—-—<•'. - M "7 *^
United States Office of Water EFA ^fl/E-ffl 044
Environmental Protection Regulations and Standards October 19f!0
Agency Criteria and Standards Division — •
Washington DC 20460 C' • |
vvEPA Ambient
Water Quality
Criteria for
2,4-dimethylphenol
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AMBIENT WATER QUALITY CRITERIA FOR
2,4-DIMETHYLPHENOL
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
Jr'v - --^;ucn Agency
*-'•-' '•',' -'. ''
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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
(O.D.C. 1975), 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:
Martha Radike (author)
University of Cincinnati
John F. Risher (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
Jerry F. Stara (doc. mgr.) ECAO-Cin
U.S. Environmental Protection Agency
A. Wallace Hayes
University of Mississippi
Steven D. Lutkenhoff, ECAO-Cin
U.S. Environmental Protection Agency
Gary Osweiler
University of Missouri
Geraldine L. Krueger
University of Cincinnati
Herbert Cornish
University of Michigan
Patrick Durkin
Syracuse Research Corporation
Alfred Garvin
University of Cincinnati
Si Duk Lee, ECAO-Cin
U.S. Environmental Protection Agency
David McKee, ECAO-RTP
U.S. Environmental Protection Agency
Rudy Richardson
University of Michigan
Philip J. Wirdzek, OWPS
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, D. Jones, B.J. Bordicks,
B.J. Quesnell, P. Gray, R. Rubinstein.
iv
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TABLE OF CONTENTS
Page
Criteria Summary
Introduction A-1
Aquatic Life Toxicology B-1
Introduction B-1
Effects B-2
Acute Toxicity B-2
Chronic Toxicity B-3
Plant Effects B-3
Residues B-4
Miscellaneous B-4
Summary B-5
Criterion B-5
References B-7
Mammalian Toxicology and Human Health Effects C-l
Introduction C-l
Exposure C-4
Ingestion from Water C-4
Ingestion from Food C-9
Inhalation C-ll
Dermal C-12
Pharmacokinetics C-12
Absorption C-12
Distribution C-13
Metabolism C-13
Excretion C-16
Effects C-16
Acute, Subacute and Chronic Toxicity C-16
Synergism and/or Antagonism C-27
Teratogenicity and Mutagenicity C-27
Carcinogenicity C-28
Criterion Formulation C-33
Existing Guidelines and Standards C-33
Current Levels of Exposure C-33
Special Groups at Risk C-33
Basis and Derivation of Criterion C-33
References C-35
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CRITERIA DOCUMENT
2,4-DIMETHYLPHENOL
Criteria
Aquatic Life
The available data for 2,4-dimethylphenol indicate that acute
toxicity to freshwater aquatic life occurs at concentrations as low
as 2,120 yg/1 and would occur at lower concentrations among species
that are more sensitive than those tested. No data are available
concerning the chronic toxicity of dimethylphenol to sensitive
freshwater aquatic life.
No saltwater organisms have been tested with 2,4-dimethyl-
phenol and no statement can be made concerning acute or chronic
toxicity.
Human Health
Sufficient data are not available for 2,4-dimethylphenol to
derive a level which would protect against the potential toxicity
of this compound. Using available organoleptic data, for control-
ling undesirable taste and odor quality of ambient water, the esti-
mated level is 400 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.
VI
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INTRODUCTION
2,4-Dimethylphenol (2,4-DMP) is a naturally occurring, sub-
stituted phenol derived from the cresol fraction of petroleum or
coal tars by fractional distillation and extraction with aqueous
alkaline solutions (U.S. EPA, 1976; Lowry, 1963; Gruse and Stevens,
1942; Rudolfs, 1953). 2,4-DMP is also known as m-xylenol, 2,4-xy-
lenol or m-4-xylenol, and has the empirical formula CgH,QO (Weast,
1972). 2,4-DMP is used commercially as an important chemical feed-
stock or constituent for the manufacture of a wide range of commer-
cial products for industry and agriculture. It is used in the
manufacture of phenolic antioxidants, disinfectants, solvents,
Pharmaceuticals, insecticides, fungicides, plasticizers, rubber
chemicals, polyphenylene oxide, wetting agents, and dyestuffs, and
is an additive or constituent of lubricants, gasolines, and cre-
sylic acid. No direct commercial application for 2,4-DMP appears
to exist presently.
Five other positional isomers of dimethylphenol or xylenol
exist and include 2,3-, 2,5-, 2,6-, 3,4-, and 3,5-dimethylphenol.
Since these isomers result from the different positioning of the
two methyl groups on the phenol ring, they are referred to as posi-
tional isomers. As would be expected, variations in their physi-
cal, chemical, and biological properties exist.
2,4-DMP has a molecular weight of 122.17 and in its normal
state exists as a colorless, crystalline solid (Weast, 1972; Ben-
net, 1974). It has a melting point of 27 to 28°C, a boiling point
of 210 C (760 mm Hg), a vapor pressure of 1 mm Hg at 52.8°C, and a
density of 0.9650 at 20°C (Weast, 1972; Bennet, 1974; Jordan,
1954) .
A-l
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2,4-DMP is slightly soluble in water and as a weak acid
(pka-10.6) it is also soluble in alkaline solutions (Sober, 1970).
2,4-DMP readily dissolves in organic solvents such as alcohol and
ether (Weast, 1972).
2,4-DMP can be oxidized to form pseudoquinone (Rodd, 1952).
However, the conditions required for this reaction generally are
not found in the environment. 2,4-DMP reacts with aqueous alkaline
solutions to form the corresponding salt. Such salts are readily
soluble in water, provided that an alkaline pH is maintained. The
free position on the aromatic ring, ortho to the hyroxyl group, may
be alkylated (Kirk and Othmer, 1964) or halogenated (Rodd, 1952).
However, such reactions under normal environmental conditions have
not been reported.
Information regarding the concentration, persistence, fate
and effects of 2,4-DMP in the environment is limited. However, its
presence in petroleum fractions and coal tars, together with its
use as a chemical feedstock or constituent for the manufacture of
numerous products, clearly indicates the potential for both point
and non-point source water contamination. The complete biodegrada-
tion of 2,4-DMP has been reported to occur in approximately two
months although the conditions were not stated (Rodd, 1952).
A large number of products utilize 2,4-DMP as a feedstock or
constituent. Hence, disposal of chemical and industrial process
wastes and distribution from normal product applications represent
feasible modes of entry of 2,4-DMP into the environment. Examples
of the latter mode include pesticide applications, asphalt and
roadway runoff, and the washing of dyed materials (U.S. EPA, 1975).
A-2
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REFERENCES
Bennet, H. 1974. Concise Chemical and Technical Dictionary. 3rd
ed. Chemical Publishing Co., Inc., New York.
Gruse, W.A. and D.R. Stevens. 1942. The Chemical Technology of
Petroleum. McGraw-Hill Book Co., Inc., New York.
Jordan, T.E. 1954. Vapor Pressure of Organic Compounds. Inter-
science Publishers, Inc., New York.
Kirk, R.E. and D.F. Othmer (eds.) 1964. Kirk-Othmer Encyclopedia
of Chemical Technology. 2nd ed. John Wiley and Sons, Inc., New
York.
Lowry, H.H. 1963. Chemistry of Coal Utilization. John Wiley and
Sons, Inc., New York.
Rodd, E.H. 1952. Chemistry of Carbon Compounds. Elsevier Pub-
lishing Co., New York.
Rudolfs, W. 1953. Industrial Wastes, Their Disposal and Treat-
ment. Reinhold Publishing Corporation, New York.
Sober, H.A. 1970. Handbook of Biochemistry. Selected Data for
microbiology. 2nd ed. CRC Press, Cleveland, Ohio.
A-3
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U.S. EPA. 1975. Identification of organic compounds in effluents
from industrial sources. Prepared for U.S. Environ. Prot. Agency.
Versar, Inc., Springfield, Virginia.
U.S. EPA. 1976. The industrial organic chemicals industry, Part
I. Prepared for U.S. Environ. Prot. Agency, Res. Triangle Inst.
Monsanto Research Corp., Dayton, Ohio.
Weast, R.C. 1972. Handbook of Chemistry and Physics. CRC Press,
Cleveland, Ohio.
A-4
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Aquatic Life Toxicology*
INTRODUCTION
A variety of data are available for freshwater aauatic life and 2,4-di-
methylphenol with no observed adverse effects at concentrations below 2,120
ug/1.
No data on the effects of 2,4-dimethylphenol on any saltwater species
are available.
