-ERA
United States
Environmental Protection
Agency
FINAL DRAFT
ECAO-CIN-G082
March, 1991
Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR 4-METHYLPHENOL
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DRAFT: DO NOT CITE OR QUOTE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 1s 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 1s being circulated for comments
g?on Us technical accuracy and policy Implications.
CO
. j:.;.'RTtRS LIBRARY
. ..'•-•li.'jIJMLNTAL PROTECTION AGENCY
WASHINGTON, D.C. 20460
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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.
1
1.1
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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 for 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 In "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 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 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. Instead,
a carcinogenic potency factor, or q^* (U.S. EPA, 1980), Is provided.
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 toxlclty and carclno-
genldty are derived. The RQ Is used to determine the quantity of a hazard-
ous substance for which notification 1s required In the event of a release
as specified under the Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA). These two RQs (chronic toxUHy and cardno-
genUlty) represent two of six scores developed (the remaining four reflect
IgnltabllUy, 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 In U.S.
EPA, 1984 and 1986a, respectively.
111
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EXECUTIVE SUMKARY
4-Methylphenol Is a solid at room temperature. It has a phenolic odor,
and 1s soluble In water and common organic solvents (Sax and Lewis, 1987;
Wlndholz et al., 1983). It Is produced commercially by the fractional
distillation of the mixture of methylphenols obtained from coal tar. It can
also be produced using p-cymene as a starting material. Production volume
In 1977 was between 30 and 90 million pounds (TSCAPP, 1989). Current
production volumes could not be located; however, combined production volume
for all methyl phenols, excluding that produced from coke and gas-retort
ovens, was >73 million pounds In 1987 (USITC, 1988).
4-Methylphenol 1s used In a wide variety of applications, Including
disinfectants, resins, ore flotation, textiles, food flavors, and as an
Intermediate In the manufacture of other organic compounds (Sax and Lewis,
1987).
In the atmosphere, 4-methylphenol Is expected to exist almost entirely
In the vapor phase (Elsenrelch et al., 1981; Cautreels and Van Cauwenberghe,
1978). The gas-phase reaction with photochemlcally-produced hydroxyl
radicals 1s expected to be rapid, with an estimated half-life of 10 hours.
The nighttime degradation of 4-methylphenol In the atmosphere over urban
areas Is also expected to be rapid (Atkinson, 1985). Rain washout and
photolysis may occur, but they are not expected to be competitive processes
(Gaffney et al., 1987; Cupltt, 1980). If released to water, blodegradatlon
Is expected to occur under both aerobic and anaerobic conditions. This
process may be rapid under certain conditions. Acclimation periods vary
widely (Lewis et al., 1986). Hydrolysis and oxidation are not expected to
be significant. Available data on the adsorption of 4-methylphenol to
1v
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sediment and suspended matter, as well as data on the photolytlc breakdown
of this compound In water, suggest that the Importance of these processes
varies with the local conditions. Under certain conditions, these processes
may be significant. If released to soil, 4-methylphenol can be expected to
undergo blodegradatlon. Adsorption to soil may be significant, but the
process 1s not well understood and 1t appears to depend on the unique
properties of each soil. Volatilization from the soil surface to the
atmosphere 1s not expected to be significant.
4-Methylphenol has been detected 1n surface water, groundwater and
rainwater. Hater concentrations can vary widely; however, high levels are
usually associated with Industrial activity. 4-Methylphenol has been
detected In surface water near the site of the Mount St. Helens eruption
(Mcknight et al., 1982). It can enter the atmosphere as a result of Indus-
trial activity, and by the burning of vegetable and plant matter (Hawthorne
et al., 1988; Ubertl et al., 1983; McKnlght et al., 1982). Also, 4-Methyl-
phenol occurs naturally In coal tar (Sax and Lewis, 1987). It Is a product
of the chemical and biological breakdown of benzenold compounds (Fatladl,
1984).
Occupational exposure to 4-methylphenol may occur by Inhalation and
dermal contact during Us manufacture and formulation Into commercial
products. The general population may be exposed by Ingesting contaminated
water, or by Inhalation and dermal contact during the use of commercial
products containing 4-methylphenol. Also, exposure to 4-methylphenol may
occur by Inhaling smoke from wood fires or from the smoke resulting from
burning other vegetable matter.
Data are available on the acute toxlclty of 4-methylphenol to salmonld,
warmwater fish and several Invertebrates. Acute toxlclty values shown In
Table 4-1 Indicate that rainbow trout, S. galrdnerl. are more sensitive than
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are fathead minnows, P. promelas. with LC5g values of 7.9 mg/t and 28.6
mg/t, respectively (DeGraeve et al., 1980). Fertilized eggs of cod fish,
G. morhua. and sea urchins, S. droebachjensls, are equally sensitive to
96-hour exposure to 4-methylphenol (Falk-Petersen et al., 1985). Damsel
flies, JL vert1cal1s. were not adversely affected by 40 mg/i (Cooper and
Stout, 1985), but the water flea, D. maqna. showed 50X lethality to a
concentration of 1.4 mg/i. Variation In sensitivity between D. maqna and
D. pullcarla, with 48-hour LC5Qs of 1.4 and 22.7 mg/i, respectively, may
be explained by the age difference at time of testing (0. magna were <24
hours old and 0. pull car la were <72 hours old) (Parkhurst et al., 1979;
DeGraeve et al., 1980).
The chronic toxlclty of 4-methylphenol In the planarlan, D. tlgrlna. was
assessed by Solskl and Plontek (1987). A 240-hour LC5Q of 11.08 mg/l
was Identified. Follow-up testing for four generations (test animals cut In
half and retested) showed successively Increased mortality at the LOEC of
2.0 mg/t, but the LOEC value did not change.
Chlorophyll content and photosynthesis are adversely affected (as
evidenced by decreased dissolved oxygen concentrations) In freshwater algae
by 4-methylphenol concentrations >0.9 mg/t (Stout and Kllham, 1983). A
72-hour LCcn of 50 mg/t was Identified for chlorophyll content with C.
t>u
pyrenoldosa. This effect was dose-dependent (Huang, 1967; Huang and Gloyna,
1968). A concentration of 100 yg/cc (100 mg/t) severely Inhibited
growth of the unicellular green alga, A. falcatus. and totally Inhibited It
at 500 tig/cc (500 mg/t) (Robinson et al., 1976).
B1oaccumulat1on/b1oconcentrat1on studies were not located 1n the
available literature, but evidence suggests that 4-methylphenol will not
accumulate appreciably In aquatic biota.
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Bacterial luminescence was reduced 50% by 5-mlnute exposure to >1.3
mg/i 4-methylphenol (Lebsack et al., 1981). An 8-hour Incubation of £.
phosphoreum with 206 mg/l 4-methylphenol reduced the number of fluorescent
cells by 50% (Delesmont and Delattre, 1983). Growth of the trlchal blue
alga, Phormldlum. was totally Inhibited by 100 yg/test spot of 4-methyl-
phenol (Benecke and Zullel, 1977). Concentrations of >500 ppm 4-methyl-
phenol totally Inhibited mycellal growth In the fungus, A. flavus (Dube et
al., 1988). A 24-hour EC5Q of 160 mg/s. 4-methylphenol was Identified
with the protozoan, T. pyMformls {Yoshloka et al., 1985).
The effects of 4-methylphenol on terrestrial fauna were assessed In
Insects, birds and small mammals. An LD™ for topical exposure to
4-methylphenol of 80 >ig/an1mal for the housefly, N. domestlea, was
reported by Marcus and Llchtensteln (1979). Oral L05Qs Of 96 mg/kg/day
for the redwing blackbird, A. phoenlceus (Schafer et al., 1983) and 1238
mg/kg/day for deer mice, £. manlculatus (Schafer and Bowles, 1985) were
reported.
Assessments of toxldty of 4-methylphenol to terrestrial plants Identi-
fied ECcns of 100, 40-60 and 150 ppm for germination, tube production and
tube growth, respectively, with 1. sultanll (Bllderback, 1981). An EC5Q
of 122.2 ppm was reported for fruit germination In U satlva (Reynolds,
1978) and reduced germination of sclerotla was noted 1n S. ceplvorum exposed
to 10 ppm 4-methylphenol (A11 et al., 1987).
The pharmacoklnetlcs of 4-methylphenol Involves documented dermal
(Green, 1975; Anderson et al., 1976; Roberts et al., 1977) and gastrointes-
tinal (Bray et al., 1950) absorption of the test chemical with distribution
to the brain, liver, blood and possibly all organs (Green. 1975). Metabo-
lism Includes oxidation of the -CK group of the 4-methylphenol to the
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Intermediates -CH2OH and -CHO and finally to -COOH, as determined In. vitro
(Sato et al., 1956). The sulfate conjugates corresponding to these Inter-
mediates and the final product are p-hydroxybenzyl alcohol, p-hydroxybenz-
aldehyde and p-hydroxybenzolc add, respectively. Small amounts of 3,4-d1-
hydroxybenzolc add were also formed by this pathway. The |ri vitro data
support Jhi vl.yo observations. Excretion data from Bray et al. (1950) and
Neuberg and Kretchmer (1911) Indicate that 4-methylphenol 1s excreted
primarily In the urine as sulfate and glucuronlde conjugates. Bray et al.
(1950) reported that an average oral dose of 65% was excreted In the urine
(as total cresols) within 24 hours.
Because of Insufficient evidence for carclnogenlclty 1n animals and no
data regarding carclnogenlclty In humans, 4-methylphenol Is placed In U.S.
EPA welght-of-evidence Group D: not classifiable as to carclnogenlclty to
humans. Cancer potency factors were not estimated and the compound was not
assigned a cancer-based RQ.
An RfD of 0.05 mg/kg/day was derived for subchronlc oral exposure based
on the NOEL of 5 mg/kg/day for maternal toxlclty In a developmental toxldty
study 1n rabbits (CMA, 1988a). The NOEL of 5 mg/kg/day also served as the
basis for an RfO of 0.005 mg/kg/day for chronic oral exposure to 4-methyl-
phenol. The LOAEL of 175 mg/kg/day associated with labored breathing 1n
rats In a 13-week subchronlc gavage study (U.S. EPA, 1967a) served as the
basis for an RQ of 1000 for chronic (noncancer) toxldty.
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TABLE OF CONTENTS
Page
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 2
2. ENVIRONMENTAL FATE AND TRANSPORT 4
2.1. AIR 4
2.1.1. Reaction with Hydroxyl Radicals 4
2.1.2. Reaction with Ozone 4
2.1.3. Photolysis 5
2.1.4. Physical Removal Processes 5
2.2. WATER 5
2.2.1. Hydrolysis 5
2.2.2. Oxidation 5
2.2.3. Photolysis 5
2.2.4. M1crob1al Degradation 6
2.2.5. B1oconcentrat1on 7
2.2.6. Adsorption 7
2.2.7. Volatilization 8
2.3. SOIL 8
2.3.1. M1crob1al Degradation 8
2.3.2. Adsorption/Leaching 8
2.3.3. Volatilization 9
2.4. SUMMARY 9
3. EXPOSURE 10
3.1. WATER 10
3.2. FOOD 12
3.3. INHALATION 12
3.4. DERMAL 12
3.5. OTHER 12
3.6. SUMMARY 13
1x
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TABLE OF CONTENTS (cent.)
Page
4. ENVIRONMENTAL TOXICOLOGY 14
4.1. AQUATIC TOXICOLOGY 14
4.1.1. Acute Toxic Effects on Fauna 14
4.1.2. Chronic Effects on Fauna 17
4.1.3. Effects on Flora 17
4.1.4. Effects on Bacteria and Other Aquatic
Microorganisms 19
4.2. TERRESTRIAL TOXICOLOGY 20
4.2.1. Effects on Fauna 20
4.2.2. Effects on Flora 20
4.3. FIELD STUDIES 21
4.4. AQUATIC RISK ASSESSMENT 21
4.5. SUMMARY 23
5. PHARMACOKINETICS " 26
5.1. ABSORPTION 26
5.2. DISTRIBUTION 27
5.3. METABOLISM 27
5.4. EXCRETION 28
5.5. SUMMARY 30
6. EFFECTS 31
6.1. SYSTEMIC TOXICITY 31
6.1.1. Inhalation Exposure 31
6.1.2. Oral Exposure 31
6.1.3. Other Relevant Information 33
6.2. CARCINOGENICITY 36
6.2.1. Inhalation 36
6.2.2. Oral 36
6.2.3. Other Relevant Information 37
6.3. GENOTOXICITY 37
6.4. DEVELOPMENTAL TOXICITY 39
6.5. OTHER REPRODUCTIVE EFFECTS 41
6.6. SUMMARY 41
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TABLE OF CONTENTS (cont.)
