297 921
Ambient Water Quality Criteria
             Criteria  and  Standards Division
             Office  of Water  Planning and Standards
             U.S.  Environmental  Protection Agency
             Washington, D.C.

                         CRITERION DOCUMENT

                         CHLOROALKYL ETHERS


                            Aquatic Life

      For freshwater aquatic life, no criterion for any chloroalkyl

 ether can be derived using the Guidelines, and there are insuffi-

 cient data to estimate a criterion using other procedures.

      For saltwater aquatic life, no criterion for any chloroalkyl

 ether can be derived using the Guidelines, and there are insuffi-

 cient data to estimate a criterion using other procedures.

                            Human Health

      For the protection of human health from the toxic properties

 of bis(2-chloroisopropyl) ether ingested through water and  through

 contaminated aquatic organisms, the ambient water criterion  is de-

 termined to be 175.8 ug/1.  For the maximum protection of human

 health from the potential carcinogenic effects of exposure  to bis-

 (2-chloroisopropyl) ether through ingestion of water and contami-

 nated aquatic organisms, the ambient water concentration is  zero.

 Concentrations of bis(2-chloroisopropyl) ether estimated to  result

 in additional lifetime cancer risks ranging from no additional

 risk to an additional risk of 1 in 100,000 are presented in  the

 Criterion Formulation section of this document.  The Agency  is

 considering setting criteria at an interim target risk level in

 the range of 10~5, 10~6, or 10~7 with corresponding criteria of

.11.5 ug/1, 1.15 ug/1, and 0.115 ug/1, respectively.  Further dis-

 cussion of levels derived via carcinogenic properties versus toxic

 properties is presented in the Criterion Formulation section.

     For the maximum protection of human health  from  the poten-
tial carcinogenic effects of exposure to bis(2-chloroethyl) ether
through ingestion of water and contaminated aquatic organisms, the
ambient water concentration is zero.  Concentrations  of bis(2-
chloroethyl) ether estimated to result  in additional  lifetime can-
cer risks ranging from no additional risk to  an  additional risk of
1 in 100,000 are presented in the Criterion Formulation section of
this document.  The Agency is considering setting  criteria at an
interim target risk level in the range  of 10""5f  io~6, or 10""^ with
corresponding criteria of 0.42 ug/1, 0.042 ug/1, and  0.0042 ug/lf
     For the maximum protection of human health  from  the potential
carcinogenic effects of exposure to bis(chloromethyl) ether
through ingestion of water and contaminated aquatic organisms, the
ambient water concentration is zero.  Concentrations  of bis-
(chloromethyl) ether estimated to result in additional  lifetime
cancer risks ranging from no additional risk  to  an additional risk
of 1 in 100,000 are presented in the Criterion Formulation section
of this document.  The Agency is considering  setting  criteria at
an interim  target risk level in the range of  10"^, 10~6, or 10~7
with corresponding criteria of 0.02 ng/1, 0.002  ng/1, and 0.0002
ng/1, respectively.

     The chloroalkyl ethers have been widely used in labor-
atories and in industrial organic synthesis, textile treatment,
preparation of ion exchange resins,  and pesticide manufacture.
They also have been used as. solvents for polymerization reactions
(Summers, 1955).   Both bis-(chloromethyl)ether (BCME) and
chloromethylmethyl ether (CMME)  are listed as human carcino-
gens.  Limited data are available on the effects of any
of the chloroalkyl ethers on aquatic life.  For this reason
no water quality criterion can be established.  However,
because of the demonstrated carcinogenicity of BCME and
CMME, human contact with these compounds should be avoided.
     The chloroalkyl ethers are compounds with the general
structure RClx-O-R1 Clx, where x may be any positive integer,
including zero, and R and R1  are aliphatic groups.  The
chemical reactivity of these compounds varies widely, depending
on the placement of chlorine atoms and the nature of the
aliphatic groups involved.  Chloromethylmethyl ether, bis-
(chloromethyl) ether, 1-chloroethylethyl ether, and 1-chloro-
ethylmethyl ether decompose in water (Hampel and Hawley,
1973).  Tou and Kallo (1974)  calculated a half-life of 14
seconds for bis(chloromethyl)  ether in aqueous solution.
chloromethylmethyl ether undergoes decomposition in water
to form methanol, formaldehyde,  and hydrochloric acid.
Bis-(chloromethyl)  ether will form spontaneously in the
presence of hydrogen chloride and formaldehyde (Frankel,
et al. 1974).

       , !,,§,, et al, 1974,  Formation  of  bis-(chloromethyl)
ethej: from formaldehyde -and hydrogen chloride.   Environ.
            , 8;
        ,C,A.f and G.G, flawley.  1973.   Encyclopedia  of  chemistry.
Van :Nostrand ^einhold Co.,  New  York.

Summers, I*. 1955,  The haloalkyl  ethers,   Chem.  Rev.  55:  301.
     J.^C.-, and GrJ. Kalios.  1974.   Study  of  aqueous HC1
and formaldehyde mixtures  for  formation of bis-(chloromethyl)
ether.  Jour, Am. Ind, Hyg.  Assoc.  35; 419.

                       FRESHWATER ORGANISMS
     The data base for freshwater organisms and chloroalkyl ethers
is limited to a few toxicity tests with 2-chloroethyl vinyl ether
and bis (2-chloroethyl) ether.  No unadjusted LC50 or EC50 values
were observed below 237,000 ug/l«  Bioconcentration of bis
(2-chloroethyl) ether by the bluegill was low.               '
Acute Toxicity
     The adjusted 96-hour LC50 for the bluegill and 2-chloroethyl
vinyl ether (U.S. EPAf 1978) is 194,000 u.g/1 and, after  this
concentration is divided by the species sensitivity factor  (3.9),
a Final Fish Acute Value of 50,000 ug/1 is derived for that
compound (Table 1).  Since no data on an invertebrate species  are
available for 2-chloroethyl vinyl ether, the Final Acute Value is
also 50,000 ug/1.
*The reader is referred to the Guidelines  for Deriving Water
Quality Criteria for the Protection of Aquatic  Life  [43  FR 21506
(May 18, 1978) and 43 FR 29028 (July 5, 1978)]  in  order  to better
understand the following discussion and recommendation.   The
following tables contain the appropriate data that were  found  in
the literature, and at the bottom of each  table  are  the  calcula-
tions for deriving various measures of toxicity as described  in
the Guidelines.

     NO 96-hour LC50 value for the bluegill could be determined
for bis (2-chloroethyl) ether in a test with exposure concen-
trations as high as 600,000 ug/1 (Table 5).  However, an
unadjusted 48-hour EC50 value for Daphnia magna was determined to
be 237,000 ug/1 for bis (2-chloroethyl) ether  (Table 2).  This
result provides a Final Invertebrate and Final Acute Value of
9,600 ug/1 for that compound.
Chronic Toxicity
     An embryo-larval  test has been conducted with bis  (2-chloro-
ethyl) ether and the fathead minnow (U.S. EPA, 1978).   No adverse
effects were observed  at test concentrations as high as 19,000
ug/1 (Table 3).  A Final Fish Chronic Value of greater  than 1,400
ug/1 is 'derived that also becomes the Final Chronic Value for bis
(2-chloroethyl) ether, since no chronic data are available for any
invertebrate species,  there are no plant data, and no Residue
Limited Toxicant Concentration is available.
Plant Effects
     No data are available on the effects of any chloroalkyl ether
on aquatic plants.
     Using 14C-bis (2-chloroethyl) ether and thin layer
chromatography (U.S.   EPA, 1978) a bioconcentration factor of 11
was determined during  a 14-day exposure of bluegills (Table 4).
The half-life was observed to be between 4 and 7 days.
     The only datum in Table 5 was discussed earlier in this

                     Freshwater-Aquatic Life
Summary of Available Data
     The concentrations below have been rounded to two significant
2-chloroethyl vinyl ether
     Final Fish Acute Value = 50,000 ug/1
     Final Invertebrate Acute Value = not available
          Final Acute Value = 50,000 ug/1
     Final Fish Chronic Value = not available
     Final Invertebrate Chronic Value = not available
     Final Plant Value = not available
     Residue Limited Toxicant Concentration = not available
          Final Chronic Value = not available
          0.44 x Final Acute Value = 22,000 ug/1
bis (2-chloroethyl) ether
     Final Fish Acute Value = not available
     Final Invertebrate Acute Value = 9,600 ug/1
          Final Acute Value = 9,600 ug/1
     Final Fish Chronic Value = greater than 1,400 ug/1
     Final Invertebrate Chronic Value = not available
     Final Plant Value = not available
     Residue Limited Toxicant Concentration = not available
          Final Chronic Value = greater than 1,400 ug/1
          0.44 x Final Acute Value = 4,200 ug/1

     lid freshwater criterion can be derived  for any  chlotoalkyl
ether using the Guidelines because no Final  Chronic  Value  for
either fish or invertebrate species or a good substitute for
either value  is available, and  there are insufficient data to
estimate a criterion using other procedures.

                             Table  1.   Freshwater  fish  acute  values  for  chloroalkyl  ethers  (U.S.  EPA,  1978)

Lepomis macrochirus

BiQoseay Test Chemical Time
Metnod* Cone.** Description thrs)
S U 2-chloroethyl 96
vinyl ether
                           Table  2.   Freshwater invertebrate acute values  for  chloroalkyl  ethers (U.S.  EPA.  1978)

                                Bioassay  Test ^    Chenucai       Time       LCbu       LOo
        Organism ...       .      ..Method*  • Cone L**   Description     (lirs)   ^_  (uii/11     J
        Cladoceran.        -.       S        U      Bis(2-Chloro-    48       237.000     201.000
        Daphnia magna                              ethyl) ether

        *  S - static

        ** U = unmeasured

           Geometric mean of  adjusted values:  bis(2-ohloroethyl)  ether  =  201.000  pg/1   20}>9°P =  9,600"

              Tafcle  3.  Freshwater fish chronic values for chloroalkyl ethers (U.S. EPA.  1978)

                                       Limits    Value
organism                     Test*      tug/1)    |mi/H

Fathead minnow,               E-L       >19,000   >9.500**
PiiTiephales promelas
*  E-L = embryo-larva

   Geometric mean of chronic values = >9.500 pg/1     >  i  •  -  >1.400  ng/1

   Lowest chronic value a >9.500 Mg/1

** Data for bis (2-chloroethyl) ether


                       Tatle   4.    Freshwater residues for chloroalkyl ethers  (U.S.  EPA,  1978)

         Organism                           Sioconcentration .ffact.oi      'i-flaysj

                                            Bis(2-chloroethyl) £ther

         Blueglll.                                    11                    14
         Lepomis macrochirus       .        .

                             Table  5.   Other  freshwater data for chloroalkyl ethers

                                 Test                                Result
         Organise          *      puratjoq  gf{ect                   fug/l>

         Bluegill.               96 hrs     LC50                     >600,000*
         I.epornis mac roc hi r us
         * Data for bis  (2-chloroethyl)  ether

                       SALTWATER ORGANISMS


     No appropriate data are available for saltwater organisms and

any chloroalkyl ether.

                      Saltwater-Aquatic Life
     No saltwater criterion can be derived for any chloroalkyl
ether using the Guidelines because no Final Chronic Value  for
either fish or invertebrate species or a good substitute for
either value is available, and there are insufficient data to
estimate a criterion using other procedures.

                      CHLOROALKYL ETHERS


U.S. EPA. 1978.  In-depth studies on health and environmen-

tal impacts of selected water pollutants.  U.S. Environ.

Prot. Agency, Contract No. 68-01-4646.

Mammalian Toxicology and Human Health Effects
The chloroalkyl ethers, a sub-class of haloethers, are widely
used in industries and laboratories.  Some of the members
of this sub-class are potent carcinogens and some have been
found in the aquatic environment. The chloroalkyl ethers
discussed in this document are listed in Table la.  Of these
compounds, BCME (bis(chloromethyl)ether), CMME (chloromethyl
methyl ether), BCEE (bis(2-chloroethyl)ether) and BCIE (bis(2-
chloroisopropyl)-ether) have received the greatest attention
because of their potential health hazards.  Comprehensive
reviews on the physical and chemical properties and biological
effects of these chemicals have been published (Summers,
1955; Van Duuren, 1969; Int. Agency Res. Cancer, 1974, 1975;
Durkin, et al.  1975; Nelson, 1976; NAS, 1977).  The physical
constants of the four environmentally most important chloroal-
kyl ethers are summarized in Table Ib.
     Because of their high reactivity, BCME and CMME have
found wide laboratory and industrial use as. intermediates
in organic synthesis, in the treatment of textiles, for
the manufacture of polymers and insecticides, in the prepara-
tion of ion exchange resins, and in industrial polymerization
reactions.  Following recognition of the high potency of
these chemicals as carcinogens by inhalation in animals,
and various epidemiological evidence linking excessive human
respiratory cancer incidence to exposure, BCME -and CMME
have been listed as two of the 14 carcinogens restricted

by Federal regulations, effective February 11, 1974  (39

FR 3756;^ Anonymous, 1974). Realization of the potential

hazard of BCME grew dramatically when it was reported  that

at high concentrations, vapors of HC1 and formaldehyde,

two commonly used chemicals in many industries and laborator-

ies, can combine spontaneously to form BCME.

