September 1992
DATA DEFICIENCIES, PROBLEM AREAS, AND
RECOMMENDATIONS FOR ADDITIONAL
DATABASE DEVELOPMENT FOR
p-CHLOROPHENYL METHYL SULFIDE,
-SULFOXIDE, AND -SULFONE (PCPMS,
PCPMSO, AND PCPMS02)
AUTHORS
Margaret E. Brower, Ph.D.
Mary B. Deardorff, Ph.D.
Welford C. Roberts, Ph.D.
PROJECT OFFICER
Krishan Khanna, Ph.D.
Office of Water
Health and Ecological Criteria Division
Office of Science and Technology
U.S. Environmental Protection Agency
Washington, DC 20460
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September 1992
DATA DEFICIENCIES, PROBLEM AREAS, AND
RECOMMENDATIONS FOR ADDITIONAL
DATABASE DEVELOPMENT FOR
p-CHLOROPHENYL METHYL SULFIDE,
-SULFOXIDE, AND -SULFONE (PCPMS,
PCPMSO, AND PCPMSO,)
AUTHORS
Margaret E. Brow»r, Ph.D.
Mary B. Deardorff, Ph.D.
Welford C. Roberts, Ph.D.
PROJECT OFFICER
Krishan Khanna, Ph.D.
Office of Water
Health and Ecological Criteria Division
Office of Science and Technology
U.S. Environmental Protection Agency
Washington, DC 20460
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PREFACE
This report was prepared in accordance with the Memorandum of Understanding between the
Department of the Army, Deputy for Environmental Safety and Occupational Health (OASA
(IL&E)), and the U.S. Environmental Protection Agency (EPA), Office of Water (OW), Office of
Science and Technology (OST) for the purpose of developing drinking water Health Advisories
(HAs) for selected environmental contaminants, as requested by the Army.
Health Advisories provide specific advice on the levels of contaminants in drinking water at
which adverse health effects would not be anticipated and which include a margin of safety so as to
protect the most sensitive members of the population at risk. These advisories normally are prepared
for One-day, Ten-day, Longer-term, and Lifetime exposure periods where available toxicological data
permit.
This report is the product of the foregoing process. Available toxicological data, including that
provided by the Army, on the chemical analogs p-chlorophenyl methyl sulfide, -sulfoxide, and
-sulfone (PCPMS, PCPMSO, and PCPMSOj) have been reviewed, and relevant findings are pre-
sented in a manner that allows for an evaluation of the data without continued reference to the
primary documents.
The available data are not sufficient to develop a HA; therefore, this report identifies deficiencies
and recommends research that will enhance and optimize the database. When the recommended
research has been conducted, it is expected that the data will allow the development of a drinking
water HA for PCPMS, PCPMSO, and PCPMS02.
I would like to thank the authors. Dr. Margaret E. Brower, Dr. Mary B. Deardorff, and Dr.
Welfoid C. Roberts, who provided the extensive technical skills required for the preparation of this
report. I am grateful to the members of the EPA Tox-Review Panel who took time to review this
report and to provide their invaluable input, and I would like to thank Dr. Edward Ohanian, Chief,
Human Risk Assessment Branch, and Ms. Margaret J. Stasikowski, Director, Health and Ecological
Criteria Division for providing me with the opportunity and encouragement to be a part of this
project.
The preparation of this Health Advisory was funded in part by Interagency Agreement (LAG)
between the U.S. EPA and the U.S. Army Medical Research and Development Command
(USAMRDC). This IAG was conducted with the technical support of the U.S. Army Biomedical
Research and Development Laboratory (USABRDL), Dr. Howard T. Bausum, Project Manager.
Krishan Khanna, Ph.D.
Project Officer
Office of Water
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
CONTENTS
Page
EXECUTIVE SUMMARY vi
I. OBJECTIVE I"1
n. BACKGROUND H'1
m. DISCUSSION m"1
IV. CONCLUSIONS AND RECOMMENDATIONS IV-1
V. REFERENCES
APPENDIX A: Review of Health Effects and Other Data: p-Chlorophenyl Methyl Sulfide,
-Sulfoxide, and -Sulfone (PCPMS, PCPMSO, and PCPMSOj)
I. GENERAL INFORMATION A-1
H. SOURCES OF EXPOSURE A-4
m. ENVIRONMENTAL FATE A-5
A. PHOTOLYSIS A-5
B. LEACHING A-5
C. HYDROLYSIS A-5
D. PLANT UPTAKE AND DEGRADATION A-5
E. VAPORIZATION A-7
IV. TOXICOKINETICS A-8
A. ABSORPTION A-8
1. PCPMS A-8
2. PCPMSO A-9
3. PCPMS02 A-9
4. Comparison between PCPMS, PCPMSO, and PCPMS02 A-9
B. DISTRIBUTION A-9
1. PCPMS A-10
2. PCPMSO A-10
3. PCPMS02 A-10
4. Comparison between PCPMS, PCPMSO, and PCPMS02 A-10
C. METABOLISM A-ll
1. PCPMS A-ll
2. PCPMSO A-12
3. PCPMS02 A-12
4. Comparison between PCPMS, PCPMSO, and PCPMS02 A-13
5. Metabolism of Chlorothiophenol A-13
iii
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
D. EXCRETION A-14
1. PCPMS A-14
2. PCPMSO A-14
3. PCPMS02 A-15
4. Comparison between PCPMS, PCPMSO, and PCPMS02 A-16
V. HEALTH EFFECTS A-17
A. HUMANS A-17
B. ANIMAL EXPERIMENTS A-17
1. Short-term Exposure A-17
a. Acute A-17
(1) PCPMS A-17
(2) PCPMSO A-19
(3) PCPMS02 A-20
(4) Comparison between PCPMS, PCPMSO, and PCPMS02 A-21
b. Primary Irritation, Dermal Sensitization, and Ophthalmologic Effects .... A-21
c. Subacute A-22
(1) PCPMS A-23
(2) PCPMSO A-25
(3) PCPMS02 A-28
(4) Comparison between PCPMS, PCPMSO, and PCPMS02 A-30
2. Longer-term Exposure A-32
(1) PCPMS A-32
(2) PCPMSO A-39
(3) PCPMS02 A-41
(4) Comparison between PCPMS, PCPMSO, and PCPMS02 A-43
3. Reproductive Effects A-45
(1) PCPMS A-45
(2) PCPMSO A-45
(3) PCPMSO, A-45
(4) Comparison between PCPMS, PCPMSO, and PCPMS02 A-45
4. Developmental Toxicity A-46
(1) PCPMS A-46
(2) PCPMSO A-46
(3) PCPMSOz A-46
(4) Comparison between PCPMS, PCPMSO, and PCPMS02 A-46
5. Carcinogenicity A-46
(1) PCPMS A-46
(2) PCPMSO A-46
(3) PCPMS02 A-46
(4) Comparison between PCPMS, PCPMSO, and PCPMS02 A-47
6. Genotoxicity A-47
(1) PCPMS A-47
(2) PCPMSO A-49
(3) PCPMS02 A-49
(4) Comparison between PCPMS, PCPMSO, and PCPMS02 A-49
C. CARCINOGENIC POTENTIAL A-50
VI. OTHER CRITERIA, GUIDANCE, AND STANDARDS A-51
iv
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
VH. ANALYTICAL METHODS A"52
Vm. TREATMENT TECHNOLOGIES A"53
IX. REFERENCES A"54
TABLES for APPENDIX A
Page
1-1. Chemical and Physical Properties of p-Chlorophenyl Methyl Sulfide, -Sulfoxide, -Sulfone
(PCPMS, PCPMSO, and PCPMSO,) A"2
1-2. Manufacturers of p-Chlorophenyl Methyl Sulfide, -Sulfoxide, -Sulfone A-3
V-l. Acute Oral LD50 Values for p-Chlorophenyl Methyl Sulfide, -Sulfoxide, -Sulfone
(PCPMS, PCPMSO, and PCPMSOz) A"18
V-2. Incidence of Compound-Related Hepatic Lesions in Male Rats Fed p-Chlorophenyl
Methyl Sulfide, -Sulfoxide, -Sulfone (PCPMS, PCPMSO, and PCPMSO^ A-34
V-3. Incidence of Compound-Related Hepatic Lesions in Female Rats Fed p-Chlorophenyl
Methyl Sulfide, -Sulfoxide, -Sulfone (PCPMS, PCPMSO, and PCPMSO2) A-35
V-4. Incidence of Hepatic Lesions in Rats Fed 3,000 ppm p-Chlorophenyl Methyl Sulfide,
-Sulfoxide, -Sulfone (PCPMS, PCPMSO, and PCPMSOj) Following a 14-Day Recovery
Period A*35
V-5. Cumulative Mortality at Selected Intervals for Mice Fed p-Chlorophenyl Methyl Sulfide,
-Sulfoxide, -Sulfone (PCPMS, PCPMSO, and PCPMSOj) for 13 weeks A-37
V-6. Incidence of Hepatic and Pulmonary Lesions in Mice Fed p-Chlorophenyl Methyl
Sulfide, -Sulfoxide, -Sulfone (PCPMS, PCPMSO, and PCPMSO^ for 13 weeks A-38
V-7. Ames Bacterial Mutagenicity Assays of p-Chlorophenyl Methyl Sulfide, -Sulfoxide,
-Sulfone (PCPMS, PCPMSO, and PCPMSOj) A_48
v
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
EXECUTIVE SUMMARY
p-Chlorophenyl methyl sulfide (PCPMS) is described as a colorless liquid; p-chlorophenyl
methyl sulfoxide (PCPMSO) is described as a waxlike solid; and p-chlorophenyl methyl sulfone
(PCPMSOz) is described as a white crystalline solid. The three compounds are intermediates in the
manufacture of the herbicide Planavin.®
p-Chlorophenyl methyl sulfide, PCPMSO, and PCPMS02 are readily and almost completely
absorbed when administered orally to rats or monkeys. Elimination is primarily in the urine. Clear-
ance from blood in rats follows first-order kinetics with an initial half-life of about 12 hours for all
three analogs. However, in monkeys, clearance from blood follows zero-order kinetics with a
constant half-life of about 7 days, indicating that renal clearance in monkeys is saturable. In rats,
urinary excretion of a single dose is rapid, up to 65% of a 2.5 mg/kg dose by 24 hours and 95% by
48 hours. In monkeys, urinary excretion is slow, and measurable quantities of about a 6 mg/kg dose
are retained in the body for up to 14 days in males and 28 days in females. Less than 5% of an
orally administered dose is eliminated in the feces of rats or monkeys for all three compounds.
Kinetics of repeated dosing have not been studied, nor has tissue distribution been examined.
p-Chlorophenyl methyl sulfide is converted to PCPMSO and then to PCPMS02 in rats and
monkeys. A large part of the urinary metabolites are conjugated to water-soluble compounds.
Conjugation of metabolites is slower in monkeys than in rats. The PCPMS02 is poorly conjugated
in monkeys. Metabolism probably proceeds by sulfoxidation, hydroxylation of a ring carbon, and
conjugation to form glucuronic acid or sulfate. Toxicity in monkeys may correlate with the slower
excretion time compared with rats. Hexobarbital "sleep-time" experiments with male rats indicate
that all three compounds induce microsomal enzymes.
The health effects of PCPMS, PCPMSO, and PCPMS 02 have not been studied in humans.
Acute oral toxicity studies indicate that PCPMS and PCPMSO are equally toxic to rats, and
PCPMSOj is slightly more toxic than the other compounds. Male rats are more resistant than
females to the adverse effects as evidenced by their higher LD^ values. In mice, PCPMS02 is
moderately less toxic than PCPMSO to males and females and moderately more toxic than PCPMS
to males. The PCPMSO is significantly more toxic than either PCPMS02 or PCPMS to male and
female mice. The oral LDjo values range from 400 to 619 mg/kg in rats and from 328 to 877 mg/kg
vi
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
in mice. At doses of 5,630 mg/kg PCPMS applied in a single 24-hour dermal exposure, rats
exhibited decreases in motor activity, prostration, lack of coordination, coma, and death.
Twenty-eight-day range-finding studies, conducted in mice (feeding study) and rats (gavage and
feeding studies) to determine dosage levels for subchronic 91-day studies, showed that these
compounds increase mortality and depress motor activity. Approximately five animals/sex/dose were
used in each study. In the gavage study in rats, mortality occurred in 60% of the animals dosed with
50 mg/kg PCPMS02 and in 100% of the animals dosed at levels greater than 50 mg/kg. No animals
survived at doses of 220 mg/kg PCPMS and above, or at 400 mg/kg PCPMSO. Rats treated with
more than 50 mg/kg of each of the three compounds exhibited marked depression of motor activity.
Eleven percent of the mice fed 4,500 ppm PCPMS (corresponding to 675 mg/kg/day), and 22% of
the mice and 70% of the rats fed 5,200 ppm PCPMSO (corresponding to 780 mg/kg/day in mice,
520 mg/kg/day in rats) died during the study. No other deaths occurred. Both body weights and
food consumption appeared depressed as a result of dosing, but data were inadequate to draw
conclusions.
In 13-week feeding studies with all three compounds, mice and rats exhibited hepatotoxicity,
mortality, weight loss, and slight anemia. Sixteen animals/sex/dose plus controls groups of 24
rats/sex or 33 mice/sex were used in these studies. Mortality occurred prior to study termination in
38% of male rats fed 3,000 ppm (corresponding to 246 mg/kg/day) PCPMSO. In mice, mortality
occurred in 100% of males and females fed 6,000 ppm PCPMS or PCPMS02 (corresponding to 840
mg/kg/day in males, 517 mg/kg/day in females for PCPMS; 890 mg/kg/day in males, 680 mg/kg/day
in females for PCPMSO^ or 5,000 ppm PCPMSO (corresponding to 628 mg/kg/day in males, 530
mg/kg/day in females for PCPMSO), 31% of males and 75% of females fed 3,000 ppm PCPMS
(corresponding to 182 mg/kg/day and 180 mg/kg/day in males and females, respectively), and 6% of
males and 44% of females fed 3,000 ppm PCPMSO (corresponding to 224 and 235 mg/kg/day in
males and females, respectively). Body weights, body weight gains, and food consumption of rats
and mice fed the three test compounds at all dose levels were significantly depressed. Erythrocyte
parameters and serum alkaline phosphatase (except low-dose PCPMS females) in all dosed rats were
significantly depressed compared with controls, and serum potassium and calcium levels in rats were
elevated for all compounds. Hematology and clinical chemistry were not evaluated in mice. Liver
weights were increased in all dosed rats and in PCPMS and PCPMSO treated mice at 3,000 ppm
(corresponding to 426 mg/kg/day in male mice, 259 mg/kg/day in female mice for PCPMS; 377 mg/
vii
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
kg/day in male mice, 318 mg/kg/day in female mice for PCPMSO). The most predominant hepatic
lesions included megalocytosis, necrosis, and vacuolar cytoplasmic change in rats and mice. The
highest incidences of hepatic lesions were exhibited in PCPMS treated rats and PCPMS and
PCPMSO treated mice. No renal lesions were found. Based on depressed body weights, hemato-
logic and serum chemistry changes, increased liver weights, and hepatic pathologic changes, the
Lowest-Observed-Adverse-Effect Level (LOAEL) for rats (all three compounds) is 750 ppm (corres-
ponding to 60 mg/kg/day in males and 57 mg/kg/day in females for PCPMS; 61 mg/kg/day in males
and 67 mg/kg/day in females for PCPMSO; and 57 mg/kg/day in males and 54 mg/kg/day in females
for PCPMSOj). Based on hepatic pathology, the LOAEL for mice (all three compounds) is 750 ppm
(corresponding to 108 mg/kg/day in males and 109 mg/kg/day in females for PCPMS; 112 mg/kg/
day in males and 70 mg/kg/day in females for PCPMSO; and 106 mg/kg/day in males and 86 mg/kg/
day in females PCPMSOj). No No-Observed-Adverse-Effect Levels (NOAELs) could be determined
because the lowest dose tested caused adverse effects.
Toxicity was assessed in 68 male and female monkeys administered PCPMS, PCPMSO, or
PCPMS02 via gavage for 14 days. The dose levels were 0, 5,10, 20, 30, 40, or 80 mg/kg/day for
PCPMS; 0, 5, 10, or 20 mg/kg/day for PCPMSO; and 0, 2.5, 5, 10, 15, 20, or 30 mg/kg/day for
PCPMS02. During the treatment period, mortality occurred in 17% of the six monkeys dosed with
20 mg/kg/day PCPMS and 33% of the six animals dosed with the same amount of PCPMS02. Fifty
percent mortality occurred in PCPMS animals dosed at 40 or 80 mg/kg/day (two animals/dose). In
addition, 100% of the two animals dosed with 30 mg/kg/day PCPMSOz were moribund by day 10
and sacrificed. No other deaths occurred during the treatment period. Monkeys treated with PCPMS
or PCPMSOj at all dose levels exhibited anorexia. Weakness and depression also occurred at all
PCPMS dose levels. The PCPMSO treated monkeys did not manifest anorexia and depression below
10 mg/kg/day. Reticulocyte counts were significantly depressed at 10 mg/kg/day or greater
PCPMSO. Blood urea nitrogen was increased over pretreatment levels in animals receiving
PCPMSO at 10 mg/kg/day and in PCPMSOz animals at 20 mg/kg/day or greater. Alkaline
phosphatase and blood glucose levels also were depressed in some animals. Organ weight data were
inconclusive. Pathologic liver lesions, observed in monkeys treated with all three compounds, were
most severe in PCPMSO and PCPMS treated monkeys. Pathologic lesions also occurred in the
lymphoid system of animals treated with all three compounds. Based on the incidence of anorexia,
depression, and weakness at the lowest dose, the LOAEL for PCPMS is 5 mg/kg/day. Based on the
incidence of liver and lymphoid system lesions at the lowest dose, the LOAEL for PCPMSO is
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
5 mg/kg/day. Based on the clinical observation of anorexia at the lowest dose, the LOAEL for
PCPMS02 is 2.5 mg/kg/day.
