Agency
500ECAOCING013
> 1987
>EPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR CHLORINATED PHENOLS
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
U.S. Environmental Protection Agen^pj. QO NOT CITE OR QUOTE
Region V, Library
230 South Dearborn Street^,
Chicago, Illinois 60604 *$ NOTICE
This document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It is being circulated for comments
on its technical accuracy and policy Implications.
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DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
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PREFACE
Health and Environmental Effects Documents (HEEOs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
1s Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
'Information obtained from Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for In this document
and the dates searched are Included 1n "Appendix: Literature Searched."
Literature search material 1s current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfOs)
for chronic and subchronlc exposures for both the inhalation and oral
exposures. The subchronlc or partial lifetime RfD, is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval, for example, one that does
not constitute a significant portion of the lifespan. This type of exposure
estimate has not been extensively used, or rigorously defined as previous
risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. A
carcinogenic potency factor, or q-f* (U.S. EPA, 1980a), Is provided
Instead. These potency estimates are derived for both oral and Inhalation
exposures where possible. In addition, unit risk estimates for air and
drinking water are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxiclty and carclno-
genldty are derived. The RQ 1s used to determine the quantity of a hazar-
dous substance for which notification is required in the event of a release
as specified under the CERCLA. These two RQs (chronic toxiclty and carclno-
genlcity) represent two of six scores developed (the remaining four reflect
1gn1tabil1ty, reactivity, aquatic toxiclty, and acute mammalian toxiclty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxldty and cancer-based RQs are defined in U.S.
EPA, 1983a and 1986a, respectively.
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EXECUTIVE SUMMARY
All the chlorophenols discussed with the exception of 2-chlorophenol are
crystalline solids at room temperature. The monochlorophenols are slightly
soluble in water, but as the number of chlorine substitution Increases, the
higher substituted phenols become less and less soluble in water. Thus, the
di-, tr1- and tetra-substltuted chlorophenols are sparingly soluble In
water. These compounds are, in general, soluble in ethanol, ethyl ether or
benzene (Verschueren, 1983; Weast, 1980). The presence of chlorophenols
Imparts unpleasant taste and odor In water. The taste threshold for
2,3-d1chlorophenol 1s 0.00004 mg/8. (Verschueren, 1983). Currently, five
companies 1n as many locations manufacture chlorophenols in the United
States. The current annual U.S. production volumes for the chlorophenols
are not available. The estimated annual world production volume of chloro-
phenols is 150 kllotons (Hutzinger et al., 1985). Chlorophenols are commer-
cially produced either by direct chloMnatlon of phenol or by the alkaline
hydrolysis of polychlorobenzenes (Kozak et al., 1979). Trace amounts of
highly toxic polychlorlnated dibenzo-p-dloxlns and dlbenzofurans have been
found as contaminants In some commercial chlorophenols (Hutzinger et al.,
1985). The monochlorophenols are primarily used 1n the synthesis of higher
chlorinated phenols. The higher chlorinated phenols are used as germicides
and as Intermediates In the manufacture of pesticides (Krljgsheld and
Vandergen, 1986; Kozak et al., 1979).
The two Important processes that may have a significant effect on the
fate of chlorophenols in water are photolysis and blodegradatlon. The photo-
lytic half-lives of 4-chloro-, 2,4-d1chloro- and 2,4,5-trichlorophenols at
the top surface of distilled water under midday sunlight irradiation were
iv
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estimated to be 2.6 days, 0.8 and 0.5 hours, respectively (Hwang et al.,
1986). From an outdoor pond experiment, Suglura et al. (1984) estimated the
photolytlc half-life of 2,4,6-trlchlorophenol at a depth of 10 cm to be 4
days. The photolysis of chlorophenols will be Important 1n clear shallow
bodies of water, but as the depth and turbidity of water Increase, the
Importance of photolysis will decrease because of light attenuation. The
blodegradatlon half-lives of chlorophenols In natural waters range from
>1-17 days. The half-life values Increase as the number of chlorine substi-
tutions Increases and the temperature of the water decreases. The half-lives
of the compounds also decrease In sediments of surface waters because of the
presence of a greater number of microorganisms (Lee and Ryan, 1979; Banerjee
et al., 1984; Hwang et al., 1986). Hydrolysis and evaporation are not
Hkely to be Important processes for chlorophenols In water (Krljgsheld and
Vandergen, 1986). Oxidation may be a significant process In water but
experimental data on such reactions could not be located In the available
literature. The removal of chlorophenols from water by sorptlon onto
suspended solids and sediments may be Important and will depend on the pH of
water and the organic content of the sorbents. Sorptlon will Increase at
lower pH and higher organic content of the sorbents, and will also be higher
for higher chlorinated than lower chlorinated phenols (Schellenberg et al.,
1984; Isaacson and Fink, 1984; Krljgsheld and Vandergen, 1986). Experi-
mental data Indicate that mono- and dlchlorophenols will not bloconcentrate
but that the higher chlorinated phenols may bloconcentrate significantly In
aquatic organisms (Velth et al., 1980; Kobayashl et al., 1979; Hattula et
al., 1981a; Vlrtanen and Hattula, 1982).
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In the atmosphere, the chlorophenols are likely to undergo significant
photolysis (Korte and Klein, 1982). Based on the rate constant of phenol
reaction with OH radicals 1n the atmosphere (Atkinson, 1985), it 1s con-
cluded that such reactions may be significant for the lower chlorinated
phenols. The detection of these compounds in rainwater and snow indicate
that they will be removed from the atmosphere by wet deposition (leuenberger
et a!., 1985b; PaasWirta et al., 1985a).
Based on data regarding chlorophenols In water, photolysis, hydrolysis
and evaporation will not be significant processes In soils. The two Impor-
tant processes in soil are sorption and blodegradation. While 2-chloro-,
4-chloro-, 2,4-dichloro- and 2,4,6-tMchlorophenols were found to be easily
biodegradable 1n a natural soil, 3-chloro-, 2,5-dichloro-, 2,4,5-trichloro-
and 2,3,4,6-tetrachlorophenols were persistent 1n soil (Alexander and Aleem,
1961). The sorption of chlorophenols in soils Increases with a decrease 1n
soil pH and Increase in chlorine substitution. Chlorophenols are especially
susceptible to leaching from sandy soils and soils with pH >10 (Schwarzen-
bach and Westall, 1985; Sutton and Barker, 1985; Boyd, 1982; Johnson et al.,
1985).
Although chlorophenols have been detected in municipal and industrial
effluents (X1e et al., 1986; Kringstad and Lindstrom, 1984; Ellis et al.,
1982; Callahan et al., 1979), in urban runoff water (Cole et al., 1984), and
in surface and groundwater near effluent discharge and waste disposal sites
(Valo et al., 1984; Bedient et al., 1984; Salkinoja-Salonen et al., 1984;
Watanabe et al., 1985; Xie et al., 1986), these compounds have been detected
Infrequently in drinking waters. According to Callahan et al. (1979), the
frequency of detection of chlorophenols In U.S. tap waters was 0%. Kopfler
et al. (1977), however, qualitatively detected 2,4-di-, 2,4,5-tri- and
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2,4,6-trlchlorophenol 1n U.S. drinking waters. 2-Chloro-, 4-chloro-,
2,4-d1chloro- and 2,4,6-trlchlorophenol at respective maximum concentrations
of 39, 34, 17 and 60 ng/2. have been detected 1n Canadian drinking waters
(Slthole et al., 1986). A few of these compounds have also been detected In
waters from England, the Netherlands and Germany (Crathorne et al., 1984;
KMjgsheld and Vandergen, 1986). The available data are Inadequate to esti-
mate the dally exposure of a U.S. Individual to these compounds by Ingestlon
of drinking water.
2,4,5-TMchlorophenol was detected 1n air samples In Love Canal, NY,
(Hauser and Bromberg, 1982) and 2-chloro-, 4-chloro-, 2,6-dlchloro-,
2,4,5-tMchloro- and 2,4,6-trlchlorophenol were Identified In the exhaust
gases from an experimental Industrial Incineration facility (James et al.,
1984). Quantitative air monitoring data on chlorophenols In the United
States or elsewhere, however, are not available. Occupational exposure to
chlorophenols 1n a Finnish sawmill was reported by Kaupplnen and Llndroos
(1985). The mean concentration of 2,4,6-trlchlorophenol 1n one work area
was 58 ng/m3. but the concentrations of chlorophenols In the air were
usually well below the Finnish occupational limit value of 500 yg/m3.
Chlorophenols have been detected In a few edible aquatic organisms
collected from contaminated surface waters In Finland. The muscles of
salmon, Salmo salar. and trout, Salmo trutta. collected from these waters
contained maximum average concentrations of 5.9, 2.5 and 29.3 yg/kg of
2,4,6-trlchloro-, 2,4,5-trlchloro- and 2,3,4,6-tetrachlorophenol, respec-
tively (Paaslvlrta et al., 19855; VuoMnen et al., 1985). Although the
available data are Insufficient to estimate the average exposures through
air, food or drinking water, the data Indicate that exposure of the general
public to the various chlorinated phenols Is low and sporadic.
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In general, the tox1c1ty of chlorinated phenols to aquatic biota
Increases with Increasing chlorlnatlon (U.S. EPA, 1979a, 1980b,c). This Is
probably due to higher uptake of the more chlorinated compounds (Kobayash!
et al., 1979). The toxldty of chlorophenols also Increases with decreasing
pH (Konemann and Musch, 1981; Saar1kosk1 and Vlluksela, 1981, 1982).
Structure-activity studies with aquatic organisms Indicated that the
presence of chloro substHuents 1n the ortho position decreased toxldty,
while substHuents In the para position Increased toxldty (Devlllers and
Chambon, 1986; R1bo and Kaiser, 1983).
There Is a large volume of data concerning toxldty of chlorophenols to
freshwater species. The most sensitive species for which there was a large
amount of data were salmonlds (rainbow trout, Salmo qalrdnerl and brown
trout, Salmo trutta) and bluegllls (Lepomls macrochlrus). The lowest
reported acutely toxic concentration for freshwater fishes was 0.085 mg/J.
2,3,4,6-tetrachlorophenol, a 96-hour LC5Q for rainbow trout (Mayer and
Ellersleck, 1986). The lowest reported acutely toxic concentration for
freshwater Invertebrates was 0.29 mg/8. 2,3,4,6-tetrachlorophenol, a
48-hour LC5Q for Daphnla magna (U.S. EPA, 1978a). Data for freshwater
plants, fungi and bacteria Indicated toxic concentrations similar to those
for freshwater fishes and Invertebrates. The lowest reported toxic concen-
tration for freshwater plants was 0.603 mg/i 2,3,4,6-tetrachlorophenol,
the 48-hour EC5Q for chlorosis 1n duckweed (Blackman et al., 1955). For
bacteria and fungi, the lowest reported toxic concentration was 0.176 mg/J.
2,3,4,5-tetrachlorophenol, a 30-mlnute EC for Inhibition of luminescence
of PhotobacteMum phosphoreum (R1bo and Kaiser, 1983).
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Relatively IHtle Information was available concerning marine species.
The lowest reported acutely toxic concentration for marine species was 1.1
mg/l 2,3,4,6-tetrachlorophenol, a 96-hour LC,._ for the cypMnodontld
fish, RWulus marmoratus (Koenig and McLean, 1980). The lowest reported
toxic concentration for marine plants was 0.44 mg/J. 2,3,5,6-
tetrachlorophenol, a 96-hour EC for Skeletonema costatum (U.S. EPA,
1978a).
Few studies concerning chronic toxlclty of chlorophenols to aquatic
organisms were available. The only study Involving a full Hfecycle
exposure was that of Koenig and McLean (1980) who found that fin erosion
occurred In all fish (Rlvulus marmoratus) exposed to 0.055 mg/J.
2,3,4,6-tetrachlorophenol, the lowest concentration tested.
Chlorinated phenols have been shown to Impair the flavor of freshwater
fish flesh at concentrations much lower than those that are toxic (Shumway
and Palensky, 1973; U.S. EPA, 1980b,c,d). The lowest reported concentration
for flavor Impairment was 0.0004 mg/Z 2,4-d1chlorophenol, a threshold for
largemouth bass (Mlcropterus salmoldes) (Shumway and Palensky,* 1973). As
discussed by U.S. EPA (1980b,c,d), threshold concentrations for tainting of
fish flesh may be more Important than toxic concentrations 1n establishing
water quality criteria for aquatic biota.
The chlorophenols seem to be readily absorbed from the gastrointestinal
tract and from parenteral sites of Injection (Delchmann and Kepllnger, 1981;
Carpenter et al., 1985). Rats dosed orally with l4C-2,4,6-tr1chlorophenol
absorbed at least 82.3% of the dose based on urinary excretion of radio-
activity (Korte et al., 1978). Roberts et al. (1977) found that .2- and
4-chlorophenol, 2,4-d1chlorophenol and 2,4,6-trlchlorophenol can penetrate
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human epidermis .In. vitro. Acutely toxic levels of 2,4,5- and 2,4,6-trl-
chlorophenol were not absorbed through the Intact skin of rabbits or guinea
pigs, while toxic levels of 2,3,4,6-tetrachlorophenol were absorbed through
the skin (Gosselln et al.. 1976).
Pharmacoklnetic studies of the chlorophenols In laboratory animals
Indicate that the compounds are distributed rapidly, but do not accumulate
In any tissue (Exon and Koller, 1982; Somanl and Khallque, 1982; Korte et
al., 1978; PekaM et al., 1986; Hattula et al., 1981b). Metabolism studies
Indicate that the chlorophenols are conjugated to glucuronldes and sulfates,
with glucuronldes predominating In rats (Karpow, 1893, Koster et al., 1981;
Somanl and Khallque, 1982; Bahlg et al., 1981). Other metabolites that have
been Identified are dlchloromethoxyphenols Identified 1n an Uj_ vitro study
of the metabolism of 2,4-d1chlorophenol (Somanl et al., 1984), tetrachloro-
hydroqulnone as a metabolite of 2,3,5,6-tetrachlorophenol and tMchloro-
hydroqulnone as a minor metabolite of 2,3,4,5- and 2,3,4,6-tetrachlorophenol
(Ahlborg and Larsson, 1978). In addition, Bahlg et al. (1981) found that
other trlchlorophenol Isomers are excreted when 2,4,6-trlchlorophenol was
administered orally to rats.
Studies using laboratory animals (Karpow, 1893; Korte et al., 1978;
Bahlg et al., 1981; Ahlborg and Larsson, 1978) Indicate that the
chlorophenols are excreted predominantly In the urine as glucuronlc and
sulfurlc acid conjugates, and as the unchanged compounds. Kalman and
Horstman (1983) found that the half-time of elimination of
2,3,4,6-tetrachlorophenols In occupatlonally exposed humans was ~63±34 hours.
In a subchronlc Inhalation study of 4-chlorophenol (Gurova, 1964), rats
exposed to 2 mg/m3, 6 hours/day for 4 months showed neuromuscular excit-
ability, a reduction of endurance. Increased myoneural excitability, slight
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congestion of organs and minor flbrotlc changes In alveolar septa. Gurova
(1964) also reported symptoms of nervous exhaustion, Insomnia, Irritability,
frequent mood changes and rapid fatlgabUHy In workers exposed to 4-chloro-
phenol 1n an aniline dye plant. The lack of detail 1n these studies
precludes adequate assessment of their reliability.
Kleu and Goeltz (1971) reported symptoms of chloracne, decreased sexual
activity, easy fatlgablllty, Irritability, muscular weakness, loss of appe-
tite and memory, discouragement, alcohol Intolerance and loss of Interest In
workers occupatlonally exposed to a tMchlorophenol formulation for up to 15
years. A causal relationship was not established. Alexandersson and
Hedenstlerna (1982) found pulmonary effects 1n workers exposed to low levels
of trlchlorophenols 1n gas masks for up to 10 years.
Exon and Keller (1985) found 1mmunolog1cal effects 1n rats exposed sub-
chronically to 2,4-d1chlorophenol at 30 and 300 ppm In their drinking water.
Similar effects were not noted 1n rats exposed to up to 500 ppm 2-chloro-
phenol, or up to 300 ppm 2,4,6-trlchlorophenol. Kobayashl et al. (1972)
reported minor, hlstologlcal changes 1n the livers of mice fed 2,4-d1chloro-
phenol at 230 mg/kg/day for 6 months. No effects were noted at 100
mg/kg/day.
A subchronlc drinking water study of 2,4-d1chlorophenol In mice found no
consistent effects that could be related to treatment at up to 2 ppm
(Borzelleca et al., 1985a). The study was confounded by the addition of
Emulphor to the dosing solution.
McColllster et al. (1961) studied the toxlclty of 2,4,5-tMchlorophenol.
In a 28-day gavage study, microscopic changes were noted 1n the liver and
kidneys of rabbits dosed with 0.1 and 0.5 mg/kg but not 0.01 mg/kg 20 times
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over the study period. No changes were noted 1n rats dosed with 2,4,5-tr1-
chlorophenol at up to 1.0 g/kg 18 times over 24 days. In a 98-day study,
pathologic changes 1n the livers and kidney were noted In rats provided with
diets containing 2,4,5-trlchlorophenol at 0.03 and 1.0% but not at <0.01%.
In a 70-day dietary study, Vlzethum and Goerz (1979) reported that 0.05%
2,4,5-trlchlorophenol was not porphyrogenlc In rats. The NCI (1979) sub-
chronic study noted an Increase 1n splenic hematopolesis and mldzonal
vacuolatlon of hepatocytes In rats fed 2,4,5-trlchlorophenol In the diet at
46,000 ppm for 7 weeks. Survival of rats fed >21,500 ppm but not <14,700
ppm was also affected. In mice, survival was affected at 31,500 ppm but not
at <21,500 ppm (NCI, 1979); no hlstopathologlcal data were reported. A
dose-dependent decrease 1n body weight was observed 1n both rats and mice In
the NCI (1979) study.
Kawano et al. (1979) observed changes 1n growth, organ weights, several
biochemical parameters and liver drug metabolizing enzymes In rats fed diets
containing 2,3,5-tMchlorophenol or 2,3,4,5-, 2,3,5,6- or 2,3,4,6-tetra-
chlorophenol at 0.2% for 3 weeks. Dose-related hlstopathologlc changes In
the Hver were noted 1n rats treated by gavage with 2,3,4,5-tetrachloro-
phenol for 55 days at >50 mg/kg/day but not at 10 mg/kg/day (Hattula et al.,
1981b).
In a chronic study, numbers of RBC and hemoglobin levels were Increased
1n rats provided with drinking water containing 500 ppm 2-chlorophenol or
300 ppm 2,4-dlchlorophenol, but not at 10-fold lower concentrations (Exon
and Koller, 1985). The NCI (1979) found a dose-related Increase 1n the
Incidences of bone marrow hyperplasla and leukocytosis in rats at 5000 and
10,000 ppm. In mice, dose-related hyperplasia of the liver was noted 1n
males at 5000 and 10,000 ppm (NCI, 1979).
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In studies of the Induction of enzymes by the chlorinated phenols,
Carlson (1978) found that 2,4,5-trlchlorophenol reduced mlcrosomal NADPH-
cytochrome c reductase activity and cytochrome P-450 content. Denomme et
al. (1983) reported that 4-d1methylam1noant1pyrlne N-demethylase was Induced
by 3,4,5-trlchlorophenol. The other tr1- and tetrachlorophenols had no
effects on enzyme Induction. The mutagenldty of 2-am1noanthracene and
benzo[a]pyrene were enhanced In an Ames assay by S-9 from rats treated with
2,3,4,5-tetrachlorophenol (Sussmuth et al., 1980).
MHsuda et al. (1963) observed that chlorophenols Inhibit oxldatlve
phosphorylatlon jm vitro, with the Inhibiting activity Increasing with
Increasing chlorlnatlon.
The acute toxldty of the chlorinated phenols has been studied by a
number of Investigators (Delchmann, 1944; Bubnov et al., 1969; Borzelleca et
al., 1985a,b; Farquharson et al., 1958; Chrlstensen and Luglnbyhl, 1975;
Delchmann and Mergard, 1948; Angel and Roberts, 1972; Gurova, 1964;
Schrotter et al., 1977; Kobayashl et al., 1972; Vernot et al., 1977;
HcColllster et al., 1961; Ahlborg and Larrsson, 1978; Hattula et al.,
1981b); In general, the toxldty Increases as the chlorlnatlon Increases.
Ep1dem1olog1cal studies that are confounded by some small study popula-
tions and multiple exposures Indicate that a mixture of compounds Including
chlorophenol are associated with soft tissue sarcomas and malignant
lymphomas (Lynge, 1985; Cook, 1981; Honchar and HalpeMn, 1981; Pearce et
al., 1986). The Influence of the chlorophenols alone, however, cannot be
determined.
Increased tumor Incidences were not observed In rats exposed to up to
500 ppm 2-chlorophenol or up to 300 ppm 2,4-d1chlorophenol 1n their drinking
water for 2 years (Exon and Keller, 1985). Innes et al. (1969) found Incon-
clusive results In a carclnogenldty study of 2,4,6-tMchlorophenol In mice.
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In the NCI (1979) study of 2,4,6-trlchlorophenol, an Increased Incidence of
leukemia was observed In male rats, while an Increase 1n the Incidence of
Hver carcinoma and adenoma was observed 1n male and female mice.
Exon and Keller (1985) found that 2-chlorophenol Increased tumor Inci-
dence and decreased tumor latency of transplacental tumors In rats Initiated
by END. This effect was not observed with 2,4-d1chlorophenol although the
rats were exposed to a lower level of ENU.
In a study by Boutwell and Bosch (1959), 2-, 3-chlorophenol, 2,4-d1-
chlorophenol and 2,4,5-tMchlorophenol acted as promoters of skin tumors In
mice treated with a single dose of DMBA. 2,4,6-TMchlorophenol was negative
1n the skin tumor promoting study. 2,4,6-Trlchlorophenol was also negative
1n a lung adenoma bloassay 1n which strain A/J mice were dosed by gavage or
Intraperltoneal Injection (Stoner et a!., 1986). Tumor Incidences were not
Increased 1n mice observed for- 18 months following a single subcutaneous
Injection of 2,4,5-, 2,4,6-trlchlorophenol or 2,3,4,6-tetrachlorophenol
(BRL, 1968a).
2-, 3-, 4-Chlorophenol, 2,3-, 2,4-, 2,5-, * 2,6-, 3,4-, 3,5-d1chloro-
phenol, 2,3,5-, 2,4,5-, 2,4,6-trlchlorophenol and 2,3,4,6-tetrachlorophenol
have tested negative In at least one assay for reverse mutation In £.
tvphlmuMum (Haworth et a!., 1983; Probst et al., 1981; Simmon et a!., 1977;
Rasanen and Hattula, 1977). Haworth et al. (1983) found equivocal results
for 2,4- and 3,5-d1chlorophenol.
In Chinese hamster V79 cells, 2,4-, 2,6-d1chlorophenol, 2,4,6-trlchloro-
phenol and 2,3,4,6-tetrachlorophenol did not cause an Increase 1n mutation
(Jansson and Jansson, 1986; Hattula and Knuutlnen,. 1985). In contrast,
weakly positive results were noted 1n Chinese hamster V79 cells with
2,4,6-trlchlorophenol and . 2,3,4,6-tetrachlorophenol In the absence of
x1v
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but not In the presence of S-9 (Hattula and Knuutlnen, 1985). 2,4-D1chloro-
phenol did not cause an Increase 1n unscheduled ONA synthesis In primary rat
hepatocytes (Probst et a!., 1981).
An Increase In chromatld deletions was noted 1n rats dosed with
2-chlorophenol (Chung, 1978). 2,4,6-TMchlorophenol was weakly positive In
a spot test using mice (Fahrlg et a!., 1978).
Teratogenlc studies of the chlorinated phenols Indicate that the com-
pounds are not potent teratogens although they are fetotoxlc. Fetotoxldty
as evidenced by Increased embryonic death was found for 2,4-d1chlorophenol
at oral doses of 750 mg/kg/day (Rodwell et al., 1984) and 2,4,5-tMchloro-
phenol at >9 mg/kg/day (Neubert and Dlllmann, 1972; Hood et al., 1979;
Chernoff and Kavlock, 1982). Schwetz et al. (1974) reported an Increase of
subcutaneous edema 1n rats treated through gestation with 2,3,4,6-tetra-
chlorophenol at 10 mg/kg/day. This effect was not observed at 30 mg/kg/day,
although at the higher dose an Increase 1n delayed ossification of the skull
bones was observed. The only study 1n which an Increase'd Incidence of
anomalies was observed was In a study by BRL (1968b) 1n which an Increase In
anomalies 1n AKR mice given subcutaneous Injections of 2,4-d1chlorophenol at
74 mg/kg/day during gestation was noted. This effect was not observed In
C57B16 mice or 1n either strain of mice when they were treated with 85
mg/kg/day 2,4,5-trlchlorophenol.
Research Triangle Institute (1987) In a teratology study observed
maternal toxldty In pregnant CD rats exposed by gavage to 200 mg/kg/day
tetrachlorophenol (TCP). Embryo/fetal growth and prenatal viability were
not adversely affected by TCP exposure, nor was there any definitive
evidence of an effect of TCP upon fetal morphological development.
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Reproductive studies of 2-chlorophenol, 2,4-d1chlorophenol and
2,4,6-tMchlorophenol also resulted In reduced Utter sizes of rats treated
from 3 weeks of age with >300 ppm 1n drinking water through mating and
lactation (Exon and Koller, 1982). Blackburn et al. (1986) reported no
significant effects on reproduction In rats treated by gavage with up to
1000 mg/kg 2,4,6-trlchlorophenol 5 days/week. In an jun vitro study, Seyler
et al. (1984) found that 2,5-, 3,4- and 3,5-d1chlorophenol significantly
depressed sperm penetration of ova from mice.
Data were Insufficient to derive Inhalation RfOs for monochlorophenols.
An RfO of 0.005 mg/kg/day or 0.4 mg/day for a 70 kg human was derived for
both subchronlc and chronic oral exposure to 2-chlorophenol, based on the
NOAEL for reproductive effects In rats exposed to 50 ppm (5 mg/kg/day) In
their drinking water (Exon and Koller, 1982). An uncertainty factor of 1000
(10 for Interspecles extrapolation, 10 to protect sensitive Individuals and
10 for using a subchronlc study) was used. At the LOAEL of 500 ppm (50
mg/kg/day), there were decreased IHter size and an Increased percentage of
'stillborn pups. An RQ of 1000 was derived from the LOAEL. Data were
Insufficient to derive values for 3- and 4-chlorophenol. Since data
regarding the carclnogenlclty of the monochlorophenols were limited or not
available, these chemicals were placed In EPA Group D "not classified".
Data were Insufficient to derive Inhalation RfDs for the dlchlorophenols.
An RfD of 0.003 mg/kg/day or 0.2 mg/day for a 70 kg human for both subchronlc
and chronic oral exposure to 2,4-d1chlorophenol was derived, based on a NOAEL
for Immunologlcal effects of 30 ppm (3 mg/kg/day) 1n the drinking water of
rats .(Exon and Koller, 1985). An uncertainty factor of 100 (10 for
Interspecles extrapolation and 10 to protect the most sensitive Individuals)
was used. At the LOAEL of 300 ppm (30 mg/kg/day), rats had Increased serum
antibody levels and a decrease In delayed type hypersensHWIty response.
xv1
-------
An RQ of 1000 was derived based on the LOAEL. Data were Insufficient to
derive values for the other dlchlorophenols. Since data regarding the
carclnogenlclty of dlchlorophenols were Inadequate or not available, these
chemicals were placed In EPA Group 0, "not classified".
Data were Insufficient to derive Inhalation RfDs for the trlchloro-
phenols. RfDs of 1 mg/kg/day or 70 mg/day and 0.1 mg/kg/day or 7 mg/day
were derived for subchronlc and chronic oral exposure to 2,4,5-tMchloro-
phenol based on a NOAEl of 0.1% In the diet (100 mg/kg/day) for pathological
changes In the liver and kidney of rats In the subchronlc study by
McColllster et al. (1961). Uncertainty factors of 100 (10 for Interspedes
extrapolation and 10 for the protection of the most sensitive Individuals)
for the subchronlc RfD and 1000 (an additional factor of 10 for the use of a
subchronlc NOAEL). for the chronic RfD were used. At the LOAEL of 0.3% (300
mg/kg/day), rats had mild hlstopathologlcal lesions 1n the liver and kidney.
An RQ of 1000 was derived from the LOAEL. Data regarding the
cardnogenlc'Hy of 2,4,5-trlcnlorophenol were not available; therefore, this
chemical 1s placed In EPA Group D, "not classified".
The data for the carclnogenlclty of 2,4,6-trlchlorophenol were considered
sufficient to classify It as a EPA Group 82 chemical, that 1s, a probable
human carcinogen. A q,* of 1.94x10~a (mg/kg/day)'1 for oral exposure
was derived for 2,4,6-trlchlorophenol using the data for hepatocellular
carcinoma/adenoma In male mice In the NCI (1979) bloassay. The concentra-
tions In drinking water associated with an Increased lifetime risk of cancer
at levels of 10~5, 10~* and 10~7 are 1.8xlO~2, 1.8xlO~3 and
1.8x10"* mg/i, respectively. An F factor of 1.4xlO"2 (mg/kg/day)'1
was derived for 2,4,6-trlchlorophenol based on the bloassay data for liver
tumors In mice (NCI, 1979); therefore, this chemical was placed 1n Potency
xv11
-------
Group 3. Chemicals 1n EPA Group B2 and In Potency Group 3 are ranked LOW in
the Hazard Ranking Scheme. A LOW ranking Indicates an RQ of 100 based on
cardnogenldty.
Data were Insufficient to derive RfOs, q *s or RQs for the other
trlchlorophenols, and these chemicals are placed in EPA Group D, "not
classified".
Data were insufficient to derive Inhalation RfDs for the tetrachloro-
phenols. RfDs of 0.1 mg/kg/day or 7 mg/day and 0.01 mg/kg/day or 0.7 mg/day
for subchronic and chronic oral exposure to 2,3,4,6-tetrachlorophenol were
derived based on NOAELs of 10 mg/kg/day In the subchronic study by Hattula
et al. (1981b) and 1n the teratology study by Schwetz et al. (1974). An
uncertainty factor of 100 (10 for Interspedes extrapolation and 10 for the
protection of sensitive Individuals) for the subchronic RfD and of 1000 (an
additional factor of 10 for the use of a subchronic NOAEL) for the chronic
RfD were used. At the LOAEL of 30 mg/kg/day, there was delayed ossification
of the skull bones In the offspring of rats treated during gestation
(Schwetz et al., 1974). An RQ of 1000 was derived based on hlsto-
pathologlcal liver lesions in rats treated at 50 mg/kg/day (Hattula et al.,
1981b). Data were insufficient to derive values for other
tetrachlorophenols. Since data regarding the carcinogenlclty of the tetra-
phenols were not available, these chemicals are placed 1n EPA Group D, "not
classified".
