CHLORINATED PHENOLS
Ambient Water Quality Criteria
Criteria and Standards Division
Office of Water Planning and Standards
U.S. Environmental Protection Agency
Washington, D.C.
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CRITERION DOCUMENT
CHLORINATED PHENOLS
CRITERIA
Aquatic Life
For 4-chlorophenol the criterion to protect freshwater
aquatic life as derived using the Guidelines is 45 ug/1 as a
24-hour average and the concentration should not exceed 180 ug/1
at any time.
For 2 ,4,6-trichlorophenol the criterion to protect freshwater
aquatic life as derived using the Guidelines is 52 ug/1 as a
24-hour average and the concentration should not exceed 150 ug/1
at any time.
For saltwater aquatic life, no criterion for any chlorinated
phenol can be derived using the Guidelines, and there are insufficient
data to estimate a criterion using other procedures.
Human Health
For the prevention of adverse effects due to the organoleptic
or toxic properties of chlorinated phenols in water, the following
criteria are recommended:
Monochlorophenols
3-chlorophenol 50 ug/1
4-chlorophenol 30 ug/1
Dichlorophenol
2,5-dichlorophenbl 3.0 ug/1
2,6-dichlorophenol 3.0 ug/1
Trichlorophenol
2,4,5-trichlorophenol 10 ug/1
2,4,6-trichlorophenol 100 ug/1
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Tetrachlorophenol*
2/3,4,6-tetrachlorophenol 263 ug/1
Chlorocresol
Insufficient Data
*Th.is criterion is based on toxicological effects; all other
criterion are based on organoleptic effects.
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CHLORINATED PHENOLS
Introduction
The chlorinated phenols represent a group of commercially
produced, substituted phenols and cresols referred to as
chlorophenols and chlorocresols. Chlorinated phenols are
used as intermediates in the synthesis of dyes, pigments, .
phenolic resins, pesticides, and herbicides. Certain chloro-
phenols also are used directly as flea repellants, fungicides,
wood preservatives, mold inhibitors, antiseptics, disinfectants,
and antigumming agents for gasoline. (The compounds 2-chloro-
phenol, 2,4-dichlorophenol and pentachlorophenol are discussed
in separate criteria documents.),
The chlorinated phenols represent a group of substituted
phenols and cresols prepared by direct chlorination or the
hydrolysis of the higher chlorinated derivatives of benzene.
Purified chlorinated phenols exist as colorless crystaline
solids, with the exception of 2-chlorophenol which is a
clear liquid, while the technical grades may be light tan
or slightly pink 'due to impurities (Bennett, 1962; Kirk
and Othmer, 1963; Heilbron, et al. 1946-75; Sax, 1975; Weast,
1974; Windholz, 1976; Hawley, 1975). As a group, the chloro-
phenols are characterized by an odor which has been described
as unpleasant, medicinal, pungent, phenolic, strong, or
persistent (Kirk and Othmer, 1963; Sax, 1975; Lange, 1952).
A summary of the various pertinent physical properties
is presented in Table 1. In general, the volatility of
the compounds decreases and the melting and boiling points
increase as the number of substituted chlorine atoms increases.
A-l
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A
TABLE 1
Physical Properties of Chlorinated Phenols
Compound
Chlorophenols
2-
3-
4-
2,3-di-
2,4-di-
2,5-di-
2,6-di-
3,4-di-
3,5-di-
2,3,4-tri
2,3,5-tri-
2,3,6-tri-
2,4,5-tri
2,4,6-tri-
2,3,4 ,5-tetr a-
2,3,5,6-tetra-
Pentachlorophenol
Chloro-o-cresols
3-
4-
5—
6-
4,5-di-
4,6-di-
3,4,5-di-
3,4,6-di-
3,4,6-tri-
4,5,6-tri-
3,4,5,6-tetra-
MW
128.56
128.56
128.56
163
163.
163.
163.
163.
163.
197 e 5
197.5
197.5
197.5
197.5
232.
232.
266.35
142,55
142.59
142.59
142.59
177.03
177.03
177.03
177.03
211.5
211.5
245.9
pK
8.48
9.08
9.42
7.70
7.85
7.51
6.79
8.59
8.19
7.0
6.1
5.3
4.8
__-.
- —
___
.._.«
___
«••••••
..ME.'
(deg. C)
8.7
33.
43.2
57.
45.
58.
67.
68.
68
83.5
62
58
68
69.5
116.
115.
190-191
86.
51.
73.
— —
101.
55.
101.
55.
62.
77.
190.
.BP
(deg, C)
175
214
219
206
210
212
219
253
233
Sublimes
255
272
245
246
Sublimes
309-310
225
223
_ --
118
266.5
226
269
MB » «•
Density
1.2634
1.2680
1.2651
1.3830
— -
.
1.4901
1.6700
1.9780
-__
___
_ —
— .
""""^ *"*
Water sol..
(g/100g)*
0.1-2.85
0.26
2.71
si.
si.
si.
s.
s.
si.
0.2
0.1
0.1
0.0014
si.
si.
si.
si.
si.
si.
si.
— -
si.
— **" *"*
Vapor
pressure
(mm Hg/
deg. C)
1/12.1
1/12.1
1/59.5
1/72.0
1/76.5
si. - slightly soluble, s. - soluble
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TABLE 1 (contd.)
Physical Properties of Chlorinated Phenols
i
OJ
Compound
Chloro-m-cresols
2-
4-
6-
2,4-di-
2,6-di-
4,6-di-
2,4,6-tri-
2,4,5, 6-tetra-
Chloro-p-cresols
2-
3-
2,6-di-
2,3,5,6-tetra-
MW
142.59
142.59
142.59
177.03
177.03
177.03
211.48
252.9
142.59
142.59
177.03
245.42
MP
pK (deg. C)
55.
66.
45.
27.
58.
72.
45.
189.
195.
55.
39.
190.
BP
(deg. C) Density
196
235
196
241
235
235
265
---
228
138
w«« •»_«•
Water sol.
(g/100g)
si.
0.38
s.
si.
s.
si.
s.
si.
_B ••« -»
Vapor
pressure
(mm Hg/
deg. C)
References:
1. Bennett, 1962
2. Kirk and Othmer, 1963
3. Heilbron, 1946
4. Weast, 1978
5. Sax, 1975
6. Weast, 1974
7. Windholz, 1976
8. Pearce & Simkins, 1968
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The solubility of the chlorophenols and chlorocresols, with
tte exception of 2,4,6-trichloro-m-cresol, range from soluble
to very soluble in relatively non-polar solvents such as
benzene and petroleum ether. Although chlorophenols are
considered weak acids, they are stronger acids than phenol
and can be converted to the corresponding phenoxide salt
by various bases including soduira car.bonate. The dissociation
constants (pKa) for the chlorinated phenols progressively
decrease with increased substitution of chlorine atoms into
the aromatic ring. Although the solubility of chlorinated
phenols in aqueous solutions is relatively low, it increases
markedly when the pH of the solution exceeds the specific
pKa, since the more readily soluble phenoxide salt is formed.
The phenoxide salts are also more soluble than the corresponding
phenol in water and neutral pH.
A summary of the methods of synthesis and principal
uses of the commercially most important chlorinated phenols
is presented in Table 2. Since the hydroxyl group of the
phenol molecule exerts a relatively strong ortho-, para-
directing influence over the electrophylic substitution
of chlorine atoms, the compounds preferentially formed during
the direct chlorination of phenol are 4-chlorophenol, 2-
chlorophenol, 2,4-dichlorophenol, 2,6>dichlorophenol, 2,4,6-
trichlorophenol, and 2,3,4,6-tetrachlorophenol. Other positional
isomers may be synthesized by the hydrolysis of higher chloro-
benzenes. Many of the chlorinated phenols have no commercial
application presently due to their high cost of production,
complex synthetic procedures, or lack of useful chemical,
physical, or toxicological properties (Kirk and Othmer,
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TABLE 2
Chlorinated Phenol
4-chlorophenol
(4-CP)
2,4-dichlorophenol
(2,4-DCP)
2,4,5-tr ichloro-
phenol (2,4,5-
TCP)
i
tn
2,4,6-trichloro-
phenol (2,4,6-TCP)
2,3,4,6-tetra-
chlorophenol
(2,3,4,6-TCP)
Pentachlorophenol
(PCP)
4-chloro-o-cresol
(4-c-o-c)
Summary of the Synthesis and Uses
of Various chlorinated Phenols
Method of Synthesis Principal Uses
Direct chlorination
of phenol
Direct chlorination
of phenol
Hydrolysis of 1,2,4,
5-tetrachlorobenzene
Direct chlorination
of phenol
Direct chlorination
of phenol or lower
chlorophenols
Direct chlorination
of phenol or lower
phenols
Direct chlorination
of o-cresol
To produce 2,4-DCP, and a
germicide 4-chlorophenol-
o-cresol
To produce herbicide
2,4-D, also a mothproofing
cpd., an antiseptic and a
miticide
To produce defoliant 2,4,5-T
and related products. Also
used directly as a fungicide,
antimildew and preservative
agent, algicide, bactericide
To produce 2,3,4,6-TCP and
PCP. Used directly as
germicide, bactericide,
glue and wood preservative
and antimildew treatment
Used directly as bac-
tericide, fungicide,
insecticide, wood and
leather preservative
Used directly as a wood
preservative, herbicide,
insecticide and moluscicide
To produce the herbicide
MCPA
References
Kirk &
Othmer/ 1964
U.S. EPA, 1973
Kirk &
Othmer, 1964
U.S. EPA, 1973,
Kirk &
Othmer, 1964
U.S. EPA, 1973,
Kirk &
Othmer, 1964
U.S. EPA, 1973
Kirk &
Othmer, 1964
Kirk &
Othmer, 1964
U.S. EPA, 1973,
Kirk &
Othmer, 1964
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1963). These include 3-chlorophenol, 2,3-dichlorophenol.,
2,S-dichlorophenol, 3,4-dichlorophenol, 3,5-dichlorophenol,
2,3,4-trichlorophenol, 2,3,5-trichlorophenol, 2,3,4,5-tetra-
chlorophenol, and 2,3,5,6-tetrachlorophenolo However, each
Qf these compounds is produced to some extent as a byproduct
during the production of the commercially important chloro-
phenols. Prom a commercial standpoint, 4-chloro-o-cresol
is the most important of the chlorinated cresols (Kirk and
Othmer, 1963).
i
It is well known that the highly toxic polychlorinated
dibenzo-p-dioxins may be formed during the chemical synthesis
t
of some chlorophenols and that the amount of contaminant
formed is dependent upon the temperature and pressure control
of the reaction (Fishbein, 1973? Milnes, 1971? Schulz, 1968;
Higginbotham, et al. 1968; Muelder and Shadoff, 1973).
The toxicity of the dioxins varies with the position and
number of substituted chlorined atoms and those containing
chlorine in the 2,3 and 7 positions are particularly toxic
(Burger, 1973). The 2,3,7,8-tetrachloridibenzo-p-dioxin
(TCDD) is considered the most toxic of all the dioxins (Sparschu,
et alo 1971).
TCDD is apparently formed during the synthesis of 2,4,5-
trichlorophenol and before 1968 was reported to be present
in the subsequent product 2,4,5-trichlbrophenoxy acetic
acid (2,4,5-T) at levels up to 10 mg/kg (Kearney, et al.
1973; Fishbein, 1973). By 1971 TCDD levels in commercial
2,4,5-T were below 1 mg/kg (Greig, et al. 1973; Hussain,
et al. 1972) arid are currently reported to be be3.ow 0.099
A-6
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mg/kg (Dow, 1977). These TCDD levels are below the limit
of 0.1 mg/kg recommended to the U.S. Environmental Protection
Agency Administrator on May 7, 1971 by the Advisory Committee.
No TCDD was reported present in samples of commercial
grade tetrachlorophenol although 28, 80, and 30 mg/kg of
the hexachloro, heptachloro-, and octachlorodibenzo-p-dioxins
and 55, 100, and 25 mg/kg of the hexachloro-heptachloro,
and octachlorodibenzofurans were present, respectively (Schwetz,
et al. 1974a). No TCDD has been reported present in commercial
pentachlorophenol products although hexa-, hepta-, and octo-
chlorodibenzo-p-dioxins have been detected at concentrations
of 4 to 27 mg/kg, 125 mg/kg, and 50 to 2,510 mg/kg, respect-
ively (Johnson, et al. 1973; Jensen and Reuberg, 1973; Schwetz,
et al. 1974b).
Evidence has accumulated that the various chlorophenols
are formed as intermediate metabolites during the microbio-
logical degradation of the herbicides 2,4-D and 2,4,5-T
and pesticides sivex, ronnel, lindane, and benzene hexachloride
(Kearney and Kaufman, 1972; Steenson and Walker, 1957; Fernley
and Evans, 1959; Loos, et al. 1967; Aly and Faust, 1964;
Crosby and Tutass, 1966; Watts and Stonherr, 1973; Crosby
and Wong, 1973; Goto, et al. 1972; Leng, 1976). In veiw
of the information presented, it is clear that chlorinated
phenols represent important compounds with regard to potential
point source and non-point source water contamination.
Chlorophenols may be produced inadvertently by chlorina-
tion reactions which take place during the disinfection
of waste water effluents or drinking water sources. Phenol
has been reported to be highly reactive to chlorine in dilute
A-7
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aqueous solutions over a considerable pH range (Carlson
and Caple, 1975; Middaugh and Davis, 1976). The formation
of 2- and 4-chlorophenol and higher phenols has been reported
under conditions similar to those employed during the disinfec-
tion of waste water effluents (Aly, 1968; Barnhart and Campbell,
1972) and the synthesis of 2-chlorophenol took place in
1 hour in aqueous solutions containing as little as 10 mg/1
phenol and 20 mg/1 chlorine (Barnhart and Campbell, 1972).
Other studies have demonstrated the formation of up to 1.7
ug/1 2-chlorophenol during the chlorination of sewage effluents
and cooling tower waters (Jolly, 1973; Jolly, et al. 1975).
Limited data are available on levels of chlorinated
phenols present in industrial and municipal wastes, natural
waters, drinking waters, or soils and sediments. 3-Chloro-
phenol, 4-chlorophenol, and 4-chloro-3-methylphenol (4-chloro-
m-cresol) have been identified in chlorinated samples of
both primary and secondary effluents and pentachlorophenol
was found in domestic sewage treatment effluents (U.S. EPA,
1975). However, no quatitative data were reported. Examples
of some findings ares The presence of 2,4-dichlorophenol
in a local water intake system at a concentration of 6.6
jag/1 has been noted. Pentachlorophenol concentrations of
4.3 jig/1 (1 to 5 jag/1 range) in some sewage effluent have
been reported. In another case a river used as a drinking
water supply contained 0.10 to 0.70 ^ig/1 pentachlorophenol
with 40 percent of these levels retained in the finished
drinking water. The presence of 10 to 18 mg/1 pentachloro-
phenol was found in a study of a small stream near a wood
A-8
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preservation site with surface oil slicks containing 5,800
mg/1 pentachlorophenol. In the same study, pentachlorophenol
concentrations of 0.1 to 0.2 mg/1 and 0.05 mg/1 were found
in samples take 1/2 mile and 2 miles downstream, respectively.
It is generally accepted that chlorinated phenols will
undergo photolysis in aqueous solutions as a result of ultra-
violet irradiation and that photodegradation leads to the
substitution of hydroxyl groups in place of the chlorine
atoms with subsequent polymer formation. Studies by Grabowski
(1961) and Joscheck and Miller (1966) indicated that UV
irradiation of 2-chlorophenol produced catechol and/or 2,2-
dihydroxydiphenyl. Omura and Matsuura (1971) reported that
UV irradiation (290 mu) of 2-chlorophenol produced a complex
mixture of products, including a large quantity of resinous
material while the photolysis of 3-chlorophenol produced
a high yield of resorcinol. Photolysis of 2,4-dichlorophenol
in dilute aqueous solutions at a peak wavelength of 253.7
mu was virtually complete within 2 to 40 minutes depending
upon the pH (Aly and Faust, 1964).
Other studies have demonstrated that photodegradation of
2,4-dichlorophenol following 5 hours of daily solar irradia-
tion for 10 days (Crosby and Tutass, 1966). They observed
the formation of the intermediates 4-chlorocatechol and
1,2,4-benzenetriol. The principal product of degradation
recovered was a dark brown residue tentatively identfied
as a mixture of dechlorinated polyquinoids. Although it
has been speculated that photolysis of chlorophenols may
produce dibenzo-p-dioxins, no 2,3,7,8-tetrachlorodibenzo-
A-9
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p-dioxin was detected during the riboflavin-sensitized photo-
oxidation of 2,4-dichlorophenol to tetrachlorinated diphenol
ethers (Plimmer and Klingebiel, 1971). Pentachlorophenol
was shown to undergo photochemical degradation in aqueous
solutions by ultraviolet irradiation and sunlight, with
the formation of several chlorinated benzoquinones, 2,4,5,6-
tetrachlororesorcinol, and chloranilic acid (Mitchell, 1961;
Hamadmad, 1967) . Wong and Crosby (1977) reported the degrada-
tion by sunlight or UV light of dilute solutions (100 mg/1)
of pentachlorophenol to lower chlorophenols, tetrachlorodi-
hydroxy benzenes, and non-aromatic fragments such as dichloro-
maleic acid. Subsequent irradiation of the tetrachlorodiols
produced hydroxylated trichlorobenzoquinones, trichlorodiols*
dichloromaleic acid, and non-aromatic compounds. The irradia-
tion of dichloromaleic acid produced chloride ions and carbon
dioxide.
Microbial degradation of chlorophenols has been reported
by numerous investigators. Loos, et al. (1967) demonstrated
the complete dechlorination and aromatic ring degradation
of 2-chloro-, 4-chlosro-, and 2,4-dichlorophenol by 2,4-D-
grown cells of an Arthobacter species isolated from silt
loam. Evans, et al. (1971), reported the degradation of
2-chlorophenol by several Pseudomonas species isolated from
soil. Nachtigall and Butler (1974), using a Warburg respiro-
metric technique, observed the oxidation of all monochloro-
rj
phenols, 2,4- and 2,6-dichlorophenol, and 2,4,6-trichlorophenol
by Pseudomoas sp. obtained through enrichment of and isolation
from activated sludge. Alexander and Aleem (1961) reported
A-10
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the resistance of 2,4,5-trichlorophenol to microbial decom-
position by certain soil bacteria. They observed that compounds
containing a meta-substituted chlorine atom (position 3
or 5) appeared to be more resistant to microbial degradation.
Ingols, et al. (1966), reported the complete aromatic ring
degradation of 2,4-dichloro- and 2,4,6-trichlorophenol within
5 days by microbial action of an acclimated sludge, while
2,5-dichlorophenol was degraded only 52 percent.
Conversely, the destruction of 2,3,4,6-tetrachlorophenol
by numerous fungal species of Aspergillus, Penicillium,
and Scopulkriopsis obtained from broiler house litter has
been reported (Gee and Peel, 1974). In the same study,
t
the tetrachlorophenol was completely metabolized by a mixed
bacterial suspension also isolated from the litter. Although
Ingols, et al. (1966), observed no alteration of sodium
pentachlorophenol (NaPCP) by activated sludge microbes after
4 days of incubation, Watanabe (1973) reported the growth
of an isolated species of Pseudomonas from PCP-perfused
culture samples using PCP as the sole carbon source.
•
Organoleptic properties manifest themselves in 2 forms;
the ability of a compound to impart an odor to water, and
to cause tainting in fish flesh as a result of exposure
to chlorophenol contaminated water. The organoleptic proper-
ties of chlorophenols have undergone rather extensive investi-
gation. The threshold levels of monochlorophenols causing
odor in water have been reported to be as low as 0.33 to
2.0 ug/1 for 2-chlorophenol (Hoak, 1957; Burttschell, et
al. 1959), 100 to 1,000 pg/1 for 3-chlorophenol (Hoak, 1957;
A-ll
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Campbell, et al. 1958; Ruchoft and Ettinger, 1947), and
33 to 1,000 ug/1 for 4-chlorophenol (Hoak, 1957; Burttschell,
et al. 1959; Ruchoft and Ettinger, 1947). Threshold odor
levels in water have also been reported to be 0.65 to 20 ug/1
for dichlorophenols, 11 to 1,000 ug/1 for trichlorophenols,
915 to 47,000 ug/1 for tetrachlorophenols, and 857 to 12,000
ug/1 for pentachlorophenol (Hoak, 1957; Burttschell, et al.
1959,; Kinney, 1960; Ruchoft and Ettinger, 1947). It is
apparent that the odor threshold progressively increases with
an increase in substituted chlorine atoms.
The odor threshold of the cresols in water has been
reported to be 71 ug/1, 333 ug/1 and 45.4 ug/1 for o-, m-,
p-cresol, respectively, while the odor thresholds of the
chlorinated cresols, 4-chloro and 6-chloro-o-cresol, have
reported to be 75 ug/1 and 3 ug/1, respectively (Hoak, 1975).
/
Several studies have reported the threshold concentrations
of chlorinated phenols in water that impart unfavorable flavors
in the edible portions of aquatic organisms (Schulze, 1961;
Teal, 1959; Shumway, 1966). These threshold values in certain
cases are lower than the odor threshold levels in water.
Virtually no data are available on the bioconcentration
or bioaccumuiation of the lower chlorophenols and limited
data are available regarding pentachlorophenol bioconcentration,
Studies using 14C-labled 2,4-dichlorophenol (DCP) demonstrated
A-12
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that oats and soybean seedlings concentrated DCP from dilute
solutions (0.2 mg/1) by factors of 9.2 and 0.65-fold, respect-
ively (Isensee and Jones, 1971). Bioconcentration data on
pentachlorophenol may be found in the perttachlorophenol
criterion document.
Chlorophenols, their sodium salts, and certain chloro-
cresols have been shown to be toxic to aquatic life, mammals,
and man. In aquatic organisms it appears that the acute
toxicity increases directly with the degree of chlorination.
In addition, the production of odors in water and the tainting
of fish flesh by the lower Chlorophenols and chlorocresols
has been reported to occur at extremely low concentrations.
These findings, in conjunction with the potential pollution
of chlorinated phenols from waste sources, inadvertent chlori-
nation of phenols during disinfection, waste treatment degrada-
tion of herbicides and pesticides, and direct industrial
and agricultural applications lead to the conclusion that
chlorinated phenols represent a potential hazard to aquatic
and terrestrial life.
A-13
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Aly, O.M., and S.D. Faust. 1964. Studies on the fate of
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Jour. Agrie. Food Chem. 12: 541.
t
Barnhart, E.L., and G.R. Campbell. 1972. The effect of chlori-
nation on selected organic chemicals. 12020 EXG 03172.
!•
IKS. Government Printing Office, Washington, D.C.
Bennett, H*, ed. 1962. Concise chemical and technical dic-
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Boetius, 3. 1954. Foul taste of fish and oysters caused
by chloropnenol. Medd. Dan. Fisk. Eavunders. 1: 1.
Burger, E.J., Jr. 1973. Summary: Conference on dibenzodioxins
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Burttschell, R.H., et al. 1959. Chlorine derivatives of
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51: 205,
A-14
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Campbell, C.L., et al. 1958. Effect of certain chemicals
in water on the flavor of brewed coffee. Food Res. 23: 575.
Carlson, R.M., and R. Caple. 1975. Organo-chemical implica-
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Crosby, D.G., and H.O. Tutass. 1966. Photodecomposition
of 2,4-dichlorophenoxyacetic acid. Jour. Agric. Food Chem.