Page
7. EXISTING GUIDELINES AND STANDARDS 42
7.1. HUMAN 42
7.2. AQUATIC 42
8. RISK ASSESSMENT 43
8.1. CARCINOGENICITY 43
8.1.1. Inhalation 43
8.1.2. Oral 43
8.1.3. Other Routes 43
8.1.4. Weight of Evidence 43
8.1.5. Quantitative Risk Estimates 43
8.2. SYSTEMIC TOXICITY 43
8.2.1. Inhalation Exposure 44
8.2.2. Oral Exposure 44
9. REPORTABLE QUANTITIES 47
9.1. BASED ON SYSTEMIC TOXICITY 47
9.2. BASED ON CARCINOGENICITY 51
10. REFERENCES 52
APPENDIX A: LITERATURE SEARCHED 75
APPENDIX B: SUMMARY TABLE FOR 4-METHYLPHENOL 78
APPENDIX C: DOSE/DURATION RESPONSE GRAPH(S) FOR EXPOSURE TO
4-METHYLPHENOL 79
X1
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LIST OF TABLES
No. Title Page
4-1 Acute Effects of 4-Methylphenol on Aquatic Fauna 15
6-1 Acute Effects of 4-Methylphenol 34
6-2 Mutagenldty and GenotoxUHy of 4-Hethylphenol 38
9-1 Tox1c1ty Summary for 4-Methylphenol 48
9-2 Composite Scores for Orally Administered 4-Methylphenol ... 49
9-3 4-Methylphenol: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 50
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LIST OF ABBREVIATIONS
AEL
BCF
BOD
CAS
CNS
cs
D/h2
DM8A
DNA
"50
PEL
FR
Km
LC50
LD50
LDfr
LOAEL
LOEC
Adverse effect level
Bloconcentratlon factor
Biological oxygen demand
Chemical Abstract Service
Central nervous system
Composite score
Ratio of the diffusion coefficient to the square
of the membrane thickness
Dimethyl benzanthracene
Deoxyrlbonuclelc acid
Concentration effective to 50% of recipients
(and all other subscripted concentration levels)
Frank effect level
Treated food refused as a percentage of food
offered over a 3-day period
Median mobilization concentration
Membrane: vehicle partition coefficient
Soil sorptlon coefficient
Octanol/water partition coefficient
Permeability coefficient
Concentration lethal to 50% of recipients
(and all other subscripted concentration levels)
Dose lethal to 50% of recipients
(and all other subscripted dose levels)
Amount of chemical Ingested during FR test that
killed 50% of test animals
Lowest dose lethal to recipients
Lowest-observed-adverse-effect level
Lowest observed effects concentration
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LIST OF ABBREVIATIONS (cont.)
NEO Minimum effective dose
NOAEL No-observed-adverse-effect level
NOEC No-observed-effect concentration
NOEL No-observed-effect level
PLAN Plasma leuclne amlnonaphthylamldase
ppb Parts per billion
ppm Parts per million
ppt Parts per trillion
RfD Reference dose
RQ Reportable quantity
RV
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
4-Methylphenol 1s also known by the synonyms p-cresol, 4-cresol,
p-cresyllc acid, p-hydroxytoluene, p-methylhydroxybenzene, p-tolyl alcohol,
4-toluol and others (Chemllne, 1989; SANSS, 1989). The structure, CAS
Registry number, empirical formula and molecular weight are given below:
OH
CAS Registry number: 106-44-5
Empirical formula: C,HQ0
/ o
Molecular weight: 108.13
1.2. PHYSICAL AND CHEMICAL PROPERTIES
4-Methylphenol 1s a solid at room temperature and has a phenolic odor.
It Is soluble 1n polar organic solvents (for example, chloroform, ether and
alcohol) and In water (Sax and Lewis, 1987; VMndholz et al.t 1983}.
Selected physical properties for 4-methylphenol are given below:
Melting point:
Boiling point:
Density (20°C):
Vapor pressure (25DC):
Water solubility (25°C):
Log Kou:
Flash point:
Conversion factor:
34.8°C
201.9°C
1.0178 g/ma
0.11 mm Hg
21,520 mg/i
1.94
86'C
1 ppm =4.42 mg/m3;
1 mg/m3 = 0.226 ppm
Weast et al., 1988
Weast et al., 1988
Weast et al., 1988
Chao et al., 1983
Yalkowsky et al., 1987
Hansch and Leo, 1985
Wlndholz et al., 1983
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1.3. PRODUCTION DATA
4-Methylphenol 1s manufactured by the fractional distillation of a
mixture of Isomerlc cresols (methylphenols), which are components of coal
tar. It can also be obtained by the cumene process using p-cymene as a
starting material (Sax and Lewis, 1987). Data from the U.S. EPA TSCA pro-
duction file (TSCAPP, 1989) Indicate that during 1977, 27 U.S. manufacturing
plants produced between 30.1 and 90.1 million pounds of 4-methylphenol.
Primary production sites were located In Chicago, IL; Dublin, OH;
Follansbee, WV; Venango, PA; and Elizabeth, NJ (TSCAPP, 1989). More recent
production data could not be located; however, combined production volume
for all methyl phenols, excluding that produced from coke and gas-retort
ovens, was >73 million pounds In 1987 (USITC, 1988).
1.4. USE DATA
4-Methylphenol Is used as a disinfectant, In phenolic resins, ore flota-
tion and synthetic food flavors, as a textile scouring agent, surfactant and
organic Intermediate, and In the manufacture of saHcylaldehyde, coumarln
and herbicides (Sax and Lewis, 1987).
1.5. SUMMARY
4-Methylphenol 1s a solid at room temperature. It has a phenolic odor,
and Is soluble In water and common organic solvents (Sax and Lewis, 1987;
Hlndholz et al., 1983). It Is produced commercially by the fractional
distillation of the mixture of methylphenols obtained from coal tar. It can
also be produced using p-cymene as a starting material. Production volume
In 1977 was between 30 and 90 million pounds (TSCAPP, 1989). Current
production volumes could not be located; however, combined production volume
for all methyl phenols, excluding that produced from coke and gas-retort
ovens, was >73 million pounds In 1987 (USITC, 1988).
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4-Methylphenol Is used 1n a wide variety of applications, Including
disinfectants, resins, ore flotation, textiles, food flavors, and as an
Intermediate In the manufacture of other organic compounds {Sax and Lewis,
1987).
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2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Based on a vapor pressure of 0.11 mm Hg at 25°C (Chao et al., 1983),
4-methylphenol Is expected to exist almost entirely 1n the vapor phase In
the ambient atmosphere (ElsenreUh et al., 1981). Participate 4-methyl-
phenol was not found In urban air samples containing this compound
(Cautreels and Van Cauwenberghe, 1978).
2.1.1. Reaction with Hydroxyl Radicals. An experimental rate constant
for the gas phase reaction of photochemically-produced hydroxyl radicals
with 4-methylphenol was determined to be 3.8xlO~11 cmVmolecule-sec at
26°C (Atkinson, 1985). If the average atmospheric hydroxyl radical concen-
tration Is 5xl05 molecules/cm3 (Atkinson, 1985), then the half-life for
this reaction 1s 10 hours. Thus, the atmospheric destruction of 4-methyl-
phenol by hydroxyl radicals Is expected to be a dominant fate process.
The experimental rate constant for the reaction of 4-methylphenol with
nitrate radicals was determined to be 13xlO"12 cmVmolecule-sec at 27°C
(Atkinson et al., 1984; Carter et al., 1981). Using a nitrate radical
concentration of 2.4x10" molecule/cm3 (Atkinson, 1985), the half-life
for this reaction would be 3.7 minutes. This value suggests that the night-
time degradation of 4-methylphenol 1n urban areas will be an Important
atmospheric fate process.
2.1.2. Reaction with Ozone. Experimental rate constants for the reaction
of 4-methylphenol near room temperature were reported to range from
1.4xlO"18 to 4.71xlO~" cmVmolecule-sec (Atkinson and Carter, 1984).
If an average atmospheric ozone concentration Is IxlO12 molecule/cm3,
then the half-life for this reaction can be calculated to be 5.7-13.4 days.
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2.1.3. Photolysis. Since 4-methylphenol can absorb light In the environ-
mentally significant range >290 nm, It Is a candidate for direct photochemi-
cal degradation. This process Is not expected to be able to compete with
the blmolecular pathways discussed previously, however, and H may not be a
significant fate process (Smith et al., 1978).
2.1.4. Physical Removal Processes. The relatively high water solubility
of 4-methylphenol, 21,520 mg/i at 25°C (Yalkowsky et al., 1987), suggests
that atmospheric removal by wet deposition may be a significant process
(Gaffney et al.. 1987). However, CupHt (1980) suggested that this removal
process would be unlikely for this compound because of Us expected rapid
rate of chemical degradation.
2.2. WATER
2.2.1. Hydrolysis. Since 4-methylphenol contains no hydrolyzable func-
tional groups, hydrolysis at environmentally significant pHs 1s not expected
to be an Important fate process (Harris, 1982; Kolllg et al., 1987).
2.2.2. Oxidation. A rate constant for the reaction of 4-methylphenol
with peroxy radicals was estimated to be 20 i/molecule-sec In aquatic
media (Smith et al., 1978). If the average peroxy radical concentration
equals 1x10-9 mol/8. (Hill et al., 1980), then the half-life for the
oxidation of 4-methylphenol In aquatic media would be 1 year. Humlc acid
accelerated this process slightly (Smith et al., 1978). Oxidation of
4-methylphenol In water Is, therefore, not expected to be a significant fate
process.
2.2.3. Photolysis. 4-Methylphenol 1n distilled water had an estimated
half-life of 70 days when 1t was exposed to 8 hours of natural sunlight per
day (Smith et al., 1978). When humlc add was present In solution (10
wg/l), the rate of photodegradatlon Increased by a factor of 12. Based
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on literature quantum yield values, the authors estimated that the half-life
for photodegradatlon was between 200 and 400 days using a hand calculator
and a computer model, respectively. No rationale was given for the dis-
crepancy. Different results were obtained when 4-methylphenol was subjected
to sunlight photolysis In water from Lake Grelfensee, Switzerland. The
half-life In the top meter of water was determined to be 4.4 days (Faust and
Holgne, 1987). Therefore, photochemical degradation 1n water may be an
Important fate process 1n clear surfaclal water where the attenuation and
scattering of sunlight are minimal.
2.2.4. H1crob1al Degradation. 4-Methylphenol blodegraded rapidly In
environmental waters Including eutrophlc lakes and ponds, rivers, creeks and
bays (Smith et a!., 1978; Rogers et al., 1964; Van Veld and Spain. 1983;
Spain and Van Veld, 1983). Complete degradation of 4-methylphenol occurred
within 6 days In water obtained from Lake Tahoe, NV. In a eutrophlc pond,
degradation was complete within 8.5 hours, after an Initial 5.5- to 6-hour
lag period. In two fish ponds, the half-life for the blodegradatlon of
4-methylphenol was 2-7 hours after a 30- to 56-hour acclimation period
(Smith et al., 1978). In three rivers located 1n the Pacific Northwest, the
half-life for blodegradatlon ranged from 1-10 hours after a 2-day Induction
period (Rogers et al., 1984). The lag time for acclimation of the mlcroblal
population to 4-methylphenol was found to vary widely as a function of
nutrients present 1n the media (Lewis et al., 1986).
Blodegradatlon of 4-methylphenol was slow In ollgotrophlc lake water,
with an estimated half-life MOO days (Smith et al., 1978). 4-Methylphenol
blodegraded rapidly 1n screening studies using sewage, activated sludge and
freshwater Inocula (Alexander and Lustlgman, 1966; Babeu and Valshnav, 1987;
Balrd et al., 1974; Heukeleklan and Rand, 1955; KHano, 1978; Lund and
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Rodriguez, 1984; Fitter, 1976; Thorn and Agg, 1975). Phenol was Identified
as an Intermediate 1n these blodegradatlons (Young and Rivera, 1985).
Under anaerobic conditions, the mineralization of 4-methylphenol was
complete In 3 and 8 weeks In different studies that used a digester sludge
seed (Boyd et al., 1983; Shelton and Tledje, 1984). No degradation of
4-methylphenol was observed In a study that used a lake sediment seed;
however, using two different sewage sludge seeds, degradation occurred at a
rate equal to 51% removal after 4 weeks, and complete loss after 3 weeks,
respectively (Horowitz et al., 1982). 4-Hethylphenol, at an Initial
concentration of 100 and 400 ppb, underwent mineralization after a 15- and
39-day acclimation period, respectively, using an anaerobic sludge Inoculum
(Fedorak and Hrudey, 1984). 4-Methylphenol degraded completely In 8 days 1n
groundwater under anaerobic conditions (Delflno and Miles, 1985). Using
lake water and swamp water Inocula, 4-methylphenol underwent aerobic
degradation (Hwang et al.. 1989).
2.2.5. Bloconcentratlon. The BCF for 4-methylphenol, as determined by
the regression equation log BCF = 0.76 log K - 0.23 (Bysshe, 1982), can
be determined to be 17.6, based on the log K of 1.94 (Hansch and Leo,
1985). This value suggests that the bloconcentratlon of 4-methylphenol In
fish and aquatic organisms may not be an Important fate process.
2.2.6. Adsorption. Adsorption to sediment was determined to be -0.3X of
the total 4-methylphenol concentration In ponds, 0.0554 1n lakes and 0.1% 1n
rivers (Smith et al., 1978). These data suggest that adsorption to sediment
and suspended organic matter may not be an Important fate process. However,
the adsorption characteristics of phenols are Influenced by a wide range of
factors (Section 2.3.2.), and under certain conditions, adsorption can be a
significant fate process.
0219d
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2.2.7. Volatilization. Based on the water solubility, 21,520 mg/l at
25°C (Yalkowsky et a!., 1987), and the vapor pressure, 0.11 mm Hg at 25°C
(Chao et al., 1983), a Henry's Law constant of 7.95xlO~7 atm-m3/molecule
can be calculated (Thomas, 1982). Using the group method of H1ne and
Mookerjee (1975), a value of 7.05xlO~7 atm mVmolecule at 25°C can be
obtained. Based on these values, a volatilization half-life from a model
river 1 m deep, flowing at 1 m/sec, with a wind velocity of 3 m/sec can be
estimated to be -50 days (Thomas, 1982).
