v>EPA
United States
Environmental Protection
Agencv
Office of Pesticides and
Toxic Substances
Washington DC 20460
EPA-560/13-79-018
December 1980
Pesticides and Toxic Substances
Metabolism Summaries
of Selected Halogenated
Organic Compounds in
Human and Environmental
Media, A Literature Survey
First Update
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Metabolism Summaries of Selected
Halogenated Organic Compounds
In Human and Environmental Media,
A Literature Survey
FIRST UPDATE
SYED M. NAQVI
Department of Biology
Southern University
Baton Rouge, Louisiana
Environmental Protection Agency
Summer Faculty Program
MARION C. BLOIS
Department of Biology
Northern Virginia Community College
Manassas, Virginia
Environmental Protection Agency
Summer Faculty Program
December, 19SO
Joseph J. Breen
Cindy Stroup
Project Officers
Exposure Evaluation Division
Office of Pesticides and Toxic Substances
Environmental Protection Agency
Washington, DC 20460
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DISCLAIMER
This report has been reviewed and approved for publication by the
Office of Toxic Substances, Office of Pesticides and Toxic
Substances, U.S. Environmental Protection Agency. Approval does
not signify that the contents necessarily reflect the views and
policies of the Environmental Protection Agency, nor does mention
of trade names or commercial products constitute the endorsement
or recommendation for use.
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TABLE OF CONTENTS
INTRODUCTION
METABOLISM REPORTS:
Bromobenzene 1
Bromoform 2
Carbon Tetrachloride 3
o-Chlorobenzaldehyde 4
Chloroform 5
Chloronaphthalene 6
p-Dichlorobenzene 7
1,2-Dichloroethane 8
1,1-Dichloroethylene 10
Hexachlorobenzene 14
Lindane 18
Methylene Chloride 21
Pentachloroanisole 24
Pentachlorobenzene 25
Pentachlorophenol 27
Tetrachloroethylene 29
Tetrachlorophenol 32
1, 2, 4-Trichlorobenzene 34
Trichloroethylene 35
iii
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Introduction
The Office of Pesticides and Toxic Substances' Exposure
Evaluation Division is continuing a preliminary assessment of
halogenated organic compounds in human and environmental media.
This effort was initiated in 1978 in response to the detection
and identification of numerous halogenated hydrocarbons in the
environment, notably in drinking water supplies. Although
detected levels have generally been low, several halocarbons have
entered the environment at relatively high concentrations as a
result of accidental spills or contamination of animal feed. The
reporting of halogenated pesticides in human blood, serum, and
adipose tissue further heightens concern over the potential
health effects which may be associated with a halocarbon insult.
The major thrust of the preliminary assessment is a
comprehensive and systematic analysis of selected halocarbons in
man and the environment being conducted under contract by the
Research Triangle Institute (RTI). To complement the RTI effort,
Tracor-Jitco, Inc., under contract to the EPA, conducted a
literature survey on the metabolism of selected halocarbons for
use in evaluating the human body burden associated with
environmental exposure. The result of this project was the
publication of Metabolism Summaries of Selected Halogenated
Organic Compounds in Human and Environmental Media, A Literature
Survey EPA 560/6-79-008, April 1979.
Forty-nine halogenated hydrocarbons (HHC) were selected for
the first metabolism review based on the following information:
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1. halocarbons occurring in air, water, food, biological
fluids and tissues;
2. halocarbon production, usage and disposal facilities in
the selected study areas; and
3. halocarbon mutagenicity and carcinogenicity data.
Details of HHC selection process are included in the report
produced by RTI entitled Formation of A Preliminary Assessment of
Halogenated Organic Compounds in Man and Environmental Media EPA
560/13-79-006.
The first literature survey provided metabolism summaries as
well as basic information on the physical properties of the 30
HHC's reviewed. This present report updates information on 15 of
the original HHC's plus provides physical data and metabolism
summaries for four additional HHC's not included in the first
survey.
Basic information on the physical properties of the
compounds at the beginning of each summary include molecular and
structural formulas, the Chemical Abstracts Registry (CAS)
number, accepted synonyms, molecular weight (mol wt), boiling
point (bp), and vapor pressure (vp). The text summarizes the
available information on the uptake and retention of the
compound, its subsequent distribution and elimination patterns,
the identification and observed concentrations of metabolites,
and the metabolic pathways involved.
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BROMOBENZENE
CAS: 000108861
Syn: phenyl bromide
Mol wt: 157.02 g/mole
bp: 156°C (at 760 mm Hg)
vp: 4.3 mm Hg (at 25°C)
Urinary metabolites of bromobenzene in rats were reported by
Mizutani et al. (1). The levels of bromo(methylthio)benzenes and
their precursors did not increase when rats were given a higher
amount of bromobenzene or were pretreated with diethyl maleate.
Isomeric bromo(methylthio)benzenes were identified by gas
chromatographic and mass spectral comparisons with authentic
samples. The three peaks were identified as JD-, JTV-, and _o_ -
bromo(methylthio)benzenes. In addition, they also recorded two
known metabolites trans-1,2-dihydro-l,2-dihydroxy-3-bromobenzene
and trans-1,2-dihydro-l,2-dihydroxy-4-bromobenzene. The authors
suggested that isomeric metabolites of bromobenzene were not
formed due to the covalent binding of bromobenzene to liver
tissue.
Reference
1. Mizutani, T. , K. Yamamoto, and K. Tajima. 1*578. Bromo-
(methylthio)benzenes and related sulfur-containing compounds
minor urinary metabolites of bromobenzene in rats. Biochem.
& Biophys. Res. Commun. 82(3):805-810.
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BROMOFORM
Br
CHBr3
Br—C—Br
A
CAS: 000075252
Syn: tribromomethane; methenyl tribromide
Mol wt: 252.75 g/raole
bp: 149.5°C (at 760 mm Hg)
vp: 6.11 mm Hg (at 25°C)
Anders et al. (1) reported in vivo studies in rats
concerning metabolism of haloforms to carbon monoxide. The
administration of C labeled bromoform (CHEr-,) led to the
formation of similarly enriched CO. A dose-dependent
relationship between CHBr^ dose and CO production was observed.
Phenobarbital (but not 3-methyl-cholanthrene) treatment increased
the blood CO levels soon after the administration of CHBr3, but
no increase occurred in the saline-treated controls. In
o
addition, lower blood CO levels were found in rats give H-
bromoform as compared to rats given bromoform. Administration of
either diethylmaleate or D-penicillamine did not alter the blood
CO level produced in response to bromoform administration. The
in vivo metabolism of haloforms to CO followed the halide order;
thus, administration of iodoform yielded the highest blood CO
levels, whereas chloroform yielded the lowest levels.
Reference
1. Anders, M.W., O.L. Stevens, R.W. Spraque, Z. Shaath and A.E.
Ahmed. 1978. Metabolism of haloforms to carbon monoxide.
II. in vivo studies. Metabolism and Disposition
6(5):556-560.
