TECHNICAL REPORT DATA
frUae read Instruction! on the rtvtru before completing)
. REPORT NO.
EPA/600/8-88/052
2.
3. RECIPIENTS ACCESSION NO.
PB88-178942
.TITLE AND SUBTITLE
6. REPORT DATE
Health Effects Assessment for 2-Chlorophenol and
2,4-Dichlorophenol
6. PERFORMING ORGANIZATION CODE
AUTHOR(S)
«. PERFORMING ORGANIZATION REPORT NO.
PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
'2. SPONSORING AGENCY NAME AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE OF REPORT AND PERIOD COVERED
14. SPONSORING AGENCY CODE
EPA/600/22
. SUPPLEMENTARY NOTES
«. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). The first, RfD5 or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to cause adverse effects when exposure occurs for a significant portion
of the lifespan. For compounds for which there is sufficient evidence of
carcinogenicity, qi*s have been computed, if appropriate, based on oral and
inhalation data if available.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Croup
. DISTRIBUTION STATEMENT
Public
19. SECURITY CLASS (This Report)
Unclassified
21. NO. OF PAGES
20. SECURITY CLASS (Thispage)
Unclassified
22. PRICE
EPA POT* 2220>1 (1Uv. 4-77) PREVIOUS COITION i* OMOLKTE
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EPA/600/8-88/052
June, 1987
HEALTH EFFECTS ASSESSMENT
FOR 2-CHLOROPHENOL AND 2,4-DICHLOROPHENOL
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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DISCLAIMER
This document has been reviewed 1n accordance with the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with selected
chlorinated phenols. All estimates of acceptable Intakes and carcinogenic
potency presented In this document should be considered as preliminary
reflecting limited resources allocated to this project. Pertinent toxlco-
loglc and environmental data were located through on-'llne literature
searches of the TOXLINE, CANCERLINE and the CHEMFATE/DATALOG data bases.
The basic literature searched supporting this document 1s current up to May,
1986. Secondary sources of Information have also been relied upon In the
preparation of this report and represent large scale health assessment
efforts that entail extensive peer and Agency review. The following Office
of Health and Environmental Assessment (OHEA) sources have been extensively
utilized:
U.S. EPA. 1979a. Review of the Environmental Effects of Pollut-
ants. XI. Chlorophenols. Office of Research and Development,
Health Effects Research Laboratory, U.S. EPA, Cincinnati, OH. EPA
600/1-79-012.
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for
2-Chlorophenol. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Water Regulations and Standards, Wash-
ington, DC. EPA 440/5-80-034. NTIS PB81-117459.
U.S. EPA. 1980b. Ambient Water Quality Criteria Document for
2,4-D1chlorophenol. Prepared by the Office of Health and Environ-
mental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Water Regulations and Standards,
Washington, DC. EPA 400/5-80-042. NTIS PB81-117533.
U.S. EPA. 1980c. Hazard Profile for Chlorinated Phenols.
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. 1983a. 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. 1983b. Reportable Quantity Document for 2,4-D1chloro-
phenol. Prepared by the Office of Health and Environmental Assess-
ment, Environmental Criteria and Assessment Office, Cincinnati, OH
for the Office of Emergency and Remedial Response, Washington, DC.
111
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The Intent In these assessments Is to suggest acceptable exposure levels
for noncarclnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose. Is
an estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval 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 been primarily directed
towards exposures from toxicants 1n ambient air or water where lifetime
exposure Is assumed. Animal data used for RFD$ estimates generally
Include exposures with durations of 30-90 days. Subchronlc human data are
rarely available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure. These
values are developed for both Inhalation (RfD$j) and oral (RfD$g)
exposures.
The RfO (formerly AIC) 1s similar 1n concept and addresses chronic
exposure. It Is an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the Hfespan [see U.S. EPA (1980d) for a discussion of this concept]. The
RfO 1s route-specific and estimates acceptable exposure for either oral
(RfDg) or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development Is explained 1n U.S.
EPA (1984).
For compounds for which there Is sufficient evidence of carcinogenic!ty
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980d). Since cancer 1s a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data 1f available.
1v
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ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
Data were located only for oral exposure to 2-chlorophenol and 2,4-d1-
chlorophenol. An RfDn, and RfD$o for exposure to 2-chlorophenol of 0.35
mg/day was derived from a NOAEL of 50 ppm for reproductive effetfts In a
subchronlc drinking water study using rats (Exon and Koller, 1982). A CS of
10.4 was derived for effects on reproduction 1n rats at 500 ppm, the next
higher level 1n the same study.
For 2,4-dlchlorophenol, an RfD$o value of 0.2 mg/day for oral exposure
was derived from a NOAEL of 3 ppm In a 15-week drinking water study In rats
(Exon and Koller, 1985). Since the test animals were exposed both In utero
and through milk before the 15-week administration In drinking water, an
additional factor for use of subchronlc study was not considered necessary.