2.3. SOIL
2.3.1. Mlcroblal Degradation. A concentration decrease as a function of
depth for 4-methy!phenol In well samples taken near a wood preserving
facility could not be accounted for by dilution, and the discrepancy was
attributed to the blodegradatlon of this compound In soil (Goer 1 Hz et al.,
1985). 4-Hethylphenol degraded completely In soil after 7 days with an
application rate of 500 mg/kg (Huddleston et al., 1986).
2.3.2. Adsorption. Experimental K values for 4-methylphenol ranged
from 19-49 (Boyd, 1982; Roy and Griffin, 1985), suggesting a very high
mobility In soil (Swann et al., 1983). The pH, mineral or metal content,
and organic make-up of the soil appear to be Important factors that
Influence the ability of 4-methylphenol to leach through soil; under certain
conditions, Its mobility may decrease, and H can be strongly held to soil
(Artlola-Fortuny and Fuller, 1982).
The potential for 4-methylphenol to leach Into groundwater varies. If
rapid blodegradatlon or strong adsorption to soil occurs, then contamination
of groundwater would not be expected. Since high concentrations of
4-methylphenol can be toxic to the mUroblal population, however, the
compound may leach Into groundwater. This phenomenon has been observed 1n
0219d -8- 08/04/89
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leachate from land fills or dump sites, and near underground coal gasifica-
tion sites (Sawhney and Kozloskl, 1984; Dunlap et al., 1976; Stuermer et
al.. 1982; McCreary et al., 1983).
2.3.3. Volatilization. The vapor pressure of 4-methylphenol, 0.11 mm Hg
at 25°C (Chao et al., 1983), suggests that volatilization from dry soil may
occur, but It Is not expected to be a rapid fate process. Volatilization
from moist soil 1s not expected to be significant.
2.4. SUMMARY
In the atmosphere, 4-methylphenol Is expected to exist almost entirely
In the vapor phase (Elsenrelch et al., 1981; Cautreels and Van Cauwenberghe,
1978). The gas-phase reaction with photochemically-produced hydroxyl
radicals Is expected to be rapid, with an estimated half-life of 10 hours.
The nighttime degradation of 4-methylphenol 1n the atmosphere over urban
areas Is also expected to be rapid (Atkinson, 1985). Rain washout and
photolysis may occur, but they are not expected to be competitive processes
(Gaffney et al., 1987; CupHt, 1980). If released to water, blodegradatlon
Is expected to occur under both aerobic and anaerobic conditions. This
process may be rapid under certain conditions. Acclimation periods vary
widely (Lewis et al., 1986). Hydrolysis and oxidation are not expected to
be significant. Available data on the adsorption of 4-methylphenol to
sediment and suspended matter, as well as data on the photolytlc breakdown
of this compound In water, suggest that the Importance of these processes
varies with the local conditions. Under certain conditions, these processes
may be significant. If released to soil, 4-methylphenol can be expected to
undergo blodegradatlon. Adsorption to soil may be significant, but the
process Is not well understood and It appears to depend on the unique
properties of each soil. Volatilization from the soil surface to the
atmosphere 1s not expected to be significant.
0219d
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3. EXPOSURE
4-Methylphenol can enter the environment In wastewater from a broad
range of Industrial classifications. It has also been found In emissions
from automobile and dlesel engines, wood pulping and brewing glass fiber
manufacture, as well as In tobacco smoke (Graedel, 1978). 4-Methylphenol
occurs naturally and can be formed by the high temperature breakdown of
other naturally-occurring materials (Hawthorne et al., 1988). It can enter
the environment through the chemical and biological breakdown of benzenold
compounds (Fatladl, 1984). 4-Methylphenol can be produced by the photo-
oxidation of toluene (Shepson et al., 1985), and as a metabolite from
exposure to toluene and other aromatic solvents (Fatladl, 1984).
The National Occupational Exposure Survey, conducted between 1981 and
1983, estimated that 3269 workers are occupatlonally exposed to 4-methyl-
phenol (NIOSH, 1984). Occupational exposure may result from Inhalation or
dermal contact with the compound during Its manufacture and formulation.
The general population may be exposed by the Ingestlon of contaminated
waters obtained from either surface or ground sources. Inhalation of smoke
from wood fires may also be a route of exposure. Also, the general popula-
tion can be exposed during the use of commercial products containing
4-methylphenol.
3.1. HATER
4-Methylphenol, analyzed as a mixture with 3-methylphenol, was detected
In groundwater samples near an abandoned pine-tar manufacturer In Galns-
vllle, FL, at concentrations ranging from 2300-11,100 ppb, 3100-6200 ppb and
<0.3-95 ppb at wells on the original site, at downgradlent sites and at
upgradlent sites, respectively (McCreary et al., 1983). 4-Methylphenol was
0219d -10- 08/04/89
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4»
found as a mixture with 3-methylphenol at the Hoe Creek underground coal
gasslflcatlon site, HY, at 9.6-16,000 ppb, 15 months after gasslfIcatlon had
ceased (Stuermar et a!., 1982). 4-Methylphenol was found In groundwater
samples obtained near municipal landfill sites 1n Oklahoma and Connecticut,
(14.6 and 15 ppb, respectively) (Dunlap et al., 1976; Sawhney and Kozloskl,
1984), and In Barcelona, Spain (Albalges et al., 1986). It was also found
In a sand aquifer at a wood preserving facility In Pensacola, FL, at concen-
trations up to 6.17 ppm (Goerlltz et al., 1985). It was not found In the
leachate of Industrial landfills (Brown and Donnelly, 1988).
4-Methylphenol was detected In the lower Tennessee River below Calvert
City, KY, at a concentration of 200 ppb (water/sediment sample) (Goodley and
Gordon, 1976). It was Identified near the site of a leather Industry on the
Hayashlda River, Japan, at 204 ppb (Yasuhara et al., 1981), and 1n Spirit
Lake, HA, shortly after the Mount St. Helens eruption (McKnlght et al.,
1982). 4-Methylphenol was detected In rain water 1n seven out of seven
rainfalls In Portland, OR (Leuenberger et al., 1985). 4-Methylphenol was
detected qualitatively 1n drinking water (Lucas, 1984).
In a comprehensive survey of the wastewater from 4000 Industrial and
publicly-owned treatment works, 4-methylphenol was Identified In discharges
from the following Industries (Including percent occurrence and median
concentration): timber products (15%, 166.5 ppb), leather tanning (7X, 31.9
ppb). Iron and steel manufacturing (8X, 33.2 ppb), petroleum refining (IX,
10298 ppb), nonferrous metals (3X. 18.4 ppb), paving and roofing (IX, 18.5
ppb), organlcs and plastics (24X, 477.2 ppb), Inorganic chemicals (3X, 37.7
ppb), textile mills (9X, 50.9 ppb), pulp and paper (5X, 36.7 ppb), rubber
processing (2X, 17659.4 ppb), soaps and detergents (2X, 94.2 ppb), auto and
other laundries (2X, 31.6 ppb), photographic Industries (3X, 327.7), gum and
0219d
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08/04/89
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wood Industries (3%. 3.6 ppb), Pharmaceuticals (4%, 89.2 ppb), explosives
(IX, 3.7 ppb), foundries (16X. 47 ppb), aluminum (13X, 95.7 ppb), elec-
tronics (7%, 66.6 ppb), oil and gas extraction (10%, 6.4 ppb)., organic
chemicals (13X, 95.7 ppb), mechanical products (8X, 398.5 ppb), transporta-
tion equipment (IX, 0.3 ppb), synfuels (15X, 181.1 ppb), publicly-owned
treatment works (44.7X, 134 ppb) and the rum Industry (3X, 87.5 ppb)
(Shackelford et al., 1983).
3.2. FOOD
4-Methylphenol was Identified as a volatile component of fried bacon (Ho
et al., 1983) and roasted filberts (Klnlln et al., 1972). Also, 4-methyl-
phenol 1s used as a synthetic flavor additive for food (Sax and Lewis, 1987).
3.3. INHALATION
4-Methylphenol was not detected In urban or rural air samples obtained
In Utah and Western Colorado (Hawthorne and Slevers, 1984). It was detected
1n seven of seven samples taken In Portland, OR, at 19-52 ppt (avg.=29.4
ppt), and was analyzed as a mixture with 3-methylphenol (Leuenburger et al.,
1985). It was detected In urban air over Belgium (Cautreels and Van
Cauwenberghe, 1978).
3.4. DERMAL
Pertinent data rergardlng dermal exposure to 4-methylphenol were not
located In the available literature cited In Appendix A.
3.5. OTHER
4-Methylphenol was Identified as a component of tobacco smoke and as an
emission of automobile and dlesel engines (Graedel, 1978). It was detected
In the emission from burning vegetable matter that Is likely to be present
In urban waste (Llbertl et al., 1983), and In the smoke from residential
0219d -12- 08/04/89
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wood stoves (Hawthorne et al., 1986). 4-Hethylphenol is a naturally-
occurring component of coal tar (Sax and Lewis, 1987). It 1s a volatile
component of poultry manure (Yasuhara, 1987).
4-Hethylphenol has been detected 1n the urine of varnish workers
(Angerer and Wulf, 1985) and others exposed to benzenold solvents (Fat1ad1,
1984). It Is believed to be a metabolite resulting from exposure to these
solvents (Fat1ad1, 1984).
3.6. SUMMARY
4-Hethylphenol has been detected 1n surface water, groundwater and
rainwater. Water concentrations can vary widely; however, high levels are
usually associated with Industrial activity. 4-Methylphenol has been
detected In surface water near the site of the Hount St. Helens eruption
(Mcknight et al., 1982). It can enter the atmosphere as a result of Indus-
trial activity, and by the burning of vegetable and plant matter (Hawthorne
et al.. 1988; Ubertl et al., 1983; HcKnlght et al., 1982). Also, 4-Methyl-
phenol occurs naturally In coal tar (Sax and Lewis, 1987). It 1s a product
of the chemical and biological breakdown of benzenold compounds (Fatladl,
1984).
Occupational exposure to 4-methylphenol may occur by Inhalation and
dermal contact during Its manufacture and formulation Into commercial
products. The general population may be exposed by Ingesting contaminated
water, or by Inhalation and dermal contact during the use of commercial
products containing 4-methylphenol. Also, exposure to 4-methylphenol may
occur by Inhaling smoke from wood fires or from the smoke resulting from
burning other vegetable matter.
0219d
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4. ENVIRONMENTAL TOXICOLOGY
4.1. AQUATIC TOXICOLOGY
4.1.1. Acute Toxic Effects on Fauna. Acute toxlclty data on 4-methyl-
phenol for freshwater fish, Invertebrates, cod fish and sea urchin eggs (the
only saltwater species data located) are summarized In Table 4-1. Addition-
ally, Hattson et al. (1976) reported 24-, 48-, 72- and 96-hour LC5_s of
26, 21, 21 and 19 mg/i, respectively, for Juvenile fathead minnows,
Plmephales promelas. Dissolved oxygen concentration was low (<4.0 mg/i)
during these tests and may have enhanced the toxlclty of 4-methylphenol,
thus rendering these data questionable. Total lethality was noted at a
concentration of 20 mg/i from a 96-hour dynamic acute study by Cooper and
Stout (1985). No effect on survival or growth of £. promelas larvae
occurred with exposures to 5 nig/a, 4-methylphenol for 96 hours (Barron and
Adelman, 1984). Fertilized eggs of codfish, Gadus morhua. and sea urchins.
Strongylocentrotus droefaachlensls. showed equal sensitivity, with 96-hour
EC5Qs of 5 mg/8. (Falk-Petersen et al., 1985). Damsel flies, Ischnura
vertlcalls. showed no effects from a 48-hour exposure to 40 mg/t, 4-methyl-
phenol (Cooper and Stout, 1985) and thus appear to be the least sensitive of
the Invertebrates tested. The water flea, Daphnla magna. may be the most
sensitive Invertebrate. One-hundred percent mortality was noted when this
species was exposed to 10 mg/8. 4-methylphenol for 48 hours (Cooper and
Stout, 1985). A 24-hour IC5Q of 12.44 mg/t (Devlllers, 1988) for D.
maqnla and a 48-hour LC5Q of 22.7 mg/i for Daphnla pullcarla (OeGraeve
et al., 1980) were for older animals (<72 hours old at the start of tests).
A 48-hour LC5Q of 1.4 mg/l for animals <24 hours old was determined by
Parkhurst et al. (1979). Survival of the amphlpod, Hyallela azteca. from a
96-hour acute dose of 8 ppm was estimated at -50% (Cooper and Stout, 1985).
0219d -14- 08/04/89
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Hodson et al. (1984) reported a 96-hour Intraperltoneal LD,-n of 0.73
t)U
mmol/kg (78.94 mg/kg) and a static acute 96-hour LC5Q of 0.069 mmol (7.45
ppm) for 4-methylphenol 1n rainbow trout, Salmo galrdnerl. Bols et al.
