption  by  the oral  route  gives  an Inhalation q,*  of
1.23  {mg/kg/day)"1.   If 1t  Is assumed that  humans  weigh 70 kg and  Inhale
20 mVday of  air,  the  concentrations of  b1s(2-chloroethyl) ether  In  air
associated with  Increased  lifetime  risk  of   cancer  at  risk  levels of  10~s,
10"*    and     10~7    are    2.8xlO"5,    2.8xlO~6   and    2.8xlO"7   mg/m3,
respectively.
    A q.* for Inhalation  exposure  to  technical  b1s(2-chloro-l-methylethyl)
ether can  be  calculated  from the  oral  q,*  (Section  8.1.5.2.)  using  the  *
same  approach  as for  b1s(2-chloroethyl)  ether.   Multiplication  of the* oral
q.j*  of   6.97xlO"2   (mg/kg/day)"1,  derived  from  the  NTP  (1982)  study,  by
the ratio of  assumed percentage of  absorption by, the tnhalatVon route: (50%),
to  assumed   percentage  of  absorption  by. the  oral  route  (100%),  gives  an
inhalation   q*   of  3.49xlO~2   (mg/kg/day)"1.    If   H-  1s  assumed   that
humans  weigh  70  kg  and  inhale  20  mVday  of  air,  the concentrations  of
b1s('2-chloro-l-me.thylethyl).  ether   Vn: air   associated   with an  increased;-
lifetime  risk  of  cancer ' at   rtsk  -levels  of   TOT*.  T0~*  and  TO"7,  are
l.OxlO"3, l.OxlO"4 and l.OxlO"5 mg/m3,  respectively.
                                    8-7                              07/08/87

-------
    8.1.5.2.   ORAL — Oral  cardnogenldty   data   are   not  available  for
bls(chloromethyl)  ether  or  chloromethyl  methyl ether,  which are  recognized
as  carcinogenic  for  humans  by  Inhalation.   It Is  possible to  use  the q  *
for Inhalation exposure  to b1s(chloromethyl)  ether  (see Section  8.1.5.1.) as
the oral  q.*, however,  by assuming equal potency  by  both routes and  recog-
nizing  the  mode  of carcinogenic  action.   The  Induction  of nasal  epithelial
tumors  (esthesloneuroepHhellomas)  by  Inhalation  Indicates that b1s(chloro-
methyl) ether 1s a contact carcinogen that exerts Its effects at the site of
contact  Independent  of   systemic  absorption.   Since  1t  1s  reasonable to
expect  that  bls(chloromethyl)  ether may also  be  carcinogenic at the site of
exposure   following  oral   administration,   the   Inhalation   q *   of   59.5
(mg/kg/day)~a can  be  adopted  as  the oral q  * without adjustment  for  oral
absorption.   If  1t  1s  assumed   that  a 70 kg human  consumes   2 I/day, the
concentrations of  bls(chloromethyl). ether associated with  Increased lifetime
risk  of  cancer  at  risk  levels  of  10~5,   10"6   and  10~7  are  5.9x10"*,
5..9xTO~7  and 5.9xlO~8  mg/i,  -respectively.    These  levels  cannot  be  used
for practical  purposes,  however,  as  rapid  hydrolysis  of  bls(chloromethyl)
ether 1n water precludes exposure (U.S. EPA, 1980b).
    The  U.S. EPA  (1980b) ambient  water  quality  criterion  for b1s(chloro-
methyl)  ether,  however,  Is  based   on   a   q *  of  9299.8  (mg/kg/day)"1,
calculated from the, Kus.chner, et  al. (1975) Inhalation study.  As 4e:UVle4, in
Section 6'.:Z.T.,v  rat's  were.exposed ;-to .Oil- ppmy 6 hours/day, "5 .days/week for
TOVI.OO  exposures.  this. s?tudy  w^lKnot; be.; usejd) fior, caiTcuTat:tan;a£  an. inhala-
fforr  or-oraT .q"=*  Because  tfi*  Le^g*  *f'«T.  PT981) stutfy-:Twh1ch  was not
available-  for ',considerafclorr  by?,.Ul.S. ;:EPW. (IWOb^I used
-------
(1980b), as  H  Is  reported  that  the rats were given 100 exposures of various
concentrations  of  bls(chloromethyl) ether rather  than  10-100  exposures of a
single  concentration.   This statement  Is  consistent  with the  doses  used  In
the U.S.  EPA (1980b)  evaluation, but  the  origin  of the doses,  which was not
reported by  Kuschner et  al.  (1975), was not  Indicated.   An exposure duration
of 728  days  and an assumed  tumor  Incidence  of  0/240  1n colony controls were
also used without explanation.
    A  q * for  oral exposure  to  b1s(2-chloroethyl)  ether  can be  based  on
the Induction  of  hepatomas  1n mice  that were  treated by gavage at a dose  of
100 mg/kg/day  on  days  7-28  of life,  and subsequently  1n  the diet at  a con-
centration  of  300  ppm- for the  next  76  weeks  (BRL,   1968;  Innes et al.,
1969).  If 1t  1s assumed that  mouse food consumption  Is equivalent to  1354  of
body weight/day, then  the dosage during the  dietary  part  of the study 1s  39
mg/kg/day and  the  TWA  dosage for the  entire  study Is 41.3 mg/kg/day.-  Using
this  dosage,  the  hepatoma  Incidence  1n  the  66C3F1   strain  males and  the
computerized  multistage  model  developed by  Howe  and  Crump  (1982),  the
unadjusted   q  *  Is  calculated   to  be  8.14xlO~2  (mg/kg/day)'1  (Appendix
B2).   This   q,*  may  be  somewhat   conservative, . however,  as  the? number:  of   •
treated animals  used  1n the  calculation  was  relatively  small.   The  human
q,* calculated by  multiplying  the  unadjusted  q,* by  the cube  root  of  the
ratVo of  reference  human body weight  170  kg)  to reference mousfr; body  weight
£07.0$ k"g;)and  by t-fte. cube of the-. raWo oF. assumed mouse: Hfespan  (T0'4  weeks):
to experiment  duration  (79  weeks);  1s  2.46  (mg/kg/day)'1.  Assuming  that a
70  kg  human  consumes   2 a/day,  the  concentrations'  of  t>T?f2-chToroethyl)
ether Vn drinking, water  associated; with. Incr.eaisedv.VlfebVme rVstf o.f cancer  a.t
risk   levels  of   TO~V  10"«>   antf   TO"^ are   1.4xTO~4,   1.4xlO"5  land '
1.4xlO~7 mg/a, respectively.

0044d                     '          8-9                              07/08J/87  '

-------
    U.S.  EPA  (1980b)  used  the same study (BRL, 1968; Innes et al.,  1969)  and
tumor  Incidences  used  to  calculate  a  human  q *  of  1.144   (mg/kg/day)'1
for  b1s(2-chloroethyl) ether.   This q *  Is  lower  than  the  q * calculated
above  because the U.S.  EPA  (1980b)  computation  used a different dose and  a
Hfespan  that was  the same as the treatment/study duration (560  days), which
obviated  the  Hfespan correction.  The dose  used by U.S. EPA (1980b) was 39
mg/kg/day, which does  not  account  for the period  of  gavage treatment.
    Gavage  administration   of   technical  grade  b1s(2-chloro-l-methylethyl)
ether  at doses  of  100 or  200 mg/kg,  5 days/week  for  103  weeks  produced
hepatocellular  carcinomas  or  adenomas  and  alveolar/bronchlolar  adenomas or
carcinomas  1n B6C3F1  mice  (NTP,  1982)  but was not  tumorlgenlc  In F344 rats
(NCI,  1979).   Dietary administration of  high purity (98.5%) b1s(2-chloro-l-
methylethyl)  ether  at concentrations of 80-10,000 ppm  (927  or 961 mg/kg/day
at  the  high  dose)  for  104  weeks  was  not  tumorlgenlc  1n   SPF-ICR  mice
(Mltsumorl et al.,  1979).   Since  1t Is  probable  that most human exposure to
b1s(2-chloro-l-methylethyl)  ether  1s   to; technical  grade  compound,   1t  Is
appropriate  to  use  the NTP  (1982)  carc1nogen1c1ty  data to derive  an oral
q *    Using  doses  adjusted  for partial  weekly exposure, the  liver  hepato-
cellular  adenomas  or  carcinomas  1n  the  male  mice  and the   computerized
multistage model  developed by  Howe  and  Crump  (1982),  the unadjusted q * 1s
calculated  to  be  5.78jclO~3  (mg/kg/day)"1   (Appendix  B31-,   The human;  q,.*-
calculated* by; mu-Ttfprl-y^ng the  unadjusted- cu**v by tfter cttte, roat of the; ratio-
of  reference; human  bo'dy  wel'ght  (70' k;g)~  to  eitf ma ted. average,, mouse/ body
wetgtrt'.|0,0^ feg),/ rr  fr,97xia"»  (ing/kg/dayr*. '  Assuming   ttttt  a  TO kg
human;  consumes   2  I/day,  the  concentrations  o'fi .technical  b1s|2>chTona~W
methylethyl)  ether  In drinking water associated wTth 'Increased lifetime 
-------
8.2.   SYSTEMIC TOXICITY
8.2.1.   Inhalation Exposure.
    8.2.1.1.   LESS  THAN  LIFETIME  EXPOSURES  (SUBCHRONIC)  -- Mortality  and
hlstopathologlc  lesions  of the respiratory epithelium  were  observed 1n rats
exposed  to  chloromethyl  methyl ether at  1  or 10 ppm (3  or  33 mg/m3), prob-
ably  for  6 or 7  hours/day  for 30 days (Drew  et  al.,  1975).  High mortality
was also observed  1n  rats  and hamsters  exposed to bls(chloromethyl) ether at
1  ppm  (5.  mg/m3),  6  hours/day  for  up  to  30  days   (Drew  et   al.,  1975).
Hyperplasla  and  metaplasia  with atypical  appearance  of  the   nuclei  were
observed  1n  tracheal  and  bronchial  epithelium In  the  rats  and  hamsters
exposed  to  bls(chloromethyl)   ether.   Gage  (1970)  exposed  rats  to  b1s(2-
chloro-1-methylethyl)  ether at 20  or 70  ppm (140-490 mg/m3),  6 hours/day,
5  days/week for  4  weeks.   Exposure  to 70 ppm was  associated  with lethargy
and  reduced  body weight  gain,  but  there were no  effects  on hematology,
urlnalysls  or  gross or microscopic  pathology.  There  were  no  effects at 20
ppm.  RfDs  for  subchronlc  Inhalation  exposure to these  chloroethers will not
be derived because they have been shown to be  carcinogenic.
    8.2.1.2..  CHRONIC EXPOSURES  —  Leong et  al. (1981)  exposed male  rats
and mice by  Inhalation to  bls(chloromethyl) ether at 0, 1, 10 or 100 ppb (0,
5,  47  or 470  vg/m3),  6 hours/day,  5 days/week  for 6 months  with lifetime
observation.    High  concentration   group  rats  had   Increased  mortality
attributed  to  tumor development.   There  appeared to be  no  significant non-
neoplastlc  hlstopathologlc  effects and  no effects on; hematology.  No effects
were reported tn mice.
    In a, lifetime exposure  study,. Laskln- et a.!.; {1.9,75)" exposed male,, rats and^
hamsters to chloromethyl methyl  ether at 1   ppm  (3 mg/m3), 6  hours/day,   5
days/week.    The  Incidence  of  metaplastlc or  hyperplastlc  lesions  In  the
ep1.thel1um  of  various  segments  of  the   respiratory-  tract  appeared ., to  be
0044d                               8-11                             07/08/87