Therefore, an RfOg of 0.2 mg/day was derived. A CS of 11.9 was associated
with mild hlstopathologlcal lesions 1n the livers of mice exposed to
2,4-d1chlorophenol 1n the diet for 6 months (Kobayashl et al., 1972; U.S.
EPA, 1983b).
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Or. Christopher OeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents 1n this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and Kim Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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TABLE OF CONTENTS
5.
6.
ENVIRONMENTAL CHEMISTRY AND FATE. ....
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS . . .
2.1. ORAL
2.2. INHALATION
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS. . . .
3.3.1. Oral
3.3.2. Inhalation
3.4. TOXICANT INTERACTIONS
CARCINOGENICITY :
4.1. HUMAN DATA
4.1.1. Oral
4.1.2. Inhalation
4.2. BIOASSAYS
4.2.1. Oral
4.2.2. Inhalation
4.3. OTHER RELEVANT DATA
4.4. HEIGHT OF EVIDENCE
REGULATORY STANDARDS AND CRITERIA
RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfDs)
6.1.1. Oral (RfDso)
6.1.2. Inhalation (RfDci)
Paqe
. . . 1
. . . 4
... 4
4
. . . 5
... 5
. . . 5
. , . 6
. . . 6
. . . 6
7
. . . 7
. . . 7
8
. . . 8
, , . 9
, 9
. . . 9
9
9
. . . 9
10
. . . 10
11
. . . 12
13
, , . 13
. . . 13
. . . 14
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TABLE OF CONTENTS (cont.)
Page
6.2> REFERENCE DOSE (RfD) 14
6.2.1. Oral (RfD0) 14
6.2.2. Inhalation (RfDj) 17
6.3. CARCINOGENIC POTENCY (q-|*) 17
6.3.1. Oral 17
6.3.2. Inhalation 17
7. REFERENCES 18
APPENDIX A: Summary Table for 2-Chlorophenol 24
APPENDIX B: Summary Table for 2,4-D1chlorophenol 25
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LIST OF ABBREVIATIONS
BCF B1oconcentrat1on factor
CAS Chemical Abstract Service
CS Composite score
DMBA Dimethyl benzanthracene
DWEL Drinking water equivalent level
Koc Soil sorptlon coefficient
MED Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEL No-observed-effect level
ppm Parts per million
RfD Reference dose
RfDj Inhalation reference dose
RfDg Oral reference dose
RfDs Subchronlc reference dose
RfDsj Subchronlc Inhalation reference dose
RfD$o Subchronlc oral reference dose
RVd Dose-rating value
RVe Effect-rating value
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected chemical and physical properties and environmental fate of
2-chlorophenol (CAS No. 95-57-8) and 2,4-d1chlorophenol (CAS No. 120-83-2)
are presented 1n Table 1-1. Synonyms for 2-chlorophenol are o-chlorophenol
and l-chloro-2-hydroxybenzene.
If present 1n the atmosphere, 2-chlorophenol and 2,4-dkhlorophenol
should exist primarily 1n the vapor phase. The atmospheric half-lives
listed In Table 1-1 are for the oxidation of vapor-phase chlorophenols by
photochemlcally generated hydroxyl radicals. These values were calculated
using estimated reaction rate constants of 5.1xlO~12 cm3/molecule-sec
for 2-chlorophenol and 1.53xlO~12 cm3/molecule-sec for 2,4-d1ch1oro-
phenol at 25°C and an ambient hydroxyl radical concentration of 8.0x10*
molecules/cm3 (U.S. EPA, 1986a). In water, the chlorophenols will exist
1n both Ionic and nonlonlc forms, with the extent of lonlzatlon Increasing
with Increasing pH. B1odegradat1on and photolysis are expected to be the
Important fate processes (Callahan et al., 1979). The half-life of
2,4-d1chlorophenol 1n water (see Table 1-1) Is the minimum blodegradatlon
half-life for this compound reported by Callahan et al. (1979). Since
2,4-d1chlorophenol Is structurally comparable with 2-chlorophenol, the two
compounds are expected to have similar half-lives. K values of the
chlorophenols suggest that adsorption to sediments would be significant, and
the BCF values suggest that bloaccumulatlon In aquatic organisms would not
be significant.
In soil, the chlorophenols appear to be removed primarily by mlcroblal
decomposition (U.S. EPA, 1980a,b; Baker et al., 1980). The soil half-lives
listed above are based on the observation that 94X loss of 2-chlorophenol
0080h -1- 06/12/87
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occurred In 6.5 days and 82X loss of 2,4-d1chlorophenol occurred In 12 days
when 119.05 vg/g soil of each compound were Incubated Individually under
aerobic conditions at 4°C (Baker et al., 1980). The relatively high KQ(.
values of 2-chlorophenol and 2,4-d1chlorophenol Indicate that these
compounds should have low mobility In acidic soils where hydrogen bonding Is
possible; however, these compound will become reasonably mobile as the pH of
the soil Increases (U.S. EPA, 1979a).