EFFECTS
Acute Toxicity
The 48-hour EC5Q value for Daphnia magna is 2,120 ug/1 (Table 1) and
the 96-hour LCcn value, obtained using flow-through conditions and meas-
ured concentrations, is 16,750 ug/1 for juvenile fathead minnows (Table 1).
The 192-hour LCcn obtained from this same exposure (Phipps, et al. Manu-
script) is 13,650 ug/1 (Table 5) which indicates little additional mortali-
ty. The 96-hour LCrn value for the bluegill is 7,750 ug/1.
Chronic Toxicity
An early-life-stage test (U.S. EPA, 1978) with the fathead minnow has
been conducted, and the chronic value derived from those results is 2,191
ug/1 (Table 2). An additional embryo-larval test (Holcombe, et al. Manu-
script) with the fathead minnow duplicated that result well. The acute-
chronic ratio for the fathead minnow is 6.8 (Table 2). No chronic test with
an invertebrate species has been performed. Since Daphnia magna appears to
be more acutely sensitive than the fathead minnow or bluegill, a chronic
test for this invertebrate species would be desirable.
*The reader is referred to the Guidelines for Deriving Water Quality Cri-
teria for the Protection of Aauatic Life and Its Uses in order to better
understand the following discussion and recommendation. The following
tables contain the appropriate data that were found in the literature, and
at the bottom of each table are calculations for deriving various measures
of toxicity as described in the Guidelines.
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Plant Effects
Huang and Gloyna (1967) exposed the freshwater alga, Chlorella pyrenoi-
dosa> to 2,4-dimethylphenol and observed complete destruction of chlorophyll
after 48 hours at a concentration of 500,000 wg/l (Table 3). Duckweed
demonstrated chlorosis at a concentration of 292,800 wg/l (Blackman, et al.
1955).
Residues
The bluegill was exposed for 28 days to 14C-2,4-dimethylphenol (U.S.
EPA, 1978) and the bioconcentration factor for whole body is 150 (Table 4).
The half-life in the bluegill is less than 1 day, which indicates that 2,4-
dimethylphenol residues are probably not a potential hazard for aquatic or-
ganisms.
Miscellaneous
As stated earlier, the 192-hour LC5Q value is 13,650 ug/l (Table 5).
Since the 96-hour LC5Q value obtained by the same investigators (Phipps,
et al. manuscript) is 16,750 ug/l, there appears to be no appreciable cumu-
lative mortality.
Summary
The acute toxicity levels for 2,4-dimethylphenol and Daphnia magna and
two warmwater fish species range from 2,120 to 16,750 wg/l. The 96- and
192-hour LC5Q values for the fathead minnow using flow-through tests with
measured concentrations were 16,750 and 13,650 wg/1, respectively. These
results indicate little cumulative mortality. Two embryo-larval tests with
the fathead minnow have been conducted by different investigators. The
chronic values were 2,191 and 2,475 wg/l. The resultant acute-chronic ratio
is 6.8. An alga and duckweed were much more resistant with effects occur-
8-2
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ring at 292,800 ug/1 and higher. The bluegill accumulated 2,4-dimethylphe-
nol to a bioconcentration factor of 150. The half-life was less than one
day, which indicates little likelihood of residue problems.
No data are available for 2,4-dimethylphenol and saltwater organisms.
CRITERIA
The available data for 2,4-dimethylphenol indicate that acute toxicity
to freshwater aquatic life occurs at concentrations as low as 2,120 ug/1 and
would occur at lower concentrations among species that are more sensitive
than those tested. No data are available concerning the chronic toxicity of
2,3-dimethylphenol to sensitive freshwater aquatic life.
No saltwater organisms have been tested with 2,4-dimethylphenol and no
statement can be made concerning acute or chronic toxicity.
B-3
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Table t. Acute values for 2,4-dlnethy(phenol
SpecIes
LC50/EC50 Species Acute
Method* (pg/U Value (ug/l)
Reference
FRESHWATER SPECIES
Cladoceran, S, U 2,120
Daphnla magna
Fathead minnow (juvenile), FT, M 16,750
Pimephales promelas
Bluegl II, S, U 7,750
Lepomls macrochlrus
2,120 U.S. EPA, 1978
16,750 Phlpps, et al.
Manuscript
7,750 U.S. EPA, 1978
CO
I
* S = static, FT = f low-through, U = unmeasured, M = measured
No Final Acute Values are calculable since the minimum data base requirements are not met.
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Table 2. Chronic values for 2,4-dlmethyIphenol
co
I
I/I
Spec 1 as
Fathead minnow,
Plmephales promelas
Fathead minnow,
Plmephales promelas
* E-L = embryo- larval
Chronic
Limits Value
Method* ((ig/l) (yg/l) Reference
FRESHWATER SPECIES
E-L 1,500-3,200 2,191 U.S. EPA, 1978
£-L 1,970-3,110 2,475 Holcombe, et al.
Manuscript
Acute-Chronic Ratio
Chronic Acute
Value Value
Species (ug/1) (ug/l) Ratio
Fathead minnow, 2,475* 16,750** 6.8
Plmephales promelas
**These two values were selected to calculate the acute-chronic ratio because
both tests were conducted in the same dilution water (Lake Superior).
Geometric mean acute-chronic ratio = 6.8
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Table 3. Plant values for 2,4-dlmethy(phenol
Result
Species Effect (ug/l) Reference
FRESHWATER SPECIES
Alga, Complete 500,000 Huang 4 G loyna, 1967
Chi ore I la pyrenoldosa destruction of
chlorophyll after
48 hrs
Duckweed, Chlorosis 292,800 Blackman, et al. 1955
Lemna minor (LC50)
to
I
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Table 4. Residues for 2,4-dI methylphenol (U.S. EPA, 1978)
BIoconcentratIon Duration
Species TI ssue Factor (days)
FRESHWATER SPECIES
Blueglll, whole body 150 28
Lepomls macrochirus
W
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Table 5. Other data for 2,4-dlmethyIphenol (Phipps, et al. Manuscript)
Result
Species Duration Effect dig/I)
FRESHWATER SPECIES
Fathead minnow (juvenile), 192 hrs LC50 13,650
Pimephales promelas
W
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REFERENCES
Blackman, G.E., et al. 1955. The physiological activity of substituted
phenols. I. Relationships between chemical structure and physiological
activity. Arch. Biochem. Biophys. 54: 45.
Holcombe, G.L., et al. Effects of phenol, 2,4-dimethylphenol, 2,4-dichloro-
phenol, and pentachlorophenol on embryo, larval and early juvenile fathead
minnows (Pimephales promelas). (Manuscript)
Huang, J. and E. Gloyna. 1967. Effects of toxic organics on photosynthetic
reoxygenation. Environ. Health Engin. Res. Lab. PB 216-749.
Phipps, G.L., et al. The acute toxicity of phenol and substituted phenols
to the fathead minnows. (Manuscript)
U.S. EPA. 1978. In-depth studies on health and environmental impacts of
selected water pollutants. U.S. Environ. Prot. Agency, Contract No.
68-01-4646.
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Mammalian Toxicology and Human Health Effects
INTRODUCTION
The compound 2,4-dimethylphenol is one of a group of substi-
tuted phenols which are derived from petroleum or coal tar acids.
The compound also occurs naturally in plants and has been detected
in tea, tobacco, and cigarette smoke.
A common name of the dimethylphenols is xylenol, a name fre-
quently used in the literature. Throughout this document, di-
methylphenol rather than xylenol, and methylphenol rather than cre-
sol will be used. Cresol and cresylic acids will designate the
complex mixtures produced commercially.
This document is intended to deal specifically with 2,4-di-
methylphenol; however, three methylphenol isomers and six dimethyl-
phenol isomers generally occur together in nature, as well as in
several industrial processes, commercial products, and phenolic
wastes. It is unlikely that any large segment of the population
would be exposed to 2,4-dimethylphenol alone. Because quantitative
and qualitative data are not available for human exposure to
2,4-dimethylphenol, it is difficult to establish a direct relation-
ship between this compound and health effects in humans.
The six dimethylphenol isomers of [(CH,)2CgH3OH| are substituted
derivatives of phenol; when the hydroxyl group is assigned the num-
ber one position, they are designated as follows: 2,3-, 2,4-, 2,5-,
2,6-, 3,4-, and 3,5-dimethylphenol. The isomers can occur alone
but are usually derived from fossil fuels as complex mixtures con-
taining phenol, the three cresol isomers (2-, 3-, and 4-methyl-
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phenol),and other substituted phenols. Commercial cresol and ere-
sylic acids usually contain phenol, the three methylphenols, and
the dimethylphenols. Some chemical and physical properties of the
dimethylphenols are listed in Table 1.