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CARBON TETRACHLORIDE
Cl
I
ci-c—ci
I
Cl
cci4 ,
CAS: 000056235
Syn: methane tetrachloride; tetrachlororaethane;
perchloromethane
Mol wt: 153.82 g/mole
bp: 76.54°C (at 760 ram Hg)
vp: 98.9 mm Hg (at 25°C)
Kubic and Anders (1) reported the metabolism of carbon
tetrachloride (CCl*) to phosgene in rats hepatic microsomal
fractions. Rats were pretreated with 50 mg/kg phenobarbital for
4 days before sacrifice. Hepatic microsomal fractions were
prepared and incubated for 15 min in reactions mixtures of 32.5
/amoles CCl* and 4 /imoles of NADPH in buffered medium. Samples
were then quantitatively analyzed by gas chromatography-mass
spectrometry. Phosgene was identified as a metabolite of CCl* in
this experiment. Phosgene was identified as the adduct, 2-
oxothiazolide-4-carboxylic acid, formed with its reaction with
cysteine. [ C]-CC14 was metabolized to 2-[ C]-oxothiazolidene-
4-carboxylic acid and when CC14 was incubated in the presence of
[ O]-O2/ 2-[ °o]-oxothiazolidine-4-carboxylic acid was
produced. The metabolism of CCl* to phosgene may be an important
factor in the hepatotoxicity of CC14«
Reference
1. Kubic, V.L. and M.W. Anders. 1980. Metabolism of carbon
tetrachloride to phosgene. Life Sci. 26: 2151-2155.
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0-CHLOROBENZALDEHYDE
CyH5C10
CAS: 000089985
Syn: 2-chlorobenzaldehyde; ortho-chlorobenzaldehyde
Mol wt: 140.57 g/mole
bp: 211.9°C (at 760 mm Hg); 84.3°C (at 10 mm Hg)
vp: 1.07 mm Hg (at 32.1°C)
Caszynski et al. (1) investigated the suitability of
experimental bypass of the rabbit liver and kidney to study the
biotransformation of rapidly metabolized substances using o-
chlorobenzylidenemalonic nitrile as a model compound. The
animals were exposed to this compound by intravenous
administration of 9.1 mg/kg. The two major metabolites
identified were o-chlorobenzaldehyde and o-chlorobenzylmalonic
nitrile. In the animals with liver bypass, approximately 90% of
the parent compound was metabolized, whereas only 30% was
metabolized in the control animals.
Reference
1. Caszynski, W. , M. Paradowski and S. Andrzejewski. 1978.
Experimental bypass of the liver and kidneys in rabbits as a
method for studying the biotransformation of rapidly
metabolized substances. Anest. Reanim. Intensywna Ter. 10
(1):1-10.
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CHLOROFORM
Cl
CHC1., I
3 Cl —C —Cl
H
CAS: 000067663
Sym formyl trichloride; methane trichloride; methynyl
trichloride; methyl trichloride; trichloroform;
trichloromethane
Mol wt: 119.38 g/mole
bp: 61.7°C (at 760 mm Hg)
vp: 173.1 mm Hg (at 25°C)
The in vivo metabolism of chloroform to phosgene (COC^) was
confirmed by recent studies of Pohl et al. (1). Phenobarbital
pretreated rats were treated with cysteine (l.Og/kg, intraperi-
toneally (i.p.), followed by CHClj (4.98 mmole/kg, i.p.) 30
minutes later. Livers were removed after 1 hour and analyzed for
COClj as the cysteine conjugate and for 2-oxothiazolidine-4-
carboxylic acid by gas chromatography-mass spectrometry. A
fraction with the same retention time and mass spectrometry value
as the synthetic standard was detected in the liver extract. The
identification of the fraction as trapped COCl^ was confirmed by
repeating the experiment with C-labeled CHC13.
Reference
1. Pohl, L.R., J.W. George and G. Krishna. 1979. Phosgene: an
in vivo metabolite of chloroform. Toxicol. Appl.
Pharmacol. 48(1):A110. Abstr.
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CHLORONAPHTHALENE
Mol wt: 162.62g/mole
1-chloronaphthalene
CAS: 000090131
Syn: alpha-chloronaphthalene
bp: 258. 8 °C (at 753 mm Hg ) ; 106. 5 °C (at 5 mn Ha>
vp: 1.36 mm Hg (at 80.6 °C)
Cl
2-chloronaphthalene
CAS:
Syn:
bp:
000091587
beta-chloronaphthalene
256°C (at 760 mm Hg); 106.5°C (at 5 mm Hg)
Chu et al. (1) studied the metabolism of 2,6-dichloro-
naphthalene. Rabbits were given a single dose of this ctompound
(300 mg/kg) in 1% aqueous gum tragacanth. A dose of 1 g/kg was
similarly given to 4 rats and their urine collected for one
week. The three metabolites identified from the urine samples
were: 6-chloro-2-naphthol, 7-chloro-2-naphthol, and 6-chloro-l-
naphthol. More than 50% of the 2,6-dichloronaphthalene was
recovered unchanged from the urine.
Reference
1. Chu, I., V. Secours and A. Vieau. 1976. Metabolites of
chloronaphthalene. Chemosphere 5:439-444.
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p-DICHLOROBENZENE
CAS: 000106467
Syn: p-dichlorobenzene; paradichlorobenzene;
paradichlorobenzol
Mol wt: 147.01 g/mole
bp: 174°C (at 760 mm Hg)
vp: 1.1 mm Hg (at 30.0°C)
Kimura et al. (1) examined the levels of two metabolites of
p-dichlorobenzene in blood and some other tissues (adipose,
kidney, lung, liver, heart, and brain) as well as the excretion
levels of these metabolites in urine and feces of treated rats.
A dosage of 200 mg/kg of p-dichlorobenzene was administered
orally to fasted male rats. The two metabolites identified by
gas chromatography were 2,5-dichlorophenyl methyl sulfoxide (M-l)
and 2,5-dichlorophenyl methyl sulfone (M-2). The initial
concentrations of the sulfoxide (M-l) in the blood were initially
higher than M-2 levels, but the level of M-2 persisted in the
blood for up to 120 hours (compared to 70-80 hours for M-l). Of
the organ tissues analyzed, the kidneys contained the highest
concentration of M-l. However, the highest absolute
concentrations of M-2 were found in blood samples. Excretion of
M-l and M-2 in urine and feces was less than .013% of the dosage
administered.
Reference
1. Kimura, R., T. Hayaahi, M. Sato, T. Aimoto and T. Murata.
1979. Identification of sulfur-containing metabolites of p-
dichlorobenzene and their disposition in rats. J. Pharmacol.
Dyn. 2:237-244.
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C2H4C12
1,2, -DICHLOROETHANE
| |
H — C— C— H
I I
H H
CAS: 000107062
Syn: sym-dichloroethane; alpha ,beta-dichloroethane;
dichloroethylene; EDC ; ethane dichloride; ethylene
chloride; ethylene dichloride; glycol dichloride
Mol wt: 98.96 g/mole
bp: 83.47°C (at 760 mm Hg)
vp: 76.2 mm Hg (at 25 °C)
Kokarozetseva and Kiselea (1) recently reported the
identification of two metabolites of 1,2-dichloroethane as
monochloroacetic acid and chloroethanol. Albino rats were
administered intragastrically a single dose of 750 mg/kg 1,2-
dichloroethane. The authors pointed out that the metabolites are
more toxic than the parent compound and may be considered an
example of lethal synthesis.