0080h -3- 06/17/87
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Quantitative absorption data on 2-chlorophenol or 2,4-d1chlorophenol
after oral administration were not available; however, the U.S. EPA
(1980a,b) Indicated that chlorophenols are readily absorbed because of their
high llpld solubility and low degree of 1on1zat1on at physiological pH.
Gastrointestinal absorption may be Inferred since hematologlcal and repro-
ductive toxlclty were reported 1n rats given oral doses of 2-chlorophenol or
2,4-d1chlorophenol (Chapter 3).
2.2. INHALATION
Quantitative absorption data after Inhalation exposure to 2-chlorophenol
or 2,4-d1chlorophenol could not be located 1n the available literature.
0080h -4- 11/28/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRQNIC
3.1.1. Oral. Conventional subchronlc toxlclty studies with 2-chloro-
phenol, In which known doses of test chemical were administered and a
comprehensive set of parameters of toxldty was evaluated, could not be
located In the available literature. As part of a larger study, Exon and
Koller (1985) Investigated the effects of pre- and postnatal exposure to
2-chlorophenol or 2,4-d1chlorophenol on the Immune response of Sprague-
Dawley rats. Drinking water concentrations of 2-chlorophenol at 0, 5, 50
and 500 ppm or of 2,4-d1chlorophenol at 0, 3, 30 and 300 ppm were provided
to dams from ~3 weeks of age through parturition and lactation and to the
progeny following weaning at 3 weeks. Groups of eight pups, randomly
selected from among the progeny of dams treated with drinking water contain-
ing the test chemicals, were given drinking water containing these chemicals
for an additional 12-15 weeks. Humoral Immunity was evaluated by the
enzyme-linked Immunosorbent assay, cell-mediated Immunity was evaluated by
measuring a delayed-type hypersens1t1v1ty reaction to various antigens and
macrophage function was evaluated by assessing ability to phagocytlze sheep
red blood cells 1_n vitro. No statistically significant effects on Immune
function were noted In rats treated with 2-chlorophenol, although a consis-
tently reduced level of humoral antibody to one antigen, bovine serum
albumin, did occur In all treated groups. 2,4-Dlchlorophenol seemed to
enhance humoral Immunity and depress cell-mediated Immunity, both 1n a
dose-related manner, and appeared to have no effect on macrophage formation.
Depression of cell-mediated Immunity became statistically significant at
30 ppm.
0080h -5- 09/02/86
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Kobayashl et al. (1972) microscopically observed "slight unfavorable
changes" 1n the livers of male mice given 0.2X dietary 2,4-dlchlorophenol
for 6 months. There were no effects on behavior, growth rate, hematology or
clinical chemistry at this level. The Investigators measured food consump-
tion and body weights and determined that this concentration provided 230
mg/kg/day. No changes were seen at the 0.02-0.1% dietary levels and the
authors concluded that 0.1% (100 mg/kg/day) constituted a maximum no effect
level. Borzelleca et al. (1985) found that mice exposed to drinking water
containing 0.02-2.0 mg/ma 2,4-d1chlorophenol 1n Emulphor for 90 days
showed no consistent compound-related differences In respect to terminal
body weight or absolute or relative organ weight, hematology or clinical
chemistry from mice receiving Emulphor-treated water only. There were major
differences, however, In hematologlcal and clinical chemistry values, mixed
function oxldase activity and organ weights, between control mice receiving
Emulphor-treated water and those receiving untreated delonlzed water. These
findings obscure the significance of the results from the 2,4-dlchloro-
phenol -exposed mice. The Investigators calculated 2,4-d1chlorophenol to be
50, 143 and 491 mg/kg/day for females and 40, 114 and 383 mg/kg/day for
males 1n the low-, middle- and high-dose groups, respectively. They
concluded that Emulphor was "not without effect" 1n this study and that
2,4-d1chlorophenol elicited no consistent treatment- or dose-related effects
In this experiment.
3.1.2. Inhalation. Pertinent data regarding subchronlc Inhalation
exposure to either 2-chlorophenol or 2,4-d1chlorophenol could not be located
In the available literature.
3.2. CHRONIC
3.2.1. Oral. As part of a larger carc1nogen1c1ty-cocarc1nogen1c1ty
study, Exon and Koller (1985) treated groups of 24-32 Sprague-Dawley
0080h -6- 11/28/86
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rats/sex with 0, 5, 50 or 500 ppm 2-chlorophenol or 0, 3, 30 or 300 ppm
2,4-dlchlorophenol In drinking water from weaning to -2 years of age. These
rats were the progeny of dams exposed to the same treatments from 3 weeks of
age through the weaning of their offspring. After 14 months, administration
of the high concentration of either compound led to elevations 1n erythro-
cyte counts and hemoglobin levels. Packed cell volume was Increased by
2-chlorophenol administration. Hematologlcal effects at lower doses and
other parameters of toxlclty were not discussed.