Dimethylphenols are derived from petroleum or coal tar acids.
The initial fractionation of petroleum or coal tar acids yields a
complex mixture composed primarily of phenol and methylated deriva-
tives. In 1976, Klapproth, in reviewing cresols and cresylic
acids, stated that dimethylphenols, methylphenols, and phenol are
removed from petroleum in the naphtha-cracking process and are
present in the spent caustic liquor used to wash petroleum distil-
late. Coal tar acids are obtained from coke oven by-products, gas-
retort oven tars, and distilled tar by-products. It is estimated
that 151 million pounds of cresol and cresylic acids were produced
in the United States in 1975, down 21 percent from 1974. Cresol is
used as a disinfectant, commercial degreasing agent, and in many
manufacturing processes. The National Institute for Occupational
Safety and Health (NIOSH, 1978) estimated that 11,000 people in the
United States are occupationally exposed to cresol containing
2,4-dimethylphenol.
Considerable amounts of dimethylphenols are discharged in tar
water from shale distillation along with oxybenzene, methylphenols,
and other phenolic compounds (Maazik, 1968). The dimethylphenol
content of the waste material was reported to reach 22.1 percent of
the total monohydric phenols in tar waters. According to data
reported by the Tallin Polytechnical Institute (Maazik, 1968), the
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TABLE 1
Some Physical and Chemical Properties of Dimethylphenol
Molecular Formula (CH3)2CgH
o
1
Ul
Isomer, methyl
Molecular Weight
Boiling Point (°C)
Melting Point (°C)
Crystalline Form
Solubility in:
Water
Ethyl Alcohol
Density3
2,3-
122.17
218
75
Needles
Slightly
Soluble
-
2,4-
122.17
210
27-28
Crystals
Slightly
Soluble
0.9650 20°/4
2,5-
122.17
211 5 ^ 62mm
75
Needles
Soluble
Soluble
-
2,6-
122.17
212
49
Leaflets
Soluble
Soluble
0
3,4-
122.17
225
66-68
Needles
Slightly
Soluble
.9830 20°/4
3,5-
122.17
219 (Subliming)
68
Crystals
Soluble
Soluble
0.9680 20°/4
*Source: Weast, 1976.
Values, e.g., 20°/4 means 20°C, referred to water at 4°C.
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River Purtse discharges about 800 kg of dimethylphenols daily into
the Gulf of Finland.
Methyl and dimethylphenols were found in relatively high con-
centrations in the water-soluble fraction from four fuel oils (Win-
ters, et al. 1976). The fuel oils were refined in four different
locations (Baytown, Texas; Baton Rouge, Louisiana; Billings, Mon-
tana; and Linden, New Jersey). All six isomers of dimethylphenol
were present in the water-soluble fraction.
Ingestion from Water
In 1975, Versar, Inc., prepared for the U.S. EPA an initial
assessment of the possible sources of 154 organic compounds which
have been identified in drinking water supplies (Versar, 1975).
The manufacturing point source of 2,4-dimethylphenol was designated
as coal tar fractionation and coal processing. Commercial utiliza-
tion of 2,4-dimethylphenol included: use as an intermediate in the
manufacture of phenolic antioxidants, use as a cresylic acid con-
stituent, and use in the manufacture of Pharmaceuticals, plastics,
resins, disinfectants (microbicides) solvents, insecticides,
fungicides, rubber chemicals, polyphenylene oxide, wetting agents,
and dyestuffs. The gross estimate of the United States annual dis-
charge was 100 tons.
Small quantities of 2,4-dimethylphenol were reported to be
formed during sewage treatment (biological step) and biological
degradation of municipal, biological, and industrial wastes (Ver-
sar, 1975). There was no evidence that 2,4-dimethylphenol was
formed during water purification, although the report states that
the compound is probably formed in small quantities.
C-4
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Leachates from municipal and industrial wastes contained the
2,4-DMP compound, which was also formed by the degradation of high
molecular weight tars and polymers. Anthropogenic nonpoint sources
of 2,4-dimethylphenol were reported to be from asphalt and roadway
runoff; the general use of Pharmaceuticals, fuels, plastics, and
pesticides; washing of dyed materials; and domestic sewage (Versar,
1975).
Biological treatment of wastes containing 2,4-dimethylphenol
was reported to be 95 to 100 percent effective, activated carbon
filtration 95 to 100 percent effective, and incineration approxi-
mately 95 percent effective. The persistence of the compound in
the environment was considered to be low, with complete degradation
accomplished in approximately two months (Versar, 1975).
Fitter and Kucharova-Rosolova (1974) determined the biologi-
cal degradability of 123 organic compounds and found that 2,4-di-
methylphenol was 94.5 percent removed based on chemical oxygen
demand (COD). The rate of degradation was 28.2 mg of 2,4-dimethyl-
phenol removed per hour by a gram of the initial dry matter of bio-
logical inoculum. The percent of dimethylphenols removed based on
COD ranged from 89.3 percent (for the 3,5-dimethyl isomer) to 97.5
percent (for the 3,4-dimethyl isomer). The rates of degradation
ranged from 9.0 mg/g inoculum (2,6-dimethyl isomer) to 35 mg/g
inoculum (2,3-dimethyl isomer).
Bad taste or odor in drinking water is often reported and has
been ascribed to constituents of industrial wastes or microscopic
organisms and decaying vegetation. Phenolic compounds are widely
blamed for causing medicinal odors and tastes in water supplies.
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In 1957, Hoak reported the odor threshold of phenol and 19 phenolic
compounds. In a study conducted at the Mellon Institute in Pitts-
burgh, Pennsylvania, a panel of 2 or 4 persons sniffed samples of
pure phenolic compounds in odor-free water, which had been heated
to 30°C. A flask of plain odor-free water was provided for com-
parison. The various samples were placed in random order before
the test persons, and the flask with the lowest perceptible odor
was noted by each individual sniffer. The lowest concentration
detected was considered to be the threshold. Chlorinated phenols
were the compounds most easily detected; at 30°C, the odor thresh-
old for 2,4-dimethylphenol was determined to be 55.5 ug/1
(Table 2) .
Dietz 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 -
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.
To determine taste threshold concentrations of selected pheno-
lic compounds, a panel of four test individuals tasted water sam-
ples containing various amounts of phenolic additives. As a point
of comparison, water without phenolic additives was tasted first.
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TABLE 2
Odor Thresholds of Selected Phenolic Compounds*
Compound
Phenol
2-methylphenol
3-methylphenol
4-methylphenol
2 , 4-dimethylphenol
2 , 5-dimethylphenol
3 , 4-dimethylphenol
3 , 5-dimethylphenol
2 , 4-dichlorophenol
2, 5-dichlorophenol
Threshold
60°C
5,000
25
100
200
100
11
5,000
714
6.5
0.45
Cone., ppb**
30°C
10,000
71
333
45.5
55.5
33
5,000
333
0.65
3.3
*Source: Hoak, 1957.
**Lowest concentration perceptible by a panel of two or four
individuals.
C-7
-------
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 "neutra-
lize" the taste.
Geometric mean detection level values for both tests provided
threshold levels of 500 yg/1 for taste and 400 yg/1 for odor for
the chemical 2,4-dimethylphenol.
Neither the Hoak nor Dietz and Traud studies., however, indi-
cated whether the determined threshold levels made the water unde-
sirable or unfit for consumption.
Difficulty in developing analytical techniques for the separa-
tion of phenolic substances in water supplies had in the past been
a factor in attributing odors and bad taste in water to phenol
alone. The distilled 4-aminoantipyrine method measured all sub-
stances which react with the reagent to form a dye. Even though it
was recognized that the technique was nonspecific, it became cus-
tomary to report results as phenol. As late as 1967, Faust and
Mikulewicz presented data which showed the limitations of the
analytical application of 4-aminoantipyrine for the determination
of phenols in water and waste water. Literature published before
1965 does not contain quantitative or qualitative information on
2,4-dimethylphenol in water.
Analytical techniques have since been developed to separate
and identify methylphenol and dimethylphenol isomers in known mix-
tures (Freedman and Charlier, 1964; Dietz, et al. 1976; Husain, et
al. 1977; Buryan, et al. 1978), although many procedures could not
separate 2,4-dimethylphenol from at least one other isomer. An
C-8
-------
analytical method based on solvent extraction of complex mixtures,
concentration of the extract, and analysis by GC/MS has been used
by the EPA and industry to detect 2,4-dimethylphenol at concentra-
tions as low as 0.2 yg/1; however, analytical interferences were
also encountered in these studies. The applicability of this
method to real-world waters must be verified to guard against
interferences which are likely to be present.