(1985) compared these data with that for cytotoxlclty and found a signifi-
cant correlation between effect levels. Cell cultures from gonadal tissue
of $. galrdnerl were treated with 10 concentrations of 4-methylphenol, and
viability was determined by the number of cells able to attach to the
surface of the Petrl dish. A 30-mlnute EC5Q of 26.4 mmol/i was
determined.
The acute sublethal toxldty of 4-methylphenol administered by Intra-
perltoneal Injection or In a water medium to rainbow trout, S. galrdnerl.
was examined by D1xon et al. (1984, 1985, 1987). Injections of 4-methyl-
phenol dissolved In ethanol were administered to 10 fish at five doses
ranging from 10-75X of the Intraperltoneal 96-hour LD5Q of 74.94 rag/kg
(experimental) and 0% (controls). Blood samples were taken 96 hours after
Injection and analyzed for SSDH and PLAN activity as Indicators of hepato-
toxlclty. An Increase In PLAN activity was noted at an Intraperltoneal dose
of 1.0 mH/kg. and SSDH activity Increased at 0.275 mM/kg. Exposure to a
waterborne concentration of 0.028 mM 4-methylphenol for 48, 96 and 192 hours
led to a statistically significant dose-dependent Increase 1n these enzymes
(doses ranged from 0.25-4.0 mmol/kg) (Dlxon et al., 1984). Doses of
0.075-0.75 of the 96-hour LD5Q Induced elevations of 27-63* of PLAN.
Biochemical lesions preceded evidence of hlstopathology, detected by light
microscope. SSDH responded at lower doses of toxicant than PLAN and,
therefore, may be a more sensitive indicator of toxic stress (Dlxon et al.,
1985, 1987). These data suggest that rainbow trout, S. qalrdnerl. are more
0219d -16- 08/04/89
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sensitive than fathead minnows, P. promelas. to 4-methylphenol and that
variability of several magnitudes exists with respect to sensitivity among
crustaceans.
4.1.2. Chronic Effects on Fauna.
4.1.2.1. TOXICITY — Solskl and Plontek (1987) assessed the chronic
toxUHy of 4-methylphenol with the planaMan, Dugesla tigrlna. Thirty
animals were exposed to five concentrations for 240 hours. The 240-hour
LC5Q was 11.08 mg/dm3 (11.08 mg/i). Surviving animals were then cut,
exposed to the same concentrations of 4-methylphenol for another 240 hours
and counted for mortality. This procedure was repeated for four generations
(animals regenerated from cuttings of four successive groups of exposed
planaMans). The LOEC (mortality of 2.5X) occurred at a concentration of
2.0 mg/i 4-methylphenol In the second generation, a concentration about
one-fourth that of the LC Successive generations showed Increasingly
higher mortality rates with exposures >1 rag/i, but no effects were noted
at lesser concentrations.
4.1.2.2. BIOACCUMULATION/BIOCONCENTRATION — Pertinent data regarding
the b1oaccumulat1on/b1oconcentrat1on potential of 4-methylphenol In aquatic
fauna were not located In the available literature cited In Appendix A.
Mackay et al. (1985) concluded that reaction (blodegradatlon and photolysis)
In water 1s the dominant removal process, with only a small concentration
enhancement 1n biota.
4.1.3. Effects on Flora.
4.1.3.1. TOXICITY — Stout and Kllham (1983) conducted a series of
Investigations on physiological effects of 4-methylphenol 1n the filamentous
green alga, Splrogyra spp. The algae were exposed In a system closely
approximating natural systems. Two closed-cycle streams were used, each 3.4
0219d
-17-
03/21/90
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km long and 4 m wide, with alternating pools and riffles ranging In depth
from 0.5-1.0 m. The channels were continuously monitored for 4-methylphenol
concentrations, dissolved oxygen, pH, temperature, velocity, depth and solar
radiation. Clumps of Spyrogyra were maintained 1n six concentrations of
4-methylphenol. After 3 hours of exposure, samples from each treatment
level were placed In BOD bottles directly In the channel for 1 hour.
Dissolved oxygen levels decreased from a control value of 7.0 ppm to 6.2,
6.8, 5.4, 5.2 and 5.6 ppm at 4-methylphenol concentrations of 0.9, 4.6, 14,
34 and 71 ppm, respectively. These results Indicate that low concentrations
of 4-methylphenol Inhibit photosynthesis and Increase algal respiration
rates. The data agree with findings by Cooper and Stout (1985) In which
48-hour exposure to concentrations of 8 ppm 4-methylphenol Inhibited
respiration 1n filamentous green algae (species not reported).
Huang (1967) and Huang and Gloyna (1968) grew the alga, Chlorella
pyrenoldosa. for 72 hours In test tubes under constant temperature, Illumi-
nation and nutrient conditions and assessed the effects of 4-methylphenol on
chlorophyll content. Destruction of chlorophyll was dose-dependent.
Concentrations of 50 mg/8. 4-methylphenol reduced chlorophyll content to
5054 of Its pretreatment value at 72 hours, whereas 1000 mg/l 4-methyl-
phenol reduced chlorophyll content to ~OX within 24 hours of exposure.
Robinson et al. (1976) tested the effects on axenlc cultures of the
unicellular green alga, Anklstrodesmus falcatus. Experimental cultures were
prepared by Inoculating 40 cc of nutrient medium with 500 cells/cc of algae
In the log phase of growth. Concentrations of 1, 10, 25, 50. 100, 500 and
1000 yg 4-methylphenol/cc of culture medium yielded 10-day growth rates
(measured as optical densities at 660 nm) of 0.38, 0.34, 0.29, 0.26. -0.03,
0219d -18- 08/04/89
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0.07 and 0.01, respectively. These data Indicate that 4-methylphenol
severely Inhibits growth at 100 yg/cc, and no growth occurs at >500
yg/cc.
4.1.3.2. BIOCONCENTRATION — Pertinent data regarding the bloconcen-
tratlon potential of 4-methylphenol In aquatic flora were not located In the
available literature cited 1n Appendix A. Mackay et al. (1985) concluded
that reaction (blodegradatlon and photolysis) 1n water Is the dominant
removal process, with only a small concentration enhancement In biota.
4.1.4. Effects on Bacteria and Other Aquatic Microorganisms. Lebsack et
al. (1981) measured luminescence Inhibition to assess toxlclty of 4-methyl-
phenol to the marine bacterium, PhotobacteMum MscheM {now known as £.
phosphoreum). Blolumlnescence was measured by a Mlcrotox toxlclty meter. A
decrease 1n bacterial light output was noted after 5 minutes exposure of
bacterial suspension to four toxicant concentrations {4-methylphenol In 2%
sodium chloride) and a control. The 5-mlnute EC™ was 1.3 mg/i for
luminescence Inhibition.
Bullch and Isenberg (1980) and Btillch et al. (1981) Identified a
5-mlnute EC of 1.5 mg/s. for exposure of P. phosphoreum to
4-methylphenol. The authors concluded that this value, obtained by the
Mlcrotox Assay, generally agreed with those found In fish bloassays.
Delesmont and Delattre (1983) measured the toxlclty of 4-methylphenol to
P. phosphoreum and Identified an 8-hour Incubation IC5Q of 206 mg/t
(concentration that reduced the number of fluorescent cells by 50%).
The spreading of trlchal blue alga, Phormldlum. cultured 1n petrl dishes
was completely Inhibited by 100 vg/test spot of 4-methylphenol (Benecke
and Zullel, 1977).
0
0219d
-19-
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Dube et al. (1988) assessed the toxlclty of 4-methylphenol to the
fungus, Asperglllus flavus. Test concentrations of 0, 500, 700, 1000 and
2000 ppm were added to presteMUzed petrl plates containing 9 ml of
Czapek's agar medium. Plates were Inoculated with mycellal discs 5 mm In
diameter and Incubated for 6 days. Percent mycellal Inhibition calculated
on day 7 was 82% for 500 ppm 4-methylphenol and 100% for higher doses.
Yoshloka et al. (1985) assessed the acute toxldty of 4-methylphenol to
the protozoan, Tetrahymena pyMformls. and Identified a 24-hour EC,- of
160 mg/a at 30°C.
4.2. TERRESTRIAL TOXICOLOGY
4.2.1. Effects on Fauna. Marcus and Hchtensteln (1979) tested the
toxlclty of extracts of anise plants, Plmplnella an Is urn, a widely used spice
and flavoring agent. Topical exposure (duration not reported) of
houseflles, Husca domestlea, to 4-methylphenol yielded an LDcn of 80
au
ijg/anlmal. Schafer et al. (1983) administered 4-methylphenol to trapped
wild birds 2-6 weeks from preconditioning to captivity to assess the com-
pound's acute oral toxlclty. An oral L05Q of 96 mg/kg/day was Identified
for the redwing blackbird, Agelalus phoenlceus.
The acute oral toxlclty and repellency of 4-methylphenol to deer mice,
Peromyscus manlculatus. was assessed by Schafer and Bowles (1985).
Repellency tests yielded an FR value of 1% and an LD, of 1238 mg/kg/day.
4.2.2. Effects on Flora. Bllderback (1981) assessed the Inhibitory
effects of 4-methylphenol In a basal growth medium on germination and tube
elongation of Impatlens sultan11 pollen. The EC^s for germination, tube
production and tube growth were 100, 40-60 and 150 ppm 4-methylphenol,
respectively.
0219d -20- 03/21/90
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Reynolds (1978) tested 4-methylphenol for Inhibitory effects on fruit
germination In lettuce, Lactuca satlva. The EC5Q for percent germination
after 3 days exposure to 4-methylphenol In aqueous solution was 1.13i0.19 mH
(122.2±20.5 ppm).
All et al. (1987) tested the Inhibitory effects of 4-methylphenol on
sclerotla of the fungus, Sclerotlum ceplvorum. a pathogen of onions and
other All 1 urn species. After 44 hours growth on potato-dextrose agar medium
at 20°C, 10 ppm 4-methylphenol caused reduced germination and germtube
elongation and totally Inhibited both at concentrations >50 ppm.
4.3. FIELD STUDIES
Cooper and Stout (1985) conducted multlspedes toxlclty tests 1n eight
channels, 500 m In length, with alternating pools and riffles. The
biologically diverse nature of these facilities closely approximated natural
streams and, therefore, their findings may be viewed as either laboratory or
field data. See Section 4.1.1. for data pertinent to this document.
4.4. AQUATIC RISK ASSESSMENT
The lack of pertinent data regarding the effects of exposure of aquatic
fauna and flora to 4-methylphenol prevented the development of a freshwater
criterion (U.S. EPA/OHRS, 1986) (Figure 4-1). Available data Indicate that
acute toxic effects can occur at concentrations >1.4 mg/i. Additional
data required to develop a freshwater criterion Includes the results of
acute assays with an additional fish species or an amphibian, a benthlc
crustacean, an Insect, a nonarthropod and nonchordate species and an Insect
or species from a phylum not previously represented. The development of a
freshwater criterion also requires data from chronic toxldty tests with two
species of fauna and one species of algae or vascular plant and at least one
bloconcentratlon study.
0219d
-21-
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TEST TYPE
Family
#1
Chordate (Salmonid-f ish)
12
Chordate (warmwater fish)
#3
Chordate (fish or amphibian)
#4
Crustacean (planktonic)
#5
Crustacean (benthic)
#6
Insectan
17
non-Arthropod/ -Chordate
#8
New Insectan or phylum
repr esenta t i ve
#9
algae
#10
Vascular plant
GMAVa
(mg/1)
7.9b
21.79C
NA
1.4*
NA
NA
NA
NA
XXXXXXXXXXXX
XXXXXXXXXXXX
XXXXXXXXXXXX
XXXXXXXXXXXX
GMCVa
(mg/1)
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
BCFa
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
•NA-Not available
*96-hour LCso for rainbow trout. S. galrdnerl
cMean 96-hour LCSO for fathead minnows, P. promelas
"48-hour LCso for water fleas, D. magna.
FIGURE 4-1
Organization Chart of GHAVs, GMCVs and BCFs Required to Derive Numerical
Hater Quality Criteria to Protect Freshwater Aquatic Life from Exposure to
4-Hethylphenol, according to U.S. EPA/OHRS (1986)
0219d
-22,
08/04/89
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Lack of pertinent data regarding the effects of exposure of aquatic
fauna and flora to 4-methylphenol precluded the development of a saltwater
criterion (U.S. EPA/OWRS, 1986). Additional data required to develop a
saltwater criterion Includes the results of acute assays with two chordate
species, a nonarthropod and nonchordate species, a mysld or panaeld
crustacean, two additional nonchordate species and one other species of
marine fauna. The development of a saltwater criterion also requires data
from chronic toxlclty tests with two species of fauna and one species of
algae or vascular plant and at least one bloconcentratlon study.
4.5. SUMMARY
Data are available on the acute toxlclty of 4-methylphenol to salmonld,
warmwater fish and several Invertebrates. Acute toxlclty values shown 1n
Table 4-1 Indicate that rainbow trout, S. galrdnerl. are more sensitive than
are fathead minnows, P. promelas. with LC5_ values of 7.9 mg/a and 28.6
mg/a, respectively (DeGraeve et al., 1980). Fertilized eggs of cod fish,
G. morhua. and sea urchins, S. droebachlensls. are equally sensitive to
96-hour exposure to 4-methylphenol (Falk-Petersen et al., 1985). Damsel
files, I., vertical Is. were not adversely affected by 40 mg/a (Cooper and
Stout, 1985), but the water flea, D. magna. showed 50% lethality to a
concentration of 1.4 mg/a. Variation 1n sensitivity between D. magna and
D. pullcarla. with 48-hour LC5Qs of 1.4 and 22.7 mg/a, respectively, may
be explained by the age difference at time of testing (J). magna were <24
hours old and 0. pullcarla were <72 hours old) (Parkhurst et al., 1979;
DeGraeve et al., 1980).
