>>EPA
United States
Environmental Protection
Agency
Office of Water
Regulations and Standards
Criteria and Standards Division
Washington DC 20460
EPA 440/5-80-032
October 1980
C.3-
Ambient
Water Quality
Criteria for
Chlorinated Phenols
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AMBIENT WATER QUALITY CRITERIA FOR
CHLORINATED PHENOLS
Prepared By
U.S. ENVIRONMENTAL PROTECTION AGENCY
Office of Water Regulations and Standards
Criteria and Standards Division
Washington, D.C.
Office of Research and Development
Environmental Criteria and Assessment Office
Cincinnati, Ohio
Carcinogen Assessment Group
Washington, D.C.
Environmental Research Laboratories
Corvalis, Oregon
Duluth, Minnesota
Gulf Breeze, Florida
Narragansett, Rhode Island
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DISCLAIMER
This report has been reviewed by the Environmental Criteria and
Assessment Office, U.S. Environmental Protection Agency, and approved
for publication. Mention of trade names or commercial products does not
constitute endorsement or recommendation for use.
AVAILABILITY NOTICE
This document is available to the public through the National
Technical Information Service, (NTIS), Springfield, Virginia 22161.
11
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FOREWORD
Section 304 (a)(l) of the Clean Water Act of 1977 (P.L. 95-217),
requires the Administrator of the Environmental Protection Agency to
publish criteria for water quality accurately reflecting the latest
scientific knowledge on the kind and extent of all identifiable effects
on health and welfare which may be expected from the presence of
pollutants in any body of water, including ground water. Proposed water
quality criteria for the 65 toxic pollutants listed under section 307
(a)(l) of the Clean Water Act were developed and a notice of their
availability was published for public comment on March 15, 1979 (44 FR
15926), July 25, 1979 (44 FR 43660), and October 1, 1979 (44 FR 56628).
This document is a revision of those proposed criteria based upon a
consideration of comments received from other Federal Agencies, State
agencies, special interest groups, and individual scientists. The
criteria contained in this document replace any previously published EPA
criteria for the 65 pollutants. This criterion document is also
published in satisifaction of paragraph 11 of the Settlement Agreement
in Natural Resources Defense Council, et. al. vs. Train, 8 ERC 2120
(D.D.C. 1976), modified, 12 ERC 1833 (D.D.C. 1979).
The term "water quality criteria" is used in two sections of the
Clean Water Act, section 304 (a)(l) and section 303 (c)(2). The term has
a different program impact in each section. In section 304, the term
represents a non-regulatory, scientific assessment of ecological ef-
fects. The criteria presented in this publication are such scientific
assessments. Such water quality criteria associated with specific
stream uses when adopted as State water quality standards under section
303 become enforceable maximum acceptable levels of a pollutant in
ambient waters. The water quality criteria adopted in the State water
quality standards could have the same numerical limits as the criteria
developed under section 304. However, in many situations States may want
to adjust water quality criteria developed under section 304 to reflect
local environmental conditions and human exposure patterns before
incorporation into water quality standards. It is not until their
adoption as part of the State water quality standards that the criteria
become regulatory.
Guidelines to assist the States in the modification of criteria
presented in this document, in the development of water quality
standards, and in other water-related programs of this Agency, are being
developed by EPA.
STEVEN SCHATZOW
Deputy Assistant Administrator
Office of Water Regulations and Standards
111
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ACKNOWLEDGEMENTS
Aquatic Life Toxicology:
William A. Brungs, ERL-Narragansett
U.S. Environmental Protection Agency
David J. Hansen, ERL-Gulf Breeze
U.S. Environmental Protection Agency
Mammalian Toxicology and Human Health Effects:
Gary Van Gelder (author)
University of Missouri
Terence M. Grady (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
Bonnie Smith (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
Patrick Durkin
Syracuse Research Corporation
Nachman Gruener
School of Public Health & Tropical
Medicine
Don Hinkle, HERL
U.S. Environmental Protection Agency
J.B. Lai
National Institute for Occupational
Safety and Health
Steven D. Lutkenhoff, ECAO-Cin
U.S. Environmental Protection Agency
Gary Osweiler
University of Missouri
Alan B. Rubin
U.S. Environmental Protection Agency
Roy E. Albert*
Carcinogen Assessment Group
U.S. Environmental Protection Agency
Joseph C. Arcos
Tulane University
Richard Carchman
Medical College of Virginia
Hans L. Falk
National Institute of Environmental
Health Sciences
Rolf Hartung
University of Michigan
Van Kozak
University of Wisconsin
Ted Loomis
University of Washington
Frederick Oehme
Kansas State University
John Risher, ECAO-Cin
U.S. Environmental Protection Agency
Technical Support Services Staff: D.J. Reisman, M.A. Garlough, B.L. Zwayer,
P.A. Daunt, K.S. Edwards, T.A. Scandura, A.T. Pressley, C.A. Cooper,
M.M. Denessen.
Clerical Staff: C.A. Haynes, S.J. Faehr, L.A. Wade, 0. Jones, B.J. Bordicks,
B.J. Quesnell, P. Gray, R. Rubinstein.
*CAG Participating Members: Elizabeth L. Anderson, Dolph Arnicar, Steven Bayard,
David L. Bayliss, Chao W. Chen, John R. Fowle III, Bernard Haberman, Charalingayya
Hiremath, Larry Anderson, Chang S. Lao, Robert McGaughy, Jeffrey Rosenblatt,
Dharm V. Singh and Todd W. Thorslund.
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TABLE OF CONTENTS
Page
Criteria Summary
Introduction A-l
Aquatic Life Toxicology B-l
Introduction B-l
Effects B-l
Acute Toxicity B-l
Chronic Toxicity B-3
Plant Effects B-3
Residue 8-4
Miscellaneous B-4
Summary 8-4
Criteria B-5
References B-13
3-Chlorophenol and 4-Chlorophenol C-l
Mammalian Toxicology and Human Health Effects C-l
Introduction C-l
Exposure C-3
Ingestion from Water C-3
Ingestion from Food C-7
Inhalation C-9
Dermal C-9
Pharmacokinetics C-10
Effects C-10
Acute, Subacute, and Chronic Toxicity C-10
Synergism and/or Antagonism, Teratogenicity,
and Mutagenicity C-18
Carcinogenicity C-18
Criterion Formulation C-20
Existing Guidelines and Standards C-20
Current Levels of Exposure C-20
Special Groups at Risk C-20
Basis and Derivation of Criterion C-20
References C-22
2,3-Dichlorophenol, 2,5-Dichlorophenol
2,6-Dichlorophenol, 3,4-Dichlorophenol, and
4,6-Dichlorophenol C-27
Mammalian Toxicology and Human Health Effects C-27
Introduction C-27
Exposure C-29
Ingestion from Water C-29
Ingestion from Food C-30
Inhalation C-31
Dermal C-30
Pharmacokinetics C-30
Metabolism C-33
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Effects c-33
Acute, Subacute, and Chronic Toxicity C-33
Synergism and/or Antagonism C-34
Mutagenicity C-34
Carcinogenic!ty C-36
Criterion Formulation C-37
Existing Guidelines and Standards C-37
Current Levels of Exposure C-37
Special Groups at Risk C-37
Basis and Derivation of Criterion C-37
References C-39
Trichlorophenols C-42
Mammalian Toxicology and Human Health Effects C-42
Introduction C-42
Exposure C-45
Ingestion from Water C-45
Ingestion from Food C-46
Inhalation C-53
Dermal C-53
Pharmacokinetics C-53
Absorption, Distribution, and Metabolism C-53
Excretion C-54
Effects C-54
Acute, Subacute, and Chronic Toxicity C-54
Synergism and/or Antagonism and Teratogenicity C-64
Mutagenicity C-64
Carcinogenicity C-65
Criterion Formulation C-72
Existing Guidelines and Standards C-72
Current Levels of Exposure C-72
Special Groups at Risk C-72
Basis and Derivation of Criteria C-72
References C-76
Tetrachlorophenol C-83
Mammalian Toxicology and Human Health Effects C-83
Introduction C-83
Exposure C-83
Ingestion from Water C-83
Ingestion from Food C-85
Inhalation C-88
Dermal C-88
Pharmacokinetics C-88
Absorption and Distribution C-88
Metabolism and Excretion C-88
Effects C-89
Acute, Subactue, and Chronic Toxicity C-89
Synergism and/or Antagonism C-96
Teratogenicity C-96
Mutagenicity C-96
Carcinogenicity C-96
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Criterion Formulation C-99
Existing Guidelines and Standards C-99
Current Levels of Exposure C-99
Special Groups at Risk C-99
Basis and Derivation of Criterion C-99
References C-101
Chlorocresols C-105
Mammalian Toxicology and Human Health Effects C-105
Introduction C
Exposure
Ingestion from Water and Food
Inhalation and Dermal C-109
Pharmacokinetics C-110
Absorption C-110
Distribution and Metabolism C-110
Excretion C~Ti°
Effects C-110
Acute, Subacute, and Chronic Toxicity C-110
Synergism and/or Antagonism C-114
Teratogenicity C"nl
Mutagenicity TIC
Carcinogenicity C-115
Criterion Formulation C-116
Existing Guidelines and Standards C-116
Current Levels of Exposure C-116
Special Groups at Risk C-116
Basis and Derivation of Criterion C-116
References C-117
Summary-Criterion Formulation C-120
Existing Guidelines and Standards C-120
Current Levels of Exposure C-120
Special Groups at Risk r'Ton
Basis and Derivation of Criteria C-120
Appendix C-129
vn
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CRITERIA DOCUMENT
CHLORINATED PHENOLS
CRITERIA
Aquatic Life
The available freshwater data for chlorinated phenols indicate
that toxicity generally increases with increasing chlorination, and
that acute toxicity occurs at concentrations as low as 30 yg/1 for
4-chloro-3-methylphenol to greater than 500,000 yg/1 for other com-
pounds. Chronic toxicity occurs at concentrations as low as 970
yg/1 for 2,4,6-trichlorophenol. Acute and chronic toxicity would
occur at lower concentrations among species that are more sensitive
than those tested.
The available saltwater data for chlorinated phenols indicate
that toxicity generally increases with increasing chlorination and
that acute toxicity occurs at concentrations as low as 440 yg/1 for
2,3,5,6-tetrachlorophenol and 29,700 yg/1 for 4-chlorophenol.
Acute toxicity would occur at lower concentrations among species
that are more sensitive than those tested. No data are available
concerning the chronic toxicity of chlorinated phenols to sensitive
saltwater aquatic life.
Human Health
Sufficient data are not available for 3-chlorophenol to derive
a level which would protect against the potential toxicity of this
compound. Using available organoleptic data, for controlling
undesirable taste and odor qualities of ambient water, the esti-
mated level is 0.1 yg/1. It should be recognized that organoleptic
data as a basis for establishing a water quality criterion have
Vlll
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limitations and have no demonstrated relationship to potential
adverse human health effects.
Sufficient data are not available for 4-chlorophenol to derive
a level which would protect against the potential toxicity of this
compound. Using available organoleptic data, for controlling
undesirable taste and odor qualities of ambient water, the esti-
mated level is 0.1 yg/1. It should be recognized that organoleptic
data as a basis for establishing a water quality criterion have
limitations and have no demonstrated relationship to potential
adverse human health effects.
Sufficient data are not available for 2,3-dichlorophenol to
derive a level which would protect against the potential toxicity
of this compound. Using available organoleptic data, for controll-
ing undesirable taste and odor qualities of ambient water, the
estimated level is 0.04 yg/1. It should be recognized that organo-
leptic data as a basis for establishing a water quality criterion
have limitations and have no demonstrated relationship to potential
adverse human health effects.
Sufficient data are not available for 2,5-dichlorophenol to
derive a level which would protect against the potential toxicity
of this compound. Using available organoleptic data, for controll-
ing undesirable taste and odor qualities of ambient water, the
estimated level is 0.5 yg/1. It should be recognized that organo-
leptic data as a basis for establishing a water quality criterion
have limitations and have no demonstrated relationship to potential
adverse human health effects.
IX
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Sufficient data are not available for 2,6-dichlorophenol to
derive a level which would protect against the potential toxicity
of this compound. Using available organoleptic data, for controll-
ing undesirable taste and odor qualities of ambient water, the
estimated level is 0.2 yg/1. It should be recognized that organo-
leptic data as a basis for establishing a water quality criterion
have limitations and have no demonstrated relationship to potential
adverse human health effects.
Sufficient data are not available for 3,4-dichlorophenol to
derive a level which would protect against the potential toxicity
of this compound. Using available organoleptic data, for controll-
ing undesirable taste and odor qualities of ambient water, the
estimated level is 0.3 ug/1- It should be recognized that organo-
leptic data as a basis for establishing a water quality criterion
have limitations and have no demonstrated relationship to potential
adverse human health effects.
For comparison purposes, two approaches were used to derive
criterion levels for 2,4,5-trichlorophenol. Based on available
toxicity data, for the protection of public health, the derived
level is 2.6 mg/1. Using available organoleptic data, for con-
trolling undesirable taste and odor quality of ambient water, the
estimated level is 1.0 yg/1. It should be recognized that organo-
leptic data as a basis for establishing a water quality criterion
have limitations and have no demonstrated relationship to potential
adverse human health effects.
For the maximum protection of human health from the potential
carcinogenic effects due to exposure of 2,4,6-trichlorophenol
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through ingestion of contaminated water and contaminated aquatic
organisms, the ambient water concentration should be zero based on
the non-threshold assumption for this chemical. However, zero
level may not be attainable at the present time. Therefore, the
levels which may result in incremental increase of cancer risk over
the lifetime are estimated at 10~5, 10~6, and 10~7. The corres-
ponding recommended criteria are 12 yg/1, 1.2 ug/1, and 0.12 yg/1,
respectively. If the above estimates are made for consumption of
aquatic organisms only, excluding consumption of water, the levels
are 36 ug/1, 3.6 ug/1, and 0.36 ug/1, respectively. Using avail-
able organoleptic data, for controlling undesirable taste and odor
qualities of ambient water, the estimated level is 2 ug/1. It
should be recognized that organoleptic data as a basis for estab-
lishing a water quality criterion have limitations and have no
demonstrated relationship to potential adverse human health
effects.
Sufficient data are not available for 2,3,4,6-tetrachloro-
phenol to derive a level which would protect against the potential
toxicity of this compound. Using available organoleptic data, for
controlling undesirable taste and odor qualities of ambient water,
the estimated level is 1 ug/1. It should be recognized that organ-
oleptic data as a basis for establishing a water quality criterion
have limitations and have no demonstrated relationship to potential
adverse human health effects.
Sufficient data are not available for 2-methyl-4-chlorophenol
to derive a criterion level which would protect against any poten-
tial toxicity of this compound. Using available organoleptic data,
XI
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for controlling undesirable taste and odor qualities of ambient
water, the estimated level is 1,800 ug/1. It should be recognized
that organoleptic data as a basis for establishing a water quality
criterion have limitations and have no demonstrated relationship to
potential adverse human health effects.
Sufficient data are not available for 3-methyl-4-chlorophenol
to derive a criterion level which would protect against any poten-
tial toxicity of this compound. Using available organoleptic data,
for controlling undesirable taste and odor qualities of ambient
water, the estimated level is 3,000 yg/1. It should be recognized
that organoleptic data as a basis for establishing a water quality
criterion have limitations and have no demonstrated relationship to
potential adverse human health effects.
Sufficient data are not available for 3-methyl-6-chlorophenol
to derive a criterion level which would protect against any poten-
tial toxicity of this compound. Using available organoleptic data,
for controlling undesirable taste and odor qualities of ambient
water, the estimated level is 20 yg/1. It should be recognized
that organoleptic data as a basis for establishing a water quality
criterion have limitations and have no demonstrated relationship to
potential adverse human health effects.
Xll
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INTRODUCTION
The chlorinated phenols represent a group of commercially pro-
duced, 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 chlorophenols also are used directly as
flea repellents, fungicides, wood preservatives, mold inhibitors,
antiseptics, disinfectants, and antigumming agents for gasoline.
(The compounds 2-chlorophenol, 2,4-dichlorophenol, and penta-
chlorophenol are discussed in separate criteria documents.)
The chlorinated phenols represent a group of substituted
phenols and cresols prepared by direct chlorination or the hydrol-
ysis of the higher chlorinated derivatives of benzene. Purified
chlorinated phenols exist as colorless crystalline 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 impuri-
ties (Bennett, 1962; Kirk and Othmer, 1964; Heilbron, et al. 1975;
Sax, 1975; Weast, 1974; Windholz, 1976; Hawley, 1975). As a group,
the chlorophenols are characterized by an odor which has been
described as unpleasant, medicinal, pungent, phenolic, strong, or
persistent (Kirk and Othmer, 1964; Sax, 1975; Lange, 1952).
A summary of the various pertinent physical properties is pre-
sented 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. The solubility of the
chlorophenols and chlorocresols, with the exception of 2,4,6-tri-
chloro-m-cresol, range from soluble to very soluble in relatively
A-l
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TABLE 1
Physical Properties of Chlorinated Phenols
I
K)
Compound
MW
Chloro-o-cresols
,5-di-
,6-di-
,4,5-di-
,4,6-di-
,4,6-tri-
,5,6-tri-
,4,5,6-tetra-
142.55
142.59
142.59
142.59
177.03
177.03
177.03
177.03
211.5
211.5
245.9
pK
Chlorophenols
3-
4-
2,3-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-tetra-
2,3,5,6-Letra-
128.56
128.56
163
163
163
163
163
197.5
197.5
197.5
197.5
197.5
232
232
9.08
9.42
7.70
7.51
6.79
8.59
8.19
7.0
6.1
5.3
MP
(deg. C)
33.
43.2
57.
59
67
68
68
83.5
62
58
68
69.5
116
115
BP
(deg. C)
214
217
211
219
253
233
Sublimes
248.5
272
Sublimes
246
Sublimes
Density
1.2680
1.2651
1.4901
1.6700
86
51
73
101
55
101
55
62
77
190
225
223
188.9
266.5
226
269
Water Sol.
(g/100y)*
0.26
2.71
si.
si.
s.
s.
si.
0.2
0.1
0.1
si.
si.
si.
si.
si.
si.
si.
si.
Vapor
Pressure
(mm lly/
deg. C)
1/12.1
1/59.5
1/72.0
1/76.5
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TABLE 1 (Continued)
I
U)
Compound
MW
PK
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-
142.59
142.59
142.59
177.03
177.03
177.03
211.48
245.92
142.59
142.59
177.03
245.42
*sl = slightly soluble; s = soluble.
References:
1. Bennett, 1962
2. Kirk and Othmer, 1964
3. Heilbron, et al. 1975
4. Weast, 1978
5. Sax, 1975
6. Weast, 1974
7. Windholz, 1976
8. Pearce & Simkins, 1968
-
MP
(deg. C)
55
43
45
27
58
72
45
189
... .
BP
(deg. C)
196
220
196
241
235
235
265
Water Sol.
Density (g/lOOg)
si.
0.38
s.
si.
s.
Vapoc
Pressure
(nun Hg/
deg. C)
55
39
190
195.6
228
138
si.
s.
si.
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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 sodium carbonate. 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 sol-
uble phenoxide salt is formed. The phenoxide salts are also more
soluble than the corresponding phenol in water at 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 electro-
phylic 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-tri-
chlorophenol, and 2,3,4,6-tetrachlorophenol. Other positional
isomers may be synthesized by the hydrolysis of higher chloroben-
zenes. Many of the chlorinated phenols have no commercial applica-
tion presently due to their high cost of production, complex syn-
thetic procedures, or lack of useful chemical, physical, or toxico-
logical properties (Kirk and Othmer, 1964). These include
3-chlorophenol, 2,3-dichlorophenol, 2,5-dichlorophenol, 3,4-di-
chlorophenol, 3,5-dichlorophenol, 2,3,4-trichlorophenol, 2,3,5-
trichlorophenol, 2,3,4,5-tetrachlorophenol, and 2,3,5,6-tetra-
A-4
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TABLE 2
i
Ul
Chlorinated Phenol
4-chlorophenol
(4-CP)
2,4-dichlorophenol
(2,4-DCP)
2,4,5-trichloro-
phenol (2,4,5-
TCP)
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
f_ Synthesj_s 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
-------
chlorophenol. However, each of these compounds is produced to some
extent as a Dy-product during the production of the commercially
important chlorophenols. From a commercial standpoint, 4-chloro-o-
cresol is the most important of the chlorinated cresols (Kirk and
Othmer, 1964).
It is well known that the highly toxic polychlorinated
dibenzo-p-dioxins may be formed during the chemical synthesis of
some chlorophenols, and that the amount of contaminant formed is
dependent upon tne temperature and pressure control of the reaction
(Fishbein, 1973; Milnes, 1971; Schulz, 1968; Higgenbotham, 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 par-
ticularly toxic (Burger, 1973). The 2 ,3 , 7,8-tetrachlorodibenzo-p-
dioxin (TCDD) is considered the most toxic of all the dioxins
(Sparschu, et al. 1971).
TCDD is apparently formed during the synthesis of 2,4,5-tri-
chlorophenol and before 1968 was reported to be present in the sub-
sequent product 2,4,5-trichlorophenoxy 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) and are currently reported to be
below 0.099 mg/kg (Dow, 1977).