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Crosby, D.G., and A.S. Wong. 1973. Photodecomposition of
f'
2,4,5-trichlorophenoxyacetic acid (2,4,5-T) in waters. Jour.
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Dow Chemical Co. 1977. Product specifications for Dowicide 2.
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Gee, J.M., and J.Lo Peelo 1974. Metabolism of 2,3,4,6-tetra-
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Jour. Gen. Microbiol. 85: 237.
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4th ed. Oxford University Press, New York.
Higgenbotham, G.R., et al. 1968. Chemical and toxicological
evaluation of isolated and synthetic chloro derivatives
of dibenzo-p-dioxin. Nature 220: 702.
A-16
-------
Hoak, R.D. 1957. The causes of tastes and odors in drinking
water. Proc. llth Ind. Waste Conf. Purdue Univ. Eng. Bull.
41: 229.
•
Hussain, G., et al. 1972. Mutagenic effects of TCDD on
bacterial systems. Ambio 1: 32.
Ingols, R.S., et al. 1966. Biological activity of halophenols.
Jour. Water Pollut. Control Fed. 38: 629.
Isensee, A.R., and G.E. Jones. 1971. Absorption and trans-
location of root and foliage applied 2,4-dichlorophenol,
2,7-dichlorodibenzo-p-dioxin and 2,3,7,8-tetrachlorodibenzo-
p-dioxin. Jour. Agric. Food Chem. 19: 1210.
Jensen, S., and L. Reuberg. 1973. Chlorinated dimers present
in several technical chlorophenols used as fungicides.
Environ. Health Perspect. Sept. V-: 37.
Johnson, R.L., et al. 1973. Chlorinated dibenzodioxins
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Jolly, R.L. 1973. Chlorination effects on organic constituents
in effluents from domestic sanitary sewage treatment plants.
Ph.D. dissertation. University of Tennessee.
A-17
-------
Jolly, R.L*, et al. 1975. Chlorination of cooling water:
a source of environmentally significant chlorine-containing
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Corvallis, -Ore.
Joschek, H.I., and S.I. Miller. 1966. Photocleavage of
: i~
phenoxyphenols and bromophenols. Jour. Am. Chem. Soc. 88: 3269.
Kearney, P.C., and D.N. Kaufman. 1972. Microbial degradation
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Sci., Was ing ton, D.C.
Kearney, P.C., et al. 1973. Tetrachlorodibenzodioxin in
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Am. Chem. Soc
•
A— 18
-------
Loos, M.A., et al. 1967. Phenols as intermediates in the
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A-19
-------
Onrura* K« ? aitdl T.. Matstmr,a. 19)71.* Photo induced reactions
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i.
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-------
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\.
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' •
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i
Toxic Subst. V7nsington, D.C.
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A-21
-------
VJatts, R.R., and R.W, Stonherr. 1973. Negative finding
i
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%
Wong, A.S., and D.G. Crosby. 1977. Photodecomposition of
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June 27 - 29. U.S. Environ. Prot. Agency and University
of West Florida.
A-22
-------
AQUATIC LIFE TOXICOLOGY*
FRESHWATER ORGANISMS
Introduction
A review of the available literature on the effects of
chlorinated phenols on aquatic life is complicated by the variety
of common and scientific names used for these compounds. A con-
sistent set of names has been used herein and footnotes are used
to identify other names that were used in referenced publica-
tions.
The toxicity of chlorinated phenols to aquatic life varies
widely as a function of the nature and degree of ring substitution
with chlorine. In general, the toxicity increases with increasing
substitution, and in most cases, aquatic plants appear to be less
sensitive to these chemicals than aquatic animals.
Because the toxicity of chlorinated phenols to various
aquatic life forms is structure-dependent (Tables 1, 2, and 3),
giving rise to wide variability, it would be inappropriate to
derive a criterion for these chemicals as a group. Instead, these
criteria will be derived on the basis of individual chemicals.
*The reader is referred to the Guidelines for Deriving Water
Quality Criteria for the Protection of Aquatic Life [43 FR 21506
(May 18, 1978) and 43 FR 29028 (July 5, 1978)] in order to better
understand the following discussion and recommendation. The fol-
lowing tables contain the appropriate data that were found in the
literature, and at the bottom of each table are the calculations
for deriving various measures of toxicity as described in the
Guidelines.
B-l
-------
The .criteria for chlorinated phefiols will be derived from the
Cast that these Compounds have been shown to ijnpair the flavor of
the .e.dible portions of fish at concentrations lower than those at
which they are toxic to aquatic organisms.
&C3Ufce To x -lg i ty x
The adjusted 96-hour LC50 values for fathead minnows ranged
from 2.1 ug/1 for 4-chloro-3-raethylphenol (U.S. EPA, 197:2) to 9*040
ug/1 for 2,4,6-trichlorophenol (Phipps, et al. manuscript).
Paphnia magna was less sensitive than the bluegili for five
of the seven chlorinated phenols for which a comparison could be
made (Tables 1 and 2).
The 96-hour LC50 values for chlorinated phenols and the blue-
gill fp.S.i EPA, 1978) are directly related to the degree of
ehlorination. These values decrease from 6,590 ug/1 for 2-chloro-
phenol and 3,830 ug/1 for 4-chlorophenol to 60 and 77 ug/1 for
pentachlorophenol (Bentley/ et al. 1975; see pentachlorophenol
criterion document). These data and those for intermediate
chlorinated phenols can be correlated with the octanol-^water par-
tition coefficient with a correlation coefficient of 0.95. Data
for other aquatic organisms do not correlate as well.
All but one of the acute tests were run under static condi-
tions and all but three without measured concentrations. In five
of the $ight cases for which data were available, the Final Inver-
tebrate Acute Values were lower than the Final Fish Acute Values,
and thus become the Final Acute Values. These values, with the
companion Final Fish Acute Values in parentheses, are: 180 (540)
ug/1 for 4»rchXorophenol, 12 (330) ug/1 for 4-chloro-2methylphenol,
17 (230) ug/1 for 2.4-dichloro-6-methy!phenol, 12 (20) ug/1 for
B-2
-------
2,3,4,6-tetrachlorophenol, and 23 (24) ug/1 for 2,3,5,6-tetra-
chlorophenol. For two compounds, the Final Fish Acute Values be-
come the Final Acute Values. These values, and the companion
Final Invertebrate Acute Values in parentheses are: 150 (240)
ug/1 for 2,4,6-trichlorophenol and 63 (110) ug/1 for 2,4,5-tri-
chlorophenol. Finally, for 4-chloro-3-methylphenol, no Final
Invertebrate Acute Value was available, so the Final Fish Acute
Value becomes the Final Acute Value, 5.4 ug/1.
Chronic Toxicity
There are no data on the chronic toxicity of chlorinated
phenols other than those in the criterion documents for 2-chloro-
phenol, 2,4-dichlorophenol, and pentachlorophenol.
Plant Effects
The data in Table 3 indicate that aquatic plants are gener-
ally less sensitive to chlorinated phenols than fish or inver-
tebrate species. The chlorosis LC50 values for a series of ten
chlorinated phenols (Blackman, et al. 1955) with Lemna minor
ranged from 598,594 ug/1 for 2-chloro-6-methylphenol and 282,832
ug/1 for 4-chlorophenol to 603 ug/1 for 2,3,4,6-tetrachlorophenol.
Once again, the toxicity is related to increasing chlorination but
not as clearly as noted for the bluegill. As with fish and aqua-
tic invertebrate species, the derivation of a single Final Plant
Value is deemed inappropriate due to the wide variability in
toxicity for this group of compounds. The Final Plant Values
ranged from 600 ug/1 for 2,3,4,6-tetrachlorophenol to 600,000 ug/1
for 2-chloro-6-methylphenol.
9-3 . -7. ,
-------
Residues
No measured steady-state bioconeentration factors (BCF) are
available for these chlorinated phenols. Several BCFs can be
estimated using the octanpl'-water partition coefficients of 263 /
6,026, 4,898, 19,952, and 6,606 for 4-chlorophenol, 2,4,5-tri^
chlorophenol , 2,4, 6-tr ichlorophenol , 2,3,4, 6-^tetrachlorophenol ,
and 4^chloro*-3-methylphenol, respectively. These coefficients are
used to derive estimated BCFs of 41, 440, 380, 1,100, and 470 for
4s*ehlorophenolf 2,4,5-trichlorophenol, 2,4, 6-tr ichlorophenol,
2,3,4,6-tetrachlorophenol, and 4-chloro-3-methylphenol, respec-
tively, for aquatic organisms that contain about 8 percent lipids.
If it is known that the diet of the wildlife of concern contains a
significantly different lipid content, appropriate adjustments in
the estimated BCFs should be made. Partition coefficients for
Othe,r chlorinated phenols in this document cannot be estimated.
Miscellaneous
stated in the introduction, chlorinated phenols have been
shown to impair the flavor of fish flesh at concentrations much
lower than those at which it has a toxic effect (Shumway and
Palensky, 1973). In this study, rainbow trout were exposed for 48
hours to a range of concentrations of five different chlorinated
phenols, and a panel of fifteen judges scored the flavor of the
cooked and coded fish samples on an increasing impairment scale of
0 to 6. The results were then plotted against exposure concentra-
tions and graphically interpreted to arrive at an estimate of the
highest concentration which would not impair the flavor of the
flesh. The resulting estimates for five different compounds
ranged from 23 u.g/1 for 2, 5-d ichlorophenol to 84 u.g/1 for 2,3-^di^
chlorophenol (Table 4).
B-4
-------
CRITERION FORMULATION
Freshwater-Aqautic Life
Summary of Available Data
The concentrations below have been rounded to two significant
figures.
4-chlorophenol
Final Fish Acute Value = 540 ug/1
Final Invertebrate Acute Value = 180 ug/1
Final Acute Value = 180 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = 4,800 u9/l
Residue Limited Toxicant Concentration = not available
Final Chronic Value = 45 ug/1 for tainting
0.44 x Final Acute Value = 79 ug/1
2,4,6-trichlorophenol
Final Fish Acute Value = 150 ug/1
Final Invertebrate Acute Value = 240 ug/1
Final Acute Value = 150 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = 5,900 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = 52 ug/1 for tainting
0.44 x Final Acute Value = 66 ug/1
4~chloro-3-methylphenol
Final Fish Acute Value =5.4 ug/1
Final Invertebrate Acute Value = not available
B-5
-------
Final Acute Value - 5.4 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value « not available
Final Plant Value = 95,000 ug/1
Residue Limited Toxicant Concentration = not available
liFinal Chronic Value = 95,000 v.g/1
0.44 x Final Acute Value =2.4 ug/1
4-chloro-2-methylphenol
Fina^ Fish Acute Value = 330 ug/1
Final Invertebrate Acute Value =* 12 ug/1
«
Final Acute Value = 12 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value - not available
Final Plant Value «• 93,000 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = 93,000 ug/1
0.44 x Final Acute Value = 5.3 ug/1
2,4-dichloro-6-methylphenol
Final Fish Acute Value = 230 ug/1
Final Invertebrate Acute Value * 17 ug/1
Final Acute Value = 17 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
i
Final Plant Value = not available
t
-j
Residue Limited Toxicant Concentration - not available
Final Chronic Value = not available
0.44 x Final Acute Value =7.5 ug/1
B-6
-------
2,4,5-trichlorophenol
Final Fish Acute Value = 63 ug/1
Final Invertebrate Acute Value = 110 ug/1
Final Acute Value = 63 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = 1,200 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = If200 ug/1
0.44 x Final Acute Value = 28 ug/1
2 e3,4,6-tetrachlorophenol
Final Fish Acute Value = 20 ug/1
Final Invertebrate Acute Value = 12 ug/1
Final Acute Value = 12 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = 600 ug/1
Residue Limited Toxicant Concentration = not available
Final Chronic Value = 600 ug/1
0.44 x Final Acute Value = 5.3 ug/1
2,3,5,6-tetrachlorophenol
Final Fish Acute Value = 24 ug/1
Final Invertebrate Acute Value = 23 ug/1
Final Acute Value = 23 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value « 2,700 ug/1
B-7
-------
Residue Limited Toxicant Concentration = not available
Final Chronic Value = 2,700 ug/1
0.44 x Final Acute Value = 10 ug/1
Flavor impairment studies with rainbow trout exposed to
various chlorinated phenols showed that tainting occurred from 23
ug/1 to 84 ug/1; and thus tainting will become the basis for cri-
teria. Criteria can be calculated only for 4-chlorophenol and
2,4,6-trichlorophenol since these are the only two chlorinated
phenols for which both acute toxicity data and tainting data
exist. Tainting was not caused by 4-chlorophenol and 2,4,6-tri-
chlorophenol at 45 ug/1 and 52 ug/1/ respectively, which are the
24-hbur average concentrations. The maximum concentrations of
4-chlorophenol and 2,4,6-trichlorophenol are the Final Acute
Values of 180 and 150 ug/1, respectively.
No freshwater criteria can be derived for other chlorinated
phenols using the Guidelines because no Final Chronic Value for
either fish or invertebrate species or a good substitute for
either value is available. There are insufficient data to esti-
mate a criterion using other procedures.
CRITERION: For 2,4,6-trichlorophenol the criterion to pro-
tect freshwater aquatic life as derived using the Guidelines is 52
ug/1 as a 24-hour average and the concentration should not exceed
150 ug/1 at any time.
B-8
-------
Table 1. Freshwater fish acute values for chlorinated phenols
BioaEsay Test Chenucai Time
Adjusted
LCbo LCbu
(uq/H Keterence
Fathead minnow,
Pimephales promelas
Fathead minnow
(juvenile) ,
Pimephales promelas
Fathead minnow,
Pimephales promelas
Bluegill,
Lepomis macrochirus
Bluegill,
Lepomis macrochirus
W
^ Bluegill.
Lepomis macrochirus
Bluegill,
Lepomis macrochirus
Bluegill,
Lepomis macrochirus
Bluegill.
Lepomis macrochirus
Bluegill,
Lepomis macrochirus
S
FT
S
S
S
S
S
S
S
S
M
M
M
U
U
U
U
U
U
U
2,4,6-
trichlorophenol
2,4,6-
trichlorophenol
4-chloro-3-methyl
phenol
4-chlorophenol
2,4,5-
trlchlorophenol
2,4,6-
trichlorophenol
2,3.4,6-
tetrachlorophei\ol
2,3,5.6-
tetrachlorophenol
4-chloro-2-methyl-
phenol***
2,4-dlchloro-
6 -methyl phenol
96
96
96
96
96
96
96
96
96
96
600
9,040
30
3,830
450
320
140
170
2,330
1,640
426
9,040
21
2,094
246
175
77
93
1,274
897
U.S. EPA,
1972
Phipps ,
et al.
Manuscript
U.S. EPA,
1972
U.S. EPA,
1978
U.S. EPA,
1978
U.S. EPA,
1978
U.S. EPA,
1978
U.S. EPA,
1978
U.S. EPA,
1978
U.S. EPA.
1978
* S = static, FT = flow-through
** U = unmeasured, M - measured
***Data were reported for 4-chloro-6-methylphenol
2.094
Geometric mean of adjusted values: 4-chlorophenol = 2,094 »ig/l ^AUnH = 540 p
2,4.6-trichlorophenol - 586 pg/1 586
150 ug/1
21
4-chloro-3-methylphenol = 21 ng/1 ^ = 5.4 ug/1
4-chloro-2-methylphenol - 1,274 ug/1 -$£ " 330 ug/1
-------
CD
M
O
Table 1. (Continued)
Organism
bioassay Test
Method Cone.
Chemical
Description
Time
tnrs)
LCiU
tuq/lt
Keterence
2.4-dichloro-6-raethylphenyl « 897 ug/1 fpZ'- 230 yg/1
2,4,5-trichlorophenol = 246 wg/1 377° 63 "S^1
2,3.4,6-tetrachlorophenol «• 77 pg/1 375- - 20 pg/1
2,3,5,6-tetrachlorophfinol - 93 ug/1 ^^•- 24
-------
Table 2. Freshwater Invertebrate acute values for chlorinated phenols
Bioaseay Test Chemical Tine LCbu
Adjusted
LCiU
(ug/1) Rfeterence
Cladoceran,
Daphnla roagna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnla roagna
Cladoceran,
Daphnla magna
Cladoceran,
Daphnla magna
Cladoceran,
Dfjphnjji magna
S U 4-chlorophenol
S U 4-chlorophenol
S U 2.4.5-
trlchlorophenol
S U 2.4.6-
trlchlorophenol
S U 2,3,5,6-
tetrachlorophenol
S U 2,3.4,6-
tetrachlorophenol
S U 4-chloro-2-methyl-
phenol***
S U 2,4-dlchloro-
6-methyl phenol
»--— — *
48
48
48
48
48
48
48
48
.fc», i i .. ••
4,820
4,060
2,660
6.040
570
290
290
430
4,082
3,439
2,253
5,116
483
246
246
364
Kopperman ,
et al. 1974
U.S. EPA,
1978
U.S. EPA.
1978
U.S. EPA,
1978
U.S. EPA.
1978
U.S. EPA.
1978
U.S. EPA.
1978
U.S. EPA.
1978
*** Data were reported for 4-chloro-6-methylphenol
••«.,'
* S = static
-.'.-* y = unmeasured
Geometric mean of adjusted values: 4-chlorophenol ** 3,747 pg/1 *$' " 18° "8/1
2.4,6-trlchlorophenol = 5,116 pg/1
2.4.5-trlchloroph«nol - 2.253 pg/1
2,3,5,6-tetrachlorophenol = 483 ug/1
4-chloro-2-methylphenol = 246 pg/1
2.4-dlchloro-6-methylphenyl = 364 pg/1
2.3,4,6-tetrachlorophenol - 246 pg/1
240 pg/1
J Pg/1
- 12 Pg/1
•;17 .pg/1
12 Pg/1
-------
Table 3. Freshwater plant effects for chlorinated phenols
Organism
Concentration
Effect
Reference
03
I
(-•
to
Alga. •
Chlorclla
pyrenoidosa
Alga.
Chlorella
pyrenoidosa
Alga.
Selenastrutn
capricornutum
Alga.
Selenastrum
capricornutum
Alga,
Selenastrum
capricornutum
Duckweed,
Lenin a minor
Duckweed,
Lemna minor
Duckweed,
Lemna minor
Duckweed,
Lemna minor
Duckweed.
Lemna minor
Duckweed,
Lemna minor
Duckweed,
Lemna minor
Complete
destruction of
chlorophyll
Complete
destruction of
chlorophyll
50% reduction
in cell produc-
tion in 96 hrs
50% reduction
in chlorophyll a
in 96-hrs
50% reduction
in call produc-
tion in 96 hrs
Chlorosis (LC50)
Chlorosis (LC50)
Chlorosis (LC50)
Chlorosis (LC50)
Chlorosis (LC50)
Chlorosis (LC50)
Chlorosis (LC50)
. 500.000
mono-chloro-phenols
10.000
2,4.5- and 2,4.6-
trichloro-phenols
4,790
4-chlorophenol
1,220
2,4,5-
trichlorophenol
2,660
2,3,5.6-
tetrachlorophenol
282,832
4-chlorophenol
1.659
2,4,5-
trichlorophenol
5,923
2,4.6-
trichlorophenol
603
2.3.4.6-
tetrachlorophenol
92,638
4-chloro-2-
methylphenol*
598.584
2-chloro-6-
methylphenol*
95.488
4-chloro-3-
methylphenol*
Huang & Gloyna, 1968
Huang & Gloyna, 1968
U.S. EPA, 1978
U.S. EPA, 1978
U.S. EPA, 1978
Blackman, et al. 1955
Blackman. et al. 1955
Blackman, et al. 1955
Blackman, et al. 1955
Blackman, et al. 1955
Blackman. et al.. 1955
Blackman, et al. 1955
-------
Table 3. (Continued)
CD
t->
U>
Organism
Duckweed,
Lemna minor
Duckweed,
Lemna minor
Duckweed,
Lemna minor
Effect
Chlorosis (LC50)
Chlorosis (LC50)
Chlorosis (LC50)
Concentration
(uq/i)
65,479
2,6-dichioro-A-
methylphenol*
6,131
2,4,6-trichloro-3-
mefhylphenol*
1,107
2,4,5,6-tetrachloro-3-
methylphenol*
Referfcnce
Blackman, et al. 1955
Blackman, et al. 1955
Blackman, et al. 1955
*Data were reported for methyl chlorophenol for these compounds.
Final Plant Values: 4-chlorophenol = 4,800 pg/1
2,4,5-trichlorophenol » 1,200 pg/1
2,4.6-trichlorophenol = 5,900 pg/1
2,3,4,6-tetrachlorophenol =• 600 pg/1
2.3.5,6-tetrachlorophenol = 2,700 ug/1
2-methyl-4-chlorophenol ° 93,000 wg/1
2-methyl-6-chlorophenol ° 600,000 Mg/1
3-methyl-4-chlorophenol = 95,000 pg/1
4-raethyl-2,6-dichlorophenol = 65,000 pg/1
3-methyl-2.4,6-trichlorophenol » 6.100 pg/i
3-methyl-2,4.5,6-tetrachloroph«nol - 1,100 pg/1
-------
Table 4.. Other freshwater data for chlorinated phenols
Organism
Test
Duration Etfect
Result
Peterencfe
03
I
Lymnaeid snails, 2"4'hra
Pseudosuccinea columella
ao(r~Fossaria cubensis
Lymnaeid' snails, 24 hrs
Pseudosuccinea columella
and Fossaria cubensis
Lymnaeid snails, 24 hrs
Pseudosuccinea columella
and Fossaria cubensis
Rainbow trout,
Salmo gatrdneri
Rainbow trout,
Salmo gairdneri
Rainbow trout,
Salmo gairdneri
Rainbow trout,
Salmo gairdhert
Rainbow trout,
Salmo
Rainbow trout,
Salmo gairdnert
Rainbow trout,
Salmo gatrdneri
Goldfish.
Carassius auratus
48 hrs
48 hrs
48 hrs
1001 mortality
100% mortality
100% mortality
Lowest concentra-
tion which killed
50% or more of
the test fish
ETC*
ETC*
10,00ft
2.4,5-
trichlorophenol
BaEte & Swanson, 1952'
2,500 Batte & Swanson, 1952
sodium 2,4,5-
trichlorcphenate
(85%)
5,000
2,4.6-
trichloropheriol
Batte & Swanson, 1952
10.000 Shumway & Palensky, 1973
3-chlorophenol
48 ters ETC*
48 bra ETC*
48 hrs Lowest concentra-
tion which killed
50% or more of
the test fish
48 hrs ETC*
8 hrs 62% mortality
45
4-chlorophenol
84
2,3-
dichloropheaol
23
2.5-
dichlorophenol
35
2.6-
dichlorophenol
1,000
2.4.5-
trichlorophenol
52
2.4.6-
trichlorophenol
20.600
3-chlorophenol
Shumway & Palensky, 1973
Shumway & Palensky, 1973
Shumway & Palensky, 1973
Shuaway & Palensky, 1973
Shumway & Palensky, 1973
Shumway & Palenoky, 1973
Cersdorff & Smith. 1940
-------
to
I
»-
01
Table 4. (Continued)
Test Result
Organism Duration fttect (uu/il Reterencfa
Goldfish. 8 hrs 54% mortality 6,300 Gersdorff £ Sraith. 1940
Carasstus auratus 4-chlorophenol
* ETC = Che highest estimated concentration of material that will not impair the flavor of the
flesh of exposed fish.