XV111
-------
TABLE OF CONTENTS
1. INTRODUCTION 1-1
1.1. STRUCTURE AND CAS NUMBER 1-1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1-1
1.3. PRODUCTION DATA 1-5
1.4. USE DATA 1-6
1.5. SUMMARY 1-6
2. ENVIRONMENTAL FATE AND TRANSPORT 2-1
2.1. WATER 2-1
2.1.1. Photodegradatlon 2-1
2.1.2. Hydrolysis 2-2
2.1.3. Oxidation 2-3
2.1.4. Blodegradatlon 2-3
2.1.5. Evaporation 2-5
2.1.6. Sorptlon 2-6
2.1.7. B1oconcentrat1on 2-6
2.2. AIR. . .' 2-9
2.3. SOIL 2-10
2.4. SUMMARY 2-11
3. EXPOSURE 3-1
3.1. WATER 3-1
3.2. AIR 3-2
3.3. FOOD 3-3
3.4. SUMMARY 3-4
4. AQUATIC TOXICITY 4-1
4.1. ACUTE TOXICITY 4-1
4.2. CHRONIC EFFECTS 4-7
4.3. PLANT EFFECTS 4-13
4.4. OTHER RELEVANT INFORMATION 4-16
4.5. SUMMARY 4-21
5. PHARMACOKINETCS 5-1
5.1. ABSORPTION 5-1
5.2. DISTRIBUTION 5-3
5.3. METABOLISM 5-4
5.4. EXCRETION 5-5
5.5. SUMMARY 5-7
x1x
-------
TABLE OF CONTENTS (cont.)
Page
6. EFFECTS 6-1
6.1. SYSTEMIC TOXICITY 6-1
6.1.1. Inhalation Exposures 6-1
6.1.2. Oral Exposures 6-3
6.1.3. Other Relevant Information 6-10
6.2. CARCINOGENICITY 6-11
6.2.1. Inhalation 6-11
6.2.2. Oral 6-15
6.2.3. Other Relevant Information 6-17
6.3. MUTAGENICITY 6-22
6.4. TERATOGENICITY 6-26
6.5. OTHER REPRODUCTIVE EFFECTS 6-31
6.6. SUMMARY 6-35
7. EXISTING GUIDELINES AND STANDARDS 7-1
7.1. HUMAN 7-1
7.2. AQUATIC 7-1
8. RISK ASSESSMENT 8-1
8.1. CARCINOGENICITY '. 8-1
8.1.1. Inhalation 8-1
8.1.2. Oral 8-1
8.1.3. Other Relevant Information 8-2
8.1.4. Weight of Evidence 8-3
8.1.5. Quantitative Risk Estimates 8-4
8.2. SYSTEMIC TOXICITY 8-6
8.2.1. Inhalation Exposure 8-6
8.2.2. Oral Exposure 8-7
9. REPORTABLE QUANTITIES 9-1
9.1. BASED ON SYSTEMIC TOXICITY 9-1
9.2. BASED ON CARCINOGENICITY 9-19
10. REFERENCES 10-1
APPENDIX A: LITERATURE SEARCHED A-l
APPENDIX B: CANCER DATA SHEETS FOR DERIVATION OF q-j*s B-l
APPENDIX C: SUMMARY TABLES FOR CHLORINATED PHENOLS . C-l
xx
-------
LIST OF TABLES
No. TUIe Page
1-1 Symonyms, Empirical Formulas, Molecular Weights, Structure
and CAS Numbers of the Selected Chlorophenols 1-2
1-2 Selected Physical Properties of Chlorophenols 1-4
2-1 BCFs of Chlorophenols In Aquatic Organisms 2-7
4-1 Acute Toxldty of Chlorinated Phenols to Freshwater
Fishes 4-2
4-2 Acute Toxldty of Chlorinated Phenols to Freshwater
Invertebrates 4-8
4-3 Acute Toxldty of Chlorinated Phenols to Marine Fishes. . . . 4-11
4-4 Acute Toxldty of Chlorinated Phenols to Marine
Invertebrates 4-12
4-5 Toxldty of Chlorinated Phenols to Freshwater Plants 4-14
4-6 Toxldty of Chlorinated Phenols to Aquatic Bacteria
and Fungi 4-17
4-7 Toxldty of Chlorinated Phenols to Marine Plants 4-19
4-3 Concentrations of Chlorinated Phenols that Impair
the Flavor of Fish , 4-20
5-1 Permeability Coefficients and Threshold Concentrations
for Damage 1n Human Epidermis for Chlorophenols 5-2
6-1 Acute Toxldty Data for Chlorophenols 6-12
6-2 Incidence of Neoplasms In F344 Rats and B6C3F1 Mice
Treated with 2,4,6-TMchlorophenol (96-97% pure) In
the Diet for 105-107 Weeks 6-18
6-3 Mutagenldty Testing of Chlorophenols 6-23
6-4 Teratogenldty Studies of 2,4-D1chlorophenol,
2,4,5-TMchlorophenol and 2,3,4,6-Tetrachlorophenol 6-32
7-1 Guidelines and Standards for Chlorophenols 7-2
9-1 Oral Toxldty Summary for Chlorophenols 9-2
9-2 Oral Composite Scores for 2-Chlorophenol Using the Rat. . . . 9-4
9-3 2-Chlorophenol: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 9-5
xx1
-------
LIST OF TABLES (cont.)
No. Title Page
9-4 3-Chlorophenol and 4-Chlorophenol: Minimum Effective
Dose (MED) and Reportable Quantity (RQ) 9-6
9-5 Oral Composite Scores for 2,4-01chlorophenol 9-7
9-6 2,4-D1chlorophenol: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 9-9
9-7 2,3-, 2,5-, 2,6-, 3,4- and 3,5-D1chlorophenol: Minimum
Effective Dose (MED) and Reportable Quantity (RQ) 9-10
9-8 Oral Composite Scores for 2,4,5-Trlchlorophenol 9-11
9-9 2,4,5-Trlchlorophenol: Minimum Effective Dose (MED)- and
Reportable Quantity (RQ) 9-13
9-10 2,3,4-, 2,3,5-, 2,3,6-, 3,4,5-Trlchlorophenol: Minimum
Effective Dose (MED) and Reportable Quantity (RQ) 9-14
9-11 Oral Composite Scores for 2,3,4,6-Tetrachlorophenol
Using the Rat 9-15
9-12 2,3,4,6-Tetrachlorophenol: Minimum Effective Dose (MED)
and Reportable Quantity (RQ) 9-17
9-13 2,3,4,5- and 2,3,5,6-Tetrachlorophenol: Minimum Effective
Dose (MED) and Reportable Quantity (RQ) 9-18
9-14 Derivation of Potency Factor (F) for 2,4,6-Trlchlorophenol. . 9-20
xxll
-------
LIST OF ABBREVIATIONS
AWQC Ambient water quality criterion
BCF B1oconcentrat1on factor
bw Body weight
CAS Chemical Abstract Service
CS Composite score
CV Closing volume
DMBA Dimethyl benzanthracene
DMSO Dimethyl sulfoxlde
DNA DeoxyMbonuclelc add
DWEL Drinking water effect level
ECso Concentration effective to 50% of recipients
EMU EthylnHrosurea
ETC Estimated highest concentration that will not
Impair the flavor of exposed fish
FEV-) Forced expired volume In 1 second
FEVC Forced expired vital capacity
159 Inhibition concentration to 50% of recipients
Koc Soil sorptlon coefficient standardized with
respect to soil organic matter
Kow Octanol/water partition coefficient
LC5Q Concentration lethal to 50% of recipients
HATC Maximum acceptable threshold concentration
MED Minimum effective dose
MEF Maximum expiratory flow rate
NADPH N1cot1nam1de adenlne dlnucleotlde phosphate
NOAEL No-observed-adverse-effect level
NOEC No-observed-effect concentration
XX111
-------
LIST OF ABBREVIATIONS (cont.)
NOEL No-observed-effect level
ppm Parts per million
RBC Red blood cell
RfD Reference dose
RfD$ Subchronlc reference dose
RPAR Rebuttable Presumption Against Registration
RQ Reportable quantity
RV(j Dose-rating value
RVe Effect-rating value
SGPT Serum glutamlc pyruvlc transamlnase
TCDD Tetrachlorod1benzo-p-d1ox1n
TWA Time-weighted average
UV Ultraviolet
WBC White blood cell
w/v Weight per volume
xxlv
-------
1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
The 18 chlorophenols selected for examination In this document are 2-,
3- and 4-chlorophenol; 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5-d1chlorophenol;
2,3,4-, 2,3,5-, 2,3,6-, 2,4,5-, 2,4,6- and 3,4,5-tMchlorophenol; and
2,3,4,5-, 2,3,4,6- and 2,3,5,6-tetrachlorophenol. The synonyms, structures,
empirical formulas, molecular weights and CAS Registry numbers for these
chlorophenols are given 1n Table 1-1.
1.2. PHYSICAL AND CHEMICAL PROPERTIES
At room temperature, all the chlorophenols are crystalline solids except
2-chlorophenol, which Is a colorless liquid. The monochlorophenols are
slightly soluble In water, but as the number of chlorine substitution
Increases the higher substituted phenols become less and less soluble 1n
water. Thus, the dl-, tr1- and tetra-substltuted chlorophenols are
sparingly soluble In water. These compounds are, In general, either soluble
In ethanol, ethyl ether or benzene, although several of these compounds are
soluble 1n all three solvents (Weast, 1980; Verschueren, 1983). Selected
physical properties of the chlorophenols are given 1n Table 1-2. Consider-
able variability exists for these parameters and the best possible values
are given In Table 1-2. The water solubility of the various chlorophenols
1s Influenced greatly by the pH of the water, and the addition of chloro-
phenols to distilled water affects the pH. Because the chlorinated phenols
are weak acids they are expected to form salts with strong bases. The water
solubilities of the sodium and potassium salts that are formed are higher
than the parent compounds. The formation of 1on1c salt becomes Important at
pH of water above the pK of the Individual chlorophenols (Schellenberg et
a
a!., 1984).
0015d 1-1 06/17/87
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The presence of chlorophenols Imparts unpleasant taste and odor In
water. The odor thresholds for 2-chloro-, 4-chloro-, 2,4-d1chloro- and
2,6-d1chlorophenol are 0.0002, 0.0005, 0.00065 and 0.0075 mg/8., respec-
tively. The taste thresholds for these compounds are even lower and their
respective values are 0.0001, 0.0001, 0.008 and 0.0002 rng/l,
respectively. 2,3-D1chlorophenol has the lowest reported taste threshold of
any chlorophenol, 0.00004 mg/8. (Verschueren, 1983).
1.3. PRODUCTION DATA
According to the TSCA production data base (U.S. EPA, 1977), one U.S.
company at one location either produced or had the capability to produce
2,3-d1chloro-, 2,5-d1chloro-, 2,6-d1chloro-, 2,3,6-trlchloro- and 2,3,4,6-
tetrachlorophenol 1n 1977. 4-Chloro-, 2,4,5-trlchloro- and 2,4,6-tMchloro-
phenol were produced by three companies 1n the United States In 1977,
although one company reported no production of 4-chlorophenol 1n 1977 (U.S.
EPA, 1977). 3-Chlorophenol was produced by two or possibly three companies
In 1977 In the United States at as many locations. 2,4-Dlchlorophenol was
produced In the United States by five companies at five locations In 1977
(U.S. EPA. 1977).
As of January 1986 1n the United States, Aldrlch Chemical Co.,
Milwaukee, HI, manufactured 3-chlorophenol, 2,6-, 3,4- and 3,5-dlchloro-
phenol; Specialty Organlcs, Inc., Irwlndale, CA, manufactured 3-chloro-
phenol, 2,3-, 2,6- and 3,5-d1chlorophenol; Dow Chemical, Midland, MI,
manufactured 2,4-d1chlorophenol; and Farley Northwest Industries, Inc.,
Beaumont, TX, produced 2,6-d1chlorophenol (SRI, 1986).
In addition to the companies listed above, USITC (1986) also lists
Vertac Chemical Corp., Jacksonville, AR, as a current manufacturer of
0015d 1-5 06/17/87
-------
2,4-d1ch1orophenol. Chlorophenols not Included among those listed are
presumably not manufactured 1n the United States In significant quantities.
The current U.S. production volumes for the Chlorophenols were not
available. The estimated annual production volumes for 2-chloro-,
4-chloro- and 2,4-d1chlorophenol In Europe were 5, 5 and 20 kHotons,
respectively (KMJgsheld and Vandergen, 1986). The estimated annual world
production of Chlorophenols was 150 kllotons (Hutzlnger et a!., 1985).
Chlorophenols are commercially produced either by direct chloMnatlon of
phenol or by the alkaline hydrolysis of polychlorobenzenes in methanol,
ethylene glycol or a mixture of similar solvents. Higher chlorinated
phenols are also manufactured by chloMnatlon of lower Chlorophenols (Kozak
et a!., 1979). Trace amounts of highly toxic polychlorlnated
d1benzo-p-d1ox1ns and dlbenzofurans have been found as contaminants In
commercial Chlorophenols (Hutzlnger et al., 1985).
1.4. USE DATA
The monochlorophenols are used as Intermediates In the synthesis of
higher Chlorophenols and phenolic resins; In the synthesis of dyes and
drugs; and as selective solvents 1n refining of mineral oils. 2,4-D1chloro-
and 2,4,5-trlchlorophenol are principally used as Intermediates 1n the manu-
facture of pesticides and herbicides. 2,4.5-Trlchloro-, 2,4,6-tMchloro-
and 2,3,4,6-tetrachlorophenol and their salts are used as germicides for the
preservation of wood, glue, latex, leather and textiles (KMjgsheld and
Vandergen, 1986; Kozak et al., 1979).
1.5. SUMMARY
All the Chlorophenols discussed with the exception of 2-chlorophenol are
crystalline solids at room temperature. The monochlorophenols are slightly
soluble 1n water, but as the number of chlorine substitution Increases, the
higher substituted phenols become less and less soluble In water. Thus,
0015d 1-6 06/17/87
-------
the d1-, tr1- and tetra-substltuted chlorophenols are sparingly soluble In
water. These compounds are, 1n general, soluble In ethanol, ethyl ether or
benzene (Verschueren, 1983; Weast, 1980). The presence of chlorophenols
Imparts unpleasant taste and odor In water. The taste threshold for
2,3-d1chlorophenol Is 0.00004 mg/i (Verschueren, 1983). Currently, five
companies 1n as many locations manufacture chlorophenols In the United
States. The current annual U.S. production- volumes for the chlorophenols
are not available. The estimated annual world production volume of chloro-
phenols 1s 150 kllotons (Hutzlnger et al., 1985). Chlorophenols are commer-
cially produced either by direct chlorlnatlon of phenol or by the alkaline
hydrolysis of polychlorobenzenes (Kozak et al., 1979). Trace amounts of
highly toxic polychloMnated d1benzo-p-d1ox1ns and dlbenzofurans have been
found as contaminants 1n some commercial chlorophenols (Hutzlnger et al.,
1985). The monochlorophenols are primarily used In the synthesis of higher
chlorinated phenols. The higher chlorinated phenols are used as germicides
and as Intermediates 1n the manufacture of pesticides (KMjgsheld and
Vandergen, 1986; Kozak et al., 1979).
0015d 1-7 05/07/87
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. WATER
An Important factor that determines the environmental fate of
chlorophenols 1n water and soil 1s the degree of 1on1zat1on as dictated by
the pH of the medium. At an environmental pH range of 6-9, the
monochlorophenols with pka values of 8.5-9.2 will exist primarily 1n the
undlssodated form. Therefore, acidification of surface by add
precipitation 1s expected to have little effect on their fate; however,
higher chlorinated phenols with pka values as low as 5.4 may transform from
dissociated to undlssodated forms as the pH of the surface water 1s
decreased because of add precipitation. This may alter the environmental
fate and transport of the chlorophenols.
2.1.1. Photodegradatlon. The light absorption capability of the chloro-
phenols will depend on the state of 1on1zat1on of the specific compound In
water (see Table 1-2). The dissociated forms will absorb light at higher
wavelengths. Therefore, the absorption of light by the higher chlorinated
phenols Is expected to Increase as the pH of water 1s Increased (Aly and
Faust, 1964; . Boule et al., 1984a). Photolysis of the molecular form of
2-chlorophenol produces pyrocatechol as the primary product. The anlonlc
form, on the other hand, produces cyclopentadlenolc add, which dlmerlzes
during Isolation. Photolysis of 3-chlorophenol both 1n the molecular and
anlonlc form leads to the formation of resordnol. The main Irradiation
products of 4-chlorophenol 1n both the 1on1c and molecular state are hydro-
qulnone, benzoqulnone, trlhydroxybenzenes and d1hydroxyb1phenyls (KMjgsheld
and Vandergen, 1986; Tlssot et al., 1985). The photolysis of 3,5-, 3,4- and
2,4-d1chlorophenols was reported by Boule et al. (1984b). With 3,5- and
3,4-d1chlorophenols, hydroxylatlon occurred at the meta position. In the
case of 2,4-d1chlorophenol, chlorocyclopentadlene carboxyllc was also
0016d 2-1 06/17/87
-------
formed. The photolysis occurred preferentially at the meta position and was
easier with the anlonlc than with the molecular form. The photolysis of
2,4,6-tMchlorophenol formed polyhydroxylated products and qulnones (Tlssot
et al., 1985). Irradiation of 2,3,4,5-, 2,3,4,6- and 2,3,5,6-tetrachloro-
phenol with light of wavelength >287 nm produced the dechloMnated products
and several hydroxylated and blphenyl-substltuted products (Choudhry et al.,
1985). In acetonltrlie/water solution, >69% of the parent compound dis-
appeared 1n 24 hours (Choudhry et al., 1985). The photolytlc fate of
chlorophenols 1n natural waters under field conditions Is uncertain. From
the experimental measurement of quantum yield 1n aqueous solution, Lemalre
et al. (1985) estimated that the photolytlc half-life of 2,4-d1chlorophenol
1n the top few mm of natural water 1n midsummer, midday sunlight at 40-50
degrees North Is ~3 minutes. The photolytlc half-lives for 4-chloro-,
2,4-d1chloro- and 2,4,5-trlchlorophenols at the top surface of distilled
water under midday sunlight Irradiation were estimated to be 2.6 days, 0.8
and 0.5 hours, respectively. The half-lives were longer during winter artd
shorter 1n estuary water. The more rapid photodegradatlon In estuarlne
water may have been due to photosensltlzatlon by humlc substances present 1n
the water (Hwang et al., 1986). From an outdoor pond experiment, Suglura et
al. (1984) estimated the photolytlc half-life for 2,4,6-trlchlorophenol at a
depth of 10 cm to be 4 days. It can be concluded from the above discussion
that photolysis of chlorophenols will be Important 1n clear shallow bodies
of water. As the depth and turbidity of water Increase, however, the
Importance of photolysis will decrease because of light attenuation.
2.1.2. Hydrolysis. Although no experimental data were available, these
compounds are not likely to hydrolyze significantly because aryl chlorides
0016d 2-2 06/17/87
-------
have a low tendency for dech 1 or 1 nation and the presence of the hydroxyl
group further hinders nucleophlllc substitution (KMjgsheld and Vandergen,
1986).
2.1.3. Oxidation. Chlorophenols are likely to be oxidized by free
radicals present 1n most natural waters with the formation of qulnones.
This reaction may be further accelerated by silica, clay and various metal
Ions present 1n water (Krljgsheld and Vandergen, 1986); however, pertinent
data regarding the occurrence of such reactions under environmental con-
ditions could not be located 1n the available, literature as cited In
Appendix A.
2.1.4. B1odegradat1on. The blodegradatlon of Chlorophenols has been
studied with pure cultures, mixed microorganisms and natural waters. The
bacteria NCIB 8250 (Beverldge and Tall, 1969) and KC3 (Chu and Klrsch,
1973), Candida alblcans and TMchophyton gypseum and Trlchophyton qypseum
var. Kaufman-Wolf (Polster et a!., 1986), a gram negative nonmotlle coccus
(Banerjee et al., 1984), Pseudomonas sp., and Alcallgenes eotrophus
(Knackmuss and Hellwlg, 1978) are a few microorganisms known to blodegrade
these Chlorophenols. Mixed microorganisms obtained from activated sludge
(Beltrame et al., 1982; Patterson and Kodukala, 1981; PHter, 1976), from
aerated lagoons (Patterson and Kodukala, 1981), from petroleum refinery
lagoons (Tabak et al., 1964), from settled domestic wastewaters (Tabak et
al., 1981) and from catalytic plant waste lagoons (Chambers et al., 1963)
have been shown to degrade mono-, d1- and trlchlorophenols. Thorn and Agg
(1975) also reported that o-, m-, p- and 2,4-d1chlorophenol should be
biodegradable by biological sewage treatment, provided suitable acclimation
can be achieved. Based on a blodegradatlon study under the Japanese MITI
test conditions (Sasaki, 1978), which consist of a 5-day Incubation with
activated sludge, Kawasaki (1980) concluded that the monochlorophenols and
0016d 2-3 06/17/87
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2,4,5-tMchlorophenol would be resistant to degradation In natural waters.
It Is concluded from the studies described that significant blodegradatlon
of chlorophenols requires adaptation of microorganisms to phenol or chloro-
phenols. In addition, the degradation rate will depend on pH, substrate
concentration, oxygen availability, nature and concentration of nutrient,
and the water temperature. At high concentrations, failure to degrade may
be due to tox1c1ty to microorganisms (Section 4.3.).
The blodegradabUHy of chlorophenols under anaerobic conditions was
studied by several authors. Although a few Investigators (Johnson and
Young, 1983; Horowitz et al., 1982) failed to observe anaerobic bio-
degradation of chlorophenols and Inhibition of the anaerobic process by some
chlorophenols, others (Sahm et al., 1986; Boyd and Shelton, 1984; Salklnoja-
Salonen et al., 1984) found that the three monochlorophenols, 2,3-d1chloro-,
2,4-d1chloro-, 3,4-d1chloro-, 3,5-d1chloro-, 2,4,6-trlchloro- and 2,3,4,6-
tetrachlorophenol were susceptible to anaerobic blodegradatlon by micro-
organisms from lake sediments and sewage sludge. Although 3,4- and 3,5-d1-
chlorophenols were more resistant, specific cross-acclimation with mono-
chlorophenols degraded these compounds (Boyd and Shelton, 1984).
The blodegradatlon of chlorophenols with natural waters was also
reported by several authors. WHh Skldaway River water In Savannah, 6A, the
blodegradatlon half-lives of 2-chlorophenol and 2,4,5-tMchlorophenol at
21°C were 20 and 690 days, respectively. At 9°C, the half-life of 2-chloro-
phenol Increased to 490 days. The half-lives for both compounds decreased
1n the presence of river sediments. For example, the half-life of 2-chloro-
phenol at 22°C was 3 days and that of 2,4,5-trlchlorophenol at 21°C was 23
days (Lee and Ryan, 1979). WHh the mean of the experimental values of the
blodegradatlon rate constants 1n five surface waters (T.lxlO"11
l/organlsm-hour) given by Paris et al. (1983) and a value of 108
0016d 2-4 06/17/87
-------
organlsms/i as the concentration of microorganisms, the half-life of
4-chlorophenol In natural water 1s estimated to be 4 days. The
blodegradatlon half-life of 2,4,6-trlchlorophenol with suspended sediment
was reported to be 7 days (Blades-Flllmore et al., 1982). The
blodegradatlon half-lives of 2-chloro-, 2,4-dlchloro-, 2,4,5-trlchloro- and
2,3,4,5-tetrachlorophenols In natural waters can be estimated from the
experimentally determined rate constant values given by Banerjee et al.
(1984) and range from 14 hours to 17 days. The half-lives Increased as the
number of chlorine substitutions Increased. In the summer, the half-life
for microblal transformation of 4-chlorophenol 1n an estuarlne water was 28
hours (Hwang et al., 1986). It 1s concluded from the above discussion that
blodegradatlon of chlorophenols 1n natural waters will be an Important
process.
2.1.5. Evaporation. The evaporation half-lives of 2- and 4-chlorophenol
from a water depth of 0.38 cm 1n stirred solution was experimentally deter-
mined to be -1.5 and 13 hours, respectively (Chlou et al., 1980). Since
the evaporation rate 1s Inversely proportional to the water depth, an
Increase of water depth from 0.38 cm to 1 m will Increase the evaporation
half-life of 2-chlorophenol to -15 days (Krljgsheld and Vandergen, 1986).
Therefore, 1n most natural waters evaporation may not be Important unless
the body of water Is extremely shallow. The evaporation half-life of
2,4,6-trlchlorophenol from a pond at a depth of 10.2 cm, a water temperature
of 20.7°C and a wind speed of 1.7 m/sec was estimated to be 4 days (Suglura
et al., 1984). Klncannon et al. (1983) and Leuenberger et al. (1985a)
showed that evaporation was Insignificant for 2,4-dlchloro-, 2,4,6-tr1-
chloro- and 2,3,4,6-tetrachlorophenol during treatment of waste-waters. The
evaporation half-life should also be strongly Influenced by the pH of the
water.
0016d 2-5 06/17/87
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2.1.6. Sorptlon. The sorptlon of chlorophenols depends on the organic
matter in sediment and suspended solids and the pH of the water. If the pH
of the water is such that the compound remains undlssoclated, the sorption
can be related to the K value of the compound and hence with the organic
carbon content of the sorbent. For tetrachlorophenols that are usually
present predominantly 1n the Ionized form at pH >7, the sorption by the
phenolate form cannot be neglected. The sorption of the phenolate species
may depend on the partitioning process between the aqueous and organic phase
present in a natural sorbent and the sorptlon may be dependent on the 1on1c
strength of the aqueous phase. The prediction about the distribution of
such sorblng species based on simple partitioning of the nondlssociated
species will be erroneous (Schellenberg et al., 1984). Isaacson (1985)
concluded that hydrogen-bonding was the main mechanism of sorptlon and that
increasing the degree of cnlorinatlon of phenol would Increase adsorption
(Krijgsheld and Vandergen, 1986; Isaacson and Fink, 1984). The average
values for the KQC of 2,3-d1-, 2,4-di-, 2,4,6-trl-, 2,4.5-tM-,
3,4,5-tri-, 2,3,4,6-tetra- and 2,3,4,5-tetrachlorophenols in sediments from
three lakes and rivers were 426, 545, 1070, 2330, 3680, 6640 and 13,200,
respectively (Schellenberg et al., 1984). Thus, it can be concluded that
sorptlon will be an Important process in the removal of these compounds from
most aquatic media (Leuenberger et al., 1985a).
2.1.7. B1oconcentrat1on. The experimentally determined BCFs for several
aquatic species are shown in Table 2-1. The BCFs given by Hattula et al.
(1981a) and Kobayashl et al. (1979) were obtained by administering lethal
concentrations of the compounds and by measuring the tissue concentrations
1n dead fish. Based on the equation, log BCF = 0.76 log KQW - 0.23 (Velth
et al., 1980), the BCF is expected to increase as the K values increase.
0016d 2-6 05/08/87
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As can be seen from Table 1-2, the BCF should also Increase as the number of
chlorine substitutions Increases. The experimental values given In Table
2-1, however, differ considerably from the estimated values and do not show
the Increasing trend as predicted. The difference between the estimated and
the experimental values may be due to several factors Including use of
nonstatlonary state conditions, high concentrations of test compounds and
the determination of BCF values 1n whole tissue rather than In I1p1d. In
addition, at physiological pH, higher chlorinated phenols should exist
significantly 1n the dissociated form with a lower K , which makes the
experimental BCFs lower than predicted by the equation.
2.2. AIR
The fate and transport of chlorophenols In the atmosphere has not been
studied comprehensively. When 2,4,6-trlchlorophenol was sorbed onto silica
gel and Irradiated with mercury lamps at wavelengths >290 nm, 65.8% of the
compound photom1neral1zed Into carbon dioxide In 17 hours (Freltag et al.,
1985; Korte and Klein, 1982). Although the available data cannot be used In
estimating the half-life of the compound under natural sunlight conditions,
1t can be concluded from these Investigations that the chlorophenols may be
susceptible to significant photolysis In the atmosphere. Kanno and Nojlma
(1979) also showed that the monochlorophenols can react with nitrogen oxides
1n air to form chloronltrophenols. The reaction of chlorophenols with OH
radicals 1n the atmosphere may also be Important. The half-life of phenol
reaction with OH radicals at an atmospheric concentration of 10* radicals
cm3 Is estimated to be -7 hours based on a rate constant for the reaction
of 28.3xlO"12 cmVmolecule-sec (Atkinson, 1985). Increasing the
chlorine substitution 1s expected to Increase the half-life of the reaction.
Therefore, this reaction may be significant for mono- and dlchloro-
substHuted phenols.
0016d 2-9 06/17/87
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The detection of d1-, tr1- and tetrachlorophenols 1n rainwater and snow
obtained from Portland, OR, and Finland (Leuenberger et al., 1985b;
Paas1v1rta et al., 1985a) Indicates that these compounds are removed from
the atmosphere by wet deposition. From their study of chlorophenol concen-
trations 1n snow collected In southern, central and northern Finland,
PaasWIrta et al. (1985a) concluded that these compounds, which originated
from anthropogenic sources, precipitate before being transported by air to
northern parts of Finland.
2.3. SOIL
The fate and transport of chlorophenols In soil 1s less well studied
than 1n water. An examination of the fate of these compounds In water (see
Section 2.1.) reveals that photodegradatlon and blotransformatlon are Hkely
to be Important 1n determining the fate of these compounds In soils.
Although photodegradatlon may be significant on the surface of soil, this
process Is unlikely to have much significance beyond the surface because of
reduced light Intensity, which 1s due to attenuation and scattering. The
blodegradatlon of chlorophenols with pure cultures of microorganisms
Isolated from soil was reported by Bollag et al. (1968) and Haider et al.
(1974); Arthrobacter sp. and both Pseudomonas sp. and Nocardla sp.
precultlvated on benzene degraded chlorophenols. The Incubation of
2-chloro-, 4-chloro-, dlchloro- and trlchlorophenols 1n a natural soil for 1
week degraded 13, 22.2, 31.4 and 35% of the respective original compounds to
complete mineralization (Haider et al., 1974). On the other hand, the
complete disappearance of the parent chlorophenols In two natural soils took
the following time periods: 2-chlorophenol, 14-47 days; 3-chlorophenol, >47
to >72 days; 4-chlorophenol, 3-9 days; 2,4-d1chlorophenol, 5-9 days;
2,5-d1chlorophenol, >72 days; 2,4,5-trlchlorophenol, >47 to >72 days;
0016d 2-10 06/17/87
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2,4,6-tMchlorophenol , 5-13 days; 2,3,4,6-tetrachlorophenol , >72 days
(Alexander and Aleem, 1961). It can be concluded that while some
chlorophenols are easily biodegradable 1n soils, others are more resistant.