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 octachlorodibenzo-
A-6
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furans were present, respectively (Schwetz, et al. 1974a). No TCDD
has been reported present in commercial pentachlorophenol products
although hexa-, hepta-, and octochlorodibenzo-p-dioxins have been
detected at concentrations of 4 to 27 rag/kg, 125 mg/kg, and 50 to
2,510 mg/kg, respectively (Johnson, et al. 1973; Jensen and Reu-
berg, 1973; Schwetz, et al. 1974b).
Evidence has accumulated that the various chlorophenols are
formed as intermediate metabolites during the microbiological
degradation of the herbicides 2,4-0 and 2,4,5-T and pesticides
Silvex®, Ronne^, 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 chlorination
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 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 disinfection of waste water effluents (Aly, 1968; Barnhart and
Campbell, 1972) and the synthesis of 2-chlorophenol took place in
one hour in aqueous solutions containing as little as 10 mg/1
phenol and 20 mg/1 chlorine (Barnhart and Campbell, 1972). Other
A-7
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studies have demonstrated the formation of up to 1.7 ug/l 2-chloro-
phenol 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, drink-
ing waters, or soils and sediments. 3-Chlorophenol, 4-chloro-
phenol, 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 treat-
ment effluents (U.S. EPA, 1975). However, no quantitative data
were reported. Examples of some findings are: the presence of
2,4-dichlorophenol in a local water intake system at a concentra-
tion of 6.6 ug/l has been noted. Pentachlorophenol concentrations
of 4.3 ug/l (1 to 5 ug/l 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 ug/l pentachlorophenol with 40 percent of
these levels retained in the finished drinking water. The presence
of 10 to 18 mg/1 pentachlorophenol was found in a study of a small
stream near a wood preservation site with surface oil slicks con-
taining 5,800 mg/1 pentachlorophenol. In the same study, penta-
chlorophenol concentrations of 0.1 to 0.2 mg/1 and 0.05 mg/1 were
found in samples taken 1/2 mile and 2 miles downstream, respec-
tively.
It is generally accepted that chlorinated phenols will undergo
pnotolysis in aqueous solutions as a result of ultraviolet irradia-
tion and that photodegradation leads to the substitution of hy-
droxyl groups in place of the chlorine atoms with subsequent poly-
A-8
-------
mer formation. Studies by Grabowski (1961) and Joschek 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 my) 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 my was virtually
complete within 2 to 40 minutes depending upon the pH (Aly and
Faust, 1964).
Other studies have demonstrated the photodegradation of
2,4-dichlorophenol following five hours of daily solar irradiation
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-p-
dioxin was detected during the riboflavin-sensitized photooxida-
tion of 2,4-dichlorophenol to tetrachlorinated diphenol ethers
(Plimmer and Klingebiel, 1971). Pentachlorophenol (PCP) was shown
to undergo photochemical degradation in aqueous solutions by ultra-
violet 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 degradation by sunlight or UV light of dilute
solutions (100 mg/1) of pentachlorophenol to lower chlorophenols,
A-9
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tetrachlorodihydroxybenzenes, and non-aromatic fragments such as
dichloromaleic acid. Subsequent irradiation of the tetrachloro-
diols produced hydroxylated trichlorobenzoquinones, trichloro-
diols, dichloromaleic acid, and non-aromatic compounds. The irra-
diation 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 com-
plete dechlorination and aromatic ring degradation of 2-chloro-,
4-chloro-, and 2,4-dichlorophenol by 2,4-D-grown cells of an Arth-
obacter 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 respirometric technique, observed the oxidation of all
monochlorophenols, 2,4- and 2,6-dichlorophenol, and 2,4,6-tri-
chlorophenol by Pseudomonas sp. obtained through enrichment of, and
isolation from, activated sludge. Alexander and Aleem (1961)
reported the resistance of 2,4,5-trichlorophenol to microbial
decomposition by certain soil bacteria. They observed that com-
pounds 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 five days by micro-
bial 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 Scopu-
A-10
-------
lariopsis ootained from broiler house litter has been reported (Gee
and Peel, 1974). In the same study, the tetrachlorophenol was com-
pletely 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 four days of incubation, Watanabe (1973) reported
the growth of an isolated species of Pseudomonas from PGP-perfused
culture samples using PGP as the sole carbon source.
Organoleptic properties manifest themselves in two forms; the
ability of a compound to impart taste or odor to water, and to cause
tainting in fish flesh as a result of exposure to chlorophenol-
contaminated water. The organoleptic properties of chlorophenols
are well documented. The threshold levels of monochlorophenols
causing odor in water have been reported to be as low as 0.33 to 2.0
Ug/l for 2-chlorophenol (Hoak, 1957; Burttschell, et al. 1959), 100
to 1,000 ug/1 for 3-chlorophenol (Hoak, 1957; 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 yg/1 for dichlorophenols, 11 to 1,000
yg/1 for trichlorophenols, 915 to 47,000 ug/1 for tetrachloro-
phenols, 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 in-
creases 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, respec-
A-ll
-------
tively, while the odor thresholds of the chlorinated cresols,
4-chloro- and 6-chloro-o-cresol, have been reported to be 75 yg/1
and 3 yg/1, respectively (Hoak, 1957).
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.
The threshold level of 2-chlorophenol in water causing taint
in eel flesh and oysters has been reported to be 0.125 yg/1
(Boetius, 1954). Although no data demonstrating the tainting prop-
erties of other specific chlorophenols and chlorocresols appears to
be available, it is likely that they exhibit this property and
probably follow a dose-effect relationship similar to that observed
in the case of their odor producing properties.
Virtually no data are available on the bioconcentration or
bioaccumulation of the lower chlorophenols and limited data are
available regarding pentachlorophenol bioconcentration. Studies
using 14C-labeled 2,4-dichlorophenol (DCP) demonstrated that oats
and soybean seedlings concentrated DCP from dilute solutions (0.2
mg/1) by factors of 9.2 and 0.65-fold, respectively (Isensee and
Jones, 1971). Bioconcentration data on pentachlorophenol may be
found in the pentachlorophenol criterion document.
Chlorophenols, their sodium salts, and certain chlorocresols
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 produc-
A-12
-------
tion 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 chlorination of phenols during disinfection, waste
treatment degradation 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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Barnhart, E.L. and G.R. Campbell. 1972. The effect of chlori-
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Bennett, H. (ed.) 1962. Concise Chemical and Technical Dictio-
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Burttschell, R.H., et al. 1959. Chlorine derivatives of phenol
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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.
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Crosby, D.G. and H.O. Tutass. 1966. Photodecomposition of 2,4-
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Crosby, D.G. and A.S. Wong. 1973. Photodecomposition of 2,4,5-
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Dow Chemical Co. 1977. Product specifications for Dowicide^ 2.
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Evans, W.C., et al. 1971. Bacterial metabolism of 2,4-dichloro-
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Fernley, H.N. and W.C. Evans. 1959. Metabolism of 2,4-dichloro-
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Fishbein, L. 1973. Mutagens and potential rautagens in the bio-
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Gee, J.M. and J.L. Peel. 1974. Metabolism of 2,3,4,6-tetrachloro-
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Microbiol. 85: 237.
Goto, M., et al. 1972. Contributions to ecological chemistry.
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Grabowski, z.R. 1961. Photochemical reactions of some aromatic
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Greig, J.B., et al. 1973. Toxic effects of 2,3,7,8-tetrachloro-
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Hamadmad, N. 1967. Photolysis of pentachloronitrobenzene,
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Hawley, G.G. 1975. Condensed Chemical Dictionary. 9th ed. Van
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Heilbron, I., et al. 1975. Dictionary of Organic Compounds. 4th
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Higgenootham, G.R., et al. 1968. Chemical and toxicological
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Hoak, R.D. 1957. The causes of tastes and odors in drinking water.
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Hussain, G., et al. 1972. Mutagenic effects of TCDD on bacterial
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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 translocation
of root and foliage applied 2,4-dichlorophenol, 2,7-dichlorodi-
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Agric. Food Chem. 19: 1210.
Jensen, S. and L. Reuberg. 1973. Chlorinated dimers present in
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Johnson, R.L., et al. 1973. Chlorinated dibenzodioxins and penta-
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Jolly, R.L. 1973. Chlorination effects on organic constituents in
effluents from domestic sanitary sewage treatment plants. Ph.D.
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Jolly, R.L., et al. 1975. Chlorination of cooling water: A source
of environmentally significant chlorine-containing organic com-
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Joschek, H.I. and S.I. Miller. 1966. Photocleavage of phenoxy-
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Kearney, P.C. and D.N. Kaufman. 1972. Microbial Degradation of
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Molecules in the Biosphere. Natl. Acad. Sci., Wasington, D.C.
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Kearney, P.C., et al. 1973. Tetrachlorodibenzodioxin in the
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Kinney, J.E. 1960. Evaluating the taste and odor control problem.
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Kirk, R.E. and D.F. Othmer. 1964. Kirk-Othmer Encyclopedia of
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Lange, N.A. (ed.) 1952. Lange's Handbook of Chemistry. 8th. ed.
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Loos, M.A., et al. 1967. Phenols as intermediates in the decompo-
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Middaugh, D.P. and W.P. Davis. 1976. Impact of Chlorination Pro-
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Milnes, M.H. 1971. Formation of 2 ,3 , 7 , 8-tetrachlorociibenzo-p-
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Mitchell, L.C. 1961. Effect of ultraviolet light (2537A) on 141
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A-19
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Muelder, W.W. and L.A. Shadoff. 1973. The preparation of uni-
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Nachtigall, H. and R.G. Butler. 1974. Metabolism of phenols and
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Omura, K. and T. Matsuura. 1971. Photoinduced reactions - L.
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Schulz, K.H. 1968. Klinische and experimentelle untersuchungen
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A-21
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Aquatic Life Toxicology*
INTRODUCTION
A review of the available literature on the effects of chlorinated phe-
nols on aquatic life is complicated by the variety of common and scientific
names used for these compounds. A consistent set of names has been used
herein and footnotes are used to identify other names that were used in ref-
erenced publications.
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 those chemicals than
aquatic animals.
Because the toxicity of chlorinated phenols to various aquati-e life
forms is structure-dependent, giving rise to wide variability, it would be
inappropriate to derive a criterion for these chemicals as a group. In-
stead, criteria should be derived on the basis of individual chemicals, when
sufficient information becomes available.
In aeneral, chlorinated phenols have been shown to impair the flavor of
the edible portions of fishes at concentrations lower than those at which
they are toxic to aquatic organisms.
EFFECTS
Acute Toxicity
Daphnia magna was less sensitive than the bluegill for five of the seven
chlorinated phenols for which a comparison could be made and the acute values
*The reader is referred to the Guidelines for Deriving Water Quality Cri-
teria for the Protection of Aquatic Life and Its Uses in order to better un-
derstand the following discussion and recommendation. The following tables
contain the appropriate data that were found in the literature, and at the
bottom of the appropriate table are calculations for deriving various mea-
sures of toxicity as described in the Guidelines.
B-l
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for Daphrna magna range from 290 yg/1 for 2,3,4,6-tetrachlorophenol to 6,040
yg/1 for 2,4,6-tHchlorophenol (Table 1).
The 96-hour LC5Q values for fathead minnows range from 30 yg/1 for 4-
chlore-3-methylphenol (U.S. EPA, 1972) to 9,040 yg/1 for 2,4,6-trichloro-
phenol (Phipps, et al. Manuscript).
The 96-hour LCrQ values for chlorinated phenols and the bluegill (U.S.
EPA, 1978) are directly related to the degree of chlorination. These values
decrease from 6,590 yg/1 for 2-chlorophenol (see 2-chlorophenol criterion
document) and 3,830 yg/1 for 4-chlorophenol to 60 and 77 ug/l for penta-
chlorophenol (see pentachlorophenol criteria document).
All but one of the acute tests were run under static conditions and all
but three without measured concentrations. Since many chlorinated phenols
are only slightly soluble in water, and since some of the chemical could be
expected to be absorbed by the animals and the testing environment, the
above conditions could result in a low estimate of the toxicity.
Acute toxicity tests with saltwater invertebrate species consist of
three 96-hour static tests with the mysid shrimp, and three chlorophenols
(Table 1). Of these, 2,4,5-trichlorophenol was the most toxic with a 96-
hour LC5Q of 3,830 yg/1; the 96-hour LC50 for the least toxic compound
was 29,700 ug/l for 4-chlorophenol.
Toxicity tests with the saltwater sheepshead minnow have also been con-
ducted with the same three chlorophenols (Table 1). The 96-hour LC5Q val-
ues range from 1,660 yg/1 for 2,4,5-trichlorophenol to 5,350 yg/1 for 4-
chlorophenol (U.S. EPA, 1978).
Comparable data (U.S. EPA, 1978) are available for effects of other
chlorinated phenols on fishes and invertebrate species (see criteria docu-
ments for 2-chlorophenol, 2,4-dichlorophenol, and pentachlorophenol for de-
B-2
-------
tails). In general, toxicity of chlorophenols, except 2,3,5,6-tetra-chloro-
phenol with the mysid shrimp, appears to increase with increasing chlorina-
tion.
Chronic Toxicity
The only freshwater chronic data found were for 2,4,6-trichlorophenol
(U.S. EPA, 1978). The chronic value was 720 ug/1 from an early life stage
test with the fathead minnow (Table 2). Additional data on the freshwater
chronic toxicity of chlorinated phenols may be found in the criterion docu-
ments for 2-chlorophenol, 2,4-dichlorophenol, and pentachlorophenol.
The only saltwater chronic data were those from an early life stage test
with the sheepshead minnow and 2,4-dichloro-6-methylphenol (Table 2). The
lowest concentration tested, 360 ug/1, affected the fish in a 28-day expo-
sure. Since no acute toxicity test was conducted with this chlorophenol,
the value of this chronic test in formulating a water quality criterion is
limited.
No chronic test has been conducted with any of the chlorinated phenols
discussed in this document on any aquatic invertebrate species.
Plant Effects
The data in Table 3 indicate that freshwater aquatic plants are general-
ly less sensitive to chlorinated phenols than fish or invertebrate species.
The LC™ values for chlorosis for a series of ten chlorinated phenols
(Blackman, et al. 1955) with Lemna minor ranged from 598,584 yg/1 for 2-
chloro-6-methylphenol and 282,832 ug/1 for 4-chlorophenol to 603 pg/1 for
2,3,4,6-tetrachlorophenol. Once again, the toxicity is related to increas-
ing chlorination but not as clearly as noted for the bluegill. As with fish
and aquatic invertebrate species, the derivation of a single criterion for
all chlorinated phenols is inappropriate due to the wide variability in tox-
icity for this group of compounds.
B-3
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Toxicity tests with chlorophenols and the saltwater alga, Skeletonema-
costatum, also revealed differences in toxicity, depending upon the compound
tested (Table 3). Reductions in chlorophyll a_ and cell numbers showed that
2,3,5,6-tetrachlorophenol was the most toxic and 4-chlorophenol the least
toxic.
Comparable test procedures (U.S. EPA, 1978) were used for other chloro-
phenols and, as with the sheepshead minnow and mysid shrimp, toxicity gener-
ally increased with increased degree of chlorination.
Residues
No measured steady state bi©concentration factors are available for the
chlorinated phenols discussed in this document and aquatic organisms.
Miscellaneous
As stated in the introduction, chlorinated phenols have been shown to
impair the flavor of freshwater 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 15 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 yg/1 for 2,5-dichloro-
phenol to 84 yg/1 for 2,3-dichlorophenol (Table 4).
The additional toxicity data (Table 4) do not appear to differ signifi-
cantly from the data already discussed.
Summary
The acute values for freshwater fish and invertebrate species ranged
from 30 ug/1 for the fathead minnow and 4-chloro-3-methyphenol to 9,040 yg/1
B-4
-------
for the same species and 2,4,6-trichlorophenol. Freshwater aquatic plants
are generally less sensitive. One early life stage test yielded a chronic
value of 720 ug/1 for the fathead minnow and 2,4,6-trichlorophenol. Flesh-
tainting data indicate that the edible portions of freshwater fishes may be-
come tainted at water concentrations as low as 23 ug/1 for rainbow trout and
2,5-dichlorophenol. In general, the acute toxicity of chlorinated phenols
increases with amount of chlorination.
The data base for saltwater organisms is more limited with data only for
the sheepshead minnow, mysid shrimp, and an algal species. The EC™ and
LC50 values ranged from 440 to 29,700 ug/1 with the algal species being
the most sensitive. The pattern of increasing toxicity with increasing
chlorination appears to be generally valid for saltwater species also.
CRITERIA
The available freshwater data for chlorinated phenols indicate that tox-
icity generally increases with increasing chlorination, and that acute tox-
icity occurs at concentrations as low as 30 yg/1 for 4-chloro-3Hnethylpheno1
to greater than 500,000 ug/1 for other compounds. Chronic toxicity occurs
at concentrations as low as 970 ug/1 for 2,4,6-trichlorophenol. Acute and
chronic toxicity would occur at lower concentrations among species that are
more sensitive than those tested.
The available saltwater data for chlorinated phenols indicate that tox-
icity generally increases with increasing chlorination, and that acute tox-
icity occurs at concentrations as low as 440 ug/1 for 2,3,5,6-tetrachloro-
phenol and 29,700 ug/1 for 4-chlorophenol. Acute toxicity would occur at
lower concentrations among species that are more sensitive than those test-
ed. No data are available concerning the chronic toxicity of chlorinated
phenols to sensitive saltwater aquatic life.
B-5
-------
Table 1. Acute values for chlorinated phenols
Spec les
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
C ladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
W
^ Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Cladoceran,
Daphnia magna
Fathead minnow.
Pimephales promelas
Fathead minnow
( juveni le).
Pimephales promelas
Fathead minnow.
Pimephales promelas
Bluegi 1 1,
Lepomis macrochirus
Bluegi 1 1,
Lepomis macrochirus
Method* Chemical
FRESHWATER
S, U 4-ch lorophenol
S, U 4-ch lorophenol
S, U 2, 4,5- trich loro-
phenol
S, U 2, 4, 6-trich loro-
phenol
S, U 2,3,5,6-tetra-
ch lorophenol
S, U 2,3,4,6-tetra-
ch lorophenol
S, U 4-chloro-2-methy 1-
phenol**
S, U 2,4-dichloro-
6-methy (phenol
S, M 2, 4, 6-trich loro-
phenol
FT, M 2, 4, 6-trich loro-
phenol
S, M 4-chloro-3-itiethy !-
phenol
S, U 4-ch lorophenol
S, U 2, 4, 5-trich loro-
phenol
LC50/EC50
SPECIES
4,820
4,060
2,660
6,040
570
290
290
430
600
9,040
30
3,830
450
Species Mean
Acute Value
(ug/l) Reference
Kopperman, et al
1974
4,420 U.S. EPA, 1978
2,660 U.S. EPA, 1978
6,040 U.S. EPA, 1978
570 U.S. EPA, 1978
290 U.S. EPA, 1978
290 U.S. EPA, 1978
430 U.S. EPA, 1978
U.S. EPA, 1972
9,040 Phipps, et al.
Manuscript
30 U.S. EPA, 1972
3,830 U.S. EPA, 1978
450 U.S. EPA, 1978
-------
Table 1. (Continued)
a
-j
Species
Bluegill,
Lepomis macrochirus
Bluegl 1 1,
Lepomis macrochirus
Bluegill,
Lepomis macrochirus
Bluegl 1 1,
Lepomis macrochirus
Bluegi 1 1,
Lepomis macrochirus
Mysid shrimp,
Mysidopsls bah I a
Mysid shrimp,
Mysidopsis bah la
Mysid shrimp,
Mysidopsis bah la
Sheepshead minnow,
Cyprlndon varlegatus
Sheepshead minnow,
Cyprinodon varlegatus
Sheepshead minnow,
Cyprinodon variegatus
Method* Chemical
S, U 2,4,6-trichloro-
phenol
S, U 2,3,4,6-tetra-
ch lorophenol
S, U 2,3,5,6-tetra-
ch lorophenol
S, U 4-chloro-2-methy 1-
phenol**
S, U 2, 4-dich loro-
6-methy (phenol
SALTWATER
S, U 4-ch lorophenol
S, U 2, 4, 5-trich loro-
phenol
S, U 2,3,5,6-tetra-
ch lorophenol
S, U 4-ch lorophenol
S, U 2,4,5-trichloro-
phenol
S, U 2.3,5,6-tetra-
ch lorophenol
LC50/EC50
(U9/D
320
140
170
2,330
1,640
SPECIES
29. 700
3,830
21,900
5,350
1,660
1,890
Species Mean
Acute Value
(ug/l) Reference
320 U.S. EPA, 1978
140 U.S. EPA, 1978
170 U.S. EPA, 1978
2,330 U.S. EPA, 1978
1,640 U.S. EPA, 1978
29,700 U.S. EPA, 1978
3,830 U.S. EPA, 1978
21,900 U.S. EPA, 1978
5,350 U.S. EPA, 1978
1,660 U.S. EPA, 1978
1,890 U.S. EPA, 1978
* S = static, FT = flow-through, U = unmeasured, M = measured
**Data were reported for 4-chloro-6-methyI phenol
-------
Table 2. Chronic values for chlorinated phenols (U.S. EPA, 1978)
Fathead minnow,
Plmephales promelas
Method"
Chemical
FRESHWATER SPECIES
ELS 2,4,6-trichloro- 530-970
phenol
Species Mean
Limits Chronic Value
(ug/l) (wg/l)
720
Sheepshead minnow,
Cyprlnodon variegatus
SALTWATER SPECIES
ELS 2,4-dichloro-
6-methy I phenol
<360
03
* ELS = early Iife stage
Fathead minnow,
Pimephales promelas
Acute-Chronic Ratio
Chemical
2,4,6-trichloro-
phenol
Acute
Value
(ug/l)
9,040
Chronic
Value
(lig/l) Ratio
720
13
-------
Table 3. Plant values for chlorinated phenols
to
Spec i es
A Iga,
Chlorella pyrenoldosa
Alga,
Chlorella pyrenoidosa
Alga,
Selenastrum capr Icornutum
Alga,
Selenastrum capr icornutum
Alga,
Selenastrum capr icornutum
Duckweed,
Lemna minor
Duckweed,
Lemna minor
Duckweed,
Lemna minor
Duckweed,
Lemna minor
Duckweed,
Lemna minor
Duckweed,
Lemna minor
Duckweed,
Lemna minor
Duckweed,
Lemna minor
Chemical
Effect
FRESHWATER SPECIES
Monoch loro-
phenol s
2,4,5- and 2,4,6-
trich lorophenols
4-ch lorophenol
2, 4, 5-trich loro-
phenol
2,3,5,6-tetra-
ch lorophenol
4-ch lorophenol
2, 4, 5-trich loro-
phenol
2, 4, 6-trich loro-
phenol
2,3,4,6-tetra-
ch lorophenol
4-ch loro-2-
methy 1 phenol*
2-ch lor 0-6-
methyl phenol *
4-ch loro-3-
methy 1 phenol *
2, 6-d ich lor o-4-
methy 1 phenol *
Comp 1 ete
destruction of
ch lorophy 1 1
Comp lete
destruct ion of
ch lorophy 1 1
96-hr EC50,
eel 1 production
96-hr EC50,
ch lorophy 1 1 a
96-hr EC50,
eel 1 production
Chlorosis (LC50)
Chlorosis (LC50)
Chlorosis (LC50)
Chlorosis (LC50)
Chlorosis (LC50)
Ch lorosls (LC50)
Chlorosis (LC50)
Chlorosis (LC50)
Result
(U9/I)
500,000
10,000
4,790
1,220
2,660
282,832
1,659
5,923
603
92,638
598,584
95,488
65,479
Reference
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
Blackman, et al.