-------
Increased  In  both species compared  with  controls.   Because both  b1s(chloro-
methyl) ether  and chloromethyl methyl ether  are  EPA Group A  carcinogens,  no
attempt  Is  made  to  calculate  RfDs  for chronic  Inhalation exposure to  these
compounds.
8.2.2.   Oral  Exposure.
    8.2.2.1.   LESS   THAN  LIFETIME   EXPOSURES   (SUBCHRONIC) — NCI   (1979)
administered  b1s(2-chloro-l-methylethyl)  ether by  gavage to  rats  at  0,  10,
25, 50,  100 or 250  mg/kg,  7  days/week for 13 weeks.   There were no  effects
on  survival,   gross  or hlstopathologlcal  appearance at  any  dosages.    High-
dose males  had a  hunched  or  thin appearance and occasional urine  stains.   In
an  Identical  study using  mice  (NTP,  1982), focal  pneumonltis  occurred at  >50
mg/kg.   Because  b1s(2-chloro-l-methylethyl)  ether  Is  carcinogenic,  no  RfD
will be derived for  subchronlc oral  exposure  to this chemical.
    Groups  of  five   rats/sex   (unspecified  strain)   were  treated  with
2,4,4'-tr1chloro-2'-hydroxyd1phenyl  ether 1n gum  arable  by  gavage at  doses
of  0,  5.0V 100, 200,  500  or 1000  mg/kg,  6 days/week for 4 weeks (Lyman  and
Furla, 1969).   Mortality  -(2/10  rats)  and slightly  reduced  weight gain  (not
quantified)  reportedly occurred  at 0000  mg/kg'.    Unspecified? hfcto^oglca;!'
examinations  and  unspecified  blood  and  urine analyses  were  unremarkable  1n
all of  the treatment  groups.   Although  this study  1s  limited by undetailed
report 1 ng,,,*ho*t> duration aiiut.anSyFT? grou& s^t«sj,, fft cast  fei used? *r the1:bases,
o£  a  suttchrontc'  RfDV for   2v4,4:t-tr1chlora-2l^hydroxyd1phenyl   ether.    The
htfgttestl NGE.U.  Vs. 500  mg/kg,  whichsTs,;. eqUjtyalent .to 429, tng/kg/day when multi-
plied by  6 tf*y$/7days --ttfadjust' for' part'tolweekly exposure.   Dit-VHVoft  of
the  adjusted   NOElr  by  an^  uncertainty factor  of AvTOO'  (10  for  farters'pec-fesv
extrapolation  and  TO to* protect the*most  sensitive  humans") gives an  RfD  for
subchronlc  exposure   of   4  mg/kg/day,  or  300  mg/day  for  a  70  kg  human.


0044d:                                8-12        ^                    07/08/87

-------
Although  adequate  parameters appear  to have  been  evaluated  1n  this study,
confidence  1n  the  RfD should be regarded  as  low because the study was short
and  limited In scope.   In  addition,  only a  factor  of  2  exists  between the
NOEL and a dosage associated with mortality.
    8.2.2.2.   CHRONIC  EXPOSURES — Welsburger  et   al.   (1981)  administered
b1s(2-chloroethyl) ether  to rats by  gavage  at 25 or  50 mg/kg,  twice weekly
for  78  weeks,  followed by  a 26-week observation period.   Mean  body weights
were reduced 1n treated  females  and high-dose males, and Increased mortality
occurred 1n high-dose females.
    Chronic cancer experiments were conducted with  rats  (NCI, 1979) and mice
(NTP, 1982)  1n which  b1s(2-chloro-l-methylethyl) ether  was  administered by
gavage at  0,  100  or  200 mg/kg,  5 days/week  for 103-105  weeks.  Survival was
reduced  In high-dose  male  rats and both  treated  groups  of  female  rats.
High-dose  rats of  both  sexes had esophageal  lesions  and high-dose male rats
had  centrllobular  liver  necrosis.    There were  no  effects  on  survival  of
mice.   The only  nonneoplastlc  lesions  In   mice  occurred  1n both  treated
groups of  males  and  Included  fatty changes  and  chronic Inflammation of the
nasal  epithelium.  ; Because  b1s(2-chloroethyl)  ether  and  b1s(2-chlor-o^l;--
methylethyl) ether are  carcinogens, RfDs will  not be  calculated  for chronic
oral exposure to these compounds.
    The Lymin  and  Furt* fl969>}' gavage  studx  with rats was used as the- basis
for calcuTtfflon of an: Rffffor•• s-ubc.hr on Tc  oraT'exposure to- 2,"4,4!-tr1chloro--
2'-hydroxyd1phenyl ether  (see Section  8.2.2.1.); however,, given the Inade-
quate study duration  (4 weefcsj, 1t  Is inappropriate'to use.v the  NOEL from-*
this study to calculate,, an RfD ""fair  chromic oral exposurev:
0044d                               8-13'                            OT/08/8T

-------
                           9.   REPORTABLE QUANTITIES
9.1.   BASED ON SYSTEMIC TOXICITY
    The  Inhalation  and  oral  toxldty  of  bls(chloromethyl)  ether,  chloro-
methyl  methyl  ether,  b1s(2-chloroethyl)  ether,  b1s(2-chloro-l-methylethyl)
ether   and   2,4,4'-tr1chloro-2'-hydroxyd1phenyl   ether   are   discussed   1n
Sections 6.1.1.  and 6.1.2., and  dose-response  data for  these chemicals are
summarized 1n Table 9-1.
    Inhalation exposure  to b1s(chloromethyl) ether at a  concentration  of  1
ppm, 6  hours/day  for  30 days caused mortality  and  bronchial hyperplasla and
metaplasia  with   atypla  1n  rats and  hamsters   (Drew  et  al.,  1975).   Rats
exposed  by  Inhalation  to  100  ppb  b1s(chloromethyl)  ether,  6  hours/day,   5
days/week for  6  months  died from  nasal tumors  (Leong  et al.,  1981).   The
subchronlc  data   are   Inappropriate  for  derivation  of   an  RQ  because  the
chronic  data  Indicate  that the.  hyperplasla  and metaplasia  are likely to be
preneoplastlc alterations,  and  because division of  the subchronlc equivalent
human doses by an  uncertainty  factor of 10 (to  approximate chronic exposure)
gives  the  same equivalent  human dose  as  that  associated  with the carcino-
genic  response  1n  the Leong  et al.  (1981)  study.   Adequate data  for the
derivation of  a  toxlclty-based RQ for  bls(chloromethyl)  ether are therefore
not available (Table 9-2).
    Chronic (Laskln et al., 1975) and  subchronlc  (Drew et al., 1975), Inhala-
tion; studies wtth -ra-ts prav-Tde toxTclty data for.:xhTorometnyt methyl, ether.
Chronic  exposure  produced  squamous  metaplasia  1n  the' trachea and bronchial
hyperplasla; at an equivalent human  dose of Q..Q5- mg/kg/day :• (-s.ee Table-9-1)..
S.1m,1lar  trachea1!, and.  bronchial  h1:stolog1,c4T alterations  and mortality were
associated  with   subchronlc  exposures  ta- .a>TO-foW'. higher  cancentrattom of
chloromethyl methyl  ether.  Although  the most severe effect  was mortality


0045;d:                               9-1                              05/29/87

-------
            TABLE  9-1



loxlclty Summary for Chloroethers
en
Q.


10
1
ro




05/29/8
Chemical/Vehicle/
Purity
bls(Chlpromethyl)
ether/air/NP


Chloromethyl methyl
ether/alr/NB
Chlororaethyl methyl
ether/air /commer-
cial grade
b1s(2-Chloroethyl)
ether/SSy/lOOX
b1s(2-Chloro-l-
methylejhyl) ether/
alr/NR' ;
bts(2-Chloro-l-
methylethyl) ether/
corn p^l/technlcal
grade* "'' ' '.

Route
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
oral
(gavage)
Inhalation
oral
(gavage)
oral
(gajrage)
Species/. No. at
Strain/Sex Start
rat/Sprague, 50
Dawley/N .'
hamster/ 50
Syrlan/N
rat/SPf 120
Sprague-Dawley
Spartan/M
rat/Sprague- 25
Dawley/H
rat/Sprague- 74
Oawley/M
rat/Charles 26/sex
illyer.CD/M.f
'--?' "is, •
rat/SPf 4/sex
Park/M.f
rat/F344/M.f 10/sex
j :M- '. • " ;- .;'"•
r,al/F344/N,£ 50/sex
Avera'ge
Body
Weight
(kg)
.. *•*
0.35b
0.1 4b
0.35b
0.35b
0.35b
0.35b
0.35b
0.35b
0.20 (F)f
Exposure Transformed
Animal Dose
(mg/kg/day)
1 ppm (5 mg/m1) 0.8C
6 hours/day for
30 days
1 ppm (5 mg/m') 1.2C
6 hours/day for
30 days
100 ppb (0.47 0.05C
rag/re"), 6 hours/
day, 5 days/week
for 6 months
1 ppm (3 mg/m»). 0.5C
6-7 hours/day for
30 days
1 ppm (3 mg/m»). 0.3e
6 hours/day, 5
days/week for life
50 ing/kg, twice 14
weekly for 78
weeks
70 ppm (490 55.8
mg/m"), 6 hours/
day, 5 days/week
for 4 weeks
250 ng/kg/day. 7 250
days/week for 13
weeks
100 rag/kg, 5 71.4
days/week .for
103-105 weeks
Equivalent
Human Dose3
(mg/kg/day)
0.01d
0.02d
0.01
0.009d
0.05
2.4
0.954d
4.3d
10.1
Response
Mortality, tracheal and
bronchial hyperplasla
and metaplasia with
atypla
Same as above
Mortality resulting
from nasal tumor
development
Mortality, minimal
tracheal /bronchial
hyperplasla or meta-
plasia
Tracheal squamous meta-
plasia and bronchial
hyperplasla
Mortality and decreased
body weight gain In the
females
Reduced weight gain
and lethargy
Reduced weight gain In
males
Reduced weight gain In
both sexes, decreased
survival In females
Reference
Drew et al.
1975
Drew et al.
1975

t
•
Leong
et al.. 1981
Drew et al.
1975
»
Laskln
et al.. 1975
Welsburger
et al.. 1981
Gage. 1970
NCI. 1979
NCI. 1979




-------
                                                                           TABLE 9-1 (cent.)
W 	 *rr— 	
o
ex Chemical/Vehicle/
Purity

bls(2-Ch)oro-l-
methylethyl) ether/
olive oIl/NR
bts(2-Chloro-l-
Rp.ule

oral
Species/
Straln/Seii

rat/NR/NR
Average
No. at Body " Exposure
Start Weight
(kg)
NR 0.35b 10 rog/kg. 22
Transformed
Animal Dose
(mg/kg/day)
7.1
Equivalent
Human Oosea
(mg/kg/day)
Response

O.ld Decreased

growth rate
(gavage) doses In 31 days

ora)
methylethyl) ether/(gavage)
corn oil/technical
grade* ..-. '


^ ,*
"\
oral
( gavage |

mouse/
B6C3F1/M


mouse/
B6C3F1/M.F

10/sex 0.03 (N)b SO mg/kg/day.
days/week for
weeks

50/sex 0.04 (M)f 100 mg/kg/day
days /week for

7 50
13


. 5 71.4
103

0.38d Focal



5.92 Fatty
liver


pneuroonltls






metamorphosis of
In
males
Reference

Dow


Chemical.
n.d.
NTP,



NTP.


1982



1982

     bls(2-Chloro-l-       oral
     raethylethyl) ether/   (gavage)
     NR/NR      -••            .:'•'"
05
I
                                                                        weeks

                                   npuse/NR/N.f      NR        0.03b       10 rog/kg. 5
                                             '"                          days/week for
                                                                        728 days

                                   mouse/SPF-ICR/   56/sex    0.04|F)f    2000 ppm for
7.1          0.5        Centrllobular necrosis   NCI. 19789
                        of liver In both sexes
                                                                                                       194h     16.1        Reduced weight gain.     Hltsumort
methylethyl) ether/
diet/98. SX
2,4.4'-Tr1chloro-
2' -hydroxydlphenyl
ether/gun arablc/>97X
ora|
(gavage)
H.F
rat/NR/H.F 5/sex 0.35b
104 weeks
1000 rog/kg
days/week
weeks
. 6 857.1 1'
for 4
anemia, polychromatic
erythrocytes In females
*.7d Mortality and reduced
weight gain
et al.. 1979
lyman and
Furla. 1969
 00
dCalcu1ated by multiplying the animal  transformed dose by  the  cube root of the ratio of the animal body weight to the human body weight.