3.2.2. Inhalation. Pertinent data regarding the toxlclty of either
2-chlorophenol or 2,4-d1chlorophenol after chronic Inhalation exposure could
not be located 1n the available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. Exon and Keller (1985) performed a single generation repro-
ductive study In groups of 12-14 female Sprague-Dawley rats exposed 1n
drinking water. Concentrations of 2-chlorophenol at 0, 5, 50 and 500 ppm
and of 2,4-dlchlorophenol at 0, 3, 30 and 300 ppm were provided from time of
weaning, through mating to untreated males at 90 days of age, and through
parturition. Reproductive parameters evaluated Included percent conception.
Utter size, number of stillborn, body weight of offspring at birth and
weaning, and survival to weaning. Administration of 500 ppm 2-chlorophenol
1n drinking water led to decreased Utter sizes and Increased number of
stillborn pups (p<0.10). Lower concentrations had no effects on parameters
of reproductive performance or fetal toxlclty. In rats treated with 2,4-dl-
chlorophenol, the 30 ppm concentration decreased (p<0.10) the number of pups
surviving to weaning, and 300 ppm decreased (p<0.10) Utter size. A slight
but not statistically significant Increase 1n the number of stillborn pups
was associated with all treatment levels of 2,4-dlchlorophenol.
0080h -7- 11/28/86
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Rodwell et al. (1984) observed no Increase 1n the Incidence of terato-
loglcal malformation 1n pups of F344 rats given 200, 375 or 750 mg/kg/day
2,4-d1chlorophenol 1n corn oil by gavage throughout organogenesls. Maternal
toxldty, manifested as a statistically significant and dose-related Inhibi-
tion of maternal weight gain, was observed In all treated groups. Fetotoxlc
effects were observed In the high-dose group only and Included reduced fetal
body weight and a slight Increase 1n early embryonic death.
3.3.2. Inhalation. Pertinent data regarding the reproductive effects of
either 2-chlorophenol or 2,4-d1chlorophenol after Inhalation exposure could
not be located In the available literature.
3.4. TOXICANT INTERACTIONS
There were no pertinent data located In the available literature regard-
Ing toxicant Interactions of either 2-chlorophenol or 2,4-dlchlorophenol.
The U.S. EPA (1980a,b) speculated that since both compounds are weak
uncouplers of oxldatlve phosphorylatlon, concomitant exposure to other
uncouplers may Increase the severity of metabolic disorders.
0080h -8- 09/02/86
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4. CARCINOGENICITY
4.1. HUMAN DATA
4.1.1. Oral. Pertinent data regarding human oral exposure to either
2-chlorophenol or 2,4-dlchlorophenol could not be located 1n the available
literature.
4.1.2. Inhalation. An occupational study of 4459 workers exposed to
2,4-dlchlorophenol and 4-chloro-o-cresol based phenoxy herbicides, 1n addi-
tion to other pesticides and chemical Intermediates, was conducted by Lynge
(1985). In male workers, significant Increases In relative risk ratios for
lung cancer, rectal cancer and soft tissue sarcomas were reported; for
females, there were Increases In the relative risk of cervical cancer.
Lynge (1985) considered only the soft tissue sarcoma Incidence to be of
significance, because H was also found to be elevated 1n several other
occupational studies (Cook, 1981; Honchar and Halperln, 1981) Involving
exposure to phenoxy herbicides. In addition to the problem of exposure to a
mixture of chemicals, the small cohort sizes In all of these studies
obscures the significance of the findings.
4.2. BIOASSAYS
4.2.1. Oral. Exon and Koller (1985) exposed Sprague-Dawley rats to 0, 5,
50 or 500 ppm 2-chlorophenol, or 0, 3, 30 or 300 ppm 2,4-dlchlorophenol 1n
drinking water for ~2 years (see Section 3.2.1.). The dams of treated rats
were exposed from 3 weeks of age through breeding, parturition and lacta-
tion, and the offspring were maintained on the same schedule until death or
24 months of age. Between 24 and 32 offspring/sex were used at each
treatment level. Microscopic examination of major organs did not reveal
Increased tumor Incidences, decreased latency to tumor formation or varia-
tions In tumor types, compared with control rates, 1n either 2-chlorophenol
or 2,4-dlchlorophenol-treated rats.
0080h -9- 11/28/86
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4.2.2. Inhalation. Pertinent data regarding the carcinogenic potency of
either 2-chlorophenol or 2,4-d1chloropheno1 after Inhalation exposure 1n
experimental animals could not be located In the available literature.
4.3. OTHER RELEVANT DATA
Exon and Keller (1985) studied the potential synerglstk effects of the
human carcinogen, ethylnltrosourea, with each of the chlorophenols. Rat
dams were orally exposed to ethylnltrosourea as the precursor ethylurea In
the diet and sodium nitrite In the drinking water during gestation.