-------
SALTWATER ORGANISMS
Introduction
Phenol, and three of the chlorinated phenols, 2-chlorophenol,
2,4-dichlorophenol, and pentachlorophenol are treated in separate
water quality criteria documents. The acute toxicity of chloro-
phenols varies widely, depending on the chlorophenol tested and,
therefore, water quality criteria should be derived for individual
chlorophenols.
.Acute Toxicity
Toxicity tests with the sheepshead minnow have been conducted
with three chlorophenols (Table 5). The 96-hour LC50 values, ad-
justed for static exposures and unmeasured concentrations, range
from 908 ug/1 for 2,4,5-tetrachlorophenol to 2,924 ug/1 for
4-chlorophenol (U.S. EPA, 1978). The Final Fish Acute Values
derived from these data using a species sensitivity factor of 3.7
are 790, 250, and 280 ug/1 for 4-, 2,4,5-tri-, and 2,3,5,6-tetra-
chlorophenol, respectively.
Acute toxicity tests with invertebrate species consist of
three 96-hour static tests with the mysid shrimp, Mysidopsis
bahia, and three chlorophenols (Table 6). Using adjusted LC50
values and a species sensitivity factor of 49, the Final Inver-
tebrate Acute Values from these data are 510, 66, and 380 ug/1
for 4-, 2,4,5-tri-, and 2,3,5,6-tetrachlorophenol. Final Acute
Values are based on Fish or Invertebrate Acute Values, depending
on the chlorophenol tested.
Comparable data (U.S. EPA, 1978) are available for effects of
other chlorinated phenols on fishes and invertebrate species (see
Criterion Documents for 2-chlorophenol, 2,4-dichlorophenol, and
B-16
-------
pentachlorophenol for details). Adjusted LC50 values for fish
range from greater than 20,000 ug/1 for 2-chlorophenol to 21 ug/1
for pentachlorophenol. Adjusted LC50 values for invertebrate
species range from 25,155 ug/1 for 4-chlorophenol to 34 ug/1 for
pentachlorophenol. Toxicity of chlorophenols, except 2,3,5,6-
tetrachlorophenol and mysid shrimp, appear to increase with
increasing degree of chlorination.
Chronic Toxicity
The only chronic data available are those of an embryo-larval
test with the sheepshead minnow and 2,4-dichloro-6-methylphenol
(Table 7). The lowest concentration tested, 360 ug/lr affected
them in a 28-day exposure. Since no acute toxicity test was con-
ducted with this chlorophenol,the value of this chronic test in
formulating a water quality criterion is limited.
Plant Effects
Toxicity tests with chlorophenols and the alga, Skeletonema
costatum, also revealed differences in toxicity, depending upon
the compound tested (Table 8). Reductions in chlorophyll a_ and
cell numbers showed that 2,3,5,6-tetrachlorophenol was the most
toxic and 4-chlorophenol the least toxic. The Final Plant Values
for the tested chlorophenols ranged from 440 ug/1 for 2,3,5,6-
tetrachlorophenol to 3,270 ug/1 for 4-chlorophenol.
Comparable test procedures (U.S. EPA, 1978) were used for
other chlorophenols and, as with sheepshead minnows and mysid
shrimp, toxicity generally increased with increased degree of
chlorination.
B-17
-------
FORMULATIOK
The concentrations below have been founded to two significant
figures.
Final Pish Acute Value «= 790 ug/1
Final Invertebrate Acute Value * 516 ug/1
final Acute Value * 510 ug/1
final Pish Chronic Value = not available
final Invertebrate Chronic Value * not available
<
final Plant Value * 3,300 ug/1
Residue Limited toxicant Concentration not available
final Chronic Value * 3,300 ug/1
0.44 x final Acute Value = 220 ug/1
final fish Acute Value a 2SO ug/1
final Invertebrate Value =66 u<3/l
final Acute Value = 66 ug/1
finM fish 6hi?onie Value * not available
final invertebrate Chronic Value «* not available
final Plant Value » ^90 uf/1
Residue Liifiifeed Toxicant Concentration & not available
Final Shronie Value « 690 u^/1
b*44 x final -Acute Value a1 29
Fish Aeute Value a 280 u§/l
Final Invertebrate Acute Value « 380
B-lfe
-------
Final Acute Value = 280 ug/1
Final Fish Chronic Value = not available
Final Invertebrate Chronic Value = not available
Final Plant Value = 440 ug/1
* 'i • i
Residue Limited Toxicant Concentration = not available
Final Chronic Value = 440 u.g/1
0.44 x Final Acute Value = 120 ug/1
2,4-d ichloro-6-methylphenol
Final Fish Acute Value = not available
Final Invertebrate Acute Value = not available
Final Acute Value = not available
Final Fish Chronic Value = less than 27 ug/1
Final Invertebrate Chronic Value = not available
Final Plant Value = not available
Residue Limited Toxicant Concentration = not available
Final Chronic Value = less than 27 ug/1
0.44 x Final Acute Value = not available
Flavor impairment studies with aquatic organisms indicate
that flavor impairment may be an especially important factor in
determining water quality criteria for chlorophenols.
Unfortunately, data necessary to establish a saltwater criterion
based on tainting are unavailable.
For saltwater aquatic life, no criterion for any chlorinated
phenol can be derived using the Guidelines, and there are insuffi-
cient data to establish a criterion using other procedures.
B-1'9
-------
Table 5. Marine fish acute values for chlorinated phenols (U.S. EPA, 1978)
I
KJ
o
Bioacsay Test Chemical Time
Mc-tnod* r Cong. ** peaciiptiog (hrs)
Adjusted
LCbO
IK; /11 fug/11
Sheepshead minnow,
Cyprinodon variegatus
Sheepshead minnow,
Cyprinodon variegatus
Sheepshead minnow,
Cyprinodon variegatus
S U 4-chlorophenol 96
S U 2,4,5- 96
trichlorophenol
S U 2,3.5,6- 96
tetrachlorophenol
5,350 2,924
1,660 908
1,890 1,033
* S = static
** U = unmeasured
Geometric mean of adjusted values:
4-chlorophenol = 2,924 vg/l
2,4,5-trichlorophenol = 908 -
2,3.5,6-tetrachlorophenol <= 1,033 ng/1
79°
250 ng/1
280 pg/1
-------
Table
6. Marine invertebrate acute values for chlorinated phenols (U.S. EPA, 1978)
03
I
NO
O r >4 n n i 5 tn
Mysid shrimp,
Mysidopsis bahia
Mysid shrimp,
Mysidopsis bahia
Mysid shrimp,
Mysidopsis bahia
bioussay
Metnod*
•ii i —. " — . —
S
S
S
Test
Cone .**
U
U
U
Cheoucai
Description
4-chlorophenol
2.4,5-
trichlorophenol
2,3.5,6.
tetrachlorophenol
Time
(hra)
96
96
96
LCbu
29.700
3,830
21.900
Adjusted
LCSO
(uq/ll
25.155
3.244
18,549
* S = static
** U = unmeasured
Geometric mean of adjusted values: 4-chlorophenol = 25,155 Mg/1 Z3iQ3J - 510 wg/1
2,4,5-trichlorophenol - 3,244 ug/1 ^9^ = 66 ^S/1
18.549
25.155
2,3,5.6-tetrachlorophenol = 18.549 ug/1
380 ug/1
-------
EB
r
NJ
Tacle 7. Marine fish chronic values for chlorinated phenols (U.S. EPA. 1978)
Chronic**
£ioti€6** Value
Or-qan-i-sm-
SheepShead Einfiow,
o - 1JT
E-L <360 <180
* E-t. = em&ryo-larval
** Data for 214-dichloro-6-methylphenol
Geomecrie mean of chronic values - <180 pg/1 * ™ *27 yg/1
Lowest chronic value - <18G'
-------
Table 8. Marine plant effects for chlorinated phenols (U.S. EPA, 1978)
Concentration
03
I
NJ
to
Organism
Alga.
Skeletoneroa costatum
Alga.
Skeletonema costatum
Alga.
Skeletonema costatum
Alga.
Skeletonema costatum
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Etrect
EC50 96-hr
chlorophyll a
4-chlorophenol
3,270
EC50 96-hr
cell count
3,560
2,4,5-trichlorophenol
EC50 96-hr
chlorophyll a
EC50 96-hr
cell count
890
960
EC50 96-hr
chlorophyll a
EC50 96-hr
cell count
2,3,5,6-tetrachlorophenol
440
500
Final plant value: 4-chlorophenol = 3,270 ng/1
2,A,5-trichlorophenol = 890 pg/1
2,3,5.6-te.trachlorophenol = 440 ug/1
-------
CHLORINATED PHENOLS
REFERENCES
Batte, E.G., and L.E. Swanson. 1952. Laboratory evaluation
of organic compounds as molluscicides and ovicides, II.
Jour. Parasitol. 38: 65.
Blackman, G.E*, et al. 1955. The physiological activity
of substituted phenols. I. Relationships between chemical
structure and physiological activity. Arch. Biochem. Biophys.
54: 45.
Gersdorff, W.A., and L.E. Smith. 1940. Effect of introduc-
tion of the halogens into the phenol molecule on toxicity
to goldfish. I. Monochlorophenols. Am. Jour. Pharmacol.
112: 197.
Huang, J., and E.F. Gloyna. 1968, Effect of organic compounds
on photosynthetic oxygenation. I. Chlorophyll destruction
and suppression of photosynthetic oxygen production. Water
Res. 2: 347.
Kopperman, H.L., et al. 1974. Aqueous chlorination and
ozonation studies. I. Structure-toxicity correlations of
phenolic compounds to Daphnia magna. Chem. Biol. Interact.
9: 245.
B- 2 4
-------
Phipps, G.L., et al. The acute toxicity of phenol and sub-
stituted phenols to the fathead minnow. (Manuscript).
Shumway, D.L., and J.R. Palensky. 1973. Impairment of
the flavor of fish by water pollutants. EPA-R3-73-Q10.
U.S. Environ. Prot. Agency, U.S. Government Printing Office,
Washington, D.C.
U.S. EPA, 1972. The effect of chlorination on selected
organic cnemicals. Water Pollut. Control Res. Ser. 12020.
U.S. EPA. 1978. In-depth studies on health and environmental
impacts on selected water pollutants. Contract No. 68-01-
4646.
B-25
-------
3-CHLOROPHENOL AND 4-CHLOROPHENOL
Mammalian Toxicology and Human Health Effects
EXPOSURE
Introduction
Monochlorophenol has three isomeric forms, each distin-
guished by the position of the chlorine atom relative to
the hydroxy-group on carbon one of the six-carbon ring.
The three isomers are 2-chlorophenol or o-chlorophenol;
3-chlorophenol or m-chlorophenol; and 4-chlorophenol or
p-chlorophenol. This document will discuss only 3- and
4-chlorophenol since 2-chlorophenol was addressed in a separate
criterion document.
Monochlorophenols have been used as antiseptics since
1893 (Von Oettingen, 1949). They occur as intermediates
in the formation of other chlorophenol-containing product's
and as metabolic breakdown products of other chlorophenols
or chlorobenzene. They may also be formed by the chlorination
of water containing natural phenol or phenolic wastes.
The chemical properties of 3- and 4-chlorophenol are
listed in Table 1. One important property is the ability
of relatively low concentrations of chlorophenols to produce
a medicinal odor and taste in water. This low organoleptic
threshold may call attention to a state of contamination
and aid in protecting humans from unacceptable levels of
exposure.
Phenols are known to occur naturally in the environment
(Hoak, 1957). For example, some aquatic plants release
sufficient phenol to establish water levels of 300-960 jig/1.
Phenols are found in raw domestic sewage at levels of 70-
C-l
-------
TABLE 1
Properties of Mono-Ghlorophenols
3 *-G h 1 o r o phe no 1
Alternate name
Molecular weight
Specific gravity
Form at room temperature
Melting point
Boiling point
Solubility
water
alcohol
ether
benzene
Vapor pressure
CAS number
Odor threshold in
water-30°G
Alternate name
Molecular weight
Specific gravity
Form at room temperature
Melting point
Boiling point
Solubility
water
alcohol
ether
benzene
Vapor pressure
GAS number
Odor threshold in
water-30°G
m-chiorophenol
128.56
1.260
needles
325G
2145C
slightly soluble
soluble
soluble
very soluble
1 mm Hg at 44.2 C
000108430
0.2 ^jg/1 (Hoak, 1957)
p-chlorophenol
128.56
1.306
needles
41°C
2175G
very slightly soluble
very soluble
very soluble
very soluble
1 mm Hg at 49.8 C
000106489
0.03 pg/1 (Hoak> 1957)
-------
100 ug/1. Complex phenols are at least partially released
by bacterial action in sewage treatment trickling filters.
The decomposition of surface vegetation such as oak leaves
also releases phenol.
, , ' • i
The association of bad taste or odor in tap water with
chlorophenols has been of interest for a number of years.
Hoak (1957) reviewed aspects.of this problem. Some chloro-
phenols have odor thresholds in the ppb concentration range.
The addition of 0.2-0.7 ppm chlorine to water containing
100 ppo phenol results in the development of a chlorophenol
taste. Increasing the level of chlorine or increasing the
reaction time reduces the taste. Odor thresholds for chloro-
phenols in water are shown in Table 2. The thresholds for
mono- and dichlorophenol are very low.
The threshold concentrations of the monochlorophenols in
water that impart an offensive flavor to the edible portion of
the flesh of aquatic organisms have been reported. A summary
of the data is presented in Table 2a.
Burttschell, et al. (1959) proposed a mechanism for
the chlorination of phenol in water. According to their
scheme 2- and 4-chlorophenol are formed early. These mole-
cules are further chlorinated to 2,6- or 2,4-dichlorophenol.
The final product is 2,4,6-trichlorophenol. After 18 hours
of reaction, the chlorophenol products in Burttschell's study
consisted of less than 5 percent each 2- and 4-chlorophenol,
25 percent 2,6-dichlorophenol, 20 percent 2,4-dichlorophenol
and 40 to 50 percent 2,4,6-trichlorophenol.
C-3
-------
TABLE 2
Comparison of Odor Thresholds 'for Chlorophenols in Water
Threshold-ppb
-------
TABLE 2 a
SUMMARY OF THRESHOLD CONCENTRATIONS OF CHLORINATED PHENOLS
IN WATER THAT CAUSE TAINTING OF THE FLESH OF AQUATIC ORGANISMS
Compound Threshold(ug/1) Reference _f/
2-chlorophenol 15.0 5
15.0 6
3-chlorophenol 60.0 5
4-chlorophenol 60.0 5
50.0 6
5.-0 6
10.0 7
a) 5 - Schulze, E. 1961. The effect of phenol-containing waste on
the taste of fish. Int. Revue Ges. Hydrobiol. 46, No. 1,
p. 81
6 - Teal, J. L. 1959. The control of waste through fish taste.
Presented to American Chemical Society, National Meeting.
7 - Shuriway, D. L. 1966. Effect of effluents on flavor of salmon.
Dept. Fisheries and Wildlife. Agri. Exper. Sta. Oregon State U.
C-
-------
Ingestion from Water
Burttschell, et al. (1959) demonstrated that the chlori-
nation of water containing phenol 'could result in the forma-
tion of chlorophenols including mono-, di-, and trichlorophenol
isomers. Piet and De Grunt (1975) found monochlorophenols
in surface waters in the Netherlands at concentrations of
2 to 20 )ig/l (ppb). A level of 20 ug/1 in water, consumed
at a rate of 2 I/day by a 70 kg individual, would result
in an exposure of 0.57 pg/kg.
Another source of chlorophenols in water is the chlorina-
tion of sewage. Jolley, et al. (1975) analyzed chlorinated
sewage treatment plant effluents and found 0.5^ag/l of 3-
chlorophenol and 0.7 >ig/l of 4-chlorophenolo Ingols, et
al. (1966) studied the biological degradation of chlorophenols
in activated sludge. Both 3- and 4-chlorophenol at levels
of 100 mg/1 were completely degraded in three days with
100 percent ring degradation.
Alexander and Aleem (1S61) studied the microbial decompo-
sition of chlorophenols in soil suspensions. 3-Chlorophenol
did not disappear completely in 47 or 72 days when tested
with two soil.types. 4-Chlorophenol disappeared in three
or nine days in the two soil types.
The ingestion of chlorobenzene may also give rise to
an internal metabolic exposure to chlorophenol. The mammalian
metabolism of chlorobenzene yields 2-, 3-, and 4-chlorophenol
as the major products (Lindsay-Smith, et al. 1972).
C-5
-------
Ingestion from Foods
No data were found demonstrating the presence of mono-
chlorophenols in food.
A bioconcentration factor (BCF) relates the concentration
of a chemical in water to the concentration in aquatic organisms/
but BCF's are not available for the edible portions of all
four major groups of aquatic organisms consumed in the United
States. Since data indicate that the BCF for lipid-soluble
compounds is proportional to percent lipids, BCF's can be
adjusted to edible portions using data on percent lipids
and the amounts of various species consumed by Americans.
A recent survey on fish and shellfish consumption in the
United States (Cordle, et al. 1978) found that the per capita
consumption is 18.7 g/day. From the data on the nineteen
major species identified in the survey and data on the fat
content of the edible portion of these species (Sidwell,
et al. 1974) , the relative consumption of the four major
groups and weighted average percent lipids for each group
can be calculated;
Consumption Weighted Average
Group (Percent) Percent Lipids
Freshwater fishes 12 4 4.8
Saltwater fishes 61 2.3
Saltwater molluscs 9 1.2
Saltwater decapods 18 1.2
Using the percentages for consumption and lipids for each
of these groups, the weighted average percent lipids is
2.3 for consumed fish and shellfish.
C-6
-------
No measured steady-state bioconcentration factor (BCF)
is available for 4-chlorophenol/ but the equation "Log BCF
=0.76 Log P - 0.23" can be used (Veith, et al. Manuscript)
to estimate the BCF for aquatic organisms that contain about
eight percent lipids from the octanol-water partition coef-
ficient (P). An adjustment factor of 2.3/8.0 = 0.2875 can
be used to adjust the estimated BCF from the 8.0 percent
lipids on which the equation is based to the 2.3 percent
lipids that is the weighted average for consumed fish and
shellfish. Thus, the weighted average bioconcentration
factor for the edible portion of all aquatic organisms consumed
by Americans can be calculated.
Compound P BCF Weighted BCF
4-chlorophenol 260 40 12
Inhalation
No data were found regarding the presence of monochloro-
phenols in air.
Dermal
Roberts, et al. (1977) used human autopsy skin epidermal
membranes in an in vitro test system to determine the permea-
bility of the human skin to various chemicals. 4-Chlorophenol
was shown to permeate the skin, and to produce damage at
a threshold concentration of 0.75 percent (w/v).
C-7
-------
PHARMACQKINETICS
No systematic studies of the pharmacokinetics of 3-
or 4-chlorophenol in man or laboratory animals were found.
However, Karpow.1 (1893) reported that 87 percent of 4-chloro*
phenol was excreted in urine of dogs as sulfuric and glucuronie
conjugates.
EFFECTS
Acute, Sub-acute, and Chronic Toxicity
M
The acute oral, subcutaneous, dermal, intraperitoneal,
and inhalation LDSO's for 3- and 4-chlorophenol are shown
i
in Table 3. Because 3-chlorophenol is a liquid at room
temperature, some of the early workers reported LDSO's as
ml/kg. The oral LD50 for each isomer is on the order of
500 to 600 mg/kg. The dermal LD50 for 4-chlorophenol is
1,500 mg/kg, indicating dermal absorption. Interestingly,
both 3- and 4- chlorophenol are less toxic when given subcu-
taneously than when taken orally. This may reflect a slower
absorption from the injection site and a rapid metabolism
of the absorbed compounds.
4-Chlorophenbl applied dermally causes skin irritation
and necrosis in rabbits, rats, and guinea pigs. Dermal
exposure can result in convulsive seizures (Gurova, 1964).
Cats survived four doses of 40 mg/kg of 4-chlorophenol
administered intraperitoneally at three-hour intervals (Miller,
et al. 1973) .
The monochlorophtrnols act on the nervous system to
produce tremors and convulsions, an effect reported several
times in the literature. The monochlorophenols with a pKa
C-8
-------
TABLE 3
Acute Toxicity of Monochlorophenols
CHEMICAL
SOLVENT
SPECIES
3-chlorophenol
4-chlorophenol
n
i
vo
olive oil
olive oil
olive oil
not stated
olive oil
not stated
olive oil
not stated
olive oil
rat
rat
rat
rat
rat
mouse
rat
rat
rat
mouse
TOXIC RESPONSE
oral LD50 =0.56 ml/kg
subQ LD50 =1.39 ml/kg
i.p. LD50 = 335 rag/kg
oral LD50 = 500 mg/kg
oral LD50 = 660 mg/kg
oral LD50 = 860 mg/kg
subQ LD50 = 1030 mg/kg
dermal LD50 = 1500 mg/kg
i.p. LD50 = 250 mg/kg
inhalation LD50 11 mg/m
REFERENCE
Deichmann and Mergard, 1948
Deichmann and Mergard, 1948
Farquharson, et al. 1958
Gurova, 1964
Deichmann and Mergard, 1948
Schrotter, -et al. 1977
Deichmann and Mergard, 1948
Gurova, 1964
Farquharson, et al. 1958
Gurova, 1964
-------
of 8 or greater are convulsants. At body pH (7.0 to 7.4),
these chlorophenols are largely undissociated.
Binet' (18S6) repotted that subcutaneous injections
of raonochlorophenols in rats and guinea pigs caused muscle
twitching,- spasms, generalized tremors, weakness, staggering,
and finally collapse. Kuroda (1926) found that intravenous
doses of 100 mg/kg of any of the three moficchlorophenol
isomers caused convulsions in rabbits.
In acutely toxic doses 3-chlorophenoi causes restlessness
and increased respiration followed by rapidly developing
motor weakness (Dtsichnu-um, 1943) . Clonic convulsive seizures
follow and continue until death. Th® clinical signs are
similar with 4^ehloroph«gne>l but che convulsions are more
severe.
Farquharson, &t al, {1958} £ilso repcrted tiuac 2-, 3-,
or 4-chloropntir:ol ptoduced convulsive seizures In rats.
j
' /"*•
Body temperature was reduced 2 to 5"*C, and rigor mortizs
did not develop-within five minutes: of drath as with t«ri-,
tetra-y and pentaehlorophenol* IDfeath occcccyc! one hour
after dosing in rats given the LD50. Ac higher doses, deaths
i>
occurred iti five to fifreer: minutes. Th^rt? wejce nc further
j
deaths in rats surviving three- hosjrs- Convulsionij occurred
as soon as one to two min-CESS £cliov>ing iritrap^ritonfcel
injection. 4-Chloropherici anc i-chlo^opherjC?! £lsa stimulated
oxygen uptake by r^t brain Uoiuegfeii&t^1" at -r^uc&ntraticns
between 2*5 s 19'"° a^d I a Itt"^:,
-------
Angel and Rogers (1972) used urethane-anesthetized
mice to determine the CD50, i.e., the intraperitoneal dose
required to produce convulsions in 50 percent of the test
animals. The CDSO's were 100.6 mg/kg for 3-chlorophenol
and 115.7 mg/kg for 4-chlorophenol. Both of these monochloro-
phenols have approximately 1.2 times the convulsant potency
of phenol. These CD50 values are approximately one-half
to one-third of the intraperitoneal LD50.
Hanig, et al. (1976) demonstrated that hexachlorophene
elevacec* the cerebrospinal fluid pressure in the rat and
cat; 4-chlorophenol did not.