"Reference body weight (U.|, EPA,  1985)

^Calculated by multiplying  the  concentration  by the number of hours/day, number of exposures/duration of study and by  the  animal  dally Inhalation rate and
 by dividing by the animal.body weight.   Inhalation rates  of 0.223 nVday for rats and 0.131 a*/day for hamsters were used.

dThe dose was "divided by an uncertainty  factor of 10 to approximate chronic exposure.

e~70X pure as detailed If) Section 6.2.2

fEstimated froa growth CMrye

^Unpublished data sunroarlzed by U.S.  EPA (1980b)

"Intake estimated by Investigators

NR = Not reported

-------
                                   TABLE  9-2



                            bls(Chloromethyl)  Ether



           Minimum Effective Dose  (MED) and Reportable  Quantity  (RQ)









Route:



Dose:



Effect:



Reference:



RVd:



RVe:.



Comppslte Score:



RQ:           -t.         Data ararnot sufficient for deriving an;RQ
Off45d}.                             9^4'*.*                            05/29/87

-------
resulting  from  the subchronlc exposure,  this  1s an  inappropriate  basis  for
derivation  of  an  RQ  because  mortality  1s  an  acute  affect  and  because
adequate chronic  data are  available.   Therefore,  0.05 mg/kg/day represents a
MED  for  tracheal  and  bronchial  alterations.  Multiplication of  this  dose by
70  kg  yields  a human MED  of  3.5 mg/day  (Table  9-3).  The  RVd corresponding
to  the  human  MED  1s  4.7.   The  most  appropriate  RV   for  the more  severe
respiratory  tract  alteration,  squamous  metaplasia  of  the  trachea,   1s  7.
Multiplication  of  the  RVrf and  the  RV  gives  a  CS  of  32.9,  which  corre-
sponds to  an RQ of  100  (Table 9-4).   A CS of 30.4 was calculated by the U.S.
EPA  (1983b) using earlier  methodology  1n which  the  human  MED  was  calculated
by assuming equivalent absorbed doses among species.
    Twice  weekly  gavage administration of  50  mg/kg  b1s(2-chloroethyl)  ether
for up to  78 weeks  caused  treatment-related mortality 1n rats  (Helsburger et
al., 1981).  The  equivalent  human dose 1s  2.4  mg/kg/day (see  Table 9-1)  and
the  human  MED  1s 168  mg/day (see  Table 9-3).  Multiplication of the  RVg
for  this  MED  (2.2) and the  RVg  for  mortality  (10)  results  In a  CS  of  22,
which corresponds  to an RQ of 100 (Table 9-5).
    Several subchronlc  and chronic  oral studies  provide  toxldty  data  for
b1s(2-chloro-l-methylethyl) ether  1n  rats  and mice  (see  Table 9-1).   Sub-
chronic  Inhalation  toxlclty  data for  rats  are also  available  (Gage,  1970).
The most  suitable bases for  possible RQ derivation  are the  chronic studVes
because- of the1 more appropriate  treatment durations  and more severe effects-;
The  primary  effect  Identified   tn  the  subcnronic  studies  with rats  (NCI,
19.75;  Dow  Chemical, .n.d.).  V* decreased! growth.  Focal  pneumonttVs occurred
ttr  mice; as:  a  resuTt  of daily- subchroniiog.avage:  treatment  (rNTP*.  t982)>
Chronic  gavage  treatment  with  technical  grade  compound  caused  decreased
survival  In rats  (NCI,  1979) at  an  equivalent human  dose  of  10.1  mg/kg/day
0045d                               9-5                              07/08/87

-------
o
o
tn
o.
                                                                               TABLE  9-3


                                                                  Composite Scores for Chloroethers
Chemical
Chloromefhyl methyl
ether .
b1s(2-Chlo>oethyl)
ether '"^ >"
b1s(2-Chloro-l-
roethyle'thyl) ether*1

bls(2-Ch)oro-l-
methyletjjyl) ether**
bls(2-Chloro-l-
raethylethyl) ether*

2.4.4|-lr»«:hloro-
2'-hydroi(ydlphenyl
etljgr , ]'"'•'-
^ ^^ s<
Route
Inhalation

oral

&*
ocal

oral
oral

• f-
oral


<*' * '• ;~
Species Animal Dose
, :-'^ (mg/kg/day)
rat 0.3
) * *
ral 14
**•?-
rat 71.4

mouse 71.4
mouse 194


rat 857.1
' * h

Chronic
Human MED^ RVd Effect RVe
(mg/day)
3.5 4.7 squamous metaplasia of 7
the trachea
168 2.2 mortality 10
.......
707 1.2 mortality 10

414 -- 1.6 fatty metamorphosis In 5
the liver
1127 1 anemia, polychromatic 5
erythrocytes. reduced
weight gain
1029 1 mortality 10


CS RQ Reference
32.9 100 Laskln
et al.. 1975
22 100 Welsburger
et al.. 1981
12.0 1000 NCI. 1979

8 1000 NTP. 1982
5 5000 Nltsuroorl
et al.. 1979

10 1000 Lyman and
Furla. 1969

          dOer|yed  by  multiplying the equivalent  human dose expressed  In terms of mg/kg/day In Table  9-1  by 70 kg  to express the chronic  human NED  In

           terjis of rag/day  for 4 70  kg human.


          blec|;nlcal grade  (-7QJI p.ure) ;•       ••*-••-•>•-


          £9fl.5X pure
o
00

-------
                                  TABLE 9-4
                          Chloromethyl Methyl Ether
           Minimum Effective Dose  (MED) and Reportable Quantity (RQ)

Route:                  Inhalation
Dose3:                  3.5  mg/day
Effect:                 squamous metaplasia  of the trachea
Reference:              Laskln et al.,  1975
RVd:                    4.7
RVe:                    7
Composite Score:        32.9b
RQ:                     100

Equivalent human dose
bA  composite  score  of  30.4  was   calculated   by  U.S.   EPA  (1983b)   using
 different, methodology »t  '
00*5d                               y-7                              07/08/87

-------
                                   TABLE  9-5
                           b1s(2-Chloroethyl) Ether
           Minimum Effective  Dose (MED)  and Reportable Quantity (RQ)
Route:
Dose*:
Effect:
Reference:
RVd:
RVe:
Composite Score:
                        oral
                        168 mg/day
                        mortality
                        Welsburger et al., 1981
                        2.2
                        10
                        22
                        100
*E'qv#v*Tertfc human;
0045d-
                                    $-fl!'-':
                                                                      05729/87

-------
 (see  Table 9-1).   The human  MED  Is  707  mg/day,  the  RVd  Is  1.2,  the  RVg
 for  life  shortening 1s 10 and  the CS  1s  12  (see Table  9-3).  Chronic gavage
 treatment  with  technical  grade compound produced  fatty  metamorphosis In  the
 livers  of mice  (NTP,  1982) at  an  equivalent  human  dose of  5.92 mg/kg/day
 (see  Table 9-1).   The human  MED  1s  414  mg/day,  the  RVd  1s  1.6,  the  RVg
 for  fatty  alterations  Is  5  and the  CS Is  8 (see Table 9-3).   Unpublished NCI
 (1978)  data  reported  by  the U.S.  EPA (1980b) showed that  chronic exposure
 produced  centrllobular necrosis 1n  mice  at  a  lower  equivalent  human  dose
 (0.5  mg/kg/day)  than  the one  producing  fatty metamorphosis, but  this  Is an
 Inappropriate basis  for  RQ derivation because  of  apparent  data Inadequacies
 (see  Section  6.1.2.2.).    Chronic   dietary   administration  of  high  purity
 b1s(2-chloro-l-methylethyl)  ether  caused  reduced  weight gain  and  effects
 Indicative of erythrocyte destruction  1n mice (M1tsumor1  et  al.,  1979)  at an
 equivalent human  dose  of  16.1  mg/kg/day (see  Table 9-1).  These effects  are
 consistent  with  an RV   of  5  (reversible   cellular  changes)  because  the
 erythrocyte  alterations  were  most  prevalent  during  the  first  half of  the
 study  (see Section  6.1.2.2.).  The  CS derived  from the  HHsumorl et  al.
 (1'9X9)  data  1s  5.0  (see  Table 9-3).  The NCI (1979) tox1c1ty  data, there-
 fore,  are the  most appropriate  basis for   the  RQ because  they  yield  the
 highest CS (12.0),  which  corresponds to  an  RQ  of 1000  (Table  9-6).   The
 derivation of this RQ 4s  VdervUcal  tor thatprevlou&YY; reported b&lLS/.  EPAr
 (;T983c%
    Subchronlc.  gavage  administration  of  2,4t4':-trTchToro-2l-hydroxyd1pheny,t
 ether produced  reduced weight  gain  and some  mortality 1n  rats  at an equiva-
 lent  human, dose  at  14.7;  mg/kg/day  when  adjusted  to  approximate  chronlt
 exposure with an  uncertainty facto'r of*' TO  (Lyman and  FuMa,  1969)" (see Table
9-1).  This study 1s  limited by small group  sizes,  short  treatment duration
and undetailed  reporting  but can be used  to  calculate an  RQ./;  The human MED

0045tf                               9-9                              07/08/87

-------
                                   TABLE 9-6
                       b1s(2-Chloro-l-methylethyl) Ether
           Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Dose*:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ:.
oral
707 mg/day
mortality
NCI, 1979
1.2
10
12
1000
*Bqiu.ttai-1ertt human dose
0045d
            9-10
05/29V87

-------
 1s  1029  mg/day,   the  RVd  Is  1,  the RVg  associated  with  mortality  Is  10
 and  the  CS  Is  10  {see  Table  9-3),  which corresponds  to  an RQ  of  1000
 (Table 9-7).
 9.2.   BASED  ON CARCINOGENICITY
    Inhalation  exposure  to b1s(chloromethyl)  ether and  commercial chloro-
 methyl  methyl  ether   1s  associated  with  the  Induction  of   lung  tumors  In
 humans  (see Section  6.2.1.),  and Inhalation of  bls(chloromethyl)  ether  has
 produced  nasal  and  lung  tumors  1n  rats  and  mice  (Leong  et  al.,   1981;
 Kuschner  et  al.,   1975;  Dulak  and   Snyder,  1980)  (see  Section  6.2.1.  and
 Tables  6-2 and  6-3).   These  data  are  sufficient   to  classify b1s(chloro-
 methyl)  ether  and commercial  chloromethyl  methyl ether  In  EPA Group A  (see
 Section  8.1.4.).   Although both these haloethers are recognized as  carcino-
 gens, suitable  data for quantitative risk  estimation are available  only  for
 bls(chloromethyl)  ether.
    Using  the  reasoning  applied  1n the  derivation of  a q,*  (see Section
 8.1.5.1.),  the most  appropriate basis  for calculation  of  an  F  Factor  for
 bls(chloromethyl)  ether  1s  the  study   of  Leong  et  al.  (1981)   1n   which
 exposure  to 100 ppb  vapor, 6 hours/day,  5 days/week  for  6  months  produced
 nasal esthesloneuroepHhellomas  1n  96/111  mice  (see Table  6-2).   To derive
 the F factor,  the  exposure  concentrations of 0, 1, 10 and 100 ppb are trans-
 formed;  to, doses/ of Q*. (UQQftl,  0.00-11 and  a.OV69 mg/kg^/(Uyy 4v detaVTe* in:
 Secttbrr  ff.T.5'.?.   Usrttog'  ttfeste dose*  wTtif'  the--corresponding esthes 1-one.uro-
 ep.tthelloma tumor  Incidences and the computerized multistage !modeT .developed
 by.  Howe  and  Crump ^1982),  the ^unadjusted 1/E01(J  t?  caTcuTated to be' 15*
 (mg/kg/dayrr  (Table  :9:-8;)'.   Th:e.  adjusted^  l/Ettjg,(,F  Factor)  caTcuIa;ted;  by.-,
multlplylng the  unadjusted 1/ED,0 byvthe.cube root  of  the  ra'tlo of assumed
 human body  weight  (70  kg)  to assumed  mouse body  weight (0.03 kg), Is  924


0045d  '                              9-11                              07/08/87

-------
                                   TABLE 9-7
                   2,4,4'-Tr1chloro-2'-hydroxyd1phenyl Ether
           Minimum Effective Dose (MED)  and Reportable Quantity (RQ)
Route:
Dose*:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ:
oral
1029 mg/day
mortality
Lyman and FuMa, 1969
1
10
10
1000
*Equ,fva-Ten.t .human dose.-:
0045d
            9-T2   :
05/29/87