As mentioned previously, Maazik (1968) reported that large
amounts (800 kg daily) of dimethylphenols were discharged into the
Purtse River in Finland. However, the presence of dimethylphenols
in public water supplies was not reported.
Phenol, 2- and 3-methylphenol, and 2,4-dimethylphenol have
been identified in samples of raw and treated water (Goren-Strul,
et al. 1966). The sources of raw surface water and treated waters
from two unspecified plants were not named in this study conducted
in the Netherlands.
The amount of 2,4-dimethylphenol in drinking water will vary
according to the concentration of the compound in untreated water
and the efficiency of water treatment systems in removing phenolic
compounds. No data were found which estimated the ingestion by
humans of 2,4-dimethylphenol via drinking water.
Ingestion from Food
Dimethylphenols have been identified as naturally-occurring
constituents of some plants: tea (Kaiser, 1967), tobacco (Baggett
and Morie, 1973; Spears, 1963), marijuana (Hoffmann, et al. 1975),
and a conifer (Gornostaeva, et al. 1977). Although evidence is
lacking that the compound occurs in a great number of plants used
C-9
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for food, it may reasonably be assumed that small amounts are
ingested.
A bloconcentration 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 seems to be propor-
tional to the percent lipids 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 of fish and shellfish consumption in
the United States was anlyzed 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.
A measured steady-state bloconcentration factor of 150 was
obtained for 2,4-dimethylphenol using bluegills (U.S. EPA, 1978).
Similar bluegills contained an average of 4.8 percent lipids (John-
son, 1980). An adjustment factor of 3.0/4.8 = 0.625 can be used to
adjust the measured BCF from the 4.8 percent lipids of the bluegill
to the 3.0 percent lipids that is the weighted average for consumed
fish and shellfish. Thus, the weighted average bioconcentration
C-10
-------
factor for 2,4-dimethylphenol and the edible portion of all fresh-
water and estuarine aquatic organisms consumed by Americans is cal-
culated to be 150 x 0.625 = 93.8.
Inhalation
No literature was found which indicated that humans are
exposed to 2,4-dimethylphenol other than as a component of complex
mixtures. Even though adverse health effects have been reported
due to the exposure of workers to complex mixtures containing
dimethylphenols, the compounds were present in low concentrations
relative to other hydrocarbons, and the adverse effects were not
attributed to dimethylphenols (NIOSH, 1978). Health effects
observed following inhalation exposures to cresol vapors (Corcos,
1939) are similar to those observed in the chronic exposure of rats
to orally administered 2,6- or 3,4-dimethylphenol (Maazik, 1968).
Many workers are exposed by inhalation to commercial degreas-
ing agents which contain methylphenols and dimethylphenols; how-
ever, no adverse health effects have been reported to date (NIOSH,
1978) .
The compound 2,4-dimethylphenol has been identified in ciga-
rette smoke condensate (Smith and Sullivan, 1964; Hoffmann and
Wynder, 1963; Baggett and Morie, 1973). Concentrations in smoke
condensates from six different brands of American cigarettes ranged
from 12.7 to 20.8 mg per cigarette with filters removed, and 4.4 to
9.1 mg per cigarette with filters in place (Hoffmann and Wynder,
1963). The compound has also been identified in the smoke of mari-
juana cigarettes (Hoffmann, et al. 1975) .
C-ll
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Combustion and pyrolysis of building materials containing
phenolic resin produce phenol, 2- and 3-methylphenol, 2,4- and
2,6-dimethylphenol and 2,4,6-trimethylphenol in approximate
descending order of quantity (Tsuchiya and Sumi, 1975). Phenolic
resins are used in the building industry as foam insulation and
adhesives in laminates. Combustion of such materials may expose
humans to 2,4-dimethylphenol.
Due to the paucity of mammalian toxicity data, a quantitative
estimate of the amounts of 2,4-dimethylphenol inhaled by the gen-
eral population cannot currently be made.
Dermal
The ability of cresols to be absorbed through the skin and
produce local and systemic effects has been demonstrated in humans
(Berwick and Treweek, 1933; Cason, 1959; Green, 1975). The skin is
considered to be the primary route of occupational exposure to com-
plex mixtures containing 2,4-dimethylphenol. In addition to
workers exposed in petroleum, coal and coke processing, and
degreasing operations, the general public uses many commercial
products containing complex mixtures of phenol and the mono- and
dimethylphenols.
PHARMACOKINETICS
Absorption
Uzhdovini, et al. (1974) determined that all of the dimethyl-
phenol isomers produced necrosis when applied in a molten state to
rat skin. Only 2,4-dimethylphenol was lethal in the molten state,
with an LD^Q of 1040 mg/kg. In only one case was an isomer reported
to be applied in a solvent, namely 2,6-dimethylphenol in ethanol.
C-12
-------
In this instance, the solubilized compound was lethal, with an LE>5Q
of 920 mg/kg.
In mouse skin bioassays, Boutwell and Bosch (1959) tested five
of the six dimethylphenol isomers (2,3-dimethylphenol was not
tested) and observed that irritation and hair loss paralleled the
ability of each compound to promote a carcinogenic response to a
single subcarcinogenic dose of dimethylbenzathracene (DMBA). A 20
percent solution of the 2,4-dimethyl isomer in benzene applied 2
times a week was the most active promoting agent among the isomers.
In these bioassays, phenol was more damaging to the skin and more
active in initiating and promoting skin carcinomas than was 2,4-di-
methylphenol when the two were applied in equal concentrations.
These results from animal studies suggest that the 2,4-dimethyl
isomer is readily absorbed through the skin.
Distribution
No literature was found showing the distribution of 2,4-di-
methylphenol in humans or animals. In an 8-month chronic study of
rats orally administered 2,6-dimethylphenol (0.06 or 6 mg/kg) or
3,4-dimethylphenol (0.14 or 14 mg/kg), pathological damage was
observed in the liver, spleen, kidneys, and heart; distribution of
2,6- or 3,4-dimethylphenol (and/or their metabolites) through these
organs may be postulated (Maazik, 1968).
Metabolism
In 2 to 3 kg female rabbits, the pattern of metabolism of the
six isomers of dimethylphenol was shown to be quite similar for the
various isomers (Bray, et al. 1950). In a single oral dose of 850
mg of 2,4-dimethylphenol, 8 to 16 percent was excreted conjugated
C-13
-------
with sulfuric acid and 50 to 72 percent with glucuronic acid. A
small proportion was also hydroxylated, but was not identified.
Observations obtained from identification of the metabolites of
2,4-dimethylphenol in urine are reported in Table 3.
In 1967, Gilbert, et al. demonstrated induction of microsomal
enzyme activity in the liver by pretreatment of weanling rats with
2,4-dimethylphenol (6 daily oral doses of 1.5 raillimoles per kg).
The activities of hexobarbitone oxidase and aminopyrine demethylase
were measured in microsomal fractions derived from the livers of
treated and untreated animals. It was observed that the inducing
capacity of a compound was stimulated by the presence of an alkyl
substituent in position 4.
The metabolism of 2,4-dimethylphenol has been studied in a
Pseudomonas species isolated from river mud (Chapman and Hopper,
1968). Metabolism was initiated by the oxidation of the methyl
group in position 4 relative to the hydroxyl group. Three inter-
mediates identified were 4-hydroxy-3-methylbenzoic acid, 4-hy-
droxyisophthalic acid, and protocatechuic acid.
That 2,4-dimethylphenol can be produced in the body by metabo-
lism of 1,3-dimethylbenzene has been demonstrated in at least two
studies. In whole animal studies of rats that received 1,3-di-
methylbenzene orally, 2,4-dimethylphenol was the only phenolic
metabolite reported in the urine (Bakke and Scheline, 1970).
Approximately 2 percent of the dose was excreted as 2,4-dimethyl-
phenol. The 2,6 and 3,5-dimethyl isomers were not detected.
Jerina, et al. (1971) and Kaubisch, et al. (1972) presented data
which showed that 2,4-dimethylphenol was the major metabolite
C-14
-------
TABLE 3
Urinary Excretion of Metabolites of
2,4-Dimethylphenol* in the Rabbit**
Percent of Dose Administered
Metabolic Product
Free nonacidic phenol
Ethereal sulphate
Ester glucuronide
Ether glucuronide
Ether-soluble acid
Range
0-5
12-14
0-4
35-56
49-75
Average
2
13
1
46
64
*A dose of 850 mg administered by stomach tube.