Gurova (1964) conducted inhalation studies of 4-chloro-
phenol using mice and rats. The inhalation LD50 for mice
was 11 mg/m , with the duration of exposure not reported.
Single inhalations of 20 mg/m for an unknown duration did
not produce acute poisoning in rats. Rats exposed to 13
mg/m for two hours showed increased neuromuscular excitability
based on response to peripheral nerve electrical stimulation.
These animals also experienced increased oxygen consumption.
Mice were more sensitive since 2 mg/m increased their oxygen
consumption.
Rats exposed 6 hrs/day for four months to 2 mg/m showed
a weight loss during the first 30 days followed by an increased
weight gain. These animals also showed an increased myoneural
excitability. Body temperature, hemoglobin, RBC, WBC, and
sedimentation rate were not altered.
Lesions in inhalation-exposed and inhalation-poisoned
animals were described by Gurova (1964). Congestion and
C-ll
-------
fo.es! hemorrhages were observed in brain, lungs* live>r,
^ idraey, and myocardium,, Lung pathology consisted of thickened
alveolar septa„ atelectasis, and emphysema. Degenerative
changes occurred in brain cortical and glia cells and in
liver and myocardium.
Banna and Jabbur (1970) studied the effects of phenols
on nerve synaptic transmission in cats. Phenol, like the
raoEiochlorophenols, is a convulsant. The mechanism of action
apparently involves an increase in the amount of neurotrans-
mitter released at the nerve synapse.
In terms of mechanism of action studies most efforts
have been directed toward effects on oxidative phosphorylation
and enzymes involved in carbohydrate and intermediary metabo-
lism and ATP.
Parker (1958) studied the effect of chlorophenols on
isolated rat liver mitochondria metabolism. 2,4-Dinitrophenol
was used as a reference compound because of its known ability
to uncouple oxidative phosphorylation, 4-Chlorophenol at
2,8 ; 10~4M had 21 percent of the activity of 2 x 10~5M
of 2,4-dinitrophenol.
Mitsuda, et al. (1963) studied the effects of various
chlorophenols on oxidative phosphorylation in isolated rat
liver mitochondria. The test system used a 2.75 ml reaction
medium at pH 7.0, containing 0.05 ml of mitochondrial suspen-
sion with 0.43 mg N. The 1D50 (concentration of chlorophenol
required to produce a 50 percent inhibition in the produc-
tion of ATP) was determined. The I5Q values for the mono-
chlorophenols were 520 uM, 150 jiM, and 180 JIM for 2-, 3-,
C-12
-------
and 4-chlorophenol, respectively. For comparison, the ICQ'S
for pentachlorophenol and 2,4-dinitrophenol are 1 juM and
17 jiM, respectively.
Weinbach and Garbus (1965) tested the ability of various
substituted phenols to completely uncouple oxidative phos-
phorylation iii vitro. 3-Chlorophenol and 4-chlorophenol
caused complete uncoupling at 2.5 mM. For comparison, the
known uncoupler 2,4-dinitrophenol completely uncoupled the
test system at 0.1 mM. There was a positive relationship
between mitochondria protein binding and uncoupling properties.
During the past years one research group has developed
a novel approach to studying the potential effects of chemicals
on the eye. Ismail, et al. (1976) studied the permeation
of a number of chemicals, including 2-chlorophenol into
the bovine lens capsule and examined the subsequent effects
on lens enzymes. Their hypothesis was that environmental
chemicals may be responsible for eye diseases or lens opacities,
3,4-Dichlorophenol was found to rapidly permeate the lens
capsule. Using a concentration of 10~ M (16 mg/1) of 3,4-
dichlorophenol, the activity of various enzymes in the bovine
lenses was compared with control lenses. No statistical
analysis was reported; the results are presented in Table
4. For comparison the activity of 2-chlorophenol, the only
other chlorophenol tested, is presented. The response pattern
is complex and difficult to interpret in the absence of
statistical analysis.
C-13
-------
E 4
Effect3 of Chlorophenols on Enzyme Activities of Isolated
Bovine Lenses. (Ismail, et al. 1976)
Enzyme 2-chlorophenol 3,4-dichlorophenol
Lactic dehydrogenase
Malate dehydrogenase
Sorbitol dehydrogenase
Glucose-6-phosphate dehydrogenase
Fructose-diphosphate aldolase
Pyruvate kinase
Glutamate-oxalacetate-transaminase
Flutamate-pyruvate-transaminase
94.0
64.4
91.9
129.9
80.4
f\ *> A''
92.9
92.7
142.9
85.5
86.3
107.3
70.0
85.7
99.0
111 . 9
92.9
wThe effect is expressed as percent of control.
Each chemical was tested at 10 M.
Korte, et al. (1976) have used the isolated bovine
lens system to study the metabolic effects of various chemi-
cals on this part of the eye. One lens .is used as a control
and the other as the experimental. 4-Chlorophenol at 10~"3M
reduced ATP, glucose-6-phosphate, glucose and fructose levels
after a 48-hour incubation. 3-Chlorophenol reduced levels
of fructose, ATP and ADP, and increased AMP levels. Korte,
et al. (1976) did not find changes in the following dehydroge-
nases: lactate, malate, sorbital, glucose-6-phosphate or
in fructose 1,6-diphosphate aldolase or pyruvate kinase.
Harrison and Madonia (1971) pointed out that 4-chloro-
phenol has been used since the nineteenth century at a concen-
tration of 35 percent in camphor for endodontic therapy
in dentistry. They conducted ocular and dermal toxicity
tests with one or two percent aqueous solutions of 4-chloro-
phenol and 35 percent camphorated 4-chlorophenol. The one
percent aqueous solution caused slight hyperemia when 0.15
C-14
-------
ml was placed on the cornea of white rabbits. A two percent
aqueous solution (0.15 ml) produced a more severe response,
characterized by moderate to severe hyperemia, mild to moderate
edema, cloudy'cornea and exudation. The 35 percent camphorated
4-chlorophenol produced a severe response. The changes
induced by the one percent and two percent aqueous solutions
became evident after five minutes, were most intense after
five hours, and subsided by 96 hours post-administration.
Harrison and Madonia also injected 0.1 ml of each solution
intraderrnally in rabbits. The one and two percent aqueous
parachlorophenol solutions produced mild inflammation after
24 and 72 hours. The 35 percent camphorated 4-chlorophenol
caused a severe inflammatory response including necrosis.
The authors concluded that one percent aqueous parachlorophenol
was a better choice for an antimicrobial intracanal medication.
Gurova (1964) reported the effects of 4-chlorophenol
in industrial workers in an aniline dye plant in Russia.
Air levels ranged from 0.3 to 21 mg/m depending on the
work site and operation. Two accidental acute poisonings
were reported with clinical signs consisting of headache,
dizziness, respiratory disorder, vomiting, loss of coordina-
tion, tremor and, in one case, liver enlargement. Other
workers not acutely affected reported experiencing headache,
dizziness, weakness, nausea, vomiting and paresthesia (abnormal
spontaneous sensation). A health survey was done comparing
workers exposed to 4-chlorophenol with unexposed workers
in the same plant. The 4-chlorophenol workers had a signifi-
cantly higher incidence of neurologic disorders. Symptoms
C-15
-------
reported included neurasthenia (nervous exhaustion) g insomnia,,
r.rritability, frequent mood changes and rapid fatigability.
Peripheral nerve stimulation studies showed increased myoneural
excitability in exposed workers. A decreased response to
a two-point touch discrimination was apparent, in that the
minimum detection distance between the points was increased.,
Changes in the capillaries of the nail fold of the fingers
were said to occur, but were not described. An average
permissible air concentration of 3 mg/m was reported for
industrial workers.
Synergism and Antagonism
No information was found describing synergistic or
antagonistic effects associated with 3- or 4-chlorophenol.
Teratogenicity
No information was found regarding the presence or
absence of teratogenic properties of 3- or 4-chlorophenol.
Mutagenicity
No information was found regarding the presence or
abs mce of mutagenic properties of 3- or 4-chlorophenol„
Carcinogenicity
No adequate information was found to determine whether
or not. 3- or 4-chlorophenol possess carcinogenic properties.
Boutwell and Bosch (1959) conducted a series of experi-
ments on the tumor promoting action of substituted phenols
•^sing repeated applications of concentrated solutions to
the backs of mice. A 20 percent solution of 3-chlorophenol
in benzene increased the number of papillomas, but no carci-
nomas were found after 15 weeks (Table 5). The tumor initiator
C-16
-------
DMBA (9,10-dimethyl-l,2-benzanthracene) was used. Papillomas
occurred at the application site.
TABLE 5
Papilloma Promoting Action of 3-Chlorophenola.
(Boutwell and Bosch, 1959)
Group
Number of mice
(survivors/original)
Average number of
papillomas per survivor
Percent survivors with
papillomas
Percent survivors
with carcinomas
Control
15/20
0.07
7
0
3-chlorophenol (20%)
21/33
1.38
67
0
Promoter applied twice weekly. Initiator 0.3% DMBA in benzene.
Promoter in benzene.
C-17
-------
CRITERION FORMULATION
The information of this section is presented in a composite
treatment of the chlorophenols at :the end of .the document. 4
C-18
-------
REFERENCES
Alexander, XM., and M.I.H. Aleem. 1961. Effect of chemical
structure on microbial decomposition of aromatic herbicides.
Jour. Agric. Food Chem. 9: 44.
Angel, A., and K.J. Rogers. 1972. An analysis of the convul-
sant activity of substituted benzenes in the mouse. Toxicol.
Appl. Pharmacol. 21: 214.
Banna, N.R., and S.J. Jabbur. 1970. Increased transmitter
release induced by convulsant phenols. Brain Res. 20: 471.
Binet, P. 1896. Comparative toxicity of phenols. Rev.
med. Suisse rom. 16: 449. Cited by W.F. von Oettingen, 1949,
Boutwell, R.K., and D.K. Bosch. 1959. The tumor-promoting
action of phenol and related compounds for mouse skin.
Cancer Res. 19: 413.
Burttschell, R.H., et al. 1959. Chlorine derivatives of
phenol causing taste and odor. Jour. Am. Water Works Assoc.
51: 205.
Campbell, C.L., et al. 1958. Effect of certain chemicals
in water on the flavor of brewed coffee. Food Res. 23: 575.
Cordle, F., et al. 1978. Human exposure to polychlorinated
biphenyls and polybrominated biphenyls. Environ. Health
Perspect. 24: 157.
C-19
-------
Deichmann, W.B. 1943. The toxicity of chlorophenols for
rats. Fed. Proc. 2: 76.
Deichmann, W.B., and E.G. Mergard. 1948. Comparative evalua-
tion of methods employed to express the degree of toxicity
of a compound. Jour. Ind. Hyg. Toxicol. 30: 373.
' • ' '. '
Farquharson, M.E., et al. 1958. The biological action
of chlorophenols. Br. Jour. Pharmacol. 13: 20.
Gurova, A.I. 1964. Hygienic characteristics of p-chlorophenol
in the aniline dye industry. Hyg. Sanita. 29: 46.
Hanig, J.P., et al. 1976. Toxicity and effects upon rat
cerebrospinal fluid pressure of hexachlorophene analogs.
Toxicol. Appl. Pharmacol. 37: 186.
Harrison, J.W., and J.V. Madonia. 1971. The toxicity of
parachlorophenols. Oral Surgery 32: 90.
Hoak, R.D. 1957. The causes of tastes and odors in drinking
water. Purdue Eng. Exten. Service. 41: 229.
Ingols, R.S., et al. 1966. Biological activity of halophenols,
Jour. Water Pollut. 38: 629.
s.
Ismail, R., et si. 1976. Environmental chemical permeation
of bovine Ocular lens capsule. Cheraosphere 2: 145..
C-20
-------
Jolley, R.L., et al. 1975. Analysis of soluble organic
constituents in natural and process waters by high-pressure
liquid chromatography. Trace Subst. Environ. Hlth. 9: 247.
-. i i .1.
Karpow, G. 1893. On the antiseptic action of three isomer
chlorophenols and of their salicylate esters and their fate
in the metabolism. Arch. Sci» Bid. St. Petersburg. 2:
304. Cited by W.F. von Oettingen, 1949.
Korte, I., et al. 1976. Studies on the influences of some
environmental chemicals and their metabolites on the content
of free adenine nucleotides, intermediates of glycolysis
and on the activities of certain enzymes of bovine lenses
ir\ vitro. Chemosphere 5: 131.
Kuroda, T., et al. 1926. Comparative studies on the action
of o-, m-, and p-chlorophenol. Arch. Exp. Path. Pharmakol.
112: 60. (as cited by W.F. von Oettingen, 1949).
Lindsay-Smith, Jr., et'al. 1972. Mechanisms of mammalian
hydroxylation: Some novel metabolites of chlorobenzene.
Xenobiotica 2: 215.
Miller, J.J., et al. 1973. The metabolism and toxicity
of phenols in cats. Biochem. Soc. Trans. 1: 1163.
Mitsuda, H., et al. 1963. Effect of chlorophenol analogues
on the oxidative phosphorylatioh in rat liver mitochondria.
Agric. Biol. Chem. 27: 366.
C-21
-------
Parker, V.H. 1958» Effect of nitrophenols and halogenophenols
on the enzymic activity of rat-liver mitochondria. Biochem.
J?ur. 69: 306.
Piet, G.J., and F. De Grunt. 1975. Organic chloro compounds
in surface and drinking water of the Netherlands. Pages
81-92 Iri Problems raised by the contamination of man and
his environment. Comm. Eur. Communities, Luxembourg.
Roberts, M.S., et al» 1977. Permeability of human epidermis
to phenolic compounds. Jour. Pharm. Pharmacol. 29s 677.
Schrotter, E., et al. 1977. Organische syntehtica und
ihre vermizden eigenschaften. Pharmazie 32s 171.
Sidwell, V.D., et al. 1974. Composition of the edible portion
of raw (fresh or frozen) crustaceans, finfish, and mollusks.
I. Protein, fat, moisture, ash, carbohydrate, energy value,
and cholesterol. Mar. Fish. Rev* 36: 21.
Veitn, G.D., et al. An evaluation of using partition coef-
ficients and water solubility to estimate bioconcentration
factors for organic chemicals in fish» (Manuscript)„
von Oettingen, W.F. 1949. Phenol and its derivatives:
the relation beti^een their chemical constitution and their
effect on the organism. National Inst. Health Bull. 190s
193.
C-22
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Weinbach, E.G., and J. Garbus. 1965. The interaction of
uncoupling phenols with mitochondria and with mitochondrial
protein. Jour. Biol. Chera. 210: 1811.
C-23
-------
< 2,5-DICHLOROPHENOL, 2,6-DICHLOROPHENOL,
3,4-DICHLOROPHENOL AND 3,5-DICHLOROPHENOL
Mammalian Toxicology and Human Health Effects
*
SUMMARY
There are several isomers of dichlorophenol. The most
common is 2,4-dichlorophenol, which is reviewed in another
document in this series. The remaining dichlorophenol iso-
mers apparently have not found use as primary chemicals.
The following isomers are discussed in this document: 2,5-,
2,6-, 2,3-, 4,6- and 3,4-dichlorophenol. Physiochemical
properties of these compounds are listed in Table 1. The
dichlorophenols can be formed either as intermediates in
the chlorination of phenol to higher chlorophenols, or as
degradation products. A limited amount of work has been
reported on dichlorophenols other than the 2,4-isomer.
C-24
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Property
TABLE 1
Physiochemical Properties3
Dichlorophenol Isomer
Molecular weight
Formula
Melting point °C
Boiling point C
Density
Solubility
water
alcohol
ether
acetone
benzene
Vapor pressure-nun Hg
(pressure/ C)
CAS number*
2/5-
163
C6H4C120
59
211
—
slightly
very
very
-
soluble
—
N.L.
2,6-
163
C6H4C120
68-9
219
—
-
very
very
-
soluble
1mm, 59°
N.L.
3.4-
163
C6H4C120
68
253
—
slightly
very
very
-
soluble
—
N.D.
3.5-
163
C6H4C120
68
233
—
slightly
very
very
-
—
—
N.L.
*N.L. not listed in toxic substance list
N.D. listed in toxic substances list, but no CAS registery number
given
Source: Handbook of Chemistry and Physics/ 59th Edition/ R.C.
Weast/ Editor/ CRC Press/ 1978.
C-25
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Phenols are known to occur naturally in the environment (Hoak,
1957). For example, some aquatic plants release sufficient phenol
to establish water levels of 300-960 ug/1. Phenols are found in
raw domestic sewage at levels of 70-100 ug/1. Complex phenols are
at least partially released by bacterial action in sewage treatment.
trickling filters. The decomposition of surface vegetation such
as oak leaves also releases phenol.
The association of bad taste or odor in tap water with chloro-
phenols has been of interest for a, number of years. Hoak (1957)
reviewed aspects of this problem. Some chlorophenols have odor
thresholds in the ppb concentration range. The addition of 0.2-0.7
ppm chlorine to water containing 100 ppb phenol results in the
development of a chlorophenol taste. Increasing the level of chlorine
or increasing the reaction time reduces the taste. Odor thresholds
for chlorophenols in water are shown in Table 2. The thresholds
for mono- and dichlorophenol are very low.
The threshold concentration of 2,4-dichlorophenol in water
that imparts an unfavorable odor to the flesh of aquatic organisms
is presented in Table 2a. In this instance the reported odor
threshold level of this compound in water is lower than the tainting
threshold level.
Burttschell, et al. (1959) proposed a mechanism for the chlor-
ination of phenol in water. According to their scheme 2- and
4-chlorophenol are formed early. These molecules are further
chlorinated to 2,6- or 2,4-dichlorophenol. The final product is
2,4,6-trichlorophenol. After 18 hours of reaction, the chlorophenol
products in Burttschell's study consisted of less than 5 percent
each 2- and 4-chlorophenol, 25 percent 2,6-dichlorophenol, 20 percent
2,4-dichlorophonol and 40 to 50 percent 2,4,6-trichlorophenol.
C-26
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TABLE 2
Comparison of Odor Thresholds for Chlorophenols in Water.
2-chlorophenol
3-chlorophenol
4-chlorophenol
2,4-dichlorophenol
2,5-dichlorophenol
2,6-dichlorophenol
2,4,5-tr ichlorophenol
2,4,6-tr ichlorophenol
2,3,4,6-tetrachlorophenol
Threshold-ppb (pg/1.) Reference'
0.33 ppb - 3<)
2 ppb - 25°
6 ppb - NS
p
o
!b
200 ppb
33 ppb
250 ppb
900 - 1350 ppb
- 30°C
- 30°C
- 25°C
0.65 ppb - 30°C
2 ppb - 25°C
3.3 ppb - 30°C
3 ppb
11 ppb
- 25°C
- 25°C
- 30°C
100 ppb
1000 ppb - 25°C
915 ppb
- 30°C
1
2
3
1
2
3
1
2
1
2
1
1
2
a) 1 - Hoak, 1957
2 - Burttschell, et al., 1959
3 - Campbell, et al., 1958
b) NS - temperature not specified
G-27
y
-------
TABLE 2 a
SUMMARY OF THRESHOLD CONCENTRATIONS OF CHLORINATED PHENOLS
IN WATER THAT CAUSE TAINTINX5 OF THE FLESH OF AQUATIC ORGANISMS
Compound Threshold(ug/1) Reference
2-chlorophenol 15.0 5
15.0 6
3-chlorophenol 60.0 5
4-chlorophenol 60.0 5
50.0 6
2,-l-dicblsrcchanol 5-0 6
10.0 7
a) 5 — Schulze, E. 1961. The effect of phenol-containing waste on
the taste of fish. Int. Revue Ges. Hydrobiol. 46, No. I,
p. 81
6.- Teal, J. L. 1959. The control of waste through fish taste.
Presented to American Chemical Society, National Meeting.
7 - Shumway, D. L. 1966. Effect of effluents on flavor of salmon.
Dept. Fisheries and Wildlife. Agri. Exper. Sta. Oregon State U.
-------
EXPOSURE
Introduction
There are no quantitative data available to indicate
that humans are exposed to the dichlorophenols under discus-
sion. This section will briefly review existing reports
regarding potential exposure to dichlorophenols.
C-28
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Ingestion from Water
Piet and DeGrunt (1975) found unspecified dichlorophenol
isomers in Dutch surface waters in concentrations of 0.OI-
LS pg/1. Burttschell, et al. (1959) demonstrated that the
chlorination of phenol-laden water could result in the forma-
tion of mono-, di-, and trichlorophenol isomers.
Ingols, et al. (1966) studied the biological degrada-
tion of chlorbphenols in activated sludge. 2,5-Dichloro-
phenoi was more resistent to degradation than 2,4-dichloro-
phenol. While 2,4-dichlorophenol was 100 percent
degraded, including ring degradation, in five days/ 2,5-
dichlorophenol was only 52 percent ring degraded in four
days.
Crosby and Wong (1973) reported that the photodecompo-
sition of the herbicide 2,4,5-T results in the formation
of small amounts of 2,5-dichlorophenol.
Alexander and Aleem (1961) determined the midrobial
decomposition of 2,5-dichlorophenol in a Dunkirk soil suspen-
sion. Disappearance was not complete at the end of 72
days.
Ingestion from Foods
No data were available regarding exposure via ingestion
of dichlorophenols from foods.
Inhalation
Olie, et al. (1977) reported finding di-, tri- and
tetrachlorphenols in flue gas condensates from municipal
incinerators. The levels were not quantified.
Dermal
No data were available.
C-29
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PHARMACQK INE.TI.C S
Phaenraco kinetic-1 data specific fco. these diiefttEarophe-no!
isomers were not available. It is reasonable to assume
that dicrilorophenol isomers are absorbed through the skin
and. -from the gut, and rapidly eliminated, from the body,
as are other chlorophenols.
Metabolism
Dichlorobenzenes are metabolized by mammals to dichiQEo-
phenols (Kohli, et al. 1976). For example, 1,2-dichloro-
benzene gives rise to 3,4-dichlorophenol. and smaller amounts
of 2,3-dichlorophenol, 3,4- and 4,5-dichlorophenol and 3,4-
dichlorophenylmercapturic acid.
Foster and Saha (1978) reported that chicken liver
homogenates would metabolize lindane and the alpha and delta
but not the beta isomers of 1,2,3,4,5,6, hexachlorocyclo-
hexane. jThe metabolic products included 2,4,6-trichloro-
phenol, 2,3-dichlorophenol as well as di- and trichlorobenzenes.
EFFECTS
Acute, Sub-acute, and Chronic Toxicity
Farquharson, et al. (1958) reported that 2,6-dichloro-
phenol produced convulsions in rats. The intraperitoneal
LD50 was 390 mg/kg. Rats given the LD50 died in one hour?
deaths did not occur later in rats surviving three hours.
Body temperature was depressed 0.7°C, and rigor mortis did
not occur within five minutes of death as it does with higher
chlorinated phenols. Oxygen consumption by rat brain homo-
genate was stimul&tsd at concentrations between 2.5 x 10
and 1 x ItT3 M»
Banna and Jdbbur (1970) studied the effects of phenols,
but not chlojLophsnols directly? on nerve synaptic transmis-
~C-30
-------
sion in cats. Phenol is a convulsant, as are the lower
chlorinated phenols. Experimental results suggest that
the mechanism of action involves an increase in the amount
of neurotransmitter released at the new synapse.
Hanig, et al. (1976) demonstrated that hexachlorophene,
but not 4,6-dichlorophenol, elevated the cerebrospinal fluid
pressure in rat and cat.
