297 921
CHLOROALKYL ETHERS
Ambient Water Quality Criteria
Criteria and Standards Division
Office of Water Planning and Standards
U.S. Environmental Protection Agency
Washington, D.C.
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CRITERION DOCUMENT
CHLOROALKYL ETHERS
CRITERIA
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.
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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
respectively.
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
i
with corresponding criteria of 0.02 ng/1, 0.002 ng/1, and 0.0002
ng/1, respectively.
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Introduction
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).
A-l
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, !,,§,, 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.
A-2
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AQUATIC LIFE TOXICOLOGY*
FRESHWATER ORGANISMS
Introduction
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.
B-l
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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.
Residues
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.
Miscellaneous
The only datum in Table 5 was discussed earlier in this
document.
B-2
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CRITERION FORMULATION
Freshwater-Aquatic Life
Summary of Available Data
The concentrations below have been rounded to two significant
figures.
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
B-3
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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.
6-4
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CO
I
en
Table 1. Freshwater fish acute values for chloroalkyl ethers (U.S. EPA, 1978)
Organism
Bluegill.
Lepomis macrochirus
BiQoseay Test Chemical Time
Metnod* Cone.** Description thrs)
S U 2-chloroethyl 96
vinyl ether
Adjusted
LCbu LOU
(Uy/i)
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00
I
CM
Table 2. Freshwater invertebrate acute values for chloroalkyl ethers (U.S. EPA. 1978)
Adjusted
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"
21
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Tafcle 3. Freshwater fish chronic values for chloroalkyl ethers (U.S. EPA. 1978)
Chronic
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
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00
i
Tatle 4. Freshwater residues for chloroalkyl ethers (U.S. EPA, 1978)
.Time»
Organism Sioconcentration .ffact.oi 'i-flaysj
Bis(2-chloroethyl) £ther
Blueglll. 11 14
Lepomis macrochirus . .
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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
GJ
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SALTWATER ORGANISMS
Introduction
No appropriate data are available for saltwater organisms and
any chloroalkyl ether.
B-10
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CRITERION FORMULATION
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.
B-ll
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CHLOROALKYL ETHERS
REFERENCES
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.
B-12
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Mammalian Toxicology and Human Health Effects
EXPOSURE
Introduction
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
C-l
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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).
02
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TABLE la
Chloroalkyl Ethers Covered in this Document
Names, Abbreviations and Synonyms
Chloromethyl methyl ether (CMME)
other names: dimethylchloroether; methyl
chloromethyl ether
Formula
C1CH2OCH3
Bis (chloromethyl)ether (BCME)
other names: chloromethyl ether;
Chloro(chloromethoxy) methane; dichloromethyl ether;
dimethy1-1,1-dichloroether
C1CH2OCH2C1
methyl ether
other name: 1,1-dichloromethyl methyl ether
C12CHOCH3
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
CH3GHOCHCH3
Cl Cl
C1CH2CH2OCH2CH2C1
ClCH-CHOCHCHnCl
I \
CH3 CH3
2-Chloroethyl vinyl ether
C1CH2CH2OCH=CH2
Octachloro-di-n-propyl-ether
C13CCHCH2OCH2CHCC13
Cl
C-3
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Table la cont,
2,3-Dichlorotetrahydrofuran
2,3-trans-Dichloro-p-dioxane
Cl
Cl
Bis-l,2-(chloromethoxy)ethane
C1CH2-O-CH2CH2-O-CH2C1
Bis-l,4-(chloromethoxy)butane
C1CH2-O-CH2CH2CH2CH2-0-CH2C1
Bis-l,6-(chloromethoxy)hexane C1CH2-O-CH2CH2CH2CH2CH2CH2-O-CH2C1
Tr is-1,2,3-(chloromethoxy)propane
CH2-Q-CH2C1
CH -O-CH2C1
CH2-0-CH2C1
Bis-(2-chloroethoxy)methane (BCEXM) C1CH2CH2-O-CH2-O-CH2CH2C1
Bis-l,2-(2-chloroethoxy)ethane (BCEXE) C1CH2CH2-O-CH2-CH2-0-CH2CH2C1
C-4
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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
20
Solubility
o
i
LTI
CHI-IE
BCME
BCEE
80.5 colorless liquid
115.0
colorless liquid
143.01 colorless liquid
BCIE 171.07 colorless liquid
59°C d2^= 1.0605
104°C
1.3974
=1.328 1.435
-24.5°Ca 176-178°C d*° =1.213 1.457
-51.9°Cb
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
solvents.