     The concern over BCEE and BCIE arose mainly because

of their presence in river water and the dr.inking water

of several U.S. cities.  These chemicals were found  at high

concentrations in waste water from chemical plants involved

in the manufacturing of glycol products, rubber, and insecti-

cides.  As an end product, BCEE is an excellent solvent

for fats, waxes and greases.  It can be used as a scouring

agent for textiles and has also been employed as an  insecti-

cide, ascaricide, and soil fumigant.  The Environmental

Protection Agency has included these two compounds in  its

National Organics Monitoring Survey of U.S. drinking water

(U.S.  EPA, 1977).

                                TABLE  la

              Chloroalkyl Ethers Covered in this Document

Names, Abbreviations and Synonyms

Chloromethyl methyl ether (CMME)
   other names: dimethylchloroether; methyl
   chloromethyl ether
Bis (chloromethyl)ether (BCME)
   other names: chloromethyl ether;
   Chloro(chloromethoxy) methane; dichloromethyl ether;
                   methyl ether
   other name: 1,1-dichloromethyl methyl ether
Bis (pS-chloroethyl) ether
   other name: bis (1-chloroethyl)ether
Bis (2-chloroethyl)ether (BCEE)
   other names: 1,1'-oxybis(2-chloro)ethane;
   bis0-chloroethyl) ether;
   l-chloro-2-(4-chloroethoxy)ethane; etc.
Bis (2-chloroisopropyl)ether  (BCIE)
   other name: bis(2-chloro-l-methylethyl)ether
                                                            Cl Cl

        I    \
                                                           CH3 CH3
2-Chloroethyl vinyl ether

                             Table  la cont,

Bis-l,6-(chloromethoxy)hexane     C1CH2-O-CH2CH2CH2CH2CH2CH2-O-CH2C1
Tr is-1,2,3-(chloromethoxy)propane

                 CH -O-CH2C1

Bis-(2-chloroethoxy)methane (BCEXM)        C1CH2CH2-O-CH2-O-CH2CH2C1
Bis-l,2-(2-chloroethoxy)ethane (BCEXE)  C1CH2CH2-O-CH2-CH2-0-CH2CH2C1

                                                        TABLE  Ib

                     Physical Constants of Four Environmentally Most  Significant  Chloroalkyl  Ethers
                       Appearance at
   Compound   Mol.  Wt.   roo.Ti temperature    m.p.  b.p. (760 mm Hg)     Density
 80.5     colorless liquid
colorless liquid
143.01    colorless liquid
   BCIE       171.07     colorless liquid
                              59°C      d2^= 1.0605
=1.328    1.435
                    -24.5°Ca  176-178°C  d*° =1.213    1.457

                                        187-188UC                1.4474
Immediately hydrolyze in
water; miscible with
ethanol, ether and many
other organic solvents.

Immediately hydrolyze in
water; miscible with ethanol,
ether and many other organic

Practically insoluble in water;
miscible with most organic
solvents (especially, benzene
and chloroform)

Practically insoluble in water;
miscible with most
organic solvents.
   aIARC  (1975)

   bSchrenk,  et  al.  (193'J)
   ~n  for  refractive  index

Ingestiori from Water
     Chloroalkyl ethers do not occur as such in nature;
their occurrence is entirely anthropogenic.  Discharges
from industrial and manufacturing processes represent the
       ' i
major source of these organic pollutants in the aquatic
environment.  Chlorination of drinking water could also
be a potential source.
     The stability of chloroalkyl ethers in aqueous systems
plays a crucial role in determining their persistence in
the water.  In general, ^(-chloroalkyl ethers have an extreme-
ly short, lifetime in aqueous solutions and are therefore
not expected to persist for any extended period of time
in water.   On the other hand, non-c(-chloroalkyl ethers are

quite stable and may persist in the aqueous environment.
The rate of hydrolysis of a number of ^-chloroalkyl-ethers
in an aqueous system has been measured by Van Duuren, et

al. (1972). in a solution of water-dimethylformamide  (3:1)
kept at 0°C, the four 
is even more reactive than BCME.   Its half-life in aqueous
solution cannot be directly measured with accuracy.  Jones
and Thornton (1967) have measured the hydrolysis rate of
CMME in aqueous isopropanol. Extrapolation of the data to
pure water yielded a t,  of less than one second (Tou and
Kallos, 1974b). In aqueous methanol at 45°C, the hydroly-
sis rate of CMME was about 5,000 times faster than that
of BCME (Nichols and Merritt, 1973).
     In contrast to cA-chloroalkyl ethers, the <^-chloro
compounds are much more stable. Van Duuren, et al. (1972)
found that the half-life of BCEE was more than 23 hours
in water-dimethylformamide  (3:1)  at 30°C.  Bohme and Sell
(1948) estimated the half-life of BCEE to be 12.8 days in
a mixture of water-dioxane solution at 100°C.  Kleopfer
and Fairless (1972) observed that BCIE appeared to be quite
persistent in contaminated river water; there was no sign
of biodegradation.
     The occurrence of chloroalkyl ethers in river water
and finished drinking water has been reported by various
investigators.   Among the chloroalkyl ethers covered in
this document,  BCEE and BCIE have been consistently detected
in some areas of the country and quantitatively determined
in some cases.   Shackelford and Keith  (1976) have recently
compiled information on the frequency of organic compounds
identified in water from published literature and unpublished
survey analyses from EPA laboratories.  Occurrence of BCEE
and BCIE in various types of water has been reported 10
and 19 times, respectively.  Other chloroalkyl ethers oc-

casionally  reported  included  BCEXM,  BCEXE,  vinyl 2-chloroethyl

ether,  2-chloroethyl methyl ether,  BCME,  and chloromethyl

ethyl et'her.   In  view of the  extremely short lifetime of

c^-chloroalkyl  ethers in aqueous  systems,  reports of their

presence  in water  are probably erroneous.   Schulting and

Wils  (1977) have  noted that even the sophisticated GC-MS

selected  ion monitoring (SIM)  method may  yield false results.

Using 1SIM on a SE-30 column,  the authors  demonstrated that

l-chloro-2-propanol  could be  mistaken for  BCME.   Reports

of occurrence  of \B-chloroalkyl ethers in  water appear to

be more reliable  and in some  cases  quantified; the major

findings  of these  reports are summarized  in Table 2.

     Rosen, et al.  (1963)  were the  first  to detect the pre-

sence of  BCEE  and  BCIE in contaminated river water.  Investi-
gation  of the  cause  of odor of the  Kanawha River at Nitro,

West  Virginia, led  to the qualitative identification of

BCEE and  BCIE  as  two of the pollutants.   The threshold odor

concentration  for  BCEE and BCIE  was  estimated to be 360

jug/1 and  200 jaq/1, respectively.

     The  presence  of BCIE in  river  water  and finished drink-

ing water at Evansville, Indiana, was noted by Kleopfer

and Fairless  (1972).  An industrial  outfall located about

150 river miles upstream from the Evansville water intake

was found to be the  probable  source  of the pollutant.  Samples

from this outfall  were analyzed  using flame ionization and

electron  capture  detection gas chromatography verified by

IR and  mass spectrometry on several  occasions during the

fall of 1971.   In  each case BCIE was found with  concentra-

                                       TABLE 2

      Occurrence of Principal Chloroalkyl  Ethers  in  Various Types of Water
       Location and
     Source of Water
Type of  Compound,   Cone.
water3 identified   (/ig/l)c
Rosen, et al.  (1963)
Kleopfer and
   Fairless (1972)
Webb, et al. (1973)

Webb, et al. (1973)

Keith, et al. (1976)
Nitro, W.Va.
Kanawha River

Evansville, Ind,
Ohio River
Effluent from
synthetic rubber plant


   n. q.
   n. q.
 BCIE   500-35,000
 BCIE 2.0(0.5-5.0)
 BCIE       0.8
Glycol plant's thickening    WW
and sedimentation pond

New Orleans, La.
Mississippi River:


   n. q.

U.S. EPA (1975)
U.S. EPA (1975)
Manwaring, et al.
Sheldon and Kites
Carrollton station
Jefferson station #1
Jefferson station #2
Philadelphia, Pa.
Delaware River
Philadelphia, Pa.
Delaware River
Philadelphia, Pa.
Delaware River
et al. (1977) and U.S.
EPA (1977
) — see Table
.d. -trace
    RW=river water; FDW=finished drinking water; WW=waste  water  or  effluent
from chemical plant.

   bBCEE=bis(2-chloroethyl)ether; BCIE=bis(2-chloroisopropyl)ether;  BCEXM=
bis(2-chloroethoxy)methane;  BCEXE=bis(2-chloroethoxy)ethane.

   cn.q.=not quantified; n.d.=not detectable.

tions ranging  from 0.5  to  35 mg/1;  the  estimated discharge

was 68 kg/day. Concentrations  of  BCIE found  in  the Ohio

River at Evansville  ranged from 0.5  to  5.0 jag/1.  The conven-

tional drinking water treatment was  capable  of  removing

only 60 percent of BCIE from the  raw river water.  BCIE

concentration  of 0.8 jug/1  was  found  in  the finished  drinking

water .

     The detection of BCEE and BCEXM in the  treated  effluent

from, synthetic rubber plants was  reported by Webb, et al.

(1973); the concentration  was  in  the order of 0.16 mg/1

and 140 mg/1,  respectively.  BCIE was also readily detected

in a thickening and  sedimentation pond  of glycol plants.

     The lower region of the Mississippi River  is well known

for being heavily contaminated with  organic  pollutants from

industrial discharges.   The drinking water of the New Orleans

area has been  closely monitored by  EPA  since 1969. Detection

of various pollutants has  been frequently reported.  Keith,

et al.  (1976)  have recently compiled detailed quantitative

data from these studies.   At the  Carrollton  station  and

two sites in Jefferson  parish, the  finished  drinking water

was found to contain BCEE  at levels  of  0.04, 0.16, and 0.12

jag/1, respectively.  The corresponding  values for BCIE were

0.18, 0.08, and 0.03 jug/1.

     In a .report to  Congress,  U.S.  EPA  (1975) summarized

the findings of organics in U.S.  drinking water.  A  number

of chloroalkyl ethers were detected, the highest concentra-

tions reported for BCEE, BCIE, .and  BCEXE were 0.42 jug/1,

1.58 jug/1, and 0.03 ;ug/l,  respectively.  In  a ten-city study,

the drinking water of Philadelphia  was  found to contain


0.5 pg/1 BCEE and 0.03 /ag/1 BCEXE.  The drinking water of
the other nine cities did not contain these chloroalkyl
ethers (U.S. EPA, 1975).
     The discovery of BCEE in Philadelphia's drinking water
initiated a flurry of activity to determine the source and
find means of elimination (Manwaring, et al. 1977).  A chem-
ical manufacturing plant located near the city's water intake
admitted that it had discharged approximately 61.4 kg/day
of the compound into the river (Anonymous, 1975).  The efflu-
ent from the chemical plant contained up to 41 pg/1 BCEE.
Samples of the river adjacent to the discharges showed the
presence of up to 10 pg/1 of the chemical.  Between February
and July of 1975, the city's finished drinking water contained
BCEE ranging from 0.04 to 0.6 jug/1.  The chemical company
has since developed a BCEE destruction system for the treat-
ment of its effluent and this system resulted in a greater
than 99 percent reduction in the discharge of BCEE into
the river (Manwaring, et al. 1977).  In a more recent survey
by Sheldon and Kites  (1978), BCEE was barely detectable
( 0.01 pg/1) in the river water.  However, a high concentra-
tion of another chloroalkyl ether  (BCEXE  (15 pg/1)) was
detected in two out of the five samples examined.
     A National Organics Monitoring Survey of the U.S. drink-
ing water has recently been undertaken by U.S. EPA (1977).
Three phases of the study were carried out in March-April
1976, May-July 1976, and November 1976-January 1977.  The
drinking water of up to 113 cities have been analyzed for
organic pollutants including chloroalkyl ethers.  In phase
I, BCEE was not found in 112 cities at the minimum quanti-

fiable limit of 5 >ig/l.  In phases II and III, the limit

was lowered to 0.01 pg/1. In phase II, the drinking water

of 13 of the 113 cities was found to contain BCEE with a

mean concentration of 0.10 >ig/l.  BCIE was also found in

8 of the 113 cities.  The quantitative data of the phase

II study have been published by Dressman, et al. (1977)

and are summarized in Table 3.  In phase 111,8/110 (7.27

percent) cities had BCEE with a mean of 0.024 jug/1.  For

BCIE, 7/110 (6.36 percent) cities gave positive results

with a mean of 0.11 fig/1  (U.S.  EPA, 1977).