1955
-------
Table 3. (Continued)
Species
Duckweed,
Lemna minor
Duckweed,
Lemna minor
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
7 Alga,
M Skeletonema costatum
i_>
Alga,
Skeletonema costatum
Alga,
Skeletonema costatum
Chemical
Effect
2,4,6-trichloro-3- Chlorosis (LC50)
methyl phenol*
2,4,5,6-tetrachloro- Chlorosis (LC50)
3-m ethyl phenol*
SALTWATER SPECIES
4-ch lorophenol
4-ch lorophenol
2, 4, 5- t rich loro-
phenol
2, 4, 5-trich loro-
phenol
2,3,5,6-tetra-
ch lorophenol
2,3,5,6-tetra-
ch lorophenol
96-hr EC50,
ch lorophy 1 1 a
96- hr EC50,
eel 1 count
96-hr EC50,
ch lorophy 1 1 a
96- hr EC50,
ce 1 1 count
96-hr EC50,
ch lorophy 1 1 a
96-hr EC50,
eel 1 count
Result
(uq/l)
6,131
1,107
3,270
3,560
890
960
440
550
Reference
Blackman, et al.
1955
Blackman, et al.
1955
U.S. EPA, 1978
U.S. EPA, 1978
U.S. EPA, 1978
U.S. EPA, 1978
U.S. EPA, 1978
U.S. EPA, 1978
* In the original report, the methyl substituent was named first, and the chloro second.
-------
Table 4. Other data for chlorinated phenols
03
Species
Chemical
Duration
Effect
Result
(tig/1) Reference
Lymnaeid snai Is,
Pseudosucc 1 nea columel la
and Fossaria cubensis
Lymnaeid sna i Is,
Pseudosucc i nea columel la
and Fossaria cubensis
Lymnaeid snai Is,
Pseudosocc i nea columel la
and Fossaria cubensis
Rainbow trout.
Sal mo gairdneri
Rainbow trout.
Sal mo gairdneri
Rainbow trout.
Sal mo gairdneri
Rainbow trout,
Sal mo gairdneri
Rainbow trout.
Sal mo gairdneri
Ra i nbow trout.
Sal mo gairdneri
Ra i nbow trout.
Sal mo gairdneri
Goldfish,
FRESHWATER
2,4,5-trichloro- 24 hrs
phenol
Sodium 2,4,5-tri- 24 hrs
ch lorophenate
(85*)
2,4,6-trichloro- 24 hrs
phenol
3-chlorophenol 48 hrs
4-ch lorophenol 48 hrs
2,3-dichloro- 48 hrs
pheno 1
2,5-dichloro- 48 hrs
phenol
2,6-dich loro- 48 hrs
phenol
2,4,5-trichloro- 48 hrs
phenol
2,4,6-trichloro- 48 hrs
phenol
3-chlorophenol 8 hrs
SPECIES
100* mortality 10,000
100* mortality 2,500
100* mortality 5,000
Lowest concentra- 10,000
tion which kil led
50* or more of
the test fish
ETC* 45
ETC* 84
ETC* 23
ETC* 35
Lowest concentra- 1,000
tion which ki 1 led
50* or more of
the test fish
ETC* 52
62* mortality 20,600
Batte & Swanson, 1952
Batte & Swanson, 1952
Batte & Swanson, 1952
Shumay & Palensky,
1973
Shumway 4 Palensky,
1973
Shumway & Palensky,
1973
Shumway & Palensky,
1973
Shumway & Palensky,
1973
Shumway & Palensky,
1973
Shumway & Palensky,
1973
Gersdorff & Smith,
Carassius auratus
1940
-------
Table 4. (Continued)
Spec 1 es
Goldfish,
Carassius auratus
Goldfish,
Carassius auratus
Goldfish,
Carassius auratus
Goldfish,
Carassius auratus
Goldfish,
Carassius auratus
w * ETC = the highest
i fish.
!-•
K)
Result
Chemical Duration Effect (ug/l) Reference
4-ch lorophenol 8 hrs 54% mortality 6,300 Gersdorff
1940
4-ch lorophenol 24 hrs LC50 9,000 Kobayashi
1979
2,4,5-trichloro- 24 hrs LC50 1,700 Kobayashi
phenol 1979
2,4,6-trichloro- 24 hrs LC50 10,000 Kobayashi
phenol 1979
2,3,4,6-tetra- 24 hrs LC50 750 Kobayashi
ch lorophenol 1979
estimated concentration of material that will not
impair the flavor of the flesh of
& Smith,
, et al.
, et al.
, et a 1 .
, et al.
exposed
-------
REFERENCES
Batte, E.G. and I.E. Swanson. 1952. Laboratory evaluation of organic com-
pounds as molluscacides and ovocides. II. Jour. Parasitol. 38: 65.
Blackman, 6.E., et al. 1955. The physiological activity of substituted
phenols. I. Relationships between chemical structure and physiological ac-
tivity. Arch. Biochem. Biophys. 54: 45.
Gersdorff, W.A. and I.E. Smith. 1940. Effect of introduction of the halo-
gens into the phenol molecule on toxicity to goldfish. I. Monochlorophe-
nols. Am. Jour. Pharmacol. 112: 197.
Huang, J. and E.F. Gloyna. 1968. Effect of organic compounds on photosyn-
thetic oxygenation. I. Chlorophyll destruction and suppression of photo-
synthetic oxygen production. Water Res. 2: 347.
Kobayashik, et al. 1979. Relationship between toxicity and accumulation of
various chlorophenols in goldfish. Bull. Japan. Soc. Sci. Fish. 45: 173.
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.
Phipps, G.L., et al. The acute toxicity of phenol and substituted phenols
to the fathead minnow. (In review)
B-13
-------
Shumway, D.L. and J.R. Palensky. 1973. Impairment of the flavor of fish by
water pollutants. U.S. Environ. Prot. Agency, EPA-R3-73-010, U.S. Gov.
Print. Off., Washington, D.C.
U.S. EPA. 1972. The effect of chlorination on selected organic chemicals.
Water Pollut. Control Res. Series 12020.
U.S. EPA. 1978. In-depth studies on health and environmental impacts on
selected water pollutants. U.S. Environ. Prot. Agency, Contract No.
68-01-4646.
-------
3-CHLOROPHENOL AND 4-CHLOROPHENOL
Mammalian Toxicology and Human Health Effects
INTRODUCTION
Monochlorophenol has three isomeric forms, each distinguished
by the position of the chlorine atom relative to the hydroxyl group
on carbon one of the benzene ring. The three isomers are 2-chloro-
phenol 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 sepa-
rate criteria document.
Monochlorophenols have been used as antiseptics since 1893
(von Oettingen, 1949) . They occur as intermediates in the forma-
tion of other chlorophenol-containing products 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 un-
acceptable 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 yg/1. Phenols are found in
raw domestic sewage at levels of 70-100 yg/1. Complex phenols are
-------
TABLE 1
Properties of Monochlorophenols
3-Chlorophenol
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-20 to 22°C
Taste threshold in
water-20 to 22°C
4-Chlorophenol
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°C
Taste threshold in
water-20 to 22 C
m-chlorophenol
128.56
1.268
needles
32°C
214°C
slightly soluble
soluble
soluble
very soluble
1 mm Hg at 44.2°C
000108430
50 ug/1 (Deitz and Traud,
1978)
0.1 yg/1 (Deitz and Traud,
1978)
p-chlorophenol
128.56
1.306
needles
41°C
217°C
very slightly soluble
very soluble
very soluble
very soluble
1 mm Hg at 49.8°C
000106489
33 ug/1 (Hoak, 1957)
0.1 ug/1 (Dietz and Traud,
1978)
C-2
-------
at least partially released by bacterial action in sewage treatment
trickling filters. The decomposition of surface vegetation such as
oak leaves also releases phenol.
Burttschell, et al. (1959) proposed a mechanism for the chlo-
rination of phenol in water. According to their scheme, 2- and 4-
chlorophenol are formed early. These molecules are further chlo-
rinated to 2,6- or 2,4-dichlorophenol. The final product is
2,4,6-trichlorophenol. After 18 hours of reaction, the chloro-
phenol products in Burttschell1s study consisted of less than 5
percent each of 2- and 4-chlorophenols, 25 percent 2,6-dichloro-
phenol, 20 percent 2,4-dichlorophenol and 40 to 50 percent
2,4,6-trichlorophenol.
EXPOSURE
Ingestion from Water
Burttschell, et al. (1959) demonstrated that the chlorination
of water containing phenol could result in the formation of chloro-
phenols 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 yg/1 (ppb) . A level of
20 yg/1 in water, consumed at a rate of 2 I/day by a 70 kg indi-
vidual, would result in a daily exposure of 0.57 yg/kg.
Another source of chlorophenols in water is the chlorination
of sewage. Jolley, et al. (1975) analyzed chlorinated sewage
treatment plant effluents and found 3-chlorophenol at 0.5 yg/1 and
4-chlorophenol at 0.7 yg/1. Ingols, et al. (1966) studied the bio-
logical degradation of chlorophenols in activated sludge. Both
C-3
-------
3- and 4-chlorophenol at levels of 100 mg/1 were completely de-
graded in three days with 100 percent ring degradation.
Alexander and Aleem (1961) studied the microbial decomposition
of chlorophenols in soil suspensions. 3-Chlorophenol did not dis-
appear completely in 47 or 72 days when tested with two soil types.
4-Chlorophenol disappeared in 3 or 9 days in the same two soil
types.
The association of unpleasant taste or odor of tap water with
chlorophenols has been of interest for a number of years (Hoak,
1957; Burttschell, et al. 1959; Campbell, et al. 1958; Deitz and
Traud, 1978). 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. In-
creasing the level of chlorine or increasing the reaction time
reduces the taste. Odor thresholds for chlorophenols in water are
shown in Table 2.
Odor and taste thresholds for chlorophenols in water have been
reported by a number of investigators (Hoak, 1957; Dietz and Traud,
1978; Burttschell, et al. 1959). Hoak (1957) reported the odor
threshold of phenol and 19 phenolic compounds. In a study con-
ducted at the Mellon Institute in Pittsburgh, Pennsylvania, a panel
of 2 or 4 persons sniffed samples of pure phenolic compounds in
odor-free water, which had been heated to 30 or 60°C. A flask of
plain odor-free water was provided for comparison. The various
samples were placed in random order before the test persons, and
the flask with the lowest perceptible odor was noted by each
C-4
-------
TABLE 2
Summary of Odor Thresholds for Monochlorophenols in Water
Threshold-ppb Reference
(yg/1) ( °C)
2-chlorophenol 0.33 30 1
2 25 2
10 20-22 3
3-chlorophenol 200 30 1
50 20-22 3
4-chlorophenol 33 30 1
250 25 2
60 20-22 3
1 - Hoak, 1957
2 - Burttschell, et al. 1959
3 - Deitz and Traud, 1978
C-5
-------
individual sniffer. The lowest concentration detected was con-
sidered to be the threshold of the chemicals tested. Chlorinated
phenols were the compounds most easily detected. The odor thresh-
olds reported for 3-and 4-chlorophenol were 200 yg/1 and 33 vig/1,
respectively (Table 2).
Deitz and Traud (1978) used a panel composed of 9 to 12 per-
sons of both sexes and various age groups to test the organoleptic
detection thresholds for 126 phenolic compounds. To test for odor
thresholds, 200 ml samples of the different test concentrations
were placed in stoppered odor-free glass bottles, shaken for
approximately five minutes, and sniffed at room temperature (20 to
22°C). For each test, water without the phenolic additive was used
as a background sample. The odor tests took place in several indi-
vidual rooms in which phenols and other substances with intense
odors had not been used previously. Geometric mean values were
used to determine threshold levels. Odor detection thresholds are
summarized in Table 2. To determine taste threshold concentrations
of selected phenolic compounds, a panel of four test individuals
tasted water samples containing various amounts of phenolic addi-
tives. As a point of comparison, water without phenolic additives
was tasted first. Samples with increasing phenolic concentrations
were then tested. Between samples, the mouth was rinsed with the
comparison water and the test person ate several bites of dry white
bread to "neutralize" the taste. Geometric mean detection level
values for 3- and 4-chlorophenol indicated threshold levels of 0.1
ug/1 for taste for both chemicals.
C-6
-------
Burttschell, et al. (1959) made dilutions of chlorophenols
including 3- and 4-chlorophenol in carbon-filtered tap water and
used a panel of from 4 to 6 persons to evaluate odor and taste.
Tests were carried out at room temperature, which the investigator
estimated to be 25°C. If a panel member's response was doubtful,
the sample was considered negative. The geometric mean of the
panel responses was used as the odor threshold. The odor detection
threshold for 4-chlorophenol was 250 ug/1 (Table 2).
Ingestion from Food
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 3.
A bioconcentration factor (BCF) relates the concentration of a
chemical in aquatic animals to the concentration in the water in
which they live. The steady-state BCFs for a lipid soluble com-
pound in the tissues of various aquatic animals seem to be propor-
tional to the percent lipid in the tissue. Thus, the per capita
ingestion of a lipid-soluble chemical can be estimated from the per
capita consumption of fish and shellfish, the weighted average per-
cent lipids of consumed fish and shellfish, and a steady-state BCF
for the chemical.
Data from a recent survey on fish and shellfish consumption in
the United States were analyzed by SRI International (U.S. EPA L
1980). These data were used to estimate that the per capita con-
sumption of freshwater and estuarine fish and shellfish in the
United States is 6.5 g/day (Stephan, 1980). In addition, these
C-7
-------
TABLE 3
Summary of Threshold Concentrations of Monochlorophenols
in Water that Cause Tainting of the Flesh of Aquatic Organisms
Compound Threshold (ug/1) Reference
2-chlorophenol 15.0 1
15.0 2
3-chlorophenol 60.0 1
4-chlorophenol 60.0 1
50.0 2
1 - Schulze, 1961
2 - Teal, 1959
C-i
-------
data were used with data on the fat content of the edible portion of
the same species to estimate that the weighted average percent
lipids for consumed freshwater and estuarine fish and shellfish is
3.0 percent.
No measured steady-state BCF is available for 3- or 4-chloro-
phenol, but the equation "Log BCF = (0.85 Log P - 0.70" can be used
(Veith, et al. 1979) to estimate the BCF for aquatic organisms that
contain about 7.6 percent lipids from the octanol-water partition
coefficient (P). A measured log P value of 2.4 for 4-chlorophenol
was obtained from Hansch and Leo (1979) . The adjustment factor of
3.0/7.6 = 0.395 can be used to adjust the estimated BCF from the
8.0 percent lipids on which the equation is based to the 3.0 per-
cent lipids that is the weighted average for consumed fish and
shellfish. Thus, the weighted average BCF for the edible portion
of all freshwater and estuarine aquatic organisms consumed by
Americans is calculated to be 8.6.
Inhalation
Pertinent data could not be located in the available litera-
ture regarding the presence of monochlorophenols in air.
Dermal
Roberts, et al. (1977) used human epidermal membranes obtained
at autopsy in an in vitro test system to determine the permeability
of the human skin to various chemicals. 4-Chlorophenol was shown
to permeate the skin, and to produce damage at a threshold concen-
tration of 0.75 percent (w/v).
C-9
-------
PHARMACOKINETICS
No systematic studies of the pharmacokinetics of 3- or
4-chlorophenol in man or laboratory animals were found. However,
Karpow (1893) reported that 87 percent of 4-chlorophenol was ex-
creted in urine of dogs as sulfuric and glucuronic acid conjugates.
The ingestion of chlorobenzene may also give rise to an inter-
nal metabolic exposure to chlorophenol. The mammalian metabolism
of chlorobenzene yields 2-, 3-, and 4-chlorophenol as the major
products (Smith, et al. 1972).
EFFECTS
Acute, Subacute, and Chronic Toxicity
The acute oral, subcutaneous (s.c.), dermal, intraperitoneal
(i.p.), and inhalation LD^s for 3- and 4-chlorophenol are shown in
Table 4. Because 3-chlorophenol is a liquid at room temperature,
some of the early workers reported I^gS as ml/kg. The oral LDcQ
for each isomer is on the order of 500 to 900 mg/kg. The dermal
LD^Q for 4-chlorophenol is 1,500 mg/kg, indicating dermal absorp-
tion. Interestingly, both 3- and 4-chlorophenol are less toxic
when given subcutaneously than when taken orally. This may reflect
a slower absorption from the injection site and/or rapid metabolism
of the absorbed compounds.
4-Chlorophenol 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 admin-
istered intraperitoneally at 3-hour intervals (Miller, et al.
1973) .
-------
o
I
TABLE 4
Acute Toxicity of Monochlorophenols
Chemical
Solvent
Species
Toxic Response
-chlorophenol
-chlorophenol
olive
olive
olive
oi
oi
oi
1
1
1
not stated
olive
oi
1
not stated
olive
oi
1
not stated
olive
oi
1
rat
rat
rat
rat
rat
mouse
rat
rat
rat
mouse
oral
s.c.
i.p.
oral
oral
oral
s.c.
der .
i.p.
inh .
LD
LD
LD
LD
LD
LD
LD
LD
LD
LC
50
50 =
50 =
50 =
50 =
50 =
50 =
50 =
50 =
sn =
0.
1.
335
500
660
860
1,030
1,500
250
11
56 ml/kg
39 ml/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
mg/kg
rng/m
Deii
Deii
Fan
Gur
Dei
Sch
Dei
Gur
Far
Gur
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
-------
The monochlorophenols act on the nervous system to produce
tremors and convulsions, an effect reported several times in the
literature. The monochlorophenols with a pKa of 8 or greater are
convulsants. At body pH (7.0 to 7.4), these chlorophenols are
largely undissociated.
Binet (1896) reported that subcutaneous injections of mono-
chlorophenols in rats and guinea pigs caused muscle twitching,
spasms, generalized tremors, weakness, staggering, and finally col-
lapse. Kuroda (1926) found that intravenous doses of 100 mg/kg of
any of the three monochlorophenol isomers caused convulsions in
rabbits. In acutely toxic doses, 3-chlorophenol causes restless-
ness and increased respiration followed by rapidly developing motor
weakness (Deichmann, 1943). Chronic convulsive seizures follow and
continue until death. The clinical signs are similar with
4-chlorophenol but the convulsions are more severe.
Farquharson, et al. (1958) also reported that 2-, 3-, or
4-chlorophenol produced convulsive seizures in rats. Body tempera-
ture was reduced 2 to 5 C, and rigor mortis did not develop within
five minutes of death as with tri-, tetra-, and pentachlorophenols.
Death occurred one hour after administration of the LD5Q to rats.
At higher doses, deaths occurred in 5 to 15 minutes. There were no
further deaths in rats surviving three hours. Convulsions occurred
as soon as 1 to 2 minutes following intraperitoneal injection.
4-Chlorophenol and 3-chlorophenol also stimulated oxygen uptake by
rat brain homogenate at concentrations between 2.5 x 10~5 and 1 x
10~3M.
C-12
-------
Angel and Rogers (1972) used urethane-anesthetized mice to de-
termine the intraperitoneal dose required to produce convulsions in
50 percent of the test animals, i.e., the CD5Q. The CD5Qs were
100.6 mg/kg for 3-chlorophenol and 115.7 mg/kg for 4-chlorophenol.
Both of these monochlorophenols have approximately 1.2 times the
convulsant potency of phenol. These CD5Q values are approximately
one-half to one-third of the intraperitoneal LD5Q.