The chronic toxlclty of 4-methylphenol In the planarlan, D. tlgrlna. was
assessed by Solskl and Plontek (1987). A 240-hour LC5(J of 11.08 mg/a
was Identified. Follow-up testing for four generations (test animals cut In
0219d
-23-
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half and retested) showed successively Increased mortality at the LOEC of
2.0 mg/l, but the LOEC value did not change.
Chlorophyll content and photosynthesis are adversely affected (as
evidenced by decreased dissolved oxygen concentrations) 1n freshwater algae
by 4-methylphenol concentrations >0.9 mg/l (Stout and KHham, 1983). A
72-hour LC5Q of 50 mg/l was Identified for chlorophyll content with C_.
pyrenoldosa. This effect was dose-dependent (Huang, 1967; Huang and Gloyna,
1968). A concentration of 100 yg/cc (100 mg/l) severely Inhibited
growth of the unicellular green alga, A. fa_l.cjLt.us. and totally Inhibited H
at 500 yg/cc (500 mg/l) (Robinson et al., 1976).
B1oaccumulat1on/b1oconcentrat1on studies were not located In the
available literature, but evidence suggests that 4-methylphenol will not
accumulate appreciably In aquatic biota.
Bacterial luminescence was reduced 50% by 5-m1nute exposure to >1.3
mg/l 4-methylphenol (Lebsack et al, 1981). An 8-hour Incubation of £.
phosphoreum with 206 mg/l 4-methylphenol reduced the number of fluorescent
cells by 50% (Delesmont and Delattre, 1983). Growth of the trUhal blue
alga, Phorm1d1um. was totally Inhibited by 100 yg/test spot of 4-methyl-
phenol (Benecke and Zullel, 1977). Concentrations of >500 ppm 4-methyl-
phenol totally Inhibited mycellal growth 1n the fungus, A. flavus (Dube et
al., 1988). A 24-hour EC5Q of 160 mg/l 4-methylphenol was Identified
with the protozoan, T. pyrlformls (Yoshloka et al., 1985).
The effects of 4-methylphenol on terrestrial fauna were assessed In
Insects, birds and small mammals. An LDgQ for topical exposure to
4-methylphenol of 80 yg/an1mal for the housefly, M. domestlca. was
reported by Marcus and Llchtensteln (1979). Oral LD50$ of 9& mg/kg/day
0219d -24- 03/21/90
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for the redwing blackbird, A. phoenlceus (Schafer et al., 1983) and 1238
mg/kg/day for deer mice, P. manlculatus (Schafer and Bowles, 1985) were
reported.
Assessments of toxIcHy of 4-methylphenol to terrestrial plants Identi-
fied EC^s of 100, 40-60 and 150 ppm for germination, tube production and
tube growth, respectively, with I.. sultan11 (Bllderback, 1981). An EC5Q
of 122.2 ppm was reported for fruit germination In L. satlva (Reynolds,
1978) and reduced germination of sclerotla was noted 1n S. cepIvor urn
exposed to 10 ppm 4-methylphenol (AH et al., 1987).
0219d
-25-
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5. PHARMACOKINETICS
5.1. ABSORPTION
Delchmann and Kepllnger (1961) report that cresol (a mixture of Isomers
Including paracresol) can be absorbed through skin, wounds and the mucous
membranes of the respiratory and gastrointestinal tracts. The absorption of
4-methylphenol (paracresol) following dermal and oral exposure was studied.
Anderson et al. (1976) measured the desorptlon of the test article and other
phenolic compounds In vitro from human stratum corneum to estimate the
stratum corneum-water partition coefficient and the relative diffusion
coefficient of phenolic compounds 1n human stratum corneum. The D/h2 was
11.0+?.8 sec"1 x 10* and the Km was determined to be 10.6+0.8 using four
samples of hydrated stratum corneum equilibrated with a nondamaglng aqueous
solution of 4-methylphenol (concentration not reported). Likewise, Roberts
et al. (1977) determined the k of 4-methylphenol In vitro through human
P
abdominal epidermal membranes. The k was estimated from the steady-state
slope of the ratio between the cumulative amount of the test article
penetrating through a unit area of membrane with time. The k for
4-methylphenol at concentrations that did not damage the stratum corneum was
2.92x10* cm/minute. The k Increased after the threshold concentration
P
was reached, Indicating that damage to the membrane had occurred. The
threshold concentration resulting 1n damage was 8.85% w/v.
Green (1975) reported mortality 1n a 12-month-old Infant dermally
exposed to coal tar fluid (90% cresols In water), Indicating that
substantial dermal absorption had occurred. Cresols are a mixture of
ortho-, meta- and paracresol (4-methylphenol). There was no evidence of
Inhalation or oral Ingestlon. Clinical and hlstologlcal observations taken
>4.25 hours after exposure Included "burns" on the face, scalp, hands and
0219d -26- 03/21/90
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forearms and destruction of the epidermis with loss of the stratum corneum.
Cresols were Identified In the blood, urine, liver and brain. The mother of
the Infant reportedly washed the head and scalp of the Infant -5 minutes
after exposure. At that time, the Infant was unconscious and "blue In the
face."
Oral absorption was studied where 2-3 kg rabbits were administered
4-methylphenol (250-500 mg/rabblt) 1n a NaHCOg solution by gavage {Bray et
al., 1950). Within 24 hours of dosing, -65% of the administered dose was
recovered In the urine as total cresol metabolites, Indicating that >65% was
absorbed through the gastrointestinal tract.
5.2. DISTRIBUTION
Pertinent data regarding actual concentrations of 4-methylphenol In body
tissues following exposure were not located In the available literature
cited In Appendix A; however, Green (1975) detected cresols (Section 5.1.)
In the brain, liver, blood and urine of an Infant dermally exposed to coal
tar fluid. All of the organs had a strong cresol odor.
5.3. METABOLISM
According to OeUhmann and WHherup (1944), Embody et al. (1940), Hunakl
(1940) and KUnger and Norton (1945), the metabolism of 4-methylphenol Is
similar to that of phenol. These Isomers are oxidized and conjugated with
sulfurlc and glucuronlc acids (DeUhmann and KepHnger, 1981; Williams,
1938). Bray et al. (1950) concluded that 4-methylphenol and other cresol
Isomers form conjugates primarily at the hydroxyl group. Williams (1938)
recovered 16% of a gavage dose of 290 mg 4-methylphenol/kg administered to 2
kg female rabbits as an ethereal sulfate conjugate In the urine within 2
days following dosing. Likewise, the urine of rabbits administered
4-methylphenol by gavage at a level of 250-500 mg/rabblt contained an
average 15% of the dose as ethereal sulfate and 61% as ether glucuronlde
O
0219d
-21-
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of the parent compound within 24 hours of dosing {Bray et al., 1950). Free
and conjugated hydroxybenzolc acid were also detected In the urine. Neuberg
and Kretchmer (1911) also detected sulfate and glucuronlde forms of
4-methylphenol In the urine following oral administration of the test chemi-
cal to dogs. These forms were double barium salts of p-cresylg!ucuron1de
and p-cresylsulfurlc acid.
These in vivo results are supported by the in vitro metabolic experiment
by Sato et al. (1956) In which the Intermediates, which had not previously
been Isolated, were Identified. 4-Methylphenol was Incubated for 1 hour
with S35-sulfate and supernatant or liver slices prepared from livers from
white rats. The supernatant mixture yielded p-cresylsulfate, Indicating
that oxidation had not occurred. However, Incubation with the liver slices
produced the sulfate conjugate of p-hydroxybenzo1c add, which Investigators
hypothesized arose from formation of the Intermediate p-hydroxybenzaldehyde,
Indicating that oxidation of the methyl group had occurred. "Meager"
amounts of 3,4-d1hydroxybenzo1c add were formed from the p-hydroxybenzo1c
add. The Intermediate between the test chemical and p-hydroxybenzaldehyde
was tentatively Identified as p-hydroxybenzyl alcohol. The authors concluded
that sulfate conjugation 1s preceded by the oxidation of the -CH~ group of
4-methylphenol through the probable Intermediates of -CH-OH and -CHO to
-COOH (Figure 5-1).
5.4. EXCRETION
The major route of 4-methylphenol excretion In rabbits Is through the
urine. Within 24 hours of administration of a 250-500 mg oral dose of
4-methylphenol, an average of 65% of the dose was recovered In the urine of
rabbits In the form of various metabolites. Williams (1938) detected 16% of
a 290 mg/kg dose of 4-methylphenol administered orally to rabbits as a
0219d -28- 08/04/89
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CH,
sup
OH
CHgOH CHO
COOH
COOH
•up
OH
OH
•» pup
CHO
OH
OH
OH
COOH*
COOH
OH
\
OH \A
OH
OH
OH
FIGURE 5-1
Metabolic Pathway of 4-Methylphenol
Source: Sato et al.» 1956
0219d
-29-
08/04/89
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sulfate conjugate (ethereal sulfate) In the urine. This urine was collected
on the day of the dosing through the day after dosing. Data regarding
excretion following dermal or Inhalation exposure were not located In the
available literature; however, cresols were detected In the urine of an
Infant dermally exposed to coal tar fluid (90% cresols In water) (Green,
1975}. Wandel (1907) also reported that cresols can be excreted In bile and
exhaled air, but further details were not available.
5.5. SUMMARY
The pharmacok1net1cs of 4-methylphenol Involves documented dermal
(Green, 1975; Anderson et al., 1976; Roberts et al., 1977) and gastrointes-
tinal (Bray et al., 1950) absorption of the test chemical with distribution
to the brain, liver, blood and possibly all organs (Green, 1975). Metabo-
lism Includes oxidation of the -CH« group of the 4-methylphenol to the
Intermediates -CH_OH and -CHO and finally to -COOH, as determined In vitro
i ^
(Sato et al., 1956). The sulfate conjugates corresponding to these Inter-
mediates and the final product are p-hydroxybenzyl alcohol, p-hydroxybenz-
aldehyde and p-hydroxybenzolc add, respectively. Small amounts of
3,4-d1hydroxybenzo1c add were also formed by this pathway. The !n yHro
data support In v1vo observations. Excretion data from Bray et al. (1950)
and Neuberg and Kretchmer (1911) Indicate that 4-methylphenol 1s excreted
primarily 1n the urine as sulfate and glucuronlde conjugates. Bray et al.
(1950) reported that an average oral dose of 65% was excreted 1n the urine
(as total cresols) within 24 hours.
0219d -30- 03/21/90
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposure.
6.1.1.1. SUBCHRONIC — Pertinent data regarding the subchronlc
Inhalation toxlclty of 4-methylphenol were not located 1n the available
literature dted 1n Appendix A.
6.1.1.2. CHRONIC — Pertinent data regarding the chronic Inhalation
toxlclty of 4-methylphenol were not located In the available literature
cited In Appendix A.
6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC — The oral toxlclty of 4-methylphenol was
evaluated In groups of 30 male and 30 female Sprague-Dawley rats admin-
istered the compound (99.9% pure) by gavage In corn oil at levels of 0, 50,
175 and 600 mg/kg/day, 7 days/week for 13 weeks (Dletz and Mulligan, 1988).
Mortality was observed 1n three high-dose females during the first 3 days of
the study. Two of these animals experienced tremors and were comatose
before death. Clinical observations Included signs of CNS Impairment
(lethargy, tremors and occasional convulsions and comas) and reduction 1n
body weight gain In high-dose animals of both sexes. Decreased body weight
and decreased body weight gain were also observed In mid-dose males, but
only during the first 3 weeks of the study. Terminal body weights were not
significantly different from controls. Complete gross and microscopic
examination of 29 organs and tissues revealed hepatotoxlc and nephrotoxlc
effects. Statistically significant (p<0.05) Increases In relative organ
weights were observed 1n the livers and kidneys of mid- and high-dose males;
the heart, testes and brain of high-dose males; the spleens of low-dose
females; and the kidneys of high-dose females. Chronic nephropathy
0219d
-31-
03/21/90
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was observed at a statistically significant (p<0.05) Increased Incidence 1n
low- and high-dose male rats. Epithelial metaplasia of the trachea was
observed at a significantly (p<0.05) greater Incidence In high-dose animals
of both sexes. Comprehensive hematologlcal, urlnalysls and clinical
chemistry observations revealed mild anemia In mid- and high-dose females.
Dose-related reductions In red blood cell count, hemoglobin concentration
and hematocrlt were observed In mid- and high-dose females. Significant
elevations 1n SGPT and SGOT levels were observed 1n four high-dose females,
two of which also had chronic hepatic Inflammation. Total serum protein was
significantly Increased In mid- and high-dose males. The authors concluded
that no toxic effects occurred at 50 mg/kg/day.
A subchronU gavage study was performed on groups of 10 male and 10
female CO rats administered 4-methylphenol In corn oil at a level of 50, 175
or 600 mg/kg/day for 13 weeks (U.S. EPA, 1987a). Mortality was observed In
4 males'and 4 females at the high-dose level; however, the deaths of 2 males
and 2 females were caused by aspiration or Inhalation of the test compound.
