Chlorohydrins

GORDON Y. T. LIU, The Dow Chemical Company, Midland, MIUnited States

W. FRANK RICHEY, The Dow Chemical Company, Midland, MIUnited States
JOANNE E. BETSO, The Dow Chemical Company, Midland, MIUnited States
BRIAN HUGHES, The Dow Chemical Company, Midland, MIUnited States
JOANNA KLAPACZ, The Dow Chemical Company, Midland, MIUnited States
JOERG LINDNER, Dow Deutschland Anlagengesellschaft mbH, Werk Stade, Germany

1. Introduction . . . . . . . . . . . . . . . . . . . . 1 7. Storage and Transportation . . . . . . . . . 8

2. Physical Properties . . . . . . . . . . . . . . . 1 8. Uses . . . . . . . . . . . . . . . . . . . . . . . . . 8
3. Chemical Properties . . . . . . . . . . . . . . 1 9. Toxicology and Occupational Health. . . 10
4. Production . . . . . . . . . . . . . . . . . . . . . 4 References . . . . . . . . . . . . . . . . . . . . . 20
5. Environmental Protection . . . . . . . . . . . 8
6. Chemical Analysis. . . . . . . . . . . . . . . . 8

1. Introduction chlorides. This combination is responsible for

Chlorohydrins are compounds with one or more
chlorine and hydroxyl groups in the non-
aromatic portion of their structure. The com-
pounds of greatest industrial importance are the
propylene chlorohydrins and glyceryl chloro-
hydrins (see Table 1). Ethylene chlorohydrin is
no longer an important intermediate for the
production of ethylene oxide, one of the classic
commodity chemicals.
Nomenclature. Many different names for the
various chlorohydrins appear in the literature.
Some of these synonyms for the major chloro-
hydrins are given in Table 1.
2. Physical Properties
Most dilute solutions of chlorohydrins in water
have a somewhat sweet, pleasant odor, particu-
larly 3-chloro-1,2-propanediol (5), 1,3-dichloro-
2-propanol (7), and 3-chloro-1-propanol (4). The
general physical properties of the more signifi-
cant chlorohydrins are listed in Table 2.
3. Chemical Properties
Chlorohydrins undergo reactions which are
characteristic of both alcohols and alkyl
the most common reaction of chlorohydrins,
which is dehydrochlorination to form epoxides:
The mechanism of dehydrochlorination of
ethylene chlorohydrin has been studied by
comparing the relative rates of reaction in
H2O and D2O [1]. The kinetics of the conver-
sion of propylene chlorohydrin to propylene
oxide were determined with both NaOH and
Ca(OH)2 [2]. The relative rates of solvolysis of
ethylene chlorohydrin, propylene chlorohydrin,
and butylene chlorohydrin in water at 97
C are
1.0 : 0.81 : 5.5 [3].
Hydroxyalkyl ethers may be prepared by
reacting chlorohydrins with alcohols or phenols
under basic conditions [4]. Ethers of cellulose
and starch are manufactured by treating these
materials with various chlorohydrins. Cationic
starch is made by treating 3-chloro-2-hydrox-
ypropyl trimethylammonium chloride with a
starch slurry at pH 1112 [5].
Chlorohydrins react with carboxylates in the
presence of base to give hydroxyalkyl esters. On
the other hand, b-chloro esters are formed by
reaction with carboxylic acids under acid

# 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

10.1002/14356007.a06_565.pub2
Table 1. Chlorohydrin nomenclature 2
Chlorohydrin CAS registry Formula Mr Synonyms
number

Ethylene C2H5ClO 80.52

2-Chloro-1-ethanol (1) [107-07-3] ClCH2CH2OH ethylene chlorohydrin, 2-chloroethyl alcohol, 1-chloro-2-hydroxyethane, 2-chloro-1-hydroxyethane, b-chloroethyl alcohol,
b-chloroethanol, ethylene glycol chlorohydrin, glycol chlorohydrin, glycol monochlorohydrin, glycolmonochlorohydrin,
2-monochloroethanol
Propene C3H7ClO 94.54
2-Chloro-1-propanol (2) [78-89-7] CH3CHClCH2OH 2-propylene chlorohydrin, 2-chloropropyl alcohol, b-chloropropyl alcohol, propylene b-chlorohydrin, 2-chloro-1-
hydroxypropane
Chlorohydrins

1-Chloro-2-propanol (3) [127-00-4] CH3CHOHCH2Cl b-chloroisopropyl alcohol, sec-propylene chlorohydrin, 1-chloroisopropyl alcohol, propylene a-chlorohydrin, 1-propylene
chlorohydrin, 1-chloro-2-hydroxypropane
3-Chloro-1-propanol (4) [627-30-5] Cl(CH2)3OH 1-chloro-3-hydroxypropane, trimethylene chlorohydrin
Glycerol C3H7ClO2 110.54
3-Chloro-1,2-propanediol (5) [96-24-2] CH2OHCHOHCH2Cl 3-monochloro-1,2-propanediol, 3-MCPD, a-chlorohydrin, 1-chloropropane-2,3-diol, glycerol a-chlorohydrin, 3-chloro-1,2-
dihydroxypropane, 3-chloro-1,2-propanediol, 3-chloropropylene glycol, glycerol a-monochlorohydrin,
a-monochlorohydrin, 1-chlorohydrin, chlorodeoxyglycerol, 1-chloro-2,3-dihydroxypropane, 3-chloropropane-1,2-diol, 2,3-
dihydroxypropyl chloride, glycerin a-monochlorohydrin, a-glycerol chlorohydrin, monochlorhydrin, monochlorohydrin
2-Chloro-1,3-propanediol (6) [497-04-1] HOCH2CHClCH2OH 2-monochloro-1,3-propanediol, 2-MCPD, 2-chlorotrimethylene glycol, glyceryl b-monochlorohydrin, b-chlorohydrin, 2-
chlorohydrin, chloro-1,3-propanediol, chloropropanediol-1,3
Glycerol dichlorohydrins C3H6Cl2O 128.99
1,3-Dichloro-2-propanol (7) [96-23-1] CH2ClCHOHCH2Cl 1,3-DCP, 1,3-dichlorohydrin, a,g-dichlorohydrin, b,b-dichloroisopropyl alcohol, glycerin a,a0 -dichlorohydrin,
a-dichlorohydrin, 1,3-dichloro-2-hydroxypropane
2,3-Dichloro-1-propanol (8) [616-23-9] CH2ClCHClCH2OH 2,3-DCP, 1,2-dichlorohydrin, a,b-dichlorohydrin, b,g-dichloropropyl alcohol, allyl alcohol dichloride, asymmetric glycerin
dichlorohydrin, b-dichlorohydrin, 2,3-dichloro-1-hydroxypropane
Butene C4H9ClO 108.57
2-Chloro-1-butanol (9) [26106-95-6] CH3CH2CHClCH2OH 2-chloro-n-butyl alcohol, 2-chloro-1-hydroxybutane
3-Chloro-1-butanol (10) [2203-35-2] CH3CHClCH2CH2OH 3-chloro-n-butyl alcohol, 3-chloro-1-hydroxybutane
4-Chloro-1-butanol (11) [928-51-8] CH2ClCH2CH2CH2OH 4-chloro-n-butyl alcohol, 4-chloro-1-hydroxybutane, 4-chloro-1-butane-ol, 4-chlorobutanol, tetramethylene chlorohydrin
1-Chloro-2-butanol (12) [1873-25-2] CH3CH2CHOHCH2Cl 1-chloro-sec-butyl alcohol, 1-chloro-2-hydroxybutane
3-Chloro-2-butanol (13) [563-84-8] CH3CHClCHOHCH3 3-chloro-sec-butyl alcohol, 3-chloro-2-hydroxybutane
4-Chloro-2-butanol (14) [2203-34-1] CH2ClCH2CHOHCH3 4-chloro-sec-butyl alcohol, 4-chloro-2-hydroxybutane
Isobutene C4H9ClO 108.57
2-Chloro-2-methyl-1- [558-38-3] (CH3)2CClCH2OH b-isobutylene chlorohydrin
propanol (15)
1-Chloro-2-methyl-2- [558-42-9] (CH3)2COHCH2Cl
propanol (16)
Isobutene dichlorohydrins C4H8Cl2O 143.01
1-Chloro-2-chloro-methyl-2- [597-32-0] CH3C(OH)(CH2Cl)2
propanol (17)
1,2-Dichloro-2-methyl-3- [42151-64-4] HOCH2CCl(CH3)
propanol (18) CH2Cl
Other
2-Chloro-1-phenyl-1-ethanol [1004-99-5] C8H9ClOC6H5CH(OH) 151.61 styrene chlorohydrin
(19) CH2Cl
Table 2. Physical properties of chlorohydrins

Chlorohydrin mp,
C bp,
C Flash d 20

4 , g/mL h, mPa  s Azeotrope Solubility
(at 25
C)