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
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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
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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-
C-7
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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-
C-8
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TABLE 2
Occurrence of Principal Chloroalkyl Ethers in Various Types of Water
Reference
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
RW
RW
WW
RW
FDW
WW
WW
BCEE
BCIE
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:
BCEXM
BCEE
BCIE
140,000
160
n. q.
U.S. EPA (1975)
U.S. EPA (1975)
Manwaring, et al.
(1977)
Sheldon and Kites
(1978)
Dressman,
Carrollton station
•
Jefferson station #1
Jefferson station #2
Unspecified
Philadelphia, Pa.
Delaware River
Philadelphia, Pa.
Delaware River
Philadelphia, Pa.
Delaware River
et al. (1977) and U.S.
FDW
FDW
FDW
FDW
FDW
FDW
FDW
FDW
FDW
WW
FDW
RW
RW
EPA (1977
BCEE
BCIE
BCEE •
BCIE
BCEE
BCIE
BCIE
BCEE 0
BCEXE
BCEE 0
BCEE 0
BCEE n
BCEXE
) — see Table
0.04
0.18
0.16
0.08
0.12
0.03
1.58
.42-0.5
0.03
.23-41
.04-0.6
.d. -trace
15
3
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.
C-9
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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
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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-
i
C-ll
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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
s
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
i
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.
C-12
-------
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.
City
number
17
18
32
40
56
60
65
67
75
77
80
88
102
109
121
122
BCEE
0.19
0.14
0.02
0.01
0.17
0.13
0.01
0.30
0.06
0.06
0.36
—
0.02
0.01
BCIE
0.03
0.03
:
0.14
0.17
0.09
0.09
0.55
0.02
. .
Mean cone. 0.10 '0.17
of positives
Percent .
incidence
among cities 11.5% 7.1%
surveyed
aSummarized from Dressman, et al. (1977)
C-13
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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
C-14
-------
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
i
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.
C-15
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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-
fr
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.
C-16
-------
Inhalation
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
C-17
-------
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.
C-18
-------
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
f
found to be generated during the reaction of 100 ppm of
each of the reactants in dry nitrogen.
Dermal
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
C-19
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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
•c.r
IBHARMAGOKI^ET-ICS
?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-
i
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.
C-21
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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.
EFFECTS
Acute, Sub-acute and Chronic Toxicity
Animal Studies: The acute toxicity of a variety of
chloroalkyl ethers has been studied in different animal
C-22
-------
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.
C-23
-------
TABLE 4
Acute Toxicity of Chloroalkyl Ethers
Compound
Bis(chlocomethyl)ether,
BCME
Bis(2-chloroethy1)ether,
BCEE
n
i
Test species Route
Chloromethylmethyl ether. Rat
CMME
Hamster
Rat
Mouse
Rabbit
Hamster
Rat
Guinea Pig
Bis(2-chloroisopropyl)ether, Rat
BCIE
Rabbit
2-Chloroethylvinyl ether
Rat
Rabbit
Oral
Inhalation
Inhalation
Oral
Inhalation
Inhalation
Skin
Inhalation
Oral
Inhalation
Skin
Inhalation
Oral
Inhalation
Skin
Oral
Inhalation
Skin
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
hr
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.