No reproductive or developmental toxicity studies have been conducted with PCPMS, PCPMSO,
or PCPMSOj.
No conclusions can be reached regarding the potential genotoxicity of the three compounds. The
findings from Salmonella typhimurium gene mutation assays indicated that PCPMS, PCPMSO, and
PCPMS02 were not mutagenic in the absence or presence of S9 metabolic activator of either Aroclor
1254 or phenobarbital-induced rat liver microsomes. However, the individual assays were considered
to be either incomplete (an unstable form of the PCPMS was tested with Aroclor 1254 S9) or
inadequate to conclude a valid negative response (PCPMSO and PCPMS02 were not assayed to an
appropriately high concentration). No other genetic toxicology studies were found in the available
literature.
p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone each are classified as Group D: not
classifiable as to human carcinogenicity.
The health effects data for PCPMS, PCPMSO, and PCPMS02 were reviewed by the U.S. EPA
Reference Dose/Reference Concentration (RfD/RfQ Work Group and were determined to be inade-
quate for the derivation of an oral RfD. Thus, the current verification status of the chemical is
classified as "not verifiable." Apparent liver changes observed in rats treated subchronically with
each analog were potential endpoints for establishing RfDs. However, comparisons between gross,
histologic and clinical chemical parameters were not consistent. Additionally, subacute effects
observed in monkeys treated for 14 days were more severe {e.g., neurotoxicity and lethality) and
developed in a period of time that was much shorter than in rodents. These observations suggest
that primates, including humans, may be more sensitive than rodents to the effects of PCPMS,
PCPMSO, and PCPMS02. Hie 14-day exposure period to monkeys is not a sufficient duration to
derive an RfD, which is protective for lifetime exposure.
ix
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
I. OBJECTIVE
The objective of this document is to provide an evaluation of data deficiencies and problem areas
encountered after a careful review of the literature on p-chlorophenyl methyl sulfide, -sulfoxide,
and -sulfone (PCPMS, PCPMSO, and PCPMSO2) and to make recommendations for additional data-
base development. This document is presented as an independent analysis of the current data related
to PCPMS, PCPMSO, and PCPMS02 in drinking water, and it includes a summary of the back-
ground information that was considered for the development of a Health Advisory (HA). For greater
detail on the toxicology of PCPMS, PCPMSO, and PCPMS02, the Review of Health Effects and
Other Data: p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone (PCPMS, PCPMSO, and
PCPMSO2) (Appendix A) should be consulted.
1-1
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
n. BACKGROUND
p-Chlorophenyl methyl sulfide (PCPMS) is described as a colorless liquid; p-chlorophenyl
methyl sulfoxide (PCPMSO) is described as a waxlike solid; and p-chlorophenyl methyl sulfone
(PCPMSOj) is described as a white crystalline solid (Fairfield Chemical, 1985). The three
compounds are intermediates in the manufacture of the herbicide Planavin® and are degradation
products of sulfide-containing pesticides (Tetrasul®, Ovex®, and carbophenolthion). p-Chlorophenyl
methyl sulfide, -sulfoxide, and -sulfone have been found in groundwaters of an Army arsenal
(Burrows, 1978). Concentrations in groundwater at the Rocky Mountain Arsenal, reported as an
organosulfur composite (summed concentration of the analogs), were measured in the fall of 1989
and ranged from 2.62 jig/L to 7,950 jxg/L (PMRMA, 1991). These compounds are taken up by
plants, and the sulfide form readily evaporates from the soil (Guenzi et al., 1981; Miller et al.,
1976). An increase in the concentrations of the compounds follows a linear relationship in both the
plant tissues and soil; however, an inverse linear relationship was found between soil compound
concentration and plant growth. The compounds bioconcentrate more in plant tops than in plant
roots. Damage to plant tissues depends on the method of compound application; the foliage method
was reported to cause no damage. The PCPMS moiety was shown to undergo aerobic sulfoxidation
to PCPMSO in plant cell cultures (Blair et al., 1982,1984). This finding indicated the presence of
sulfide oxidase in these cell cultures. The PCPMSO and PCPMSOz analogs tend to persist in soil
more than the does PCPMS (Guenzi and Beaid, 1981). Gas chromatography (GC) with a sulfur-
specific flame photometric detector is the most sensitive method used to detect and quantify the three
sulfur compounds (Miller et al., 1976). Other methods include GC with an electron capture detector
and GC/mass spectrometry.
p-Chlorophenyl methyl sulfide, PCPMSO, and PCPMS02 are readily and almost completely
absorbed when administered orally to rats or monkeys (Thake et al., 1979). Elimination is primarily
in the urine. Clearance from blood in rats follows first-order kinetics with an initial half-life of
about 12 hours for all three analogs. However, in monkeys, clearance from blood follows zero-order
kinetics with a constant half-life of about 7 days, indicating that renal clearance in monkeys is
saturable. In rats, urinary excretion of a single dose is rapid, up to 65% of a 2.5 mg/kg dose by 24
hours and 95% by 48 hours. In monkeys, urinary excretion is slow, and measurable quantities of
about a 6 mg/kg dose are retained in the body for up to 14 days in males and 28 days in females.
Less than 5% of an orally administered dose is eliminated in the feces of rats or monkeys for all
n-i
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
three compounds. The kinetics of repeated dosing have not been studied. Tissue distribution studies
in very small numbers of cattle and sheep indicate that PCPMS and PCPMS02 (the only analogs
tested) are widely distributed but favor fat and liver tissues (Oehler and Ivie, 1983). No distribution
studies are available in rats and monkeys.
The PCPMS is converted to PCPMSO and to PCPMS02 in rats and monkeys (Thake et al.,
1979). A large part of the urinary metabolites are conjugated, producing water-soluble compounds.
Conjugation of metabolites is slower in monkeys than in rats. The PCPMS02 is particularly slow to
conjugate in monkeys. Metabolism probably proceeds by sulfoxidation, hydroxylation of a ring
carbon, and conjugation with glucuronic acid or sulfate (Dacre et al., 1980). Toxicity in monkeys
may correlate with the slower excretion time compared with rats. Hexobarbital "sleep-time"
experiments with male rats indicate that PCPMS, PCPMSO, and PCPMS02 each have an inductive
effect on microsomal enzymes.
The health effects of PCPMS, PCPMSO, and PCPMS02 have not been studied in humans.
Acute oral toxicity studies by TTiake et al. (1979) indicate that PCPMS and PCPMSO are equally
toxic to rats, and PCPMS02 is slightly more toxic than either of the other compounds. The LDM
values for male rats are 619, 611, and 529 mg/kg for PCPMS, PCPMSO, and PCPMS02, respecti-
vely. For female rats, the LDJ0 values are 479, 463, and 400 mg/kg for PCPMS, PCPMSO, and
PCPMS02, respectively. Male rats are more resistant than females to adverse effects as evidenced
by their higher LDM values. Rats exhibited decreases in motor activity, prostration, lack of
coordination, coma, and death at PCPMS doses of 5,630 mg/kg applied in a single 24-hour dermal
exposure (Thake et al., 1979). The LDjo values for male mice are 877, 328, and 600 mg/kg for
PCPMS, PCPMSO, and PCPMS02, respectively (Thake et al., 1979). For female mice, the LDJ0
values are 672, 440, and 606 mg/kg for PCPMS, PCPMSO, and PCPMS02, respectively. In mice,
the PCPMS02 analog is moderately less toxic than PCPMSO to males and females and moderately
more toxic than PCPMS to males. The PCPMSO is significantly more toxic than either PCPMS02
or PCPMS to male and female mice.
In a 28-day range finding study, rats (feeding and gavage studies) and mice (feeding study)
showed increased mortality and depressed motor activity in response to all three analogs (Thake et
al., 1979). Data were inadequate to compare body weight gain and food consumption. Approxi-
mately five animals/sex/dose were used in each study. In rats fed PCPMS at 9,000 ppm (corres-
H-2
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
ponding to 900 mg/kg/day; highest dose), deaths were not attributed directly to the compound, but
rats fed PCPMSO at 5,200 ppm (corresponding to 520 mg/kg/day; highest dose) exhibited 80%
mortality in males and 60% mortality in females. No mortality occurred in rats fed PCPMS02
(highest dose given was 2,250 ppm [corresponding to 225 mg/kg/day]). In the mouse feeding study,
11% of the mice died taking 4,500 ppm PCPMS (corresponding to 675 mg/kg/day, highest dose) and
22% died taking 5,200 ppm PCPMSO (corresponding to 780 mg/kg/day, highest dose). Mice exhibi-
ted depression prior to death. No deaths were reported in PCPMS02 mice (highest dose, 675 mg/kg/
day).
Rats appear more sensitive to all three compounds when administered by gavage rather than by
feeding (Thake et al., 1979). The PCPMS02 produced 60% mortality in males and females at the 50
mg/kg/day dose (the lowest dose at which deaths occurred), indicating that the rats were less
resistent to PCPMS02 than to PCPMS or PCPMSO. Mortality from PCPMS02 increased to 100% at
higher doses. Mortality from PCPMS was 100% in females at 330 mg/kg/day (highest female dose)
and in males at 220 mg/kg/day or greater. The PCPMSO gavaged rats exhibited 100% mortality at
400 mg/kg/day (highest dose tested) in both sexes. Decreased motor activity was observed at 50
mg/kg/day or greater for all three compounds.
In a 14-day gavage study, monkeys exhibited compound-related effects at the lowest doses tested
(5 mg/kg/day for PCPMS and PCPMSO, and 2.5 mg/kg/day for PCPMSOJ (Thake et al., 1979).
Sixty-eight monkeys were used in this study. The dose levels were 0, 5, 10, 20, 30, 40, or 80
mg/kg/day for PCPMS; 0, 5, 10, or 20 mg/kg/day for PCPMSO; and 0, 2.5, 5, 10, 15, 20, or 30
mg/kg/day for PCPMS02. Groups ranged in size from one animal/sex to three/sex for each analog.
The lowest dose at which deaths occurred during the treatment period was 20 mg/kg/day for PCPMS
and PCPMSOj. No deaths occurred in monkeys treated with PCPMSO. However, animals at 20 mg
PCPMSO/kg/day (highest dose tested) were depressed, one severely. Monkeys treated with PCPMS
or PCPMS02 at all dose levels exhibited anorexia. Weakness and depression also occurred at all
PCPMS dose levels. The PCPMSO treated monkeys did not manifest anorexia and depression below
10 mg/kg/day. Blood urea nitrogen showed a significant increase over pretreatment levels in
PCPMSO treated males and females (combined data) at 10 mg/kg/day or greater and in PCPMS and
PCPMSOj animals at 20 mg/kg/day or greater. Alkaline phosphatase was significantly depressed at
10 mg/kg/day or greater in PCPMS and PCPMSO monkeys. No effect was observed in PCPMS02
rats for this parameter. Glucose levels were significantly depressed in PCPMS and PCPMSOj
H-3
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
treated monkeys at 20 mg/kg/day but not in PCPMSO monkeys. The PCPMSO analog produced the
only significant hematological change, a depressed reticulocyte count at 10 mg/kg/day or greater.
Although the organ weight data were difficult to assess in the monkeys, PCPMS and PCPMSO
were associated with a significant increase in relative liver and kidney weights over controls, and
PCPMSOj with increased adrenal weights. The PCPMS analog also significantly increased adrenal
weights but only at higher doses than for PCPMS02. Pathologic changes were observed in the livers
of PCPMSO monkeys at all doses and in PCPMS monkeys at 10 mg/kg/day or greater. Only minor
liver pathology occurred in PCPMSOz animals at 15-30 mg/kg/day (pooled data). Significant
pathologic lesions also occurred in the lymphoid system in monkeys treated with all three analogs.
Lymphoid lesions were most prominent at the higher doses but did occur in PCPMSO and
PCPMS02 treated rats at 5 mg/kg/day. The LOAEL for PCPMS is 5 mg/kg/day based on the
incidence of anorexia, depression, and weakness at the lowest dose. The LOAEL for PCPMSO is
5 mg/kg/day based on the incidence of liver and lymphoid system lesions at the lowest dose. The
LOAEL for PCPMSOz is 2.5 mg/kg/day based on the incidence of anorexia at the lowest dose. A
NOAEL could not be determined for any of the compounds because adverse effects occurred at the
lowest dose tested.
In 13-week feeding studies with all three compounds, mice and rats exhibited hepatotoxicity,
mortality, weight loss, and slight anemia. Sixteen animals/sex/dose plus control groups of 24 rats/
sex or 33 mice/sex were used in these studies. Mortality occurred prior to study termination in 38%
of male rats fed 3,000 ppm (corresponding to 246 mg/kg/day) PCPMSO. In mice, mortality occur-
red in 100% of males and females fed 6,000 ppm PCPMS or PCPMS02 (corresponding to 840 mg/
kg/day in males, 517 mg/kg/day in females for PCPMS; 890 mg/kg/day in males, 680 mg/kg/day in
females for PCPMSO^ or 5,000 ppm PCPMSO (corresponding to 628 mg/kg/day in males, 530 mg/
kg/day in females for PCPMSO), 31% of males and 75% of females fed 3,000 ppm PCPMS (corres-
ponding to 182 mg/kg/day and 180 mg/kg/day in males and females, respectively), and 6% of males
and 44% of females fed 3,000 ppm PCPMSO (corresponding to 224 and 235 mg/kg/day in males
and females, respectively). Body weights, body weight gains, and food consumption of rats and
mice fed the three test compounds at all dose levels were significantly depressed. Erythrocyte
parameters and serum alkaline phosphatase (except low-dose PCPMS females) in all dosed rats were
significantly depressed compared with controls, and serum potassium and calcium levels in rats were
elevated for all compounds. Hematology and clinical chemistry were not evaluated in mice. Liver
E-4
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
weights were increased in all dosed rats and in PCPMS and PCPMSO treated mice at 3,000 ppm
(corresponding to 426 mg/kg/day in male mice, 259 mg/kg/day in female mice for PCPMS; 377 mg/
kg/day in male mice, 318 mg/kg/day in female mice for PCPMSO). The most predominant hepatic
lesions included megalocytosis, necrosis, and vacuolar cytoplasmic change in rats and mice. The
highest incidences of hepatic lesions were exhibited in PCPMS treated rats and PCPMS and
PCPMSO treated mice. No renal lesions were found. Based on depressed body weights, hemato-
logic and serum chemistry changes, increased liver weights, and hepatic pathologic changes, the
Lowest-Observed-Adverse-Effect Level (LOAEL) for rats (all three compounds) is 750 ppm (corres-
ponding to 60 mg/kg/day in males and 57 mg/kg/day in females for PCPMS; 61 mg/kg/day in males
and 67 mg/kg/day in females for PCPMSO; and 57 mg/kg/day in males and 54 mg/kg/day in females
for PCPMSOj). Based on hepatic pathology, the LOAEL for mice (all three compounds) is 750 ppm
(corresponding to 108 mg/kg/day in males and 109 mg/kg/day in females for PCPMS; 112 mg/kg/
day in males and 70 mg/kg/day in females for PCPMSO; and 106 mg/kg/day in males and 86 mg/kg/
day in females PCPMSOj). No-Observed-Adverse-Effect Levels (NOAELs) could be determined for
any of the compounds because adverse effects occurred at the lowest dose tested..
No reproductive or developmental toxicity studies have been conducted with PCPMS, PCPMSO,
or PCPMSOz. Data regarding treatment technologies are lacking.
No conclusions can be reached regarding the potential genotoxicity of the three compounds. The
findings from Salmonella typhimurium gene mutation assays with PCPMS, PCPMSO, and PCPMS02
indicated that the three compounds were not mutagenic in the absence or presence of S9 metabolic
activator of either Aroclor 1254 or phenobarbital-induced rat liver microsomes (Thake et al., 1979).
However, the individual assays were considered to be either incomplete (an unstable form of the
sulfide was tested with Aroclor 1254 S9) or inadequate to conclude a valid negative response
(PCPMSO and PCPMSOj were not assayed to an appropriately high concentration). No other
genetic toxicology studies were found in the available literature.
p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone each are classified as Group D: not
classifiable as to human carcinogenicity.
The health effects data for PCPMS, PCPMSO, and PCPMS02 were reviewed by the U.S. EPA
Reference Dose/Reference Concentration (RfD/RfC) Work Group and were determined to be inade-
n-5
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
quate for the derivation of an oral RfD. Thus, the current verification status of the chentfcal is
classified as "not verifiable." Apparent liver changes observed in rats treated subchronically with
each analog were potential endpoints for establishing RfDs. However, comparisons between gross,
histologic, and clinical chemical parameters were not consistent. Additionally, subacute effects
observed in monkeys treated for 14 days were more severe (e.g., neurotoxicity and lethality) and
developed in a period of time that was much shorter than in rodents. These observations suggest
that primates, including humans, may be more sensitive than rodents to the effects of PCPMS,
PCPMSO, and PCPMS02. Hie 14-day exposure period to monkeys is not a sufficient duration to
derive an RfD, which is protective for lifetime exposure.
n-6
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
m. DISCUSSION
In reviewing the available data on exposure, toxicokinetics, health effects, analytical methods,
and treatment of p-chlorophenyl methyl sulfide, -sulfoxide, and -sulfone (PCPMS, PCPMSO, and
PCPMSOj), it is evident that some important data deficiencies exist. All toxicity studies to date
have been conducted by the same investigators.
The toxicokinetic studies of PCPMS, PCPMSO, and PCPMS02 in rats and monkeys provide
some useful data regarding the rate and speed of absorption of these compounds and their conjuga-
tion and elimination in urine and feces. However, the toxicokinetics were evaluated only for a single
dose, and the monkey study was limited by the small number of animals of a single sex. Also,
lacking in these studies is the tissue distribution of the compounds and the kinetics of repeated
dosing, which is useful in supporting Health Advisory determinations.