(p, kPa) point,
C Component bp,
C wt% Water Ethanol Acetone Benzene
Ethylene
2-Chloro-1-ethanol (1) 69 129 57 1.2133 3.43 water 97.8 42 miscible miscible miscible miscible
(63 to 40
C)
Propylene
2-Chloro-1-propanol (2) 133 1.1032 water 96.0 48 very soluble soluble soluble
1-Chloro-2-propanol (3) 127 52 1.1154 4.67 water 95.4 54 miscible miscible miscible miscible
3-Chloro-1-propanol (4) 16 1.1318 very soluble soluble soluble soluble
Glycerol
3-Chloro-1,2- 213 138 1.3204 159 soluble miscible miscible miscible
propanediol (5)
2-Chloro-1,3- 146 1.3219 300 high soluble soluble
propanediol (6) (2.4)
Glycerol dichlorohydrins
1,3-Dichloro-2-propanol (7) 4 174 58 1.3645 water 99 23 15.6 very soluble soluble
2,3-Dichloro- 182 91 1.3607 dichloro- 170.8 30 12.7 miscible miscible miscible
1-propanol (8) benzene
Butene
2-Chloro-1-butanol (9) 75 1.0622 high
(3.3)
3-Chloro-1-butanol (10) 138 1.0671
4-Chloro-1-butanol (11) 84 1.0883 high
(2.7)
1-Chloro-2-butanol (12) 141 1.0683 soluble
3-Chloro-2-butanol (13) 139 1.0669 water 94.5 59 high
4-Chloro-2-butanol (14) 70 high
(1.7)
Isobutene
2-Chloro-2-methyl-1-propanol (15) 132.5 1.0472 decomp.
1-Chloro-2-methyl-2-propanol (16) 128 93.5 66.0
Isobutene dichlorohydrins
1-Chloro-2-chloromethyl-2-propanol (17) 174
1,2-Dichloro-2-methyl-3-propanol (18) 180
Other
Chlorohydrins

Styrene chlorohydrin (19) 110 soluble soluble soluble soluble

(0.8)

In g/100 g.
3
4 Chlorohydrins
conditions [6] or from acid chlorides [7]. Cyclic
carbonates may be produced by the reaction of
a chlorohydrin with carbon dioxide in the pres-
ence of an amine [8].
A comparison of the rate of reaction of
ethylene chlorohydrin with various amines
gives the following order: n-amylamine >
cyclohexylamine > aniline [9]. The reaction
of ethylene chlorohydrin with ammonia gives
monoethanolamine [10]. Quaternary ammo-
nium compounds result from chlorohydrins
and tertiary amines [11, 12].
Other chlorohydrin reactions include forma-
tion of nitriles from cyanides [13], acetals from
aldehydes [14], oxazolidinones from cyanates
[15], and the oxidation of ethylene chlorohy-
drin to monochloroacetic acid [16].
4. Production
In 1863, CARIUS [17] reported that chlorohy-
drins could be synthesized by reacting olefins
with hypochlorous acid. As early as 1904,
BASF began production of ethylene chlorohy-
drin by introducing ethylene and CO2 into an
aqueous solution of bleaching powder [18].
Ethylene Chlorohydrin. The reaction of chlo-
rine and water (1) produces very little hypo-
chlorous acid because of an unfavorable
equilibrium (K 4.2  104) [19].
Cl2 H2 O HOCl HCl 1
GOMBERG [20] reasoned that if the reaction
between ethylene and hypochlorous acid
(Eq. 2) is significantly more rapid than the
reaction of ethylene and chlorine to form
dichloroethane (Eq. 3), then as the ethylene
is added to the aqueous system, chlorohydrin
1 should be produced preferentially.
He showed that with good stirring to mini-
mize reaction (3) in the gas phase, little
dichloroethane is produced until the chlorohy-
drin concentration reaches 68%.
In reaction (1), the concentration of hypo-
chlorous acid declines steadily as the HCl
concentration increases. Significant quantities
of dichloroethane are observed when the HCl
concentration exceeds 3%. Because the solu-
bility of dichloroethane in water is low (0.869
g/100 mL at 20
C), it quickly forms a separate
phase into which both chlorine and ethylene are
preferentially dissolved to produce even more
dichloroethane.
In a laboratory process study of the
hypochlorination of ethylene, the effects of
various reaction parameters were determined
with both single-column and recycle-reactor
arrangements [21]. Reaction temperatures of
3550
C and ca. 50% excess of ethylene are
preferred because these conditions allow much
of the dichloroethane to be stripped from the
reaction medium as it is formed.
For a continuous run with recycle at a
chlorohydrin concentration of 6.4%, a reactor
temperature of 35
C, an ethylene : chlorine
ratio of 1.42, and a chlorine feed rate of 71
g/h, the average yield of ethylene chlorohydrin
was 88.0% with a dichloroethane yield of
10.1%. Lowering the chlorine feed rate to
42 g/h raised the chlorohydrin yield slightly
to 88.9% and lowered the dichloroethane yield
to 9.1%.
For many years, ethylene chlorohydrin was
manufactured on a large industrial scale as a
precursor to ethylene oxide. This process has
been completely supplanted by the direct oxi-
dation of ethylene to ethylene oxide using silver
catalysts (! Ethylene Oxide). However, since
other commercially important epoxides, such
as propylene oxide and epichlorohydrin, can
still not be made in the same way by direct
oxidation of the parent olefin, chlorohydrin
intermediates are still important in manufactur-
ing these products. Although it is scarcely
practiced today, a review of the ethylene chlo-
rohydrin technology is valuable because of the
close similarity of all of the chlorohydrin
processes.
In a typical industrial plant, chlorine, ethyl-
ene, and water were concurrently passed
upward through packed towers [22, 23]. These
reactors were designed to minimize the contact
between ethylene and gaseous chlorine and to
 Chlorohydrins 5

provide adequate contact between the hydro- formation of bis(2-chloro-1-methylethyl) ether

carbon feed and the liquid phase [24]. The feed [108-60-1]:
lines were positioned a sufficient distance apart
so that the chlorine could be completely dis-
solved in the water before the ethylene was
introduced into the system. In some plants,
there was a separate mixing column for chlorine
and water followed by an ethylene reaction
tower.
The reaction product was removed at the
top of the tower as a 4.55.0% solution of
ethylene chlorohydrin, the yield of which may
be as high as 8589% of the ethylene con- Propylene chlorohydrin reacts with a strong
verted. In addition to dichloroethane, small base, such as calcium hydroxide, to give pro-
amounts of bis(2-chloroethyl) ether were pylene oxide [75-56-9] by dehydrochlorination
formed as byproducts. (! Propylene Oxide):

Propylene Chlorohydrin. The hypochlorina-

tion of propene [25] gives two isomers:

A typical flowchart for the production of

The major side reactions are chlorine addi-
tion to give 1,2-dichloropropane [78-87-5], and
propylene oxide via the chlorohydrin is shown
in Figure 1 [26].
In the propylene chlorohydrin process, the
separation of the feed points for chlorine and
propene is even more critical than in the case

Figure 1. Typical arrangement for propylene oxide via the chlorohydrin route
a) Chlorohydrin absorber reactor; b) Chlorohydrin saponification and flashing; c) Propylene oxide purification train
Reproduced with permission from [26].
6 Chlorohydrins
Figure 2. Hypochlorite route to propylene oxide
Reproduced with permission from [36].
with ethylene. The benefits of a recirculating-
type, double-chamber reaction system have
been described [27]. Chlorine was dissolved
in a recycle stream of dilute aqueous propylene
chlorohydrin together with makeup water.
From this vessel, the effluent passed to a second
chamber into which the propene was fed. This
arrangement gave a propylene chlorohydrin
yield of 87.5% with 11.0% dichloropropane
and 1.5% dichloroisopropyl ether. In contrast,
a single-reactor system produced a 69.2% chlo-
rohydrin yield with 21.6% dichloropropane and
9.2% dichloroisopropyl ether.
Modern plants show propylene chlorohydrin
yields of 8790% with 69% dichloropropane.
There are numerous patents that claim technol-
ogy to boost chlorohydrin yields to 9095%
[2834].
A novel approach to hypochlorination
involves the use of tertiary alkyl hypochlorites
[35] and is based on the following chemistry:
The preferred alcohol in reaction (4) is tert-
butanol. The resulting tert-butyl hypochlorite
has very slight water solubility and may be
separated by phase. Thus, the reaction of the
hypochlorite with propene and water (Eq. 5)
occurs in an environment essentially free of
chloride ions to reduce formation of the dichlor-
ide. A 95.8 mol% selectivity to propylene
chlorohydrin is claimed [35]. A diagram of
this process is shown in Figure 2 [36].
Current propylene chlorohydrin process
technology and alternative, newer process
routes to propylene oxide that do not require
a chlorohydrin as an intermediate are described
in more detail in (! Propylene Oxide).
Glycerol Monochlorohydrins. Hypochlorina-
tion of allyl alcohol gives glycerol
monochlorohydrins:
The reaction of allyl alcohol with chlorine
and water at 5060
C is reported to give an 88%
yield of monochlorohydrins and 9% dichloro-
hydrins [37].
Glycerol Dichlorohydrins. The hypochlorina-
tion of allyl chloride generates a mixture of
the glycerol dichlorohydrins2,3-dichloro-1-
propanol (8) and 1,3-dichloro-2-propanol (7),
in about a 70 : 30 ratio.