The mechanism of action studies reported have primarily
focused on effects on oxidative phosphorylation. Korte,
et al. (1976) studied the effect of 3,4-dichlorophenol on
carbohydrate metabolism and enzyme activity in the incubated
bovine lens. At a concentration of 10 M, 3,4-dichloro-
phenol decreased ATP and ADP levels while increasing AMP
levels. There was no effect on glucose or fructose-6-phos-
phate levels. Activities of malate dehydrogenase, glucose-
6-phosphate dehydrogenase and pyruvate kinase were reduced.
The dichlorophenol caused swelling of the lens.
Ismail, et al. (1976) studied the permeation of chem-
icals into the bovine lens capsule and the affects on lens
enzymes. Their hypothesis is that environmental chemicals
may be responsible for eye diseases or lens opacities.
3,4-Dichlorophenol was found to permeate the lens capsule
—4
rapidly. Using a concentration of 10 M (16 mg/L) of 3,4-
dichlorophenol, the activity of various enzymes in the bovine
lenses was compared with control lenses. Since no statistical
analysis was reported, the results are presented in Table
3. For comparison, data on the activity of 2-chlorophenol,
the only other chlorophenol tested, are presented. The
response pattern is complex and difficult to interpret in
the absence of statistical analysis.
C-31
-------
Effect3 of Chlorophenois on Enzyme Activities of
Isolated Bovine Lenses. {Ismail, et al. 1976)
Enzyme 2-chlorQphenol 3,4-dichloropheaol
Lactic dehydrogenase
Ma late dehydrogenase
Sorbitol dehydrogenase
Glucose-6-phosphate dehydrogenase
Fructose-diphosphate aldolase
Pyruvate kinase
Glutamate-oxalacetate-transaminase
Glutamate-pyruvate-transaminase
94.0
64.4
91.9
129.9
80 . 4
92.9
92.7
142.9
8.5 ,.5
86.3
107.3
70.0
85.7
99.0
111,9
9:2.9
?The effect is expressed as percent of control.
Each chemical was tested at 10~ M.
Synergism and/or Antagonism
No information was found describing synergistic or
antagonistic effects associated with the dichlorophenols.
Teratogenicity
No reports were found relating to the presence or absence
of teratogenic properties of the dichlorophenol isomers
covered in this document.
Mutagenicity
Rasanen and Hattula (1977) tested chlorophenols for
mutagenicity using the Salmonella-mammalian microsome Ames
test with both the non-activated and liver homogenate added
systems. The following dichlorophenol isomers were tested
and reported as non-mutagenic in both test systems: 2,3-,
2,4-, 2,5-, 2,6-, 3,4- and 3,5-dichlorophenol. Mutageni-
city in mammalian test systems has not been evaluated,
Carcinogenicity
No reports were found in which the carcinogenic proper-
ties of the dichlorophenol isomers covered in this document
were determined.
C-32
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CRITERION FORMULATION
The information of this section is presented in a composite
treatment of the chlorophenols at the end of the document.
C-33
-------
REFERENCES
Alexander, M., and M.I.H. Aleem. 1961. Effect of chemical
structure on microbial .decomposition of aromatic herbicides.
Jour. Agric. Food Chem. 9s 44.
Banna, N.R., and S.J. Jabbur, 1970. Increased transmitter
release induced by convulsant phenols. Brain Res. 20: 471.
Burttschell, R.H., et al. 1959. Chlorine derivatives of
phenol causing taste and odor. Jour. Am. Water Works Assoc. 51: 205,
Campbell, C.L., et al. 1958. Effect of certain chemicals
in water on the flavor of brewed coffee. Food Res. 23: 575.
Crosby, D.G., and A.S. Wong. 1973. Photodecomposition of
2,4,5-Trichlorophenoxyacetic acid (2,4,5-T) in water. Jour.
Agric. Food Chem. 21: 1052.
Farquharson, M.E., et al, 1958. The biological action of
chlorophenols. Br. Jour. Pharmacol. 13s 20.
Foster, T.S., and J.G. Saha. 1978. The i.n vitro metabolism
of lindane by an enzyme preparation from chicken liver.
Jour. Environ. Sci. Health 13: 25.
Hanig, J.p., et al. 1976. Toxicity and effects upon rat
cerebrospinal fluid pressure of hexachlorophene analogs.
Toxicol. Appl. Pharmacol. 37: 186.
C-34
-------
Hoak, R.D. 1957. The causes of tastes and odors in drinking
water. Purdue Eng. Exten. Service. 41: 229.
Ingols, R.S., et al. 1966. Biological activity of halophenols.
Jour. Water Pollut. 38: 629.
Ismail, R., et al. 1976. Environmental chemical permeation
of bovine ocular lens capsule. Chemosphere 2: 145.
Kohli, J., et al. 1976. The metabolism of higher chlori-
nated benzene isomers. Can. Jour. Biochem. 54: 203.
Korte, I., et al. 1976. Studies on the influences of some
environmental chemicals and their metabolites on the content
of free adenine nucleotides, intermediates of glycolysis
and on the activities of certain enzymes of bovine lenses
iri vitro. Chemosphere 5: 131.
Olie, K., et al. 1977. Chlorodibenzo-p-dioxins and chlorodi-
benzoflurans are trace components of fly ash and flue gas
of some municipal incinerators in the Netherlands. Chemosphere 8: 445,
Piet, G.J., and F. De Grunt. 1975. Organic chloro compounds
in surface and drinking water of the Netherlands. Pages
81-92 in Problems raised by the contamination of man and
his environment. Comm. Eur. Communities, Luxembourg.
Rasanen, L., and M.L. Hattula. 1977. The mutagenicity of
MCPA and its soil metabolites, chlorinated phenols, catechols
and some widely used slimicides in Finland. Bull. Environ.
Contain. Toxicol. 18: 565.
C-35
-------
TRICHLOROPHEtJOLS
Mammalian Toxicology and Human Health Effects
SUMMARY
Trichlorophenols are used as antiseptics and disinfect-
ants, as well as being intermediates in the formation of
other chemical products. The most widely recognized of .
a number of possible isomers is 2, 4, 5-trichlorophenol.
Other isomers include: 3, 4, 5-, 2, 4, 6-, 2, 3, 4-, 2,
3, 5-, and 2, 3, 6-trichlorophenol. The physiochemical
properties of these isomers are listed in table 1. The
toxic substances list includes only the 2, 4, 6- and 2,
4, 5- isomers.
In the evaluation of the trichlorophenols there is
a related contaminant that is the subject of specific but
separate consideration by regulatory agencies, including
the U.S. Environmental Protection Agency.
A major use of 2, 4, 5- trichlorophenol is as a feedstock
in the synthesis of various pesticides, including the herbi-
cides 2, 4, 5- trichlorophenoxyacetic acid (2, 4, 5-T),
silvex, erbon and the insecticide ronnel. All of these
products involve 2, 4, 5- trichlorophenol in their manufacturing
processes and may involve 2, 3, 7, 8- tetrachlorodibenzo-
p-dioxin (TCDD). This highly toxic contaminant caused EPA
to publish a Rebuttable Presumption Aganist Registration
(RPAR) and Continued Registration of Pesticide Products
Containing 2, 4, 5-T (Federal Register 43: 17116). The
published RPAR indicated that 2, 4, 5- trichlorophenol is
C-36
-------
Properties
TABLE 1
Physiochemical Properties of Trichlorophenols
Trichlorophenol Isomers
Moleclar weight
Formula
Melting point °C
Boiling point °C
Density
Solubility
water
alcohol
ether
acetone
benzene
Vapor pressure
nun Hg
(pressure, C)
CAS Number*
2,3,4
197.45
CgH3Cl30
83.5
sublimes
soluble
2,3,5
197.45
CCH,C1,0
O J J
62
248.5
2,3,6
197.45
C6H3C130
58
very
2,4,5
197.45
C6H3C130
68-70
sublimes
- —
soluble
soluble
slightly
soluble
soluble
slightly
very
very
slightly
soluble
—
NL
NL
NL
1 mm, 72"
000095954
Source: Handbook of Chemistry and Physics, 59th Edition, R.
C. Weast, Ed., CRC Press, 1978
*NL = not listed in toxic substances list
037
-------
Properties
Molecular weight
Formula
Melting point °C
Boiling point °G
Density
Solubility
water
alcholol
ether
acetone
benzene
Vapor pressure
nun Hg
(pressure, C)
CAS Number*
TABLE 1 CCont)
PhysioeheiBical Properties of Trichlorophenols
(continuedy
Trichlorophenol Isomers
2,4,6. 3,4,5
197.5 197.5
C6H3C130
69.5
246
1.490
slightly
soluble
soluble
Imin, 76
000088062
101
271-7
slightly
soluble
Source:
*NL * not listed in toxic substances list
Handbook of Cheinistty and Physics,
R . C. Weast, Ed./ CRC Press, 1978
C-38
-------
the subject of a separate potential RPAR.
TCDD is a known teratogen (Courtney, 1976) and carcino-
gen (Van Miller, et al., 1978). Its extreme toxicity is
not disputed. The water solubility of TCDD is 0.2 ug/1.
TCDD is produced during .the formation of 2, 4, 5- trichloro-
phenol. Most documented cases of adverse health effects
have involved industrial accidents where exothermic reactions
resulted in explosions and exposure to humans and the environ-
ment. Whiteside (1977) reported on a 1949 explosion of
a 2t 4, 5-T process that resulted in 228 cases of chloracne.
Chloracne is generally recognized as one of the outward
and early symptoms of TCDD toxicosis. Others have reported
chloracne in employees in 2, 4-D and 2, 4, 5-T plants (Bleiberg,
et al., 1964). The 1976 explosion in Seveso, Italy in which
1-5 kg of TCDD were released has received much lay and scientific
attention.
A complete assessment of the toxicity of TCDD in trichloro-
phenol derived chemicals is beyond the scope of this document.
The RPAR published in the Federal Register presents the
critical studies for evaluation. No tolerance level has
been established for TCDD.
EXPOSURE
Introduction
Currently available data regarding general population
and occupational exposure to trichlorophenols are limited.
Available data will be discussed in this section.
Chlorophenols as a chemical class tend to be rapidly
eliminated in the urine. Hence, analyzing urine for tri-
C-39
-------
chlorophenol residues is a reasonable approach to estimating
exposure, regardless of the source and route of exposure.
r^ugherty and Piotrowska (1976) used negative chemical ioni-
zation mass spectrometry to analyze urine samples for chloro-
phenols. Evidence was obtained suggesting the presence
of trichlorophenol or trichlorophenoxyl herbicides in 9
to 67 percent of the 57 samples analyzed. The levels were
not quantified,
Kutz, et al. (1978) analyzed 418 human urine samples
collected from the general population via the Health and
Nutritional Examination Survey. Residues of 2, 4, 5-trich-
lorophenol were found in 1.7 percent of the samples. The
average level found was less than 5 ug/1 (ppb) and the maximum
value found was 32.4 ^ag/1.
Assuming that the exposure to chlorophenol is steady-
state, that 100 percent of absorbed chlorophenol is excreted
in the urine, and that the average urine void is 1.4 I/day
per 70 kg person, initial exposure levels can be estimated
frora residual levels found in the urine. For example, the
exposure level leading to the 5 ug'/l* residue can be calculated
as follows; ;
Exposure = (5 ug/1) + (1.4 I/day) = 0.1 ug/kg/day
Level 70 kg
A similar calculation using the maximum urine residue value
observed by Kutz, et al. of 32.4 ug/1 gives an exposure
of 0.648 ug/kg/day.
Possible sources of exposure are discussed below.
C-40
-------
Ingestion from Water
Piet and DeGrunt (1975) found unspecified isoraers of
trichlorophenols in surface waters in The Netherlands, in
concentrations from 0.003-0.1 ug/1 (ppb).
Phenols are known to occur naturally in the environment
(Hoak, 1957) . For example, some aquatic plants release
sufficient phenol to establish water levels of 300-960 >ig/l.
Phenols are found in raw domestic sewage at levels of 70-
100 jig/1. Complex phenols are at least partially released
by bacterial action in sewage treatment trickling filters.
The decomposition of surface vegetation such as oak leaves
also releases phenol.
The association of bad taste or odor in tap water with
chlorophenols has been of interest for a number of yea-s.
Hoak (1957) reviewed aspects of this problem. Some chloro-
phenols have odor thresholds in the ppb concentration range.
The addition of 0.2-0.7 ppm chlorine to water containing
100 ppb phenol results in the development of a chlorophenol
taste. Increasing the level of chlorine or increasing the
reaction time reduces the taste. Odor thresholds for chloro-
phenols in water are shown in Table 2
Burttschell, et al. (1959) proposed a mechanism for
the chlorination of phenol in water. According to their
scheme 2- and 4-chlorophenol are formed early. These mole-
cules are further chlorinated to 2, 6- or 2, 4-dichlorophenol.
i
The final product is 2, 4, 6-trichlorophenol. After 18
hours of reaction, the chlorophenol products in Burttschell1s
C-41
-------
&f OS&£ Thresholds t&t
2~chlorepfcen6l
(5.33
in Watei?
Reference
2,5 dichloEophenbl
2 , 3 , 4 , 6 -
1* Hdak, 1957
2. Burttsc:hellf ef al*
200 (30.V
33 (306C.)
250 (2$0G.}
0*65 (30%.
2 (25°G. )
3,3 (30°C*>
3(25°G. )
100 (30G*)
1(500 C25°C*)
$15
2
1
2
-------
study consisted of less than 5 percent each 2- and 4-chloro-
pehnol, 25 percent of 2, 6-dichlorophenol, 20 percent 2,
4-dichlorophenol and 40 to 50 percent 2, 4, 6-trichlorophenol.
Ingestion from Foods
One possible source of trichlorophenol exposure for
humans is through the food chain, as a result of the ingestion
by grazing animals of the chlorophenoxy acid herbicides
2, 4, 5-T (2, 4, 5-trichlorophenoxyacetic acid) or silvex
(2-(2, 4, 5-trichlorophenoxy)-propionic acid). Residues
of the herbicides on sprayed forage are estimated to be
in the range of 100-300 ppm. In view of this, Clark, et
al. (1976) fed cattle silvex at levels of 300, 1000 and
2000 ppm in the diet for 28 days, and fed sheep 2, 4, 5-
T or silvex at 2000 ppm in the diet for 28 days. Based
on feed consumption, the exposures are equivalent to 9 mg/kg
(300 ppm), 30 mg/kg(1000 ppm) and 60 mg/kg (2000 ppm).
Some animals were fed a clean diet during a seven day with-
drawal before tissue samples were obtained. Muscle, fat,
liver and kidney were analyzed for 2, 4, 5 trichlorophenol.
In the sheep fed 2000 ppm 2, 4, 5-T and killed at the end
of the 28 day feeding period, the 2, 4, 5-trichlorophenol
residues were 0.13 ppm in muscle,less than 0.05 ppm in fat,
6.1 ppm in liver, and 0.9 ppm in kidney. Sheep held for
the seven day withdrawal had 2, 4, 5-trichlorophenol residues
of 4.4 ppm in liver and 0.81 ppm in kidney, and less than
0.05 ppm in fat and muscle. Levels of the 2, 4, 5-T herbicide
at the end of 28 days ranged from 0.27 ppm in fat to 27
ppm in kidney. In sheep and cattle fed 2000 ppm of silvex,
C-43
-------
2, 4, 5-trichlorophenol was not detected in muscle or fat
at the end of 28 days. Residues in the liver were 0.2-0.5
^pm and in kidney were 0.1~0ol7 ppm.
Bjerke, et al. (1972) fed lactating cows the herbicide
2, 4, 5-T and analyzed the milk for trichlorophenol. At
feeding levels of 100 ppm 2, 4, 5-T in the diet, an occasional
residue of 0;06 ppm or less of trichlorophenol was isolated.
At a feeding level of 1000 ppm 2, 4, 5-T in the diet, residues
of 0.15-^-0.23 ppm trichlorophenol were found in milk and
cream. Three days after 2, 4, 5-T feeding at the 1000 ppm
level was stopped, trichlorophenol residues in milk and
cream were below detection limits of 0.05 ppm. Acid hydrolysis
of milk samples indicated that there was no binding of the
trichlorophenol.
Wright, et al. (1970) found that sheep metabolize
the herbicide Erbon (2-(29 4, 5-trichlorophenoxy)-ethyl
2, 2-dichloropropionate). Two metabolites were found in
urine, (2-(2, 4, 5-trichlorophenosy)-ethanol and 2, 4, 5-
tri'"hlorcphenol) „ About 33 percent of the administered
Erbon dose was eliminated as 2, 4, 5-trichiorophenol in
urine in 96 hours. A dose of 100 rag Erbon/kg in sheep for
seven days proved lethal. 2, 4, 5:-Trichlorophenol residues
in tissue were 0,21 ppm in brain, 5.54 ppm in kidney,
3<,i4' ppm in liver, 2.06 ppm in omental fat, and 1.00 ppm
in muscle. Dosages of 50 mg Erbon/kg for 10 days followed
by slaughter on day 11 resulted in no detectable 2, 4, 5--
tr ichloro-phenol residues in tissues.
Stanhard. and Scotter (1977) from New Zealand determined
the residues of various chlorophenols in dairy products
C-44
-------
following the use of chlorophenol containing dairy teat
sprays, dairy soaps and antiseptics. The compound 3, 5-
dimethyl-4-chlorophenol was shown to carry over into milk
following application to the cow udder. While this particular
compound is not of direct interest in this document, the
possible mechanism of exposure deserves recognition.
Crosby and Wong (1973) found that 2, 4, 5-trichloro-
phenol is a photodecomposition product of the herbicide
2, 4, 5-T. About 38 percent of the 2, 4, 5-T was converted
to the trichlorophenol.
Exposure to other chemicals could result in exposure
to trichlorophenols via metabolic degradation of the parent
compound. Kohli, et al. (1976) found that the major rabbit
urinary metabolites of 1, 2, 4-trichlorobenzene were 2,
4, 5- and 2, 3, 5-trichlorophenol. 1, 2, 3-trichlorobenzene
was metabolized to 2, 3, 4-trichlorophenol and smaller amounts
of 2, 3, 6- and 3, 4, 5-trichlorophenol„ 1, 3, 5-trichloro-
benzene was metabolized to 2, 3, 5- and 2, 4, 6-trichloro-
phenol. The yields of metabolites ranged from 1 to 11 percent,
Foster and Saha (1978) reported that chicken liver homogenates
would metabolize lindane and the alpha and delta but not
the beta isomers of 1, 2, 3, 4, 5, 6 hexachlorocyclohexane.
The metabolic products included 2, 4, 6-trichlorophenol,
and 2, 3-dichlorophenol, as well as di- and trichlorobenzenes.
Tanaka, et al. (1977) found that isolated rat liver micro-
somes metabolized the alpha, beta, gamma, delta and epsilon
isomers of benzene hexachloride (BHC) to 2, 4, 6-trichloro-
phenol.
C-45
-------
Shafik, et al. (1972) showed that in one to two days,
30-50 percent of the insecticide Ronnel (0, 0-dimethyl 0-
'2, 4, 5-trichlorophenyl) phosphorothioate) was excreted
in the urine of rats as 2, 4, 5-trichlorophenol.
Even plants can metabolize another chemical to form
a trichlorophenol metabolite. Moza, et al. (1974) demonstrated
that corn and pea plants could metabolize pentachlorocyclo-
hexene to the 2, 4, 6-, 2, 3, 5- and 3, 4f 6-trichloropehnol
isomers. -
A bioconcentration factor (BCF) relates the concentration
of a chemical in water to the concentration in aquatic organisms,
but BCF's are not available for the edible portions of all
four major groups of aquatic organisms consumed in the United
States. Since data indicate that the BCF for lipid-soluble
compounds is proportional to percent lipids, BCF's can be
adjusted to edible portions using data on percent lipids
and the amounts of various species consumed by Americans.
A recent survey on fish and shellfish consumption in the
United States (Cordle, et al, 1978) found that the per capita
consumption is 18.7 g/day. From the data on the nineteen
major species identified in the survey and data on the fat
content of the edible portion of these species (Sidwell,
et al. 1974) , the relative consumption of the four major
groups and the weighted average.percent lipids for each
group can be calculated:
C-46
-------
Consumption Weighted Average
Group (Percent) Percent Lipids
Freshwater fishes 12 4.8
Saltwater fishes 61 2.3
Saltwater molluscs 9 1.2
Saltwater decapods 18 1.2
Using the percentages for consumption and lipids for each
of these groups, the weighted average percent lipids is
2.3 for consumed fish and shellfish.
No measured steady-state bioconcentration factor (BCF)
is available for any of the following compounds, but the
equation "Log BCF =0.76 Log P - 0.23" can be used (Veith,
et al. Manuscript) to estimate the BCF for aquatic organisms
that contain about eight percent lipids from the octanol-
water partition coefficient (P). An adjustment factor of
2.3/8.0 = 0.2875 can be used to adjust the estimated BCF
from the 8.0 percent lipids on which the equation is based
to the 2.3 percent lipids that is the weighted average for
consumed fish and shellfish. Thus, the weighted average
bioconcentration factor for the edible portion of all aquatic
organisms consumed by Americans can be calculated.
Compound
2,4, 5- tr ichlorophenol
2 , 4 , 6- tr ichlorophenol
P
6,000
4,900
BCF
440
380
Weighted BCF
130
110
Inhalation
No quantitative data on inhalation studies were found.
From Table 1 it is noted that the vapor pressures of 2,
C-47
-------
4, 5- and 2, 4, 6-trichlorophenol are about 1 iranHg at 72-
76 degrees C= Consequently the tricolorophenols can be
expected to vaporize to some extent.
Olie, et alo (1977) reported finding di-, tri- and
tetrachlorophenols in flue gas condensates from municipal
incinerators. The levels were not quantified.
Dermal
Roberts, et al. (1977) used human autopsy skin epidermal
v
membranes in an i.n vitro test system to determine the per-
meability of human skin to various chemicals. 2f 4, 6-Trich-
lorophenol permeated the skin membrane and did not cause
damage when tested at the maximum aqueous solubility of
0.09 percent (w/v) concentration.
PHARMACOKINETICS
Absorption? Distribution^ and Metabolism
No data were available regarding these processes.
Excretion
2, 4, S-Trichlorophenol is cleared rapidly from blood.
Wright, et al. (1970) dosed sheep with Erbon, an herbicide
that is metabolized to 2, 4, 5-trichlorophenol, and observed
the disappearance of 2, 4, 5-trichlorophenol from the blood.
An approximate blood half-life of 20 hours was estimated
from the graphed data.
Another study showed the rapid clearance of 2, 4, 6-
trichlorophenol, predominantly in urine. Korte, et al.
(1978) administered 1 ppic 2, 4, 6-trichlorophencl in the
diet to rats for three days and then studied elimination.
Eighty-two $82) percent of the dcse was eliminated in the
C-48
-------
urine and 22 percent in the feces. Radio-labelled trichloro-
phenol was not detected in liver, lung or fat obtained five
days after the last dose.
EFFECTS
Acute, Sub-acute, and Chronic Toxicology
Table 3 presents data regarding acute toxicity of several
trichloropehnol isomers. Differences in observed LD50's
may be due to the use of different solvents.
The clinical signs of acute poisoning with 2, 4, 5-
triehlorophenol include decreased activity and motor weak-
ness (Deichmann, 1943). Convulsive seizures occur but are
not as severe as with the monochlorophenols. The monochloro-
phenols with a pk_ of eight or higher are convulsants.