\
The only acute toxicity studies arc oral LDy, studies in mice and rats. Subacute studies in these
same species (28-day) reveal mortality and depressed motor activity for all three compounds, but
they provide essentially no other useful data for deriving a Health Advisory. The body weight and
food consumption data from these studies were difficult to interpret or not completely reliable, owing
to the use of control data extracted from other studies, divergent initial body weights, or decreased
food consumption in control animals. A NOAEL could not be determined.
Thake et al. (1979) conducted pathologic examinations, blood and clinical chemistry assays, and
organ weight measures on monkeys following 14 days of oral dosing with PCPMS, PCPMSO, and
PCPMSOj. Small numbers of animals were used for some dose groups, and male and female data
for relative organ weights and clinical chemistry and hematological parameters were combined.
Also, body weights and absolute organ weights were not measured, making it difficult to assess the
importance of the relative organ weight data. Further, the 2-week exposure period is inadequate for
deriving an RfD and most HAs. However, lymphoid system and liver pathology and possible central
nervous system effects at doses as low as 5 mg/kg/day in some animals suggest that the monkey
may be sensitive to these compounds and should be studied further.
The 13-week studies of rats and mice included evaluations of body weight, body weight gain,
food consumption, absolute organ weights, and pathology. The rat study also included an evaluation
m-i
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
of hematologic and clinical chemistry. However, lower dose levels could have been tested to
achieve a NOAEL for these studies. Also, the 750 ppm PCPMSO low-dose mouse group (corres-
ponding to 112 mg/kg/day males, 70 mg/kg/day females) was placed into the study owing to high
mortality at 5,000 ppm PCPMSO (corresponding to 628 mg/kg/day in males, 530 mg/kg/day in
females); no date of study initiation for this group was reported.
Several other areas lack sufficient data to support development of a Health Advisory. No
lifetime toxicity or carcinogenicity studies on PCPMS, PCPMSO, or PCPMS02 are available. Study
deficiencies in existing genotoxicity data on PCPMS, PCPMSO, or PCPMS02 require that further
study of all major genotoxic endpoints be conducted prior to a final assessment of the genotoxic
potential of these compounds. No studies on the reproductive or developmental effects of PCPMS,
PCPMSO, or PCPMS02 are available. No data treatment technologies for PCPMS, PCPMSO, and
PCPMS02 are available. Although PCPMS, PCPMSO, and PCPMS02 are manufactured and used in
various forms in this country, measures of its presence in the environment are lacking, and no
occupational studies currently are available.
m-2
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
IV. CONCLUSIONS AND RECOMMENDATIONS
The following conclusions and recommendations are based upon the proceeding discussion:
• The available studies on PCPMS, PCPMSO, and PCPMS02 toxicity are inadequate for develop-
ment of Health Advisories to deal with potential contamination of drinking water.
• It is recommended that the kinetics of repeated dosing with all three compounds and tissue
distribution be examined in rats and in monkeys, which appears to be the more sensitive specie.
• It is recommended that additional subacute and subchronic studies be performed in rats and
subchronic studies be performed in monkeys.
• It is recommended that chronic toxicity/carcinogenicity studies be performed in rats, mice, and
preferably monkeys.
• It is recommended that adequate reproductive toxicity studies be performed in at least one rodent
species and developmental toxicity studies in two species.
• It is recommended that adequate genotoxicity studies be performed in microbial and
nonmicrobial cell systems.
The recommended order of completion for these studies is as follows: chronic toxicity/
carcinogenicity (preferably in monkeys), subchronic monkey, subacute and subchronic rat, pharmaco-
kinetics, genotoxicity, and reproductive/developmental toxicity.
It is recommended that the human health effects of these compounds be studied. Potential study
groups are people occupationally exposed and people ingesting water containing measurable quanti-
ties of PCPMS, PCPMSO, or PCPMS02. Investigation of the potential existence of these
compounds in the environment also is needed.
IV-1
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone
September 1992
V. REFERENCES
Blair LC, Plewa MJ, Gentile JM. 1982. Hie use of a model sulfide compound to study mono-
oxygenase activity in cultured plant cells. Environ. Mutagen. 4:308.
Blair LC, Slife FW, Felsot A, Plewa MJ. 1984. Rates of sulfide oxidation in cotton, carrot, and
tobacco cultured plant cells measured with a model aromatic alkyl-sulfide. Pest. Biochem. Physiol.
21:291-300.
Burrows WD. 1978. Development of guidelines for contaminated soil and groundwater at U.S.
Army installations. In: Proc. 4th Joint Conf. on Sensing of Environmental Pollutants, New Orleans,
LA, 6-11 Nov. 1977, pp. 80-82. Am. Chem Soc., Washington, DC.
Dacre JC, Leber AP, Bavda LT, Mays DC. 1980. Pharmacokinetic and metabolism study of p-
chlorophenyl methyl sulfide, p-chlorophenyl methyl sulfoxide, and p-chlorophenyl methyl sulfone in
rats and monkeys. Toxicol. Lett. 0(Sp. Iss. 1):226.
Fairfield Chemical Co. 198S. Material Safety Data Sheet for Chloroanisole.
Fairfield Chemical Co. 1985. Material Safety Data Sheet for p-Chlorophenyl methyl sulfone.
Fairfield Chemical Co. 1985. Material Safety Data Sheet for p-Chlorophenyl methyl sulfoxide.
Guenzi WD, Beard WE, Bowman RA, Olsen SR. 1981. Plant uptake and growth responses from p-
chlorophenyl methyl sulfide, -sulfoxide, and -sulfone in soil. J. Environ. Qual. 50(4):532-536.
Guenzi WD, Beard WE. 1981. Degradation of p-chlorophenyl methyl sulfide, -sulfoxide, and -
sulfone in soil. Soil Sci. 131(3):135-139.
Miller TA, Rosenblatt DH, Dacre JC, Pearson JG, Kulkarni RK, Welch JL, Cogley DR, Woodaid G.
1976. Physical, chemical, toxicological, and biological properties of benzene, toluene, xylenes, and
p-chlorophenyl methyl sulfide, sulfoxide, and sulfone. Fort Detrick, MD: U.S. Army Medical
Bioengineering Research and Development Laboratory; Technical Report No. 7605. Available from
the National Technical Information Service (NTIS), Springfield, VA. Order no. ADA040435.
Oehler DD, Ivie GW. 1983. Metabolism of 4-chlorophenyl methyl sulfide and its sulfone analog in
cattle and sheep. Arch. Environ. Contain. Toxicol. 12:227-233.
PMRMA. 1991. Program Manager for Rocky Mountain Arsenal. Contract No. DAAA 15-87-0095.
Annual groundwater report for 1990. Final Report. Version 1.1. Commerce City, CO: U.S. Army
Program Manager for Rocky Mountain Arsenal.
Thake D, Mays D, Leber P, Metcalf D, Bavda L. 1979. Mammalian toxicological evaluation of p-
chlorophenyl methyl sulfide, p-chlorophenyl methyl sulfoxide and p-chlorophenyl methyl sulfone.
Fort De trick, MD: U.S. Army Medical Research and Development Command. Contract No.
DAMD17-77-C-7083. Available from NTIS, Springfield, VA. Order no. ADA082824.
V-l
-------
APPENDIX A
REVIEW OF HEALTH EFFECTS AND OTHER DATA:
p-CHLOROPHENYL METHYL SULFIDE, -SULFOXIDE, AND -SULFONE
(PCPMS, PCPMSO, AND PCPMSOj)
-------
p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
I. GENERAL INFORMATION
p-Chlorophenyl methyl sulfide (PCPMS), p-chlorophenyl methyl sulfoxide (PCPMSO), and p-
chlorophenyl methyl sulfone (PCPMSOj) are three distinct chemical species with differences in
appearance, boiling point, and other physical properties. p-Chlorophenyl methyl sulfide appears as a
colorless liquid at room temperature, PCPMSO as a waxlike solid, and PCPMS02 as a white crystal-
line solid (Fairfield Chemical Co., 1985). All three are combustible compounds, decomposing upon
combustion to release toxic and hazardous vapors. The general physical and chemical properties of
PCPMS (CAS No. 123-09-1), PCPMSO (CAS No. 934-73-6), and PCPMS02 (CAS No. 98-57-1),
are presented in Table 1-1.
All three compounds are intermediates in the manufacture of the herbicide Planavin®, but they
are also produced by other means. p-Chlorophenyl methyl sulfide is synthesized via two processes:
(1) methylation of the p-chlorobenzenethiol with either chloromethane or dimethyl sulfate in the
presence of alkali; and (2) pyrolysis of S-p-chlorophenyl-O-methyl dithiocarbonate. p-Chlorophenyl
methyl sulfoxide is found in trace amounts in PCPMS02. It arises from incomplete oxidation of the
sulfide with hydrogen peroxide. It can be manufactured by a variety of methods; however, industrial
production utilizes a mixture of oxygen and nitrogen dioxide in the oxidation process. The
PCPMSO analog can be produced in the environment via oxidation of PCPMS in air following
discharge of the sulfide (Miller et al., 1976). The PCPMS02 analog can be synthesized via vigorous
oxidation of either PCPMS or PCPMSO; however, oxidation of PCPMS is 50 times faster than
oxidation of PCPMSO. The PCPMS02 can also be made from chloroaniline via substitution of the
amino group with sulfur dioxide followed by methylation. Friedel-Crafts acylation of chlorobenzene
with methanesulfonyl chloride followed by recrystallization can also be used. Only a few domestic
companies produce these three chemicals (Table 1-2).
A-l
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
Table 1-1. Chemical and Physical Properties of p-Chlorophenyl Methyl Sulfide, -Sulfoxide, -Sulfone
(PCPMS, PCPMSO, and PCPMSOj)
Property
Sulflde
Sulfoxide
Sulfone
Reference
CAS No.
Synonyms
Empirical formula
Structure
Boiling point
(at 760 mm)
Density
Solubility
water, mg/L
Conversion factors
(in air):
ppm (v/v)* to
mg/m3 (20°C)
mgAn3 to ppm
(v/v)'
123-09-1
p-Chlorothioanisole,
4-chlorothioanisole,
methyl-p-chloro-
phenyl sulflde,
methyl-4-chloro-
phenyl sulfide
C,H7C1S
934-73-6
4-Chlorophenyl
sulfoxide, methyl-4-
chlorophenyl sulfoxide,
methyl-4-chlorophenyl
sulfoxide
98-57-7
4-Chlorophenyl
methyl sulfone,
methyl-4-chloro-
phenyl sulfone
C^CISO
~
Molecular weight 158.65
Melting point 17-19°C
174.65
37-48°C
220-224°C
1.202 g/mL (at
49°C)
Insoluble
Insoluble
1 ppm «¦ 6.5 mgAn3 1 ppm « 7.1 mgAn3
1 mgAn3 « 0.15 ppm 1 mgAn3 ¦ 0.14 ppm
QH^lSOj
o-s«o
~
190.65
92-99°C
Miller el al.
(1976)
Sax (1984)
Sax (1984)
Miller et al.
(1976)
Insoluble
1 ppm » 7.8 mgAn3
1 mgAn3 » 0.13 ppm
Miller et al.
(1976)
Miller et al.
(1976),
Fairfield
Chemical (1985)
Miller et al.
(1976)
Fairfield
Chemical (1985)
MW x mgAn3 1 mgAn3 = 24.5 x ppm
24.5 MW
'Calculated using the following formulas: 1 ppm =
SOURCE: Adapted from Sax (1984), Miller et al. (1976), Fairfield Chemical (1985)
A-2
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
Table 1-2. Manufacturers of p-Chlorophenyl Methyl Sulfide, -Sulfoxide, -Sulfone
Analog
Manufacturer
Location
Sulfide
American Tokyo Kasei, Inc.
Lancaster Synthesis Ltd.
Fairfield Chemical Company
Alfa Products
Aldrich Chemical Co., Inc.
Portland, OR
Windham, NH
Blythewood, SC
Danvers, MA
Milwaukee, WI
Sulfoxide
Fairfield Chemical Company
Blythewood, SC
Sulfone
Chem Service, Inc.
Lancaster Synthesis Ltd.
Fairfield Chemical Company
Aldrich Chemical Company, Inc.
West Chester, PA
Windham, NH
Blythewood, SC
Milwaukee, WI
A-3
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/j-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
n. SOURCES OF EXPOSURE
Information concerning occupational and environmental exposure is limited. Occupational
exposure to p-chlorophenyl methyl sulfide (PCPMS), p-chlorophenyl methyl sulfoxide (PCPMSO),
and p-chlorophenyl methyl sulfone (PCPMSO2) may occur during manufacturing and munitions
incorporation. The wastewaters could contaminate groundwater, soil used for agriculture, and public
drinking water supplies. However, quantitative data are not available.
The analogs PCPMS, PCPMSO, PCPMS02 are degradation products of sulfide-containing pesti-
cides (Tetrasul,* Ovex,® and carbophenothion) and are intermediates in the synthesis of the herbicide
Planavin* These pesticides are applied to crop plants or natural flora. If wastewaters resulting from
the manufacture or use of PCPMS, PCPMSO, or PCPMS02 were discharged into the environment,
they could present a potential for aquatic pollution. Seepage into groundwater may occur from
sediment deposits generated in Army ammunition plants (Burrows, 1978; Miller et al., 1976).
Concentrations in groundwater at the Rocky Mountain Arsenal, reported as an organosulfur
composite (summed concentration of the analogs), were measured in the fall of 1989 and ranged
from 2.62 pg/L to 7,950 jig/L (PMRMA, 1991).
A-4
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
HI. ENVIRONMENTAL FATE
A. PHOTOLYSIS
There is little information to indicate that p-chlorophenyl methyl sulfide, -sulfoxide, -sulfone
(PCPMS, PCPMSO, and PCPMSO2) undergo photolysis (Miller et al., 1976). If such a reaction
occurs, it is most likely to be air oxidation of PCPMS to PCPMSO and, consequently, to PCPMS02.
B. LEACHING
No information was reported on the leaching of PCPMS, PCPMSO, or PCPMS02.
C. HYDROLYSIS
No information was reported on the hydrolysis of PCPMS, PCPMSO, or PCPMS02.
D. PLANT UPTAKE AND DEGRADATION
The pesticides Tetrasul*, Ovex®, and carbophenothion are reported to degrade forming PCPMS,
PCPMSO, or PCPMS02 (Guenzi et al., 1981). Guenzi et al. (1981) investigated the effects of [14C]-
ring-labeled PCPMS, PCPMSO, or PCPMSOj on seedling growth and uptake by alfalfa, corn, tall
fescue, sugarbeet, and spring wheat. Each crop was tested separately at concentrations of O.S, 5, and
25 ppm (dry soil weight basis) for 3 months in sandy loam soil. The results for each of the three
compounds were, in general, comparable for the five plant species. The increases in the concentra-
tion of the compounds followed a linear relationship in both the plant tissues and soil; the r values
were 0.894 for plant tops and 0.942 for plant roots. There was an inverse linear relationship (p
<0.01) between soil compound concentration and plant growth (r = -0.46 to -0.96 for tops and -0.76
to -0.92 for roots). The root growth was generally affected to a greater degree than was the top
growth at a given soil compound concentration. Hie mean soil compound concentrations that caused
20% reduction in top growth were 4.7, 6.3, 7.3, and 15.5 jig/g for alfalfa, fescue, sugarbeet, and
wheat, respectively; the top growth in corn was depressed only at 25 ppm PCPMS02. The mean
plant top compound concentrations that caused 20% reduction in top growth were 216, 250, 379,
559, and 1,320 jig/g for alfalfa, fescue, sugarbeet, wheat, and com (sulfone only), respectively. No
A-5
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
data were reported for root growth. Bioconcentration of the compounds was, on the average, eight
times greater in plant tops than in plant roots. The mean bioconcentration values for the tops of
corn, alfalfa, wheat, fescue, and sugarbeet were 28, 34, 37, 44, and 62, respectively; the cor-
responding values in roots were 6, 5, 8, 3, and 5, respectively.
Knaus (as cited in Miller et al., 1976) applied these three compounds to six grass and herb
species at two dosages using three methods of application (foliage, soil, and solution). Minor to
severe plant damage was observed using the soil and solution application methods; however, no
damage was observed using the foliage application of all three compounds.
Guenzi and Beard (1981) evaluated degradation and residue of [14C]-ring-labeled PCPMS,
PCPMSO, and PCPMSOz in soil. They measured total C02, [uC]-02, and residual [14C] in soil
incubated for 160 days with 0.5, 5.0, and 50 ppm of each compound at 30°C. Total C02 production
from PCPMS in soils treated with 50 ppm of the compound was significantly higher (p <0.05) at
160 days than from the PCPMSO and PCPMS02. All three compounds at the 50-ppm soil treatment
level showed a significant (p <0.05) reduction in total C02 production compared with the untreated
control soil. However, total C02 production was not affected by soil compound concentrations of
0.5 and 5.0 ppm. Production of [14C]-02, an indicator of ring cleavage and oxidation, decreased as
concentration increased and was lowest (p <0.05) for the sulfone when the three compounds were
compared. Residual [UC] activity accounted for the total activity in the 0.5- and 5.0-ppm treatments
of the PCPMSO and PCPMS02 (91-97%), but not from the 50 ppm treatment (83%) for these
compounds. Recovery from the PCPMS decreased as the concentration increased and ranged from
51 to 82%. Degradation of chemicals was significantly correlated with degradation of soil organic
caibon at the two low concentrations (r = 0.928 and 0.813 for 0.5 and 5.0 ppm, respectively).
Blair et al. (1984) reported that PCPMS was enzymatically sulfoxidized to PCPMSO under
aerobic conditions in cotton, carrot, and tobacco cell suspension cultures. The PCPMSOz was not
produced in any of the three species. Rates of sulfoxidation were linearly related to PCPMS
concentrations. The rates of PCPMS sulfoxidation were cotton>carrot>tobacco. The apparent
Michaelis-Menten constant (K,„) value for carrot cells was 88 jiM PCPMS (14 jig/mL), and the
apparent maximum rate (V^ was 7 nmol PCPMSO/mg whole-cell protein/hr. The study concluded
that PCPMS-sulfide-oxidase was present in cell cultures prior to exposure to PCPMS.