These may be subsequently saponified to
epichlorohydrin [106-89-8]:
Because of the low water solubility of allyl
chloride, it is essential to minimize formation
of an organic phase, which leads to formation of
the undesired byproduct 1,2,3-trichloropropane
[24, 38]. This is commonly done by maintain-
ing the allyl chloride as a fine dispersion by
vigorous agitation in an aqueous system con-
taining 1050 volumes of water for each vol-
ume of allyl chloride [3941]. Under such
conditions, dichlorohydrin selectivities of
8893% are reported.
Another method of achieving a well-dis-
persed allyl chloride is by the use of a surfac-
tant [42, 43]. Anionic or nonionic surfactants in
amounts of 0.20.5 wt% based on allyl chloride
give reported dichlorohydrin yields of 9395%
based on allyl chloride.
An alternative way of making dichlorohy-
drins is by chlorination of allyl alcohol [107-
18-6], which may be produced by the hydro-
genation of acrylaldehyde [107-02-8]. This
route gives reported dichlorohydrin yields of
9498% with a 2,3-dichloro-1-propanol yield
of 8897% [44, 45].
Butene Chlorohydrins. Butylene chlorohydrin
is prepared as a precursor to butene oxide. A
laboratory study of the hypochlorination of 2-
butene has been reported [46]. The dehydro-
chlorination of 3-chloro-2-butanol (13) with
calcium hydroxide gave an 87% yield of 2,3-
butene oxide with 11% glycol and 2% methyl
ethyl ketone [47].
Chlorohydrins 7
Styrene Chlorohydrin. A laboratory prepara-
tion of styrene chlorohydrin (19) has been
described [48]. Styrene was dispersed in water
with a surfactant. Calcium hypochlorite solu-
tion was added to the vigorously stirred sus-
pension through which carbon dioxide was
bubbled. A 76% yield of styrene chlorohydrin
was obtained.
Long-Chain Chlorohydrins. Unsaturated fatty
acids, such as oleic or elaidic acids, are con-
verted to chlorohydrins as intermediates in
making the epoxides or diols of these materials
[49]. Long-chain olefins may be hypochlori-
nated with good selectivity (8090%) by using
short reaction times, which result in low olefin
conversion (525%) [50].
Process Improvements and New Approaches.
Some process improvements and new
approaches for chlorohydrin production are
the continuous production of glycerol dichlor-
ohydrins [51], glycerol dichlorohydrins from
allyl chloride [52], electrochemical chlorohy-
droxylation of olefins [53], 4-halo alcohols
from ring cleavage of tetrahydrofuran [54],
improved continuous production of aqueous
propylene chlorohydrin solutions [55], high-
yield continuous preparation of propylene chlo-
rohydrin [56], ethylene chlorohydrin from etha-
nol [57], and chlorohydrins from immobilized
halogenating enzymes [58, 59], and more
recently the direct synthesis of glycerol dichlor-
ohydrin from glycerol.
With the growing attention for the utilization
of renewable resources as chemical feedstocks
and the increased demand for glycerol dichlor-
ohydrin as precursor for the production of
epichlorohydrin, several producers have devel-
oped alternative industrial-scale routes to glyc-
erol dichlorohydrin starting from bio-sourced
glycerol instead of propene [6063].
Reaction of anhydrous HCl with glycerol at
elevated temperature and pressure, in presence
of a carboxylic acid as catalyst yields the two
glycerol dichlorohydrin isomers: 1,2-glycerol
dichlorohydrin (20) and 1,3-glycerol dichloro-
hydrin (21):
8 Chlorohydrins
Further conversion of these intermediates,
corresponding to the conventional epoxidation
route, leads to epichlorohydrin. In comparison
to the conventional routes, the glycerol-based
route gives a more favorable isomer ratio and
decreased amount of chlorinated byproducts.
Favorable costs and sufficient availability of
glycerol feedstock are other important aspects
to make this process economically attractive
and competitive. Sufficient availability of glyc-
erol as feedstock depends largely on the con-
tinuous growth of oleochemicals and of certain
technologies for biodiesel production, with
glycerol as a significant byproduct of that nat-
ural-oils-based refinery process [64].
In February 2012 Vinythai (an affiliate of
Solvay) commissioned a 100 000 t/a epichlor-
ohydrin plant at Map Tha Phut in Thailand [65],
based on Solvays proprietary Epicerol process
technology, starting from glycerol as feedstock.
A second plant of equal size is scheduled to
start up in 2014 at Taixing, P. R. China [66].
5. Environmental Protection
Available data for chlorohydrin compounds are
summarized in Table 3. Chlorohydrins are read-
ily biodegradable and practically nontoxic to
aquatic organisms according to GHS categori-
zation system for chemicals.
6. Chemical Analysis
In addition to the conventional wet quantita-
tive method, modern spectroscopic analyses
are used, including Raman spectroscopy [90]
and gas chromatographic analysis [91].
Potentiometric determination of propylene
chlorohydrins [92] and enzymatic determina-
tion of ethylene chlorohydrin [93] were also
reported.
7. Storage and Transportation
Chlorohydrins generally can be stored in acid-
resistant tanks with a small or low-pressure
rating. Titanium metal is resistant to corrosion
by most chlorohydrins [94]. Potentiometric
study of the corrosion of chlorohydrins up to
120
C on titanium and steel has been reported
[95]. Generally, regulations for shipment of
dangerous goods must be followed.
8. Uses
Chlorohydrins find their greatest utility as
intermediates in the manufacture of epoxides,
especially propylene oxide and epichlorohy-
drin. For reviews of these processes, see
[26, 9698] (! Epoxides, ! Ethylene Oxide,
! Propylene Oxide).
Adducts of ethylene chlorohydrin with tung-
sten or molybdenum halides plus an organo-
aluminum compound have been patented as
catalysts for olefin metathesis and cycloalkene
ring-opening polymerization [99102].
Chlorohydrins are used as synthons for the
following:
 Intermediate for plasticizers [103]
 Wet-strengthening agent for paper [104,
105]
 Etherizing agent of phenolic resin to pro-
duce a high-temperature heavy-metal che-
lating compound [106]
 Preservation of biological fluids and solu-
tions [107]
 Treatment of sulfonyl halides and
dimethylamine aromatic compounds for
fluorescent whitening agents and photo-
sensitizers [108]
 Raw material for lubricating oil intermedi-
ates and additives [109, 110]
 Reaction with 1,3-bis(dimethylamino)-2-
propanol to form a flocculant [111]
 Production of low molecular mass epoxy
resins [112]
 Raw material for flame retardants for
polymers [113]
 Soil-resistant yarn-treating agent [114,
115]
 Hardener for polyurethane elastomers
[116]
 Intermediate for etching compositions for
etching surfaces or semiconductor devices
[117]
 Intermediate for silicone elastomer com-
positions [118]
Table 3. Environmental data and relevant physicochemical properties available for selected chlorohydrins

Compound Biodegradation Ecotoxicity Physicochemical Properties

Ethylene chlorohydrin [107-07-3] (1)
3-Chloro-1,2-propanediol
[96-24-2] (5)
1,3-Dichloro-2-propanol [96-23-1] (7)
2,3-Dichloro-1-propanol [616-23-9] (8)
1-Chloro-2-propanol [127-00-4] (3)
3-Chloro-1-propanol [627-30-5] (4)
2-Chloro-1-butanol [26106-95-6] (9)
4-Chloro-1-butanol [928-51-8] (11)
3-Chloro-2-butanol [563-84-8] (13)