**Source: Bray, et al. 1950.
C-15
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produced in the metabolism of 1,3-dimethylbenzene by rat liver
microsomes. The 2,6-dimethyl isomer was also a metabolic product,
but production of the 2,4-isomer was 10 times that of the 2,6-
isomer. These studies suggest that metabolic pathways exist in the
liver for the production of dimethylphenols from phenolic compounds
which find their way into the blood stream.
Excretion
The excretion of metabolites of 2,4-dimethylphenol was studied
in rabbits by Bray, et al. in 1950. The pattern of metabolism of
the six isomers was quite similar, and only the results for the
2,4-isomer are reported in Table 3. These data indicate rapid
metabolism and excretion. Analytical techniques of the 1950's made
the quantitation of metabolites difficult.
EFFECTS
Acute, Subacute, and Chronic Toxicity
The germicidal activity of phenol and substituted phenols was
recognized more than 50 years ago (Schaffer and Tilley, 1927) .
Data were presented which compared the germicidal activity of
2,4-dimethylphenol and other substituted phenols to the activity of
phenol. It was observed that 5.8 times as much phenol as 2,4-di-
methylphenol was required to kill the test organism (Bacillus
typhosus) in the same period of time.
Woodward, et al. (1934) reported data from testing 37 deriva-
tives of phenol for their fungicidal activity. Dialkyl compounds
were more powerful fungicides than the corresponding monoalkyl com-
pounds. In comparison to phenol (1.0), the fungicidal activity of
C-16
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2,4-dimethylphenol was 6.3 times greater in experiments with the
yeast, Monilia tropicalis.
In 1975, Leifertova, et al. studied the relationship between
the biological activity of phenolic compounds as antifungal and
antibacterial agents and the chemical structure of the compounds.
The dialkyl- and trialkylphenols were the most active. Activity
was increased when alkyl groups were in the 2- and 4-positions, as
in 2,4-dimethylphenol.
Dimethylphenols and methylphenols were among compounds tested
as a chemotherapeutic treatment to selectively destroy plant neo-
plasms without injuring normal plant tissues (Schroth and Hilde-
brand, 1968) . Solutions were applied with a swab to tumors and
surrounding areas. The most selective of the methylated phenols
tested were 3-methylphenol and 2,4-dimethylphenol. At concentra-
tions of 1.5 percent (v/v), 60 to 80 percent of tumor tissues (2 to
2.5 cm in diameter) on tomato plants were destroyed with little
injury to adjacent stem tissues. The compounds that indicated
selectivity in destroying plant neoplasms were further studied for
their activity in killing the bacterium, Agrobacterium tumefaciens,
responsible for producing neoplastic growth in plants. At 0.6 per-
cent, 2,4-dimethylphenol was bacteriocidal to this organism.
Ascites sarcoma BP8 cells, cultured in suspension in vitro,
were used to study the toxicity of more than 250 compounds which
have been identified in tobacco and tobacco smoke (Pilotti, et al.
1975). Phenol, methylphenols, and dimethylphenols all inhibited
the growth of cells; among these compounds, 2,4-dimethylphenol was
the most active (Table 4). The moderate toxicity of phenol to BP8
C-17
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TABLE 4
Inhibition of Ascites Sarcoma BP8 Cell Culture Growth
Rate by Phenol and Methylated Phenols*
Compound
Phenol
2-methylphenol
3 -me thy Iphenol
4 -me thy Iphenol
2 , 3-dimethy Iphenol
2 , 4-dimethylphenol
2 , 5-dimethylphenol
2 , 6-dimethy Iphenol
3 , 4-dimethylphenol
3 , 5-dimethylphenol
*Source: Pilotti, et al.
Percent
1 mM
25
56
31
93
78
99
74
79
75
44
1975.
Inhibition
0.1 mM
5
7
5
13
2
11
0
5
5
7
C-18
-------
cells was increased by the introduction of electron-donating sub-
stituents such as alkyl groups.
The acute toxicities of phenol, methylphenols, and dimethyl-
phenols in 422 mice and 289 rats were reported in 1974 by Uzhdo-
vini, et al. The number of animals used for each experiment was not
reported. Compounds were administered by inhalation, intubation,
intraperitoneal injection, or by application to the skin.
Uzhdovini, et al. (1974) reported that inhalation of dimethyl-
phenol vapors at "levels of hundreds of milligrams per liter" did
not cause death in the animals. A mixture of vapors and aerosols
condensed in the chamber and deposited on the chamber walls and
skin of the animals. Toxic effects were attributed to penetration
of compounds through the skin. Signs observed during inhalation
included irritation of mucous membranes, enlargement of blood ves-
sels of the ears and extremities, and excitation followed by
lethargy.
Ten percent solutions of phenol, methylphenols, or dimethyl-
phenols in oil were intubated into the stomachs of animals to test
the acute toxicities of ingested compounds (Uzhdovini, et al.
1974). As shown in Table 5, LDcQ data indicated that dimethyl-
phenols were less toxic than phenol and methylphenols in mice. In
rats, 2,4-dimethylphenol was the least toxic.
Solutions of 2,6-dimethylphenol were injected intraperitone-
ally into mice (Uzhdovini, et al. 1974). In these experiments each
group consisted of 10 mice. When the same concentration (0.5 per-
cent) of 2,6-dimethylphenol was administered in oil or water, the
toxicity of the water solution was greater than the oil solution.
C-19
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TABLE 5
Acute Toxicity of Phenol and Methylated Phenols*
Compound
(mg/kg)
Mice
Rats
phenol
2-methylphenol
3-methylphenol
4-methylphenol
2,4-dimethylphenol
2, 5-dimethylphenol
2,6-dimethylphenol
3,4-dimethylphenol
3, 5-dimethylphenol
436 (311-610)
344 (270-436)
828 (695-985)
344 (266-433)
809 (724-914)
1140 (797-1530)
980 (823-1166)
948 (658-1365)
836 (733-906)
1470 (1170-1830)
2010 (1240-3200)
1460 (1260-1670)
3200 (2780-3680)
1270°
1750 (1420-2150)
1620
1915C
*Source: Uzhdovini, et al. 1974.
alntubated into the stomach 10% in oil.
LD50 calculated according to the method of Prozorovskii, 1962;
figures in parentheses interpreted as extreme values observed.
LD50 according to Deichmann and LeBlanc, 1943.
C-20
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Following a dose of 300 mg/kg, 60 percent (+ 15.4) of the mice that
received the aqueous solution died, as compared to 20 percent
( + 12.6) fatalities among the mice injected with the oil solution.
Apparently more than one group of mice was dosed per treatment; the
number of groups was not reported.
The application of molten or crystalline compounds to the skin
of rats produced necrosis on contact (Uzhdovini, et al. 1974).
Molten methylphenols and 2,4-dimethylphenol were lethal (Table 6).
Solid dimethylphenols (2,5-; 2,6-; 3,4-; 3,5-) and molten 2,6-di-
methylphenol did not produce fatal toxicity in rats; however, an
ethanol solution of 2,6-dimethylphenol was lethal to mice, with an
LD5Q of 920 mg/kg. From these experiments, Uzhdovini, et al. con-
cluded that the greatest danger of poisoning to man is by absorp-
tion through the skin.
Maazik (1968) presented data on the short-term toxic effects
of four dimethylphenol isomers (2,5-; 2,6-; 3,4-; 3,5-). Even
though 2,4-dimethylphenol was not used as a test compound, Maazik's
observations will be summarized because of the limited data on the
toxicity of dimethylphenols in mammals. Compounds were admin-
istered in a single dose by mouth in the form of finely dispersed
aqueous suspensions, and the animals were observed for 15 days.
LD5Q values for white mice and albino rats were determined by
probit analysis as modified by Prozorovskii (1962); in rabbits,
LDcgS were determined by the method of Deichmann and LeBlanc (1943)
(Table 7) . The clinical signs of acute poisoning were dyspnea,
C-21
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TABLE 6
Acute Toxicity of Methylated Phenols Applied
to the Skin of Rats*
Compound3
2-methylphenol
3-methylphenol
4-methylphenol
2 , 4-dimethylphenol
LD50
620
110
750
1040
(mg/kg)b
(370-1110)
(800-1400)
(510-1100)
(630-1716)
*Source: Uzhdovini, et al. 1974.
Compounds were described as "molten".
Values in parentheses interpreted as extreme values
observed.