3L
At body pH (7.0-7.4) these chloropehnols are mainly undissociated.
The tri- and tetrachlorophenols have lower pka°s and tend
not to be convulsants, with the exception of 2, 4, 6-trichlor-
ophenol.
Farquharson, et alo (1958) determined the LD5Q of
isomers of trichlorophenol (Table 3)„ 2, 4, 6-Trichlorophenol
produced convulsions when injected intraperitoneally. The
2, 3, 6- isomer occasionally resulted in convulsions when
dosed animals were handled. All of the trichlorophenol
isomers (3f 4, 5-, 2, 4, 5-, 2, 4, 6- and 2, 3, 6-) elevated
body temperature 0.5 degrees Co Onset of rigor mortis occurred
within five minutes of death as compared to 50 minutes for
controls. Rats dosed with 2, 3, 6-, 3, 4, 5- or 2, 4, 5-
trichlorophenol developed hypotonia in the hind limbs two
to three minutes after intraperitoneal injection. The hypotonia
then spread to the forelimbs and neck. All of the trichloro-
C-49
-------
CHEMICAL
SOLVEHT
TABLE 3
At ute Tosicity of Trlchlorophenola
SPECIES TOXIC RESPONSE
o
Ul
o
2 , 4 , 5-Tr ichlorophenol
3,4, 5-Tr icho lor phenol
2,4, 6-Tr icholorphenol
2 , 3, 6-Tr ichlorophenol
fuel oil
corn oil
fuel oil
olive oil
olive oil
olive oil
olive oil
rat
rat
rat
rats
rats
rats
rats
oral Ld,0=820 mg/kg
oral LD3Q=2S60 mg/kg
subcutaneous LD5_=2260 mg/kg
intraperitoneal Lb_n
intraperitoneal LD_fl
intraperitoneal LD__
intraperitoneal LD,.
"355 mg/kg
=372 mg/kg
-276 mg/kg
=308 mg/kg
REFERENCE
Deichraann &
Hergard, 1948
McCollister, et
al. 1961
Delchman &
Mergard, 1948
Farquharson, et
al. 1958
•
Farquharson, et
al. 1958
Farquharson, et
al. 1958
Farquharson, et
al.1958
-------
phenol isomers stimulated oxygen consumption of rat brain
homogenate at concentrations of 5 x 10- to 10- M.
McCollister, et al. (1961) conducted a variety of toxico-
logic studies on 2, 4, 5-trichlorophenol in rats. The 2,
4, 5-trichlorophenol used in the acute studies was 97-98
percent pure; and, for the 90-day study, it was 99 percent
pure. The acute oral LDcn was 2960 mg/kg.
Rabbits were given 28 daily oral doses of 2, 4, 5-tri-
chlorophenol in 5 percent gum acacia solution (McCollister,
et al, 1961). No effect was observed at doses of 1 or 10
mg/kg. At 100 mg/kg, slight renal pathology was reported.
At 500 mg/kg, slight kidney and liver lesions were noted.
In rats, 18 daily doses of 1000 mg/kg during 24 days
caused a transient weight loss that disappeared withir| 14
!
days (McCollister, et al. 1961). Dosages of 30, 100, 300
or 1000 mg/kg for 18 out of 24 days did not affect mortality,
hematological variables (unspecified), blood urea nitrogen,
final body weight or organ weight ratios. There were no
microscopic lesions in lung, heart, liver, kidney, spleen,
adrenal, pancreas or testes.
Rats in groups of 10 males and 10 females were fed
2, 4, 5-trichlorophenol at dietary levels of 100, 300, 1000,
3000 or 10,000 mg of trichlorophenol per kg of feed for
98 days (McCollister, et al. 1961). Assuming an average
rat eats an amount of feed equivalent to 10 percent of its
body weight each day, the equivalent doses are 10, 30, 100,
300 and 1000 mg/kg body weight.
Dosages of 100 mg/kg body weight or less produced no
adverse effects as judged by behavior, mortality, food con-
C-51
-------
sumption, growth, terminal hematology, body and organ weights
and gross microscopic pathology0
At 1000 mg/kg (10,000 mg/kg in diet), growth was slowed
in females. There were no significant hematologic changes.
Changes were noted in kidney and liver on histopathologic
examination. The kidneys showed moderate degenerative changes
in the convoluted tubular epithelium and early proliferation
of interstitial tissue. The liver showed mild centrilobular
degenerative changes characterized by cloudy swelling and
occasional focal necrosis. There was1 slight proliferation
of the bile ducts and early portal cirrhosis. The rats
c
fed 300 mg/kg (3000 mg/kg feed) also showed histopathologic
changes in. kidney and liver that were milder than those
observed in the higher dose. The histopathologic changes
were considered to be reversible.
Anderson, et al. (1949) fed steers various levels
of 2, 4, 5-trichlorphenyl acetate or zinc 2, 4, 5-trichloro-
phenate, as shown in Table 4. Feed consumption, daily
weight gain, hemoglobin and packed cell volume were deter-
mined. The results are summarized in Table 5. Because
of the limited number of animals per group, statistical
analysis was not used. For day 154 there was only one control
animal per compound. The authors concluded that the compounds
were relatively nontoxic to the animals. Examination of
Table 5 shows no clinically significant changes in hemoglobin
or packed cell volume values. No gross lesions were observed
at slaughter. The feed consumption data hint that with
both compounds, the high dose groups were consuming leas
feed/kg/day. Tissues were not analyzed for the active agents.
C-52
-------
Table 4
Design of Steer Feeding Study of Anderson, et al. (1949)
Group N Compound Dose-mg/kg Duration-days
1 2 zinc 2,4,5 tri- 0
chlorophenate
2 2 " 17.64 78
3 2 • • " 52.92 154
42 " 158.77 78
5 2 2,4,5-trichloro- 0
phenyl acetate
62 " 17.64 78
72 " 52.92 154
82 " 158.77 78
C-53
-------
Table 5
Average Results of Anderson, et al. (1949) Trichlorophenol Steer
Feeding Study
Part 1; Results of feeding zinc 2,4,5-trichlorophenate
Dose - mg/kg
Daily gain - 78 day
(kg/day)
Daily gain - 154 day
(kg/day)
Feed consumption
gm/kg day-;~-78 day
gin/kg day- -154 day
Hemoglobin
gm/100 ml -78 day
gm/100 ml -154 day
Packed cell volume
PCV -78 day
PCV -154 day
Part 2: Results
Daily gain
kg/day 78 day
Daily gain
! "t/^ay -154 day
Peer consumption
gm/kg-day-. -78 day
gm/kg-day- -154 day
Hemoglobin
gm/100 ml -78 day
gm/100 ml -154 day
Packed cell volume
PCV -154 day
PCV -154 day
0
0.73
J
0.77
35
30
10.3
10.9
34
36
of feeding
0
1.05
0.77
36
30
9.1
--
31
—
17.64
0.97
'•
--
32 ;
--
11.1
--
37
. — ~
52.92
0.83
0.71
33
37
10.3
10.4
34
35
2/4,5-trichlorophenyl
Dose - mg/kg
17.64
0.37
37
—
12.1
--
40
--
52.92
0.84
0.68
37
39
11.1
11.3
37
38
158.77
0.68
--
24
--*•
10.9
— —
37
• M
acetate
158.77
0.65
--
30
--
11.7
—
38
--
C-54
-------
Tissue analyses showed an increase in zinc, but phenol was
not detected. Meat prepared from the animals did not have
any unusual taste or odor.
McCollister, et al. (1961) reported on skin irritation
and sehsitization studies in 200 humans. A five percent solu-
tion of 2, 4, 5-trichlorophenol in sesame oil was midly
k
irritating in a few individuals upon prolonged contact,
but there was no evidence of sensitization.
Bleiberg, et al. (1964) described various adverse health
effects in 29 workers involved in the manufacture of 2,
4-D and 2, 4, 5-T. The workers had varying degrees of chlor-
acne, hyperpigmentation and hirsutism. Eleven had elevated
urinary uroporphyrins. Eleven of the 29 were diagnosed
as having evidence of porphyria cutanea tarda, which i,»
associated with liver dysfunction, porphyrinuria and bullous
skin lesions. It is likely that some of these symptoms
represent TCDD toxicosis.
Studies on the mechanism of action or subcellular ef-
fects of these compounds have primarily focused on effects
on oxidative phosphorylation. Weinbach and Garbus (1965)
tested the ability of various substituted phenols to com-
pletely uncouple oxidative phosphorylation in vitro. 2,
4, 5-Trichlorophenol caused complete uncoupling at 0.05
mM. The known uncoupler 2, 4-dinitrophenol completely un-
coupled the test system at 0.1 mM for comparison. There
was a positive relationship between mitochondria protein
binding and uncoupling properties.
C-55
-------
Parker (1958) studied the effect of chlordphenols on
isolated rat liver mitochondria. 2, 4-Dinitrophendl was
used as a reference compound because of its known ability
to uncouple oxidative phosphorylation. An unspecified isomer
of trichlorophenol, at 1.8 x 10 M, had 70 percent of the
activity of 2.0 x 10" M of 2, 4-dinitrophenol. Mitsuda,
et al. (1963) studied the effects of various chlorophenols
on oxidative phosphorylation in isolated rat liver mitochon-
dria. The test system used a 2.75 ml reaction medium at
pH 7.0, containing 0.05 ml of mitochondria! suspension with
0.43 mg N. The concentration of chlorophenol required to
produce a 50 percent inhibition in the production of ATP
was determined (^Q) • The I^Q was 3 JJM for 2, 4, 5-trichloro-
i
phenol and 18 joM for 2, 4, 6-trichlorophenol.
Stockdale and Selwyn (1971) reported that '2, 4, 6-tri-
chlorophenol at 0.005 M resulted in'50 percent inhibition
of lactate dehydrogenase, and that 0.0028 M resulted in
50 percent inhibition of hexokinase in. vitro. Isolated
ATPase was stimulated by 60 ^iM and inhibited by 1120 joM
of 2, 4r 6™trichlorophenol.
"* ' .
Arrhenius, et al. (1977) studied the effects of chloro-
phenols on microsomal detoxication mechanisms using rat
liver preparations. The experimental system examined the
effects of the test chlorophenol on the microsomal metabolism
of N, N-dimethylaniline (DMA) to formaldehyde and N-methylani-
line (C-oxygenation) or to N, N-dimetbylaniline~N-oride
(N-oxygenation). In essence, the study examined disturbances
in the detoxification electron tsaospoet chain. 'The
as stated 'by Arrhenius, et al, was that compounds that
C-56
-------
could increase N-oxygenation could also influence the meta-
bolism of other chemical toxicants, such as aromatic amines,
which are formed by N-oxygenation. It is suggested that
agents that increase N-oxygenation could be considered as
synergists for the carcinogenic action of aromatic amines.
A concentration greater than 1 mM of 2, 4, 6-trichlorophenol
inhibits of C-oxygenation of DMA. A 3 mM concentration
produces a small increase in N-oxygenation of DMA. In order
to set this in a dose-response context, a concentration
of 1 mM is equivalent to 197.46 mg trichlorophenol per 1
and 3 mM is equivalent to 592.38 mg/1.
Two studies have looked at the effect of trichlorop-
henol on the bio-chemistry of the lens portion of the eye.
Korte, et al. (1976) showed that 10~3 M 2, 4, 5-trichloro-
phenol would reduce bovine lens content of ATP, ADP, glucose-
6-phosphate and fructose following a 48-hour incubation.
Levels of AMP and glucose were increased. Trichlorophenol
decreased glucose-6-phosphate dehydrogenase activity but
had no effect on lactate dehydrogenase, malate dehydrogenase,
sorbitol dehydrogenase, fructose-1, 6-diphosphate aldolase
or pyruvate kinase. Ismail, et al- (1975) showed that
small amounts of 2, 4, 6-trichlorophenol would penetrate
the rabbit eye. Small amounts of the chemical were placed
in the eye and one hour later various parts of the eye were
analyzed for the chemical. Highest amounts of the adminis-
tered dose were found in the cornea (2.4 percent) and con-
junctiva (2.49 percent). The aqueous and vitreous humor,
lens, iris and choroid contained less than 0.17 percent
each.
C-57
-------
Synergism and/or Antagonism
No da.ta were available.
'geratogenicity
No studies were found reporting on the presence or
lack of teratogenic properites of trichlorophenols.
Mutagenicity
Fahrig, et al. (1978) found that 400 mg 2, 4, 6-trichloro-
phenol increased the mutation rate in a strain of Saccharomyces
cerevisial. There was no effect on the rate of intragenic
recombination.
In a mouse mammalian spot test females were treated
with an intraperitoneal dose of test chemical on day 10
of gestation and the response was a change in hair coat
color representing a genetic change in the offspring(Fahrig,
1978). At 50 mg/kg, 2, 4, 6-trichlorophenol produced two
spots in two of 340 animals from 74 females. At 100 mg/kg
there was one spot out of 175 mice from 42 females.
Rasanen, et al. (1977) tested chlorophenol for mutageni-
city using the Salmonella-mammalian microsome Ames test
wit'i both the nonactivated and liver homogenate added systems.
The following trichlorophenol isomers were tested and reported
as non-mutagenic in both test systems; 2, 3, 5-, 2, 3,
6-, 2, 4, 5- and 2, 4, 6-trichlorophenol.
Carcinogenicity
Boutwell and Bosch (1959) conducted a series of experi-
ments on the tumor promoting action of substituted phenols
using repeated applications of concentrated solutions to
the shaved backs of mice. The tumor initiator DMBA (9,
10-dimethyl-l, 2-benzanthracene) was used. A 20 percent
C-58
-------
solution of 2, 4, 6-trichlorophenol in benzene did not in-
crease the incidence of papillomas in mice pretreated with
the initiator DMBA. No carcinomas developed during the
15 week experiment. A 21 percent solution of 2, 4, 5-tri-
chlorophenol in acetone increased the incidence of papillomas
in mice pretreated with DMBA. Carcinomas did not develop
during the 16-week experiment.
Innes, et al. (1969) dosed two strains of mice with
2, 4, 6-trichlorophenol for 18 months. Eighteen males (18)
and 18 females of each strain were used, for a total of
72 animals. Beginning at seven days of age and continuing
through 28 days, the mice were gavaged daily with the compound
at 100 mg/kg. From one month to 18 months the mice were
fed a diet containing 260 ppm, which resulted in an estimated
exposure of 20-25 mg/kg. The results were inconclusive.
In this large study, which involved 120 pesticides, each
chemical was grouped into one of three categories. If the
incidence of tumors was significantly increased, it was
classified as a carcinogen. If the incidence of tumors
was low and statistically insignificant, it was classified
as a non-carcinogen. The third category, in which 2, 4,
6-trichlorophenol was placed, comprised compounds requiring
further study. The authors did not provide the actual data,
but indicated that there was an elevation of tumor incidence
in an uncertain range, and that additional statistical evaluation
or experimentation would be required before an interpretation
could be made.
C-59
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CRITERION FORMULATION
The information of this section is presented in a composite
treatment of the chlorophenols at the end of the document.
C-60
-------
REFERENCES
Anderson, G. W., et al. 1949. Cattle-feeding trails with
derivatives of 2, 4, 5 trichloropehnol. Jour. Am. Vet.
Med. Assoc. 115: 121.
Arrhenius, E., et al. 1977. Disturbance of microsomal
detoxication mechanisms in liver by chlorophenol pesticides.
Chem.-Biol. Interact. 18: 35.
Bjerke, E. L., et al. 1972. Residue study of phenoxy herbi-
cides in milk and cream. Jour. Agric. Food Chem. 20: 963.
Bleiberg, J., et al. 1964. Industrially acquired porphyria.
Arch. Dermatol. 89: 793.
Boutwell, R. K., and D. K. Bosch. 1959. The tumor-promoting
action of phenol and related compounds for mouse skin.
Cancer Res. 19: 413.
Burttschell, R. H., et al. 1959. Chlorine derivatives
of phenol causing taste and odor. Jour. Am. Water Works
Assoc. 51: 205.
Clark, D. E., et al. 1976. Residues of chlorophenoxy acid
herbicides and their phenolic metabolites in tissues of sheep
and cattle. Jour. Agric. Food Chem. 23: 573.
C-61
-------
Cordle, F., et al. 157*8. Human exposure to polychlorinated
biphenyls and polybrominated biphenyls. Environ. Health
Perspectives 24: 157.
Courtney, K. D. 1976. Mouse teratology studies with chloro-
dibenzo-p-dioxins. Bull Environ. Contam. Toxicol. 16: 674,
Crosby, D. G., and A. S. Wong. 1973. Photodecomposition
of 2, 4, 5-Trichlorophenoxyacetic acid (2, 4, 5-T) in water.
Jour. Agric. Pood Chem. 21: 1052.
Deichmann, w. B. 1943. The toxicity of chlorophenols for
rats. Fed. Proc. 2: 76.
>
Deichmann, w. B., and E. G. Mergard. 1948. Compartive
evaluation of methods employed to express the degree of
toxicity of a compound. Jour. Ind. Hyg. Toxicol. 30: 373.
/*•
Dougherty? R. C., and K. Piotrowska." 1976. Screening by
negative chemical ionization mass spectrometry for environ-
mental contamination with toxic residues: Application to
human urines. Proc. Natl. Acad. Sci'., USA. 73: 1777.
i
Drinking Water and Health. 1977. Printing and Publishing
Office. National Academy of Sciences, 2010 Constitution
Avenue. Washington, D.C. 20418.
C-62
-------
and chlorophenol impurities. In Pentachlorophenol: Chemistry/
pharmacology and environmental toxicology K. Rango
Rao, Plenum Press, New York.
Farquharson, M. E., et al. 1958. The biological action
of chlorophenols. Br. Jour. Pharmacol. 13: 20.
Foster, T. S., and J. G. Saha. 1978. The in vitro metab-
olism of lindane by an enzyme preparation from chicken liver.
Jour. Environ. Sci. Health 13: 25.
Hoak, R. D. 1957. The causes of tastes and odors in drinking
water. Purdue Eng. Exten. Service. 41: 229.
Irines, J. R. M., et al. 1969. Bioassay of pesticides and
industrial chemicals for tumorigenicity in mice: A preliminary
note. Jour. Natl. Cancer Inst. 42: 1101.
Ismail, R., et al. 1975. Permeability of the isolated
bovine lens capsule for environmental chemicals. Exp. Eye
Res. 20: 179.
Kohli, J., et al. 1976. The metabolism of higher chlorinatd-
benzene isomers. Can. Jour. Biochem. 54: 203.
Korte, I., et al. 1976. Studies on the influences of some
environmental chemicals and their metobolites on the content
of free adenine nucleotides, intermediates of glycolysis
and on the activities of certain enzymes of bovine lenses
iH vitro* Chemosphere 5: 131.
C-63
-------
Korte, F., et al. 1978. Ecotoxicologic profile analysis,
a concept for establishing ecotoxicologic priority list
for chemicals. Chemosphere 7: 79.
Kutz, F. W., et al. 1978. Survey of pesticide residues
and their metabolites in urine from the general population.
Pages 363-369 Iri K. Rango rao, ed. Pentochlorophenol:
Chemistry, pharmacology and environmental toxicology, Plenum
Press, New York.
McCollister, D. D., et al. 1961. Toxicologic information
on 2, 4, 5-trichlorophenol. Toxicol. Appl. Pharmacol.
3; 63.
Mitsuda, H., et al. 1963. Effecr of chlorophenol analogues
on the oxidative phosphorylation in rat liver mitochondria.
Agric. Biol. Chenu 27: 366.
Moza, P., et al, 1974. Beitrage zur okologischen chemie
LXXXIX. Orientierer.de versuche zuin metabolisnius von -pento-
chlorcyclohex~l-en in hoheren pflanzen in hvdrokultur.
Chemosphere 6: 255.
National Academy of Sciences. 1977. Drinking water and
health. Washington, D.C.
Olie, K,, t;t al. 1977. Cblorodibenzo-p-dioxins and chloro-
dibenzofurcms are trace components of fly ash and flue gas
ot; sc-.T;e inunicipai inciiiercitbrs in the Netherlands. Cfc&mo-
syr.ere 8: 445,
C-64
-------
Parker/ V. H. 1958. Effect of nitrophenols and halogeno-
phenols on the enzymic activity of rat-liver mitochondria.
Biochem. Jour. 69; 306,
Piet, G. J.f and F. De Grunt. 1975. Organic chloro compounds
in surface and drinking water of the Netherlands. Pages
81-92. In Problems raised by the contamination of man
and his environment. Comm» Eur. Communities/ Luxembourg.
Rasanen, L., et al. 1977. The mutagenicity of MCPA and
its soil metabolites/ chlorinated phenols/ catechols and
some widely used slimicides in Finland. Bull. Environ.
Contam. Toxicolo 18s 565.
Roberts/ M. S./ et al 1977. Permeability of human epidermis
to phenolic compounds. Jour. Pharm. Pharmac. 29: 677.
Shafik, T. M./ et al. 1972. Multiresidue procedure for
halo-and nitrophenols. Measurement of exposure to biodegradable
pesticides yielding these compounds as metabolites. Jour.
Agric. Food Chenu 21; 295.
Sidwell/ V.D., et al. 1974. Composition of the edible portion
of raw (fresh or frozen) crustaceans, finfish, and mollusks.
I. Protein/ fat/ moisture/ ash/ carbohydrate/ energy value/
and cholesterol. Mar. Fisheries Review 36: 21.
Stannard, D. J., and A. Scotter,, 1977. The determination
of phenol residues in dairy products. N. Zealand Jour.
Dairy Sci. Technol. 12: 140.
C-65
-------
Stockdale, M., and M. J. Selwyn. 1971. Influence of
substituents on the action of phenols on soine dehydrogenases,
phosphokinases and tie soluble ATPase from mitochondria.
Eur. Jour. Biochem. 21: 416.
Tanaka, K., et al. 1977. Pathways of chlorophenol formation
in oxidative biodegradation of BHC. Agric. Biol. Chem.
41: 723.
VanMiller, Jf P., et al. 1978. Increased incidence of
neoplasma in rats exposed to low levels of 2, 3, 7, 8-tet'racti-
lorodibenzo-p-dioxin. Cited in Federal Register 43: 17145,
April 21, 1978.
Veith, G.D. , et al. An evaluation of using partition coef-
ficients and water solubility to estimate bioconcentration
factors .for| organic chemicals in fish. (Manuscript) .
Weinbach/ ^. C., and J. Garbus. 1965, The interaction
of uncoupling phenols with mitochondria and with jnitochondrial
protein. Jour. Biol. Chem. 210: 1811.
Whiteside, T. 1977. A reporter at large: the pendulum
and toxic cloud. The New Yorker, July ;25,
Wright, F. C, , et al. 1970. Metabolic and residue
with 2-(2, 4, 5-trichlorophenoxy) -ethyl 2, 2-dichloropropionate.
Jour. Agric. Food Chem. 18: 845.
-------
TETRACHLOROPHENOL
Mammalian Toxicology and Human Health Effects
SUMMARY
Tetrachlorophenol is a fungicide and wood preserva-
tive. It is used as a water soluble salt to treat freshly
cut lumber with either a spray or dip treatment. The treat-
ment prevents sap stain organisms from growing in wood while
it is drying or waiting further processing.
Commercial pentachlorophenol contains three to ten
percent tetrachlorophenol (Goldstein, et al., 1977; Schwetz,
et al., 1978). The annual production of 25 million kg of
pentachlorophenol means that 0.75-2.5 million kg of tetrach-
lorophenol are produced concurrently and end up in the same
places as pentachlorophenoi.