A-6
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A September 1992
E. VAPORIZATION
The PCPMS compound readily evaporated following application to soil, and losses of up to 58%
were reported (Guenzi et al., 1981; Guenzi and Beard, 1981).
A-7
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
IV. TOXICOKINETICS
Based on toxicokinetic and metabolic studies of p-chlorophenyl methyl sulfide, -sulfoxide, and -
sulfone (PCPMS, PCPMSO, and PCPMSOz) in rats and monkeys, there may be species differences
in absorption, excretion, and metabolism (Thake et al., 1979). Monkeys appear to absorb and
excrete PCPMS, PCPMSO, and PCPMS02 (and metabolites) slower than rodents. Because the dose
given to monkeys was approximately double that of rats, dose-related kinetics might have influenced
experimental results. The metabolism of the unmethylated p-chlorophenyl sulfide, which is the
proximal metabolic product of several thioaryl organophosphorus pesticides, has also been studied in
rats and is discussed below. Toxicokinetics of PCPMS and PCPMS02 have also been investigated in
cattle and sheep. These studies provide some information on tissue distribution and are included
even though ruminant metabolism is not expected to be similar to human metabolism.
A. ABSORPTION
1. PCPMS
Thake et al. (1979) administered a single dose (2.5 mg/kg) of 20 pCi [14C]-benzene-labeled
PCPMS by gavage (in corn oil) to groups of 48 rats of each sex. Blood samples were collected
from groups of six/sex at 0.5, 1, 2, 6, 12, and 24 hours and at 3 and 7 days post-treatment. The
groups bled at 7 days were housed individually in glass metabolism cages, and urine and feces were
collected daily. Excretion was primarily in urine with less than 5% eliminated in feces, indicating
nearly complete absorption. Excretion data from this study are described in paragraph IV.D of this
review. Blood levels of radioactivity peaked rapidly (probably within 2 hours) indicating rapid
absoiption of the analog.
In another study, Thake et al. (1979) administered PCPMS (in corn oil) by gavage to groups of
four male and an unspecified number of female Rhesus monkeys fasted overnight. No control
animals were reported. Each animal received one 25 mg dose of the analog, which included 100
pCi of [14C]-labeled analog. This corresponded to a dose of about 6 mg/kg. Post-treatment blood
samples were collected at 0.5,1, 2, 6, 12, and 24 hours and at 3, 7, 14, and 28 days. The monkeys
were kept in restraint chairs for 7 days, and urine and feces samples were collected at 24-hour
intervals. Blood levels of radioactivity peaked at about 24 hours suggesting slower absorption of the
A-8
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September 1992
analog than that observed in rats. However, like the rat, excretion was primarily in urine with less
than 5% eliminated in feces (see paragraph IV.D of this review), which suggests that oral doses of
PCPMS are nearly completely absorbed.
2. PCPMSO
The Thake et al. (1979) studies in rats and monkeys (described above for PCPMS) were repeated
for PCPMSO, and the peak blood levels for each species occurred at approximately the same time as
the other analogs. Excretion data (see paragraph IV.D of this review) suggest that oral doses of
PCPMSO are nearly completely absorbed.
3. PCPMSO,
The Thake et al. (1979) studies in rats and monkeys (described above for PCPMS) were repeated
for PCPMS02, and the peak blood levels for each species occurred at approximately the same time
as the other analogs. Excretion data (see paragraph IV.D of this review) suggest that oral doses of
PCPMS02 are nearly completely absorbed.
4. Comparison between PCPMS. PCPMSO. and PCPMSO-.
All three analogs (PCPMS, PCPMSO, and PCPMSO2) showed essentially the same absorption
patterns (Thake et al., 1979). Blood levels peaked in rats within 2 hours following a 2.5 mg/kg dose
and in monkeys at about 24 hours following about a 6 mg/kg dose. Absorption of all three analogs
appeared to be nearly complete by the end of 7 days observation in both species.
B. DISTRIBUTION
Tissue distribution for PCPMS, PCPMSO, and PCPMS02 was not determined for rats and
monkeys.
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
1. PCPMS
In two lactating cattle, 4 days after receiving six consecutive doses of PCPMS and one dose of
[14C]-PCPMS by gavage at 10 mg/kg/day (total 7 days dosing with compound), [14C]-labeled residues
were equally distributed throughout the body with the highest levels generally in fat and liver tissues
(Oehler and Ivie, 1983).
2. PCPMSO
No data are available in the literature.
3. PCPMSO,
In two lactating cattle, 4 days after receiving six consecutive doses of PCPMS02 and one dose of
[14C]-PCPMS02 by gavage at 10 mg/kg/day (total 7 days dosing with compound), [14C]-labeled
residues were equally distributed throughout the body with the highest levels generally in fat and
liver tissues (Oehler and Ivie, 1983).
In two adult sheep treated orally with unlabeled PCPMS02 at 0.022 or 22 mg/kg/day via gelatin
capsule for 5 days followed by a single dose of [14C]-PCPMS02, [14C]-labeled residues were equally
distributed throughout the body with the highest levels generally in fat and liver tissues, especially at
the highest dose (Oehler and Ivie, 1983).
4. Comparison between PCPMS. PCPMSO. and PCPMSO,
Distribution studies in very small numbers of cattle and sheep (Oehler and Ivie, 1983) indicate
that PCPMS and PCPMS02 (the only analogs tested) show similar tissue distribution patterns, which
favor fat and liver tissues.
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September 1992
C. METABOLISM
1. PCPMS
For identification of urinary metabolites, Thake et al. (1979) pooled urine samples (0-24 hours)
from Fischer 344 rats (48/sex) that had received 2.5 mg/kg of 20 pCi[14C]-benzene-labeled PCPMS
by gavage. Pooled samples were acidified and extracted with chloroform prior to or after hydrolysis
with glusulase/sulfatase. Extracts were subjected to gas chromatography (GC), and peaks were
analyzed for radioactivity. Urine samples were not pooled from Rhesus monkeys, but the samples
were analyzed similarly. Four males and an unspecified number female monkeys were given 25 mg
PCPMS including 100 jaCi of [14C]-labeled compound by gavage for 7 days.
Only 5 to 6% of the [14C] in rat urine was extracted by chloroform, whereas for monkeys, about
24% of the urinary [14C] was extracted after treatment (Thake et al., 1979). Rats converted PCPMS
to water-soluble compounds (conjugates) more readily than monkeys. After enzymatic hydrolysis in
monkeys, an additional 45 to 55% of the [14C] in urine became extractable with chloroform. In the
PCPMS treated rats, PCPMS and PCPMSO were found in all urine samples; PCPMS02 presence
was uncertain. Smaller amounts of free PCPMS were found in monkey urine, and PCPMS02 was
found prior to hydrolysis. The presence of PCPMSO in monkey urine was inconclusive. From the
GC data, it can be concluded that PCPMS is converted to the PCPMSO and further metabolized to
PCPMSOz. There is some interconversion of PCPMS to PCPMSO and PCPMSO to PCPMS02
when urine samples of undosed rats are spiked with test compound and kept at room temperature for
24 hours, but interconversion of PCPMS and PCPMSO to PCPMS02 occurs much more rapidly and
completely in vivo. This was tested by mass spectral analysis of chloroform extracts of urine of
undosed rats or rats dosed with 50 mg/kg unlabeled compound. It does not take into account the
conjugated metabolites in dosed rats.
Thake et al. (1979) conducted a hexobarbital "sleep-time" experiment in male Fischer 344 rats to
determine whether hepatic microsomal enzymes are induced by treatment with PCPMS. Rats (ten/
group), weighing 150-180 g, received an oral dose of 50 mg PCPMS/kg in corn oil or 5 mL/kg com
oil (vehicle control) for 3 consecutive days. An additional (positive control) group of ten rats
received an intraperitoneal injection of 175 mg hexobaibital/kg in distilled water. On day 4, treated
rats were given a single intraperitoneal injection of 175 mg hexobarbital/kg and observed for time to
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
loss of righting reflex and duration of loss of the righting reflex. When group means were compared
to vehicle controls, significant differences (p <0.001) were found in animals treated with PCPMS and
hexobarbital. The investigators concluded that PCPMS has an inductive effect on microsomal
enzymes in male rats.
2. PCPMSO
Following the protocol for PCPMS (see paragraph IV.C.l of this review), Thake et al. (1979)
extracted only 5 to 6% of the [14C] in rat urine following treatment with PCPMSO, whereas for
monkeys, about 16% of the urinary [14C] was extracted after treatment with PCPMSO (Thake et al,
1979). Rats converted PCPMS to water-soluble compounds (conjugates) more readily than monkeys.
After enzymatic hydrolysis in monkeys, an additional 45 to 55% of the [14C] in urine became
extractable with chloroform. There is some interconversion of PCPMSO to PCPMS 02 when urine
samples of undosed rats are spiked with test compound and kept at room temperature for 24 hours,
but interconversion is much more rapid in vivo. This was tested by mass spectral analysis of
chloroform extracts of urine of undosed rats or rats dosed with 50 mg/kg unlabeled compound. It
does not take into account the conjugated metabolites in dosed rats.
Thake et al. (1979) conducted a hexobarbital "sleep-time" experiment in male Fischer 344 rats to
determine whether hepatic microsomal enzymes are induced by oral treatment with 50 mg PCPMSO/
kg in corn oil (see paragraph IV.C.l of this review for experimental details). Significant differences
(p <0.001) were found in animals treated with PCPMSO and hexobarbital when compared with
vehicle controls, indicating that PCPMSO has an inductive effect on microsomal enzymes in male
rats.
3. PCPMSO.
Following the protocol for PCPMS (see paragraph IV.C.l of this review), Thake et al. (1979)
extracted only 5 to 6% of the [14C] in rat urine following treatment with PCPMS02, whereas for
monkeys, about 59% of the urinary [14C] was extracted after administration of PCPMS02 (Thake et
al., 1979). Rats converted the chemicals to water-soluble compounds (conjugates) more readily than
monkeys. After enzymatic hydrolysis in monkeys, an additional 45 to 55% of the [14C] in urine
became extractable with chloroform.
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September 1992
Thake et al. (1979) conducted a hexobarbital "sleep-time" experiment in male Fischer 344 rats to
determine whether hepatic microsomal enzymes are induced by oral treatment with 50 mg
PCPMS Oj/kg in com oil (see paragraph IV.C.1 of this review for experimental details). Significant
differences (p <0.001) were found in animals treated with PCPMS02 and hexobarbital when
compared with vehicle controls, indicating that PCPMS02 has an inductive effect on microsomal
enzymes in male rats.
4. Comparison between PCPMS. PCPMSO. and PCPMSO,
Metabolites extracted from rat and monkey urines indicate that PCPMS is converted to PCPMSO
and to PCPMS02. Rats convert all three analogs to water soluble conjugates more rapidly than
monkeys. The PCPMS02 analog is the most poorly conjugated of the three compounds in monkeys.
Metabolism probably proceeds by sulfoxidation, hydroxylation of a ring compound, and conjugation
with glucuronic acid or sulfate. Hexobarbital "sleep-time" experiments with male rats indicate that
all three compounds induce microsomal enzymes.
5. Metabolism of Chlorothiophenol
Menn et al. (1975) examined the urinary metabolites of [MC]-4-chlorothiophenol 144 hours after
administration of 8.3 mg/kg to rats. About 70% of the administered radioactivity was excreted in the
urine and 30% in the feces. Seven metabolites were separated by thin-layer chromatography of urine
and were identified: p-chlorophenyl methyl sulfone (8.1%), 4-chlorobenzene sulfonic acid (4%), p-
chloro-3-hydroxy phenyl methyl sulfone (15.4%), the glucuronide conjugate (16%) and O-sulfate
conjugate (21%) of the above 3-hydroxy compound, and 4-chlorophenyl thio-S-glucosiduronic acid
(27%). The glucosiduronic acid conjugate was refractory to enzyme hydrolysis and was found in the
free acid and lactone forms. Chlorothiophenol is the primary cleavage product of the thioarylorgano-
phosphorous insecticides (e.g., Dyphonate® and trithion), and earlier studies indicated that in plants
and animals, metabolism of these insecticides proceeded by cleavage of the thiophenol and chloro-
thiophenol moiety, methylation to chloromethylphenyl sulfide or methylphenyl sulfide, sulfoxidation,
ring hydroxylation, and conjugation. It is reasonable to expect that metabolism of the p-chloro-
phenyl methyl sulfide, -sulfoxide, and -sulfone would follow a pathway similar to that of chloro-
thiophenol.
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September 1992
D. EXCRETION
1. PCPMS
Thake et al. (1979) administered a single dose (2.5 mg/kg) of 20 }iCi [14C]-benzene-labeled
PCPMS by gavage (in corn oil) to groups of 48 rats of each sex (see paragraph IV.A. for experi-
mental details). Disappearance of [14C] from blood followed first-order kinetics for both sexes; the
alpha phase had a half-life of 9.5 to 12 hours, and the half-life for the second (beta) phase was 3.1
and 3.4 days in males and females, respectively. Excretion was primarily in the urine. Rats
excreted 35 to 65% of the dose in urine by 24 hours and 50 to 90% by 48 hours, with less than 5%
eliminated in feces. Half-lives of urinary excretion were not reported.
Thake et al. (1979) administered PCPMS (in com oil) by gavage to groups of four male and an
unspecified number of female Rhesus monkeys fasted overnight (see paragraph IV.A. for experi-
mental details). Blood levels appeared to follow zero-order kinetics with a half-life of approximately
7 days, and the rate of decline was much slower than in rats. Blood clearance was somewhat slower
in females than in males, with detectable levels of radioactivity still present in the blood of females
at 28 days. Excretion was primarily in the urine with constant amounts excreted daily for 7 days.
Elimination in feces was less than 5% of the total dose administered.
Oehler and Ivie (1983) gave PCPMS orally in a gelatin capsule to two lactating cattle at 10 mg/
kg/day for six consecutive days before administering a single oral dose of the [14C] radiolabeled
analog. p-Chlorophenyl methyl sulfide was rapidly metabolized to PCPMS02 and slowly excreted in
the urine. After 4 days, 22% of the [14C]-PCPMS had been recovered in the urine. Also, within 4
days post-treatment, 1 to 3% of the dose had been secreted in milk, nearly all of it as PCPMS02.
2. PCPMSO
Thake et al. (1979) administered a single dose (2.5 mg/kg) of 20 pCi [14C]-benzene-labeled
PCPMSO by gavage (in com oil) to groups of 48 rats of each sex (see paragraph IV.A. for experi-
mental details). Disappearance of [14C] from the blood followed first-order kinetics for both sexes;
the alpha phase had a half-life of 9.5 to 12 hours, and the half-life for the second (beta) phase was
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
2.5 and 2.1 days in males and females, respectively. Elimination in feces was less than 5% of total
dose.
Thake et al. (1979) administered PCPMSO (in com oil) by gavage to groups of four male and an
unspecified number of female Rhesus monkeys fasted overnight (see paragraph IV.A. for experi-
mental details). Blood levels appeared to follow zero-order kinetics with a half-life of approximately
7 days, and the rate of decline was much slower than in rats. Blood clearance was somewhat slower
in females than in males, with detectable levels of radioactivity still present in the blood of females
at 28 days. Excretion was primarily in the urine with constant amounts excreted daily for 7 days.
Elimination in feces less than 5% of the total dose administered.
3. PCPMSO,
Thake et al. (1979) administered a single dose (2.5 mg/kg) of 20 fiCi [14C]-benzene-labeled
PCPMS02 by gavage (in com oil) to groups of 48 rats of each sex (see paragraph IV.A. for experi-
mental details). Disappearance of [14C] from blood followed first-order kinetics for both sexes; the
alpha phase had a half-life of 9.5 to 12 hours, and the half-life for the second (beta) phase was 1.6
and 2.8 days in males and females, respectively. Elimination in feces was less than 5% of total
dose.
Thake et al. (1979) administered PCPMS02 (in com oil) by gavage to groups of four male and
an unspecified number of female Rhesus monkeys fasted overnight (see paragraph IV.A. for experi-
mental details). Blood levels appeared to follow zero-order kinetics with a half-life of approximately
7 days, and the rate of decline was much slower than in rats. Blood clearance was somewhat slower
in females than in males, with detectable levels of radioactivity still present in the blood of females
at 28 days. Excretion was primarily in the urine with constant amounts excreted daily for 7 days.
Elimination in feces was less than 5% of the total dose administered.
Oehler and Ivie (1983) gave PCPMS02 orally in a gelatin capsule to two lactating cattle at
10 mg/kg/day for 5 consecutive days before administering a single oral dose of the [14C] radiolabeled
analog at the same dose. p-Chlorophenyl methyl sulfone, which appeared quite resistant to further
metabolism, was slowly excreted in the urine. After 4 days, 13% of the [14C]-PCPMS02 had been
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
recovered in the urine. Also, within 4 days post-treatment, 1 to 3% of the dose had been secreted in
milk, nearly all of it as PCPMS02.
Oehler and Ivie (1983) similarly dosed two adult sheep with unlabeled PCPMS02 for 5 days
(0.022 or 22 mg/kg) followed by a single [14C]-PCPMS02 dose at the same dose levels. At the low
dose, there was complete urinary excretion in 14 days. At the high dose by day 14, 35% and 23%
of the radioactivity had been eliminated in the urine and feces, respectively.