C-22
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TABLE 7
Toxicity of Dimethylphenol Isomers in Animals Following
A Single Peroral Dose (mg/kg)*
o
i
Isomer
2 , 5-dimethylphenol
2 , 6-dimethylphenol
3 , 4-dimethylphenol
3 , 5-dimethylphenol
LD50
White Mice
383 +
479 +
400 +
477 +
36
47
43
49
+ SE
Albino Rats
444 +
296 +
727 +
608 +
26
36
70
44
LD50
Rabbits
938
700
800
1,313
*Source: Maazik, 1968
-------
disturbance of motor coordination, rapid onset of clonic spasms,
and asymmetrical body position. Most of the animals died within 24
hours.
Guinea pigs were relatively insensitive to the dimethylphenols
(Maazik, 1968). Administration of 2,115 mg 2,6-dimethylphenol per
kg caused signs of poisoning, but these disappeared after 10 min-
utes. Administration of 1,200 mg 3,4-dimethylphenol per kg caused
only mild poisoning.
In longer-term experiments 30 male albino rats, divided into 3
groups of 10, received perorally for 10 weeks 29.5 mg 2,6-dimethyl-
phenol per kg, 72.5 mg 3,4-dimethylphenol per kg, or no treatment
(Maazik, 1968). Since the doses were described as being 10 percent
of the LDcn for albino rats, the reporting of doses in the publica-
tion as yg amounts is concluded to be an error. Animals treated
with 2,6-dimethylphenol exhibited a depressed weight gain in com-
parison to controls and increased weight coefficients of the liver
and spleen. Rats treated with 3,4-dimethylphenol exhibited a
statistically significant lag in weight gain and a statistically
significant increase of the weight coefficients of the spleen,
heart, and lungs. Histological examination revealed marked atrophy
and parenchymatous dystrophy of the hepatic cells in both experi-
mental groups. No differences were observed in the morphological
picture of the blood, prothrombin time, ratios of the serum protein
fractions, or the concentration of phenol in the urine.
A long-term experiment was performed with 53 male albino rats,
using 6 or 0.06 mg 2,6-dimethylphenol per kg and 14 or 0.14 mg
3,4-dimethylphenol per kg; the doses represent 2 x 10 and
C-24
-------
2 x 10~4 r respectively, of the LE>cQ for rats (Maazik, 1968). The
compounds were administered perorally for eight months. No sig-
nificant differences were noted in animals receiving the lower
doses. Some of the effects of the higher doses are summarized in
Table 8. Pathological changes observed in animals receiving the
high doses of dimethylphenols included fatty dystrophy and atrophy
of the hepatic cells, hyaline-droplet dystrophy in the kidneys,
proliferation of myeloid and reticular cells, atrophy of the lym-
phoid follicles of the spleen, and parenchymatous dystrophy of
heart cells.
The 2,4-isomer is known to be an ATP blocking agent and as
such has been used as an experimental tool. Hauge, et al. (1966)
observed the development of vasoconstriction in isolated blood-
perfused rabbit lung preparations as a function of time after
arterially injecting ATP (50 yg). Vasoconstriction resulting from
physiological causes or added ATP was "surprisingly" inhibited by
the addition of a commercial preparation of tri-cresol which was
found to contain phenol, methylphenols, and dimethylphenols.
In 1968, Lunde, et al. reported the effects of the individual
compounds found in tri-cresol on vasoconstriction in the isolated
perfused lung. The effectiveness of the substituted phenols in
inhibiting vasoconstriction was related to the position of the
methyl groups relative to the hydroxy group. Among the dimethyl-
phenol isomers, 2,4- and 2,6-were the most effective in inhibiting
vasoconstriction; 2,3-, 2,5-, and 3,4- were less effective, and
3,5-had no effect. Inhibition of vasoconstriction can be reversed
by additional ATP. The mechanism of ATP-induced vasoconstriction
and 2,4-dimethylphenol inhibition of vasoconstriction is unknown.
C-25
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TABLE 8
Toxic Effects of Dimethylphenol Administered
Perorally for 8 Months*
Compound
Dose
Observation
2,6-dimethylphenol
6 mg/kg
o
3,4-dimethylphenol
14 mg/kg
Significant decrease in blood serum SH.
Decrease in blood pressure.
Increase in concentration of SH groups
in liver, spleen, and brain.
Pathological changes in liver, spleen,
kidneys, and heart.
Decrease in blood serum SH.
Decrease in erythrocytes and hemoglobin.
Increase in concentration of SH groups
in liver, spleen, and brain.
Pathological changes in liver, spleen,
kidneys, and heart.
*Source: Maazik, 1968,
-------
Lunde, et al. (1968) suggested that the most likely explanation is
that the 2,4-dimethylphenol directly inhibits the effect of ATP on
smooth muscle at a receptor level.
In a study of the role of histamine in hypoxic pulmonary
hypertension in the rat, Hauge (1968) showed that semicarbazide, a
histaminase inhibitor, potentiated the induced hypoxic vasocon-
strictor response in isolated and ventilated lungs perfused with
homologous blood. This response was blocked by 2,4-dimethylphenol
through the dose range of 1 to 10 mg (administered through a 35 ml
blood reservoir). This demonstration of physiological activity
indicates that the compound may cause adverse health effects in
humans as a result of chronic exposure.
Synergism and/or Antagonism
Apart from the tumor-promoting activity of 2,4-dimethylphenol
(Boutwell and Bosch, 1959) , data were not found concerning com-
pounds which compete with or enhance the biological activity of
2,4-dimethylphenol.
Teratogenicity and Mutagenicity
No investigations of the teratogenic or mutagenic potential of
2,4-dimethylphenol were found in the literature.
Phenol was found to be mutagenic to E. coli strain B/Sd-4
(Demerec, et al. 1951). Phenol was also shown to be mutagenic in
Drosophila in a study in which isolated gonads were exposed in
vitro and then implanted into host larvae (Hadorn and Niggli,
1946). Levan and Tjio (1948a,b) observed C-mitosis in root tips of
Allium cepa exposed to phenol or methylphenol isomers, but chromo-
some fragmentation was rare.
C-27
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Carcinogenicity
Boutwell and Bosch (1959) reported that 2,4-dimethylphenol in
high concentrations produced papillomas and carcinomas on the skin
of tumor-susceptible female mice of the Sutter strain. Five mg in
benzene (25 yl of 10 percent 2,4-dimethylphenol) applied twice
weekly produced carcinomas in 12 percent of 26 mice at 28 weeks
(Table 9). It should be noted, however, that the mice were housed
in wood cages treated with creosote, which may have initiated the
carcinogenic response. In this experiment, benzene alone was not
evaluated; the only data related to benzene itself refer to a test
of its promoting activity following a subcarcinogenic dose of DMBA.
Benzene was applied twice weekly to the skin of mice after a single
application of 75 ug DMBA in benzene; observation at 24 weeks of
the 27 surviving mice showed no carcinomas and an 11 percent inci-
dence of papillomas.
In the 1959 study by Boutwell and Bosch, over 50 different
compounds related to phenol were tested for their ability to initi-
ate or promote the appearance of tumors. (Only those results with
compounds closely related to 2,4-dimethylphenol are reported here.)
In these experiments, 2,4-dimethylphenol was shown to promote the
appearance of papillomas and carcinomas after a single subcarcino-
genic application of DMBA. Animals were selected at random from a
common pool of 2- to 3-month old female Sutter mice. The fur was
shaved from the test area of the mid-dorsal region of mice about
one week prior to the first application of the test substance.
Because of the possibility of mechanical irritation and damage to
papillomas, the mice were not shaved again after the experiment was
C-28
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TABLE 9
Carcinogenic Effects of Dimethylphenol and Phenol on Mouse Skin*
Amount (mg)
Administered Twice
Agent in Weekly in 25 *}! Duration
2,
2,
2,
^ 3,
O
N> 3'
Benzene
4-dimethylphenol
5-dimethylphenol
6-dimethylphenol
4-dimethylphenol
5-diraethylphenol
phenol
Applications
5.
2.
2.
2.
2.
2.
5.
2.
2.
1.
