Investigation of Selected
Potential Environmental
Contaminants: Haloalcohols
Syracuse Research Corp., NY
Prepared for
Environmental Protection Agency
Washington, DC
Mar 80
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LIST OF TABLES
Structure and Nomenclature of Haloalcohols
Physical Properties of Haloalcohols
Commercial Specifications for Haloalcohols
Kinetic Data for Epoxide Formation from Haloalcohols
in Water
Dehydrochlorination of Mixtures of Propylene Chlorohydrin
(PCH) Isomers in a Boiling Aqueous Suspension of Mg (OH)2
and Ni (0H)2
Observed Oxidation Hates for Various Haloalcohols
Specific Sate Constants (£moles ^"sec for Reactions
of Haloalcohols with H, .OH, and e~
aq
Estimated 1977 Annual Production Volumes of Haloalcohols
1977 Market Prices for Haloalcohols
Products from Enzymatic Conversion of Epihalohydrins and
Haloalcohols
Monitoring Information on Haloalcohols in Water
Acute
Toxicity
of
3—Chloro-1,2-propanediol
Acute
Toxicity
of
2-Chloroethanol
Acute
Toxicity
of
Trifluoroethanol
Acute
Toxicity
of
2-Fluoroethanol
Acute
Toxicity
of
Trichloroethanol
Acute
Toxicity
of
2-Chloro-l-propanol
x
-------
LIST OF FIGURES
Figure Page
1 Production of Propylene Oxide through Chloropropanols 35
2 Epichlorohydrin Manufacture 38
3 Production of Glycerine (glycerol) via Epichlorohdryin 39
4 Chlorohydrin Process for Manufacturing Ethylene Oxide 41
5 Production of 2,3-Dibromo-l-propanol 43
6 Production of 2,2,2-Xrifluoroethanol through Reduction
with LiAlH4 44
7 The Metabolism of 3-Chloro-l,2-propanediol CHI) 90
8 Proposed Intermediary Metabolism of TCE 91
9 Metabolism of Trifluoroethanol 93
xi
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I. Physical and Chemical Data
A. Structure and Properties
1. Chemical Structure and Nomenclature
The ten haloalcohols reviewed herein are derivatives of ethanol,
1- or 2-propanol or 1,2-propanediol which contain one or more halide atoms
(fluoride, chloride, or bromide). Table 1 lists the following information on
the haloalcohols under study: International Union of Pure and Applied Chemistry
(IUPAC) system names, common names, molecular formulae, molecular structures,
and CAS numbers. These ten compounds were selected because of their commercial
significance; however in some cases, information on environmental fate and
toxicity on other haloalcohols will be reviewed when the information is
available.
Throughout this review the haloalcohols are referred to by
their IUPAC system names. In this system, the names are based upon the parent
alcohol and the carbon skeleton is numbered from the end of the chain closest
to the alcohol group (OH). The skeletons and numbering for the parent alco-
hols of the haloalcohols under review are as follows:
C2 - Cx - OH
ethanol
c3 - c2 " ci ~ OH
1-propanol
1
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Table 1. Structure and Nomenclature of Haloalcohols
Molecular CAS Registry
Formula Molecular Structure Number
C^BrO
BrCH2CH2OH
540-51-2
IUPAC System Name
2-Bromoethanol
Synonymous
Trivial Names
B-Bromoethyl alcohol
Ethylene bromohydrin
Glycol bromohydrin
2-Bromo-l-hydroxyethane
c2h5cio cich2ch2oh
107-07-3
2-Chloroethanol
B-Chloroethyl alcohol
Ethylene chlorohydrin
Glycol chlorohydrin
Chloro-l-hydroxyethane
C»H_C1_0 CI CCH_0H
2 3 3 3 2
115-20-8
2,2,2,-Trichloroethanol
Trichloroethyl alcohol
2,2,2-Trichloro-l-
hydroxyethane
c2h3f3o f3cch2oh
78-89-8
2,2,2-Trifluoroethanol
Trifluoroethyl alcohol
2,2,2-Trifluoro-1-
hydroxyethane
c3h7cio ch3chcich2oh
78-89-7
2-Chloro-l-propanol
B-Chloropropyl alcohol
Propylene-B-chlorohydrin
2-Chloro-l-hydroxypropane
c3h7cio ch3chohch2ci
127-00-4
l-Chloro-2-propanol
B-Chloroisopropyl alcohol
Propylene a-chlorohydrin
sec-Propylene chlorohydrin
l-Chloro-2-hydroxypropane
C.H,Br„0 BrCHoCHBrCH„0H 96-13-9
J O 2. / I
2,3-Dibromo-l-propanol
B-Dibromohydrin
Glycerin - a, 3-dibromohydrin
2,3-Dibromo-l-hydroxypropane
-------
/
Table 1. (Continued)
Molecular
Formula Molecular Structure
CAS Registry
Number
IUPAC System Name
Synonymous
Trivial Names
C3H6C12°
C3H6C12°
C1CH2CHC1CH20H
C1CH2CH0HCH2C1
616-23-9
96-23-9
2,3-Dichloro-l-propanol 0,Y-Dichloropropy1
alcohol
Allyl alcohol dichloride
Assym. glycerin
dichlorohydrin
0-Dichlorohydrin
2,3-Dichloro-l-hydroxy
propane
1,3-Dichloro-2-propanol 3,0*-Dichloroisopropyl
alcohol
Glycerin a,a'-dichlorohydrin
a-Dichlorohydrin
1,3-Dichloro-2-hydroxypropane
c3h?cio2
hoch2chohch2ci
96-24-2
3-Chloro-l,2-propanediol a-Monochlorohydrin
a-Chlorohydrin
3-Chloro-l,2-dihydroxy
propane
-------
OH
c3 - C2 - C,
2-propanol
OH
C3 - C2 - Cj-OH
1,2-propanediol
Several alternative, common nomenclature systems exist for halo-
alcohols. The most widely used common system names the haloalcohols as "olefin
halohydrins"; 2-chloroethanol is called ethylene chlorohydrin and the mono-
chlorinated propanols are referred to as propylene chlorohydrin. The litera-
ture very often refers to the haloalcohols by this system rather than by the
1UPAC nomenclature.
2. Physical Properties of the Pure Material
The haloalcohols are characterized as colorless, dense, hygro-
scopic liquids at ambient temperature (Lichtenwalter and Riesser, 1964).
Their odors are characterized as "ether-like" or "ethanol-like" (Windholz,
1976; Halocarbon Products, 1967). The hydroxide group and its ability to
hydrogen bond have dominant influence upon physical properties. The halide
substituents affect the physical properties through its addition to molecular
weight and its inductive and electronic effects. Table 2 lists the salient
physical properties of the ten haloalcohols. The brominated and chlorinated
ethanol and propanol derivatives have similar properties, while trifluoro-
ethanol and chloropropanediol differ considerably.
4
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Physical Properties of Haloalcohols (Adapted from Beilsteins Handbuch
der Organischen Chemie - Prager and Jacobson, 1918; Richter, 1928, 1941,
1958; Lange, 1967; McCabe and Warner, 1948; Hodgeman, 1961; Windholz,
1976; and manufacturers data - Aldrich Chemical Co., 1977; Halocarbon
Products, 1967; Great Lakes, 1972 - Ballinger and Long, 1959;I960)
h«£«rl2
Miliculir Height (|)
Ht 11Inft Folnt (*C)
ftwllIng Point {*C)
IrCNjCH^OM
12*.9?
149-150
(J50 torr)4
56-57 (20 torr)
ClUI^CHjOM
80.52
&H Vaporlcatloo
0«nal(y 20/4(g/cc)
10
"u
Vipoi prtiiuii (loir)
1.7720
1.49608
DiiiMlilloo Conatant
I (waiar)
12).9-128.1
(760 lore)
I) ()-4 tori)
122.97 c«l/d«g
•I 126.55*
1-20190
1.19116
).* i 10 '
(25*C)
Mac. miii
alcohol, i(h«t
CI jCIMjOH
149.42
17. *
15) (7)7 core)
111 (170 toir)
52-54 110 lorr)
Allotropa wllh
-•t.fi Co
(X tUloalcohol)
&M coabuilIon
(Const. Vol.)
Flash Point, aF
J.7 . 10" '
(25*C)
Hlac. Hitaf
aolubla Mil
org. Solvaota
eacapt pat athot
99. I* 1762. 4 ton) 97 .85*
)5i 45.n
0 OH95f/c» acc 0.02688g/ca ate
(20*)
Sol. I pari to
12 parta watar;
¦lac. alcohol,
athar
)604cal/«
1)5
100.04
-45.00
77-00
CM ^CHClCHjOM
94.54
(762 lorr)
40-41 (15 lorr)
24 . 5(10*0
5)(20*C)
9)()0*C)
Sol. Miai, alic.
oif|«Mtfd organic
aolvanta, low ael.
mi. aroaailc aolvanta
as4 aoaa haloganatad
hydrocarbooa
0.0l995|/c« mc
(20*)
211.9 Kxal/aola
1055 (12 loir)
52 (5 torr)
1)67
1.48)5
50(55*C)
Sol. In 10 patta
waUl,
•lac. athanol,
atbar
)151cal/g
125
riCH^CIIOHI.H^UH
II0.H
JIM
116 (II torr)
0.02(20*C)
0 05(10*0
0.1 (40*CI
•lac. Macar«
alhaool,
acatona. athcr
1. 59 t/tm aac
(20*C)
401. tkcal /*>!•
1)8
d»dccu*poaltIon
-------
Although the pure materials are colorless liquids, the bromin-
ated and chlorinated alcohols usually appear slightly colored since they
partially decompose and turn yellow as they age. Trifluoroethanol appears to
be an exception since it is more stable (see Subsection I.B.I). Since the
haloalcohols have flash points in excess of 100°F, they are not classified as
flammable liquids by DOT standards. Also, dibromopropanol is a fire-retardant
and does not support combustion (Great Lakes Chemical, 1972).
The haloalcohols as a class are water soluble. Bromoethanol,
chloroethanol, trifluoroethanol, and chloropropanediol are miscible in all
proportions with water. The least soluble are trichloroethanol and the
dihalopropanols. When available, water solubility data for the individual
haloalcohols are included in Table 2.
Vapor pressure data was only available for four haloalcohols.
Trifluoroethanol, unlike the chlorinated and brominated alcohols, is fairly
volatile. It has a vapor pressure of 53 torr at ambient temperature (20°C).
Chloropropanediol, at the other extreme, has a vapor pressure of 0.02 torr
(20°C). This low vapor pressure is attributed to greater hydrogen bonding by
glycols. The vapor pressure data for chloroethanol (6.3 torr, 17.5°C) is the
only other value available for ambient temperature. By comparing the molecular
formula and boiling point, it is reasonable to estimate about 5 to 10 torr
(ambienc temperature) for vapor pressure of the monochloropropanols and
lower vapor pressures of the remaining haloalcohols.
The haloalcohols will dissociate in water according to the
equilibrium:
K
ROH — R0~ + H
6
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Table 2 lists the ionization constants, K , for four haloalcohols. Two of
a
these, bromoethanol and chloroethanol, are weaker acids than water by approxi-
mately three orders of magnitude. Trifluoroethanol and trichloroethanol are
slightly more acidic than water (Roberts et al., 1956).
Levitt and Levitt (1971) have determined the basicity constants
of alcohols in aqueous solution:
K.
RGH + H-,0* ^ ROH„+ + H„0
3 2 2
Ihey reported pK of -4.20 to -4.30 and -4.27 to -4.35 for trichloroethanol
and trifluoroethanol, respectively.
Trifluoroethanol is a useful solvent because of the combined
properties of its ioniziation constant (Halocarbons Products, 1967), high
ionizing power, and low nucleophilicity (Harris et al., 1974; Schadt et al.,
1974). It is an excellent solvent for organic reactions which require the
formation of a carboniuo ion.
Haloalcohols do not absorb U.V. light above the cut-off for
natural sunlight, 300 nn (Calvert and Pitts, 1966). From the limited infor-
mation available, the compounds do appear to absorb at lower wavelengths.
Continuous absorption is reported below 214 nm for liquid bromoethanol and
below 221 nm and 204 nm for chloroethanol as liquid and vapor, respectively
(Richter, 1958).
3. Physical Properties of Commercial Materials
Because the bulk of chloroalcohols produced are captive inter-
mediates, relatively small amounts are refined for sales (see Subsection
IX.B.l). The commercial materials are marketed in high purity and do not
significantly differ in properties from the pure materials.
7
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I
In some applications, freedom from certain impurities is more
important than chemical uniformity. Chloropropanols, for example, are pro-
duced and sold as isomeric mixtures for certain purposes. While the mixtures
naturally differ physically in minor ways from the pure isomers, the differ-
ences are of no consequence in their chemical intermediate application.
Table 3 summarizes specifications for the commercial haloalcohols.
4. Principle Contaminants of Commercial Products
Because preparation methods vary for the different haloalcohols,
the impurities also differ. Relatively little information on impurities was
available and none was quantitative.
The mono- and dichloroalcohols are produced by similar reaction
sequences and as the result of analogous side reactions, similar impurities
are formed. As discussed above (see Subsection 1.A.3) relatively little
information was available which described specifications or impurities of the
small amounts of these haloalcohols refined for commercial markets. So the
information on these impurities is not always verified.
Chloroethanol, chloropropanols, and dichloropanols are prepared
by the addition of hypochlorous acid (H0C1) to ethylene, propylene and allyl
chloride, respectively (see Section II.A.3). Major by-products of this reac-
tion are chlorinated ethers and chlorinated olefins. Subsequent cyclization
reactions could yield the corresponding epoxides. Propylene chlorination to
produce allyl chloride can produce dihalopropenes as well. In summary, poten-
tial impurities in each compound are as follows:
8
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Table 3. Commercial Specifications for Haloalcohols
(Adapted from Manufacturers' Product
Data Sheets)
3 4
2,3-Dibromo-l-propanol 2-Chloroethanol 2,2,2-Trichloroethanol
Appearance clear liquid, no clear liquid, colorless liquid
suspended matter pale amber
Color, AFHA max 50*
Water, %, max 0.05^" 0.1^
I
Acidity, mgKOH/gm 0.05"*", 0.1^
max
2
Bromine, % 73
2
Viscosity, 33
Assay 98% min 98% min
^ Great Lakes Chemical Co., West Layfayette, Indiana
2
Velsicol, Chicago, Illinois
3
Evans Chemetics, Darian, Connecticut
4
Aldrich Chemical Co., Milwaukee, Wisconsin
9
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In dichloropropanols (Gruber, 1976)
\ cis- and trans- 1,3-Dichloropropene
1,2-Dichloropropene
1,2,3-Tr ichloropropene
Chlorinated ethers
Chlorinated saturated and unsaturated,
short-chained aliphatic hydrocarbons
Epichlorohydrin
In chloroethanol (Lichtenwalter and Riesser, 1964)
Ethylene dichloride
Vinyl chloride
Chlorinated ethers
Ethylene oxide
Ethylene glycol
In chloropropanols
Chloropropylenes
Chlorinated ethers
Ep ichlorohydr in
Propylene glycol
3-Chloro-l,2-propanediol is an intermediate during dichloropropanol conversion
to glycerin (see Subsection II.A.3). The by-products already present in the
dichloropropanols are potential impurities of 3-chloro-l,2-propanediol.
Glycidol which is an intermediate in the reaction sequence and glycidol
ethers which are formed as by-products are potential impurities.
Bromoethanol production, which consists of the addition of
hydrogen bromide to ethylene oxide, could be accompanied by brominated ether
formation as a by-product (see Subsection II.A.3) and therefore brominated
ethers are potential contaminants.
Trifluoroethanol is manufactured by the reduction of trifluoro-
acetyl chloride (see Subsection II.A.3). An intermediate of this reduction is
trifluoroacetaldehyde, and, therefore, it is a possible contaminant. Trichloro-
ethanol, which is similarly prepared, has trichloroacetaldehyde as a potential
contaminant.
10
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2,3-Dibromo-l-propanol is manufactured by catalyzed bromine
addition to allyl alcohol (see Subsection II.A.3). The major side reaction
yields 1,2,3-tribromopropane (demons and Overbeek, 1966). Other by-products
are brominated ethers, brominated short-chain hydrocarbons and isomeric
brominated propyl alcohols. Also, epoxide (epibromohydrin) forms during
storage and handling (Great Lakes, 1972).
B. Chemistry and Environmental Chemical Reactions
The environmental chemistry of the selected haloalcohols has been
estimated from laboratory studies on their hydrolysis, oxidation, and free-
radical reactions. Haloalcohols are expected to react in water and in the
atmosphere.
Water chemistry of the haloalcohols included hydrolysis reactions
(which would be present in any aqueous solution) and oxidation reactions (which
may assume importance in water purification processes). Haloalcohols, with the
possible exception of trifluoroethanol, will be hydrolyzed in aqueous solution by
a complex kinetic scheme to yield glycols. In alkaline solution the process
initiates with cyclization to epoxides. At neutral or acid pH, hydrolysis
yields glycol directly. The description of haloalcohol oxidation was derived
from studies of reaction with a wide variety of oxidants including permanganate,
bromate, bromine, and chlorine. The expected initial products are analogous
carbonyl compounds (e.g., halogenated aldehydes and ketones). Under normal
conditions of water treatment and potable water distribution, the hydrolysis
reactions account for virtually all haloalcohol degradation.
Haloalcohol chemistry in the atmosphere approximately consists of
oxidation reactions initiated by atmospheric free-radicals and chemical oxidants.
11
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It would appear that direct photolysis of the haloalcohols does not significantly
contribute to degradation since these materials do not absorb ultraviolet light
of wavelengths found in sunlight.
1. Hydrolysis and Related Reactions
The hydrolysis reactions of simple haloalcohols have been
partially characterized. Most of the work has consisted of mechanistic
studies and mainly has evaluated ethylene halohydrins (2-haloethanols). Since
most studies evaluated alkaline hydrolysis, the reactions of haloalcohols are
best characterized in aqueous alkali. Less information is available concern-
ing their hydrolysis in neutral or acidic solution. Table 4 summarizes the
specific rate constant for hydrolysis of various halohydrins. The hydrolysis
kinetics were measured by determining the rate of chloride formation:
k
HO-C-OC1 * organic products + Cl
The hydrolysis of the chlorohydrins was reviewed by Frost and
Pearson (1951). Their characterization remains the most complete description
of known data and of predicted behavior. Their review took information from
studies by Br
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Table 4. Kinetic Data for Epoxide Formation
from Haloalcohols in Water
Halohydrin (R^CHOH)
R1 R~
Temperature
CO
k0H"
Keq (lmole ^min ^")
k
neutral
(min
BrCH2
H
0
5
10
0.987b
2.03b
b 3*95b
25
AO
70
2.7 x lO"*17
4.74 x
2.07 x
io"6C
; lO"4'
C1CH0
H
18
0.31(est.)a
0
15
25
30
0.0167b
0.153b
17b .
3.6 x 10 0.600
5.4 x
10 "^(ext.)d
35
2.17b
8.4 x
10 ^(ext.)^
65
81.6 x
10~7(ext.)c
99
300 x
10 ^(ext.)c
FCH
H
30
0.150b
z
40
0.00508b
60
70
0.0380b
1.8 x
lO"7'
CH3CHC1
H
18
25
1.7(est.)a
7.8 x
10~3(est.)d
ch7ci
ch3
18
25
6.5a
6.0 x
10 ^(est.)^
(CH3)2CC1
K
18
77a
0.393 x
10-2*
{ch3)2cci
ch3
18
633a
0.206 x
xo-2*
(C2H5)2CC1
H
18
358a
2.67 x
10-2"
(a) Nilsson and Smith,
1933
(b) McCabe
and Warner,
1948
(c) Cowan
et al., 1950
(d) Ketola et al., 1978
13
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Frost and Pearson considered pathways by which the chlorohydrins
hydrolyze to initially yield epoxides or glycols. The epoxide, when it is
formed, is in equilibrium with the halonydrin. They demonstrated the equilibria
with 2-chloroethanol:
kl
hoch2ch2ci + oh\ :, ?. c2hao + ci~ + h2o
k2
k' +
H0CH_CH_C1 C0H. 0 + H + CI
2 2 2 4
k3
The specific rate constants k^, k2, and were measured and they estimated a
-13 -1
value for k. froo the data as 6.4 x 10 s at 2QaC. Direct studies on the
4
halohydrin's epoxidation in alkali has demonstrated that the epoxide does form
through the anion of the halohydrin;
k_
2
H0~ + H0CH2CH2C1 ^ " 1 H20 + OCl^CH^l »- C^O + Cl~
Direct studies on the hydrolysis of 2-chloroethanol disclosed that it directly
hydrolyzed to glycol (Cowan et al, 1950):
+
C1CH2CH2QH + H20 2-b. HOCH2CH2OH + H + CI
The specific hydrolysis rate (estimated to 20°C) was 6 x 10 ^ s \ which is
three factors of ten faster than the estimated k..
4
14
-------
Some controversy exists over the possible "spontaneous epoxida-
tion" of chlorohydrin. Frost and Pearson suggested that the direct epoxidation
could occur when chlorides were activated (for example, tertiary chlorides).
None of the selected haloalcohols are expected to epoxidize by this pathway.
Ketola and coworkers (1978) recently suggested a so-called "neutral" hydro-
lysis accompanied the alkali promoted dehydrochlorination of 2-chloroethanol,
l-chloro-2-propanol and 2-chloro-l-propanol. Rates were measured as formation
of chloride ion as described above. They estimated the "neutral" reaction
(k ) which accompanied the alkaline reaction (k ). Observed hydrolysis rate,
0 OH
k^, was expressed as
kt " ko + k0H ^t
where Cc was the average hydroxide ion concentrations. The meaning of kQ is
not clear. Their estimated values are far faster than measured hydrolysis
rates of these or analogous chlorohydrins in neutral aqueous solution. And,
they did not define the "neutral" reaction in terms of organic reaction pro-
duct, i.e., they did not determine if the product was an epoxide.
The haloalcohols can also hydrolyze in alkali by an alternative
route of dehydrohalogenation (elimination of HX). This route initially
yields carbonyl compound, aldehyde or ketone. This alternative pathway appears
controlled by the cation present. Myszkowski and coworkers (1966) reported
product distribution for hydrolysis of propylene chlorohydrin mixtures (1-
chloro-2-propanol and 2-chloro-l-propanol) with ten cations. They noted a
variation in the percentage of acetone; highest production occurred with Ba^+,
Ca^+ and Co^+, and lowest production with K+. Zimakov and Kogan (1951) have
15
-------
described the product composition from refluxing aqueous suspensions of mag-
\
nesium hydroxide or nickel hydroxide with mixtures of l-chloro-2-propanol and 2-
chloro-l-propanoi (ratios of 91:9 and 75:25). Table 5 summarizes their results.
The authors concluded that propionaldehyde directly forms from 2-chloro-
1-propanol and is not a subsequent rearrangement product derived from propylene
oxide. The authors did not speculate on the reason allyl alcohol was a
major product from reflux with nickel hydroxide but a minor product from
reflux with magnesium hydroxide. Also, it is noteworthy that Zimakov and
Kogan did not report any acetone production.
Chloroethanol, bromoethanol, and the chloropropanols react over
solid acid or solid base (aluminosilicates, metal oxides, molecular sieves,
etc.) to yield a variety of products (Anju et al., 1973; Mochida et al.,
1972). Reactions observed included dehydrohalogenation, dehydration, and
elimination of H0C1. On solid acid, (e.g., the aluminosilicates) the reac-
tions appeared to pass through carbonium ion intermediates and products were
either carbonyl compounds or enols from dehydrohalogenation or aliphatic
halides from dehydration:
(Al^O^ or
Si02 - Al 0„)
XCH„CH,OH CH?=CROH —~ CH CHO
-HX
(X=C1 or Br)
16
-------
Base
Table 5. Dehydrochlorination of Mixtures of Propylene Chlorohydrin (PCH)
Isomers in a Boiling Aqueous Suspension of Mg(OH)„ and Ni(OH)_
% Base
(from Zimakov and Kogan, 1951)
Isomeric comp
of PCH, %
Yield, % of initial PCH
PO + PG
CI
S—> 0)
(X T»
O *H
L. V
PL,
fll v ¦* ^ ¦»
~—V
3
V '
1
r-4 <;
n) PL,
f—¦ V .
PA + AA
iH r-H /—V
^ o •
a. U u-i
O >> U-i
t. i ¦
t 1
o
r-i JZ
O
«H O
o o -a
r-H r-H
(D
Mg(OH)2
15
91
9
7.5
62.5
22.2
1.9
5.9
11.2
Mg(OH)2
15
91
9
7.1
52.0
33.4
1.9
5.6
11.4
Mg(OH)2
15
91
9
6.5
61.6
24.6
1.7
5.6
11.8
Mg(OH)2
30
75
25
1.0
64.5
23.0
2.3
6.4
9.7
Mg(OH)2
30
75
25
1.3
67.2
6.3
0.2
25.0
2.9
Ni(OH)2
20
75
25
69.2
4.2
4.8
21.3
0.1
Ni(OH)2
20
75
25
69.8
3.6
4.3
21.6
0.1
Ni(OH)-
20
75
25
71.8
4.6
5.0
18.3
0.5
-------
CH3CHC1CH20H
Al^O^ or SiO^'Al^O^
-HC1
ch3ch2cho
ch2=chch2oh
CH3CH0HCH2C1
*2°3
-HC1
Si0^Al203
-HC1
CH3COCH3
CH3COCH3
~ CH3CH=CHC1
On solid bases the halohydrins can yield epoxides. Some transition metals (such
as Pt or Pd) can catalyze the HOX elimination and the product is the olefin:
hoch2ch2ci
catalyst
-H0C1
ch2=ch2
2. Oxidation
The two types of oxidation reactions that have been studied
will be discussed separately: (1) chemical oxidants (such as bromine, bromate,
permanganate and chloramine-T) and (2) free-radical oxidants. Studies on the
chemical oxidants describe the behavior expected when haloalcohols are
treated by conditions analogous to those of water disinfection (e.g., chlorina-
tion). The latter process, free-radical oxidation, relates to the atmospheric reactions
expected to participate in haloalcohol degradation in the photochemical smog
cycle.