-------
                                   TABLE  9-8
         Derivation of Potency Factor (F) for b1s(Chloromethyl)  Ether
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:

Ufespan of animal:

Target organ:
Tumor type:
Experimental doses/exposures (ppb):
Transformed doses (mg/kg/day):
Tumor Incidence:,
Unadjusted*' T/EDro:
Adjusted 1/EDio (f factor):
Leong et al., 1981
Inhalation
rat
Sprague-Dawley
male
vapor
0.35 kg*
6 months
28 months (control, low and middle
dose); 19 months (high dose)
28 months control, low and middle
dose); 19 months (high dose)
nose
esthesloneuroepltheHoma
0         1          10
0         0.0001     0.0011
0/D2     Q/1W
T58 (mg/kg/day)"1
924 mg/kg/day)"1"
                                   100
                                   0.0169
*Reference value.
0045d>
9-T3 ;••
                              05/29787'

-------
(mg/kg/day)"1.   This  F   factor  places  bls(chloromethyl)  ether   In  Potency
Group 2.   An  EPA Group A chemical  that  1s  1n Potency Group  2  ranks  HIGH 1n
the  Hazard  Ranking Scheme under  CERCLA.   A HIGH  hazard  ranking  Is assigned
an RQ of 1.
    Commercial  grade  b1s(2-chloroethyl)  ether  {composition not  specified)
produced Increased  Incidences  of hepatomas  1n  males of  two  strains  of mice
and  In  females  of  one  strain  when  administered  predominantly 1n  the diet
(BRL,   1968;   Innes   et   al.,   1969)   (see   Table  6-5),   but   100%  pure
b1s(2-chloroethyl)  ether  was not carcinogenic  In rats when  administered by
gavage  (Welsburger  et al.,  1981)  (see Section  6.2.2.).   Although hepatomas
1n mice often occur  spontaneously  and  are  difficult to  classify,  the high
Incidences  and  occurrence  In   two  strains  and   sexes   Indicate  that  the
hepatomas   In   the   BRL   (1968)   and  Innes  et   al.   (1969)  studies  were
treatment-related.   On the  basis  of  these  data and  predominantly positive
responses  1n  mutagenlclty  assays   (see Section  6.3.),  b1s(2-chloroethyl)
ether can be classified 1n EPA Group B2.
    The  hepatomas were  Induced  by treatment  by gavage  at a  dose  of : 100
mg/kg/day  on  days 7-28 of  life  and subsequently by  diet  at  a  concentrations
of 300  ppm for  the  next  76 weeks  (BRL,  1968;  Innes et  al., 1969);  the TWA
dose for  the  entire  study  1s  41.3  mg/kg/day.  Using  this dose,  the highest
Incidence of  hepatooas (B6C3F1 strain males), and the^ compeer lied multistage
model   developed < by   Howe-  antf  Crump1,  (T982;jj,,  ttte^unadjustedT/CD^g. Is
calculated  td  be  0.453  (mg/kg/day,),'1  tTafrte  M)U   tttfs T/E01(J,. may, be
ssmewhat conservative,., haweverv as  the number of  treated animals  useditm the;
caTctr.Tat 1 on was' relativeTyl smaTT.  ., The; adjusted- 1:/ED,0 pF;  Fatetor);,  calc;u;-<
lated by  multiplying  the  unadjusted kl/ED10  by the  cube  root  of the ra*1o   '-••
of assumed  human body weight (70 kg)  to assumed  mouse  body weight (0.03 kg)
and  by   the  cube  of   the . ratio  of; assumed'  mouse  Hfespan, (104  weeks\to
0045d               '                9-14           '        "  <• •       071/08/87-

-------
                                   TABLE 9-9
         Derivation of Potency Factor (F) for b1s(2-Chloroethyl) Ether
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:
Tumor type:
Experimental doses/exposures:
Transformed doses:
Tumor Incidence:
Adjusted T/EDTO- f F- factor h-
      BRL, 1968; Innes et al., 1969
      oral
      mouse
      B6C3F1
      male
      water (gavage) and diet*
      0.03 kg*
      79 weeks
      79 weeks
      104 weeks
      liver
      hepatomas
      0, 41.3 mg/kg/day TWA*
      0, 41.3 mg/kg/day
      8/79, 14.16
      13°. 7 mg/lcg/day ) ~*
^Treatment- consisted  of,  dally Intubation", of  TOO .'rag/leg" \n distilled  water  on:
 days 7-28  of  life,  followed  by dietary administration  of  300 ppm  until  80
 weeks of age.   Mouse food  consumption was  assumed  to  b.e. equivalent  to. 13%'
 of body we1ght/da^ for. calculation of,  the 'TWA dose:.
(HKSd?  .
9-T5
a5/29/87

-------
experiment  duration   (79  weeks),  1s  13.7   (mg/kg/day)"1.   This  F factor
places  b1s(2-chloroethyl)  ether  1n Potency Group  2.   An  EPA Group B2 chemi-
cal  that  Is  In  Potency Group  2  ranks MEDIUM In the  Hazard Ranking Scheme
under CERCLA.  A MEDIUM Hazard ranking 1s assigned an RQ of 10.
    Chronic gavage  administration  of  commercial grade b1s(2-chloro-l-methy1-
ethyl)  ether,  which was -70%  pure containing -28.5% 2-chloro-l-methylethyl-
(2-chloropropyl) ether and 2% bls(2-chloro-n-propyl)  ether,  was not tumorl-
genic  1n  F344  rats of  either sex  (NCI,  1979),  but  1t  produced Increased
Incidences  of  alveolar/bronchlolar adenomas  In male and  female B6C3F1  mice
and  hepatocellular  carcinomas  In  male  B6C3F1 mice  (NTP, 1982)  (see  Table
6-6).   A  low  Incidence of  stomach  or  forestomach squamous cell  papHlomas or
carcinomas  1n  the   high-dose  female  mice  was  considered  to   be  probably
related  to treatment  because  of  the  rarity  of stomach tumors  In  B6C3F1
mice.     Chronic    dietary    administration    of   high    purity   (98.5%)
b1s(2-chloro-l-methylethyl)  ether  was   not   tumorlgenlc  to   SPF-ICR  mice
                                                                            *
(MHsumorl  et  al.,  1979)  (see  Section  6.2.2.).  Although there Is evidence
of  carclnogenldty   In the  B6C3F1  mice  (NTP, 1982),  the effect  cannot  be
attributed  definitely  to  b1s(2-chloro-l-methylethyl) ether because 1t cannot
be  determined   If   1t  Is  due   to  compound   Impurity   or  mouse  strain
sensitivity.   b1s(2-Chloro-l-methylethyl)  ether  Is  therefore  classified  1n
EPA Group C.  .....
    Settee  ft-  fspro&ab'Te tha-t" most human' exposure'to b^stZ-chToro-T^ffiethyT-
ethyl)  ether  Vsr to: commercta:!:  grade,  compound;,. It ts  appropriate .to- use;the
NTP  (1982)i carcinogen 1 city data  itas derive* an^F* {•'actor.:  Ttte ortce  were
exposed'? by;  gavage: at  doses of 1QQ or  200 imgyfkgr 5  days/weeK .for 103:'weeks.
Using these doses  adjusted  for partial 'weekly exposure,  the  corresponding
liver tumor  Incidences and  the computerized multistage  model  developed  by
Howe  and   Crump   (1982),   the  unadjusted   1/ED-m   1s =  calculated:  to  be,
0045d                               9-W:                            07/08/8*

-------
3.48xlO'2  (mg/kg/day)'1  (Table  9-10).    The  adjusted  1/ED10  (F  factor),
calculated  by  multiplying  the unadjusted  T/ED,Q by  the cube  root of  the
ratio  of  assumed human  body  weight (70 kg)  to  measured average mouse  body
weight  (0.04  kg)  1s  4.19X10'1  (mg/kg/day)'1.    This  F  factor  places  b1s-
(2-chloro-l-methylethyl) ether  In  Potency  Group  3:   An EPA Group C  chemical
that  Is  1n Potency  Group  3  ranks LOW  1n the  Hazard  Ranking Scheme  under
CERCLA.  A LOW hazard ranking 1s assigned an RQ  of 100.
    IARC (1979) and U.S. EPA  (1980b) considered  chloromethyl methyl  ether  to
be  a  human carcinogen  on  the basis of  occupational  data,  and the  chemical
was assigned to  EPA  Group  A (see Section  8.1.4.).  Data  were  not  sufficient
for derivation  of  a  Potency  (F)  factor,  and  It  appears  most  appropriate  to
assign chloromethyl  methyl  ether  to  Potency  Group 2.   An  EPA Group A  com-
pound  1n Potency Group  2 ranks HIGH 1n the CERCLA Hazard Ranking Scheme for
RQs.  A HIGH hazard ranking corresponds to an  RQ of  1.
    Hazard ranking based on  cardnogenldty  Is   not possible  for  the  other
haloethers that are the subject of this report.
0045d                               9-17                             07/08/87

-------
                                  TABLE 9-10
    Derivation of Potency Factor (F) for b1s(2-Chloro-l-methylethyl) Ether
                              (Commercial Grade)
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Llfespan of animal:
Target organ:-
Tumor-type: •;.
Experimental- doses/exposures (mg/kg):
Transformed doses {mg/kg):
Tumor Incidence:
Unadjusted 1/ED]0:
Adjusted l/E&io (F factor):  ,
NTP, 1982
oral (gavage)
mouse
B6C3F1
male
corn oil
0.04 kga
103 weeks
107 weeksb
107 weeks
liver
hepatocellular adenoma or
carcinoma
0
0
13/50
100
68.8
23/50
200
27/50
3.48xlO-2 (mg/kg/day)~l
4.19xlO~1 (mg/kg/dayr1
a'E-s.ttmate«t. from graphic data provided by:, InventVgator ,
0045d
                         OS/Z9/87v.

-------
                                10.   REFERENCES

ACGIH  (American Conference  of  Governmental   Industrial  Hyglenlsts).  1986.
Threshold  Limit  Values  and  Biological  Exposure  Indices   for  1986-1987.
Cincinnati, OH.

Albert,  R.E.,  et  al.   1975.   Mortality patterns  among workers  exposed  to
chloromethyl ethers  —  A  preliminary report.   Environ. Health Perspect.  11:
209.  (Cited In U.S. EPA, 1980b)

Anderson,  D.  and J.A.  Styles.   1978.   An  evaluation of  6  short-term tests
for  detecting  organic  chemical  carcinogens.   Appendix  2.  The  bacterial
mutation test.  Br. J. Cancer.  37: 924-930.

Bettendorf, U.   1976.   Gewerbllch  Induzlerty Lungerkarzlnome  nach Inhalation
alkyllerender  Verblndunger  (Blschloromethylather und Monochloromethylather).
Zlb. ArbeHsmed.  27: 140.  (Cited 1n U.S. EPA,  1980b)

Branson, D.R.   1977.   An new  capacitor fluid  — A  case study  1n  product
stewardship.   In;   Aquatic   Toxicology  and  Hazard  Evaluation.    American
Society  for,  TesitVng  and  Materials.,  P^adftlpn1i*.r PA^;"-pv 44-61'.;    AISW
STP 634.

BRL  {Blonetlcs, Research  Labs).   T968.   Evaluation  of Carcinogenic,  Terato-
genie, and;  Muta^en:1;c; Activities; of? Se^ectedf Pes^fcTde* and1. Indiistr/fal-,  Chemt-c
cals.   Vol.  1.  Carcinogenic  Study.   Prepared  for  NCI, August  1968.    NTIS
Publ. no. 223-159.

0046¥                               10-1                       .       07/09/87

-------
Buccafusco,  R.J.,  S.J.  Ells  and  G.A.  LeBlanc.   1981.   Acute  toxldty  of
priority  pollutants  to  blueglll   (Lepomls  macrochlrus).   Bull.   Environ.
Contain. Toxlcol.  26(4): 446-452.

Callahan,  M.A.,  H.W.   Sllmak,   N.W.  Gabel,  et  al.   1979.  Hater -Related
Environmental   Fate  of   129  Priority  Pollutants—Volume  II.   U.S.   EPA,
Washington, DC.  EPA 440/4-79-029B.