     BCME can be chemically produced by saturating a solution

of paraformaldehyde in cold sulfuric acid with HC1.  Van

Duuren, et al.  (1969) studied the reaction of BCME with

deuterium oxide in dioxane.  Rapid disappearance of BCME
was observed with 70 percent of the compound hydrolyzed

within two minutes.  However, after 18 hours, about 20 percent

of BCME s:till appeared to be present.  This suggested a

possible equilibrium between BCME and its hydrolysis products,

HC1 and formaldehyde, and further raised the question of

whether BCME could be formed spontaneously from HC1 and

formaldehyde.  This question received great attention, when

the Rohm and Haas Company disclosed that BCME could be detected

in humid .air or aqueous or nonaqueous liquid-phase systems

containing high concentrations of HC1 and formaldehyde  (Anony-

mous, 1972).  However, more recent studies by Tou and Kallos

(1974a, 1976) have indicated that, at least for aqueous

systems, there was no evidence of BCME formation from HC1

and formaldehyde at a detection limit of an order of magni-

tude of parts per trillion.


                           TABLE 3

    The Levels of BCEE and BCIE Detected  in  the Finished
        Water of 113 Cities in the Phase  II  Studv of
            National Organics  Monitoring Survey.
. . 	
Mean cone.                    0.10              '0.17
of positives
   Percent     .
among cities                  11.5%               7.1%

aSummarized from Dressman, et al. (1977)

Invest ion  from Foods

     There is  ao information on the possible human exposure.

to, chlo-roalfespL e.the>rs via ingestion of food.  The levels

of: chloroallcYl ethers in food have not b.een monitored noc

has there  been any attempt, to study the- biQaecumulation

of eb.loxoalk'yl, ethers.  However, £n view, of. their- relative

stability  and low water: solubility,-fi--ehloroalkyl ethers.

may hav/e a high tendency to be bi ©accumulated..

     Nieely;,  et al. (1974)  have noted a' linear correlation

between  the  octanol-water coefficients (Poctancy].), an<^ bio.con-

centration factors of chemicals in trout muscle.  The relation-
ship can be  expressed by the equation:;

     log,  (bio-concentration factor) - 0.542 log  ^octanol^

     +  0.124..

The poctanol f°r cnl-oroal' = 1'142 lo*:  -t'Q7Q

From these data, it can be calculated that the bloconcentra-

tion factor  of BCEE in trout muscle should be around 11.7.

     The poctano]_0f chioroalkyl ethers may also be calculated

based on their solubility in water according to the method

outlined by  Chiou and Freed (1977).  Using the above method,

the  information on water solubility of chloroalkyl ethers

 (Durkin, et  al. 1975), and the linear regression model of


Neely, et al. (1974), the extrapolated bioconcentration

factors for BCEE, BCIE and 2-chloroethyl vinyl ether are

12.6, 56.2, and 34.2, respectively.

     Another approach to calculating bioconcentration factors

has been recommended by the EPA's ecological laboratory

in Duluth.  This approach states that a bioconcentration

factor  (BCF) relates the concentration of a chemical in

water to the concentration in aquatic, organisms, but that

BCF's are not available for the edible portion of all four

major groups of aquatic organisms consumed in the United

States.  Since data  indicate that the BCF for lipid-soluble

compounds is proportional to percent lipids, BCF's can be

adjusted to edible portions using data on percent lipids

and the amounts of various species consumed by Americans.

A recent survey on fish and shellfish consumption in the

United States (Cordle, et al. 1978) found that the per capita

consumption is 18.7  g/day.  From the data on the 19 major

species identified in the survey and data on the fat content

of the edible portion of these species  (Sidwell, et al. 1974),

the relative consumption of the four major groups and the

weighted average percent lipids for each group can be calculated:

                         Consumption       Weighted Average
     Group                (Percent)         Percent Lipids

Freshwater fishes             12                   4.8

Saltwater fishes              61                   2.3

Saltwater molluscs             9                   1.2

Saltwater decapods            18                   1.2

Using the percentages for consumption and lipids for each

of these groups, the weighted average percent lipids is

2.3 for consumed fish and shellfish.


2.3 for consumed fish and shellfish.
     A measured steady-state bioconcentration factor of
11 was obtained for bis  (2-chloroethyl) ether using bluegills
containing about one percent lipids  (U.S. EPA, 1978).  An
adjustment factor of 2.3/1.0 = 2.3 can be used to adjust
the measured BCF from the 1.0 percent lipids of the bluegill
to the 2.3 percent lipids that is the weighted average for
consumed fish and shellfish.  Thus,  the weighted average
bioconcentration factor  for bis  (2-chloroethyl) ether and
the edible portion of all aquatic organisms consumed by
Americans is calculated  to be 11 x 2.3 = 25.
     No measured steady-state bioconcentration factor  (BCF)
is available for bis  (chloromethyl)  ether or bis  (2-chloro-
isopropyi) ether.  A weighted average BCF of 25 is available
for bis  (2-chloroethyl)  ether and the calculated octanol-
water partition coefficients for the three compounds are
11.5, 5.8, and 8.7, respectively.  The proportionality (Veith,
et al. Manuscript) BCF/BCF = antilog (0'.76 log  (P/P) ) can
be used  to calculate weighted average bioconcentration factors
of 31 and 106 for bis  (chloromethyl) ether and bis  (2-chloro-
isopfopyl) ether, respectively,  for  the edible portion of
all aquatic organisms consumed by Americans.
     The use of aquatic  organisms as a typical exposure
factor requires the quantification of pollutant residues
in the edible portion of the ingested species.  For this
reason,  the EPA recommended calculations, based upon the
percent  lipids of aquatic organisms, were used in the formula-
tion of  the criterion.

     There is no evidence of occurrence of chloroalkyl ethers
in the atmosphere.  Human exposure to compounds via inhalation
appears to be confined to occupational settings.   It is
important to note that,  in contrast to its instability in
aqueous solution, BCME is considerably more stable in humid
air.  Frankel, et al.  (1974) found that BCME introduced
into a Saran bag containing moist air was stable for at
least 18 hours.  Tou and Kallos (1974b) have studied the
stability of BCME and CMME in humid air.  At an ambient
temperature with a relative humidity of 81 percent, the
t^ of BCME in the gaseous phase could be as long as 25 hours.
The rate of hydrolysis was dependent on the surface of the
container.  In a ferric oxide-coated Saran reactor, the       •
t^ of BCME was in the order of seven to nine hours.  A similar
surface effect on the hydrolysis of CMME in the gaseous
phase was also observed.  The t,  of CMME in the gaseous
phase ranged from 2.3 minutes to 6.5 hours.
     The extreme potency of BCME and/or CMME as inhalation
carcinogens has prompted industrial hygienists and research-
ers to closely monitor the atmospheric level of these com-
pounds in the work place.  Various such methods have been
developed (e.g., Collier, 1972; Solomon and Kallos, 1975;
Sawicki, et al. 1976; Parkes, et al. 1976; Kallos, et al.
1977; Bruner, et al. 1978).  The finding of spontaneous
formation of BCME from HC1 and formaldehyde vapor has expanded
the potential site of BCME exposure to any place where high
atmospheric levels of these two reactants may co-exist.
Rohm and Haas Company first disclosed information on the

            formation. of BCME from. HCI and formaldehyde.
(, Anangrnrexis , 19>72) ,  At room temperature of about 71°F and
     a 4!§> percent relative humidity, a steady state  level
of. BCME cotnldl be reached within one minute.  In general,
ppm- levels of: tfoe reactarvts yielded ppb levels of BCME.
This important finding has since been confirmed; however,
tfoe yield in srachi a reaction  is much lower than was  previously
anticipated.  Frankel, et al.  (1974) reported that at  25°C
and 4.0- percent relative humidity,  fewer than 0.5 ppb of
BCME was formed from 20 ppm each of HC1 and formaldehyde.
At 100 ppm or 300 ppm of each reactant, the average  yield
was Z..7 or 23 ppb BCME, respectively.  The factors that
affect the .yield included the reactant concentration,  the
surface of the reactor, the reaction time, the humidity
and temperature.  A substantially  lower yield was observed
by Kallos and Solomon  (1973) .  At  100 ppm of each of the
reactants, only 0.1 ppb BCME  was detected.  Nevertheless,
with high concentrations of the reactants, substantial amounts
of BCME could be detected.  The National Institute of  Occupa-
tional Safety and Health is currently investigating  the
possible formation of BCME in various work places where
HC1 and formaldehyde may be used simultaneously  (Lemen,
et al. 1976) .
     In addition to HC1 and formaldehyde, a number of  other
chemicals are potential reactants  for forming of BCME. Gamble
(1977) reported that BCME could be detected in an animal
.room that had been washed with a 15 percent hypochlprite
solution followed by routine  gassing; with formaldehyde.

Duplicate air samples were taken from both high levels (3

m)  and low levels (1m).   No BCME was detected in the high-

level sample whereas 0.2  ppb of BCME was found in the low-

level sample.  The author recommended that chlorine-contain-

ing disinfectants should  not be used when animal rooms are

gassed with formaldehyde.  Another possible source of BCME

in the work place was suspected to be from the reaction

of dimethyl ether and chlorine in air.  Kallos and Tou (1977)

have investigated this possibility.  The reaction was found

to be photochemical in nature.  In ambient air BCME was

barely detectable; the highest amount detected was 2 ppb

from 100 ppm each of chlorine and dimethylether.  However,

it is interesting to note that as much as 1.5 ppm BCME was

found to be generated during the reaction of 100 ppm of

each of the reactants in  dry nitrogen.


     There is no information available on the dermal exposure

of humans to chloroalkyl  ethers; no evaluations can be made

regarding the relative importance of dermal exposure.  One

potential source of dermal exposure has, however1, been investi-

gated by Loewengart and Van Duuren(1977).  Tetrabis(hydroxy-

methyl)phosphonium chloride (THPC), a widely used flame

retardant in children's sleepwear, is synthesized from phosphine,

hydrochloric acid and formaldehyde and may decompose ther-

mally or chemically to these chemicals.  Thus, THPC is also

a potential source of BCME reactants under the right condi-

tions.  Because of the high add-on(up to 35 percent of the

final fabric weight) of the flame retardant, it seems likely

ttfhatt -ra KrcSett&em idf TlttRC may -be loosely -bound :arid 'that ^common

rsioiluittuifidws ^sxeih -sees  "sv*.eatt>, utei'nef,  and "saliva may be  abtbe Ufo
                                               •» .
«e>xt?Ka:e?t £s"Oiiue l£ase;e  THPC-.  *A -sample 
afes lall'sb »marrvglitn!a11?l,y laTcttU^v-e 'a's a sk'in ^carcd'ttDigen vand acttive

Ms fa tt,unfiar  ^pc'om'cit<3r^,  -C'lioewengart aivd  'Van
       ?Nl.  !(i969;) sdbser-ved .a  signlif.ic'an't sincre^ase ?in tthe •virtci^

>o-f 'Lung  tumors ,atf't.e:r .rs-.'.c.  Injectvi'dn  ocf '.BCME tto vaewbotn

'•rhii's ifd'nddng /way .%nd?iir'ec.t'l:
             14         n
labeled with   C at the.fi-position, in female r^ts and mon-


keys.  However, subsequently it was ascertained that labeling

actually occurred in theo<-position (Lingg, personal communi-

cation) .  After single oral doses, BCIE appeared to be readily

absorbed by both species.  In the monkey, the blood radioac-

tivity level reached a high peak within two hours and then

declined in a biphasic manner with a t^ of about five hours

and greater than two days for the first and second phase,

respectively.  In the rat,  the blood radioactivity level

reached £ maximum between two arid four hours after dosing

and then slowly declined with a t, of two days.  There was

a substantial difference in the tissue distribution and

excretion pattern seven days after a single parenteral dose

        '       14
of 30 mg/kg of   C-BCIE.  The monkey retained substantially

higher amounts of radioactivity in the liver (equivalent

to 28.8 pq/g BCIE) than did the rat (3.2 pg/g).  Higher

quantities were also found in the muscle and brain of the

monkey.  On the other hand, with  respect to the percentage

of administered dose recovered in the tissues and excreta.,

higher amounts of radioactivity were found in the fat  (1.98

percent), urine (63.36 percent),  feces (5.87 percent), and

expired air  (15.96 percent) of the rat.  The corre-sponding

figures in the monkey were 0.78 percent, 28.61 percent,

1.19 percent, and 0 percent.  Metabolites of BCIE in the

rat included l-chloro-2 propanol, propylene oxide, 2-(l-

methyl-2-chloroethoxy)-propionic  acid and carbon dioxide.

Initial attempts to analyze the urinary metabolites of BCIE

in the monkey have been inconclusive because of the presence

of interfering substances.


     The fate of BCEE in rats after acute oral administration
has been studied by Lingg, et al.  (1978). Bis((l-14C) chloro-
ethyl)ether (40 mg/kg) was administered to male Sprague-
Dawley rats by intubation.  Preliminary results showed that
virtually all of the BCEE was excreted as urinary metabolites
with more than 60 percent of the compound excreted within
24 hours.  One major metabolite was thiodiglycolic acid.
A lesser metabolite was identified as 2-chloroethanol- -4-
D-glucuronide.  The presence of these two metabolites sug-
gests that cleavage of the ether linkage is a major step
in the biotransformation of BCEE.  The products of this
cleavage then conjugate with nonprotein free sulfhydryl
groups or with glucuronic acid with the former as the major
route of conjugation in the rat.
     The metabolic fate of other chloroalkyl ethers is not
known.  However, it is interesting to note that cleavage
of the ether linkage also appears  to be a route of metabolism
for diethyl ether in mice (Geddes, 1971).  For p-dioxane,
a cyclic ether, ring hydroxylation has been postulated as
the first step of metabolism in the rat (Woo, et. al. 1977).
The major urinary metabolite has been identified as 2-hydroxy-
ethoxyacetic acid (Braun and Young, 1977) or p-dioxane-2-
one (Woo, et al. 1977) which are readily interconvertible
depending on the pH of the system.
Acute, Sub-acute and Chronic Toxicity
     Animal Studies:  The acute toxicity of a variety of
chloroalkyl ethers has been studied in different animal

species.  Tables 4 and 5 summarize the acute toxicity data.