18
-------
a. Chemical Oxidants
\ The information available on haloalcohol oxidation with
chemical oxidants was limited to a few chlorinated and brominated derivatives
of ethanol and propanol, but the results were consistent and should apply to
the remaining haloalcohols reviewed in this study. The chemical oxidants all
converted the alcohols to the corresponding carbonyl group:
R^RjCHOH + [Ox] ~ HjR^O
The oxidants evaluated include single election transfer transition metal com-
plexes (e.g., Co**, Ce*\ and Mn**1) (Waters and Littler, 1965), metal and
halogen oxides (e.g., bromate, chromate, and permanganate) (March, 1968;
Banerji, 1973a; Radhakrishnamurti and Behera, 1971; Natarajan and
Venkatasubramanian, 1969; 1974), halogens (e.g., Br^ and C^) (Banerji, 1973b;
Myszkowski et al., 1974) and Chloramine-T (Natarajan and Thiagarajan, 1975).
Since water is commonly disinfected by a chemical oxidant,
usually chlorine, oxidation of haloalcohols has been considered a potentially
important reaction (Morris, 1975). Quantitative data has been published on
alcohol and haloalcohol oxidation with a variety of the oxidants. No speci-
fic rate data were published for kinetics of haloalcohol oxidation with chlorine.
The available kinetic information suggests that the usual concentrations of
chlorine applied to water (generally less than 10 ppm) are not sufficient to
oxidize chloroalcohols or bromoalcohols at rates which would compete with
their degradation by hydrolysis. Table 6 describes some oxidation rates.
Based upon this data, it is reasonable to assume that haloalcohol oxidation
19
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Table 6: Observed Oxidation Rates for Various Haloalcohols
Oxidant
Kinetic Data
Bro3-
ftlcohol
2-Propanol
1,3-D1ch1oro-2-propano1
Observed Rate
Constant.K
36.8 x 10"4lw"1s"1
13.5 x lo"4lm~1s"1
Rate Expression
- k[A1c][Br(V)]
Conditions of
Oxidation
55°C In 501 aqueous
acetic acid + 0.1M H^SO^
Reference
Natarajan and
Venkatasubramanlan, 1969
Cr03"
Ethanol
2-Chloroethanol
1.36 x lO^lm'V
0.178 x 10"4lm"1s"1
"dC5iV1) 3 k[Alc][Cr(Vl)]
35°C In 70S acetone - Radhakrlshnamarti and
30% water t 0.02S H HC104 Behera, 1971
Mn04-
BrQ
Ethanol
1-Propanol
2-Chloroethanol
2-Bromoethanol
Ethanol
2-Chloroethanol
17.4 x 10"Zl3m"2s"1
25.0 x lO-'lW1
0.166 x lO'^l^m'^s"1
0.200 x 10"2lZm"2s"1
480 x 10"4la»_1 s"1
0.86 x lO^lm'V1
-d(Mn04 ) = |([Alc][Mn(VI)][H+] 35°C
St
d[Br2] = k[Alc][Br ]
~ar
35°f. In 501 aqueous
acetic acid + 0.25 H
sodium acetate
Banerji, 1973a
BanerJI, 1973b
Chloronilne-T 2-Butanol
N-chlorotoluene- l-3-Dichloro-2-propanol
p-sul fonainide)
-S -i«
2.0 x 10 Ds 1
.5 -1*«
0.64 x 10 as 1
= k[CAT]
55°C in 50S aqueous Natarajan
acetic acid: * 0.2H H^SO^ and Thiagarajan, 1975
* 1.0H H2S04
-------
with chlorine will proceed with an apparent bimolecular rate no greater than
-5 2 -2 -1
\ 10 I M s in typical conditions of water treatment (25°C and neutral
pH). If so, the haloalcohol oxidation would proceed at an observed rate of
-9 -1 -1
less than 10 £M s with typical chlorine concentration. This estimated
rate is less than the observed hydrolysis rates for the chlorinated and bro-
minated alcohols (see above).
Myszkowski and coworkers (1974) examined the aqueous
chlorination of several chloroalcohols in a temperature range of 20°C to 60°C.
The selected haloalcohols which they studied were 2-chloroethanol, 1-chloro-
2-propanol, 3-chloro-l,2-propanediol, 2,3-dichloro-l-propanol, and 1,3-dichloro-
2-propanol. The alcohols were oxidized to the corresponding carbonyl compounds
by the reaction:
R]lR2CHOH + HOC1 ~ R1R2C=0 + HC1 + H20
They did not measure rate constants, but did compare rates by means of curves
either of chlorocarbonyl compound production versus time or active chlorine
oxidant concentration versus time. Their observations corresponded with con-
clusions set forth above. Substrates with multiple chlorine substitution were
oxidized more slowly than analogous monochloroalcohols. Terminal alcohols
were oxidized more slowly than secondary alcohols. Also, the oxidation rate
increased with increasing temperature.
b. Free-Radical Reactions
The haloalcohols are expected to degrade in the photochemi-
cal smog cycle as the result of free-radical reactions. Some free-radical re-
actions of 2-bromoethanol and 2-chloroethanol have been studied. The free-
radicals react with the haloalcohols to form radicals that are generated by
21
-------
hydrogen atom abstraction at C (carbon bearing the hydroxyl group) or C,(carbon
CI Jj
bearing the halide), or by halogen atom abstraction. By analogy, the other
\
haloalcohols are expected to react by similar pathways.
Gilbert and co-workers (1972) investigated the radicals pro-
duced in 2-chloroethanol and 2-bromoethanol by atom abstraction with hydroxyl
radical. The hydroxyl radicals were generated from titanium(IIl) - hydrogen
peroxide in an aqueous aystem. The organic free radicals were investigated by
means of electron-spin resonance spectrometry (esr). Chloroethanol yielded an
esr spectrum containing signals of several radicals. The following radicals
were identified: 'CH(OH)CH2OH(a); •CH2CH2OH(b); •CH(OH)CH2CH2CHO(c) ; -CHClCH^HU);
and *CH2CH(OH)2(e). Based upon these results Gilbert et_ al. suggested that the
radicals initially generated underwent additional radical or ion reactions. Hydrogen
abstraction at Ca was minor with respect to abstraction at C .
a
ClCHoCH0H
ClCH„CHo0H
C1CHCH-0H
minor
The remaining radicals came from hydrolysis reactions of C1CH2CH0H:
hochch2oh
-CI
HO CHCH
hochch2ci
HO
CH-CH
2
ch2ch»o
and radical reaction with enol:
ch2=choh + -C^CHO 4iochch2ch2cho
22
-------
The distribution of these radicals was strongly pH dependent. While b and c
were the major radicals at pH 2, they were not detected at pH 3.6 to 4.2. At
the higher pH, e was the major radical. At pH 2 2-bromoethanol yielded prod-
ucts from hydrogen abstraction at Ca; no -CHBrCHjOH radical was detected. The
same proportion of radicals b and c were produced from 2-bromoethanol and 2-
chloroethanol.
Anbar and Neta (1967) measured the specific reaction rate
constants for 2-chloroethanol and 2-bromoethanol with hydrogen atom, hydroxyl
radical, and solvated electron (ea(^)• The radical species were generated by
Y-irradiation of aqueous solutions of the alcohols. Specific rates for various
reactions are summarized in Table 7. Rate constants indicated that hydroxyl
radical abstracted hydrogen (to yield H^O) more rapidly than atomic hydrogen
abstracted hydrogen (to yield H2). While the rate constant for hydrogen
abstraction by hydroxyl radical was about twice as fast for ethanol as for the
2-haloethanols, its abstraction by hydrogen atom was about the same for all
three alcohols. Halide abstraction by hydrogen atom was about 100-fold faster
from bromoalcohols than from chloroalcohols.
3. Photolysis
No ultraviolet absorption data was found for the haloalcohols
(Sadtler Research Laboratory, 1976). Neither the alkyl halides nor alcohols
have absorption maxima in the sunlight region (wavelengths above 300 ran). The
absorption maxima are probably below 250 nm and therefore, they will absorb
very little light above 300 tun (see Subsection I.A.2). No significant environ-
mental photochemistry resulting from direct absorption of light energy is
expected.
23
-------
Table 7. Specific Race Constants (imoles sec ) for
Reactions of Haloalcohols with H, .OH, and
e a (Adapted from Anbar and Neta, 1967)
XCH2CH2OH (2.moles"1sec-1)
X
k0H
+
RX
+
RX T H2
^ + RX HX
ke~ + RX
aq
H
1.1
X
109
1.6
x 107
-
io5
CI
5.5
X
io8
1.5
x 107
1.5 x 106
4.6 x 108
Br
4.6
X
O
CO
1.7
x 107
1.7 x 108
1.6 x IO9
24
-------
Irradiation at lower wavelengths will initiate photochemical
\ reactions. The primary process for alkyl bromides and chlorides consists of
homolytic carbon halogen bond breakage to produce alkyl radical and halogen
atom (Calvert and Pitts, 1966):
hv
RX » R- + X"
Shortridge and Heicklen (1973) examined the photochemical reac-
tions of 2-bromoethanol in the gas phase. They irradiated systems containing
oxygen pressures of 0 to 44 torr and varying, snail concentrations of NO (36 to
140 mtorr) or NO^ (73 to 130 mtorr). They irradiated the system with either
253.7 nm or 228.8 ran light. The primary reaction was the carbon-halide bond
cleavage. The resulting alkyl radical then reacted by a chain mechanism. Pro-
ducts included RO2H, RQ2NO, RO2NQ2 (where R = HCK^H^), HOC^CHO, and formaldehyde.
25
-------
II. Environmental Exposure Factors
A. Production and Consumption
1. Quantities Produced
The approximate annual production volumes of the haloalcohols
are listed in Table 8. For the most part, the production volumes were ob-
tained by indirect methods; an explanation of how the quantities were derived
is given below.
It should be noted that there was no available import data for
most of the haloalcohols.
a. Chloropropanols
The chloropropanols (propylene chlorohydrins) are inter-
mediates in the commercial production of propylene oxide through chlorohydrin-
ation of propylene and are not isolated. The two isomers, l-chloro-2-propanol
and 2-chloro-l-propanol, are formed in an approximate ratio of 9:1 (Horsely,
1968). In 1977, 1,897 million lbs of propylene oxide was produced (USITC,
1977 preliminary) of which about 60% was made by the chlorohydrination method
(Blackford, 1976a). Assuming an average yield of 95% for chloropropanol
conversion to propylene oxide, roughly 1,950 million lbs of chloropropanols
were produced as intermediates, of which 1,755 million lbs were l-chloro-2-
propanol and 195 million lbs were 2-chloro-l-propanol. Some refined 1-chloro-
2-propanol is also produced domestically, but this amount is small compared
to the amount used to manufacture propylene oxide. It is judged that only
several thousand pounds of refined l-chloro-2-propanol is annually made (SRC
estimate).
26
-------
Table 8: Estimated 1977 Annual Production Volumes
of Haloalcohols (SRC Estimates)
Annual
Haloalcohol Production Volume
*
1-Chloro-2-propanol 1,755 million lbs
¦k
2-Chloro-l-propanol 195 million lbs
*
1.2-Dichloro-3-propanol 410 million lbs
*
1.3-Dichloro-2-propanol 175 million lbs
3-Chloro-l,2-propanediol 195 million lbs
*
2-Chloroethanol 70-150 million lbs
2,2,2-Trichloroethanol Laboratory Amounts Only
2-Bromoethanol Laboratory Amounts Only
2,3-Dibromo-l-propanol <10 million lbs
2,2,2-Trifluoroethanol <0.1 million lbs
Primarily produced as a non-isolated intermediate.
27
-------
b. Dichloropropanols
Dichloropropanols (dichlorohydrins) are Intermediates in
the commercial production of epichlorohydrin. Two isomers, l,2-dichloro-3-
propatiol and 1,3-dichloro-2-propanol, are formed in an approximate ratio of
7:3 (Lichtenwalter and Riesser, 1964). In 1973, 345 million lbs of apichloro-
hydrin were produced (Oosterhof, 1975), which would require about 505 million
lbs of dichloropropanol intermediates. Current capacity of industry to make
epichlorohydrin is slightly more than 450 million lbs annually (SRI, 1977a).
Assuming a modest growth rate for epichlorohydrin from 1973 to the present and
assuming that roughly 90% of capacity is currently utilized, then roughly 585
million lbs of dichloropropanol are currently required as intermediates to
make epichlorohydrin. Of this, 410 million lbs would be l,2-dichloro-3-
propanol and 175 million lbs would be 1,3-dichloro-2-propanol.
A refined 1,3-dichloro-2-propanol product is also produced
but is small relative to the amount consumed as an intermediate in epichloro-
hydrin production. It is judged that less than one million lbs of the refined
l,3-dichloro-2-propanol are annually produced (SRC estimate).
c. 3-Chloro-l,2-propanediol
3-Chloro-l,2-propanediol (a-monochlorohydrin) is an inter-
mediate in the manufacture of glycerine through the allyl chloride-epichlorohydrin
route (Oosterhof, 1976). In 1974, 133 million lbs of glycerine were produced
by this route (Oosterhof, 1976), requiring roughly 195 million lbs of
3-chloro-l,2-propanediol intermediate. Since the production of glycerine by
the alkyl chloride-epichlorohydrin has remained stable in recent years, the
current annual production of 3™chloro—1,2—propanediol should be about the same.
28
-------
Production of 3-chloro-l,2-propanediol for purposes other
than the intermediate use described above is very small by comparison. Less
than one million lbs are estimated to be produced for other purposes (SRC esti-
mate) .
d. 2-Chloroethanol
Chloroethanol (ethylene chlorohydrin) is produced as an
intermediate in the chlorohydrin process used only by Dow for the production
of ethylene oxide. In 1975, Dow produced 25 to 50 million lbs of ethylene oxide
by this route (Blackford, 1976b), requiring roughly 50 to 100 million lbs of
2-chloroethanol intermediate. The Dow facilities that produce 2-chloroethanol
intermediate were shutdown in 1972, and were restarted in 1975 (Blackford, 1976b).
Before the 1972 shutdown as much as 500 million lbs of ethylene oxide were
made annually through chlorohydrination; current capacity at Dow is estimated
at 200-250 million lbs (Blackford, 1976b).
Ethylene oxide can be used to manufacture 2-chloroethanol.
According to Blackford (1976b), as much as 20 million lbs of ethylene oxide were
consumed in the production of 2-chloroethanol in 1972 and 1974; this would pro-
duce roughly 40 million lbs of 2-chloroethanol.
e. 2,3-Dibromo—1-propanol
The main use of dibromopropanol has been in the production
of tris(2,3-dibromopropyl) phosphate, commonly called Tris. According to
Lande et al. (1976), between 9 to 12 million lbs of Tris were produced in 1975.
Production of this amount of Tris would require about 7.5 to 10 million lbs of
dibromopropanol. SRI (1976b) estimated the 1976 production of dibromopropanol
29
-------
\ to be somewhat greater than 10 million lbs. However, the production of
dibromopropanol has fallen dramatically since 1976 due to restrictions upon
Iris use (see Subsection II.A.5 for additional discussion). Therefore, current
2,3-dibromo-l-propanol production is definitely less than 10 million lbs.
Dibromopropanol production for purposes other than Tris manufacture probably
does not total more than one million lbs annually (SRC estimate).
f. 2,2,2-Trifluoroethanol
2,2,2-Trifluoroethanol is produced in commercial quantities,
but production volumes are not available from the manufacturer. In 1966, the
price of trifluoroethanol was $7.50/lb (Ferstandig, 1966); the current price
is $8.15/lb. Ferstandig (1966) stated that any significant increase in produc-
tion would probably reduce its price markedly. Although the current price may
be considered somewhat lower than the 1966 price due to the effect of inflation,
it is not markedly lower. This observation suggests that current production of
trifluoroethanol is not significantly higher than in 1966 since the price has not
changed much. Considering the uses and the price of trifluoroethanol, current
production is probably less than 0.1 million lbs annually (SRC estimate).
g. Other Haloalcohols
There is no data currently available which would indicate
that 2-bromoethanol and 2,2,2-trichloroethanol are produced in any quantities
other than laboratory amounts. Production is estimated to be less than 1000 lbs
per year.
30
-------
2. Producers, Production Sices, and Distributors
a. Chloropropanols
\
l-Chloro-2-propanol and 2-chloro-l-propanol are both inter-
mediates in the production of propylene oxide by chlorohydrination. The com-
panies listed below produce propylene oxide by this method; the chloropropanol
capacities are estimated from propylene oxide capacities:
Chloropropanol Capacity
(millions of lbs)
BASF Wyandotte Corp. Wayandotte, Mich. 300
Dow Chemical Freeport, TX 1570
Plaquemine, LA 580
Olin Corp. Brandenburg, KY 220
2670
In addition, the following two producers make 1-chloro-
2-propanol as a final product (SRI, 1979; EPA, 1979):
Eastman Kodak Rochester, NY
R.S.A. Corp. Ardsley, NY
b. Dichloropropanols
1,2-dichloro-3-propanol and l,3-dichloro-2-propanol are
both intermediates in the production of epichlorohydrin. The companies listed
below produce epichlorohydrin from the dichloropropanols; the dichloropropanol
capacities are estimated from epichlorohydrin capacities:
Dichloropropanol Capacity
(millions of lbs)
Dow Chemical Freeport, TX 365
Shell Chemical Houston, TX 250
Norco, LA 90
660
31
-------
In addition, the two following companies produce 1,3-
dichloro-2-propanol as a final product (SRI, 1977a; SRI, 1979):
Aceto Chemical Carletadt, NJ
Eastman Kodak Rochester, NY
c. 3-Chloro-l,2-propanediol
3-Chloro-l,2-propanediol is an intermediate in the produc-
tion of glycerine by the allyl chloride-epichlorohydrin method. The companies
listed below produce glycerine by this method; the 3-chloro-l,2-propanediol
capacities are estimated from glycerine capacities:
3-Chloro-l,2-propanediol
Capacity (millions of lbs)
Dow Chemical Freeport, TX 150
Shell Chemical Deer Park, TX 130
280
In addition, the following companies make 3-chloro-l,2-
propanediol as a final product (SRI, 1979; Environmental Protection Agency, 1979):
Aceto Chemical Carlstadt, NJ
Dixie Chemical Bayport, TX
Evans Chemetics Waterloo, NY
Mlllmaster Chemical Berkeley Heights, NJ
Tennessee Eastman
Chemical Kingsport, Tenn.
d. 2-Chloroethanol
Dow Chemical produces 2-chloroethanol as an intermediate
in the chlorohydrin method for ethylene oxide production in Freeport, TX.
Based on Dow's ethylene oxide capacity by this method (SRI, 1977a), the Freeport
plant has the capacity to produce approximately 400 to 500 million lbs of 2-
chloroethanol annually.
32
-------
The following companies also produce 2-chloroethanol
(SRI, 1979; Environmental Protection Agency, 1979):
Union Carbide Corp. Institute and South Charleston, W
Thiokol Chemical Div. Mass Point, MA
Continental Oil Co. West Lake, LA
e. 2,2,2-Trichloroethanol
The following companies produce 2,2,2-trichloroethanol
(SRI, 1979):
Aldrich Chemical Milwaukee, WS
R.S.A. Corp. Ardsley, NY
f. 2-Bromoethanol
2-Bromoethanol is produced in laboratory amounts by
(SRI, 1979; Environmental Protection Agency, 1979):
Aldrich Chemical Milwaukee, MS
Columbia Organic Chemicals Columbia, SC
Eastman Kodak Rochester, NY
g. Dibromopropanol
2,3-Dibromo-l-propanol is produced by the following com-
panies (SRI, 1977a; Environmental Protection Agency, 1979):
Great Lakes Chemical Corp. El Dorado, AR
Velsicol Chemical Corp. St. Louis, MO.
Stauffer Chemical Co. Edison, NJ
Columbia Organic Chemicals Columbia, SC
h. 2,2,2-Trifluoroethanol
2,2,2-Trifluoroethanol is produced by Halocarbon Products
Corporation in Hackensack, NJ (SRI, 1979).
33
-------
i. Distribution and Importation
The U.S. Census Bureau does not have separate listings for
importation of individual haloalcohols. However, it is judged that only small
quantities of these compounds, if any, are imported with any consistency (SRC
estimate); 2-chloroethanol is an exception. In 1977, between 0.2 and 2 million
lbs of 2-chloroethanol were imported (Environmental Protection Agency, 1979) .
In addition to the manufacturers, the companies listed
below are suppliers of the indicated haloalcohols (OPD, 1977; Chemical Week,
1977):
3-chloro-l,2-propanediol
2-chloroethanol
2,2,2-Trichloroethanol
2,2,2-Trifluoroethanol
Howard Hall & Co.
Nippon Soda, Co. Ltd.
Chemical Dynamics Corp.
Wall Chemical Corp.
Rhodia, Inc.
PCR, Inc.
Chemical Dynamics Corp.
Cos Cob, CN
New York, NY
South Plainfield, NJ
Westfield, NJ
Monmouth Jnc, NJ
Gainsville, FL
South Plainfield, NJ
3. Production Methods and Processes
a. Chloropropanols
Most of the chloropropanols produced in the U.S. are
consumed as captive intermediates in the production of propylene oxide. The
two chloropropanol isomers made during this process, l-chloro-2-propanol and
2-chloro-l-propanol (formed in approximately 9:1 ratio) are never isolated.
The overall reaction of this chlorohydrin method for propylene oxide produc-
tion can be represented as follows:
CH2CHCH3 + H0C1
CH3CH0HCH2C1 + CH3CHC1CH20H
(90%)
(10%)
2[CH3CH0HCH2C1 + CH3CHC1CH20H] + Ca(0H)2 ~ 2cQaiCH3 + CaCl2 + 2H20
(90%) (10%)
34
-------
The mixture of chloropropanols is commonly called propylene chlorohydrin.
In the commercial production of propylene oxide, propylene,
chlorine, and water are fed into a reactor tower where they react under con-
trolled conditions to form propylene chlorohydrin. The process initiates with
a preequilibrium during which the chlorine and water react to form hypochlorous
and hydrochloric acid
Cl2 + H20 * H0C1 + HC1
The conditions for the product feed to the tower reaction are chosen so that
the propylene chlorohydrin concentration leaving the tower is 3 to 4%, which
minimizes by-product formation. The propylene chlorohydrin is then dehydro-
chlorinated with slaked lime to form propylene oxide (Lowenheim and Moran,
1975). This commercial process is illustrated in Figure 1.
;h1©"ne
Figure 1. Production of Propylene Oxide through Chloropropanols
(Lowenheim and Moran, 19 75). Reprinted with permission
from John Wiley & Sons, Inc.
35
-------
l-Chloro-2-propanol, free of the 2-chloro-l-propanol isomer,
can be prepared by the acid-catalyzed hydration of allyl chloride (LiehtenwaIter
and Riesser, 1964):
h2so4
CH2=CHCH2C1 + H20
CH3CH(0H)CH2C1
b. Dichloropropanols
Host of the dichloropropanols produced in the U.S. are inter-
mediates in the manufacturer of epichlorohydrin. The two isomers produced by
this process, 1,2-dichloro-3-propanol and 1,3-dichloro-2-propanol (formed in a
7:3 ratio) are never isolated (Lichenwalter and Riesser, 1964). The production
of epichlorohydrin proceeds through the following reaction sequence (Oosterhof,
1975):
ch2«chch3 + ci2-
H2C-CHCH2C1 + HCl
H2C«CHCH2C1 + H0C1
C1CH„CHC1CH_0H
/ i.
C1CH2CH0HCH2C1
C1CH2CHC1CH,0H + NaOE
C1CH2CH0HCH2C1 + NaOH
HC„-CHCH„C1 + NaCl + H»0
^ j 2. i.
o
In the commercial production of epichlorohydrin, propylene
and chlorine are fed to a reactor to form allyl chloride which is then fed into
another reactor along with chlorine and water. The chlorine and water form
36
-------
hypochlorous acid (see above) which reacts with the allyl chloride to form the
\ propylene dichlorohydrins (Lowenheim and Moran, 1975). This commercial process
is illustrated in Figure 2.
l,3-Dichloro-2-propanol can be obtained in yields of 99.6%
by addition of epichlorohydrin to hydrochloric acid (Lichtenwalter and Riesser,
1964).
c. 3-Chloro-l,2-propanediol
Most of the 3-chloro-l,2-propanediol produced in the U.S.
is consumed as an intermediate in the production of glycerine by the allyl
chloride-epichlorohydrin route and is not isolated. The previous subsection
described epichlorohydrin production from the propylene dichlorohydrins. To
produce glyerine, the crude epichorohydrin is hydrolyzed with aqueous sodium
hydroxide. Intermediate 3-chloro-l,2-propanediol is produced in the glycerine
production as shown by the following reactions (Oosterhof, 1976):
CH„CHCHr,Cl + H„0 »- H0CHoCH(0H)CH-Cl
\ Lj I L I Z
M
HOCH2CH(OH)CH2C1 + NaOH ~ HOCH^H (OH) CH20H + NaCl
The complete glycerine production route is shown in Figure 3.
Pure 3-chloro-l,2-propanediol can be obtained from the
sulfuric acid-catalyzed hydrolysis of epichlorohydrin, or by heating glycerol
to 100°C with 2% acetic acid catalyst and adding HC1 gas to the mixture
(Lichtenwalter and Riesser, 1964).