Livesey and Anders (2) studied the in vitro metabolism of
1,2-dichloroethane to ethylene. Rat hepatic arid renal enzymes
were used as the in vitro system. The reaction was inhibited by
p-dichloromercuribenzoate and diethylmaleate; whereas, cyanide,
fluoride, or SKF 525A (B-diethylaminoethyldiphenyl propylacetate)
did not inhibit metabolism.
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References
1. Kokarovtseva, M.G. and N.I. Kiseleva. 1978. Chloroethanol
(ethylene chlorohydrin), one of the toxic metabolites of 1,2-
dichloroethane. Farmakol Toksikol (Mosc) 41(1);118-120.
2. Livesey, J.C. and M.W. Anders. 1979. Glutathione-dependent
metabolism of vicinal-dihalides to olefins. Pharmacologist
20 (3):187. Abstr.
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1 , 1-DICHLOROETHYLENE
Cl H
\=C
Cl H
CAS:
Syn: 1,1-DCE; 1, 1-dichloroethene ;
vinylidene chloride;
vinylidine chloride
Mol wt: 96.94
bp: 37°C (at 760 mm Hg )
vp: 633.7 mm Hg (at 25°C)
Reichert and Werner (1) recently confirmed the previous
findings of McKenna, Jaeger, and their co-workers that the rate
of depletion of glutathione after oral doses of 1,1-
dichloroethylene (1,1-DCE) was exponentially dependent on 1,1-DCE
concentration. After 24-hour oral administration of a sublethal
concentration of 1,1-DCE, glutathione returned to the baseline
level. A similar steep decline in concentration was also
observed in 18-hour fasted rats. The investigators fed 1000
mg/kg 1,1-DCE dissolved in 2 ml/kg olive oil to rats by stomach
tube. After 4-hours, the concentration of glutathione dropped to
approximately 30% of the control values. The conversion rate of
1,1-DCE to a metabolite by isolated perfused livers was recorded
as 7.64juraoles/g liver after 3-hours perfusion when 5000 ppm was
supplied in the gas phase. The metabolite was not identified but
the authors suggested it might be an unstable epoxide. No effect
on viability nor on the metabolism rate was noted when the livers
of 18-hour fasted rats were perfused. The concentrations of the
glutamate-oxaloacetate transaminase (SCOT) and glutamate-pyruvate
transaminase (SGPT) in the perfused rat livers failed to show an
increase. The authors concluded that there was no correlation
between the liver glutathione level and the increased lethality
of 1,1-DCE in fasted rats.
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McKenna et al. (2,3) found that fasted rats exposed to 200
ppm 14C vinylidene chloride (1,1-DCE) sustained liver and kidney
damage not observed in fed rats. The liver centriolobular damage
involved hepatic necrosis. The elimination of nonvolatile
urinary metabolites was slightly greater in fed rats, suggesting
a reduced capacity for metabolism in the fasting condition. Four
major urinary metabolites were separated by high pressure liquid
chromatography. Two of the four metabolites were identified by
gas chromatography-mass spectrometry as S-(2-hydroxyethyl)-N-
acetyl-cysteine and thiodiglycolic acid. Both the hepatotoxic
response to vinylidene chloride and the extent of its detoxi-
fication appeared to be dependent on the concentration of
glutathione (GSH) in the liver. When hepatic GSH was depleted
(i.e. in fasted rats or after high doses of vinylidene chloride),
a toxic response was elicited.
Andersen et al. (4) reported that the toxic metabolites of
1,1-dichloroethylene reacted with hepatic glutathione and that
pretreatment with epoxypropanol or styrene oxide increased the
toxicity of these metabolites. In fasted male rats,
epoxypropanol, cyclohexene oxide, and butadiene monoxide caused
prolonged depletion of H-GSH. The 2 hour LC50's of rats
pretreated with cyclohexene oxide, styrene oxide, and *
epoxypropanol were 569, 163, and 92 ppm, respectively. Epoxide-
induced enhancement of toxicity depended primarily on the
particular epoxide used and not solely on the depletion of H-
GSH. (The toxic metabolites were not identified in the
abstract.)
In a follow-up article, Andersen et al. (5) investigated the
toxicity of the epoxidic metabolite of 1,1-dichloroethylene in
fasted male rats. The epoxide metabolite of 1,1-DCE is unstable
and these authors reported it has never been isolated. The two
pathways of detoxification, i.e. reaction with glutathione (GSH)
and enzymatic hydration, along with the acute toxicity of seven
11
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of these epoxidic metabolites were compared. The seven epoxides
tested were trichloropropane oxide (TCPO), styrene oxide (SO),
cyclohexane oxide (CHO), 2,3-epoxypropan-l-ol (2,3-EP),
epichlorhydrin (EPI), epoxypropane (EP), and butadiene monoxide
(BMO) as well as the sulfhydryl depleting agent diethylmaleate
(DEM). These were administered intraperitoneally to fasted male
rats at LD5Q levels established for each compound. BMO, SO, 2,3-
EP, CHO, and DEM treatment resulted in virtually total depletion
of hepatic GSH within 2 hours following administration.
Pretreatment of the above compounds for two hours prior to
exposure of 1,1-dichloroethylene resulted in increased toxicity
levels (lowered LD^^'s) in the following order: 2,3-
EP>DEM>EPI>SO>BMO>CHO. This exacerbation of 1,1-dichloroethylene
toxicity is thought to be related to the ability of these
compounds to decrease hepatic GSH. The authors concluded that
epoxide-hydrating pathways appear to be of minimal significance
in the metabolism of 1,1-dichloroethylene reactive intermediates.
References
1. Relchert, D., W.H. Werner and D. Henschler. 1978. Role of
glutathione in 1.1-dichloroethylene metabolism and
hepatotoxicity in intact rats and isolated perfused rat
liver. Arch. Toxicol._ 41; 169-178.
2. McKenna, M.J., J.A. Zemple, E.O. Madrin and P.J. Gehring.
1978. The pharmacokinetics of ( C) vinylidene chloride in
rats following inhalation exposure. Toxicol. Appl.
Pharmacol. 45(2):599-610.
3. McKenna, M.J., J.A. Zempel, E.O. Madrin, W.H. Braun and P.J.
Gehring. 1978. Metabolism and pharamacokinetic profile of
vinylidene chloride in rats following oral administration.
Toxicol. Appl. Pharmacol. 45(3):821-836.
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4. Andersen, M., O. Thomas and L. Jenkings, Jr. 1979.
Glutathione, epoxides and multiple detoxification pathways in
the metabolism of 1,1-dichloroethylene. Toxicol. Appl.
Pharmacol. 48(1);A105. Abstr.