It is apparent from Table 4 that the route of exposure may

play a determining factor in the acute toxicity of chloro-

alkyl ethers.  In the rat, the inhalational toxicity follows

the order, BCME >> CMME>BCEE^> BCIE; by oral administration,

however, the order is changed to BCEE > BCIE_7 BCME >CMME.

Apparently, the extremely short lifetime of BCME and CMME

in aqueous solution significantly reduces their toxic poten-

tial by oral administration.  It is also of interest to

note the dramatic enhancement of toxicity of p-dioxane after

chlorination.  The acute LD eg of p-dioxane has been reported

as 5.3 gm/kg (Woo, et al. 1978).  Chlorination of p-dioxane

increases the toxicity by 10 to 1000 fold.  The stereochemis-

try of the compound also plays a significant role; the 2r,3t,

5t,6c-tetrachloro isomer was found to be 80 times more toxic

than its 2r,3c,5t,6t-stereoisomer  (Woo,  et al. 1979).

     The acute physiological response of the guinea pig

to air containing toxic concentrations of BCEE has been

studied by Schrenk, et al.  (1933).  The primary action was

the irritation of the respiratory passages and the lungs.

In the order of their appearance, the symptoms produced

were nasal irritation, eye irritation, lacrimation, disturbances

in respiration, dyspnea, gasping and death.  The principal

gross pathology findings were congestion, emphysema, edema

and hemorrhage of the lungs.

     Gage (1970) exposed rats to eight,  5-hour exposures

of 350 ppm BCIE in air;  the toxic sign observed included

respiratory difficulty,  lethargy and retarded weight gain.

                                                         TABLE 4
                                          Acute Toxicity of Chloroalkyl Ethers
Test species   Route
  Chloromethylmethyl ether.  Rat


                             Guinea Pig
  Bis(2-chloroisopropyl)ether,  Rat
  2-Chloroethylvinyl  ether





             Lethal Dose or Concentration  Reference
LD5Q=817 rag/kg
LCjQ=55 ppm for 7 hr
LC50=65 ppm for 7 hr
LD5Q=0.21 ml/kg*
LCcf,=7 ppm for 7 hr
LCc«=25 mq/nT for 6
                                                              =25  mg/nr  for"6  hr***
                                                           1^=0.28  ml/kg**
                                                           :50=7 ppm for  7  hr
LD50=75 mg/kg
LCLo-1000 ppm for 45 min
     or 250 ppm for 4 hr
LD50=300 mg/kg
LCLo=105 ppm for 250 min

LD5Q=240 mg/kg
LCLO=700 ppm for 5 hr
LD50=3000 mg/kg
LD,n=250 mg/kg
LCLo=250 ppm for 4
LD5Q=3200 mg/kg
                                                          NIOSH  (1974)
                                                          Drew,  et al.  (1975)
                                                          Drew,  et al.  (1975)
Smyth, et al
Drew, et al.
Leong, et al
Smyth, et al
Drew, et al.
Smyth and Carpenter (1948)
Smyth and Carpenter (1948)
Carpenter, et al.  (1949)
Smyth and Carpenter (1948)
Schrenk, et al.  (1933)

Smyth, et al. (1951)
Gage  (1970)
Smyth, et al. (1951)

Smyth, et al. (1949)
Carpenter, et al.  (1949)
Smyth, et al. (1949)
  LD50=lethal dose  for  50%  kill
  LC50=lethal concentration for  50%  kill

  LCLo=lowest lethal concentration published
  •equivalent to  278.mg/kg;  **equivalent  to 370 mg/kg;  ***equivalent  to 5.3  ppm

                                                      TABLE 5

                                     Acute Toxicity of Chloro-cycloalkyl Ethers
Test Species
2-Chloromethyltetrahydro-  Mouse
    f uran
2,3,5-Trichloro-p-dioxane  Rat
   (isomer I*) (m.p. 41 )

2, 3, 5-Trichloro-p-dioxane  Rat
   (isomer II*) (m.p. 71°)

2r,3t,5t,6c-Tetrachloro-   Rat
   p-dioxane  (m.p. 99 )

2r ,3c,5t,6t-Tetrachloro-   Rat
   p-dioxane  (m.p. 141 )
Lethal Dose
LDLo=250 mg/kg
LD5Q=1.41 ml/kg
LD50=435 mg/kg
LD5Q=0.44 ml/kg
LD50=83.2 mg/kg
LDcQ=146 mg/kg
LD,-n=5.3 mg/kg
                            LD5Q=424 mg/kg

NIOSH (1974)

Smyth, et al.  (1969)

Woo, et al.  (1979)

Smyth, et al  (1969)

Woo, et al,  (1979)

Woo, et al.  (1979)

Woo, et al.  (1979)

Woo, et al.  (1979)
LD50=lethal dose for 50% kill
LDLo=lowest lethal dose published
*the exact stereochemistry of the isomers has not been determined

Histological  examination  of  liver  and  kidneys  revealed  signs

of congestion.   Lethargy  and retarded  weight gain  were  also

observed  in a group exposed  20  times,  six  hours  each, to

70 ppm of BCIE  in  air.  The  highest  concentration  with  no

toxic signs was 20 ppm.

     The  National  Cancer  Institute (unpublished  results)

has recently  completed a  chronic toxicity  study  of BCIE.

The observations of non-tumor pathology  are summarized  in

Table 6.  The most significant  change  in the mouse appeared

to be an  increased incidence of centrilobular  necrosis  of

the liver.  However,  the  effect was  inexplicably higher
in the low-dose group than in the  high-dose group.   In  the

rat, the  major  effect of  BCIE was  on the lungs,  causing

congestion, pneumonia, and aspiration.

     A detailed study of  the inhalational  toxicity of BCME

and CMME  has  recently been carried out by  Drew,  et al.  (1975)

w'ith Sprague-Dawley rats  and Syrian  golden hamsters  as  the

test species.   The most characteristic acute toxic effect

of both compounds  was the irritation of  the respiratory

tract manifested by congestion, edema, and hemorrhage (mainly

of the lungs) and  acute necrotizing  bronchitis.  The lung-

to-body weight  ratios, which were  used as  an objective  criter-

ion for the evaluation of lung  damage, in  animals  exposed

to CMME were  elevated in  a dose-related  fashion.  Multiple

exposures of  animals  to sub-acutely  toxic  concentrations

of BCME or CMME resulted  in  severe shortening  of lifespan

and a variety of regenerative,  hyperplastic and metaplastic

alterations of  trachea and bronchi,  which  were often histo-

pathologically  atypical (such as nuclear abnormality).


                                                      TABLE 6
   Summary  of  Non-Tumor  Pathology  in  Mice  and  Rats  After  Repeated  Oral  Doses  of  BCIE (NCI,  unpublished results).*
Incidence (%)
Rats, male

Rats, female

Mice, male

Mice, female
Pathology Contro1
Lungs, congestion
pneumonia, aspiration
Liver, centr ilobular necrosis
Esophagus, hyperkeratosis
Lungs, congestion
pneumonia, aspiration
Liver, centr ilobular necrosis
Esophagus, hyperkeratosis
Adrenal cortex, angiectasis
Lung, hemorrhage
Liver, centr ilobular necrosis
Esophagus, inflammation
Liver, centrilobular necrosis
Vehicle LQW DQse High Dosg
100 mg/kg/day (rats) 200 mg/kg/day (rats)
. 10 mg/kg/day (mice) 25 mg/kg/day (mice)
* 20
27 .
*Animals dosed 5 days/week for total of 728 days.

Incidences of mucosal changes were generally increased in

a dose-related manner in both species.  Similar changes

were observed in studies of the long term effects of single

exposure to BCME or CMME.  For animals surviving beyond

the median life span, pathological alterations of respira-

tory epithelium, abnormality of alveolar lining cells and

bronchoalveolar squamous metaplasia were also occasionally


     Human Studies;  The effect of brief exposures of man

to BCEE vapor was studied by Schrenk, et al. (1933).  Concen-

trations of greater than 260 ppm were found to be very irrita-

ting to the nasal passages and eyes with profuse lacrimation.

Deep inhalations were nauseating in effect.  The highest

concentration with no noticeable sign of irritation was

35 ppm.  For comparison, BCME was reported  (Flury and Zernik,

1931, cited in Schrenk, et al. 1933) to be distinctly irrita-

ting at a concentration of 3 ppm.  A concentration of 100

ppm would incapacitate a person under chemical warfare condi-

tions in a few seconds, and an exposure of one to two minutes

might produce a fatal lung injury.  A fatal case, of acci-

dental, acute poisoning of a research chemist by BCME has

been reported  (Schierwater, 1971, cited in Thiess, et al.


     The respiratory effects of chronic exposures of indus-

trial workers to CMME (contaminated with BCME)  have been

extensively investigated by Weiss and coworkers.  Symptoms

of chronic bronchitis were noted more often among exposed

men, and a dose-response relationship was apparent with

smoking as a cofactor.  There was no demonstrable chemical
effect on the ventilatory function, as measured by the forced
vital capacity (FVC) and the one-second forced expiratory
volume (FEV.,) , suggesting the absence of abnormality in
the large airways (Weiss and Boucot, 1975).  The small airways
were, however, noticeably affected by the chemical exposure.
The end-expiratory flow rate (EEFR) was below 60 percent
of the predicted value in one-third of the exposed men compar-
ed to only three percent of the unexposed men.  There was
a dose-response relationship between chemical exposure and
the frequency of low EEFR (Weiss, 1977).
Synergism and/or Antagonism
     There is very little information available on the syner-
gistic or antagonistic interaction of chloroalkyl ethers
with other types of chemical carcinogens in experimental
animals.   Promotion of tumorigenesis after initiation by
chloroalkyl ethers has, however, been extensively studied.
In two-stage mouse skin carcinogenesis studies, the following
compounds have been considered as "incomplete" carcinogens
(i.e., active only as "initiators"): CMME, octachlorodi-
n-propyl ether, and <*, ,oC-dichloromethyl ether'  (Van Duuren,
et al.  1969, 1972).  Induction of papillomas was also ob-
served after promotion of the initiation by BCEE, bis(o(-
chloroethyl)ether, or 2,3-dichlorotetrahydrofuran; whether
these compounds are "complete" carcinogens or not is not
known  (Van Duuren, et al. 1972) .  Chloroalkyl ethers capable
of inducing papillomas or carcinomas on mouse skin without
promotion include BCME (Van Duuren, et al. 1969) and 2,3-

trans-dichloro p-dioxane  (Van Duuren, et al. 1974); the

carcinogenic activity of  these compounds can be substantially

enhanced by promoters (Van Duuren, 1969; Van Duuren, et

al. 1969, 1974; Slaga, et al. 1973).  The details of these

carcinogenicity data will be presented in the Carcinogenicity

section.  The promoters used included croton oil, croton

resin or the pure phorbol myristate acetate.  The tumor-

promoting activity of several chloroalkyl ethers has been

tested using benzo(a)pyrene as the initiator.  BCME was

found to decrease the latent period for induction of benign

and malignant tumors but  did not affect the tumor yield

(Van Duuren, et al. 1968, 1969).  CMME and octachlorodi-

n-propyl ether were marginally active as promoters  (Van

Duuren, et al. 1969).

     The ability of chloro derivatives of p-dioxane to modify

microsomal drug-metabolizing enzyme activity has been studied

by Woo, et al.  (1979).  Of the compounds tested (listed

in Table 5), only 2r,3c,5t,6t-tetrachloro^-p-dioxane was

found to have a significant effect.  The activities of micro-
somal aryl hydrocarbon hydroxylase and dimethylnitrosamine-

demethylas.e were decreased by 44 percent and 61 percent,


     Cigarette smoking has been found to act synergistically

with CMME to produce chronic bronchitis and small airway

disorders among exposed industrial workers  (Weiss and Boucot,

1975; Weiss, 1976,1977).  In sharp contrast, however, there

was an unexpected inverse relationship between smoking and

the induction of lung cancer by CMME (Weiss and Boucot,

1975; Weiss, 1976) .  The  reason for this apparent antagonism


is not known.   Self-selection by the workers has been sugges-

ted as a possible factor.   Heavy cigarette smokers might

have tended to avoid heavy chemical exposure because chronic

cough was directly related to both CMME exposure and cigar-

ette smoking,  and simultaneous exposure might produce a

greater effect than either one alone.  However, no data

on smoking habit changes were available to verify the self-

selection hypothesis.  Another possible factor was the protec-

tive action of bronchorrhea associated with chronic bronchi-

tis.  The excessive discharge from bronchial mucous membrane

may protect against the carcinogenic effect of CMME or its

contaminant BCME by reducing the residence time of these

chemicals because' of their instability in aqueous systems.
Finally, it is conceivable that some component of cigarette

smoke may neutralize the carcinogenicity of CMME.  It is

not known whether the apparent antagonism observed by Weiss

may be a general phenomenon.  In reviewing the case reports

of four different groups of workers, Lemen, et al.  (1976)

expressed the view that smoking may provide a promotional

or synergistic effect on the induction of lung cancer by

BCME.                                    '


     The teratogenicity of the chloroalkyl ethers covered

in this document has not been studied.  It is relevant to

note, however, that there is some epidemiological evidence

that anesthetic gases (including methoxyflurane) may/ lead

to congenital abnormalities.  Although the evidence has

been considered less than unequivocal, there is little doubt

that these gases are  teratogenic  in  experimental  animals

when administered  in  relatively high doses  (rev.,  Smith,

1974; Corbett, 1976;  Ferstandig,  1978).  A  detailed  discus-

sion of this subject  is  beyond the scope of this  document.