37
-------
BASIS: 1 KG • EPICHLOROHYDRIN
LIME SLURRY 1.009
SOLVENT
(TRIC.ILOROPROPANE)
VENT
WATER
ALLYL CHLORIDE 0.977
REACTOR -
CaCl
VENT
— EPICMLOROHYORIN 1.0
TAIL GAS ABSORBER VENT-GAS
REACTOR VENT-GAS
CHLORINE 0.0000005
HYDROGEN CHLORIDE 0.0000005
ALLYL CHLORIDE 0.002
ALLYL CHLORIDE 0.002
CHLORINE 0.0000005
TRICIILOROPROPANE 0.0005
HYDROGEN CHLORIDE 0.0000005
CPICHLOROIIYDRIN 0.0015
SOLVENT TO RECYCLE
0.9025
TO AIR
TO AIR
HEAVY ENDS
WATER
©
DICHLOROHYDRUI 0.01
1
TO WATER
©
HEAVY ENDS 0.053
CIJLORGETHERS .0074
CPICHLOROIIYDRIN .00106
OICIILC'tOIIYDRIM .0057
TRICIILOKOPROPAliE .0371
©
CaCl0.598
TO WATER
TO LAND
Figure 2. Epichlorohydrin Manufacture (Gruber, 1976)
-------
If 0*1 »D(M J«f (JtCIM
OH
©-
©-
©-
©- CD-
Figure 3. Production of glycerine (glycerol) via epichlorohydrin
(Pervier et al., 1974).
I
-------
d. 2-Chloroethanol
In the past, 2-chloroethanol (ethylene chlorohydrin) has
been manufactured commercially by two different processes. Currently, it
is produced only as an unisolated intermediate in the manufacture of ethylene
oxide through the chlorohydrin process (see Subsection Il.A.l.d). Synthesis of
ethylene oxide begins with conversion of ethylene to 2-chloroethanol with
hypochlorous acid (see above), and the resulting chlorohydrin is dehydro-
chlorinated with slaked lime. The reaction can be represented as follows:
ch2=ch2 + hoci ~ cich2ch2oh
2C1CH2CH20H + Ca(OH)2 ~ 2CHCH2 + CaCl2 + 2H2Q
0
The commercial process is illustrated in Figure 4.
A second production route to 2-chloroethanol is not
currently in commercial operation. In this process 2-chloroethanol is
manufactured by reacting ethylene oxide with HC1 or MgCl2- Union Carbide
produced 2-chloroethanol in this way in 1972 and 1974 (Blackford, 1976b).
e. 2,2,2-Trichloroethanol
2,2,2-Trichloroethanol is not produced in commercial
amounts, but rather is made only in laboratory quantities (<1000 lbs per
year). It can be synthesized by at least two routes. One method consists of
reduction of trichloroacetic acid or a derivative (ester or acyl chloride)
40
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Water and Chlorohydrin Ethylene oxide
caustic soda reactor and distillation
scrubbers condenser Hydrolyzer system
I
Ethylene
Cooling
water
Recycle
ethylene
w
Chlorine -
Water •
I
2^
Ws'?/
m
wk
Plate
SSSBSOS
Milk ol lime
>>LCV
\k
Precooler.
Rellux J
(condense!
Water +
calcium
chloride
and some
ethylene
dichlonde
FCV
—S-i 51_
Chlorinated
hydrocarbon
by-products
to recovery
unit
S|H
i
Ofl
C±D
;3>fcv
jd
Refined
ethylene
oxide to
storage
Figure 4. Chlorohydrin process for manufacturing ethylene oxide (Schultze, 1965).
Reprinted with permission from John Wiley & Sons, Inc.
-------
with lithium aluminum hydride (Vindholz, 1976). This synthesis, which is
similar to commercial production of trifluoroethanol, may be represented by
the following reaction (Royals, 1954):
0
II
4CC13C-0H + 3LiAlH4 ~ (CCl3CH20)4LiAl + 2LiA102 + 4H2
Manufacture of 2,2,2-trichloroethanol can also be accomplished by reducing
chloral hydrate with an amine borane (Chamberlain and Schechter, 1959) or by
reducing chloral with aluminum ethylate (Turi, 1966).
f. 2-Bromoethanol
2-Bromoethanol is not produced in commercial amounts, but
is made only in laboratory quantities (<1000 lbs per year). 2-Bromoethanol
can be synthesized by the action of hydrobromic acid with ethylene oxide
(Windholz, 1976); a similar synthesis of 2-bromoethanol involves reaction of
dry HBr and ethylene oxide in liquid SO^ (Gebhart, 1949).
g. 2,3-Dibromo-l-propanol
2,3-Dibromo-l-propanol is produced commercially by reacting
allyl alcohol with bromine. The reaction may be represented as follows:
catalyst
CH9=CHCH20H + Br2 ——- ¦ ¦ ¦> BrO^CHBrCH^H
One patent describes the synthesis as follows (Thomas and Levek, 1971):
" 1.01 moles allyl ale. and 1 mole Br were added to 60% aq. LiBr at
35-40°, the org. phase sepd., 60% aq. LiBr solu. added, the entire procedure
repeated up to conversion of 21 moles Br, and the combined org. phases washed
to give 2,3-dibromopropanol of 99.9% purity." The process may be illustrated
42
-------
by the simple flow diagram shown in Figure 5. demons and Overbeek (1966)
indicated that the product yield can be upgraded by recycling the reaction
products.
Product RbcvcIb
2.3 - Dibromo- 1 — Propano
Li8f Solution
Figure 5. Production of 2,3-Dibromo-l-propanol (adapted from Thomas
and Levek, 1971; Clemons and Overbeek, 1966)
In the past, most 2,3-dibromo-l-propanol was consumed
as an unisolated intermediate in the manufacture of Tris (see Subsection Il.A.l.e
Now, however, since the production of Tris has been severely curtailed due to
its restricted use for clothing flame retardancy, most dibromopropanol is
isolated as a final product.
h. 2,2,2-Trifluorethanol
2,2,2-Trifluorethanol was first prepared by the reduction
of trifluoroacetic anhydride. Other syntheses used alternative reduction
methods: trifluoroacetamide with a platinum catalyst; trifluoroacetic esters
43
-------
with LiAlH^, and trifluoroacetic acid with LiAIH^ (Ferstandig, 1966). It can
also be made from trifluoroethyl chloride by acetolysis followed by hydrolysis
(Ferstandig, 1966). More recent production methods involve catalytic hydrogen-
ation of CF^COCl using Pd/Al^O^ (Wolownik, 1976) and hydrogenation of 2,2,2-
trifluoroethyl trifluoroacetate (Agnello and Cunningham, 1967).
The production of 2,2,2-trifluoroethanol by reduction of
trifluoroacetic acid with LiAlH^ can be represented as follows (Royals, 1954):
0
II
4CF--C-0H + 3LiAlH. ~ (CF_CHo0). LiAl + 2LiAlO. + 4H„
3 4 3 2 4 2 1
The production process would involve the introduction of trifluoroacetic acid
into a reactor containing excess lithium aluminum hydride and refluxing the
acid until the reaction is as complete as possible. The metal alkoxide would
be hydrolyzed and the excess lithium aluminum hydride would be decomposed with
water (LiAlH^ + 211^0 »- LiAlO^ + 41^) • The 2,2,2-trifluoroethanol is then
obtained by fractionation. This production process is illustrated in Figure
6 below.
2,2,2 -Tnflucroethanoi
Hydrogen
Trifluoroacetic Acid
UAIR
Bottomi: UAIO* and Water
Figure 6. Production of 2,2,2-Trifluoroethanol through Reduction with LiAlH^
(adapted from Royals, 1954)
44
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4. Market Prices
Current market prices for the haloalcohols are listed in Table 9.
The quoted prices apply to the largest quantity available from the manufacturer.
5. Market Trends
a. Chloropropanols
Growth of chloropropanol production is directly dependent
upon growth of propylene oxide production through the chlorohydrin process.
The propylene oxide market grew at a rate of about 12% per year from 1965
to 1976; it is projected that growth will, average 10% per year to 1980
(Chemical Profiles, 1976). A corresponding growth rate can be expected for
the chloropropanols, provided the percentage of propylene oxide manufactured
by the chlorohydrin process is not significantly altered.
b. Dichloropropanols
Overall production growth of the dichloropropanols is
directly dependent upon growth of epichlorohydrin production since their
primary consumption is as intermediates in this process (see Section II.A.l.b).
Oosterhof (1975) ha9 projected that the market for crude epichlorohydrin will
grow at a rate of 2% to 3% per year while the market for refined epichlorohydrin
will grow at a rate of 6% to 7% per year. A corresponding growth rate can be
expected for the dichloropropanols produced as intermediates.
Growth rates for the 1,3-dichloro-2-propanol produced as a
final product aire not available. However, this market is only a fraction of
the volume of the intermediate production.
45
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Table 9: 1977 Market Prices for Haloalcohols
(Various Personal Contacts with Manufacturers)
Haloalcohol
l-Chloro-2-propanol
1,3-Dichloro-2-propanol
3-Chloro-l,2-propanediol
2,2,2-Trichloroethanol
2-Bromoethanol
2,3-Dibromo-l-propanol
2,2,2-Irifluoroethanol
Price
$55-113.60/kg (largest avail-
able quantities)
$1.75/lb (bulk)
$1.10/lb (bulk)
$270/10 kg
$11.20/100 grams
$0.67/lb (bulk)
$8.15/lb (bulk)
46
-------
c. 3-Chloro-l,2-propanediol
Overall production growth for 3-chloro-l,2-propanediol is
directly dependent upon growth of glycerine made through the allyl chloride-
epichlorohydrin process, because 3-chloro-l,2-propanediol is formed as an
intermediate during this process. Oosterhof (1976) has projected that the
glycerine production will grow at a low rate of only 27. to 3% per year. A
corresponding growth rate can be expected for the 3-chloro-l,2-propanediol
produced as an intermediate.
Growth rates for the 3-chloro-l,2-propanediol produced as
a final product are not available. However, this market is only a fraction of
the volume of the intermediate production.
d. 2-Chloroethanol
2-Chloroethanol is produced as an intermediate in ethylene
oxide production through chlorohydrination. Production of ethylene oxide
through chlorohydrination has been somewhat unstable in recent years. Listed
below are the annual amounts of ethylene oxide (in million lbs) made by this route
from 1965 to 1975 (Blackford, 1976b):
1975 25-50 1969 361
1974 0 1968 310
1973 0 1967 358
1972 50 1966 491
1971 205 1965 482
1970 363
In 1972, Dow Chemical terminated production of ethylene oxide by chlorohydrin-
ation. In 1975, Dow converted between 200 to 250 million lbs of annual chloro-
hydrination process capacity from propylene oxide manufacture to ethylene
oxide manufacture (Blackford, 1976b). If future production of ethylene oxide
47
-------
through chlorohydrination increases to a substantial percentage of annual
\ capacity, production of 2-chloroethanol would increase correspondingly.
It is also feasible to manufacture 2-chloroethanol from
ethylene oxide on a commercial scale. Blackford (1976b) estimated that in
1972 and 1974 about 20 million lbs of ethylene oxide were consumed in 2-
chloroethanol production. Union Carbide, Che producer at that time, is no
longer making 2-chloroethanol. Exactly what has happened to this market for
2-chloroethanol is not certain. It is possible that either imports or Dow
Chemical has taken over the market. Projections of growth rates are not
possible from the limited data.
e. 2,3-Dibromo-l-propanol
The following market trends have been indicated for 2,3-
dibrono-l-propanol (SRI, 1977b).
"Until recent years, it is believed that practically all
2,3-dibromo-l-propanol was used as an intermediate for the manufacture of the
flame retardant, tris(2,3-dibromopropyl) phosphate (so-called TRIS). More
recently it is believed to have found some use as an intermediate for reactive
flame retardants (e.g., dibromopropyl acrylate and methacrylate) and as a
reactive flame retardant itself."
"Although TRIS has found some use as a flame retardant in
a variety of other applications, it is believed that its major application
since 1973 has been in the treatment of fabrics for use in infants' and child-
ren's sleepwear. As a result of concern about the mutagenic and carcinogenic
properties of TRIS, the manufacturers of this sleepwear stopped using TRIS-treated
fabrics in January 1977 and the Consumer Product Safety Commission banned the
48
-------
sale of TRIS-treated sleepwear in April 1977. Since that time, users of TRIS
for other flame retarding purposes have announced decisions to stop using it.
Consequently, it seems very likely the total U.S. production of 2,3-dibromo-l-
propanol has already decreased dramatically and will continue to do so. Its
use in reactive flame retardants for such products as polyurethane foams,
which is believed to be still in the development stage, is likely to be ad-
versely affected by the fact that 2,3-dibromo-l-propanol itself has been found
to be mutagenic also."
f. 2,2,2-Trifluoroethanol
As explained in Section II.A.l.f., production of trifluoro-
ethanol is not considered to be significantly greater at present than in the
mid-1960s. Future projections are not available; however, the historical
trend would indicate a stable market in the near future.
B. Uses of Haloalcohols
1. Uses and Their Chemistry
a. Chloropropanols
Nearly all of the two isomers of chloropropanol produced
domestically in conmercial quantities (l-chloro-2-propanol and 2-chloro-
1-propanol) are consumed captively as intermediates in the production of
propylene oxide. The production methods and chemistry of these uses are
discussed in Section II.A.3.a.
The l-chloro-2-propanol isomer is produced in small com-
mercial amounts; perhaps several thousand lbs per year. Its uses are not
available from the manufacturers. However, a survey of patent literature in-
dicates that many derivatives of l-chloro-2-propanol have potential use in
49
-------
nematocides, herbicides, and insecticides. Other possible uses include rubber
stabilizers, lubricants, and general use in organic syntheses.
b. Dichloropropanols
Most of the two isomers of dichloropropanol produced
domestically in commercial quantities (1,3—dichloro-2-propanol and 1,2-dichloro
-3-propanol) are consumed captively as intermediates in the production of epi-
chlorohydrin. The production method and chemistry are discussed in Section
II.A.3.b.
l,3-Dichloro-2-propanol is produced in commercial quanti-
ties as a refined, industrial product, although its production is much smaller
than the quantity produced as an intermediate. Its major use is for metal
cleaning and plating. According to the principal manufacturer of 1,3-dichloro-
2-propanol (refined), the product is sold to a large number of solvent blend-
ers who mix the dichloropropanol into many solvent formulations, most of which
are destined for metal cleaning and plating applications.
1,3-Dichloro-2-propanol has minor applications in textile
finishing and permanent wave fixing (Lichtenwalter and Riesser, 1964), in
manufacture of photographic and Zappon lacquer, in celluloid cement, in
binders for water colors, in resin and cellulose solvents, and in general
organic syntheses (Windholz, 1976; Rose and Rose, 1956).
c. 3-Chloro-l,2-propanediol
Most of the 3-chloro-l,2-propanediol produced domestically
is captively consumed as an intermediate in the production of glycerine through
the allyl chloride-epichlorohydrin method. This production method and chemistry
are discussed in Section II.A.3.C.
50
-------
3-Chloro-l,2-propanediol is also marketed as a final prod-
uct, although in much smaller quantities than that consumed as an intermediate.
One of the more important uses is in the preparation of glyceryl guaiacolate.
3-Chloro-l,2-propanediol is reacted with sodium guaiacolate to make guaiacol
glyceryl ether (glyceryl guaiacolate), which is an ingredient of commercial
cough remedies and expectorants. The glyceryl guaiacolate reaction may be
represented by the following:
+ ch2ohchohch2ci
och2chohch2oh
+ NaCl
Glyceryl guaiacolate is manufactured by six American manufacturers (SRI, 1977a):
Arsynco, Inc. (Carlstadt, NJ); MWM Chemical Corp. (Plainview, NY); S.B. Penick
(Montville, NJ); Ganes Chem. Labs. (Fennsville, NJ); Hexagon Labs (Bronx, NY);
and Millmaster Chem. (Berkeley Heights, NJ).
3-Chloro-l,2-propanediol is also a reactant in the chemical
syntheses of other glyceryl derivatives which are consumed in plasticizers and
in dyes (Lichtenwalter and Riesser, 1964). Minor uses of 3-chloro-l,2-propane-
diol include applications for the lowering of the freezing point of dynamite
(Windholz, 1976) and solvent for acetylcellulose, glyceryl phthalate, resins,
and gums (Rose and Rose, 1956).
3-Chloro-l,2-propanediol is also used as the active ingredient
-------
d. 2-Chloroethanol
Host of the 2-chloroethanol currently produced in the
United States is captively consumed as an intermediate in the production of
ethylene oxide by the Dow Chemical Company. This use of 2-chloroethanol is
discussed in Section II.A.3.d.
2-Chloroethanol is also an intermediate in the production
of several other chemicals, including indigo and dichloroethyl formal, an
intermediate for polysulfide elastomers (Blackford, 1976b). Thiodiethylene
glycol prepared from 2-chloroethanol is useful in textile printing as a gen-
eral solvent and hygroscopic agent for dye pastes and as an antioxidant for
vat, basic, and acid dyes (Lichtenwalter and Riesser, 1964). 2,2'-Dichloro-
diethyl ether, another 2-chloroethanol derivative, is utilized in the manu-
facture of morpholine and in the Chlorex process as an extractive solvent for
refining of lubricating oils. However, these uses are not considered to be
commercially important any more, although the ether has been used in commercial
synthesis of surfactants (Durkin et al., 1975). In addition, 2-chloroethanol
derivatives have been consumed in insecticides, herbicides, anesthetics,
growth modifiers, and therapeutics agents (Lichtenwalter and Riesser, 1964).
e. 2,2,2-Trichloroethanol
2,2,2-Trichloroethanol is manufactured in relatively small
amounts. Some trichloroethanol is consumed in pharmaceuticals. Trichloro-
ethanol, by itself, is a powerful hypnotic that is sometimes used in control
of motion sickness, but this application is now limited since it also causes
respiratory depression (Turi, 1966). A recently prepared hypnotic agent is
derived by shaking an equivalent of hexamethylene tetramine with three
52
-------
equivalents of trichloroethanol in water until crystals are formed; this
material yields a complex with the formula [CC1,CH_0H],-(CH.),N, (Turi, 1966).
j L J Z 0 H
f. 2-Bromoethanol
2-Bromoethanol is currently not produced in commercial
quantities. A survey of patent literature indicates that 2-bromoethanol has
potential applications in pesticides, for preparing pesticide intermediates,
in preparing fire-resistant intermediates, in photographic emulsions, as a
general solvent, and in preparing intermediates for other chemical synthesis.
g. 2,3-Dibromo-l-propanol
The major use of 2,3-dibromo-l-propanol has been in the
production of tris(2,3-dibromopropyl)phosphate, a flame retardant which is
commonly known as Tris. Iris is commercially produced by the reaction of
dibromopropanol and phosphorus oxyc'nloride as shown:
3 C^BrCHBrCHjOH + POCl-j ~ (CHjBrCHBrCH^) 3?0 + 3 HC1
A base is required to neutralize the HC1 produced. As explained in Section
II.A.5.g., Tris production has fallen dramatically. At this time other uses
of dibromopropanol might be more important commercially than Tris production.
2,3-Dibromo-l-propanol is employed as a reactive flame
retardant ingredient for the production of flexible polyurethane foam with
reduced combustion properties and is also an important raw material for the
production of useful retardant additives (Velsicol Chemical Co., 1977).
Two of the more important retardant additives are thought to be dibromopropyl-
acrylate and the methacrylate analog (SRI, 1977b).
Dibromopropanol has potential use as an intermediate in
production of pesticidal and pharmaceutical chemicals (Great Lakes, 1972).
53
-------
\
h. 2,2,2-Trifluoroethanol
A bulletin from Halocarbon Products (1967) describes the
following uses for 2,2,2-trifluoroethanol:
"Trifluoroethanol because of its hydrogen bonding ability
and ionization constant is an excellent solvent for ionic
reactions, conductometric titrations and the like. Small
amounts of water (1-5%) enhance the properties desired for
these types of uses.
The room temperature solubility of nylons in trifluoro-
ethanol lends itself to many unusual applications. For
example, if a loop of dry nylon rope is dipped in the
alcohol for a few seconds it immediately becomes stiff
upon removal. After evaporation of the trifluoroethanol
the stiff section is permanently sealed and can be cut to
give nonfraying ends with shoelace-like tips. Using a hot
air blower the ends of tightly braided 1/4" line can be
processed in about 30 seconds. Similarly ordinary knots
made with nylon monofilament can be permanently sealed
with trifluoroethanol. Under abnormally high humidity
conditions a high moisture content in the nylon can inter-
fere with the sealing process.
Nylon solutions in the trifluoroethanol can be used
as vehicles for adhesives, pigments, metal powders or
dyes. These mixtures yield nylon toughened adhesives
or, upon evaporation, deposit tough surface coatings."
Trifluoroethanol derivatives have other potential applications in a number of
fields. Often the trifluoroethoxy group is profoundly different from the
ethoxy group. For example, hexafluorodiethyl ether is a convulsant drug
(Indoklon) used in place of electric shock therapy while its analog, diethyl
ether, is an anesthetic. Trifluoroethyl vinyl ether is marketed as the low
flammability anesthetic "Fluoromar," which is made by the Ohio Chemical and
Surgical Equipment Co. of Madison, Wisconsin. Various polymers and co-
polymers of trifluoroethanol derivatives have been prepared. A trifluoroethyl
substituted dye has a different color from the related ethyl dye and is usually
54
-------
more color stable than the unsubstituted dye. Trifluoroethoxy substituted
\
anilides have been reported to have excellent germicidal activity in soaps.
The major commercial users and use sites for 2,2,2-tri-
fluoroethanol are not available.
2. Alternatives to Uses for Haloalcohols
a. Chloropropanols
l-Chloro-2-propanol and 2-chloro-l-propanol are primarily
produced as intermediates in propylene oxide production via chlorohydrination.
An alternative to this major use of chloropropanols is the production of pro-
pylene oxide by peroxidation of propylene, a route used commercially since 1969.
It has been estimated that in 1978, about 41% of industry's capacity to make
propylene oxide will be based on peroxidation while 59% will be based on
chlorohydrination (Blackford, 1976a).
The peroxidation of propylene to produce propylene oxide
can be represented by the following reactions:
2 (CH3)3CH + 3/2 02 ~ (CH3)3COOH + (CH^COH
0
/ \
CR2-CHCH3 + (CH3)3COOH ~ CH2CHCH3 + (CH3)3COH
It is a two-step process in which isobutane (or another hydrocarbon such as
ethylbenzene) is air-oxidized in the liquid phase to tert-butyl hydroperoxide
or the corresponding hydrocarbon hydroperoxide, which is used to oxidize
propylene to the oxide. This process eliminates the need to dispose of the
chlorinated by-products produced via the chlorohydrin route.
55
-------
A new procedure for direct propylene oxidation to form
\
propylene oxide using hydrogen peroxide has recently been reported (Anon.,
1978a). The method, which was developed by Products Chimique Ugine Ruhlman
(PCUK) has only been partially described. Propylene in an unspecified solvent
is oxidized with the hydrogen peroxide in the presence of a metal catalyst. A
spokesman for PCUK described metaboric acid as a catalyst component, but did
not detail the catalyst composition or reaction conditions. The epoxidation
selectivity was reported as being on the order of 95%.
b. Dichloropropanols
1,3-Dichloro-2-propanol and 1,2-dichloro-3-propanol are
primarily produced as intermediates in epichlorohydrin production. An alter-
native to this major use of dichloropropanols would be the production of
epichlorohydrin by a route which does not require dichloropropanol intermedi-
ates. Such an alternative, commercially competitive route does not exist
at present and it is uncertain whether such a route will be available in the
future. Phillips and Starcher (1957) patented a process by which epi-
chlorohydrin can be produced from allyl chloride by oxidation with peracids,
but no information is available to describe its commercial status.
Most of the refined 1,3-dichloro-2-propanol produced in
commercial quantities is consumed in solvents blended for metal cleaning and
plating. The exact need of this isomer in the solvent blends is not clear.
Other chlorinated compounds or solvents might be acceptable alternatives to
these applications.
c. 3-Chloro-l,2-propanediol
3-Chloro-l,2-propanediol is primarily produced as an
56
-------
intermediate in glycerine production via the allyl chloride-epichlorohydrin
route. An alternative to this use is glycerine production by different com-
mercial methods; such commercial methods include the acrolein-allyl alcohol
route and the allyl alcohol-peracetic acid-glycidol route. As of 1976, 71% of
industrial capacity to make synthetic glycerine was based on the allyl chloride-
epichlorohydrin route, 16% was based on the acrolein-allyl alcohol route, and
13% was based on the glycidol route (Oosterhof, 1976).
The acrolein-allyl alcohol method consists of the follow-
ing three steps (Oosterhof, 1976; Shell Oil Co., 1979-personnel communication):
CH2=CHCH3 + 02 •" CH2 = CHCHO + H20
CH„ - CHCHO + CH.CHCH. ~ CH„«CHCH.OH + CH,CHoC0CH,
2 3|3 2 2 3/3
OH
ch2=chch2oh + h2o2 ~ CH2(OH)CH(OH)CH2OH
The allyl alcohol-peracetic acid-glycidol method includes the following three
steps (Oosterhof, 1976):
0
CH-CHCH, isomerization, CH =CHCH OH
2 3 catalyst 2 2
0 0
/ \
CH2-CHCH2OH + CH3COOOH ~ CH2CHCH2OH + CH3COOH
0
/ \
CH2CHCH20H + H20 ~ CH2(0H)CH(0H)CH20H
3-Chloro-l,2-propanediol is used in small quantities as
the active incredient in a rodenticide. Alternative, commercial rodenticides
include ANTU (a-naphthylthiourea) and Warfarin.
57
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d. 2-Chloroethanol
Currently, 2-chloroethatiol is primarily produced as an
\
intermediate in ethylene oxide production via the chlorohydrin process. An
alternative to this major use is the production of ethylene oxide by the
direct oxidation of ethylene. In 1975 about 99% of the ethylene oxide manu-
factured was made by direct oxidation while only 1% was made by chlorohydrin-
ation (Blackford, 1976b).
The direct oxidation of ethylene to ethylene oxide can be
represented by the following reaction:
0
CH2»CH2 + 1/2 02 ^2—~ CH2CH2
This process eliminates the disposal problems created by the chlorinated by-
products produced via chlorohydrination.
e. 2,3-Dibromo-l-propanol
At present, 2,3-dibrotao-l-propanol is mainly used as a
flame retardant. Other organic chemicals which can be used for this purpose
include phosphate esters and alternative brominated substrates such as iso-
decyl diphenyl phoshate and hexabronocyclododecane (Sanders, 1978), dibromo-
butenediol, dibromoneopentyl glycol and tribromoneopentyl alcohol (Levek and
Williams, 1975).