4. Comparison between PCPMS. PCPMSO. and PCPMSQ,
In the rat study, in which Thake et al. (1979) administered a single dose (2.5 mg/kg) of 20 jaCi
[14C] -benzene-labeled PCPMS by gavage (in corn oil) to groups of 48 rats of each sex, blood levels
of radioactivity peaked rapidly (probably within 2 hours), and disappearance of [14C] from blood
followed first-order kinetics. The alpha phase had a half-life of 9.5 to 12 hours for both sexes for all
three analogs. The alpha half-lives for PCPMS02 were slightly slower than for PCPMS. The half-
life for the second (beta) phase for PCPMS was 3.1 and 3.4 days in males and females, respectively;
for PCPMSO, the half-lives were 2.5 and 2.1 days in males and females respectively; and for
PCPMS02, the half-lives were 1.6 and 2.8 days in males and females, respectively. Elimination in
feces was less than 5% of total dose.
In the Thake et al. (1979) gavage study with Rhesus monkeys that received one 25 mg dose of
each analog (corresponding to a dose of about 6 mg/kg), blood levels for all three analogs peaked at
about 24 hours. Excretion was primarily in the urine with constant amounts excreted daily for 7
days. Elimination from the blood appeared to follow zero-order kinetics indicating saturability for
all three analogs. Although PCPMSO cleared more slowly from the blood than PCPMS or PCPMS2,
there were no significant differences reported for the blood levels of the different analogs. Recovery
of radioactivity in 7 days was somewhat less with the sulfide (26%) than with the sulfoxide (50%) or
sulfone (42%). Elimination in feces was less than 5% of the total dose administered for all analogs.
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
V. HEALTH EFFECTS
A. HUMANS
No studies on the health effects of p-chlorophenyl methyl sulfide (PCPMS), -sulfoxide
(PCPMSO), and -sulfone (PCPMSO2) in humans were found in the literature.
B. ANIMAL EXPERIMENTS
1. Short-term Exposure
a. Acute
(1) PCPMS
In an acute, oral toxicity study, Thake et al. (1979) gavaged Fischer 344 rats with a single dose
of PCPMS dissolved in corn oil and observed the animals twice daily for mortality and toxic
symptoms. Ten rats/sex/dose, except two female dose groups, each with 20 rats, were treated with
the compound. Ten rats/sex served as controls. The dose levels, which ranged from 398 to 708 mg/
kg in males and 355 to 794 mg/kg in females, had been established to cover a range of 0-100%
mortality. At all treatment levels in both sexes, there was an immediate decrease in locomotor
activity. At the higher doses, this was followed by a loss of coordination, prostration, loss of
consciousness, severe lacrimation, labored respiration, and death. The investigators indicated that
dehydration and starvation in prostrate animals may have contributed to the deaths of treated
animals, although death occurred within 4 hours in some rats at the highest dose. No toxicity or
mortality was observed in controls. Table V-l presents the LD^s for PCPMS, which were higher
for males (619 mg/kg) than for females (479 mg/kg).
In a similar, acute gavage study with BjCjFi mice (10/sex/dose, except one male treatment group
with 20 mice), Thake et al. (1979) administered PCPMS dissolved in corn oil and observed the mice
twice daily for mortality and toxic symptoms. The dose levels, established to induce 0-100%
mortality, ranged from 501 to 1,122 mg/kg in males and 631 to 1,000 mg/kg in females. Ten
mice/sex served as controls. At all treatment levels in both sexes, there was an immediate decrease
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
Table V-l. Acute Oral LD50 Values for p-Chlorophenyl Methyl Sulfide, -Sulfoxide, -Sulfone
(PCPMS, PCPMSO, and PCPMSOj)
Chemical
Species/Strain
LD*
(mg/kg)
Effects
Male
Female
PCPMS
PCPMSO
pcpmso2
Mouse/BgC^Fj
Rat/F344
Mouse/BjCjFj
Rat/F344
Mouse/B6C3F1
Rat/F344
877
619
328
611
600
529
672
479
440
463
606
400
Toxic signs included an
immediate decrease in
locomotor activity,
prostration, loss of
consciousness, labored
respiration, and death.
Severe lacrimation was
characteristic of animals
treated with sulfide and
sulfoxide analogs.
SOURCE: Adapted from Thake et al. (1979)
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A September 1992
in locomotor activity. At the higher doses, this was followed by a loss of coordination, prostration,
loss of consciousness, severe lacrimation, labored respiration, and death. The investigators indicated
that dehydration and starvation in prostrate animals may have contributed to the deaths of treated
animals, although death occurred within hours in some mice at the highest dose. No toxicity or
mortality was observed in controls. Table V-l presents the LDjgS for PCPMS, which were higher
for males (877 mg/kg) than for males (672 mg/kg).
In an acute dermal toxicity study, Thake et al. (1979) applied gauze sponges with PCPMS in
acetone to the shaved backs of Fischer 344 rats (2/sex/dose) for 24 hours and observed the animals
daily for 14 days. The dose levels were 0, 1,000, 2,190, or 5,630 mg/kg. All animals at the highest
dose died within 24 hours following removal of the gauze. Also, at the highest dose, locomotor
activity immediately decreased, followed by a loss of coordination, prostration, severe lacrimation,
diarihea, loss of consciousness, labored respiration, and death. Similar, but less severe, toxic
symptoms occurred in the 2,190 mg/kg treatment group and were noted for 7 days. Rats in the
1,000 mg/kg group showed decreased locomotion for approximately 24 hours following removal of
the gauze.
(2) PCPMSO
In an acute, oral toxicity study, Thake et al. (1979) gavaged Fischer 344 rats (10/sex/dose, except
two male dose groups with 20 rats) with PCPMSO dissolved in corn oil and observed the animals
twice daily for mortality and toxic symptoms. The dose levels, which ranged from 398 to 794 mg/
kg in males and 316 to 631 mg/kg in females, had been established to produce 0-100% mortality.
Ten rats/sex served as controls. The results were the same as those for PCPMS (see paragraph
V.B.I.a.(l) of this review). Table V-l presents the LDjgS for PCPMSO, which were higher for
males (611 mg/kg) than for females (463 mg/kg).
In a similar, acute gavage study with B6CjFi mice (10/sex/dose, except one female treatment
group with 20 mice), Thake et al. (1979) gave PCPMSO dissolved in corn oil and observed the mice
twice daily for mortality and toxic symptoms. The dose levels, which had been established to
produce 0-100% mortality, ranged from 158 to 501 mg/kg in males and 251 to 631 mg/kg in
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September 1992
females. Ten mice/sex served as controls. The results were essentially the same as those for
PCPMS (see paragraph V.B.l.a.(l) of this review). Table V-l presents the LDS0s for PCPMSO,
which were higher for females (440 mg/kg) than for males (328 mg/kg).
In an acute dermal toxicity study, Thake et al. (1979) applied gauze sponges with PCPMSO in
acetone to the shaved backs of Fischer 344 rats (2/sex/dose) for 24 hours and observed the animals
daily for 14 days. The dose levels were 0, 1,000, 2,190, or 5,630 mg/kg. No deaths occurred with
this analog. However, at the highest dose, locomotor activity immediately decreased, followed by a
loss of coordination, prostration, severe lacrimation, diarrhea, loss of consciousness, and labored
respiration. A gradual recovery followed. Similar, but less severe, toxic symptoms occurred in the
2,190 mg/kg treatment group, but animals were normal within 24 hours following removal of the
gauze.
(31 PCPMSO,
In an acute, oral toxicity study, Thake et al. (1979) gavaged Fischer 344 rats (10/sex/dose, except
one male and four female dose groups with 20 rats) with PCPMS02 dissolved in corn oil and
observed the animals twice daily for mortality and toxic symptoms. The dose levels, which ranged
from 464 to 708 mg/kg in males and 282 to 473 mg/kg in females, had been established to produce
0-100% mortality. Ten rats/sex served as controls. At all treatment levels in both sexes, there was
an immediate decrease in locomotor activity. This was followed, at the higher doses, with a loss of
coordination, prostration, diarrhea, loss of consciousness, labored respiration, and death. Hie
investigators indicated that dehydration and starvation in prostrate animals may have contributed to
the deaths of treated animals, although death occurred within 4 hours in some rats at the highest
dose. No toxicity or mortality was observed in controls. Table V-l presents the LDjqS for
PCPMS02, which were higher for males (529 mg/kg) than for females (400 mg/kg).
In a similar, acute gavage study with B6C3F1 mice (10/sex/dose, except one female treatment
group with 9 mice), Thake et al. (1979) administered PCPMSOz dissolved in corn oil and observed
the mice twice daily for mortality and toxic symptoms. The dose levels, which had been established
to produce 0-100% mortality, ranged from 562 to 794 mg/kg for both sexes. Ten mice/sex served as
controls. At all treatment levels in both sexes, there was an immediate decrease in locomotor
activity. This was followed at the higher doses with a loss of coordination, prostration, loss of
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September 1992
consciousness, diarrhea, labored respiration, and death. The investigators indicated that dehydration
and starvation in prostrate animals may have contributed to the deaths of treated animals, although
death occurred within hours in some mice at the highest dose. No toxicity or mortality was observed
in controls. Table V-l presents the LDjqS for PCPMS02, which were 600 mg/kg for males and 606
mg/kg for females.
In an acute dermal toxicity study, Thake et al. (1979) applied gauze sponges with PCPMS02 in
acetone to the shaved backs of Fischer 344 rats (2/sex/dose) for 24 hours and observed the animals
daily for 14 days. The dose levels were 0, 1,000, 2,190, or 5,630 mg/kg. No deaths and no toxic
symptoms occurred with this analog.
(4) Comparison between PCPMS. PCPMSO. and PCPMSCX
Acute oral doses of PCPMS and PCPMSO were equally toxic to male and female Fischer 344
rats and slightly less toxic than PCPMS02 to this strain (Thake et al., 1979). However, the investi-
gators reported that while PCPMS and PCPMSO were readily soluble in com oil, PCPMS02 was
not, and, thus, required higher vehicle volumes, which could have enhanced compound absorption.
This effect, however, was not observed in similar experiments with mice. Thake et al. (1979)
observed in B6C3Fj mice that while oral PCPMS02 was more toxic than PCPMS to male mice,
PCPMSO was far more lethal than either PCPMS02 or PCPMS to both sexes. Thus, while
PCPMS02 was slightly more toxic than PCPMS or PCPMSO when administered orally in rats, mice
were more sensitive to the lethal effects of PCPMSO. Severe lacrimation was observed in rats and
mice given PCPMS or PCPMSO but not in PCPMS02 treated animals.
The types of toxic symptoms observed in rats following oral exposure to all three analogs
were similar to those observed following dermal applications of PCPMS or PCPMSO. Dermal appli-
cation of PCPMS02, however, had no effect The investigators did not indicate whether PCPMS02
had been absorbed through the skin.
b. Primary Irritation. Dermal Sensitization, and Ophthalmologic Effects
Thake et al. (1979) conducted skin irritation studies of PCPMS, PCPMSO, and PCPMS02 on 18
male and female New Zealand albino rabbits. Three animals/sex/compound were treated with
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September 1992
slurries or solutions of the compounds at 50% (w/v) concentrations in corn oil according to the
Modified Draize Procedure. The animals' skin was graded and evaluated at 24, 48, and 72 hours
post-treatment. Hie PCPMS analog did not produce irritation in any of the treated rabbits. The
PCPMS02 analog produced a mild irritation in one male and one female, and PCPMSO produced a
mild irritation in two males and two females and a severe reaction in one female rabbit.
In an eye irritation study, liquid PCPMS (0.1 mL), solid PCPMSO (100 mg), and solid
PCPMS02 (100 mg) were tested in groups of five male New Zealand albino rabbits according to the
Modified Draize Procedure (Thake et al., 1979). Eye examinations were conducted at 24, 48, and 72
hours, and at 7 days post-treatment. The PCPMS produced positive corneal responses in four of five
animals; eyes were normal by day 7. The PCPMSO produced positive responses in all treated
animals for the cornea, iris, and conjunctivae. Lesions of the iris and conjunctivae were completely
reversible by day 7; however, the corneal lesions were considered to be irreversible. The PCPMS02
did not produce a positive response in any of the treated animals.
Thake et al. (1979) studied skin sensitization of PCPMS, PCPMSO, and PCPMS02 in female
Hartley albino guinea pigs. Groups of eight guinea pigs were induced by a two-stage operation:
first, with an intradermal injection of the compounds in Freund's adjuvant and then, after 1 week,
with topical application of the compounds in petrolatum. The animals received a topical challenge
2 weeks later and were examined 24 and 48 hours post-treatment. Animals treated with PCPMS
showed no adverse effects. Animals treated with PCPMSO exhibited minimal focal intracellular
vacuolation (2/8) and mild multifocal papillar dermatitis (1/8). Animals treated with PCPMS02
exhibited minimal focal acantholysis (one of eight, 1/8) and minimal focal intracellular vacuolation
(2/8). The changes observed with PCPMSO and PCPMS02 were considered to represent background
changes, not the result of dosing.
c. Subacute
Because PCPMS, PCPMSO, and PCPMS02 were expected to be unpalatable at high doses,
Thake et al. (1979) conducted parallel 28-day feeding and gavage studies (range finding studies) in
rats to determine dietary dosages for a 91-day rat study (paragraph V.B.2 of this review). They also
conducted a 28-day feeding study in mice to determine appropriate dosages for a 91-day mouse
A-22
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/7-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
study (paragraph V.2 of this review). Thake et al. (1979) conducted an additional gavage study with
Rhesus monkeys.
(1) PCPMS
Thake et al. (1979) fed Fischer 344 rats (five/sex/dose) diets containing PCPMS for 28 days at
levels of 0, 281, 562, 2,250, or 9,000 ppm, which correspond to calculated doses of 0, 28.1, 56.2,
225, and 900 mg/kg/day, respectively (Lehman, 1959). Mortality, body weight, and food consump-
tion were observed throughout the study. All rats at the 9,000 ppm dose died within the first week,
but the investigators attributed these deaths to starvation rather than to the test compound. No
mortality occurred at lower dietary levels. Although, it appeared that body weights and food
consumption decreased in a dose-related manner throughout the study, body weight and food
consumption recordings were compared to control data conducted on another chemical (not
specified); for this reason, initial body weights of the animals differed and interpretation of these
data is not completely reliable.
In the mouse feeding study, BjQF! mice (five/sex/dose, except highest male dose group with
four mice) were given diets containing PCPMS at levels of 0, 281, 562, 2,750, or 4,500 ppm for 28
days (Thake et al., 1979). These levels correspond to calculated doses of 0, 42.2, 84.3, 412.5, and
675 mg/kg/day, respectively (Lehman, 1959). Except for one female in the highest treatment group,
no mortalities were observed. Death was preceded by a marked depression in motor activity. Food
consumption data showed no consistent trends, and the investigators could not adequately interpret
the body weight gain data.
In the gavage study, Fischer 344 rats (five/sex/dose) received PCPMS in com oil for 28 days at
dose levels of 0, 18.8, 37.5, 75,150, 180, 220, 265, or 530 mg/kg/day for males and 0, 9.4, 18.8,
37.5, 75,150, or 330 mg/kg/day for females (Thake et al., 1979). Mortality was 100% in males at
220, 265, or 530 mg/kg/day levels and in females at the 330 mg/kg/day dose. Below these levels,
mortality decreased in a dose-related manner, though females exhibited a higher rate of mortality.
The investigators reported difficulty in interpreting body weight and food consumption data, noting
that most treated animals consumed greater amounts of feed than controls. Generally, at doses
greater than 50 mg/kg/day, the rats showed an immediate decrease in motor activity after each daily
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
treatment. Rats that died became progressively depressed with each subsequent dose. Signs of
depression completely disappeared before termination of the study in all surviving rats.
In a 14-day gavage study, Thake et al. (1979) administered PCPMS to male and female Rhesus
monkeys at dose levels of 0, 5, 10, 20, 30, 40, or 80 mg/kg/day. The control group and the 5, 10,
and 20 mg/kg/day treatment groups each contained six animals (three/sex). The remaining groups
each contained two animals (one/sex). Twenty-four hours after the final treatment, half of the
animals in each group were randomized for immediate sacrifice and necropsy while the other half
were observed throughout a 14-day recovery period. The animals were observed for mortality, toxic
symptoms, clinical chemistry, and hematological parameters before treatment began and on days
7 and 14 (as well as on days 21 and 29 during recovery). Statistical analyses for hematology and
clinical chemistry parameters were done only for days 7 and 14; thus, no conclusions for these
parameters can be drawn for the recovery period. The clinical chemistry parameters were compared
statistically with pretreatment levels, the hematology parameters with controls. Clinical chemistry
and hematology parameters, pathologic data, and relative organ weights were combined for males
and females. Body weights and absolute organ weights were not measured.
Three deaths occurred during the treatment period; one at the highest dose (80 mg/kg/day) on
day 6, one at the 40 mg/kg/day dose on day 9, and one at the 20 mg/kg/day dose on day 12. One
death occurred 2 days into the recovery period at the 20 mg/kg/day level. In the 20 mg/kg/day
group one monkey that survived to the end of the recovery period appeared normal at necropsy, two
monkeys were moribund by the 13 or 14 day of treatment, and one was depressed when sacrificed
post-treatment. At doses greater than 20 mg/kg/day, all animals were dead or moribund at necropsy.
Anorexia, weakness, and depression were observed in all treatment groups. Adipsia was observed at
the 40 and 80 mg/kg/day levels. Hypothermia occurred in the 10, 20 and 30 mg/kg/day groups.
Thake et al. (1979) attributed the diarrhea and emesis exhibited in control animals and sporadically
in treated animals to the com oil vehicle. No statistically significant changes in hematologic
parameters were reported. In the 20-80 mg/kg/day (pooled data) groups, blood urea nitrogen (BUN)
increased significantly over pretreatment levels on days 7 and 14, and total bilirubin significantly
increased on day 7 and remained at that level through the treatment period. Blood glucose levels
decreased significantly over pretreatment levels on day 14 in the 20-80 mg/kg/day (pooled) dose
group. Serum alkaline phosphatase levels significantly decreased at dose levels of 10 mg/kg/day and
higher on day 14. Although hematology and clinical chemistry parameters fluctuated in control
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
animals, all parameters (with the exception of one male) were back within pretreatment limits by
necropsy at either day 15 or 29.