Offspring were exposed, starting either prenatally or postnatally, to drink-
Ing water containing either 2-chlorophenol or 2,4-d1chlorophenol for <24
months (see Section 4.2.)- The Investigators stated that tumor Incidence
Increased, and t1me-to-tumor latency decreased, 1n all groups of male rats
exposed both pre- and postnatally to 2-chlorophenol, compared with those
exposed to ethylnltrosourea alone. These conclusions are tentative,
however, because of the high tumor Incidence 1n offspring exposed to ethyl-
nltrosourea only and the lack of a concentration-response relationship. No
synerglstlc effects were observed 1n female rats exposed to ethylnltrosourea
and 2-chlorophenol, or In rats of either sex exposed to ethylnltrosourea and
2,4-d1chlorophenol. The authors suggested that 2-chlorophenol may be a
promotor or cocarclnogen with ethylnltrosourea.
Boutwell and Bosch (1959) found that 20% 2-chlorophenol, when applied as
a promotor 1n 12- to 15-week sk1n-pa1nt1ng studies, with or without an
Initiator, led to papllloma formation 1n mice. Similar results were
obtained with 2,4-dlchlorophenol In 15- to 24-week studies. A total of 62%
of survivors given 0.3% DHBA as an Initiator and 2,4-dlchlorophenol as a
promotor had skin carcinomas 15 weeks after cessation of treatment. The
U.S. EPA (1980a) criticized these studies on several grounds, Including the
0080h -10- 11/28/86
-------
severe Irritation caused by the high concentration, and the reporting of
only gross pathological results. Moreover, the U.S. EPA (1979b) noted that,
1n the 2-chlorophenol studies, a solvent control group was not Included.
With or without metabolic activation, 2-chlorophenol did not Induce
reverse mutations In Salmonella typhlmurlum (Haworth et al., 1983). The
effects of 2,4-dlchlorophenol on this test system were equivocal.
Amer and AH (1968, 1969) found effects of 2,4-dlchlorophenol on mitosis
and melosls In the vetch Vlda faba. The U.S. EPA (1980b) observed that the
relationship of these changes to mutagenlclty In mammalian cells was unclear.
4.4. WEIGHT OF EVIDENCE
Exon and Keller (1985) found that neither 2-chlorophenol nor 2,4-dl-
chlorophenol act as complete carcinogens, although 2-chlorophenol may act as
a cocardnogen 1n male rats. These studies used Inadequate sample sizes,
which makes definitive conclusions difficult. In the occupational exposure
studies (Lynge, 1985), 1t was unclear which herbicide Intermediates were
responsible for the Increased relative risk of soft tissue sarcomas although
chlorophenols were always present. Assays for reverse mutation (Haworth et
al., 1983) Indicate that neither compound Is strongly genotoxlc In bacterial
cells.
The Exon and Koller (1985) studies with 2-chlorophenol and 2,4-dkhloro-
phenol should be considered Inadequate for assessment of risk of human
cardnogenlclty. 2-Chlorophenoi and 2,4-dlchlorophenol should be classified
In EPA Group D (I.e., Inadequate evidence of carclnogenlclty In animals)
(U.S. EPA, 1986b) or IARC Group 3 (I.e., cannot be classified as to their
cardnogenlclty In humans). However, while available evidence Is Inadequate
for 2- and 2,4-chlorophenol, the related chlorophenals 2,4-D and 2,4,6-T are
known carcinogens.
0080h -11- 06/12/87
-------
5. REGULATORY STANDARDS AND CRITERIA
The U.S. EPA (1980a,b) determined ambient water quality criteria of 0.1
for 2-chlorophenol and 0.3 yg/l for 2,4-d1chlorophenol, based
upon organoleptlc (taste threshold) data provided by Dletz and Traud (1978).
An RfD for 2,4-d1chlorophenol of 0.003 mg/kg/day was derived based on
a NOAEL for altered Immune function of 3 ppm In the drinking water of rats
exposed prenatally and for an additional 15 weeks (Exon and Koller, 1985;
U.S. EPA, 1986c). An equivalent dose of 0.3 mg/kg/day was obtained assuming
that dally water Intake of rats 1s equivalent to 10% of their body weight.
Using an uncertainty factor of 100 (10 for Interspedes differences and 10
for Individual differences), an RfDQ of 0.003 mg/kg/day or 0.2 mg/day was
derived for humans. Since the test animals were exposed both in utero and
through milk before 15-week administration In drinking water, an additional
factor for use of a subchronlc study was not considered necessary (U.S. EPA,
1986c).