5. Andersen, M., O. Thomas, M. Gargas, R. Jones and L. Jenkings,
Jr. 1980. The significance of multiple detoxification
pathways for reactive metabolites in the toxicity of 1,1-
dichlorethylene. Toxicol. Appl. Pharmacol. 52:422-432.
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HEXACHLOROBENZENE
C6C16
CAS: 118.74-1
Syn: HCB, Perchlorobenzene
Mol wt: 284.79 g/mole
bp: 322 (at 760 mm Hg)
vd: 9.84
latropoulos et al. (1) gave a single intragastric dose of 150
ug l4C-labeled hexachlorobenzene to rats and examined the animals
1 to 48 hours later. Little hexachlorobenzene was absorbed
during the first hour. After 5 hours, increasing concentrations
of hexachlorobenzene were observed in the lining of the jejunum
and ileum, with the highest amounts recorded in lymph and adipose
tissues.
In another study, Mehendale et al. (2) gave a single oral
dose of C-labeled hexachlorobenzene to adult male rats.
Approximately 16% of the dose was excreted in the feces and less
than 1% in urine. Seventy percent of the hexachlorobenzene
remained in the body 7 days after administration with adipose
tissue fat being the major site of deposition. Reductive
dechlorination of hexachlorobenzene was catalyzed by an enzyme
located in the microsomal fraction of liver, lung, kidney, and
intestine. Most of the studies on chlorinated benzenes have
shown that the greater number of chlorine atoms the halogenated
benzene contained, the less rapidly the compound is meta-
bolized. Oxidative hydroxylation and reductive dechlorination
have been shown to be the main routes of conversion in metabolic
pathways of this compound.
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Engst et al. (3) gavaged male rats daily with 8 mg
hexachlorobenzene at a concentration of 8 mg/kg for 19 days.
Pentachlorobenzene and pentachlorophenol were found at low
concentrations in the organs and tissues of the treated
animals. Urine collected from treated animals contained
hexachlorobenzene and pentachlorophenol (the main metabolite)
together with 2,3,4,6- and/or 2,3,4,5-tetrachlorophenol, 2,4,6-
trichlorophenol, pentachlorobenzene, and traces of 2,3,4- and
other trichlorophenols. Small amounts of the glucuronides of
2,4,6-trichlorophenol and 2,3,4,6-tetrachlorophenol were also
present in the urine. The main degradation route for
hexachlorobenzene in rats has been proposed by Engst (3).
Pentachlorobenzene and its main metabolite 2,3,4,5-
tetrachlorophenol were detectable at trace levels only.
HEXACHLOROBENZENE
PENTACHLOROPHENOL
2,3,4,6-TETRACHLOROPHENOL
PENTACHLOROBENZENE
2,3,4,5-TETRACHLOROPHENOL
2,3V^-TRICHLOROPHENOL
2,4,6-TRICHLOROPHENOL
DEGRADATION ROUTE FOR HEXACHLOROBENZENE
Engst et al. (3)
Koss et al. (4) gave female rats of ^ C-labeled
hexachlorobenzene in 2 or 3 intraperitoneal injections over a
period of 5 or 10 days to attain a total dose of 260 or 290
mg/kg. The mean excretion of labeled 14C totalled 7% in the
15
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urine and 27% in the feces. In the feces, about 30% of the
excretory products labelled were in the form of metabolites and
70% as unchanged hexachlorobenzene. 90% of urinary labelled
excretory products were in the form of metabolites, principally
pentachlorophenol, tetrachlorohydroquinone, and pentachlorothio-
phenol. In the tissues, the only metabolite detected in
measurable amounts was pentachlorophenol: 10% in blood> 3.5% in
liver, 2% in kidney, 1% in brain, and 0.1% in body fat.
In 1978, Rozman et al. (5) reported the pharmacokinetics of
hexachlorobenzene in rhesus monkeys Macaca mulatta. The animals
were fed a diet containing 1 ppm 14c-labeled hexachlorobenzene
for 18 months. The radioactive products excreted in the feces
were: 99% as hexachlorobenzene, 1% as pentachlorobenzene, and a
trace of pentachlorophenol. The major urinary metabolite was
pentachlorophenol. Other urinary metabolites identified were
pentachlorobenzene, tetrachlorobenzene, and hexachlorobenzene.
The only metabolite identified in the plasma was
hexachlorobenzene. In the red blood cells, the metabolites
identified were 95% hexachlorobenzene and about 5% pentachloro-
phenol. According to the authors, none of the monitored
parameters indicated harmful effects to the rhesus monkey from a
110/ig/day (1 ppm) hexachlorobenzene-exposure over a period of
550 days.
Koss et al. (6) have recently reported the presence of
sulphur-containing metabolites of hexachlorobenzene in rat
excretion. The rats received oral doses of 178jumoles/kg
hexachlorobenzene. They identified pentachlorothiophenol and
pentachloroanisole in the livers of animals treated with
hexachlorobenzene. The metabolites of pentachlorothiophenol and
pentachlorothioanisole were excreted in both conjugated and free
forms. The extracts of the excreta of treated rats yielded
tetra- and trichlorobenzene with two or three S-containing
substitutions on the ring. Following administration of the
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sulphoxide and of the sulphone of pentachlorothionanisole under
analogous conditions, pentachlorothioanisole and pentachloro-
thiophenol and their metabolites were detected in the excreta of
the test animals.
References
1. latropoulos, M.J. 1975. Absorption, transport and
organotropism of dichlorobiphenyl (DCB), dieldrin, and
hexachlorobenzene (HCB) in rats. Environ. Res. 10:384-389.
2. Mehendale, H.M., M. Fields and H.B. Matthews. 1975.
Metabolism and effects of hexachlorobenzene on hepatic
microsomal enzymes in the rat. J. Agric. Food Chem.
23(2):261-265.
3. Engst, R., R.M. Machloz and M. Kujawa. 1976. The metabolism
of hexachlorobenzene (HCB) in rats. Bull. Environ. Contam.
Toxicol. 16(2):248-252.
4. Koss, G., W. Koransky and K. Steinbach. 1976. Studies on
the toxicity of HCB II: identification of metabolites.
Arch. Toxicol. 35(2):107-114.
5. Rozman, K., W.F. Miller, F. Coulston and F. Korte. 1978.
Chronic low dose exposure of rhesus monkeys to
hexachlorobenzene (HCB). Chemosphere 7(2);177-184.
6. Koss, G., W. Koransky and K. Steinbach. 1979. Studies on
the toxicology of hexachlorobenzene IV: sulfur-containing
metabolites. Arch. Toxicol. 42(1):19-31.