Gurova (1964) conducted inhalation studies of 4-chlorophenol
using mice and rats. The inhalation LC5Q for mice was 11 mg/m ,
with the duration of exposure not reported. Single inhalations of
20 mg/m3 did not produce acute poisoning in rats. Rats exposed to
13 mg/m3 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 con-
sumption.
Gurova (1964) additionally reported a study in which rats and
mice inhaled 4-chlorophenol in supraliminal concentrations for
4-hour periods for 28 days. Considerable changes in the morphology
of the internal organs of killed animals were observed. These
changes included congestion and focal hemorrhages in the brain,
lungs, liver, and myocardium, as well as thickening of the alveolar
septa and some atelectasis and emphysema in the lungs.
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 ex-
citability. Body temperature, hemoglobin, RBC, WBC, and sedimenta-
C-13
-------
tion rate were not altered. Microscopic examination of organs of
killed animals revealed only slight congestion; minor fibrotic
changes in the alveolar septa which were noted in some animals.
Banna and Jabbur (1970) studied the effects of phenols on
nerve synaptic transmission in cats. Phenol, like the monochloro-
phenols, is a convulsant. The mechanism of action apparently in-
volves an increase in the amount of neurotransmitter released at
the nerve synapse.
In terms of mechanism of action studies, most efforts have
been directed toward effects on oxidative phosphorylation and enzy-
mes involved in carbohydrate and intermediary metabolism 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 oxida-
tive phosphorylation. 4-Chlorophenol at 2.8 x 10 M had 21 percent
of the activity of 2 x 10~5M of 2,4-dinitrophenol.
Mitsuda, et al. (1963) studied the effects of various chloro-
phenols on oxidative phosphorylation of isolated rat liver mito-
chondria. The test system used a 2.75 ml reaction medium at pH 7.0,
with 0.05 ml of mitochondrial suspension containing 0.43 mg N. The
IDcQ (concentration of chlorophenol required to produce a 50 per-
cent inhibition in the production of ATP) was determined. The ID-,,
values for the monochlorophenols were 520 uM, 150 yM, and 180 yM
for 2-, 3-, and 4-chlorophenol, respectively. For comparison, the
ID^QS for pentachlorophenol and 2,4-dinitrophenol are 1 pM and 17
MM, respectively.
C-14
-------
Weinbach and Garbus (1965) tested the ability of various sub-
stituted phenols to completely uncouple oxidative phosphorylation
iH vitro. 3-Chlorophenol and 4-chlorophenol caused complete un-
coupling at 2.5 mM. For comparison, the known uncoupler 2,4-dini-
trophenol completely uncoupled the test system at 0.1 mM. There
was a positive relationship between mitochondrial 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 hypoth-
esis 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 3,4-dichlorophenol con-
centration of 10~4M (16 mg/1), the activities of various enzymes in
the bovine lenses were compared with those of the control lenses.
No statistical analysis was repor.ted; the results are presented in
Table 5. For comparison, the activity of 2-chlorophenol, the only
other chlorophenol tested, is also presented. The response pattern
is complex and difficult to interpret in the absence of statistical
analysis.
Korte, et al. (1976) have used the isolated bovine lens system
to study the metabolic effects of various chemicals on this part of
the eye. One lens is used as a control and the other as the experi-
mental. 4-Chlorophenol at 10~3M reduced ATP, glucose-6-phosphate,
and glucose and fructose levels after a 48-hour incubation.
3-Chlorophenol reduced levels of fructose, ATP and ADP, and
C-15
-------
TABLE 5
a
Effect of Chlorophenols on Enzyme Activities of Isolated Bovine Lenses*
2-chlorophenol 3,4-dichlorophenolb
Lactic dehydrogenase 94.0 85.5
Malate dehydrogenase 64.4 86.3
Sorbitol dehydrogenase 91.9 107.3
Glucose-6-phosphate dehydrogenase 129.9 70.0
Fructose-diphosphate aldolase 80.4 85.7
Pyruvate kinase 92.9 99.0
Glutainate-oxalacetate-transaminase 92.7 111.9
Flutamate-pyruvate-transaminase 142.9 92.9
*Source: Ismail, et al. 1976
aThe effect is expressed as percent of control
Each chemical was tested at 10~4M
-------
increased AMP levels. Korte, et al. (1976) did not find changes in
the following dehydrogenases: lactate, malate, sorbitol, glucose-
6-phosphate, or in fructose 1,6-diphosphate aldolase or pyruvate
kinase.
Harrison and Madonia (1971) pointed out that 4-chlorophenol
has been used since the nineteenth century at a concentration of 35
percent in camphor for endodontic therapy in dentistry. They con-
ducted ocular and dermal toxicity tests with 1 or 2 percent aqueous
solutions of 4-chlorophenol and 35 percent camphorated 4-chloro-
phenol. The 1 percent aqueous solution caused slight hyperemia
when 0.15 ml was placed on the cornea of white rabbits. A 2 percent
aqueous solution (0.15 ml) produced a more severe response, char-
acterized by moderate to severe hyperemia, mild to moderate edema,
cloudy cornea and exudation. The 35 percent camphorated 4-chloro-
phenol produced a severe response. The changes induced by the 1
percent and 2 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 intradermally in rabbits. The 1 and 2 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.
Gurova (1964) reported the effects of 4-chlorophenol in indus-
trial workers in an aniline dye plant in Russia. Air levels ranged
from 0.3 to 21 mg/m3 depending on the work site and operation. Two
accidental acute poisonings were reported with clinical signs con-
sisting of headache, dizziness, respiratory disorder, vomiting,
loss of coordination, tremor and, in one case, liver enlargement.
C-17
-------
Other workers not acutely affected reported experiencing headache,
dizziness, weakness, nausea, vomiting, and paresthesia (abnormal
prickling 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 significantly higher incidence of
neurologic disorders. Symptoms reported included neurasthenia
(nervous exhaustion), insomnia, irritability, frequent mood
changes and rapid fatigability. Peripheral nerve stimulation stud-
ies showed increased myoneural excitability in exposed workers. A
decreased response to a two-point touch discrimination was appar-
ent, in that the minimum detection distance between the points was
increased. Changes in the capillaries of the nail fold of the fin-
gers were said to occur, but were not described. An average per-
missible air concentration of 3 mg/m was reported for industrial
workers.
Synerqism and/or Antagonism, Teratogenicity, and Mutagenicity
Pertinent data could not be located in the available liter-
ature.
Carcinogenicity
Adequate information was not found to determine whether 3- or
4-chlorophenol possess carcinogenic properties.
Boutwell and Bosch (1959) conducted a series of experiments on
the tumor promoting action of substituted phenols using 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 carcinomas were found after 15 weeks
(Table 6). The tumor initiator DMBA (9,10-dimethyl-l,2-benzan-
thracene) was used. Papillomas occurred at .the application site.
C-18
-------
TABLE 6
Papilloma Promoting Action of 3-Chlorophenola*
Group
Control 3-chlorophenol (20%)
Number of mice
(survivors/original)
Average number of
papillomas per survivor
Percent survivors with
papillomas
Percent survivors
with carcinomas
15/20
0.07
7
0
21/33
1.38
67
0
*Source: Boutwell and Bosch, 1959
Promoter applied twice weekly. Initiator 0.3% DMBA in benzene
Promoter in benzene.
C-19
-------
CRITERION FORMULATION
Existing Guidelines and Standards
Standards have not yet been established for 3-chlorophenol or
4-chlorophenol.
Current Levels of Exposure
Pertinent data could not be located in the available litera-
ture concerning current exposure levels of 3- and 4-chlorophenol.
Special Groups at Risk
Pertinent data could not be located in the available litera-
ture concerning groups at special risk of exposure to 3- or 4-chlo-
rophenol.
Basis and Derivation of Criterion
Insufficient data exist to indicate that 3-chlorophenol is
carcinogenic. The only study performed (Boutswell and Bosch, 1959)
was designed to detect the promoting activity of 3-chlorophenol
with dimethylbenzanthracene (DMBA). In this study, 3-chlorophenol
exhibited promoting activity in the formation of papillomas.
A paucity of information pertaining to the acute or chronic
effects of 3-chlorophenol or 4-chlorophenol precludes the possibil-
ity of deriving a health effects-based criterion level for these
compounds. Consequently, the recommended criterion is based on
organoleptic properties.
Monochlorinated phenols have been shown to impart a medicinal
taste and odor to water and to fish residing in contaminated waters
(Schultze, 1961; Teal, 1959; Dietz and Traud, 1978; Burttschell, et
al. 1959; Hoak, 1957). Data from the available studies of odor
detection thresholds of 3- and 4-chlorophenols indicate threshold
C-20
-------
ranges of 50 to 200 ug/1 and 33 to 250 ug/1, respectively (see
Table 2). Within these ranges, also lie the threshold concentra-
tions for tainting of the flesh of aquatic organisms residing in
contaminated waters (see Table 3). Dietz and Traud (1978) have
also determined the taste and odor threshold concentrations of 36
phenolic compounds, including 3- and 4-chlorophenols, in water.
The odor threshold values obtained for these compounds were 50 and
60 ug/1, respectively. The taste threshold value obtained by these
authors for both 3- and 4-chlorophenols was 0.1 ug/1.
The taste threshold determined by Dietz and Traud (1978) for
the detection of 3-chlorophenol and 4-chlorophenol in water is used
as the basis for the ambient water quality criterion. The Deitz
and Traud study was chosen for a number of reasons. These authors
present a recent study involving well-defined procedures and a num-
ber of documented controls. This study utilized "fresh" water from
the base outlet of the Verse Dam (Germany) for all experiments.
The water was described as clear and neutral with respect to both
odor and taste. These conditions are considered to more closely
approximate the conditions of ambient water found in lakes, rivers,
and streams than would those of the Hoak (1957) and Burttschell, et
al. (1959) studies, which utilized carbon-filtered laboratory
distilled water. The 20 to 22°C temperature of the water in the
Dietz and Traud odor and taste tests might also more closely
approximate the temperature at which water is normally consumed
than do the 30°C or 25°C temperatures used in the studies of Hoak
(1957) and Burttschell, et al. (1959), respectively. However, it
is recognized that the temperature of water consumed by humans is
C-21
-------
quite obviously variable, and no study will represent the tempera-
ture of water consumed by all Americans.
Thus, based on the prevention of adverse organoleptic effects,
the criterion recommended for 3-chlorophenol and 4-chlorophenol is
0.1 yg/1. It is emphasized that this is a criterion based on
aesthetic rather than health effects. Data on human health effects
must be developed as a more substantial basis for recommending a
criterion for the protection of human health.
C-22
-------
REFERENCES
Alexander, M. and M.I.H. Aleem. 1961. Effect of chemical struc-
ture on microbial decomposition of aromatic herbicides. Jour.
Agric. Food Chem. 9: 44.
Angel, A. and K.J. Rogers. 1972. An analysis of the convulsant
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.
C-23
-------
Deichmann, w.B. 1943. The toxicity of chlorophenols for rats.
Fed. Proc. 2: 76.
Deichmann, W.B. and E.G. Mergard. 1948. Comparative evaluation of
methods employed to express the degree of toxicity of a compound.
Jour. Ind. Hyg. Toxicol. 30: 373.
Deitz, F. and J. Traud. 1978. Odor and taste threshold concentra-
tions of phenol bodies. Guf-wasser/abwasser. 119: 318.
Farquharson, M.E., et al. 1958. The biological action of chloro-
phenols. Br. Jour. Pharmacol. 13: 20.
Gurova, A.I. 1964. Hygienic characteristics of p-chlorophenol in
the aniline dye industry. Hyg. Sanita. 29: 46.
Hansch, C. and A.J. Leo. 1979. Substituent constants for correla-
tion analysis in chemistry and biology. Wiley Interscience, New
York.
Harrison, J.W. and J.V. Madonia. 1971. The toxicity of para-
chlorophenols. Oral Surgery. 32: 90.
Hoak, R.D. 1957. The causes of tastes and odors in drinking water.
Purdue Eng. Exten. Service. 41: 229.
C-24
-------
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.
Jolley, R.L., et al. 1975. Analysis of soluble organic constitu-
ents in natural and process waters by high-pressure liquid chroma-
tography. Trace Subst. Environ. Hlth. 9: 247.
Karpow, G. 1893. On the antiseptic action of three isomer chloro-
phenols 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 environ-
mental chemicals and their metabolites on the content of free
adenine nucleotides, intermediates of glycolysis and on the activi-
ties of certain enzymes of bovine lenses in 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.
Cited by W.F. von Oettingen, 1949.
Miller, J.J., et al. 1973. The metabolism and toxicity of phenols
in cats. Biochem. Soc. Trans. 1: 1163.
C-25
-------
Mitsuda, H., et al. 1963. Effect of chlorophenol analogues on the
oxidative phosphorylation in rat liver mitochondria. Agric. Biol.
Chem. 27: 366.
Parker, V.H. 1958. Effect of nitrophenols and halogeriophenols on
the enzymic activity of rat-liver mitochondria. Biochem. Jour.
69: 306.
Piet, G.J. and F. De Grunt. 1975. Organic Chloro Compounds in Sur-
face and Drinking Water of the Netherlands. In: Problems Raised by
the Contamination of Man and his Environment. Comm. Eur. Communi-
ties, Luxembourg, p. 81
Roberts, M.S., et al. 1977. Permeability of human epidermis to
phenolic compounds. Jour. Pharm. Pharmacol. 29: 677.
Schrotter, E., et al. 1977. Organische syntehtica und ihre ver-
mizden eigenschaften. Pharmazie. 32: 171 (Ger.)
Schulze, E. 1961. The effect of phenol-containing waste on the
taste of fish. Int. Revue Ges. Hydrobiol. 46: 81.
Smith, J.R.L., et al. 1972. Mechanisms of mammalian hydroxyla-
tion: Some novel metabolites of chlorobenzene. Xenobiotica.
2: 215.
Stephan, C.E. 1980. Memorandum to J. Stara. U.S. EPA. July 3.
C-26
-------
Teal, J.L. 1959. The control of waste through fish taste. Pre-
sented to Amer. Chem. Soc., Natl. meeting.
U.S. EPA. 1980. Seafood consumption data analysis. Stanford
Research Institute International, Menlo Park, California. Final
rep., Task II. Contract No. 68-01-3887.
Veith, G.D., et al. 1979. Measuring and estimating the bioconcen-
tration factors of chemicals in fish. Jour. Fish. Res. Board Can.
36: 1040.
Veith, G.D. 1980. Memorandum to C.E. Stephan. U.S. EPA.
April 14.
von Oettingen, W.F. 1949. Phenol and its derivatives: The rela-
tion between their chemical constitution and their effect on the
organism. National Inst. Health Bull. 190: 193.
Weinbach, B.C. and J. Garbus. 1965. The interaction of uncoupling
phenols with mitochondria and with mitochondrial protein. Jour.
Biol. Chem. 210: 1811.
C-27
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2,3-DICHLOROPHENOL
2,5-DICHLOROPHENOL[ 2,6-DICHLOROPHENOL[
3,4-DICHLOROPHENOL AND 4,6-DICHLOROPHENOL
Manunalian Toxicology and Human Health Effects
INTRODUCTION
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 isomers apparently have
not found use as primary chemicals. The following isomers are dis-
cussed in this document: 2,3-, 2,5-, 2,6-, 3,4-, and 4,6-dichloro-
phenol. 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 de-
gradation products. A limited amount of work has been reported on
dichlorophenols other than the 2,4-isomer.
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 to 960 yg/1. Phenols are found in
raw domestic sewage at levels of 70 to 100 ug/1. Complex phenols
are at least partially released by bacterial action in sewage
treatment trickling filters. The decomposition of surface vegeta-
tion such as oak leaves also releases phenol.
Burttschell, et al. (1959) proposed a mechanism for the chlo-
rination of phenol in water. According to their scheme, 2- and
4-chlorophenol are formed early. These molecules are further chlo-
rinated to 2,6- or 2,4-dichlorophenol. The final product is
:-28
-------
o
I
TABLE 1
Physiochemical Properties*
Property
Molecular weight
Formula
Melting point C
Boiling point C
Solubility
water
alcohol
ether
benzene
Vapor pressure
CAS number
2,5-
163
C6H4C120
59
211
slightly
very
very
soluble
-
-
Dichlorophenol
2,6-
163
C6H4C120
68-9
219
very
very
soluble
1mm Hg, 59°C
87-65-0
I some r
3,4-
163
CgH4Cl2O
68
253
slightly
very
very
soluble
-
-
3,5-
163
C6H4C120
68
233
slightly
very
very
-
—
*Weast, (ed.) 1978
-------
2,4,6-trichlorophenol. After 18 hours of reaction, the chloro-
phenol products in Burttschell1s study consisted of less than 5
percent each of 2- and 4-chlorophenols, 25 percent 2,6-dichloro-
phenol, 20 percent 2,4-dichlorophenol and 40 to 50 percent
2,4,6-trichlorophenol.
Crosby and Wong (1973) reported that the photodecomposition of
the herbicide 2,4,5-T (2,4,5-trichlorophenoxyacetic acid) results
in the formation of small amounts of 2,5-dichlorophenol.
EXPOSURE
Ingestion from Water
Piet and DeGrunt (1975) found unspecified dichlorophenol iso-
mers in Dutch surface waters at concentrations of 0.01 to 1.5 yg/1.
Burttschell, et al. (1959) demonstrated that the chlorination of
phenol-laden water could result in the formation of mono-, di-, and
trichlorophenol isomers.
Ingols, et al. (1966) studied the biological degradation of
chlorophenols in activated sludge. 2,5-Dichlorophenol was more re-
sistent to degradation than 2,4-dichlorophenol. While 2,4-di-
chlorophenol was 100 percent degraded, including ring degradation,
in five days, 2,5-dichlorophenol was only 52 percent ring-degraded
in four days.
Alexander and Aleem (1961) determined the microbial decomposi-
tion of 2,5-dichlorophenol in a Dunkirk soil suspension. Disap-
pearance was not complete at the end of 72 days.
The association of unpleasant taste or odor of tap water with
chlorophenols has been of interest for a number of years (Hoak,
1957; Burttschell, et al. 1959; Campbell, et al. 1958). Hoak
(1957) reviewed aspects of this problem. Some chlorophenols have
C-30
-------
odor thresholds in the ppb concentration range. The addition of
0.2 to 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 dichlorophenols in water are shown in Table 2.
Taste threshold data are summarized in Table 3.
Odor and taste thresholds for chlorinated phenols in water
have been reported by a number of authors (Hoak, 1957; Dietz and
Traud, 1978; Burttschell, et al. 1959). These studies are dis-
cussed in the Monochlorophenols portion of this document (see In-
gestion from Water).
Ingestion from Food
Pertinent data could not be located in the available litera-
ture.
Inhalation
Olie, et al. (1977) reported finding di-, tri- and tetra-
chlorphenols in flue gas condensates from municipal incinerators.
The levels were not quantified.
Dermal
Pertinent data could not be located in the available litera-
ture .
PHARMACOKINETICS
Pharmacokinetic data specific to the dichlorophenol isomers
discussed in this document were not available. It is reasonable to
assume that dichlorophenol isomers are absorbed through the skin
and from the gut, and rapidly eliminated from the body, as are
other chlorophenols.
C-31
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TABLE 2
Comparison of Odor Thresholds for Dichlorophenols in Water
Threshold-ppb
(ug/1) ( °C
1 - Hoak, 1957
2 - Burttschell, et al. 1959
3 - Deitz and Traud, 1978
Reference
2 , 3-dichlorophenol
2 , 4-dichlorophenol
2 , 5-dichlorophenol
2 , 6-dichlorophenol
3 , 4-dichlorophenol
30
0.65
2
40
33
30
3
200
100
20-22
30
25
20-22
30
20-22
25
20-22
20-22
3
1
2
3
1
3
2
3
3
C-32
-------
TABLE 3
Summary of Taste Threshold Concentrations
of Dichlorophenols in Water
Compound
2 , 3-dichlorophenol
2 , 4-dichlorophenol
2 , 5-dichlorophenol
2 , 6-dichlorophenol
3 , 4 -d ichlorophenol
Threshold (yg/1)
0.04
0.3
8.0
0.5
0.2
2.0
0.3
Reference
1
1
2
1
1
2
1
1 - Deitz and Traud, 1978
2 - Burttschell, et al. 1959
C-33
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Metabolism
Dichlorobenzenes are metabolized by mammals to dichloro-
phenols (Kohli, et al. 1976). For example, 1,2-dichlorobenzene
gives rise to 3,4-dichlorophenol and smaller amounts of 2,3- and
4,5-dichlorophenols 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, hexachlorocyclohexane. The metabolic pro-
ducts included 2,4,6-trichlorophenol, 2,3-dichlorophenol as well
as di- and trichlorobenzenes.
EFFECTS
Acute, Subacute, and Chronic Toxicity
Farquharson, et al. (1958) reported that 2,6-dichlorophenol
produced convulsions in rats. The intraperitoneal LDcn was 390
mg/kg. Rats given the LDcn died within one hour; deaths did not
occur later in rats surviving at least three hours. Body tempera-
ture was depressed by 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 homogenate was stimulated at con-
centrations between 2.5 x 10 and 1 x 10~3 M.
Banna and Jabbur (1970) studied the effects of phenols, but
not chlorophenols directly, on nerve synaptic transmission in cats.
Phenol is a convulsant, as are the lower chlorinated phenols. Ex-
perimental results suggest that the mechanism of action involves an
increase in the amount of neurotransmitter released at the new syn-
apse.