Currently, one commercial use of 2,3-dibromo-2-propanol is
the synthesis of the flame retardant dibromopropyl acrylate. Flame retardants
which have the same use as dibromopropyl acrylate include vinyl bromide,
vinylidiene chlorobromide, and epibromohydria (Levek and Williams, 1975).
58
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f. Trifluoroethanol
\
Trifluoroethanol appears to be fairly unique in its com-
mercial applications, especially in synthesis reactions. Its use to stiffen
the ends of nylon rope can probably be imitated by plastic bands as found on
shoe laces but the utility of this alternative is not clear.
0* Env ironmental Contfl^n nation Pot en t x a1
1. General
Release of haloalcohols to the environment is poorly defined.
Host of the haloalcohols are consumed as intermediates soon after production
and receive little handling other than transfer between process units. Very
little information was available which described their loss to the environment
as the result of fugitive emissions, venting, or disposal. Because the amount
of haloalcohol annually produced is so large, even a low percentage of loss
would represent a large environmental emission. The evidence at hand suggests
that while the atmospheric emissions during production and consumption as an
intermediate are very low, some wastes destined for disposal with little or no
treatment could contain residual haloalcohol. Disposal appears to be the
greatest hazard. Xo facilitate the following discussions of the problems of
release, haloalcohols consumed as a reaction intermediate are discussed along
with haloalcohols manufactured as a final product.
Because most haloalcohols are directly used, emissions as the result
of transport and storage can only occur from a relatively small fraction of
the annual production.
2. From Production
Very limited information was available which described emissions
59
-------
during haloalcohol production. Virtually no information was available for
environmental loss during the production of commercial, refined haloalcohols.
Some information was available for missions within production processes for
individual epoxides, epichlorohydrin and glycerine in which chloroalcohols
were intermediates. No haloalcohol was reported among the intermediates,
solvents, or products emitted during the actual processing, but they were
observed among disposed wastes (see Section II.C.4).
a. Chloropropanols
Almost all chloropropanols are consumed as captive inter-
mediates in propylene oxide manufacture. No information was available on
release during production or use. Release seems associated with liquid waste
effluent (see Section II.C.4.a).
b. Dichloropropanols
Dichloropropanol is primarily produced and consumed as an
intermediate in epichlorohydrin production. Atmospheric losses of dichloro-
propanols from manufacturing plants are considered insignificant (Pervier
et al., 1974). The major source of release would appear to be the waste water
effluent and heavy ends destined for solid waste disposal (see Section II.C.4.b)
(Gruber, 1976; Pervier et al., 1974).
c. 3-Chloro-l,2-propanediol
Environmental release of 3-chloro-l,2-propanediol inter-
mediate produced in glycerine manufacture as the result of epichlorohydrin
hydrolysis is associated with disposal of still pot residues (see Section
II.C.4.c). The 3-chloro-l,2-propanediol produced as an intermediate in glycerine
60
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manufacture is generated and consumed within a batch process kettle, so it has
little chance for escape (Pervier et al., 1974).
Refilling of 3-chloro-l,2-propanediol for marketing as
a pure material has potential for emissions from process equipment such as
vents, distillation columns and reactors. No specific information was avail-
d. 2-ChloroetHanoi
Potential emissions of 2-chloroethanol are probably similar
to those of the chloropropanols, since both are produced and consumed by
similar chemical process plants. The emissions are primarily associated with
waste disposal (see Section II.C.4.d).
e. 2,3-Dibromo-l-propanol
No specific monitoring data or other information is avail-
able on losses of 2,3-dibromo-l-propanol from production. In the production
of Tris (see Section Il.A.l.e), the dibromopropanol is formed in a batch
kettle, purified by washing, and then consumed without isolation. Chances of
emission are probably highest during product purification stage and kettle
transfers or from waste effluent disposal.
f. Other haloalcohols
No information was-available for emissions of 2-bromo-
ethanol, 2,2,2-trichloroethanol, or 2,2,2-trifluoroethanol during their pro-
duction. These chemicals have limited annual production and no specific de-
tails on engineering aspects were available. They are probably manufactured
by batch processes in reaction kettles and purified by fractionation. The
greatest source for release would appear to be from emissions during the
61
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purification stage and from wastes from kettle and equipment washing and still
\
bottoms (see Section II.C.4).
3. From Transport and Storage
The bulk of the haloalcohols produced in the United States
are formed as intermediates during manufacture of such compounds as ethylene
oxide, propylene oxide, epichlorohydrin, or glycerine. During these processes,
the haloalcohols are neither isolated from the system nor stored. Therefore,
the potential for contamination from transport and storage does not apply.
The haloalcohols that are transported in product form are
usually shipped in special drums, barrels, or tankers. Barring highway or
railway accidents, the potential for contamination is probably small.
The haloalcohol discharged to the environment would consist
primarily of vapor loss during transfer to and from containers, and venting of
any storage facilities or transport tankers. No quantitative information is
available on these various vapor losses.
4. From Use
Most haloalcohols are consumed without isolation as chemical
synthesis intermediates. The potential discharge for these reaction intermediates
was discussed in Section II.C.2. Potential release from other uses of the
haloalcohols to the environment are discussed below.
l,3-Dichloro-2-propanol is blended into solvents which are
consumed for metal plating and cleaning. No specific information was avail-
able on the cleaning procedure with the dichloropropanol solvent blend
62
-------
(Schwartzkopf, 1967). Atmospheric emissions could result from solvent evapor-
\
ation off the metal surface, from solvent evaporation from treatment baths, or
from solvent disposal.
2,3-Dibromo-l-propanol is used as a flame retardant, especially
in polyurethane foams. For the most part, the dibromopropanol is adequately
bound into the urethane matrix. However, it may be possible that small con-
centrations of the dibromopropanol could diffuse out under abnormal circum-
stances.
Uses of other haloalcohols as solvents (trifluoroethanol,
bromoethanol, etc.) have potential for atmospheric release from evaporation.
No information was available which described the quantities used as solvent,
pollution controls to prevent atmospheric emission from solvent evaporation, or
evaporation rates.
Dibromopropanol could potentially be lost to the environment
from fabrics and other materials treated with Tris. Some Tris, lost when
treated fabrics are laundered, could hydrolyze in alkaline conditions to yield
dibromopropanol (Lande et al., 1976). No quantitative information was avail-
able from which the potential importance of this pathway could be estimated.
Since Tris is being phased out as a fire retardant for fabric, the potential
for release will be reduced.
5. From Disposal
Since most haloalcohols produced each year are consumed as
chemical intermediates, only a small fraction of the total production will
require disposal. The waste streams potentially containing haloalcohols include
those generated in all processes where haloalcohols are produced or used as
intermediates.
63
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a. Chloropropanols
The major potential for chloropropanol release to the en-
vironment from propylene oxide manufacture via chlorohydrination is in waste
water effluents. This chlorohydrin process generates about 60 tons of waste
water per ton of propylene oxide (Anon., 1978b). The waste water effluent is
unsuitable for direct disposal into natural drainage and will not be accepted
in municipal sewage systems without expensive pretreatment (Hancock, 1973).
While the waste water's primary contaminant is calcium chloride, it will
normally contain small amounts of the chloropropanols. Insufficient monitor-
ing data was available to estimate the chloropropanol concentration within
these effluents. In 1977, the production of about 570,000 tons of propylene
oxide via chlorohydrination were estimated to produce about 34 million tons
of waste waters. Even a small concentration of chloropropanol in these effluents
could therefore release significant total amounts of chloropropanols to the
environment.
Recently, a new treatment was proposed to resolve the
water effluent disposal problem (Anon., 1978b). The C-E Lummus Company
demonstrated on a laboratory scale that the calcium chloride (or sodium
chloride) brine solution can be fed to an electrolytic diaphragm cell to re-
generate chlorine gas and caustic, which could be recycled back to the chloro-
hydrination process. Although not yet tested under production conditions,
this waste treatment method appears to be commercially feasible.
Organic residues in heavy ends from product fractionation
could possibly contain chloropropanols. These residues would most likely be
disposed by landfills. Monitoring information has identified some haloalcohols
in landfill leachate (see Section II.E), which supports this suggestion. No
information was available on the haloalcohol content of the residuals.
64
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b. Dichloropropanols
X Dichloropropanols (dichlorohydrlns) are by-products from
che epichlorohydrin manufacturing process In two places (refer to Figure 2 in
Section II.A.3.b.). They are released in waste water effluents and as a con-
stituent in the heavy ends from the fractionator. It has been estimated that
the total production of epichlorohydrin in 1973 was about 345 million lbs
(Oosterhof, 1975). Growth projections would indicate that current epichloro-
hydrin production is roughly 400 million lbs. (180 million kg). Utilizing
this production figure and the monitoring data on Figure 2, the quantity of
dichloropropanols annually emitted in waste waters would be about 4 million
lbs and the quantity in the heavy ends would be about 2.3 million lbs.
The waste water effluents containing dichloropropanols are
treated in on-site facilities; treatment efficiency with respect to dichloro-
propanols is not available. The heavy liquid ends are stored in large steel
tanks at the plant site (Gruber, 1976). Heavy end wastes of this kind can be
effectively destroyed by incineration with proper control to eliminate air
pollution (Gruber, 1976). The only monitoring information was identification
of dichloropropanols in waste water effluent from a chemical plant (Shackelford
and Keith, 1976) and in barrels of chemical waste dumped at sea (Greve, 1971)
(see Section II.E.).
c. 3-Chloro-l,2-propanediol
No information was available concerning 3-chloro-l,2-
propanediol disposal. Pervier and coworkers (1974) described waste streams
from glycerol production via epichlorohydrin hydrolysis with aqueous alkali.
Since chloropropanediol was not included among the components, it appears that
65
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it is not present in significant quantities. Other possible sources are
residues from fractionation processes used to isolate and purify commercial
chloropropanediol.
d. 2-Chloroethanol
The potential for 2-chloroethanol residues from the pro-
duction of ethylene oxide via chlorohydrination is probably quite similar to
the potential residues for chloropropanols from the propylene oxide manufac-
ture discussed above. Waste water effluent might be the major disposal
problem. Waste water at a Russian ethylene oxide plant had the following
content of various chemicals (Antipina, 1957): 0.7-4.8 g11 ethylene glycol;
0.01-0.45 g/f- ethylene chlorohydrin (2-chloroethanol); 32-48 g/i CaC^; 0.9-
1.4 g/£ CaCOH)^, and traces of acetaldehyde. These data appear to be
effluent concentrations before discharge; no information on the composition of the
discharged waste was found. The total amounts of 2-chloroethanol released in
waste water effluents could be significant. Information was not available on
either water waste quantities or on-site treatment efficiency with respect to
2-chloroethanol reduction. The only monitoring information consisted of
identification of 2-chloroethanol in industrial waste-water effluents
(Shackelford and Keith, 1976) (see Section II.E). 2-Chloroethanol is also
present in distillation column bottoms obtained during the ethylene chlorohydrination
process for ethylene oxide (Aries et al., 1950). Although these bottoms can
probably be incinerated (see Section Il.C.j.b) it is possible that still bottoms
are disposed by landfill (see Section II.E).
e. 2,3-Dibromo-l-propanol
Generation of 2,3-dibromo-l-propanol wastes should follow
a pattern similar to the wastes from other halopropanols consumed as reaction
66
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intermediates. Dibromopropanol has been identified as a constituent of waste-
water effluent, in landfill leachate, and in well water apparently polluted by
a landfill (see Section II.E) (Shackelford and Keith, 1976; Alford, 1975).
Ho quantitative information was available concerning the amounts of waste
dibromopropanol disposed on land or in aqueous effluents. The aqueous wastes
probably originate from water used in product purification and for washing kettles
and other equipment, and land-disposed wastes came from heavy ends which were
landfilled rather than incinerated. There was no information on incineration
as an alternate route for dibromopropanol disposal. Since it is a fire-
retardant, incineration would require additional fuel to support combustion,
f. Other Haloalcohols
Very little information was available concerning the waste
disposal of the other haloalcohols. The only data found was the reported
identification of 2,2,2-trichloroethanol in industrial waste water (Shackelford
and Keith, 1976). As discussed for other haloalcohols, the wastes could
include washings from product purification or production equipment clean-up.
Organic wastes, which are expected from haloalcohol purification, potentially
contain residues and will probably be disposed by landfill.
6. Potential Inadvertent Production In Industrial Processes
Although there was no information available on inadvertent pro-
duction of the haloalcohols during industrial processes, some pathways could
be suggested based upon known chemical reactions (March, 1968).
Hydrolysis reactions of vicinal dihalides could yield halo-
alcohols:
h2o , >¦ rchxch2oh
rchxch2x 7^ ( rchohch2x
67
-------
Substitution of a hydroxide group for a halide ion at the primary carbon is
more likely than at the secondary position for steric reasons. Substitution
at the secondary carbon would only become important if hydrolysis would pro-
ceed by a carbonium ion mechanism, and this is considered unlikely for most
industrial uses of the halogenated hydrocarbons.
Reactions of epoxides with halide ions can yield haloalcohols:
n ~ RCHOHCH-X
X~ /
RCH-CH0 f (
*. n2u/_H \ ~ RCHXCH2OH
This reaction represents the reverse reaction of the final stage of epoxide
production by the commercial chlorohydrination process (see Section II.A.3).
So any process in which the epoxides (ethylene oxide or propylene oxide) or
epichlorohydrin are exposed to an inorganic halide could yield haloalcohols.
Haloalcohol production by this process results from disinfection and fumiga-
tion with epoxides; this is discussed further in Section II.C.7. Some uses of
epoxides, in which reactions are catalyzed by Lewis acids, yield haloalcohols
as by-products. It has been observed that ethylene oxide reacts with fluoride
from BF^ to yield 2-fluoroethanol (Bedford et al., 1977). Also, any release
to the environment of epichlorohydrin could be followed by hydrolysis to a
haloalcohol.
The reaction of olefins with hypohalous acid (HOX) will yield
haloalcohols; in fact, haloalcohols are commonly prepared in this manner (see
Section II.A.3). This reaction could also be important where industrial waste
water is treated by chlorination before discharge (Gould, 1959; Morris, 1975):
HO CI
l i
C=C + H0C1 ~ -C-C-
I I
66
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7. Potential Inadvertent Production in the Environment
\
Haloalcohols are produced in the environment by chemical or metabolic
pathways. Ethylene oxide and propylene oxide are converted to haloalcohols
in the environment by apparent metabolic pathways. Both epoxides are applied
to stored and packaged foods as fumigants for insect control and for sterilization
of microbes. In 1975 about 0.1 million lbs of ethylene oxide and smaller amounts
of propylene oxide were consumed domestically as fumigants (Landels, 1976).
Wesley et al. (1965) showed that the chlorohydrins (2-chloroethanol, chloropropanols)
were formed by the reaction of residues of ethylene or propylene oxide with water
and natural chlorides present in fumigated commodities. Heuser and Scudamore (1967)
determined that 2-bromoethanol can be formed in wheat and wheat flour during
fumigation with ethylene oxide. The bromine was derived either from naturally
occurring inorganic bromide or from bromide produced during prior fumigation with
methyl bromide. The concentrations of the chloroalcohols or bromoalcohols
which may be formed is dependent upon a number of variables and can, there-
fore, vary widely. Concentrations of 2-chloroethanol up to 1,000 ppa were
found in whole spices and ground spice mixtures after commercial fumigation
with ethylene oxide (Wesley et al., 1965); however, concentrations usually
detected appear to be one or two orders of magnitude lower. Because the
formation of the chloro- or bromoalcohols is thought to occur from residual
ethylene or propylene oxide, the amount of these halohydrins annually formed
from fumigation should total only a fraction of the approximate 0.1 million
lbs of oxides used.
69
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Ethylene oxide is also used for sterilizing manufactured goods,
\
including surgical equipment, and it can subsequently degrade to chloroethanol
(Weinberger, 1971). No information on the amount of epoxide consumed in these
applications is available.
D. Environmental Pathways and Fate Effects
1. Persistence
a. Biological Degradation Organisms and Products
Studies on the enzyme-catalyzed hydrolysis of 2,3-dibromo-
1-propanol suggest that all chloroalcohols and bromoalcohols degrade in the
environment (Castro and Sartnicki, 1968; Bartnicki and Castro, 1969). These
were the only available studies on biological degradation. No information on
fluoroalcohols was available. Castro and Bartnicki (1968; Bartnicki and
Castro, 1969) examined the products and qualitative rates of product formation
from dibromopropanol hydrolysis with enzyme extracts of a gram-negative flavo-
bacterium which was grown from an alfalfa field soil in an aqueous broth
-3
containing 5 x 10 M dibromopropanol. The enzyme was extracted from the cells
by a combination of centrifugation and sonication. The enzyme activity in the
extracted solution was equivalent to activity of the bacterium cell suspen-
sion. The crude enzyme extract was partially purified, precipitated, and part
of the protein fraction was placed onto Sephadex G-200. Dibromopropanol, the
epihalohydrins, and epihalohydrin hydrolysis products were metabolized with the
crude enzyme extract and the partially purified enzyme at pH 7. If the enzyme
solution was boiled, its hydrolysis activity was lost. The earlier study
(Castro and Bartnicki, 1968) demonstrated that 2,3-dibromo-l-propanol is
initially converted to epibromohydrin. The subsequent reaction depends, in
part, upon the added salt (KC1 or KBr). Table 10 summarizes products and rates
70
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for reactions of Che epihalohydrins and their degradation products; these data
-3
were derived from incubation of 10 M substrate in 10 ml of a 0.01 M phosphate
buffer (pH 7.0) and 0.25 mg of protein thermostated at 24"C. The hydrolysis of
2,3-dibromo-l-propanol followed the reaction sequence:
0
/ \ +
BrCH^CHBrCH2OH BrCH2CH - CH2 + Br +• H
0 OH
/ \ I
BrCH^CH - CH2 + H20 ~ BrCH2CHCH20H
OH 0
I / \ _¦ +
BrCH2CHCH2OH »¦ CH2~CHCH20H + Br + H
0 OH
/ \ I
CH2-CHCH2OH + H20 ~ HOCH2CHCH2OH
propanol:
Bromide ion can open the epoxide to yield 1,3-dibromo-
n 0H
_ I
H20 + Br + BrCH2CH - CH2 ~ BrCH2CHCH2Br + OH
Incubation with the addition of 0.1 M KC1 established the following equilibrium:
0 OH
+ / \ I
H + CI + BrCH2CH - CH2 ~ BrCH2CHCH2Cl
OH ,0
I / \ + +
BrCH2CCH2Cl »• CH2 - CHCH2C1 + Br + H
0 OH
+ _ / \ I
H + CI + CH2 - CHCH2C1 >¦ C1CH2CHCH2C1
0 OH
/ \ t
H20 + C1CH2CH - CH2 ~ C1CH2CHCH20H
OH ,0
I / \ +
C1CH2CHCH20H ~ CH2 - CHCH20H + CI + H
71
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Table 10. Products from Enzymatic Conversion of Epihalohydrins and Haloalcohols
(Bartnicki and Castro, 1969)
Added Salt Time
Substrate (0.1 M) (min)
Epibromohydrin KC1 1
KC1 60
KBr 1
KBr 60
None 1
None 60
Epichlorohydrin KC1 1
KCl 60
KBr 1
KBr 60
None 1
None 60
l-Bromo-3-chloro-2-hydroxypropane None 5
None 120
l-3-Dibronio-2-hydroxypropane None 1
1,3-l)ichloro-2-hydroxypropane None 10
30
%
Conversion Products (% yield)
7.4 l-Bromo-3-chloro-2-hydroxypropane
100 1,3-Dichloro-2-hydroxypropane, 1-
chloro-2,3-d ihydroxypropane, 1-bromo-
2,3-d ihydroxypropane
2.0 1,3-Dibromo-2-hydroxypropane
95 l-Bromo-2,3-dihydroxypropane, glycidol
(trace)
1.7 l-Bromo-2,3-dihydroxypropane
81 l-Broino-2,3-diliydroxypropane, glycidol
(trace)
1.6 1,3-Dichloro-2-hydroxypropane
100 1,3-Dichloro-2-ltydroxypropane, 1-chloro-
2,3-dihydroxypropane
1.2 l-Bromo-3-chloro-2-hydroxypropane
60 l-Chloro-2,3-dihydroxypropane, 1-bromo-
2,3-dihydroxypropane, epibromohydrin
0.4 l-Chloro-2,3-dihydroxypropane
31 l-Chloro-2,3-dihydroxypropane
30 Epichlorohydrin (85), epibromohydrin (15)
100 l-Chloro-2,3-dihydroxypropane (86),
l-bromo-2,3-dlhydroxypropane (1 A)
10 Epibromohydrin
50 Epichlorohydrin
69 1-Chloro-2,3-dihydroxypropane, epi-
chlorohydrin
a Where yields are not given, products are listed in a decreasing order of significance. Yield = (moles of
product/moles of substrate converted) 100.
k Yields of all single products are 100%.
-------
Monitoring information (see Section II.E) supports a
rapid degradation rate for dibromopropanol. Alford (1975) reported that
dibromopropanol at a landfill test well had a concentration of 23.8 mg/1,
but none was detected in leachate drawn from test wells sited outside the
landfill.
In summary, the bromoalcohols and the chloroalcohols
appear to be susceptible to metabolic hydrolysis in soils. Products vary as
the result of the ionic content of the media and the metabolic transformations
parallel chemical reactions (see Section I.B).
b. Chemical Degradation in the Environment
The haloalcohols should chemically hydrolyze in soil
and in natural water. However, their absolute hydrolysis rates, though not
quantitatively known, are apparently too slow to compete with the enzyme
catalyzed hydrolysis, except at high pH (10 or above). Multiple hydrolysis
mechanisms could operate. Hydrolysis could proceed by pathways analogous to
that described for the enzyme catalyzed hydrolysis in natural waters:
HO CI 0 H-0 HO OH
I I ~HC1 , / \ z , I |
-C - C- -C - C- -C - C-
II II
The initial product is the epoxide, which subsequently hydrolyzes to glycol.
Chemical hydrolysis varies with pH. Alkaline hydrolysis follows a pathway
similar to the above. At neutral or mildly acidic pH the haloalcohols directly
hydrolyze:
HO CI H.,0 OH OH
I I —± v 1 i
-C - C- -HC1 -C - C-
II II
A carbonate-catalyzed pathway could yield glycol through a cyclic intermediate
(see Section I.B.I).
73
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Environmental oxidation should not be important in water
> or in soil but could be a significant reaction in potable water or waste water
treated by chlorination or a similar chemical oxidant (Morris, 1975). The
expected product is the corresponding haloketone, haloaldehyde, or haloacid:
Cl OH f , CI 0
l I tQXJ ) I I! 4.
-C - C-H -C - C- +2H
I I II
No rate data was available for oxidation with chlorine under water treatment
conditions.
The haloalcohols are expected to degrade in the atmosphere
through the free-radical reactions of the photochemical smog cycle. No direct
photochemical reactivity is expected. Neither the oxidation rates nor the
products from the free-radical degradation can be estimated from the informa-
tion available.
2. Environmental Transport
No specific information was available on environmental trans-
port for any haloalcohols. The physical properties (see Section I.A.I,
Table 2) permit some speculation on the transport characteristics.
All haloalcohols are characterized as water soluble. They
ranged from 52 g/i (25°C) for 2,3-dibromo-l-propanol to "miscxble" for several
haloalcohols, including 2-chloroethanol and 3-chloro-l,2-propanediol. So,
they are expected to be transported as a solution in water. And, unless strong
chemical or physical bonding occurs, they are expected to leach from soil.
Interphase transfer of compounds of low solubility from water
to air can be estimated from water solubility and vapor pressure data (Dilling,
1977; MacKay and Leinonen, 1975). Some estimation of interphase transfer is
possible, but calculated transfer rates are precluded by high solubility of
74
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the haloalcohols. From Che high solubility and the low vapor pressure (0.02 torr
at 20°C) of 3-chloropropane-l,2-diol it is estimated that virtually no volatil-
ization will occur. Other haloalcohols have vapor pressures apparently in the
range 5 to 60 torr at ambient temperature, so some volatilization is expected.
3. Bioaccumulation and Biomagnification
The high haloalcohol solubilities in water indicate that they
will probably not bioaccuaulate or biomagnify. Neely et al. (1974) suggested
calculation of a bioconcentration factor (BF) as an index:
logBF = 0.542 log K + 0.124
where K is the n-octanol:water partition coefficient. The high water solu-
bilities (0.24 moles/liter) of haloalcohols lead to very low BF values, 5 or
less, (X values were estimated by extrapolation, Freed et al., 1977).
E. Detection in Environmental and Biological Samples
1. Analytical Methods
Haloalcohols have been qualitatively and quantitatively analyzed
by several approaches including chromatographic methods, wet chemical methods
based upon halide ion analysis, and spectrometric methods. Chromatography,
especially gas chromatography (GC), appears the best quantitative analytical
approach with respect to selectivity and detection limit.
GC has apparently replaced older, alternative forms of chroma-
tography such as paper chromatography and thin layer chromatography for halo-
alcohol analysis. GC has been applied to the analyses of haloalcohols in food
(Fishbein, 1972), air (Taylor, 1977), and water (Alford, 1975). Information on
GC detection methods, analytical columns, and sample collection and pretreatment
will be presented in detail.
75
-------
The most common GC procedures utilize stainless steel or glass
columns packed with Carbovax M on Chromosorb W (Fishbein and Zielinski, 1967;
Ragelis et al., 1966, 1968; Brobst and Tai, 1971; Webb et al., 1973; Garrett
and Lambert, 1966); the carbowax M content varied from 4% to 20%. Operating
temperatures of 65°C to 115°C were used. Other columns include 10% FFAP on
Chromosorb W (Taylor, 1977), Poropak Q (Pagington, 1968), silicone oil on
Diatoports, polyethylene glycol on celite (Fishbein, 1972), QV-17 on Gas-Chrom
Q (Humbert and Fernandez, 1976; Breimer et al., 1974); SE-30 on Chromosorb G or W
(Herbolsheimer and Funk, 1974; Vesterberg et al., 1975), and SF-1150 on
Chromosorb W (Anderson et al., 1966).