BOD: biochemical oxygen demand; EC50: medium effective concentration to 50% of the test organisms in a specified time; ErC50: EC50 in terms of reduction of growth rate after exposure in a specified time; Koc:
soil organic carbon/water partition coefficient; LC50: lethal concentration to 50% of the test organisms in a specified time; LOEC: lowest observed effect concentration; MATC: maximum acceptable toxicant
concentration; NOEC: no observed effect level; OECD: Organization for Economic Co-operation and Development; Pow: octanol/water partition coefficient; ThBOD: theoretical biological oxygen demand;
ThOD: theoretical oxygen demand.
BOD/ThOD 73% [67] fathead minnow LC50 > 100 mg/L [67] estimated Koc 1.3 [73]
day 20 biodeg 57% [70] fathead minnow LC50 (96-h) 67112 mg/L [72] log Pow 0.03 [74]
day 28 93% 10-d window: passed water flea Daphnia magna: LC50 (48-h) 100 mg/L [71] Henrys law constant (calculated) 7.70105 kPa m3 mol1
OECD 301F [71] at 25
C [75]
day 28 > 95% 10-d window: passed
OECD 301B Test [70]
ThOD 1.01 [76] water flea Daphnia magna EC50 (48-h) >100 mg/L; estimated Henrys law constant 6.18106 kPa m3 mol1
NOEC (48-h) 100 mg/L [68] at 25
C [77]
day 28 77% 10-d window: passed OECD Pseudokirchnerella subcapitata (green alga) estimated log Pow 0.53 [78]
301B [68] EC50 > 100 mg/L [68]
water flea Daphnia magna EC50 (24-h) 983 mg/L [79] measured Koc 10 [67]
alga Scenedesmus sp. EC50 (48-h) 300 mg/L [80] estimated log Pow 0.20 [81]
water flea Daphnia magna 21-d NOEC 16 mg/L; Henrys law constant 6.08105 kPa m3 mol1 [82]
LOEC 31 mg/L; MATC 22 mg/L [79]
estimated log Pow 0.78
estimated Koc 4 [83]
Henrys law constant 4.05107 kPa m3 mol1 [83]
ThBOD 1.35 [84] fathead minnow LC50 (96-h) 245 mg/L [85] Koc 2 [86]
Henrys law constant 1.72104 kPa m3 mol1 [86]
fathead minnow LC50 (96-h) 801 mg/L estimated Henrys law constant 1.69104 kPa m3 mol1 [87]
log Pow 0.5 [87]
estimated Henrys law constant 2.42105 kPa m3 mol1 [88]
estimated log Pow 1.02 [88]
estimated Koc 4 [88]
log Pow 0.85 [69]
estimated Henrys law constant 2.25104 kPa m3 mol1 [69]
estimated log Pow 0.950 [89]
Chlorohydrins
9
10 Chlorohydrins
 Preparation of polyglycerols [119]
 Microgel-containing vulcanizable compo-
sitions [120]
 Raw material for starch networks as
adsorbents or superadsorbants [121]
 Intermediate for optical brighteners
[122]
Pharmaceutical and agricultural chemical
applications have been explored. Chlorohy-
drins are used as base chemicals for various
drugs and chemicals, such as the following:
 Cabrioles derivative for treatment of anx-
iety [123]
 Pharmaceutically acceptable salts [124]
 Quaternary ammonium polymeric antimi-
crobial agents [125]
 Substituted nitrodiphenyl ethers [126]
 Phenoxyalkanol antirhinovirus agents
[127]
 Quaternary salts of promethazine bron-
choconstriction releasing agent [128]
 Substituted oxobenzothiazolines plant
growth regulators [129]
 Phenyl urea derivative herbicides [130]
 Pesticidal compositions [131]
 Fungicidal compositions [132]
 Modified soy proteins [133]
 Formulation of peptide proteasome inhib-
itors [134]
 Nebivolol useful in treating essential
hypertension [135]
 Modified soy proteins for skin-tightening
compositions [136]
 Amino epoxides as intermediates for HIV
Protease Inhibitors [137]
9. Toxicology and Occupational
Health
Of the various chlorohydrins, ethylene chloro-
hydrin and a-chlorohydrin (3-monochloro-1,2-
propanediol, 3-MCPD) have been the most
extensively studied, the former because it is a
residue produced when poly(vinyl chloride)
plastics are sterilized with ethylene oxide.
Recently, renewed interest in chloropropanols,
especially 3-MCPD and 1,3-DCP, was triggered
by their detection in some thermally processed
foods [138140]. Both 3-MCPD and 1,3-DCP,
as well as their isomers 2-MCPD and 2,3-DCP,
respectively, are formed as byproducts during
processing of acid-hydrolyzed vegetable pro-
tein, most notably in soy sauce, with 3-MCPD
being detected at highest levels compared to
other chloropropanols [138143].
Ethylene Chlorohydrin. Ethylene chlorohy-
drin can be extensively absorbed through the
dermal, oral, and inhalation routes. Safe han-
dling requires skin, eye, and respiratory protec-
tion due to the high dermal toxicity as well as
the moderate oral and inhalation toxicity. The
main routes of exposure are through the skin
and lungs.
The odor threshold in air is 0.4 ppm [144].
For those workers aware of the sweet ether-like
smell of ethylene chlorohydrin the odor may
be sufficient to signal the danger of acute
exposures.
Exposure. Under REACH, ethylene chlorohy-
drin has been registered as a chemical interme-
diate used in closed processes with no
likelihood of exposure or in closed continuous
processes with occasional controlled exposure
[145]. Ethylene chlorohydrin is used in the
manufacture of pesticides, plasticizers, plant-
protection agents, and dye intermediates [146].
For human exposures a volume of ca. 5 mL
could be lethal to the average adult male (70 kg)
if it contacts the skin and is not washed off
immediately. One fatality due to a 2-h inhala-
tion exposure to ethylene chlorohydrin vapor at
ca. 1 mg/L (ca. 306 ppm) has been reported
[147]. Two fatal and several nonfatal cases of
intoxication by ethylene chlorohydrin were
investigated [148]. The average concentration
in the nonfatal cases was 18 ppm. Nonfatal
cases showed signs of circulatory shock, lack
of coordination, repeated vomiting, epigastric
pain, headache, heavy urine output, cough, and
skin reddening. In another case report [149],
autopsy findings showed damage to the lungs,
liver, kidneys, brain, and other organs.
Oral Toxicity. Ethylene chlorohydrin is mod-
erately toxic, with LD50 values in the range of
6095 mg/kg for the rat [150, 145, 151]. Signs
of intoxication include hemorrhages in the

stomach and lung, lung edema, and dis-
coloration of the kidney and liver.
Skin Contact. Ethylene chlorohydrin can be
absorbed, in potentially harmful amounts,
through the skin. The acute dermal LD50 in
rats is 68 mg/kg. Irritation studies indicate that
ethylene chlorohydrin produces none to slight
irritation when applied to rabbits. Ethylene
chlorohydrin was not a skin sensitizer when
tested in the guinea pig [152] and the local
lymph node assay [153].
Eye Contact. In rats, exposure to saturated
vapor concentrations (ca. 20 mg/L) of ethylene
chlorohydrin can damage the eye within 30
min.
Undiluted liquid ethylene chlorohydrin
caused serious damage to the eyes of rabbits
and eye irritation at a concentration of 20%. No
irritant effects were observed at a 10% concen-
tration [144]. Permanent impairment of vision,
even blindness, may result from such contact.
Affected eyes should be immediately flushed
with flowing water for at least 15 min.
Repeat-Dose-Toxicity. In 90 day repeat dose
studies with dogs and monkeys fed ethylene
chlorohydrin in the diet revealed no adverse
effects when fed 13.3 and 16.9 mg kg1 d1
in male and female dogs, respectively, and
62.5 mg kg1 d1 in monkeys, which were
the maximum doses in each experiment. A
subchronic study in rats, at doses up to 67.5
mg kg1 d1, indicated excess mortality and
decreased food consumption at the highest
dose. Target tissues included heart liver, thyroid
and lung. A NOEAL was set at 45 mg kg1 d1
in the rat [154].
Inhalation. An inhalation LC50 (4 h) was esti-
mated between 16 ppm (53 mg/m3) and 62 ppm
(207 mg/m3). At saturated vapor concentra-
tions, estimated between 8 and 20 mg/L, 11
of 12 rats died within 10 min of exposure [144].
Reproductive/Developmental Toxicity. No
studies were located on the reproductive
effects of ethylene chlorohydrin in laboratory
animals. Teratogenicity studies in rabbits given
ethylene chlorohydrin intravenously up to
36 mg kg1 d1 show a lack of embryo/feto-
toxic or teratogenic effects [155]. In mice
Chlorohydrins 11
orally gavaged with up to 150 mg kg1 d1
from gestation day (GD) 6 through 16, a dose
of 150 mg kg1 d1 was maternally toxic.
However, no embryotoxic or teratogenic
effects were observed. When mice were intro-
duced to ethylene chlorohydrin through drink-
ing water on GD 6 through GD 16, at doses
up to 227 mg kg1 d1, there was no evidence
of maternal or developmental toxicity [156].
Mutagenicity. In the Ames bacterial mutage-
nicity test, ethylene chlorohydrin is sometimes
positive and negative, with some of the pos-
itives only occurring after metabolic activation
by rat liver tissue homogenates [157159].
Activity in certain Salmonella typhinurium
strains TA1530, TA1535 and TA100 indicate
that ethylene chlorohydrin is a base-pair sub-
stitution mutagen [160, 161]. Ethylene chloro-
hydrin is also weakly and sporadically
mutagenic when tested in animal cell systems.
It is reported to have induced chromosome
aberrations in rat bone marrow cells [162],
but it did not produce a significant increase
in the number of translocation heterozygotes
(heritable translocation) when administered to
male mice at 3060 mg kg1 d1 for five weeks
[163]. It was also negative in tests with fruit
flies [164].
The toxicity of ethylene chlorohydrin (and
presumably other activity, such as mutagenic-
ity) is believed to be due to its conversion to
chloroacetaldehyde in vivo. Chloroacetalde-
hyde and chloroacetic acid, which are meta-
bolic intermediates, are to a great degree
conjugated and inactivated by reaction with
glutathione. Thus, when ethylene chlorohydrin
levels are highly elevated, glutathione is
depleted and chloroacetaldehyde cannot be
detoxified. When chloroacetaldehyde levels at
intracellular sites are elevated, other cell com-
ponents are alkylated, damage to major organs
occurs, and toxic symptoms are produced [165,
166].
Carcinogenicity. Lifetime dermal exposures to
laboratory rats up to 100 mg/kg for 103 weeks
and mice up to 411 mg/kg at end of a 104 week
study yielded no evidence for carcinogenicity.
There was no statistically significant incidence
of tumors at the site of application [161]. Ethyl-
ene chlorohydrin was also evaluated for
12 Chlorohydrins

carcinogenic effects on the skin in the trans-
genic TgAc mouse assay. Dermal applications
of 20 mg five times per week for 20 weeks were
negative in this test [167].
Epidemiological evidence for cancer causa-
tion in humans has not been established. One
study reported an excess of pancreatic cancer
and leukemia using standard mortality ratios
from workers with two or more years of expe-
rience in a chlorohydrins production unit. How-
ever, a similar study in other production units
failed to find any such increase [173].
Classification and Permissible Exposure Lim-
its. Ethylene chlorohydrin is classified under
GHS as follows: Flammable liquid 3, H226:
Flammable liquid and vapor Acute Oral Tox. 2,
H300 swallowed. Acute Dermal Tox. 1 H310:
Fatal in contact with skin Acute Inhalation Tox.
2, H330: Fatal if inhaled. Serious Eye Damage
1, H318, Causes serious eye damage.
The ACGIH reviewed ethylene chlorohydrin
and set a TLV-TWA occupational exposure
level at 1 ppm; the OSHA PEL remains at
5 ppm [153]. The DFG has set an MAK value
at 1 ppm (3.3 mg/m3). See Table 4 for a listing
of occupational exposure values for available
chlorohydrins.
to share the same characteristics with its
analogues.
In general, the health hazards associated
with the propylene chlorohydrins are associated
with moderate toxicity through the oral, inha-
lation, and dermal routes as well as skin and eye
irritation.
Exposure. 1-Chloro-2-propanol and 2-chloro-
1-propanol are chemical intermediates for
propylene oxide used as a starting material
for polyurethane polyols and propylene gly-
col. It is also a contaminant of foodstuffs
fumigated with ethylene or propylene oxide
[168, 169].
Oral Toxicity. The acute oral LD50 values of
propylene chlorohydrin are in the range of
190270 mg/kg in rats and considered moder-
ately toxic [170].
Skin Contact. The acute dermal LD50 for pro-
pylene chlorohydrin in rabbits is approximately
480 mg/kg and considered moderately toxic
[170]. Both compounds are slightly irritating
to the skin [170].
Eye Contact. Both compounds are severely
irritating to the eyes of rabbits [170].