(1969)
(1975)
(1971)
(1969)
(1975)
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
Compound
Test Species
2-Chloromethyltetrahydro- Mouse
f uran
Trans-2,3-dichloro-p-
dioxane
Rat
Rabbit
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 )
Route
i.p.
oral
i.p.
skin
i.p.
i.p.
i.p.
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
Reference
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
,f
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).
C-26
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TABLE 6
Summary of Non-Tumor Pathology in Mice and Rats After Repeated Oral Doses of BCIE (NCI, unpublished results).*
Incidence (%)
Organism
Rats, male
Rats, female
Mice, male
Mice, female
Untreated
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
2
0
8
0
0
0
0
0
10
0
0
0
0
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)
2
4
10
18
0
2
2
26
4
6
2
0
0
0
14
4
* 20
2
33
2
20
1
2
27
2
19
14
24
22
82
15
46
15
65
27 .
14
0
5
6
*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
noted.
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.
1973).
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
C-28
-------
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-
C-29
-------
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,
respectively.
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
C-30
-------
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.
f
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. '
Teratogenicity
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
C-31
-------
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
t
be classified as a chloroalkyl ether, the teratogenicity
of other chloroalkyl ethers (especially the environmentally
important and stable BCEE and BCIE) should be critically
studied.,
Cl F H
111
H-C—C-O-C-H
1 I I
Cl F H
methoxyflurane
Mutagenicity
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,
C-32
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TABLE 7
Comparison of Carcinogenic and Mutagenic (in Microbial
System) Activity of Chloroalkyl Ethers
Compound
Mutagenicity
Carcinogenicity
CMME
BCME
BCIE
, -^Dichloromethylmethyl ether
Bis( -chloroethyl)ether
BCEE
Octachloro-di-n-propyl ether
2,3-Dichlorotetrahydrofuran
2,3-trans-Dichloro-p-dioxane
+
+
+b
+
+
-,+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).
C-33
-------
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-
G-34
-------
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.
Carcinogenicity
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-
tion.
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-
C-35
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TABLE 8
Comparison of Carcinogenic Potency
of Alkylating Agents on Mouse Skin
Compound
Dose,
(mg)1
Days Mice with
to 1st carcinoma/no.
tumor of mice tested
Median
survival
time (days)
BCME
2.0
161
12/20'
313
vB-Butyrolactone
10
252
15/30C
438
-Propiolactone
2.5
9/301
200
Glycidaldehyde
3.0
212
8/30'
496
D,L-l,2:3,4-Di-
epoxybutane
3.0
326
6/30'
475
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
C-36
-------
TABLE 9
Carcinogenicity of Chloroalkyl Ethers by Skin Application or s.c. Injection*
n
i
Carcinogenicity on Mouse Skin
(mice with papillomas/group size )
Compound
CMME
BCME
o< ,s.-Dichloromethylmethyl ether
Bis (<-chloroethyl ether
BCEE
Octachlorodi-n-propyl ether
2,3-Dichlorotetrahydrofuran
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"complete"
carcinogen
0/40
13/20
0/20
—
—
0/20
2/50
4/50
1/50
0/50
6/50
(0)
(12)
(0)
(0)
(0)
(4)
(1)
(0)
(3)
as "initiator"
12/40
5/20
3/20
7/20
3/20
3/20
5/20
8/30
—
—
—
(5)
(2)-
(1)
(0)
(0)
(1)
(1)
(2)
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-
C-38
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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
agent.