Carpenter, C.P.,  et  al.  1949.   The  assay  of acute vapor toxldty, and  the
grading  and  Interpretation of  results  on  96 chemical  compounds.   J.  Ind.
Hyg. Toxlcol.  31: 343.  (Cited  In  U.S.  EPA, 1980b)

Choudhry, G.6., G. Sundstrom, L.O. Ruzo and  0. Hutzlnger.  1977.  Photochem-
istry of chlorinated dlphenyl  ether.   J. Agrlc.  Food Chera.  25: 1371-1376.

Cole, R.H.,  R.E.  Frederick,  R.P.  HeaT-y and R.G.  Rolan.   1984.   Preliminary
finding of the  priority pollutant  monitoring  project of  the  Nationwide  Urban
Runoff Program.  0.  Water Pollut. Control  Fed.  56:  898-908.

CupHt,  L.T.   1980.    Fate  of   Toxic and  Hazardous  materials  1n  the  Air
           .. ?..1&SU E&A* Resea^ck Triangle  Par** NO. .
                                                                           to
chloTomethyT methyl ether: An  epIdemVologlcaT study-.   Arch.  Environ.  Health.
3Vffl-: 125-130'. ,
0046d                               TO-?                             07/09/87

-------
Dewalle, F.B.  and  E.S.K.  Chlan.   1981.  Detection of  tract  organlcs In well
water  near  a  solid  waste  landfill.   J.  Am.   Water  Works  Assoc.   April
p. 206-211.

DojUdo,  J.R.   1979.   Investigations  of  BlodegradabUHy  and  Toxldty  of
Organic  Compounds;  Final Report  1975-79.   Municipal  Environmental  Research
Lab., Cincinnati, OH.   118 p.  EPA 600/2-79-163.

Dow  Chemical  Co.   1984a.   The static  acute  toxldty  of  b1s(2-chloroethoxy)-
methane  and  2-sec-butyl-4,6-d1n1trophenol  to  the fathead minnow  with  cover
letter dated 04/10/86.  TSCA 8{d) Submission 868600033. Flche No. OTS0510185.

Dow  Chemical  Co.   1984b.  The  static  toxldty of b1s(2-chloroethoxy)methane,
dlnoseb, aniline,  prChlorp-m-cresol and si 1 vex to the water  flea  with  cover
letter dated 04/10/86.  TSCA 8(d) Submission 868600034. Flche No. OTS0510186.

Dow  Chemical,   n.d.   Unpublished  data.   Biochemical  Research Laboratory, Dow
Chemical1- Co.  (.Cited 1n Klrwln and Sandmeyer, 1981)

Drew,  R.T.,  S.  Laskln,  M.   Kuschner  and  H.   Nelson.   1975.    Inhalation
carcfifogtttfelfcy ef* a;Tptte tola' 'etherss'.-!^ Jbef acute fnhfflattfofl? to*Tctty *of ;
chloromethyT  methyl  ether  and • bls(chloromethyl)1  ether.   Arch.:  Errvlron.
Health.  3Q{'2J: 6T-&91
Dulak, N.c:  and  C.A.. Snyder.  1980".   Ttte- reTat'lonshtp.. between .the' chefntcal
reactivity and the  Inhalation  carcinogenic  potency of direct-acting chemical
agents.  Proc. Am. Assoc. Cancer Res.  21: 106.

0046d                               10-3 '                            07/09/87

-------
Dulln, D.,  H.  Drossman and T. Mm.   1986.   Products  and quantum yields for
photolysis of chloroaromatlcs In water.  Environ. Sd. Techno!.  20: 72-77.

Durkln, P.R.,  P.H.  Howard and J. Saxena.   1975.   Investigations  of Selected
Potential  Environmental  Contaminants:  Haloethers.    Office  of  Toxic  Sub-
stances, U.S. EPA, Washington, DC.  EPA 560/2-75-006.

E1senre1ch,  S.J.,  B.B.  Looney  and D.J.  Thornton.   1981.   Airborne organic
contaminants  1n  the  Great  Lakes  ecosystem.   Environ.  Sc1.  Technol.   15:
30-38.

Ellersteln,  S.M.  and  E.R.   Bertozzl.   1982.  .Polymers  containing  sulfur
(pps).   Iri:  K1rk-0thmer  Encyclopedia  of  Chemical  Technology, Vol.  18,  3rd
ed.,  M.  Grayson and  D.  Eckroth,  Ed.   John  Wiley  and Sons.,  Inc.,  New York.
p. 814-816.

Flgueroa, W.G*.  R.  Raszkowskl and  W.  Weiss.  1973.   Lung. cancer  1n chloro-r
methyl methyl- ether workers.   New Eng.  J. Med.  288: 1096. ;          .     *.•'

Flshbeln,   L.    1977. .   Potential   Industrial   Carcinogens   and   Hutagens.
560/5-77-005.:  N-TIS
Frost, il.KX P.K.  Gupta,  Y.FV;  Erozamv Ov  Carter,  Dl.Hr. Hellander  and M.L:
Levin. . 1973;   PuJmortar.y Cytology  alterations M-a'toxI'cvenvlronmental .llnhal'a-
tlon.  Human Pathol.  4: 521-535.  (Cited In IARC, 1979)
0046d                               10-4                             07/09/87

-------
Gage, J.C.   1970.  The  subacute  Inhalation  toxlclty of 109 Industrial chemi-
cals.  Br. J. Ind. Med.  27: 1.

Gargus,  J.L.,  W.H.  Reese,  Jr.  and  H.A  Rutter.   1969.   Induction  of  lung
adenomas   1n  newborn   mice   by   bis   chloromethyl   ether.   Toxlcol.  Appl.
Pharmacol.  15(1): 92-96.

Hansch,  C.  and  A.J.  Leo.   1985.   Medchem  Project.   Issue No.  26.   Pomona
College, Claremont, CA.

Hauser,  T.R.  and  S.H.  Bromberg.  1982.   EPA's monitoring program  at  Love
Canal 1980.  Environ. Monlt. Assess.   2: 249-272.

Hawley,  G.G.   1981.   The   Condensed   Chemical  Dictionary,  10th  ed.   Van
Nostrand Relnhold Co., New York.   p.  132, 335-336,  1049.

H1ne, J. and  P.K.  Mookerjee.   1975.   The Intrinsic  hydrophlUc character of
organic  compounds.?  Correlations 1n  terms  of  structural  contributions.   0.
Org. Chem.  40:  292-298.
     ,, R.A^  and v: Lopei-A,vVlia.  T9€0.   Sed1tnenUry; accumulatVons of tndui-
tr'TaT orga'n'tc  compounds  rffscharge
-------
Howe,  R.B.  and  K.S.   Crump.    1982.   GLOBAL  82.   A  Computer  Program  to
Extrapolate  Quanta!  Animal  Tox1c1ty Data  to Low-Doses.  Office  of  Carcinogen
Standards,   OSHA,   U.S.   Dept.   of  Labor,  Washington,  DC.    Contract   No.
4HUSC252C3.

IARC  (International  Agency for  Research  on  Cancer).   1974.  IARC  Monographs
on  the  Evaluation of  Carcinogenic  Risk of  Chemicals  to Humans.   IARC,  WHO,
Lyons, France.  Vol. 4.  p. 231-237; 239-245.

IARC  (International  Agency for  Research  on  Cancer).   1975.  IARC  Monographs
on  the  Evaluation of  Carcinogenic  Risk of  Chemicals  to Humans.   IARC,  WHO,
Lyons, France.  Vol. 9.  p. 117-123.

IARC  (International  Agency for  Research  on  Cancer).   1977.  IARC  Monographs
on  the  Evaluation of  Carcinogenic  Risk of  Chemicals  to Humans.   IARC,  WHO,
Lyons, France.  Vol. 15.  p. 31-35; 301-305.

IARC  (International  Agency for  Research  on Cancer).^.. 1979.  ^ARC Monograph*
on  the Chemicals  and Industrial Processes Associated  with  Cancer  In  Humans.
IARC, WHO, Lyons, France.  Vol.  1-20, Suppl. 1.  p. 26-27.
       ..J'.fcff-..  BXff.  UTFla'ndY H.ff. VaTeflo, ~et  a'T.   1969V-: .B1o'a&&yi- of  pesti-
cides:  and'. T«du'str.t.a"T  chemicals  for  tumorigenl-clty  1n mice:*/' A",  preliminary,
note.;  JvMtatT. Cancer Irrstv  42: 110V.?
0046d                               10-6                             05729/87

-------
James,  R.H.,  R.E.  Adams, J.M.  Flnkel,  H.C.  Miller and  J.D.  Johnson.   1984.
Evaluation of analytical methods  for  the  determination  of  POHC 1n combustion
products.   J.  Proc.  A1r  Pollut.  Control  Assoc. Annu.  Meet,  Vol.  77th.
1(84-18.5): 25.

Jorgenson, T.A., C.J. Rushbrook,  G.W.  Newell  and  R.G.  Tardlff.  1977.   Study
of  the  mutagenlc  potential  of  b1s(2-chloroethyl )  and  b1s(2-chloro1sopropyl)
ethers   In  mice   by  the   heritable   translocatlon  test.    Toxlcol.   Appl .
Pharmacol.  41: 196-197.

Jorgenson, T.A., C.J. Rushbrook,  G.W.  Newell  and  R.G.  Tardlff.  1978.   Study
of  the  mutagenlc  potential  of  b1s(2-chloroethyl)  and  b1s(2-chloro1sopropyl )
ethers 1n mice by the heritable translocatlon test.  Mutat.  Res.  53: 124.

Jungclaus, G.A., V. Lopez-Avlla and R.A.  HHes.   1978.   Organic compounds In
an  Industrial waste  water:  A case  study  of  their  environmental  Impact.
Environ. Sc1.  Technol.  12:  88-96.

Keith,  L.H.,  A.W.   Garrison,  F.R. Allen,  et  al.   1976.  Identification of
organic  compounds  In  drinking water  from thirteen U.S. cities.   In:  Ident.
Anal. Organic  Pollut. Water.  L.H.  Keith, Ed.   Ann Arbor Press,  Ann  Arbor,
Mt.  p., 32*-3J3.
      . C.J.  afltf E.f.  Sartdroeyer.   T9&T.   Ethers  (rflchToratsopropyl ether).
IJK  Patty,1 s.  Industrial Hygiene and; Tbxtf eulogy*  Vo,.T-  2Ar  3rd  ed.r  G..D.
Clayton  and  F.E.  Clayton,   Ed.  'John   Wiley  and  Sons,   Inc.',  New  York*.
p. 2519-2520.


0046rf                               T0-7:                             05/29/87

-------
Kleopfer,  R.D.  and  B.J.  Falrless.   1972.   Characterization  of  organic
compounds 1n a municipal water supply.  Environ. Sc1. Technol.  6: 1036-1037.

Koneman,  H.    1981.   Quantitative  structure-activity  relationships  In  fish
toxldty  studies.   Part  1:  Relationship  for  50  Industrial  pollutants.
Toxicology.  19(3): 209-221.

Kuschner,  M.,  S.  Laskln,  R.T.   Drew,  V.  Capplello and  H.  Nelson.   1975.
Inhalation carclnogenldty  of alpha  halo ethers:  III.  Lifetime  and limited
period  Inhalation  studies  with  bls(chloromethyl)  ether  at 0.1  ppm.   Arch.
Environ. Health.   30(2): 73-77.

Laskln,  S.,  M.  Kuschner,  R.T.  Drew,  V.P.  Capplello  and N.  Nelson.   1971.
Tumors  of  the  respiratory  tract Induced  by Inhalation of  bis chloromethyl
ether.  Arch. Environ. Health.  23(2): 135-136.

Laskln,  S.,  R.T.  Drew,  V.  Capplello,  M.  Kuschner and  N.  Nelson.   1975.
Inhalation  carc1nogen1dty  of  alpha  halo  ethers:   II.  Chronic  Inhalation
studies  with  chloromethyl  methyl  ether.   Arch.  Environ.  Health.   30(2):
70-72.
Lemen,r R.AT.,  W.K.  Johrrsw, J.K.  Wa-goirer,  et al;   T976.   CytologEtc; o&servar-
tlons and1 cane erv incidence  fo-??owtn$- exposure- to? BCWEK,  Annv B?.^, Atfa*.: Sc^f.
271: IT.
0046d                               10-8                             07/09/87

-------
Leong, B.K.J., H.N. MacFarland and W.H.  Reese,  Jr.   1971.   Induction of lung
adenomas by  chronic  Inhalation of bis  (chloromethyl )  ether.   Arch.  Environ.
Health.  22(6): 663-666.