Several detection systems have either been applied to halo-
alcohols or to analogous halogenated alkanes. Flame-ionization detection
(FID) has been perhaps the most common GC detector used. It has been generally
recommended for haloalcohol analysis in foods (Ragelis et al., 1966, 1968;
Brobst and Tai, 1971) and for air analysis (Taylor, 1977). The absolute
detection limit is on the order of 10 ng. The limits of detection for food
analysis (which includes sample collection and treatment, as well as the
detector response is consistently in the ppm (mg haloalcohol/kg sample) range
for ethylene and propylene chlorohydrin and bromohydrin detection. The NIOSH
Manual of Analytical Methods (Taylor, 1977) suggests the flame-ionization
detector for 2-chloroethanol (ethylene chlorohydrin) analysis in air. The
flame-ionization detector is non-selective, so interferences could become a
problem.
76
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The thermal conductivity detector has a detection limit in the
yg range. Like the flame-ionization detector, the thermal conductivity
detector is non-selective.
Electron capture detection (ECD) is more selective than flame-
ionization or thermal detection, since haloalcohol measurement is based upon
halogen content. It will respond to other halogenated hydrocarbons, and other
organics with low ionization potentials such as polyaromatics, and substrates
with other functional groups containing heteroatoms (Zweig, 1970). The detec-
tion limit depends upon the number of halogen substituents; limits are below
the nanogram range. ECD has been applied to haloalcohol analysis (Fishbein,
1972) and haloalcohols (e.g., trichloroethanol) have been used for preparing
chlorinated esters to increase the ECD detection limits of organic acids
(Smith and Tsai, 1971). A disadvantage of ECD is that it does not have a
linear response.
Microcoulometric detection is a highly selective and sensitive
system for halogenated organic substrates. It operates by degrading the
organic compound (oxidation or reduction procedures can be employed) and
subsequently measuring the liberated halide. It has a good linear response
range and is capable of measuring halogenated hydrocarbons in the nanogram
range (Hall, 1974). No information on its application to haloalcohol analysis
was available.
Pagington (1968) described use of a ozatron type J detector
element from A.E.I, leak detector type HA for chlorohydrin analysis. A detec-
tion level of 0.2 ppm was reported for injection of 25 u£ samples.
77
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Mass spectral detection (MS) is the most selective method for
identification of an organic substrate and also has potential for detection at
the nanogram range. Alford (1975) has reported the application of GC-MS for
identifying 2,3-dibromo-l-propanol in environmental samples. The method used
for this identification was the general approach of Webb and co-workers (1973).
Sample preparation appears to be a critical stage of any
analytical procedure. The haloalcohols are chemically reactive and could
eliminate HC1 to yield the epoxides, bond with hydroxylated materials, or
participate in other reactions. Pfellsticker and co-workers (1974) also noted
that samples containing ethylene oxide (such as would be expected from a plant
manufacturing or using the epoxide) can react with chlorides (e.g., NaCl or
CaCl^) added during work-up, thus yielding 2-chloroethanol.
Haloalcohol (2-chloroethanol and the chloropropanols) analysis
in foodstuffs is complicated by its bonding to hydroxyl groups in starch. The
halohydrins cannot be quantitatively recovered by simple ether extraction.
Brobst and Tai (1971) employed an acid hydrolysis treatment with 2 N in
a pressure bottle. The hydrosylate was then extracted with ether and the ex-
tract was concentrated on a Kuderna-Danish system. They claimed recovery of
90% for 5 ppm of the propylene chlorohydrins (chloropropanols).
Whitbourne and co-workers (1969) evaluated recovery of chloro-
ethanol from plastic and rubber utilized in surgical equipment. Their pro-
cedure was to heat samples in conventional round-bottom flask (ground-glass
joints) at 80°C to 90°C under vacuum (20 u) and collect all distilled material
in a cold U-tube (liquid nitrogen). Chloroethanol recovery was excellent from
PVC plastic (100%), somewhat lower for latex rubber (ca. 87%), and poor in
synthetic rubber (38.0%).
Weinberger (1971) described a co-sweep distillation process for
sampling ethylene chlorohydrin in manufactured goods, including natural and
78
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synthetic fiber. Preweighed samples were heated (110°C) with water. Carrier
\ gas (nitrogen) was swept through the system. Isooctane, which was intermittently
injected into the system, was trapped along with chloroethanol in Teflon cooling
coils. The isooctane solution was subsequently analyzed by GC. Weinberger
reported about 90% to 102% recovery for 1.5 to 48.0 ug of chloroethanol added
to 1.0 to 1.6g of sample.
Several groups have evaluated GC for analysis of trichloro-
ethanol in blood and in urine. It is an important analysis, since trichloro-
ethanol is a metabolite of trichloroethylene and is a sedative. Until GC
became the preferred analytical method, trichloroethanol was examined by a
colorimetric method (see below). It is present in blood and in urine as free
alcohol and bound with D-glucuronide. Methods have been published for anal-
ysis of both free alcohol and total alcohol. The latter analysis requires
hydrolysis of glucuronide.
Two methods of hydrolysis of bound trichloroethanol have been
reported. An enzymatic hydrolysis utilizes ^-glucuronidase (Garrett and
Lambert, 1966; Ogata and Saeki, 1974), which can be obtained from liver extracts.
Concentrated sulfuric acid has also been used to hydrolyze the trichloroethyl
glucuronide (Humbert and Fernandez, 1976; Breimer et al., 1974; Vesterberg
et al., 1975; Ogata and Saeki, 1974; Herbolsheimer and Funk, 1974). The
trichloroethanol can be subsequently taken for sampling either by extraction
(Garrett and Lambert, 1966; Ogata and Saeki, 1974; Humbert and Fernandez,
1976) or head-space sampling (Breimer et al., 1974; Triebig at al., 1976). No
study has systematically attempted to compare combinations of these treatments.
Both methods, when utilized with GC-ECD, have detection limits in the pg/ml
range or below.
79
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Anderson et al. (1966) evaluated recovery of 0.1 ppm trichloro-
ethanol added to animal tissue and crops (wet and dry). Their method homogen-
ized the sample plus 0.1 N I^SO^, then extracted organic substrates with ethyl
ether and analyzed them by GC-ECD. Trichloroethanol recovery ranged from 44% to
68% in dry crops, from 61% to 68% in animal tissues, and from 51% to 92% in
moist crops.
No specific procedure for sample treatment was available for
haloalcohol analysis in water. The general procedure described by Webb and
co-workers (1973) was used in a study which identified 2,3-dibromo-l-propanol
in a water sample and it appears generally applicable. It consists of ex-
tracting the water (applicable solvents include chloroform, petroleum ether,
hexane, and ethyl ether); the haloalcohols will be present in the neutral
(pH 5-7.5) range. The solution is then concentrated by Kuderna-Danish system.
No information on haloalcohol analytical recovery from water was available.
For atmospheric analysis NIOSH (Taylor, 1977) has developed a
standard procedure for 2-chloroethanol (ethylene chlorohydrin) using com-
mercially available two-section activated charcoal tubes. These contain 150
mg of coconut shell charcoal split by a polyurethane plug into sections of 100
mg (front) and 50 mg (rear). The rear section was designed to test if the
sample broke through the front section. The NIOSH method was tested by sampling
20 I of air at a rate of 0.2 £/min. The chloroethanol was desorbed with 5% isopropyl
alcohol in carbon disulfide and then measured by GC-FID analysis. The coeffi-
cient of variation for the overall sampling and analysis was 0.076 for 2-
3 3
chloroethanol concentrations of 7 to 30 mg/m . At 5 ppm (16 mg/m ) the stand-
ard deviation was +1.22 mg/m^. Analytical recovery was 5.8% greater than the
"true" value when 5 ppm was analyzed.
80
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Baker and co-workers (1971) evaluated photoelectron spectrometry
(PES) as an alternative method to GC for quantitative analysis of haloalcohol
residues in food as the result of fumigation with propylene oxide and with
ethylene oxide. They stated that the method was feasible, since PES of the
individual haloalcohol residues could be distinguished, but no detection
limits were reported.
The Fujiwara reaction has been used for screening trichloro-
compounds, including trichloroethanol, in urine. (Moss and Kenyon, 1964;
Tanaka and Ikeda, 1968; Ogata et al., 1970). The method requires oxidation
of the trichloroethanol to trichloroacetic acid and then reaction of the acid
with pyridine. The analysis consists of colorimetric measurement of the
reaction product at S30 nm. The method is not specific for trichloroethanol
but is a general approach for trichloro-compounds. The method is now dated
and gas chromatographic analysis has replaced it (see above).
Dolmatova-Guseva and Aizenshadt (1971) described a wet chemical
analytical method for atmospheric 2-chloroethanol. The haloalcohol was trapped
in a sparging tube with water as solvent. It was hydrolyzed to ethylene
glycol, which was then quantitatively measured by colorimetric assay of its
phenylhydrazone. Analytical recovery and detection limits were not available.
Kheifets and co-workera (1969) described a polarographic pro-
cedure for measuring mixtures of 3-chloro-l,2-propanediol and 2,3-dichloro-l-
propanol. The method first required converting these chloroalcohols to the
corresponding iodoalcohols by refluxing with KI in glycerol. With differen-
tial analysis the authors reported analysis of samples containing 37.-57. of
2,3-dichloro-l-propanol.
81
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Haloalcohols can be quantitatively analyzed by combustion to
\
liberate halide (Sokolov, 1964). The resulting halide can be measured by a variety
of titrimetric methods, specific ion electrode, or other analysis. The method
can detect low concentrations (1 yg or less as halide) but has virtually no
selectivity.
2. Monitoring
Available monitoring data has indicated the presence of halo-
alcohol only in industrial waste water and near industrial waste land disposal
sites. Although no haloalcohol detection has been reported in ambient samples
or in the atmosphere nearby industrial sites, few monitoring studies definitively
attempted to identify haloalcohols.
Pervier and co-workers (1974) and Gruber (1976) described en-
vironmental discharge of two haloalcohols (dichloropropanol and 3-chloro-l,2-
propanediol) from epichlorohydrin and glycerol (via epichlorohydrin hydrolysis)
production plants. Their description was derived from information submitted
by manufacturers, but the report had no specific information on how the manu-
facturers generated the data. According to both reports, haloalcohols are not
emitted to the atmosphere. If it is safe to assume that the information was
derived, at least in part, from monitoring by the manufacturer and that the
manufacturers specifically sought haloalcohols, then it appears chat insigni-
ficant quantities are emitted. Both Pervier et al. and Gruber have noted that
land disposed wastes contain dichloropropanols. Gruber also reports dichloro-
propanol in wastewater effluent.
Shackelford and Keith (1976) have collected and summarized
monitoring data for organic chemicals. The haloalcohol identifications which
82
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they indexed are summarized in Table 11. All haloalcohol observations were
associated with industrial waste disposal; these include their identification
in waste-water discharge and landfill leachate. The dichloropropanol obser-
vation at sea refers to its observation in a group of barrels of industrial
waste dumped at sea (Greve, 1971).
Alford (1975) was the source of the Shackelford and Keith
citation of 2,3-dibromo-l-propanol in well water. The referenced wells were
built to monitor and recover leachate that was entering a ground water supply
from a Newcastle, Delaware landfill (Table 11). A dibromopropanol concentration
of 23.8 mg/& was measured at a well drilled at the landfill; it was the organic
pollutant present in the highest concentration. However, no dibromopropanol
was detected at recovery wells sited below the landfill.
Antipina (1957) reported that the concentration of 2-chloroethanol
was 0.01-0.45 g/Z in waste water at an ethylene oxide manufacturing plant.
The citation apparently referred to the waste water before its treatment. The
effluent composition was not available in this citation.
83
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Table 11. Monitoring Information on Haloalcohols in Water
(Shackleford and Keith, 1976)
Haloalcohol
City or
Reference
Source
2-Chloroethanol
Calvert City, KY
Calvert City, KY
Pacolet and Enoree River
Effluent (Chem)
Effluent (Latex)
Effluent (Chem)
Trichloroethanol
Calvert City, KY
Calvert City, KY
Effluent (Cham)
Effluent (Latex)
2,3-Dibrooo-l-propanol
Dover, DE
Dover, DE
Alford, 1975
Newcastle County, DE
WHO Tech. Report 7
Landfill leachate
Landfill leachate
Well
Effluent (Land-
fill leachate)
Effluent (Acryl)
1,3-Dichloro-2-propanol
Louisville, KY
Louisville, KY
Effluent (Chem)
Effluent (Chem)
Dichloropropanol
Greve (1971)
Sea
84
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III. Health and Environmental Effects
A. Humans
1. Occupational Exposure and Poisoning Incidents
Fluoroethanol, in common with other alkyl fluorocarbons of even
numbered chain length, is a potent mammalian poison (Chenoweth, 1949). By
lethal synthesis of fluorocitrate these halocarbons prevent dehydration of citric
acid by aconitase and produce a blockade of the Krebs cycle (Peters, 1952).
Numerous cases of accidental poisoning have been reported
(Chenoweth, 1949) with initial symptoms of nausea, apprehension and subsequent
epileptiform convulsions. Exposure to high concentrations of fluoroethanol
leads to loss of consciousness and ventricular fibrillation. A case of a
two-year old boy who licked a rodenticide bottle was cited by Moeschlln (1965).
After a six hour delay, vomiting, irregular breathing, tetanic convulsions, and
coma developed. Improvement was not seen until after approximately four days.
The incidence of cardiac or central nervous system symptoms may relate to diet
(Saunders, 1957) since carnivores seem to develop more incidences of fibrillation
than do herbivores. Three cases of industrial poisoning by fluoroethanol vapor
were examined by Colamussi et al. (1970). Initial symptoms included nausea,
headache, and tremors. Vertigo and asthemia were noted in two cases. One worker
had slight hypoglycemia and another had signs of a moderately enlarged liver.
Since these were accidental situations, no concentration estimates could be
deduced.
Industrial exposure to chloroethanol at high concentrations
has resulted in several fatalities. Two cases were described in an early
report by Koelsch (1927). A paper factory worker cleaning a metal cylinder with
cloth dipped in chloroethanol developed nausea, headache, vomiting, and stupor
85
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continuing through death. Autopsy revealed hyperemia of the liver and lungs.
>
In the second case a linoleum factory worker developed early morning symptoms of
drowsiness and slight vomiting followed by recovery. Later that evening he
developed fatal breathing difficulties. Edema of the lungs and brain was
shown at autopsy. Dierker and Brown (1944) described a worker exposed to
305 ppm vapor and cutaneous absorption who expired. Kidney congestion was
noted at autopsy.
Goldblatt and Chiesman (1944) described a fatality involving a
worker exposed to a high concentration of hot chloroethanol vapor for 90
minutes. Death occurred in 14 hours, and slight cerebral edema was noted post
mortem. Another worker (Goldblatt and Chiesman, 1944) exposed to chloro-
ethanol vapor over a two month period showed symptoms of headache, confusion,
and hematuria. Autopsy revealed renal necrosis, especially in the convoluted
tubules, and gross edema of the basal ganglia. Ballotta et al. (1953) reported
a fatality resulting from oral ingestion of a small quantity of chloroethanol.
Nausea and headache were followed by excitement and coma. Hyperemia of the
brain, liver, and kidneys were shown by pathology. Several deaths of agri-
cultural workers who used chloroethanol to accelerate potato sprouting have
been reported (Bush et al., 1949). Vomiting, nausea, weakness, and respiratory
failure were symptoms described. Saitanov and Kononova (1976) reported a
poisoning incident with chloroethanol in a 24 year-old subject. Central
nervous system effects led to depressed respiration and cardiovascular acti-
vity, collapse, and ensuing hypoxia. Kidney and liver function were disturbed
and protein, electrolyte and serum enzyme changes were noted. Irreversible
damage to the heart, kidneys and liver was reported, but the role of systemic
hypoxia could not be evaluated as a contributing cause in this damage.
86
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Trichloroethanol exposures have not been described in mail.
\
However, since metabolism of both trichloroethylene and chloral hydrate in
human subjects has been shown to produce rapid blood levels of trichloro-
ethanol, and this alcohol in itself has equipotent hypnotic effects (Imboden
and Lasagna, 1956), any reported human toxicity for chloral hydrate and tri-
chloroethylene should be considered relevant. Chloral hydrate is irritating
to the skin, induces nausea, vomiting and gastric distress. Ingestion of
5 grams or less of chloral hydrate has produced fatalities. Central nervous
system effects include respiratory depression and hypotension. At high levels
of exposure, renal irritation, liver damage, and depressed myocardial contractility
have been shown. Chronic use in addicts has resulted in dermatitis, gastritis,
and parenchymatous renal damage. Bauer and Rabens (1974) investigated trichloro-
ethylene toxicity resulting from occupational exposure in four male workers
using this compound for cleaning or degreasing. Resulting dermatitis included
exfoliative, papulovesicular forms and erythroderma. Other symptoms included
mucous membrane irritation of the eyes and upper respiratory tract, inebriation,
and one case of toxic hepatitis. Trichloroacetic acid was found in the urine,
and trichloroethanol in the serum, of these workers.
Acute trichloroethylene exposure in industrial accident situa-
tions has elicited symptoms of nausea, vomiting, mental agitation, abdominal
cramps, and lower back pains (Waters et al., 1977). Death resulting from
accidental ingestion of a large quantity of trichloroethylene in one worker
revealed, on autopsy, liver necrosis as well as pancreatitis and nephrosis
(Kleiafeld and Tabershaw, 1954). The "psycho-organic syndrome" developed
during long term exposure to trichloroethylene has been described repeatedly
(Waters et al., 1977); symptoms include unrest, sleeplessness, fatigue,
87
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disturbed vision, vomiting, burning of the eyes, and intolerance to alcohol.
In general, these symptoms disappeared when the subject was removed from the
source of exposure. Exposure to 100 ppm trichloroethylene for 4-6 hours can
produce blood levels of ^3 mg/1 trichloroethanol with accompanying CNS effects
(Guberan, 1977). In a study of seventy workers exposed chronically to tri-
chloroethylene, Gravoac-Leposavic et al. (1964) reported dysprotejnema,
decreased serum albumin levels, positive thymol turbidity tests, and positive
cephalin-cholesterol tests, thus indicating some impaired hepatic function.
No direct human exposure data for trifluoroethanol has been
found. In animal studies, trifluoroethanol is the most toxic urinary metabo-
lite identified after halothane anesthesia (Airaksinen, 1970). Both halothane
and fluroxene anesthesia result in exposure to trifluoroethanol, but human
metabolism produces less of this toxic metabolite than other species (rodents,
dogs). Phenobarbital pretreatment of monkeys increases the ratio of trifluoro-
ethanol to trifluoroacetic acid produced from fluroxene and correspondingly
increases toxicity (Fiserova-Bergerova, 1977); this interaction should be
considered relative to human exposures. Human toxicity data relating to
fluorothane and fluroxene should also be reviewed in evaluating trifluoroethanol.
Halothane was implicated in human liver damage in a number of cases (Lindenbaum
and Leifer, 1963). In a major review, Little (1968) found that over a ten-
year period (1957-1967) there were 404 reported cases of halothane related
liver injury, of which 144 were fatal. A significantly higher incidence of
death was found if this population was screened for patients having received
halothane anesthesia more than once. Symptoms of halothane-induced injury
reported were fever, anorexia, nausea, and vomiting. Autopsy revealed hepato-
cellular necrosis, mainly in the centrolobular region. Fluroxene toxicity
88
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after anesthesia has been, reported (Harris and Cromwell, 1972; Reynolds et al.,
1972; Wollman and Surks, 1973; Tucker, 1973), with hepatic damage as the major
toxic effect.
Since all of the haloalcohols have potential for toxicity to
the liver, and since human metabolism of these alcohols takes place at this
site as well, this interrelationship should be kept in mind when evaluating
biological half-life and bioaccumulation of these compounds. The evidence
from evaluation of patients who have experienced multiple halothane anesthesia
(Little, 1968) is suggestive. Work by Ertle et al. (1972) on trichloroethanol
blood levels in volunteers, indicates that the alcohol accumulates over suc-
cessive days' exposure to trichloroethylene. If elimination and biotransfor-
mation would become impeded, toxic potential would thereby increase.
2. Epidemiology Studies
No epidemiological studies on the haloalcohols have been reported.
3. Controlled Human Studies
Controlled human studies involving the haloalcohols have not
been conducted.
B. Reported Effects on Nonhuman Animals from Industrial Release,
Spills, and Accidents
No data concerning accidental exposures to animals from industrial
sources, spills, or accidents are available.
C. Experimental Studies on Nonhuman Animals
1. Toxicity and Effects on Mammals
a. Absorption, Transport, Tissue Distribution, Metabolism,
and Excretion
3-Chloro-l,2,-propanediol
Jones et al. (1969) observed that Wistar rats dosed orally
or iritraperitoneally with 3-chloro-l,2-propanediol (50 mg/kg) excreted the
urinary metabolites 2,3-dihydroxypropyl-5-cysteine and its N-acetate, as well
89
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as the unchanged compound. Further studies by Jones (1975) indicated that the
3-chloro, 3-bromo, and 3-iodo propanediols were detoxified by conjugation with
glutathione. Twenty to thirty percent of 3-chloro-l,2-propanediol is excreted
as CC^, and 10% is found unchanged in the urine. The postulated pathway for
metabolism (Figure 7) is conversion first to the epoxide, glycidol (VI), via
dehalogenation, and subsequent hydrolysis of the epoxide to glycerol. The
epoxide could be formed enzymatically (Castro and Bartinicki, 1968)
Cn_Cl
I L
CHOH
ICHO _
II
CH.C1
i L
CHOH
I
CH20H
III
CH.C1
I L
-* CHOH
I
C00H
IV
CH„
I ¦
CH
bo
CH2OH
VI
C00H
I
C00H
IX
NHR
I
CH„SCH_CH
I 2 Z i
CHOH
I
CH20H
C00H
VII
Figure 7. The metabolism of 3-chloro-l,2,-propanediol (III)
and this more reactive species (^50 times) would interact with glutathione
either directly or via the enzymatic activity of glutathione-S-epoxide trans-
ferase (Boyland and Williams, 1965). Jones (1975) has shown that epoxide
formation occurs readily in vitro at pH 8. However, attempts to produce
glutathione alkylation in vitro with the propanediols and a rat liver enzyme
preparation did not succeed. Glycidol (VI) in the presence of rat liver
enzymes did produce 50% to 60% alkylated glutathione in vitro over a three hour
incubation period. Edwards et al. (1975) found labelling of the lipid fractions
90
-------
of brain, testis, caput epididymis, and cauda epididymis after intravenous
14
injection of ( C) 3-chloro-l,2,-propanediol (uniform label). Jones et al.
(1977) discusses 3-chloro-l,2-propanediol oxidation (see Figure 7) to chloro-
lactic acid (IV) through a postulated aldehyde (II) by the action of a NAD
linked dehydrogenase.
Crabo and Appelgren (1972) carried out whole body autoradio-
graphs in albino mice and rats that were given an intravenous injection of
14
radioactive ( C) 3-chloro-l,2-propanediol (position of label not specified).
The rat specimens showed a high concentration of drug in the cauda epididymis,
unlike comparable sections from the mouse. Both species showed high concen-
trations of radioactivity in liver, bile, kidney, and urinary bladder shortly
after injection (60 minutes).
2T 2,2-Trichloroethanol
Trichloroethylene inhalation in man produces the major
metabolites trichloroethanol, trichloroacetic acid, and trichloroethanol
glucuronide (Figure 8). The biological half-life of trichloroethanol in the
blood of
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Figure S. Proposed intermediary metabolism of TCE (Waters et al., 1977)
91
-------
volunteers exposed to 50 or 100 ppm trichloroethylene Is ^12 hours (Ertle
et al., 1972). MUller et al. (1974) determined a biological half life (plasma)
of VL3 hours in humans given 10 tng/kg oral trichloroethanol. Glucuronidation
occurs in the liver, and excretion of the trichloroethanol glucuronide by the
kidneys is rapid. A major increase in the urinary half-life of trichloro-
ethanol has been reported in a patient addicted to trichloroethylene (Ikeda,
1977). Plasma half-life values for trichloroethanol vary with species;
Clifford (1977) reported values of 10 hours in the Rhesus monkey and two
hours in the squirrel monkey. Fernandez et al. (1975) in a study of human
absorption of trichloroethylene (97 ppm, 8 hrs.) has shown that only ^50% of
the trichloroethylene absorbed is recovered as the urinary metabolites tri-
chloroethanol (32.7%) and trichloroacetic acid (17.7%) within 16 days after
exposure; other metabolites are therefore believed to result in man. Dalbey
and Bingham (1978) have shown that phenobarbital pretreatment of rats (75 mg/kg
for 4 days) increased trichloroethanol formation from trichloroethylene.
Administration of ethanol simultaneously with chloral hydrate increases tri-
chloroethanol levels in vivo for mice (Gessner, 1973), dogs (Kaplan et al.,
1969), and man (Kaplan et al., 1967), most probably through inhibition of
trichloroacetic acid formation.
2,2,2-Trifluoroethanol
Blake et al. (1967) investigated the metabolism of radio-
14
actively labelled ( CF^) trifluoroethanol administered intraperitoneally to
mice (Figure 9). Analysis of pooled 48-hour urine samples indicated that
trifluoroethanol glucuronide and trifluoroacetate in a ratio of 6:1 could
account for over 80% of the urinary radioactivity. Further studies (Blake et al.,
1969) indicated that increasing the initial dose of injected radiolabelled
92
i
-------
to Glucuroaide
cf3ch2oh
Trifluoroethanol
Microsomal ethanol oxidizing
system [MEOS]
Alcohol dehydrogenase [ADH]
Catalase
Carbon tetrachloride
Pyrazole
Aminotriazole
cf3coh
Trifluoroacetaldehyde
Acetalde'nyde oxidase
Disulfiram
CF^OOH
Trifluoroacetic acid
Figure 9. Metabolism of Trifluoroethanol.