However, in view of the  fact  that methoxyflurane  can actually
be classified as a chloroalkyl ether,  the teratogenicity

of other chloroalkyl  ethers  (especially the environmentally

important and stable  BCEE and BCIE)  should  be critically


                         Cl F  H
                          1   I  I
                         Cl F  H



     The mutagenicity of chloroalkyl ethers has been investi-

gated* in bacterial, eukaryotic, and  mammalian systems.

Table 7 compares the  carcinogenicity data to the  mutagenicity

data in microbial  systems for a variety of  chloroalkyl  ethers.

With a few exceptions, there  is a relatively good correlation

between mutagenicity  and carcinogenicity.   For most  of  these

studies, £_._ coli and  S_._  typhimurium  were used as  the test

organisms and the  test was designed  for direct-acting muta-

gens that do not require metabolic activation.

     There are some disagreements regarding the mutagenicity

of BCEE. Shirasu,  et  al.  (1975) have found  BCEE to be a

direct-acting, base-change mutagen using different tester

strains of E_._ coli, S_._ typhimurium,  and §_._  subtilis.  Also
Simmon; et al. (1977; cited in Fishbein, 1977) reported

that BCEE, when tested in a desiccator containing  the vapor,


                           TABLE 7

   Comparison of Carcinogenic and Mutagenic  (in Microbial
           System) Activity of Chloroalkyl Ethers



 ,  -^Dichloromethylmethyl ether

Bis( -chloroethyl)ether


Octachloro-di-n-propyl ether







 -,+b  -

not tested

not tested
      The mutagenicity data were mainly from Mukai and Hawryluk
(1973), Mukai, et al. (cited in Nelson, 1976)

      Positive mutagenic activity of BCEE was observed by
Shirasu, et al. (1975) and the mutagenicity of BCEE and
BCIE were observed by Simmon, et al.  (1977; cited  in Fishbein,1977).

was mutagenic to S_^ typhimurium strains TA 1535 and TA 100
and weakly mutagenic to strains TA 1538, TA 98, and E^ coli
WP2i  In suspension assays, BCEE also proved  to be mutagenic
toward strain TA 1535.  BCEE was not mutagenic in host-media-
ted assays when given  as a single oral dose or when adminis-
tered for two weeks prior to the injection of S. typhimurium
into the peritoneal cavity.
     In eukaryotic and non-mammalian systems, BCEE was report-*
e'd to be mutagenic to  Saccharomyces cerevisiae D3 in  suspen-
sion assay  (Simmon, et al. 1977; cited in Fishbein, 1977).
BCEE has been quoted as mutagenic to Drosophila melanogaster
(Fishbein, 1976, 1977); however, a careful examination of
the original publication Of Auerbach, et al.  (1947) failed
to confirm the quotation.  It was bis(2-chloroethylmercapto-
eth'yl)ether  (not BCEE) that was mutagenic.
     The mutagenic potential of BCEE and BCIE in mice has
:been studied by Jorgenson, et al.  (1977) using the heritable
translbcation test.  Adult male mice were treated by  gavage
daily for three weeks  with three dose levels  of BCEE  or
BCIE.  They  were then  mated to virgin females to produce
an F, generation.  The F, males were bred twice and examined
cytbgenetically.  Preliminary evaluation of the breeding
and cytogenetic data suggests that BCEE and BCIE were not
mutagenic; no heritable translocations were observed.
     The genetic risks of occupational exposures to CMME
and BCME have been evaluated by Zudova and Landa  (1977).
Cytogenetic  analysis of peripheral lymphocytes was performed.
Scoring 200  cells per  person, the authors detected 6.7 per-
cent of aberrant cells in exposed workers while the corres-

ponding value in the controls reached only two percent.
The frequency of aberrant cells in exposed workers decreased
toward the control value after the removal of exposure.
It was proposed that cytogenetic analysis of peripheral
lymphocytes should become a part of a routine medical check-
up of workers at risk.
     Animal Studies:  Van Duuren, et al.  (1968) were the
first to demonstrate the carcindgenicity of chloroalkyl
ethers.  Application of 2 mg BCME three times a week, for
325 days led to the induction of papillomas in 13/20 mice,
12 of which developed to squamous cell carcinomas.  A compar-
ison with a number of other carcinogenic alkylating agents
(Table 8) indicated that BCME was, for the mouse skin, more
potent than theji-lactones and epoxides listed, in terms
of tumor yield, dose, and latency.  In contrast, CMME was
found to be inactive as a complete carcinogen by skin applica-
     In an effort to delineate the structure-activity rela-
tionships of chloroalkyl ethers, Van Duuren and coworkers
have extended their cutaneous carcinogenicity studies to
a variety of compounds.  The test procedures used included
s.c. injection in mice, repeated direct application to mouse
skin, and tests in mice by the initiation-promotion procedure
involving a single application of the test compound followed
by repeated applications of phorbol myristate acetate.
Table 9 summarizes the results of this extensive series
o£ studies.  By skin application, BCME, trans-2,3-dichloro-
p-dioxane, bis-1,2-(chloromethoxy)ethane, and tris-1,2,3-

                                TABLE 8
               Comparison of Carcinogenic  Potency
              of Alkylating Agents on Mouse Skin
 Days    Mice with
to 1st  carcinoma/no.
tumor   of mice tested
              time (days)

       From Van Duuren, et al.  (1968)

       Administered 3 times/week in 0.1 ml solvent; the solvents
      used were benzene for the first 4 compounds and acetone
      for diepoxybutane.

      GFemale Swiss ICR/Ha mice

       Male Swiss mice

                                                           TABLE 9
                        Carcinogenicity of Chloroalkyl Ethers by Skin Application or s.c. Injection*
Carcinogenicity on Mouse Skin
(mice with papillomas/group size )
o< ,s.-Dichloromethylmethyl ether
Bis (<-chloroethyl ether
Octachlorodi-n-propyl ether
2, 3-trans-Dichloro-p-dioxane
Bi s-1, 2- (chloromethoxy (ethane
Bis- 1,4- (chloromethoxy) butane
Bis- 1,6- (chloromethoxy) hexane
Tris-1,2,3- (chloromethoxy) propane

as "initiator"

s.c. Injection in s.c. Injection in
Mice: (sarcomas Rats: (sarcomas
at injection at injection
site/group size) site/group size)
10/30 l/20b
21/50 7/20
— _^
4/30 —
2/30 —
— • —
1/30 —
14/30° — '
9/50 —
0/50 —
1/50 —
10/50d —
          *Summarized  from  Van  Duuren,  et  al.  (1968,  1969,  1971,  1972,  1974,  1975)
          aNumber  of mice with  carcinomas  given  in  parentheses.
          Considered  inactive.
          °Two  additional animals  had  squamous cell carcinomas and  one  had adenocarcinoma.
          Two  additional animals  had  carcinomas.

(chloromethoxy)propane were found to be active as complete
carcinogens.  Most of the other compounds  tested were  active
as initiators.  From these studies, three  salient features
of structure-activity relationships were observed.   (1)
The bifunctional ^-chloroalkyl ethers  (e.g., BCME)  are more
active than their monofunctional analogs(e.g., CMME).   (2)
The carcinogenic activity of chlbroalkyl ether decreases
                                !         *'
as chlorine moves further away from the ether oxygen.   Thus,
J-chloroalkyl ethers  (e.g., BCEE) are  substantially less
active than their <*.-chloro isomers or  analogs(e.g., bis
(0f-chloroethyl) ether).  (3) The carcinogenic activity decreas-
es as the alkyl chain length increases.  For example,  if
one considers BCME, bis-1,2-(chloromethoxy)ethane,  bis-1,4-
(chloromethoxy)butane, and bis-1,6-(chloromethoxy)hexane
as a homologous series of di-e<-chloro  ethers of  increasing
length,  it is clear that in general the longer the  chain
length the lower  is the  carcinogenicity.
     The carcinogenicity of .BCME and CMME  in newborn ICR
Swiss random bred mice has been tested by  Gargus, et al.
(1969) by s.c, injection.  A single dose of 12.5jul BCME/kg
body weight was found to increase the  pulmonary  tumor  inci-
dence after six months.   In 50 males and 50 females injected
with BCME, pulmonary  tumors developed  in 45 percent of the
animals, with a multiplicity of 0.64 tumors per  mouse.
In addition, one mouse developed an  injection site  piapillo'ma
and another a  fibrosarcoma; such tumors were not seen  in
control  animals.  In  the vehicle  (peanut oil) controls,
the pulmonary  tumor  incidence was 14 percent with a multipli-

city of 0.14.  Mice receiving CMME (125 jal/kg) had an inci-
dence of 17 percent with a multiplicity of 0.21? these values
were slightly higher but not significantly different from
the controls.  It is of particular interest to point out
the high carcinogenic potency of BCME in this study.  A
single, very small dose of 12.5 jul (equivalent to 0.017
mg/kg) was sufficient to induce pulmonary adenomas within
six months.  Furthermore, this study indicated that, despite
its short lifetime in an aqueous system, the biological
effects of BCME were not confined to the site of injection.
On the other hand, using rats, s.c. injection of BCME produced
no increase  in the incidence of tumors remote from the injection
site  (Van Duuren, et- al. 1969) .
     The tumor initiating ability of BCME and CMME has also
been studied by Slaga, et al. (1973) using female Charles
River CD 1 mice.  A single dose of 9  moles  (1.03 mg) BCME
was sufficient to induce papillomas within 15 weeks after
promotion by croton oil.  CMME, up to a dose of 25  moles
 (2.0 mg), was found to be a very weak or inactive initiating
     The high vapor pressure of CMME  (b.p. 59°C) and BCME
 (b.p. 104°C) at ambient temperatures and their extensive
industrial uses have prompted investigators  to examine the
inhalational carcinogenicity of these compounds.  Leong,
et al.  (1971) were the first to test the inhalational carcin-
ogenicity of BCME and CMME in mice.  Strain  A/Heston male
mice, which  are known to be highly responsive to pulmonary
tumor induction with a spontaneous incidence of about 40
percent were used in this study.  The animals were exposed

six hours/day, five days/week to  filtered  room  air  (negative

control) , aerosols of urethane  (positive control).,  or vapors

of BCME or CMME for up to a maximum of six months.  The

CMME used contained 0.3  to 2.6 percent BCME  as  an  impurity.

The animals were sacrificed at the end of  the six-month

period  (Table 10 summarizes the results).  Mice in  the BCME

exposed group had a 34 percent increase in the  incidence

of lung tumors and a 3.3-fold enhancement  in the average

number of tumors/animal/treatment group.   The corresponding

figures in the CMME exposed group were 21  percent  and 1.75-

fold.  It was concluded  that BCME was a potent  inhalational

carcinogen. .CMME was also, for practical  purposes, carcin-
ogenic although it was not certain whether the  effect was
exerted by CMME itself or its contaminant, BCME.