OOSOh -12- 06/24/87
-------
6. RISK ASSESSMENT
6.1. SUBCHRONIC REFERENCE DOSE (RfD$)
6.1.1. Oral (RfDSQ). Subchronlc toxlclty studies with 2-chlorophenol
1n which adequate parameters of toxldty were evaluated could not be located
In the available literature. A NOAEL of 50 ppm 1n drinking water for
reproductive effects (Exon and Koller, 1982) and a NOAEL of 500 ppm for
effects or measurements of Immune functions (Exon and Koller, 1985) were
Identified In short-term studies using rats. An RfnSQ of 0.005 mg/kg/day
for 2-chlorophenol can be calculated from a NOAEL of 50 ppm In drinking
water In the reproduction study by Exon and Koller (1982). In this study,
rats were exposed pre- and postnatally up to weaning age, and parameters
were evaluated on reproduction Including decreased Utter sizes and number
of stillborn. In the derivation of the RfD$0, the NOAEL of 50 ppm In
drinking water was transformed to an equivalent dose of 5 mg/kg/day based on
the assumption that rats drink water equivalent to 10X of their body
weight/day. In spite of the serious limitations In the parameters of
toxldty evaluated In these studies, this RfO Is adopted as the RfDQ for
2-chlorophenol. Because little confidence can be placed 1n this data base,
the RfOQ of 0.005 mg/kg/day (0.35 mg/day) 1s adopted as the RfOSQ-
Subchronlc studies with 2,4-d1chlorophenol Include a 6-month dietary
study using mice (Kobayashl et al., 1972) In which 2000 ppm (100 mg/kg/day)
was a NOAEL for hlstologlcal effects on the liver and a short-term study
using rats In which 30 ppm In the drinking water was a NOAEL for effects on
measures of Immune function (Exon and Keller, 1985). An RfD of 0.003 mg/kg/
day for 2,4-d1chlorophenol was derived by applying an uncertainty factor of
1000 to the dosage (0.3 mg/kg/day) estimated for the 3 ppm drinking water
concentration NOAEL. The RfD, expressed as 0.02 mg/day for a 70 kg human,
0080h -13- 06/24/87
-------
was adopted as the RfDQ for 2,4-dlchlorophenol. Because the uncertainty
factor of TOO 1s appropriate for derivation of an Rfnso from subchronlc
data, the RfOso for 2,4-dlchlorophenol 1s 0.2 ing/day.
6.1.2. Inhalation (RfD-j). The lack of data regarding subchronlc
Inhalation exposure to 2-chlorophenol or 2,4-dlchlorophenol precludes
derivation of RfDs* values.
6.2. REFERENCE DOSE (RfD)
6.2.1. Oral (RfDQ). An RfD for 2-chlorophenol of 0.005 mg/kg/day Is
derived from the oral subchronlc reproduction and hematology NOAEL of 50 ppm
In the short-term drinking water rat study by Exon and Koller (1982).
Assuming that rats drink water equivalent to 10% of their body weight/day,
the U.S. EPA (1986a) estimated an Intake of 5 mg/kg/day associated with the
concentration of 2-chlorophenol 1n drinking water. Application of an
uncertainty factor of 1000 (10 for Individual variability, 10 for
Interspecles differences, and 10 for use of subchronlc study) resulted 1n
the RfD of 0.005 mg/kg/day, or 0.35 mg/day for a 70 kg human, which Is
adopted as the RfD- for 2-chlorophenol.
Although a longer-term carclnogenlcHy experiment with 2-chlorophenol In
rats has been performed more recently (Exon and Koller, 1985), adequate
parameters of toxIcHy were not evaluated and this study Is not useful for
risk assessment. In another shcrt-term experiment (Exon and Keller, 1985),
prenatal and postnatal exposure to 2-chlorophenol at 5, 50 and 500 ppm In
the drinking water had no adverse effects on measurements of Immune function
1n rats. Because few parameters of toxldty were evaluated 1n these
studies, little confidence can be placed on the data base from which the
RfD- for exposure to 2-chlorophenol 1s derived.
0080h -14- 06/24/87
-------
An RfDg of 0.003 mg/kg/day for 2,4-d1ch1orophenol can be derived from
the NOAEL of 3 ppm In drinking water for effects on measurements of Immune
functions 1n rats (Exon and Koller, 1985). Depressed cell mediated Immune
function was observed at 30 ppm, the higher concentration tested. The 3 ppm
level 1s equivalent to 0.3 mg/kg/day when assumption Is made that rats dally
water Intake Is 10% of their body weight. This value was substantially
below the NOAEL for Hver changes 1n mice observed by Kobayashl et al.
(1972). An uncertainty factor of 100 was applied resulting In the RfD of
0.003 mg/kg/day, or 0.02 mg/day for a 70 kg human (U.S. EPA, 1986d), which
1s adopted as the RfD_ for 2,4-d1chlorophenol.
Although In an earlier analysis, the U.S. EPA (1983a) did not have
sufficient data to calculate a CS for 2-chlorophenol, the Exon and Koller
(1982) reproductive study can be used for CS derivation. Repeated exposure
of dams to 500 ppm (39 mg/kg/day, assuming rats drink 0.049 I of water/day
and weigh 0.35 kg) of 2-chlorophenol In drinking water led to small
decreases In Utter size and a slight Increase In the number of stillbirths.