Propylene Chlorohydrins. The most common Repeat-Dose Exposure. In a National Toxicol-

propylene chlorohydrins used are 2-chloro-1- ogy Program (NTP) study, male and female
propanol, 1-chloro-2-propanol, and 3-chloro-1- rats and mice were exposed to technical grade
propanol. Although little information was 1-chloro-2-propanol (7576% 1-chloro-2-prop-
found for 3-chloro-1 propanol, it is assumed anol; 2425% 2-chloro-1-propanol) in drinking

Table 4. Available occupational exposure limit values for chlorohydrins

ACGIH DFG MAK

TLV STEL
3
ppm mg/m ppm mg/m3 ppm mg/m3

2-Chloro-1-ethanol [107-07-3] (1) (skin) C 1 (A4) C 3.3 1 3.3

2-Chloro-1-propanol [78-89-7] (2) (skin) 1 (A4) 3.9
1-Chloro-2-propanol [127-00-4] (3) (skin) 1 (A4) 3.9
1,3-Dichloro-2-propanol [96-23-1] (7) (skin) (2) (2)
3-chloro-1,2-propanediol [96-24-2] (5) (skin) 0.005 (3, D) 0.023 (3, D)

ACGIH: A4: not classifiable as a human carcinogen. Skin: This notation indicates that air sampling alone is insufficient to quantify exposure
accurately and that measures to prevent significant cutaneous absorption may be required. C: Ceiling.

DFG MAK: Carcinogenicity category 2: Considered to be carcinogen; Carcinogenicity category 3: Substances that cause concern that they
could be carcinogenic for man but cannot be assessed conclusively because of lack of data. Pregnancy risk group D: Either there are no data for
an assessment of damage to the embryo or fetus or the currently available data are not sufficient for classification in one of the groups AC. Skin:
This designation is intended to suggest appropriate measures for the prevention of cutaneous absorption so that the threshold limit is not
invalidated.

water for 14 days and 14 weeks. In the 14 day
study, rats were exposed up to 10 000 ppm. Two
female rats died in the 10 000 ppm group.
Decreases in body weight and body weight
gains were observed in the 3300 and 10 000
ppm group. In the highest-dose group, there
was a decreased thymus weight and histopatho-
logical changes in the pancreas, bone marrow,
and spleen. Similarly, mice were exposed up to
10 000 ppm. One male mouse died in the 10 000
ppm group. A decrease in the mean body weight
gains occurred in the 10 000 ppm group. Liver
weights were increased in the 1000, 3300, or
10 000 ppm treatment groups in both males and
females and thymus weights were decreased in
the 10 000 ppm group. Exposure to 1-chloro-2-
propanol caused hepatocellular vacuolization at
exposures greater than or equal to 1000 ppm,
cytoplasmic alteration and degeneration of the
pancreas acinar cells at exposures greater than or
equal to 3300 ppm, as well as atrophy of the
spleen in males and females in the highest-dose
group [168].
Subchronic studies in rats and mice elicited
similar effects. Rats exposed up to 3300 ppm in
drinking water for 14 weeks had decreased
body weight gains at the highest dose. Anemia
was most pronounced in the female groups
receiving 1000 and 3000 ppm. Males exposed
to 3300 ppm had decreased cauda epididymis
and epididiymis weights with a higher percent-
age of abnormal sperm. Kidney and liver
weights of female and male rats treated at or
above 100 ppm were generally increased. His-
topathological changes occurred in the liver,
kidney, and pancreas. Female and male mice
were similarly exposed up to 3300 ppm. The
most pronounced effects were a minimal ane-
mia and an increased right epididymis weight
of males in the 3300 ppm group. Effects
observed in high dose groups of either male
or females mice were increases in kidney, liver,
and thymus weights along with histopatholog-
ical changes in the liver, pancreas, and kidney
[151].
A mixture of 2-chloro-1-propanol and
1-chloro-2-propanol was also fed to rats and
dogs for 90 d at doses ranging from 1 to 50 mg
kg1 d1 [171]. No significant effects
occurred in rats at any dose or in dogs at
1 or 7 mg kg1 d1. Only reduced food
consumption, reduced body weight, and
Chlorohydrins 13
increased relative liver weight occurred at
50 mg kg1 d1 in dogs.
Inhalation. One out of six rats died when
exposed to 500 ppm of propylene chlorohydrin
for 4 h. The reported LC50 for 1-chloro-2-
propanol was 1000 ppm for 4 h [170]. In a
pharmacokinetic study with 1-chloro-2 propa-
nol, no acute toxic effects were observed in
male F344/N rats 72 h after exposure to 8 and
80 ppm for 6 h [172].
For subacute inhalation exposures, rats were
exposed via inhalation to 30, 100, 250, and
1000 ppm of 1-chloro-2-propanol. No effects
were observed in rats given 14 exposures for 6 h
at 30 ppm. At 100 ppm for 15 exposures of 6 h,
the animals showed no overt signs of toxicity.
However, at necropsy the lungs were congested
with perivascular edema. Rats exposed for a
similar period at 250 ppm exhibited lethargy,
irregular weight gain, and congested lungs and
perivascular edema. The adverse effects were
more pronounced when 2 male and 2 female
rats were given two 6 h exposures to 1000 ppm.
The rats were lethargic and one died after the
second exposure. Upon necropsy, the lungs
were edematous and congested and the liver
pale. Histopathology revealed interstitial
inflammatory exudates in the lung and liver
cells that were swollen and vacuolated with
nuclear degeneration [173].
Teratogenicity. A developmental study in rats
was conducted in five pregnant female rats
administered 8, 20, 50, or 125 mg of propylene
chlorohydrin on GD 6 through 15. No effects
were observed on maternal growth or growth
and survival of fetuses. The investigators con-
cluded that propylene chlorohydrin may be a
weak teratogen due to the occurrence of gross
malformations in one of the dose groups [174].
Reproduction. A continuous breeding study
was conducted with technical grade 1-chloro-
2-propanol for its effects on reproduction and
fertility in Sprague-Dawley rats. Rats were
exposed to concentrations of 0, 300, 650, and
1300 ppm. Results indicated that 1-chloro-2-
propanol caused no adverse effects on fertility
in either the F0 or F1 generation. The statisti-
cally significant effects on testis weights and
sperm abnormalities may indicate very slight
14 Chlorohydrins
male reproductive toxicity at high doses. No
effects were observed in females [152].
Mutagenicity. Both pure and technical-grade
1-chloro-2-propanol and 3-chloro-1-propanol
were considered mutagenic in the Ames assay
with strains TA1535 and/or TA100 with and
without metabolic activation [175178]. The
technical grade (75/25 mixture of 1-chloro-2-
propanol/2-chloro-1-propanol) was also muta-
genic in a mouse lymphoma assay and in the rat
bone marrow cytogenetic test [154].
The NTP study included a battery of geno-
toxic tests with technical grade (75:25 mixture)
of chloropropanols. The mixture was positive in
the Ames assay in only TA100 and TA1535
strains with metabolic activation and positive in
the TA1537 without metabolic activation. In
vitro assays with Chinese hamster ovary cells
indicated that the technical mixture induced
sister chromatid exchanges and chromosomal
aberrations with and without metabolic activa-
tion. No chromosomal aberrations were
induced in the in vivo mouse micronucleus
assay [152]. 1-Chloro-2-propanol was also pos-
itive in the Syrian Hamster Embryo assay, but
did not induce the level of p53 tumor suppressor
protein in vitro [179]
Carcinogenicity. The NTP conducted a two-
year carcinogenicity study in rats exposed to
150, 325, or 650 ppm and in mice exposed to
250, 500, or 1000 ppm of technical-grade 1-
chloro-2-propanol via drinking water. The NTP
concluded there was no evidence of carcinoge-
nicity in either species [152].
A human epidemiology study was con-
ducted to determine whether workers exposed
to ethylene chlorohydrin and propylene chloro-
hydrin production processes were at increased
mortality risk from pancreatic cancer and lym-
phopoietic and hematopoietic cancers. The
analysis of death records from a cohort of
1361 male employees from 1940 to 1992 failed
to show any increase cancer risk [180].
Classification and Exposure Limits. Both
1-chloro-2-propanol and 2-chloro-1-propanol
are classified by GHS as follows: Flammable
liquid Cat. 3, H226: Flammable liquid and
vapor. Acute Oral Cat. Tox. 3, H301: Toxic if
swallowed. Acute Inhalation Tox., Cat 2, H330:
Fatal if inhaled. Acute Dermal Tox., Cat 3,
H311: Toxic in contact with skin. Skin Irritation
Cat. 2, H315: Causes skin irritation. Serious
Eye Damage, Cat. 1, H318: Causes serious eye
damage. The ACGIH 8 h exposure limit (TLV-
TWA) is 1 ppm. See Table 4 for a list of
occupational exposure values for available
chlorohydrins.
a-Chlorohydrin or 3-Monochloro-1,2-Pro-
panediol (3-MCPD). This member of the chlo-
rohydrin series has also been extensively
studied for its toxicological effects. Its chronic
toxicological profile differs greatly from that of
ethylene chlorohydrin.
Exposure. Under REACH, 3-MCPD has been
registered as chemical intermediate used under
strictly controlled conditions for the manufac-
ture of other substances [68]. 3-MCPD is used
as chemosterilant for rodent control. It has been
reported that chemosterilants are not widely
used in pest control because their effects are
transient and their use do not lead to elimination
of pest problems [181]. The risks of occupa-
tional exposure from use of chemosterilants
containing 3-MCPD were considered by the
U.S. EPA [182]. The risk of occupational expo-
sure from this use was considered unlikely, as
the end-product is contained in tamper-resistant
sachet systems.
3-MCPD is also a food-borne contaminant
formed during high-heat processing of various
foods; however, in recent years the levels have
significantly decreased [140]. The highest lev-
els were identified in soy sauce, soy-sauce-
based products, oyster sauce, and in foods
that contain acid-hydrolyzed vegetable protein
(HVP). Free 3-MCPD levels in foodstuffs have
been regulated in many jurisdictions. 3-MCPD
can also be detected in foods as fatty acid ester
[140]. SCF (2001) and JECFA derived a toler-
able daily intake and provisional maximum
tolerable daily intake (PMTDI) of 2 mg/kg
bw, respectively [183, 184, 139]. JECFA also
estimated an average 3-MCPD intake from a
variety of foods of 0.7 mg kg1 d1 with a range
of 0.06 to 2.3 mg kg1 d1 for the general
population [139].
As 3-MCPD can also be found in drinking
water, The UK Drinking Water Inspectorate
(1999) has set controls on exposure and on