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LINDANE
C6H2C16
CAS: 58-89-9 Cl
Syn: ganuna-Hexachlorocyclohexane, gamma-1,2,3,4,5,6-
Hexachlorocyclohexane, gamma HCH, HCH
Mol wt: 290.83 g/mole
bp: 288°C (at 760 mm Hg)
vp: .14 mm Hg (40° C)
Karapally et al. (1) examined the ether-soluble urinary
14
metabolites of lindane in rabbits. C lindane was fed to
rabbits in gelatin capsules over a period of 26 weeks. 54% of
the labeled lindane was excreted in the urine and 13% in the
faces of the test animals. The following ether-soluble urinary
metabolites were identified by infrared spectrometry: 2,3,5-,
2,4,5-, and 2,4,6-trichlorophenol and 2,3,4,6-tetrachloro-
phenol. Other metabolites identified by gas chromatography
were: 2,3- and 2,4-dichlorophenol and 2,3,4,5-tetrachloro-
phenol. Tentative identification was made by gas chromatography
of seven other chlorophenols and six chlorobenzenes: 2,5-, 2,6-,
and 3,4-dichlorophenol, 2,3,4-, 2,3,6-, and 3,4,5-trichloro-
phenol, pentachlorophenol, 1,2-dichlorobenzene, 1,2,4 trichloro-
benzene, 1,2,3,4-, 1,2,4,5-, and/or 1,2,3,5-tetrachlorobenzene,
and pentachlorobenzene.
In another article, Chadwick and Freal (2) identified five
unreported lindane metabolites in rat urine. Rats were fed diets
of 400 ppm lindane and their urine was collected. The following
metabolites were identified by gas chromatography and/or infrared
spectrometry: 3,4-dichlorophenol, 2,4,6-trichlorophenol,
2,3,4,5-tetrachlorophenol, 2,3,4,6-tetrachlorophenol, and
2,3,4,5,6-pentachloro-2-cyclohexen-l-ol. In addition, the
18
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previously identified metabolites 2,3,5- and 2,4,5-
trichlorophenol were also identified in this study. The
following lindane metabolic pathway was also included in this
article. Lindane is dehydrochlorinated to "5 pentachloro-
cyclohexane which is further metabolized to either 2,4-
dichlorophenyl mercapturic acid or 2,3,5- and 2,4,5-
trichlorophenol.
R-CH2-CH-CO2H
NH'CO-CH3
Cl
THE LINDANE METABOLIC PATHWAY PROPOSED BY GROVER AND SIMS
Chadwick and Freal (2).
19
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References
1. Karapally, J., J. Saha and Y. Lee. 1973. Metabolism of
1 4
lindane- C in the rabbit: ether-soluble urinary
metabolites. J. Appl. Food Chem. 21(5):811-817.
2. Chadwick, R.W. and J.J. Freal. 1972. The identification of
five unreported lindane metabolites recovered from rat
urine. Bull. Environ. Contain. Toxicol 7:137-146.
20
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METHYLENE CHLORIDE
CH~C1 Cl
H-C-CI
I
H
CAS: 000075092
Syn: methane dichloride; dichloromethane;
methylene bichloride; methylene
chloride; methylene dichloride
Mol wt: 84.93 g/mole
bp: 40°C (at 760 mm Hg)
vp: 430.4 mm Hg (at 25°C)
Recently, the pharmacokinetics and metabolism of inhaled 14C-
methylene chloride (CH-Cl^) were studied by McKenna et al. (1).
Rats were exposed one time only to 50, 500, or 1500 ppm for 6
hours. The two major metabolites found in the exhaled air were
CO and CO^• The net uptake and rate of metabolism was not
proportional to the increase in dosage. The relationship* of
total CH^Clj metabolism relative to exposure concentration
followed the model of Michaelis-Menten kinetics. This model can
be used to predict the body burden of C^C^ in inhalation
exposure.
Hake (2) examined the uptake by hemoglobin of CO derived from
CH-Cl^. Its subsequent release into breath was measured by
computer-predicted blood carboxyhemoglobin levels which are
reached when a physically active worker is exposed to vapors.
Simulated values of CH2C12 in breath and blood carboxyhemoglobin
were first compared with experimental values obtained from
sedentary humans previously exposed in the laboratory. When
increased ventilation and cardiac output values were applied to
21
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the simulated exposures at 50, 100, 250, and 500 ppm for 3 and
7.5 hours, blood carboxyhemoglobin levels did not increase
proportionally to uptake. At 500 ppm exposure, simulated
carboxyhemoglobin values were higher without exercise than with
exercise.
In another study on the increased uptake by hemoglobin of CO
derived from methylene chloride, Stewart and Hake (3) examined
the possible complications in persons with cardiovascular
problems resulting from inhalation of paint-remover vapors. Many
paint removers contain up to 80% methylene chloride. Exposure of
human volunteers to paint remover vapors at a range of exposure
from 77-186 ppm methylene chloride under limited ventilation
conditions for periods of three hours resulted in 5-10% COHb
saturation. In heavy smokers, the levels were even higher since
a heavy smoker can have up to a 10% saturation of COHb due to
smoking alone. More physically active persons exhibited higher
levels of COHb as a result of absorbing larger quantities of
methylene chloride in the bloodstream. Since it has been shown
by other studies that COHb levels of 5-10% can adversely affect
patients with cardiovascular disease or angina pectoris, these
researchers pointed out the potential danger of the use of paint
removers by such individuals.
Peterson (4) exposed eleven men to methylene chloride
(dichloromethane) concentrations of 50, 100, 250, and 500 ppm and
nine women to a concentration of 250 ppm for up to five
successive days. It has long been known that this material is
converted to carbon monoxide endogenously. The author devised
equations by which breath concentration of the solvent as well as
the blood concentration of the metabolite carbon monoxyhemoglobin
(COHb) following exposure were related mathematically to exposure
parameters. The resulting empirical equations of this study can
be used to predict the consequences of many industrial and non-
industrial exposure situations. The author recommended that
these equations be used for interpolation only and not for
22
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extrapolation. The equations were valid for exposures to
concentrations above 50 or below 500 ppm, for durations less than
1 hour or more than 7.5 hours, or for not more than 5 successive
days of exposure. COHb level elevations of up to 10% saturation
following inhalation exposure to methylene chloride were
predicted by these equations using a knowledge of exposure
parameters. Measurement of the breath concentration in the 24
hour period following exposure allowed for calculation of the
duration of exposure, the number of successive exposure days, and
the time-weighted average concentration inhaled during the
exposure.
Reference
1. McKenna, M.J-. J.A. Zempel and WH. Braun. 1979. The
pharmacokinetics and metabolism of inhaled methylene chloride
in rats. Toxicol. Appl. Pharmacol. 48(l,pt.2);A10. Abstr.
2. Hake, C.L. 1979. Simulation studies of blood
carboxyhemoglobin levels associated with inhalation exposure
to methylene chloride. Toxicol. Appl. Pharmacol.
48(1):A56. Abstr.
3. Stewart, Richard D. and Carl L. Hake. 1976. Paint-remover
hazard. JAMA 235(4);398-401.
4. Peterson, Jack E. 1978. Modeling the uptake and excretion
of dichloromethane by man. Amer. Ind. Hyg Assoc. J. 39:41-
47.