Schwarzenbach and Westall (1985) studied the dependence of the K on
the pH of soils. At neutral soil pH, higher chlorinated phenols with lower
pka values will exist primarily 1n the 1on1c state and will not be signifi-
cantly sorbed onto soils, although sorptlon to soil, particularly clay soil,
may be due to 1on1c attraction. The sorptlon of chlorophenols on soils will
also Increase with an Increase of organic carbon content of soil. Thus, In
a sandy aquifer, Sutton and Barker (1985) observed very little sorptlon of
chlorophenol. Boyd (1982) measured the following K values In a natural
soil at a neutral pH: 2-chloro-, 51; 3-chloro-, 66; 4-chloro-, 70;
2,4-d1chloro-, 126; 2,4,5-trlchloro-, 363. In another natural soil of pH
10, the following K values were reported: 2,4-d1chloro-, 0;
2,6-dlchloro-, 0; 2,4,6-tMchloro-, 0; 2,3,4,6-tetrachloro-, 75 (Johnson et
al., 1985). It 1s concluded that chlorophenols are susceptible to leaching
from soils to groundwater particularly from sandy soils and soils with a pH
2.4. SUMMARY
The two Important processes that may have a significant effect on the
fate of chlorophenols In water are photolysis and blodegradatlon. The photo-
lytlc half-lives of 4-chloro-, 2,4-dlchloro- and 2,4,5-tMchlorophenols at
the top surface of distilled water under midday sunlight Irradiation were
estimated to be 2.6 days, 0.8 and 0.5 hours, respectively (Hwang et al.,
1986). From an outdoor pond experiment, Suglura et al. (1984) estimated the
photolytlc half-life of 2,4,6-trlchlorophenol at a depth of 10 cm to be 4
days. The photolysis of chlorophenols will be Important In clear shallow
bodies of water, but as the depth and turbidity of water Increase, Us
0016d 2-11 06/17/87
-------
importance will decrease with light attenuation. The blodegradatlon
half-lives of chlorophenols In natural waters range from >1-17 days. The
half-life values Increase as the number of chlorine substitutions increases
and the temperature of the water decreases. The half-lives of the compounds
also decrease in sediments of surface waters with the presence of a greater
number of microorganisms (Lee and Ryan, 1979; Banerjee et a!., 1984; Hwang
et a!., 1986). Hydrolysis and evaporation are not likely to be Important
processes for chlorophenols 1n water (KMjgsheld and Vandergen, 1986).
Oxidation may be a significant process 1n water but experimental data on
such reactions could not be located In the available literature as cited in
Appendix A. The removal of chlorophenols from water by sorptlon onto
suspended sol Ids and sediments may be Important and will depend on the pH of
water and the organic content of the sorbents. Sorption will Increase at
lower pH and higher organic content of the sorbents; 1t will also be higher
for higher chlorinated than lower chlorinated phenols (Schellenberg et al.,
1984; Isaacson and F1nk, 1984; KMjgsheld and Vandergen, 1986).
Experimental data Indicate that mono- and dlchlorophenols will not
bloconcentrate but that the higher chlorinated phenols may bloconcentrate
significantly In aquatic organisms (Velth et al., 1980; Kobayashl et al.,
1979; Hattula et al., 1981a; Vlrtanen and Hattula, 1982).
In the atmosphere, the chlorophenols are likely to undergo significant
photolysis (Korte and Klein, 1982). Based on the rate constant of phenol
reaction with OH radicals In the atmosphere (Atkinson, 1985), It 1s con-
cluded that such reactions may be significant for the lower chlorinated
phenols. The detection of these compounds 1n rainwater and snow Indicate
that they will be removed from the atmosphere by wet deposition (Leuenberger
et al., 1985b; Paaslvirta et al., 1985a).
0016d 2-12 06/17/87
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Based on data regarding chlorophenols in water, photolysis, hydrolysis
and evaporation will not be significant processes In soils. The two Impor-
tant processes 1n soil are sorptlon and blodegradatlon. While 2-chloro-,
4-chloro-, 2,4-d1chloro- and 2,4,6-trIchlorophenols were found to be easily
biodegradable In a natural soil, 3-chloro-, 2,5-d1chloro-, 2,4,5-trlchloro-
and 2,3,4,6-tetrachlorophenols were persistent 1n soil (Alexander and Aleem,
1961). The sorptlon of chlorophenols In soils Increases with a decrease 1n
soil pH and Increase 1n chlorine substitution. Chlorophenols are especially
susceptible to leaching from sandy soils and soils with pH >10 (Schwarzen-
bach and Westall, 1985; Sutton and Barker, 1985; Boyd, 1982; Johnson et al.,
1985).
0016d 2-13 05/08/87
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3. EXPOSURE
3.1. WATER
Sources of chlorophenols in the environment are effluents from the
manufacturing industry, effluents from wastewater treatment, degradation of
the pesticide 2,4-D in the environment, effluents from kraft pulp mills and
sawmills, waste disposal sites and Incineration of Industrial wastes
(Krijgsheld and Vandergen, 1986; James et al., 1984).
In kraft bleaching process wastewaters, up to 7.5 yg/i of
2,3,4,6-tetra-, 8.3 wg/i of 2,4,5-tri-, 0.75 vg/i of 2,4,6-tr1-,
0.093 pg/i of 2,6-dl- and 0.27 ug/8. of 2,4-d1chlorophenol were
detected (Xie et al., 1986; Krlngstad and Llndstrom, 1984; Paaslvlrta et
al., 1985b). Chlorophenols have also been reported In effluents from
municipal and Industrial treated wastewaters (Ellis et al., 1982; Young et
al., 1983; Bulsson et al., 1984; Callahan et al., 1979). In a Nationwide
Urban Runoff Program, Cole et al. (1984) detected 2-chlorophenol In 1% of
the samples at a concentration of 2 yg/l; 2,4-d1- and 2,4,6-trlchloro-
phenol were not detected 1n any of the samples.
Chlorophenols were detected In groundwater and surface water near
contaminated sites (Valo et al., 1984; Mauser and Bromberg, 1982; Bedlent et
al., 1984). The concentrations of 2,4-d1-, 2,4,6-tr1-, 2,4,5-tr1-,
2,3,4,6-tetra- and 2,3,4,5-tetrachlorophenols In ditch waters within a
sawmill were 390, 957, 47, 14,300 and 6 vg/1, respectively (Valo et al.,
1984). These authors also detected chlorophenols In groundwaters and lake
waters collected around the saw mills. In the groundwater near an abandoned
creosote facility In Conroe, TX, Bedlent et al. (1984) detected concentra-
tions as high as 80 and 135 wg/i of 2,4-d1chloro- and 2,4,6-trlchloro-
phenol, respectively. 2,4-01chorophenol was reported 1n 17.2% of the
sampled groundwater supplies In the United States (Dyksen and Hess, 1982).
0017d 3-1 05/08/87
-------
Chlorophenols were also found 1n several surface waters and In their
sediments (Salklnoja-Salonen et al., 1984; Hegman and Vandenbroek, 1983;
Watanabe et al., 1985; X1e, 1983). Concentrations of 2,4-d1-, 2,6-dl-,
2,4,6-tr1- and 2,3,4,6-tetrachlorophenol as high as 10, 1.2, 1.2 and 0.1
vg/l, respectively, were found In a lake water that received bleaching
effluents from kraft pulping (Salklnoja-Salonen et al., 1984). X1e et al.
(1986) detected chlorophenols In seawater receiving effluents from a pulp
mill.
According to Callahan et al. (1979), the frequency of detection of
chlorophenols In U.S. tap water was 0%. Morgade et al. (1980) detected no
chlorophenols other than pentachlorophenol 1n several drinking waters from
Dade County, FL; however, Kopfler et al. (1977) qualitatively detected
2,4-d1-, 2,4,5-tr1- and 2,4,6-trlchlorophenol In U.S. drinking waters. A
survey of six unspecified cities In Canada showed concentrations as high as
39 ng/j, of 2-chloro-, 34 ng/l of 4-chloro-, 17 ng/l of 2,4-dlchloro-
and 60 ng/i of 2,4,6-trlchlorophenol 1ri the treated drinking waters
(SHhole et al., 1986). In British drinking waters, 2,4,6-trlchlorophenol
has been detected (Crathorne et al., 1984). Both 2-chloro- and 4-chloro-
phenol were reported In the tap water In the Netherlands at a maximum
concentration of 2.2 vg/l. 2,4-01chlorophenol was detected at a concen-
tration range of 0.003-0.006 yg/l 1n German drinking waters (KMjgsheld
and Vandergen, 1986).
3.2. AIR
None of the chlorophenols have been detected In ambient air other than
air from contaminated sites; however, the detection of 2,4-d1-, 2,6-d1-,
2,4,5-trl-, 2,4,6-tr1- and 2,3,4,6-tetrachlorophenols 1n rainwater and snow
In the United States and elsewhere (Leuenberger et al., 1985a; Paas1v1rta et
0017d 3-2 06/18/87
-------
al., 1985a) Indicates that these compounds are also present in the ambient
air. Mauser and Bromberg (1982) qualitatively detected 2,4,5-trlchloro-
phenol 1n air samples 1n Love Canal, NY. Incineration of Industrial wastes
at four different test facilities produced 2-chloro-, 4-chloro-,
2,6-d1chloro-, 2,4,5-trlchloro- and 2,4,6-trlchlorophenol In the exhaust
gases from one facility; produced 2-chloro-, 4-chloro- and 2,6-d1chloro-
phenol from the second facility; and produced no chlorophenols from the two
other facilities (James et al., 1984).
Kaupplnen and Undroos (1985) studied occupational exposure to chloro-
phenols 1n 10 Finnish sawmills where a chlorophenolate formulation was used
as a wood preservative. The machine stacking area, on the average, con-
tained the maximum atmospheric concentration of chlorophenols. The mean
concentration of the sum of tr1-, tetra- and pentachlorophenol 1n this area
was 75 yg/m3. The mean concentration of 2,4,6-trlchlorophenol alone In
this area was 58 yg/m3. Thus, the concentrations of chlorophenols In the
air were usually well below the Finnish occupational limit value of
500 yg/m3.
*
3.3. FOOD
Chlorophenols have been detected In urine of humans; this Is possibly
due to the metabolism of various pesticides by the body (Kutz et al., 1978;
Fat1ad1, 1984) or to direct exposure to these compounds through Inhalation
(Kaupplnen and Undroos, 1985) or to the 1ngest1on of water and foods. Data
on the exposure to these compounds through foods are limited. Fishes
collected from coastal Finnish water and from lake waters receiving pulp
mill effluents were found to contain chlorophenols. The average
concentrations of 2,3,4,6-tetrachloro- and 2,4,6-trlchlorophenol In the
muscle of pike, Esox ludus. were 34 and 13.6 yg/kg, respectively.
Similarly, the muscles of salmon, Salmo salar, and trout. Salmo trutta,
0017d 3-3 06/18/87
-------
collected from these waters contained maximum average concentrations of 5.9,
2.5 and 29.3 ug/kg of 2,4,6-tMchloro-, 2,4,5-trlchloro- and
2,3,4,6-tetrachlorophenol, respec- tlvely (Paas1v1rta et al., 1985b;
VuoMnen et al., 1985). Ho et al. (1983) Identified 4-chlorophenol In the
volatile flavor constituents of fried bacon.
3.4. SUMMARY
Although chlorophenols have been detected 1n municipal and Industrial
effluents {Xle et al., 1986; KMngstad and Llndstrom, 1984; Ellis et al.,
1982; Callahan et al., 1979), In urban runoff water (Cole et al., 1984), and
1n surface and groundwater near effluent discharge and waste disposal sites
(Valo et al., 1984; Bedlent et al., 1984; Salklnoja-Salonen et al., 1984;
Watanabe et al., 1985; Xle et al., 1986), these compounds have been detected
Infrequently In drinking waters. According to Callahan et al. (1979), the
frequency of detection of chlorophenols 1n U.S. tap waters was 0%. Kopfler
et al. (1977), however, qualitatively detected 2,4-d1-, 2,4,5-trl- and
2,4,6-trlchlorophenol In U.S. drinking waters. 2-Chloro-, 4-chloro-,
2,4-d1chloro- and 2,4,6-trlchlorophenol at respective maximum concentrations
of 39, 34, 17 and 60 ng/l have been detected In Canadian drinking waters
(SUhole et al., 1986). A few of these compounds have also been detected In
waters from England, the Netherlands and Germany (Crathorne et al., 1984;
KMJgsheld and Vandergen, 1986). The available . data are Inadequate to
estimate the dally exposure of a U.S. Individual to these compounds by
Ingestlon of drinking water.
2,4,5-Trlchlorophenol was detected In air samples 1n Love Canal, NY
(Hauser and Bromberg, 1982) and 2-chloro-, 4-chloro-, 2,6-d1chloro-,
2,4,5-trlchloro- and 2,4,6-trlchlorophenol were Identified In the exhaust
gases from an experimental Industrial Incineration facility (James et al.,
0017d 3-4 06/18/87
-------
1984). Quantitative air monitoring data on chlorophenols In the United
States or elsewhere, however, are not available. Occupational exposure to
chlorophenols 1n a Finnish sawmill was reported by Kaupplnen and Undroos
(1985). The mean concentration of 2,4,6-trlchlorophenol 1n one work area
was 58 yg/m3, but the concentrations of chlorophenols In the air were
usually well below the Finnish occupational limit value of 500 yg/m3.
Chlorophenols have been detected 1n a few edible aquatic organisms
collected from contaminated surface waters in- Finland. The muscles of
salmon, Sal mo salar. and trout, Salmo trutta, collected from these waters
contained maximum average concentrations of 5.9, 2.5 and 29.3 yg/kg of
2,4,6-tMchloro-, 2,4,5-tMchloro- and 2,3,4,6-tetrachlorophenol, respec-
tively (Paasivirta et al., 1985b; Vuorlnen et al., 1985). Although the
available data are Insufficient to estimate the average exposures through
air, food or drinking water, the data Indicate that exposure of the general
public to the various chlorinated phenols 1s low and sporadic.
0017d 3-5 05/08/87
-------
-------
4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
Toxldty of chlorophenols to aquatic organisms generally Increases with
Increasing degree of chlorlnatlon (U.S. EPA, 1979a, 1980b,c). Kobayashl et
al. (1979) proposed that this Increased toxlclty was related to Increased
uptake of the more chlorinated compounds. The most toxic of the chloro-
phenols Is pentachlorophenol (U.S. EPA, 1979a), which Is not a subject of
this document.
Data concerning acute toxlclty of chlorophenols to freshwater fishes are
presented In Table 4-1. The most sensitive species for which a large amount
of data was available were salmonlds (rainbow trout, Salmo qalrdnerl. and
brown trout. Salmo trutta) and bluegllls (Lepomls macrochlrus). The lowest
reported acutely toxic concentration for freshwater fishes was 0.085 mg/a,
2,3,4,6-tetrachlorophenol, a 96-hour IC for rainbow trout (Mayer and
Ellersleck, 1986).
Table 4-1 also contains data concerning pH-1nduced variation In acute
toxlclty of chlorophenols to gupples, PoeclHa retlculata. Chlorophenol
toxlclty Increased with decreasing pH (see Table 4-1). Holcombe et al.
(1980) reported Increasing toxlclty of 2,4-d1chlorophenol to fathead
minnows, Plmephales promelas with decreasing pH. At lower pH, the undlsso-
dated form of the chlorophenols 1s more prevalent. The undlssoclated form
Is more toxic than the dissociated form because of Us greater ability to
penetrate biological membranes (Holcombe et aT., 1980). Water hardness had
little effect on toxlclty of chlorophenols to freshwater fishes (B1rge et
al., 1979; Pickering and Henderson, 1966).
0018d 4-1 06/18/87
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0018d
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05/08/87
-------
Information about acute toxlclty of chlorophenols to freshwater Inverte-
brates Is summarized In Table 4-2. Toxlclty again appears to Increase with
Increasing chlorlnatlon. The lowest reported toxic concentration was 0.29
mg/J. 2,3,4,6-tetrachlorophenol, a 48-hour LC5Q for Daphnla magna (U.S.
EPA, 1978a).
Devlllers and Chambon (1986) studied structure-activity relationships
for chlorophenol toxlclty to Daphnla magna (see Table 4-2) and found that
the presence of chloro substltuents 1n the ortho (2- or 6-) or para (4-)
positions of the phenol ring affected toxlclty. Chloro substltuents In the
ortho position decreased toxlclty, while para substltuents apparently
Increased toxlclty.
Relatively Uttle Information 1s available concerning toxlclty of
chlorophenols to marine species.- The only marine fishes for which there are
data are the sheepshead minnow, CypMnodon varlegatus, and the cyprlnodontld
Rlvulus marmoratus (Table 4-3). Data for marine Invertebrates are presented
In Table 4-4. The lowest reported toxic concentration for marine fishes was
1.1 mg/5, 2,3,4,6-tetrachlorophenol, a 96-hour LC-n for Rlvulus marmo-
ratus (Koenlg and McLean, 1980), and for marine Invertebrates was 1.5 mg/Z.
3,5-d1chlorophenol, a 96-hour lethal threshold for sand shrimp, Crangon
septemsplnosa (McLeese et al., 1979).
4.2. CHRONIC EFFECTS
Holcombe et al. (1982) conducted a 32-day continuous flow embryo-larval
test with fathead minnows exposed to various concentrations of 2,4-d1chloro-
phenol. They found that survival was decreased by concentrations >0.46
mg/a, and growth was depressed at concentrations >1.24 mg/1. A MATC of
0.29-0.46 mg/l 2,4-d1chlorophenol was estimated based on these results.
U.S. EPA (1978a, 1980b) reported a chronic value of 0.72 mg/l 2,4,6-trl-
chlorophenol determined 1n an early life stage test with fathead minnows.
0018d 4-7 06/18/87
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0018d
4-12
05/08/87
-------
No adverse effects occurred at 3.9 mg/8. 2-chlorophenol, the highest
concentration used (U.S. EPA, 1978a, 1980c).
Koenig and McLean (1980) conducted full Hfecycle (8-month) exposures of
the brackish water cyprlnodontld fish, Rlvulus marmoratus. to 2,3,4,6-tetra-
chlorophenol concentrations of 0, 0.055, 0.110 and 0.220 mg/i. Fish were
held singly, and all solutions were changed weekly. Gill erosion occurred
In all of the exposed fish and none of the controls. Exposed fish also
experienced fin erosion that was dose-related In Incidence. There was also
a dose-related trend 1n percent survival of the F. 'generation. Parental
mortality, percent hatching and embryo mortality were unaffected by
2,3,4,6-tetrachlorophenol.
Trabalka and Burch (1978) reported that 10 mg/i 3-chlorophenol
decreased hatching of carp (Cyprlnus carplo) eggs In a static renewal
exposure, but 3 mg/i had no effect. Llndstrom and Llndstrom (1980) found
that exposure to 0.1 mg/1 4-chlorophenol for 10 days decreased swimming
activity of the amphlpod, Pontoporela aff1n1s.
4.3. PLANT EFFECTS
Table 4-5 summarizes the available Information on toxldty of chloro-
phenols to freshwater plant species. The more chlorinated chlorophenols
again seem to be more toxic. This variation 1n toxldty was especially
large 1n the studies by Blackman et al. (1955) with duckweed, Lemna minor.
where a 500-fold difference In toxldty was observed between 4-chlorophenol
and 2,3,4,6-tetrachlorophenol as measured by the 48-hour EC5Q causing
chlorosis. The lowest reported toxic concentration for freshwater plants
was 0.603 mg/z, 2,3,4,6-tetrachlorophenol, the 48-hour EC5_ for chlorosis
1n this study.
0018d 4-13 06/18/87
-------
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4-14
05/08/87
-------
airways and chest X-rays were taken. Results were compared with standard
lung function values form various sources. HEF75« was significantly
reduced In 6/7 subjects and all 7 showed Increased CV.,, the Increases
7»
being greater In the smokers. Changes In other lung function parameters
were not noted. Results of the questionnaire showed that complaints of
upper airway symptoms were -60% 1n the 7 subjects compared with 10% In a
control group of 126 office employees of similar age and smoking habits.
Chest X-rays of two subjects showed Increased Interstitial densities. This
change disappeared 1n one subject after 1 month of no exposure. Although
the effects could have been caused by exposure to tMchlorophenols, they may
also have been due to long-term and repeated use of gas masks, which
Involves Us own occupational stresses.
6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC Immunologlc competence was assessed 1n groups
of 8-10 Sprague-Oawley rats exposed to 2-chlorophenol (Exon and Keller,
1983a, 1985), 2,4-d1chlorophenol (Exon et al., 1984; Exon and Keller. 1985)
or 2,4,6-tMchlorophenol .In. utero and continued on chlorophenol treatment
for an additional 12-15 weeks (Exon and Koller, 1985). Both dams and their
progeny were provided with chlorophenols In their drinking water at 0, 5, 50
or 500 ppm 2-chlorophenol or 0, 3, 30 or 300 ppm 2,4-dlchlorophenol or
2,4,6-trIchlorophenol. The 1mmunolog1ca1 parameters examined were as
follows: humoral Immunity, measurement of the ratio of serum IgG antibody
levels to bovine serum albumin or keyhole limpet hemocyanln; cell-mediated
Immunity, measurement of delayed-type hypersens1t1v1ty response; and
macrophage function, assessed by the ability of peritoneal cavity derived
cells to phagocytlze sheep red blood cells In vitro. In addition, body,
liver, spleen and thymus weights of these rats were recorded.
0020d 6-3 06/18/87
-------
Exposure of rats to 2-chlorophenol did not significantly affect any of
the Immune functions examined. The ratios of serum antibody levels to
bovine serum albumin were consistently decreased In 2-chlorophenol-treated
rats but these decreases were not statistically significant. In 2,4-d1-
chlorophenol-exposed rats, the ratios of serum antibody levels to keyhole
limpet hemocyanln were consistently greater than controls. These Increases
appeared to be dose-related and reached statistical significance (p<0.05 by
analysis of variance and least square means) In the 300 ppm exposed group.
Delayed-type hypersens1t1v1ty responses showed a dose-related suppression
that was significant (p<0.05) 1n the 30 and 300 ppm groups. No effect on
macrophage function was noted In the rats treated with 2,4-d1chlorophenol.
In the 2,4,6-tMchlorophenol-exposed rats, antibody levels, delayed-type
hypersensHlvlty reactions and macrophage numbers were consistently greater
than controls, but the Increases were not statistically significant.
No significant changes In body weights were noted In any of the chloro-
phenol-exposed rats. The only significant (p<0.04) organ weight differences
were Increased liver and spleen weights In the 300 ppm 2,4-d1chlorophenol
and 2,4,6-trlchlorophenol groups and Increased liver weights 1n the 30 ppm
2,4,6-tMchlorophenol group.
Kobayashl et al. (1972) fed male strain dd mice 2,4-d1chlorophenol 1n
the diet at levels of 0.02-0.2% for 6 months. The number of mice used In
the experiment was not stated and 1t was not clear If controls were used.
By measuring body weights and food consumption, the authors estimated that
the mice consumed 45, 100 and 230 mg/kg bw/day. No effects on behavior,
growth rate or hematology were observed. The only changes noted were hyper-
plasla of hepatic cells 1n one high-dose mouse and slightly reduced liver
weights and SGPT levels 1n the high-dose group. The authors concluded that
the maximum no effect level of 2,4-d1chlorophenol In feed was 100 mg/kg/day.
0020d 6-4 06/18/87
-------
In a study by Borzelleca et al. (1985a), groups of 20 male and 20 female
CD-I mice were provided with 2,4-d1chlorophenol (99% pure) In their drinking
water at 0.2, 0.6 or 2.0 mg/9. for 90 days. The drinking water solutions
also contained Emulphor, a polyoxyethylated vegetable oil, which was added
to Improve solubility and to Increase palatabllUy. Control mice were
provided with delonlzed water or a 10% Emulphor solution. The 2,4-d1chloro-
phenol doses calculated by the authors were 50, 143 and 491 mg/kg/day for
females and 40, 114 and 383 mg/kg/day for males In the low-, middle- and
high-dose groups, respectively. The results of the study Indicated no
consistent compound-related differences 1n terminal body weight or absolute
or relative organ weights, hematology or clinical chemistry when compared
with Emulphor-treated mice. There were major differences In hematologlcal
and clinical chemistry values, mixed-function oxldase activity and organ
weights, between control mice receiving Emulphor and those receiving
delonlzed water. The authors concluded that Emulphor was "not without
effect" and that 2,4-dlchlorophenol elicited no consistent treatment- or
dose-related effects.
McColHster et al. (1961) studied the toxldty of 2,4,5-tMchlorophenol
In rabbits and rats. Groups of 1-3 rabbits were dosed by gavage with
2,4,5-trlchlorophenol 1n 5X gum acacia solution at 0, 0.001, 0.01, 0.1 or
0.5 g/kg 20 times over 28 days. The only changes noted were very slight
microscopic kidney changes at the 0.1 g/kg level and very slight kidney and
liver changes at the 0.5 g/kg level. In the rat study, groups of five males
were dosed by gavage with 2,4,5-trlchlorophenol 1n olive oil at 0, 0.03,
0.1, 0.3 or 1.0 g/kg 18 times over 24 days. No evidence of adverse effects
was noted. The parameters examined were growth, mortality, hematologlc
parameters, blood urea nitrogen levels, body and organ weight ratios and
0020d 6-5 06/18/87
-------
microscopic examinations of lung, heart, liver, kidney, spleen, adrenal,
pancreas and testes.
In a 98-day study of the toxldty of 2,4,5-tMchlorophenol (McColllster
et al., 1961), groups of 10 male and 10 female 50-day-old Hlstar rats were
fed diets containing the test compound at 0, 0.01, 0.03, 0.1, 0.3 or 1.0%.
No effects 1n gross appearance, behavior, mortality, food consumption,
growth, terminal hematologlc values, final average body and organ weight
ratios or gross or microscopic examinations of tissues were noted In rats
fed 0.01, 0.03 or 0.1% (0.01, 0.03 or 0.1 g/kg/day calculated by the
authors). Wetness of the abdominal area Indicating a diuretic effect was
noted In rats treated at 0.3 or 1.0%. Body weights of both male and female
rats were reduced at 1.0% but the average final body weights were signifi-
cantly (p=0.03) decreased only 1n females. Microscopic examination of
tissues revealed slight pathologic changes In the liver and kidneys of rats
treated at 0.03 and 1.0%. These changes, which were milder In the 0.3%
group, Involved moderate degenerative changes 1n the epithelial lining of
the convoluted tubules and early proliferation of the Interstitial tissue In
the kidneys, and mild centMlobular degenerative changes characterized by
cloudy swelling and an occasional area of focal necrosis 1n the liver. In
addition, slight proliferation of the bile ducts and early portal cirrhosis
were noted at 1.0%. The authors concluded that the liver and kidney changes
observed at both 0.3 and 1.0% "were of a mild and reversible nature and
probably of minor significance.*
Vlzethum and Goerz (1979) fed rats 2,4,5-trlchlorophenol In their diets
at 0.05% for >70 days and concluded that the compound was not porphyrogenlc.
No other parameters were examined.
To determine doses of 2,4,6-tMchlorophenol to be used 1n a cardnogen-
1c1ty study, NCI (1979) conducted a subchronlc feeding study using F344 rats
0020d 6-6 06/18/87
-------
and B6C3F1 mice. Groups of five male and five female rats and mice were fed
2,4,6-tMchlorophenol In the diet for 7 weeks followed by 1 week of observa-
tion. The rats were fed dietary concentrations of 0, 10,000, 14,700,
21,500, 31,500 or 46,000 ppm, while the mice were fed 0, 6800, 10,000,
14,700, 21,500 or 31,500 ppm. In rats, survival was not affected at <14,700
ppm, but at the 21,500 ppm level one male died, at 31,500 ppm one male and
two females died, while at 46,000 ppm two males and three females died. The
only hlstopathologlc lesions noted 1n rats were In the 46,000 ppm group 1n
which moderate to marked Increases 1n splenic hematopo1es1s was noted and
mldzonal vacuolatlon of hepatocytes was observed 1n two males. Except for
one control female that died, survival of mice was not affected at <21,500
ppm, but at 31,500 ppm two males and two females died. Tissues of mice
dosed at 21,500 ppm were essentially normal. Whether hlstopathologlcal
effects were observed 1n mice fed 31,500 ppm was not stated. A dose-related
decrease In body weight was observed In both rats and mice. The decrease
was >10X In rats treated at >14,700 ppm, 1n male mice at >14,700 ppm and In
female mice at >21,500 ppm. This decrease In body weight was used to select
the doses for the chronic study.
Kawano et al. (1979) described an experiment 1n which female Wlstar JCL
rats were fed diets containing 2,3,5-trlchlorophenol or 2,3,4,5-,
2,3,5,6- or 2,3,4,6-tetrachlorophenol at 0.2% for 3 weeks. The purity of
the compounds was not stated. At the level provided, the compounds caused
considerable changes 1n growth, organ weights, serai biochemical data and
liver drug metabolizing enzymes. 2,3,4,6-Tetrachlorophenol caused a
relatively strong growth Inhibition. Further details concerning this study
were not available.
Hattula et al. (1981b) dosed 2-month-old male Wlstar rats (322±27 g)
with 2,3,4,6-tetrachlorophenol 1n olive oil by gavage at 0, 10, 50 and 100
0020d 6-7 06/18/87
-------
mg/kg/day for 55 days. The number of rats per dose group was not provided.
After 55 days the rats were sacrificed and samples of the "liver, kidney,
spleen, stomach, small and large Intestine, muscle and brain were examined
h1stolog1cally. There were no changes 1n the brain, muscle or large
Intestine. In the stomach, mild dilation of the veins of the mucosa was
observed, but the dose level at which this effect occurred was not stated.
Necrosis of tie small Intestines was noted In the high-dose rats. The most
significantly affected organ was the liver. The authors provided three
levels of hlstopathologlcal changes of the liver: level I, mild prolifera-
tion of the bile canallcull, swelling of the endothellal cells of the bile
tract and occasional necrosis of the endothellal cells of canallcull and
some hepatocytes; level II, focal areas of necrosis of several hepatocytes
and prominent proliferation of the bile canallcull and Inflammatory Infil-
trates around the bile duct; level III, large necroses (which Included most
of the liver parenchyma). At 10 mg/kg, no changes were observed 1n the
liver parenchyma (whether other changes were noted Is not clear), while at
50 mg/kg one rat showed level III changes and at 100 mg/kg two rats "had
changes In the liver corresponding to the levels (II) and (III).' Further
details concerning this study were not reported.