     An extensive series of inhalational carcinogenicity

studies of BCME and CMME in rat and hamster  has been carried

out by Laskin, et al.  (1971,1975), Drew, et  al.  (1975),

and Kuschner, et al.  (1975).  Table 11 summarizes  the results

of their findings.  BCME was found to be an  extremely potent

respiratory carcinogen in the rat.  Limited  exposures  (no

more than 100 daily exposures of  six hours eaqh) of 200

rats to 0.1 ppm BCME led to the induction  of respiratory

cancers in 40 animals.  The type  of tumors induced  and the

time required for the induction are summarized  in Table

12.  Twenty-six rats had tumors of the nose  with esthesio-

neuroepithelioma as the major histological type.  Fourteen

rats had tumors of the lung, 13 of them squamous cell carcino-

mas.  The carcinogenic effect of  BCME was  clearly dependent

on the number of exposures (see Table 13)  showing an excel-


                               TABLE  10

           Pulmonary Tumors  in  Strain  A/Heston Mice Following
            Inhalation Exposures  to  BCME,  CMME and Urethane
                  Exposure  Incidence of lung tumor  Average  number  of
          Cone.   duration  (no. tumor-bearing    tumors/animal/treatmen'
Compound  (ppm)   (days)    animals/no, examined)      group
20/49 (41%)
Urethane  138
46/49 (94%)
26/47 (55%)
25/50 (50%)
           Summarized from Leong, et al.  (1971)

                                                          TABLE 11

                             Inhalational Carcinogenicity of  BCME ana CMME in Rats ana Hamsters
Species i
Co.iipGijrici strain
BCME Sprague-
male rats

o hamsters

CMME Sprague-
male rats
Cone. „ „ , . . a NO. of No. of animal Mean latent D «-.««.. -~

                                TABLE 12
         Cancers  and  Induction Times Seen in 200 Rats Following
                   Limited Exposures to 0.1 ppm BCME
Origin and type of cancer
            Mean latent   Range,
           period  (days)   days
   Malignant olfactory tumor
   Squamous cell carcinoma
   involving turbinates
   and gingiva
   Poorly differentiated
   epithelial tumors
   (nasal cavity)







   Squamous cell carcinoma    13
   Adenocarcinoma              1
    From Kuschner, et al.  (1975)

                                TABLE 13

            Incidence of Tumors of Respiratory Tract in Rats
              Following Limited Exposures to 0.1 ppm BCME
                                                Cancer  incidence
                                              (no.  of  tumor-bearing
  No. of                                         animals/no,  of,
exposures                                      animals  observed )
     100                                        12/20  (60.0%)
     80                                         15/34  (44.1%)
     60                                          4/18  (22.2%)
     40                                          4/18  (22.2%)
     20                   .                       3/46  (6.5%)
     10                                          1/41  (2.4%)
     3Summari2ed from  Kuschner,  et al.  (1975)

     bAnimals surviving  beyond  210 days.

lent dose-response.  The exposure-response curve (probit
vs. log dose) showed a sigmoid type of relationship, and
a linear relationship was obtained by plotting log probit
vs. log dose.  The number of exposures at 0.1 ppm required
to induce tumors in 50 percent of the rats was calculated
to be 88.  In experiments designed for sub-acute toxicity
study, exposure of rats to 1 ppm BCME for three days (six
hours/day) led to the induction of squamous cell carcinoma
of skin in 1 of the 50 animals. Syrian golden hamsters appeared
to be very resistant to carcinogenesis by BCME.  Lifetime
exposure of hamsters to 0.1 ppm BCME resulted in only one
undifferentiated carcinoma of the lung in one of the 100
animals, whereas limited exposures(one or three exposures)
brought about one tumor of the nose in one of each of the
two groups of 50 animals.
     The inhalational carcinogenicity of commercial grade
CMME, which is usually contaminated with one to seven percent
BCME, has also been tested in rats and hamsters.  Lifetime
exposure to 1 ppm CMME led to the induction of one pulmonary
and one nasal tumor in 74 exposed rats or two respiratory
tumors in 90 exposed hamsters.  Thus, in practical terms,
commercial grade CMME must be considered as a respiratory
carcinogen, although of a lower order of activity than BCME.
     The carcinogenicity of BCEE by oral administration
has been evaluated by Innes, et al. (1969) ; more recently,
in view of its frequent occurrence in finished drinking
water, further evaluations have been undertaken by Theiss,
et al. (1977) and in the National Cancer Institute  (Ulland,
et al. 1973;  Weisburger, personal communication).  The major


findings of these studies are summarized in Table 14.  Two

strains of mice of both sexes were used by Innes, et al.

(1969).  They received 100 rag/kg/day of BCEE for 80 weeks,

first by intubation for three weeks followed by ingestion

of food containing 300 ppro BCEE  (estimated to be equiva-

lent to daily intake of 100 mg/kg).  The most significant

finding was a substantially increased incidence of hepatoma,

especially  in male mice.  The incidence of hepatomas in

male and female controls of the  strains were 8/79 and 0/87

in (C57BL/6X GSR/Anf^ mice and  5/90 and 1/82 in (C57BL/6XAKR)F1

mice.  The incidence of hepatomas" in male treated mice was

significantly different from that: in controls at the p=0.01

level.  In contrast to the above  study, Theiss, et al.  (1977) ,

using strain A mice  (which have  a high spontaneous pulmonary

tumor incidence), were unable to  detect any enhancement

of pulmonary tumor incidence after repeated i.p. injections

of BCEE.  The average number of  lung tumors/mouse was actually

smaller in the treated group (0.11 to 0.15) than that in

the tricaprylin vehicle controls  (0.39).  In the study by

the National Cancer Institute on  the oral carcinogenicity

of BCEE, Charles River CD rats of both sexes were used.

Although, detailed statistical analyses have not yet been

completed, preliminary analyses  suggest that BCEE did not

cause any significant increase in the tumor incidence in

the rat (Olland, et al.  1973; Weisburger, personal communi-

     The oral carcinogenicity of!BCIE, another compound

detected in the finished drinking water, has also been recent-

ly evaluated by the National Cancer Institute (unpublished).


                                                      TABLE 14

                      Caccinogenicity of BCEE  in Mice and  Rats by Oral or  i.p. Administration
   Species & strain
    Carcinogenic response'
7   7-day-old
£   (C57BL/6XAKR)F1
6-3 weeks old,
ma 1 e
Strain A/St
Charles River CD
oral, 100 mg/kg/day for 80 weeks
(BCEE given by intubation for the
first 21 days followed by 300 ppm
in diet), mice sacrificed at the
end of treatment

oral, 100 mg/kg/day for 80 weeks
(BCEE given by intubation for the
first 21 days followed by 300 ppm
in diet), mice sacrificed at the
end of treatment

i.p., 3x/week to a maximum of
24 injections; 3 dose levels:
4 x 40 mg/kg, 24 x 20 mg/kg,
24 x 8 mg/kg; mice sacrificed 24
weeks after the first injection

oral, 50 mg/kg/day or
25 mg/kg/day, 5 days/week
for two years
Male: 14/16 hepatoma(p 0.01)
       2/16 Lymphoma
Female: 4/18 hepatoma
                                                            Male: 9/17 hepatoma(p  0.01)
                                                                  2/17 pulmonary tumor
                                                            Female: 1/17 lymphoma
                                                                                                 Innes, et al.  (1969)
                                Innes, et al.  (1969)
Pulmonary tumor response
not significantly different from
that of the control animals
                                                                                                Theiss, et al.  (1977)
Preliminary analyses suggest
no significant increase in the
development of tumors
                                                                                                Ulland, et al.  (1973)

                                                                                                Weisburger (personal
      No. of tumor-bearing animals/no, of animals observed at the end of experiment.

Mice of both sexes were  intubated with BCIE at doses of

10 tag or 25 rag/kg/day, five days a week, for two years*

Rats were similarly treated at doses of 100 or 200 mg/kg/day.

The results of this study are summarized in Tables 15a &

b.  Although these data  have not yet been fully analyzed,

they suggest that no marked increase in tumor incidence

is induced by BCIE exposure.

     The carcinogenicity of BGME and a number of other chloro-

alkyl ethers in mice by  i.p. administration has been studied
           • 1

by Van Duuren, et al.  (1974, 1975).  The results are summa-

rized in Table 16.  In general, these compounds led to the

induction of local tumors.  However, papillary tumors of

the lung were observed in 12 of the 30 animals treated with


     Human Data:  There  is now sufficient epidemiological

evidence to indicate unequivocally that BCME and, for practi-

cal purposes, CMME are human respiratory carcinogens.  Includ-

ing as yet unreported cases, a total of at least 47 cases

of respiratory cancer deaths in association with occupational

exposure to these compounds has been observed (Nelson, 1976).

A German report  (Bettendorf, 1976) has placed the total

figure at a minimum of 60 cases.  Table 17 summarizes the

published case reports of respiratory cancer deaths among

exposed workers.  These  cases were observed in the United

States, Germany, and Japan among, exposed workers in the

chemical manufacturing plants and laboratories.  It is impor-

tant to point out the  relatively short latency for the induc-

tion of respiratory cancers by these chemicals.  The latency

period may be as short as eight years.  Short durations


                                               TABLE 15a

     Summary of Total Tumor Incidence in Rats After Repeated Oral Doses of BCIE  (NCI,  unpublished)
Animals Initially in Study
Animals Necropsied
Animals Examined Histopathologically
Tumor Summary
Total animals with primary tumors*
Total primary tumors
Total animals with benign tumors
Total benign tumors
Total animals with malignant tumors
Total malignant tumors
Total animals with secondary tumors
Total secondary tumors
Total animals with tumors uncertain-
benign or malignant
Total uncertain tumors
Animals Initially in Study
Animals Necropsied
Animals Examined Histopathologically
Tumor Summary
Total animals with primary tumors*
Total primary tumors
Total animals with benign tumors
Total benign tumors
Total animals with malignant tumors
Total malignant tumors
Total animals with secondary tumors
Total secondary tumors










Low Dose
100 mg/kg/day





High Dose
200 mg/kg/day





         "Primary Tumors:  All tumors except secondary tumors,
          Secondary Tumors:  Metastatic tumors or" tumors invading into an adjacent organ,


                                              TABLE 15b

    Summary of Total Tumor Incidence in Mice After Repeated Oral Doses of BCIE  (NCI, unpublished)
, Co'ntrol
Animals Initially in Study
Animals Missing
Animals Necropsied
Animals Examined Histopathologically
Tumor Summary
Total animals with primary tumors*
Total primary tumors
Total animals with benign tumors
Total benign tumors
Total animals with malignant tumors
Total malignant tumors
Total animals with secondary tumors
Total secondary tumors
Animals Initially in Study
Animals Missing
Animals Necropsied
Animals Examined Histopathologically
Tumor Summary
Total animals with primary tumors*
Total primary tumors
Total animals with benign tumors
Total benign tumors
Total animals with malignant tumors
Total malignant tumors










Low Dose
10 mg/kg/day






High Dose
25 mg/kg/day





        "Primary Tumors:  All tumors except secondary tumors.

         Secondary Tumors: Metastatic tumors or tumors invading into an adjacent organ.

                                               TABLE 16

                Carcinogenicity of Chloroalkyl Ethers  in Mice  by  i.p. Administration4
                               Dose  regime
                               and duration
                         Carcinogenic response
                                Median survival
                                 time  (days)
o    p-dioxane


   1,2,3-Tr is-(chloro-
0.02 mg, once/week
   for 424 days

0.5 mg, once/week
   for 450 days
0.3 mg, once/week
   for 546 days
0.1 mg, once/week
   for 567 days

0.3 mg, once/week
   for 567 days

0.3 mg, once/week
   for 532 days
 4/30 local sarcoma                 287

12/30 papillary tumor of lung       	

 1/30 local undifferentiated
      malignant tumor

 2/30 local sarcoma                 481
 2/30 undifferentiated malignant
      tumor at injection site

 no tumor response                  478

 no tumor response                  472

 5/30 local sarcoma                 428
         Summarized from Van Duuren, et al.  (1974,  1975).   The  mice  were  6-8  weeks old ICR/Ha
   Swiss female mice.
         No. of tumor-bearing animals/no, of  animals  tested.

                                  TABLE 17

Case Reports of Respiratory Cancers Among  Workers Exposed to BCME and/or CMME
Years of Induction
[Jo. of Age at possible -latency
Reference cases cancer exposure period (yr)
Sakabe (1973) 5 37-47 4-9 9-14

Thiess, et al. 6 31-65 6-9 8-16

Figueroa, et al. 14 33-55 1-14 —
o (1973)

Weiss and 11 36-55 2.2-16.6 10-24

DeFonso and 20 33-66 . 0.1-16.5 8.3-25.2
Kelton (1976)
Lemen, et al. 5 35-61 8-13 8-26

Bettendorf 1 42 6 —
Reznik-, et al. 1 45 2 12-13
Working activity
Dyestuff factory

Chemical plant

Chemical plant

Chemical plant

Chemical plant "
resin plant

Research chemist
Research chemist
Smoking habit
All moderate
to heavy

6 moderate
to heavy
2 unknown
3 nonsmokers
1 pipe smoker
10 smokers

3 nonsmokers
1 cigar smoker
2 ex-smokers
5 smokers

4 smokers
1 unknown



Histologic type
of cancer
1 oat cell
1 adenocar-
3 unspecified
5 small cell-
undif fer-
3 unspecified
12 small cell-
undif fer-
entiated or
oat cell
1 epidermal
1 unknown
10 small cell-
undif fer-
1 oat cell

4 small cell-
undif f er-
1 large cell-
undif fer-


of exposures may be sufficient to initiate carcinogenesis.
Respiratory cancers occurred among cigarette smokers, cigar
or pipe smokers, ex-smokers as well as non-smokers.  The
average age of cancer death was around 42.  The predominant
histologic type of cancer was small-cell-undifferentiated
carcimona.  The calculated increased risk factors of cancer
due to chemical exposure are summarized in Table 18.
     The five cases of lung cancer reported in Japan (Sakabe,
1973) occurred among 32 employees exposed to BCME and many
other noxious chemicals in a dyestuff factory.  Four of
the workers exposed were involved.in the synthesis of dye-
stuffs; the fifth case was exposed only in the laboratory.
This represents a very high increased lung cancer risk.
     Thiess, et al. (1973) reported eight cases of respira-
tory cancer deaths in a chemical plant in Germany.  Six
of the cases occurred among 18 experimental technical depart-
ment workers, a group known to experience very high exposures.
In contrast, among the manufacturing workers, only two
cases, were observed among 50. Heavy exposures to BCME and
CMME have been attributed as the cause of induction of lung
adenocarcinomas in two research chemists in Germany  (Bettendorf,
1976; Reznik, et al. 1977). One of the chemists was exposed
for only two years; this individual was not involved with
other known pulmonary carcinogens, although his contact
with unspecified agents cannot be excluded (Reznik, et al.
1977) .
     In the United States, two of the most well known groups
of cases occurred in an anion-exchange resin plant in Califor-
nia and a chemical manufacturing plant in Philadelphia.