C-34
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Studies on the mechanism of action of chlorophenols have pri-
marily 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-dichlorophenol decreased ATP and ADP
levels while increasing AMP levels. There was no effect on glucose
or fructose-6-phosphate levels. Activities of malate dehydro-
genase, glucose-6-phosphate dehydrogenase and pyruvate kinase were
reduced. The dichlorophenol caused swelling of the lens.
Ismail, et al. (1976) studied the permeation of chemicals into
the bovine lens capsule and the 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
permeate the lens capsule rapidly. 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. The results
are presented in Table 4. For comparison, data on the effect 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.
Synergism and/or Antagonism and Teratogenicity
Pertinent data could not be located in the available litera-
ture.
Mutagenicity
Rasanen and Hattula (1977) tested chlorophenols for muta-
genicity using the Salmonella-mammalian microsome Ames assay in
both activated and nonactivated systems. The following
C-35
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o
I
(jO
o\
TABLE 4
Effect of Chlorophenols on Enzyme Activities of Isolated Bovine Lenses*
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
92.9
92.7
142.9
85.5
86.3
107.3
70.0
85.7
99.0
111.9
92.9
*Source: Ismail, et al. 1976
aThe effect is expressed as percent of control
b —4
Each chemical was tested at 10 M
-------
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-dichloro-
phenols. Mutagenicity in mammalian test systems has not been
evaluated.
Carcinogenicity
Pertinent data could not be located in the available litera-
ture.
C-37
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CRITERION FORMULATION
Existing Guidelines and Standards
Standards have not been established for the dichlorophenols.
Current Levels of Exposure
Pertinent data could not be located in the available litera-
ture concerning current exposure levels of dichlorophenols.
Special Groups at Risk
Pertinent data could not be located in the available litera-
ture concerning groups at special risk of exposure to dichloro-
phenols.
Basis and Derivation of Criterion
A paucity of information pertaining to the acute or chronic
effects of dichlorophenols precludes the possibility of deriving a
health effects based criterion level for these compounds. Conse-
quently, the recommended criteria are based on organoleptic proper-
ties.
Dichlorophenols have been shown to impart a medicinal taste
and odor to water (Hoak, 1957; Deitz and Traud, 1978). Details of
the Hoak (1957), Burttschell, et al. (1959), and Deitz and Traud
(1978) studies are discussed in the section of this document deal-
ing with monochlorophenols. Data from the available studies of
odor detection thresholds of dichlorophenols are summarized in
Table 2. Deitz and Traud (1978) have determined the taste and odor
threshold concentrations of 36 phenolic compounds, including
dichlorophenols, in water. The taste and odor threshold values for
dichlorophenols are summarized in Tables 2 and 3.
C-38
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The taste thresholds determined by Dietz and Traud (1978) for
the detection of the various dichlorophenols in water are used as
the bases for the ambient water quality criteria. The Dietz and
Traud study was chosen for a number of reasons. These authors pre-
sent a recent study involving well-defined procedures and a number
of documented controls. This study utilized "fresh" water from the
base outlet of the Verse Dam (Germany) for all experiments. The
water was described as clear and neutral with respect to both odor
and taste. These conditions are considered to more closely approx-
imate the conditions of ambient water found in lakes, rivers, and
streams than would those of the Hoak (1957) and Burttschell, et al.
(1959) studies, which utilized carbon-filtered laboratory dis-
tilled water. The 20 to 22°C temperature of the water in the Dietz
and Traud odor and taste tests might also more closely approximate
the temperature at which water is normally consumed than do the
30°C or 25°C temperatures used in the studies of Hoak (1957) and
Burttschell, et al. (1959), respectively. However, it is recog-
nized that the temperature of water consumed by humans is quite
obviously variable, and no study will represent the temperature of
water consumed by all Americans.
Thus, based on the prevention of undesirable organoleptic
qualities, the criteria recommended for 2,3-, 2,5-, 2,6-, and
3,4-dichlorophenols are 0.04 yg/1, 0.5 yg/1, 0.2 yg/1, and 0.3
yg/1, respectively. It is emphasized that these are criteria based
on aesthetic rather than health effects. Data on human health
effects must be developed as a more substantial basis for recom-
mending a criterion for the protection of human health.
C-39
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REFERENCES
Alexander, M. and M.I.H. Aleem. 1961. Effect of chemical struc-
ture on microbial decomposition of aromatic herbicides. Jour.
Agric. Food Chem. 9: 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-tri-
chlorophenoxyacetic acid (2,4,5-T) in water. Jour. Agric. Food
Chem. 21: 1052.
Deitz, F. and J. Traud. 1978. Odor and taste threshold concentra-
tions of phenol bodies. Gwf-wasser/abwasser. 199: 318.
Farquharson, M.E., et al. 1958. The biological action of chloro-
phenols. Br. Jour. Pharmacol. 13: 20.
C-40
-------
Foster, T.S. and J.G. Saha. 1978. The iri vitro metabolism of lin-
dane by an enzyme preparation from chicken liver. Jour. Environ.
i^. Health. 13: 25.
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 chlorinated ben-
zene isomers. Can. Jour. Biochem. 54: 203.
Korte, I., et al. 1976. Studies on the influences of some environ-
mental chemicals and their metabolites on the content of free
adenine nucleotides, intermediates of glycolysis and on the activi-
ties of certain enzymes of bovine lenses _in vitro. Chemosphere.
5: 131.
Olie, K., et al. 1977. Chlorodibenzo-p-dioxins and chlorodibenzo-
flurans are trace components of fly ash and flue gas of some muni-
cipal incinerators in the Netherlands. Chemosphere 8: 445.
C-41
-------
Piet, G.J. and F. De Grunt. 1975. Organic Chloro Compounds in Sur-
face and Drinking Water of the Netherlands. In; Problems Raised by
the Contamination of Man and his Environment. Comm. Eur. Communi-
ties, Luxembourg, p. 81.
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.
Weast, R.C. (ed.) 1978. Handbook of Chemistry and Physics. 59th
ed. CRC Press.
C-42
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TRICHLOROPHENOLS
Mammalian Toxicology and Human Health Effects
INTRODUCTION
Trichlorophenols are used as antiseptics and disinfectants, as
well as being intermediates in the formation of other chemical pro-
ducts. 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-trichlorophenols. The physiochemical
properties of these isomers are listed in Table 1.
In the evaluation of the trichlorophenols there is a related
contaminant that is the subject of separate consideration by regu-
latory agencies, including the U.S. EPA. A major use of 2,4,5-tri-
chlorophenol is as a feedstock in the synthesis of various pesti-
cides, including the herbicides 2,4,5-trichlorophenoxyacetic acid
(2,4,5-T), Silvefe} Erbort^ and the insecticide Ronne@ All of
these products involve 2,4,5-trichlorophenol in their manufactur-
ing processes and may contain 2 ,3 ,7 ,8-tetrachlorodibenzo-p-dioxin
(TCDD). This highly toxic contaminant caused the U.S. EPA to pub-
lish a Rebuttable Presumption Against Registration (RPAR) and Con-
tinued Registration of Pesticide Products Containing 2,4,5-T (43 FR
17116). The published RPAR indicated that 2,4,5-trichlorophenol is
also the subject of a separate potential RPAR.
TCDD is a known teratogen (Courtney, 1976) and carcinogen (Van
Miller, et al. 1978). Its extreme toxicity is not disputed. The
water solubility of TCDD is 0.2 yg/1. TCDD is produced during the
formation of 2,4,5-trichlorophenol. Most documented cases of ad-
verse health effects have involved industrial accidents where
C-43
-------
n
i
TABLE 1
Physiochemical Properties of Trichlorophenols*
Properties
Moleclar Weight
Formula
Melting point °C
Boiling point °C
Solubility
water
alcohol
ether
benzene
Vapor pressure
CAS Number
Trichlorophenol Isomers
2,3,4-
197.45
C6H3C13O
83.5
sublimes
—
soluble
soluble
soluble
--
—
2,3,5-
197.45
C6H3C130
62
248.5
slightly
soluble
soluble
--
--
--
2,3,6-
197.45
C6H3C130
58
—
slightly
very
very
very
--
933-75-5
2,4,5-
197.45
C6H3C130
68-70
sublimes
slightly
soluble
—
--
1 mm Hg, 72°C
95-95-4
-------
TABLE 1 (Continued)
o
I
*>.
U1
Properties
Molecular weight
Formula
Melting point °C
Boiling point °C
Density
Tr
2,4,6-
197.5
C6H3C130
69.5
246
1.490
ichlorophenol
Isomers
3,4,5-
197.5
C6H3C130
101
271-7
_ —
Solubility
water
alcholol
ether
Vapor pressure
CAS Number
slightly
soluble
soluble
1 mm Hg, 76(
88-06-2
slightly
soluble
609-19-8
*Weast (ed.), 1978
-------
exothermic reactions resulted in explosions and exposure of humans
and the environment. Whiteside (1977) described a 1949 explosion
of a 2,4,5-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 em-
ployees in 2,4-D and 2,4,5-T plants (Bleiberg, et al. 1964). The
1976 explosion in Seveso, Italy in which 1 to 5 kg of TCDD were re-
leased has received much 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 stud-
ies for evaluation. No tolerance level has yet been established
for TCDD.
CroSuby and Wong (1973) found that 2,4,5-tr ichlorophenol is a
photodecomposition product of the herbicide 2,4,5-T. About 38 per-
cent of the 2,4,5-T was converted to the trichlorophenol.
EXPOSURE
Ingestion from Water
Piet and DeGrunt (1975) found unspecified trichlorophenol iso-
mers in surface waters in The Netherlands, at concentrations from
0.003 to 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 result in water concentrations of 300 to 960 ug/1. Phenols are
found in raw domestic sewage at levels of 70 to 100 ug/1. Complex
C-46
-------
phenols are at least partially released by bacterial action in sew-
age treatment trickling filters. The decomposition of surface veg-
etation such as oak leaves also releases phenol.
The association of unpleasant taste or odor of tap water with
chlorophenols has been of interest for a number of years (Hoak,
1957; Burttschell, et al. 1959; Campbell, et al. 1958).' Hoak (1957)
reviewed aspects of this problem. Some chlorophenols have odor
thresholds in the ppb concentration range. The addition of 0.2 to
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 trichlorophenols in water are shown in Table 2.
Table 3 contains a summary of taste threshold data for the tri-
chlorophenols in water.
Burttschell, et al. (1959) proposed a mechanism for the chlo-
rination of phenol in water. According to their scheme, 2- and
4-chlorophenols 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 chloro-
phenol products in Burttschell1s study consisted of less than
5 percent each 2- and 4-chlorophenol, 25 percent of 2,6-dichloro-
phenol, 20 percent 2,4-dichlorophenol and 40 to 50 percent
2,4,6-trichlorophenol.
Ingestion from Food
One possible source of trichlorophenol exposure for humans is
through the food chain, as a result of the ingestion by grazing
C-47
-------
TABLE 2
Odor Thresholds for Trichlorophenols in Water
Threshold Reference
(ug/1) ( °C)
2
2
2
, 3 , 6-Tr ichlorophenol
,4 ,5-Trichlorophenol
, 4 , 6-Tr ichlorophenol
300
11
200
100
1,000
300
20-22
25
20-22
30
25
20-22
3
1
3
1
2
3
1 - Hoak, 1957
2 - Burttschell, et al. 1959
3 - Dietz and Traud, 1978
C-48
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TABLE 3
Summary of Taste Threshold Concentrations of
Trichlorophenols in Water
Compound
Threshold
(yg/D
Reference
2,3,6-Trichlorophenol
2,4,5-Trichlorophenol
2,4,6-Trichlorophenol
0.5 Deitz and Traud, 1978
1.0 Deitz and Traud, 1978
2.0 Deitz and Traud, 1978
C-49
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animals of the chlorophenoxy acid herbicides 2,4,5-T (2,4,5-tri-
chlorophenoxy-acid) or Silvex-^ (2-(2,4,5-trichlorophenoxy) pro-
pionic acid). Residues of the herbicides on sprayed forage are
estimated to be in the range of 100 to 300 ppm. In view of this,
Clark, et al. (1976) fed Silvex^ cattle at levels of 300, 1,000,
and 2,000 ppm in the diet for 28 days, and fed 2,4,5-T or Silvex—'to
sheep at 2,000 ppm in the diet for 28 days. Based on feed consump-
tion, the exposures were equivalent to 9 mg/kg (300 ppm), 30 mg/kg
(1,000 ppm) and 60 mg/kg (2,000 ppm). Before tissue samples were
obtained some animals were fed a clean diet during a 7-day with-
drawal. Muscle, fat, liver, and kidney were analyzed for 2,4,5-
trichlorophenol. In the sheep fed 2,000 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 7-day with-
drawal period 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 2,000 ppm of Silvex-', 2,4,5-trichlorophenol was not
detected in muscle or fat at the end of 28 days. Residues in the
liver were 0.2 to 0.5 ppm and in kidney were 0.1 to 0.17 ppm.
Bjerke, et al. (1972) fed lactating cows 2,4,5-T and analyzed
the milk for tr ichlorophenol. At feeding levels of 100 ppm
2,4,5-T, an occasional residue of 0.06 ppm or less of trichloro-
phenol was detected. At 1,000 ppm 2,4,5-T in the diet, residues of
0.15 to 0.23 ppm tr ichlorophenol were found in milk and cream.
Three days after 2,4,5-T feeding at the 1,000.ppm level was stopped,
C-50
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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 herbi-
cide ErborV^ (2- (2,4 ,5-trichlorophenoxy) ethyl-2, 2-dichloropropion-
ate). Two metabolites were found in urine, 2-(2,4,5-trichloro-
phenoxy)-ethanol and 2,4,5-trichlorophenol. About 33 percent of
(R)
the administered Erboit-' dose was eliminated as 2,4,5-trichloro-
phenol in urine in 96 hours. A dose of 100 mg Erbors-ykg 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, 3.14 ppm in
liver, 2.06 ppm in omental fat, and 1.00 ppm in muscle. Dosages of
50 mg Erbon-ykg for 10 days followed by slaughter on day 11 re-
sulted in no detectable 2,4,5-trichlorophenol residues in tissues.
Stannard and Scotter (1977) from New Zealand determined the
residues of various chlorophenols in dairy products 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 docu-
ment, the possible mechanism of exposure deserves recognition.
Exposure to other chemicals could result in exposure to tri-
chlorophenols via metabolic degradation of the parent compound.
Kohli, et al. (1976) found that the major rabbit urinary metabo-
lites of 1,2,4-trichlorobenzene were 2,4,5- and 2,3,5-trichloro-
phenol. 1,2,3-trichlorobenzene was metabolized to 2,3,4-tri-
chlorophenol and smaller amounts of 2,3,6- and 3,4,5-trichloro-
C-51
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phenol. 1,3,5-trichlorobenzene was metabolized to 2,3,5- and
2,4,6-trichlorophenol. 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-hexachlorocyclO'hexane. The
metabolic products included 2,4,6-trichlorophenol, and 2,3-di-
chlorophenol, as well as di- and trichlorobenzenes. Tanaka, et al.
(1977) found that isolated rat liver microsomes metabolized the
alpha, beta, gamma, delta, and epsilon isomers of hexachlorocyclo-
hexane to 2,4,6-trichlorophenol.
Shafik, et al. (1972) showed that in 1 to 2 days, 30 to 50
/R)
percent of the insecticide RonneJS-' (0,0-dimethyl-O-(2,4,5-tri-
chlorophenyl)phosphorothioate) was excreted in the urine of rats as
2,4,5-tr ichlorophenol.
Even plants can metabolize another chemical to form a tri-
chlorophenol metabolite. Moza, et al. (1974) demonstrated that
corn and pea plants could metabolize pentachlorocyclohexene to the
2,4,6-, 2,3,5-, and 3,4,6-trichlorophenol isomers.
A bioconcentration factor (BCF) relates the concentration of a
chemical in aquatic animals to the concentration in the water in
which they live. The steady-state BCFs for a lipid-soluble com-
pound in the tissues of various aquatic animals seem to be propor-
tional to the percent lipid in the tissue. Thus, the per capita
ingestion of a lipid-soluble chemical can be estimated from the per
capita consumption of fish and shellfish, the weighted average per-
cent lipids of consumed fish and shellfish, and a steady-state BCF
for the chemical.
C-52
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Data from a recent survey on fish and shellfish consumption in
the United States were analyzed by SRI International (U.S. EPA,
1980). These data were used to estimate that the per capita con-
sumption of freshwater and estuarine fish and shellfish in the
United States is 6.5 g/day (Stephan, 1980). In addition, these
data were used with data on the fat content of the edible portion of
the same species to estimate that the weighted average percent
lipids for consumed freshwater and estuarine fish and shellfish is
3.0 percent.
No measured steady-state BCF is available for trichloro-
phenols, but the equation "Log BCF = (0.85 Log P) - 0.70" can be
used (Veith, et al. 1979) to estimate the steady-state BCF for
aquatic organisms that contain about 7.6 percent lipids from the
octanol-water partition coefficient (P) . Measured log P values
were obtained from Hansch and Leo (1979). An adjustment factor of
3.0/7.6 = 0.0395 is used to adjust the estimated BCF from the 7.6
percent lipids on which the equation is based to the 3.0 percent
lipids that is the weighted average for consumed fish and shell-
fish. Thus, the weighted average BCF 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
Log P
Meas. Calc.
3.72
3.87
BCF
290
389
Weighted BCF
110
150
C-53
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Inhalation
No quantitative data on inhalation studies were found. From
Table 1 it is noted that the vapor pressures of 2,4,5- and
2,4,6-trichlorophenol are about 1 mmHg at 72 to 76°C. Consequently
the trichlorophenols can be expected to vaporize to some extent.
Olie, et al. (1977) reported finding di-, tri- and tetra-
chlorophenols in flue gas condensates from municipal incinerators.
The levels were not quantified.
Dermal
Roberts, et al. (1977) used human epidermal membranes obtained
at autopsy in an in vitro test system to determine the permeability
of human skin to various chemicals. 2,4,6-Trichlorophenol per-
meated 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
Chlorophenols as a chemical class tend to be rapidly elimi-
nated in the urine. Hence, analyzing urine for trichlorophenol
residues is a reasonable approach to estimating exposure, regard-
less of the source and route of exposure. Dougherty and Piotrowska
(1976) used negative chemical ionization mass spectrometry to ana-
lyze urine samples for chlorophenols. Evidence was obtained sug-
gesting the presence of trichlorophenol or trichlorophenoxy herbi-
cides in 9 to 67 percent of the 57 samples analyzed. The concentra-
tions were not quantified.
Kutz, et al. (1978) analyzed 418 samples of human urine col-
lected from the general population via the Health and Nutritional
C-54
-------
Examination Survey. Residues of 2,4,5-trichlorophenol were found
in 1.7 percent of the samples. The average level found was less
than 5 yg/1 (ppb) and the maximum value found was 32.4 ug/1.
Excretion
2,4,5-Trichlorophenol is cleared rapidly from blood. Wright,
et al. (1970) dosed sheep with Erbort£/ a herbicide that is metabo-
lized 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-trichloro-
phenol, predominantly in urine. Korte, et al. (1978) administered
1 ppm 2,4,6-trichlorophenol in the diet to rats for three days and
then studied elimination. Eighty-two percent of the dose was
eliminated in the urine and 22 percent in the feces. Radio-labeled
trichlorophenol was not detected in liver, lung or fat obtained
five days after the last dose.
EFFECTS
Acute, Subacute, and Chronic Toxicology
Table 4 presents data regarding acute toxicity of several tri-
chlorophenol isomers. Differences in observed LD5Q values may be
due to the use of different solvents.
The clinical signs of acute poisoning with 2,4,5-trichloro-
phenol include decreased activity and motor weakness (Deichmann,
1943). Convulsive seizures also occur, but are not as severe as
with the monochlorophenols, which at physiological pH (7.0 to 7.4),
are mainly undissociated. The tri- and tetrachlorophenols have
lower pka values and, hence, are more extensively dissociated at
C-55
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o
I
TABLE 4
Acute Toxicity of Trichlorophenols
Ihemical Solvent
,4 , 5-Tr ichlorophenol Fuel oil
Corn oil
Fuel oil
Olive oil
1 ,4 , 5-Tr ichlorophenol Olive oil
1,4 , 6-Tr ichlorophenol Olive oil
!, 3 ,6-Tr ichlorophenol Olive oil
Species
Rat
Rat
Rat
Rat
Rat
Rat
Rat
Toxic Response
Oral LD5Q = 820
mg/kg
Oral LD3Q = 2,960 mg/kg
Subcutaneous LD
Intraper i toneal
In traperi toneal
Intraper i toneal
Intraper itoneal
50 = 2,260 mg/kg
LD5Q = 355 mg/kg
I-D50 = 372 mg/kg
">50 = 276 mg/kg
LD50 = ^^ mg/kg
Reference
Deichmann &
Mergard, 1948
McCollister ,
al. 1961
Deichman &
Mergard, 1948
Farquharson,
al. 1958
Farquharson,
al. 1958
Farquharson,
al. 1958
Farquharson,
et
et
et
et
et
-------
physiological pH. These compounds, with the exception of
2,4,6-trichlorophenol tend not to be convulsants.