6.1.2.2. CHRONIC -- As part of a carc1nogen1c1ty-cocarc1nogen1c1ty
study (Sections 6.2.2. and 6.2.3.), Exon and Koller (1985) provided drinking
water containing 0, 5, 50 or 500 ppm 2-chlorophenol or 0, 3, 30 or 300 ppm
2,4-d1chlorophenol to groups of 24-32 Sprague-Oawley rats/sex from weaning
to -2 years of age. These rats were offspring of dams exposed to the same
treatments from 3 weeks of age through weaning of their progeny. In rats
treated with 500 ppm 2-chlorophenol or 300 ppm 2,4-d1chlorophenol, numbers
of RBC and hemoglobin levels were Increased compared with controls. Packed
cell volume was also Increased 1n 500 ppm 2-chlorophenol rats. These
0020d 6-8 06/18/87
-------
effects were significant (p<0.05) at H months of exposure. Hematologlcal
parameters at lower doses and other signs of toxlclty were not discussed.
To examine the ' cardnogenldty of 2,4,6-tMchlorophenol, NCI (1979)
conducted a 2-year feeding study using F344 rats and B6C3F1 mice (Section
6.2.2.). In this study, groups of 50 male and 50 female rats were fed
2,4,6-trlchlorophenol 1n the diet at 5000 or 10,000 ppm for 106 weeks.
Groups of 50 male mice were fed 5000 or 10,000 ppm for 105 weeks, while
groups of 50 female mice were fed at TWA doses of 5214 or 10,428 ppm. The
actual dietary levels the female mice were fed were 10,000 or 20,000 ppm for
38 weeks, followed by 2500 and 5000 ppm for an additional 67 weeks. Groups
of 20 male and 20 female rats and 20 male and female mice maintained on the
basal diet for 105-107 weeks served as controls.
Throughout the study, rats and mice were checked twice dally for sick,
and moribund animals or animals with tumors. The animals were weighed,
examined clinically and were palpated for tumors monthly. Moribund animals
and those that survived the study were sacrificed and necropsled. Gross and
microscopic examinations of major tissues, organs and all gross lesions were
conducted. In addition, peripheral blood smears were made for rats and mice
whenever possible.
In addition to the carcinogenic effects of 2,4,6-tMchlorophenol
observed In this study (Section 6.2.2.), a dose-related decrease In body
weight was observed throughout the study 1n both rats and mice. Results of
hlstopathologlc examinations 1n rats revealed that the only noncardnogenlc
effects Increased above controls were bone marrow hyperplasla and leukocyto-
sls. Bone marrow hyperplasla was noted In 0/20, 26/50 and 15/50 control,
low-dose and high-dose male rats, respectively, and 1n 0/20, 16/50 and 2/50
control, low-dose and high-dose female rats, respectively. Leukocytosls was
0020d 6-9 06/18/87
-------
observed in 0/20, 13/50 and 11/50 control, low-dose and high-dose male rats
and in 0/20, 6/50 and 3/50 control, low-dose and high-dose female rats,
respectively. In mice, except for hyperplasla of the liver in males,
similar nonneoplastlc lesions were found In both control and treated mice.
The incidences of hyperplasla of the liver in male mice were 2/20, 12/49 and
6/47 1n control, low- and high-dose groups.
6.1.3. Other Relevant Information. Carlson (1978) found that 2,3,5-,
2,3,6-, 2,4,5- and 2,4,6-trlchlorophenol administered orally to rats at
doses as high as 400 mg/kg/day for 14 days did not Induce xenoblotlc metabo-
lism. 2,4,5-TMchlorophenol at 400 mg/kg did reduce mlcrosomal NADPH-
cytochrome c reductase activity and levels of cytochrome P-450.
Oenomme et al. (1983) examined the ability of the trl- and tetrachloro-
phenols to Induce rat hepatic drug-metabolizing enzymes. The compounds
examined, 3,4,5-, 2,4,6-, 2,4,5-, 2,3,6-, 2,3,5-, 2,3,4-trlchlorophenol,
2,3,5,6- and 2,3,4,5-tetrachlorophenols, were Injected 1ntraper1toneally In
corn oil Into 1-month-old male Wlstar rats. The enzyme activities assayed
were 4-d1methylam1noant1pyr1ne N-demethylase, benzo[a]pyrene hydroxylase,
aldrln epoxldase and mlcrosomal EROO. The Induction of 4-d1methylam1noant1-
pyrlne N-demethylase by 600 ymol/kg 3,4,5-trlchlorophenol was the only
significant (p<0.01) finding.
Sussmuth et al. (1980) found that S-9 from rats treated Intraperltoneally
with 2,3,4,5-tetrachlorophenol at 0.43 or 1.3 mmol enhanced the mutagenlcHy
of 2-am1noanthracene and benzo[a]pyrene in an Ames assay using Salmonella
typh1mur1um strain TA1538 compared with results with unlnduced S-9.
MHsuda et al. (1963) studied the effects of chlorophenols on oxldatlve
phosphorylatlon In rat liver mitochondria in vitro. The compounds studied
0020d 6-10 06/18/87
-------
were 2-, 3-, 4-chlorophenol, 2,4-, 2,6-d1chlorophenol, 2,4,5-, 2,4,6-tM-
chlorophenol and 2,3,4,6-tetrachlorophenol. At low concentrations, all
compounds studied uncoupled oxldatlve phosphorylatlon and accelerated
respiration. The most active compound was 2,3,4,6-tetrachlorophenol with a
I50 concentration of 2xlO~* H. As the number of chlorine atoms
decreased, the Inhibiting activity of the compound also decreased, so that
the Igfl values for trlchlorophenols, dlchlorophenols and monochlorophenols
were 3-18xlO~*. 42-400xlO~» and 150-520xlO~« M, respectively.
Acute toxldty values for the chlorinated phenols are listed In Table
6-1. In general, the acute toxldty of the chlorinated phenols Increases
with Increasing chloMnatlon (Exon, 1984). The mode of action of the
chlorinated phenols changes from convulsant-llke effects In the monochloro-
phenols to an Increase In the uncoupling of oxldatlve phosphorylatlon 1n the
higher chlorinated phenols.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Ep1dem1olog1cal studies of workers provide evidence
that chlorophenol exposure Is associated with soft tissue sarcomas and
malignant lymphomas. In a follow-up study, Lynge (1985) reported signifi-
cant Increases In relative risk ratios for lung cancer, rectal cancer and
soft tissue sarcomas In men exposed to 2,4-dlchlorophenol and 4-chloro-o-
cresol based phenoxy herbicides. In female workers, an Increase In the
relative risk of cervical cancer was observed. Lynge (1985) considered only
the soft tissue sarcoma Incidence to be of significance. Several other
ep1dem1olog1cal studies (Cook, 1981; Honchar and Halperln, 1981) also
reported elevated Incidences of soft tissue sarcoma. In a case-control
study, Pearce et al. (1986) found an Increased risk of non-Hodgk1ns lymphoma
(ICO code 202) 1n New Zealand meat workers who were exposed to chemicals
0020d 6-11 08/11/87
-------
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NR - Not reported
0020d
6-14
05/11/87
-------
Including 2,4,6-trlchlorophenol, but not In farmers, who were more likely to
be exposed to phenoxyherblcldes. All the ep1dem1olog1cal studies are con-
founded by multiple exposures and some have small study populations; never-
theless, the Influence of the chlorophenols cannot be determined from the
available data. The studies Involve exposures to multiple chemicals Includ-
ing phenoxyacetate herbicide compounds with dloxln (TCOO) contaminants.
According to the U.S. EPA (1986c) Carcinogen Risk Assessment Guidelines, the
evidence 1s limited; that 1s, Group 81 for this mixture of exposures.
6.2.2. Oral. 2,4-Olchlorophenol has been tested for cardnogenldty by
the NTP 1n a dietary study using rats and mice, but the report 1s not yet
available (NTP, 1986).
In an examination of the cardnogenldty of 2-chlorophenol and 2,4-d1-
chlorophenol In Sprague-Dawley rats, 24-32 offspring/sex of chlorophenol
exposed dams (Section 6.5.) were provided with drinking water containing 0,
5, 50 or 500 ppm 2-chlorophenol or 0, 3, 30 or 300 ppm 2,4-d1chlorophenol
from weaning until death or 24 months (Exon and Koller, 1985).
Microscopic examination of major organs of 2-chlorophenol and 2,4-dl-
chlorophenol exposed rats did not reveal Increased tumor Incidences,
decreased latency to tumor formation or variations 1n tumor types compared
with controls.
Innes et al. (1969) examined the cardnogenldty of 2,4,6-tMchloro-
phenol 1n B6C3F1 and B6AKF1 mice. Details of this study were also reported
In BRL (1968a) and evaluated by IARC (1979). Groups of at least 18 male and
18 female mice were dosed by stomach tube with 100 mg/kg/day 2,4,6-trl-
chlorophenol (maximum tolerated dose) In 5X gelatin beginning at 7 days of
age. Control mice were treated with gelatin. After the mice were weaned,
2,4,6-trlchlorophenol was added to the diet at 260 ppm and the mice were
0020d 6-15 08/11/87
-------
maintained until they reached 78 weeks of age. Since Innes et al. (1969)
examined a total 120 compounds (Including 2,4,6-trIchlorophenol), the actual
time of onset and termination were staggered to effectively conduct hlsto-
pathologlcal evaluations. Several groups of both positive and negative
controls were Included 1n this study to account for the staggering schedule.
Appropriate statistical evaluations were conducted to examine heterogenldty
among different control groups with respect to tumor types. Since this test
was not significant at the 5% level with any of the four categories of
tumors, the respective control groups were lumped together to give an
approximate figure with which the tumor1gen1c1ty of experimental compounds
could be compared. Total tumor Incidences were 10/18 and 8/18 In male and
female B6C3F1 mice, respectively, and 4/18 and 2/18 In male and female
86AKF1 mice, respectively (BRL, 1968a). Pooled control Incidences were
22/79 and 8/87 In male and female B6C3F1 mice and 16/90 and 7/82 In male and
female B6AKF1 mice (BRL, 1968a). When matched with pooled control Inci-
dences the combined Incidences of hepatomas (5/36) and retlculum-cell
sarcomas (6/36) In male and female B6C3F1 mice were Increased significantly
(p<0.05). In their evaluations, IARC (1979) observed that the results were
no longer significant when the data for males and females were considered
separately or when matched controls are considered. Thus, the IARC Working
Group considered the studies to be Inadequate to support cardnogenlclty of
2,4,6-tMchlorophenol. Innes et al. (1969) concluded that the results were
Inconclusive and that the cardnogenlclty of 2,4,6-tMchlorophenol should be
evaluated further.
The NCI (1979) conducted an oral cardnogenlclty study of 2,4,6-trl-
chlorophenol In F344 rats and B6C3F1 mice. Male and female rats and male
mice were fed 2,4.6-trlchlorophenol at dietary levels of 0, 5000 or 10,000
0020d 6-16 08/11/87
-------
ppm for up to 106 weeks. Female mice were fed 2,4,6-tMchlorophenol at TWA
doses of 0, 5214 or 10,428 ppm for 105 weeks (see Section 6.1.2.2.}-
In male rats, a dose-related significantly Increased Incidence of mono-
cytlc leukemia and malignant lymphoma or leukemia (Table 6-2) was observed.
The Incidence of leukemia was also Increased In female rats, but not
significantly. That 2,4,6-trlchlorophenol affects the hematopoletlc system
1s supported by the finding of bone marrow hyperplasla and leukocytosls (see
Section 6.1.2.2.). In mice, the Increased Incidence of hepatocellular
adenoma and hepatocellular carcinoma was significant (see Table 6-2). From
their results, NCI (1979) concluded that under the conditions of the study,
2,4,6-trlchlorophenol was carcinogenic In male F344 rats, Inducing lymphomas
or leukemlas and was carcinogenic In male and female mice. Inducing
hepatocellular carcinomas and adenomas.
6.2.3. Other Relevant Information. Exon and Roller (1983b, 1985) studied
the ability of 2-chlorophenol and 2,4-d1chlorophenol to promote the trans-
placental carcinogen ENU In Sprague-Oawley rats. Control and chlorophenol-
exposed dams (5, 50 or 500 ppm 2-chlorophenol or 3. 30 or 300 ppm 2,4-d1-
chlorophenol In drinking water) were also treated with ENU on gestation days
14-21. ENU was provided as precursors: ethylurea 1n the diet at 0.316X for
2-chlorophenol rats and at 0.15% for 2,4-dlchlorophenol rats, and sodium
nitrite 1n the drinking water at 1 ppm NO. for both groups. At weaning,
groups of 24-32 progeny of these dams were maintained on the parental
chlorophenol treatment for up to 2 years.
Increased tumor Incidences and decreased time-to-tumor latency occurred
In all groups of male rats from ENU treated dams exposed pre- and post-
natal 1y to 2-chlorophenol, compared with those from dams exposed to ENU
alone. These effects were not observed In female rats treated with ENU and
0020d 6-17 08/11/87
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2-chlorophenol or In either sex of the rats treated with ENU and 2,4-d1-
chlorophenol. The results of the 2,4-d1ch1orophenol study were confounded
by similar tumor Incidences In ENU and untreated control rats, so that all
or most tumors that developed may have been spontaneous.
Boutwell and Bosch (1959) studied the ability of 2- and 3-chlorophenol,
2,4-d1chlorophenol, 2,4,5- and 2,4,6-tMchlorophenol to promote tumors In
mouse skin treated with a single application of DMBA. The Initiator, DMBA
In benzene, was applied to the shaved skin of 2- to 3-month-old female
Sutter mice, followed with biweekly applications of 1 drop of a 20-21%
chlorophenol solution In benzene for 12-24 weeks. Tumors were Identified by
gross examination with periodic confirmation by microscopic examination.
All the chlorophenols examined, except 2,4,6-tMchlorophenol, exhibited
tumor promoting activity. In addition, an experiment with 2-chlorophenol In
dloxane also resulted In papllloma formation without application of the
Initiator. A dloxane control was not tested so It Is uncertain whether the
tumors were a result of 2-chlorophenol or dloxane treatment. The U.S. EPA
(1980c) criticized these studies on the basis of the severe Irritation
caused by the high chlorophenol concentrations used and the reporting of
only gross pathological results. U.S. EPA (1986c) also stated that the mice
were housed In wood cages treated with creosote, which may have Increased
the promoting activity.
Stoner et al. (1986) reported negative results when 2,4,6-trlchloro-
phenol was tested In a lung adenoma bloassay In strain A/J mice. Groups of
16 male and 16 female 8-week-old mice were treated with 2,4,6-trlchloro-
phenol In trlcaprylln by 1ntraper1toneal Injection or by gavage 3 times/week
for 8 weeks. The total dose each mouse received was 1200 mg/kg In the oral
experiment and 1200, 600 or 240 mg/kg In the Intraperltoneal experiment.
0020d 6-21 08/11/87
-------
Controls were treated wHh trlcapryHn. After the 8-week treatment period,
the mice were observed for 16 weeks, when they were sacrificed and examined
for tumors.
BRL (1968a) studied the carclnogenldty of 2,4,5- and 2,4,6-trlchloro-
phenol and 2,3,4,6-tetrachlorophenol 1n mice following a single subcutaneous
Injection. Groups of 18 male and 18 female B6C3F1 mice and groups of 18
male and 18 female B6AKF1 mice were Injected at 28 days of age. All mice
were observed for -18 months. The exposure levels used were 1000 mg/kg
2,4,5-trlchlorophenol In corn oil, 464 mg/kg 2,4,6-trlchlorophenol 1n corn
oil and 100 mg/kg 2,3,4,6-tetrachlorophenol 1n DMSO. The Incidence of
tumors In all three groups was not Increased compared with untreated
controls, or controls treated with corn oil or DMSO.
6.3. HUTAGENICITY
Hutagenlclty studies of the chlorinated phenols are summarized 1n Table
6-3. In Ames type assays, Haworth et al. (1983) observed negative results
for 2-, 3-, 4-chlorophenol, 2,3-, 2,5-, 2,6-, 3,4-d1chlorophenol, 2,4,5-
and 2,4,6-trlchlorophenol and equivocal results for 2,4- and 3,5-d1chloro-
phenol. In similar assays, Probst et al. (1981) and Simmon et al. (1977)
reported negative results for 2,4-d1chlorophenol; Rasanen and Hattula (1977)
reported negative results for 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-d1chloro-
phenol, 2,3,5-, 2,4,5-, 2,4,6-trlchlorophenol and 2,3,4,6-tetrachlorophenol.
Nestmann and Lee (1983) observed negative results for 2.6-d1chlorophenol
and 2,4,5-trlchlorophenol In Saccharomyces cerevlslae. In contrast, 2,4,6-
trlchlorophenol caused weak but significant results In a mutation study
using S. cerevlslae (FahMg et al., 1978). In DrosophUa melanogaster.
2,4,6-trlchlorophenol was negative for sex-linked recessive mutations
(Valencia et al., 1985).
0020d 6-22 08/11/87
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-------
In Chinese hamster V79 cells, Jansson and Jansson (1986) found negative
results for 2,4-, 2,6-d1chlorophenol, 2,4,6-trlchlorophenol and 2,3,4,6-
tetrachlorophenol without metabolic activation. In a study by Hattula and
Knuutlnen (1985), 2,6-d1chlorophenol tested negative In Chinese hamster V79
cells, while 2,4,6-trlchlorophenol and 2,3,4,6-tetrachlorophenol were weakly
positive In the absence of S-9, but negative when S-9 metabolic activation
was present. Probst et al. (1981) found negative results when 2,4-d1chloro-
phenol was tested for unscheduled DNA synthesis 1n primary rat hepatocytes.
Rats dosed orally with 130 mg/kg 2-chlorophenol every other day for 1
week showed a 5-fold Increase In chromatld deletions In their bone marrow
(Chung, 1978). Complete Inhibition of mitosis was noted In the bone marrow
of rats exposed to 2-chlorophenol for 2-3 weeks.
FahMg et al. (1978) found weak positive results when 2,4,6-trlchloro-
phenol was tested In a spot test In mice Injected with the compound on day
10 of gestation.
6.4. TERATOGEHICITY
Rodwell et al. (1984) examined the teratogenlclty of 2,4-dlchlorophenol
1n Fischer 344 rats. Pregnant rats were dosed with the compound In corn oil
by gavage at 0, 200, 375 or 750 mg/kg on gestation days 6-15. Throughout
the study, females were observed for toxIcUy and weighed at regular
Intervals. On gestation day 20, the dams were sacrificed and the fetuses
were weighed, sexed and examined for gross anomalies. Half of the fetuses
were examined for skeletal anomalies while the remaining were examined for
visceral anomalies. A dose-related statistically significant (p value' not
stated) Inhibition In maternal body weight occurred 1n all dose groups. The
only effects on the offspring were a slight Increase In early embryonic
death and reduced fetal weights In the high-dose group.
0020d 6-26 08/11/87
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BRL (19685) conducted teratogenldty studies of 2,4-d1ch1orophenol and
2,4,5-trlchlorophenol In AKR and C57B16 mice. The compounds were given by
subcutaneous Injection In OMSO on gestation days 6-14 for C57B16 mice or
days 6-15 for AKR mice. The mice were sacrificed and the fetuses were
weighed and examined for anomalies on gestation day 18 (C57B16 mice) or 19
(AKR mice). Additional parameters examined were maternal body weight,
maternal liver weight, amnlotlc fluid per fetus, placenta! weight and the
number of live fetuses and Implantations per litter. Control mice were
treated with DMSO.
In the 2,4-dlchlorophenol study, six C57B16 dams and six AKR dams were
treated as stated above at a dose of 74 mg/kg. The results showed an
Increase In anomalies 1n the AKR mice (18%) when compared with controls.
Half of the anomalies were extended legs. The fetal weights and maternal
liver weights of the AKR mice were also decreased and the amount of amnlotlc
fluid per fetus was Increased compared with controls. In contrast, C57B16
mice did not show an Increase In the number of anomalies noted (3%) and
fetal weights were comparable with controls. Changes In other parameters
were not noted.
In the 2,4,5-trlchlorophenol study, seven C57B16 dams and eight AKR dams
were treated by the previously stated protocol at a dose of 85 mg/kg. No
changes 1n maternal or fetal parameters were noted 1n either strain.
In a study by Neubert and DUlmann (1972), pregnant mice were dosed by
gavage with 2,4,5-trlchlorophenol at 0, 0.9 or 9.0 mg/kg bw on gestation
days 6-15. No teratogenlc effects (ascertained by the Incidence of cleft
palate 1n the offspring) were noted at either dose level. At 9 mg/kg,
slightly higher embryo mortality was noted. This Increase was marginally
statistically significant.
0020d 6-27 08/11/87
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Hood et al. (1979) conducted teratogenldty studies of 2,4,5-trlchloro-
phenol In CD-I mice. Groups of at least eight pregnant mice were treated by
gavage with 2,4,5-trlchlorophenol 1n honey and water (1:1) at 800-900 mg/kg
on 1 of gestation days 8-15 or at 250-300 mg/kg on 3 consecutive gestation
days (7-9, 10-12 or 13-15). Groups of control mice were treated with honey
and water or were left untreated. The dams were sacrificed on gestation day
18 and the numbers of live, dead and resorbed fetuses were determined. All
live fetuses were examined for gross malformations, while several fetuses
from each Utter were examined h1stopatholog1cally or were examined for
visceral or skeletal malformations. The only significant finding was an
Increase In prenatal mortality when dams were treated on day 14 as compared
with solvent treated controls (p<0.05); however, this Increase was not
significant when compared with untreated controls. The authors concluded
that under the study conditions, 2,4,5-trlchlorophenol produced no
significant effects on development.
Chernoff and Kavlock (1982) found that 2,4,5-trlchlorophenol In corn
oil, administered by gavage to CD-I mice at 800 mg/kg on gestation days 8-12
resulted 1n a significant reduction (p<0.05) In litter size compared with
controls. No effects were noted on maternal weight gain, survival of pups
at day 3 postpartum and pup weights on postpartum days 1 and 3. Gray and
Kavlock (1984) observed the growth and viability of the F. generation from
the Chernoff and Kavlock (1982) study for 250 days, and noted that 2,4,5-
trlchlorophenol treatment had no effects on postnatal growth, viability or
morphology. Ratings of the F, generation resulted In smaller Utters.
The reduction was significant by the t-test (p<0.05) but not by MANOVA or
ANOVA, although the comparison was made to an unusually high control value.
0020d 6-28 08/11/87
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Schwetz et al. (1974) examined the effect of 2,3,4,6-tetrachlorophenol
on the fetal development of rats. Groups of 20-40 pregnant Sprague-Dawley
rats were dosed by gavage with purified (99.6%) or commercial grade (73%)
2,3,4,6-tetrachlorophenol 1n corn oil at doses of 10 or 30 mg/kg on
gestation days 6-15. Control rats were dosed with corn oil. The dams were
sacrificed on gestation day 21 and the number and position of live, dead and
resorbed fetuses were recorded. The fetuses were weighed, examined for
gross anomalies and the crown-rump length was measured. Part of each Utter
was examined for visceral defects, while the remaining fetuses were examined
for skeletal abnormalities. No changes In maternal weight gain or other
signs of maternal toxIcHy occurred 1n dams treated with either purified or
commercial grade 2,3,4,6-tetrachlorophenol. The treatments also had no
effect on resorptlons, fetal body weight, fetal crown-rump length or gross
anomalies. A significant Incidence of subcutaneous edema was observed In
the 10 mg/kg groups, but not 1n the 30 mgAg groups. Significantly
Increased Incidences of delayed ossification of the skull bones occurred In
fetuses (23/88, p<0.05) and litters (8/16, p<0.05) of the 30 mg/kg commer-
cial grade tetrachlorophenol group compared with controls (14/143 fetuses,
6/31 Utters). In the 30 mg/kg purified tetrachlorophenol group, the
Incidence of delayed ossification of the skull In fetuses (18/104) was
significantly Increased, but net the Incidences 1n Utters (7/20).
In order to clarify and extend the work of Schwetz et al. (1974),
Research Triangle Institute (1987) (sponsored by the Office of Solid Waste,
U.S. EPA) conducted a teratology study with rats gavaged at different doses
of purified grade of 2,3,4,6-tetrachrlorophenol. The study was conducted
using a two-repl1cate design; the second replicate was Initiated (gestation
day 0) 21 days after Initiation of the first replicate. Sperm-positive
0020d 6-29 08/11/87
-------
females (14-20 animals/group 1n each replicate) were exposed by gavage to
TCP suspended In olive oil at doses of 0, 25, 100 and 200 mg/kg/day on
gestation days 6-15. Dams were weighed on gestation days 0, 6 through 15
(prior to dally dosing), and on gestation day 20 (prior to sacrifice), and
were observed dally during the treatment period and prior to sacrifice on
gestation day 20 for clinical signs of toxldty. On gestation 20, dams were
anesthetized with CO. and sacrificed by cervical dislocation. At
sacrifice, dams were weighed and examined for gross signs of toxlclty.
Liver weight, gravid uterine weight, and status of uterine contents were
determined. Live fetuses were dissected from the uterus and Immediately
anesthetized by hypothermia. Individual live fetuses were weighed, sexed,
and examined for external morphological abnormalities. All live fetuses
were examined for visceral malformations using a fresh tissue dissection
method. Half of the fetal heads were removed, fixed in Bouln's solution,
and examined by free hand sectioning of the whole fetal head. All fetal
carcasses were double-stained w1h Aldan Blue/Alizarin Red S and examined
for skeletal malformations. Results of this study Indicated no
statistically significant adverse maternal effects at 25 or 100 mg/kg/day.
However, dams 1n the 100 mg/kg/day group exhibited a corrected gestatlonal
weight gain that was only 87% of the control group, so that the mid-dose
appeared to approach the low effect level for this endpolnt. Maternal
toxldty was Indicated at 200 mg/kg/day by a significant reduction In
corrected gestatlonal weight gain to 74% of the control value. During the
posttreatment period, all TCP-exposed groups consumed significantly more
food than the control group. Embryo/fetal growth and prenatal viability
were not adversely affected by TCP exposure, nor was any definitive evidence
obtained for an effect of TCP upon fetal morphological development. Thus,
QQ20d 6-30 08/11/87
-------
TCP did not appear to be a selective developmental toxicant with regard to
Jhn utero development of the postlmplantatlon conceptus.
These teratogenlclty studies are summarized In Table 6-4.
6.5. OTHER REPRODUCTIVE EFFECTS
Exon and Roller (1982, 1985) studied the reproductive effects of
2-chlorophenol, 2,4-dlchlorophenol and 2,4,6-trlchlorophenol In Sprague-
Dawley rats. Groups of 12-20 female rats were treated with a chlorophenol
In their drinking water from 3 weeks of age through breeding and lactation.
The females were mated at 90 days of age with untreated males. The drinking
water contained 0, 5, 50 or 500 ppm 2-chlorophenol or 0, 3, 30 or 300 ppm
2,4-d1chlorophenol or 2,4,6-tMchlorophenol. Statistical methods Included
analysis of variance and chl-square tests. The Investigators considered
results to be statistically significant If p<0.10.
Significantly (plO.10) smaller IHter sizes compared with controls
occurred In rats treated with 500 ppm 2-chlorophenol, 300 ppm 2,4-dlchloro-
phenol or 300 ppm 2,4,6-tMchlorophenol. The percent of stillborn pups was
significantly (p<0.10) Increased 1n the 500 ppm 2-chlorophenol treated group.
In the 2,4-d1chlorophenol and 2,4,6-trlchlorophenol groups, the percent of
stillborn pups tended to be Increased over controls, but the Increase was
not statistically significant. In the group of rats given 2,4-dlchloro-
phenol, survival to weaning was significantly (p<0.10) less than controls.
Treatment with any of the chlorophenols examined did not have any effects on
the birth weight of pups. No data concerning effects on dams were reported.
Blackburn et al. (1986) examined reproductive effects In male Long Evans
hooded rats treated by gavage with 2,4,6-trlchlorophenol. Groups of >15
male rats were treated with 2,4,6-trlchlorophenol (99X pure) In corn oil at
0, 100, 500 or 1000 mg/kg, 5 days/week for 11 weeks. Before treatment began
0020d 6-31 08/11/87
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and after 10 weeks of treatment, copulatory behavior and semen profiles
(sperm count, motlllty and morphology) were examined. At 11 weeks, the
males were mated with untreated females. The females were sacrificed on
gestation day 18 .and the sex, weight and viability of the fetuses were
determined. No effect on male reproduction was noted. The only effects
observed were In the high-dose group 1n which a reduction In weight gain
occurred and eight rats died during the flrs.t 4 weeks of treatment.
Blackburn et al. (1986) also studied the effects of 2,4,6-tMchloro-
phenol on female reproduction In groups of >30 rats treated with 0, 100, 500
or 1000 mg/kg. The rats were dosed 5 days/week for 2 weeks and then mated
with untreated controls. Dally dosing continued from the beginning of
mating through gestation day 21. The females were allowed to deliver, and
the sex ratio of the litter and body weight of the pups were recorded. On
day 4 postpartum the Utters were reduced to eight pups and at weaning the
Utters were further reduced to four pups (two males and two females).
These remaining pups were sacrificed on day 42 postpartum.
Body weights weVe significantly depressed In high-dose females (p<0.05)
during the 2 weeks of dosing before mating and on days 1, 7 and 14 of
gestation. The only other effect noted was a decrease In body weight of the
fetuses from the 500 and 1000 mg/kg treated groups on postpartum day 1. By
postpartum day 4 these differences were no longer detected. Blackburn et
al. (1986) stated that this decrease may have been a result of a slight
Increase 1n Utter size In the 500 and 1000 mg/kg groups. The authors
concluded that at maximally tolerated doses, 2,4,6-trlchlorophenol did not
affect male or female reproduction.
OQ20d 6-34 08/11/87
-------
Seyler et al. (1984) found that 2,5-, 3,4- and 3,5-d1chlorophenol
significantly (p<0.05) depressed sperm penetration of ova from mice In vitro
at a concentration of 1 mM. This effect was not observed with 2,4-dlchloro-
phenol. In addition, no effects on sperm penetration of ova were noted
using sperm from mice given drinking water containing 2,4-dlchlorophenol at
0, 0.2, 0.6 or 2.0 mg/mt for 90 days.
6.6. SUMMARY
In a subchronlc Inhalation study of 4-chlorophenol (Gurova, 1964), rats
exposed to 2 mg/m3, 6 hours/day for 4 months showed neuromuscular excit-
ability, a reduction of endurance. Increased myoneural excitability, slight
congestion of organs and minor flbrotlc changes In alveolar septa. Gurova
(1964) also reported symptoms of nervous exhaustion, Insomnia, Irritability,
frequent mood changes and rapid fat1gab1!1ty In workers exposed to 4-chloro-
phenol In an aniline dye plant. The lack of detail In these studies
precludes adequate assessment of their reliability.