0
5
5
5
5
5
0
5
5
25
(weeks)
24
20
20
20
20
20
24
24
20
24
No. of
Survivors
Original
19/24
26/29
25/30
26/30
28/29
22/30
20/33
19/33
24/30
25/33
Average
Pa/
Survivor
1.42
0.66
0.40
0.15
0.71
0.91
2.25
2.68
0.62
1.16
Percent
Survivors
with Pa
63
31
24
8
50
55
90
95
33
56
Percent
Survivors
with Ca
5
0
0
0
4
5
15
37
33
4
(42
(12
(8
(14
(14
(65
(68
(29
(12
at
at
at
at
at
at
at
at
at
39 wk)
28 wk)
28 wk)
28 wk)
28 wk)
40 wk)
39 wk)
28 wk)
40 wk)
*Source: Boutwell and Bosch, 1959.
Pa = Papilloma
Ca = Carcinoma
-------
started. A single application of 75 ug DMBA (25 yl of 0.3 percent
in benzene) was given; after one week, the promoting agent in ben-
zene was applied twice weekly for the duration of the experiment.
The gross identifications of benign and malignant tumors were con-
firmed periodically by microscopic examination. Five mg of 2,4-di-
methylphenol in benzene (25 yl of 20 percent) , applied twice a week
after a single application of 75 yg DMBA, elicited a carcinogenic
response in 18 percent of the mice at 23 weeks (Table 10) . All four
of the dimethylphenol isomers promoted the appearance of papillomas
and carcinomas; 2,4-dimethylphenol was the most active in promoting
carcinomas. Results reported with phenol as the promoting agent
suggest that the solvent used for the initiator and promoter may
alter the biological response.
The Boutwell and Bosch (1959) data were inconclusive regarding
the possible carcinogenic effect of 2,4-dimethylphenol. The study
did indicate that 2,4-dimethylphenol was a promoting agent. Al-
though promoters have a potential carcinogenic risk to humans,
there was no dose-response data with which to formulate a quantita-
tive risk extrapolation.
The cresol isomers (2-, 3-, and 4-methylphenol) tested by
Boutwell and Bosch (1959) did not promote carcinogenesis in animals
at 12 weeks. Five mg of a cresol isomer in acetone was applied
twice weekly to the backs of mice initiated with a subcarcinogenic
dose of DMBA (75 yg) in acetone. At 12 weeks the incidence of
papillomas observed in the survivors ranged from 35 to 59 percent.
Phenolic fractions of cigarette smoke condensate have been
shown to promote carcinogenesis in mouse skin bioassays (Lazar, et
C-30
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TABLE 10
Carcinogenic Promoting Effects of Dimethylplienol and Phenol on Mouse Skin
Following the Single Application of 75 bg DMBA*
Amount (mcj)
Promoting Administered Twice
Agent in Weekly in 25 *sl
Benzene Applications
None (Benzene
2 , 4-dimethylphenol
2, 6 -dimethyl phenol
3 , 4-dimethylphenol
3, 5-dimethylphenol
^j phenol
h-1
phenol**
phenol***
5
5
5
5
5
2
1
5
5
control)
.0
.0
.0
.0
.0
.5
.75
.0
.0
Duration
(weeks)
24
15
15
15
15
24
24
24
12
12
No. of Average
Survivors/ Pa/
Original Survivor
27/32
28/30
27/30
21/30
20/30
10/33
15/33
27/33
22/27
21/24
0
1
0
2
0
3
3
1
1
.15
.21
.44
.66
.90
.20
.94
.67
.50
Percent "Percent
Survivors Survivors
with Pa with Ca
11
50
30
95
40
100
100
74
64
58
0
11
4
0
0
20
33
4
0
5
(18
(11
(14
(5
(70
(93
(26
at 23 wk)
at 23 wk)
at 23 wk)
at 23 wk)
at 38 wk)
at 39 wk)
at 40 wk)
* Source: Boutwell and Bosch, 1959.
** Initiator, 75 ijg DMBA in acetone.
***Initiator and promotor in acetone.
'Pa = Papilloma
Ca = Carcinoma
-------
al. 1966; Bock, et al. 1971; Roe, et al. 1959). Phenol and methyl-
phenols were contained in the fraction in yg amounts per cigarette;
therefore the carcinogenic promoting action cannot be directly
ascribed to 2,4-dimethylphenol alone.
No reports of epidemiologic studies of workers exposed to
2,4-dimethylphenol were found in the literature. It is unlikely
that any segment of the population is exposed to this compound
alone. Large segments of the population are exposed to small
amounts of 2,4-dimethylphenol in complex mixtures in petroleum and
coke oven industries, commercial cresol, cigarettes, and commercial
products using fractions obtained from coal tar acids and petroleum
distillates.
No data were found relating the exposure of humans to 2,4-di-
methylphenol to the incidence of cancer. In general, the complex
mixtures in which 2,4-dimethylphenol is often present are so toxic
that contact is avoided when the toxicity of the mixture is known.
C-32
-------
CRITERION FORMULATION
Existing Guidelines and Standards
Standards have not been promulgated for 2,4-dimethylphenol for
any sector of the environment or workplace.
Current Levels of Exposure
Data are not available for estimating the exposure of humans
to 2,4-dimethylphenol.
Special Groups at Risk
Workers involved in the fractionation and distillation of
petroleum or coal and coal tar products comprise one group at risk.
Workers who are intermittently exposed to certain commercial
degreasing agents containing cresol may also be at risk. Cigarette
and marijuana smoking groups and those exposed to cigarette smoke
inhale ug quantities of 2,4-dimethylphenol.
Basis and Derivation of Criterion
The data are insufficient to indicate that 2,4-dimethylphenol
is a carcinogenic agent. The only study found (Boutwell and Bosch,
1959) was designed to detect promoting activity and the effect of
2,4-dimethylphenol as a primary carcinogen was not well defined.
In addition, the dermal route of administration in this study ren-
ders the data inappropriate for extrapolation of the carcinogenic
risk of ingesting small amounts in drinking water. The Carcinogen
Assessment Group of the U.S. EPA and the National Academy of
Sciences (1977) concur in the judgement that the role of 2,4-di-
methylphenol as a primary cancer-producing agent is uncertain.
The recommended criterion for 2,4-dimethylphenol is based on
organoleptic properties. The data of Dietz and Traud (1978) and
C-33
-------
Hoak (1957) indicated that microgram concentrations of 2,4-di-
methylphenol in water are capable of causing a discernable odor.
Dietz and Traud further observed a distinct flavor alteration of
water also at microgram levels of 2,4-dimethylphenol.
The odor threshold determined by Dietz and Traud (1978) for
the detection of 2,4-dimethylphenol in water is used to arrive at
the criterion level of 400 yg/1. The study of Dietz and Traud was
chosen as the basis for the criterion for a number of reasons. The
authors present a recent study involving a reasonably substantial
number of individuals and with 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
"cool and clear" and "neutral with respect to both odoc 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 study, which utilized carbon-filtered
laboratory distilled water at 30°C. This level is closely sup-
ported by the taste threshold for 2,4-dimethylphenol in water
(500 yg/1) reported by Dietz and Traud in the same paper.
Therefore, based on the prevention of undesirable organoleptic
qualities, the criterion level for 2,4-dimethylphenol in water is
400 ug/1. This criterion is based on aesthetic rather than health
effects. Data on mammalian health effects need to be developed as
a more substantial basis for setting a criterion for the protection
of human health.
C-34
-------
REFERENCES
Baggett, M.S. and G.P. Morie. 1973. Quantitative determination of
phenol and alkylphenols in cigarette smoke and their removal by
various filters. Tob. Sci. 17: 30.
Bakke, O.M. and R.R. Scheline. 1970. Hydroxylation of aromatic
hydrocarbons in the rat. Toxicol. Appl. Pharmacol. 16: 691.
Bock, F.G., et al. 1971. Composition studies on tobacco. XLIV.
Tumor-promoting activity of subfractions of the weak acid fraction
of cigarette smoke condensate. Jour. Natl. Cancer Inst. 47: 427.
Boutwell, R.K. and O.K. Bosch. 1959. The tumor-producing action
of phenol and related compounds for mouse skin. Cancer Res.
19: 413.
Bray, H.G., et al. 1950. Metabolism of derivatives of toluene. 5.
The fate of the xylenols in the rabbit, with further observations
on the metabolism of the xylenes. Biochem. Jour. 47: 395.
Buryan, P., et al. 1978. Investigation of the composition of
coal-tar phenols and xylenols by capillary chromatography. Jour.
Chromatogr. 148: 203.
Cason, J.S. 1959. Report on three extensive industrial chemical
burns. Br. Med. Jour. 1: 827.
C-35
-------
Chapman, P.J. and D.J. Hopper. 1968. Bacterial metabolism of
2,4-xylenol. Biochem. Jour. 110: 491.