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
C-39
-------
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-
1
ogenic although it was not certain whether the effect was
3
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-
C-40
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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
Control
130
20/49 (41%)
0.37
Urethane 138
130
46/49 (94%)
54.20
BCME
82
26/47 (55%)
2.89
CMME
101
25/50 (50%)
1.53
Summarized from Leong, et al. (1971)
C-41
-------
TABLE 11
Inhalational Carcinogenicity of BCME ana CMME in Rats ana Hamsters
Species i
Co.iipGijrici strain
BCME Sprague-
Oawley
male rats
Syrian
golden
male
o hamsters
&
CMME Sprague-
Dawley
male rats
Syrian
golden
male
hamsters
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
Nose
Esthesioneuroepithelioma
Malignant olfactory tumor
(unclassified)
Ganglioneuroepithelioma
Squamous cell carcinoma
involving turbinates
and gingiva
Poorly differentiated
epithelial tumors
Adenocarcinoma
(nasal cavity)
17
1
1
1
447
405
334
594
462
696
266-853
405
334
594
253-676
652-739
Lung
Squamous cell carcinoma 13
Adenocarcinoma 1
411
877
215-578
877
From Kuschner, et al. (1975)
C-43
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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.
C-44
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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
C-45
-------
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-
«•.
cation).
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).
C-46
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TABLE 14
Caccinogenicity of BCEE in Mice and Rats by Oral or i.p. Administration
Species & strain
Treatment
Carcinogenic response'
Reference
7-dav-oid
(C57BL/6XC3H/Anf)Fi
7 7-day-old
£ (C57BL/6XAKR)F1
mice
6-3 weeks old,
ma 1 e
Strain A/St
mice
Charles River CD
rats
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
communication)
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
X
• 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
2,3-trans-dichloro-p-dioxane.
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
G-48
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o
I
*k
10
TABLE 15a
Summary of Total Tumor Incidence in Rats After Repeated Oral Doses of BCIE (NCI, unpublished)
Untreated
Control
RATS, MALE:
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
RATS, FEMALE:
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
50
50
50
50
102
47
67
29
35
1
1
50
50
49
36
59
29
43
14
16
3
4
Vehicle
Control
50
50
50
45
84
43
56
22
27
1
1
50
50
50
39
62
31
47
13
15
1
1
Low Dose
100 mg/kg/day
50
50
50
47
82
46
63
17
18
4
6
1
1
50
49
49
32
51
28
39
12
12
1
1
High Dose
200 mg/kg/day
50
50
50
34
48
30
38
8
8
1
1
2
2
50
48
48
15
22
11
15
7
7
1
1
"Primary Tumors: All tumors except secondary tumors,
Secondary Tumors: Metastatic tumors or" tumors invading into an adjacent organ,
-------
o
01
o
TABLE 15b
Summary of Total Tumor Incidence in Mice After Repeated Oral Doses of BCIE (NCI, unpublished)
Untreated
, Co'ntrol
MICE, MALE:
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
MICE, FEMALE:
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
50
50
50
13
13
3
3
10
10
50
50
50
6
6
1
1
5
5
Vehicle
Control
50
-
50
50
11
11
4
4
7
7
1
1
50
1
49
49
5
5
2
2
3
3
Low Dose
10 mg/kg/day
50
50
50
10
10
2
2
8
8
50
49
48
4
4
1
1
3
3
High Dose
25 mg/kg/day
50
1
49
49
12
12
3
3
9
9
50
50
50
4
4
2
2
2
2
"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
Compound
Dose regime
and duration
Carcinogenic response
Median survival
time (days)
-BCME
2,3-trans-Dichloro-
o p-dioxane
i
en
1,2-Bis-(chloro-
methoxy)ethane
1,4-Bis-(chloro-
methoxy)butane
l,6-Bis(chloro-
methoxy)hexane
1,2,3-Tr is-(chloro-
methoxy)propane
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
(1973)
Figueroa, et al. 14 33-55 1-14 —
o (1973)
i
Ln
to
Weiss and 11 36-55 2.2-16.6 10-24
Figueroa
(1976)
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
(1976)
Bettendorf 1 42 6 —
(1976)
Reznik-, et al. 1 45 2 12-13
(1977)
Working activity
Dyestuff factory
(Japan)
Chemical plant
(Germany)
Chemical plant
(Philadelphia)
Chemical plant
(Philadelphia)
Chemical plant "
(Philadelphia
Anion-exchange
resin plant
(California)
Research chemist
(Germany)
Research chemist
(Germany)
Smoking habit
All moderate
to heavy
smokers
6 moderate
to heavy
smokers
2 unknown
3 nonsmokers
1 pipe smoker
10 smokers
3 nonsmokers
1 cigar smoker
2 ex-smokers
5 smokers
4 smokers
1 unknown
nonsmoker
Histologic type
of cancer
1 oat cell
1 adenocar-
carcinoma
3 unspecified
5 small cell-
undif fer-
entiated
3 unspecified
12 small cell-
undif fer-
entiated or
oat cell
1 epidermal
1 unknown
10 small cell-
undif fer-
entiated
1 oat cell
4 small cell-
undif f er-
entiated
1 large cell-
undif fer-
entiated
adenocarcinoma
adenocarcinoma
-------
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.
