United States
Environmental Protection
Agency
Toxic Substances
Washington DC 20460
EPA 560/7-82-003
November 1982
Toxic Substances
METABOLISM SUMMARIES OF SELECTED
HALOGENATED ORGANIC COMPOUNDS
IN HUMAN AND ENVIRONMENTAL MEDIA,
A LITERATURE SURVEY
* ** • •
SECOND UPDATE
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560/7-82-003
November, 1982
METABOLISM SUMMARIES OF SELECTED
HALOGENATED ORGANIC COMPOUNDS
IN HUMAN AND ENVIRONMENTAL MEDIA,
A LITERATURE SURVEY
SECOND UPDATE
Verna L. Halpin
Daniel E. Meyer
Eugene W. Lowe, Jr.
Regina Origoni
Project Manager
Contract No. 68-01-6021
Technical Directive 40
Technical Managers
Marion C. Blois - Academic Faculty Program
Joseph J. Breen - Exposure Evaluation Division
Project Officer
Douglas W. Sellers - Management Support Division
Office of Toxic Substances
Washington, DC 20460
Prepared for
Environmental Protection Agency
Office of Pesticides and Toxic Substances
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
Page
INTRODUCTION i
METABOLISM SUMMARIES:
Bromobenzene 1
Bromodichloromethane 3
Bromoform 5
Carbon Tetrachloride 7
Chlorobenzaldehyde 10
Chloroform ..... 11
Chloronaphthalene 14
Dibromochloromethane 16
Dichlorobenzene 18
1,2-Dichloroethane 21
1,1-Dichloroethylene 23
1,2-Dichloropropane 27
Hexachlorobenzene 29
Hexachloroethane 32
Methylene Chloride 33
Pentachloroanisole 36
Pentachlorobenzene 38
Tetrachlorobenzene 41
Tetrachloroethylene 43
Trichlorobenzene 46
1,1,1-Trichloroethane 49
1,1,2-Trichloroethane 51
Trichloroethylene 53
APPENDIX: Summary Table of Experimental Data 59
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Acknowledgements
We wish to acknowledge the assistance of Dr. Edo D. Pellizzari, Research
Triangle Institute; Dr. Evelyn Murrill, Midwest Research Institute; Dr. Harold
Seifried, Tracor Jitco, Inc.; and Mr. Ken Falahee, Tracor Jitco, Inc. for
their technical review of this document.
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Introduction
The Office of Pesticides and Toxic Substances' Exposure Evaluation
Division (EED) 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.
1 2
This document represents the third in a series of literature surveys '
of the metabolism of halogenated hydrocarbons. These surveys complement EED
efforts to evaluate human body burden associated with environmental exposure.
1 Metabolism Summaries of Selected Halogenated Organic Compounds in Human
and Environmental Media, A Literature Survey EPA 560/6-79-008, April 1979.
2 Metabolism Summaries of Selected Halogenated Organic Compounds in Human
and Environmental Media, A Literature Survey: First Update EPA
560/13-79-018, December 1980.
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Forty-nine halogenated hydrocarbons (HHC) were selected for the first
metabolism review based on the following information:
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 Formulation of A
Preliminary Assessment of Halogenated Organic Compounds in Man and
Environmental Media EPA 560/13-79-006, July 1979.
The first literature survey provided metabolism summaries as well as basic
information on the physical properties of the 30 HHC's reviewed. The first
update report updated information on 15 of the original HHC's plus provided
physical data and metabolism summaries for 4 additional HHC's not included in
the first survey. This second update provides information on 23 HHC's found
in the literature from January 1978 through November 1980.
Basic information on the physical properties of the compounds at the
beginning of each summary includes molecular and structural formulas, the
Chemical Abstracts Service Registry number (CAS RN), accepted synonyms (syn),
molecular weight (mol wt), boiling point (bp) , and vapor pressure (vp). The
ii
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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.
The basis of this second update reflects a more extensive search strategy
than did the first update. The databases were updated from 1978 and include
the following:
Agricola
Biosis
Chemical Abstracts
Commonwealth Agricultural Bureau Abstracts
Comprehensive Dissertation Abstracts
Conference Papers Index
Enviroline
Environmental Periodicals Bibliography
Excerpta Medica
IRL Life Sciences
Medline
National Technical Information Service
Pollution Asbtracts
Scisearch
Toxline
iii
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METABOLISM SUMMARIES
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BROMOBENZENE
C6H5Br
CAS: 000108861
Syn: phenyl bromide
Mol wt: 157.02 g/mol
bp: 156°C (at 760 mm Hg)
vp: 4.3 mm Hg (at 25°C)
The i_n vitro pathway of bromobenzene enzymatic activation to either
bromobenzene 3,4-epoxide or bromobenzene 2,3-epoxide is by hepatic cytochrome
P-450 as shown in Figure 1. Metabolite formation in rat liver microsomes is
proportional to the enzyme concentration and is markedly changed after
pretreatment with various inducers (Lau and Zannoni, 1979; Zannoni and Lau,
1979). The amount of metabolite produced is dependent upon the inducer:
phenobarbital induces both the o- and p-bromophenol pathway while
3-methylcholanthrene or beta-naphthoflavone markedly induces the o-bromophenol
pathway. Discontinuous polyacrylamide gel electrophoresis was used to
correlate the relative activity of the 3,4-epoxide and 2,3-epoxide pathways
with various molecular forms of cytochrome P-450. Multiple bands in the
40,000 to 60,000 molecular weight range showed significant differences
depending upon the inducer. The two pathways of bromobenzene metabolism each
preferentially require different forms of cytochrome P-450.
Wiley et al. (1979) measured the in vitro disappearance of 1 mM
tritium-labelled bromobenzene from rat liver microsomes (8-12 mg) to be 0.864
nmol/mg protein/min. At substrate concentrations greater than 0.3 nmol, the
reaction velocity markedly increases, suggesting multi-enzyme metabolism.
Phenobarbital induced a 9-fold increase in bromobenzene covalent binding to
microsomal protein. Covalent binding is completely inhibited by 0.1 mM
glutathione, which is due to competition for the arene oxides by the
glutathione transferase reactions.
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3,4-epoxide
p-bromophenol
o-bromophenol
Fig. 1. Bromobenzene metabolism.
Reprinted from: Hepatic microsomal epoxidation of bromobenzene to phenols
and its toxicological implication. Toxicology and Applied Pharmacology,
50:309-318, 1979 by Serrine S. Lau and Vincent G. Zannoni with permission
of Academic Press, Inc.
REFERENCES
Lau SS, Zannoni VG. 1979. Hepatic microsomal oxidation of bromobenzene to
phenols. Fed. Proc. 38(3 part 1):426.
Wiley RA, Hanzlik RP, Gillesse T. 1979. Effect of substituents on in vitro
metabolism and covalent binding of substituted bromobenzenes. Toxicol. Appl.
Pharmacol. 49(2):249-255.
Zannoni VG, Lau SS. 1979. Hepatic microsomal epoxidation of bromobenzene to
phenols and its toxicological implication. Toxicol. Appl. Pharmacol.
50(2):309-318.
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BROMODICHLOROMETHANE
CHBrCl2 Br
I
H-C-CI
I
CAS: 000075274 '
Syn: bromodichloromethane; dichlorobromomethane; monobromodichloromethane
Mol wt: 163.8 g/mol
bp: 90°C (at 760 mm Hg)
Bromodichloromethane metabolism to carbon monoxide in rat liver microsomes
was studied by Ahmed et al. (1977). Bromodichloromethane (26 mM) incubated
with hepatic microsomes (2.4-3.0 mg protein) resulted in a carbon monoxide
formation rate of 0.04 nmol/mg/min (enzymatic: 37°C for 15 minutes). This
was a relatively low rate when compared to other halomethanes but was three
times the control rate observed with boiled microsomes. Anders et al. (1978)
did not find elevated blood carbon monoxide levels after administering a
single 1 mmol/kg intraperitoneal dose of bromodichloromethane.
Pfaffenberger et al. (1979) measured the distribution of
bromodichloromethane between rat blood serum and adipose tissue by a
gas-liquid chromatography procedure. Rats dosed for 25 days with
bromodichloromethane showed tissue storage but these levels did not increase
with time. Average values for adipose (hexane extracted) and serum
bromodichloromethane concentrations were 51 ppb and 1 ppb, respectively, for
the 0.5 mg/day dose group. Increased levels of 1800 ppb (adipose) and 23 ppb
(serum) were noted for the 5.0 mg/day dose groups. Three to 6 days after
cessation of dosing, adipose levels decreased rapidly to 4 ppb for the 0.5
mg/day dose group and to 3 ppb for the 5.0 mg/day dose group. Serum levels in
both groups dropped to 1 ppb.
REFERENCES
Ahmed AE, Kubic VL, Anders, MW. 1977. Metabolism of haloforms to carbon
monoxide. I. In vitro studies. Drug Metab. Dispos. (U.S.A.) 5(2):198-204.
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Anders MW, Stevens JL, Sprague RW, Shaath Z, Ahmed, AE. 1978. Metabolism of
haloforms to carbon monoxide. II. In vitro studies. Drug Metab. Dispos .
6(5):556-560.
Pfaffenberger CD, Peoples AJ, Enos HF. 1979. Distribution study of volatile
halogenated organic compounds between rat blood serum and adipose tissue using
a purge/trap procedure. Adv. Chromatogr. 14:639-652.
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BROMOFORM
CHBr3 Br
Br— C —Br
CAS: 000075252 H
Syn: tribromomethane; methenyl tribromide
Mol wt: 252.75 g/mol
bp: 149.5°C (at 760 mm Hg)
vp: 6.11 mm Hg (at 25°C)
Stevens and Anders (1979) studied the in vitro biotransformation of
bromoform to carbon monoxide (CO) by the microsomal mixed function cytochrome
P-450 oxygenase system involving glutathione (GSH) and proposed the following
metabolic pathway: CHBr3-» COHBr3~»Br2CO; Br2CO + GSH—GS(C=0)Br;
GS(C=0)Br + GSH—GSSG + (:C=0)
Microsomal incubation with either l-^CHB^ or ^02 confirmed that the
sources of carbon and oxygen in released carbon monoxide are bromoform and
molecular oxygen, respectively, as shown by Ahmed et al. (1977). Two moles of
glutathione disappear during the formation of 1 mole of carbon monoxide and 1
mole of oxidized glutathione (GSSG). Carbon monoxide formation is 1.23
nmol/mg/min for the microsomes. The addition of glutathione to an NADPH
incubation mixture increases carbon monoxide formation as much as 8-fold
implying a direct involvement in the reactions. Phenobarbital or
3-methylcholanthrene pretreatment increases the carbon monoxide formation rate
by 75% or 60% respectively, while cobaltous chloride treatment decreases and
SKF-525-A treatment inhibits carbon monoxide formation.
Anders et al. (1978) studied the in vivo bromoform metabolism in rats by
intraperitoneal administration of 1, 2, or 4 mmol/kg doses. Increasing
bromoform concentration resulted in increasing levels of carbon monoxide in
the blood. Phenobarbital pretreatment markedly increased blood carbon
monoxide levels while SKF-525-A lowered blood carbon monoxide levels following
bromoform injection. 3-Methylcholanthrene pretreatment did not increase the
blood levels.
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REFERENCES
Ahmed AE, Kubic VL, Anders MW. 1977. Metabolism of haloforms to carbon
monoxide. I. In vitro studies. DrugMetab. Dispos. (U.S.A.) 5(2):198-204.
Anders MW, Stevens JL, Sprague RW, Shaath Z, Ahmed AE. 1978. Metabolism of
haloforms to carbon monoxide. II. In vitro studies. Drug Metab. Dispos.
6(5):556-560.
Stevens JL, Anders, MW. 1979. Metabolism of haloforms to carbon monoxide.
III. Studies on the mechanism of the reaction. Biochem. Pharmacol.
28(21):3189-3194.