There are three isomers of tetrachlorophenols the most
important of which is 2,3,4,6-tetrachlorophenol. Table
1 lists the physiochemical properties of the three isomers.
Like tri- and pentachlorophenols, tetrachlorophenol
contains toxic non-phenolic impurities. Schwetz, et al.
(1974) reported that commercial grade 2,3,4,6-tetrachloro-
phenol contained chlorodioxin isomers at levels of 28 ppm
(hexa-), 80 ppm (hepta-), and 30 ppm (octachlorodibenzo-
p-dioxiri) as well as chlorodibenzofurans at levels of 55
ppm (hexa-), 100 ppm (hepta-) and 25 ppm (octachlorodibenzofuran)
The commercial tetrachlorophenol was composed of 73 percent
•(.6tra- and 27 percent pentachlorophenol.
068
-------
Property
TABLE 1
Physiochemical Properties of Tetrachlorophenol3
Tetrachloroghenol Isomer
Molecular weight
Formula
Melting point °C
Boiling point C
Density
2,3,4,5
231.89
116-7
sublimes
231*89
70
sublimes
2,3,5,6
231.89
115
150
Solubility
water
alcohol
ether
acetone
benzene
Vapor pressure-iron Kg
(pressure, C)
CAS Number*
very
a.
Imia, 100°
N.L.b
slightly
soluble
—
soluble
000058902
slightly
—
very
aSource: Handbook of Chemistry and Physics, 59th Edition,
, R.C. Weast, Editor, CRC Press, 1978.
DN.L. « not listed in toxic substances list
N.D. = listed in toxic substances list but no CAS number
given.
C-69
-------
EXPOSURE
Introduction
There is no direct evidence that the human population
is being directly exposed to tetrachlorophenol. Residues
have not been reported in foods nor have levels been reported
in blood or urine. This lack of evidence reflects one of
two possibilities. First, there may actually be little
or no exposure. Second, exposure may be occurring without
being discovered or quantified.
C-7C
-------
Ingestion from Water
There are reports suggesting the presence of lower
chlorophenols occurring in drinking water, but the presence
of tetrachlorophenol has not been documented. The odor
threshold for 2,3,4,6-tetrachlorophenol in drinking water
is 915 ppb at 30°C (Hoak, 1957).
Ingestion from Food
There is no evidence to suggest that tetrachlorophenols
may be ingested from foods. If such compounds were in food,
they could probably be absorbed from the gut.
One interesting problem associated with exposure of
poultry to tetrachlorophenol-treated wood shavings has been
the resulting musty taint that developed in meat and eggs.
Parr, et al. (1974) conducted a small survey on the amount
of tetra- and pentachlorophenol entering poultry housing
as a result of using treated wood shavings. The problem
developed when a musty taint was observed in broiler chickens.
The musty taint was due to the fungal formation of tetra-
and pentachloroanisoles formed by the methylation of the
parent chlorophenol. The average 2,3,4,6-tetrachlorophenol
level in fresh shavings was 54 ug/g (ppm). The spent litter
contained 0.7 pg/g tetrachlorophenol and 0.5 pg/g tetrachloro-
anisole. The tetrachloroanisole was only occasionally detected
in fresh shavings. For comparison, the fresh shavings contained
an average of 12 ug/g of pentachlorophenol, and spent litter
contained 0.02 jag/g of pentachloroanisole and 0.3 ug/g of
pentachlorophenol. The odor threshold for 2,3,4,6-tetra-
chloroanisole was reported to be 4 x 10-6 jag/g (4 ppt).
C-71
-------
Harper and Balnove (1975) analyzed tissues from chickens
I
raised in contact with tetrachlorophenol treated wood shavings.
The levels of tetrachloroanisole in the chickens ranged
from 1.2 ng/g in the edible portion to 7.6 ng/g in bone.
Engel, et al. (1966) fed 1 mg of 2,3,4,6-tetrachloro-
anisole/kg to chickens. A musty taint developed in eggs
and broiler meat similar to that associated with keeping
chickens on tetrachlorophenol treated wood shavings.
There is a possibility that the metabolism of other
compounds could result in the formation of tetrachlorophenols.
j
Engst, et al. (1976) reported that rats partially metabo-
lized pentachlorophenol to 2,3,4,6- and 2,3,5,6-tetrachloro-
phenol. Ahlborg (1978) could not replicate the Engst results
but rather found that rats metabolized pentachlorophenol
to 2,3,5,6-tetrachlorohydroquinone and trichlorohydroquinone.
Kohli, et al. (1976) studied the metabolism of tetra-
chlorobenzene in rabbits. Both 1,2,3,4- and 1,2,3,5-tetra-
chlorobenzene were metabolized to 2,3,4,5- and 2,3,4,6-tetra-
chlorophenol. In addition, 1,2,3,5-tetrachlorobenzene resulted
in 2,3,4,6-tetrachlorophenol,, 1,2,4,5-Tetrachlorobenzene
resulted in only one metabolite 2,3,5,6-tetrachlorophenol.
All metabolites were isolated from urine.
A bioconcentration factor (BCF) relates the concentration
of a chemical in water to the concentration in aquatic organisms,
but BCF's are not available for the edible portions of all
four major groups of aquatic organisms consumed in the United
States. Since data indicate that the BCF for lipid-soluble
compounds is proportional to percent lipids, BCF's can be
adjusted to edible portions using data on percent iipids
and the amoijnts of various species consumed by Americans.
C-72
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A recent survey on fish and shellfish consumption in the
United States (Coddle, et al. 1978) found that the per capita
consumption is 18.7 g/day. Prom the data on the nineteen
major species identified in the survey and data on the fat
content of the edible portion of these species (Sidwell,
et al. 1974), the relative consumption of the four major
groups and the weighted average percent lipids for each
group can be calculated:
Consumption Weighted Average
Group (Percent) Percent Lipids
Freshwater fishes 12 4.8
Saltwater fishes v 61; 2.3
Saltwater molluscs 9 1.2
Saltwater decapods 18 1.2
Using the percentages for consumption and lipids for each
of these groups, the weighted average percent lipids is
2,3 for consumed fish and shellfish.
i
No measured steady-state bioconcentration factor {BCF)
is available for any of the following compounds,, but the
equation, "Log BCF » 0076 Log F p 0,23" can be used (?eithr
et al. Manuscript) to estimate, the BCF for aquatic organisms
that contain about eight percent lipids from the octanQl-
water partition coefficient (P), An adjustment factor o/f
i
2.3/8cO = 0.2875 can be used tq adjust the estimated BCF
from the 80Q percent lipids on which the equation is based!
to the 2.3 percent lipids that is the weighted average foe
consumed fish and shellfish.. Thus, the weighted average
bioconcentration factor for the edible portion of all aquatic
organisms consumed by Americans can be calculated.
C-73;
-------
Compound P BCF Weighted BCF
2,3,4,6-tetrachlorophenol 20,000 1,100 320
Inhalation
Olie, et al. (1977) reported finding di-, tri-, and
tetrachlorophenols in flue gas condensates from municipal
incinerators. The levels were not quantified.
Dermal
No » ailable data.
PHARMACOKINETICS
Absorption and Distribution
No available data.
Metabolism and Excretion
Ahlborg and Larsson (1978) studied the urinary metabo-
lites of tetrachlorophenol in rats following intraperitoneal
doses of 10 mg/kg. 2,3,5,6-tetrachlorophenol was excreted
as unchanged tetrachlorophenol and as tetrachloro-p-hydro-
quinone. No trichloro-p-hydroquine was found in the urine
of rats given the 2,3,5,6-tetrachlorophenol isomer. In
a quantitative study rats were given 5.3 mg of 2,3,5,6-tetra-
chlorophenol, and the urine was collected for 24 hours.
Over 98 percent of the administered dose was recovered in
the urine in 24 hours, indicating an excretion half-life
of less than one day. About 66 percent of the chlorophenol
was excreted as unchanged 2,3,5,6-tetrachlorophenol and
35 percent was eliminated as tetrachloro-p-hydroquinone.
After 24 hours neither parent compound nor metabolite could
be found in the urine. This may indicate a one to two per-
C-74
-------
cent fecal exgeetion, The 2,3,4,5,- and 2,3,4,6 tetrachloro-
phenql isomers are not metabolized tQ any large extent.
The 2,3,4,5-isQmer is primarily excreted as unchanged chloro-
phenol with trace amounts of trichlgrQ-p-hydroquinone appearing
in the urine. Fifty^-one perqent of the administered dose
was recovered in the urine in 24 hours. During the second
24 h.p,urs, an additional seven percent of the dose appeared
in feh_e uEine. Altogether, 59 percent of the intraperitoneal
d©ge wa§ recovered in the urine with the disposition of
the remainder o,f the dose not identified.
The 2,3,4,6-tetrachlorophenol isomer is rapidly elimi-
nated in the urine as, unchanged chlorophenol. About 94
percent o,f the intraperitoneal dose was recovered in the.
urine in 24 hours. Trace amounts of trichloro-p-hydroqui-
n.Qne were found in the urine. In the experiments of Alhbarg.
and Larsspn the urine was boiled in HC1 to split any conju-
gates, s.uch as glucornides.
EFFECTS
Acute,. S^b-acute, and C.hronic Toxicity '
The acute toxicity of tetrachlorophenol isomers via
various routes and in several species is shown in Table
2. €jn an amcute oral LD50 basis,, tetrachlorophenol is les.s
i
toxic, than pentachlorophenol. In the studies, of Ahlborg
an,d L,acsson, (;1978) pentachlorophenol had an oral LD.5'0 of
L50; rn;gi/Kg in 'mice and 294 mg/kg in ger^ils.. The comparative
tc>ferach,lprophenol LD50' s ranged from 5.33 to, 9.79 mg/kg.
This; po,int wi'll be important in setting' the criterion.
Tetrachlorophenol toxicosis c,on,s-,ists o.f. depressed:
and njOitpr weakness (Deichmana, 1943.) . Tremor.s, and convul-
C-75
-------
TABLE 2
Acute Toxicity of Tetcachlorophenol and Metabolites.
CHEMICAL
Tetrachlorophenol
2,3,4,6-Tetrachlorophenol
o
-4
-------
o
I
CHEMICAL
2,3,5,6-Tetrachlorophenol
2,3,4,S-Te trachlorophenol
Tetrachloro-p-hydroquinone
Tetrachloropyrocatechol
Tetrachloro-p-hydroquinone
Tetrachloropyrocatechol
SOLVENT
ethanoi
ethanol
propylene
glycol
propylene
glycol
ethanol
ethanol
ethanol
propylene
glycol
ethanol
ethanol
ethanol
ethanol
ANIMAL
nouse, C57
female
nouse, C57
male
mouse, C57
female.
gerbil,
female
mouse, C57
female
mouse, C57
male
mouse; C57
female
mouse, C57
female
mouse, C57
female
mouse, C57
female
mouse , CS7
male
mouse, C57
•ale
TOXIC RESPONSE
oral LD50 - 109 mg/kg
oral LD50 » 89 mg/kg
oral LD50 - 677 mg/kg
oral LDSO - 533 mg/kg
oral LDSO - 400 mg/kg
oral LDSO - 572 mg/kg
intraper Itoneal
LDSO • 97 mg/kg
intraper itoneal
LDSO - 133 rag/kg
oral LDSO - 500 mg/kg
oral LDSO - 612 mg/kg
oral LDSO - 750 mg/kg
oral LDSO - 750 mg/kg
REFERENCE
Ahlborg and Larsson,
1978
Ahlborg and Larsson,
1978
Ahlborg and Larsson,
1978
Ahlborg and Larsson,
1978
Ahlborg and Larsson,
1978
Ahlborg and Larsson,
1978
Ahlborg and Larrson,
1978
Ahlborg and Larsson,
1978
Ahlborg and Larsson,
1978
Ahlborg and Larsson,
1978
Ahlborg and Larsson,
1978
Ahlborg and Larsson,
ma
-------
CHEMICAL SOLVENT ANIMAL TOXIC RESPONSE REFERENCE
Tetrachloro-p-hydroquinone ethanol mouse, C57 intreaperitoneal Ahlborg and Larsson,
female LD50 = 35 mg/kg 1978
Tetrachloropyrocatechol ethanol mouse, CS7 intrapecltoneal Ahlbocg and Larsson,
female LD50 » 136 mg/kg 1978
Pentachlorophenol pcopylene mouse, C57 oral LD50 » 150 rag/kg Ahlborg and Larsson,
glycol female 1978
propylene geibil, oral LD50 » 294 mg/kg Ahlborg and Larsson,
glycol female 1978
ethanol mouse, C57 oral LD50 = 74 mg/kg Ahlborg and Larsson,
female 1978
o
-j ethanol mouse, C57 oral LD50 •= 36 mg/kg Ahlborg and Larsson,
00 male 1978
ethanol mouse, C57 intraperitoneal Ahlborg and Larsson,
female LD50 » 32 mg/kg 1978
propylene mouse, C57 intraperitoneal Ahlborg and Larsson,
glycol female LD50 » 59 mg/kg 1978
-------
sions do not occur except in extremes.
Ahlborg and Larsson (1978) determined the acute oral
and intraperitoneal LD50 of three isomers of tetrachloro-
phenol and related compounds in mice and gerbils (Table
2). The effect of solvent is shown by the increased toxi-
city of the chlorophenols when dissolved in ethanol versus
propylene glycol.
Ahlborg and Larsson (1978) also determined the acute
oral and intraperitoneal toxicity of tetrachloro-p-hydro-
quinone, which is the major urinary metabolite of 2,3,5,6-
tetrachlorophenol in rats. When administered orally the
metabolite was less toxic than any of the three tetrachloro-
phenol isomers in either male or female mice. However,
when the metabolite was administered intraperitoneally in
female mice it was more toxic than any of the three tetra-
chlorophenol isomers, and the LD 50 was similar to the intra-
peritoneal LD50 of pentachlorophenol (Table 2).
Parquharson, et al. (1958) showed that the intraperi-
toneal LD50 of 2,3,4,6-tetrachlorophenol in rats was 130
mg/kg. Convulsions did not occur, but there was a marked
4°C rise in body temperature, and rigor mortis occurred
•
within five minutes of death. Brain homogenate oxygen con-
sumption was stimulated at 5 x 10" M.
Schwetz, et al. (1974) reported that the ten day maximum
tolerated dose for commercial 2,3,4,6-tetrachlorophenol
in rats was 30 mg/kg day" . Deaths occurred in groups given
100 or 300 mg/kg day"1.
Several investigators have examined the effect of tetra-
chlorophenol on cellular metabolism. Mitsuda, et al. (1963)'
C-79
-------
studied the effects of various chlorophenols on oxidative
phosphorylation in isolated rat liver mitochondria. The
test system used a 2.75 ml reaction medium at pH 7.0, containing
0.05 ml of mitochondrial suspension with 0.43 mg N. The
concentration of chlorophenol required to produce a 50 percent
inhibition in the production of ATP was determined (I50)•
2,3,4,6-Tetrachlorophenol had an I50 of 2 uM. For comparison,
the ICQ for pentachlorophenol was 1 pM and for 2,4-dinitro-
phenol the ICQ was 17 ;uM.
Weinbach and Garbus (1965) tested the ability of various
substituted phenols to completely uncouple oxidative phosphor-
ylation in vitro. There was a positive relationship between
mitrochondria protein binding and uncoupling properties.
2,3,4,6-Tetrachlorophenol caused complete uncoupling at
0.05 mM. For comparison, the known uncoupler 2,4-dinitro-
phenol completely uncoupled the test system at 0.1 mM.
Arrhenius, et al. (1977) studied the effects of chloro-
phenols on microsomal detoxication mechanisms using rat
liver preparations. The experimental system examined the
effects of the test chlorophenol on the microsomal metabo-
lism of N, N-dimethylaniline (DMA) to formaldehyde and N-
methylaniline (C-oxygenation) or to N, N-dimethylaniline-
N-oxide (N-oxygenation). In summary, the study examined
disturbances in the detoxification electron transport chain.
The concern as stated by Arrhenius, et al. was that compounds
that increased N-oxygenation could influence the metabolism
of other chemical toxicants, such as aromatic amines, which
are formed by N-oxygenation. Agents that increase N-oxygen-
ation could be considered as synergists for the carcinogenic
C-80
-------
action of aromatic amines.
At a concentration greater than 0.3 mM, 2,3,4,6-tetra-
chlorophenol inhibits C-oxygenation of DMa and stimulates
N-oxygenation of DMA. To help put this in a dose-response
context, a concentration of 0.3 mM is equivalent to 69.57
rag of tetrac,hlorophenol/l.
Butler (1937) reported 21 cases of chloracne in workers
handling a mixture of 2-chlorophenyl and tetrachlorophenol
sodium.
Levin and Nilsson (1977) analyzed wood dust from saw-
mills in Sweden where chlorophenol fungicides are applied
to green timber after sawing to prevent sapstain. The fungi-
cide used consisted of 10 percent 2,4,6-trichlorophenol,
70 percent 2jf 3 ,4,6-tetrachlorophenol, and 20 percent penta-
chlorophenol, and contained 1600 ppm chlorophenoxyphenols,
70 ppm
-------
phenol. Schwetz, et al. (1978) fed rats a low non-phenolic
content commercial pentachlorophenol containing 10.4 + 0.2
percent tetrachlorophenol and 90.4 + 1.0 percent pentachloro-
phenol at levels of 1, 3, 10 or 30 mg/kg for 22 months (males)
and 24 months (females). The results showed a no-observable
effect level (NOEL) of 3 mg/kg (females) and 10 mg/kg (males)
based on clinical chemistry, hematology, pathology and organ
weight changes. This represents a tetrachlorophenol expo-
sure of 0.312 mg/kg for females and 1.04 mg/kg for males.
Synergism and/or Antagonism
No data are available.
Teratogenici ty
Schwetz, et al. (1974) administered commercial or puri-
fied tetrachlorophenol to rats on days six through 15 of
gestation. Dosage levels used were 10 or 30 mg/kg. Neither
grade of tetrachlorophenol was embryolethal or teratogenic.
Both forms were fetotoxic at 30 mg/kg, with the effect being
delayed ossification of the skull bones.
The only fetotoxic effect observed at 10 mg/kg was
subcutaneous edema, which was not observed at 30 mg/kg.
The non-phenolic impurities in commercial grade tetrachloro-
phenol did not alter the prenatal effects.
Mutagenicity
Rasanen, et al. (1977) tested chlorophenols for mutageni-
city using the Salmonella-mammalian microsome Ames test
with both the non-activated and liver homogenate added systems.
2,3,4,6-Tetrachlorophenol was reported as non-mutagenic
in both test systems.
C-82
-------
Care i nogenic i ty
Ho studies were found that'were specifically designed
to determine the carcinogenic properties of tetrachlorophenol.
The study of Schwetz, et al. (1978) is of indirect value.
This study is described in the effects section. The inci-
dence of tumors is shown in Table 3. The authors concluded
that low non-phenolic content pentachlorophenol containing
90,4 + 1.0 percent pentachlorophenol and 10.4 + 0.2 percent
tetrachlorophenol was non-carcinogenic when tested at doses
Hr
of 1, 3, 10 or 30 mg/kg in a rat life-time feeding study.
The high dose represents a tetrachlorophenol exposure of
3.12 mg/kg.
While the data base is limited and less direct than
desired, there is presently no indication that tetrachloro-
phenol is carcinogenic. The obvious long term consideration
is the potential carcinogenicity of the chlorodibenzo-p-
dioxins that may be present in commercial tetrachlorophenol.
C-83
-------
TABLE 3
Incidence of Primary Tumors (Based on Histopathological Diagnosis) in Rats fed
Pentachlorophenol (PCP) for 22 Months (Males) and 24 Months (Females)
(Schwetz, et al. 1978)
o
CO
Dose: mgPCP/kg/day 0 1
Number of rats examined: 27 26
Number of rats with tumors: 11 13
Number of tumors: 17 14
Number of tumors/rats
with tumors: 1.6 1.1
Number of morphologic
malignant tumors: 1 3
Males
3
27
13
17
1.3
10
27
12
15
1.4
30
27
11
61
2.3
0
27
27
62
2.6
1
27
26
67
1.7
Females
3
27
25
42
1.7
10
27
25
63
30
27
25
63
2.5 2.!
-------
CRITERION FORMULATION
The information of this section is presented in a composite
treatment of the chlorophenols at the end of the document.
C-85
-------
REFERENCES
Ahlborg, U.G. 1978. Dechlorination of pentachlorophenol
In vivo and iji vitro. Pages 155-130 Iri K. Rango Rao, ed.
Pentachlorophenol: Chemistry, pharmacology and environmental
toxicology, Plenum Press, New York.
Ahlborg, U.G., and K. Larsson. 1978. Metabolism of tetra-
chlorophenols in the rat. Arch. Toxicol. 40: 63.
Arrhenius, E., et al. 1977. Disturbance of microsomal detoxi-
cation mechansims in liver by chlorophenol pesticides.
Chem.-Biol. Interact. 18: 35.
Butler, M.G. 1937. Acneform dermatosis produced by ortho
(2 chlorophenyl) phenol sodium and tetra-chlorophenol sodium.
Arch. Dermatol. Syphilol. 35: 251.
Deichmann, W.B. 1943. The toxicity of chlorophenols for
rats. Fed. Proc. 2: 76.
Engel, C., et al. 1966. Tetrachloroanisol: A source of
musty taste in eggs and broilers. Science 154: 270.
Engst, R.t et al. 1976. The metabolism of lindane and its
metabolites gamma-2,3,4,5,6,-pentachlorocyclohexene, penta-
chlorobenzene. and pentachlorophenol in rats and the pathways
of lindane metabolism. Jour. Environ. Sci. Health 2: 95.
C-86
-------
Farguharsen, M.E., et al. 1958. The biological action of
chlorophenols. Br. Jour. Pharmacol. 13: 20.
Goldstein, J.A., et al. 1977. Effects of pentachlorophenol
on hepatic drug-metabolizing enzymes and porphyria related
to contamination with chlorinated dibenzo-p-dioxins and
dibenzQfurans. Bioehem. Pharmacol. 26: 1549.
Harper, D.B., and D. Balnove. 1975. Chloroanisole residues
in broiler tissues. Pestic.~ Sci. 6: 159.
Hoak, >R.p. 1957. The causes of tastes and odors in drinking
water. Purdue Eng. Ext. Serv. 41: 229. :
Kohli, J., et al. 1976. The metabolism of higher chiLori~
nated benzene isomers. Can. Jour. Bioehem. 54: 203.
1 "/' i
Levin, J.Q. et al. 1976, Use of chlorophenols as fungicides
in sawmills. Scand. Jour. Work Environ. Health 2: 71.
inr J., and C. NiJLsspn. 197,7. Chromatographic determine*
tion of polychlorinated phenols:, phenoxyphenols, diben??0fuifaini
and dibenzodipxins in wood^-dugt from workers environments,
Chemosphere 7: 443.
Mitsuda, H. , et al. 1963. Effect of chlorophenQl analaguea
on the oxidative phosphorylation in rat liver mitochondria,
Agric. Biql. Chem. 27: 366.
C'87
-------
Olie, K., et al. 1977. Chlorodibenzo-p-dioxins and chlorodi-
benzofurans are trace components of fly ash and flue gas
of some municipal incinerators in the Netherlands. Chemosphere
8: 445.
Parr, L.J., et al. 1974. Chlorophenols from wood preserva-
tives in broiler house litter. Jour. Sci. Food Agric. 25: 835.