23
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PENTACHLOROANISOLE
Cl
Cl
CAS: 1825-21-4
Syn: pentachloromethoxybenzene; 2,3,4,5,6-pentachloroanisole;
methyl pentachlorophenate
Mol wt: 280.34 g/mole
bp: 289° (at 745 mm)
vp:
Pentachloroanisole is a major degradation product of
pentachlorophenol as reported by Pierce and Victor (1). They
studied the fate of pentachlorophenol in aquatic ecosystems where
its accidental release had caused extensive fish kills. Other
degradation products of pentachlorophenol identified in this
study were 2,3,5,6- and 2,3,4,5-tetrachlorophenol isomers. These
products persisted in fish and in sediment for up to 2 years.
The investigators suggested the formation of pentachloroanisole
in water whereas tetrachlorophenol appeared to be formed by
photodegradation before entering the lake.
Reference
1. Pierce, R.H., Jr., and D.M. Victor. 1978. The fate of
pentachlorophenol in an aquatic ecosystem. Env. Sci. Res. 12
(Pentachlorophenol); Chem. Pharmacal. Environ. Toxicol;41-
52.
24
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PENTACHLOROBENZENE
C6HC15
CAS: 000608935
Syn: quintachlorobenzene;
1,2,3,4,5-pentachlorobenzene
Mol wt: 250.34
bp: 277 (at 760 mm Hg)
vp: 1.04 mm Hg (at 98.6°C)
Recently, Rozman et al. (1) reported the metabolism of
pentachlorobenzene in rhesus monkeys. The animals were orally
administered 4C-labeled pentachlorobenzene (0.5 mg/kg) in a
single dose. Several blood samples were taken within 40 days
following treatment. Two monkeys (one male, one female) were
then sacrificed. At least 95% of the compound was absorbed as
indicated by fecal excretion in the first 4 days. About twice
the compound level was present in feces as was present in
urine. The half-life of pentachlorobenzene in rhesus monkey was
estimated to be 2 to 3 months. The level of pentachlorobenzene
in blood peaked between 2 and 4.5 hours. The highest
concentrations of pentachlorobenzene occurred in fat and bone
marrow, followed by decreasing concentrations in the lymph nodes,
thymus, adrenal cortex, and large intestine. The metabolites of
pentachlorobenzene identified were: pentachlorophenol, 2,3,4,5-
tetrachlorophenol, 2,3,5,6-tetrachlorophenol, and 1,2,3,4-
tetrachlorobenzene. The authors did not find any significant
difference in metabolism patterns between male and female
monkeys. They also postulated that in addition to hepatic
cytochrome P-450, there may exist an additional metabolic pathway
which involves the hyroxylation of higher chlorinated benzenes.
25
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Reference
1. Rozman, K., J. Williams, W.F. Miller, F. Coulston and F.
Kate. 1979. Metabolism and pharmacokinetics of
pentachlorobenzene in the rhesus monkey. Bull. Environ.
Contam. Toxicol. 22(1-2):190-195.
26
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PENTACHLOROPHENOL
Gas: E 7-86-5
Syn: PGP, Penchlorol
Mol wt: 266.34 g/mole
bp: 309.10
vp: .00011 mm (at 20°C)
Ahlborg et al. (1) studied the metabolism of pentachloro-
phenol (PGP). Rats and mice were administered 10-25 mg/kg
pentachlorophenol either intraperitoneally or orally. Excretion
of PGP in the urine of test animals was measured by gas
chromatography-mass spectrometry. 43-44% of the excretion
products were unchanged PGP- The metabolite tetrachlorohydro-
quinone represented 5-24% of excreted products. This metabolite
has also been reported in the urine of occupationally exposed
workers.
In a follow-up report, Ahlborg et al. (2) addressed the in
vivo and in vitro metabolism of PGP to tetrachloro-p-hydroquinone
in rats and rat microsomal incubate, respectively. The rats were
pretreated with phenobarbital (PB) and SKF-525A (B-diethylamino-
ethyldiphenyl propylacetate). The in vivo rats were administered
PB or SKF-525A intraperitoneally (i.p.) for three consecutive
days. On the fourth day, PGP was injected i.p. at
10 mg/kg. The urine was collected and analyzed by gas
chromatography-mass spectrometry. In the in vitro experiment,
the rats were pretreated for five consecutive days with PB or
SKF-525A i.p., sacrificed, and the liver microsomal incubate
prepared. The microsomal incubate was treated with PGP dissolved
in acetone. PB pretreatment increased the metabolism of PGP to
27
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tetrachloro-p-hydroquinone in both cases. SKF-525A inhibited in
vitro metabolism, but enhanced in vivo metabolism if given less
frequently than every six hours.
References
1. Ahlborg, U.G., J.E. Lindgren and M. Mercier. 1974.
Metabolism of pentachlorophenol. Arch. Toxicol. 32:271-281.
2. Ahlborg, U.S., K. Larsson and T. Thunberg. 1978. Metabolism
of pentachlorophenol in vivo and in vitro. Arch Toxicol.
40(l):45-53.
28
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TETRACHLOROETHYLENE
Cl Cl
c9ci, \ /
24 c = c
/ \
Cl Cl
CAS: 000127184
Syn: carbon bichloride; carbon dichloride;
ethylene tetrachloride; perchloroethylene;
tetrachloroethylene; tetrachloroethene;
1,1,2,2-tetrachloroethylene
Mol wt: 165.83 g/mole
bp: 121°C (at 760 mm Hg)
vp: 18.0 mm Hg (at 25°C)
Pegg et al. (1) administered 14c-tetrachloroethylene to rats
orally (1 or 500 mg/kg) or by inhalation (10 or 600 ppm, for 6
hours). Following a 1 mg/kg oral dose or inhalation of 10
ppm C-tetrachloroethylene, approximately 70% of the
radioactivity was excreted (as C-tetrachloroethylene) in
expired air, 26% as CO nonvolatile metabolite in urine and
feces, and 3 to 4% remained in the carcasses. After oral
administration of 500 mg/kg or inhalation of 600 ppm of ^ C
tetrachloroethylene, 89% of radioactivity was recovered as
tetrachlorethylene in expired air, 9% as urinary and fecal
metabolites, and 1 to 2% remained in the carcasses. The authors
estimated the half-life of tetrachloroethylene to be 7 hours
irrespective of dose or route of administration. The
radioactivity in the carcasses was mainly concentrated liver,
kidney, and adipose tissue. Exposure to 600 ppm
tetrachloroethylene vapor 6 hours per day, 5 days a week for 12
months did not result in organ toxicity.
Monster et al. (2) recently reported their investigations of
six male volunteers exposed for 4 hours to a range of
concentrations of 72 and 144 ppm tetrachloroethylene while at
29
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rest and to 142 ppm combined with exercise. The uptake dropped
to 60% during the initial exposure and was influenced more by
lean body mass than by respiratory volume or adipose tissue. One
notable feature was a three- to four-fold increase in uptake
during exercise. Approximately 80 to 100% of the uptake was
excreted unchanged by the lungs after exposure. After 70 hours
of exposure, the amount of trichloroacetic acid excreted in urine
was approximately 1% of the uptake.