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CARBON TETRACHLORIDE
CC14 C]
I
ci— c~— ci
CAS: 000056235 C]
Syn: methane tetrachloride; tetrachloromethane; perchloromethane
Mol wt: 153.82 g/mol
bp: 76.54°C (at 760 mm Hg)
vp: 98.9 mm Hg (at 25°C)
Carbon tetrachloride appears to be metabolized to phosgene and carbon
dioxide through biotransformation via the heme system and cytochrome P-450, as
demonstrated by Mansuy et al. (1980) and Shah et al. (1979).
Mansuy et al. (1980) propose that carbon tetrachloride converts primarily
to phosgene from a reaction of dioxygen either with intermediate FeCCl3 or
FeCCl2 carbene complexes, depending on the nature of the reducing agent. It
is suggested that phosgene could react with nucleophilic groups (NuH) of cell
macromolecules producing unstable Nu-COCl intermediates which then could react
with an additional nucleophilic group to create stable covalent adducts . This
proposed pathway, as shown in Figure 1, yields carbon dioxide as the main
stable metabolite of carbon tetrachloride metabolism.
The metabolism of carbon tetrachloride was studied by Shah et al. (1979)
to investigate the mechanism of its carcinogenicity. Liver homogenates from
male rats were incubated with labelled carbon tetrachloride and NADH or NADPH
in the presence or absence of carbon tetrachloride metabolites or substrates
for reaction with carbon tetrachloride metabolites. The conversion of carbon
tetrachloride to carbon dioxide as well as its binding to lipid and protein
were observed after incubation with NADPH. The formation of
2-oxothiazolidine-4-carboxylic acid demonstrates the metabolic formation of
phosgene from carbon tetrachloride.
Pfaffenberger et al. (1979) using gas-liquid chromatography studied the
distribution of carbon tetrachloride between rat blood serum and adipose
tissue. Blood and adipose tissue were collected and analyzed from rats
gavaged for 25 days with 1 or 10 mg carbon tetrachloride. On day 25, the
blood serum carbon tetrachloride levels averaged 11 ppb and the fat carbon
tetrachloride levels averaged 1.9 ppm for the 10-mg dosed rats. The
metabolite chloroform was detected in the blood serum (59 ppb) and fat (2.62
ppm) in the 10-mg dosed rats. Following cessation of dosing, levels dropped
roughly 10-fold.
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Statham et al. (1978) studied the uptake, elimination, distribution, and
toxic effects of carbon tetrachloride in rainbow trout. Uptake was determined
by exposing 15 trout to labelled carbon tetrachloride for 0 to 1.5 hours at a
dose of 1 mg/liter in water. Fat, liver, blood, and muscle all showed carbon
tetrachloride uptake. During exposure, fat levels steadily increased to near
1 nmol/g while liver, blood, and muscle peaked between 15 to 30 minutes and
then steadily declined. Following 2 hours of exposure, blood, bile, liver,
heart, muscle, gill, brain, skin, and spleen all showed decreasing levels
through 8 hours. Fat levels continued to rise through the second hour
following cessation of exposure.
HCI
(b)
Fig. 1: Proposed mechanism for CC14 biotransformation by the heme
system and cytochrome P450 (P=TPP or cytochrome P450; NuH and Nu'H =
or nucleophilic groups of microsomal proteins).
Reprinted from: A heme model study of carbon tetrachloride metabolism:
mechanisms of phosgene and carbon dioxide formation. Biochemical and
Biophysical Research Communications, 95:1536-1542, 1980 by D. Mansuy, M.
Fontecave and J. C. Chottard with permission of Academic Press, Inc.
REFERENCES
Mansuy D, Fontecave M, Chottard JC. 1980. A heme model study of carbon
tetrachloride metabolism: mechanisms of phosgene and carbon dioxide
formation. Biochem. Biophys. Res. Commun . 95(4):1536-1542.
Pfaffenberger CD, Peoples AJ, Enos HF- 1979. Distribution study of volatile
halogenated organic compounds between rat blood serum and adipose tissue using
a purge/trap procedure. Adv. Chromatogr. 14:639-652.
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Shah H, Hartman SP, Weinhouse S. 1979. Formation of carbonyl chloride in
carbon tetrachloride metabolims by rat liver in vitro. Cancer Res .
39 (10)-.3942-3947.
Statham CN, Croft WA, Lech JJ. 1978. Uptake, distribution and effects of
carbon tetrachloride in rainbow trout (Salmo gairdneri). Toxicol. Appl.
Pharmacol. 45(1):131-140.
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CHLOROBENZALDEHYDE
C7H5C10
CAS: 000089985
Syn: 2-chlorobenzaldehyde; ortho-chlorobenzaldehyde
Mol wt: 140.57 g/mol
bp: 211.9°C (at 760 mm Hg)
vp: 1.07 mm Hg (at 25°C)
A study of chlorobenzaldehyde as a metabolite of o-chlorobenzylidene
malononitrile was presented by Paradowski (1979). Toxic doses of
o-chlorobenzylidene malononitrile were intravenously administered to rabbits
and the following metabolic pathway determined. o-Chlorobenzylidene
malononitrile biotransformation occurred mainly in the blood by two
independent pathways: rapid hydrolysis to o-chlorobenzaldehyde and
malononitrile as the dominant reaction (30%-40% of o-chlorobenzylidene
malononitrile) or reduction to o-chlorobenzyl malononitrile (10% of
o-chlorobenzylidene), while the remaining 50%-60% of the o-chlorobenzylidene
malononitrile administered disappeared from blood by other pathways.
o-Chlorobenzaldehyde was about twice as toxic (average LD5Q = 8.5 mg/kg) as
o-chlorobenzylidene malononitrile (average L^Q = 18.3 mg/kg). Exclusion of
the liver from the circulatory path increased the amount of
o-chlorobenzaldehyde produced to 75% of administered o-chlorobenzylidene
malononitrile with about 15% of the o-chlorobenzylidene malononitrile being
reduced to o-chlorobenzyl malononitrile. Renal exclusion from circulation
followed by o-chlorobenzylidene malononitrile dosing did not alter its
biotransformation in blood. The in vitro metabolism of o-benzylidene
malononitrile was quantitatively different from its in vivo metabolism, with
considerably slower reaction rates of formation and elimination of metabolites
in blood. The toxic activity of o-chlorobenzylidene malononitrile was due to
its metabolism to the more toxic o-chlorobenzaldehyde. o-Chlorobenzylidene
malononitrile reduction to the benzyl malononitrile demonstrated a minor
detoxication pathway.
REFERENCE
Paradowski M. 1979. Metabolism of toxic doses of o-chlorobenzylidene
malononitrile in rabbits. Pol. J. Pharmacol. Pharm. 31(6):563-572.
10
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CHLOROFORM
CHC13 CI
ci—c —ci
CAS: 000067663 H
Syn: formyl trichloride; methane trichloride; methynyl trichloride; methyl
trichloride; trichloroform; trichloromethane
Mol wt: 119.38 g/mol
bp: 61.7°C (at 760 mm Hg)
vp: 173.1 mm Hg (at 25°C)
Chloroform is reported to be metabolized in phenobarbital-treated animals
to phosgene, which reacts with cysteine to form 2-oxothiazolidine-4-carboxylic
acid. Carbon dioxide is the final metabolic product (Ahmed et al., 1980;
Mansuy, 1977; Pohl et al., 1977; Pohl et al., 1978; Pohl et al., 1979).
Mansuy (1977) studied the in vitro metabolism of chloroform to a reactive
metabolite. Adult male rats were pretreated with 80 mg/kg phenobarbital each
day for 3 days prior to sacrifice. Liver microsomal suspensions were
incubated for 15 minutes with or without cysteine. Phosgene appeared to be
the reactive metabolite, and could be hydrolyzed to carbon dioxide or trapped
with cysteine to form 4-carboxy-thiazolidine-2-one.
Pohl et al. (1977) also studied the metabolism of chloroform to phosgene
by liver microsomes. Male rats, pretreated with phenobarbital 1, 2, and 3
days before dosing, were sacrificed and these liver microsomal proteins were
incubated with 1.00 mmol labelled chloroform. Chloroform was hydroxylated to
trichloromethanol by cytochrome P-450 monoxygenases. The alcohol then
underwent spontaneous dehydrochlorination to form phosgene which could react
with excess cysteine or microsomal proteins.
Pohl and Krishna (1978) continued their earlier work to investigate the In
vitro metabolism of chloroform to a reactive metabolite. Male rats were
pretreated with phenobarbital 1, 2, and 3 days prior to preparation of
microsomes. Following incubation of 1 nmol chloroform at 37°C for 10
minutes with microsomes, approximately 2 nmol of phosgene appeared as the
major metabolite and was trapped with cysteine forming 2-oxathiazolidine-4-
carboxylic acid. Pohl et al. (1979) continued their studies to show phosgene
as a possible hepctotoxic metabolite of chloroform.
Kluwe (1979) investigated the covalent binding of chloroform metabolites
in the liver and kidney. Labelled chloroform was administered in a 1.75
mmol/kg dose to male mice. The mice were sacrificed 3 hours after
11
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administration and subcellular fractions were prepared from liver and kidney.
Covalent binding of the radioactivity to subcellular fractions was variable,
with the highest levels observed in liver cytosol and kidney mitochondria, the
lowest in liver mitochrondria and kidney cytosol. It is suggested that the
chloroform metabolite covalently bound to the liver and kidney is not the same
metabolite that causes hepatic and renal injury.
Ahmed et al. (1980) have summarized the metabolism studies on chloroform.
Chloroform is metabolized in vivo and in vitro to carbon dioxide.
Phenobarbital and 3-methyldSblanthrene~~pretreatments increased the metabolic
rate and hepatotoxic effects. Phosgene appeared as an intermediate and
reacted with cysteine forming 2-oxothiazolidine-4-carboxylic acid. Covalent
binding of chloroform to hepatic proteins and lipids may be attributed to the
highly reactive phosgene metabolite which can acylate tissue nucleophiles and
crosslink macromolecules.
In a study to determine if carbon monoxide was a metabolite of chloroform,
Ahmed et al. (1977) studied the in vitro metabolism of chloroform. Hepatic
fractions from 3-methylcholanthrene- or phenobarbital-treated rats were
incubated with 60 umol of chloroform. Nonenzymatic rates of carbon monoxide
formation were determined by heating the reaction mixture for 4 minutes at
100°C. The microsomal conversion of chloroform to carbon monoxide was 0.03
nmol/mg/min for enzymatic incubations and 0.00 nmol/mg/min for nonenzymatic
reactions.
Anders et al. (1978) studied the metabolism of chloroform to carbon
monoxide. Male rats received a single 1 mmol/kg intraperitoneal dose of
chloroform and blood carbon monoxide levels were measured for 4 hours at 1
hour intervals. The administration of chloroform did not increase blood
carbon monoxide levels.
Pfaffenberger et al. (1979) studied the distribution of chloroform between
rat blood serum and adipose tissue using a purge/trap/desorb-gas-liquid
chromatography procedure. Rats were administered varied doses of chloroform
followed by collection and analysis of blood and adipose tissue samples.
Increased levels of chloroform appeared in the blood and adipose tissue within
2 hours after dosing. In the first experiment, eight rats were administered
40 mg of chloroform by gavage for 2 consecutive days. Two rats were killed 2
hours after the second dose and the level of chloroform in the fat was between
3 and 15 ppm. Rats killed 26 hours after dosing had chloroform levels in fat
approximately equal to levels in controls. In a second study, ten rats
received 5 mg of chloroform by gavage and killed 2 hours after dosing.
Chloroform levels of 20 ppm in the fat and 18 ppb in the serum were detected.
Vogt et al. (1979) investigated the formation of chloroform in vivo and in
vitro. Sprague-Dawley rats were fasted for 15 hours prior to intTragasTric
intubation of sodium hypochlorite containing 20-80 mg chlorine. Tissue
homogenates were incubated with sodium hypochlorite i_n vitro. Chloroform
levels were highest 1.5 hours after intubation and were almost completely
eliminated after 24 hours. Increased doses of sodium hypochlorite resulted in
greater chloroform formation both rn vitro and rn vivo, with the highest
levels occurring in the blood and fat.