A statistically significant increase in the relative liver and kidney weights (compared with
controls) were observed in the monkeys receiving 10 mg/kg/day or greater PCPMS. Animals
receiving 20 mg/kg/day or greater doses also exhibited increased relative brain, adrenal, and atrial
(weights of other heart sections not reported) weights. The investigators did not indicate whether the
comparisons of organ weight included animals necropsied at the end of the recovery period. Further,
without body weights or absolute organ weights, these data are difficult to assess.
Treated monkeys that died or were sacrificed at the end of the treatment period exhibited
compound-related pathologic changes in liver, kidney, adrenal and thyroid glands, lymphoid system,
and intestine. Thake et al. (1979) pooled the pathology data for treatment groups 20, 30, 40, and 80
mg/kg/day and combined the results for males and females. Hepatocyte vacuolization, vacuolar
degeneration, and hepatocyte necrosis occurred primarily in the 20-80 mg/kg/day dose groups and far
less frequently at the 10 mg/kg/day level. Vacuolization and pigmentation of renal tubular
epithelium was observed at 10 mg/kg/day or greater dose levels. Animals mainly at the 20-80 mg/
kg/day levels exhibited adrenal cortex hyperplasia, hemorrhage, and congestion; follicular cell hyper-
plasia and degeneration of the thyroid, vacuolization and degeneration of gastric and intestinal
epithelium with cell cycle alterations; and lymphoreticular proliferative lesions in lymph nodes,
spleen, and bone marrow and lymphoid depletion. None of the monkeys exhibited ophthalmic
lesions. A few recovery group animals at all dose levels exhibited hepatic, renal, and adrenal
pathologic changes. Based on symptoms of anorexia, depression, and weakness, the Lowest-
Observed-Adverse-Effect Level (LOAEL) for PCPMS is 5 mg/kg/day, which was the lowest dose
tested. A NOAEL could not be determined.
(2) PCPMSO
In the 28-day feeding study, Thake et al. (1979) fed Fischer 344 rats (five/sex/dose except the
control group of 10 rats/sex) diets containing 0,162, 325, 650, 1,300, 2,600, or 5,200 ppm
PCPMSO, which corresponds to calculated doses of 0,16.2, 32.5, 65, 130, 260, 520 mg/kg/day,
respectively (Lehman, 1959). Mortality, body weight, and food consumption were recorded through-
out the study. At the highest dose, four males (80%) and three females (60%) died. No other
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
mortalities occurred. Food consumption was depressed throughout the study in rats fed 5,200 or
2,600 ppm PCPMSO. Rats receiving 1,300 ppm or less returned to near control levels of food
consumption during weeks 2, 3, and 4 for males and weeks 3 and 4 for females. Except at the
highest dose, body weight gain decreased as the study progressed.
In the mouse feeding study, B6C3F, mice (five/sex/dose, except highest male dose with four
mice) were given diets containing PCPMSO at levels of 0, 188, 375, 750, 1,300, 2,600, or 5,200
ppm for 28 days (Thake et al., 1979). These levels correspond to calculated doses of 0, 28.2, 56.3,
112.5, 195, 390, and 780 mg/kg/day, respectively (Lehman, 1959). Two females died during the
first week in the 5,200 ppm group. Death was preceded by a marked depression in motor activity.
No other mortalities occurred. Food consumption data showed no consistent trends, and the
investigators could not adequately interpret the body weight gain data, though they reported that the
750 ppm or higher dose groups showed decrements in body weights.
In the gavage study, Fischer 344 rats (five/sex/dose) received PCPMSO in com oil for 28 days at
dose levels of 0, 6.25, 12.5, 25, 50, 100, 200, 400 mg/kg/day (Thake et al., 1979). Mortality was
100% at the highest dose in both sexes. No other deaths occurred among the males. One death
occurred in the 200 mg/kg/day female group and three deaths in the female control group. Body
weight gain showed a dose-related decrease in both sexes. However, during the final week of the
study, weight gain approached that of controls. The investigators attributed this finding to an
increased tolerance to treatment. Weekly food consumption for several treatment groups often
exceeded that for controls. Generally, at doses greater than 50 mg/kg/day, the rats showed an
immediate decrease in motor activity after each daily treatment. Rats that died became progressively
depressed with each subsequent dose. Signs of depression completely disappeared before termination
of the study in all surviving rats.
In a 14-day gavage study, Thake et al. (1979) administered PCPMSO to male and female Rhesus
monkeys at dose levels of 0, 5,10, or 20 mg/kg/day. The control group, which also served as the
PCPMS and PCPMS02 controls, and the 10 and 20 mg/kg/day treatment groups each contained six
animals (three/sex). Seven animals (three females, four males) were given the lowest dose. The
remaining experimental details are the same as those for PCPMS (see paragraph V.B.l.c.(l) of this
review).
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
There were no mortalities. At post-treatment necropsy (day 15), three monkeys at the highest
dose were depressed, one severely. Another high dose monkey sacrificed after 14 days of recovery
also was depressed. All other animals appeared normal at necropsy on day 15 or 29. Anorexia,
weakness, depression, and hypothermia were observed at the 20 mg/kg/day dose, and the same
symptoms except weakness were observed at 10 mg/kg/day. Thake et al. (1979) attributed the diar-
rhea exhibited in some treated animals at the 5 and 10 mg/kg/day dose levels as well as in controls
to the com oil vehicle. Monkeys treated at 10 or 20 mg/kg/day exhibited a statistically significant
decrease in the reticulocyte count compared with controls on day 14, and no recovery occurred by
day 29. Monkeys at the highest dose (20 mg/kg/day) on day 7 and at the intermediate or highest
dose on day 14 exhibited significantly elevated BUN levels compared to pretreatment levels. Only
25% of monkeys at the highest dose recovered to pretreatment BUN levels by the end of the
recovery period. Alkaline phosphatase was significantly decreased from pretreatment levels on day
14 at the 10 and 20 mg/kg/day doses. Sporadic, moderate to marked elevations of serum glutamate
oxalate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), and calcium levels
also occurred but were not statistically significant. Although hematology and clinical chemistry
parameters fluctuated in control animals, all parameters (with the exception of one male) were back
within pretreatment limits by necropsy at either day 15 or 29.
A statistically significant increase in the relative liver and kidney weights (compared with
controls) were observed in the monkeys receiving 10 or 20 mg/kg/day PCPMSO. The investigators
did not indicate whether the comparisons of organ weight included animals necropsied at the end of
the recovery period. Further, without body weights or absolute organ weights, these data are
difficult to assess.
Treated monkeys that died or were sacrificed at the end of the treatment period exhibited
compound-related pathologic changes in liver, kidney, adrenal and thyroid glands, lymphoid system,
and intestine. Thake et al. (1979) combined the results for males and females. Lymphoreticular
proliferative lesions in lymph nodes, spleen, and bone marrow were most severe in the highest dosed
animals, but occurred in one animal at 5 mg/kg/day. Also, at the 5 mg/kg/day dose, hepatocyte
vacuolization, vacuolar degeneration, and hepatocyte necrosis occurred in two monkeys during the
treatment period. Liver lesions were also observed at the high dose. Other lesions, which occurred
most frequently at the highest dose, included vacuolization and pigmentation of renal tubular epi-
thelium; adrenal cortex hyperplasia, hemorrtiage, and congestion; follicular cell hyperplasia and
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
degeneration of the thyroid, vacuolization and degeneration of gastric and intestinal epithelium with
cell cycle alterations. None of the monkeys exhibited ophthalmic lesions. A few recovery group
animals at all dose levels exhibited hepatic, renal, and adrenal pathologic changes. Based on the
incidence of hepatic and lymphoreticular proliferative lesions, the LOAEL is 5 mg/kg/day, the lowest
dose tested. A NOAEL could not be determined.
(3) PCPMSQ,
In the 28-day feeding study, Thake et al. (1979) fed Fischer 344 rats (five/sex/dose) diets
containing 0, 281, 562, or 2,250 ppm PCPMS02, which corresponds to calculated doses of 0, 42.2,
84.3, 337.5, and 675 mg/kg/day, respectively (Lehman, 1959). Mortality, body weight, and food
consumption were recorded throughout the study. No mortalities occurred during the study.
Generally, body weight and food consumption decreased in a dose-related manner, however, these
parameters were compared to a control group of Fischer 344 rats used in another feeding study. For
this reason, initial body weights of the animals differed and interpretation of the data is not
completely reliable.
In the mouse feeding study, BsQFj mice (five/sex/dose, except highest male dose with four
mice) were given diets containing PCPMS02 at levels of 0, 281, 562, 2,250, or 4,500 ppm for 28
days (Thake et al., 1979). These levels correspond to calculated doses of 0, 28.1, 56.2, 225, and 450
mg/kg/day, respectively (Lehman, 1959). No deaths occurred. Food consumption data showed no
consistent trends, and the investigators could not adequately interpret the body weight gain data.
In the gavage study, Fischer 344 rats (five/sex/dose) received PCPMS02 in com oil for 28 days
at dose levels of 0, 50, 100, 200, 460 mg/kg/day in 28 mL/kg and 3.12, 6.25, 12.5, 25, 50, or 100
mg/kg/day in 5 mL/kg volumes (Thake et al., 1979). Both sexes exhibited high mortality at 50 mg/
kg/day (60%) and greater dose levels (100%). Hie investigators reported difficulty in interpreting
body weight and food consumption data, noting that most treated animals consumed greater amounts
of feed than controls. At doses greater than 50 mg/kg/day, the rats showed an immediate decrease in
motor activity after each daily treatment. Rats that died became progressively depressed with each
subsequent dose. Signs of depression completely disappeared before termination of the study in all
surviving rats.
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
In a 14-day gavage study, Thake et al. (1979) administered PCPMS02 to male and female
Rhesus monkeys at dose levels of 0, 2.5, 5, 10, 15, 20, or 30 mg/kg/day. The control group, which
served for the PCPMS and PCPMSO controls as well, and the 10 mg/kg/day treatment group each
contained six animals (three/sex). The 2.5 mg/kg/day group contained four animals (two/sex), the 20
mg/kg/day group contained three animals (two females, one male), and the remaining groups each
contained two animals (one/sex). Animals from the three highest dose levels were grouped together
for statistical purposes. The 2.5 and 5 mg/kg/day groups were combined for statistical purposes.
Otherwise, the experimental protocol was the same as that for PCPMS (see paragraph V.B.I.c.(l) of
this review).
One female died on day 9 in the 20 mg/kg/day group and another animal at this dose was
moribund at necropsy on day 15. Both animals at the highest dose (30 mg/kg/day) were moribund
by day 10 and were sacrificed. All other animals appeared normal at necropsy on either day 15 or
29. Anorexia was observed at all dose levels, and depression, weakness, hypothermia, and adipsia at
the 20 and 30 mg/kg/day levels. Thake et al. (1979) attributed the dianhea and emesis exhibited in
control animals and sporadically in treated animals to the corn oil vehicle. No statistically signifi-
cant differences in hematologic parameters were reported. Significantly elevated BUN levels over
pretreatment values were observed on day 7 at 20-30 mg/kg/day (pooled data). This effect persisted
until termination on day 15. At 20-30 mg/kg/day (pooled data), monkeys exhibited a significant
decrease in blood glucose levels, which remained depressed through termination on day 15. Several
other clinical parameters tended to fluctuate in treated as well as control animals.
A statistically significant increase in relative adrenal weights (compared with controls) was
observed in the 20 and 30 mg/kg/day dose groups (pooled data). The investigators did not indicate
whether the comparisons of organ weight were limited to animals sacrificed on or before the end of
the treatment period or included animals necropsied at the end of the recovery period as well.
Further, without body weights or absolute organ weights, these data are difficult to assess.
Treated monkeys that died or were sacrificed at the end of the treatment period exhibited
compound-related pathologic changes in the lymphoid system, kidney, adrenal and thyroid glands,
liver, and intestine. Lymphoreticular proliferative lesions in lymph nodes, spleen, and bone marrow
and lymphoid depletion were more severe in animals dosed with 15 mg/kg/day or greater (pooled
data), but occurred in one animal at 5 mg/kg/day. Animals at 10 mg/kg/day or greater dose levels
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
exhibited adrenal cortex hyperplasia and hemorrhage. Minor hepatocyte vacuolization occurred in
one animal in the pooled 15-30 mg/kg/day groups. Other lesions, observed mainly at doses of
10 mg/kg/day or higher, included vacuolization and pigmentation of renal tubular epithelium;
follicular cell hyperplasia and degeneration of the thyroid; and vacuolization and degeneration of
gastric and intestinal epithelium with cell cycle alterations. None of the monkeys exhibited
ophthalmic lesions. A few recovery group animals at all dose levels exhibited lymphoid, renal,
adrenal, and liver pathologic changes. Based on clinical observations of anorexia, the LOAEL is
2.5 mg/kg/day, the lowest dose tested. A NOAEL could not be determined.
(4) Comparison between PCPMS. PCPMSO. and PCPMSO-,
The 28-day range finding studies in rats (feeding and gavage studies) and mice (feeding study)
showed increased mortality and depressed motor activity in response to all three analogs (Thake et
al., 1979). Data were inadequate to compare body weight gain and food consumption. In rats fed
PCPMS at 9,000 ppm (corresponding to 900 mg/kg/day; highest dose), deaths were not attributed
directly to the compound, but rats fed PCPMSO at 5,200 ppm (corresponding to 520 mg/kg/day;
highest dose) exhibited 80% mortality in males and 60% mortality in females. No mortality occur-
red in rats fed PCPMS02 (highest dose given was 2,250 ppm [corresponding to 250 mg/kg/day]).
Rats appeared more sensitive to all three compounds when administered by gavage rather than by
feeding (Thake et al., 1979). The PCPMS02 analog produced 60% mortality in males and females at
the 50 mg/kg/day dose (the lowest dose at which deaths occurred), indicating that the rats were less
resistent to PCPMS02 than to PCPMS or PCPMSO. Mortality from PCPMS02 increased to 100% at
higher doses. Mortality from PCPMS was 100% in females at 330 mg/kg/day (highest female dose)
and in males at 220 mg/kg/day or greater. Hie PCPMSO gavaged rats exhibited 100% mortality at
400 mg/kg/day (highest dose tested) in both sexes. Decreased motor activity was observed at 50
mg/kg/day or greater for all three compounds.
In the mouse feeding study, 11% of the mice died taking PCPMS at 675 mg/kg/day (highest
dose) and 22% died taking PCPMSO at 780 mg/kg/day (highest dose). Mice exhibited depression
prior to death. No deaths were reported in PCPMS02 mice (highest dose, 675 mg/kg/day).
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
In the 14-day gavage study, monkeys exhibited compound-related effects at the lowest doses
tested (5 mg/kg/day for PCPMS and PCPMSO, and 2.5 mg/kg/day for PCPMSOj). The lowest dose
at which deaths occurred during the treatment period was 20 mg/kg/day for PCPMS and PCPMS02.
No deaths occurred in monkeys treated with PCPMSO. However, animals at 20 mg PCPMSO/kg/
day (highest dose tested) were depressed, one severely. Monkeys treated with PCPMS or PCPMS02
at all dose levels exhibited anorexia. Weakness and depression also occurred at all PCPMS dose
levels. The PCPMSO treated monkeys did not manifest anorexia and depression below 10 mg/kg/
day. Blood urea nitrogen showed a significant increase over pretreatment levels in PCPMSO treated
males and females combined at 10 mg/kg/day or greater and in PCPMS and PCPMS02 animals at 20
mg/kg/day or greater. Alkaline phosphatase was significantly depressed at 10 mg/kg/day or greater
in PCPMS and PCPMSO monkeys. No effect was observed in PCPMS02 rats for this parameter.
Glucose levels were significantly depressed in PCPMS and PCPMS02 treated monkeys at 20 mg/kg/
day but not in PCPMSO monkeys. The PCPMSO analog produced the only significant hemato-
logical change, a depressed reticulocyte count at 10 mg/kg/day or greater.
Although the organ weight data were difficult to assess in the monkeys, PCPMS and PCPMSO
were associated with a significant increase in relative liver and kidney weights over controls, and
PCPMS02 with increased adrenal weights. The PCPMS analog also significantly increased adrenal
weights but only at higher doses than for PCPMS02. Pathologic changes were observed in the livers
of PCPMSO monkeys at all doses and in PCPMS monkeys at 10 mg/kg/day or greater. Only minor
liver pathology occurred in PCPMS02 animals at 15-30 mg/kg/day (pooled data). Significant patho-
logic lesions also occurred in the lymphoid system in monkeys treated with all three analogs.
Lymphoid lesions were most prominent at the higher doses but did occur in PCPMSO and
PCPMS02 treated rats at 5 mg/kg/day. The LOAEL for PCPMS is 5 mg/kg/day based on the
incidence of anorexia, depression, and weakness at the lowest dose. The LOAEL for PCPMSO is
5 mg/kg/day based on liver and lymphoid system lesions at the lowest dose. The LOAEL for
PCPMS02 is 2.5 mg/kg/day based on the incidence of anorexia at the lowest dose. A NOAEL could
not be determined for any of the compounds.
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September 1992
2. Longer-term Exposure
(1) PCPMS
Thake et al. (1979) studied the effects of PCPMS on Fischer 344 rats (16/sex/dose plus 24
controls/sex) fed the compound in the diet for 13 weeks. Rats were fed diets containing 0, 750,
1,500, or 3,000 ppm PCPMS, which based on reported body weight and food consumption data
correspond to calculated doses of 0, 60, 113, and 223 mg/kg/day, respectively, for males and 0, 57,
111, or 211 mg/kg/day, respectively, for females. Interim sacrifices at week 4 and 8 and after a 14-
day recovery group were conducted at all dose levels. The number of rats sacrificed at each interim
period was not specified. Clinical observations were not reported. Body weight, food consumption,
and hematology and clinical chemistry parameters were evaluated in rats sacrificed at 4, 8, and 13
weeks. All tissues from high-dose and control animals sacrificed at 4 and 13 weeks were examined
histopathologically. If lesions were present in these animals, the tissues that contained the lesions
were examined at succeedingly lower doses until a level was reached where the lesions were not
apparent.