Hake and Stewart (3) reported several documented cases of
accidental human exposure of tetrachloroethylene through skin
contact and/or inhalation. In these cases of accidental human
exposure, the narcotic effects as well as the liver and kidney
damage suffered by the victims appeared reversible. In
controlled inhalation studies carried out by the authors as well
as other researchers, factors such as the levels of physical
activity, individual metabolic differences, and length and
concentration of exposure were found to be critical factors in
determining individual reactions to tetrachloroethylene
exposure. Light exercise increased the blood levels up to four-
fold after 30 min. of moderate exercise during 100 ppm
exposure. Alcohol and valium did not affect blood levels. In
general, the authors felt that exposures of 100 ppm
tetrachloroethylene normally does not pose a serious health
threat. However, due to individual differences in metabolism and
different levels of physical activity during individual
exposures, the authors suggested that the determination of body
burden of this chemical in individuals exposed in the workplace
would be advisable.
30
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References
1. Pegg, D.G., J.A. Zempel, W.H. Braun and P.J. Gehring.
1978. Disposition of [ C] tetrachloroethylene following
oral and inhalation exposure in rats. Toxicol. Appl.
Pharmacol. 45(1):276-77.
2. Monster, A.C., G. Boersma and H. Steenweg. 1979. Kinetics of
tetrachloroethylene in volunteers: influence of exposure
concentration and work load. Int. Occup. Environ. Health.
42(3-4):303-309.
3. Hake, C.L. and R.D. Stewart. 1977- Human exposure to
tetrachloroethylene: inhalation and skin contact. Environ.
Hlth. Perspect. (21):231-238.
31
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TETRACHLOROPHENOL
C6H2C140
CAS: 25167-83-3
Syn:
Mol. wt: 231.9 g/mole
bp: 164°C (at 23mm)
vp:
60 mm (at 190°C); 400 mm (at 250°C)
2,3,4,6-tetrachlorophenol
isomer
Tetrachlorophenols are used as fungicides and they have been
reported as mammalian metabolites of gamma-benzenehexachloride
(lindane) in rats (1), and rabbits (2). (See "Lindane" section
for further details of these articles).
Jondorf et al. (3) reported tetrachlorophenol as a metabolite
of tetrachlorobenzene in the urine of doe chinchilla rabbits.
The test animals were administered tetrachlorobenzene by stomach
tube or subcutaneously in a 10% solution. The urine was
collected and was analyzed by mass spectrometry and by paper
chromatography.
Ahlborg and Larsson (4) studied the metabolism of
tetrachloro.phenols in rats. Three isomers of tetrachlorophenol
were adminstered intraperitoneally to rats. During the first 24
hours, the rats excreted tetrachloro-p-hydroquinone as a major
urinary metabolite of 2,3,4,6-tetrachlorophenol (about 35% of the
given dose). Trichloro-p-hydroquinone was considered as a minor
urinary metabolite of both 2,3,4,5- and 2,3,4,6-
tetrachlorophenols. Only 60% of the given dose of 2,3,4,5-
tetrachlorophenol was recovered within 72 hours while 2,3,4,6-
tetrachlorophenol was eliminated in the urine of treated animals
within 48 hours. The metabolites were identified by gas
chromatography.
32
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References
1. Chadwick, R.W., and J.J. Freal. 1972. The identification of
five unreported lindane metabolites recovered from rat
urine. Bull Environ. Contam. Toxicol. 7:137-146.
2. Karapally, J.C., J.G. Saha, and Y.W. Lee. 1973. Metabolism
of lindane 4c in the rabbit: ether-soluble metabolites. J.
Agri. Food Chem. 21:811-818.
3. Jondorf, W.R., D.V. Parke and R.T. Williams. 1958. Studies
in detoxification. 76. The metabolism of
halogenobenzenes: 1:2:3:4-, 1:2:3:5- and 1:2:4:5:-
tetrachlorobenzenes. Biochem. J. 69(2):181-189.
y
4. Ahlborg, U.G. and K. Larsson. 1978. Metabolism of
tetrachlorophenols in the rat. Arch. Toxicol. 40(l):63-74.
33
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1,2,4-TRICHLOROBENZENE
CAS: 000120821
Syn: unsym-trichlorobenzene
Mol wt: 181.45 g/mole
bp: 213.5°C (at 760 mm Hg): 84.8°C at 10 mm Hg)
vp: 1.04 mm Hg (at 38.4°C)
Recently, the uptake and elimination kinetics and
biotransformation of trichlorobenzene were studied in rainbow
trout (1). The fish were exposed to aqueous trichlorobenzene in
static systems for short exposure conditions and continuous flow
delivery for long exposure conditions. The results were
evaluated by a computer program (BIOFAC). Bioconcentration
factors of approximately 100 were achieved from an 8 hour
exposure (0.02 mg/ml). A four day exposure (.001 and .01 mg/ml)
gave a bioconcentration factor of approximately 400. Trout bile,
which was exposed to 0.25 mg/ml trichlorobenzene for 24 hour
contained 5 mg/ml of the parent compound and 10 mg/ml of
biotransformation products. Muscle and liver extracts contained
0.8% and 3.7% biotransformation products, respectively. (The
biotransformation products were not identified in the abstract.)
Reference
1. Melancon Jr., M.J., D.R. Branson and J.J. Lech. 1979. The
uptake elimination and metabolism of 1,2,4-trichlorobenzene
in rainbow trout. Toxicol. & Appl. Pharmacol. 48(1):A170.
Abstr.
34
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TRICHLOROETHYLENE
Cl Cl
C-HCI., \ /
23 c = c
Cl H
CAS: 000079016
Syn: Acetylene trichloride; l-chloro-2,2-dichloroethylene;
l,l-dichloro-2-chloroethylene; ethinyl trichloride;
ethylene trichloride; TCE; TRI; trichloroethene; 1,1,2-
trichloroethylene; 1,2,2-trichloroethylene; trilene
Mol wt: 131.39 g/mole
bp: 87°C (at 760 mm Hg)
vp: 72.9 mm (at 25°C)
Relative to interactions between trichloroethylene and
ethanol, Stewart et al. (1) investigated the role of
trichloroethylene (TCE) in eliciting "degreasers flush." This
phenomenon has been observed in workers constantly exposed to
trichloroethylene in the workplace who visited neighborhood
taverns to drink beer. This is a dermal response in many of
these workers of vivid red symmetrical blotches on the face,
neck, shoulders, and back. To establish the role of TCE in this
phenomenon, these researchers exposed seven male volunteers to
TCE vapors at levels of 20, 100, and 200 ppm for varying periods
of 1-7^ hours. Dosages of ethanol (less than 0.5 ml/kg body
weight) were then ingested by the volunteers. In six of the
seven volunteers tested, the dermal response occurred after three
weeks of the first TCE exposure. This led the investigators to
speculate that a metabolite of TCE rather than the TCE itself
must reach a threshold level to elicit the dermal response.
However, the metabolite was not identified.