Rasanen, L., et al. 1977. The mutagenicity of MCPA and
its soil metabolites, chlorinated phenols, catechols and
some widely used slimicides in Finland. Bull. Environ.
Contain. Toxicol. 18: .565.
Schwetz, B.A., et al. 1974. Effect of purified and commer-
cial grade tetrachlorophenol on rat embryonal and fetal
development. Toxicol. Appl. Pharmacol. 28: 146.
Schwetz, B.A., et al. 1978. Results of two-year toxicity
and reproduction studies on pentachlorophenol in rats.
Ijr^ K Rango Rao, ed. Pentachlorophenol: Chemistry, pharmacology
and environmental toxicology. Plenum Press, New York.
weinbach, E.C., and J. Garbus. 1965. The interaction of
uncoupling phenols with mitochondria and with mitochondrial
protein. Jour. Biol. Chem. 210: 1811.
C-88
-------
CHLOROCRESOLS
Mammalian Toxicology and Human Health Effects
SUMMARY
(The chlorocresols structurally consist of a benzene
ring with the substitution of one hydroxyl group, one methyl
group and one or more chlorines. They are named either
chlorocresols or chlorohydroxytoluenes. It is possible
to have mono-, di-, tri- or tetrachlorocresols. Interestingly,
no information was found on the chemical properties of tri-
chlorocresols. Tables 1-3 list the physicochemical properties
of the chlorocresols. The toxic substances list does not
mention any of the chlorocresols, under either the cresol
or hydroxytoluene names. Gosselin, et al. (1976) indicate
that 6-chloro-m-cresol and p-chloro-m-cresol may be used
as antiseptics and disinfectants. The United States Pharma-
copeia does not list any of the chlorocresols. Goodman
and Gilman (1975) do not discuss any of the chlorocresols.
An unspecified isomer of chlorocresol has been used in England
as a preservative in Pharmaceuticals (Ainley, et al. 1977).
34-Chloro-m-cresol is a commercial microbicide marketed
as Preventol CMK (Bayer) (Voets, et al. 1976).
Rapps (1933) found that p-chloro-m-cresol had antiseptic
properties with a phenol coefficient of 13-25.
C-89
-------
TABLE 1
Chemical Properties of Monochlorocresols.
o
1
to
0
Property
Molecular wt.
Formula
Melting point
Boiling point
Density
Solubility
water
alcohol
ether
acetone
benzene
Alternate
name
2-Chloro-
p-cresol
142.59
C?H7C10
195-6
1.1785
slightly
soluble
soluble
soluble
3-chloro-
4-hydroxy-
toluene
6-Chloro-
0-cresol
142.59
C7H7C10
188-9
soluble
.
.-..
3-chloro-
2-hydroxy-
toluene
3-Chloro-
0-cresol
142.59
C7H7C10
86
225
_ — •
slightly
soluble
soluble
• soluble
2-chloro-
6-hydroxy-
toluene
4-Chloro-
m-cresol
142.59
C7H7C10
66-8
235
slightly
soluble
soluble
•
r-
2-chloro-
5-hydroxy-
toluene
3-Chloro-
p-cresol
142.59
C7H7C10
55-6
228
soluble
soluble
soluble
soluble
2-chloro-
4-hydroxy-
toluene
2-Chloro-
m-cresol
142.59
C?H7C10
55-6
196
slightly
•
2-chloro-
3-hydroxy
toluene
Source: Handbook of Chemistry and Physics, 59th Edition, R.C. Weast, Editor, CRC Press, 1978.
-------
Property
Molecular wt.
formula
Meltihi point
Boiling .point
fcenslty
i
i
Solubility
water
alcohol
ether
acetone
benzene
Alternate
ftalhe
TABLE 2
Chemical Properties of Dichiorbcresols.
4»6-dichlorb- 2,6-dichloro- 2>4-dichlofb- 4,6-dichlote-
m-cresol m-cresol Q-cresol
4,5-dichloro
0-cfesol ;
23S-6
177.03
5B-9
soluble
tbiueftte
% » 4-
a-hy
toluefte
177.03
241-242,5
soluble
2 -,€-a ichldrfe
3-hydtbxy-
toluene
177.03
U
266.5
•UA«»
slightly
Very
very
v^^_
3<,5-dichlQft>-
2-aydrbxy-
tbluene
177.03
39
138-9
4^^^'«i
slightly
soluble
soluble
._&«.
<4*-hydroxy-
toluene
177.D3
C^Cl^O
•^.tf-Um.
slightly
'soluble
•^•MBB.
soluble
o- 4,5-dichlorc
2-hydiroxy-
toluene
Source: Handbook of Chemistry and Physics* S9th Edition, R.£. Weast, Editor* CftG Press, 1978.
-------
TABLE 3
Chemical Properties of Tetrachlorocresols.
Property
3,4,5,6-tetra-
chloro-o-cresol
2,4,5,6-tetra-
chloro-m-cresol
2,3,5,6-tetra-
chloro-p-cresol
Molecule wt.
Formula
Melting point
Boiling point
Density
245.92
C7H4C140
190
245.92
C?H4C140
189-90
245.92
C7H4C140
190
Solubility
Vdter
alcohol
ether
acetone
benzene
soluble
soluble
soluble
soluble
soluble
soluble
soluble
soluble
soluble
Alternate
name
2-hydroxy-
3,4,5,6-tetra-
chlorotoluene
3-hydroxy-
2,4,5,6-tetra-
cnlorotoluene
4-hydroxy-
2,3,5,6-tetra-
chlorotoluene
Source: Handbook of Chemistry and Physics, 59th Edition, R.C. Weast,
Editor, CRC Press, 1978.
C-92
-------
EXPOSURE
Introduction
In general, there are no published data available for
the determination of current human exposure to chlorocresols.
Although this- fact may reflect an actual lack of exposure,
it is also possible that exposures are simply going undetected
and unquantified. Some studies have been done on the occur-
rence and use of chlorocresols.
An unspecified isomer of chlorocresol, assumed to be
p-chloro-m-cresol, is used at a concentration of 0.15 percent
to preserve mucous heparin in England (Ainley, et al. 1977).
The intravenous use of this product in anticoagulation therapy
results in human exposure. Heparin solutions marketed in
the United States are preserved with benzl alcohol or thimer-
osal (Physicians Desk Reference).
The potential occurrence of chlorocresols in the environ-
ment was suggested by Jolley, et al. (1975) who reported
1.5 ug/1 of 4-chloro-3-methylphenol (p-chloro-m<-cresol)
in chlorinated sewage treatment effluent. Another potential
source is soil degradation of the hormone herbicide MCPA
(4-chloro-2-methylphenoxyacetate). One metabolite of MCPA
is 5-chloro-o-cresol (Gaunt and Evans, 1971). Rasatien,
et al. (1977)-found that technical MCPA contains 4 percent
4-chloro-O-cresol as an impurity. '•
Voets, et al. (1976) reported that p-chloro«-m-cresol
degraded 30 percent in two weeks in an aerobic minimal test
and degraded 100 percent in two weeks in an aerobic activated
sludge test system. There was no degradation in either
test system under anaerobic conditions. In both series
of tests the p-chloro-m-cresol concentration was 20 mg/1.
C-93
-------
Ingestion from Water
No data are available.
Ingestion from Food
No data are available.
Inhalation
No data are available.
Dermal
No data are available.
PHARMACOKINETICS
Absorption
Roberts, et al. (1977) used human autopsy skin epidermal
membranes in an in vitro test system to determine the permea-
bility of chemicals through human skin. Chlorocresol, isomer
aot specified, permeated the membrane at a 0.4 percent (w/v)
concentration after a 17 minute time lag. A concentration
of 0.5 percent (w/v) damaged the membrane. Chlorocresol
permeated more readily than either 2- or 4-chlorophenol
bjJt less readily than 2,4,6-trichlorophenol.
Distribution
No data are available.
Metabolism
No data are available.
Excretion
Zondek and Shapiro (1943) injected 1000 mg of p-chloro-
m-cresol subcutaneously into a one kilogram rabbit. Not
much detail was provided on effects other than that 15 to
20 percent of the dose was recovered in the urine. The
same compound was given intramuscularly to humans and was
not', recovered in the urine to any appreciable extent. The
dose was not specified but in a companion study 7 to 12
grams of p-chloro-m-xylenol was injected into humans.
-------
EFFECTS
Acute, Sub-acute,, and Chronic Toxicity
Von Oettingen (1945) reviewed the use and toxicity
of the chlorocresols as part of an effort for the Experimental
Biology and Medicine Institute, National Institutes of Health.
In 1939 Wien reported on acute toxicity studies with
p-chloro-m-cresol. It was suggested that 0.3 to 0.25 percent
p-cbloro-m.-cr.esol. be used in place of 0.5 percent phenol
for sterilization of solutions of thermolabile substances.
Tables 4 and 5 list the available toxicity data.
TABLE 4
Acute- Toxicity of p-Chloro-m-cresol (Wien, 1939).
•>
Animal Route Effect
Mouse Subcutaneous LD5Q = 360 mg/fcg
Mouse Intravenous LD50 = 70 rag/kg
Rat Subcutaneous LD50 = 400 rag/Jcg
TABLE 5
*•
Acute Toxicity of Monodilorocresol (Schrotter, efc al. 1977).
Chemical Animal Oral LD50
p-Chloro-b-cresol. mouse 1330 fltg/kg
m-Ch,loro-o-cresol mouse 710 mg/kg
Like the monochloropheno-Is, p-cftloro-m-ccesol produced
severe muscle tremors and death in a few ttdtsrs. Damage
to renal tubules was noted at high dosages (Wien, 19>39) .
-------
Wien also conducted some short term toxicity studies.
A dose of 80 mg/kg given subcutaneously for 14 days did
not adversely affect the growth of young rats. No lesions
were found in kidney, liver, or spleen. Mild inflammation
was reported at the injection site. Rabbits weighing 1.5
to 2.3 kg were injected subcutaneously with 12.5 mg p-chloro-
m-cresol daily for four weeks. The dose represented 5 ml
of a 1 in 400 solution, such as might be used to preserve
a pharmaceutical. Only three experimental rabbits and no
controls were used, making interpretation of the clinical
data tenuous. No obvious changes were noted. Liver and
kidney were normal histologically.
In the one report found on trichlorocresol (Eichholz
and Wigand, 1931, cited by Von Oettingen, 1949), trichloro-
cresol, isomer not stated, was an effective intestinal anti-
septic in a 0.25 percent solution. Rabbits tolerated 500
mg/kg oral doses for four consecutive days, but 600 mg/kg
killed two of three rabbits. Clinical signs included convulsions.
Para-chloro-m-cresol has been reported to cause vesicular
dermatitis in humans (Guy and Jacob, 1941). Concentrations1
of 1.5 percent (aqueous) cause a pruritic vesicular dermatitis
in sensitive individuals. Symptoms occur in four hours
and regress in a week.
Hancock and Naysmith (1975) reported two cases of gener-
alized and seven cases of local reactions to mucous heparin
preserved with 0.15 percent chlorocresol. The systemic
reactions included collapse, pallor, sweating, hypotenion,
C-96
-------
tachycardia and generalized urticarial rash. Intradermal
testing with chlorocresol-preserved heparin and non-chloro-
cresol heparin identified the cause to be the chlorocresol-
preserved heparin.
Ainley, et al. (1977) also reported an adverse reaction
involving heparin preserved with 0.15 percent chlorocresol.
The reaction involved a local severe burning pain at the
injection site that radiated up the arm. Shortly afterwards
nausea and lightheadedness followed. The patient then became
drowsy with pallor and sweating. Formal intradermal skin
testing produced a reaction to the preserved heparin but
not to the preservative-free heparin.
Synergism and/or Antagonism
r No data are available.
Tera togenic ity
No information was found reporting the presence or
absence of teratogenic properties of any member of the chloro-
cresols group of chemicals.
Mutagenicity
Rasanen, et al. (1977) tested some chlorocresols for
mutagenicity using the Salmonella-mammalian microsome Ames
test with both the non-activated and liver homogenate added
systems. The following chlorocresols were tested and reported
as non-mutagenic in both test systems: 3-chloro-O-cresol,
4-chloro-0-
-------
CRITERION FORMULATION
The information of this section is presented in a composite
treatment of the chlorophenols at the end of the document.
098
-------
REFERENCES
Ainley, E.J., et al. 1977. Adverse reaction to chlorocresol-
preserved heparin. Lancet 1803: 705.
Eichholz, P., and R, Wigand. 1931. Uber die wirkung von darmdesin-
i
fektion smilleln. Eingegangen. 159: 81.
Gaunt, J.K., and W.C. Evans. 1971. Metabolism of 4-chlor-
2-methylphenoxyacetate by a soil pseudomonad. Biochem.
Jour. 122: 519.
Goodman, L.S., and A. Gilman. 1975. The Pharmacological
Basis of Therapeutics. MacMillian Publishing Co., Inc.,
New York, New York.
Gosselin, et al. 1976. Clinical Toxicology of Commercial
Products. Williams and Wilkins, Co., Baltimore.
!
Guy, W.H., and P.M. Jacob. 1941. Occupational dermatitis
due to parachlorometacresol. Jour. Am. Med. Assoc. 116:
2258.
Hancock, B.W., and A. Naysmith. 1975. Hypersensitivity
of chlorocresol preserved heparin. Br. Med. Jour. 746.
Jolley, R.L., et al. 1975. Analysis of soluble organic
constituents in natural and process waters by high-pressure
liquid chromatography. Trace Subs. Environ. Hlth; 9: 247.
C-99
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McCollister, D.D., et al. 1961. Toxicologic information
on 2,4,5-trichlorophenol. Toxicol. Appl. Pharmacol. 3: 63.
National Academy of Sciences. 1977. Drinking water and
health. Washington, D.C.
Rapps, N.F. 1933. The bactericidal efficiency of chlorocresol
and chloroxylenol. Jour. Soc. Chem. Ind. 52: 175.
Rasanen, L., et al. 1977. The mutagenicity of MCPA and
its soil metabolites, chlorinated phenols, catechols and
some widely used slimicides in Finland. Bull. Environ.
Contain. Toxicol. 18: 565.
Roberts, M.S., et al. 1977. Permeability of human epidermis
to phenolic compounds. Jour. Pharm. Pharroac. 29: 677.
Schrotter, E., et al. 1977. Organische synthetica und
ihre vermizden eigenschaften. Pharmazie. 32: 171.
Voets, J.P., et al. 1976. Degradation of microbicides
under different environmental conditions. Jour. Appl. Bact.
40: 67.
von Oettingen, W.F. 1949. Phenol and its derivatives:
the relation between their chemical constitution and their
effect on the organism. National Inst. Health Bull. 190:
193.
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Wien, R. 1939. The toxicity of parachlorometacresol and
of phenylmercuric nitrate. Quarterly Jour, and Yearbook
of Pharmacy. 12: 212.
Zondek, B., and B. Shapiro. 1943. Fate of halogenated
phenols in the organism. Biochem. Jour. 37: 592.
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CRITERION FORMULATION
Existing Guidelines and Standards
No standards have yet been established for the monochloro-
phenols, dichlorophenols, tetrachlorophenols or chlorocresols.
,No existing standards were found for the trichlorophenols;
however, the National Academy of Sciences report Drinking
Water and Health (1977) calculated a no-adverse-effect level
of 0.7 mg 2,4,5-trichlorophenol/1 based on the toxicity .
studies with that compound showing no-observable-effect
levels (NOEL) of 10 mg/kg in dogs and mice and 30 mg/kg
in rats. These levels were used to determine an ADI (acceptable
daily intake) of 0.1 mg/kg.
Current Levels of Exposure
There are no available data for any of the chlorophenols
on exposure levels.
Special Groups at Risk
There are no special groups at risk for the monochloro-
phenols, dichlorophenols, trichlorophenols or chlorocresols.
Special groups at risk for the tetrachlorophenols include
manufacturers, users in wood sawmills, and wood treaters.
Basis and Derivation of Criteria
The chlorinated phenols which are the subject of this
document are the monochlorophenols (3- and 4-chlorophenol);
the dichlorophenols (2,5-; 2,6-; 2,3-; 4,6-; and 3,4-dichloro-
phenols) the trichlorophenols (2,4,5-; 3,4,5-; 2,4,6-; 2,3,4-;
2,3,5-; and 2,3,6-trichlorophenol) and the tetrachlorophenols
(2,3,4,5-; 2,3,4,6-; and 2,3,5,6-tetrachlorophenols). In
addition, the monochlorocresols are discussed.
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Three chlorinated phenols have been the subject of
separate criteria documents: 2-chlorophenol, 2,4-dichlorophenol
and pentachlorophenol.
There are very little data on most of these compounds
on chronic mammalian effects. However, the organoleptic
effects of these compounds have been well documented (Table 1).
There are toxicity data on 2,4,5-trichlorophenol.
McCollister,, et al. (1961. Toxicol. Appl. Pharmacol. 3: 63)
in 98 day feeding study on rats, demonstrated the No-Observable-
Effect-Level^ (NOEL) for 2,4,5-trichlorophenol to be 100
mg/kg. Using the National Academy of Science's recommended
uncertainty factor of 1000 (Drinking Water and Health, 1977)
the Acceptable Daily Intake (ADI) is calculated to be 0.1
mg/kg of body weight, or 7 mg for a 70 kg. person.
For the sake of establishing water quality criteria,
it is assumed that on the average a person ingests 2 liters
of water and 18.7 grams of fish. Since fish may bioaccumulate
substances, a bioconcentration factor (BCF) is used in the
calculation.> The BCF for 2,4,5-trichlorophenol is 130 and
was derived by U.S. EPA ecological laboratories in Duluth,
Minnesota.
The equation for calculating an acceptable amount of
2,4,5-trichl6rophenol in water based on the ingestion of
2 liters of drinking water and 18.7 grams of fish is:
(2 1) x + (0.0187 x F) x = ADI
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where
21 =2 liters of drinking water
0.0187 kg = amount of fish consumed daily
F = bioconcentration factor
(130 for 2,4,5-trichlorophenol)
ADI - Allowable Daily Intake
(mg/day for a 70 kg person)
(21) x + (0.0187 x 130) x = 7.0 mg
2 x + 2.43 x = 7.0
4.43 x = 7.0
x = 1.6 mg/1
There are no toxicity data for tetrachlorophenol, but
because of the similarities between tetra- and penta- chloro-
phenol and the lower acute toxicity of tetrachlorophenol,
it is reasonable to set the water criterion on the basis
of the more extensive toxicologic data base for pentachloro-
phenol.
The criterion is established as follows. The no observ-
able effect level (NOEL) for pentachlorophenol is 3 mg/kg.
Since the chlorophenols are rapidly excreted by mammals,
an uncertainty factor of 100 is used to establish the acccept-
able human exposure of 0.03 mg/kg per day. A water intake
of 2 I/day and an average body weight of 70 kg are assumed.
The acceptable whole body exposure is then 70 kg times 0.03
mgAg/day which equals 2.1 mg/day.
Assuming that the total exposure is from ingesting
2 liters of drinking water and 18.7 grams of fish, the calcula-
tion previously described is employed:
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(21) x + (0.0187 x 320) « 2.1 mg
2 X + 5.98 X = 2.1 mg
7.98 x - 2.1 mg
X =, .263 mg
Thus, for tetrachlorophenol", which is ba.sed on the
use of chronic toxicologies data and an uncertainty factor
of 100, the recommended criterion level 263 /ag/1. Drinking
water contributes 25 percent of the assumed exposure while
eating contaminated fish products accounts for 75 percent.
The criterion level can alternatively be expressed as 351
ug/lif exposure is assumed to'be from the consumption of
fish and shellfish products alone.
The organoleptic properties of the chlorinated phenols
are well known. These compounds have been reported to impart
a medicinal-like odor and taste to water and to the flesh
of aquatic organisms raised on contaminated water. Summaries
of the reported taste/odor threshold levels of various chloro-
phenols in water or in aquatic organisms are presented in
Table 1 and Table 2, respectively.
Water quality criteria for 2-chlorophenol and 2,4-dichloro-
phenol based on organoleptic effects were published in PR
15946, 1979. These criteria of 0.3 jug/1 and 0.5 )ig/l, respec-
tively, were derived from the data reported by Hoak (1957J
and are based on the odor threshold of these compounds in
water.
1 The criteria for various other mono-, di,- and tri-
chlorophenols have been derived and are based on the lower
of the odor threshold in water or the tainting threshold
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TABLE 1
Comparison of Odor Thresholds for Chlorophenols in Water.
Threshold-ppb (pg/1).
2-chlorophenol
3-chlorophenol
4-chlorophenol
2,4-dichlorophenol
2,5-dichlorophenol
2,6-dichlorophenol
2,4,5-tr ichlorophenol
2,4,6-trichlorophenol
2,3,4,6-tetrachlorophenol
0.33 ppb - 30*
2 ppb
6 ppb
200 ppb
33 ppb
250 ppb
900 - 1350 ppb
- 25h
- NSb
- 30°C
- 30°C
- 25°C
0.65 ppb - 30UC
2 ppb - 25°C
3.3 ppb - 30°C
3 ppb
11 ppb
- 25°C
- 25°C
100 ppb - 30°C
1000 ppb - 25°C
915 ppb
Reference*
2
3
4
2
3
4
2
3
2
3
2
2
3
- 30°C
a) 2 - Hoak, R.D. 1957. The causes of tastes and odors
in drinking water. Proc. llth Industrial Waste
Conf. 41: 229. Purdue U.
3 - Burttschell, R.H., et al. 1959. Chlorine derivatives
of phenol causing taste and odor. Jour. A.N.W.A.
51, 205.
4 - Campbell, C.L. et.al. 1958. Effect of certain chemicals
in water on the flavor of brewed coffee. Food Res.
23: 575.
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TABLE 2
Summary of Theshold Concentrations of Chlorinated Phenols
in Water That Causes Tainting of the Flesh
of Aquatic Organsisms
Compound Theshold Qug/1) Reference3
2-chlorophenol 15.0 5
15.0 6
3-chlorophenol 60.0 5
4-chlorophenol 60.0 5
50.0 6
2,4-dichlorophenol 5.0 6
10.0 7
a) 5 - Schulze, E. 1961. The effect of phenol-containing
waste on the taste of fish. Int. Revue Ges. Hydrobiol.
46, No. 1, p.81
6 - Teal, J.L. 1959. The control of waste through
fish taste. Presented to American Chemical Society,
National Meeting.
7 - Shumway, D.L. 1966. Effect of effluents on flavor of
salmon. Dept. Fisheries and Wildlife. Agri. Exper.
Sta. Oregon State U.
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in aquatic organisms.
Since the criterion derived for tetrachlorophenol based
on its toxic effects is lower than that derived as a result
of its organoleptic properties, the former criterion is
recommended.
There are no available data on monochlorocresols upon
which to base a criterion.
A summary of the recommended criteria is presented
in Table 3.
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Compound
TABLE 3
Recommended water Quality Criteria
Criterion from
Organoleptic
Effects
Criterion from
Toxicological
Data
Monochlorophenols
3-chlorophenol
4-chlorophenol
Dichlorophenols
2,5-dichlorophenol
2,6-dichlorophenol
Tr ichlorophenols
2,4,5-tr ichlorophenol
2,4,6-tr ichlorophenol
•
Tetrachlorophenol*
2,3,4,6-tetrachlorophenol
Chlorocresol
50 ug/1
30 ug/1
3.0 ug/1
3.0 Jig/1
10 ug/1
100
915 jmg/1
Insufficient data on which to base a criterion
none
none
none
none
1600
263 jig/1
* The criterion will be based on toxicological effects
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