                                                          TABLE 18

                          Increased Risk of Respiratory Cancers After Exposure to BCME and/or CMME
Sakabe (1973)
Figueroa, et al. (1973)
prospective study
Lemen, et al. (1976)
Albert, et al. (1975)*
total of 6 U.S. firms
heavy exposure for
more than 5 yrs.
heavy exposure for
1-5 yrs.
heavy exposure for
less than 1 yr.
OeFonso and Kelton
Cancer incidence
No. of Population Cancer incidence in control
cases at risk in risk group (X) group (Y)











5/32/16 yrs.

4.54/100/5 yrs
5/136/18 yrs





1 "'•' "
0.024/32/16 yrs
. - . . -
0.57/100/5 yrs.
0.54/136/18 yrs.





risk p-value
208 10.001

7.96 <0.0017
9.24 <0.01

2.53 —
23.7 ^~

8.97 —

l.Sfi —

3.8 <0.01
        *age-adjusted rate

In the anion-exchange resin plant,  five cases occurred among

136 manufacturing employees.  Only 0.54 cases were expected
 /           '
among them if they were not exposed;  thus, a 9.24 fold in-

crease in the respiratory cancer risk was observed.  The

average age of cancer death was 47 and the mean induction

time was 15 years (Lemen, et al. 1976).  Heavy exposures

to CMME, contaminated with BCME, occurred among workers

in the Philadelphia chemical plant.  In 1962, the management

became aware that an excessive number of workers who were

suspected of having lung cancers were reported in one area

of the plant where CMME was used.  Extensive prospective

and retrospective studies have since been carried out indepen-

dently by several groups of investigators (Figueroa, et

al. 1973; Weiss and Figueroa, 1976; Weiss and Boucot, 1975;

Weiss, 1976; DeFonso and Kelton, 1976).  The latest figure

shows that a total of 20 cases of respiratory cancer deaths

had occurred (DeFonso and Kelton, 1976).  In one of the

prospective studies including 88 exposed workers, an increased

risk of 7.96 was observed  (Figueroa, et al. 1973).  A more

recent analysis on an age-specific basis revealed an increased

risk of lung cancer 3.8 times higher  in 669 exposed compared

to 1616 unexposed workers  (DeFonso and Kelton, 1976).

     An extensive retrospective cohort mortality study of

the respiratory cancer death among employees of six of the

seven major users and producers of CMME in the U.S. has

been carried out by Albert, et al. (1975) and Pasternack,

et al.  (1977).  .The cohort chosen included 1827 exposed

workers and 8870 controls.  The age-adjusted respiratory

cancer death rate for  the exposed group as a whole was found

to be 2.53 times that  in the control group, whereas death

rates due to other causes were comparable.  Most of the

CMME-related deaths were associated with one of the six

industrial firms in which heavy exposures occurred.  Among

workers who were reported to be heavily exposed for more

than five years, a 23.7-fold increase in the respiratory

cancer risk was observed (Albert, et al. 1975).  The increas-

ed risk was clearly dependent on the duration  and intensity

of exposure.  Based on job description, personnel records,

and information supplied by the supervisory personnel, Pasternack,

et al. (1977) estimated the duration (years) and cumulative

weighted exposure index (duration of exposure  X intensity)

of workers and compared with their relative respiratory

cancer risk.  As shown in Table 19, there was  a clear dose-

response relationship.  The linear trend J( tests gave a

highly significant p-value of less than 0.00001.  Similar

dose-response relationships were reported by DeFonso and

Kelton (1976) , and Weiss and Figueroa (1976).  Thus, there

is no doubt that BCME and CMME are potent human respiratory


                          TABLE 19

  Relationship of Respiratory Cancer Mortality to Duration
       and Intensity of Exposure to BCME and/or CMME
Duration of



at-r isk

   aAdapted from Pasternack, et al. (1977)

    CWEI = jDuration of Exposure X Intensity  (varing across
exposure periods)

                    CRITERION FORMULATION

Existing Guidelines and  Standards

     Both BCME and CMME  have  been  recognized  as  human carcin-

ogens; all contact with  them  should  be  avoided.   In  1973,

these two chloroalkyl  ethers  were  listed as 2 of the 14

carcinogens  restricted by  Federal  regulation. Emergency

temporary standards were established for limiting  occupation^

al exposure.  These regulations  applied to all preparations

containing 1 percent  (w/w) or  more of the chloroalkyl ethers.

The use, storage, or handling  of these  chemicals must be

limited to a "controlled area"  in which elaborate  precautions

were specified to minimize worker  exposure.   Decontamination,

waste disposal, monitoring and medical  surveillance  programs

were also required (38 FR  10929).  More detailed regulations

have recently been established;  they apply to all  prepara-

tions containing 0.1 percent of  the  chloroalkyl  ethers by

volume or weight (39 FR  3756; Anonymous, 1974).  Based on   -

the known carcinogenicity of BCME  in animal inhibition stu-

dies, the American Conference of Governmental and  Industrial

Hygienists (1978) has  recommended a  Threshold Limit  Value

(TLV) of 1 ppb (4.71 jug/m3) for • BCME.   This value  is  for
                               i '

the time-weighted average  (TWA)  concentration for  a  normal

eight-hour workday or  40-hour work-week, to which  nearly

all workers may be repeatedly exposed,  day after day, without

adverse effect.

     The Federal standard for BCEE is 15 ppm  (90 mg/m^')

(Tabershaw, et al.  1977). The ACGIH  has recommended a time-' '.

weighted-average threshold limit value  (TLV-TWA)  of 5 ppm

(30 mg/m )  for BCEE.  For a short-term exposure limit, the

tentative value (TLV-STEL)  suggested is 10 ppm  (60 mg/m ).

These values are based on the irritant properties of the •••

chemical to the eye and the respiratory tract.  It is also

recommended that appropriate measures should be taken for

the prevention of cutaneous absorption (Am. Conf. Gov. Ind.

Hyg., 1978).  The guideline level adopted by the Philadelphia

regional office of EPA for BCEE level permitted in Philadel-

phia's drinking water is 0.02 jug/1.  This value is based


on ah evaluation of the available toxicological data for

BCEE by the National Environmental Research Center; a safety

factor of 500,000 has been applied in the calculation  (Mahwaring,

et al. 1977).

     The TLV's for the other chloroalkyl ethers are not

available.   The provisional operational limit suggested

for BCIE was 15 ppm  (Gage, 1970).  The value was based on

the irritant properties of the compound to the  eye and respir-

atory tract.

Current Levels of Exposure

     There is no information available on the levels of

chloroalkyl ethers in food or in the atmosphere; hence,

no estimates can be made of the extent of human exposures

to these compounds via these two routes.  Information on

the dermal exposure  is also virtually nonexistent.  Only

incomplete data are available for the calculation of exposure

via ingestion of drinking water; therefore, only rough esti-

mates can be made.  The highest concentration of BCEE, BCIE,

and BCEXE in drinking water reported by U.S. EPA  (1975)

was 0.5, 1.58 and 0.03 ;ug/l, respectively.  Assuming that


(i) these values are  representative of yearly  averages,

(ii) the average daily  intake of water is  2  liters and  (iii)

the average body weight  is  70 kg,  then the maximum possible

daily exposure from water to BCEE, BCIE and  BCEXE would

be 14.3, 45.1 and 0.86  ng/kg.  These  values  are of course

the upper limits and  are based on  the dubious  assumption

that the highest value  is representative of  the yearly average

and that they only apply to specific  contaminated areas.

For national averages,  the  data of Dressman, et al.  (1977)

and U.S. EPA (1977) may  be  used.   The national average concen-

tration of BCEE or BCIE  in  drinking water  is calculated

as the mean concentration multiplied  by the  percent  incidence

of occurrence.  Thus, the average  concentration in drinking

water of BCEE and BCIE  was  respectively 11.5 ng/1  (0.1 jug/lxll.5

percent), and 12.1 ng/1  (0.17 jug/lx7.1 percent) in phase

II and 1.7 ng/1  (0.024 jag/Ixl.21 percent)  and  7.0 ng/1  (0.11

jjg/lx6.36 percent) in phase III.   Using the  same three assump-

tions mentioned above,  the  estimated  daily exposure  to BCEE

and BCIE would be, respectively, 0.33 ng/kg  and 0.35  ng/kg

in phase II and 0.05  ng/kg  and 0.20 ng/kg  in phase III.

Special Groups at Risk

     Exposure to BCME and CMME appears to  be confined to

occupational settings.   A partial  list of  occupations in

which exposure may occur includes: ion-exchange resin makers,

specific organic chemical plant workers, laboratory  workers,

and polymer makers  (Tabershaw, et  al. 1977). Of these groups,

workers in small non-commercial laboratories should  probably

be particularly cautious because of the lack of monitoring ;

and surveillance and because of the fact that this group
is more likely to be relatively more heavily exposed.  Poten-
tial exposure to BCME may also occur in workplaces where
vapors of hydrochloric acid and formaldehyde may co-exist.
The National Institute of Occupational Safety and Health
(NIOSH) has already found trace levels of BCME in the textile
industry.  Other such places include biological, medical
and chemical laboratories, and particle-board and paper
manufacturing plants (Lemen, et al. 1976).
     Exposure to-^-chloroalkyl ethers may occur in residents
in areas where the source of drinking water  is from  the
contaminated river water and the treatment of drinking water
is inadequate to remove the contaminants.  Individuals consum-
ing the water in these areas may be at a greater risk than
the general population.  Occupational exposure to BCEE may
also occur.  A partial list of occupations in which  exposure
may occur includes: cellulose ester plant workers, degreasers,
dry cleaners, textile scourers, varnish workers, and proces-
sors or makers of ethyl cellulose, fat, gum, lacquer, oil,
paint, soap and tar  (Tabershaw, et al. 1977).
Basis and Derivation of Criterion
     There is no empirical evidence that BCIE is carcinogenic;
however, some chronic toxic effects of the compound  have
been noted (see table 6). One approach to estimating a
safe level of BCIE in drinking water utilizes the following
general equation:
     NOAEL x SF x BW= WxZ  +  RxFxZ  +A  D-(RxFxZ)
     where NOAEL = no apparent adverse effect level  in mammals
          SF = safety factor
          BW = body weight of average human  (assume  70 kg)

           W = daily consumption of water (assume 2 liters)

           Z = safe level for water

           ,R = bioconcentration factor (in I/kg)

           F = daily consumption of fish (assume 0.0187 kg)

           A = daily amount absorbed from air

           D = daily amount from total diet  (including fish)

Since  vadid estimates on current exposure from air and total

diet cannot be made, the equation can be simplified to NOAEL

•x 'SF 'X .BW=(W + R x F) x Z. Referring to Table 6, the lowest

dose 'tested Which caused minimum adverse effects was 10

mg/'kg/day for the mice.  However, even at this dose, there

was an Increased incidence of centrilobular necrosis of

the liver which was not seen in the high-dose group.  To

be conservative, a safety factor of 1/1,000 will be applied.

.'Assuming  an average human body weight of 70 kg, acceptable

tdaily  intake calculated is 700 jug/day.  Using the estimated.

:b'ioconcentration factor of 106 for BCIE and assuming daily

•consumption of 0.0187 kg fish and 2 liters of water, the

safe level calculated from these data is 175.8 /ig/1.  Since

:th'is safe level is calculated on the .basis of several assump-

tions  that ca'nnot be defended,.it should be regarded as

a -very crude estimate.

     Another approach to deriving a criterion has been sug-

gested by the Carcinogens Assessment Group, EPA (see Appendix

I).  As  previously stated, BCIE has not been empirically

proven to be a carcinogen; nevertheless, it is mutagenic

and  is in a class of compounds that are known carcinogens.

Based  on  these facts, credence can be lent to deriving a

suggested criterion based upon NCI preliminary data (1978)

as applied to the linear, non-treshold model described in


Appendix I.  Therefore,  a lower bound water concentration
of 11.5 jug/1 has been calculated such that there is a 95
percent confidence that  this level is lower than the actual
level which- would produce a 10"  lifetime cancer risk due
to exposure to BCIE.
     Although both approaches to calculating a criterion
are somewhat tenuous, the weight of evidence for the carcino-
genic potential of BCIE  is sufficient to be "qualitatively
suggestive" and must not be ignored from a public health
point of view.  Until further conclusive data become available,
the Agency feels it is prudent to consider BCIE a,s a potential
carcinogen.                                     •'
     The estimated,safe  level of BCEE in drinking water
may be calculated using  the same linear, non-threshold model
as applied to BCIE.  The data of Innes, et al.  (1969) on
the carcinogenicity of this compound by oral administration
to male mice are used in the calculation.  The  bio-accumula-
tion factor used is 25.   Based on this approach, the calculated
water quality criterion for BCEE is  .42 jug/1.   Compliance
to this level should limit human lifetime  risk  of carcinogene-
sis from BCEE in drinking water to not more than 10"   (one
case in 100,000 persons at risk), assuming water to be  the
only source of exposure.  It should  also very adequately
protect against noncarcinogenic toxicity since  the daily
dose of contaminant that would be absorbed from water contain-
ing the criterion limit is many times less than the minimal
daily oral dose required to produce  a detectable toxic  res-
ponse in animals.