(Cascorbi and Singh-Amaranth, 1973)
93
-------
trifluoroethanol decreases the proportion of radioactivity appearing in the
urine at 48 hours. Ethanol treatment (1200 mg/kg every four hours for 12
hours) decreased the percentage of urinary trifluoroacetate excreted after
trifluoroethanol injection. Allopurinol increased the toxicity of trifluoro-
ethanol and trifluoroacetaldehyde hydrate in mice, suggesting that inhibition
of trifluoroethanol conversion to trifluoroacetate via xanthine oxidase
resulted in accumulation of the more toxic metabolite trifluoroethanol
(Airaksinen, 1970). Cascorbi et al. (1976) showed that trifluoroethanol
toxicity was greater in male mice than in females, and that this sex differ-
ence could be reversed by treatment with the opposite sex hormones. This may
be related to greater hepatic microsomal enzyme activity in males. Trifluoro-
ethanol metabolism in two human volunteers was shown to result in urinary
excretion of primarily trifluoroacetate (Cascorbi and Blake, 1971). Only 15%
of injected radiolabelled trifluoroethanol could be identified as the glucur-
onide conjugate. However, it should be noted that the total percentage of
radioactive urinary metabolites collected in six days varied markedly in the
two subjects (80.5%, 53.3%). Phenobarbital pretreatment in rhesus monkeys has
increased the toxicity of fluroxene (Munson et al., 1975) by the postulated
mechanism of increasing the ratio of trifluoroethanol to trifluoroacetate
produced by metabolism in this species. Drugs that have been shown to affect
trifluoroethanol metabolism and toxicity include (besides ethanol, allopurinol,
and phenobarbital) disulfuram, carbon tetrachloride, methylcholanthrene, and
pyrazole (Fiserova-Bergerova, 1977).
2-Chloroethano1
The observation by Johnson (1965) that oral administration
(55 mg/kg) of 2-chloroethanol reduced rat kidney and liver glutathione levels
94
-------
prompted this group to investigate 2-chloroethanol metabolism iji vivo.
\ Chromatography of rat liver and kidney tissue extracts after oral administra-
tion of 2-chloroethanol (100 mg/kg) showed that S-carboxymethyl glutathione
had been formed (Johnson, 1967). Reaction of 2-chloroethanol with glutathione
in vitro could not produce this metabolite. Ethanol (500 mg/kg) was found to
protect against the _i^i vivo 2—chloroethsnol xnduced glutathione depletion.
Johnson showed that 2-chloroethanol is both a substrate for, and an active
inhibitor of, yeast and liver alcohol dehydrogenase. Based on this evidence,
a postulated metabolic pathway was proposed by which chloroethanol is con-
verted to the -SH reactive metabolite, chloroacetaldehyde, by the action of
alcohol dehydrogenase. Blair and Vallee (1966) has shown that purified human
liver alcohol dehydrogenase will oxidize 2-chloroethanol at approximately 20%
of the rate of ethanol (pH 9.3). Evidence from numerous in vitro mutagenicity
assays confirms that the activity of 2-chloroethanol increases after activation
with liver microsomal enzymes. (Section III, C., 1., f.)
No data concerning tissue distribution of 2-chloroethanol
in vivo is available. However, work on vinyl chloride (VCM) distribution
(Hefner et al., 1975) should be considered relevant. Monochloroacetic acid
has been found as a urinary metabolite after VCM inhalation by rats, and has
been found in the urine of workers exposed to VCM (Grigorescu and Toba,
1966); 2-chloroethanol is a likely intermediate in the formation of this
metabolite. VCM inhalation produces decreased rat liver sulfhydryl group
content, and ethanol inhibits VCM metabolism in vivo (50 ppm exposure).
Hefner et al. (1975) reported that rats exposed to 50 ppm VCM for 65 minutes showed
58% of radioactive label in the urine, 2.7% in the feces, and 9.8% in expired
CO2 within 15 hours. By 70 hours, 67% of the radioactivity had been excreted
95
-------
in the urine, 3.8% in the feces, and 14% as expired CO^. Five hours later
examination of tissues showed that 1.6% of the radioactivity remained in the
liver, 0.2% in the kidneys, 3% in the skin, and 7.6% remained in the carcass,
b. Acute Toxicity
3-Chloro-l,2-propanediol
Acute toxicity data for 3-chloro-l,2-propanediol are
summarized in Table 12. Jackson and Robinson (1976) investigated the toxicity
of 3-chloro-l,2-propanediol and found that 5 of 12 male Wistar rats died after
a single oral dose of 100 mg/kg. An investigation in mice indicated an LD^o
of 73 mg/kg for 3-chloro-l,2-propanediol by intraperitoneal injection (Hirsch
and Kolwyck, 1975). Commercial 3-chloro-l,2-propanediol is an unstable racemic
mixture. Jackson et al. (1977), using redistilled 3-chloro-l,2-propanediol,
reported an of 100 mg/kg after a single oral dose of the racemic mixture.
Resolution of the mixture into its isomers and preliminary testing indicates
that the R(-) (dextrorotatory) form shows lethal toxicity at 75 mg/kg in Wistar
rats (oral) while the S(+) 3-chloro-l,2-propanediol is not lethal at 150 mg/kg.
The 1-amino analogue is also an. active antifertility agent, and shows a similar
stereospecificity. Coppola and Saldarini (1974) have shown that the 1-amino
analog of 3-chloro-l,2-propanediol has a differential toxicity when resolved,
the l(-) form being at least 10 times less toxic since it is not lethal at
500 mg/kg in rats. The d(+) amino analog had an oral LD^q of ^50 mg/kg in male
rats. Dorobantu et al. (1970) injected rats of both sexes (injection route
not specified) with 3-chloro-l,2-propanediol (unknown purity) and determined
an LD__ of 127 mg/kg. Subsequent pathology revealed extensive cortical necrosis
50
of the kidneys. Para-aminosalicylic acid (PAS) staining casts were found in
the lumina. At 7 to 21 days intense regenerative phenomena in the tubular
96
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Table 12. Acute Toxicity of 3-Chloro-l,2-propanediol
Route Sex Species Strain ^50 Reference
Oral M rat Wistar "^100 mg/kg Jackson et al. ,
1977
l.p. rat 10 mg/kg National Academy of
Sciences, 1953
Ihl. rat n^125 ppm/240 min Carpenter et al.,
1949
Oral mouse 160 mg/kg Hine et al., 1956
I.p. mouse 73 mg/kg Hirsch and Kolwyck,
1975
Oral M rat 55 mg/kg Paul et al., 1974
S.c. rat 127 mg/kg Dorobantu et al.,
1970
*
Approximate LC^q.
97
-------
epithelia were noted. Circulatory congestion was seen in other organs, including
the brain, lungs, liver, and myocardium. Kidney damage was reflected in
significantly (p<0.01) reduced kidney levels of the enzymes glutamic-oxalacetic
transaminase (GOT) and glutamate-pyruvate transaminase (GPT). Jones et al. (1977)
has postulated that kidney damage is the result of metabolic formation of
6-chlorolactic acid and oxalic acid in the rat.
2-Chloroethanol
Acute toxicity data for 2-chloroethanol are summarized in
Table 13. The inhalation by rats (150 minutes) of air, which was passed
through pure liquid chloroethanol, produced fatalities (Ambrose, 1950). Rats
exposed for 60 minutes to air passing through aqueous 2-chlocoethanol solu-
tions of 12.5%, 25%, or 50% died one to two hours after being removed from the
chamber, while those exposed for 60 minutes to air filtered through a 6.25%
solution were not affected. A concentration of 7.5 ppm for one hour was
reported to be fatal, while 4 ppm over the same time was not. This lethal
range is lower than the value of 32 ppm reported by Carpenter et al. (1949).
However, two exposures of one hour each with an interspersed two hour interval
did produce fatalities at 4 ppm, indicating a cummulative effect. Lawrence
et al. (1971a) placed mice in inhalation chambers with air (1 £/min) bubbled
through 30% aqueous 2-chloroethanol. With 80% vapor saturation being reached
in 14 minutes, mice showed 50% mortality in 13.3 minutes. In the same proce-
dure, but with a doubled air flow rate, Lawrence et al. (1972) showed that
male ICR mice had 50% mortality in three minutes exposure to the chloroethanol
metabolite, chloroacetaldehyde (80% vapor saturation in 7 min).
Dermal toxicity studies of 2-chloroethanol indicate that
it is very effectively absorbed through the skin. Lawrence et al. (1971a) found
98
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Table 13. Acute toxicity of 2-Chloroethanol
Route
Sex
Species
Strain
^50
Reference
S.c.
neonatal
rat
56 mg/kg
Balazs, 1976
I.p.
M
rat
Charles
River
64 mg/kg
Lawrence et al.,
1971a
I.p.
M
rat
Sprague
Dawley
44 mg/kg
Peterson et al.,
1968
Ihl
rat
32 ppm/240 min
Carpenter et al.,
1949
Dermal
guinea pig
285 mg/kg
Wahlberg and Bomai
1978
I.p.
Ihl
F
guinea pig
guinea pig
Huntly
84 mg/kg
918 ppm/113 min
Lawrence et al.,
1972
NIOSH, 1977
Oral
M
mouse
Swiss
81.4 mg/kg
Lawrence et al.,
1971a
I. p.
M
mouse
Swiss
98.3 mg/kg
Lawrence et al.,
1971a
Ihl
mouse
385 mg/m^
NIOSH, 1977
S.c.
frog
250 mg/kg
Goldblatt and
Chiesman, 1944
I.p.
M,F
rabbit
New
Zealand
84.6 mg/kg
Lawrence et al.,
1971a
Dermal
M, F
rabbit
New
Zealand
67.8 mg/kg
Lawrence et al.,
1971a
ik
99
-------
that 68 mg/kg of compound in cotton gauze pads applied to unabraded rabbit
skin for 24 hours was an LDjq concentration. No significant dermal irritation
in rabbit skin was noted. However, when 2-chloroethanol was injected intra-
dermal^ in undiluted form, marked irritation was produced. Solutions of 1%
to 5% (v/v) gave marginal irritation. Guess (1970) noted trypan blue skin
spreading and severe erythema following intracutaneous injection of 2-chloro-
ethanol (undiluted and 1/10 aqueous dilution) in rabbits. Only a faint reaction
was observed at 1/30 dilution of compound. Histologic examination revealed local-
ized edema, cellular destruction, and infiltration with numerous polymorpho-
nuclear leucocytes and lymphocytes. Wahlberg and Boman (1978) found that 0.1
ml 2-chloroethanol administered percutaneously killed all guinea pigs in 24
hours, while 0.25 ml of a 35% aqueous solution was lethal to half of the
animals during the same time.
Ocular irritation studies by Guess showed that undiluted
2-chloroethanol caused a transient clouding of the cornea, iritis, and inflam-
mation of the conjunctiva. This reaction sequence became diminished at 1/5
aqueous dilution of 2-chloroethanol, particularly at 72 hours after application.
Studies by Lawrence et al. (1971a) confirmed the eye irritation effects of the
undiluted compound, and found that aqueous solutions of 1.25% (v/v) failed to produce
this irritation. Guess (1970) found mucosal tissue to be more sensitive to 2-
chloroethanol than eye or muscle tissues since 1/100 aqueous dilutions produced
mild, transient signs of irritation in rabbit penile mucosa. McDonald et al.
(1972) tested the ocular toxicity of 2-chloroethanol in rabbits and found maximum
nontoxic aqueous concentrations to be 1% for topical application and 0.5% for
intraocular administration. These investigators noted that intraocular toxicity at
100
-------
2% or higher concentrations produce irreversible changes in opacity of the
cornea and lens.
Lawrence et al. (1971a) observed dose-related depression of
systolic and diastolic blood pressure in rabbits injected i.v. with 2-chloro-
ethanol at doses of 606 mg/kg and higher. Death followed in 1 to 2 hours due
either to CNS effects or direct cardiotoxicity. At this dose, sciatic nerve
conduction was impaired and skeletal muscle contraction eventually blocked, with
fasiculation observed.
Drug interactions between 2-chloroethanol and acetaminophen
were studied by Balazs (1976). Pretreatment of rats s.c. with 10 mg/kg of 2-
chloroethanol promoted liver necrosis by 200 mg/kg of acetaminophen. This hepato-
toxicity was seen only with the combination of agents. Reduction of liver
glutathione reserves by chloroethanol lowers the capability of the liver to
detoxify metabolites that produce irreversible damage (Balazs, 1976).
2,2,2-Trifluoroethanol
Acute toxicity data for 2,2,2-trifluoroethanol are summar-
ized in Table 14. Airaksinen (1968) noted that mice given a median lethal dose
(158 mg/kg) of 2,2,2-trifluoroethanol interperitoneally showed initial "drunkenness,"
followed 24 hours later by tremor, stiffness, difficulty in moving, and death.
After a dose of 250 mg/kg, analysis of the liver 18 hours after injection showed
a marked decrease in lactate content while tissue citrate values showed little
effect. A block of glycolytic rather than Krebs cycle metabolism was indicated.
Rosenberg et al. (1970), after administering 200 mg/kg of 2,2,2-trifluoroethanol
i.p. to mice, noted decreased liver ATP levels, increased ADP, decreased
ATP/ADP ratio, and decreased total glycogen content. This glycolytic inhibition
occurred within 5 hours and continued until the death of the animal, i.e., up
to several days. Further work by this group (Rosenberg, 1971) indicated that
101
-------
Table 14. Acute Toxicity of Trifluoroethanol
Route
Sex
Species
Strain
^50
Reference
I.v.
M
mouse
Swiss
250 mg/kg
Airaksinen, 1968
Oral
M
mouse
Swiss
366 mg/kg
Blake et al., 1969
I.p.
M
mouse
Swiss
195 mg/kg
Rosenberg, 1971
I.p.
M
mouse
Swiss
100 mg/kg
Rosenberg, 1971
Ihl.
H
mouse
Swiss
85 ppm/10 min*
Rosenberg, 1971
Oral
M
rat
Sprague-
Dawley
240 mg/kg
Hazel ton Labs, 1965
Ihl.
M
rat
Sprague-
Dawley
550 ppm/360 min*
Hazelton Labs, 1965
Dermal
M,F
rabbit
1680 mg/kg
Hazelton Labs, 1965
Oral
dog
100-200 mg/kg
Johnston et al., 1974
102
-------
LEJ^q levels of 2,2,2-trifluoroethanol given l.p. to mice produced significant
(p<0.01) reduction in liver glutathione (12 hrs.) and erythrocyte glutathione
(24 hrs). Following a median lethal dose (200 mg/kg), reduced liver gluthathione
levels were observed, which recovered by 24 hours. This pattern was also
observed with liver glucose-6-phosphate dehydrogenase activity, which showed
maximal inhibition 12 hours after chemical injection (200 mg/kg).
Blake et al. (1969) found that median lethal doses of 2,2,2-
trifluoroethanol (350 mg/kg, i.p.) administered to mice produced symptoms
after a latent period of five hours. These symptoms included salivation,
lacr1mation, erythema (face and ears), tremors, labored respiration, and
hyperreflexia. Dogs injected with 400 mg/kg showed immediate violent vomiting,
hind leg ataxia, and bloody diarrhea. Eighteen to 24 hours later the animals
were still lethargic, had persistent tremors, and labored, rapid breathing.
Hazleton Laboratories (1965) conducted a series of acute
toxicity studies with rats and rabbits for Halocarbon Products Corp.
Oral administration of a median lethal dose (300 mg/kg) of 2,2,2-trifluoroethanol to
rats produced symptoms of marked depression, salivation, bloody lacrimation,
labored respiration, tremors, ataxia, sprawling of the limbs, and vasodilation
of the ears, feet, and tail. Necropsy showed marked congestion of the lungs,
liver, kidneys, and adrenals. Acute dermal application (abraded skin) to
rabbits (1385 mg/kg) produced symptoms similar to those just described in
rats, as well as depression of righting and placement reflexes. Pathology
showed congestion and/or hemorrhage of the lungs, congested kidneys, pale
colored liver, spleen and kidneys (one animal). Slight erythema was seen at
lower 2,2,2-trifluoroethanol doses after dermal application (138 mg/kg).
Single application of 0.1 ml of undiluted 2,2,2-trifluoroethanol into the
103
-------
conjunctival sack of rabbits followed by aqueous irrigation, produced severe aye
^ irritation. Conjunctivitis, iritis, and corneal opacity were seen. Sodium
fluorescein staining showed corneal damage. Some recovery (2/9) from chemosis,
erythema, and corneal opacity was seen by days 7 to 14, but was not observed in
those rabbit eyes which were not irrigated after 2,2,2-trifluoroethanol treat-
ment.
Acute inhalation studies with rats (Uazleton Laboratories,
1965) indicated that after exposure to 350 ppm 2,2,2-trifluoroethanol for six
hours animals showed marked depression and a hunched position. Following exposure,
depression continued for five days, piloerection and sneezing were observed, and
eye irritation and bloody nasal discharge were noted. Necropsy showed pulmonary
congestion (3/10) and severe kidney congestion (2/10). At a concentration of
500 ppm (^LC^q) lung surfaces showed discoloration and some instances of pin-
point gray-yellow nodes. Blake et al. (1967) determined an concentra-
tion of 85 ppm for mice exposed 10 minutes. Based on this work a threshold
limit value (TLV) between that of carbon tetrachloride (10 ppm) and trichloro-
ethylene (100 ppm) was proposed by Blake et al. for 2,2,2-trifluoroethanol.
2-Bromoethanol
2-Bromoethanol was tested for toxicity in male ICR mice
and found to have an approximate LD5Q level of 120 mg/kg by intraperitoneal
injection (Dillingham et al., 1973). This level is comparable to that found
for 2-chloroethanol given intraperitoneally to mice CLD5Q, 120 mg/kg).
2-Fluoroethanol
2-Fluoroethanol was more toxic for rats than bromoethanol,
showing an LD50 of 20 mg/k8 following i.p. administration. Table 15 summarizes
the acute toxicity of 2-fluoroethanol.
104
-------
Table 15. Acute Toxicity of 2-Fluoroethanol
Route
Sex
Species Strain
ID
50
Reference
I.p. rat 5 mg/kg
S.c. rat 2-3 mg/kg
Oral rat 2.5 mg/kg
I.p. M rat Sprague- 1.75 mg/kg
Dawley
I.p. mouse 10 mg/kg
S.c. mouse 15 mg/kg
I.v. dog 0.05-0.07 mg/kg
l.v. monkey Rhesus 4 mg/kg
I.p. guinea pig 0.4 mg/kg
S.c. rabbit 0.3 mg/kg
. *
Ihl. mouse 419 ppm/10 min.
. *
Ihl. monkey 57 2 ppm/10 min.
*
Ihl. dog 3 ppm/10 min.
*
Ihl. cat 13 ppm/10 min.
Ihl. rabbit 10 ppm/10 min.
Chenoweth, 1949
Fobs, 1948
Kalmbach, 1945
Peterson at al.,
1968
Ward and Spencer,
1947
Pattison, 1953
Chenoweth, 1949
Chenoweth, 1949
Hutchens et al.,
1949
Hutchens et al.,
1949
OSRD, 1946
OSRD, 1946
OSRD, 1946
OSRD, 1946
OSRD, 1946
LC
50
105
-------
2,3-Dichloro-l-propapol
Smyth and Carpenter (1948) evaluated the toxicity of 2,3-
dichloro-l-propanol in rats and determined an oral ^ mg/kg.
Inhalation of 500 ppm 2,3-dichloro-l-propanol for four hours was lethal to two
of six rats. Application of this compound to intact rabbit skin (one day with
rubber cuff) showed significant absorption, since 270 mg/kg produced 50%
mortality. Eye injury tests of 2,3-dichloro-l-propanol 9howed damage graded
as 5 on a scale of 1 to 10.
2,3-Dibromo-l-propanol
2,3-Dibromo-l-propanol is lethal to mice when administered
intraperitoneally at 125 mg/kg (National Institute for Occupational Safety and
Health, 1977).
Trichloroethanol
Acute toxicity data for trichloroethanol are summarized in
Table 16. Whether liver toxicity is produced by inhalation of trichloroethylene
vapors has been a subject of debate (Joron et al., 1955), since this compound
shows moderate liver effects. Kylin et al. (1963) studied fatty changes in
the liver following a single four-hour exposure of albino mice to trichloro-
ethylene vapor. Moderate fatty infiltration was histologically confirmed
three days after exposure to 3200 ppm trichloroethylene. No increase in total
extracta'ole liver fat or serum levels of ornithine carbamoyl transferase was
shown. On the basis of these fatty infiltration studies, relative hepatotoxic
effects for trichloroethylene, tetrachloroethylene, and chloroform were assessed
at the ratios of 1:10:20, respectively.
Inhalation studies in rats (Smyth and Carpenter, 1969)
indicated that a single four-hour exposure to 500 ppm of trichloroethanol vapor
killed one of six animals.
106
-------
Table 16. Acute Toxicity of Trichloroethanol
Route
Sex
Species Strain
LD
50
Reference
Oral
I.p.
I. v.
I. V.
rat
rat
mouse
rabbit
^600 mg/kg
^400 mg/kg
201 mg/kg
¦^60 mg/kg
Lehmann and
Knoeffel, 1938
Lehmann and
Knoeffel, 1938
NI0SH, 1977
Lehmann and
Knoeffel, 1938
Table 17. Acute Toxicity of 2-Chloro-l-propanol
Route
Sex
Species Strain
LD
50
Reference
Oral
Oral
Ihl.
Dermal
M
rat
guinea pig
rat
rabbit
Wistar 220 mg/kg
7 20 mg/kg
-500 ppm*
480 mg/kg
Smyth et al.,
1941
Smyth et al.,
1941
Smyth and
Carpenter, 1969
Smyth and
Carpenter, 1969
LC
50
107
-------
Lehmann and Knoeffel (1938) investigated the effects of
trichloroethanol and tribromoethanol in anesthetized dogs and in the isolated,
perfused rabbit heart. Both compounds produced respiratory depression (50 mg/kg)
in dogs, with tribromoethanol showing greater depression (not corrected for
molecular weight differences). Circulatory effects included slowing of heart
rate and fall in arterial pressure (dogs, perfused rabbit heart), indicating
effects on both the CNS vasomoter centers and directly on the heart. Tri-
chloroethanol and tribromoethanol in 3 percent aqueous solution applied topically
to rabbit eyes produced moderate conjunctivitis but had no effect on pupil size.
2-Chloro-1-propanol
Acute toxicity data for 2-chloro-1-propanol are summarized
in Table 17. Smyth and Carpenter (1969) observed an LD^q of 220 mg/kg for 2-
chloro-l-propanol administered orally to male Wistar rats. This compound is
less toxic by the oral route than either 2-chloroetha.nol or 3-chloro-l,2-
propanediol.
c. Sub-Chronic Toxicity
3-Chloro-l,2-propanediol
Kirton et al. (1970) observed toxic symptoms such as lack
of coordination and muscular weakness in Rhesus monkeys (Macaca mulatta) orally
dosed with 3-chloro-l,2-propanediol at the rate of 30 mg/kg/day for 6 weeks.
Hemorrhage (site unspecified) and depression were noted in the fifth and sixth
weeks. Blood tests showed severe anemia, leukopenia, and thrombocytopenia,
implicating bone marrow damage by the drug. Necropsy on two of six monkeys showed
hemorrhage, pneumonia, enteritis, pleurisy, and peritonitis. No microscopic
examination of organs was described. In a preliminary report covering 110 days
of observation, Jackson (1977) observed no apparent adverse effects in dogs
that received 50 oral doses of double-distilled 3-chloro-l,2-propanediol at
30 mg/kg/day followed by another 50 doses at 60 mg/kg. Samojlik and Chang (1970)
108
-------
observed paralysis and impaired reflexes in Sprague-Dawley rats treated s.c. with 40
mg/kg/day 3-chloro-l,2-propanediol (purity not described) for 20 days.
2,2,2-Trifluoroethanol
Blake et al. (1969) noted that mice treated intraperitoneally
with 100 mg/kg of 2,2,2-trifluoroethanol daily for 18 days failed to gain weight
while controls increased by 40%. Rosenberg and Wahlstrom (1971) observed fat
accumulation in liver cells with electron microscopy after 2,2,2-trifluoro-
ethanol (160 mg/kg) was given intraperitoneally, but was unable to show liver
cell necrosis after administering the compound every second day for two weeks.
Stevens et al. (1975) exposed rats, mice, and guinea pigs to a series of
concentrations of halothane for a constant 35-day period. At 1/100 to 1/200 of
the maximum allowable concentration (70 to 150 ppm) all species showed an increased
incidence of degenerative hepatic lesions, including granular and vacuolar
degeneration, zonal centrilobular lipidosis, focal lipidosis, and focal necrosis.
Hazleton Laboratories (1975) studied the effects of 2,2,2-
trifluoroethanol inhalation on rats (5 days/wk, 6 hours/day) for four weeks.
Mean testis weight decreased in rats exposed at the level of 150 ppm. Microscopic
examination showed hypospermatogenesis in these rats. Occasional fusion
bodies were seen in the seminiferous tubules of rats exposed at 50 ppm.
Regeneration and normal spermatogenesis in "many" seminiferous tubules was
seen after 150 ppm in a subsequent 57-day recovery period. Rats exposed to 50
and 150 ppm 2,2,2-trifluoroethanol showed functional impairment of reproduc-
tive capability as determined by decreased conception rates, decreased number
of corpora lutea, decreased implantation sites, decreased live fetuses, increased
pre-implantation losses and increased post-implantation losses. Effects were
109
-------
attributed mainly to hypospermatogenesis produced at these two concentrations.
Extensive pathology of other organs in rats exposed to 50 and 150 ppm 2,2,2-
trifluoroethanol showed no histomorphologic differences from controls (Hazleton
Laboratories, 1975).