Leong, B.K.J., R.J. Koclba and G.C.  Jersey.   1981.   A lifetime study of rats
and  mice  exposed  to  vapors  of  bls(chloromethyl)   ether.   Toxlcol.  Appl .
Pharmacol.   58: 269-281.

Llngg,  R.D.,  W.H.  Kaylor,  J.W.   Glass,  S.M. Pyle  and R.G. Tardlff.   1979.
Th1od1glycol1c  add:   A   major   metabolite  of   b1s(2-chloroethyl)  ether.
Toxlcol. Appl. Pharmacol.   47(1): 23-34.

Llngg, R.D., W.H. Kaylor, S.M. Pyle,  M.M.  Domino,  C.C. Smith and G.F. Wolfe.
1982.   Metabolism  of  b1s{2-chloroethyl )ether   and  b1s(2-chloro1sopropyl )
ether 1n the rat.   Arch. Environ. Contam. Toxlcol.  11(2):  173-183.

Ludzack, F.J.  and  B.M.  Ettlnger.  1963.   B1odegradab1l1ty  of  organic chemi-
cals  Isolated  from  rivers.    Purdue  Univ.,  Eng.  Bull. Ext.  Ser.   No.  115.
p. 278-282.
       F.U and T., Fur-Va«  '1569.
dTplYeay.T ei'hef..  Ind. Med.   3Ei *
Lyman, W.J.,  W.F.  f?eeht  and D-.H.1: Rosenblatt.   T9W.   Handbook  of  ChemlcaT
Property; . EstTraart ton Methods..  McGraw-Ml
-------
Mabey, W.R.,  J.H.  Smith,  R.T.  Podoll, et  al.   1981.  Aquatic  Fate  Process
Data  for  Organic  Priority Pollutants.   U.S. EPA,  Washington,  DC.   434 p.
EPA 440/4-81-014.

MHsumoM,  K.,   T.  Usu1,  K.   Takahashl  and  Y.   Shlrasu.    1979.   24  Month
chronic toxldty  studies of  d1chlorod11sopropyl  ether  1n mice.   3.  Pestle.
Sc1.  4(3): 323-336.

Mueller,  G., K. Norpoth  and R.  Eckard.   1979.  Identification  of S-(carboxy-
methyl)-L-cyste1ne and  thlodlglycollc  acid, urinary  metabolites of  2,2-b1s-
(chloroethyl) ether 1n the rat.  Cancer Lett.   7(5): 299-306.

NCI (National Cancer  Institute).   1978.  Unpublished  report.   (Cited  1n U.S.
EPA, 1980b:)

NCI (National Cancer  Institute).   1979.   Bloassay  of Technical  Grade B1s(2-
Chloro-1-Methylethyl)  Ether  for  Possible  Cardnogenlclty.   NCI  Carcinogen.
Tech.  Rep. Ser.  No. 191.  84 p.  [Also published  as DHHS (NIH)  79-1747]

Nelson, N.   1976.   The  chloroethers  —  Occupational carcinogens: A  summary
of  laboratory ;  and epidemiology  studies.   Ann.  NT Acad.  Scf.   271:  8T.
                    1980a.)r
NIOSH  (National  Institute for accupatronaT SaTety anrf Healtn}'..   T9TCv\
toxic substances list,; 197'4- ed.  U.S.  Dep't.  Health,  Education,  WeTfrar^ Pub:T.
74: 134.  (CHed In U.S.  EPA,  1980b)
0046d                               Tff-10                            07/09/87

-------
NTP  (National  Toxicology  Program).   1382.   Carclnogenesls Bloassay of B1s(2-
Chloro-1-Methylethyl)   Ether   (-70%)   Containing  2-Chloro-l-Methylether-{2-
Chloropropyl)  Ether  (-30)  1n  B6C2F1  Mice  (Gavage Study).   NCI Carcinogen.
Tech. Rep. Ser. No. 239.  105 p.  [Also published as DHHS (NIH)  83-1795]

OSHA  (Occupational  Safety  and  Health Administration).   1985.   Occupational
Standards.  Permissible Exposure Limits.  29 CFR 1910.1000.

Pasternack, B.S.,  R.E.  Shore and R.E. Albert.   1977.   Occupational exposure
to chloromethyl  ethers: A  retrospective cohort  mortality study (1948-1972).
J. Occup. Med.  19(11): 741-746.

Reznlk,  G.,  et  al.   1977.  Lung  cancer  following  exposure  to b1s(chloro-
methyl) ether: A case  report.   J.  Environ.  Pathol.  Toxlcol.  1: 105.  (CUed
1n U.S. EPA, 1980b)

Rosen,  A.A.,  R.T.  Skeel  and M.B.  Ettlnger.   1963.   Relationship  of river
water odor  to  specific  organic  contaminants.  J. Water  Pollut. Control  Fed.
35: 777-782.

Russell,  L.B.  and C.S.. Montgomery,.;-'  1980,   Use of  the mouse: spot test to
Investigate  the.  mutagerrtcppterrttal  of  trtclosan  (Irga'san-DPSOO).   Mutat.
Res.  BU),: 7-12.

Sakabe, Hf.  19,13.,  Lung cancer,  due; to exposure to; b.te.-tohlaro.-methyl); ether.,
Ind. Health.  Tl: T45:  (Cited In U;S. EPA', T?80b)
0046d                               TO-TT                            07/09/87

-------
Sanjlvamurthy, V.A.   1978.   Analysis of organlcs  1n  Cleveland  water supply.
Water Res.  12: 31-33.

Sasaki, S.   1978.   The scientific aspects of  the  Chemical  Substance Control
Law   1n   Japan.    IJK   Aquatic   Pollutants:   Transformation  and  Biological
Effects,  0.  Hutzlnger,  L.H.  Von Letyoeld and  B.C.J.  Zoeteman,  Ed.   Pergamon
Press, Oxford, UK.  p. 283-298.

Schrenk,  H.H. et al.   1933.   Acute  response  of guinea pigs to vapors of some
new  commercial  organic  compounds.   VII. Dlchloroethyl  ether.    Pub.  Health
Rep.  48:  1389.  (Cited 1n U.S.  EPA, 1980b)

Shackelford,  VI. M.  and  L.H.   Keith.   1976.    Frequency  of  Organic  Compounds
Identified 1n Water.  U.S. EPA,  Athens, GA.   p. 125, 129.  EPA 600/4-76-062.

Sheldon,  L.S.  and  R.A.  HUes.   1978.   Organic  compounds  In   the  Delaware
River.  Environ.  Scl. Techno!.  12: 1188-1194.                     :

Sheldon,  L.S. and  R.A.  HHes.  1979.  Sources  of  movement  of organic chemi-
cals 1n the Delaware River.  Environ. Scl. Technol.  13: 574-579.
       , Y^. «.  Korfyav fc. Kato an'd :Tv  Kada*.   T975V' Mutagen:l;c;;tty~.s;cpee**rtgL
af pe&ttcfrtes InsinterobjteT sys^temi^ 11.^, HufcatU Res;« ' \31i=:
Simmon,  V;yF^, ...KW  Kauttanen; and  Rv£^ Tartftfifc.,  1977au-  Hu^agen 1 c 1;% as:sa,y,si
with  b1s(2-Chloroeth"yT)  %f«erv  AbStf of ;Keef^ fnftemat!  Corfgru TbxTcol?,
Toronto, March 3-Aprll 2.  31  p.   (Cited In F1shbe1n, 1977)


0046d                               10-12                            07/09/87

-------
Simmon, 'V.F.,  K.  Kauhanen and  R.G.  Tardlff.  1977b.  Mutagenk  activity of
chemicals  Identified  In  drinking water.   Dev.  Toxlcol.  Environ.  Sc1.   2:
249-258.

Simmon,  V.F.,  L.  Hedden, D.  Poole  and R. Tardlff.   1978.   Mutagenlc assays
with b1s-(2-chlorod!1sopropyl) ether.  Mutat. Res.  53: 261-262.

Slaga,  T.J.,  G.T.  Bowden,   B.G.  Shapas  and R.K.  Boutwell.   1973.   Macro-
molecular synthesis  following a  single application  of alkylatlng agents used
as Initiators of mouse skin tumorlgenesls.  Cancer Res.  33: 769-776.

Smith, C.C., R.D.  L1ngg  and R.G. Tardlff.   1977.   Comparative metabolism of
haloethers.   Ann.  N.Y. Acad. Sc1.  298: 111-123.

Smyth,  H.F.,  Jr.   and  C.P.   Carpenter.   1948.   Further  experience  with  the
range  finding  test  1n the  Industrial  toxicology  laboratory.   J.  Ind.  Hyg.
Toxlcol.  30:  63.   (Cited 1n U.S. EPA, 1980b)

Smyth, H.F., Jr.,  et al.  1949.  Range-finding  toxldty  data; List III.   J.
Ind.  Hyg. Toxlcol.  31: 60.   (CHed In U.S. EPA, 1980b)

Smyth,. H-.F.,. Jr..., at sT.   TOST..   Range-find.^ .toxfolty -..da**;- Us* IV.   I.,
Ind.  Hyg ., Occup,. Med- ,4s- lift,  dttted \n U.S.. EP/W mob);,
Smyth;, OL,- Jr.,  etr.aiK.  T96*.  Rarcge-f.1fnd*ngr ' to»terty.> teta-;, L1:s* VIL.
Ind. Hyg. Assoc.. ! 31: 60.  (Cited In If.S. EPrA, T980b)
0046d                               10-13                            07/09/87

-------
SRI  (Stanford  Research  Institute).   1986.    1986   Directory   of   Chemical
Producers:  United  States  of  America.   SRI  International, Menlo  Park,  CA.
p. 503, 587, 856, 1069.

Staples,  C.A.,  A.  Werner  and  T.  Hoogheem.   1985.   Assessment  of  priority
pollutant   concentrations   In   the  United  States  using  STORE!   database.
Environ. Toxlcol. Chem.  4: 131-142.

Suffet,  I.H.,  L.  Brenner  and P.R.  Cairo.   1980.   Gas chromatography-mass
spectrometry Identification  of trace organlcs 1n Philadelphia, Pennsylvania,
USA drinking water during a two year period.  Water Res.  14: 853-867.

Tabak, H.H., S.A. Quave, C.I. Mashnl and E.F. Barth.   1981.  B1odegradab1l1ty
studies with organic  priority  pollutant compounds.  J. Water Pollut.  Control
Fed.  53: 1503-1518.

Thless,  A.M.,   et  al.   1973.   Zur  Tox1kolog1e  von  Dlchlorodlmethylather-
Verdacht auf kanzerogene Wlrkung auch  belm  Menschen.   Zbl. Arbeltsmed.   23:
97.  (Cited In U.S. EPA. 1980b)

Thless.iJ-C.,  e.t al.   1977*  Test  for carclnogenldty ,of organ,Vcv contanrt-
narvt^af- OnTt"etf. Sit'&tes: 
-------
U.S.  EPA.   1975.   Preliminary Assessment of  Suspected  Carcinogens In Drink-
Ing Water.   Interim Report  to  Congress,  June, 1975.   U.S.  EPA, Washington,
DC.

U.S.  EPA.    1977.   Computer  print-out of  non-confidential  production  data
from TSCA Inventory.  OPTS, CID, U.S. EPA, Washington,  DC.

U.S.  EPA.   1978.    In-Depth  Studies on Health and  Environmental  Impacts of
Selected  Water   Pollutants.    U.S.  EPA,  Washington,  DC.   Contract  No.
68-01-4646.

U.S.  EPA.   1980a.   Guidelines  and  Methodology Used  1n the  Preparation of
Health  Effect  Assessment  Chapters of  the  Consent  Decree  Water  Criteria
Documents.   Federal Register.  45(231): 49347-49357.

U.S.  EPA.   1980b.  Ambient  Water  Quality Criteria  Document for Haloethers.
Prepared by  the Office  of  Health  and Environmental Assessment,  Environmental
Criteria and-. Assessment  Office,  Cincinnati,  OH   for   the  Office  of  Water
Regulations   and   Standards,  Washington,   DC.    EPA   440/5-80-050.    NTIS
PB81-117616.