     The setting of drinking water standards  for BCME and

CMME is of academic interest only, since these <^ -chloroalkyl

ethers may not, under ordinary conditions, exist in water

for periods of time longer  than a few hours.  Carcinogenicity

data generated by oral administration of these compounds

are not available.

     In the case of CMME, no criterion was calculated due

to its extremely short half-life in aqueous solution.  Jones

and Thornton  (1967) have measured the hydrolysis rate of

CMME in aqueous isopropanol.  Extrapolation of the data

to pure water yielded a t,  of less than one second.  BCME

has a slightly longer half-life.  Therefore,  as  a guideline,

the safe level of BCME in drinking water may  be  calculated

using the tumor incidence data from chronic rat  inhalation

studies (Kuschner, et al. 1975).  In this study, Sprague-

Dawley rats were exposed to 0.1 ppm BCME six  hours per day,

five days per week throughout their lifetime.  Additional

groups of rats were given 10, 20, 40, 60, 80  and 100 exposures

to 0.1 ppm BCME.  The validity of the incidence  rates for

humans was established by evaluating the cancer  incidence

in workers after accounting for their exposure  (Pasternack,

et al. 1977) .

     Therefore, using the linear, non-threshold  model (Appen-

dix I) and a  bioconcentration factor of 31, the  recommended

maximum permissible concentration of BCME for the ingested

water is .02  ng/1.  Compliance to this level  should limit

human lifetime risk of carcinogenesis from BCME  in drinking

water to not  more  than 10~  , assuming water to be the only

source of exposure.


     Under the Consent Decree in  NRDC vs.  Train,  criteria

are to state "recommended maximum permissible concentrations

(including where appropriate, zero)  consistent with the

protection of aquatic organisms,  human health, and recreation-

al activities."  BCIE, BCEE,  and  BCME are suspected of being

human carcinogens.'  Because there is no recognized safe

concentration for a human carcinogen, the recommended concen-

tration of these chloroalkyl ethers in water for maximum

protection of human health is zero.

     Because attaining a zero concentration level may be

infeasible in some cases and in order to assist the Agency

and States in the possible future development of water quality

regulations, the concentrations of BCIE, BCEE, and BCME
corresponding to several incremental lifetime cancer risk

levels have been estimated.  A cancer risk level provides

an estimate of the additional incidence of cancer that may

be expected in an exposed population.  A risk of 10    for

example, indicates'a probability of one additional case

of cancer for every 100,000 people exposed, a risk of  10~

indicates one additional case of cancer for every million

people exposed, and so forth.

     In the Federal Register notice of availability  of draft

ambient water quality criteria, EPA stated thait  it  is  consider-

ing setting criteria at an interim target risk,  level of

10~ , 10~ , or 10"  as shown in the following table.

Exposure Assumptions
Risk Levels and .Cor r e spending Crite r i a

2 liters of drinKing water
and consumption of 18.7 grains
of fish and shellfish (2)
Bis (2-chloroisopr:opyl) ether
Bis (2-chloroethyD.ether
Bis (chloromethyl) ether
Consumption of fish and
shellfish only
Bis (2-chloroisopropyl) 4ther
Bis (2-chloroethyi) ether
Bis (chloromethyl) ether

(jug/1) (>ig/l)


.0042 .


042 .

219 .




      (1)  Calculated by applying a modified "one hit" extrapolation

     model described in the FR 15926, 1979. "Appropriate bioassay

     data used in the calculation of the model are presented

      in Appendix 1.  Since the extrapolation mpdel is linear

      to low doses, the additional lifetime risk is directly propor-

      tional to the water concentration.  Therefore, water concen-

      trations corresponding to other risk levels can be derived

      by multiplying or dividing one of the risk levels and corres-

      ponding water concentrations shown in the table by factors

      such as 10, 100, 1,000, and so forth.

      (2)  Fifty percent of BCIfr exposure results from the consump-

      tion of aquatic organisms which exhibit an average bioconcen-

      tration potential of 106 fold.  The remaining 50 percent

      of BCIE exposure results from drinking water.

          Nineteen percent of BCEE exposure results from the

      consumption of aquatic organisms which exhibit an average

      bioconcentration potential of 25 fold.  The remaining 81

      percent oE BCEE exposure results from drinking water.


     Twenty-two percent of BCME exposure results from the
consumption of aquatic organisms which exhibit an average
biocpncentration potential of 31 fold.  The remaining 78
percent of BCME exposure results from drinking water.
     Concentration levels were derived assuming a lifetime
exposure to various amounts of BCIE, BCEE, and BCME,  (1)
occurring from the consumption of both drinking water and
aquatic life grown in water containing the corresponding
chloroalkyl ether concentrations and, (2) occurring solely
from consumption of aquatic life grown in the waters contain-
ing the corresponding chloroalkyl ether concentrations.
     Although total exposure information for these chloroalkyl
ethers is discussed and an estimate of the contributions
from other sources of exposure can be made, this data will
not be factored into the ambient water quality criteria
formulation because of the tenuous estimates.  The criteria
presented, therefore, assume an incremental risk from ambient
water exposure only.


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                          APPENDIX  I

            Summary and Conclusions Regarding the
            Carcinogenicity  of  Chloroalkyl  Ethers*

     Chloroalkyl ethers have a wide variety of industrial

and laboratory uses in organic synthesis, treatment of textiles,

manufacture of polymers and insecticides, and as degreasing

agents.  Bis(chloromethyl) ether (BCME) and chloromethylmethyl

ether  (CMME) have been included in OSHA's list of restricted

chemicals  (1974) based on animal studies and human epidemio-

logical evidence indicating that these compounds are carcino-

genic by inhalation.  An additional occupational hazard

is the spontaneous combination at high concentrations of

vapors of HCL and formaldehyde to form BCME.  Bis(2-chloroethyl)

ether  (BCEE) is present in rivers and drinking water in

several cities, and is found in high concentrations in waste

water from chemical plants.

     Several of the Chloroalkyl ethers including BCME, CMME,

BCEE, and BCIE were mutagenic  in bacterial systems without

metabolic activation, indicating that they are direct-acting

mutagens.  Data for BCME, CMME, and BCEE indicate that these

compounds are both mutagenic and carcinogenic.

     BCME has been shown to be carcinogenic in animals following

inhalation or dermal exposure.  In an inhalation study by

Kuschner, et al. (1975), BCME  induced malignant tumors of

*This  summary  has  been prepared and approved by the Carcinogens

 Assessment Group,  EPA,  on July 20,  1979.

the respiratory tract in male Sprague-Dawley rats.  Application

of BCME to mouse skin induced skin tumors  (van Duuren, et

al. 1968) , while s.c. injection of BCME to newborn ICR Swiss

random-bred mice induced pulmonary tumors  (Gargus/ et al.

1969).  There were no studies reported using oral administra-

tion of BCME.

     The carcihogenicity of BCEE by oral administration

was investigated by  innes, et al.  (1969) in two strains

of mice.  There was  a statistically significant increase

of hepatdmas in the  male mice of both strains  (C57BL/6 x

CSH/AnfJF^ and G57BL/6 x AKR)Flf respectively) and in the

female mice of one strain  (C57BL/6 x CSH/Anf)?-^).

f    Epidemiological studies- of workers in the United States,

Germany, and Japan who were occupationally exposed to BCME

and/or CMME  (choromethylmethyl ether) have indicated that

these compounds are  human  respiratory carcinogens.

     The water quality criterion for BCEE  is based on the

results of the Innes study in which hepatomas were induced

in mice given a daily oral dose of 300 ppm (i.e., 39 mg/kg/day),

The concentration of BCEE  in drinking water calculated to

limit human  lifetime cancer risk from BCEE to less than

10   is 0.42 micrbgram per liter*

     There is no careinogenicity data from oral exposure

to BCME.  The rapid  hydrolysis irate of BCME in water precludes

a  realistic  exposure.  However, a  criterion is calculated

in the event that levels are monitored in  the water.  Since

BCME is a locally acting carcinogen and it is expected that

the stomach  would be the target organ from oral exposure,


the lung tumor data from the inhalation study was accepted

for estimating human risk, and 100 percent absorption of

BCME was assumed.  The water quality criterion was calculated

using data from the Kuschner, et al. inhalation study, where

rats given 100 exposures of 0.1 ppm BCME for six hours per

day, five days per week, developed malignant respiratory

tract tumors.  The concentration of BCME calculated to maintain
                             _ c
lifetime cancer risk below 10   is 0.02 nanograms per liter.

     The only oncogenicity study available for BCIE (Bis(2-

chloroisopropyl)ether) is an NCI rat study which showed

no carcinogenic response.  However, BCIE is probably a direct-

acting alkylating agent as suggested by its mutagenicity

without activation and its structural similarity to BCME.

Thus, although the NCI study was negative, based on the

other ancillary information, it was decided to take a conserv-

ative approach by calculating a water quality criterion.

Using the data from the NCI study, a lower bound water concen-

tration of 11.5 micrograms per liter is calculated such

that there is a 95 percent confidence that this level is
lower than the actual level which would produce a 10   life-

time cancer risk  due to exposure to BCIE.

                  Summary of Pertinent Data
                Bis  (2-Chloroisopropyl) Ether
     A 95 percent lower bound estimate of the water concentra-
tion of BCIE producing 10   cancer risk is calculated from
the preliminary data of the NCI study in Osborne-Mendel
rats.  Since there is no statistically significant tumor
incidence in any treated group compared with controls, the
incidence of total malignant tumors in the male rats of
the low dose group is compared with that of the respective
vehicle control male group.  The low dose group was given
100 mg/kg/day of BCIE by intubation five days per week for
two years, so that the average lifetime exposure was 71.4
mg/kg/day.  The lower bound water concentration is calculated
from the values and  the equation shown below.  To obtain
an upper 95 percent  confidence bound on the slope, the following
estimate was used
where P  (1) is the lower 2.5 percent confidence limit on
the control malignant tumor rate and Pfc(u) is the upper
97.5 percent confidence bound on the malignant tumor rate
in the treated group.
n't =  17       d = 71.4 mg/kg/day
Nt =  50       w = .550 kg
nc =  22       F = .0187 kg
N  =  50       R = 106
Le = 104 wk
lo = 104 wk
L  = 104 wk

     Based on these parameters, the upper 95 percent confidence

limit on the one-hit slope (Buu) is 1.53 X 10~2  (mg/kg/day)-1..

Therefore, the 95 percent lower bound estimate of the

water concentration of BCIE produc

risk is 11.5 micrograms per liter.
water concentration of BCIE producing 10   lifetime cancer

                  Bis  (2-Chloroethyl) ether

     The water quality criterion  for BCEE  is  based  on  the

induction of hepatomas in male mice  (strain C57BL/6 x  C3H/An-f)F^)

given a daily oral dose of 300 ppm for  80  weeks  (Innes,

et al. 1969) .  The tumor incidence was  14/16  in  the treated

group compared with 8/79 in  the control group.   The criterion

was calculated from the following parameters.

nfc = 14-        d = 300 ppm X 0.13 =  39  mg/kg/day

Nfc = 16        w = .030 kg

nc =8'        F = .0187 kg

NC = 79        R = 25

Le = 80 wk

ler = 80' wk

L  = 80 wk

     Batsed on these parameters, the  one-hit slope  (BH)  is

6.8510 x 10"  (mg/kg/day)  .  The resulting water concentration

of BCEE calculated to  keep the individual  lifetime  cancer

risk below 10   is 0.42 micrograms per  liter.

                   Bis  (Chloromethyl)  Ether

     The water quality criterion for BCME is based on the

induction of malignant respiratory tract tumors in male

Sprague-Dawley rats given 100 exposures of 0.1 ppm by inhala-

tion six hours per day, five days per week (Kuschner, et al.

1975).   The average lifetime exposure was calculated to

             — 4
be 3.510 x 10   mg/kg/day.  The tumor incidence was 12/20

in the treated group and 0/240 in the control rats.  The

criterion was calculated from the following parameters.

nfc = 12        d = 3.510 x 10~4 mg/kg/day

Nfc =  20       w = .500 kg

n  =   0       F = .0187 kg

NC = 240       R = 31

Le = 104 wk

le = 104 wk

L  = 104 wk

     Based on these parameters, the one-hit slope  (Bu) is

           4            -1
1.3603  x 10  (mg/kg/day)  .  The resulting water concentration

of BCME calculated to maintain the individual lifetime cancer

risk below 10~  is 0.02 nanograms per liter.