1-Chloro-2-propanol
Gage (1970) conducted a number of inhalation tests with
rats on the toxicity of repeated exposures to l-chloro-2-propanol. At 1000 ppm,
l-chloro-2-propanol induced one death after two 6-hour exposures, 3 days
apart. Pathology revealed edema of the lungs, inflammatory exudate of the
lungs, and swelling and vacuolization of liver cells. A concentration of 250 ppm
produced signs of lethargy, irregular weight gain, and congestion of the lungs
with perivascular edema; 100 ppm produced no toxic symptoms, but pathology
indicated some edema of the lungs. The material used in these inhalation
studies was not purified and therefore could contain as much as 25% of the
isomer 2-chloro-l-propanol.
Trichloroethanol
Kylin (1965) treated female albino mice, four hours daily
for six days a week, with trichloroethylene vapor (1600 ppm). Increased fatty
degeneration of the liver was noted relative to controls. This deleterious effect
increased through two weeks exposure and then declined after four and eight weeks
of trichloroethylene treatment. Total extractable fat from the liver of
trichloroethylene treated animals showed a small increase (p<0.01). No cirrhosis
or liver cell necrosis was seen, and no kidney lesions were observed.
2-Chloroethanol
Oral feeding of 4.5 to 180 mg of 2-chloroethanol daily to rats
induced fatalities in all animals (Ambrose, 1950). Deaths occurred in 7 to 49 days.
110
-------
Oser et al. (1975) conducted feeding studies in rats, dogs, and monkeys for 90
days. Rats dosed at 67.5 mg/kg/day showed decreased food intake, decreased body
weight, and 70% fatalities. Necropsies indicated a high incidence of myocarditis
and fatty liver in short term survivors. Dogs fed 13 to 18 mg/kg/day of 2-chloro-
ethanol failed to gain weight, nor did monkeys given 45-63 mg/kg daily. There
was some lowering of the dogs' hemoglobin and hematocrit ranges by week six,
and recovery by week 12. In other studies, intraperitoneal administration of
2-chloroethanol to rats was performed three times per week for 90 days, and daily
for 30 days (Lawrence et al., 1971b). The intermittent schedule produced no deaths
in rats dosed at 6.4 mg/kg or 12.8 mg/kg, but at 32 mg/kg six of 12 test animals
died. With daily administration of 2-chloroethanol at 12.8 mg/kg, toxicity was
seen after 30 days. At this level there was a slightly increased leucocyte
count. Weight gain was poor in animals receiving toxic levels of drug, but no
significant histopathological lesions were observed. Kinden et al. (1969)
found liver parenchymal lesions and serum enzyme changes in rabbits given
30 mg/kg of 2-chloroethanol daily for five days by intravenous injection.
2-Chloroethanol (10 mg/kg, s.c.) on three consecutive days
caused impairment in a conditioned reflex test in cats (Balazs, 1976).
Subacute toxicity tests in rats (^65 mg/kg) with 2-chloro-
ethanol have shown myocardial lesions (route and duration of exposure not
specified) (Balazs, 1976).
Toxicity induced by repeated one-hour inhalations of 2-
chloroethanol at 2 ppm in rats has been reported by Ambrose (1950). Paralysis
in "some" rats and deaths were observed, but no quantitation was presented.
Ill
-------
Dermal application of 6.25% aqueous 2-chloroethanol to intact
skin in rats was fatal when repeated twice within three days (Ambrose, 1950). Four
dermal applications of 0.5 ml of undiluted compound to rabbits over four days
produced fatalities, while a single application at this concentration did not.
Oral administration of 2-chloroethanol to rats at 70 mg/kg
daily for one week increased serum amylase and decreased quinine-resistant
lipase (Strusevich and Ekshtate, 1973). Inhalation of 36 to 42 ppm 2-chloro-
ethanol (duration not specified) decreased serum amylase and cholinesterase,
and increased serum lipase activity. Both hepatic and pancreatic toxicity
have been inferred from these results.
Taylor (1969) investigated the toxicity of 2-chloroethanol
in feeding studies with rats, dogs, and monkeys. Results of feeding studies
(26 weeks) with laboratory rat chow containing 2-chloroethanol cannot be
evaluated since less than 20% of the desired 2-chloroethanol concentration was
found after chemical analysis of seven-day old feed. Daily feeding of rats by
stomach tube for 90 days at 67.5 mg/kg resulted in 70% deaths in the first three
weeks. Pathology showed abnormal color of the liver, gastrointestinal tract
reddening, and hemorrhagic adrenals and pituitary. Microscopic examination showed
fatty changes of the liver, colloid depletion of the thyroids, congestive changes
in the thymus, and subacute myocarditis. Those animals surviving this level of
2-chloroethanol showed decreased weight gain. Oral feeding studies (stomach tube)
with rats for 23 weeks cannot be interpreted since the concentration of 2-chloro-
ethanol was changed twice during the course of the investigation. Emesis produced
by 2-chloroethanol in feeding studies with dogs, and subsequent alterations in
chemical levels imposed by the investigators to compensate for this loss, make
112
-------
results from these studies uninterpretable. Studies with monkeys fed 2-chloroethanol
by stomach tube indicate some effects of the chemical on reducing the weight of
the testes. No dose response data were presented, and the small size of the groups
tested indicates that this was a preliminary study,
d. Chronic Toxicity
2-Chloroethanol
Ten groups of five rats each that were fed 2-chloroethanol
for 220 days began to show decreased weight gain at 0.16% dietary concentration
of compound (^5 mg/kg) (Ambrose, 1950). Pathology of these animals showed no
abnormal histopathology in organ sections from the heart, lung, liver, kidney,
spleen, adrenal, pancreas, intestine, bladder, testis, and thyroid.
Injection of rats twice weekly for one year indicated that
2-chloroethanol given at 10 mg/kg subcutaneously was tolerated without major
weight loss or gross organ pathology (Mason et al., 1971). However, mild
changes in liver, kidneys, heart, and lungs were noted but not quantitated.
Pneumonia was seen in some rats, but the rate was not significantly different
from that seen in controls.
Kovyazin (1971) has reported central nervous system effects
and liver injury in rats exposed to 3 ppm 2-chloroethanol by chronic inhalation.
Strusevich et al. (1972) found increases in blood lecithin
and cholesterol of rats subjected to either 0.3 ppm or 3 ppm chloroethanol for
four months. Recovery was seen in two weeks after the low dose inhalation.
113
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3-Chloro-l,2-propanediol
Purified 3-chloro-l,2-propanediol was given orally, 5
days/week, at 50 mg/kg to male rats (Jackson, 1977). All animals survived
this treatment regimen for one year, and 15 of 20 rats were alive two years
after administration of the first dose (^1/2 of the U^q)• This preliminary
study indicates that the pure compound is less toxic than previously reported,
e. Reproductive Effects
3-Chloro-l,2—propanediol
Since early reports (Coppola, 1969; Ericsson, 1968) of the
antifertility effects of 3-chloro-l,2-propanediol indicated it had potential
as a reversible, post-testicular agent, much research on this application of
3-chloro-l,2-propanediol has ensued. Coppola (1969) showed that at a level of
5 mg/kg daily (oral) for 12 days, sterility could be induced in male Wistar rats.
Fertility was partially restored immediately after compound withdrawal.
Higher levels of 3-chloro-l,2-propanediol (25 mg/kg) produced spermatogenic
arrest at the level of the primary spermatocyte. Samojlik and Chang (1970)
showed that 3-chloro-l,2-propanediol administered s.c. at 15 mg/kg daily for
six days in rats caused a marked reduction in sperm motility and a significant
decrease of oxygen uptake by sperm cells. Ericsson (1970) determined that minimal
amounts of 3-chloro-l,2-propanediol needed to produce permanent lesions in the
caput epididymis of the rat were 35 mg/kg (daily oral doses) or 45 mg/kg (single
oral dose). Formation of spermatoceles caused irreversible blockage of the caput,
with subsequent degeneration of the germinal epithelium. Reversible anti-
fertility effects with 3-chloro-l,2—propanediol have been observed in certain
species (rat, ram, boar, monkey, guinea pig) but not in others (mouse, rabbit)
(Ericsson et al., 1971). The biochemical mechanism of action in sperm is the
114
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inhibition of formation of 3-phosphoglycerate from glyceraldehyde-3-phosphate
(Mohri et al., 1975). Mashford and Jones (1978) tested 3-chloro-l,2-
propanediol phosphate in vitro and showed it to be a strong competitive inhibi-
tor of glyceraldehyde-3-phosphate dehydrogenase. Both epichlorohydrin and
glycidol, which are effective anti-fertility agents in vivo, have no effect on
this enzyme in vitro, nor does 3-chloro-l,2-propanediol. All three agents
probably share the common end metabolite, 3-chloro-l,2-propanediol phosphate,
in order to inhibit spenn glycolysis.
Dixit and Lohiya (1976) observed inhibition of new
spermatogonia in the testes of male rats and gerbils given 3-chloro-l,2-
propanediol orally (gerbils: 20 mg/kg for 50 days; rats 25 mg/kg for 24
days). This testicular effect produced changes in the anterior pituitary
resembling those produced by castration in controls. A rise in the activity
of gonadotrophic cells after 3-chloro-l,2-propanediol treatment was indicated
by an increased percentage of pituitary basophilic cells,
f. Mutagenicity
3-Chloro-l,2-propanediol
Glycidol, a possible 3-chloro-l,2-propanediol metabolite
(see Figure 7), has been shown to be mutagenic in Drosophila, Hordeum, and
Neurospora test systems (Loveless, 1966), but was found noncarcinogenic after
long term painting of mouse skin by Van Duuren et al. (1967). Jackson et al. (1970)
found glycidol to be negative in the dominant lethal assay for mutation effects;
similar results were reported earlier (Jones et al., 1969) for 3-chloro-l,2-
propanediol.
2-Chloropropanol
2-Chloropropanol, a residue found in foodstuffs after
propylene oxide sterilization, was tested in the Ames system for mutagenicity
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(Rosenkranz et al., 1975). The compound tested was 75% l-chloro-2-propanol
and 25% 2-chloro-l-propanol, and was incorporated directly into the agar
overlay. Tester strain TA 1530 showed increased mutations (base substitution)
while strain TA 1538 was unaffected (frameshift mutation sensitive). A graded
increase in the number of revertants was seen at concentrations of 2.2 to
22 mg/plate in the absence of liver S-9 mix activation.
1,3-Dichloro-2-propanol
Testing of 1,3-dichloro-2-propanol in the Ames mutagen-
icity assay was carried out (Gold et al., 1978) because this compound is a suspected
metabolite of the flame retardant Tyrol FR2. This compound (50 to 1000 ug/plate)
was found to increase mutation frequency in tester strain TA 100 when pheno-
barbital-induced rat-liver homogenate was present. However, this increase in
the number of revertants was not shown when Aroclor (PCB)-induced rat-liver
homogenate (S-9 mix) wa3 used for activation. The authors caution that several
liver preparations from different species and with various inducers should be
tried when evaluating mutagenicity in the Ames system.
2,3-Dibromo-l-propanol
Investigation of 2,3-dibromo-l-propanol for mutagenicity
was initiated by the finding (St. John et al., 1976) that this compound could
be found in the urine of rats treated dermally with the flame retardant (and
mutagen) Tris. Blum and Ames (1977) reported that 2,3-dibromo-l-propanol
(50 yg/plate) increased the mutation rate in tester strain TA 100 when Aroclor
S-9 activation mix was included. Frival et al. (1977) tested this compound in
the Ames assay with tester strains TA 1535 and TA 1538. The results showed
that when 0.1 or 1 ml of compound was applied to the TA 1535 plates, the
mutation frequency was increased (with Aroclor S-9 mix). This activity was
not seen in TA 1538 plates, with or without S-9.
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2,2,2-Tr ifluoroethano1
Waskell (1978) studied the e££ects of 2,2,2-trifluoro-
ethanol in the Ames assay system (strains TA 98 and TA 100) and found no
increased number of revertants at 69 mg/plate, either with or without S-9
enzyme mix added. Baden et al. (1978) reported that 2,2,2-trifluoroethanol
was not mutagenic to tester strains TA 1535, TA 1537, TA 98, and TA 100 when
assayed in liquid suspension. Concentration of drug and presence or absence of
S-9 mix was not specified.
Trichloroethanol
Waskell (1978) examined the mutagenicity of 2,2,2-trichloro-
ethanol (69 mg/plate) in the Salmonella system developed by Ames. The micro-
somal enzyme preparation (S-9 mix) was obtained from Sprague-Dawley rats
induced with both Aroclor and phenobarbital. Trichloroethanol was not muta-
genic either with or without the microsomal enzyme mix. Chloral hydrate (1 to
10 og) produced moderate mutagenic activity (^100 revertants above controls)
either with or without S-9 mix; this compound rapidly produces trichloro-
ethanol _in vivo (see Figure 8).
Trichloroethylene has been shown to be mutagenic in the
Ames assay (Simmon, 1977), particularly after addition of S-9 mix (rat, mouse).
In vivo metabolism of trichloroethylene will produce trichloroethanol (see
Figure 8). The trichloroethylene used may contain sufficient epichlorohydrin
impurity to account for the observed effect.
2-Chloroethanol
Investigation of the effects of 2-chloroethanol in the
Ames test indicated that this compound (5-20 ul/plate) induced an increased
number of revertants in tester strains TA 1530 and TA 1535, but not in strain
TA 1538 (Rosenkranz et al., 1974). 2-Chloroethanol (10 yl) also showed some
117
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preferential inhibition of DNA polymerase deficient E. coli growth. Bartsch
et al. (1975) showed that 2-chloroethanol (8 mg/plate) produced increased
revertants in strains TA 1530 and that this frequency doubled if S-9 enzyme
mix was added. McCann et al. (1975) found that 1 to 5 mg 2-chloroethanol induced
increased mutations in IA 100, primarily after addition of S-9 mix for activa-
tion. Chloroacetaldehyde, a chloroethanol metabolite (see Section C.l), was
several hundredfold more effective in inducing mutations, on a molar basis.
Similar potent mutagenicity of chloroacetaldehyde monomer hydrate and chloro-
acetaldehyde in Salmonella TA 100 and in a repair deficient Bacillus subtilis
strain was reported by Elmore et al. (1976). Rannug et al. (1976) found that
1 H 2-chloroethanol was weakly mutagenic (without activation) for TA 1535
strain Salmonella. As little as 0.5 jM chloroacetaldehyde produced an increase
in revertants in this same test system.
The haloalcohol series 2-bromoethanol, 2-iodoethanol, and
2-chloroethanol was investigated for relative mutagenicity. Roaenkranz et al.
(1974) reported that bromoethanol was most mutagenic (strains TA 1530 and
TA 1535) followed in order by iodoethanol and chloroethanol. Investigation of
the same series for mutagenicity with Klebsiella pneumoniae (Voogd and Vet, 1969)
showed that iodoethanol was most mutagenic, followed in order by bromoethanol
and chloroethanol. All the haloalcohols were compared at the same concentration
in the Klebsiella study, but not in the Salmonella study.
In vitro reaction of chloroethanol, bromoethanol, and
iodoethanol for varying time periods with calf thymus DNA has been shown to
increase the DNA buoyant density (Rosenkranz et al., 1974), indicating mutation
potential following physical interaction.
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Mutation induction by 2-chloroethanol was studied by
\
Huberman et al. (1975) in Chinese hamster V79 cells. Using 8-azaguanine
resistance and ouabain resistance as genetic markers, 2-chloroethanol did not
increase the mutation frequency. Chloroacetaldehyde at 6.4 yH concentration
was mutagenic> but this concentration also reduced the cloning efficiency
of treated cells. In an assay system measuring forward mutations and gene
conversions in yeast (Loprieno et al., 1977), 2-chloroethanol was not found
to be mutagenic. Chloroacetaldehyde was weakly mutagenic, producing a 2 to 7
fold increase at 6 to 12,5 uM concentration.
Isakova et al. (1971) reported that rats exposed by inhalation
to 0.3 to 30 ppm 2-chloroethanol for three months showed bone marrow abnormalities.
The frequency of aneuploid cells increased, and chromatid type aberrations as
well as prolonged mitosis was observed in the first two months of exposure. This
pattern of abnormal cells subsequently diminished with time, since the statistical
significance of chromosomal changes at six months is less than that seen at two
months.
g. Teratogenicity
2-Chloroethanol
2-Chloroethanol was administered to pregnant mice from the
sixth to the sixteenth day of gestation by Courtney and Andrews (1977) in an
unpublished study. With chloroethanol given by gastric intubation, a dose
level of 150 mg/kg was lethal to 75% of the mice. At the concentration of
100 mg/kg, 2-chloroethanol caused decreased maternal weight gain, decreased
fetal body weight, and decreased fetal liver weight. The number of implants
or the number of live fetuses was not affected. No results were reported on
the survivors of the high dose (150 mg/kg) regimen; this test group (8 animals)
was significantly smaller than the others evaluated (18 animals).
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Verrett (1974) found an increased number of fetal abnor-
> malities in chicks treated at the embryo stage with 2-chloroethanol (injection
into the air cell). Of these abnormalities, the most frequently seen was
anterior hydrophthalmos. However, most of the teratogenic affects were noted
at 2-chloroethanol concentrations approaching or exceeding an LDjq level. In
addition, the control used in the experiment (H^O) may not be adequate. Ethanol,
at an equimolar concentration, probably would have presented a more valid comparison,
since nonspecific membrane effects at this concentration could result from
the lipophilic activity of the compound.
h. Carcinogenicity
2-Chloroethanol
In a long term study of Fischer weanling rats injected
twice weekly for a year with 2-chloroethanol (10 mg/kg, s.c.), Mason et al.
(1971) found that the incidence of pituitary adenomas was increased. Untreated
controls showed 1/120 incidence while 2-chloroethanol treated rats had an
incidence of 7/200, all occurring in the 100 female test group.
Balazs (1976) has reported on a study in which rats were
injected subcutaneously with 10 mg/kg chloroethanol twice a week for a year, then
observed for an additional six months. No increased tumor incidence was seen
in this preliminary study.
Homburger (1968) in an unpublished study administered
1.2 mg 2-chloroethanol subcutaneously to one hundred C57BL/6 mice (male),
transfered minced skin pieces five weeks after the 2-chloroethanol injections
(to shorten tumor latency) into mice from the same litter, and evaluated these
recipients, 18 weeks later for tumor incidence. No increased tumor incidence
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was observed In the 2-chloroethanol-treated animals. The relevance of this
N system for assessing carcinogenicity has not been shown. Also, since the
number of injections of 2-chloroethanol and their scheduling was not reported,
it is not possible to assess the significance of these negative results.
In another part of this study designed to evaluate 2-
chloroethanol effects in producing lung adenomas, Homburger (1968) injected
female CFl mice with either one or seven monthly i.v. doses of 1.2 mg of com-
pound. Mice injected with a single intravenous dose did not show an increase
in adenomas over controls at 28 weeks. Those animals receiving multiple doses
did show a slight increase in adenomas (5/18 versus control 2/18), but the
high spontaneous rate of this tumor in this strain and the small number of
animals tested make interpretation of this increase difficult.
Trichloroethanol
Trichloroethanol is formed rapidly in vivo following
inhalation of trichloroethylene (Ertle et al., 1972). Unpublished results
from Stanford Research Institute have indicated that trichloroethylene is
weakly mutagenic after metabolic activation (Simmon, 1977). Therefore, con-
sideration of data on trichloroethylene effects may be relevant in assessing
trichloroethanol.
The results of a carcinogenicity bioassay of trichloro-
ethylene by the National Cancer Institute (1976) indicated that this compound
produced hepatocellular carcinomas in mice after high-dose feeding for 78
weeks. Loprieno, in a letter to the Manufacturing Chemists Association
(Clark, 1978) stated that the small amount of epichlorohydrin impurity (0.09%)
present in the trichloroethylene used can produce positive results in the Ames
assay; testing of pure trichloroethylene did not show any mutagenic activity.
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Caution is therefore advised in interpreting positive trichloroethylene
carcinogenicity data, unless the sample has been shown to be free of
epichlorohydrin.
2. Toxicity and Effects on Other Vertebrates
No data are available concerning effects of the haloalcohols on
other vertebrates.
3. Toxicity and Effects on Invertebrates
2-Chloroethanol
2-Chloroethanol has been widely used as an acaricide. Mites,
which have been reported to be sensitive to 2-chloroethanol, include spider
mites, hawthorn mites, and fruit tree mites (Margzhanyan et al., 1971).
Sukhoruchenko and Tolstova (1974) have reported on the sensitivity of the
Chrysopa species to 2-chloroethanol toxicity.
D. Toxicity and Effects on Plants
The herbicidal activity of several haloalcohols was studied by
Poignant and Richard (1958). 2-Chloroethanol and 2,3-dibromo-l-propanol
destroyed flax and white mustard plants when applied at the rate of 40 kg/hectare.
At this same concentration l-chloro-2-propanol, 1,3-dichloro-l-propanol, and
3-chloro-l,2-propanediol were without effect.
2-Chloroethanol
2-Chloroethanol has been widely used to increase the rate of sprout-
ing of potatoes, probably by increasing amylase levels during the germination
period (Arai, 1954). The opening of dormant grapevine buds has also been
promoted with 2-chloroethanol (Alleweldt, 1960). Wheat seeds soaked in 2-
chloroethanol have shown an increased resistance to high soil salt concen-
trations (Miyamoto, 1963). Vegetative growth of the Zinna has been impaired
by this compound, with chlorosis of the leaves and stems observed (Alberte,
1970).
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E. Toxicity and Effects on Microorganisms
2,2,2-Trichloroethanol
Prins and Seekles (1968) studied the effect of 2,2,2-trichloroethanol
on rumen metabolism in cattle. 2,2,2-Trichloroethanol decreased the breakdown
of cellulose, probably through direct action on rumen microorganism metabolism.
F. In Vitro and Biochemical Studies
2.2,2-Trifluoroethanol
Rosenberg et al. (1970) determined that 10 Si to 10 2,2,2-trifluoro-
ethanol added to mouse liver homogenates inhibited anaerobic glycolysis by
about 30%. Incubation of creatine phosphokinase with trifluoroethanol did not
block enzyme function, but addition of the -SH group reactive metabolite tri-
fluoroacetalde'nyde hydrate did produce a dose-dependent inhibition (Airaksinen,
1970). Rosenberg and Wahlstrom (1971) were unable to inhibit glucose-6-
phosphate dehydrogenase activity in vitro by the addition of either 2,2,2-
trifluoroethanol or trifluoroacetaldehyde hydrate. Marsh et al. (1977) showed
in vitro degradation of hepatic P-450 cytochrome with microsomes, fluroxene,
and NADPH. This cytochrome destruction correlated linearly with 2,2,2-tri-
fluoroethanol generated in the in vitro system under varying conditions of
induction. Rosenberg (1971) demonstrated that 2,2,2-trifluoroethanol at 0.1 mM
to 50 mM did not inhibit human fibroblast growth in vitro, while the acetalde-
hyde hydrate metabolite did so in a dose dependent fashion.
Ishii and Corbascio (1971) were unable to show effects of 1 mM 2,2,2-
trifluoroethanol or trifluoroacetate on hepatoma cell uridine uptake, thymidine
uptake, or leucine and acetate uptake. Halochane, which may produce trifluoro-
ethanol after metabolism, did increase acetate uptake in these cells indicating
stimulation of lipid synthesis. At a concentration of 100 mg/100 ml, halothane
was cytotoxic to both hepatoma and Hela cell lines.
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Blair and Vallee (1966) studied the effects of 2,2,2-trifluoro-
ethanol on purified human liver alcohol dehydrogenase. At pH 9.3, 50% inhi-
-4
bition of enzyme activity was produced by a 5 x 10 M solution of the drug.
Blake et al. (1969) found that 2,2,2-trifluoroethanol inhibited yeast alcohol
dehydrogenase activity in a competitive manner (relative to ethanol) at pH 8.2.
Trichloroethanol
Krieglstein and Stock. (1973) studied metabolic changes induced in
the isolated perfused rat brain by trichloroethanol. At a concentration of
3.5 mM, trichloroethanol caused an accumulation of creatine phosphate, an
increase in glucose concentration, and a decrease in glucose-6-phosphate
levels (p<0.05). The glucose increase after addition of trichloroethanol appears
to be concentration dependent, and a mechanism involving inhibition of brain
hexokinase has been proposed.
Amnion et al. (1967) administered trichloroethanol (i.v., 269 mg/kg)
to white mice and determined the acetyl donating activity of liver acetyl
coenzyme A in the presence of transacetylase. This high concentration of
trichloroethanol produced "^10% reduction in liver coenzyme A activity. Tri-
bromoet'nanol at a concentration near the level, produced no reduction in
liver coenzyme A activity.
Griiner et al. (1973) investigated EEG changes in the isolated,
perfused rat brain after administering trichloroethanol. Trichloroethanol
(1.5 to 5 mM) showed CNS depressant activity, with increasing concentration of
chemical producing progressively fewer brain waves over 50 microvolt/sec amplitude.
The EEG changes were complete in 10 minutes, indicating a rapid onset and short
duration of action.
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2-Chloroethanol
Feuer et al. (1977) investigated the effect of subcutaneous admin-
istration of 2-chloroethanol on rat liver microsomal drug metabolizing enzymes.
Daily administration of 20 mg/kg of 2-chloroethanol for seven days to female rats
produced a decrease in the activity of aminopyrine N-demethylase (p<.05); this
same schedule in male rats produced decreases in coumarin 3-hydroxylase
(p<.05) and aminopyrine N-demethylase activities (no statistics for the
latter). No morphological changes in the liver were observed after this
dosage schedule.
The inhibitory growth effects of 2-chloroethanol were investigated
on an L cell culture, NCTC clone 929 (Dillingham et al., 1973). 2-Chloroethanol
inhibited fibroblast growth by 50% at a concentration of 3 x 10 ^M, while 2-
_2
fluoroethanol and 2-bromoethanol showed higher toxicity » 2 x 10 M and
2 x 10 respectively). These same authors reported that 50% lysis of
rabbit erythrocytes in isotonic saline is produced in one hour by 0.6 M 2-
chloroethanol. Ethanol, in comparison, shows this activity at 2 M concentration.