C-53
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o
I
TABLE 18
Increased Risk of Respiratory Cancers After Exposure to BCME and/or CMME
Reference
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
(1976)
Cancer incidence
No. of Population Cancer incidence in control
cases at risk in risk group (X) group (Y)
5
4
5
22
3
12
4
•
19
32
88
136
1800
12
91
188
699
5/32/16 yrs.
4.54/100/5 yrs
5/136/18 yrs
1.48/1000/yr
23/1000/yr.
8.7/1000/yr.
1.5/1000/yr.
1 "'•' "
0.024/32/16 yrs
. - . . -
0.57/100/5 yrs.
0.54/136/18 yrs.
0.59/1000/yr.
0.97/1000/yr.
0.97/100fl/yr.
0.97/1000/yr,
.
Increased
risk p-value
(X/Y)
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
C-55
-------
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
carcinogens.
C-56
-------
TABLE 19
Relationship of Respiratory Cancer Mortality to Duration
and Intensity of Exposure to BCME and/or CMME
Duration of
Exposure
(years)
10-19
5-9.9
2-4.9
0.1-1.9
Control
Cumulative
Weighted
Exposure
Index0
20-50
10-19.9
5-9.9
0.1-4.9
Control
Observed
Deaths
3
7
10
3
18
Observed
Deaths
8
8
4
3
18
Expected
Deaths
0.2
1.9
2.8
6.7
29.4
Expected
Deaths
0.9
2.4
1.6
0.7
29.4
Relative
Risk
26.6
6.0
5.7
0.7
1.0
Relative
Risk
14.5
5.4
4.2
0.7
1.0
Man-year-
at-risk
97
1,024
1,981
5,591
21,909
Man-year-
at-r isk
482
1,398
1,176
5,637
21,909
aAdapted from Pasternack, et al. (1977)
CWEI = jDuration of Exposure X Intensity (varing across
exposure periods)
C-57
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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
C-58
-------
(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,
i
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
C-59
-------
(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 ;
C-60
-------
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)
C-61
-------
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
C-62
-------
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.
C-63
-------
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
*5
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.
C-64
-------
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
f
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.
C-65
-------
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
0
io-7
10
-6
(jug/1) (>ig/l)
0
0
0
0
0
0
0
0
0
0
0
0
.115
.0042 .
i.02xlO~b
.231
.0219
.09x10'^
1.
0.
0.
2.
0.
0.
15
042 .
02x10"*
31
219 .
09xlO~4
10
-5
jug/D
11.
0.
0.
23.
2.
0.
5
42
02x10
1
19
09x10
-3
-3
(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.
C-66
-------
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.
C-67
-------
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i -
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-• '
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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.
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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,
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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
_c
lower than the actual level which would produce a 10 life-
time cancer risk due to exposure to BCIE.
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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
\*t
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
\~r
Le = 104 wk
lo = 104 wk
L = 104 wk
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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..
n
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
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Bis (2-Chloroethyl) ether
The water quality criterion for BCEE is based on the
t
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.
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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
C«»
NC = 240 R = 31
Le = 104 wk
le = 104 wk
L = 104 wk
Based on these parameters, the one-hit slope (Bu) is
ti
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.
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