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Withey and Collins (1980) studied the pharmacokinetics of chloroform
metabolism in male Wistar rats. Varied doses (3, 6, 9, 12, or 15 mg/kg) of
chloroform were administered intravenously and blood samples were collected at
selected time intervals. Tissue samples yielded meaningful kinetic data only
at the highest dose level (15 mg/kg).
REFERENCES
Ahmed AE, Kubic VL, Anders, MW. 1977. Metabolism of haloforms to carbon
monoxide. I. In vitro studies. Drug Metab. Dispos. (U.S.A.) 5(2):198-204.
Ahmed AE, Kubic VL, Stevens JL, Anders MW. 1980. Halogenated methanes:
metabolism and toxicity. Fed. Proc. 39(13):3150-3155.
Anders MW, Stevens JL, Sprague RW, Shaath Z, Ahmed AE. 1978. Metabolism of
haloforms to carbon monoxide. II. In vitro studies. Drug Metab. Dispos.
6(5):556-560.
Kluwe, WM. 1979. Covalent binding of chloroform metabolites in liver and
kidney. Relationship to acute toxicity. Fed. Proc. 38(3 part 1):539.
Mansuy D, Beaune P, Cresteil T, Lange M, Leroux JP- 1977. Evidence for
phosgene formation during liver microsomal oxidation of chloroform. Biochem.
Biophys. Res. Commun . 79(2): 513-5.17 .
Pfaffenberger CD, Peoples AJ, Enos HF. 1979. Distribution study of volatile
halogenated organic compounds between rat blood serum and adipose tissue using
a purge/trap procedure. Adv. Chromatogr. 14:639-652.
Pohl LR, Bhooshan B, Whittaker NP, Krishna G. 1977. Phosgene: a metabolite
of chloroform. Biochem. Biophys. Res. Commun. 79(3):684-691.
Pohl LR, Krishna G. 1978. Deuterium isotope effect in bioactivation and
hepatotoxicity of chloroform. Life Sci. 23(10):1067-1072.
Pohl LR, George JW, Martin JL, Krishna G. 1979. Deuterium isotope effect in
in vivo bioactivaLion of chloroform to phosgene. Biochem. Pharmacol.
28"(4773"61-563.
Vogt CR, Liao, JC, Sun GY, Sun AY. 1979. In vivo and in vitro formation of
chloroform in rats with acute dosage of chlorinated water and the effect of
membrane function. Trace Subst. Environ. Health 13:453-460.
Withey JR, Collins BT. 1980. Chlorinated aliphatic hydrocarbons used in the
foods industry: the comparative pharmacokinetics of methylene chloride,
1,2-dichloroethane, chloroform and trichloroethylene after i.v. administration
in the rat. J. Environ. Pathol. Toxicol. 3(5-6):313-332.
13
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CHLORONAPHTHALENE
C10H?C1
Mol wt: 162.62 g/mol
1-chloronaphthalene
CAS: 000090131
Syn: alpha-chloronaphthalene; alpha-chlornaphthalene
bp: 258.8°C (at 753 mm Hg); 106.5°C (at 5 mm Hg)
vp: 1.36 mm Hg (at 80.6°C)
2-chloronaphthalane
CAS: 000091587
Syn: beta-chloronaphthalene
b.p.: 256°C (at 760 mm Hg)
Ruzo et al. (1976) studied the concentrations of 1- or 2-chloronaphthalene
substrates and their metabolites during the first 6 hours after retrocarotid
injection (300 mg) in blood and after 6 hours in blood, urine, bile, and organ
samples from two female Yorkshire pigs. The 1-chloronaphthalene concentration
was 5.1 ug/g in blood 10 minutes after injection and decreased with time. Its
metabolite, 4-chloronaphthol, was first detected in blood after 160 minutes
and increased with time. 2-Chloronaphthalene concentrations were similar to
those observed for the 1-chloro isomer. 3-Chloro-2-naphthol, the major
metabolite of 2-chloronaphthalene, was first detected in the blood after 200
minutes and increased with time. The chloroisomer substrates 6 hours after
injection were distributed primarily in the brain (6.7 ug/g 1-C1; 21.4 ug/g
2-C1) and kidney (16.1 ug/g 1-C1; 14.4 ug/g 2-C1). The fat tissue
concentrations were low (0.6 ug/g 2-C1) indicating that these lipophilic
substrates were not concentrated during the first 6 hours. Metabolites were
identified in the kidney tissues (1.4 ug/g 4-C1; 0.6 ug/g 3-Cl-2-Naph.), liver
tissues (1.0 ug/g 4-C1; 0.7 ug/g 3-Cl-2-Naph.), urine (440 ug/g 2-C1; 60 ug/g
3-Cl-2-Naph.) and bile (900 ug/g 2-C1; 260 ug/g 3-Cl-2-Naph.).
Chloronaphthalenes were rapidly metabolized, most probably by the liver which
possesses oxidative enzymes.
Secours et al. (1977) administered a single oral dose of various
dichloronaphthalenes (400 mg/kg) to male rats and identified urinary
metabolites. 1,2-Dichloronaphthalene yielded the glucuronide conjugate of
5,6-dichloro-l ,2-dihydroxy-l,2-dihydronaphthalene; 2,7-dichloronaphthalene was
14
-------
metabolized to free and conjugated 7-chloro-2-naphthol; and
2,6-dichloronaphthalene yielded free and conjugated 6-chloro-2-naphthol and
2,6-dichloronaphthol.
REFERENCES
Ruzo LO, Safe S, Jones D, Platonow N. 1976. Uptake and distribution of
chloronaphthalenes and their metabolites in pigs. Bull. Environ. Contain.
Toxicol. 16(2): 233-239.
Secours V, Chu I, Viau A, Villeneuve DC. 1977. Metabolism of
chloronaphthalenes. J. Agric. Food Chem. 25(4):881.
15
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DIBROMOCHLOROMETHANE
CHBr2Cl Br
Br-C-H
I
Cl
CAS: 000124481
Syn: chlorodibromomethane; dibromochloromethane; dibromomonochloromethane;
monochlorodibromomethane
Mol wt: 208.3 g/mol
bp: 119-120°C (at 748 mm Hg)
The in vitro metabolism of dibromochloromethane to carbon monoxide in rats
was investigated by Ahmed et al. (1977). Hepatic microsomes containing
2.4-3.0 rag protein were incubated with 26 mM dibromochloromethane at 37°C
for 15 minutes. The microsomal conversion of dibromochloromethane to carbon
monoxide was 0.42 nmol/mg/min for enzymatic incubations and 0.03 nmol/mg/min
for the nonenzymatic rate.
Anders et al. (1978) measured in vitro metabolism of dibromochloromethane
to carbon monoxide. After rats received a single 1 mmol/kg intraperitoneal
injection of dibromochloromethane, blood carbon monoxide levels increased (see
Figure 1).
16
-------
2000
T3
O
1500
o 1000
o
O
500
0
1 2 3
Time (hours)
Fig. 1. Blood carbon monoxide levels after the administration of
bromoform, chloroform, dibromochloromethane, dichlorobromomethane, or
iodoform. Control ( • ), dichlorobromomethane ( A ), chloroform ( • ),
dibromochloromethane ( O )» bromoform ( A ), and iodoform ( D ).
Reprinted from: Metabolism of haloforms to carbon monoxide. II. In vivo
studies. Drug Metabolism and Disposition, 6(5):556-560, 1978 by M.wT
Anders, J.L. Stevens, R.W. Sprague, Z. Shaath, and A.E. Ahmed with
permission of The Williams and Wilkens Company.
REFERENCES
Ahmed AE, Kubic VL, Anders MW. 1977. Metabolism of haloforms to carbon
monoxide. I. In vitro studies. Drug Metab. Dispos. (U.S.A.) 5(2):198-204.
Anders MW, Stevens JL, Sprague RW, Shaath Z, Ahmed A.E. 1978. Metabolism of
haloforms to carbon monoxide. II. In vitro studies. Drug Metab. Dispos.
6(5):556-560.
17
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DICBLOROBENZENE
C6H4C12
Mol wt: 147.01 g/mol
ortho-dichlorobenzene
CAS: 000095501
Syn: o-dichlorobenzene; 1,2-dichlorobenzene; ODB; ODCB;
orthodichlorobenzene; orthodichlorobenzol
bp: 180.5°C (at 760 mm Hg)
vp: 1.5 mm Hg (at 25°C)
meta-dichlorobenzene
CAS: 000541731
Syn: m-dichlorobenzene; 1,3-dichlorobenzene; metadichlorobenzene;
metadichlorobenzol
bp: 173°C (at 760 mm Hg)
vp: 2.3 mm Hg (at 25°C)
para-dichlorobenzene
CAS: 000106467
Syn: p-dichlorobenzene; paradichlorobenzene; paradichlorobenzol
bp: 174°C (at 760 mm Hg)
vp: 1.1 mm Hg (at 30.0°C)
No pertinent literature was available on ortho- or meta-dichlorobenzene
during the search period.
p-Dichlorobenzene, a volatile environmental contaminant, was found in
human fat, pigeon fat, and ambient air (Tokyo, Japan) by Morita et al. (1978)
in concentrations of 1.88 + 2.13 ppm; 1.85 + 0.75 ppm; and 2.63 + 0.32 ppm,
respectively. Less variation was found in pigeon fat concentrations due to
their exposure to nearly constant ambient air concentrations, whereas
variations in human fat reflected the diversity of physical exposure times and
concentrations of p-dichlorobenzene. The chemical is used primarily as a moth
18
-------
repellent and reaches concentrations of several hundred ug/nH in indoor
air. No p-dichlorobenzene was detected in water, fish, dairy products, and
cereals.
Hawkins et al. (1980) studied -^C-p-dichlorobenzene metabolism in rats by
three administration routes: oral (250 mg/kg/day), subcutaneous (250 mg/kg/
day), and inhalation (1000 ppm for 3 hr/day). Inhalation and oral routes
displayed similar distribution and excretion patterns. Tissue levels were
highest in liver and kidney. Subcutaneous dosing produced lower peak
concentrations but maintained steady state levels for a longer period. Fat
tissue had the highest p-dichlorobenzene tissue concentration. Each route
-OH
SULPHATE
ANDGLUCURONIDE
Cl
Cl
SG
H
OH
H
NHCOCH-
I 1 "
SCH2CHC02H
Fig. 1.
rats.
Postulated biotransformation pathway of p-dichlorobenzene in
Reprinted from: The distribution, excretion and biotransformation of
p-dichloro(-'-^C)benzene in rats after repeated inhalation, oral and
subcutaneous doses. Xenobiotica 10(2):81-95, 1980 by D.R. Hawkins, L.F.
Chasseaud, R.N. Woodhouse and D.G. Cresswell with permission of Taylor and
Francis, Ltd.
19
-------
produced p-dichlorobenzene tissue concentrations after repeated dosing, with
rapid decline in all tissues and extremely low level detection in fat only 5
days after dosing. p-Dichlorobenzene was rapidly absorbed and cleared from
the lungs. Clearance from fat tissue was slower but by 120 hours had
decreased nearly 500 times. A proposed metabolic pathway in rats is shown in
Figure 1. Between 90%-97% of the eliminated doses appeared in urine within 5
days regardless of the route. Approximately 50%-60% of the eliminated dose
was excreted in the bile within 48 hours but most was reabsorbed and
eliminated in urine. The major urinary metabolites were the sulfate (46%-54%)
and glucuronide conjugates (31%-34%) of 2,5-dichlorophenol. A
dihydroxydlchlorobenzene conjugate (possibly 2,5-dichloroquinol) and
mercapturic acid were also identified as minor urinary components after acid
hydrolysis. There were some quantitative differences in urinary metabolites
depending upon the dosage route but larger variations were noted in the
distribution of metabolites from bile. A major biliary metabolite was
2,5-dichlorophenol glucuronide (30%-42%). A second major component not
identified was assumed to be reabsorbed and further metabolized before
elimination in urine.