maximum usage rates of flocculant addition to
water to achieve a maximum theoretical level in
drinking water of 0.1 mg/L [185, 186].
Acute Oral Toxicity. 3-MCPD was tested for
acute oral toxicity in number of rodent species
and strains. The lowest oral LD50 value for
3-MCDP was reported at 55 mg/kg in rats
[187]. Generally, oral LD50 values for
3-MCDP were established at  150 mg/kg bw
in male rats [188, 184]. Oral LD50 for female rats
was determined to be between 126 and 252 mg/
kg bw [67]. Oral LD50 value of 160 mg/kg was
reported in male mice, whereas for cavies, LD50
value falls between 600 and 1000 mg/kg [67].
Skin Contact. According to recent in vitro skin
irritation tests with reconstructed human epi-
dermis, 3-MCPD was classified as skin irritant
[68]. When applied to rabbit ear, the pure
material did not produce irritation after one
application and slight hyperemia after repeated
applications [67]. Application of 0.5 mL of
pure material to rabbit skin for 24 h under
occlusion resulted in no irritation on intact
abdomen skin and slight erythema and edema
at the abraded site [67]. Repeated applications
resulted in slight erythema on intact skin and
continued slight erythema at an abraded site; no
signs of systemic toxicity were observed [67].
Dermal LD50 in rabbit was determined to be
1190 mg/kg [67]. Application of the material to
cavy skin did not cause death in test animals at
3000 mg/kg [67]. 3-MCPD was not sensitizing
in guinea pig maximization test (GPMT) [68].
Eye Contact. Based on the recent in vitro HET-
CAM Test, 3-MCPD was classified as severely
irritating [68]. In an in vivo test, 3-MCPD
induced moderate to severe conjunctival
inflammation, moderate corneal injury and
moderate iritis in rabbit eye that had resolved
by day 7 post-installation [67].
Repeated-Dose Toxicity. Several studies of
varying duration were conducted with
3-MCPD in laboratory animals. The target
organs for 3-MCPD toxicity were identified
as kidney and reproductive organs. Oxalic
acid, a metabolite of 3-MCPD, was shown to
play a role in the development of kidney dam-
age [189]. In a four-week study, treated
Sprague-Dawley rats had lower body weight
Chlorohydrins 15
gain and significantly increased relative kidney,
liver, and testis weights as well as altered
hematocrit parameters [184]. Histopathological
examination revealed chronic progressive
nephropathy in high dose females and mild
tubule dilatation in the testis of treated males.
In a six-week study, 3-MCPD was given orally
to six male macaque monkeys at a daily dose of
30 mg/kg [184]. Three of six monkeys showed
hematological abnormalities whereas two mon-
keys died due to bone marrow depression. In a
13-week study with B6C3F1 mice, 3-MCPD
increased relative kidney weights of the mid
and high dose animals without corresponding
histopathological changes and reduced body
weight gains in the high dose animals [190].
Decreased sperm motility and degeneration of
the germinal epithelium was seen in male mice.
In females, a delayed total estrus cycle was
observed without any histopathological
changes. In a 90-d study with Fischer 344
rats, slight anemia was seen in mid and high
dose groups and changes in clinical chemistry
parameters [184]. Increased relative kidney and
liver weights were found. The epididymides of
treated rats had an increased number of exfo-
liated spermatozoids.
Reproductive/Developmental Toxicity.
3-MCPD exhibits testicular toxicity in number
of mammalian species although it was reported
to have no effect on fertility in mice, quail, or
rabbits [184]. The effect of 3-MCPD on male
reproduction has been extensively studied with
only the S enantiomer reported to show anti-
fertility activity [191]. 3-MCPD and epichlor-
ohydrin produce similar antifertility effects on
the male reproductive system of the rat, i.e.,
epididymal sperm granulomas, spermato-
coeles, and an increase in the number of mor-
phologically abnormal spermatozoa [192, 188,
193]. Decreased activity of glycolytic enzymes
in the epididymal and testicular tissue of rats
was reduced following administration of 3-
MCPD [194]; the inhibition in rats was revers-
ible at low doses [191, 195]. Exposure to 3-
MCPD in vitro and in vivo inhibited glycolysis
of spermatozoa and resulted in reduced sperm
motility in vitro [195197]. Rats that received
3-MCPD had significantly decreased levels of
RNA and protein in the testis and epididymis,
and increased concentrations of proteinase and
16 Chlorohydrins
ribonuclease [198]. The spermatotoxic effect is
mediated by reduced proton-adenosine triphos-
phatase expression in the cauda epididymis
[199].
BAN et al. (1999) [200] and PARISH (1989)
[184] reported decreased pregnancy rates and
sperm effects at doses of equal and greater 3 mg
3-MCPD per kilogram and day in rats. 3-MCPD
had no adverse effect on male fertility at doses
< 3 mg kg1 d1 and with respect to pregnancy
rate and total numbers of implantations and live
embryo [184]. Analysis of sperm motility
revealed treatment-related decreases in the per-
centage of motile sperm, sperm velocity, and
amplitude of lateral head displacement at the
highest dose and decreased sperm velocity and
amplitude of lateral head displacement at the
intermediate dose. Sperm reaching the oviducts
of females decreased with increasing dose of
3-MCPD and similarly, the percentage of fer-
tilized eggs in the oviducts of mated females
decreased with increasing dose [200].
Mutagenicity. 3-MCPD is mutagenic in vitro at
high treatment doses [201, 202, 140, 184, 203].
A number of studies have shown that 3-MCPD
is mutagenic in the Ames assay in Salmonella
strains with and without metabolic activation
[201, 202, 140, 184, 204, 203], in mouse lym-
phoma assay in the presence of metabolic
activation [140, 184], and in yeast without
metabolic activation [184]. 3-MCPD also
induced sister chromatid exchanges in Chinese
hamster V79 cells [184]. Malignant transfor-
mation in cultured mouse M2 fibroblasts in
culture has been reported with 3-MCPD
[140]. 3-MCPD and its major metabolite in
rat, b-chlorolactic acid, did not statistically
increase the number of DNA breaks up to the
testing limit of 10 mM in an in vitro
Comet assay in CHO-K1 cells; increased
DNA breaks were seen at very high treatment
doses [205].
In vivo genotoxicity studies produced uni-
formly negative results, suggesting that a non-
genotoxic mechanism underlies the 3-MCPD-
induced carcinogenicity in rodents. 3-MCPD
was negative in the dominant lethal tests in the
mouse and rat [140, 184]. 3-MCPD did not
induce somatic mutation and recombination in
the wing spot test of Drosophila melanogaster
[206]. Negative results for increased micro-
nucleus formation in bone marrow have been
reported following oral gavage of 40120 mg/
kg 3-MCPD to OF1 mice [184]. No increase in
formation of micronuclei in bone marrow
erythrocytes was reported and no unscheduled
DNA synthesis in hepatocytes occurred follow-
ing administration of 25 or 60 mg/kg 3-MCPD
to male rats [140]. DNA reactivity was also
studied in vivo following oral administration of
3-MCPD to Sprague-Dawley and Fisher 344
male adult rats. The absence of genotoxic
effects was reported in selected target (kidneys
and testes) and nontarget (blood leukocytes,
liver, and bone marrow) organs with the
in vivo alkaline Comet assay [205]. Overall,
3-MCPD is regarded as having no significant
genotoxic potential in vivo.
Carcinogenicity. Several chronic studies were
conducted with 3-MCPD in rodents. In mice,
3-MCPD produced no carcinogenic effects via
skin painting and subcutaneous injection [207].
Recent cancer bioassay with BDF1 mice
revealed no evidence of carcinogenic potential
following administration of 3-MCPD in drink-
ing water for 104 weeks [208]. One long-term
oral gavage study conducted in CD rats showed
no evidence of carcinogenic activity of
3-MCPD [209]. Other cancer bioassays indi-
cated that high doses were carcinogenic in rats.
Therefore, the mechanism of action for carci-
nogenicity may be species-specific [210]. A
recent drinking-water cancer bioassay in
Sprague-Dawley rats showed statistically sig-
nificant increase in kidney tumors in both sexes
at the highest dose secondary to chronic pro-
gressive nephropathy and sustained cyto-
toxicity [211, 212, 197]. Also noted was
significantly increased incidence of Leydig-
cell tumors at the highest dose in these males
compared to control incidence. Following
administration of 3-MCPD in drinking water
to F344 rats over 104 weeks, incidence of
Leydig-cell and mammary gland tumors in
males and of benign kidney tumors in both
sexes were reported at high doses [213]. How-
ever, the high-dose level in this cancer bioassay
exceeded the maximum tolerated dose. In addi-
tion, Leydig-cell and mammary gland tumors
were suggested to result from hormonal