Clinical observations Included salivation, tremors, urine-wet abdomens,
hypoactlvUy. rapid respiration, myoclonus and low body posture 1n males and
females of all treatment groups; however, these clinical signs occurred
primarily during the first hour after dosing and during the first week of
dosing. The signs were low In Incidence and sporadic thereafter, suggesting
that they were a response to the rapid bolus administration of the test
article. Myotonus was observed in only high-dose group animals and labored
respiration was observed 1n mid- and high-dose males and females.
Neurobehavloral toxldty (clinical observations and several performance
and reflex tests) was evaluated once during pretreatment, 1 and 6 hours
after the first dose, and before dosing on days 2, 7, 14, 30, 60, and 90.
0219d -32- 03/21/90
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Slightly Increased urination and decreased locomoter activity were observed
1n high-dose males and females. The urination Increase occurred at the end
of the study for both sexes; however, the locomotor activity decrease was
observed at the end for males only. Females had statistically significant
(p<0.05) decreases In activity 24 hours after the first dose only.
Increases 1n palpebral closure, rales and labored respiration were observed
In both sexes at the high dose level during the Initial part of the study.
Food consumption was decreased (p<0.01) 1n male and female rats In the
high-dose group during the first week of the study. Decreased mean body
weights (p<0.05) were reported 1n high-dose males during the first week of
the study. A slight but nonsignificant reduction In mean relative brain
weight was reported In high-dose females.
HlstopathologUal examination, limited to selected rats of both sexes
from the control and the high-dose groups and rats that died during the
study, consisted of hematoxylln and eosln-stalned sections of the central
and peripheral nervous systems, esophagus, stomach, lungs and trachea and
sections of selected gross lesions. No compound-related lesions were
reported 1n the test animals.
6.1.3. Other Relevant Information. Mortality, convulsions and decreases
1n weight gain, apparent In rats during subchronlc oral exposure to
4-methylphenol, were also observed In rabbits, rats, mice, guinea pigs and
cats following acute exposure to the test article by oral, dermal,
Intraperltoneal, Intravenous or subcutaneous routes (Table 6-1). Skin
corrosion was also a result of dermal exposure to 4-methylphenol (Vernot et
al., 1977) (see Table 6-1). Clinton (1948) reported severe eye burns
following cresol exposure with subsequent necrosis of the cornea, scarring
and blindness. Further Information was not reported.
O
0219d
-33-
03/21/90
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The LQ50 values reported for oral exposure 1n rats are 207 mg/kg (Sax,
1984} and 1800 mg/kg (Delchmann and WHherup, 1944). Mortality was not
observed until 600 mg/kg/day In the subchronlc studies described previously
(Dletz and Mulligan, 1988; U.S. EPA, 1986b). The oral LD . for mice 1s
344 mg/kg (Sax, 1984} and the LD.- for rabbits Is 620 mg/kg (Delchmann and
WHherup. 1944}. The dermal LD5Q for rabbits Is 300 mg/kg (Vernot et al.,
1977); therefore, 4-methylphenol appears to be more toxic through the dermal
route for rabbits. The apparently rapid dermal absorption and resulting
mortality (see Section 5.1.) reported by Green (1975) corroborate these
acute data. Subcutaneous exposures resulted In LD s that were similar
for rats, mice, rabbits and guinea pigs (Sax, 1984; Gordon and McCandless,
1959).
Subchronlc dermal (Shelley, 1974) and Intravenous (Yehuda et al.t 1977)
studies with 4-methylphenol were also performed on mice and rats, respec-
tively. An unoccluded dose of 0.5X 4-methylphenol 1n acetone (total amount
not reported) was sprayed on the clipped or epllated caudal half of the
backs of CBA/J agouti and black mice 3 times/week for 6 weeks (Shelley,
1974). By 6 months following exposure, deplgmentatlon of the hair and skin
was observed. Intravenous administration of 4-methylphenol to rats as a
dally 0.1 mg/kg Injection for 7 weeks at room temperatures of 4, 20 and 37°C
resulted In convulsions, with minimum seizures at 20°C (Yehuda et al., 1977).
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the cardnogenHHy of
4-methylphenol following Inhalation exposure were not located 1n the
available literature cited in Appendix A.
6.2.2. Oral. Pertinent data regarding the cardnogenldty of 4-methyl-
phenol following oral exposure were not located In the available literature
cited In Appendix A.
0219d
-36-
03/21/90
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6.2.3. Other Relevant Information. The only relevant cancer data on
4-methylphenol In the literature was an experiment promoting skin tumors 1n
young adult albino mice of several strains (Boutwell and Bosch, 1959). A
single Initiating dose of 75 vq DMBA as a 0.3% solution In acetone was
applied to shaved back skin of groups of 28 animals. One week later,
4-methylphenol, as a 20% solution 1n benzene, was applied twice each week
for 12 weeks. A control group of 12 animals was exposed only to benzene
following DMBA Initiation. Clinical observations Included eight mortalities
In the 4-methylphenol group. Examination of the test group revealed 0.55
paplllomas per survivor and 35% of the survivors bearing paplllomas, but no
carcinomas were observed. No paplllomas or carcinomas were observed In the
control group. A 20-week experiment with DMBA Initiation (Identical to the
12-week experiment) and 4-methylphenol promotion as a 5.7% solution In
benzene revealed mortality 1n 2/20 control animals and In 6/20 treated
animals. Evaluation revealed 0.36 paplllomas per treated survivor and 29%
of the survivors had paplllomas; no paplllomas or carcinomas were observed
1n control animals. Further experimental protocol was not reported. The
Investigators concluded that 4-methylphenol was a tumor promoter In this
test.
6.3. GENOTOXICITY
Available data regarding the mutagenlclty and genotox1c1ty of 4-methyl-
phenol are summarized 1n Table 6-2. 4-Methylphenol has not been found to be
mutagenlc when tested up to levels of toxUlty In reverse mutation assays
with Salmonella typhlmurlum strains TA1535, TA1537, TA1538. TA98 or TA100
(Florin et a!., 1980; Douglas et al., 1980; Haworth et al., 1983; Crowley
and Margard, 1978; Case Western Reserve, 1980; Pool and Lin, 1982).
0219d
-37-
03/21/90
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07/19/90
-------
ID. vivo and itt vUro SCE assays with human dlplold flbroblasts and DBA/2
mice (CUT, 1983; Cheng and KUngerman, 1984) revealed no significant
Increases 1n SCE. A cell transformation assay with C3H10T1/2 mouse flbro-
blasts was negative (Crowley and Hargard, 1978).
Crowley and Margard (1978), however, found 4-methylphenol to be positive
In an unscheduled DNA synthesis assay using human lung flbroblasts (HI-28)
and biological activation (further protocol not provided).
6.4. DEVELOPMENTAL TOXICITY
A range finding developmental toxlclty study with groups of eight mated
female New Zealand White rabbits administered 4-methylphenol 1n corn oil by
gavage at levels of 50, 150, 300 and 500 mg/kg/day for days 6-18 of gesta-
tion was performed for CMA (1987). Dose-related maternal mortality was
observed In the three highest dose levels (2/8, 4/8 and 7/8, respectively).
There were no mortalities 1n controls. Gasping and labored respiration were
observed at all dose levels, but only In a few rabbits at 50 mg/kg/day.
More Intense CNS and cardlopulmonary effects (hypoactlvlty, ataxla, twitch-
Ing and breathing problems) were observed In the dams at the two highest
levels. Significant maternal weight loss was observed at the 150 and 300
mg/kg levels; excessive (7/8) mortality at the highest level precluded
statistical analysis. External malformations possibly attributed to the
test chemical were restricted to forellmb and pectoral girdle variations at
300 mg/kg/day. There was no mention of examination for Internal malfor-
mations.
In the final study, groups of 14 mated New Zealand white rabbits were
treated by gavage with 4-methylphenol 1n corn oil at doses of 5.0, 50.0 or
100.0 mg/kg/day on gestation days 6-16 (CMA, 1988a). The day on which
mating was observed was designated gestation day 0. A negative control
group of 28 rabbits was treated on the same schedule with corn oil alone.
0219d
-39-
03/13/91
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The dams were observed for clinical signs, and body weights and food con-
sumption were measured until sacrifice on gestation day 29. Upon necropsy,
the dams were evaluated for body, liver and gravid uterine weight and the
number and condition of Implantation sites. Live fetus were weighed and
examined for external. Internal and skeletal variations. Approximately
one-half of the fetuses from each Utter were examined for soft tissue and
cranlofaclal malformations. Maternal mortality claimed 5/14 (p<0.01) and
2/14 (p>0.10) rabbits treated with 100.0 and 50.0 mg/kg/day, respectively,
(Fisher exact test performed at SRC). The Investigators attributed these
deaths to 4-methylphenol. Respiratory distress, cyanosis, ocular discharge
and hypoactlvlty were observed In dams treated with >50.0 mg/kg/day. There
were no effects on food consumption or body weight at any dose level and no
maternal effects of any kind at 5.0 mg/kg/day. There were no effects on
gestatlonal parameters, fetal body weight/litter or the frequency of
Internal, external or skeletal variation.
CMA (1988b) used a similar protocol to evaluate the developmental
toxldty of 4-methylphenol In rats. Groups of 25 mated Sprague-Dawley rats
were treated with 30.0, 175.0 or 450.0 mg/kg/day on days 6-15 of gestation.
Fifty rats were maintained as negative (vehicle) controls. The dams were
sacrificed on gestation day 21. Approximately one-half the fetuses 1n each
litter were examined for visceral and cranlofaclal malformations and
one-half were examined for skeletal variations. Maternal effects, limited
to the high dose group. Included clinical signs (CNS signs, labored respira-
tion), reduced food consumption, body weight and body weight gain during the
treatment period, and reduced body weight at termination. There were no
effects on gestatlonal parameters or on the Incidence of external, soft
tissue or skeletal variations. Fetal body weight/Utter was significantly
decreased at 450.0 mg/kg/day.
0219d -40- 03/13/91
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6.5. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding other reproductive effects of 4-methylphenol
were not located In the available literature cited 1n Appendix A.
6.6. SUMMARY
Data are lacking on the chronic toxlclty and carcinogenic potential of
4-methylphenol following oral or Inhalation exposure. 4-Hethylphenol
appeared to be a tumor promoter In the two-stage skin tumor assay In mice
following Initiation by DMBA (Boutwell and Bosch, 1959). Mutagenlclty and
genotoxlcty studies resulted In negative responses In reverse mutation
assays, In vitro and in vivo SCE tests and cell transformation assays (see
Table 6-2); however, Crowley and Margard (1978) reported positive results In
an unscheduled DNA synthesis assay. Subchronlc and acute Inhalation data
are lacking. Oral, IntraperHoneal, Intravenous, dermal or subcutaneous
acute, subchronlc and developmental toxldty studies resulted In common
toxlcologlcal effects. Mortality, CNS effects and decreases In body weights
were observed In each of these types of studies {Dletz and Mulligan, 1988;
U.S. EPA, 1987a; Yehuda et al., 1977; CMA, 1987, 1988a,b). Labored respira-
tion was also observed following subchronlc oral (U.S. EPA, 1987a) and
developmental toxldty (CMA, 1987) studies using rats and rabbits treated by
gavage at 50 mg/kg/day, the lowest dose tested. Subchronlc dermal exposure
1n mice resulted In deplgmentatlon of the skin and hair (Shelley, 1974).
0219d
-41-
03/15/91
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
ACGIH (1988) and OSHA (1989) adopted a TLV-TWA of 22 mg/m3 (5 ppm) for
cresols (all Isomers). NIOSH (1978), however, recommended a TLV-THA of 10
mg/m3 for cresol. The cresol TLV recommended by ACGIH 1s based on analogy
to the toxlclty of phenol (ACGIH, 1986).
U.S. EPA (1987b) reported a verified oral RfD of 5E-2 mg/kg/day for
4-methylphenol. The derivation of this RfD 1s explained In Chapter 8.
7.2. AQUATIC
Cresol (p-) 1s listed as a hazardous substance (U.S. EPA, 1982) and 1s a
substance designated for ground-water monitoring (U.S. EPA, 1988).
0219d -42- 03/13/91
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the Inhalation cardnogen-
Iclty of 4-methylphenol were not located 1n the available literature dted
1n Appendix A.
8.1.2. Oral. Pertinent data regarding the oral carclnogenlclty of
4-methylphenol were not located In the available literature dted In
Appendix A.
8.1.3. Other Routes. 4-methylphenol appeared to be a promoter 1n the
two-stage mouse skin assay In mice Initiated with DMBA (Boutwell and Bosch,
1959).
8.1.4. Height of Evidence. There Is Insufficient evidence regarding the
carclnogenlclty of 4-methylphenol 1n animals. There are no data regarding
the carclnogenlclty In humans; therefore, 4-methylphenol 1s most appro-
priately placed In Group 0, not classifiable as to human carclnogenlclty,
according to U.S. EPA (1986b) classification schene.
8.1.5. Quantitative Risk Assessment.
8.1.5.1. INHALATION — No pertinent Inhalation carclnogenlclty
studies with 4-methylphenol are available, precluding the derivation of
• v-
8.1.5.2. ORAL — No pertinent oral carclnogenlclty studies with
4-methylphenol are available, precluding the derivation of a q *.
8.2. SYSTEMIC TOXICITY
In this section, "Rec. #" refers to the data records for the dose/
duration-response graphs In Appendix C.