Kleu and Goltz (1971) reported symptoms of chloracne, decreased sexual
activity, easy fatlgabllHy, Irritability, muscular weakness, loss of
appetite and memory, discouragement, alcohol Intolerance, and loss of
Interest In workers occupatlonally exposed to a tMchlorophenol formulation
for up to 15 years. A causal relationship was not established. Alexanders-
son and Hedenstlerna (1982) found pulmonary effects In workers exposed to
low levels of trlchlorophenols In gas masks for up to 10 years.
Exon and Keller (1985) found 1mmunolog1cal effects In rats exposed sub-
chronically to 2,4-d1chlorophenol at 30 and 300 ppm In their drinking water.
Similar effects were not noted In rats exposed to up to 500 ppm 2-chloro-
phenol, or up to 300 ppm 2,4,6-trlchlorophenol. Kobayashl et al. (1972)
reported minor hlstologlcal changes In the livers of mice fed 230 mg/kg/day
2,4-d1chlorophenol for 6 months. No effects were noted at 100 mg/kg/day.
0020d 6-35 08/11/87
-------
A subchronlc drinking water study of 2,4-d1ch1orophenol In mice found no
consistent effects that could be related to treatment at up to 2 ppm
(Borzelleca et a"L, 1985a). The study was confounded by the addition of
Emulphor to the dosing solution.
McColllster et al. (1961) studied the toxlclty of 2,4,5-trlchlorophenol.
In a 28-day gavage study, microscopic changes were noted In the liver and
kidneys of rabbits dosed with 0.1 and 0.5 mg/kg but not 0.01 mg/kg 20 times
over the study period. No changes were noted 1n rats dosed with 2,4,5-trl-
chlorophenol at up to 1.0 g/kg 18 times over 24 days. In a 98-day study,
pathologic changes In the livers and kidney were noted 1n rats provided with
diets containing 2,4,5-trlchlorophenol at 0.03 and 1.0% but not at <0.01%.
In a 70-day dietary study, Vlzethum and Goerz (1979) reported that 0.05%
2,4,5-trlchlorophenol was not porphyrogenlc In rats. The NCI {1979} sub-
chronic study noted an Increase In splenic hematopolesls and mldzonal
vacuolatlon of hepatocytes 1n rats fed 2,4,5-trlchlorophenol In the diet at
46,000 ppm for 7 weeks. Survival of rats fed >21,500 ppm but not <14,700
ppm was also affected. In mice, survival was affected at 31,500 ppm but not
at <21,500 ppm (NCI, 1979); no h1stopatholog1cal data were reported. A
dose-dependent decrease In body weight was observed In both rats and mice In
the NCI (1979) study.
Kawano et al. (1979) observed changes In growth, organ weights, several
biochemical parameters and liver drug metabolizing enzymes 1n rats fed diets
containing 2,3,5-trlchlorophenol or 2,3,4,5-, 2,3,5,6- or 2,3,4,6-tetra-
chlorophenol at 0.2% for 3 weeks. Dose-related hlstopathologlc changes In
the liver were noted In rats treated by gavage with 2,3,4,5-tetrachloro-
phenol for 55 days at >50 mg/kg/day but not at 10 mg/kg/day (Hattula et al.,
1981b).
0020d 6-36 08/11/87
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In a chronic study, numbers of R8C and hemoglobin levels were Increased
In rats provided with drinking water containing 500 ppm 2-chlorophenol or
300 ppm 2,4-dlchlorophenol, but not at 10-fold lower concentrations (Exon
and Koller, 1985). The NCI (1979) found a dose-related Increase In the
Incidences of bone marrow hyperplasla and leukocytosls in rats at 5000 and
10,000 ppm. In mice, dose-related hyperplasla of the liver was noted In
males at 5000 and 10,000 ppm (NCI, 1979).
In studies of the Induction of enzymes by the chlorinated phenols,
Carlson (1978) found that 2,4,5-trlchlorophenol reduced mlcrosomal NADPH-
cytochrome c reductase activity and cytochrome P-450 content. Oenomme et
al. (1983) reported that 4-d1methylam1noant1pyr1ne N-demethylase was Induced
by 3,4,5-trlchlorophenol. The other tr1- and tetrachlorophenols had no
effects on enzyme Induction. The mutagenlclty of 2-aralnoanthracene and
benzo[a]pyrene were enhanced in an Ames assay by S-9 from rats treated with
2,3,4,5-tetrachlorophenol (Sussmuth et al., 1980).
HHsuda et al. (1963) observed that the chlorophenols Inhibit oxldative
phosphorylatlon ^n vitro, with the Inhibiting activity increasing with
Increasing chlorlnatlon.
The acute toxlclty of the chlorinated phenols has been studied by a
number of Investigators (Delchmann, 1944; Bubnov et al., 1969; Borzelleca et
al., 1985a,b; Farquharson et al., 1958; ChMstensen and Luglnbyhl, 1975;
Oelchmann and Mergard, 1948; Angel and Roberts, 1972; Gurova, 1964;
Schrotter et al., 1977; Kobayashl et al., 1972; Vernot et al., 1977;
McColllster et al., 1961; Ahlborg and Larrsson, 1978; Hattula et al.,
1981b); In general, the toxlclty Increases as the chlorlnatlon Increases.
0020d 6-37 08/11/87
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Ep1dem1olog1cal studies that are confounded by multiple exposures
Indicate that chlorophenol exposure 1s associated with soft tissue sarcomas
and malignant lymphomas (Lynge, 1985; Cook, 1981; Honchar and HalpeMn,
1981; Pearce et aT.. 1986).
Increased tumor Incidences were not observed In rats exposed to up to
500 ppm 2-chlorophenol or up to 300 ppm 2,4-d1chlorophenol In their drinking
water for 2 years (Exon and Keller, 1985). Innes et al. (1969) found
Inconclusive results In a carclnogenlcHy study of 2,4,6-trlchlorophenol In
mice. In the NCI (1979) study of 2,4,6-trlchlorophenol, an Increased
Incidence of leukemia was observed 1n male rats, while an Increase In the
Incidence of liver carcinoma and adenoma was observed In male and female
mice.
Exon and Koller (1985) found that 2-chlorophenol Increased tumor
Incidence and decreased tumor latency of transplacental tumors In rats
Initiated by ENU. This effect was not observed with 2,4-dlchlorophenol
although the rats were exposed to a lower level of ENU.
In a study by Boutwell and Bosch (1959), 2-, 3-chlorophenol, 2,4-dl-
chlorophenol and 2,4,5-tMchlorophenol acted as promoters of skin tumors In
mice treated with a single dose of DMBA. 2,4,6-TMchlorophenol was negative
In the skin tumor promoting study. 2,4,6-Trlchlorophenol was also negative
In a lung adenoma bloassay In which strain A/J mice were dosed by gavage or
1ntraper1toneal Injection (Stoner et al., 1986). Tumor Incidences were not
Increased In mice observed for 18 months following a single subcutaneous
Injection of 2,4,5-, 2,4,6-trlchlorophenol or 2,3,4,6-tetrachlorophenol
(BRL, 1968a).
0020d 6-38 08/11/87
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2-, 3-, 4-Chlorophenol, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, 3,5-d1chlorophenol,
2,3,5-, 2,4,5-, 2,4,6-trlchlorophenol and 2,3,4,6-tetrachlorophenol have
tested negative In at least one assay for reverse mutation 1n !5. typhlmuMum
(Haworth et al., 1-983; Probst et al., 1981; Simmon et al., 1977; Rasanen and
Hattula 1977). Haworth et al. (1983) found equivocal results for 2,4- and
3,5-d1chloropheno1.
In Chinese hamster V79 cells, 2,4-, 2,6-d1chlorophenol, 2,4,6-trlchloro-
phenol and 2,3,4,6-tetrachlorophenol did not cause an Increase 1n mutation
(Jansson and Jansson,. 1986; Hattula and Knuutlnen, 1985). In contrast,
weakly positive results were noted 1n Chinese hamster V79 cells with
2,4,6-trlchlorophenol and 2,3,4,6-tetrachlorophenol In the absence of S-9
but not 1n the presence of S-9 (Hattula and Knuutlnen, 1985); 2,4-01chloro-
phenol did not cause an Increase 1n unscheduled DMA synthesis In primary rat
hepatocytes (Probst et al., 1981).
An Increase In chro:nat1d deletions was noted 1n rats dosed with
2-chlorophenol (Chung, 1978). 2,4,6-TMchlorophenol was weakly positive 1n
a spot test In mice (FahMg et al., 1978).
Teratogenlc studies of the chlorinated phenols Indicate that the com-
pounds are not potent teratogens although they are fetotoxlc. Fetotoxlclty
as evidenced by Increased embryonic death was found for 2,4-dlchlorophenol
at oral doses of 750 rag/kg/day (Roduell et al., 1984) and 2,4,5-tMchloro-
phenol at >9 ng/kg/day (Neubert and OHlmann, 1972; Hood et al., 1979;
Chernoff and Kavlock, 1982). Schwetz et al. (1974) reported an Increase of
subcutaneous edema In rats treated through gestation with 2,3,4,6-tetra-
chlorophenol at 10 mg/kg/day. This effect was not observed at 30 mg/kg/day,
although at the higher dose an Increase In delayed ossification of the skull
bones was observed. In a similar study (Research Triangle Institute, 1987)
0020d 6-39 08/11/87
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where CD mice were gavaged with 0, 25, 100 and 200 mg/kg/day TCP on
gestation days 6-15, there were no adverse effects of TCP exposure on
embryo/fetal growth and prenatal viability, nor was there any definitive
evidence of an effect of TCP upon fetal morphological development. At the
200 mg/kg/day TCP dosage, corrected maternal weight gain was significantly
depressed below controls. The only study In which an Increased Incidence of
anomalies was observed was In a study by BRL (1969b) In which an Increase In
anomalies In AKR mice given subcutaneous Injections of 2,4-d1chlorophenol at
74 mg/kg/day during gestation was noted. This effect was not observed In
C57B16 mice or In either strain of mice when they were treated with 85
mg/kg/day 2,4,5-tMchlorophenol.
Reproductive studies of 2-chlorophenol, 2,4-d1chlorophenol and
2,4,6-tMchlorophenol also resulted In reduced Utter sizes of rats treated
from 3 weeks of age with >300 ppm 1n drinking water through mating and
lactation (Exon and Keller, 1982). Blackburn et al. (1986) reported no
significant effects on reproduction In rats treated by gavage with up to
1000 mg/kg 2,4,6-trlchlorophenol 5 days/week. In an hj. vitro study, Seyler
et al. (1986) found that 2.5-, 3,4- and 3,5-dlchlorophenol significantly
depressed sperm penetration of ova from mice.
0020d 6-40 08/11/87
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
Existing guidelines and standards for the chlorophenols covered 1n this
document are given In Table 7-1. No guidelines or standards were located
for 3,5-d1chlorophenol, 2,3,4-, 2,3,5-, 2,3,6- or 3,4,5-trlchlorophenol or
2,3,4,5- or 2,3,5,6-tetrachlorophenol.
The U.S. EPA (1978b) Issued an RPAR for 2,4,5-tMchlorophenol. The
concern was based solely on oncogenlclty and fetotoxlclty data for TCOD, a
common contaminant 1n 2,4,5-tMchlorophenol. U.S. EPA (1979b) requested
that additional Information be submitted regarding 2,4,5-trlchlorophenol/TCOD
exposure and estimated safety. U.S. EPA (1986d) stated that all uses of
2,4,5-trlchlorophenol have been voluntarily cancelled or suspended.
7.2. AQUATIC
U.S. EPA (1980b) noted that the derivation of a single criterion for all
chlorophenols was Inappropriate because of 'the wide variability In toxlclty
of these compounds; therefore, criteria for Individual chlorophenols were
not calculated. U.S. EPA (1980b) did, however. Identify the lowest reported
toxic concentrations for freshwater and saltwater organisms. For freshwater
species, acute toxlclty occurred at concentrations as low as 0.03 mg/i
4-chloro-3-methylphenol, a methylated derivative of 4-chlorophenol, and
chronic toxlclty occurred at concentrations as low as 0.97 mg/i 2,4,6-tr1-
chlorophenol. Among saltwater species, acute toxlclty occurred at concen-
trations as low as 0.44 mg/i 2,3,5,6-tetrachlorophenol. No data concern-
Ing chronic toxlclty to saltwater species were available.
U.S. EPA (1980c) summarized aquatic toxlclty data for 2-chlorophenol and
concluded that acute toxldty to freshwater species occurred at concentra-
tions as low as 4.38 mg/i, and that flavor Impairment had been reported In
one fish species at 2 mg/l. No other conclusions were made.
0021d 7-1 06/18/87
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TABLE 7-1
Guidelines and Standards for Chlorophenols
Chlorophenol
Guideline/Standard
Reference
2-Chlorophenol
3-Chlorophenol
4-Chlorophenol
2,3-D1chlorophenol
2,4-01chlorophenol
2,5-Olchlorophenol
2,6-01chlorophenol
3,4-01chlorophenol
2,4,5-TM Chlorophenol
2.4,6-TMchlorophenol
2.3,4,6-Tetrachlorophenol
DWEL, 0.175 mg/l
RfO, 0.005 mg/kg/day
organoleptlc AWQC, 0.1 ug/i
organoleptlc AWQC, 0.1 yg/l
organoleptlc AWQC, 0.1 yg/i
organoleptlc AWQC, 0.04 »g/l
DWEL, 0.105 mg/l
RfO, 0.003 mg/kg/day
RfO, 0.003 mg/kg/day
health AWQC, 3.09 mg/l
organoleptlc AWQC, 0.3 vg/l
organoleptlc AWQC, 0.5 yg/l
organoleptlc AWQC, 0.2
organoleptlc AWQC, 0.3 wg/l
oral RfO, 0.1 mg/kg/day
RfO$g, 70 mg/day
RfOQ, 7.0 mg/day
health AWQC, 2.6 mg/l
organoleptlc AWQC, 1.0 yg/l
qi*. 0.0114 (mg/kg/day)"1
10~s risk level, 3.07xlO"2 mg/l
q-j*. 0.01984 (mg/kg/day)"1
10~» risk level, 36 Mg/l*
organoleptlc AWQC, 2.0 wg/l
q-|*, 0.0198 (mg/kg/day)"1
organoleptlc AWQC. 1.0 wg/l
oral RfO, 0.01 mg/kg/day
U.S. EPA, 1986b
U.S. EPA, 1986b
U.S. EPA, 1980c
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
U.S.
EPA,
EPA,
EPA,
EPA,
EPA,
ERA,
EPA,
EPA,
EPA,
EPA,
EPA,
EPA,
EPA,
EPA,
EPA,
EPA,
EPA.
EPA,
EPA,
EPA,
EPA.
1980b
1980b
1980b
1986b
19865
1986c
19804
1980d
1980b
1980b
1980b
1985a
1984a
1984a
1980b
1980b
1986b
1986b
198Qb
1980b
1980b
U.S. EPA, 1984b
U.S. EPA. 1980b
U.S. EPA, 1985b
*Assum1ng consumption of 2 I/day drinking water and 6.5 g/day fish and
shellfish.
0021d
7-2
06/18/87
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U.S. EPA (1980d) summarized aquatic toxlclty data for 2,4-d1chlorophenol
and concluded that acute and chronic toxlclty to freshwater species occurred
at concentrations as low as 2.02 and 0.365 mg/l, respectively. Mortality
to early life stages of one fish species occurred at concentrations as low
as 0.07 mg/i. No data concerning 2,4-d1chlorophenol toxlclty to saltwater
species were available.
U.S. EPA (1980b,c,d) did not recommend criteria for the chlorinated
phenols for the protection of aquatic life, but stated that lower concentra-
tions might be toxic to species more sensitive than those that were tested.
0021d 7-3 06/18/87
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-------
8. RISK ASSESSMENT
8.1. CARCIN06ENICITY
8.1.1. Inhalation. Ep1dem1o1og1cal studies provide limited evidence that
occupational exposure to chlorophenols may be associated with soft tissue
sarcomas and malignant lymphomas although the Influence of chlorophenols
alone cannot be determined. Lynge (1985) found an Increase 1n soft tissue
sarcoma \n male workers exposed to 2,4-d1chlorophenol and 4-chloro-o-cresol
based phenoxy herbicides. In a case-control study, Pearce et al. (1986)
reported an Increased risk of non-Hodgklns lymphoma In New Zealand meat
workers exposed to chemicals Including 2,4,6-tMchlorophenol. These studies
are confounded by some small study populations and multiple exposures.
Other data concerning the cardnogenlcHy of the chlorophenols following
Inhalation exposure could not be located In the available literature as
cited In Appendix A.
8.1.2. Oral. Exon and Koller (1985) reported negative results In a
cardnogenlcHy study of 2-chlorophenol and 2,4-dlchlorophenol 1n rats.
Rats exposed to the compounds J_n utero were provided with drinking water
containing 2-chlorophenol at 0, 5, 50 or 500 ppra, or 2,4-d1chlorophenol at
0, 3, 30 or 300 ppm for up to 24 months.
Results of a cardnogenlcHy study of 2,4,6-tMchlorophenol (Innes et
al., 1969; BRL, 1968a; IARC. 1979) were Inconclusive. Two strains (B6C3F1
and B6AKF1) of male and female mice were treated with 2,4,6-trlchlorophenol
at 100 mg/kg/day by gavage starting at 7 days of age. After weaning, the
mice were provided with diets containing 2,4,6-trlchlorophenol at 200 ppm
for -18 months. IARC (1979) stated that the combined Incidences of
hepatomas and retlculum-cell sarcomas In male and female B6C3F1 mice were
Increased significantly (p<0.05), but that the significance disappeared when
the data for males and females were considered separately.
0022d 8-1 08/11/87
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The NCI (1979) oral carclnogenldty study of 2,4,6-trlchlorophenol
reported dose-related statistically significant Increases In the Incidence
of leukemia In male F344 rats and the Incidence of liver carcinoma and
adenoma 1n male and female B6C3F1 mice. Male and female rats and male mice
were fed diets containing 2,4,6-trlchlorophenol at 0, 5000 or 10,000 ppm for
up to 106 weeks, while female mice were fed TWA doses of 0, 5214 or 10,428
ppm for 105 weeks.
8.1.3. Other Relevant Information. Exon and Koller (1985) observed
Increased tumor . Incidence and decreased time-to-tumor latency 1n male
offspring of rat dams exposed orally to 2-chlorophenol both pre- and post-
natally and treated orally with ENU during gestation compared with rats
given ENU alone. This effect was not observed In rats exposed to ENU and
2,4-d1chlorophenol.
Boutwell and Bosch (1959) found that 2-, 3-chlorophenol, 2,4-dlchloro-
phenol and 2,4,5-tMchlorophenol applied to the skin promoted the formation
of skin tumors In mice following a single application of DHBA. This effect
was not observed with 2,4,6-trlchlorophenol. This study has been criticized
on the basis of severe Irritation caused by the high concentrations of
chlorophenols used and the reporting of only gross pathological results
(U.S. EPA, 1980c).
2,4,6-Trlchlorophenol tested negative In a mouse lung adenoma bloassay
by both oral and Intraperltoneal routes of exposure (Stoner et al., 1986).
The mice were treated over an 8-week period with a total dose of 1200 mg/kg
In the oral experiment and 1200, 600 or 240 mg/kg 1n the Intraperltoneal
experiment. After dosing, the mice were maintained for 16 weeks when they
were examined for tumors.
0022d 8-2 06/18/87
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BRL (1968a) found no Increased tumor Incidences In mice given single
s.c. Injections of 2,4,5-, 2,4,6-tMchlorophenol or 2,3,4,6-tetrachloro-
phenol and observed for -18 months. The exposure levels used were 1000
mgAg 2,4,5-tMchlorophenol, 464 mg/kg 2,4,6-tMchlorophenol and 100 mg/kg
2,3,4,6-tetrachlorophenol.
8.1.4. Height of Evidence. The only available carclnogenlclty study of a
monochlorophenol 1s a- negative drinking water study of 2-chlorophenol In
mice (Exon and Keller, 1985). Studies by both Exon and Keller (1985) and
Boutwell and Bosch (1959) Indicate that 2-chlorophenol may be a promoter.
The study by Boutwell and Bosch (1959) also Indicated that 3-chlorophenol
may be a promoter. No human data concerning the carclnogenlclty of the
monochlorophenols were available. The limited data concerning the carclno-
genlclty of the monochlorophenols Indicate that 2-, 3- and 4-chlorophenol
should be classified as CAG Group 0 chemicals (U.S. EPA, 1986e), Inadequate
human and animal evidence of carclnogenlclty.
2,4-01chlorophenol tested negative 1n an oral carclnogenlclty study In
mice (Exon and Koller, 1985). In addition 2,4-d1chlorophenol tested
negative In a promotion study using EMU (Exon and Koller, 1985), although
Boutwell and Bosch (1959) found positive results for the promotion of
DMBA-lnduced skin tumors In mice. The ep1dem1olog1cal study by Lynge (1985)
Indicates that there may be an association between the chlorophenols and
soft tissue sarcomas. Because of exposures to other chemicals, however,
this study -Is considered Inadequate evidence of human carclnogenlclty. The
remaining dlchlorophenol Isomers (2,3-, 2,5-, 2,6-, 3,4- and 3,5-) have not
been* tested for carclnogenlclty. The lack of data concerning the
carclnogenlclty of the dlchlorophenols Indicate that they should also be
classified as CAG Group D chemicals (U.S. EPA, 1986e), Inadequate human and
animal evidence of carclnogenlclty.
0022d 8-3 08/11/87
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Pearce et al. (1986) reported an Increase In the risk of non-Hodgk1ns
lymphoma In New Zealand meat workers exposed to 2,4,6-trlchlorophenol and
other chemicals. This study provides Inadequate evidence of human cardno-
genldty of 2,4,6-trlchlorophenol. The Increased Incidence of hepatomas and
retlculum-cell sarcoma In B6C3F1 mice (BRL, 1968a) suggests that 2,4,6-trl-
chlorophenol may be a carcinogen. Further evidence that 2,4,6-trlchloro-
phenol Is a carcinogen Is provided by the NCI (1979) study. In which an
Increased Incidence of leukemia was observed In male rats, and an Increased
Incidence of hepatomas was observed 1n male and female mice. The NCI (1979)
study provides sufficient animal evidence of cardnogenlclty of 2,4,6-trl-
chlorophenol. Therefore, according to the CAG classification scheme (U.S.
EPA, 1986e) 2,4,6-trlchlorophenol can be classified as an EPA 82 chemical,
probable human carcinogen.
The remaining tMchlorophenols (2,3,4-, 2,3,5-, 2,3,6-, 2,4,5- and
3,4,5-) and the tetrachlorophenols (2,3,4,5-, 2,3,4,6- and 2,3,5,6-) have
not been adequately studied 1n cardnogenlclty bloassays. Therefore, these
compounds are placed In EPA Group 0 (U.S. EPA, 1986e), Inadequate evidence
of human and animal cardnogenlclty or no data available.
8.1.5. Quantitative Risk Estimates.
8.1.5.1. INHALATION There were no Inhalation studies concerning
the cardnogenlcUy of 2,4,6-trlchlorophenol located In the available
literature cited In Appendix A. The NCI (1979) oral bloassay Indicates that
2,4,6-trlchlorophenol 1s an animal carcinogen by 1ngest1on.
8.1.5.2. ORAL The NCI (1979) oral bloassay Indicates that
2,4,6-trlchlorophenol Is a carcinogen 1n rats and mice. Male rats and mice
were provided with diets containing 2,4,6-trlchlorophenol at 0, 5000 or
10,000 ppm for up to 107 weeks. In male rats, the Incidences of leukemia
e
0022d 8-4 08/11/87
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were 4/20 controls, 25/50 low dose and 28/50 high dose. In male mice, the
incidences of liver carcinoma or adenoma were 4/20 controls, 32/49 low dose
and 39/47 high dose. Both tumor Incidences are statistically significant by
the Cochran-ArmUage test for linear trend and the Incidences of the treated
groups are statistically significant by the Fisher Exact test. Further
details of this study were presented 1n Section 6.2.2.
Values for q * can be calculated using the data for Increased Inci-
dences of leukemia, leukemia or malignant lymphoma In male rats or hepato-
cellular adenoma or carcinoma 1n male mice In the NCI (1979) studies
(Appendices B-l, B-2 and B-3). Dietary concentrations were transformed to
mg/kg/day by multiplying by a factor of 0.05 for rats and 0.13 for mice (It
Is assumed that rats and mice consume a dally amount of food equal to 5 and
13%, respectively, of their body weight). The unadjusted q,*s were calcu-
lated using the computerized multistage model developed by Howe and Crump
(1982). The human q *s were calculated by multiplying the unadjusted
q,*s by the cube roots of the ratios of the reference human body weight
(70 kg) to the animal body weights (0.36 kg for male rats and 0.04 kg for
male mice, as estimated from growth curves 1n the study). The most
conservative q * of 1.94xlO~a (mg/kg/day)"1 was obtained using the
data for hepatocellular adenoma/carcinoma In male mice. Using the q^ and
assuming that a 70 kg man consumes 2 l water/day, the concentrations In
drinking water corresponding to Increased lifetime risk of cancer at risk
levels of 10"5, 10"» and 10"7 are 1.8xlO"a, 1.8xlO~» and
1.8x10"* mg/l.
In deriving a q,* of 1.4xlO~a (mg/kg/day)"1 for 2,4,6-trlchloro-
phenol, U.S. EPA (1986b) used the leukemia Incidence levels In male rats.
0022d 8-5 08/11/87
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The reason that the leukemia Incidences, rather than the Incidences of liver
tumors 1n male mice were used was not discussed. U.S. EPA (1980b, 1984b)
derived a q,* of 1.98xlO~2 (mg/kg/day)'1 using the liver tumor data In
male mice. The reason for the small difference In q,* derived In Appendix
B-3 and that derived by U.S. EPA (1980b, 1984b) 1s not apparent; however. It
may be due to differences In the multistage model program (GLOBAL 79) used
by U.S. EPA (1980b) and GLOBAL 82, used In Appendix B.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) -- The lack of
data concerning subchronlc Inhalation toxldty of the chlorophenols pre-
cludes the derivation of Inhalation RfOs for all 18 chlorophenol congeners
discussed In this document.
The only subchronlc Inhalation study available was a Russian study
concerning the toxldty of 4-chlorophenol In rats (Gurova, 1964). .This
study (see Section 6.1.1.1.) examined the Inhalation toxlclty of 4-chloro-
*
phenol at one dose In an unstated number of white rats. No Information
concerning control rats was provided. In rats exposed to 4-chlorophenol at
2 mg/m3, 6 hours/day for 4 months, changes In weight gain, neuromuscular
excitability, reduction In endurance. Increased myoneural excitability,
slight congestion of organs and minor flbrotlc changes 1n the alveolar septa
of some rats were noted. Because the significance of these effects Is
uncertain, and because there are no supporting data, this study Is not
appropriate for risk assessment.
8.2.1.2. CHRONIC EXPOSURES -- Data concerning chronic Inhalation
exposure to the chlorophenols were not available; therefore, chronic Inhala-
tion RfOs cannot be derived.
0022d 8-6 08/11/87
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8.2.2. Oral Exposures. The lack of data concerning the oral tox1c1ty of
3-, 4-chlorophenol, 2,3-, 2,5-, 3,4-, 3,5-d1chlorophenol, 2,3,4-, 2,3,5-.
2,3,6-, 3,4,5-tMchlorophenol, 2,3,4,5- and 2,3,5,6-tetrachlorophenol pre-
cludes the derivation of subchronlc and chronic oral RfDs. U.S. EPA (1986g)
proposed an RfD of 0.003 mg/kg/day for 2,6-dlchlorophenol based on analogy
to 2,4-d1chlorophenol (Section 8.2.2.2.), but this RfD has not yet been
verified. While It may be possible to derive RfOs for 3- and 4-chlorophenol
by analogy to 2-chlorophenol; for 2,3-, 2,5-, 3,4- and 3,5-d1chlorophenol by
analogy to 2,4-d1chlorophenol; for 2,3,4-, 2,3,5-, 2,3,6- and 3,4,5-trl-
chlorophenol by analogy to 2,4,5-trlchlorophenol; and for 2,3,4,5- and
2,3,5,6-tetrachlorophenol by analogy to 2,3,4,6-tetrachlorophenol, because
of the lack of data regarding toxlclty and cardnogenlcHy of the chlori-
nated phenols specified above, H would not be prudent to base their risk
assessments on analogy to a single Isomer within the groups of mono-, d1-,
tr1- and tetrachlorophenols. 2,4,6-Tetrachlorophenol was carcinogenic to
rats and mice (NCI,. 1979} and results of a cardnogenlcHy study of
2,4-d1chlorophenol are forthcoming (NTP, 1986).
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) Subchronlc oral
toxlclty studies of 2-chlorophenol 1n which adequate parameters of toxldty
were examined are not available. Exon and Koller (1983a, 1985) found no
limunologlcal effects 1n rats exposed both pre- and postnatally to 2-chloro-
phenol In their drinking water at levels up to 500 ppm for 12-15 weeks. In
a reproductive study, Exon and Koller (1982) found reduced Utter sizes and
an Increase In the number of stillborn pups from dams provided with drinking
water containing 2-chlorophenol at 500 pom from 3 weeks of age through
breeding and lactation. No effects were noted at 50 ppm.
0022d 8-7 08/11/87
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U.S. EPA (19865) used the reproductive NOAEL of 50 ppm to calculate a
chronic RfD of 0.005 mg/kg/day or 0.4 mg/day for a 70 kg human. Because
little confidence can be placed In the subchronlc toxldty data base of
2-chlorophenol, the chronic oral RfD (Section 8.2.2.2.) will be adopted as
the subchronlc oral RfO.
In a subchronlc dietary study of 2,4-dlchlorophenol In mice, Kobayashl
et al. ("1972) found a NOAEL for hlstologlcal liver effects at 2000 ppm (100
mg/kg/day). Exon and Keller (1985) reported a NOAEL for Immunologlcal
effects In rats of 30 ppm 2,4-dlchlorophenol In the drinking water. At 300
ppm. Increased serum antibody levels and a decrease In delayed type hyper-
sensHWHy response was observed. The rats were exposed both pre- and
postnatally.
Using the Exon and Keller (1985) study, U.S. EPA (1986b,c) derived a
chronic RfO for 2,4-dlchlorophenol. Assuming a rat dally water Intake of
10% the rat body weight, an experimental dose of 0.3 mg/kg bw/day was
estimated. Applying an uncertainty factor of 100 (10 for 1nterspec1es
extrapolation and 10 to protect sensitive Individuals) a human chronic RfO
of 0.003 mg/kg/day or 0.2 mg/day for a 70 kg human Is derived. This RfO Is
adopted for subchronlc oral exposures as well. Confidence In this RfO Is
low; the endpolnts examined In the study are not commonly used In the deri-
vation of human health risk, and the other toxldty studies of 2,4-dlchloro-
phenol did not examine a variety of parameters.