All rats survived the study period. Body weights and body weight gains of all treated males and
females were significantly (p <0.05) depressed throughout the dosing period when compared with
concurrent controls, and the body weights of these animals remained depressed following the 14 days
of recovery even though there was increased growth during this time, especially in animals at the
highest dose. Food consumption was significantly depressed in animals at 3,000 ppm and was
depressed in 1,500 ppm dosed animals at weeks 4 and 8. Total food consumption was significantly
less for males and females in the mid- and high-dose groups. Depressed food and water consump-
tion in the initial stages of treatment was attributed to poor palatability, especially at the highest
dose, as well as to toxicity. Also at the highest dose, animals exhibited ocular and nasal discharges,
similar to those observed following acute exposure (see paragraph V.B.I.a), and inactivity was
common.
Hemoglobin, hematocrit, and erythrocyte counts for male and female rats at 13 weeks were
significantly (p <0.05) depressed compared with controls at all dose levels, and among females at the
highest dose these parameters remained depressed following the recovery period. Because these
changes were beyond the normal range for this species, they were considered biologically important.
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September 1992
Small but statistically significant changes in mean corpuscular volume, mean corpuscular hemo-
globin, and mean corpuscular hemoglobin concentration were not considered biologically significant.
Significant differences in the clinical chemistry of treated animals compared with controls were
observed, but most of the differences were small and not considered biologically important (Thake et
al., 1979). Serum potassium and calcium levels in both sexes at all treatment levels were signifi-
cantly elevated, and potassium and alkaline phosphatase levels were significantly depressed at all
dose levels in males and at the mid- and high-dose levels in females. Males at all treatment levels
and females at the high dose exhibited significantly depressed SGOT values. Clinical chemistry
parameters for recovery group rats were not compared to rats sacrificed at 13 weeks.
In female rats at all dose levels, significant decreases between treated animals and controls
occurred in the absolute weights of uterus, spleen, pituitary, and heart, and significant increases
occurred in the kidney and liver weights. Also in females, brain weights at the mid- and high-dose
levels were significantly decreased and adrenal weights were significantly decreased at the 3,000
ppm (high) dose. Males in all dose groups exhibited a significant decrease in brain and seminal
vesicle weights and an increase in adrenal and liver weights. Also in males, heart and testicle
weights were decreased significantly at the high dose; at the mid- and high-dose, spleen weight was
decreased. Lower heart, pituitary, thyroid, brain, spleen, testicle, and ovary weights in treated rats
were approximately proportional to decreases in body weight
The principal pathological changes included hepatic megalocytosis of centrilobular hepatocytes
with syncytial cell formation, multifocal coagulative hepatic necrosis, and hepatic vacuolar
cytoplasmic change in males and females. The incidence of these findings for both sexes is
presented in Tables V-2 and V-3, respectively. The incidence of hepatic megalocytosis, the most
prevalent finding, occurred in 100% of the animals examined at each dose level. The incidence of
hepatic lesions in high-dose male and female rats following the 14-day recovery period is presented
in Table V-4. Generally, the incidence of hepatic lesions decreased following recovery but remained
prevalent in male rats. Based on depression of body weights, hematologic and serum chemistry
changes, increased liver weights, and hepatic pathology, the LOAEL is 750 ppm (calculated to be 60
mg/kg/day in males and 57 mg/kg/day in females). The NOAEL cannot be determined.
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
Table V-2. Incidence of Compound-Related Hepatic Lesions in Male Rats Fed p-Chlorophenyl
Methyl Sulfide, -Sulfoxide, -Sulfone (PCPMS, PCPMSO, and PCPMS O2)
Number
Findings
Chemical
Dose
(ppm)
Animals
Examined
Necrosis
Megalocytosis
Vacuolar Cyto-
plasmic Change
PCPMS
3,000
10
0
10
0
1400
10
0
10
0
750
10
2
10
1
PCPMSO
3,000
10
3
7
0
1,500
10
1
10
0
750
10
0
10
0
PCPMSOj
3,000
10
0
9
0
1,500
10
0
10
1
750
10
0
9
0
Control
0
24
0
0
0
SOURCE: Adapted from Thake et al. (1979)
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
Table V-3. Incidence of Compound-Related Hepatic Lesions in Female Rats Fed p-Chlorophenyl
Methyl Sulfide, -Sulfoxide, -Sulfone (PCPMS, PCPMSO, and PCPMS Oj)
Chemical
Dose
(ppm)
Number
Findings
Animals
Examined
Necrosis
Megalocytosis
Vacuolar Cyto-
plasmic Change
Sinusoidal
Ectasia
PCPMS
3,000
10
1
9
0
0
1,500
10
0
10
5
0
750
10
0
10
5
0
PCPMSO
3,000
10
0
9
2
0
1,500
10
0
10
8
0
750
10
0
10
0
0
PCPMSOj
3,000
10
0
10
0
0
1,500
10
1
10
5
0
750
10
0
10
10
1
Control
0
24
0
0
0
0
SOURCE: Adapted from Thake et al. (1979)
Table V-4. Incidence of Hepatic Lesions in Rats Fed 3,000 ppm p-Chlorophenyl Methyl Sulfide,
-Sulfoxide, -Sulfone (PCPMS, PCPMSO, and PGPMSOj) Following a 14-Day Recovery
Period
PCPMS
PCPMSO
PCPMSO,
Hepatic Lesion
Males (3)'
Females (3)
Males (5)
Females (3)
Males (3)
Females (3)
Necrosis
1
0
0
0
0
0
Megalocytosis
3
0
3
0
2
0
Vacuolar Cyto-
plasmic Change
0
0
2
1
0
1
*Number of animals examined
SOURCE: Adapted from Thake et al. (1979)
A-35
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
Thake et al. (1979) studied the effects of PCPMS on B6C3F, mice (16/sex/dose plus 33 male and
34 female controls) fed the compound in the diet for 13 weeks. Mice were fed diets containing 0,
750, 1,500, 3,000, or 6,000 ppm PCPMS, which based on reported body weight and food consump-
tion data correspond to calculated doses of 0, 108, 182, 426, and 840 mg/kg/day, respectively, for
males and 0, 109,180, 259, and 517 mg/kg/day, respectively, for females. Body weight and food
consumption data were not reported for the 6,000 ppm PCPMS group, which died early in the study.
Interim sacrifices at week 4 and 8 and after a 14-day recovery group were conducted at all dose
levels. The exact number of mice sacrificed at each interim period was not specified. Body and
absolute organ weights and food consumption were evaluated. Clinical observations and hematology
and clinical chemistry parameters were not measured. All tissues from high dose and control
animals sacrificed at 4 and 13 weeks were examined histopathologically. If lesions were present in
these animals, the tissues that contained the lesions were examined at succeedingly lower doses until
a level was reached where the lesions were not apparent.
All mice dosed with 6,000 ppm PCPMS died within the first two weeks. Twelve females and
five males at the 3,000 ppm dose died during the first week of treatment (Table V-5). One male and
one female control mouse died as a result of wounds received during group housing or handling.
Weekly body weights were significantly depressed compared with controls throughout the study in
male mice at all treatment levels. Weekly body weights and total body weight gains for female mice
were statistically equivalent to control mice. Food consumption, though highly variable, was
generally depressed in treated mice compared with controls. Both sexes at the 3,000 ppm dose
exhibited a significant increase in absolute liver weights compared to controls. Absolute kidney
weights in all treated males were significantly less than those of controls. Males also exhibited
significantly decreased brain weights at the 1,500 and 3,000 ppm dose levels and decreased seminal
vesicle weight at the 3,000 ppm dose. Dose-related hepatic lesions, similar to those described in the
rat 13-week study (Thake et al., 1979), were observed in both sexes but more frequently in males
(Table V-6). Pulmonary lesions, characterized by bronchial and bronchiolar epithelial degeneration,
were observed in females at the 3,000 ppm dose. Based on hepatic lesions at the low dose, the
LOAEL is 108 mg/kg/day for males and 109 mg/kg/day for females. A NOAEL could not be
determined.
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
Table V-5. Cumulative Mortality at Selected Intervals for Mice Fed p-Chlorophenyl Methyl Sulfide,
-Sulfoxide, -Sulfone (PCPMS, PCPMSO, and PCPMSO^ for 13 weeks*
Chemical/
Dose (ppm)
Week 1
Week 2
Week 7
Week 13
Males
Females
Males
Females
Males
Females
Males
Females
PCPMS
6,000
h
—
—
—
—
—
—
—
3,000
5
12
5
12
5
12
5
12
1,500
0
0
0
0
0
0
0
0
750
0
0
0
0
0
0
0
0
PCPMSO
5,000
16
16
16
16
16
16
16
16
3,000
1
4
1
7
3"
7
3
7
1,500
0
0
0
0
3C
2C
3
2
750
0
0
0
0
0
0
0
0
PCPMSO,
6,000
12
10
16
15
16
15
16
15
3,000
0
0
0
0
0
0
0
0
1,500
0
0
0
0
0
0
0
0
750
0
0
0
0
0
0
0
0
Control
l °
0
0
0
lc
1
1
1
'Based on 33 male and 34 female controls and 16 mice/sex/compound
bAll animals died before week 2; specific mortality data were not reported
'Deaths of animals attributed to trauma from fighting, which occurred during weeks 4 and S from a
24-hour period of multiple housing (with the exception of one male dosed with 3,000 ppm
PCPMS02 that died during week 2)
SOURCE: Adapted from Thake et al. (1979)
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
Table V-6. Incidence of Hepatic and Pulmonary Lesions in Mice Fed p-Chlorophenyl Methyl
Sulfide, -Sulfoxide, -Sulfone (PCPMS, PCPMSO, and PCPMSO2) for 13 weeks
Organ Lesions
Liver
Lung
Chemical/
Dose (ppm)/
Sex
Necrosis
Megalocytosis
Vascular
Cytoplasmic
change
Bronchial and
Bronchiolar
Epithelial
Degeneration
Bronchiolar
Papillary
Hyperplasia
PCPMS
3,000 M (10)*
3
6
0
0
0
F (10)
1
4
1
3
0
1,500 M (10)
0
3
0
0
0
F (9)
0
0
0
0
0
750 M (9)
0
1
0
0
0
F (11)
0
0
0
0
0
PCPMSO
3,000 M (10)
7
8
0
2
1
F (10)
3
7
0
0
0
1,500 M (10)
0
3
0
0
0
F (10)
0
0
0
0
0
750 M (10)
0
1
0
0
0
F (10)
0
1
0
0
0
PCPMSOi
3,000 M (10)
2
4
3
10
0
F (10)
0
4
2
10
0
1,500 M (10)
0
4
0
0
0
F (9)
0
0
0
0
0
750 M (10)
0
1
0
0
0
F (10)
0
1
0
0
0
Control M (24)
0
0
3
0
0
F (22)
0
0
0
0
0
*Numbers in parentheses indicate the number of animals examined
SOURCE: Adapted from Thake et al. (1979)
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
(2) PCPMSO
Thake et al. (1979) studied the effects of PCPMSO on Fischer 344 rats (16/sex/dose plus 24
controls/sex) fed the compound in the diet for 13 weeks. Rats were fed diets containing 0, 750,
1,500, or 3,000 ppm PCPMSO, which based on reported body weight and food consumption data
correspond to a calculated doses of 0, 61,123, and 246 mg/kg/day, respectively, for males and 0, 67,
127, and 234 mg/kg/day, respectively, for females. For further experimental details, see PCPMS
(paragraph V.B.2.(1) of this review).
Deaths, considered compound related by the investigators, occurred at the 3,000 ppm level in six
male rats, which like most male rats at this level were severely emaciated throughout the study.
Body weights and body weight gains of all treated males and females were significantly (p <0.05)
depressed throughout the dosing period when compared with concurrent controls, and the body
weights of these animals remained depressed following the 14 days of recovery even though there
was increased growth during this time, especially in animals at the highest dose. Food consumption
decreased in a dose-related manner. Significant decreases in food consumption occurred during
week 8 in males and females at the 3,000 ppm level. Depressed food and water consumption in the
initial stages of treatment was attributed to poor palatability, especially at the highest dose, as well as
to toxicity. At the highest dose, animals exhibited ocular and nasal discharges, similar to those
observed following acute exposure (see V.B.l.a), and inactivity was common.
Hematocrit and erythrocyte count in males and hemoglobin and hematocrit in female rats at 13
weeks were significantly depressed at all dose levels compared with controls, and among females at
the highest dose these parameters remained depressed following the recovery period. The investi-
gators considered these changes to be beyond the normal range for this species, and thus biologically
important (Thake et al., 1979). Small but statistically significant changes in mean corpuscular
volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were not
considered biologically significant. Significant differences in the clinical chemistry of treated
animals compared with controls were observed, but most of the differences were small and probably
not biologically important. SGOT and alkaline phosphatase were significantly depressed, and
potassium and calcium levels significantly elevated in males at all dose levels. Sodium was signifi.
cantly depressed in males at the high dose. In females, alkaline phosphatase and sodium were
significantly depressed in all dose groups. Other significant changes in females included a depressed
A-39
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
SGOT and elevated calcium levels at the mid- and high-doses, and depressed SGPT at the high dose.
Clinical chemistry parameters for recovery group rats were not compared with rats sacrificed at 13-
weeks.
In all dose groups of both sexes, significant decreases between treated animals and controls
occurred in the absolute weights of the pituitary, and significant increases occurred in the liver. In
addition, males exhibited a significant decrease in the heart and adrenal gland weights at all dose
levels and in brain, testicles, and seminal vesicles at mid- or high-doses. Significant decreases in
females occurred in spleen, ovaries, and uterus at all dose levels and in brain and heart at the high
dose. Kidney weights significantly increased in females at all doses. Decrements in heart, pituitary,
thyroid, brain, spleen, testicle, and ovary weights in treated rats were approximately proportional to
decreases in body weight.
The principal pathological changes included hepatic megalocytosis of centrilobular hepatocytes
with syncytial cell formation, multifocal coagulative hepatic necrosis, and hepatic vacuolar cyto-
plasmic change. The incidence of these findings for male and female rats is presented in Tables V-2
and V-3, respectively. The incidence of hepatic megalocytosis, the most prevalent finding, occurred
in 70 to 100% of the animals examined at each dose level. The incidence of hepatic lesions in high-
dose male and female rats following the 14-day recovery period is presented in Table V-4.
Generally, the incidence of hepatic lesions decreased following recovery but remained prevalent in
male rats. Based on depression of body weights, hematologic and serum chemistry changes,
increased liver weights, and hepatic pathology, the LOAEL is 750 ppm (calculated to be 61 mg/kg/
day in males and 67 mg/kg/day in females). The NOAEL could not be determined.
Thake et al. (1979) studied the effects of PCPMSO on BgC^Fj mice (16/sex/dose plus 33 male
and 34 female controls) fed the compound in the diet for 13 weeks. Mice were fed diets containing
0,750, 1,500, 3,000, or 5,000 ppm PCPMSO, which based on reported body weight and food
consumption data correspond to calculated doses of 0, 112, 224, 377, and 628 mg/kg/day, respect-
ively, for males and 0, 70, 235, 318, and 530 mg/kg/day, respectively, for females. Body weight and
food consumption data were not reported for the 5,000 ppm PCPMSO group, though the investi-
gators noted that marked decreases in these measures occurred prior to death, which occurred in all
animals at this dose during the first week of treatment. See PCPMS (paragraph V.B.2.(1) of this
review) for experimental details.
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
Seven female mice and one male at the 3,000 ppm dose died by the end of week 2 (Table V-5).
Seven other deaths occurred at the 1,500 or 3,000 ppm dose levels, but these deaths were attributed
to trauma from fighting when multiple housed for 24 hours during week 4, rather than treatment.
Weekly body weights were significantly depressed compared with controls throughout the study in
male mice at the 1,500 and 3,000 ppm dose levels. At week 13, females also showed a significant
decrease in body weight compared to controls at the 1,500 and 3,000 ppm levels. Food consump-
tion, though highly variable, was significantly depressed at week 13 in males at the 1,500 and 3,000
ppm dose levels. Both sexes at the 3,000 ppm dose exhibited a significant increase in absolute liver
weights compared to controls, and both sexes had decreased spleen weights at the 1,500 and 3,000
ppm level at week 13. Ovaries in females and adrenals in males also were significantly decreased at
the 1,500 and 3,000 ppm dose levels. Dose-related hepatic lesions, similar to those described in the
rat 13-week study (Thake et al„ 1979), were observed in both sexes (Table V-6). Two males at the
3,000 ppm dose exhibited bronchial and bronchiolar epithelial degeneration. Based on hepatic
lesions at the low dose, the LOAEL is 112 mg/kg/day for males and 70 mg/kg/day for females. The
NOAEL could not be determined.
(3) PQPMSOj
Thake et al. (1979) studied the effects of PCPMS02 on Fischer 344 rats (16/sex/dose plus 24
controls/sex) fed the compound in the diet for 13 weeks. Rats were fed diets containing 0, 750,
1,500, or 3,000 ppm PCPMS02, which based on reported body weight and food consumption data
correspond to a calculated doses of 0, 57,115, and 240 mg/kg/day, respectively, for males and 0, 54,
122, or 220 mg/kg/day, respectively, for females. See experimental details for PCPMS (paragraph
V.B.2.(1) of this review).