Multiplication of the animal dosage by the cube root of the ratio of the rat
body weight to the reference human body weight [assumed to be 0.35/70 kg
(U.S. EPA, 1980dJ], and again by 70 kg, results In a human MED of 469
mg/day. This MED corresponds to an RV. of 1.3. Multiplication of the
RVd by an RVg of 8 (for slight fetotoxldty) results 1n a CS of 10.4 for
2-chlorophenol and RQ of 1000.
The U.S. EPA (1983b) determined a CS of 11.9 for 2,4-d1chlorophenol,
based upon minor hlstopathologlcal changes In mice (Kobayashl et al., 1972).
A summary of this derivation Is provided 1n Table 6-1.
Alternatively, the decrease In Utter size observed In rats at 300 ppm
by Exon and Koller (1985) suggests an effect level at 300 ppm. Using
current methodology (U.S. EPA, 1984) and assuming rats weigh 0.35 kg and
OOSOh -15- 06/24/87
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drink 0.049 l of water/day, the concentration of 300 ppm corresponds to an
Intake of 42 mg/kg/day, associated with a human MED of 503 ing/day. The MED
corresponds to an RVd of 1.4. The effect of slightly Increased
fetotoxlclty corresponds to an RVg of 8. Multiplying the RVrf by the
RV results In a CS of 11.2 for 2,4-dlchlorophenol and an RQ of 1000.
The CS based upon the hepatic changes In mice (Kobayashl et al., 1972)
1s recommended to represent the toxldty of 2,4-d1chlorophenol, since It Is
the higher of the two CSs calculated for 2,4-d1chlorophenol.
6.2.2. Inhalation (RfD,). The lack of pertinent data regarding the
toxldty of 2-chlorophenol or 2,4-dkhlorophenol after chronic Inhalation
exposure precludes derivation of RfD values.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. Neither 2-chlorophenol nor 2,4-d1chlorophenol was found to
be carcinogenic when administered for 2 years In drinking water (Exon and
Keller, 1985); however, 2-chlorophenol may have acted synerglstkally with
ethylnltrosourea In Inducing tumors 1n male rats (Exon and Koller, 1985).
In both experiments, the lack of significantly Increased tumor Incidences
precludes assessment of the carcinogenic potency of either compound.
6.3.2. Inhalation. Occupational studies (Lynge, 1985; Cook, 1981;
Honchar and HalpeMn, 1981) Involving exposure to phenoxy-based herbicides
have suggested Increased Incidences of soft tissue sarcoma 1n exposed
workers; however, lack of definition of the chemicals used and small cohort
sizes, obscure the significance of these findings. In the absence of
pertinent data from animal studies, assessment of risk from Inhalation
exposure to 2-chlorophenols or 2,4-dlchlorophenol cannot be performed.
OOSOh -17- 06/24/87
-------
7. REFERENCES
Amer, S.M. and E.M. A11. 1968. Cytologlcal effects of pesticides. II.
Melotlc effects of some phenols. Cytologla. 33: 21. (Cited In U.S. EPA,
19805)
Amer, S.M. and E.M. AH. 1969. Cytologlcal effects of pesticides. IV.
MHotlc effects of some phenols. Cytologla. 34: 533. (Cited In U.S. EPA,
1980D)
Baker, M.D., C.I. Mayfleld and W.E. Innlss. 1980. Degradation of chloro-
phenol 1n soil, sediment and water at low temperature. Water Res. 14:
1765-1771.
Borzelleca, J.F., J.R. Hayes, L.W. Condle and J.L. Egle, Jr. 1985. Acute
and subchronlc toxldty of 2,4-d1chlorophenol 1n CD-I mice. Fund. Appl.
Toxlcol. 5(3): 478-486.
Boutwell, R.K. and O.K. Bosch. 1959. The tumor-promoting action of phenol
and related compounds for mouse skin. Cancer Res. 19: 413-427.
Callahan, M.A., M.W. Sllmak, N.W. Gabel, et al. 1979. Water-related envi-
ronmental fate of 129 priority pollutants. Vol. II. U.S. EPA, Washington,
DC. EPA 400/4-79-029B.
Cook, R.R. 1981. D1ox1n, chloracne and soft-tissue sarcoma. Lancet. 1:
618. (Cited 1n Lynge, 1985)
0080h -18- 09/02/86
-------
01etz, F. and J. Traud. 1978. [Geruchs- and Gesehmacks-Schulellen-Konzen-
tratlonen vou Pheurelkoyreln GasWasserfach](Ger). Wasser-Abwasser. 119:
318. (Cited In U.S. EPA, 1980a,b)
Exon, J.H. and L.D. Koller. 1982. Effects of transplacental exposure to
chlorinated phenols. Environ. Health Perspect. 46: 137-140.