0219d
-43-
03/15/91
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8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURE (SUBCHRONIC) — Pertinent data
regarding the Inhalation toxldty of 4-methylphenol were not located In the
available literature cited 1n Appendix A.
8.2.1.2. CHRONIC EXPOSURE — Pertinent data regarding the Inhalation
toxldty of 4-methylphenol were not located In the available literature
cited In Appendix A.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURE ~ The subchronH oral toxlclty
of 4-methylphenol 1s discussed In Section 6.1.2.1. Results from both D1etz
and Mulligan (1988) and U.S. EPA (1987a) Indicate that the NOAEL for
decreased body weights, hepatic and kidney effects and CNS Impairment 1n
rats Is 50 mg/kg/day (Recs. #7, 10) for a 90-day exposure to 4-methylphenol.
The LOAEL In each study was 175 mg/kg/day (Recs. 18, 11). Clinical signs of
CNS stimulation were observed at the 50 mg/kg/day level (Rec. #7) 1n the
U.S. EPA (1987a) study; however, these effects were observed principally In
the first hour after dosing during the first week of exposure, suggesting
that they occurred 1n response to the rapid bolus administration of the test
chemical and that some degree of tolerance may have developed.
This also suggests that the 50 mg/kg/day dose Is near the threshold for
adverse CNS effects In rats.
Recent development toxlclty gavage studies Identify the rabbit as more
sensitive than the rat to the maternal toxlclty of 4-methylphenol. A range-
finding study using groups of eight rabbits reported gasping and labored
respiration 1n "a few rabbits" treated with 50 mg/kg/day (Rec. #3); maternal
mortality occurred 1n rabbits treated with 150 (Rec. #3), 300 and 500
mg/kg/day (2/8, 4/8 and 7/8, respectively) (CMA, 1987). In the final study,
0219d -44- 03/15/91
-------
groups of 14 rabbits were treated with 5, 50 or 100 mg/kg/day during 13 days
of gestation (CHA, 1988a). There were no signs of maternal toxlclty In
rabbits treated with 5 mg/kg/day (Rec. #1), which 1s a NOEL 1n this study.
Respiratory distress, cyanosis, ocular discharge and hypoactlvlty were
observed In rabbits treated with 50 (Rec. #2) or 100 mg/kg/day. In
addition, deaths of two dams treated with 50 mg/kg/day and five dams treated
with 100 mg/kg/day were attributed to 4-methylphenol. The 50 mg/kg/day
dose, therefore, 1s a PEL (Rec. #2) associated with maternal mortality.
U.S. EPA (1978b) derived a chronic oral RfD from the NOAEL of 50 mg/kg/
day (Rec. #7, 10) 1n the two subchronlc studies 1n rats described above.
The Identification of 50 mg/kg/day as a FEL (Rec. #2) associated with
maternal mortality In rabbits 1n a more recent study (CMA, 1988a), however,
compels a reevaluatlon of the data.
The most defensible basis for a subchronlc oral RfD for 4-methylphenol
Is the NOEL of 5 mg/kg/day (Rec. #1) In the developmental toxlclty study In
rabbits (CHA, 1988a). Although the developmental toxlclty study was not of
sufficient duration to be considered subchronlc, the rabbit NOEL of 5
mg/kg/day 1s less than the NOAEL of 50 mg/kg/day (Rec. #7, 10) 1n the two
rat subchronlc studies. Furthermore, the rat data (U.S. EPA, 1987a) suggest
that tolerance may develop with continued exposure. The application of an
uncertainty factor of 100 (10 for Interspedes sensitivity and 10 for
Intraspecles sensitivity) to the NOEL of 5 mg/kg/day (Rec. #1) results 1n a
subchronlc oral RfD of 0.05 mg/kg/day. Confidence 1n the key study 1s high,
because an appropriate protocol applied to a suitable animal model Identi-
fied a NOEL and FEL for maternal toxlclty. Confidence 1n the data base Is
low; the subchronlc toxlclty of 4-methylphenol In rabbits, the more
sensitive species, has not been adequately Investigated. Confidence 1n the
subchronlc oral RfD 1s medium.
0219d -45- 03/15/91
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8.2.2.2. CHRONIC EXPOSURE — Chronic oral exposure data were not
located In the available literature cited In Appendix A. A chronic oral
RfD, however, can be derived from the data chosen as the basis of the
subchronlc RfO. As discussed In Section 8.2.2.1., the most defensible basis
for the subchronlc oral RfD 1s the NOEL of 5 mg/kg/day (Rec. #1) for
maternal toxlclty 1n rabbits. Application of an uncertainty factor of 1000
(10 for Interspedes variability, 10 for Intraspedes variability and 10 to
extrapolate from subchronlc to chronic exposure) results 1n a chronic oral
RfD of 0.005 mg/kg/day. Confidence In the key study 1s high, confidence In
the data base 1s low, and confidence In the RfD Is medium.
0219d
-46-
03/15/91
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
A previous RQ of 100 was derived for cresols based on an Inhalation
study by Uzhdav1n1 et al. (1972) with rats exposed to ortho-cresol (U.S.
EPA, 1983a, 1985).
Data pertaining specifically to 4-methylphenol Inhalation exposure are
not available. The most severe effects occurring at each dosage In the
subchronlc oral exposure studies are summarized 1n Table 9-1. These studies
are described more fully 1n Section 6.1.2. Mortality occurring within the
first 3 days In female rats at 600 mg/kg/day 1n the D1etz and Mulligan
(1988) study was not Included 1n Table 9-1 because 1t was an acute effect.
For this reason, maternal mortality In rabbits 1n the developmental toxlclty
study by CMA (1988a) Is not Included In Table 9-1. The forellmb and
pectoral girdle malformations reported 1n rabbits at 300 mg/kg/day (CMA,
1987) were not Included In Table 9-1 because of maternal mortality at that
dosage. Oral exposure 1n rats resulted In mortality and CNS Impairment
(D1etz and Mulligan, 1988; U.S. EPA, 1987a). M1ld anemia, organ weight
changes (D1etz and Mulligan, 1988) and labored respiration (U.S. EPA, 1987a)
were also observed. The CSs and corresponding RQs for these effects are
summarized 1n Table 9-2. All of the resulting RQs were 1000. The labored
respiration observed In male and female rats at 175 mg/kg/day (U.S. EPA,
1987a) resulted 1n the highest CS, which Is selected as most stringently
representative of the chronic (noncancer) toxlclty of 4-methylphenol
(Table 9-3).
0219d
-47-
03/15/91
-------
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TABLE 9-3
4-METHYLPHENOL
(CAS No. 106-44-5)
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Species/sex: rats/male and female
Dose*: 209.47 mg/day
Duration: 13 weeks
Effect: labored breathing
RVd: 2.0
RVe: B
CS: 16.2
RQ: 1000
Reference: U.S. EPA. 1987a
^Equivalent human dose
0219d -50- 03/13/91
-------
9.2. BASED ON CARCINOGENICITY
Pertinent data regarding the carclnogenldty 1n humans or animals of
4-methylphenol were not located In the available literature and the compound
was assigned to EPA Group D: not classifiable as to carclnogenldty to
humans. Hazard ranking 1s not performed for EPA Group D compounds; there-
fore an RQ based on carclnogenldty cannot be assigned to 4-methylphenol.
0219d
-51-
03/15/91
-------
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for 17 drinking water, 16 advanced waste treatment and 3 process blank
concentrates. Prepared by Battelle Columbus Laboratories, Columbus, OH for
Health Effects Research Laboratory, Office of Research and Development, U.S.
EPA, Research Triangle Park, NC. EPA-600/l~84-020a. NTIS PB85-128221.
p. 321.
Lund, F.A. and O.S. Rodriguez. 1984. Acclimation of activated sludge to
mono-substituted derivatives of phenol and benzole acids. J. Gen. Appl.
Mlcroblol. 30: 53-61.
Mackay, D., S. Paterson, B. Cheung and W.B. Neely. 1985. Evaluating the
environmental behavior of chemicals with a Level III fugadty model.
Chemosphere. 14(3-4): 335-374.
Mantel, N. and M.A. Schnelderman. 1975. Estimating "safe" levels, a
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Marcus, C. and P. L1chtenste1n. 1979. Biologically active components of
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Food Chem. 27(6): 1217-1223.
0219d
-65-
03/15/91
-------
Hattson, V.R., J.W. Arthur and C.T. Walbrldge. 1976. Acute toxldty of
selected organic compounds to fathead minnows. U.S. EPA, Office of Research
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McCreary, J.J., J.G. Jackson and J. Zoltek. 1983. Toxic chemicals In an
abandoned phenolic waste site. Chemosphere. 12: 1619-1632.
McKnlght, P.M., W.E. Perelra, M.L. Ceazan and R.C. Wlssmar. 1982. Charac-
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U.S. EPA, Athens, GA.
Mlzutanl, T., I Ishlda, K. Yamamoto and K. Taj 1ma. 1982. Pulmonary
toxldty of butylated hydroxytoluene and related alkylphenols: Structural
requirements for toxic potency 1n mice. Toxlcol. Appl. Pharmacol. 62:
273-280.
Neuberg, C. and E. Kretschmer. 1911. Ober p-Kreso1glucuronsa*ure.
Blochemlsche. ZeHschrlft Band. 36: 15-21. (Ger.)
NIOSH (National Institute for Occupational Safety and Health). 1978.
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DHEW, PHS, COC, Cincinnati, OH. Publ. No. 78-133.
0219d
-66-
03/15/91
-------
NIOSH (National Institute for Occupational Safety and Health). 1984.
National Occupational Exposure Survey (NOES).
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0219d -67- 03/15/91
-------
Rogers, 3.E., S.W. l\ and L,J. Felice. 1984. Microbiological transforma-
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Sawhney, B.L. and R.P. Kozloskl. 1984. Organic pollutants In leachates
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0219d
-68-
03/15/91
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Schafer, E.W., Jr., H.A. Bowles, Jr. and J. Hurlbut. 1983. The acute oral
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0219d -69- 03/15/91
-------
Spain, J.C. and P.A. Van Veld. 1983. Adaptation of natural mlcroblal com-
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Stuermer, O.H., O.J. Ng and C.J. Morris. 1982. Organic contaminants 1n
groundwater near an underground coal gasification site In northeastern
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0219d
-70-
03/15/91
-------
U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
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Office of Health and Environmental Assessment, Environmental Criteria and
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Response, Washington, DC.
U.S. EPA. 1984. Methodology and Guidelines for Ranking Chemicals 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 Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1985. Health and Environmental Effects Profile for Cresols.
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. Methodology for Evaluating Reportable Quantity Adjust-
ments Pursuant to CERCLA Section 102. Prepared by Carcinogen Assessment
Group, Office of Health and Environmental Assessment for the Office of
Emergency and Remedial Response, Washington, DC.
0219d -71- 03/15/91
-------
U.S. EPA. 1986t>. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1987a. Subchronlc neurotoxlclty study In rats of o- , m- and
p-Cresol. Office of Solid Waste, Washington, DC.
U.S. EPA. 19875. Integrated Risk Information System (IRIS): Reference dose
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and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OK.
U.S. EPA. 1988. Standards for owners and operators of hazardous waste
treatment, storage and disposal facilities. 40 CFR 264. App. IX. Ground
Water Monitoring List. p. 598.
f
U.S. EPA/OWRS. 1986. Guidelines for Deriving Numerical National Water
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Chemicals. United States Production and Sales, 1987. Publ. No. 2118.
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Inhalation toxlclty of o-cresol. Tr. Uf1m. Nauchno-Issled Inst. Gig.
Profzabol. 7: 115-119. (Cited In U.S. EPA, 1983, 1985)
0219d
-72-
03/15/91
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Van Veld, P.A. and J.C. Spain. 1983. Degradation of selected xenoblotlc
compounds 1n three types of aquatic test systems. Chemosphere. 12:
1291-1305.
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toxlclty and skin corrosion data for some organic and Inorganic compounds
and aqueous solutions. ToxHol. Appl. Pharmacol. 42: 417-423.
Wandel, 0. 1907. Zur pathologle der lysol-und kresolver-glftung. Arch.
Exp. Pathol. Pharmakol. 56: 161. (Ger.)
Weast, R.C.. M.J. Astle and W.H. Beyer. 1968. CRC Handbook of Chemistry
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Williams, R.T. 1938. Studies 1n detoxlcatlon. I. The Influence of (a)
dose and (b) o-, m- and p-substHutlon on the sulfate detoxlcatlon of phenol
In the rabbit. Blochem. J. 32: 878-887.
Wlndholz, M., S. Budavarl, R.F. Blumettl and E.S. Otterbeln. 1983. The
Merck Index. Merck and Co., Inc., Rahway, NY.
Yalkowsky, S.H., S.C. Valvanl, W.Y. Kuu and R. Dannenfelser. 1987. Arizona
database of aqueous solubility.
Yasuhara, A. 1987. Identification of volatile compounds 1n poultry manure
by gas chromatography mass spectrometry. J. Chromatogr. 387: 371-378.
0219d -73- 03/15/91
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Yasuhara, A., H. Sh1ra1sh1, H. Tsujl and T. Okuno. 1981. Analysis of
organic substances 1n highly polluted river water by mass spectrometry.
Environ. Sc1. Technol. 15: 570-573.