REFERENCES
Hawkins DR, Chasseaud LF, Woodhouse RN, Cresswell DG. 1980. The
distribution, excretion and biotransformation of carbon-14 labeled
p-dichlorobenzene in rats after repeated inhalation, oral and subcutaneous
doses. Xenobiotica 10(2):81-96.
Morita M, Ohi G. 1978. p-Dichlorobenzene in pigeon and human adipose
tissue. Chemosphere 7(10):839-842.
20
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1,2-DICHLOROETHANE
C2H4C12 Cl Cl
I I
H—C—C—H
CAS: 000107062 ^ ^
Syn: sym-dichloroethane; alpha,beta-dichloroethane; dichloroethylene; EDC;
ethane d:chloride; ethylene chloride; ethylene dichloride; glycol
dichloride
Mol wt: 98.96 g/mol
bp: 83.47°C (at 760 mm Hg)
vp: 76.2 mm Hg (at 25°C)
Kokarovsteva et al. (1978) identified chloroethanol in the blood and liver
of rats after a single oral 750 mg/kg dose of 1,2-dichloroethane. In blood,
the chloroethanol concentration was 5.6 ug/ml after 1 hour, peaking at 4 hours
(67.8 ug/ml) and declining through 12 hours (37.6 ug/ml), 24 hours (14.1
ug/ml), and 48 hours (8.2 ug/ml). In the liver, chloroethanol was not found
after 1 and 4 hours, but was detected after 12 hours (0.5 ug/g), 24 hours
(13.5 ug/g); the concentration slowly decreased through 48 hours (13.0 ug/g).
Chloroethanol was highly toxic (LD5Q = 87 mg/kg) and was rapidly absorbed
into blood and metabolized within 24 hours to monochloroacetic acid.
Livesey et al. (1979) investigated an alternate pathway of
1,2-dichloroethane metabolism to ethylene in vitro involving conjugation with
glutathione (see Figure 1). Various rat tissue cytosol fractions incubated
with 255 umol 1,2-dichloroethane showed linear ethylene production rates for
at least 1 hour: liver (10.3 pmol/min/mg), kidney (5.2 pmol/min/mg), and lung
(0.8 pmol/min/mg). No activity was observed in muscle. Metabolic inhibitors
such as cyanide, fluoride, SKF-525-A, and EDTA had no inhibitory effect.
p-Chloromercuribenzoic acid, diethyl maleate, or methyl iodide (substrates for
GSH-S transferases) markedly inhibited ethylene production.
Withey et al. (1980) studied the pharmacodynamics of 1,2-dichloroethane in
rats by intravenous administration of 3, 6, 9, 12, or 15 mg/kg.
1,2-Dichloroethane was rapidly eliminated from the blood and tissue. Tissue
samples yielded meaningful kinetic data at only the highest dose level (15
mg/kg); elimination was essentially complete after 300 minutes except in
perirenal fat. 1,2-Dichloroethane uptake/elimination in fat is described by a
one compartment model: time for maximal accumulation = 32.5 minutes, peak
concentration = 24.92 ug/g, and elimination half-life = 78 minutes.
21
-------
A. GS*HO
-------
1,1-DICHLOROETHYLENE
C2H2C12 Cl. H
C = C
/ \
CAS: 000075354 Cl H
Syn: 1,1-DCE; 1,1-dichloroethene; vinylidene chloride; vinylidine chloride
Mol wt: 96.94 g/mol
bp: 37°C (at 760 mm Hg)
vp: 633.7 mm Hg (at 25°C)
The major metabolites of 1,1-dichloroethylene have been reported to be
thiodiglycolic acid, S-(carboxymethyl)-N-acetylcysteine, and methylthio-
acetylaminoethanol by Reichert (1979) and Reichert et al. (1979). Jaeger
(1977) proposed that 1,1-dichloroethylene is metabolized to monochlorocitric
acid. Jones and Hathway (1977) suggest thiodiglycolic acid and an
N-acetyl-S-cysteinyl-acetyl derivative as the major urinary metabolites with
substantial levels of chloroacetic acid, dithioglycolic acid, and thioglycolic
acid.
Jaeger (1977) studied the inhibition of hepatic mitochondrial metabolism
in fasted rats exposed to 1,1-dichloroethylene. Male rats received a single
250 ppm inhalation exposure to 1,1-dichloroethylene and selected tests on
isolated mitochondria were conducted for 1 to 24 hours after exposure.
1,1-Dichloroethylene toxicity appeared to result from mitochondrial injury.
The author proposed that 1,1-dichloroethylene is metabolized via
monochloroacetic acid to monochlorocitric acid which may inhibit aconitase and
block citrate oxidation in the mitochondria.
The metabolism of 1,1-dichloroethylene in adult male rats was investigated
by Jones and Hathway (1977). Doses of 500 ug/kg or 350 mg/kg of labelled
1,1-dichloroethylene were administered via gavage, intravenous, or
intraperitoneal routes for 72 hours. Almost all radioactivity was recovered
during the first 72 hours after dosing. Most of the 1,1-dichloroethylene was
eliminated via the lungs. As shown in Figure 1, 1,1-dichloroethylene could be
metabolized primarily to thiodiglycolic acid and an N-acetyl-S-cysteinyl-
acetyl derivative and excreted by the kidneys although significant levels of
chloroacetic acid, dithioglycolic acid, and thioglycolic acid were present.
Reichert and Werner (1978) studied the metabolic fate of labelled
1,1-dichloroethylene by administering a single oral dose (0.5, 5.0, or 50
mg/kg) to rats. The urine and feces were collected for 72 hours after
administration and analyzed. At the 0.5 mg/kg dose, 0.9% of the
23
-------
1,1-dichloroethylene was expired unchanged, 23% was expired as (^C) carbon
dioxide, and 52% was excreted unchanged via the urine. The major metabolite
was thiodiglycolic acid. In a 1979 abstract, Reichert identified three major
metabolites of 1,1-dichloroethylene as thiodiglycolic acid,
S-(carboxymethyl)-N-acetylcysteine, and methylthioacetylaminoethanol.
^C-CClj
(a)
C-CHCH2SCH2CC1
ON- 0
H
RC-CHCH-SCH0CR'
It ^ ' K
0 NH 0
Ac
(e)
(c)
HO-CCHCH.SCH-COJi
2 | 2 22
OH
1
S(CH2C02H)2
I
HSCI^CC^H
i
(SGH2C02H)2
(g)
(h)
(j)
Fig. 1. Scheme for the metabolism of 1,1-dichloroethylene in rats.
Reprinted from: The biological fate of vinylidene chloride in rats.
Chemico-Biological Interactions, 20:27-41, 1978 by B.K. Jones and D.E.
Hathway with permission of Elsevier/North Holland Scientific Publishers,
Ltd.
A follow-up study by Reichert et al. (1979) showed that a single oral dose
of 0.5, 5.0, or 50 mg/kg of labelled 1,1-dichloroethylene was metabolized in
rats to the three metabolites mentioned above. After 72 hours, 1.26%, 9.70%,
and 16.47%, respectively, of the total radioactivity was exhaled unchanged and
24
-------
13.64%, 11.35%, and 6.13%, respectively, was exhaled as (14C) carbon
dioxide. The main portion of the radioactivity was recovered from the urine
(43.55%, 53.88%, and 42.11%, respectively, for the three metabolites),
implying that the metabolic pathway is saturable. The amount of radioactivity
eliminated in the feces was 15.74%, 14.54%, and 7.65%, respectively. The
metabolic pathway is shown in Figure 2.
ci.
ci
c=c
-H NADPH [C|
CI
0
. / \
C-C
o
H 0
i n
CI-C-C-NH-CH7-CH9-O-phosphatidvl
I
H
CI-CH2-CO-NH-CH2-CH2-OH
3
-------
REFERENCES
Jaeger RJ. 1977. Effect of 1,1-dichloroethylene exposure on hepatic
mitochondria. Res. Commun. Chem. Pathol. Phannacol. 18(l):83-94.
Jones BK, Hathway DE. 1978. The biological fate of vinylidene chloride in
rats. Chem. Biol. Interactions 20(1):27-41.
Reichert D. 1979. Biosynthesis and identification of S-containing urinary
metabolites of 1,1-dichloroethylene. Naunyn-Schmiedeberg's Arch. Pharmacol.
307(Suppl.):R22.
Reichert D, Werner HW. 1978. Disposition and metabolism of carbon-14
1,1-dichloroethylene after single oral administration in rats.
Naunyn-Schmiederberg's Arch. Pharmacol. 302(Suppl.):R22.
Reichert D, Werner HW, Metzler M, Henschler D. 1979. Molecular mechanism of
1,1-dichloroethylene toxicity: excreted metabolites reveal different pathways
of reactive intermediates. Arch. Toxicol. 42(3):159-169.
26
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1,2-DICHLOROPROPANE
C3H6C12 Cl Cl H
H —C—C—C —H
CAS: 000078875 H H H
Syn: alpha,beta-dichloropropane; propylene chloride;
propylene dichloride; alpha,beta-propylene dichloride
Mol wt: 112.99 g/mol
bp: 96.37°C (at 760 mm Hg)
vp: 50.8 mm Hg (at 25°C)
Jones and Gibson (1980) studied the metabolism of 1,2-dichloropropane in
the rat and proposed a metabolic pathway (see Figure 1). Urinary metabolites
of 1,2-dichloropropane (20 mg/kg administered orally for 4 days or in a single
100 mg/kg intraperitoneal injection) were identified by thin layer
chromatography as N-acetyl-S-(2-hydroxypropyl)cysteine, the major metabolite
(25%-35%), N-acetyl-S-(2,3-dihydroxypropyl)cysteine, and beta-chlorolactate.
1,2-Dichloropropane excreted unchanged by the lung was identified in the 0-3
hour expired air sample (5% of the dose) and in the 9-18 hour sample (5% of
the dose) after a single 100 mg/kg intravenous injection.
27
-------
r>
CHCI
CHjCI
I
cr
[CH,
CH2CI
CH,
I
CHCI
I
CH -,-glutolhione
CHOH
CHOH
I
COOH
CO,
CHOH
Cl"
CHOH NHR
I I
CH2SCH2CHCOOH
CHO
I
CHOH
VII
it
CHOH
COOH
I
CHOH
VIII
COOH|
I I
COOH:
IX
».
CH,OH
1
CH
1 O
CH,
CH.OH
1 '
. CHOH NHR
1 1
CH SCH ,CHCOOH
XI XII
Fig. 1. The proposed metabolic pathways of 1,2-dichloropropane in the
rat. (Compounds in parentheses are proposed intermediates).
Reprinted from: 1,2-Dichloropropane: Metabolism and fate in the rat.
Xenobiotica, 10(11):835-846, 1980 by A.R. Jones and J. Gibson with
permission of Taylor and Francis, Ltd.
REFERENCE
Jones AR, Gibson J. 1980. 1,2-Dichloropropane:
rat. Xenobiotica 10(11):835-846.
metabolism and fate in the
28
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HEXACHLOROBENZENE
CAS: 000118741
Syn: HCB; perchlorobenzene
Mol wt: 284.79 g/mol
bp: 322-326°C (at 760 mm Hg)
vp: 9.84 mm Hg
Hexachlorobenzene is metabolized to pentachlorophenol (Koss & Koransky,
1978; Yang et al. 1978; Rozman et al. 1978) as well as tetrachlorohydroquinone
and pentachlorothiophenol (Koss & Koransky, 1978). 2,4,5-trichlorophenol
(Renner & Schuster, 1977), pentachlorobenzene, (Yang et al. 1978; Rozman et
al. 1978), and tetrachlorobenzene (Rozman et al. 1978).
Lunde and Bjorseth (1977) measured the level of hexachlorobenzene in the
blood of three occupational groups: Group A, 9 employees with no occupational
exposure to chlorinated hydrocarbons; Group B, 9 workers in a plant producing
vinyl chloride; Group C, 17 employees in a plant producing magnesium where
chlorinated hydrocarbons are used in the process. The average value for
hexachlorobenzene in the blood showed little difference between Group A (1.04
ppb) and B (1.54 ppb) but was significantly higher in Group C (29.61 ppb).