Farquharson, et al. (1958) determined LDt-g values of isomers
of trichlorophenol (Table 4). 2,4,6-Trichlorophenol produced con-
vulsions when injected intraperitoneally. The 2,3,6-isomer occa-
sionally caused convulsions when dosed animals were handled. All
of the trichlorophenol isomers (3,4,5-, 2,4,5-, 2,4,6-, and 2,3,6-)
elevated body temperature by 0.5 C. Onset of rigor mortis occurred
within five minutes of death as compared to 50 minutes for con-
trols. Rats dosed with 2,3,6-, 3,4,5-, or 2,4,5-trichlorophenol
developed hypotonia in the hind limbs 2 to 3 minutes after intra-
peritoneal injection. The hypotonia then spread to the forelimbs
and neck. All of the trichlorophenol isomers stimulated oxygen
consumption of rat brain homogenate at concentrations of 5 x 10-
to 10-3M.
McCollister, et al. (1961) conducted a variety of toxicologic
studies on 2,4,5-trichlorophenol in rats. The 2,4,5-trichloro-
phenol used in the acute studies was 97 to 98 percent pure; and, for
the 90-day study, it was 99 percent pure. The acute oral LDcn was
2,960 mg/kg.
Rabbits were given 28 daily oral doses of 2,4,5-trichloro-
phenol 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 1,000 mg/kg during 24 days caused a
transient weight loss that disappeared within 14 days (McCollister,
C-57
-------
et al. 1961). Dosages of 30, 100, 300, or 1,000 mg/kg for 18 of 24
days did not affect mortality, hematological variables (unspeci-
fied) , 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-tri-
chlorophenol at dietary levels of 100, 300, 1,000, 3,000, or
10,000 mg of compound per kg of feed for 98 days (McCollister, et
al. 1961). Assuming that an average rat consumes an amount of feed
equivalent to 10 percent of its body weight daily, the equivalent
doses were 10, 30, 100, 300, and 1,000 mg/kg body weight.
Dosages of 100 mg/kg body weight or less produced no adverse
effects as judged by behavior, mortality, food consumption, growth,
terminal hematology, body and organ weights, and gross and micro-
scopic pathology.
At 1,000 mg/kg (10,000 mg/kg in diet), growth was slowed in
fe males. 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 tu-
bular epithelium and early proliferation of interstitial tissue.
The liver showed mild centrilobular degenerative changes character-
ized by cloudy swelling and occasional focal necrosis. There was
slight proliferation of the bile ducts and early portal cirrhosis.
The rats fed 300 mg/kg (3,000 mg/kg feed) also showed histopatho-
logic changes in kidney and liver that were milder than those ob-
served in the higher dose. The histopathologic changes were con-
sidered to be reversible.
058
-------
Anderson, et al. (1949) fed steers various levels of
2,4,5-trichlorphenyl acetate or zinc 2,4,5-trichlorophenate, as
shown in Table 5. Feed consumption, daily weight gain, hemoglobin,
and packed cell volume were determined. The results are summarized
in Table 6. Because of the limited number of animals per group,
statistical analysis was not done. Additionally, for day 154,
there was only one control animal per compound. The authors con-
cluded that the compounds were relatively nontoxic to the animals.
Examination of Table 6 shows no clinically significant changes in
hemoglobin or packed cell volume values. No gross lesions were
observed at slaughter. The feed consumption data suggest that with
both compounds, the high dose groups were consuming less
feed/kg/day. Tissues were not analyzed for the active agents.
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
sensitization studies in 200 humans. A 5 percent solution of
2,4,5-trichlorophenol in sesame oil was mildly irritating in a few
individuals upon prolonged contact, but there was no evidence of
sensitization.
Bleiberg, et al. (1964) described various adverse health ef-
fects in 29 workers involved in the manufacture of 2,4-D and
2,4,5-T. The workers had varying degrees of chloracne, hyperpig-
mentation, and hirsutism. Eleven had elevated urinary uropor-
phyrins. Eleven of the 29 were diagnosed as having evidence of
C-59
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o
I
Table 5
Steer Feeding Study Design*
Group N
1 2
2 2
3 2
4 2
5 2
6 2
7 2
8 2
Compound Dose-mg/kg
zinc 2,4,5 tr ichlorophenate 0
17
52
158
2 , 4 , 5-tr ichlorophenyl acetate 0
17
52
158
.64
.92
.77
.64
.92
.77
Duration
78
154
78
78
154
78
*Anderson, et al. 1949
N - Number of animals tested
-------
Table 6
Average Results of Trichlorophenol Steer Feeding Study*
o
i
CTi
Daily gain - 78 day
(kg/day)
Daily gain - 154 day
(kg/day)
Peed consumption
(gm/kg/day) 1- 78 day
(gm/kg/day) 1-154 day
Hemoglobin
(gm/100 ml) 78 day
(gm/100 ml) 154 day
Packed cell volume
PCV - 78 day
PCV - 154 day
0
0.73
0.77
35
30
10.3
10.9
34
36
ing zinc 2 , 4 , 5-tr ichlorophenate
Dose - mg/kg
17.64 52.92
0.97 0.83
0.71
32 33
37
11.1 10.3
10.4
37 34
35
158.77
0.68
--
24
™ ~~
10.9
37
--
-------
TABLE 6 (Continued)
o
i
en
Part 2: Results of feeding
0
Daily gain
(kg/day) 78 day 1.05
Daily gain
(kg/day) 154 day 0.77
Feed consumption
(gm/kg/day) 1- 78 day 36
(gm/kg/day) 1-154 day 30
Hemoglobin
(gm/100 ml) 78 day 9.1
(gm/100 ml) 154 day
Packed cell volume
PCV - 154 day 31
PCV - 154 day
2,4, 5-tr ichlorophenyl
Dose - mg/kg
17.64 52.
0.37 0.
0.
37 37
39
12.1 11.
"I 1
40 37
38
ac
92
84
68
1
3
158.77
0.65
30
11.7
38
*Source: Anderson, et al. 1949
-------
porphyria cutanea tarda, which is associated with liver dysfunc-
tion, porphyrinuria, and bullous skin lesions. It is likely that
some of these symptoms represent TCDD toxicosis.
Studies on the mechanism of action or subcellular effects of
these compounds have primarily focused on effects on oxidative
phosphorylation. Weinbach and Garbus (1965) tested the ability of
various substituted phenols to completely uncouple oxidative phos-
phorylation i_n vitro. 2,4,5-Tr ichlorophenol caused complete un-
coupling at 0.05 mM. The known uncoupler 2,4-dinitrophenol com-
pletely uncoupled the test system at 0.1 mM for comparison. There
was a positive relationship between mitochondria protein binding
and uncoupling properties,
Parker (1958) studied the effect of chlorophenols on isolated
rat liver mitochondria. 2,4-Dinitrophenol was used as a reference
compound because of its known ability to uncouple oxidative phos-
phorylation. An unspecified isomer of trichlorophenol, at 1.8 x
10~4M, had 70 percent of the activity of 2,4-dinitrophenol at 2.0 x
10~bM. 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, with 0.05 ml of mitochondrial suspension containing 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 yM for 2 , 4,5-trichlorophenol and 18 yM for 2,4,6-trichloro-
phenol.
Stockdale and Selwyn (1971) reported that 2,4,6-trichloro-
phenol at 0.005 M resulted in 50 percent inhibition of lactate de-
hydrogenase, and that 0.0028 M resulted in 50 percent inhibition of
C-63
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hexokinase in vitro. Isolated ATPase was stimulated by 60 uM and
inhibited by 1,120 yM 2 , 4 , 6-trichlorophenol.
Arrhenius, et al. (1977) studied the effects of chlorophenols
on microsomal detoxication mechanisms using rat liver preparations.
The experimental system examined the effects of each tested chloro-
phenol on the microsomal metabolism of N, N-dimethylaniline (DMA)
to formaldehyde and N-methylaniline (C-oxygenation) or to N,
N-dimethylaniline-N-oxide (N-oxygenation). In essence, the study
examined disturbances in the detoxification electron transport
chain. The concern as stated by Arrhenius, et al. (1977) was that
compounds that could increase N-oxygenation could also influence
the metabolism of other chemical toxicants, such as aromatic
amines, which are formed by N-oxygenation. It was suggested that
agents which increase N-oxygenation could be considered as syner-
gists for the carcinogenic action of aromatic amines. A concentra-
tion greater than 1 mM of 2,4,6-trichlorophenol inhibits C-oxygena-
tion of DMA. A 3 mM concentration produces a small increase in
N-oxygenation of DMA. In order to set this in a dose-response con-
text, a concentration of 1 mM is equivalent to 197.46 mg trichloro-
phenol per liter and 3 mM is equivalent to 592.38 mg/1.
Two studies have examined the effect of trichlorophenol on the
biochemistry of the lens of the eye. Korte, et al. (1976) showed
that 10 M 2,4,5-trichlorophenol would reduce the bovine lens con-
tent 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 activ-
ity but had no effect on lactate dehydrogenase, malate dehydro-
>64
-------
genase, 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 administered dose were found in the cornea
(2.4 percent) and conjunctiva (2.49 percent). The aqueous and
vitreous humor, lens, iris, and choroid contained less than 0.17
percent each.
Synergism and/or Antagonism and Teratogenicity
Pertinent data could not be located in the available litera-
ture.
Mutagenicity
Fahrig, et al. (1978) found that 400 mg 2,4,6-trichlorophenol
increased the mutation rate in a strain of Saccharomyces cere-
visiae. There was no effect on the rate of intragenic recombi-
nation.
In a mouse spot test, females were administered an intraperi-
toneal dose of test chemical on day 10 of gestation; the response
was a change in hair coat color representing a genetic change in
the offspring (Fahrig, et al. 1978). At 50 mg/kg, 2,4,6-trichloro-
phenol produced two spots in 2 of 340 animals from 74 females. At
100 mg/kg, there was one spot in 175 mice from 42 females.
Rasanen, et al. (1977) tested chlorophenol for mutagenicity
using the Salmonella-mammalian microsome Ames test with both the
nonactivated and activated systems. The following trichlorophenol
C-65
-------
isomers were tested and reported as non-mutagenic in both test sys-
tems: 2,3,5-, 2,3,6-, 2,4,5-, and 2,4,6-trichlorophenol.
Carcinogenicity
Boutwell and Bosch (1959) conducted a series of experiments 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 solution of 2,4,6-trichlorophenol in benzene
did not increase the incidence of papillomas in mice pretreated
with DMBA. No carcinomas developed during the 15-week experiment.
A 21 percent solution of 2,4,5-trichlorophenol in acetone increased
the incidence of papillomas in mice pretreated with DMBA. Carcin-
omas did not develop during the 16-week experiment.
Innes, et al. (1969) dosed two strains of mice with 2,4,6-tri-
chlorophenol for 18 months. Eighteen males 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 1 to 18 months the mice
were fed a diet containing 260 ppm, which resulted in an estimated
exposure of 20 to 25 mg/kg. The results were inconclusive. In this
study, which involved 120 pesticides, each chemical was grouped in-
to 1 of 3 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 noncarcinogen. The third category, in which 2,4,6-trichloro-
phenol was placed, comprised compounds requiring further study.
The authors did not provide the actual data, but indicated that
C-66
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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.
A bioassay of 2,4,6-trichlorophenol for possible carcinogeni-
city was conducted for the National Cancer Institute (NCI) by Lit-
ton Bionetics, Inc. The test chemical was administered in feed to
groups of F344 rats and B6C3F mice using standard NCI protocols
(Table 7 and Table 8) .
The mean body weights of dosed rats and mice of each sex
showed a dose-related decrease when compared to the corresponding
controls. However, the dose-related trends in mortality were not
observed in rats or mice; nor were other clinical signs of toxicity
found.
The significant positive effects of dietary 2,4,6-trichloro-
phenol on tumor incidence in male rats, male mice, and female mice
are summarized in Table 9 and Table 10. In male rats, increases in
lymphoma or leukemia were dose-related (4/20 controls, 25/50 low
dose, 29/50 high dose). However, in female rats, the incidence of
these tumors was not significantly elevated. Leukocytosis and
monocytosis of the peripheral blood and hyperplasia of the bone
marrow occurred in both male and female rats. In both the male and
female mice, the incidence of hepatocellular carcinomas or adenomas
was increased significantly over the controls and was also dose-
related (males: controls 4/20, low dose 32/49, high dose 39/47;
females: controls 1/20, low dose 12/50, high dose 24/48).
Based on the results of this study, the National Cancer Insti-
tute concluded that 2,4,6-trichlorophenol was carcinogenic in male
C-67
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TABLE 7
a
2,4,6-Trichlorophenol Chronic Feeding Studies in Rats
n
i
en
00
Sex and
Test Group
Male
Matched-control
Low-dose
High-dose
Female
Matched -control
Low-dose
High-dose
Initial No. of
Animals
20
50
50
20
50
50
2,4, 6-Tr ichlorophenol
in Diet (ppm)
0
5,000
10,000
0
5,000
10,000
Time on
Study (Weeks)
107
106
106
107
106-107
106
^National Cancer Institute, 1979
All animals were 6 weeks of age when placed on study
°Test and control diets were provided ad libitum 7 days per week
-------
TABLE 8
2 , 4 , 6-Trichlorophenol Chronic Feeding Studies in Mice'
o
Sex and
Test Group
Male
Matched-control
Low-dose
High-dose
Female
Matched-control
Low-dose
High-dose
aNational Cancer
All animals were
cTest and control
Ti mp-wp> i ohtprl f\\j
Initial No. of 2
Animals
20
50
50
20
50
50
Institute, 1979
6 weeks of age when
diets were provided
PranP rlo«P = 2f(dose
, 4 , 6-Tr ichlorophenol
in Diet0 (ppm)
0
5,000
10,000
0
10,000
2,500
20,000
5,000
placed on study
ad libitum 7 days per
in ppm x no. of weeks
Time-Weighted
Time on Average Dose
Study (Weeks) (ppm)
105
105
105
105
38
67 5,214
38
67 10,428
week
at that dose)
(no. of weeks receiving each dose)
-------
TABLE 9
Analysis of the Incidence of Lymphoma or Leukemia in
F344 Rats Administered 2,4,6-Trichlorophenol in the Diet*
Sex
Matched Control
Low-Dose
High-Dose
Female
3/20 (15)a
b
N.S.
103°
11/50 (22)
N.S.
69
13/50 (26)
N.S.
55
lale 4/20 (20)
P = 0.006
107
25/50 (50)
P = 0.019
64
29/50 (58)
P = 0.004
69
*Source: Modified from the National Cancer Institute,
1979
aNumber of tumor-bearing animals/number of animals exam-
ined at site (percent)
DBeneath the incidence of tumors in the control group is
the probability level for the Cochran-Armitage test when P
is less than 0.05; otherwise, not significant (N.S.) is
indicated. Beneath the incidence of tumors in a dosed
group is the probability level for the Fisher exact test
for the comparison of that dose group with the matched-
control group when P is less than 0.05; otherwise, not
significant (N.S.) is indicated
°Time to first tumor (weeks)
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TABLE 10
Analysis of the Incidence of Hepatocellular
Carcinoma or Adenoma in B6C3F1 Mice Administered
2,4,6-Trichlorophenol in the Diet*
Sex
Matched Control
Low-Dose
High-Dose
Female
1/20 (5)a
P less than 0.001
105°
12/50 (24)
N.S.
105
24/48 (50)
P less than 0.001
105
Male 4/20 (20)
P less than 0.001
97
32/49 (65)
P = 0.001
102
39/47 (83)
P less than 0.001
95
*Source: Modified from the National Cancer Institute, 1979
Number of tumor-bearing animals/number of animals examined at
site (percent)
Beneath the incidence of tumors in the control group is the
probability level for the Cochran-Armitage test when P is less
than 0.05; otherwise, not significant (N.S.) is indicated.
Beneath the incidence of tumors in a dosed group is the prob-
ability level for the Fisher exact test for the comparison of
that dosed group with the matched-control group when P is less
than 0.05; otherwise, not significant (N.S.) is indicated
Time to first tumor (weeks)
:-7i
-------
F344 rats (including lymphomas or leukemias), and was also carcino-
genic in both sexes of BSCSF-^ mice (inducing hepatocellular carcin-
omas or adenomas).
C-72
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CRITERION FORMULATION
Existing Guidelines and Standards
Existing standards were not found for the trichlorophenols in
the available literature.
Current Levels of Exposure
Pertinent data could not be located in the available litera-
ture concerning current levels of exposure to the trichlorophenols.
Special Groups at Risk
No special group has been identified as being at increased
risk of exposure to the trichlorophenols.
Basis and Derivation of Criteria
The only trichlorophenol isomer for which adequate data exists
for calculation of a toxicity based criterion is 2,4,5-trichloro-
phenol. McCollister, et al. (1961), in a 98-day feeding study on
rats, demonstrated the no-observed-effect level (NOEL) for
2,4,5-trichlorophenol to be 100 mg/kg. Using the National Academy
of Sciences (1977) recommended uncertainly factor of 1,000, assum-
ing an average human body weight of 70 kg, an allowable daily in-
take (ADI) can be calculated, as follows:
a FIT 100 mq/kq _
ADI = 70 kg x 1,000 " 7 m<3
For the purpose of establishing water quality criteria, it is
assumed that on the average, a person ingests 2 liters of water per
day and 6.5 grams of fish. Since fish may bioaccumulate sub-
stances, a BCF is used on the calculation. The BCF for 2,4,5-tri-
chlorophenol is 110. The acceptable concentration of 2,4,5-tri-
chlorophenol in water is calculated, as follows:
C-73
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c _ ADI
21+ (0.0065 x F)
7 mq
2 + (0.0065 X 110
C = 2.58 mg/1 (~_or 2.6 mg/1)
where:
21=2 liters of drinking water
0.0065 kg = amount of fish consumed daily
F = bioconcentration factor = 110
ADI = Acceptable Daily Intake (mg/kg for a
70 kg person)
This criterion can alternatively be expressed as 9.8 mg/1 if expo-
sure is assumed to be from the consumption of fish and shellfish
alone.
Under the Consent Decree in NRDC v. Train, criteria are to
state "recommended maximum permissible concentrations (including
where appropriate, zero) consistent with the protection of aquatic
organisms, human health, and recreational activities". 2,4,6-Tri-
chlorophenol is suspected of being a human carcinogen. Because
there is no recognized safe concentration for a human carcinogen,
the recommended concentration of 2,4,6-trichlorophenol in water for
maximum protection of human health is zero.
Because attaining a zero concentration level may be infeasible
in some cases and in order to assist the Agency and states in the
possible future development of water quality regulations, the con-
centrations of 2,4,6-trichlorophenol corresponding to several in-
cremental lifetime cancer risk levels have been estimated. A can-
cer risk level provides an estimate of the additional incidence of
C-74
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cancer that may be expected in an exposed population. A risk of
10 D for example, indicates a probability of one additional case of
cancer for every 100,000 people exposed, a risk of 10 indicates
one additional case of cancer for every million people exposed, and
so forth. In the Federal Register notice of availability of draft
ambient water quality criteria, EPA stated that it is considering
— 5 — 6
setting criteria at an interim target risk level of 10 ,10 , or
10 as shown in the table following.
Exposure Assumptions
(per day)
2 liters of drinking
water and consumption
of 6.5 grams fish and
shellfish (2)
Consumption of fish
and shellfish only.
Risk Levels
and Corresponding Criteria (1)
0.12 ug/1
IP"6
1.2 ug/1
10
-5
0.36 yg/1 3.6 ug/1
12 ug/1
36 ug/1
;i) Calculated by applying a linearized multistage model, as
described in the Human Health Methodology Appendices to
the October 1980 Federal Register notice which announced
the availability of this document to the animal bioassay
data presented in the Appendix and Table 9. Since the
extrapolation model is linear at low doses, the addi-
tional lifetime risk is directly proportional to the
water concentration. Therefore, water concentrations
corresponding to other risk levels can be derived by
multiplying or dividing one of the risk levels and cor-
responding water concentrations shown in the table by
factors such as 10, 100, 1,000, and so forth.
C-75
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(2) Thirty-three percent of the 2,4,6-trichlorophenol expo-
sure results from the consumption of aquatic organisms
which exhibit an average bioconcentration potential of
150-fold. The remaining 67 percent of 2,4,6-trichloro-
phenol exposure results from drinking water.
Concentration levels were derived assuming a lifetime exposure
to various amounts of 2,4,6-trichlorophenol, (1) occurring from the
consumption of both drinking water and aquatic life grown in waters
containing the corresponding 2,4,6-trichlorophenol concentrations
and, (2) occcurring solely from consumption of aquatic life grown
in the waters containing the corresponding 2,4,6-trichlorophenol
concentrations. Because data indicating other sources of
2,4,5-trichlorophenol exposure and their contributions to total
body burden are inadequate for quantitative use, the figures re-
flect the incremental risks associated with the indicated routes
only.
The data of Hoak (1957), Bur'ttschell, et al. (1959), and Dietz
and Traud (1978) indicate that 2,4,5- and 2,4,6-trichlorophenol
impart disernable organoleptic characteristics to water. (These
studies have been discussed previously in the section of this docu-
ment dealing with monochlorophenols.) The organoleptic detection
thresholds for the trichlorophenols are presented in Tables 2 and 3
for odor and taste, respectively.
Since the organoleptic detection threshold concentrations for
2,4,5- and 2,4,6-trichlorophenol are well below any toxicity-based
criterion levels that may be derived, the ambient water quality
criteria are based on organoleptic data. It should be emphasized
C-76
-------
that these criteria are based on aesthetic qualities rather than
health effects. However, to the extent that these criteria are
below the levels derived for 2,4 ,5-trichlorophenol and 2,4,6-tri-
chlorophenol from toxicity and carcinogenicity data, respectively,
they are likely to also be protective of human health.