There was excellent correlation between this hemolytic effect and the fibro-
blast inhibitory effect, as well as a uniform relationship between the product
of the in vitro toxicity concentration and water/octanol partition coefficient,
versus the vivo toxicity concentration. This suggests that the toxicity
of the haloalcohols studied here is related to their membrane effects.
Osterman-Golkar et al. (1977) have investigated the alkylating
potential of various vinyl chloride metabolites. Based on theoretical eval-
uations utilizing rate constants derived from reactions with model nucleophiles
in vitro, alkylation by 2-chloroethanol has been concluded to be negligible.
Hemoglobin histidine alkylation with both chloroacetaldehyde and chloroethylene
125
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oxide has been estimated and the rate constants indicate that chloroacetalde-
hyde is several orders of magnitude less reactive than chloroethylene oxide at
37°C.
Blair and Vallee (1966) have shown that 2-chloroethanol is a sub-
strate for human alcohol dehydrogenase in vitro. The rate of oxidation is 20%
compared with ethanol as a substrate. 2-Fluoroethanol is oxidized at 10%, and
2-bromoethanol at 15%, of the natural substrate rate. Inhibition of alcohol
dehydrogenase probably takes place via competition with ethanol as a substrate.
G. Effects on Environmental Quality
There was no information available concerning the effects of the
selected haloalcohols on environmental quality.
H. Effects on Inanimate Objects
There was no information available concerning the effects of the
selected haloalcohols on environmental objects.
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IV. Current Regulations
A. Federal, State and Local Standards
1. Food, Drug, and Pesticide Authorities
Although none of the selected haloalcohols are applied as
pesticides, or are directly added to food or drugs, some are metabolites of
pesticides. Ethylene oxide and propylene oxide, which are fumigants for bulk
food stuffs and sterilants for cosmetics, drugs, medical devices and single
service items, yield the corresponding chlorohydrins and/or bromohydrins as
metabolites. The Environmental Protection Agency and Food and Drug Administration
have set tolerances for halohydrin content in various commodities, medical devices
and other goods.
FDA tolerances for residual ethylene chlorohydrin (chloroethanol)
in drugs and medical devices are as follows (Federal Register, 1978):
(Parts per million)
Ethylene
Ethylene
Ethylene
Drug product
oxide
chlorohydrin
glycol
Ophthalmics (for topical use)
10
20
60
Injectables (including veterinary
intramammary infusions)
10
10
20
Intrauterine device (containing
a drug)
5
10
10
Surgical scrub sponges
(containing a drug)
25
250
500
Hard gelatin capsule shells
35
10
35
Medical device
Implant:
Small (<10 grams)
250
250
5,000
Medium (10-100 grams)
100
100
2,000
Large (<100 grams)
25
25
500
Intrauterine device
5
10
10
Intraocular lenses
25
25
500
Devices contacting mucosa
250
250
5,000
Devices contacting blood
(ex vivo)
25
25
250
Devices contacting skin
250
250
5,000
Surgical scrub sponges
25
250
500
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Propylene oxide may be added to food starch. Propylene chloro-
X hydrin limitations are 5 ppm for residues (Code of Federal Regulations, 1977a).
Ethylene oxide and propylene oxide may be applied as a fumigant
to spices, whole grains, and other commodites including dried prunes, glace-
fruit, gums, cocoa and processed nutmeats. The Environmental Protection Agency
has established tolerances for propylene oxide (300 ppm) and propylene glycol
(700 ppm) but not on propylene chlorohydrin (Code of Federal Regulations, 1977a).
Ethylene oxide residue was established at 50 ppm, but no separate value was
assigned for ethylene halohydrin (Code of Federal Regulations, 1977b).
2. Air and Water Acts and Other EPA Authority
The haloalcohols are not specifically regulated within the air,
water, or resource conservation and recovery acts or any other Environmental
Protection Agency authorities.
3. Occupational Safety and Health Administration
OSHA has set the TLV for chloroethanol (ethylene chlorohydrin)
at 5 ppm maximum concentration for 8 hour exposure.
4. DOT, ICC, CG - Transport Regulations
None of the selected haloalcohols are listed by the DOT as
hazardous materials (Code of Federal Regulations, 1977c).
5. Foreign Countries
Foreign standards on the selected haloalcohols include the
following: suggested maximum chloroethanol in air for four hour exposure
3
(Russian) is 0.5 mg/m (Kovyazin, 1971); trichloroethanol in air at 100 ppm is
a German standard which was considered too high (Linder, 1973); Russian
occupational standard for the trichloroethanol is 1 ppm (Andrianov, 1971);
proposed occupational standard of Romania for 1,3-dichloro-2-propanol is
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3 ppm (0.005 mg/£) (Pallade et al., 1964); and atmospheric standard for tri-
3
fluoroethanol in Russia is 2.45 ppm (10 mg/m ) (Nikitenko and Tolgskaga,
1969). Russia has set the maximum concentration of chloroethanol in reservoir
water at 30.5 ppm (0.1 mg/2.) (Semenova et al., 1971).
B. Consensus and Similar Standards
Ho information on consensus or other standards was found which
differed from the information described above. ACGIH (1977) suggested the TLV
(5 ppm) for occupational exposure to ethylene chlorohydrin (chloroethanol)
which was adopted as the OSHA standard.
C. Current Handling Practices
1. Special Handling in Use
The selected haloalcohols require no special handling practices
in their use. Sax (1964) listed chloroethanol (ethylene chlorohydrin), 1-
chloro-2-propanol (propylene chlorohydrin), 1,3-dichloro-2-propanol, and
trichloroethanol and suggested standard practices for handling and use of
liquids. The areas of use should be equipped for moderate ventilation.
Workers should exercise standard personal hygiene practices to avoid contact
by dermal or inhalation routes. Rubber gloves are not effective, since some
haloalcohols, e.g., chloroethanol, will pass through rubber (Lichtenwalter and
Riesser, 1964).
The haloalcohols can hydrolyze to yield corrosive acids (in
particular hydrolysis to HC1 or to HBr). For this reason, Lichtenwalter and
Riesser (1964) suggested that process equipment should be constructed of
materials which will not be corroded by acid, such as glass, ceramics, high-
silica iron, tantalum or "Hastelloy" alloys.
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2. Storage and Transport Practices
None of the selected haloalcohols are classified as hazardous
materials by DOT. They are shipped in small containers (e.g., 5-gallon glass
containers) or in bulk quantities such as in tank cars or trucks (Lichtenwalter and
Reisser, 1964).
Since all the selected haloalcohols have low vapor pressures,
special storage facilities are not required except that facilities should be
constructed of materials which resist corrosion from halogen acid (see above).
3. Accident Procedures
Haloalcohol accidents can be handled by the response procedures
standard for organic solvents. The haloalcohols are not especially flammable,
and their low vapor pressure minimizes explosion hazard. If spilled, the
material can be diluted with water.
Haloalcohol fires can be put out with any extinguishing agent:
water; carbon dioxide; dry chemical; or carbon tetrachloride. When burned, the
haloalcohols liberate halogen acid (HC1, HBr, or HF). All of these are cor-
rosive and health hazards; the hydrofluoric acid is very hazardous (Sax,
1964).
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V. Exposure and Effects Potential
A. Human Exposure and Possible Effects
Potential human exposure to haloalcohols could occur in three
ways: occupational contact, losses to the environment from manufacturing plants
or industrial waste disposal sites, or use of products containing haloalcohol.
Very little quantitative information is available on any of the above sources of
exposure.
The haloalcohols manufactured in significant quantities (>1 million
lbs annually) are chloroethanol, the chloropropanols, and 2,3-dibromo-l-
propanol. With the exception of the dibromopropanol and small amounts of the
dichloropropanol which are consumed as solvents, most of these haloalcohols
are unisolated reaction intermediates and are both produced and consumed
(chlorohydrin process) in the same reactor. Based primarily upon the data of
Gruber (1976) and Pervier et al. (1974), it would appear that the chloroalcohols
are not among the components of plant emissions to the atmosphere; however,
surveys and monitoring studies (see Section II.E.2) have demonstrated that
chlorohydrins are released to the environment from effluents and from land
disposal of liquid residues (heavy ends from distillation pots). The only
quantitative data available on emissions from epichlorohydrin plants comes fTom
Gruber's report which sets the 1,3-dichloro-2-propanol content of water effluents,
and residues destined for land disposal at approximately 4 and 2.3 million pounds
respectively. Chloroethanol has also been observed in industrial effluent.
Information on environmental release of 2,3-dibroimo-l-propanol
depict a similar exposure risk from Industrial wastes. Monitoring studies
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have identified it in water effluent and in landfill leachate. Dibromopro-
\ panol has been detected in well water, which has apparently been contaminated
with leachate from industrial waste disposal by landfill.
In summary, exposure to haloalcohols from industrial plants is
possible. Exposure risk could be high among local populations utilizing water
supplies (surface or ground water) near plant effluent release sites or near
industrial waste disposal sites.
Few uses of the haloalcohols could result in human exposure. Perhaps
the most important exposure risks results from use of foams which are treated
with dibromopropanol as a flame retardant. Occupational exposure and perhaps
other local exposures (e.g., from wastes or emissions) could result from the
use of haloalcohols as solvents, for example, the consumption, of 1,3-dichloro-
2-proponal as a plating and metal cleaning solvent.
The inadvertent production of haloethanols and halopropanols could
be the most important route of exposure to the general population. These
haloalcohols are metabolites produced by reaction of inorganic halide with
precursor ethylene oxide or propylene oxide. While both of these epoxides are
applied as fumigants to tobacco, grains, spices, and other species, ethylene
oxide is also a sanitizing agent for single-service food containers, medical
devices, pharmaceuticals and cosmetics. Relatively small percentages of the
total annual production of the two epoxides are consumed for these uses;
approximately 100,000 pounds of ethylene oxide are annually applied as a
fumigant and somewhat less propylene oxide is applied for this purpose.
Significant factors contributing to the risk are that the products containing
these residues affect the population at large rather than a group limited by
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geographical or occupational boundaries and that the affected products include
ingested commodities and items that come into close contact with the body.
Available information is not sufficient to delineate the average residue
concentration contained in these products. Various monitoring studies have
noted high concentrations in occasional samples. For example Wesley and co-
workers (1965) reported up to 1000 ppm of chloroethanol in whole spices and
ground spices, and Gannon and Kereluht (1973) observed ethylene chlorohydrin (chloro-
ethanol) in concentrations of 260 ppm and 310 ppm in flour and spray-dried
albumen, respectively. Ragelis (1968) also detected 47 ppm l-chloro-2-propanol
in some foods. Brown (1970) noted chloroethanol concentrations in various
surgical equipment, the highest residue found was 27 ppn in heart catheters
(woven dacron). Ethylene chlorohydrin residues in medical devices have caused
some observed health effects (see below). The regulations of epoxide applica-
tions and tolerances on halohydrin residues in the above products (see Section
IV.A) should limit exposure. However, it is possible that some products will
exceed the limits.
B. Health Effects
The flame retardants Tris and Fyrol FR-2 release 2,3-dibromopropanol
and l,3-dichloro-2-propanol, respectively, after metabolism. Blum et al. (1978)
have found up to 29 ng/ml of 2,3-dibromo-propanol in the urine of children
wearing Tris-treated sleepwear. Both of these compounds have been shown to be
mutagenic in the Salmonella typhimurium system (Blum and Ames, 1977; Gold et al.,
1978) and caution has been advised in human use of materials treated with
these flame retardants, particularly where dermal and oral contact could
result.
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Sterilization of food stuffs with ethylene oxide and propylene oxide
produces residue levels of 2-chloroethanol and l-chloro-2-propanol/2-chloro-l-
propanol. An estimate carried out by the EPA (1978) indicates that exposure
to ethylene oxide residues in foodstuffs by ingestion (0.0003 mg/kg/day) would
not result in cumnulatlve toxic effects to man. This is based on a no-effect-
level calculated from reproductive effects (Hollingsworth et al., 1956) in
guinea pigs. Chronic feeding studies with chloroethanol in rats (Ambrose,
1950) indicate a no-effect-level by this route well above the level expected
from human ingestion. The fact that these residues have been shown to produce
mutations in the Ames assay (see mutagenicity section) warrants further inves-
tigation of long term effects of these agents in humans, particularly cyto-
genetic studies of bone marrow and peripheral blood.
Adverse effects have been reported after use of ethylene oxide
sterilized cardiac catheters or intravenous tubes, due apparently to the
formation of chloroethanol residues. These effects include hemolysis (Balazs,
1976), cardiovascular collapse (Lebrec et al., 1978), and anaphylaxis
(Poothullil et al., 1975). An estimate for a safe level of residual ethylene
oxide in sterilized medical equipment by Balazs (1976) indicates that release
of ethylene oxide from polymeric material could produce a genetic risk which
is comparable to 10 times the maximum permissible weekly dose of radiation (^1
rad gonadal dose). More information concerning the rate of release of the
chlorohydrins from various polymeric materials is needed to assess the actual
risk factor. The same type of cytogenetic studies needed for evaluation of
residue effects from foodstuffs would apply for exposure to sterilized medical
equipment, particularly in long term use situations such as are found with
hemodialysis tubing and cardiac pacemakers.
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Agricultural uses of 2-chloroethanol present exposure risks to
workers during application of the compound, both by vapor inhalation and rapid
cutaneous absorption. Information is not available concerning the present
extent of this type of agricultural usage. However, the reported toxicity of
2-chloroethanol to potato workers (Bush et al., 1949) indicates that inhala-
tion of high air concentrations (300-500 ppm) is extremely hazardous. Animal
studies showing the extremely high acute toxicity of inhaled chloroethanol
(see Table 13) support this hazard liability.
The haloalcohols have been used as degreasing agents in the cleaning
of metal surfaces. Worker exposure by vapor inhalation and direct dermal
contact could lead to toxic effects, particularly to the liver and kidneys.
Graovac-Leposavic et al. (1964) have reported altered liver function tests in
workers exposed to 100 ppm of trichloroethylene (trichloroethanol is a major
human metabolite following inhalation of trichloroethylene). Human exposure
to chloroethanol vapor at an estimated level of 18 ppm (Goldblatt and Chiesman,
1944) has produced renal effects. Liver and kidney function screening would
be indicated in industrial situations where worker exposure was present.
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VI. Technical Summary
The ceil haloalcohols which have been evaluated in this report can be
classified into three groups based upon production volume and uses: 2-chloro-
ethanol and the chloropropanols (2-chloro-l-propanol, l-chloro-2-propanol,
l,3-dichloro-2-propanol, 2,3-dichloro-l-propanol, and 3-chloro-l,2-propane-
diol); 2,3-dibromo-l-propanol; and the remaining haloalcohols (2,2,2-trifluoro-
ethanol, 2,2,2-trichloroethanol, and 2-bromopropanol).
While the chloroalcohols are the largest group in terms of production,
they are primarily consumed as nonisolated intermediates. Annual production
and major use of the chloropropanols are estimated as follows; monochloropro-
panols (l-chloro-2-propanol and 2-chloro-l-propanol) for propylene oxide
production - 1950 million pounds; dichloropropanols (1,3-dichloro-2-propanol
and 2,3-dichloro-l-propanol) for epichlorohydrin production - 585 million
pounds; and 3-chloro-l,2-propanediol for glycerol production - 195 million
pounds. Relatively small amounts (<1 million lbs) of each chloropropanol are
consumed for other purposes, such as solvents or intermediates in other syntheses.
Chloroethanol consumption is considerably smaller than the consumption of
chloropropanols, since it is only occasionally used aa an intermediate for ethylene
oxide production. Chloroethanol production was estimated at 50 to 100 million
pounds per year; an estimate which depends in part upon the amount used in
ethylene oxide synthesis. It is also consumed as an intermediate in a variety
of syntheses (see Sections II.A. and II.3.).
Dibromopropanol production is placed at <10 million pounds annually. While
it was formerly consumed primarily in production of the fire-retardant Tris,
tris(2,3-dibromopropyl)phosphate, this use decreased dramatically after Tris
was identified as a potential carcinogen. However, dibromopropanol itself is
136
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scill extensively used as a fire retardant, mostly in polyurethane foams. Lesser
amounts are used as synthetic intermediates (see Section II.B).
Three of the haloalcohols: 2,2,2-trifluoroethanol, 2,2,2-trichloroethanol,
and 2-bromoethanol, are produced as specialty or laboratory chemicals. Pro-
duction of each was estimated at less than 0.1 million pounds annually (see
Sections II.A and II.B).
Although the chloropropanols and chloroethanol are produced in massive
quantities, their environmental release during manufacture appears relatively
small (Gruber, 1976; Pervier et al., 1974). No information was available on
the emissions during production (fugitive emissions, vent gases, etc.). Al-
though emissions associated with production appear minor, even a small per-
centage of the total produced could potentially release several thousand
pounds per year (see Section II.C). Wastes generated during manufacture could
contain haloalcohols. Studies of manufacturing plants have found haloalcohols
in process waters and in heavy ends from distillation pots. Monitoring studies
have identified haloalcohols in chemical plant effluents and dibromopropanol
in landfill leachate (Shackelford and Keith, 1976; Alford, 1975).
Inadvertent formation of chloroethanol, bromoethanol, and chloropropanol
results when the corresponding epoxides react with inorganic halides. The pre-
cursor epoxides are fumigants and sterilants for a variety of food commodities,
drugs, medical devices, food service items, and cosmetics; estimated applica-
tion is less than 0.1 million pounds annually for ethylene oxide and somewhat
less for propylene oxide. Haloalcohol residues as high as 1000 ppo have been
detected in commercial commodities that have been treated with the epoxides,
although residues are generally less than 25 ppm (Wesley et al., 1965; Scudamore
and Heuser, 1971) (see Section II.C). Haloalcohols that are produced during
sterilization and fumigation come into direct contact with humans.
137
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The haloalcohols, with the possible exception of trlfluoroethanol, are
^ not persistent in the environment and their chemodynamic properties suggest
that they can be transported with water. In water the chloro- and bromo-
alcohols hydrolyze. Above pH 9 they initially yield epoxides, which subsequently
react to form glycols (Frost and Pearson, 1951). In neutral solutions haloalcohols
appear to hydrolyze directly to glycols. In soil the bromo- and chloroalcohols
appear to degrade in pathways similar to degradation in water. Enzyme extracts
of soil microorganisms catalyze reversible formation of epoxide (Castro and
Bartnicki, 1968). The haloalcohols are very water soluble (from 10% solubility
to completely miscible) and, therefore, are likely to remain in water until they
degrade (see Section II.D).
The haloalcohols have demonstrated fatal toxicity in man following acute
oral, dermal, or inhalation exposure. Fluoroethanol is the most toxic of
these agents by virtue of its unique metabolism to fluorocitrate and subsequent
blockade of Krebs cycle energy production; an oral dose of 2 mg/kg will produce
death in rats. Trichloroethanol is the least toxic of the haloalcohols, producing
lethal effects at concentrations 30 to 300 times higher than fluoroethanol.
Toxicity produced by the other haloalcohols involves gross effects on the central
nervous system, liver, kidneys, and lungs. Absorption through the skin is rapid,
and dermal contact does not produce marked immediate irritation. Inhalation may
result in cumulative effects, particularly in the liver and kidneys. Tissues show
depletion of glutathione and other -SH compounds as a result of interaction
with haloalcohol metabolites. Fatal toxicity is often seen after a delay of
several hours or days following exposure. Autopsy findings of adema in the lungs
and the central nervous system indicate that membrane function may be damaged
by these lipophilic agents. The haloalcohols are irritating to the eyes, and
138
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direct contact with high concentrations may produce irreversible corneal
changes- Some individuals are more markedly sensitive to exposure, developing
symptoms of nausea, headache, vomiting, and vertigo at levels that do not
produce symptoms in others. This may be due to genetically determined meta-
bolic differences or to damage to normal liver and kidney function. Liver
damage produced by the haloalcohols in turn potentiates the toxic effects of
drugs and chemicals that would normally be metabolized at this site.
Reproductive effects have been seen with 2,2,2-trifluoroethanol and 3-
chloro-1,2-propanediol. The latter has been studied extensively as a post-
testicular antifertility agent (see Jones, 1978). Both low-dose reversible
effects on sperm motility and oxygen consumption, and high-dose irreversible
effects on blockage of the caput epididymis, have been reported following
daily administration to animals for 7 to 14 days at 5 to 35 mg/kg. The resolution
of the _d,_l isomers of 3-chloro-l, 2-propanediol led to the discovery
that the active form in producing antifertility effects is less toxic to
experimental animals than the mixture (Jones et al., 1977), which produced
bone marrow depression in monkeys (Kirton et al., 1970).
A subacute inhalation study of rats exposed to 0.3 to 3 ppm of 2-chloro-
ethanol has indicated bone marrow abnormalities (Isakova et al., 1971). This
included increased numbers of aneuploid cells and chromatid aberrations.
However, the pattern of these changes appeared to be reversible with time,
thus making it difficult to interpret the biological relevance of these changes.
Investigation of the mutagenic activity of haloalcohols and their metabo-
lites has indicated that several compounds are positive mutagens. 2-Chloro-
propanol and 2-chioroethanol increased the number of revertants in the Ames
139
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Salmonella bioassay system, particularly in the presence of a aiicroscnae-
containing liver preparation (Rosenkranz and Wlodkowski, 1974; Bartsch et al.,
1975; McCann et al., 1975; Rannug, 1976; Rosenkranz et al., 1975). 2-Chloro-
ethanol has also produced forward mutations in Klebsiella pneumoniae (Voogd
and Vet, 1969). Chinese hamster cell mutants have been increased when chloro-
acetaldehyde, a possible chloroethanol metabolite, was added to the cultured
cells (Huberman et al., 1975). Loprieno et al. (1977) have shown chloro-
acetaldehyde to produce forward mutations and gene conversions in yeast. Both
l,3-dichloro-2-propanol and 2,3-dibromo-l-propanol have been shown to be
mutagenic in the Ames Salmonella bioassay system when a liver microsome-
containing preparation was added (Gold et al., 1978; Blum and Ames, 1977;
Prival et al., 1977). Glycidol, a potential metabolite of 3-chloro-l,2-
propanediol, was found to be mutagenic in Drosophila, Hordeum, and Neurospora
systems (Loveless, 1966). Trifluoroethanol, however, did not show mutagenic
activity, with or without metabolic activation, in the Ames system (Waskell,
1978).
2-Chloroethanol was shown by Verrett (1974) to produce teratogenic affects
in chick embryos after injection into the air sac. However, a mammalian study
with CD-I mice (Courtney and Andrews, 1977) in which 2-chloroethanol was fed
during the gestation period, did not show teratogenicity.
Chronic studies with 2-chloroethanol given by injection to rats (Mason
et al., 1971) have demonstrated an increase in pituitary adenomas, all in the
female half of the experimental animals. Balazs (1976) has repeated this dose
and schedule of 2-chloroethanol in rats and did not find an increased tumor
incidence. Skin painting studies for evaluating carcinogenesis are currently
underway with this compound at the National Cancer Institute.
140
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Conclusions and Recommendations
The following conclusions and recommendations are based upon assessment
of available information on the subject haloalcohols.
1. Three of the 10 selected haloalcohols (2-bromoethanol, 2,2,2-
trifluoroethanol and 2,2,2-trichloroethanol) are produced in
quantities less than 0.1 million pounds annually. Because
production is so low, they are considered insignificant.
2. Annual production and major uses of the seven important halo-
alcohols are as follows:
a) 2-chloroethanol - 50 to 100 million pounds annually. The
higher end of the production range occurs when it is prepared
as a nonisolated intermediate in ethylene oxide synthesis.
Chloroethanol is a synthesis intermediate and has some use as
a solvent.
b) Monochloropropanols (l-chloro-2-propanol and 2-chloro-l-
propanol) - 1950 million pounds. They are primarily consumed as
nonisolated intermediates in propylene oxide synthesis.
c) Dichloropropanols (1,3-dichloro-2-propanol and 2,3-dichloro-
1-propanol) - 585 million pounds. They are primarily consumed as
nonisolated intermediates in epichlorohydrin synthesis.
d) 3-Chloro-l,2-propanediol - 195 million pounds. It is mainly
consumed as a nonisolated intermediate during glycerin synthesis.
e) 2,3-Dibromo-l-propanol - <10 million pounds. It is mainly
consumed as a fire retardant.
3. The release of manufactured haloalcohols to the environment is
partially described but incomplete information is available to
conclusively describe release factors. Some haloalcohols are
released with wastes (presumably destined for disposal by land-
fill) and with waste waters. Insufficient information is avail-
able on how these wastes are handled.
4. Monochloro- and monobromoalcohols result when epoxides (ethylene
oxide or propylene oxide) react with inorganic chloride or
bromide. Since these epoxides are applied as fumigants or
sterilants for a variety of consumer products, this conversion
may expose the consumer population to haloalcohols. The scope of
the problem has been partially examined and legal limits on resi-
dues have been set by FDA. However, considerably more sampling
under actual field conditions probably is necessary in order to
examine the extent of the problem.
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5. The chloro- and bromoalcohols are subject to environmental degra-
dation. Hydrolysis converts them to the corresponding glycols.
Although the nature of the chemical hydrolysis is fairly well
delineated, the microbial degradation is not veil characterized
and it should be further studied.
6. Because of the water solubility of most haloalcohols, considerable
method development will be necessary for analysis of these compounds
at ppb levels in water samples.
7. Based upon limited bioassay data, the haloalcohols may be regarded
as potential carcinogenic agents. Further investigations are needed
to establish whether community and/or worker populations are being
exposed to these compounds, and if so, what effect has resulted.
8. If it is determined that humans are being exposed to significant
quantities of haloalcohols, further mammalian studies will be
needed in the areas of: (a) pharmacokinetics and metabolism, (b)
confirmation of carcinogenicity and toxicity, (c) in vitro
carcinogenicity/mutagenicity, (d) extent and significance of
cumulative liver and kidney toxicity. The effects of the halo-
alcohols on fish, invertebrates, wildlife, plants, and micro-
organisms should also be evaluated in experimental studies if it
is shown that significant environmental contamination is occurring.
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