Koss et al. (1976) as cited in Koss and Koransky (1978) studied the
metabolism of l^C hexachlorobenzene in female rats following intraperitoneal
injection (1.42 mmol/kg). Seven percent of the label was excreted in the
urine and 27% in the feces. Almost all of the urinary radioactivity was
contained in metabolites with 1% unchanged hexachlorobenzene while 69% of the
fecal radioactivity was unchanged hexachlorobenzene. Hexachlorobenzene
metabolites included pentachlorophenol, tetrachlorohydroquinone, and
pentachlorothiophenol. Renner and Schuster (1977) identified
2,4,5-trichlorophenol as a urinary metabolite of hexachlorobenzene in rats
after dietary administration.
Yang et al. (1978) studied the metabolism of hexachlorobenzene in rats and
monkeys. Two male Sprague-Dawley rats were administered an intravenous dose
of 1.3 uCi 1 C hexachlorobenzene (approximately 0.1 mg) and were sacrificed
2 days later. One percent of the administered dose was excreted in the feces
and 0.2% was excreted in urine. Most of the radioactivity was retained in the
animal with the highest concentration found in fat tissue. Three female
rhesus monkeys were administered an intravenous dose of 24.7 (0.38 mg/kg),
26.2 (0.32 mg/kg), or 12.9 (0.22 mg/kg) uCi of 14C hexachlorobenzene and
29
-------
were sacrificed at 100 days, 6 months, and 1 year, respectively. Radioactivity
was widely distributed with the fat and bone marrow containing the highest
levels. Pentachlorophenol was identified as a major fecal metabolite. Traces
of pentachlorobenzene were also identified.
Rhesus monkeys were also used by Rozman et al. (1978) to study chronic low
dose exposure to hexachlorobenzene (11 mg/day) in the diet. Fecal excretion
was 99% hexachlorobenzene, 1% pentachlorobenzene, and trace levels of
pentachlorophenol. The main urinary metabolite was pentachlorophenol
(50%-75%) with hexachlorobenzene, pentachlorobenzene, and tetrachlorobenzene
also present. In one male monkey sacrificed after 18 months of feeding, the
highest concentrations of hexachlorobenzene were present in the fat, bone
marrow, thymus, and adrenal cortex.
Ofstad et al. (1978) studied the uptake and accumulation of
hexachlorobenzene by different species of fish exposed to waters polluted by
industrial chemicals. Homogenates of whole fish or fish fillets and liver
were analyzed. The level of hexachlorobenzene in fish obtained near the
pollutant source ranged from 5.2-208 ppm. In fish obtained at a greater
distance, the range was 1.5-11 ppm. Hexachlorobenzene was found to accumulate
to a greater degree in the liver than in the fillet tissue.
The remaining studies describe hexachlorobenzene effects as a contaminant
to the study chemical.
Simon et al. (1979) studied the distribution and clearance of
pentachloronitrobenzene in chickens. Chickens were administered 300 ppm
pentachloronitrobenzene in the diet for 16 weeks. The concentrations of
hexachlorobenzene were 19.8 ppm in fat, 7.47 ppm in liver, 7.95 ppm in egg
yolk, 0.032 ppm in egg white, and 0.403 ppm in blood. The authors suggest
that egg laying may be the primary route of hexachlorobenzene excretion.
Parker et al. (1980) analyzed the blood from 12 heifers exposed for 160
days to similar doses of pentachlorophenol made up of varying amounts of pure
and contaminated compound. The levels of hexachlorobenzene in the blood
increased as the relative amount in contaminated pentachlorophenol in the dose
increased.
REFERENCES
Koss G, Koransky W. 1978. Pentachlorophenol in different species of
vertebrates after administration of hexachlorobenzene and pentachlorobenzene.
Environ. Sci. Res. 12:131-137.
Lunde G, Bjorseth A. 1977. Human blood samples as indicators of occupational
exposure to persistent chlorinated hydrocarbons. Sci. Total Environ.
8(3):241-246.
30
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Ofstad EB, Lunde G, Martinsen K, Rugg B. 1978. Chlorinated aromatic
hydrocarbons in fish from an area polluted by industrial effluents. Sci. Total
Environ. 10(3):219-230.
Parker CE, Jones WA, Mathews HB, McConnel EE, Hass JR. 1980. The chronic
toxicity of technical and analytical pentachlorophenol in cattle. II.
Chemical analyses of tissues. Toxicol. Appl. Phannacol. 55(2):359-369.
Renner G, Schuster KP. 1977. 2,4,5-Trichlorophenol, a new urinary metabolite
of hexachlorobenzene. Toxicol. Appl. Pharmacol. 39(2):355-356.
Rozman K, Mueller W; Coulsten F, Korte F. 1978. Chronic low dose exposure of
rhesus monkeys to hexachlorobenzene (HCB). Chemosphere 6(2-3):177-184.
Simon GS, Kuchar EJ, Klein HH, Borzelleca JP. 1979. Distribution and
clearance of pentachloronitrobenzene in chickens. Toxicol. Appl. Pharmacol.
50(3):401-406.
Yang RSH, Pittman KA, Rourke DR, Stein VB. 1978. Pharmacokinetics and
metabolism of hexachlorobenzene in the rat and rhesus monkey. J. Agric. Food
Chem. 26(5):1076-1083.
31
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HEXACHLOROETHANE
C2Cl6 C! Cl
Cl —C—C—Cl
CAS: 000067721 Cl Cl
Syn: carbon hexachloride; ethane hexachloride; 1,1,1,2,2,2-hexachloro-
ethane; perchloroethane
Mol wt: 236.74 g/mol
bp: 186°C (at 777 mm Hg)
vp: 1.2 mm Hg (at 32.7°C)
Gorzinski et al. (1979) administered hexachloroethane orally to rats for
110 days at doses of 0, 1.5, 20, or 80 mg/kg. Males given 20 or 80 mg/kg/day
showed histopathologic changes in the liver and kidneys and increased urinary
excretion of uroporphyrin, creatinine, and delta-aminolevulinic acid. The
latter two parameters were also increased in males at the 1.5 mg/kg level.
Effects in females were limited to slight histopathologic changes in the liver
at 80 mg/kg/day. Liver, kidney, blood, and adipose tissues from male rats
after 57 days were analyzed. At all dose levels, the hexachloroethane
concentration in uale kidneys was significantly higher than females,
consistent with the observed greater renal toxicity in males than females.
The renal hexachloroethane concentrations were 1.4, 24.9, and 95.1 ug
hexachloroethane/g in males, and 0.4, 0.7, and 2.0 ug hexachloroethane/g in
females for the 1.5, 20, and 50 mg/kg doses, respectively. Hexachloroethane
was cleared by apparent first-order kinetics with a half-life of 2 to 3 days.
REFERENCE
Gorzinski SJ, Nolan RJ, Kociba RJ, et al. 1979. Results of a subchronic
dietary study of hexachloroethane in rats with preliminary data on clearance
from selected tissues. Toxicol. Appl. Pharmacol. 48(1 part 2). A 108.
32
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METHYLENE CHLORIDE
CH2C12 Cl
H-C -Cl
I
H
CAS: 000075092
Syn: methane dichloride; dichloromethane; raethylene bichloride; methylene
chloride; methylene dichloride
Mol wt: 84.93 g/mol
bp: 40°C (at 760 mm Hg)
vp: 430.4 mm Hg (at 25°C)
Methylene chloride is metabolized to carbon monoxide and carbon dioxide
(Rodkey and Collison, 1977b; Anders et al. 1977; Kubic and Anders, 1978; Ahmed
et al. 1980). An alternative metabolic pathway to formaldehyde and an
inorganic halide is discussed by Ahmed et al. (1980).
Engstrom and Bjurstrom (1977) devised a method for determining methylene
chloride concentration in human subcutaneous adipose tissue. Twelve males
were exposed for 1 hour to 260 mg/m^ methylene chloride while engaged in
light exercise. Alveolar air samples were taken during and after exposure and
venous blood samples were taken throughout the experiment. Adipose tissue
samples were taken from the gluteal region immediately after exposure and 1,
2, 3, and 4 hours later- Subjects with a larger amount of body fat/kg body
weight displayed a larger total methylene chloride uptake but a lower
uptake/kg body weight.
Rodkey and Collison (1977a) measured carbon monoxide production after
methylene chloride administration using a closed rebreathing system.
Methylene chloride was injected into the system, vaporized, and inhaled by
rats. Methylene chloride caused an immediate increase in carbon monoxide
production with a simultaneous disappearance of methylene chloride from the
air. Methylene chloride had a half-life of 25 minutes with only 2% remaining
after 90 minutes. Methylene chloride injected intraperitoneally caused carbon
monoxide formation identical to that caused by inhalation, however, no
methylene chloride was present in the air. The role of intestinal bacteria on
carbon monoxide production by methylene chloride was studied, but the presence
or absence of bacteria had no effect on production levels.
Using the same system as described above, Rodkey and Collison (1977b)
investigated whether increased carbon monoxide production after methylene
chloride occurred due to direct metabolism of methylene chloride or to an
increased rate of carbon monoxide formation from endogenous carbon sources.
Sprague-Dawley rats were studied in a closed rebreathing system with exhaled
33
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carbon monoxide and carbon dioxide collected separately. Labelled methylene
chloride was administered at a single dose of 0.2 mmol/kg and the rats
remained in the system for a least 7 hours. The average amount of
administered label recovered as (l^C)-carbon monoxide was 47%, compared to
29% as (^C) carbon dioxide. No radioactivity was recovered in any tissues
tested. Extending the study to 15 hours did not increase the amount of carbon
monoxide or carbon dioxide, suggesting that all of the methylene chloride was
metabolized.
Withey and Collins (1980) studied the pharamcokinetics of methylene
chloride in male Wistar rats. Blood samples were collected from rats
administered 3, 6, 9, 12, or 15 mg/kg methylene chloride intravenously. Only
at the 15 mg/kg dose did tissue samples produce meaningful kinetic data.
Anders et al. (1977) investigated the metabolism of methylene chloride in
rats. A cytochrome P-450 dependent system seemed to be responsible for
metabolizing methylene chloride to carbon monoxide. Methylene chloride was
covalently bound to both microsomal lipid and protein with similar reaction
kinetics to carbon monoxide formation. This suggests that formyl halide is a
common intermediate acting either as an acylating agent or decomposing to
carbon monoxide. Methylene chloride may also be converted to formaldehyde or
formic acid and an inorganic halide in the hepatic cytosolic fraction with
glutathione (GSH) as cofactor. This reaction is inhibited by reagents which
react with sulfhydryl groups and known gluthathione transferase substrates.
Halide displacement is the rate limiting step.
Kubic and Anders (1978) studied the metabolism of methylene chloride in
vitro with rat liver microsomal fractions. Methylene chloride was converted
to carbon dioxide and to carbon monoxide at a rate of 0.2 and 16.7 nmol/mg of
protein/min, respectively. Carbon monoxide was the principal metabolite.
Ahmed et al. (1980) summarized the metabolism studies on methylene
chloride. Methylene chloride is metabolized to carbon monoxide in animal
systems both in vivo and in vitro. In vitro studies show that a cytochrome
P-450 dependent enzyme system localized in the hepatic microsomal fraction is
involved in the biotransformation of methylene chloride to carbon monoxide.
An alternative metabolic pathway of methylene chloride to formaldehyde and an
inorganic halide is localized in the hepatic cytosol fraction and requires
glutathione for maximal activity.
REFERENCES
Ahmed AE, Kubic VL, Stevens JL, Anders MW. 1980, Halogenated methanes:
metabolism and toxicity. Fed. Proc. 39(13):3150-3155.
Anders MW, Kubic VL, Ahmed AE. 1977. Metabolism of halogenated methanes and
macromolecular binding. J. Environ. Pathol. Toxicol. 1(2):117-124.
34
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Engstrom J, Bjurstrom R. 1977. Exposure to methylene chloride. Content in
subcutaneous adipose tissue. Scand. J. Work Environ. Health 3(4):215-224.