The only subchronlc oral study of 2,4,5-tMchlorophenol Is the study by
McColUster et al. (1961) In which young rats were fed diets containing the
compound at 0, 0.01, 0.03, 0.1, 0.3 or 1.0% for 98 days. No effects were
noted 1n the 0.1X group, while at higher levels mild pathological changes 1n
the kidneys and liver were observed. Using this study, U.S. EPA (1984a)
0022d 8-8 08/11/87
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calculated a subchronlc RfD. An animal Intake of 100 mg/kg/day was calcu-
lated from the 0.1% group assuming that young, growing rats consume food
equivalent to 10X of their body weight/day. Dividing this value by an uncer-
tainty factor of TOO (10 for Interspecles extrapolation and 10 to protect
sensitive Individuals), a subchronlc oral RfO of 1 mg/kg/day or 70 mg/day
for a 70 kg human 1s derived. Confidence 1n this RfO Is medium because the
study was well-conducted. The only other studies concerning the toxlclty of
2,4,5-trlchlorophenol are teratogenlcHy studies (BRL, 1968b; Neubert and
DUlmann, 1972; Hood et al.t 1979; Chernoff and Kavlock, 1982) In which
fetotoxlc effects were noted In mice at doses similar or higher than the
NOAEL found In the McColllster et al. (1961) study.
Data concerning the toxldty of 2,4,6-tMchlorophenol Indicate that It
Is a carcinogen (NCI, 1979); therefore, a risk assessment based on carclno-
genlclty 1s presented 1n Section 8.1.5.
Hattula et al. (1981b) found hlstopathologlc changes In the livers of
rats treated by gavage with 2,3,4,6-tetrachlorophenol at 50 and 100
mg/kg/day for 55 days. No changes In the liver parenchyma were noted In
rats treated at 10 mg/kg/day. Whether other changes In the liver were noted
was not stated.
In a teratogenlcHy study, Schwetz et al. (1974) observed an Increase In
the Incidence of delayed ossification of the skull bones In fetuses from
dams treated by gavage with 2,3,4,6-tetrachlorophenol at 30 mg/kg on gesta-
tion days 6-15. At 10 mg/kg, a significant Increase In subcutaneous edema
was noted. This change was not noted In the 30 mg/kg rats.
Based on these two studies of 2,3,4,6-tetrachlorophenol, 10 mg/kg may be
a NOAEL In rats. Dividing the NOAEL by an uncertainty factor of 100, 10 for
Interspedes extrapolation and 10 to protect sensitive Individuals, the
subchronlc oral RfD of 0.1 mg/kg/day or 7 mg/day for a 70 kg human Is
0022d 8-9 08/11/87
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UNITED STATES ENVIRONMENTAL PROTECTION AGENCY
OFFICE OF RESEARCH AND DEVELOPMENT
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
CINCINNATI. OHIO 45268
August 20, 1987
SUBJECT: Health and Environmental Effects Document
[V
FROM: Chris DeRosa
Chief
Chemical Mixtures Assessment Branch, ECAO-CIn
TO: Matthew Straus
Chief, Waste Characterization Branch
Office of Solid Waste (WH-562B)
THRU: Steven 0. Lutkenhoff ^" / / '
Acting Director '--TTT. - < 'A / //
Environmental Criteria and Assessment Offlce-CIn
^
Peter W. Preuss \ u , \ r^^ S£p 8 I98T
Director
Office of Health and Environmental Assessment (RD-689)
Attached please find two unbound copies of the Health and Environmental
Effects Document (HEED) for:
Chlorinated Phenols (ECAO-Cln-6013)
This document represents scientific summaries of the pertinent available
data on the environmental fate and mammalian and aquatic toxlclty of each
chemical at an extramural effort of about 10K. This document received
Internal OHEA, OPP and OTS reviews as well as review by two external
scientists. Any part of this document's files (e.g., drafts, references,
reviews) 1s available to you upon request.
Attachments
cc: M. Callahan (RD-689)
P. Durkln, Syracuse Research Corporation (w/enclosures)
W. Farland (RD-689)
R. Hardesty (RD-689)
J. Kooyoomjlan (WH-548B) (w/enclosures)
E. HeNamara (PH-211A) (w/enclosures)
D. McK1e (WH-562) (w/enclosures) .
J. Moore (RD-689)
M. Lee (WH-562) (w/enclosures)
M. Pfaff (RO-689) (w/enclosures)
R. Rubensteln (WH-562B)
R. Scarberry (WH-562B)
0. Vlllarl (WH-562B) (w/enclosures)
C. Zamuda (WH-548D)
-------
-------
FINAL DRAFT
United States ECAO-C1N-G013
Environmental Protection »,.nnc+ TOUT
Agency August, 1987
vEPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR CHLORINATED PHENOLS
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
NOTICE
This document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
on Its technical accuracy and policy Implications.
-------
DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
-------
PREFACE
Health and Environmental Effects Documents (HEEOs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained from Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for In this document
and the dates searched are Included 1n "Appendix: Literature Searched."
Literature search material Is current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document Is sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfDs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval, for example, one that does
not constitute a significant portion of the Hfespan. This type of exposure
estimate has not been extensively used, or rigorously defined as previous
risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfOs Is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. A
carcinogenic potency factor, or q-j* (U.S. EPA, 1980a), Is provided
Instead. These potency estimates are derived for both oral and Inhalation
exposures where possible. In addition, unit rlsic estimates for air and
drinking water are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxlclty and carclno-
genldty are derived. The RQ Is used to determine the quantity of a hazar-
dous substance for which notification Is required In the event of a release
as specified under the CERCLA. These two RQs (chronic toxlclty and cardno-
genlclty) represent two of six scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxlclty, and acute mammalian toxlclty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxlclty and cancer-based RQs are defined 1n U.S.
EPA, 1983a and 1986a, respectively.
11
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EXECUTIVE SUMMARY
All the chlorophenols discussed with the exception of 2-chlorophenol are
crystalline solids at room temperature. The monochlorophenols are slightly
soluble 1n water, but as the number of chlorine substitution Increases, the
higher substituted phenols become less and less soluble In water. Thus, the
d1-, trl- and tetra-substltuted chlorophenols are -sparingly soluble 1n
water. These compounds are, In general, soluble 1n ethanol, ethyl ether or
benzene {Verschueren, 1983; Weast, 1980). The presence of chlorophenols
Imparts unpleasant taste and odor In water. The taste threshold for
2,3-d1chlorophenol 1s 0.00004 mg/i (Verschueren, 1983). Currently, five
companies 1n as many locations manufacture chlorophenols In the United
States. The current annual U.S. production volumes for the chlorophenols
are not available. The estimated annual world production volume of chloro-
phenols 1s 150 kllotons (Hutzlnger et al.t 1985). Chlorophenols are commer-
cially produced either by direct chloMnatlon of phenol or by the alkaline
*
hydrolysis of polychlorobenzenes (Kozak et al., 1979). Trace amounts of
highly toxic polychloMnated d1benzo-p-d1ox1ns and dlbenzofurans have been
found as contaminants In some commercial chlorophenols (Hutzlnger et al.,
1985). The monochlorophenols are primarily used 1n the synthesis of higher
chlorinated phenols. The higher chlorinated phenols are used as germicides
and as Intermediates 1n the manufacture of pesticides (KMJgsheld and
Vandergen, 1986; Kozak-et al., 1979).
The two Important processes that may have a significant effect on the
fate of chlorophenols In water are photolysis and blodegradatlon. The photo-
lytlc half-lives of 4-chloro-, 2,4-d1chloro- and 2,4,5-trlchlorophenols at
the top surface of distilled water under midday sunlight Irradiation were
1v
-------
estimated to be 2.6 days, 0.8 and 0.5 hours, respectively (Hwang et al.,
1986). From an outdoor pond experiment, Suglura et al. (1984) estimated the
photolytlc half-life of 2,4,6-tMchlorophenol at a depth of 10 cm to be 4
days. The photolysis of chlorophenols will be Important In clear shallow
bodies of water, but as the depth and turbidity of water Increase, the
Importance of photolysis will decrease because of light attenuation. The
blodegradatlon half-lives of chlorophenols In natural waters range from
>1-17 days. The half-life values Increase as the number of chlorine substi-
tutions Increases and the temperature of the water decreases. The half-lives
of the compounds also decrease In sediments of surface waters because of the
presence of a greater number of microorganisms (Lee and Ryan, 1979; Banerjee
et al., 1984; Hwang et al., 1986). Hydrolysis and evaporation are not
likely to be Important processes for chlorophenols In water (Krljgsheld and
Vandergen, 1986). Oxidation may be a significant process In water but
experimental data on such reactions could not be located In the available
literature. The .removal of chlorophenols from water by sorptlon onto
suspended sol Ids and sediments may be Important and will depend on the pH of
water and the organic content of the sorbents. Sorptlon will Increase at
lower pH and higher organic content of the sorbents, and will also be higher
for higher chlorinated than lower chlorinated phenols (Schellenberg et al.,
1984; Isaacson and Fink, 1984; KMjgsheld and Vandergen. 1986). Experi-
mental data Indicate that mono- and dlchlorophenols will not bloconcentrate
but that the higher chlorinated phenols may bloconcentrate significantly In
aquatic organisms (VeUh et al., 1980; Kobayashl et al., 1979; Hattula et
al., 1981a; Vlrtanen and Hattula, 1982).
-------
In the atmosphere, the chlorophenols are likely to undergo significant
photolysis (Korte and Klein, 1982). Based on the rate constant of phenol
reaction with OH radicals In the atmosphere (Atkinson, 1985), 1t 1s con-
cluded that such reactions may be significant for the lower chlorinated
phenols. The detection of these compounds 1n rainwater and snow Indicate
that they will be removed from the atmosphere by wet deposition (Leuenberger
et al:, 1985b; Paas1v1rta et al., 1985a).
Based on data regarding chlorophenols In water, photolysis, hydrolysis
and evaporation will not be significant processes In soils. The two Impor-
tant processes In soil are sorptlon and blodegradatlon. While 2-chloro-,
4-chloro-, 2,4-dlchloro- and 2,4,6-trlchlorophenols were found to be easily
biodegradable 1n a natural soil, 3-chloro-, 2,5-d1chloro-, 2,4,5-trlchloro-
and 2,3,4,6-tetrachlorophenols were persistent In soil (Alexander and Aleem,
1961). The sorptlon of chlorophenols In soils Increases with a decrease 1n
soil pH and Increase In chlorine substitution. Chlorophenols are especially
susceptible to leaching from sandy soils and soils with pH >10 (Schwarzen-
bach and Hestall, 1985; Sutton and Barker, 1985; Boyd, 1982; Johnson et al.,
1985).
Although chlorophenols have been detected In municipal and Industrial
effluents (Xle et al., 1986; Krlngstad and Llndstrom, 1984; Ellis et al.,
1982; Callahan et al., 1979), 1n urban runoff water (Cole et al., 1984), and
1n surface and groundwater near effluent discharge and waste disposal sites
(Valo et al., 1984; Bedlent et al., 1984; Salklnoja-Salonen et al., 1984;
Hatanabe et al., 1985; X1e et al., 1986), these compounds have been detected
Infrequently 1n drinking waters. According to Callahan et al. (1979), the
frequency of detection of chlorophenols 1n U.S. tap waters was 0%. Kopfler
et al. (1977), however, qualitatively detected 2,4-dl-, 2,4,5-tr1- and
v1
-------
2,4,6-trlchlorophenol In U.S. drinking waters. 2-Chloro-, 4-chloro-,
2,4-d1chloro- and 2,4,6-trlchlorophenol at respective maximum concentrations
of 39, 34, 17 and 60 ng/i have been detected 1n Canadian drinking waters
(S)thole et al., 1986). A few of these compounds have also been detected In
waters from England, the Netherlands and Germany (Crathorne et al., 1984;
Krljgsheld and Vandergen, 1986). The available data are Inadequate to esti-
mate the dally exposure of a U.S. Individual to these compounds by Ingestlon
of drinking water.
2,4,5-TMchlorophenol was detected In air samples In Love Canal, NY,
(Mauser and Bromberg, 1982) and 2-chloro-, 4-chloro.-, 2,6-
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In general, the toxlclty of chlorinated phenols to aquatic biota
Increases with Increasing chloMnatlon (U.S. EPA, 1979a, 1980b,c). This Is
probably due to higher uptake of the more chlorinated compounds (Kobayashl
et al., 1979). The toxlclty of chlorophenols also Increases with decreasing
pH (Konemann and Musch, 1981; Saarlkoskl and Vlluksela, 1981, 1982).
Structure-activity studies with aquatic organisms Indicated that the
presence of chloro substHuents 1n the ortho position decreased toxlclty,
while substHuents In the para position Increased toxlclty (Oevlllers and
Chambon, 1986; Rlbo and Kaiser, 1983).
There Is a large volume of data concerning toxlclty of chlorophenols to
freshwater species. The most sensitive species for which there was a large
amount of data were salmonlds (rainbow trout. Salmo qalrdnerl and brown
trout, Salmo trutta) and bluegllls (Lepomls macrochlrus). The lowest
reported acutely toxic concentration for freshwater fishes was 0.085 mg/l
2,3,4,6-tetrachlorophenol, a 96-hour LC5Q for rainbow trout (Mayer and
Ellersleck, 1986). The lowest reported acutely toxic concentration for
freshwater Invertebrates was 0.29 mg/l 2,3,4,6-tetrachlorophenol, a
48-hour LC5Q for Daphnla maqna (U.S. EPA, 1978a). Oata for freshwater
plants, fungi and bacteria Indicated toxic concentrations similar to those
for freshwater fishes and Invertebrates. The lowest reported toxic concen-
tration for freshwater plants was 0.603 mg/l 2,3,4,6-tetrachlorophenol,
the 48-hour EC5Q for chlorosis 1n duckweed (Blackman et al.. 1955). For
bacteria and fungi, the lowest reported toxic concentration was 0.176 mg/l
2,3,4,5-tetrachlorophenol, a 30-mlnute ECrQ for Inhibition of luminescence
of Photobacterlum phosphoreura (Rlbo and Kaiser, 1983).
-------
Relatively little Information was available concerning marine species.
The lowest reported acutely toxic concentration for marine species was 1.1
mg/i 2,3,4,6-tetrachlorophenol, a 96-hour LC-. for the cyprlnodontld
fish, Rlvulus marmoratus (Koenlg and McLean, 1980). The lowest reported
toxic concentration for marine plants was 0.44 mg/i 2,3,5,6-
tetrachlorophenol, a 96-hour EC for Skeletonema costatum (U.S. EPA,
1978a).
Few studies concerning chronic toxldty of chlorophenols to aquatic
organisms were available. The only study Involving a full Hfecycle
exposure was that of Koenlg and McLean (1980) who found that fin erosion
occurred In all fish (Rlvulus marmoratus) exposed to 0.055 mg/l
2,3',4,6-tetrachlorophenol, the lowest concentration tested.
Chlorinated phenols have been shown to Impair the flavor of freshwater
fish flesh at concentrations much lower than those that are toxic (Shumway
and Palensky, 1973; U.S. EPA, 1980b,c,d). The lowest reported concentration
for flavor Impairment was 0.0004 mg/l 2,4-d1chlorophenol, a threshold for
largemouth bass (Mlcropterus salmoldes) (Shumway and Palensky, 1973). As
discussed by U.S. EPA (1980b,c,d), threshold concentrations for tainting of
fish flesh may be more Important than toxic concentrations 1n establishing
water quality criteria for aquatic biota.
The chlorophenols seen to be readily absorbed from the gastrointestinal
tract and from parenteral sites of Injection (Oelchmann and KepHnger, 1981;
Carpenter et al., 1985). Rats dosed orally with l4C-2,4,6-tr1chlorophenol
absorbed at least 82.3% of the dose based on urinary excretion of radio-
activity (Korte et al., 1978). Roberts et al. (1977) found that 2- and
4-chlorophenol, 2,4-d1chlorophenol and 2,4,6-trlchlorophenol can penetrate
1x
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human epidermis in vitro. Acutely toxic levels of 2,4,5- and 2,4,6-tM-
chlorophenol were not absorbed through the Intact skin of rabbits or guinea
pigs, while toxic levels of 2,3,4,6-tetrachlorophenol were absorbed through
the skin (Gosselln et a!., 1976).
Pharmacok1net1c studies of the chlorophenols In laboratory animals
Indicate that the compounds are distributed rapidly, but do not accumulate
In any tissue (Exon and Koller, 1982; Somanl and Khallque, 1982; Korte et
al., 1978; PekaM et al., 1986; Hattula et al., 1981b). Metabolism studies
Indicate that the chlorophenols are conjugated to glucuronldes and sulfates,
with glucuronldes predominating In rats (Karpow, 1893, Koster et al., 1981;
Somanl and Khallque, 1982; Bahlg et al., 1981). Other metabolites that have
been Identified are dlchloromethoxyphenols Identified In an in vitro study
of the metabolism of 2,4-d1chlorophenol (Somanl et al., 1984), tetrachloro-
hydroqulnone as a metabolite of 2,3,5,6-tetrachlorophenol and trlchloro-
hydroqulnone as a minor metabolite of 2,3,4,5- and 2,3,4,6-tetrachlorophenol
(Ahlborg and Larsson, 1978). In addition, Bahlg et al. (1981) found that
other trlchlorophenol Isomers are excreted when 2,4,6-tMchlorophenol was
administered orally to rats.
Studies using laboratory animals (Karpow, 1893; Korte et al., 1978;
Bahlg et al., 1981; Ahlborg and Larsson, 1978) Indicate that the
chlorophenols are excreted predominantly In the urine as glucuronlc and
sulfuMc add conjugates, and as the unchanged compounds. Kalman and
Horstman (1983) found that the half-time of elimination of
2,3,4,6-tetrachlorophenols 1n occupatlonally exposed humans was -63^34 hours.
In a subchronlc Inhalation study of 4-chlorophenol (Gurova, 1964), rats
exposed to 2 mg/ra", 6 hours/day for 4 months showed neuromuscular excit-
ability, a reduction of endurance, Increased myoneural excitability, slight
-------
congestion of organs and minor flbrotlc changes In alveolar septa. Gurova
(1964) also reported symptoms of nervous exhaustion, Insomnia, Irritability,
frequent mood changes and rapid fatlgabllHy In workers exposed to 4-chloro-
phenol 1n an aniline dye plant. The lack of detail 1n these studies
precludes adequate assessment of their reliability.
Kleu and Goeltz (1971) reported symptoms of chloracne, decreased sexual
activity, easy fatlgabllHy, Irritability, muscular weakness, loss of appe-
tite and memory, discouragement, alcohol Intolerance and loss of Interest In
workers occupatlonally exposed to a trlchlorophenol formulation for up to 15
years. A causal relationship was not established. Alexandersson and
Hedenstlerna (1982) found pulmonary effects In workers exposed to low levels
of tMchlorophenols 1n gas masks for up to 10 years.
Exon and Keller (1985) found Immunologlcal effects In rats exposed sub-
chronlcal'ly to 2,4-d1chlorophenol at 30 and 300 ppm 1n their drinking water.
Similar effects were net noted In rats exposed to up to 500 ppm 2-chloro-
phenol, or up to 300 ppm 2,4,6-tMchlorophenol. Kobayashl et al. (1972)
reported minor hlstologlcal changes 1n the livers of mice fed 2,4-d1chloro-
phenol at 230 mg/kg/day for 6 months. No effects were noted at 100
mg/kg/day.
A subchronlc drinking water study of 2,4-d1chlorophenol 1n mice found no
consistent effects that could be related to treatment at up to 2 ppm
(Borzelleca et al., 1985a). The study was confounded by the addition of
Emulphor to the dosing solution.
McColllster et al. (1961) studied the toxldty of 2,4,5-tMchlorophenol.
In a 28-day gavage study, microscopic changes were noted 1n the liver and
kidneys of rabbits dosed with 0.1 and 0.5 mg/kg but not 0.01 mg/kg 20 times
xl
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over the study period. No changes were noted In rats dosed with 2,4,5-trl-
chlorophenol at up to 1.0 g/kg 18 times over 24 days. In a 98-day study,
pathologic changes 1n the livers and kidney were noted 1n rats provided with
diets containing 2,4,5-trlchlorophenol at 0.03 and 1.0% but not at <0.01%.
In a 70-day dietary study, Vlzethum and Goerz (1979) reported that 0.05%
2,4,5-tMchlorophenol was not porphyrogenlc 1n rats. The NCI (1979) sub-
chronic study noted an Increase 1n splenic hematopolesis and mldzonal
vacuolatlon of hepatocytes In rats fed 2,4,5-tMchlorophenol 1n the diet at
46,000 ppm for 7 weeks. Survival of rats fed >21,500 ppm but not <14,700
ppm was also affected. In mice, survival was affected at 31,500 ppm but not
at <21,500 ppm (NCI, 1979); no hlstopathologlcal data were reported. A
dose-dependent decrease In body weight was observed In both rats and mice In
the NCI (1979) study.
Kawano et al. (1979) observed changes 1n growth, organ weights, several
biochemical parameters and liver drug metabolizing enzymes In rats fed diets
containing 2,3,5-trlchlorophenol or 2,3,4,5-, 2,3,5,6- or 2,3,4,6-tetra-
chlorophenol at 0.2% for 3 weeks. Dose-related hlstopathoToglc changes In
the liver were noted In rats treated by gavage with 2,3,4,5-tetrachloro-
phenol for 55 days at >50 mg/kg/day but not at 10 mg/kg/day (Hattula et al.,
1981b).
In a chronic study, numbers of R8C and hemoglobin levels were Increased
In rats provided with drinking water containing 500 ppm 2-chlorophenol or
300 ppm 2,4-d1chlorophenol, but not at 10-fold lower concentrations (Exon
and Koller, 1985). The NCI (1979) found a dose-related Increase 1n the
Incidences of bone marrow hyperplasla and leukocytosls 1n rats at 5000 and
10,000 ppm. In mice, dose-related hyperplasla of the liver was noted In
males at 5000 and 10.000 ppm (NCI, 1979).
xll
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In studies of the Induction of enzymes by the chlorinated phenols,
Carlson (1978) found that 2,4,5-trlchlorophenol reduced mlcrosomal NADPH-
cytochrome c reductase activity and cytochrome P-450 content. Denomme et
al. (1983) reported that 4-dlmethylamlnoantlpyrlne N-demethylase was Induced
by 3,4,5-trlchlorophenol. The other trl- and tetrachlorophenols had no
effects on enzyme Induction. The mutagenldty of 2-am1noanthracene and
benzo[a]pyrene were enhanced In an Ames assay by S-9 from rats treated with
2,3,4,5-tetrachlorophenol (Sussmuth et al., 1980).
MUsuda et al. (1963) observed that chlorophenols Inhibit oxldatlve
phosphorylatlon In vitro, with the Inhibiting activity Increasing with
Increasing chlorlnatlon.
The acute toxlclty of the chlorinated phenols has been studied by a
number of Investigators (Delchmann, 1944; Bubnov et al., 1969; Borzelleca et
al., 1985a,b; Farquharson et al., 1958; Chrlstensen and luglnbyhl, 1975;
Oekhmann and Mergard, 1948; Angel and Roberts, 1972; Gurova, 1964;
Schrotter et al., 1977; Kobayashl et al., 1972; Vernot et al., 1977;
McColHster et al., 1961; Ahlborg and Larrsson, 1978; Hattula et al.,
1981b); In general, the toxlclty Increases as the chlorlnatlon Increases.
Ep1dem1olog1cal studies that are confounded by some small study popula-
tions and multiple exposures Indicate that a mixture of compounds Including
chlorophenol are associated with soft tissue sarcomas and malignant
lymphomas (Lynge, 1985; Cook, 1981; Honchar and Halperln, 1981; Pearce et
al., 1986). The Influence of the chlorophenols alone, however, cannot be
determined.
Increased tumor Incidences were not observed In rats exposed to up to
500 ppm 2-chlorophenol or up to 300 ppm 2,4-dlchlorophenol In their drinking
water for 2 years (Exon and Koller, 1985). Innes et al. (1969) found Incon-
clusive results 1n a carclnogenldty study of 2,4,6-trlchlorophenol In mice.
-------
TABLE 9-14
Derivation of Potency Factor (F) for 2,4,6-TMchlorophenol
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment: 105 weeks
Duration of study:
Ufespan of animal:
Target organ:
Tumor type:
Experimental doses/exposures (ppm):
Transformed doses (mg/kg/day):
Tumor Incidence:
Unadjusted 1/EO]Q:
Adjusted 1/EOio (F Factor):
NCI, 1979
oral
mouse
B6C3F1
male
diet
0.04 kg
1-05 weeks
105 weeks
liver
hepatocellular adenoma and
carcinoma
0
0
5000
650
10,000
1,300
4/20 32/49 39/47
1.16158xlO~* (mg/kg/day)'1
1.39978xlO~i (mg/kg/day)"1
0023d
9-20
05/11/87
-------
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organic priority pollutants. J. Hater Pollut. Control Fed. 55: 1441-1449.
Johnson, R.L.. S.M. Brlllante, l.H. Isabelle, J.E. Houck and J.F. Pankow.
1985. Migration of chlorophenollc compounds at the chemical waste disposal
site at Alkali Lake, Oregon-2. Contaminant Distributions, Transport and
Retardation. Groundwater. 23(5): 652-666.
Juhnke, I. and 0. Luedemann. 1978. Results of the study of 200 chemical
compounds on acute fish toxldty using the Golden Orfe test. Z. Wasser
Abwasser Forsch. 11(5): 161-164.
0024
-------
Kalla, K. and J. Saarlkoskl. 1977. ToxIcHy of pentachlorophenol and
2,3,6-trlchlorophenol to the crayfish (Astacus fluvlatlUs L.). Environ.
Pollut. 12(2): 119-123.
Kalman, D.A. and S.W. Horstman. 1983. Persistence of tetrachlorophenol and
pentachlorophenol In exposed woodworkers. Clinical Toxlcol. 20(4): 343-352.
Kanno, S. and K. Nojlma. 1979. Studies on photochemistry of aromatic
hydrocarbons. V. Photochemical reaction of chlorobenzene with nitrogen
oxides In air. Chemosphere. 8: 225-232.
Karpow, G. 1893. On the antiseptic action of three Isomerlc chlorophenols
and of their sallcylate esters and their facte 1n the metabolism. Arch.
Scl. B1ol. St. Petersberg. 2: 304. (Cited In von Oettlngen, 1949)
Kaupplnen, T. and L. Llndroos. 1985. Chlorophenol exposure In sawmills.
Am. Ind. Hyg. Assoc. J. 46: 34-38.
Kawano, S., K. Hlrose, S. Iguchl and K. Hlraga. 1979. Tox1co1og1ca1
studies of polychlorlnated aromatic compounds In female rats. Tokyo Torltsu
Elsel Kenkyusho Kenkyo Nempo (Ann. Rep. Tokyo Hetrop. Res. Lab. Publlch
Health). 30(2): 116-123.
Kawasaki, H. 1980. Experiences with the test scheme under the chemical
control law of Japan: An approach to structure-activity correlations.
Ecotoxlc. Environ. Safety. 4: 444-454.
0024d 10-17 06/19/87
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Keen, R. and C.R. Balllod. 1985. Toxlclty to Daphnla of the end products
of wet oxidation of phenol and substituted phenols. Water Res. 19(6):
767-772.
Klncannon, O.F., A. Welnert, R. Padorr and E.L. Stover. 1983. Predicting
treatabllHy of multiple organic priority pollutant wastewaters from single-
pollutant treatabllUy studies. In.: Proc. 37th Industrial Waste Conf., J.H.
Bell, Ed. Ann Arbor Science, Ann Arbor, MI. p. 641-650.
Kleu, G., Jr. and R. Goltz, Jr. 1971. Late and long-term Injuries follow-
ing the chronic occupational action of chlorophenol compounds; catamneslc
neurologic-psychiatric and phychologlcal studies. Med. K11n. (Munich).
66(2): 53-58.
Knackmuss, H.J. and M. Hellwlg. 1978. Utilization and cooxldatlon of
chlorinated phenols by Pseudomonas sp. 813. Arch. M1crob1ol. 117: 1-7.
Kobayashl, S., K. Tolda, H. Kawamura, H. Change, T. Fukuda and K. Kawaguchl.
1972. Chronic toxIcHy of 2,4-d1chlorophenol 1n mice. A simple model for
the toxldty of pesticide metabolite residues. Toho Igakka! Zasshl. J.
Med. Soc. Toho Un1. 19(3-4): 356-362. (CUed 1n U.S. EPA, 1980d, 1986b)
Kobayashl, K.. H. AkHake and K. Manabe. 1979. Relation between toxldty
and accumulation of various chlorophenols In goldfish. Bull. Jap. Soc.
Sden. Fish. 45: 173-175.
Q024d 10-18 06/19/87
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Koenlg, C.C. and C. McLean. 1980. Rlvulus marmoratus: A Unique F1sh Useful
1n Chronic Marine Bloassays of Halogenated Organlcs, R.L. Jolley, W.A.
Brungs, R.B. Communing and V.A. Jacobs, Ed. Water Chlorlnatlon: Environ-
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Konemann, H. and A. Husch. 1981. Quantitative structure-activity relation-
ships In fish toxlclty studies. Part 2: The Influence of pH on the QSAR of
chlorophenols. Toxicology. 19(3): 223-228.
Kopfler, F.C., R.6. Melton, J.L. Mullaney and R.G. Tardlff. 1977. Human
exposure to water pollutants. Adv. Environ. Sc1. Techno!. 8(Fate Pollut.
A1r Water Environ): 419-433.
Kopperman, H.L., R.M. Carlson and R. Caple. 1974. Aqueous Chlorlnatlon and
ozonatlon studies: I. Structure-toxldty correlations of phenolic compounds
to Daphnla magna. Chem-81ol. Interact. 9(4): 245-251.
Korte, F. and W. Klein. 1982. Degradation of benzene In the environment.
Ecotoxlcol. Environ. Saf. 6: 311-327.
Korte. F., 0. Freltag, H. Geyer, W. Klein, A.G. Kraus and E. Lahan1at1s.
1978. Ecotox1colog1c profile analysis: A concept for establishing ecotoxl-
cologlcal priority list for chemicals. Chemosphere. 1: 79-102.
Koster, H., I. Halsema. E. Scholtens, M. Knlppers and G.J. Mulder. 1981.
Dose-dependent shifts 1n the sulfatlon and glucuronldatlon of phenolic com-
pounds In the rat hi vivo and In Isolated hepatocytes. The role of satura-
tion of phenolsulfotransferase. Blochem. Pharmacol. 30(18): 2569-2575.
0024d 10-19 06/19/87
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Kozak, V.P., G.V. Slmslman, G. Chesters, D. Stensby and J. Horkln. 1979.
Review of the Environmental Effects of Pollutants: XI. Chlorophenols. U.S.