imbalance, whereas renal tumors were associ-
ated with sustained cytotoxicity and may have
been secondary to chronic progressive nephrop-
athy [62, 184]. Overall, 3-MCPD is considered
as a nongenotoxic carcinogen [214, 183].
Classification and Permissible Exposure Lim-
its. No harmonized classification is available
for 3-MCPD (Annex VI, CLP Regulation). The
substance is classified on the basis of the avail-
able data (self-classification) as: Met. Corr. 1
H290: May be corrosive to metals; Acute Oral
Tox. 3 H301: Toxic if swallowed; Acute Inha-
lation Tox. 2 H330: Fatal if inhaled; Skin Irrit.
2 H315: Causes skin irritation; Eye Damage 1
H318: Causes serious eye damage; Repr. 1B
H360: May damage fertility or the unborn
child. Specific effect: impaired fertility; Carc.
2 H351: Suspected of causing cancer; STOT
Single Exp. 1 H370: Causes damage to organs.
Affected organs: kidneys; STOT Rep. Exp. 1
H372: Causes damage to organs. Affected
organs: testis, epididymis [68].
The IARC classified 3-MCPD as a Group 2B
carcinogen (possibly carcinogenic to humans)
based on sufficient evidence in experimental
animals [140].
No OEL values were set for 3-MCPD by
ACGIH. The MAK Commission set an advisory
8-h TWA as 0.023 mg/m3 or 0.005 ppm (Report
No. 49, 2013). See Table 4 for a listing of occupa-
tional exposure values for available chlorohy-
drins. Under REACH, the worker long-term
systemic inhalation DNEL (derived no-effect
level) was set at 0.29 mg/m3 and long-term sys-
temic DNEL for dermal exposure was set at
0.009 mg kg1 d1 based on effect on fertility
[68].
Other Chloropropanols. Alongside 3-MCPD,
2-monochloro-1,3-propanediol (2-MCPD),
1,3-dichloro-2-propanol (1,3-DCP), and 2,3-
dichloro-1-propanol (2,3-DCP) chloropropa-
nols are also formed during processing of vari-
ous foods [138, 141, 142, 214]. Processing of
defatted vegetable proteins by traditional
hydrochloric acid hydrolysis leads to the for-
mation of chloropropanols. 3-MCPD and
2-MCPD are formed first during the processing
and further chlorination of MCPDs may form
dichloropropanols.
Chlorohydrins 17
2-Monochloro-1,3-Propanediol (2-MCPD).
Exposure. The EC [138] reported that 2-MCPD
was found in 45% of tested soy sauce samples
at mean concentration of 1.8 mg/kg and a
maximum of 12 mg/kg. Other investigations
reported similar or lower occurrence and fre-
quency of 2-MCPD [141, 142, 214]. Approxi-
mately 60% of the tested malt and malt
products had detectable 2-MCPD concen-
trations of up to 0.36 mg/kg [138]. 2-MCPD
was also detected with a high variability in
refined seed oils, such as soy bean, rapeseed,
and sunflower at levels up to 5.9 mg/kg [215,
214]. Generally, 2-MCPD concentrations were
much lower compared to 3-MCPD levels; in
oils the contribution of 2-MCPD to the total
MCPD content accounted for approximately
35% [214]. ILSI calculated a margin of safety
of more than 1000 for 2-MCPD exposure
from food and with an applied ratio of 2:1 for
3-MCPD to 2-MCPD occurrence in food [215].
Repeated-Dose Toxicity. Only limited data are
available for 2-MCPD. In a 28-d study, the
highest dose induced severe effects in striated
muscles, heart, kidneys, and liver of treated
rats. An NOAEL of 2 mg kg1 d1 was reported
for 2-MCPD [216].
Mutagenicity. 2-MCPD was mutagenic in a
bacterial test system, but not in an in vitro
test with mammalian cells [216]. 2-MCPD
did not induce somatic mutation and
recombination in the wing spot test of Drosoph-
ila melanogaster [206].
Classification and Permissible Exposure Lim-
its. No relevant information was found for
2-MCPD in public domain.
1,3-Dichloro-2-Propanol (1,3-DCP)
Exposure. 1,3-DCP is a high-production-
volume industrial chemical. Under REACH,
1,3-DCP has been registered as a chemical
intermediate [217]. 1,3-DCP is also formed
during the manufacture of HVP and soy sauces
by acid hydrolysis [218]. The dietary exposure
is quite low and 1,3-DCP usually co-occurs with
3-MCPD with the exception of meat and meat
products, in which 1,3-DCP only can be
detected. JECFA (2007) calculated the dietary
18 Chlorohydrins
exposure to 1,3-DCP; estimated average intake
from all sources ranged from 0.008 to 0.048 mg
kg1 d1 [139]. Calculated margins of exposure
were high with values greater than 10 000
and the overall risk to human health is low
[214, 219].
As epichlorohydrin polyamine polyelectro-
lytes are used for water purification of drinking
water, 1,3-DCP could also be present as a
drinking water contaminant [140, 220, 221].
U.S. FDA established a limit for residues of 1,3-
DCP in the dimethylamine epichlorohydrin
copolymer resin of 1000 ppm [222]. A draft
European (CEN) standard for polyamine floc-
culants in water treatment proposed maximum
contaminant levels for 1,3-DCP of 500 ppm or
1.25 mg/L in drinking water [185].
Acute Toxicity. 1,3-DCP has moderate acute
oral toxicity with reported LD50 values between
120 and 400 mg/kg for rats [218, 67], and 25
and 125 mg/kg for mice [218]. In mice, an LC50
of 1.73.2 mg/L was reported [218], whereas in
rats, LC50 of 0.66 mg/L after 4 h inhalation
exposure was reported [184]. LD50 values for
rats after intraperitoneal application were 106
and 110 mg/kg [218].
Skin Contact. 1,3-DCP has moderate acute
dermal toxicity with an LD50 value between
500 and 1000 mg/kg in rabbits [67]; a dermal
LD50 of 800 mg/kg bw was reported for rabbits
[218]. 1,3-DCP was slightly irritating to rabbit
skin [184].
Eye Contact. When tested on rabbit eyes, 1,3-
DCP caused irritation and moderately severe
damage [184].
Repeated-Dose Toxicity. The available data
indicate target organs for 1,3-DCP were liver,
kidney, and blood cells. In a two-week study
with Sprague-Dawley rats, liver and kidney
weights were affected [218]. In 13-week oral
gavage study with Sprague-Dawley rats,
reduced food intake and body weight gain,
and changes in hematology, urine analysis,
and serum chemistry profiles were seen at
the highest dose [184]. Increased liver and
kidney weight as well as histopathological
changes of stomach, kidney, liver, and nasal
tissue were also observed. Similarly, more
recent 13-week oral study in Sprague-Dawley
rats reported hematological changes and a dose-
dependent increase in liver and kidney weight
[223]. A 13-week inhalation study with 1,3-
DCP in Fischer 344 rats reported decreased
body weight, increased liver and kidney weight,
as well as hematological and serum bio-
chemical changes. Pathological changes in liver
(necrosis, inflammation and biliary hyperpla-
sia) and kidney (nephropathy and protein casts)
were reported [224].
Reproductive/Developmental Toxicity. Data
indicate that 1,3-DCP exhibits testicular toxic-
ity. After intraperitoneal injection of 1,3-DCP
to male Wistar rats, a significant decrease in the
number of sperms in the body and tail (com-
bined) of the epididymis was reported [225].
The weights of testes and epididymis as well as
the sperm morphology remained unchanged six
weeks after the injection of 1,3-DCP. In a cited
abstract, groups of male Wistar rats treated by
gavage for 14 d showed spermatocoele or sperm
granuloma formation in the epididymides com-
pared to controls [184]. Administration of 1,3-
DCP to pregnant Sprague-Dawley dams during
gestational days 619 caused maternal toxicity
at doses 30 mg kg1 d1 [226]. Finally, no
embryotoxicity and teratogenicity were
reported at doses that were not maternally toxic
[227].
Mutagenicity. In vitro, 1,3-DCP was muta-
genic in various strains of Salmonella typhimu-
rium with or without metabolic activation [201,
202, 184, 220, 204]. It induced mutations and
influenced DNA repair in Escherichia coli
[184]. 1,3-DCP increased mutation frequency
at Tk locus in mouse lymphoma assay [220,
228]. 1,3-DCP induced sister chromatid
exchanges (SCE) in V79 lung cells and CHO
cells [184, 220, 229]. It was also mutagenic in
HeLa cells and induced chromosomal aberra-
tions in CHO cells [220]. Furthermore, 1,3-
DCP was able to cause malignant transforma-
tion in mouse fibroblasts via the induction of
mutations [184].
In vivo genotoxic studies produced negative
results. Two in vivo studies with male Han
Wistar rats were negative [220, 186]. An induc-
tion of micronuclei in the bone marrow of rats
was not observed after 1,3-DCP administration
for two consecutive days up to doses that cased