Kubic VL, Anders MW. 1978. Metabolism of dihalomethanes to carbon monoxide.
III. Studies on the mechanism of the reaction. Biochem. Pharmacol.
27(19):2349-2355.
Rodkey FL, Collison HA. 1977a. Effect of dihalogenated methanes on the iri
vivo production of carbon monoxide and methane by rats. Toxicol. Appl.
Pharmacol. 40(1):39-47.
Rodkey FL, Collison HA. 1977b. Biological Oxidation of (1<4C) methylene
chloride to carbon monoxide and carbon dioxide by the rat. Toxicol. Appl.
Pharmacol. 40(1):33-38.
Withey JR, Collins BT. 1980. Chlorinated aliphatic hydrocarbons used in the
foods industry: the comparative pharmacokinetics of methylene chloride,
1,2-dichloroethane, chloroform and trichloroethylene after i.v. administration
in the rat. J. Environ. Path. Toxicol. 3(5-6):313-332.
35
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PENTACHLOROANISOLE
CAS: 001825214
Cl
Syn: pentachloromethoxybenzene; 2,3,4,5,6-pentachloroanisole; methyl
pentachlorophenate
Mol wt: 280.34 g/mol
Glickman et al. (1977) quantified the uptake, elimination, and metabolism
of pentachloroanisole in rainbow trout. Comparison of uptake rates of
pentachloroanisole and its known metabolite, pentachlorophenol, in blood,
liver, muscle, and fat of fish exposed to 0.024 mg/liter
(14-C)-pentachloroanisole (12 hours) or 0.026 mg/liter
(14-C)-pentachlorophenol (24 hours) showed a much more rapid concentration of
pentachloroanisole in fat and a greater liver concentration of
pentachlorophenol. The high retention time of pentachloroanisole in fish
probably reflected its high lipid solubility. Pentachloroanisole half-lives
were 6.3, 6.9, 23.4, and 6.3 days in blood, liver, fat, and muscle,
respectively, compared to pentachlorophenol half-lives of 6.2, 9.8, 23.7, and
6.9 hours, respectively. Pretreatment of fish with piperonyl butoxide
decreased the conversion of pentachloroanisole by one third.
Pentachloroanisole was rapidly taken up from water and assimilated in
tissues. Pentachloroanisole could be demethylated in vivo, and piperonyl
butoxide inhibited demethylation to pentachlorophenol.
Vodicnick et al. (1980) dosed mice with a single 20 mg/kg intraperitoneal
injection of (l^C)-pentachloroanisole and recovered approximately 50% of the
14C label in excreta (urine (88-93%) + feces). 14C was eliminated with no
unchanged pentachloroanisole detected in urine or feces , suggesting
pentachloroanisole demethylation to pentachlorophenol prior to conjugation
and/or excretion. Very little free pentachlorophenol was eliminated in urine
while 30% of the fecal label was in the nonconjugated form. Radioactive label
was rapidly concentrated in liver and adipose tissue. Liver displayed the
longest tissue half-life (19 hours) and biphasic elimination. Other tissues
showed rapid elimination, with half-lives ranging from 5 to 10 hours.
36
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REFERENCES
Glickman AH, Statham CN, Wu A, Lech JJ. 1977. Studies on the uptake
metabolism and disposition of pentachlorophenol and pentachloroanisole in
rainbow trout. Toxicol. Appl. Pharmacol. 41(3):649-658.
Vodicnik MJ, Glickman AH, Rickert DE, Lech JJ. 1980. Studies on the
disposition and metabolism of pentachloroanisole in female mice. Toxicol.
Appl. Pharmacol. 56(3):311-316.
37
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PENTACHLOROBENZENE
C6HC1,
CAS: 000608935
Syn: quintachlorobenzene; 1,2,3,4,5-pentachlorobenzene
Mol wt: 250.34 g/mol
bp: 277°C (at 760 mm Hg)
vp: 1.04 mm Hg (at 98.6°C)
Pentachlorobenzene is metabolized primarily to tetrachlorophenol (Leber
et al. 1977; Koss and Koransky, 1978) in addition to pentachlorophenol, a
hydroxylated chlorothio compound, and tetrachlorohydroquinone (Koss and
Koransky, 1978).
Lunde and Bjorseth (1977) measured the level of pentachlorobenzene in the
blood of three occupational groups: Group A, 9 employees with no occupational
exposure to chlorinated hydrocarbons; Group B, 9 workers in a plant producing
vinyl chloride; Group C, 17 employees in a plant producing magnesium where
chlorinated hydrocarbons are used in the process. The average value for
pentachlorobenzene in the blood showed no difference between Group A (0.00
ppb) and B (0.00 ppb) and was only slightly higher in Group C (0.15 ppb).
Koss and Koransky (1978) studied pentachlorobenzene metabolism in female
rats. Urine and fecal samples were taken for 4 days after a single
intraperitoneal injection of 403 umol pentachlorobenzene/kg. Only 3% of the
injected pentachlorobenzene was excreted unchanged. The major metabolites
excreted in the urine and feces were 2,3,4,5-tetrachlorophenol, a hydroxylated
chlorothio compound, and pentachlorophenol. Tetrachlorohydroquinone was found
in the urine. These metabolites were also present in tissue samples.
Leber et al. (1977) investigated the pharmacokinetic properties and
metabolic fate of pentachlorobenzene in 5 male rhesus monkeys. A single oral
dose of 20 mg/monkey of labelled pentachlorobenzene was administered and the
concentration of the radioactivity was determined in the blood, urine, and
feces. Tetrachlorophenol was determined as the main urinary metabolite. Most
of the labelled pentachlorobenzene was excreted unchanged in the feces.
The uptake and accumulation of pentachlorobenzene in different species of
fish obtained from polluted water was studied by Ofstad and colleagues
(1978). Whole fish or fish fillets and liver samples were analyzed. The
level of pentachlorobenzene ranged from 0.2-24.0 ppm in fish obtained near the
polluting source. In fish obtained at a greater distance, the concentration
38
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ranged from 0.1 to 1.9 ppm. Pentachlorobenzene accumulated to a greater
degree in the liver than in the fillet tissue.
The remaining studies involve pentachloronitrobenzene metabolism to
pentachlorobenzene, or pentachlorobenzene-contaminated pentachloro-
nitrobenzene exposure to test animals.
The biotransformation of pentachloronitrobenzene was studied in rhesus
monkeys by Koegel et al. (1979a). Metabolites were analyzed in urine and
feces after single oral doses of 2 or 91 mg/kg or after chronic feeding of 2
ppm in the diet for 71 days. Due to its extensive metabolism,
pentachloronitrobenzene did not accumulate in the tissue but was rapidly
eliminated. Pentachlorobenzene was one of the major metabolites produced.
After a single oral dose of 2 mg/kg pentachloronitrobenzene,
pentachlorobenzene comprised 11.7% of the urinary extract and 1.0% of the
fecal extract. Similar percentages of pentachlorobenzene were found in urine
and feces after a single oral dose of 91 mg/kg pentachloronitrobenzene and
after chronic feeding (Koegel et al., 1979b).
Simon et al. (1979) investigated the distribution and clearance of
pentachloronitrobenzene with its contaminants in chickens. For 16 weeks, 110
Comet Red hens received pentachloronitrobenzene mixed with their food in doses
of 0, 0.5, 1, 5, 15, 75, or 300 ppm. Seventy-five White Leghorn hens were
exposed in the same manner to doses of 0, 15, 75, or 300 ppm. The
concentrations of pentachlorobenzene deposited in the tissues of the 300 ppm
exposed Comet Red hens after 16 weeks were 1.32 ppm in fat, 0.276 ppm in
liver, 0.013 ppm in blood, 0.355 ppm in egg yolk, and 0.015 ppm in excreta;
tissue levels of pentachlorobenzene were similar in the White leghorn.
Residues of pentachlorobenzene were detectable in the egg yolk for 1 year
after exposure ceased. Egg laying is proposed as the main route of
pentachlorobenzene excretion.
REFERENCES
Koegel W, Meuller WF, Coulston F, Korte F. 1979a. Biotransformation of
pentachloronitrobenzene-14C in rhesus monkeys after single and chronic oral
administration. Chemosphere 8(2):97-105.
Koegel W, Mueller WF, Coulston F; Korte F. 1979b. Fate and effects of
pentachloronitrobenzene. J. Agric. Food Chem. 27(6):1181-1185.
Koss G, Koransky W. 1978. Pentachlorophenol in different species of
vertebrates after administration of hexachlorobenzene and pentachlorobenzene,
Environ. Sci. Res. 12:131-137.
39
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Leber AP, Freudenthal RI , Baron RD , Curley A. 1977. Pharmacokinetics and
metabolism of pentachlorobenzene in rhesus monkeys. Toxicol. Appl . Pharmacol.
Lunde G, Bjorseth A. 1977. Human blood samples as indicators of occupational
exposure to persistent chlorinated hydrocarbons. Sci . Total Environ.
8(3):241-246.
Ofstad EB, Lunde G, Martinsen K, Rygg B. 1978. Chlorinated aromatic
hydrocarbons in fish from an area polluted by industrial effluents. Sci.
Total Environ. 10(3) : 219-230.
Simon GS , Kuchar EJ , Klein HH, Borzelleca JP. 1979. Distribution and
clearance of pentachloronitrobenzene in chickens. Toxicol. Appl. Pharmacol.
50(3):401-406.
40
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TETRACHLOROBENZENE
C^HoClr
Mol wt: 215.88 g/mol
1>2,3,4-tetrachlorobenzene
GAS: 000634662
Syn: benzene, 1,2,3,4-tetrachloro-
bp: 254°C (at 760 mm Hg)
vp: 1.04 mm Hg (at 68.5°C)
1,2,3,5-tetrachlorobenzene
CAS: 000634902
Syn: benzene, 1,2,3,5-tetrachloro-
bp: 246°C (at 760 mm Hg)
vp: 1.06 mm Hg (at 58.2°C)
1,2,4,5-tetrachlorobenzene
CAS: 000095943
Syn: benzene, 1,2,4,5-tetrachloro-
bp: 243-246°C (at 760 mm Hg)
vp: 0.1 mm Hg (at 25°C)
1,2,4,5-Tetrachlorobenzene steady state parameters and elimination rate
constants in fat and plasma were determined by Braun et al. (1978) in a 2-year
study of daily oral administration of 5 mg/kg tetrachlorobenzene to beagle
dogs followed by a 20 month recovery phase. The tetrachlorobenzene uptake
rate constants were very high during the study and the clearance rates were
similar: 6.64 x 10~3/day (+8.2 x 10~4) for plasma and 6.01 x 10~3/day
(+5.8 x 10~^) for fat. The corresponding half-life values were 104 and 111
days. Tetrachlorobenzene had an extremely high affinity for fat, with the fat
to plasma ratio (F/P) of 650 after 1 month decreasing to 280 after 24 months
(98% saturation level). Plasma tetrachlorobenzene levels increased as fat
attained saturation thus increasing tetrachlorobenzene concentrations in low
affinity compartments such as the liver and delaying the onset of apparant
toxicity. The F/P ratio steadily increased in the post-exposure period (20
months, F/P = 2000) as tetrachlorobenzene was cleared faster from plasma and
41
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other lower affinity compartments, possibly accounting for the reversibility
of toxicity.
Ofstad et al. (1978) investigated the bioaccumulation of polychlorinated
benzenes (including tetrachlorobenzene) in various fish species consumed by
humans. Uptake and accumulation were very efficient, and species differences
were observed. Comparison of liver and fillet oil extracts showed that
chlorinated benzene accumulated to a greater extent in the liver (0.8 ppm in
cod) due to a slower exchange of pollutants from the liver than from the
muscle tissue. The mean tetrachlorobenzene concentrations in fat ranged from
0.1-1.4 ppm in cod, whiting, plaice, eel, and sprat from the contaminated
Frierfjord area, and were less than or equal to 0.1 ppm in the Eidangerfjord.