Exon, J.H. and L.D. Koller. 1985. Toxlclty of 2-chlorophenol, 2,4-d1-
chlorophenol and 2,4,6-tMchlorophenol. Water Chlor1nat1on. Chem. Environ.
Impact Health Eff. Proc. Conf. 5: 307-30.
Frelter, E.R. 1979. Chlorophenols. In: K1rk-0thmer Encyclopedia of
Chemical Technology. John Wiley and Sons, Inc., New York. p. 864-872.
Haworth, S., T. Lawlor, K. Mortelmans, W. Speck and E. Zelger. 1983.
Salmonella mutagenlclty test results for 250 chemicals. Environ. Mutagen.
1: 3-142.
Honchar, P.A. and W.E. HalpeMn. 1981. 2,4,5-T, trlchlorophenol and
soft-tissue sarcoma. Lancet. 1: 268. (Cited 1n Lynge, 1985)
Isaacson, P.J. and C.R. FMnk. 1984. Nonreverslble sorptlon of phenolic
compounds by sediment fraction. The role of sediment organic matter.
Environ. Scl. Techno!. 18: 43-46.
OOSOh -19- 11/28/86
-------
Kobayashl, S., S. Tolda, H. Kawamura, H.S. Chang, T. Fukuda and K. Kawaguchl.
1972. Chronic toxlclty of 2,4-dlchlorophenol 1n mice. Simple design for
the toxldty of residual metabolites of pesticides. Toho Igakkal Zasshl.
19(3/4): 356-362. (Japanese with English summary)
Lynge, E. 1985. A follow-up study of cancer Incidence among workers In
manufacture of phenoxy herbicides 1n Denmark. Br. J. Cancer. 52(2):
259-270.
Rodwell, O.E., R.D. WHson, M.D. Nemec and M.D. Merdeca. 1984. A teratol-
ogy study 1n Fischer 344 rats with 2,4-d1chlorophenol. lexicologist. 4:
167-184.
U.S. EPA. 1979a. Reviews of the Environmental Effects of Pollutants. XI.
Chlorophenols. Office of Research and Development, Health Effects Research
Laboratory, U.S. EPA,'Cincinnati, OH. EPA-100/79-012.
U.S. EPA. 1979b. CHIP (Chemical Hazard Information Profile). Mono/D1-
chlorophenol. Draft Report. OTS, OPTS, U.S. EPA, Washington, DC.
U.S. EPA. 1980a. Ambient Water Quality Criteria Document for 2-Chloro-
phenol. 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.
OOSOh -20- 06/17/87
-------
U.S. EPA. 1980b. Ambient Water Quality Criteria Document for 2,4-Dlchloro-
phenol. 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 400/5-80-042. NTIS
PB81-117533.
U.S. EPA. 1980c. Hazard Profile for Chlorinated Phenols. 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. 1980d. 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. 1983a. 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. 1983b. Reportable Quantity Document for 2,4-Dlchlorophenol.
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.
.21- 06/17/87
-------
U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxldty 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. 1986a. Graphical Exposure Modeling System (GEMS). Fate of
Atmospheric Pollutants (FAP). Office of Toxic Substances, U.S. EPA,
Washington, DC.
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33991-34003.
U.S. EPA. 1986c. Integrated Risk Information System (IRIS). Reference
Dose (RfD) for Oral Exposure for 2,4-Dlchlorophenol. Online (verification
date 1/22/86). Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH.
VeHh, G.D., K.J. Macek, S.R. Petrocelll and J. Carroll. 1980. An
evaluation of using partition coefficients and water solubility to estimate
bloconcentratlon factors for organic chemicals 1n fish. [n: ASTM Spec.
Tech. Publ. 707. Aquatic Toxicology, 3.G. Easton, et al., Ed. Am. Soc.
Test. Mater, p. 116-129.
Verschueren, K. 1983. Handbook of Environmental Data on Organic Chemicals,
2nd ed. Van Nostrand Remhold Co., New York. p. 375-493.
0080h -22- 06/17/87
-------
Weber, R.C., P.A. Parker and M. Bowser. 1981. Vapor pressure distribution
of selected organic chemicals. U.S. EPA, Cincinnati, OH. EPA 600/2-81-021.
p. 39.
0080h -23- 06/17/87
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APPENDIX A
Summary Table for 2-Ch1orophenola
Species
Experimental
Dose/Exposure
Effect
Reference Dose
(RfD or RfD-s)
Oral
(formerly
AIS)
RfD0
(formerly
AIC)
Maximum
CS
rats 50 ppm 1n drinking
water from weaning
through delivery
of first Utter
(5 mg/kg/day)b
rats 50 ppm In drinking
water from weaning
through delivery
of first litter
(5 mg/kg/day)b
rats 500 ppm 1n drinking
water from weaning
through delivery
of first Utter
(39 mg/kg/day)C
(RVd.1.3)
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