Corcos, A. 1939. Contribution to the study of occupational poi-
soning by cresols. Dissertation. Vigot Freres Editeurs. (Fre)
Deichmann, W.B. and T.J. LeBlanc. 1943. Determination of the
approximate lethal dose with about six animals. Jour. Ind. Hyg.
Toxicol. 25: 415.
Demerec, et al. 1951. A survey of chemicals for mutagenic activ-
ity in E. coli. Am. Nat. 85: 119.
Dietz, F. and J. Traud. 1978. Geruchs- und Geschmacks- Schwellen-
Konzentrationen von PhenolKorpern. Gas-Wasserfack. Wasser-Abwas-
ser. 119: 318.
Dietz, F., et al. 1976. Systems for the identification of pheno-
lic compounds by thin-layer chromatography. Chromatographia.
9: 380.
Faust, S.D. and E.W. Mikulewicz. 1967. Factors influencing the
condensation of 4-aminoantipyrine with derivatives of hydroxyben-
zene. II. Influence of hydronium ion concentration on absorptiv-
ity. Water Res. 1: 509.
C-36
-------
Freedman, R.W. and G.O. Charlier. 1964. Quantitative analysis of
low-boiling phenols by capillary column separation of trimethyl-
silyl ethers. Analy. Chem. 36: 1880.
Gilbert, D., et al. 1967. Induction of liver microsomal process-
ing enzymes by substituted phenols. Biochem. Jour. 103: IIP.
Goren-Strul, S., et al. 1966. Identification and determination of
phenols and chlorophenols in very dilute aqueous solutions by gas-
liquid chromatography, paper chromatography and spectrophotometry.
Anal. Chem. Acta. 34: 322.
Gornostaeva, L.I., et al. 1977. Phenols from abies sibirica
essential oil. Khim. Pirir. Soedin; ISS 3, 417-418.
Green, M.A. 1975. A household remedy misused - fatal cresol poi-
soning following cutaneous absorption (A case report). Med. Sci.
Law. 15: 65.
Hadorn, E. and H. Niggli. 1946. Mutations in Drosophila after
chemical treatment of gonads j.n vitro. Nature. 157: 162.
Hauge, A., et al. 1966. Vasoconstriction in isolated blood-
perfused rabbit lungs and its inhibition by cresols. Acta. Phy-
siol. Scand. 66: 226.
C-37
-------
Hauge, A. 1968. Role of histamine in hypoxic pulmonary hyperten-
sion in the rat. I. Blockage or potentiation of endogenous amines,
kinins, and ATP. Circ. Res. 33: 371.
Berwick, R.P. and D.N. Treweek. 1933. Burns from anesthesia mask
sterilized in compound solution of cresol. Jour. Am. Med. Assoc.
100: 407.
Hoak, R.D. 1957. The causes of tastes and odors in drinking water.
Proc. llth Ind. Waste Conf. Purdue Univ. Eng. Bull. 41: 229.
Hoffmann, D. and E.L. Wynder. 1963. Filtration of phenols from
cigarette smoke. Jour. Natl. Cancer Inst. 30: 67.
Hoffmann, D., et al. 1975. On the carcinogenicity of marijuana
smoke. Recent Adv. Phytochem. 9: 63.
Husain, S., et al. 1977. Separation of isomeric alkylphenols by
high performance liquid chromatographic and gas-liquid chroma-
tographic techniques. Jour. Chromatogr. 137: 53.
Jerina, D.M., et al. 1971. Arene oxides as intermediates in the
metabolism of aromatic substrates. Alkyl and oxygen migrations
during isomerization of alkylated arene oxides. Proc. Natl. Acad.
Sci. 68: 2545.
C-38
-------
Johnson, K. 1980. Memorandum to D. Kuehl. U.S. EPA. March 10.
Kaiser, H.E. 1967. Cancer-promoting effects of phenols in tea.
Cancer. 20: 614.
Kaubisch, N., et al. 1972. Arene oxides as intermediates in the
oxidative metabolism of aromatic compounds. Isomerization of
methyl-substituted arene oxides. Biochemistry. 11: 3080.
Klapproth, E.M. 1976. Cresols and Cresylic Acid. In; Chemical
Economics Handbook. Stanford Res. Inst. Menlo Park, California.
Lazar, P., et al. 1966. Benzo(a)pyrene content and carcinogeni-
city of cigarette smoke condensate - results of short-term and
long-term tests. Jour. Natl. Cancer Inst. 37: 573.
Leifertova, I., et al. 1975. Antifungal and antibacterial effects
of phenolic substances. A study of the relation between the bio-
logical activity and the constitution of the investigated com-
pounds. Acta. Univ. Palacki. Olomuc., Fac. Med. 74: 83.
Levan, A. and J.H. Tjio. 1948a. Induction of chromosome frag-
mentation by phenols. Hereditas. 34: 453.
Levan, A. and J.H. Tjio. 1948b. Chromosome fragmentation by
phenols. Hereditas. 34: 250.
C-39
-------
Lunde, P.K., et al. 1968. The inhibitory effect of various
phenols on ATP-induced vasoconstriction in isolated perfused rabbit
lungs. Acta. Physiol. Scand. 72: 331.
Maazik, I.K. 1968. Dimethylphenol (xylenol) isomers and their
standard contents in water bodies. Gig. Sanit. 9: 18.
National Academy of Sciences. 1977. Drinking Water and Health.
Washington, D.C.
National Institute of Occupational Safety and Health. 1978. Occu-
pational exposure to cresol. DHEW (NIOSH) Publ. No. 78-133. U.S.
i
Dept. Hlth. Edu. Welfare, Pub. Hlth. Serv., Center for Disease Con-
trol.
Pilotti, A., et al. 1975. Effects of tobacco and tobacco smoke
constituents on cell multiplication j.n vitro. Toxicology. 5: 49.
Fitter, P. and P. Kucharova-Rosolova. 1974. Relation between the
structure and the biodegradability of organic compounds. III.
Biodegradability of aromatic hydroxy derivatives. Sb. Vys. Sk.
Chem.-Technol. Praze Technol. Vody, F19, 43.
Prozorovskii, V.B. 1962. Use of the smallest square method in the
test analysis of lethality curves. Farmakol. Toxicol. 25: 115.
C-40
-------
Roe, F.J.C., et al. 1959. Incomplete c<^
^ens in cigarette
smoke condensate: tumor-production by a phenolic
-tion. Br*
Jour. Cancer. 13: 623.
Schaffer, J.M. and F.W. Tilley. 1927. Further investigation of
the relation between the chemical constitution and the germicidal
activity of alcohols and phenols. Jour. Bacteriol. 14: 259.
Schroth, M.N. and D.C. Hildebrand. 1968. A chemotherapeutic
treatment for selectively eradicating crown gall and olive knot
neoplasms. Phytophatol. 58: 848.
Smith, G.A. and P.J. Sullivan. 1964. Determination of the steam-
volatile phenols present in cigarette-smoke condensate. Analyst.
89: 312.
Spears, A.W. 1963. Quantitative determination of phenol in ciga-
rette smoke. Anal. Chem. 35: 320.
Stephan, C.E. 1980. Memorandum to J. Stara. U.S. EPA. July 3.
Tsuchiya, Y. and K. Sumi. 1975. Toxicity of decomposition prod-
ucts - phenolic resin. Build. Res. Note-^Natl. Res. Counc. Can.,
Div. Build. Res. 106.
C-41
-------
,a studies on health and environmental
V'S- EPA. 1978> T
; u water pollutants. Contract No. 68-01-4646.
impacts of se1
^i. Prot. Agency. Washington, D.C.
U.S. Er>-
U.S. EPA. 1980. Seafood consumption data analysis. Stanford
Research Institute International, Menlo Park, California. Final
rep., Task II. Contract No. 68-01-3887.
Uzhdovini, E.R., et al. 1974. Acute toxicity of lower phenols.
Gig. Tr. Prof. Zabol. 2: 58.
Versar, Inc. 1975. Identification of organic compounds in efflu-
ents from industrial sources. EPA-560/3-75-002. U.S. Environ.
Prot. Agency.
Weast, R.C. (ed.) 1976. Handbook of Chemistry and Physics. 57th
ed. Chemical Rubber Co. Press, Cleveland, Ohio.
Winters, K., et al. 1976. Water-soluble components of four fuel
oils: Chemical characterizations and effects in growth of micro-
algae. Marine Biol. 36: 269.
Woodward, G.J., et al. 1934. The fungicidal power of phenol deri-
vatives. I. Effect of introducing alkyl groups and halogens.
Jour. Lab. Clin. Med. 19: 1216.
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