REFERENCES
Braun WH, Sung LY, Keyer DG, Kociba RJ. 1978. Pharmacokinetic and
toxicological evaluation of dogs fed 1,2,4,5-tetrachlorobenzene in the diet
for 2 years. J. Environ. Pathol. Toxicol. 2(2):225-234.
Ofstad EB, Lunde G, Martinsen K, Rygg B. 1978. Chlorinated aromatic
hydrocarbons in fish from an area polluted by industrial effluents. Sci.
Total Environ. 10(3):219-230.
42
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TETRACHLOROETHYLENE
C2C14 Cl Cl
\ /
c = c
/ \
CAS: 000127184 Cl Cl
Syn: carbon bichloride; carbon dichloride; ethylene tetrachloride;
perchloroethylene; tetrachloroethylene; tetrachloroethene;
1,1,2,2-tetrachloroethylene
Mol wt: 165.83 g/mol
bp: 121°C (at 760 mm Hg)
vp: 18.0 mm Hg (at 25°C)
Tetrachloroethylene is metabolized via the P-450 enzyme system (Costa and
Ivanetich, 1980) yielding trichloroacetic acid as the major metabolite (Costa
& Ivanetich, 1980; Ikeda, 1977; Monster, 1979). One study (Pegg et al. 1979)
reports that oxalic acid is the major metabolite of tetrachloroethylene.
Monster (1979) exposed human volunteers for 4 hours to tetrachloroethylene
at varied concentrations in air: 70 ppm at rest; 140 ppm at rest; and 140 ppm
at rest and during work. The lung clearance rate decreased over the course of
the experiment, primarily due to the insignificant metabolism (2%) of
tetrachloroethylene to trichloroacetic acid. Adipose tissue absorbed a
greater portion of tetrachloroethylene than any other tissue. Metabolism of
tetrachloroethylene proceeded by oxidation to perchloroethylene oxide,
rearrangement to trichloroacetyl chloride, and hydrolysis to trichloroacetic
acid. Trichloroacetic acid reached a peak concentration approximately 20
hours after exposure. Only 2% of the administered tetrachloroethylene was
metabolized, primarily by the liver, while 95% was excreted unchanged by the
lung.
In a study of tetrachloroethylene metabolism in humans, Ikeda (1977) also
determined trichloroacetic acid to be the main urinary metabolite.
Thirty-four male workers who were exposed to tetrachloroethylene vapors while
working in small, closed workrooms were studied. The biological half-life of
the urinary metabolite was approximately 144 hours.
Gobbato and Mangiavacchi (1979) presented a mathematical model for
simulating the respiratory absorption, tissue distribution, hepatic
metabolism, and pulmonary and renal excretion of various industrial solvents.
The validity of this model was substantiated by agreement between the
theoretical results for tetrachloroethylene and experimental results described
in the literature.
43
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Pegg et al. (1979) studied the response in rats exposed to labelled
tetrachloroethylene via oral dosing (1 or 500 mg/kg) or by inhalation (10 or
600 ppm for 6 hours). Seventy-two hours after administration, urine, blood,
feces, expired air, and tissues were analyzed for radioactivity. Urine
samples were also analyzed by HPLC for identification of metabolites. At the
low doses , approximately 70% of the administered radioactivity was recovered
in the expired air as tetrachloro(^^C)ethylene, 26% was recovered as
(l^C)-carbon dioxide, and nonvolatile metabolites were recovered in the
urine and feces. Approximately 3%-4% remained in the tissue. At the high
dose, 89% of the radioactive label was eliminated in the expired air as
tetrachloro(14C)ethylene, 9% was recovered as (•'•^C)-carbon dioxide and as
metabolites in the urine and feces. Only l%-2% was retained in the tissues.
At both doses, the major urinary metabolite was identified as oxalic acid.
Most of the radioactivity retained by the tissues was found in the liver,
kidney, and fat.
Costa and Ivanetich (1980) investigated the binding to and metabolism of
tetrachloroethylene by rat liver microsomal cytochrome proteins. The rate of
tetrachloroethylene metabolism by microsomes was assayed by measuring the
oxidation of NADPH. Identification of metabolic products showed
trichloroacetic acid to be the major metabolite. Based on selective
microsomal induction and inhibition, the P-450 enzyme system appears to be the
primary enzyme system binding and metabolizing tetrachloroethylene.
Miyake (1978) fed muscle homogenates of tetrachloroethylene-exposed eels
to rats. Concentrations of tetrachloroethylene in rat tissues were measured
by gas chromatography. The highest levels were found in adipose tissue with a
peak concentration at 6 hours. Tetrachloroethylene caused a decoupling action
of the oxidative phosphorylation process in liver mitochondria.
REFERENCES
Costa AK, Ivanetich KI. 1980. Tetrachloroethylene metabolism by the hepatic
microsomal cytochrome P-450 system. Biochem. Pharmacol. 29:2863-2869.
Gobbato F, Mangiavacchi C. 1979. Mathematical model for the simulation of
the turnover of an industrial toxicant (solvent) subject to metabolic
transformation. G. Ital. Med. Lav. 1(2):53-60.
Ikeda M. 1977. Metabolism of trichloroethylene and tetrachloroethylene in
human subjects. Environ. Health Perspect. 21:239-245.
Miyake Y. 1978. Occurrence of oily odor in fish and the food chain of
petroleum compounds: 6. Long-term change in concentration of
tetrachloroethylene in the organs of rats administered muscle homogenate of
eels reared in tetrachloroethylene solution. Okayama Igakkai Zasshi
90(5-6):623-628.
44
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Monster AC. 1979. Difference in uptake, elimination, and metabolism in
exposure of trichloroethylene, 1,1,1,-trichloroethane, and tetrachloroethylene
Int. Arch. Occup. Environ. Health 42:311-317.
Pegg DG, Zempel JA, Braun WH, Watanabe PG. 1979. Disposition of
tetrachloro(14c)ethylene following oral and inhalation exposure in rats.
Toxicol. Appl. Pharmacol. 51(3):465-474.
45
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TRICHLOROBENZENE
C6H3C13
Mol. wt: 181.45 g/mol
1,2,3-trichlorobenzene
CAS: 000087616
Syn: vic-trichlorobenzene; 1,2,6-trichlorobenzene
bp: 218-219°C (at 760 mm Hg)
vp: 0.99 mm Hg (at 40°C)
1,2,4-tri chlorobenzene
CAS: 000120821
Syn: unsym-trichlorobenzene
bp: 213.50C (at 760 mm Hg); 84.8QC (at 10 mm Hg)
vp: 1.04 mm Hg (at 38.4°C)
1,3,5-trichlorobenzene
CAS: 00108703
bp: 108°C (at 763 mm Hg)
vp: 5.1 mm Hg (at 63.8°C)
The
1,2,4-Trichlorobenzene metabolism and body burden were studied in
phenobarbital treated and starved rats by Smith et al. (1980) using C
labelled trichlorobenzene (1 mmol/kg/day) orally administered for 7 days
highest trichlorobenzene concentration was found in fat tissue. ^ C
appeared in urine through day 15 post-exposure (accounting for 72% total
radioactivity) and in feces for 8 days after dosing (4%). Hepatic microsomal
enzymes, primarily those responsible for p-nitroanisole demethylation and EPN
detoxification, were elevated for at least 16 days post-exposure.
NADPH-cytochrome c reductase activity and cytochrome P-450 content declined
rapidly after cessation of dosing. Phenobarbital treatment or starvation
immediately after trichlorobenzene exposure hastened its mobilization,
metabolism, and excretion.
Melancon et al. (1980) exposed rainbow trout and carp to radiolabelled
trichlorobenzene (0.018 mg/liter) for 8 hours or 35 days and traced the ^C
bioaccumulation in tissues. After 8 hours, liver, muscle, and blood
46
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concentrations of ^C were 102, 51, and 33 times greater, respectively, than
concentrations in the exposure water; corresponding half-lives were 0.4, 0.4,
and 0.02 days. Similar results were found for chronically exposed fish. Bile
levels were 104-240 times greater than the initial water levels. During the
35-day exposure, maximum ^C levels were 389, 89, and 84 times greater than
the initial water concentration for liver, muscle, and blood with longer
elimination half-lives of 56, 47, and less than 1 day, respectively. Bile
concentrations were 500-1400 times higher than water concentrations during the
exposure period and approximately 100 times higher afterwards. Table 1 shows
tissue levels of C and bio trans format ion products in trout and carp after
24 hours of exposure to trichlorobenzene. Bile and liver had the greatest
amount of radioactivity, with the bile containing a high proportion of polar
compounds suggestive of biotransf ormed conjugates. Blood had the only other
significant concentration of polar metabolites. The hepatic mixed-function
oxidase system inducer, beta-naphthoflavone injected intraperitoneally (100
rag/kg) increased the levels of ^C in the bile; over 90% of the
radioactivity was highly polar transformation products.
Table 1. Tissue levels of (*C) TCB and biotransfonnation products in
rainbow trout and carp after exposure to aqueous (^C) TCB for 24 hr.
a
|"L|TCB and
Tissue
Bile
Blood
Plasma
Muscle
Liver
Kidney
Iwg/g or jig/ml)
38.2 ±
5.8 t
9.6 *
19.3 t
3
1
2
1
4
2
1
2
|"C]TCB and
(MK/g or ng/ml)
6.8 i
1.3 t
1.4 t
2.5 t
4.0*
1.8 t
0.7
0.1
0.1
0.3
0.4
0.7
Trout*
Percent in water phase
pH 7.4 pH 11
45 52
8.9 t 2.3 24.8 i 4.6
2.1
2.2 2.6
3.0 1.6
,_ c
Carp
["C] TCB and Percent in water phase
(Mg/g or wg/ml) pH 7.4 pH 11
18
2
3
2
11
1
8
0
2
3
3
0
0
0
2
7.6 1
0 61 58
2 11.2 • 2.2 18.5 t 3.1
2
1
4 3.4 2.6
2
A group of 61-g (average weight) trout was exposed to |"C|TCB at 0.40 mg/l.
*A group of 139-g (average weight) trout was exposed to |"C|TCB at 0.24 mg/l.
L A group of 349-g (average weight) trout was exposed to |"C|TCB at 0.20 mg/1.
Alter shaking with hexane.
Reprinted from: Uptake, metabolism, and elimination of •'•^C-labeled
1,2,4-Trichlorobenzene in rainbow trout and carp, Journal of Toxicology
and Environmental Health, 6:645-658, 1980 by M.J. Melancon and J.J. Lech
with permission of Hemisphere Publishing Co.
Ofstad et al. (1978) found trichlorobenzene accumulations ranging from
0.1-4.0 ppm in fish from the Frierfjord area. Analysis of oil extracted from
liver and fillet indicated that the chlorinated compounds accumulate to a
larger extent in the liver than in muscle.
47
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REFERENCES
Melancon MJ, Lech JJ. 1980. Uptake, metabolism, and elimination of
•^C-labelled 1,2,4-trichlorobenzene in rainbow trout and carp. J. Toxicol.
Environ. Health 6:645-658.
Ofstad EB, Lunde G, Martinsen K, Rygg B. 1978. Chlorinated aromatic
hydrocarbons in f5.sh from an area polluted by industrial effluents. Sci.
Total Environ. 10(3):219-230.
Smith EN, Carlson GP. 1980. Various pharmacokinetic parameters in relation
to enzyme-inducing abilities of 1,2,4-trichlorobenzene and 1,2,4-tribromo-
benzene. J. Toxicol. Environ. Health 6(4):737-749.