All rats survived the study period with the exception of one male that died spontaneously during
week 4 at the 750 ppm dose level. The investigators did not consider this death to be compound
related. Body weights and body weight gains of all treated males and females (except in 750 ppm
females at week 4) were significantly (p <0.05) depressed throughout the dosing period when
compared with concurrent controls. The body weights of these animals remained depressed
following the 14 days of recovery even though there was increased growth during this time,
especially in animals at the highest dose. Total food consumption for the 13 week treatment period
was decreased in a dose-related manner for both males and females. Statistically significant dose-
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
related decreases in food consumption occurred in week 4 for both males and females at the mid-
and high-dose levels. However, by week 8 and 13, food consumption in some groups exceeded that
of the controls. Depressed food and water consumption in the initial stages of treatment was
attributed to poor palatability, especially at the highest dose, as well as to toxicity. Also at the
highest dose, animals exhibited ocular and nasal discharges, similar to those observed following
acute exposure (see paragraph V.B.I.a), and inactivity was common.
Hematocrit and erythrocyte count in both sexes and hemoglobin in females at 13 weeks were
significantly depressed (p <0.05) at all dose levels compared with controls, and among females at the
highest dose these parameters remained depressed following the recovery period. Because these
changes were beyond the normal range for this species, they were considered biologically important
(Thake et al., 1979). Small but statistically significant changes in mean corpuscular volume, mean
corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were not considered bio-
logically significant. Significant differences in the clinical chemistry of treated animals compared
with controls were observed, but the investigators considered most of these differences small and not
biologically important. Blood urea nitrogen in males and potassium in both sexes were significantly
elevated in all dose groups at 13 weeks. Sodium in females and alkaline phosphatase in both sexes
was significantly depressed at all dose levels. Clinical chemistry parameters for recovery group rats
were not compared to rats dosed for 13 weeks.
In all dose groups of both sexes, the absolute weights of liver and kidney increased significantly
over controls by week 13, and spleen weights decreased. In males, brain weights decreased and
adrenal weights increased significantly in all dose groups. Also, heart weights decreased signifi-
cantly at the high dose. In females at the mid- and high-dose levels, heart and pituitary weights
generally decreased. Lower heart, pituitary, thyroid, brain, spleen, testicle, and ovary weights in
treated rats were approximately proportional to decreases in body weight.
The principal pathological changes included hepatic megalocytosis of centrilobular hepatocytes
with syncytial cell formation, multifocal coagulative hepatic necrosis, and hepatic vacuolar cyto-
plasmic change. The incidence of these findings for males and females is presented in Tables V-2
and V-3, respectively. The incidence of megalocytosis, the most prevalent finding, occurred in 90 to
100% of the animals examined at each dose level. The incidence of hepatic lesions in high-dose
male and female rats following the 14-day recovery period is presented in Table V-4. Generally, the
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
incidence of hepatic lesions decreased following recovery but remained prevalent in male rats.
Based on depression of body weights, hematologic and serum chemistry changes, increased liver
weights, and hepatic pathology, the LOAEL is 750 ppm (calculated to be 57 mg/kg/day in males and
54 mg/kg/day in females). The NOAEL could not be determined.
Thake et al. (1979) studied the effects of PCPMS02 on BgCjFj mice (16/sex/dose plus 33 male
and 34 female controls) fed the compound in the diet for 13 weeks. Mice were fed diets containing
0, 750,1,500, 3,000, or 6,000 ppm PCPMS02, which based on reported body weight and food
consumption data correspond to calculated doses of 0, 106, 183, 445, and 890 mg/kg/day,
respectively, for males and 0, 86, 204, 340, and 680 mg/kg/day, respectively, for females. Body
weight and food consumption data were not reported for the 6,000 ppm PCPMS02 group, though the
investigators noted that marked decreases in these measures occurred prior to death, which occurred
in all but one animal at this dose within the Hist 2 weeks of treatment. See experimental details for
PCPMS (paragraph V.B.2.(1) of this review).
No deaths, other than those that occurred in the 6,000 ppm dose groups, were observed (Table
V-5). Weekly body weights were significantly depressed compared with controls throughout the
study in male and female mice at all treatment levels. Dose-related decreases in food consumption
occurred at all dose levels in both sexes. Absolute kidney weights in males showed a significant
decrease at the 3,000 ppm dose and significant increases at the lower doses. Significant decreases in
males were observed in adrenal, brain, and testicle weights at all treatment levels and in seminal
vesicles at the 1,500 and 3,000 ppm dose levels. Females at all dose levels exhibited a significant
decrease in spleen weight and a significant increase in heart weight. Brain weight was also
decreased at the highest dose in females. Dose-related hepatic lesions, similar to those described in
the rat 13-week study (Thake et al., 1979), were observed in both sexes (Table V-6). All animals
examined (10/sex) at the 3,000 ppm dose exhibited bronchial and bronchiolar epithelial degeneration.
Based on hepatic lesions at the low dose, the LOAEL is 750 ppm (106 mg/kg/day for males and 86
mg/kg/day for females). The NOAEL could not be determined.
(4) Comparison between PCPMS. PCPMSQ. and PCPMSO.
In the Thake et al. (1979) 13-week rat study, PCPMS and PCPMS02 caused no compound-
related deaths at dose levels up to 3,000 ppm (the highest dose tested). This corresponds to 223 mg/
A-43
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
kg/day in males and 211 mg/kg/day in females for PCPMS and 240 and 220 mg/kg/day in males and
females, respectively for PCPMS02. However, a 38% mortality occurred among male rats fed
PCPMSO at the 3,000 ppm level (246 mg/kg/day). All three compounds caused significant reduc-
tions in body weight, body weight gain, and food consumption compared with controls. The only
toxicological symptoms reported were ocular and nasal discharges in rats treated at the high dose
with each compound.
All compounds at all dose levels significantly depressed hematocrit and erythrocyte counts
compared with controls. The PCPMS treated rats also exhibited reduced hemoglobin at all dose
levels. All three compounds significantly depressed serum alkaline phosphatase levels in both sexes
at all dose levels except females at the low PCPMS dose. Also, all three compounds significantly
increased serum potassium and calcium levels at all dose levels. Only PCPMS and PCPMSO
significantly reduced SGOT levels at all doses in males and at the highest dose levels in females.
The PCPMS02 analog significantly depressed BUN levels in both sexes at all doses, an effect not
observed with the other compounds. Thus, in general, all three compounds had similar effects on the
hematology and clinical chemistry parameters tested. The most notable exceptions were the absence
of SGOT effects in PCPMS02 treated rats and the absence of elevated BUN levels in PCPMS and
PCPMSO treated rats.
Absolute liver weights in rats treated with all three compounds were significantly elevated
compared with controls in both sexes at all dose levels. In addition, significantly reduced spleen
weights were found in rats treated at some or all dose levels with all three compounds. Kidney
weights were increased and pituitary weights were decreased in PCPMSO and PCPMSOj rats, but
not in PCPMS rats. The most prevalent pathologic lesions were hepatic megalocytosis in 100% of
the rats treated with PCPMS, 70-100% of rats treated with PCPMSO, and 90-100% treated with
PCPMS02. Based on increased liver weights, hepatic pathology, hematologic and serum chemistry
changes, and depressed body weight, the lowest dose tested was the LOAEL for each compound. A
NOAEL could not be determined.
The mouse 13-week feeding study revealed mortality, significant reductions in body weight and
food consumption, changes in absolute organ weights, and hepatic and pulmonary pathology for all
three compounds (Thake et al„ 1979). At the 6,000 ppm PCPMS or PCPMS02 dose and the 5,000
ppm PCPMSO dose, all but one PCPMSOz animal died before the end of week 2 of the study. In
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
addition, mortality was 53% in PCPMS treated mice at 3,000 ppm (182 mg/kg/day and 180 mg/kg/
day in males and females, respectively) and 25% in PCPMSO treated mice at 3,000 ppm (224 mg/
kg/day and 235 mg/kg/day in males and females, respectively. Except for the deaths at the 6,000
ppm dose, PCPMS02 produced no other compound-related deaths. All three analogs caused signifi-
cant reductions in body weight, body weight gain, and food consumption compared with controls.
The PCPMSO and PCPMSOz analogs significantly reduced spleen weights compared with controls,
and PCPMS and PCPMS02 significantly changed kidney weights. Both PCPMS and PCPMSO
increased liver weights at the 3,000 ppm dose in both sexes. All three compounds were associated
with lesions, mainly hepatic megalocytosis at all dose levels. Based on the hepatic lesions, the
lowest dose tested was the LOAEL for each compound. A NOAEL could not be determined for any
of the compounds.
3. Reproductive Effects
(1) PCPMS
No studies on the reproductive effects of PCPMS were found in the literature.
(2) PCPMSO
No studies on the reproductive effects of PCPMSO were found in the literature.
(3) PCPMSO,
No studies on the reproductive effects of PCPMS02 were found in the literature.
(4) Comparison between PCPMS. PCPMSO. and PCPMSO,
No studies on the reproductive effects of PCPMS, PCPMSO, or PCPMS02 were found in the
literature.
A-45
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A September 1992
4. Developmental Toxicity
(1)PCPMS
No studies on the developmental effects of PCPMS were found in the literature.
(2) PCPMSO
No studies on the developmental effects of PCPMSO were found in the literature.
(3) PCPMSO,
No studies on the developmental effects of PCPMS02 were found in the literature.
(4) Comparison between PCPMS. PCPMSO. and PCPMSO,
No studies on the developmental effects of PCPMS, PCPMSO, or PCPMS02 were found in the
literature.
5. Carcinogenicity
(1) PCPMS
No studies on the carcinogenic effects of PCPMS were found in the literature.
(2) PCPMSO
No studies on the carcinogenic effects of PCPMSO were found in the literature.
(31 PCPMSO,
No studies on the carcinogenic effects of PCPMS02 were found in the literature.
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
(4) Comparison between PCPMS. PCPMSO. and PCPMSO.,
No studies on the carcinogenic effects of PCPMS, PCPMSO, or PCPMS02 were found in the
literature.
6. Genotoxicitv
m PCPMS
Samples of >99% pure PCPMS were evaluated for the potential to induce gene mutations in
Salmonella typhimurium TA1535, TA1537, TA1538, TA98, and TA100 (Thake et al., 1979). At
least two independent experiments, which included a nonactivated and an S9-activated phase with
either Aroclor 1254- or phenobarbital-induced rat liver microsomes, were performed. Summarized
results are presented in Table VI-7.
Five nonactivated and five Aroclor 1254 S9-activated doses ranging from 0.01 to 100 jiL/plate
were not mutagenic in any test strain. Cytotoxicity was, however, apparent for all strains at the two
highest doses (10 and 100 pL/plate +/-S9).
The independent trial was performed with a lower dose range (0.01 to 0.3 pL/plate) in both the
absence and presence of phenobaibital-induced S9. The study authors stated that the lower dose
range was necessary because PCPMS was found to be unstable in the solvent, dimethylsulfoxide
(DMSO). The sample assayed in the repeat trial was used within 3 hours of preparation, and the
sample evaluated in the initial trial was prepared in DMSO and stored for "longer periods of time."
The test material was not mutagenic in the repeat assay, and cytotoxicity was achieved at 0.3 pLV
plate +/-S9. However, the overall study with PCPMS should be considered incomplete. Conditions
were not optimum for the detection of potential mutagenesis induced by a "biologically active" form
of the test material in the presence of the Aroclor S9 fraction.
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p-Chlorophenyl methyl sulfide, -sulfoxide, and -sulfone: Appendix A
September 1992
Table V-7. Ames Bacterial Mutagenicity Assays of p-Chlorophenyl Methyl Sulfide, -Sulfoxide,
-Sulfone (PCPMS, PCPMSO, and PCPMSOj)
Strain
Activation
Dose/
Concentration
Toxic Effect
Independent
Evaluation*
PCPMS
Salmonella
typhimurium
TA1535, TA1537,
TA1538, TA98,
TA100
± S9 Aroclor 1254
induction
100, 10, 1, 0.1,
0.01, 0.0 pL/plate
Cytotoxic ± S9 at
doses £10
pL/plate all
strains; no
mutagenicity
Invalid; unstable form of
test material assayed
± S9 Phenobarbital
induction
0.3, 0.1, 0.05, 0.03,
0.01, 0.0 pL/plate
Cytotoxic ± S9 at
0.3 pL/plate all
strains; no muta-
genicity
Acceptable evidence of a
negative response, but
overall study is
incomplete because it
lacks acceptable Aroclor
1254 S9 activation assay
PCPMSO
Salmonella
typhimurium
TA1535, TA1537,
TA1538, TA98,
TA100
± S9 Aroclor 1254
induction
500, 100, 10, 1, 0.1,
0.0 pL/plate
No cytotoxicity;
no mutagenicity
Unacceptable; inadequate
high dose
± S9 Phenobarbital
induction
1,000, 300, 100, 30,
10, 0.0 pL/plate
No cytotoxicity;
no mutagenicity
Unacceptable; inadequate
high dose
PCPMS02
Salmonella
typhimurium
TA1535, TA1537,
TA1538, TA98,
TA100
± S9 Aroclor 1254
induction
500, 100, 10, 1, 0.1,
0.0 jig/plate
No cytotoxicity;
no mutagenicity
Unacceptable; inadequate
high dose
± S9 Phenobarbital
induction
1,000, 300, 100, 30,
10, 0.0 jig/plate
No cytotoxicity;
no mutagenicity
Unacceptable; inadequate
high dose
Independent evaluation by the authors of this review document
SOURCE: Adapted from Thake et at. (1979)
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September 1992
(2) PCPMSO
Samples of >99% pure PCPMSO were evaluated for the potential to induce gene mutations in
Salmonella typhimurium TA1535, TA1537, TA1538, TA98, and TA100 (Thake et al„ 1979). At
least two independent experiments, which included a nonactivated and an S9-activated phase with
either Aroclor 1254- or phenobarbital-induced rat liver microsomes, were performed. Summarized
results are presented in Table VI-7.
Dose ranges evaluated were 0.1 to 500 pL/plate -/+ Aroclor S9 and 10 to 1,000 pL/plate -/+
phenobarbital S9. Under both nonactivated and S9-activated conditions, the test material was neither
cytotoxic nor mutagenic in any test strain. The lack of a cytotoxic response at the highest assayed
level renders the study invalid. Without some evidence that the test material was assayed to either a
cytotoxic level, the limit of solubility, or the recommended high dose (5,000 jag PCPMSO/plate), the
findings should not be considered acceptable evidence of a negative response in this test system.
(3) PCPMSO.
Samples of >99% pure PCPMS02 were evaluated for the potential to induce gene mutations in
Salmonella typhimurium TA1535, TA1537, TA1538, TA98, and TA100 (Thake et al., 1979). At
least two independent experiments, which included a nonactivated and an S9-activated phase with
either Aroclor 1254- or phenobarbital-induced rat liver microsomes, were performed. Summarized
results are presented in Table VI-7.
Five doses of PCPMS02 ranging from 0.1 to 500 )ig/plate -/+ Aroclor 1254 S9 or from 10 to
1,000 jig/plate -/+ phenobarbital S9 failed to induce a cytotoxic or mutagenic response in any of the
tester strains. For the reasons given above, these findings are considered inadequate evidence of a
valid negative response in this test system.
(4) Comparison between PCPMS. PCPMSO. and PCPMSO.
The overall findings of this study indicate that without S9 and with phenobarbital-induced S9
activation, PCPMS is not mutagenic in S. typhimurium. No conclusions can be drawn from the
studies performed with PCPMSO or PCPMS02. With the exception of this bacterial gene mutation
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September 1992
assay, no other genetic toxicology studies with any of the three compounds were found in the
available literature.
C. CARCINOGENIC POTENTIAL
Applying the criteria described in EPA's guidelines for assessment of Carcinogenic Risk (U.S.
EPA, 1986), PCPMS, PCPMSO, and PCPMS02 are classified in Group D: not classifiable as to
human carcinogenicity.
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September 1992
VI. OTHER CRITERIA, GUIDANCE, AND STANDARDS
No information has been reported on the criteria and standards of p-chlorophenyl methyl sulfide
(PCPMS), p-chlorophenyl methyl sulfoxide (PCPMSO), and p-chlorophenyl methyl sulfone
(PCPMSOj).
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September 1992
VH. ANALYTICAL METHODS
Gas chromatography (GC) with sulfur-specific flame photometric detection is the most sensitive
method to detect and quantify the three sulfur compounds, p-chlorophenyl methyl sulfide (PCPMS),
p-chlorophenyl methyl sulfoxide (PCPMSO), and p-chlorophenyl methyl sulfone (PCPMSOj) (Miller
et al., 1976). Elution times were 14.1 minutes for PCPMS, 21.5 minutes for PCPMSO, and 27.1
minutes for PCPMS02. The extraction efficiencies were 90, 90, and 98%, respectively, for the three
compounds. The detection limit was approximately 10 ppb.
Other analytical methods include gas chromatography/mass spectroscopy (GC/MS), and electron
capture/GC (Miller et al., 1976; Blair et al., 1982). Detection methods include infrared and Raman
spectroscopy, ultraviolet spectroscopy, and proton magnetic resonance (Miller et al, 1976).
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VIE. TREATMENT TECHNOLOGIES
No information was reported on the treatment technology of p-chlorophenyl methyl sulfide
(PCPMS), p-chlorophenyl methyl sulfoxide (PCPMSO), and p-chlorophenyl methyl sulfone
(PCPMSO2).
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Blair LC, Plewa MJ, Gentile JM. 1982. The use of a model sulfide compound to study mono-
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chlorophenyl methyl sulfide, -sulfoxide, and -sulfone in soil. J. Environ. Qual. 50(4):532-536.
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Knaus JK. 1976. Acute toxicity data and plant physiology data for p-chlorophenyl methyl sulfide,
sulfoxide, and sulfone. Enclosure 3 to letter, HQDA, SAREA-CL-DC, Subject: Minutes-Analytical
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PMRMA. 1991. Program Manager for Rocky Mountain Arsenal. Contract No. DAAA 15-87-0095.
Annual groundwater report for 1990. Final Report. Version 1.1. Commerce City, CO: U.S. Army
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Sax IN. 1984. Dangerous Properties of Industrial Materials, 6th Ed. New York: Van Nostrand
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Thake D, Mays D, Leber P, Metcalf D, Bavda L. 1979. Mammalian toxicological evaluation of p-
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