The metabolism, uptake, and elimination rates in humans of
trichloroethylene, 1,1,1-trichloroethane, and tetrachloroethylene
were compared recently by Monster (2). He found that
35
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trichloroethylene was absorbed almost constantly at a relatively
higher rate than the other compounds due to its high partition
coefficient between blood and air resulting in rapid metabolism
of trichloroethylene. Although the partition coefficient between
blood and air of tetrachloroethylene was about the same as
trichloroethylene, the metabolism of tetrachloroethylene was less
complete. Only a relatively small amount of trichloroethylene
was shown to be excreted by the lungs.
In a follow-up study, the same authors (3) exposed 5 male
volunteers to 70 ppm trichloroethylene for 4 hours inhalation on
5 consecutive days. The uptake of this compound in lean body
mass was 6.6 mg/kg within 4 days. Eighteen hours after the 5th
day of exposure, the amount of trichloroethylene in exhaled air
and in blood was twice the level of the first exposure. The
amount of trichloroethanol excreted within a 24-hour period
increased from an average of 142 mg*(lst day) to 217 mg (5th day)
which indicated a diurnal rhythm. The total amount of
trichloroethylene recovery was 78%: 11% was unchanged, 43% as
trichloroethanol, and 24% as trichloroacetic acid. There was a
correlation between the lean body mass and trichloroethanol alone
and trichloroethanol with trichloroacetic acid excreted in
urine. The authors considered trichloroacetic acid in blood to
be a good monitoring parameter due to the minimal interindividual
variation.
Monster and Houtkooper (4) further reported a method for
estimating human uptake of trichloroethylene, methylchloroform,
and tetrachloroethylene from the concentrations of solvents and
metabolites in biological media at 2 and 20 hours after a single
exposure. The method involved simple linear and multiple
regression analyses. The best results were obtained by
estimations from the concentrations in blood, particularly of the
solvents themselves.
36
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In another study, Hathway (5) reported the presence of two
chloral metabolites in the urine of 5-week-old male rats in which
1,1,2-trichloroethylene (stabilized with 0.02% triethylamine) was
administered intragastrically at a level of 2.0 ml/kg. The
treated and the control animals were housed in glass metabolism
cages to collect urine and fecal samples. Analysis of the urine
of treated mice by gas chromatography-mass spectrometry
demonstrated the presence of trichloroacetic acid and a small
amount of dichloroacetic acid. These metabolites were not
detected in the urine of control animals. Dichloroacetic acid is
not thought to be formed in 1,1,2-trichloroethylene metabolism in
mammals other than mice and may be responsible for oncogenicity
in treated mice. The researcher proposed that the rearrangement
of 1,1,2-trichloroethylene oxide into chloral and its metabolic
products rather than into dichloroacetic acid is the possible
reason for the relative harmlessness of exposure to 1,1,2-
trichloroethylene in rats and man.
Ogata et al. (6) studied urinary excretion of trichloro-
ethylene in rabbits, rats, and mice. Levels of the metabolites
of trichloroethylene (trichloroethanol and trichloroacetic acid)
were determined by gas chromatography in the urine of animals
injected with 1 mmole/kg trichloroethylene. The ratio of total
excretion of these metabolites to the total dosage, as well as
the ratio of trichloroethanol to trichloroacetic acid, varied
among the three test species.
Ogata and Yamazaki (7) reported the development of a liquid
chromatographic method for the determination of trichloroacetic
acid levels in urine as a index of trichloroethylene exposure.
With this method, urine can be analyzed within ten minutes
without pretreatment or solvent extraction at a minimal detection
limit of 0.5 jag.
37
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References
1. Steward, R.D., C.L. Hake and J.E. Peterson. 1974.
"Degreasers flush": dermal response to trichloroethylene and
ethanol. Arch. Envir. Hlth. (29):1-5.
2. Monster, A.C. 1979. Differences in uptake, elimination, and
metabolism in exposure to trichloroethylene, 1,1,1-
trichloroethane and tetrachloroethylene. Int. Arch. Occup.
Environ. Hlth. 42(2-4):311-317
3. Monster, A.C., G. Boersman and W.C. Duba. 1979. Kinetics of
trichloroethylene in repeated exposure of volunteers. Int.
Arch. Occup. Environ. Hlth. 42(3-4):283-292.
4. Monster, A.C., and J.M. Houtkooper. 1979. Estimation of
individual uptake of trichloroethylene, 1,1,1-trichloro-
ethylene from biological parameters. Int. Arch. Environ.
Hlth. 42(3-4):319-323.
5. Hathway, D.E. 1980. Consideration of the evidence for
mechanisms of 1,1,2-trichloroethylene metabolism, including
new identification of its dichloroacetic acid and
trichloroacetic acid metabolites in mice. Cancer Letters
(8):263-269.
6. Ogata, M., K. Norichika., Y. Shimada and T. Meguro. 1979.
Differences in urinary trichlorethylene metabolites in
animals. Acta Med. Okayama 33(6):415-421.
7. Ogata, M. and Y. Yamazaki. 1979. Quantitative determination
of urinary trichloroacetic acid as an index of
trichloroethylene exposure by high performance liquid.
chromatography. Acta Med. Okayama. 33(6):479-481.
38
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TECHNICAL REPORT DATA
(P'lease read Instructions on the reverse before completing)
1. REPORT NO.
2.
3. RECIPIENT'S ACCESSION-NO.
4. TITLE AND SUBTITLE
. i i i uc «.IMU SUBTITLE
Metabolism Summaries of Selected Halogenated
Organic Compounds in Human and Environmental
Media, A Literature Survey FIRST UPDATE
5. REPORT DATE
December, 1980
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
Syed M. Naqvi
Marion C. Blois
8. PERFORMING ORGANIZATION REPORT NO.
9. PERF9RMING ORGANIZATION NAME AND ADDRESS
Office of Toxic Substances
Exposure Evaluation Division
Field Studies Branch
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
Office of Pesticides and Toxic Substances
U.S. Environmental Protection Agency
Washington, D.C. 20460
13. TYPE OF REPORT AND PERIOD COVERED
Final
14. SPONSORING AGENCY CODE
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This is the first update to an earlier EPA report entitled "Metabolism
Summaries of Selected Halogenated Organic Compounds in Human and Envir-
onmental Media, A Literature Survey" (EPA-560/6-79-008). This update
provides additional information on fifteen halocarbons covered in the
original report as well as information on four new halocarbons. As
did the earlier literature summary, this update deals with the uptake,
retention, distribution and elimination patterns, identification of
metabolites, and metabolic pathways of the halocarbons.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lDENTIFIERS/OPEN ENDED TERMS
c. COSATI Field/Group
Metabolism
Metabolites
Metabolic pathways
Halogenated hydrocarbons
Halocarbons
Body burden
18. DISTRIBUTION STATEMENT
19. SECURITY CLASS (ThisReport)
21. NO. OF PAGES
44
20. SECURITY CLASS (Thispage)
22. PRICE
EPA Form 2220-1 (9-73)
* U.S. GOVERNMENT PRINTING OFFICE:1981—341-082/* 228
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