The taste thresholds determined by Dietz and Traud (1978) for
the detection of 2,4,5-trichlorophenol and 2,4,6-trichlorophenol
in water are used as the bases for the ambient water quality cri-
teria. The Dietz and Traud study was chosen for a number of rea-
sons. These authors present a recent study involving well-defined
procedures and a number of documented controls. This study uti-
lized "fresh" water from the base outlet of the Verse Dam (Germany)
for all experiments. The water was described as clear and neutral
with respect to both odor and taste. These conditions are con-
sidered to more closely approximate the conditions of ambient water
found in lakes, rivers, and streams than would those of the Hoak
(1957) and Burttschell, et al. (1959) studies, which utilized
carbon-filtered laboratory distilled water. The 20 to 22°C tem-
perature of the water in the Dietz and Traud odor and taste tests
might also more closely approximate the temperature at which water
is normally consumed than do the 30°C or 25°C temperatures used in
the studies of Hoak (1957) and Burttschell, et al. (1959), respec-
tively. However, it is recognized that the temperature of water
consumed by humans is quite obviously variable, and no study will
represent the temperature of water consumed by all Americans.
Therefore, based on the prevention of undesirable organoleptic
qualities, the criterion levels for 2,4,5- and 2,4,6-trichloro-
!-77
-------
phenol in water are 1.0 ug/1 and 2.0 pg/1, respectively. These
levels should be low enough to prevent detection of objectionable
organoleptic characteristics and far below minimal no-effect con-
centrations determined in laboratory animals.
C-78
-------
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Arrhenius, E., et al. 1977. Disturbance of microsomal detoxica-
tion mechanisms in liver by chlorophenol pesticides. Chem. Biol.
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Bjerke, E.L., et al. 1972. Residue study of phenoxy herbicides in
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Bleiberg, J., et al. 1964. Industrially acquired porphyria.
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Boutwell, R.K. and O.K. Bosch. 1959. The tumor-promoting action
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Burttschell, R.H., et al. 1959. Chlorine derivatives of phenol
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Campbell, C.L., et al. 1958. Effect of certain chemicals in water
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C-79
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Clark, D.E., et al. 1976. Residues of chlorophenoxy acid herbi-
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Courtney/ K.D. 1976. Mouse teratology studies with chlorodibenzo-
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. Food
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Deichmann, W.B. 1943. The toxicity of chlorophenols for rats.
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Deichmann, W.B. and E.G. Mergard. 1948. Compartive evaluation of
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Jour. Ind. Hyg. Toxicol. 30: 373.
Deitz, F. and J. Traud. 1978. Odor and taste threshold concentra-
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Dougherty, R.C. and K. Piotrowska. 1976. Screening by negative
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C-80
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Fahrig, R., et al. 1978. Genetic Activity of Chlorophenols and
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Chemistry, Pharmacology and Environmental Toxicology. Plenum
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Farquharson, M.E., et al. 1958. The biological action of chloro-
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Foster, T.S. and J.G. Saha. 1978. The in vitro metabolism of lin-
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Hansch, C., and A.J. Leo. 1979. Substituent Constants for Cor-
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New York.
Hoak, R.D. 1957. The causes of tastes and odors in drinking water.
Purdue Eng. Exten. Service. 41: 229.
Innes, 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.
C-81
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Kohli, J., et al. 1976. The metabolism of higher chlorinate! ben-
zene isomers. Can. Jour. Biochem. 54: 203.
Korte, I., et al. 1976. Studies on the influences of some environ-
mental chemicals and their metobolites on the content of free
adenine nucleotides, intermediates of glycolysis and on the activi-
ties of certain enzymes of bovine lenses .in vitro. Chemosphere.
5: 131.
Korte, F., et al. 1978. Ecotoxicologic profile analysis, a con-
cept 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. In; K.R. Rao
(ed.), Pentochlorophenol: Chemistry, Pharmacology and Environ-
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McCollister, D.D., et al. 1961. Toxicologic information on 2,4,5-
trichlorophenol. Toxicol. Appl. Pharmacol. 3: 63.
Mitsuda, H., et al. 1963. Effect of chlorophenol analogues on the
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C-82
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Moza, P., et al. 1974. Beitrage zur okologischen chemie LXXXIX.
Orientierende versuche zum metabolismus von -pentochlorcyclohex-1-
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National Cancer Institute. 1979. Bioassay of 2,4,6-trichloro-
phenol for possible carcinogenicity. NCI-CG-TR-155.
Olie, K. , et al. 1977. Chlorodibenzo-p-dioxins and chlorodibenzo-
furans are trace components of fly ash and flue gas of some muni-
cipal incinerators in the Netherlands. Chemosphere. 8: 445.
Parker, V.H. 1958. Effect of nitrophenols and halogenophenols on
the enzymic activity of rat-liver mitochondria. Jour. Biochem.
69: 306.
Piet, G.J. and F. De Grunt. 1975. Organic Chloro Compounds in Sur-
face and Drinking Water of the Netherlands. In; Problems Raised by
the Contamination of Man and his Environment. Comm. Eur. Communi-
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Rasanen, L., et al. 1977. The mutagenicity of MCPA and its soil
metabolites, chlorinated phenols, catechols and some widely used
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Roberts, M.S., et al. 1977. Permeability of human epidermis to
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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 Chem.
21: 295.
Stephan, C.E. 1980. Memorandum to J. Stara. U.S. EPA. July 3.
Stannard, D.J. and A. Scotter. 1977. The determination of phenol
residues in dairy products. New Zea. Jour. Dairy Sci. Technol.
12: 140.
Stockdale, M. and M.J. Selwyn. 1971. Influence of ring substi-
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Tanaka, K. , et al. 1977. Pathways of chlorophenol formation in
oxidative biodegradation of BHC. Agric. Biol. Chem. 41: 723.
U.S. EPA. 1980. . Seafood consumption data analysis. Stanford
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VanMiller, J.P., et al. 1978. Increased incidence of neoplasma in
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Veith, G.D., et al. 1979. Measuring and estimating the bioconcen-
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36: 1040.
Veith, G.D. 1980. Memorandum to C.E. Stephan. U.S. EPA.
April 14.
Weinbach, E.G. and J. Garbus. 1965. The interaction of uncoupling
phenols with mitochondria and with mitochondrial 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 studies with 2-
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Agric. Food Chem. 18: 845.
Weast, R.C. (ed.) 1978. Handbook of Chemistry and Physics. 59th
ed. CRC Press.
C-85
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TETRACHLOROPHENOL
Mammalian Toxicology and Human Health Effects
INTRODUCTION
Tetrachlorophenol is a fungicide and wood preservative. As
either a spray or dip treatment, it is used as a water soluble salt
to treat freshly cut lumber. The treatment prevents sap stain or-
ganisms from growing in wood while it is drying or waiting further
processing.
Commercial pentachlorophenol contains 3 to 10 percent tetra-
chlorophenol (Goldstein, et al. 1977; Schwetz, et al. 1978). Since
the annual production of pentachlorophenol is 25 million kg, 0.75
to 2.5 million kg of tetrachlorophenol are produced concurrently.
There are three tetrachlorophenol isomers the most important
of which is 2,3,4,6-tetrachlorophenol. Table 1 lists the physio-
chemical properties of the three isomers.
Like tri- and pentachlorophenols, tetrachlorophenols contain
toxic nonphenolic impurities. Schwetz, et al. (1974) reported that
commercial grade 2,3,4,6-tetrachlorophenol contained chlorodioxin
isomers at levels of 28 ppm (hexa-) , 80 ppm (hepta-) , and 30 ppm
(octachlorodibenzo-p-dioxin) as well as chlorodibenzofurans at
levels of 55 ppm (hexa-), 100 ppm (hepta-), and 25 ppm (octachloro-
dibenzofuran). The commercial tetrachlorophenol was composed of 73
percent tetra- and 27 percent pentachlorophenol.
EXPOSURE
Ingestion from Water
There are reports suggesting the presence of lower chloro-
phenols occurring in drinking water, but the presence of
C-86
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TABLE 1
Physiochemical Properties of Tetrachlorophenol*
Property
Molecular weight
Formula
o o
^ Melting point C
Boiling point °C
Solubility
water
alcohol
benzene
Vapor pressure
CAS Number
Tetrachlorophenol Isomer
2,3,4,5-
231.89
C6H2C140
116-7
sublimes
very
1mm Hg, 100°C
2,3,4,6-
231.89
C6H2C140
70
sublimes
slightly
soluble
soluble
-
58-90-2
2,3,5,6-
231.89
C6H2C140
115
150
slightly
very
-
935-95-5
*Source: Weast, (ed.), 1978
-------
tetrachlorophenol has not been documented. The odor threshold for
2,3,4,6-tetrachlorophenol has been reported by Hoak (1957) to be
915 yg/1 at 30°C and by Deitz and Traud (1978) to be 600 ug/1. The
taste threshold of 1 ug/1 for 2,3,4,6-tetrachlorophenol in water
has been reported by Deitz and Traud (1978). These studies are
described in the monochlorophenols portion of this document (see
Ingestion from Water).
Ingestion from Food
There is no evidence to suggest that tetrachlorophenols may be
ingested from foods. If such compounds were present in foods, 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 develops in meat and eggs. Parr, et al. (1974)
conducted a small survey on the amount of tetra- and pentachloro-
phenol 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 con-
centration in fresh shavings was 54 yg/g (ppm). The spent litter
contained 0.7 ug/9 tetrachlorophenol and 0.5 ug/g tetrachloroani-
sole. The tetrachloroanisole was only occasionally detected in
fresh shavings. The odor threshold for 2,3,4,6-tetrachloroanisole
was reported to be 4 x 10~6 yg/g (4 ppt).
Harper and Balnove (1975) analyzed tissues from chickens
raised in contact with tetrachlorophenol-treated wood shavings.
C-88
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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-tetrachloroanisole/kg
to chickens. A musty taint developed in eggs and broiler meat sim-
ilar to that associated with housing chickens over tetrachloro-
phenol-treated wood shavings.
There is a possibility that the metabolism of other compounds
could result in the formation of tetrachlorophenols. Engst, et al.
(1976) reported that rats partially metabolized pentachlorophenol
to 2,3,4,6- and 2,3,5,6-tetrachlorophenols. Ahlborg (1978) could
not replicate the Engst results but rather found that rats metabo-
lized pentachlorophenol to 2,3,5,6-tetrachlorohydroquinone and
tr ichlorohydroquinone.
Kohli, et al. (1976) studied the metabolism of tetrachloro-
benzene in rabbits. 1,2,3,4- and 1,2,3,5-Tetrachlorobenzenes were
metabolized to 2,3,4,5- and 2,3,4,6-tetrachlorophenols, respec-
tively. 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 (BCP) relates the concentration of a
chemical in aquatic animals to the concentration in the water in
which they live. The steady-state BCFs for a lipid-soluble com-
pound in the tissues of various aquatic animals seem to be propor-
tinal to the percent lipid in the tissue. Thus, the per capita
ingestion of a lipid-soluble chemical can be estimated from the per
capita consumption of fish and shellfish, the weighted average per-
C-89
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cent lipids of consumed fish and shellfish, and a steady-state BCF
for the chemical.
Data from a recent survey on fish and shellfish consumption in
the United States were analyzed by SRI International (U.S. EPA,
1980). These data were used to estimate that the per capita con-
sumption of freshwater and estuarine fish and shellfish in the
United States is 6.5 g/day (Stephan, 1980). In addition, these
data were used with data on the fat content of the edible portion of
the same species to estimate that the weighted average percent
lipids for consumed freshwater and estuarine fish and shellfish is
3.0 percent.
No measured steady-state BCF is available for any tetrachloro-
phenols, but the equation "Log BCF = (0.85 Log P) - 0.70" can be
used (Veith, et al. 1979) to estimate the steady-state BCF for
aquatic organisms that contain about 7.6 percent lipids from the
octanol/water partition coefficient (P) . A measured log P value of
4.10 was obtained from Hansch and Leo (1979). The adjustment
factor of 3.0/7.6 = 0.395 can be used to adjust the estimated BCF
from the 7.6 percent lipids on which the equation is based to the
3.0 percent lipids that is the weighted average for consumed fish
and shellfish. Thus, the weighted average BCF for the edible por-
tion of all aquatic organisms consumed by Americans can be calcu-
lated.
Compound Log P BCF Weighted BCF
2,3,4,6-tetrachlorophenol 4.10 610 240
C-90
-------
Inhalation
Olie, et al. (1977) reported finding di-, tri-, and tetra-
chlorophenols in flue gas condensates from municipal incinerators.
The levels were not quantified.
Dermal
Pertinent data could not be located in the available liter-
ature.
PHARMACOKINETICS
Absorption and Distribution
Pertinent data could not be located in the available liter-
ature.
Metabolism and Excretion
Ahlborg and Larsson (1978) studied the urinary metabolites 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-hydroquinone. No tri-
chloro-p-hydroquinone 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-tetrachlorophenol, 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 chloro-
phenol 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 1 to 2 percent fecal excretion. The
2,3,4,5,- and 2,3,4,6 tetrachlorophenol isomers are not metabolized
to any large extent. The 2,3,4,5-isomer is primarily excreted as
C-91
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unchanged chlorophenol with trace amounts of trichloro-p-hydro-
quinone appearing in the urine. Fifty-one percent of the admin-
istered dose was recovered in the urine in 24 hours. During the
second 24 hours, an additional 7 percent of the dose appeared in
the urine. Altogether, 59 percent of the intraperitoneal dose was
recovered in the urine with the disposition of the remainder of the
dose not identified.
The 2,3,4,6-tetrachlorophenol isomer is rapidly eliminated in
the urine as unchanged chlorophenol. About 94 percent, of the in-
traper itoneal dose was recovered in the urine in 24 hours. Trace
amounts of trichloro-p-hydroquinone were found in the urine. In
the experiments of Alhborg and Larsson (1978) , the urine was boiled
in HC1 to split any conjugates such as glucuronides.
EFFECTS
Acute, Subacute, and Chronic Toxicity
The acute toxicity of tetrachlorophenol isomers via various
routes and in several species is shown in Table 2. Tetrachloro-
phenol appears to be less acutely toxic orally than pentachloro-
phenol. In the studies of Ahlborg and Larsson (1978), pentachloro-
phenol had an oral LD5Q of 150 mg/kg in mice and 294 mg/kg in ger-
bils. The comparative tetrachlorophenol LD^s ranged from 533 to
979 mg/kg. This point will be important in setting the criterion.
Tetrachlorophenol toxicosis consists of depressed activity
and motor weakness (Deichmann, 1943). Tremors and convulsions do
not occur except in extremes.
Ahlborg and Larsson (1978) determined the acute oral and in-
traper itoneal LDcQ of three isomers of tetrachlorophenol and
C-92
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o
i
-------
TABLE 2 (Continued)
o
I
Chemical
2,3
2,3
, 5 , 6-Tetrachlorophenol
, 4 , 5-Tetrachlorophenol
Tetrachlor o-p-hydroqui none
Tetrachioropytocatechol
Tetrachlor o-p-hydroqui none
T^1
-r anhl nroovrocatechol
Solvent
ethanol
ethanol
propylene
glycol
propylene
glycol
ethanol
ethanol
ethanol
propylene
glycol
ethanol
ethanol
ethanol
ethanol
Animal
mouse,
female
mouse,
male
mouse,
female
gerbil,
female
mouse,
female
mouse,
male
mouse,
female
mouse,
female
mouse,
female
mouse,
female
mouse,
male
mouse,
C57
C57
C57
C57
C57
C57
C57
C57
C57
C57
C57
Toxic
oral
oral
oral
oral
oral
oral
LD5Q
Response
= 109
mg/kg
LD5Q = 89 mg/kg
LD50
LD50
LD50
LD50
= 677
= 533
= 400
= 572
mg/kg
mg/kg
mg/kg
mg/kg
intraperitoneal
LDj-r. = 97 mg/kg
D U
intraperitoneal
LD5Q = 133 mg/kg
oral
oral
oral
oral
LD50
LD50
LD50
LD,n
= 500
= 612
= 750
= 750
mg/kg
mg/kg
mg/kg
mg/kg
male
-------
TABLE 2 (Continued)
O
i
<£>
Ul
Chemical
Tetrachloro-p-hydroquinone
Tetrachloropyrocatechol
Pentachlorophenol
Solvent
ethanol
ethanol
propylene
glycol
propylene
glycol
ethanol
ethanol
ethanol
propylene
glycol
Animal
mouse, C57
female
mouse, C57
female
mouse, C57
female
gerbil,
female
mouse, C57
female
mouse, C57
male
mouse, C57
female
mouse, C57
female
Toxic Response
in t reaper itoneal
LD50 = 35 mg/kg
intraper itoneal
LD^Q = 136 mg/kg
oral LD5Q = 150 mg/kg
oral LD5Q = 294 mg/kg
oral LD5Q = 74 mg/kg
oral LD5Q = 36 mg/kg
intraper itoneal
LD5Q = 32 mg/kg
intraperitoneal
LD5Q = 59 mg/kg
*Source: Ahlborg and Larson, 1978
-------
related compounds in mice and gerbils (Table 2). The effect of
solvent is shown by the increased toxicity 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-hydroquinone, 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 tetrachlorophenol 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 tetrachloro-
phenol isomers, and the LD^g was similar to the intraperitoneal
LDjQ of pentachlorophenol (Table 2).
Farquharson, et al. (1958) showed that the intraperitoneal
LD^Q of 2,3,4,6-tetrachlorophenol in rats was 130 mg/kg. Convul-
sions did not occur, but there was a rapid 4°C rise in body tempera-
ture, and rigor mortis occurred within five minutes of death.
Brain homogenate oxygen consumption was stimulated in the presence
of 2,3,4,6-tetrachlorophenol at 5 x 10~5 M.
Schwetz, et al. (1974) reported that the 10 day maximum tol-
erated 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.
Several investigators have examined the effect of tetrachloro-
phenol on cellular metabolism. 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, with 0.05 ml of mitochondrial suspension
containing 0.43 mg N. The concentration of chlorophenol required
C-96
-------
to produce a 50 percent inhibition in the production of ATP was de-
termined (ISQ) • 2,3,4,6-Tetrachlorophenol had an I5Q of 2 yM. For
comparison, the I5Q for pentachlorophenol was 1 uM and for 2,4-di-
nitrophenol the I^Q was 17 ^M.
Weinbach and Garbus (1965) tested the ability of various sub-
stituted phenols to completely uncouple oxidative phosphorylation
_in vitro. There was a positive relationship between mitrochondrial
protein binding and uncoupling properties. 2,3,4,6-Tetrachloro-
phenol caused complete uncoupling at 0.05 mM. For comparison, the
known uncoupler 2,4-dinitrophenol completely uncoupled the test
system at 0.1 mM.
Arrhenius, et al. (1977) studied the effects of chlorophenols
on microsomal detoxification mechanisms using rat liver prepara-
tions. The experimental system examined the effects of the test
chlorophenol on the microsomal metabolism 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. (1977) was that
compounds that increased N-oxygenation could influence the metabo-
lism of other chemical toxicants, such as aromatic amines, which
are formed by N-oxygenation. Agents that increase N-oxygenation
could be considered as synergists for the carcinogenic action of
aromatic amines.
At a concentration greater than 0.3 mM, 2,3,4,6-tetrachloro-
phenol inhibits C-oxygenation of DMA and stimulates N-oxygenation
C-97
-------
of DMA. To help put this in a dose-response context, a tetra-
chlorophenol concentration of 0.3 mM is equivalent to 69.57 mg/1.
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 sawmills in
Sweden where chlorophenol fungicides are applied to green timber
after sawing to prevent sapstain. The fungicide used consisted of
10 percent 2,4,6-trichlorophenol, 70 percent 2 ,3,4,6-tetrachloro-
phenol, and 20 percent pentachlorophenol, and contained 1,600 ppm
chlorophenoxyphenols, 70 ppm (Clg, C17) chlorodibenzofurans, and
less than 1 ppm chlorodibenzodioxins. The sawdust was obtained
from the milling operations where the wood was trimmed after dry-
ing. The sawdust (four samples) contained 100 to 800 ppm
2,3,4,6-tetrachlorophenol, 30 to 400 ppm pentachlorophenol, 10 to
50 ppm chlorophenoxyphenols, 1 to 10 ppm chlorodibenzofurans, and
less than 0.5 ppm chlorodibenzodioxins. Occupational, health prob-
lems such as severe skin irritation, respiratory difficulties and
headache had been reported (Levin, et al. 1976). Sweden has banned
the use of chlorophenols (Levin and Nilsson, 1977).
No toxicity studies of 90 days or longer were found. One long
term study with pentachlorophenol is of some value in assessing the
potential long term toxicity of tetrachlorophenol. Schwetz, et al.
(1978) fed rats a low non-phenolic content commercial pentachloro-
phenol containing 10.4 + 0.2 percent tetrachlorophenol and 90.4 +
1.0 percent pentachlorophenol at levels of 1, 3, 10, or 30 mg/kg
for 22 months (males) and 24 months (females). The results showed
a no-obsered-effect level (NOEL) of 3 mg/kg (females) and 10 mg/kg
C-98
-------
(males) based on clinical chemistry, hematology, pathology and
organ weight changes. This represents a tetrachlorophenol exposure
of 0.312 mg/kg for females and 1.04 mg/kg for males.
Synergism and/or Antagonism
Pertinent data could not be located in the available liter-
ature.