clinical signs of toxicity [186]. Unscheduled
DNA synthesis in hepatocytes of male rats was
not increased after 1,3-DCP exposure [186].
1,3-DCP did not induce somatic mutation
and recombination in the wing spot test of
Drosophila melanogaster [206].
Carcinogenicity. In a chronic study in Wistar
KFM/Han rats, 1,3-DCP was administered via
drinking water up to 104 weeks [140]. 1,3-DCP
caused a decrease in body weight gain and an
increase in mortality at the highest dose. Non-
neoplastic findings included elevated relative
liver, kidney and brain weights, hepatotoxicity,
and nephrotoxicity at the highest dose. Elevated
tumor incidences in liver, thyroid gland, and
tongue in both sexes as well as renal tumors in
males were observed. With the exception of
follicular-cell adenoma of the thyroid in the
mid-dose males, the increases in the tumor
incidence were only statistically significant in
the high-dose groups in male rats [139, 140].
1,3-DCP did not increase tumor incidence in
animals of the low dose group.
Classification and Permissible Exposure Lim-
its. 1,3-DCP is listed in Annex VI of CL
Regulation EC 1272/2008 (Index Number
602-064-00-0). The substance is classified as:
Acute Oral Tox. 3 H301: Toxic if swallowed;
Acute Dermal Tox. 4 H312: Harmful in contact
with skin; Carc. 1B H350: May cause cancer
[217].
IARC classified 1,3-DCP as a Group 2B
carcinogen (possibly carcinogenic to humans)
based on sufficient evidence in experimental
animals [140].
No OEL values were set for 1,3-DCP by
ACGIH and DFG MAK. However, in number
of jurisdictions, the 8-h TWA was set at 5 mg/
m3 for 1,3-DCP.
2,3-Dichloro-1-Propanol (2,3-DCP).
Exposure. 2,3-DCP also occurs in trace
amounts in food; data for 2,3-DCP indicate
that 2,3-DCP is usually found at much lower
concentrations than other chloropropanols
[143, 214]. In soy sauce products globally, the
ratio of 3-MCPD to 2,3-DCP varied between
56 and 6330 to 1 [138, 141, 214]. The EC (2004)
reported that 16% of the tested soy sauce
and soy sauce-based samples had detectable
Chlorohydrins 19
levels of 2,3-DCP with mean concentrations of
0.0130.028 mg/kg. In malt, 2,3-DCP was
found at concentrations <0.05 mg/kg [138].
2,3-DCP was not detected in cereals, meat, and
meat products, or in salts, spices, soups, and
sauces excluding soy sauce [214]. Together
withlowerexposureandnohepatotoxicityascom-
pared to 1,3-DCP, low concern for human
health from exposure to 2,3-DCP has been
concluded [214]. U.S. EPA (1990) established
the reference dose (RfD) of 3 mg kg1 d1
based on rat subchronic study and uncertainty
factor of 3000 [234]. A draft European (CEN)
standard for polyamine flocculants in water
treatment proposed a maximum contaminant
levels for 2,3-DCP of 1000 ppm [185].
Acute Toxicity. 2,3-DCP has moderate acute
oral toxicity with an LD50 of 90 mg/kg in
rats [230]. In contrast to 1,3-DCP, 2,3-DCP
seems to have no hepatotoxic effects in male
Wistar rats [231, 232]. LC50 of > 500 ppm
following 4 hour vapor exposure was reported
[230].
Skin Contact. 2,3-DCP has moderate acute
dermal toxicity with an LD50 of 200 mg/kg
[230, 233]. 2,3-DCP is moderately irritating to
skin [230].
Eye Contact. 2,3-DCP is moderately irritating
to eyes [230].
Repeated-Dose Toxicity. In a subchronic study,
2,3-DCP caused hypoactivity and mortality in
treated rats [234]. At the highest dose, rats have
shown myocardial degeneration and kidney
effects. Liver was affected with hypertrophy,
karyomegaly, and bile-duct proliferation.
Changes in the hematology and serum enzymes
were also observed at the middle and highest
dose. At the intermediate dose, toxic effects
were of lesser extent. No adverse effects were
observed at the lowest dose of 10 mg kg1 d1
(study NOAEL) [234].
Reproductive/Developmental Toxicity. Similar
to 1,3-DCP, 2,3-DCP showed reproductive
effects, causing a reduction in sperm counts
in the body and tail of the epididymis and
reduced epididymal weights in treated male
Wistar rats [225].
20 Chlorohydrins
Mutagenicity. Available data suggest muta-
genic potential for 2,3-DCP in vitro. 2,3-DCP
tested positive with bacterial systems with or
without metabolic activation [202, 204, 235,
236, 203]. 2,3-DCP induced SCE in V79 lung
cells [229]. The UK Food Standard Agency
stated that, like 1,3-DCP, 2,3-DCP did not cause
mutagenic effects in vivo in a micronucleus
assay in rat bone marrow cells or in an
unscheduled DNA synthesis test in rat liver
cells [237].
Classification and Permissible Exposure Lim-
its. No harmonized classification is available
for 2,3-DCP (Annex VI, CLP Regulation). The
substance is classified based on the available
data (self-classification) as: Acute Oral Tox. 3
H301: Toxic if swallowed; Acute Dermal Tox. 2
H310: Fatal in contact with skin; Acute Inhala-
tion Tox. 4 H332: Harmful if inhaled; Skin Irrit.
2 H315: Causes skin irritation; Eye Damage
1 H318: Causes serious eye damage; Muta. 2
H341: Suspected of causing genetic defects.
[238].
Other Chlorohydrins. Available toxicological
data for other chlorohydrins are presented
below. Data is limited to acute toxicity and
mutagenicity endpoints.
Acute Toxicity. Acute data indicate that styrene
chlorohydrin has moderate acute oral toxicity
with an LD50 between 300 and 1000 mg/kg in
rats [67]. Inhalation presents no hazard from
exposure at room temperature; however, if the
material is heated, the vapors thus generated
may cause irritation and possibly organ effects
(kidney and liver) [67]. An oral LD50 value for
4-chloro-2-butanol was determined to be
>1600 mg/kg in the rat [239]. In the mouse,
the oral LD50 value for 4-chloro-1-butanol was
determined to be 990 mg/kg, while the intra-
peritoneal LD50 was >100 mg/kg [69].
Skin Contact. Styrene chlorohydrin is irritating
to rabbit skin [67]. 4-Chloro-2-butanol is a
moderate skin irritant with approximate dermal
LD50 value of 0.050.01 mL/kg in guinea pig
[239]. A 2% aqueous solution of 1-chloro-2-
butanol tested in vivo was essentially nonirri-
tating to rabbit skin [67].
Eye Contact. Styrene chlorohydrin is irritat-
ing to the eyes of rabbits [67]. A 2%
aqueous solution of 1-chloro-2-butanol tested
in vivo was essentially non-irritating to rabbit
eye [67].
Mutagenicity. 4-chloro-1-butanol demon-
strated mutagenic response in bacterial assay
with Salmonella typhimurium strains TA100
and TA98, whereas 1-chloro-2-methyl-2-prop-
anol did not [204]. 4-chloro-1-butanol showed
negative genotoxic response in the E. coli SOS
chromotest [240]. Quantitative structureactiv-
ity relationship (QSAR) models also indicated
positive mutagenic outcomes from bacterial
reverse mutation assay with 4-chloro-1-butanol
[241].
Classification and Permissible Exposure Lim-
its. 4-chloro-2-butanol is classified based on
the available data (self-classification) as: Flam.
Liq. 3 H226: flammable liquid and vapor;
Acute Oral Tox. 4 H302: Harmful if swal-
lowed; Skin Irrit. 2 H315: Causes skin irrita-
tion; Eye Damage 2 H318: Causes serious eye
irritation; STOT SE 3 H335: may cause respi-
ratory irritation [242]. 1-Chloro-2-methyl-2-
propanol is classified based on the available
data (self-classification) as: Flam. Liq. 3 H226:
flammable liquid and vapor; Acute Tox. 4
H302: Harmful if swallowed; Acute Dermal
Inhalation Tox. 4 H312: Harmful in contact
with skin; Acute Tox. 4 H332: Harmful if
inhaled; Skin Irrit. 2 H315: Causes skin irrita-
tion; Eye Damage 2 H318: Causes serious eye
irritation [243].
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