U.S.  EPA'.   T980c.  Ambient  Water  QuaTTfy Criteria  Document for .ChfToroalkyT-
Ethers.:  Prepared  by, the. Office  of.."Health.' and  Envlr.onmenta.T Assessment,,
Environmental-  Criteria  and Assessment" Off-tee.-.  CtnclrmatV, ;OH for the- Office
of Water Regulations  and Standards, Washington, DC.  EPA, 440/5-80-0:30..  MTIS;
PB81-117418.
0046d                               10-T5                            07/09/87

-------
U.S.  EPA.   1983a.   Methodology  and   Guidelines   for   Reportable  Quantity
Determinations  Based  on  Chronic  Toxldty  Data.   Prepared  by  the Office  of
Health  and Environmental  Assessment, Environmental  Criteria and  Assessment
Office, Cincinnati, OH  for  the Office of Solid Waste  and  Emergency Response,
Washington, DC.

U.S.  EPA,   1983b.   Reportable  Quantity  Document  for  Chloromethyl  Methyl
Ether.   Prepared  by   the  Office  of  Health  and  Environmental  Assessment,
Environmental  Criteria  and Assessment Office,  Cincinnati, OH for  the  Office
of Emergency and Remedial Response, Washington, DC.

U.S.  EPA.   1983c.  Reportable Quantity  Document for b1s(2-Chloro1sopropyl)
Ether.   Prepared  by   the  Office  of  Health  and  Environmental  Assessment,
Environmental  Criteria  and Assessment Office,  Cincinnati, OH for  the  Office
of Emergency and Remedial Response, Washington, DC.

U.S.  EPA.   1985.   Reference  Values  for Risk  Assessment.   Prepared by  the
Office*-of  Health  and Environmental ^Assessment,  Environmental  Criteria '.and
Assessment Office,  Cincinnati, OH  for the Office of Solid Waste,  Washington, *
DC.

U.S.;  EP.A^'  I.;9i86av,~  Hethadotagy;' for' • Exalu&tftigt Paten,Ua:T; rCarcinogentclty  tny
Support of Repair table Qjtanmy, Ad},ustmeivls, Pursuant  .to CERCLA Section *T02.. ,-
Prepared"  by-, tnV Office-  of: He*TtW antf-En^v-Trenraental- A'ss;essment.  Carcinogen
Assessment Gr'oup, ^asMrcgtoni;,;  D[Cvfor-th:e Offices,  af>So;11d  Waste  and,,Emergency
Response,  Washington,  DC.
0046d                               10-16                             07/09/87

-------
U.S.  EPA.   1986.   Guidelines  for  Carcinogen  Risk  Assessment.   Federal
Register.  51(185): 33992-34003.

U.S. EPA.   1987.   Graphical Exposure Modeling  System (GEMS).   Octanol-Water
Partition  Coefficient  (CLOGP)  and/or  Fate  of  Atmospheric  Pollutants  (FAP)
computer data systems.   U.S. EPA, Research Triangle Park, NC.

Van Duuren,  B.L.,  8.M.  Goldschmldt, C.  Katz, L.  Langseth,  G.  Mercado and A.
S1vak.   1968.  Alpha-halo ethers a  new  type  of  alkylatlng carcinogen.  Arch.
Environ. Health.  16(4): 472-476.

Van Duuren,  B.L., A.  Slvak,  B.M.  Goldschmldt,  C.  Katz and  S.  Melchlonne.
1969.   CardnogenlcHy  of haloethers.  J.  Natl.  Cancer Inst.  43(2): 481-486.

Van Duuren,  B.L., S.  Melchlonne,   R.  Blair, B.M.  Goldschmldt and  C.  Katz.
1971.    CardnogenlcHy  of   Isoesters  of  epoxldes  and   lactones:  Azlrldlne
ethanol, propane  sulfone  and related compounds.  J.  Natl.  Cancer  Inst.   46:
143.

Van Duuren,  B.L., C. Katz,  B.M.  Goldschmldt, K. Frenkel  and A. Slvak.  1972.
CarcAnogBn^clitjt; of ;halo-ether;S?.v  llv £trvctun.£*$cttvttjj  relation- of: analogs;
of bVs^Wxjromethyi'H) ether.  IJ-RatT...''Cancer Inst.  ffttSfc U31:-l:439..

Varv  Duuren,  ff.L.,  B-.H.  GbTdschmlrftY  Cv  Katr..  I.   Seldman  and  J;.S.  Paul.
T974.    Carcinogenic  acttvl'ty  of alkyTa.tfrtg' agervts.   !„ NatT;.  Cancer Inst.
53(3):  695-700.
0046d                               10-17                            07/09/87

-------
Van  Duuren,  B.L.,  B.M.  GoldschmVdt  and  I.  Seldman.   1975.   Carcinogenic
activity  of d1- and  trlfunctlonal  alpha-chloro ethers  and of  1,4-d1chloro-
butene 2  In ICR/Ha Swiss mice.  Cancer Res.  35(9):  2553-2557.

Velth, G.D.,  K.J.  Hacek, S.R. Petrocelll  and  3.  Carroll.  1980.  An  evalua-
tion  of  using partition coefficients  and water solubility  to estimate  bio-
concentration factors for organic chemicals  In fish.   In; Aquatic Toxicology,
J.G. Easton, et  al.,  Ed.   Am Soc. Tes. Mater, Philadelphia, PA.  p. 116-129.
ASTM STP 707.

Verschueren, K.  1983.   Handbook  of Environmental  Data on Organic Chemicals,
2nd ed.  Van Nostrand Relnhold Co., New York, NY.

V1al,  T.M.    1979.    Elastomers,  synthetic   (acrylic).   In:  K1rk-0thmer
Encyclopedia  of  Chemical  Technology,  Vol.  8,  3rd ed.,  M.   Grayson  and  D.
Eckroth, Ed.  John Wiley and Sons,  Inc., New York.   p. 463.

Voets, J.P., P.  P1pyn,  R.  Van Lancker and W. Verstraete.  19-76?  Degradation
of   mlcroblddes  under   different  environmental  conditions.    J.    Appl.
Bacterlol.  40:  67-72.

Heas?t.  R'.C-.,. Ed.   H8&:  CRC.;  Handbook- afr Chemt.s,try. and::".Physics..  66thred.,
CRC Press, Inc.;» Boca Ra.tonv,FL»  p. C-2QS,., C-24&,*

Welsb'urger,, &..K.,  ,&:»-;.  UllaM,.  H-H;: Nam,  J.j;." Garland -HXJ. Welsburger.
1981.  Carc1nogen1c1ty  tests' of  certain  environmental and Industrial  chemi-
cals.  J. Natl.  Cancer Inst.  67(1): 75-88.

0046d                               10-18                            Of/09/87

-------
Weiss,  W.   1976.   Chloromethyl  ethers,  cigarettes,  cough  and  cancer.   J.
Occup. .Hed.  18: 194.  (Cited In U.S. EPA, 1980D)

Weiss,  W.   and  K.R.  Boucot.   1975.   Respiratory  effects  of  Chloromethyl
methyl ether.  J. Am. Med. Assoc.  234(15): 1139-1142.

Weiss, W.  and  W.G.  Flgueroa.  1976.  The  characteristics  of  lung cancer due
to Chloromethyl ethers.   J. Occup. Med.  18: 623-627.

Weiss, W.,  R.L.  Moser and 0.  Auerbach.   1979.  Lung  cancer  1n Chloromethyl
ether workers.   Am.  Rev.  Resplr. 01s.  129(5): 1031-1037.

Wilson,  J.  and  M.J.  Noonan.   1984.  M1crob1al  Activity  In   Model  Aquifer
Systems.. Robert S.  Kerr  Environ. Res. Lab.   35 p.   EPA 600/D-84-136.   NTIS
PB84-194893.

Wilson,  J.T.,  C.G.  Enfleld, W.3.  Dunlap,  R.L.  Cosby, D.A. Foster  and L.B.
Baskln.  1981.   Transport and fate  of  selected organic pollutants 1n a sandy
soil.  J. Environ.  Qual.   10: 501-506.

W1ndho,U.  M.,  W.    1983.   The  Merck  Index,  10th  ed.   Merck  &  Co.»  Inc..
Rahway. NJ.  p. T38T.

Zajdete,. F.r. A.. Cro,tsy-r A--. Barfctn>. £:„  MalaveVVle,  \~ Tomatts aiwt H. Bartsct»v
1980.  Caretno.genI'dty, o;f  chloroethyTene,  ox.l:de,  an, uTt'lmat'e, reacMve metabo'-.
IHe of  vinyl  chloride and b1s(chloromethyT)v ether after subcutaneous admfn-
Istratlon  and  1n Initiation-promotion  experiments  with mice.   Cancer  Res.
40: 352-35,6,
0046d                               TO-19"                            07/09/87

-------
                                  APPENDIX A

                              LITERATURE  SEARCHED



    This  HEED  1s  based  on  data  Identified  by  computerized  literature

searches of the following:


         TSCATS
         CASR online (U.S. EPA Chemical Activities Status Report)
         TOXLINE
         TOXBACK 76
         TOXBACK 65
         RTECS
         OHM TADS
         STORET
         SRC Environmental Fate Data Bases
         SANSS
         AQUIRE
         TSCAPP
         NTIS
         Federal Register


These searches were conducted  1n  February,  1987.  In addition, hand searches

were made of  Chemical  Abstracts  (Collective  Indices  5-9),  and the following

secondary sources should be reviewed:


    ACGIH (American  Conference of  Governmental  Industrial  Hyg1en1sts);.
    1986.   Documentation  of the  Threshold  Limit  Values  and  Biological
    Exposure Indices,  5th ed.  Cincinnati, OH.

    ACGIH (American  Conference of  Governmental  Industrial  Hyglenlsts).
    1986-1987.  TLVs: Threshold Limit  Values  for Chemical Substances  In
    the  Work  Environment  adopted  by  ACGIH  with  Intended  Changes  for
    1>98S-198,7;. ' Cincinnati*, QHv
    Clayton,  G.D':   and  F.E.  Clayton,  Etf.   T987.    Party's  Indus trTal.
    Hygiene  and  Toxicology;,  3rd  rev.  ed..  Vol.  2A~   John lit ley  and
    Sonsf, NY.  2878Lp.

    Clayton,  G.D.   and  F.E.  Clayton,  Ed. .  T98T.    Patty's  Industrial
    Hygiene, and; Toxicology;,,  3rd,  rev-,  ed,.,.  Vol.  2.B.-..   John Wiley  and
       su NY..  pr
    Clayton,  G.D.   and   F.E.  Clayton,  Ed.   1982.    Patty's  Industrial
    Hygiene  and  Toxicology,  3rd  rev.  ed.,  Vol.   2C.   3ohn WHey and
    Sons, NY.  p. 3817-5112.
                                      A-!-

-------
Grayson,  M.  and  D.  Eckroth, Ed.   1978-1984.   K1rk-0thmer  Encyclo-
pedia of  Chemical  Technology,  3rd ed.   John Wiley and Sons, NY.   23
Volumes.

Hamilton, A.  and  H.L.  Hardy.  1974.  Industrial Toxicology, 3rd  ed.
Publishing Sciences Group, Inc.,  Littleton, MA.  575 p.

IARC  (International  Agency  for  Research  on  Cancer).   IARC  Mono-
graphs  on  the  Evaluation   of  Carcinogenic  Risk  of  Chemicals   to
Humans.   WHO,  IARC, Lyons, France.

Jaber,  H.M.,   W.R.  Mabey,  A.T.  L1eu,  T.W.  Chou and  H.L.  Johnson.
1984.   Data   acquisition   for  environmental   transport  and  fate
screening for  compounds of  Interest  to  the Office  of Solid Waste.
SRI   International,   Menlo   Park,  CA.    EPA   600/6-84-010.   NTIS
PB84-243906.

NTP  (National  Toxicology Program).  1986.   Toxicology Research  and
Testing   Program.   Chemicals   on  Standard  Protocol.    Management
Status.

Ouellette,  R.P.  and   J.A.   King.   1977.   Chemical   Week  Pesticide
Register.  McGraw-Hill  Book  Co.,  NY.