EPA, Washington, OC. EPA 600/1-79-012. 492 p.
Krljgsheld, K.R. and A. Vandergen. 1986. Assessment of the Impact of the
emission of certain organochlorlne compounds on the aquatic environment.
Part I. Monochlorophenols and 2,4-dlchlorophenol. Chemosphere. 15: 825-860.
Krlngstad, K.P. and K. Undstrom. 1984. Spent liquors from pulp bleaching.
Environ. Sc1. Technol. 18: 236a-248a.
Kulper, J. and A.O. HanstveH. 1984. Fate and effects of 4-chlorophenol
and 2,4-dlchlorophenol In marine plankton communities In experimental
enclosures. Ecotoxlcol. Environ. Safety. 8(1): 15-33.
Kutz, F.W., R.S. Murphy and S.C. Strassman. 1978. Survey of pesticide
residues and their metabolites 1n urine from the general population. Iti;
Pentachlorophenol: Chemistry, Pharmacology and Environmental Toxicology,
K.R. Rao, Ed. Pergamon Press, New York. p. 363-369.
LammeMng, M.H. and N.C. Burbank, Jr. 1961. The toxiclty of phenol,
o-chlorophenol and o-nltrophenol to blueglll sunflsh. Proc. 15th Ind. Haste
Conf., Purdue Univ. Eng. Ext. Ser. No. 106: 541-555.
Lee, R.F. and C. Ryan. 1979. M1crob1al degradation of organochlorlne
compounds In estuarlne waters and sediments. Mlcroblal Degradation of
Pollutants In Marine Environments, A.H. Bourquln and P.H. Prltchard, Ed.
U.S. EPA, Gulf Breeze, FL. p. 443-450. EPA 600/9-79-012.
0024d 10-20 06/19/87
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Lemalre, J., 3.A. Guth, 0. Klals, et al. 1985. Ring test of a method for
assessing the phototransformatlon of chemicals In water. Chemosphere. 14:
53-77.
Leuenberger, C., H. G1ger, R. Coney, J.W. Graydon and E. Molnar-Kublca.
1985a. Persistent chemicals In pulp mill effluents. Water Res. 19:
885-894.
Leuenberger, C., M.P. L1gock1 and J.F. Pankow. 1985b. Trace organic
compounds In rain. 4. Identities, concentrations and scavenging mechanisms
for phenols In urban air and rain. Environ. Sc1. Technol. 19: 1053-1058.
Linden, E., B.E. Bengtsson, 0. Svanberg and G. Sundstrom. 1979. The acute
toxlclty of 78 chemicals and pesticide formulations against two brackish
water organisms, the bleak (Alburnus alburnus) and the... Chemosphere.
8(11-12): 843-851.
Undstrom, H. and A. Llndstrom. 1980. Changes In the swimming activity of
pontoporela afflnls (Crustacea. Amphlpoda) after exposure to sublethal
concentrations of phenol. 4-chlorophenol, and styrene. Ann. Zool. Fennlcl.
17: 221-231. (Cited 1n KMJgsheld and Vandergen, 1986)
Lynge, E. 1985. A follow-up study of cancer Incidence among workers In
manufacture of phenoxy herbicides In Denmark. Br. 3. Cancer. 52(2):
259-270.
0024d 10-21 06/19/87
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Mayer, F.L., Jr. and M.R. Ellersleck. 1986. Manual of acute toxUHy:
Interpretation and data base for 410 chemicals and 66 species of freshwater
animals. U.S. Dept. of Interior, F1sh and Wildlife Service Resource Publ.
160.
Hayes, M.A., H.C. Alexander and O.C. 0111. 1983. A study to assess the
Influence of age on the response of fathead minnows In static acute toxldty
tests. Bull. Environ. Contam. Toxlcol. 31(2): 139-147.
McColllster, O.D., O.T. Lockwood and V.K. Rowe. 1961. Toxlcologlc Informa-
tion on 2,4,5-trlchlorophenol. Toxlcol. Appl. Pharmacol. 3: 63-70.
McLeese, D.H., V. Zltko and M.R. Peterson. 1979. Structure-lethality
relationships for phenols, anilines and other aromatic compounds In shrimp
and clams. Chemosphere. 8(2): 53-57.
MHsuda, H., K. Murakami and F. Kaw1. 1963. Effect of chlorophenol
analogues on the oxldatlve phosphorylatlon In rat liver mitochondria.
AgMc. B1ol. Chera. 27(5): 366-372.
Morgade, C., A. Barquet and C.O. Pfaffenberger. 1980. Determination of
polyhalogenated phenolic compounds 1n drinking water, human blood serum and
adipose tissue. Bull. Environ. Contam. Toxlcol. 24: 257-264.
NCI (National Cancer Institute). 1979. Bloassay of 2,4,6-tMchlorophenol
for possible cardnogen1c1ty. NCI Cardnogenesls Tech Rep. Ser. No.
NCI-C6-TR-155.
0024d 10-22 06/19/87
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U.S. EPA. 1983d. Reportable Quantity Document for 2,6-01ch1orophenol.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency
and Remedial Response, Washington, DC.
U.S. EPA. 1983e. Reportable Quantity Document for 2,4,5-Trlchlorophenol.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency
and Remedial Response, Washington, DC.
U.S. EPA. 1983f. Reportable Quantity Document for 2,4,6-Trlchlorophenol.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency
and Remedial Response, Washington, DC.
U.S. EPA. 1983g. Reportable Quantity Document for 2,3,4,6-Tetrachloro-
phenol. Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1984a. Health Effects Assessment for 2,4,5-Trlchlorophenol.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency
and Remedial Response, Washington, DC. EPA 540/1-86-034.
0024d 10-33 06/19/87
-------
U.S. EPA. 1984b. Health Effects Assessment for 2,4,6-TMchlorophenol.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency
and Remedial Response, Washington, DC. EPA 540/1-86-042.
U.S. EPA. 1985a. Integrated Risk Information System (IRIS). Reference
Doses (RfDs) for Oral Exposure to 2,4,5-TMchlorophenol. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH. Verification Date 5/20/85.
U.S. EPA. 1985b. Integrated Risk Information System (IRIS). Reference
Doses (RfDs) for Oral Exposure to 2,3,4,6-Tetrachlorophenol. On-line.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH. Verification Date 7/8/85.
U.S. EPA. 1986a. Methodology for Evaluating Potential Cardnogenldty In
Support of Reportable Quantity Adjustments Pursuant to CERCLA Section 102.
Prepared by the Office of Health and Environmental Assessment, Carcinogen
Assessment Group. Washington, DC for the Office of Solid Waste and Emergency
Response, Washington, DC.
U.S. EPA. 1986b. Drinking Water Criteria Document for Chlorophenols.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking
Water, Washington, DC.
0024d 10-34 06/19/87
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U.S. EPA. 1986c. Integrated R1.sk Information System (IRIS). Reference
Dose (RfD) for Oral Exposure for 2,4-D1chlorophenol. On-line. Verification
Date 01/22/86. Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH.
U.S. EPA. 1986d. Report on the Status of Chemicals In the Special Review
Program, Registration Standards Program and Data call-In Program. Office of
Pesticide Programs, U.S. EPA, Washington, DC.
U.S. EPA. 1986e. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1986f. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington,
DC.
U.S. EPA. 1986g. Integrated Risk Information System (IRIS). Reference
Dose (RfD) for Oral Exposure for 2,6-D1chlorophenol. On-Hne. (Final
approval pending). Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH.
USITC (U.S. International Trade Commission). 1986. Synthetic Organic
Chemicals. U.S. Production and Sales, 1985. USITC Publ. 1892, Washington,
DC. p. 38.
0024d 10-35 06/19/87
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Valencia, R., J.M. Mason, R.C. Woodruff and S. ZlmmeMng. 1985. Chemical
mutagensls testing 1n Drosophlla. III. Results of 48 coded compounds tested
for the National Toxicology Program. Environ. Hutagen. 7(3): 325-348.
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nated phenols as contaminants of soil and water 1n the vicinity of two
Finnish sawmills. Chemosphere. 13: 835-844.
Velth, G.O., O.L. Delore and 8.V. Bergstedt. 1979. Measuring and estimat-
ing the bloconcentratlon factor of chemicals In fish. J. F1sh. Res. Board
Can. 36: 1040-1048.
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tion of using partition coefficient and water solubility to estimate blocon-
centratlon factors for organic chemicals 1n fish. ASTM STP 707. Aquatic
Toxicology, J.G. Easton et al., Ed. Am. Soc. Test. Mater, p. 116-129.
Vernot, E.H., J.O. MacEwen, C.C. Haun and E.E. Klnkead. 1977. Acute
toxlclty and skin corrosion data for some organic and Inorganic compounds
and aqueous solutions. Toxlcol. Appl. Pharmacol. 42: 417-423.
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2nd ed. Van Nostrand Relnhold Co., New York. p. 375-379. 492-495.
Vlrtanen, M.T. and M.L. Hattula. 1982. The fate of 2,4,6-tMchlorophenol
In an aquatic continuous flow system. Chemosphere. 11: 641-649.
0024d 10-36 06/19/87
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Vlzethum, W. and G. Goerz. 1979. Is 2,4,5-trlchlorophenol a porphyrogen?
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Vuorlnen, P.J., J. Paas1v1rta, T. P11lola, K. Surma-Aho and J. Tarhanen.
1985. Organochlorlne compounds In baltlc salmon and trout. I. Chlorinated
hydrocarbons and chlorophenols 1982. Chemosphere. 14: 1729-1740.
Hatanabe, I., T. Kashlmoto and R. Tatsukawa. 1985. Bromlnated phenols and
anlsoles In river and marine sediments In Japan. Bull. Environ. Contain.
Toxlcol. 35: 272-278.
Weast, R.C., Ed. 1980. CRC Handbook for Chemistry and Physics, 61st ed.
CRC Press, Boca Raton, FL. p. C-474-476, C-481.
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Leuclscus 1dus by testing the fish toxldty of chemicals and wastewaters.
Z. Hasser Abwasser Forsch. (Ger). 15: 49. (Cited In Pickering et a!., 1983)
X1e, T.M. 1983. Determination of trace amounts of chlorophenols and
chlorogualacols 1n sediment. Chemosphere. 12: 1183-1191.
0024d 10-37 06/19/87
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Xle, T.M., K. Abrahamsson, E. Fogelqvlst and.B. Josefsson. 1986. Distribu-
tion of chlorophenollcs In a marine environment. Environ. Sc1. Technol.
20: 457-463.
Yoshloka, Y., Y. Ose and T. Sato. 1986. Correlation of the five test
methods to assess chemical toxldty and relation to physical properties.
Ecotoxlcol. Environ. Saf. 12(1): 15-21.
Young, D.R., R.W. Gossett, R.B. Balrd, O.A. Brown, P.A. Taylor and M.J.
M1lle. 1983. Hastewater Inputs and marine bloaccumulatlon of priority
pollutant organlcs off southern California. In.: Water Chlorlnatlon:
Environmental Impact and Health Effects. 4(Book 2): 871-884.
QQ24d 10-38 06/19/87
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APPENDIX A
LITERATURE SEARCHED
This HEED 1s based on data Identified by computerized literature
searches of following:
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted In January, 1987. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 5-9), and the following
secondary sources should be reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Unit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986-1987. TLVs: Threshold Limit Values for Chemical Substances In
the Work Environment adopted by ACGIH with Intended Changes for
1986-1987. Cincinnati, OH. Ill p.
Clayton, G.O. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.O. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 28. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John WHey and
Sons, NY. p. 3817-5112.
0025d A-l 06/18/87
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Grayson, M. and D. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons,. NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. WHO, IARC, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
SRI International, Menlo Park, CA. EPA 600/6-84-010. NTIS
PB84-243906.
NTP (National Toxicology Program). 1986. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1986. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In Programs.
Office of Pesticide Programs, Washington, DC.
U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington, DC.
USITC (U.S. International Trade Commission). 1985. Synthetic
Organic Chemicals. U.S. Production and Sales. 1984, USITC Publ.
1422, Washington. DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, H., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
0025d A-2 05/12/87
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In addition, approximately 30 compendia of aquatic toxldty data were
reviewed. Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxlclty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, 0. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, 8.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, OC. EPA 540/9-79-003. NTIS PB 80-196876.
0025d A-3 05/12/87
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APPENDIX B-l
Cancer Data Sheets for Derivation of a q-j*
Compound: 2,4,6-tMchlorophenol
Reference: NCI, 1979
Specles/straln/sex: rat/F344/H
Body weight = 0.36 kg (measured)
Length of exposure (le) « 107 weeks
Length of experiment (Le) = 107 weeks
Llfespan of animal (L) * 107 weeks
Tumor site and type: hematopoletlc system/leukemia or malignant lymphoma
Route/vehicle: oral/diet
Experimental Doses
or Exposure (ppm)
0
5,000
10,000
Transformed Dose
(mg/kg/day)
0
250
500
Incidence
No. Responding/No. Tested
4/20
25/50
29/50
Unadjusted q-j* - 2.0675297x10"' (mg/kg/day)"1
Hunan q-)* » 1.197798x10"' (mg/kg/day)"1
0026d
8-1
05/12/87
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Nestmann, E.R. and E.G.H. Lee. 1983. Mutagen1c1ty of constituents of pulp
and paper mill effluent In growing cells of Saccharomyces cerevlslae.
Mutat. Res. 119: 273-280.
Neubert, 0. and I. DUlmann. 1972. Embryotoxlc effects In mice treated
with 2,4,5-trlchlorophenoxy acetic add and 2,3,7,8-tetrachlord1benzod1ox1n.
Naunyn-Schmledeberg's Arch. Pharmacol. 272: 243-264. (Cited In Kozak et
al., 1979)
NTP (National Toxicology Program). 1986. Management Status Report.
Oksama, M. and R. KMstoffersson. 1979. The tox1c1ty of phenol to Phoxlnus
phoxlnus. Gammarus duebenl and Hesldotea entomon 1n brackish water. Ann
Zool. Fenn. 16(3): 209-216.
Paas1v1rta. J., N. Knuutlla, R. Paukku and S. Herve. 198Sa. Study of
organochlorlne pollutants In snow at North Pole and comparison to the snow
at North, Central and South Finland. Chemosphere. 14: 1741-1748.
Paas1v1rta, J., K. Helnola, T. Humppl, et al. 1985b. Polychlorlnated
phenols, gualacols and catechols 1n the environment. Chemosphere. 14:
469-491.
Paris, O.F., N.L. Wolfe. H.C. Steen and G.L. Baughman. 1983. Effect of
phenol molecular structure on bacterial transformation rate constants In
pond and river samples. Appl. Environ. Mlcroblol. 45: 1153-1155.
0024d 10-23 06/19/87
-------
Patterson, J.W. and P.S. Kodukala. 1981. B1odegradat1on of hazardous
organic pollutants. Chem. Eng. Prog. 77: 48-55.
Pearce N., A.H. Smith, J.K. Howard, R.A. Sheppard, H.J. Giles and C.A.
league. 1986. Non-Hodgk1n's lymphoma and exposure to phenoxyherblddes,
chlorophenols, fencing work and meat works employment: A case-control study.
Br. J. Ind. Med. 43(2): 75-83.
Pekarl, K., C. Boudene and A. A1t1o. 1986. Kinetics of 2,4,6-trlchloro-
phenol In different organs of the rat. Arch. Toxlcol. 59(1): 41-44.
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Pickering, Q.H., E.O. Hunt, G.L. Phlpps, et al. 1983. Effects of pollution
on freshwater fish and amphibians. 3. Water Pollut. Control Fed. 55(6):
840-863.
PHter, P. 1976. Determination of biological degradabHUy of organic
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0024d 10-24 06/19/87
-------
Roister, M.t B. Rlttlch and R. Zaludova. 1986. Relationships between
biological activity of phenols and their physico-chemical parameters.
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Probst, G.S., R.E. McMahon, I.E. H111, et al. 1981. Chemically-Induced
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11-32.
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2117-2130.
Rasanen, L. and M.L. Hattula. 1977. The mutagenldty of MCPA and Us soil
metabolites, chlorinated phenols, catechols and some widely used sllmlcldes
In Finland. Bull. Environ. Contam. Toxlcol. 18: 565-571.
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Final Report submitted to the Office of Solid Waste, Washington, DC.
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luminescent bacteria and their correlations with acute and sublethal effects
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0024d 10-25 06/19/87
-------
Rodwell, O.E., R.D. Wilson, M.D. Nemlc and M.O. Meroleca. 1984. A tera-
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167.
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alga Chlorella pyrenoldosa and a duckweek Lemna perpusllla as test organisms
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747-753.
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0024d 10-26 06/19/87
-------
Sasaki, S. 1978. The scientific aspects of the chemical substances control
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In vitro methods for assessing reproductive toxldty: Dlchlorophenols.
Toxlcol Lett. (AMST). 20(3): 309-315.
0024d 10-27 06/19/87
-------
Shumway, D.L. and J.R. Palensky. 1973. Impairment of the flavor of fish by
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S1kka, H.C. and G.L. Butler. 1977. Effects of selected wastewater chloM-
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249-258.
SHhole, B.B., O.T. Williams, C. LastoMa and J.I. Robertson. 1986. Deter-
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dlchlorophenol In rats. J. Toxlcol. Environ. Health. 9(5-6): 889-897.
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OQ24d 10-28 06/19/87
-------
SRI (Stanford Research Institute). 1986. 1986 Directory of Chemical
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Stoner, G.D., P-B. Conran, E.A. Grelslger, J. Stober, M. Morgan and M.A.
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19-31.
Suglura, K., M. Aok1. S. Kaneko, et al. 1984. Fate of 2,4,6-tMchloro-
phenol, pentachlorophenol, p-chlorob1phenyl and hexachlorobenzene In an
outdoor experimental pond: Comparison between observation and predictions
based on laboratory data. Arch. Environ. Contain. Toxlcol. 13: 745-758.
Sussmuth, R., B. Ackermann-Schmldt and F. Llngens. 1980. Activation of
liver mlcrosomes by 2,3,4,5-tetrachlorophenol. Mutat. Res. 77(3): 279-282.
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23: 10-16.
Tabak, H.H.. C.W. Chambers and P.W. Kabler. 1964. Mlcroblal metabolism of
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studies with organic priority pollutant compounds. J. Hater Pollut. Control
Fed. 53: 1503-1518.
0024d 10-29 06/19/87
-------
Telford, M. 1974. Blood glucose In crayfish II. Variations Induced by
artificial stress. Comp. Blochem. Physical. 48A: 555. (CUed 1n U.S. EPA,
1980d)
Thorn, N.S. and A.R. Agg. 1975. The breakdown of synthetic organic com-
pounds In biological processes. Proc. R. Soc. Lond. B. 189: 347-357.
Thursby, G.B., R.L. Steel and M.E. Kane. 1985. Effect of organic chemicals
on growth and reproduction 1n the marine red alga Champla parvula. Environ.
Toxlcol. Chem. 4(6): 797-805.
Tlssot. A., P. Boule, J. Lemalre, S. Lambert and J.C. Palla. 1985. Photo-
chemistry and the environment. X. Evaluation of the toxlclty of the photo-
transformation products of hydroqulnone and chlorophenols In aqueous media.
Chemosphere. 14: 1221-1230.
Trabalka, J.R. and H.B. Burch. 1978. Investigation of the effects of halo-
genated organic compounds produced In cooling systems and process effluents
on aquatic organisms. R.L. Jolley, H. Gorchev and D.R. Hamilton, Jr., Ed.
Hater Chlorlnatlon: Environmental Impact and Health Effects, p. 163-173.
U.S. EPA. 1972a. The effects of Chlorlnatlon on selected organic chemicals.
Water Pollut. Control Res. Service. 12020. (Cited In U.S. EPA, 1980b)
U.S. EPA. 1972b. Water Quality Criteria 1872. A report of the committee
on water quality criteria. NTIS PB-236199.
0024d 10-30 06/19/87
-------
U.S. EPA. 1977. Computer print-out of non-confidential production data
from TSCA Inventory. OPTS, CIO, U.S. EPA, Washington, DC.
U.S. EPA. 1978a. In-depth studies on health and environmental effects of
selected water pollutants. E.G. and G. Blonetlcs, War hem, HA. Contract No.
68-01-4646.
U.S. EPA. 19785. Rebuttable presumption against registration and continued
registration of pesticide products containing 2,4,5-trlchlorophenol and Us
salts. Federal Register. 43(149): 34026-34054.
U.S. EPA. 1979a. Reviews of the Environmental Effects of Pollutants. XI.
Chlorophenols. Prepared by the Health Effects Research Lab., Cincinnati,
OH. EPA 600/1-79-012.
U.S. EPA. 1979b. 2,4,5-Trlchlorophenol and Us sodium and potassium salts:
Position document. Report, Iss. p. 70. EPA/SPRD-80/79. NTIS PB 81-10311.
(CA 094:15562U)
U.S. EPA. 1980a. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 49347-49357.
U.S. EPA. 1980D. Ambient Water Quality Criteria for Chlorinated Phenols.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Water
Regulations and Standards, Washington, DC. EPA 440/5-80-032. NTIS
PB81-117434.
0024d 10-31 06/19/87
-------
U.S. EPA. 1980c. Ambient Water Quality Criteria for 2-Chlorophenol.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Water
Regulations and Standards, Washington, DC. EPA/440-5-80-034. NTIS
PB81-117459.
U.S. EPA. 1980d. Ambient Water Quality Criteria for 2,4-D1chlorophenol.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Water
Regulations and Standards, Washington, DC. EPA 440-5-80-042. NTIS
PB81-117533.
U.S. EPA. 1983a. Mehtodology and Guidelines for Reportable Quantity
Determinations Based on Chronic Toxlclty Data. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and Assessment
Office, Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1983b. Reportable Quantity Document for 2-Chlorophenol.
Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1983c. Reportable Quantity Document for 2,4-01chlorophenol.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Emergency
and Remedial Response, Washington, DC.
0024d 10-32 06/19/87
-------
APPENDIX B-2
Cancer Data Sheets for Derivation of a q-j*
Compound: 2,4,6-tMchlorophenol
Reference: NCI. 1979
Specles/straln/sex: rat/F344/M
Body weight = 0.36 kg (measured)
Length of exposure (le) - 107 weeks
Length of experiment (Le) » 107 weeks
Llfespan of animal (L) - 107 weeks
Tumor site and type: hematopoletU system/leukemia
Route/vehicle: oral/diet
Experimental Ooses
or Exposure (ppm)
0
5,000
10,000
Transformed Dose
(mg/kg/day)
0
250
500
Incidence
No. Responding/No.
3/20
23/50
28/50
Tested
Unadjusted q-j* . 2.0347122xlO~» (mg/kg/day)"1
Human qi* » 1.1787856xlO"a (mg/kg/day)"1
0026d
B-2
05/12/87
-------
APPENDIX B-3
Cancer Data Sheets for Derivation of a q-|*
Compound: 2,4,6-trlchlorophenol
Reference: NCI, 1979
Spec1es/strain/sex: mouse/B6C3Fl/male
Body weight = 0.04 kg (measured)
Length of exposure (le) - 105 weeks
Length of experiment (Le) » 105 weeks
Llfespan of animal (L) - 105 weeks
Tumor site and type: 11ver/hepatoce11u1ar adenoma and carcinoma
Route/vehicle: oral/diet
Experimental Doses
or Exposure (ppm)
0
5,000
10.000
Transformed Dose
(mg/kg/day)
0
650
1300
Incidence
No. Responding/No. Tested
4/20
32/49
39/47
Unadjusted q-j* « 1.6119958x10"' (mg/kg/day)'1
Human q-j* « 1.9425697x10"' (mg/kg/day)'1
0026d
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05/12/87
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Data concerning toxldty of chlorophenols to aquatic bacteria and fungi
are presented 1n Table 4-6. The lowest reported toxic concentration was
0.176 mg/1 2,3,4,5-tetrachlorophenol, a 30-m1nute EC5Q for Inhibition of
luminescence of Photobacterlum phosphoreuro (R1bo and Kaiser, 1983).
R1bo and Kaiser (1983) studied structure-toxldty relationships of
chlorophenols 1n the Mlcrotox assay using Photobacterlum phosphoreum. and
found that chlorine substitution 1n the ortho (2- or 6-) positions decreased
toxldty of the chlorophenols. This effect was attributed to hydrogen
bonding and the shielding of the OH group by chloro substUuents.
Information concerning toxlclty of chlorophenols to marine plant species
are summarized In Table 4-7. The lowest reported toxic concentration was
0.44 mg/i 2,3,5,6-tetrachlorophenol, a 96-hour EC-, for Skeletonema
costatum (U.S. EPA, 1978a).
Kulper and Hanstvelt (1984) conducted experiments with natural marine
plankton communities exposed to 4-chlorophenol or 2,4-d1chlorophenol In
plastic enclosures. They found that 0.3 mg/l of either compound slightly
Inhibited phytoplankton growth. Exposure to 1 mg/l of either compound
Inhibited phytoplankton growth, changed the species composition of the
phytoplankton community and affected development of some zooplankton
species. Concentrations of 0.1 mg/t 4-chlorophenol or 2,4-d1chlorophenol
did.not affect phytoplankton or zooplankton growth.
4.4. OTHER RELEVANT INFORMATION
Chlorinated phenols Impair the flavor of freshwater fish flesh at
concentrations much lower than those that are toxic (Shumway and Palensky,
1973; U.S. EPA, 1980b,c,d). Data concerning flavor Impairment are presented
In Table 4-8. In the studies by Shumway and Palensky (1973), rainbow trout
and other fishes were exposed to various chlorophenol concentrations for 48
0013d 4-16 06/18/87
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hours. A panel of 15 judges then scored the flavor of cooked fish, and
results were plotted against exposure concentration to determine graphically
an estimate of the highest concentration that would not Impair flavor. The
lowest such concentration was 0.0004 mg/l 2,4-dlchlorophenol, the ETC for
largemouth bass (Mlcropterus salmoldes). In another study, Henderson et al.
(1960) reported that people experienced mild to severe nausea after eating
flesh of bluegllls exposed to 2 mg/l 2-chlorophenol for 1-4 weeks.
4.5. SUMMARY
In general, the toxlclty of chlorinated phenols to aquatic biota
Increases with Increasing chlorlnatlon (U.S. EPA, 1979a, 1980b,c). This Is
probably due to higher uptake of the more chlorinated compounds (Kobayashl
et al., 1979). The toxlclty of chlorophenols also Increases with decreasing
pH (Konemann and Musch, 1981; SaaMkoskl and Vlluksela, 1981. 1982).
Structure-activity studies with aquatic organisms Indicated that the
presence of chloro substHuents In the ortho position decreased toxlclty,
while substltuents In the para position Increased toxlclty (Devlllers and
Chambon, 1986; R1bo and Kaiser, 1983).
A large volume of data 1s available concerning toxlclty of chlorophenols
to freshwater species; the most sensitive species were salmonlds (rainbow
trout. Salmo qalrdnerl. and brown trout, Salmo trutta) and bluegllls
(Lepomls macrochlrus). The lowest reported acutely toxic concentration for
freshwater fishes was 0.085 mg/l 2,3,4,6-tetrachlorophenol, a 96-hour
LC,.Q for rainbow trout (Mayer and Ellersleck, 1986). The lowest reported
acutely toxic concentration for freshwater Invertebrates was 0.29 mg/l
2,3,4,6-tetrachlorophenol, a 48-hour LC5Q for Daphnla magna (U.S. EPA,
1978a). Data for freshwater plants, fungi and bacteria Indicated toxic
concentrations similar to those for freshwater fishes and Invertebrates.
0018d 4-21 06/18/87
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The lowest reported toxic concentration for freshwater plants was 0.603
mg/l 2,3,4,6-tetrachlorophenol, the 48-hour EC5_ for chlorosis \n
duckweed (Blackman et al., 1955). For bacteria and fungi, the lowest
reported toxic concentration was 0.176 mg/l 2,3,4,5-tetrachlorophenol, a
30-m1nute EC for Inhibition of luminescence of Photobacterlum
phosphoreum (Rlbo and Kaiser, 1983).
Relatively little Information was available concerning marine species.
The lowest reported acutely toxic concentration for marine species was 1.1
mg/l 2,3,4,6-tetrachlorophenol, a 96-hour LC5Q for the cyprlno- dontld
fish, Rlvulus marmoratus (Koenlg and McLean, 1980). The lowest reported
toxic concentration for marine plants was 0.44 mg/l 2,3,5,6-
tetrachlorophenol, a 96-hour EC-0 for Skeletpnema costatum (U.S. EPA,
1978a).
Few studies were available concerning chronic toxlclty of chlorophenols
to aquatic organisms. The only study Involving a full Hfecycle exposure
was that of Koenlg and McLean (1986) who found that fin erosion occurred In
all fish (Rlvulus marmoratus) exposed to 0.055 mg/l
2,3,4,6-tetrachlorophenol, the lowest concentration tested.
Chlorinated phenols have been shown to Impair the flavor of freshwater
fish flesh at concentrations much lower than those that are toxic (Shumway
and Palensky, 1973; U.S. EPA, 1980b,c,d). The lowest reported concentration
for flavor Impairment was 0.0004 mg/l 2,4-d1chloropheno1, a threshold for
largemouth bass (Hlcropterus salmoldes) (Shumway and Palensky, 1973). As
discussed by U.S. EPA (1980b,c,d), threshold concentrations for tainting of
flsn flesh may be more Important than toxic concentrations In establishing
water quality criteria for aquatic biota.
0018d 4-22 06/18/87
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5. PHARHACOKINETICS
5.1. ABSORPTION
Delchmann and Kepllnger (1981) stated that the chlorophenols are readily
absorbed from the gastrointestinal tract and from parenteral sites of Injec-
tion. Carpenter et al. (1985) reported that peak plasma levels of
radioactivity were reached 2 hours after male rats were dosed by gavage with
14C-labeled 2- and 4-chlorophenol (levels not provided).
Korte et al. (1978) administered l4C-2,4,6-tr1chlorophenol to male
rats at three dally doses equivalent to 1 ppm 1n the diet. Of the adminis-
tered radioactivity, 82.3% was detected In the urine and 22.2% 1n the feces
collected over 5 days. Thus, at least 82.3% was absorbed.
Roberts et al. (1977) examined the permeability of human epidermis to 2-
and 4-chlorophenol, 2,4-d1chlorophenol and 2,4,6-tMchlorophenol In vitro. A
2.5 cm2 area of epidermal membrane, obtained from abdominal skin at
autopsy, was supported between two halves of a cell for exposure to the
compounds that were dissolved In water. Results Indicated that all the
chlorophenols studied were absorbed by the epidermal membrane. Permeability
coefficients and threshold concentrations for tissue damage are shown In
Table 5-1.
Gosselln et al. (1976) reported that acutely toxic amounts of 2.4,5- and
2,4,6-tMchlorophenol were not absorbed through Intact skin, of rabbits or
guinea pigs. In contrast, toxic levels of 2,3,4,6-tetrachlorophenol can be
absorbed through the skin.