Teratogenicity
Schwetz, et al. (1974) administered commercial or purified
tetrachlorophenol to rats on days 6 through 15 of gestation. Dos-
age levels used were 10 or 30 mg/kg. Neither grade of tetrachloro-
phenol 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 tetrachlorophenol did not
alter the prenatal effects.
Mutagenicity
Rasanen, et al. (1977) tested chlorophenols for mutagenicity
using the Salmonella-mammalian microsome Ames test in both nonacti-
vated and activated systems. 2,3,4,6-Tetrachlorophenol was re-
ported as nonmutagenic in both test systems.
Carcinogenicity
No studies were found that were specifically designed to de-
termine 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 incidence of tumors is shown
in Table 3. The authors concluded that low nonphenolic content
C-99
-------
TABLE 3
Incidence of Primacy Tumors (Based on Ilistopathological Diagnosis) in Rats Fed
Pentachlorophenol (PCP) for 22 Months (males) and 24 Months (females)*
n
i
M
O
o
Dose: mgPCP/kg/day
Number of rats examined:
Number of rats with tumois:
Number of tumors:
Number of tumors/rats with tumors:
Number (V morphologic malignant tumors:
0
27
11
17
1.6
1
1
26
13
14
1.1
3
Males
3
27
13
17
1.3
2
10
27
12
15
1.4
1
30
27
11
61
2.3
0
0
27
27
62
2.6
2
1
27
26
67
1.7
7
Females
3
27
25
42
1.7
2
10
27
25
63
2.5
3
30
27
25
63
2.5
2
*Souice: Schwetz, et al. 1978
-------
pentachlorophenol containing 90.4 + 1.0 percent pentachlorophenol
and 10.4 + 0.2 percent tetrachlorophenol was noncarcinogenic when
tested at doses of 1, 3, 10, or 30 mg/kg in a rat life-time feeding
study. The high dose represents a tetrachlorophenol exposure of
0.312 mg/kg.
While the data base is limited and less direct than desired,
there is presently no indication that tetrachlorophenol is carcino-
genic. The obvious long term consideration is the potential car-
cinogenicity of the chlorodibenzo-p-dioxins that may be present as
impurities in commercial tetrachlorophenol.
C-101
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CRITERION FORMULATION
Existing Guidelines and Standards
Standards have not been established for the tetrachloro-
phenols.
Current Levels of Exposure
Pertinent data could not be located in the available litera-
ture concerning levels of current exposure to tetrachlorophenols.
Special Groups at Risk
Groups at increased risk of exposure to the tetrachlorophenols
include manufacturers, users in sawmills, and those who use the
compound for wood treatment.
Basis and Derivation of Criterion
There are no suitable data from which to derive a toxicity-
based criterion for any of the tetrachlorophenols. Consequently,
the organoleptic properties of 2,3,4,6-tetrachlorophenol, the only
tetrachlorophenol isomer for which any data exist, must, be used as
the basis for the criterion. Two studies report the odor threshold
for 2,3,4,6-tetrachlorophenol. Hoak (1957) found the odor thresh-
old to be 915 yg/1 at 30°C, while Deitz and Traud (1978) reported
600 ug/1 at 20 to 22°C. These two organoleptic studies were
described earlier in this document in the section dealing with
monochlorophenols. The taste threshold concentration was also
determined by Deitz and Traud (1978) to be 1 ug/1.
The taste threshold determined by Dietz and Traud (1978) for
the detection of 2,3,4,6-tetrachlorophenol in water is used as the
basis for the ambient water quality criterion. The Deitz and Traud
study was chosen for a number of reasons. These authors present a
:-102
-------
recent study involving well-defined procedures and a number of
documented controls. This study utilized "fresh" water from the
base outlet of the Verse Dam (Germany) for all experiments. The
water was described as clear and neutral with respect to both odor
and taste. These conditions are considered to more closely approx-
imate the conditions of ambient water found in lakes, rivers, and
streams than would those of the Hoak (1957) , which utilized carbon-
filtered laboratory distilled water. The 20 to 22°C temperature of
the water in the Dietz and Traud odor and taste tests might also
more closely approximate the temperature at which water is normally
consumed than does the 30°C temperature used in the Hoak (1957)
study. However, it is recognized that the temperature of water
consumed by humans is quite obviously variable, and no study will
represent the temperature of water consumed by all Americans.
Thus, based on the prevention of adverse organoleptic effects,
the criterion for 2,3,4,6-tetrachlorophenol is 1 yg/1. It is
emphasized that this is a criterion based on aesthetic rather than
health effects. Data on human health effects must be developed as
a more substantial basis for recommending a criterion for the pro-
tection of human health.
C-103
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REFERENCES
Ahlborg, U.G. 1978. Dechlorination of Pentachlorophenol _in vivo
and in vitro. In; K.R. Rao (ed.), Pentachlorophenol: Chemistry,
Pharmacology and Environmental Toxicology, Plenum Press, New York.
Ahlborg, U.G. and K. Larsson. 1978. Metabolism of tetrachloro-
phenols in the rat. Arch. Toxicol. 40: 63.
Arrhenius, E., et al. 1977. Disturbance of microsomal detoxica-
tion 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 tetrachlorophenol sodium. Arch.
Dermatol. Syphilol. 35: 251.
Deichmann, W.B. 1943. The toxicity of chlorophenolis for rats.
Fed. Proc. 2: 76.
Deitz, F. and J. Traud. 1978. Odor and taste threshold concentra-
tions of phenol bodies. Gwf-wasser/abwasser. 119: 318.
Engel, C. , et al. 1966. Tetrachloroanisol: A source of musty
taste in eggs and broilers. Science. 154: 270.
C-104
-------
Engst, R., et al. 1976. The metabolism of lindane and its metabo-
lites gamma-2,3,4,5,6,-pentachlorocyclohexene, pentachlorobenzene
and pentachlorophenol in rats and the pathways of lindane metabo-
lism. Jour. Environ. Sci. Health. 2: 95.
Farquharson, M.E., et al. 1958. The biological action of chloro-
phenols. Br. Jour. Pharmacol. 13: 20.
Goldstein, J.A., et al. 1977. Effects of pentachlorophenol on
hepatic drug-metabolizing enzymes and porphyria related to contami-
nation with chlorinated dibenzo-p-dioxins and dibenzofurans. Bio-
chem. Pharmacol. 26: 1549.
Hansch, C. and A.J. Leo. 1979. Substituents Constants for Cor-
relation Analysis in Chemistry and Biology. Wiley-Interscience,
New York.
Harper, D.B. and D. Balnove. 1975. Chloroanisole residues in
broiler tissues. Pestic. Sci. 6: 159.
Hoak, R.D. 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 chlorinated ben-
zene isomers. Can. Jour. Biochem. 54: 203.
C-105
-------
Levin, J.O. et al. 1976. Use of chlorophenols as fungicides in
sawmills. Scand. Jour. Work Environ. Health. 2: 71.
Levin, J. and C. Nilsson. 1977. Chromatographic determination of
polychlorinated phenols, phenoxyphenols, dibenzoi:urans and
dibenzodioxins in wood-dust from workers environments. Chemo-
sphere. 7: 443.
Mitsuda, H., et al. 1963. Effect of chlorophenol analogues on the
oxidative phosphorylation in rat liver mitochondria. Agric. Biol.
Chem. 27: 366.
Olie, K., et al. 1977. Chlorodibenzo-p-dioxins and chlorodibenzo-
furans are trace components of fly ash and flue gas of some muni-
cipal incinerators in the Netherlands. Chemosphere. 8: 445.
Parr, L.J., et al. 1974. Chlorophenols from wood preservatives 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. Contam. Toxicol. 18: 565.
Schwetz, B.A., et al. 1974. Effect of purified and commercial
grade tetrachlorophenol on rat embryonal and fetal development.
Toxicol. Appl. Pharmacol. 28: 146.
C-106
-------
Schwetz, B.A., et al. 1978. Results of Two-year Toxicity and
Reproduction Studies on Pentachlorophenol in Rats. In; K.R. Rao
(ed.), Pentachlorophenol: Chemistry, Pharmacology and Environ-
mental Toxicology. Plenum Press, New York.
Stephan, C.E. Memorandum to J. Stara. U.S. EPA. July 3.
U.S. EPA. 1980. Seafood consumption data analysis. Stanford
Research Institute International, Menlo Park, California. Final
rep., Task II. Contract No. 68-01-3887.
Veith, G.D., et al. 1979. Measuring and estimating the bioconcen-
tration factors of chemicals in fish. Jour. Fish. Res. Board Can.
36: 1040.
Veith, G.D. 1980. Memorandum to C.E. Stephan. U.S. EPA.
April 14.
Weast, R.C. (ed.) 1978. Handbook of Chemistry and Physics. 59th
ed. CRC Press.
Weinbach, B.C. and J. Garbus. 1965. The interaction of uncoupling
phenols with mitochondria and with mitochondrial protein. Jour.
Biol. Chem. 210: 1811.
C-107
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CHLOROCRESOLS
Mammalian Toxicology and Human Health Effects
INTRODUCTION
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 chlorohy-
droxytoluenes. It is possible to have mono-, di-f tri- or tetra-
chlorocresols. No information was found on the chemical properties
of trichlorocresols. Tables 1, 2, and 3 list the physicochemical
properties of the chlorocresols. Gosselin, et al. (1976) indicate
that 6-chloro-m-cresol (3-methyl-6-chlorophenol) and p-chloro-m-
cresol (3-methyl-4-chlorophenol) may be used as antiseptics and
disinfectants. The United States Pharmacopeia does not list any of
the chlorocresols. Goodman and Gilman (1975) also do not discuss
any of the chlorocresols. An unspecified isomer of chlorocresol
has been used in England as a preservative in Pharmaceuticals (Ain-
ley, et al. 1977) .
4-Chloro-m-cresol (3-methyl-4-chlorophenol) is a commercial
microbicide marketed as Preventol CMK^ (Bayer) (Voets, et al.
1976).
Rapps (1933) found that p-chloro-m-cresol had antiseptic prop-
erties with a phenol coefficient of 13 to 25.
EXPOSURE
In general, there are no published data available for the de-
termination of current human exposure to chlorocresols. Although
this fact may reflect an actual lack of exposure, it is also
C-108
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TABLE 1
Chemical Properties of Monochlorocresols*
Property
Molecular wt.
Formula
Melting point (°C)
Boiling point (°C)
^ Density
1
o
^ Solubility
water
alcohol
ether
benzene
AJ ternate
name
2-Chloro-
p-cresol
342.59
c7n7cio
195-6
1.1785
slightly
soluble
soluble
soluble
3-Chloro-
4-hydroxy-
toluene
6-Chloro-
0-cresol
142.59
C7H?C10
188-9
soluble
3-Chloro-
2-hydroxy-
LoJ uene
3-Chloro-
0-cresol
142.59
C7H7C10
86
225
slightly
soluble
soluble
soluble
2-Chloro-
6-hydroxy-
toluene
4-Chloro-
m-cresol
142.59
C7II7C10
66-8
235
slightly
soluble
soluble
2-Chloro-
5-hydroxy-
toluene
3-Chloro-
p-cresol
142.59
c7..7cio
55-6
228
soluble
soluble
soluble
soluble
2-Chloro-
4-hydroxy-
toluene
2-Chloro-
m-cresol
142.59
C7H?C10
55-6
196
slightly
___
2-Chloro-
3-hydroxy-
toluene
*Source: Weast, (ed.), 1978
-------
TABLE 2
Chemical Properties of Uichlorocresols*
o
1
1— '
I—1
o
Property
Molecular wt.
Formula
Melting point (°C)
Boiling point (°C)
Solubility
wa te r
alcohol
ether
bonzene
Alternate
name
4,6-»ichloro- 2
m-cresol
177.03
C7n6ci2o
72-4
235-6
2,4-Dichloro-
5-hydroxy-
toluene
,6-Uichloro-
m-cresol
177.03
C7H6C120
58-9
236-6
soluble
2,4-Uichloro-
3-hydroxy-
toluene
2,4-Dichloro-
m-cresol
177.03
C7n6ci2o
27
241-242.5
soluble
2,6-Dichloro
3-hydroxy-
toluene
4,6-Dichloro- 2
0-cresol
177.03
C7H6C120
55
266.5
slightly
very
very
3 , 5-Dichloro-
2-hydroxy-
toluene
,6-Dichloro-
p-cresol
177.03
C7H6C120
39
138-9
slightly
soluble
soluble
3,5-Dichloro-
4-hydcoxy-
toluene
4,5-Oichloro-
0-cresol
177.03
C7n6ci2o
101
slightly
soluble
soluble
4 , 5-Dichloro-
2-hydroxy-
toJuene
*Source: Weast, (ed.), 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
o
Molecule wt.
Formula
Melting point ( C)
245.92
C7H4C140
190
245.92
C7H4C140
189-90
245.92
C7H4C140
190
Solubility
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-
chlorotoluene
4-Hydroxy-
2,3,5,6-tetra-
chlorotoluene
*Source: Weast, (ed.), 1978
-------
possible that exposures are simply going undetected and unquanti-
fied. Some studies have been done on the occurrence 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 ex-
posure. Heparin solutions marketed in the United States are pre-
served with benzyl alcohol or thimerosal.
The potential occurrence of chlorocresols in the environment
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). Rasanen, 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 at
20 mg/1 was degraded 30 percent in two weeks in an aerobic minimal
test (MM-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.
Ingestion from Water and Food
Pertinent data could not be located in the available liter-
ature concerning ingestion from water and food.
Inhalation and Dermal
Pertinent data could not be located in the available liter-
ature.
C-112
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PHARMACOKINETICS
Absorption
Roberts, et al. (1977) used human epidermal membranes obtained
at autopsy in an _in vitro test system to determine the permeability
of chemicals through human skin. Chlorocresol, isomer not speci-
fied, 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 but less readily than 2,4,6-trichloro-
phenol.
Distribution and Metabolism
Pertinent data could not be located in the available liter-
ature.
Excretion
Zondek and Shapiro (1943) injected 1,000 mg of p-chloro-m-
cresol subcutaneously into a 1 kilogram rabbit. Little detail was
provided on effects. Fifteen to 20 percent of the dose was re-
covered in the urine. The same compound was given intramuscularly
to humans and was not recovered in the urine to any appreciable ex-
tent. 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, Subacute, and Chronic Toxicity
Von Oettingen (1949) 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-chloro-m-cresol be used in place of 0.5 percent phenol for ster-
ilization of solutions of thermolabile substances.
Tables 4 and 5 list the available toxicity data.
Like the monochlorophenols, p-chloro-m-cresol produced severe
muscle tremors and death in a few hours. Damage to renal tubules
was noted at high dosages (Wien, 1939).
Wien (1939) also conducted some short term toxicity studies.
A dose of 80 mg/kg given subcutaneously for 14 days did not ad-
versely 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 sub-
cutaneously with 12.5 mg p-chloro-m-cresol daily for four weeks.
The dose represented 5 ml of a 1/400 (v/v) solution, such as might
be used to preserve pharmaceutical products. Only three experi-
mental 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), trichlorocresol, iso-
mer not stated, was an effective intestinal antiseptic as a 0.25
percent solution. Rabbits tolerated 500 mg/kg oral doses for four
consecutive days, but 600 mg/kg killed 2 of 3 rabbits. Clinical
signs included convulsions.
Para-chloro-m-cresol has been reported to cause vesicular der-
matitis in humans (Guy and Jacob, 1941). Concentrations of 1.5
C-114
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TABLE 4
Acute Toxicity of p-Chloro-m-cresol*
Animal Route LDqn
Mouse Subcutaneous 360 mg/kg
Mouse Intravenous 70 mg/kg
Rat Subcutaneous 400 mg/kg
*Source: Wein, 1939
C-115
-------
TABLE 5
Acute Toxicity of Monochlorocresol*
Chemical
Animal
Oral LD
50
p-Chloro-o-cresol
m-Chloro-o-cresol
Mouse
Mouse
1330 mg/kg
710 mg/kg
*Source: Schrotter, et al. 1977
0116
-------
percent (aqueous) cause a pruritic vesicular dermatitis in sensi-
tive individuals. Symptoms occur within four hours and regress
within a week.
Hancock and Naysmith (1975) reported two cases of generalized
and seven cases of local reactions to mucous heparin preserved with
0.15 percent chlorocresol. The systemic reactions included col-
lapse, pallor, sweating, hypotension, tachycardia, and generalized
urticarial rash. Intradermal testing with chlorocresol-preserved
heparin and non-chlorocresol heparin identified the cause to be the
chlorocresol-preserved heparin.
Ainley, et al. (1977) also reported an adverse reaction in-
volving heparin preserved with 0.15 percent chlorocresol. The re-
action involved a local severe burning pain at the injection site
that radiated up the arm. Shortly afterwards nausea and light-
headedness 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
Pertinent data could not be located in the available liter-
ature.
Teratogenicity
Information could not be located reporting the presence or ab-
sence of teratogenic properties of any member of the chlorocresols.
Mutagenicity
Rasanen, et al. (1977) tested some chlorocresols for mutagen-
icity using the Salmonella-mammalian microsome Ames test with both
the nonactivated and activated systems. The following chloro-
C-117
-------
cresols were tested and reported as nonmutagenic in both test sys-
tems: 3-chloro-o-cresol, 4-chloro-o-cresol, and 5-chloro-o-
cresol.
Carcinogenicity
Information could not be located reporting the presence or ab-
sence of carcinogenic properties of any member of the chloro-
cresols.
C-118
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CRITERION FORMULATION
Existing Guidelines and Standards
Standards have not been established for the chlorocresols.
Current Levels of Exposure
Pertinent data describing current levels of exposure to
chlorocresols could not be located in the available literature.
Special Groups at Risk
There are no groups at increased risk of exposure to the
chlorocresols.
Basis and Derivation of Criterion
Insufficient data exist upon which to base a toxicity cri-
terion for any of the chlorocresols.
The data of Dietz and Traud (1978) indicate that 2-methyl-4-
chlorophenol (4-chloro-o-cresol), 3-methyl-4-chlorophenol (4-
chloro-m-cresol), and 3-methyl-6-chlorophenol (6-chloro-m-cresol)
are individually capable of imparting a discernable odor to water
when present in sufficient quantities. (This Dietz and Traud study
has been described previously in the section of this document deal-
ing with monochlorophenols.) The odor detection thresholds re-
ported were 1,800 ug/1 for 2-methyl-4-chlorophenol, 3,000 yg/1 for
3-methyl-4-chlorophenol, and 20 ug/1 for 3-methyl-6-chlorophenol.
These thresholds were used to arrive at criterion levels for these
three chlorocresols.
Therefore the recommended criterion levels for 2-methyl-4-
chlorophenol (4-chloro-o-cresols), 3-methyl-4-chlorophenol (4-
chloro-m-cresol) , and 3-methyl-6-chlorophenol (6-chloro-m-cresol)
are 1,800, 3,000, and 20 pg/1, respectively. It is emphasized that
C-119
-------
these criteria are based on asethetic quality rather than health
effects. Data on human health effects must be developed as a more
substantial basis for recommending criteria for the protection of
human health.
C-120
-------
REFERENCES
Ainley, E.J., et al. 1977. Adverse reaction to chlorocresol-
preserved heparin. Lancet. 1803: 705.
Eichholz, F. and R. Wigand. 1931. Uber die wirkung von darmdesin-
fektion smilleln. Eingegangen. 159: 81. (Ger.)
Gaunt, J.K. and W.C. Evans. 1971. Metabolism of 4-chlor-2-methyl-
phenoxyacetate 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.
Gosselin, et al. 1976. Clinical Toxicology of Commercial Pro-
ducts. Williams and Wilkins, Co., Baltimore.
Guy, W.H. and F.M. Jacob. 1941. Occupational dermatitis due to
parachlorometacresol. Jour. Am. Med. Assoc. 116: 2258.
Hancock, B.W. and A. Naysmith. 1975. Hypersensitivity of chloro-
cresol preserved heparin. Br. Med. Jour. 746.
C-121
-------
Jolley, R.L., et al. 1975. Analysis of soluble organic constit-
uents in natural and process waters by high-pressure liquid chroma-
tography. Trace Subs. Environ. Hlth. 9: 247.
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SUMMARY-CRITERION FORMULATION
Existing Guidelines and Standards
Standards have not yet been established for the monochloro-
phenols, dichlorophenols, trichlorophenols, tetrachlorophenols, or
chlorocresols.
Current Levels of Exposure
Pertinent data could not be located in the available liter-
ature concerning current levels of exposure.
Special Groups at Risk
There are no special groups at risk for the monochlorophenols,
dichlorophenols, trichlorophenols, or chlorocresols.
Special groups at risk for the tetrachlorophenols include
workers in tetrachlorophenol manufacturing plants and those who use
the compounds in sawmills and for wood treatment.
Basis and Derivation of Criteria
The chlorinated phenols which are the subjects of this docu-
ment are the monochlorophenols (3- and 4-chlorophenol); the
dichlorophenols (2,5-, 2,6-, 2,3-, 4,6-, and 3,4-dichlorophenols);
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 mono-
chlorocresols are discussed. Three chlorinated phenols have been
the subject of separate criteria documents: 2-chlorophenol, 2,4-di-
chlorophenol, and pentachlorophenol.
For most of these compounds, there are very few data concern-
ing chronic effects in mammals. However, the organoleptic effects
of these compounds have been well documented. These compounds have
a U S GOVERNMENT PRINTING OFFICE WO 720-016/4398
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