Sax,  I.N.   1984.   Dangerous  Properties  of Industrial  Materials,  6th
ed.  Van  Nostrand Reinhold Co., NY.

SRI  (Stanford  Research Institute).  1986.   Directory  of  Chemical
Producers.  Menlo Park, CA.

U.S.  EPA.  1986.   Report  on  Status  Report  1n the  Special Review
Program,  Registration  Standards   Program  and  the   Data   CalV  1n
Programs.   Registration Standards  and  the  Data Call  In Programs.
Office of Pesticide Programs, Washington, DC.
U.:S. EPA-.   1985.   CSB  Existing Chemical Assessment Tracking ^
Name and  CAS Number Ordered Indexes.  Office  of Toxic Substances,
Washington, DC.

USITC  (U.S.  International  Trade  Commission).   1985.   Synthetic
Organic Chemicals.   U.S. .Production  and  Sales,  1984,  USITC Publ.
                  ws.
Vetscttueren , -  Kv  1383L  Handbook  of EriVflronrnerrtatf". Qatat on:. Organic.
Cherolca-ls, 2nd ed.; .Van Nostrand Relnhold Co. , NY.
Wfndholz, 4*.;. Erf. '  BS^::TOe:Rercle:\rrKteKK. Tffth;ed.
Inc., Rahway, *NJ'.

Worthing:,  C.R. ,and;S.B;v  Walker-,  Ed.  19831: -.  TCfe -Pes-tfo1.de Manual.
BrHUsh Crop Protection Council,.- ; 6,95 p.,.*/--'.,'
                                  A-2-..

-------
    In addition,  approximately 30  compendia  of aquatic  toxlclty data  were

reviewed,  Including the following:


    Battelle's  Columbus  Laboratories.   1971.   Water  Quality  Criteria
    Data   Book.    Volume  3.   Effects   of   Chemicals   on   Aquatic   Life.
    Selected  Data  from the Literature  through  1968.   Prepared for  the
    U.S.  EPA under Contract No. 68-01-0007.  Washington,  DC.

    Johnson,  W.W.  and  M.T. Flnley.   1980.   Handbook  of  Acute  Toxldty
    of Chemicals  to   Fish  and  Aquatic  Invertebrates.   Summaries   of
    Toxldty  Tests  Conducted  at  Columbia  National  Fisheries  Research
    Laboratory.    1965-1978.    U.S.  Oept.   Interior,  F1sh  and  Wildlife
    Serv.  Res. Publ.  137,  Washington,  DC.

    McKee, J.E.  and H.W.  Wolf.  1963.  Water  Quality Criteria, 2nd  ed.
    Prepared  for  the   Resources   Agency   of   California,  State   Water
    Quality Control Board.   Publ.  No.  3-A.

    Plmental,  D.   1971.  Ecological Effects of  Pesticides on  Non-Target
    Species.  Prepared  for the U.S.  EPA, Washington,  DC.   PB-269605.

    Schneider, B.A.  1979.  Toxicology  Handbook.  Mammalian and Aquatic
    Data.   Book  1: Toxicology  Data.   Office of  Pesticide  Programs, U.S.
    EPA,  Washington,  DC.   EPA 540/9-79-003.  NTIS  PB  80-196876.
                                     A-3

-------
                                  APPENDIX Bl

                    Cancer Data Sheet for Derivation of q-|*
Compound:  b1s(chloromethyl) ether

Reference:  Leong et al., 1981

Spec1es/strain/sex:  rat/Sprague-Daw!ey/male

Body weight = 0.35 kg  (assumed)

                               Control      Low  Dose

Length of exposure (le)          NA             6
  (months)

Length of experiment (Le) =      28           28
  (months)

Llfespan of animal (L) =         28           28
  (months)

Tumor site and type:   nose, esthes1oneuroep1thel1oma

Route:  Inhalation
                              Mid  Dose

                                   6


                                 28


                                 28
                High Dose

                    6


                   19


                   19
Experimental Doses
   or Exposure3
      (ppb)
Transformed Doseb
   (mg/kg/day)
             Incidence
No. Responding/No. Tested
0
1
10
100
Unadjusted qj*"
Human q-j* = 59
0
0.0001
0.0011
0.0169
». T. 0*801 58 (nrg/kg/day)"1 '.
.5339 ( mg/kg/day )~l
0/112
0/113
0/111
96/ail


Exposures were 6 hours/day, ;5 days/week  for  6  months.

Exposures:  expressed,  as , mg/m3:  were; multiplied; by, 6  hours/24  hours.,  by  5y
 days/'?;, days; c byj; reference; i?a-t^  1;nhatfa£1ioa  rate:;  of:  Qi.223*  ra*/  awE
 divided by  reference  rat body'weight  of "0.35" kg.  Result' was  multiplied by
 le/Le to expand exposures for duration of  experiment.
                                      B-l

-------
                                  APPENDIX 82
                    Cancer Data Sheet for Derivation of q-|*
Compound:  b1s(2-chloroethyl) ether
Reference:  BRL, 1968;  Innes et al.,  1969
Specles/strain/sex:  mouse/B6C3Fl/male
Body weight = 0.03 kg  (assumed)
Length of exposure (le) = 79 weeks
Length of experiment (Le) =  79 weeks
Llfespan of animal (L)  = 104 weeks
Tumor site and type:   liver, hepatomas
Route/vehicle:  oral/gavage  and diet"!"
Experimental Doses
   or Exposure
   (mg/kg/day)
Transformed Dose
  (mg/kg/day)
Unadjusted q-|* = 8.14xlO~2  (mg/kg/day)'1
Human q-j* = 2.46 (mg/kg/day)~*  ;        ^
        Incidence
No. Responding/No. Tested
0
41.3 (TWA dosejt >
0
41.3
8/79
14/16
"Treatment  consisted  of  dally   Intubation   w1th>*TOO   mg/k£  In  distilled
 water on  days 7-28 of  life:,, followed :t*y  dietary adm1n1str;atton\of; 300 ppm
 uret1.li!80. weeks, of  age.   Mou-se footi caKsurtpWan wa,s  assumed.to be;, equlival enf:
 to: V3#. of body, weight/day- fror ca-Jculatton: tff the HWA*

-------
                                  APPENDIX  B3
                    Cancer  Data  Sheet  for Derivation  of  q-j*
Compound:  b1s(2-chloro-l-methylethyl) ether (technical grade)
Reference:  NTP, 1982
Spec1es/strain/sex:  mouse/B6C3Fl/male
Body weight = 0.04 kg (estimated from graphic data provided by 1ngest1gator)
Length of exposure (le) = 103 weeks
Length of experiment (Le) = 104-110 (107) weeks
Llfespan of animal (L) = 107 weeks
Tumor site and type:  liver, hepatocellular adenomas or carcinomas
Route/vehicle:  gavage/corn oil
Experimental Doses or Exposure    Transformed Dose      •    Incidence
            (mg/kg)                 (mg/kg/day)     No. Responding/No. Tested

100
200

x 5/7
x,5/7

days
days
0
X
X

103/107
103/107

weekst
weeks*
0
68
137

.8
.5
13/50
23/50
27/50 "
Unadjusted
                 5.78x10'?- ( mg/kg/day J,T
^Length of experiment assumed to be 107 weeks (midpoint of reported rangej...
                                       B-S

-------
                                                                          APPENDIX Cl



                                                           Summary Table for bls(Chloromethyl) Ether
r>
Species
Inhalation Exposure
Subchronlc NA
Chronic NA
Carclnogenlctty rat
Oral Exposure
Subchronlc " NA
Chronic. NA
Carclnogenlctty rat
RE PORTABL E QUANT 1 T 1 E S
Based on chronic tqxlclty:
Based on Carclnogenlctty:
Exposure Effect RfD or qj'
•'•
NA NA NA
NA NA NA
1, 10 or 100 ppb, 6 hours/day, nasal estheslo- 59. S (mg/kg/day)"1
6 days/week for life neuroeplthelloma

NA NA NA
NA NA NA
1. 10 or 100 ppb, 6 hours/day, nasal estheslo- S9.5 (mg/kg/day)"1
5 days/week for life neuroeplthelloma

ID
1
Reference

NA
NA
Leong et al.,
1981

NA
NA
Leong et al.,
1981

ID
Leong et al. ,
1981
        (0 > Insufficient data; NA c not applicable

-------
                                                APPENDIX C2



                                Summary Table for b1s(2-Chloroethyl) Ether
«!*
inhalation Exposure
Subchronlc '% N/\
Chronic NA
Carclnogenlclty mouse
Oral Exposure
n .-,•••• . " ' 1 "*•••'''
\
™ Subchronlc NA
':* '— 'V
Chronic . NA
Carclnogenlclty mouse
REPORTABLE QUANTITIES
Based on chronic toxlclty:
Based on Carclnogenlclty:
Exposure

NA
NA
41.3 mg/kg/day (TWA)
for 79 weeks

NA
NA
41.3 mg/kg/day (TWA)
for 79 weeks
>,
100
10
Effect RfD or qi* Reference

NA NA NA
NA NA NA
hepatomas 1.23 (mg/kg/day)'1 BRL, 1968; Innes
et al.. 1969

NA NA NA
NA NA NA
hepatomas 2.46 (mg/kg/day)'1 BRL, 1968;
Innes et al. ,
1969

Welsburger
et al., 1961
BRL, 1968; Innes
et al.. 1969
|D = Insufficient  data;  NA =  not  applicable

-------
                                                APPENDIX C3



                   Summary Table for b1s(2-Chloro-l-methylethyl) Ether (Technical Grade)
Species
Inhalation Exposure
Subchronlc NA
Chronic HA
Carclnogenlclty mouse
Oral Exposure
°* Subchronlc NA
.Chronic NA
Cardnogenlclty mouse
- - - ;-j -- . T — r~~ . "•-" =
REPORTABLE QUANTITIES
Based on chronic toxIcHy:
Based on carclnogenlclty:
Exposure Effect

NA NA
NA NA
100 or 200 mg/kg, hepatocellular adenomas
5 days/week for or carcinomas
104-110 weeks

NA NA
NA NA
100 or 200 mg/kg, hepatocellular adenomas
5 days/week for or carcinomas
104-110 weeks

1000
100
RfD or q^* Reference

NA NA
NA NA
3.49xlO~2 NTP, 1982
(mg/kg/day)"1

NA NA
NA NA
6.97xlO~2 NTP, 1982
(mg/kg/day) *

NCI, 1979
NTP, 1982
ID = Insufficient data;  NA =  not  applicable

-------
                                                APPENDIX C4



                        Summary Table for 2,4,4'-Tr1chloro-2'-hydroxyd1phenyl Ether
" '' ' V, : - ' *•» f "*"
..- Species
Inhalation Exposure .
Subchronlc ID
Chronic ID
Carcinogenic! J. y jg
Oral Exposure
Subchronlc rat
Chronic , IQi
Carclnogenlclty ID
REPORTABLi QUANTITIES
Based on chronic toxlclty:
Based on carclnogenlclty:
Exposure

ID
ID
ID
500 mg/kg,
6 days/week
for 4 weeks
ID
ID

1000
ID
Effect RfD or q^* Reference

ID ID ID
ID ID ID
ID ID ID
reduced weight 300 mg/day Lyman
gain and mortality Furla
at a higher dose
ID ID ID
ID ID ID

Lyman
Furla
ID




and
, 1969



and
, 1969

10 = Insufficient  data

-------
                                                APPENDIX C5
                                Summary Table for Chloromethyl Methyl Ether
i^> t - ,- - • • - . _-*> % .-- -
Species
Inhalation Exposure
Subchronlc ID
Chronic ID
Carclnogenjclty ID
Oral Exposure
i Subchronjc ID
Chronic " ID
Carclnogenlclty ID
REPORTABlt QUANTITIES
Based on chronic toxIcUy:
"^ *•".•* . it **-,'•' *. ' , *"
Based on carc1nogen,1c1ty:
Exposure Effect RfD or q-|* Reference

ID ID ID ID
ID ID ID ID
ID ID ID ID

ID ID ID ID
ID ID ID ID
ID ID ID ID

100 Laskln
et al.. 1975
1 ID*
'This  chemical  was  assign^  to  Potency Group 2.
ID = Insufficient data

-------