Yehuda, S., R.L. Carasso and O.I. Mostofsky. 1977. The effects of
d-amphetamlne and temperature on p-cresol and pentylenetetrazol Induced
convulsion. Int. J. Neurosd. 7: 223-226.
Yoshloka, Y., Y. Ose and T. Sato. 1985. Testing for the toxldty of chemi-
cals with Tetrahymena pyrlformls. Scl. Total Environ. 43(1-2): 149-157.
Young, L.Y. and M.D. Rivera. 1985. Nethanogenlc degradation of four
phenolic compounds. Hater Res. 19: 1325-1332.
0219 d
-74-
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
CHEHLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
SCISEARCK
Federal Research In Progress
These searches were conducted 1n May, 1988, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1987. TLVs: Threshold Limit Values for Chemical Substances 1n the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. 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. 2B. John Wiley and
Sons, NY. p. 2879-3816.
0219d -75- 03/15/91
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Clayton, G.O. 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.
Grayson, M. and D. Eckroth, Ed. 1978-1984. K1rk-0thmer 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., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. Lieu, 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.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). 1987. 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). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1966. 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.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.8. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
0219d
-76-
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In addition, approximately 30 compendia of aquatic toxklty 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
Toxlclty 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, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0219d -77- 03/15/91
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0219d
-78-
03/15/91
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APPENDIX C
DOSE/DURATION RESPONSE GRAPHS FOR EXPOSURE TO 4-METHYLPHENOL
C.I. DISCUSSION
Dose/duration-response graphs for oral exposure to 4-methylphenol
generated by the method of Crockett et al. (1985) using the computer soft-
ware by Durkln and Meylan (1989) developed under contract to ECAO-C1nc1nnat1
are presented In Figures C-1 and C-2. Data used to generate these graphs
are presented In Section C.2. In the generation of these figures, all
responses are classified as adverse (PEL, AEL or LOAEL) or nonadverse (NOEL
or NOAEL) for plotting. For oral exposure, the ordlnate expresses dose as
human equivalent dose. The animal dose In mg/kg/day 1s multiplied by the
cube root of the ratio of the animal:human body weight to adjust for species
differences In basal metabolic rate (Mantel and Schnelderman, 1975). The
result 1s then multiplied by 70 kg, the reference human body weight, to
express the human equivalent dose as mg/day for a 70 kg human.
The boundary for adverse effects (solid line) 1s drawn by Identifying
the lowest adverse effect dose or concentration at the shortest duration of
exposure at which an adverse effect occurred. From this point, an Infinite
line 1s extended upward, parallel to the dose axis. The starting point Is
then connected to the lowest adverse effect dose or concentration at the
next longer duration of exposure that has an adverse effect dose or concen-
tration equal to or lower than the previous one. This process Is continued
to the lowest adverse effect dose or concentration. From this point, a line
1s extended to the right, parallel to the duration axis. The region of
adverse effects lies above the adverse effects boundary.
0219d -79- 03/15/91
-------
T
/
0
fi
a
9
•v
9
X
10000 -r
1000 -r
100
0.0001
rn
LIB
Hi
4-
0.001 0.01 0.1
HUMAN EQUIU DURATION (fraction lifespan)
METHOC
KEY:
F - PEL
L » LOAEL
n - NOAEL
Solid Line » Adverse Effects Boundary
Dotted Line - No Adverse Effects Boundary
FIGURE C-1
Dose/Duration-Response Graph for Oral Exposure to 4-Methy1phenol,
Envelope Method
0219d
-80-
03/15/91
-------
100000 p
fr
73
-=- ioooo-t-
UJ
d
o
o
LLJ
1000--
100-
0.0001
4 methylphenol
F14
J I
I I I I
I I
N1
L6
N5
F92
L81
i i 1
0.001 0.01 0.1
HUMAN EQUIVALENT DURATION (fraction lifespan)
CENSORED MTfl fOHOD - (Oral Exposure)
KEY: F - FEL
L - LOAEL
N - NOEL
n * NOAEL
Solid Line « Adverse Effects Boundary
Dotted Line - No Adverse Effects Boundary
FIGURE C-2
Dose/Duration-Response Graph for Oral Exposure to 4-Methy!phenol,
Censored Data Method
02194
-81-
03/15/91
-------
Using the envelope method, the boundary for no adverse effects (dashed
line) 1s drawn by Identifying the highest no adverse effects dose or concen-
tration. From this point, a line parallel to the duration axis Is extended
to the dose or concentration axis. The starting point Is then connected to
the next lower or equal no adverse effect dose or concentration at a longer
duration of exposure. When this process can no longer be continued, a line
Is dropped parallel to the dose or concentration axis to the duration axis.
The no adverse effects region lies below the no adverse effects boundary.
At either ends of the graph between the adverse effects and no adverse
effects boundaries are regions of ambiguity. The area (If any} resulting
from Intersection of the adverse effects and no adverse effects boundaries
Is defined as the region of contradiction.
In the censored data method, all no adverse effect points located In the
region of contradiction are dropped from consideration and the no adverse
effect boundary Is redrawn so that 1t does not Intersect the adverse effects
boundary and no region of contradiction Is generated. This method results
In the most conservative definition of the no adverse effects region.
In Figures C-l and C-2, the adverse effects boundary 1s defined by a
dose associated with mortality In rabbits (Rec. #13), an L0cn 1n mice
t»u
(Rec. #16) and, 1t Us lowest Inflection, a dose of 50 mg/kg/day In develop-
mental studies 1n rabbits (Recs. #2 and 4), which was a LOAEL In one study
(CMA, 1987} and a PEL 1n the other (CMA, 1988a). These points are super-
Imposed and difficult to read. In Figure C-l, the no adverse effects
boundary Is defined by a NOEL for maternal and developmental effects In rats
(Rec. #5) and a NOAEL of 50 mg/kg/day 1n two, 13-week studies 1n rats (Recs.
#7 and 10, superimposed and difficult to read). Record #1, the NOEL of 5
mg/kg/day 1n the developmental study 1n rabbits chosen as the basis of the
0219d
-82-
03/15/91
-------
RfD (CMA, 1988a) 1s well below the adverse effects boundary, which
strengthens confidence 1n the choice of these data as the basis for the RfD.
In Figure C-2, generated by the censored data method, the no adverse
effects boundary Is defined only by the NOEL of 50 mg/kg/day 1n the two,
13-week studies 1n rats (Recs. #7 and 10, superimposed).
C.2. DATA USED TO GENERATE DOSE/DURATION-RESPONSE GRAPHS
C.2.1. Oral Exposure.
Chemical Name: 4-methylphenol
CAS Number: 06-44-5
Document Title: Health and Environmental Effects Document on 4-Methylphenol
Document Number: pending
Document Date: pending
Document Type: HEED
RECORD #1:
Species
Sex:
Effect:
Route:
Number
Number
: Rabbits
F ema 1 e
NOEL
Gavage
Exposed:
Responses:
Body weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
14
0
3.825 kg
5 mg/kg/day
5 mg/kg/day
13 days
24 days
Type of Effect:
SHe of Effect:
Severity Effect: 4
Comment: Doses of 5, 50 or 100 mg/kg/day were given on days 6-18 of
gestation In a developmental toxlclty study (see next record).
Citation: CMA, 1988a
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RECORD #2:
Comment:
Citation:
Comment:
Citation:
Comment:
Citation:
Species;
Sex:
Effect:
Route:
Rabbits
Female
PEL
Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Body Weight
Reported Dose:
Converted Dose:
Exposure Period;
Duration Observation:
14
2
DEATH
BODY
10
3.825 kg
50 mg/kg/day
50 mg/kg/day
13 days
24 days
See previous record; distressed respiration, cyanosis, ocular
dlschage, hypoactlvlty were also observed at this dose.
Mortality claimed 5/14 at 100 mg/gk/day.
CMA, 1988a
RECORD #3:
Species:
Sex:
Effect:
Route:
Rabbits
Female
FEL
Gavage
Body Weight
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
3.8 kg
150 mg/kg/day
150 mg/kg/day
13 days
24 days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
8
2
DEATH
BODY
10
Doses used were 50, 150, 300 and 500 mg/kg/day; dose-related
maternal mortality occurred. Forellmb and pectoral girdle
malformations were observed at 300 mg/kg/day.
CHA, 1987
RECORD #4:
Species:
Sex:
Effect:
Route:
Rabbits
Female
LOAEL
Gavage
Body Weight
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
3.8 kg
50 mg/kg/day
50 mg/kg/day
13 days
24 days
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
8
NR
FUND
LUNG
8
See previous record for other doses.
respiration were observed at all doses,
CHA, 1987
Gasping and labored
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RECORD #5:
Comment:
Citation:
Comment:
Species:
Sex:
Effect:
Route:
Rats
Female
NOEL
Gavage
Body Weight
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
25
0
0.29 kg
175 mg/kg/day
175 mg/kg/day
10 days
16 days
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
Doses of 30, 175 and 450 mg/kg/day were given on days 6-15 of
gestation (see next record).
CMA, 1988b
RECORD #6:
Comment:
Citation:
RECORD #7:
Species: Rats
Sex: Female
Effect: LOAEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
See previous record.
CMA. 1988b
Species: Rats
Sex: Both
Effect: NOAEL
Route: Gavage
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
25 25
NR NR
FUND WGTDC
CNS FETUS
8 8
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
20
NR
FUNS
CNS
7
0.29 kg
450 mg/kg/day
450 mg/kg/day
10 days
16 days
0.35 kg
50 mg/kg/day
13 weeks
13 weeks
Citation:
Doses administered were 50, 175 or 600 mg/kg/day. Some CNS
signs were observed for 1 hour after dosing during first week
of study, probably as result of bolus administration of the
compound, (see next record).
U.S. EPA, 1987a
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RECORD #8:
Comment:
Citation:
Comment:
Citation:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Gavage
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
20
NR
FUNDH
LUNG
8
0.35 kg
175 mg/kg/day
13 weeks
13 weeks
Labored respiration, tremors, hypoactWHy, rapid respiration,
myoclonus and low body posture were observed In both sexes at
this level (see previous record for further protocol).
U.S. EPA, 1987a
RECORD #9:
Species:
Sex:
Effect:
Route:
Rats
Both
PEL
Gavage
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
0.35 kg
600 mg/kg/day
13 weeks
13 weeks
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
20
8
DEATH
BODY
10
Nyotonus, labored respiration and decreased locomotor
activity were also observed (see previous records for further
protocol).
U.S. EPA, 1987a
RECORD #10:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Gavage
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period
Duration Observation:
0.35 kg
50 mg/kg/day
13 weeks
13 weeks
Number Exposed: 60
Number Responses: 0
Type of Effect:
SHe of Effect:
Severity Effect: 2
Doses administered were 50, 175 and 600 mg/kg/day (see next
record)
D1etz and Mulligan, 1988
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03/15/91
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RECORD
Comment:
Citation:
Comment:
Citation:
Species:
Sex:
Effect:
Route:
Rats
Both
LOAEL
Gavage
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
Body Weight
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
30
NR
WGTDC
BODY
4
0.35 kg
175 mg/kg/day
13 weeks
13 weeks
Females had anemia, males had Increased relative weight of
liver and kidneys (and other organs at higher doses);
Increased total serum protein. Also see previous record.
D1etz and Mulligan, 1988
RECORD #12:
Species:
Sex:
Effect:
Route:
Rats
Both
PEL
Gavage
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
0.35 kg
600 mg/kg/day
13 weeks
13 weeks
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
30
3
DEATH
BODY
10
30
NR
WGTDC
BODY
4
Comment :
Citation:
RECORD #13:
See previous records; other effects Included liver and kidney
lesions, organ weight changes, tracheal epithelial metaplasia.
D1etz and
Species:
Sex:
Effect:
Route:
Mulligan, 1988
Rabbits
NR
PEL
Oral (NOS)
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation:
3.8 kg
620 mg/kg/day
1 day
1 day
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
1
1
DEATH
BODY
10
Doses administered were 180, 280, 420,
2100 mg/kg as a 20% emulsion In water.
Dlechmann and WHherup, 1944
620, 940, 1400 and
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RECORD #14:
Comment:
Citation:
RECORD #15:
Comment:
Citation:
RECORD |16:
Comment :
Citation:
Species: Rats
Sex: NR
Effect: PEL
Route: Oral (NOS)
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
1800 mg/kg was the LOso
Dlechmann and Wltherup,
Species: Rats
Sex: NR
Effect: PEL
Route: Oral (NOS)
Number Exposed:
Number Responses:
Type of Effect:
Site of Effect:
Severity Effect:
The LDgQ was 207 mg/kg;
Sax, 1984
Species: Rats
Sex: NR
Effect: PEL
Route: Oral (NOS)
Number Exposed:
Number Responses:
Type of Effect:
SHe of Effect:
Severity Effect:
The LDso was 344 mg/kg;
Sax, 1984
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation
10
5
DEATH
BODY
10
0.35 kg
1800 mg/kg/day
1 day
: 1 day
; other doses not specified
1944; Sax, 1984
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation
NR
NR
DEATH
BODY
10
other doses not sped
Body Weight:
Reported Dose:
Converted Dose:
Exposure Period:
Duration Observation
NR
NR
DEATH
BODY
10
0.35 kg
207 mg/kg/day
1 day
: 1 day
fled
0.03 kg
344 mg/kg/day
1 day
: 1 day
other doses not specified
NR = Not reported
0219d
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