Additional quantitative data concerning the absorption of the chloro-
phenols could not be located 1n the available literature as dted In
Appendix A.
0019d 5-1 06/18/87
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TABLE 5-1
Permeability Coefficients and Threshold Concentrations for
Damage 1n Human Epidermis for Chlorophenolsa
Compound
Permeability Coefficient
(cm/mln x 104)
Threshold Concentration
for Damage
(% w/v)
2-Chlorophenol
4-Chlorophenol
2,4-01chlorophenol
2,4,6-Trlchlorophenol
5.51
6.05
10.01
9.90
0.8
0.75
no damage'1
no damage*3
aSource: Roberts et al., 1977
bAt any concentration of chlorophenol up to saturation
0019d
5-2
05/08/87
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5.2. DISTRIBUTION
Exon and Keller (1982) examined the 2-chlorophenol content of the liver
and kidneys of five female Sprague-Oawley rats that were provided with
drinking water containing 2-chlorophenol at 5, 50 or 500 ppm for 10 weeks.
The 2-chlorophenol levels 1n the liver were 2.20, 3.20 and 0.08 ppm for the
5, 50 and 500 ppm groups, respectively. In the kidney, the levels were 2.6,
2.4 and 2.0 ppm for the 5, 50 and 500 ppm groups, respectively. No explana-
tion was given for the decrease 1n tissue concentrations 1n the high-dose
group.
Somanl and Khalique (1982) studied the distribution of 2,4-dlchloro-
phenol 1n rats following Intravenous administration of a 10 mg/kg dose. The
highest concentration of 2,4-d1chlorophenol was found In the kidney,
followed by the liver, fat and brain. The plasma volume of distribution of
2,4-d1chlorophenol was 3.7 t/kg.
Korte et al. (1978) did not detect any radioactivity In the liver, lung
or fatty tissue of three rats, 5 days after the rats received three dally
doses of 14C-labeled 2,4,6-tMchlorophenol by stomach tube. The doses
were equivalent to 1 ppm 1n the diet..
PekaM et al. (1986) administered 2,4,6-tMchlorophenol at 25 mg/kg In
propylene glycol Intraperltoneally to male Ulstar rats. At 0.5, 1, 2, 4, 6,
8 and 10 hours after administration, blood samples and samples from the
liver, kidney, muscle, fat and brain were examined for 2,4,6-tMchlorophenol
and conjugates. The highest concentrations of 2,4,6-tMchlorophenol 1n all
tissues were noted 30 minutes after the dose was administered. The kidney,
with 329^117 nmol/g, contained the highest concentration of 2,4,6-tMchloro-
phenol, followed by the blood, liver, fat, muscle and brain. At 30 minutes
0019d 5-3 06/18/87
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after dosing, 70% of the 2,4,6-trlchlorophenol In the blood was In the con-
jugated form. At 10 hours after dosing, only minute amounts of 2,4,6-trl-
chlorophenol were found In the blood and tissues.
In a 55-day gavage study of the toxldty of 2,3,4,6-tetrachlorophenol,
Hattula et al. (1981b) determined tissue concentrations In male Wlstar rats.
In rats dosed at 10 mg/kg/day, no residues of 2,3,4,6-tetrachlorophenol were
found 1n muscle or brain and concentrations In the spleen, kidney and liver
were very low. At dose levels of 50 and 100 mg/kg/day, the highest
2,3,4,6-tetrachlorophenol concentrations were found In the spleen (1.4 and
3.2 ppm) and kidney (1.0 and 5.1 ppm) the smallest levels were found 1n the
muscle and brain.
5.3. METABOLISM
Karpow (1893) found that 2- and 4-chlorophenol administered to dogs
(route not stated) resulted In the excretion of sulfurlc and glucuronlc add
conjugates. In rabbits, 82% of a 150-300 mg/kg dose of 2-chlorophenol was
conjugated with glucuronlc acid, while -19% was conjugated with sulfate
(Spencer and Williams. 1950).
Koster et al. (1981) examined the metabolism of 4-chlorophenol In
anesthetized male Hlstar rats. The rats were Injected Intravenously 1n the
femoral vein with 4-chlorophenol at doses of 14-135 ymol/kg dissolved 1n 1
mt aqueous 0.9% (w/v) NaCl. 81 le and urine were analyzed for conjugates
for 4 hours postexposure. The results showed that 4-chlorophenol was
predominantly glucuronldated (61-72% of the dose), while the remainder was
sulfated (39-21% of the dose). As the Injected dose Increased, the amount
excreted as the glucuronlde Increased, and the amount of sulfate decreased,
although these changes were not large. Throughout the experiment, 100% of
the administered dose was recovered. Koster et al. (1981) also examined the
0019d 5-4 06/18/87
-------
metabolism of 4-chlorophenol In Isolated rat hepatocytes. At concentrations
of 25 and 800 nM, glucuronldatlon of 4-chlorophenol predominated, and a
concentration-dependent shift In the ratio between sulfatlon and glucuronl-
datlon was not observed.
Somanl and Khallque (1982) found that 2,4-d1chlorophenol administered
Intravenously to rats was metabolized to glucuronlde and other conjugates.
In an In vitro study using Isolated perfused rat liver, Somanl et al. (1984)
Identified two dlchloromethoxyphenols as metabolites of 2,4-d1chlorophenol.
After orally dosing Wlstar and Sprague-Oawley rats with 14C-labeled
2,4,6-trlchlorophenol for 15 days, Bahlg et al. (1981) Identified glucuro-
nlde conjugates and trlchlorophenol Isomers (2,4,6-, 2,3,6- and 2,4,5-) 1n
the urine.
Ahlborg and Larsson (1978) examined the metabolism of purified tetra-
chlorophenols In Sprague-Oawley rats. After being dosed Intraperltoneally
with 10 mg/kg of a tetrachlorophenol Isomer In propylene glycol, rats were
placed 1n metabolism cages, two per cage, and the urine was collected at
24-hour Intervals for up to 72 hours. Before the urine was analyzed for
metabolites, 1t was boiled with concentrated hydrochloric add to split
possible conjugates. Analysis of the urine revealed that tetrachlorohydro-
qulnone was a major metabolite of 2,3,5,6-tetrachlorophenol. Except for
Insignificant amounts of tr1chlorohydroqu1none Identified In the urine,
2,3,4,5- and 2,3,4,6-tetrachlorophenol were excreted In the urine essen-
tially unchanged or as conjugates.
5.4. EXCRETION
In the study by Karpow (1893), 87% of 2- and 4-chlorophenol administered
to dogs was excreted 1n the urine as sulfuMc and glucuronlc add conjugates.
0019d 5-5 05/08/87
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Somanl and Khallque (1982) found that the half-lives of 2,4-d1chloro-
phenol and Us conjugates varied from 4-30 minutes In the plasma, fat,
brain, liver and kidneys of rats treated with 10 mg/kg Intravenously.
Korte et al. (1978) found that over 5 days, rats excreted 82.3% of the
radioactivity from 14C-labeled 2,4,6-tMchlorophenol 1n the urine, while
22.2% was eliminated 1n the feces. The products excreted were not Identi-
fied. The compound was administered In three dally doses to three male rats
by stomach tube at a level equivalent to 1 ppm 1n the diet.
Bahlg et al. (1981) examined the excretion of 2,4,6-trlchlorophenol and
metabolites after six Wlstar and Sprague-Oawley rats were dosed by gavage
with 25 vg 14C-labeled 2,4,6-tMchlorophenol for 15 days. The results
showed that 28% of the applied radioactivity was found In the urine In water
soluble form (conjugates plus water soluble metabolites), 63% was found In
the urine 1n chloroform-soluble form and 6.4% was found 1n the feces. At 3
days after cessation of the 15-day dosing period, urinary and fecal excre-
tion of radioactivity decreased sharply to 4.3 and 1.9% of the dose, respec-
tively. The high recovery and rapid decline In excretion of radioactivity
Indicate that 2,4,6-tMchlorophenol Is not accumulated In rats.
PekaM et al. (1986) found that 90% of a single 25 mg/kg dose of
2,4,6-trlchlorophenol Injected 1ntraper1toneally Into male Wlstar rats was
excreted 1n 4-6 hours. The half-life of 2,4,6-trlchlorophenol ranged from
1.4-1.8 hours 1n the blood, liver, kidney, muscle, fat and brain.
After administration of an Intraperltoneal dose of 10 mg/kg of
2,3,5,6-tetrachloropnenol 1n rats, Ahlborg and Larsson (1978) found that
98.7% of the dose was excreted 1n the urine after 24 hours. Approximately
0019d 5-6 05/08/87
-------
66.5X of the dose was unchanged, while -33.5X was excreted as tetrachloro-
hydroqulnone. When 2,3,4,6-tetrachlorophenol was given to rats Intraperl-
toneally, 95.9% of the dose was recovered unchanged In the urine at 72
hours, while only 58.8% of a dose of 2,3,4,5-tetrachlorophenol was recovered
In the urine 72 hours after dosing.
Kalman and Horstman (1983) examined the excretion of 2,3,4,6-tetra-
chlorophenol In humans occupational!;/ exposed to Permatox.100 (3% penta-
chlorophenol, 21% 2,3,4,6-tetrachlorophenol). Exposures were considered to
be primarily by the dermal route rather than through Inhalation. The urine
of two workers was examined for 2,3,4,6-tetrachlorophenol every other day
during a 16-day vacation. Both workers showed an Initial period of between
2 and 3 days during which the urinary level was >100 ppb before an
exponential decay In urinary 2,3,4,6-tetrachlorophenol was observed. This
delay Is consistent with an Initial distribution phase followed by
first-order elimination. In addition, the urine of 24 workers was examined
before and after a 16-day vacation. Adjusting the data from the 24 workers
for the distribution phase observed In the 2 more frequently examined
workers, the average half-time of elimination of 2,3,4,6-tetrachlorophenol
was estimated at 63+34 hours.
5.5. SUMMARY
The chlorophenols seem to be readily absorbed from the gastrointestinal
tract and from parenteral sites of Injection (Delchmann and KepHnger, 1981;
Carpenter et al., 1985). Rats dosed orally with l4C-2,4,6-tr1chlorophenol
absorbed at least 82.3% of the dose based on urinary excretion of radio-
activity (Korte et al., 1978). Roberts et al. (1977) found that 2- and
4-chlorophenol, 2,4-
-------
human epidermis j_n vitro. Acutely toxic levels of 2,4,5- and 2,4,6-tr1-
chlorophenol were not absorbed through the Intact skin of rabbits or guinea
pigs, while toxic levels of 2,3,4,6-tetrachlorophenol were absorbed through
the skin (Gosselln et al., 1976).
Pharmacoklnetlc studies of the chlorophenols In laboratory animals
Indicate that the compounds are distributed rapidly, but do not accumulate
In any tissue (Exon and Koller, 1982; Somanl and Khallque, 1982; Korte et
al., 1978; PekaM et al., 1986; Hattula et al., 1981b). Metabolism studies
Indicate that the chlorophenols are conjugated to glucuronldes and sulfates,
with glucuronldes predominating In rats (Karpow, 1893, Koster et al., 1981;
Somanl and Khallque, 1982; Bahlg et al., 1981). Other metabolites that have
been Identified are dlchloromethoxyphenols Identified 1n an _h) vitro study
of the metabolism of 2,4-d1chlorophenol (Somanl et al., 1984), tetrachloro-
hydroqulnone as a metabolite of 2,3,5,6-tetrachlorophenol and tMchloro-
hydroqulnone as a minor metabolite of 2,3,4,5- and 2,3,4,6-tetrachlorophenol
(Ahlborg and Larsson, 1978). In addition, Sahlg et al. (1981) found that
other trlchlorophenol Isomers are excreted when 2,4,6-trlchloropnenol was
administered orally to rats.
Studies In laboratory animals (Karpow, 1893; Korte et al.. 1978; Bahlg
et al., 1981; Ahlborg and Larsson, 1978) Indicate that the chlorophenols are
excreted predominantly 1n the urine as glucuronlc and sulfuMc add conju-
gates, and as the unchanged compounds. Kalman and Horstman (1983) found
that the half-time of elimination of 2,3,4,6-tetrachlorophenols In occupa-
tional ly exposed humans was -63+34 hours.
0019d 5-8 05/08/87
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6. EFFECTS
6J. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure.
6.1.1.1. SUBCHRONIC -- In a Russian study (Gurova, 1964), rats and
mice were exposed to supraHmlnal concentrations (levels not provided) of
4-chlorophenol 4 hours/day for 28 days. Pathological changes 1n the organs
Included congestion and focal hemorrhages 1n the brain, lungs, Hver and
myocardium, thickening of the alveolar septa and some atelectases and
emphysema 1n the lungs.
In another experiment by Gurova (1964), white rats were exposed to 0.002
mg/a (2 mg/m3) 4-chlorophenol 6 hours/day for 4 months. During the
first 30 days of exposure, the exposed rats showed a weight loss compared
with controls. By the end of the study, the exposed rats gained more weight
than controls. Throughout the study, neuronuiscular excitability was
Increased and a reduction of general endurance compared with controls was
observed. The exposed rats also showed an Increased myoneural excitability.
Hemoglobin, RBC, WBC, sedimentation rate and body temperature were similar
to controls. Microscopic examination of organs revealed slight congestion
and minor flbrotlc changes 1n the alveolar septa of some rats. This study
lacked sufficient detail to adequately assess the reliability of the results.
6.1.1.2. CHRONIC Gurova (1964) studied workers exposed to
4-chlorophenol at an aniline dye plant In the Soviet Union. Exposures were
by both Inhalation and dermal routes. The authors stated that the total
quantity of 4-chlorophenol absorbed did "not exceed 10-15 mg/sh1ft." The
highest ambient air concentration was reported to be 0.021 mg/i. The
workers experienced a higher Incidence of neurologic disorders. Effects
noted Included nervous exhaustion, Insomnia, Irritability, frequent mood
0020d 6-1 05/11/87
-------
changes and rapid fatlgabUHy. A two-point touch discrimination test
showed that the workers suffered a lessening of touch sensation. Peripheral
nerve stimulation examinations Indicated Increased myoneural excitability.
Again, the lack of detail precludes adequate assessment of the reliability
of the results.
Kleu and Goltz (1971) reported the case histories of 10 patients
suffering from chloracne, who were occupatlonally exposed to an unspecified
tMchlorophenol formulation for 15 years. In addition to chloracne, a
psychopathologlcal syndrome was described. Symptoms, which Increased In
Intensity over the period of exposure, Included decreased sexual activity,
easy fatlgabllUy, Irritability, muscular weakness, loss of appetite and
memory, discouragement, alcohol Intolerance and loss of Interest. When the
report was written, a permanent defect, described as reduced vital physic
and Intellectual capacities combined with neurasthenia and mental depres-
sion, was becoming evident. However, there was no detailed Information on
the exposure history of these patients and the study made no attempt to
establish a causal relationship.
Alexandersson and Hedenstlerna (1982) studied the pulmonary function of
two men and five women who were occupatlonally exposed to an unspecified
trlchlorophenol Isomer for up to 10 years. The subjects studied were
exposed during the testing of gas masks, a process that uses trlchlorophenol
as a tracer gas. Exposure levels were probably variable, but levels of
<0.003 mg/i were measured, with each Individual testing up to 25 gas masks
per day. The subjects studied Included three smokers (15-20 cigarettes/day)
and four nonsmokers. The parameters examined Included FEVC, FEV,, HEF at
75, 50 and 25X of FEVC and CV% In percent of vital capacity. In addition,
the subjects were given a questionnaire regarding symptoms of the upper
0020d 6-2 06/18/87
-------
derived. Confidence 1n this RfD Is medium. Although the study by Hattula
et al. (19815) uses only a few animals, dosing was 7 days/week and several
parameters were examined; and the study by Schwetz et al. (1974) supports
the NOAEL.
8.2.2.2. CHRONIC EXPOSURE -- In a chronic toxlclty study (Exon and
Keller, 1985), hematologlc effects were noted In rats provided with drinking
water containing 2-chlorophenol at 500 ppm. These effects were not observed
at 50 ppm. No other parameters of toxldty were examined 1n this study.
Exon and Koller (1982) found reproductive effects In female rats exposed
to 2-chlorophenol In their drinking water at 500 ppm but not at 50 ppm.
U.S. EPA (1986b) used the reproductive NOAEL to derive a chronic RfD. The
RfD was derived from a NOAEL dose of 5 mg/kg/day, estimated by assuming that
the dally Intake of water by rats Is 10% of their body weight. Application
of an uncertainty factor of TOOO (10 for 1nterspec1es extrapolation, 10 to
protect sensitive Individuals and 10 for extrapolation from a subchronlc
study), results In a chronic RfD of 0.005 mg/kg/day, or 0.4 rag/day for a 70
kg human. Confidence In this RfD 1s low; adequate parameters of the
toxlclty of 2-chlorophenol were not examined.
U.S. EPA (1986b,c) derived an RfD for 2,4-dlchlorophenol from the
subchronlc study by Exon and Koller (1985). This RfD, 0.003 mg/kg/day or
0.2 rag/day for a 70 kg human, which was presented as the subchronlc RfO 1n
Section 8.2.2.1., 1s also adopted as the chronic RfD. An additional uncer-
tainty factor of 10 to extrapolate from subchronlc data was not considered
necessary because the rats were exposed .In. utero and through the milk before
the 15-week exposure period (U.S. EPA, 1986c). As stated 1n Section
8.2.2.1., confidence In the RfD Is low because of the limited parameters of
toxlclty that have been examined In studies of the toxlclty of 2,4-dlchloro-
phenol .
QQ22d 8-10 08/11/87
-------
No chronic oral studies concerning the toxlclty of 2,4,5-tMchlorophenol
are available. A chronic oral RfD of 0.1 mg/kg/day or 7.0 mg/day for a 70
kg human was derived by U.S. EPA (1985a) from the study by McColllster et
al. (1961) by applying an uncertainty factor of 1000 (10 for Interspedes
extrapolation, 10 for the protection of sensitive Individuals and 10 to
approximate chronic exposures) to the NOEL of 100 mg/kg/day (see Section
8.2.2.1.). Because the subchronlc study was well-conducted but because
supporting data are not available, confidence In the chronic oral RfO Is
medium to low.
Chronic studies of the oral toxlclty of the tetrachlorophenols are not
available. A chronic oral RfD of 0.01 mg/kg/day or 0.7 mg/day for a 70 kg
human for 2,3,4,6-tetrachlorophenol was derived by U.S. EPA (1985b) by
applying an uncertainty factor of 1000 to the subchronlc oral NOEL of 10
mg/kg/day In the study by Hattula et al. (1981b) (see Section 8.2.2.1.).
The uncertainty factor reflects an additional factor of 10 for subchronlc to
chronic extrapolation. For reasons stated In Section 8.2.2.1., confidence
In the RfD Is medium.
0022d 8-11 08/11/87
-------
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TQXICITY
Toxlclty data concerning the chlorophenols were discussed In Chapter 6.
Data suitable for deriving RQs are summarized In Table 9-1. No data
concerning the toxlclty of 3-, 4-chlorophenol, 2,3-, 2,5-, 2,6-, 3,4-,
3,5-d1chlorophenol, 2,3,4-, 2,3,5-, 3,4,5-tMchlorophenol or 2,3,4,5- and
2,3,5,6-tetrachlorophenol were available; therefore, RQs for these compounds
cannot be derived.
U.S. EPA (1983b) examined the data concerning the toxlclty of 2-chloro-
phenol and concluded that there were Insufficient data to derive an RQ;
however, since that time, Exon and Koller (1982) completed a reproductive
study that 1s appropriate for RQ derivation. In this study, Utter sizes
were significantly reduced 1n rat dams exposed to 2-chlorophenol 1n their
drinking water at 500 ppm from 3 weeks of age through lactation. Multiply-
ing the transformed human dose (12 mg/kg/day) by 70 kg (the human body
weight) a human MED of 840 rug/day 1s derived, which corresponds to an RV.
of 1.1. The fetotoxldty observed In the study corresponds to an RV of
8. Multiplying the RVg by the RVd, a CS of 9 Is derived. This CS
corresponds to an RQ of 1000. The data used to derive the RQ for
2-chlorophenol are shown In Tables 9-2 and 9-3. As Indicated In Table 9-4,
there were Insufficient data to derive RQs for both 3- and 4-chlorophenol.
Three studies are available for the derivation of an RQ for
2,4-d1chlorophenol (Table 9-5). In the study by Rodwell et al. (1984),
signs of maternal toxlclty and fetotoxldty were noted 1n rats treated by
gavage with 2,4-d1chlorophenol at 750 mg/kg on gestation days 6-15. In
calculating the human MED, the transformed human dose, 128.2 mg/kg/day, was
multiplied by the human body weight of 70 kg. The human MED of 8960 mg/day
0023d 9-1 06/18/87
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-------
TABLE 9-2
Oral Composite Score for 2-Chlorophenol Using the Rat*
Animal Dose
(mg/kg/day)
Chronic
Human MEO
(mg/day)
RVd
Effect
RV0 CS
RQ
70
840
1.1 Decreased Utter
size; Increase 1n
stillbirths
1000
*Source: Exon and Koller, 1985
0023d
9-4
05/11/87
-------
TABLE 9-3
2-Chlorophenol
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 840 mg/day
Effect: decrease 1n Utter size and a slight Increase 1n
stillbirths
Reference: Exon and Koller, 1982
RVd: 1.1
RVe: 8
Composite Score: 9
RQ: 1000
'Equivalent human dose
0023d 9-5 05/11/87
-------
TABLE 9-4
3-Chlorophenol and 4-Chlorophenol
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Oose:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ: Data are Insufficient for deriving an RQ for either
3- or 4-chlorophenol.
0023d 9-6 05/11/87
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corresponds to an RV, of 1. In the study by Exon and Koller (1985),
fetotoxlclty was also noted In rats exposed to 2,4-d1chlorophenol In their
drinking water at 300 ppm from 3 weeks of age through parturition. The
human MED of 504 mg/day was calculated by multiplying the human transformed
dose, 7.2 mg/kg/day, by the 70 kg human body weight. This MED corresponds
to an RVd of 1.4. The RVQs of both the Rodwell et al. (1984) and Exon
and Holler (1985) studies correspond to 8, so that the Exon and Keller
(1985) study with a CS of 11.2 would be more appropriate for the derivation
of an RQ than the Rodwell et al. (1984) study with a CS of 8.8. Despite a
lower RV , the highest CS for 2,4-d1chlorophenol. 1s calculated from the
study by Kobayashl et al.-(1972) In which hlstopathologlcal changes were
observed In the livers of rats provided with diets containing 2,4-d1chloro-
phenol at 0.2% for 6 months. The human MED, 121 mg/day, was calculated by
multiplying the human transformed dose, 17.3 mg/kg/day, by 70 kg human body
weight and by dividing by 10 to account for subchronlc exposure. This MED
corresponds to a RV. of 2.4. The liver changes correspond to an RV of
5. Multiplying the RVd by the RVg, a CS of 12 Is derived. This CS
corresponds to an RQ of 10QQ (Table 9-6).
An evaluation of the data concerning the toxlclty of 2,6-d1chlorophenol
(U.S. EPA, 1983d) found that there were Insufficient data to derive an RQ.
Table 9-7 Indicates that there were Insufficient data to derive RQs for
2,3-, 2,5-, 2,6-, 3,4- and 3,5-dlchlorophenols.
Two studies are available for the derivation of an RQ for 2,4,5-
tMchlorophenol (Table 9-8). In the study by Chernoff and Kavlock (1982), a
reduction 1n IHter size was observed In mice treated by gavage with the
compound on gestation days 6-15. The chronic human MED, 4221
0023d 9-8 06/18/87
-------
TABLE 9-6
2,4-01chlorophenol
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 121 mg/day
Effect: reversible hepatic changes
Reference: Kobayashl et al.t 1972; U.S. EPA, 1983c
RVd: 2.4
RVe: 5
Composite Score: 12
RQ: 1000
'Equivalent human dose
0023d 9-9 06/18/87
-------
TABLE 9-7
2,3-, 2,5-, 2,6-, 3,4- and 3,5-01chlorophenol
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Dose:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ: Data are Insufficient for deriving an RQ for any of
the dlchlorophenol Isomers listed above.
0023d 9-10 05/11/87
-------
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rog/day, was calculated by multiplying the transformed human dose, 60.3
mg/kg/day, by the 70 kg human body weight. This MED corresponds to an RV.
of 1. FetotoxIcHy corresponds to an RV of 8, so by multiplying the
RV. by the RV , a CS of 8 1s derived. A higher CS Is derived from the
study by McColHster et al. (1961) In which degenerative changes In the
liver and kidney were noted 1n rats fed 2,4,5-tMchlorophenol In the diet at
0.3X for 98 days. U.S. EPA (1983e, 1984a) derived an RQ from the McColllster
et al. (1961) study using a 5% food factor and a rat body weight of 0.35 kg.
Because young rats were used In this subchronlc study, a food factor of 10X
and the body weight of 0.191 kg, provided by the authors, are more appro-
priate values for use 1n calculating the transformed animal dose. Using the
more appropriate transforming values, the human MED (293.3 mg/kg) was
derived by multiplying the transformed human dose (41.9 mg/kg/day) by 70 kg
(the human body weight)., and by dividing by a factor of 10. This MED corre-
sponds to an RV. of 1.8. The liver and kidney degenerative changes
correspond to an RVg of 6. Multiplying the RVd by the RVg, a CS of
10.8 1s derived. This CS corresponds to an RQ of 1000. This RQ and the
data used to derive It are presented 1n Table 9-9.
U.S. EPA (1983f) concluded that the data were Insufficient to derive an
RQ for 2,4,6-trlchlorophenol based on chronic tox1c1ty. An RQ for
2,4,6-tMchlorophenol based on carclnogenlclty will be derived In Section
9.2. Table 9-10 Indicates the lack of toxldty data available for the
derivation of RQs for 2,3,4-, 2,3,5-, 2,3,6- and 3,4,5-trlchlorophenol.
Two studies are available for the derivation of an RQ for
2,3,4,6-tetrachlorophenol (Table 9-11). U.S. EPA (1983f) derived an RQ from
the teratogenldty study conducted by Schwetz et al. (1974) In which feto-
toxlclty (subcutaneous edema) was observed In offspring of rats treated by
0023d 9-12 06/18/87
-------
TABLE 9-9
2,4,5-Trlchlorophenol
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 293 mg/day
Effect: slight degenerative changes 1n the liver and kidney
Reference: HcColHster et al., 1961
RVd: 1.8
RVe: 6
Composite Score: 10.8
RQ: 1000
'Equivalent human dose
0023d 9-13 05/11/87
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TABLE 9-10
2,3,4-, 2,3,5-, 2,3,6- and 3,4,5-Trlchlorophenol
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Oose:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ: Data are Insufficient for deriving an RQ for any of
the tMchlorophenol Isoraers listed above.
0023d 9-14 05/11/87
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gavage with the compound on gestation days 6-15. In the derivation, U.S.
EPA (1983f) applied a factor of 10 to the dose; this Is not appropriate for
a teratogenlclty study because exposure 1s chronic to the fetus. Further-
more, the subcutaneous edema was not seen at the higher dose and was
considered nontreatment-related. Using the dose of 30 mg/kg/day from the
Schwetz et al. (1974) study that caused delayed ossification, a human MED of
322 mg/day Is derived by multiplying the transformed human dose, 4.6
mg/kg/day, by the 70 kg human body weight. This MED corresponds to an RV.
of 1.7, and the fetotoxlclty corresponds to an RV of 8. Multiplying the
RV. by the RV , a CS of 13.1 1s derived. The Research Triangle
Institute (1987) study reported maternal toxldty and no fetotoxlclty at 200
mg/kg/day tetrachlororphenol. A human MED of 239.8 mg/day Is derived from
the animal dose by using the cube root of animal/human body weight and an
uncertainty factor of 10 to account for chronic toxldty to the dam. This
MEO corresponds to an RV. of 1.9, loss of maternal body weight to an RV
of 3 and a CS of 6. A higher CS value can be derived from the study by
Hattula et al. (1981b) In which hlstopathologlcal changes In the liver were
observed In rats treated with 2,3,4,6-tetrachlorophenol by gavage at 50
mg/kg/day for 55 days. The human MED, 61.6 mg/day, 1s derived by
multiplying the transformed human dose, 8.8 mg/kg/day, by the 70 kg human
body weight and by dividing by 10 to extrapolate from a subchronlc study.
This MED corresponds to an RV. of 2.8, while the hlstopathologlcal changes
1n the liver correspond to an RV of 6. Multiplying the RV. by the
RVe, a CS of 16.8 1s derived. This CS corresponds to an RQ of 1000. The
RQ and the data used to derive It are presented In Table 9-12. As Indicated
In Table 9-13, no toxldty data were available for the derivation of RQs for
2,3,4,5- and 2,3,5,6-tetrachlorophenol.
0023d 9-16 06/18/87
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TABLE 9-12
2,3,4,6-Tetrachlorophenol
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 61.6 mg/day
Effect: histopathologlcal changes 1n the liver; one rat
most of the parenchyma Involved
Reference: Hattula et al., 1981b
RVd: 2.8
RVe: 6
Composite Score: 16.8
RQ: 1000
'Equivalent human dose
0023d 9-17 05/11/87
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TABLE 9-13
2,3,4,5- and 2,3,5,6-Tetrachlorophenol
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Dose:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ: Data are Insufficient for deriving an RQ for either
2,3,4,5- or 2,3,5,6-tetrachlorophenol.
0023d 9-18 05/11/87
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9.2. BASED ON CARCINOGENICITY
2,4,6-TMchlorophenol has been shown to be a carcinogen 1n rats and mice
(NCI, 1979). In male rats, the compound caused an Increase In the Incidence
of leukemia, while In mice, an Increase 1n the Incidence of Hver carcinoma
and adenoma were observed (see Section 6.2.2. and Table 6-2). Based on the
NCI (1979) study and the lack of human data, 2,4,6-tMchlorophenol can be
classified as an EPA Group B2 chemical, probable human carcinogen.
The data for the derivation of the F factor Is shown In Table 9-14. The
F factor of 1.4xlO~x (mg/kg/day)"1 for 2,4,6-tMchlorophenol, was calcu-
lated by multiplying the 1/ED1(], 1.16xlO~2 (mg/kg/day)'1, obtained
from the multistage model, by the cube root of the ratio of the human body
weight, 70 kg, to the animal body weight, 0.04 kg. This F factor Indicates
that 2,4,6-tMchlorophenol should be placed 1n Potency Group 3. Compounds
In EPA Group B2 and 1n Potency Group 3 are ranked LOW 1n the Hazard Ranking
Scheme. The low hazard ranking for 2,4,6-trlchlorophenol Indicates that It
should be assigned an RQ of 100.
0023d 9-19 08/11/87
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