48
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1,1,1-TRICHLOROETHANE
C2H3C13 Cl H
I I
Cl — C— C— h
CAS: 000071556 c, ^
Syn: methylchloroform; MC; alpha-trichloroethane
Mol wt: 133.41 g/mol
bp: 74.1°C (at 760 mm Hg)
vp: 121.3 mm Hg (at 25°C)
Monster (1979) exposed human volunteers for 4 hours to
1,1,1-trichloroethane gas at varying concentrations (70 ppm at rest; 140 ppm
at rest; 140 ppm at work and rest). Trichloroethane uptake was largely
determined by its solubility in blood and by its metabolism. Trichloroethane
solubility in blood was expressed as the ratio of the concentration in blood
(mg/liter) to the concentration in alveolar air (mg/liter) or the blood/gas
partition coefficient (b/g) (measured value = 5). The lung clearance rate
(uptake/minute) for trichloroethane decreased significantly over the course of
exposure. The low partition coefficient and low metabolism (3.5%) promoted a
rapidly attained counter pressure to trichloroethane absorption. Venous blood
concentrations were lower than arterial blood concentrations during exposure
due to trichloroethane entry into tissues, and were slightly higher than
arterial blood concentrations after exposure (2 and 20 hours) as tissues
released the compound. Adipose tissue had a long half-life for saturation (25
hours) presumably due to a small perfusion coefficient (0.4 liters/min) and
had a high capacity for trichloroethane absorption (volume x solubility = 800
liters). Net absorption was low compared to other tissues (4 hours
exposure). After exposure, the redistribution of trichloroethane to adipose
tissue was minor due to the rapid release of solvent from tissues and blood to
air. Biotransformation of trichloroethane to trichloroethanol (TCE) was low;
only 3.5% of all metabolites were detected in urine and 80% of a 70 ppm
exposure was eliminated in expired air. Therefore the overall capacity for
trichloroethane absorbance was small over a 4-hour exposure. The metabolism
of the chemical as proposed by the author is illustrated in Figure 1.
49
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^x ci3c-
-------
1,1,2-TRICHLOROETHANE
C2H3Cl3 Cl H
H —C—C—Cl
CAS: 000079005 Cl H
Syn: ethane trichloride; beta-trichloroethane; 1,1,2-trichloroethane;
vinyl trichloride
Mol wt: 133.41 g/mol
bp: 113.77°C (at 760 mm Hg)
vp: 23.16 mm Hg (at 25°C)
The blood concentration of 1,1,2-trichloroethane was studied by Jakobson
et al. (1977) in guinea pigs after intracutaneous, subcutaneous, or
intraperitoneal injection. All three injection routes gave essentially the
same blood concentration curves (see Figure 1). Percutaneous absorption
concentrations were also measured. Equations with three exponential terms,
with or without constants, were derived to describe the findings. No
calculations were performed with data from subcutaneous or intracutaneous
injection but the form of these two curves indicated similar, or possibly
simpler, toxicokinetics compared to that for intraperitoneal injection. Blood
concentration of 1,1,2-trichloroethane caused by percutaneous absorption gave
a different curve, possibly due to a local effect on the skin rather than to a
systemic effect.
51
-------
4 8
Tim* after injection (h)
Fig. 1. Blood concentration after administration of 50 ul
1,1,2-trichloroethane in 9 guinea pigs (intraperitoneally^-^,
subcutaneously9—•, intracutaneously^ •) .
Reprinted from: Variations in the blood concentration of
1,1,2-trichloroethane by percutaneous adsorption and other routes of
administration in the guinea pig. Acta Pharmacologica et Toxicologica,
41:497-506, 1977 by I. Jakobson, Bo Holmberg, and Jane E. Wahlberg with
permission of the Scandinavian Pharmacological Societies.
REFERENCE
Jakobson I, Homberg B, Wahlberg, JE. 1977. Variations in the blood
concentration of 1,1,2-trichloroethane by percutaneous absorption and other
routes of administration in the guinea pig. Acta Pharmacol. Toxicol.,
41(5):497-506.
52
-------
TRICHLOROETHYLENE
C2HC13 Cl Cl
\ /
C — C
CAS: 000079016 Cl H
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/mol
bp: 87°C (at 760 mm Hg)
vp: 72.9 mm Hg (at 25°C)
Trichloroethylene exposure occurs primarily through the lung where it is
absorbed into the blood at a relatively high and constant rate.
Trichloroethylene is metabolized primarily in the liver to trichloroethylene
epoxide and then transformed to chloral hydrate which can be reduced to
trichloroethanol or oxidized to trichloroacetic acid (Monster, 1977; Nomiyama
& Nomiyama, 1979; Ikeda, et al. 1980). Trichloroethanol is transformed to a
glucuronide, the main urinary metabolite, and is 2-7 times more abundant than
urinary trichloroacetic acid (Artigue et al. 1978). Most trichloroethylene is
excreted in the urine with only a small amount excreted by the lungs; a small
amount is stored in adipose tissue (Monster, 1977).
In a study on human subjects, Monster (1979) exposed the subjects for 4
hours to trichloroethylene gas concentrations of 70 ppm at rest, 140 ppm at
rest, and 140 ppm at rest and during work. A nearly constant high rate of
absorption/minute of trichloroethylene resulted from the high partition
coefficient (lambda b/g = 15) and rapid metabolism (75%). Trichloroethylene
was metabolized to trichloroethanol and trichloroacetic acid.
Trichloroethylene biotransformation occurred mainly in the liver. Maximum
blood concentrations of trichloroacetic acid occurred 20-40 hours after
exposure to trichloroethylene. Only 10% of a 70 ppm trichloroethylene
exposure dose was eliminated in exhaled air; 21% appeared in the urine as
trichloroacetic acid and 43% as trichloroethanol. Most of the
trichloroethylene was excreted in the urine.
Smith (1978) found maximum urinary excretion of trichloroethylene
metabolites 24-48 hours after determining levels of industrial exposure to
trichloroethylene. He also found that retention increased with prolonged
exposure. There were interindividual variations in the trichloroethylene
metabolic rate, but the author suggested that urinary trichloroacetic acid was
a good measure of trichloroethylene exposure.
53
-------
In a study of 15 men who were divided into 3 groups based on exposures to
different concentrations of trichloroethylene, Vesterberg et al. (1976)
analyzed blood and urine samples for trichloroacetic acid and
trichloroethanol. Trichloroacetic acid was noted after 30 minutes of exposure
and increased linearly until 30 minutes after exposure ceased.
Trichloroacetic acid and trichloroethanol were excreted in the urine and the
amount correlated with the amount of exposure.
Fernandez et al. (1977) simulated the pulmonary absorption, distribution,
and elimination of trichloroethylene in man, as well as the kinetics of forma-
tion and excretion of its metabolites, using a mathematical model. The results
predicted by the model fit the author's data for exposed human subjects. In a
follow-up study, Droz and Fernandez (1978) proposed another method of
determining the body burden of trichloroethylene and rate of urinary excretion
of metabolites. The body burden of trichloroethylene could be estimated by
comparing the pre- and post-exposure urine or alveolar air samples to
determine the rate of absorption.
Sato and Nakajima (1977) measured the rate constants for trichloroethylene
absorption, metabolism, and excretion based on analysis of urinary
metabolites. Four male volunteers were exposed to an atmosphere containing
100 ppm trichloroethylene for 4 hours. Blood and urine samples were taken at
specific time intervals. The pharmacodynamics of trichloroethylene were
described by a three compartment model.
Gobbato and Mangiavacchi (1979) presented a mathematical model for the
simulation of the respiratory absorption, tissue distribution, hepatic
metabolism and pulmonary and renal excretion of industrial solvents. A
multicompartmental model formulated by the authors in a previous work was
modified by considering hepatic metabolism and distribution of hydrosoluble
metabolites in body fluids and renal excretion. The validity of the model was
substantiated by agreement between theoretical results for trichloroethylene
and experimental results available in the literature.
Nomiyama and Nomiyama (1979) studied the metabolism of intraperitoneally
administered trichloroethylene in rats and rabbits. The primary metabolic
pathway of trichloroethylene in the rat proceeded through chloral hydrate to
trichloroethanol (35.6%). This conversion was essentially complete by the
second day following a 10 mg/kg dose. Trichloroethanol also was the main
metabolite (34.4%) in the rabbit, with only a trace amount of trichloroacetic
acid excreted in the urine.
Ikeda et al. (1980) determined that NADPH and NAD were necessary to
convert trichloroethylene to trichloroacetic acid in rat liver homogenates.
The conversion was enhanced by both phenobarbital and 3-methylcholanthrene
pretreatment. Trichloroethylene was oxidized to chloral hydrate, which
occurred only in the microsomes. Chloral hydrate reduction to trichloro-
ethanol occurred via NADPH-dependent enzymes found in the liver cytosol and
was the primary metabolite. When 0.1 ml of trichloroethylene was incubated
under complete incubation mixture conditions with 9,000 g supernatant for 60
minutes at 37°C, the following metabolites were measured: chloral hydrate
(0.5 nmol/mg); trichloroethanol (6.9 nmol/mg); and trichloroacetic acid (0.3
nmol/mg). The cytosolic fraction catalyzed the oxidation of chloral hydrate
54
-------
to trichloroacetic acid and the mitochondrial fraction had the highest
specific activity but the microsomal fraction contributed only slightly to the
formation of trichloroacetic acid.
Uehleke et al. (1977) incubated trichloroethylene and its suspected
metabolites with suspensions of rat liver microsomes. Spectrophotometrically,
only the spectrum of trichloroethylene epoxide matched that of metabolized
trichloroethylene. The maximal absorption was observed with 1 mM NADPH and 1
mM trichloroethylene.
Withey and Collins (1980) studied the pharmacokinetics of
trichloroethylene metabolism in male Wister rats. Varied doses (3, 6, 9, 12,
or 15 rag/kg) of trichloroethylene were administered intravenously and blood
samples were collected at selected time intervals. Meaningful kinetic data
were found at only the highest dose level (15 mg/kg), indicating elimination
by a three compartment model.
Pfaffenberger et al. (1979), using gas-liquid chromatography studied the
distribution of trichloroethylene between rat blood serum and adipose tissue.
Trichloroethanol was rapidly eliminated in the urine. Trichloroacetic acid
was not as readily eliminated and was decomposed to carbon dioxide and
chloroform as shown in Figure 1. Doses of 1 or 10 mg/kg trichloroethylene led
to serum levels of chloroform of 1600 or 9300 mg/1, respectively. Fat levels
were approximately 5% of these values. Trichloroethylene blood levels were
essentially zero, implying a rapid metabolism or lipid storage. Fat levels
were 0.3 or 20 mg/g. Chloroform levels dropped rapidly to below 2% of the
peak levels several days after cessation of dosing.
Traylor et al. (1977) incubated trichloroethylene with liver microsomes
from phenobarbital or 3,4-benzo(a)pyrene pretreated rats, with NADPH and
oxygen. Production of carbon monoxide (CO) was determined by ultraviolet and
infrared spectroscopy and demonstrated by the formation of carboxyhemoglobin.
Increasing the trichloroethylene incubate concentration or increasing the
incubation time increased CO levels as measured by the reduced P-450/CO
differential spectrum. A proposed chemical pathway for conversion of
cytochrome trichloroethylene to carbon monoxide in the presence of 02 and
NADPH is shown in Figure 2.
Dalby and Bingham (1978) ventilated rat lungs with 30 to 45 ppm
trichloroethylene and determined a blood/air partition coefficient of
approximately 26. Blood samples showed the presence of trichloroethanol 15-30
minutes after exposure and a linear increase with exposure duration.
Pretreatment of rats with phenobarbital for 4 days enhanced trichloroethanol
formation by approximately 2-fold.
Allemand et al. (1978) studied the in vivo and in vitro binding of
trichloroethylene metabolites to rat liver proteins. Phenobarbital increased
binding while cobaltous chloride, piperonyl butoxide pretreatments, or CO In
vitro decreased binding. Hepatic glutathione levels intially decreased by 65%
but later increased to 108% of the initial level after rn vivo administration
of 2 mg/kg trichloroethylene. Trichloroethylene expoxide was proposed as the
reactive metabolite responsible for macromolecular binding, glutathione
depletion, centrilobular necroses, and hepatotoxicity.
55
-------
CHC1,
Cl
Fig. 1. Metabolic route by which trichloroethylene is converted into
trichloroethanol and trichloroacetic acid. As indicated, trichloroacetic
acid decomposes into carbon dioxide and chloroform under the analysis
conditions given in the text.
Reprinted from: Distribution study of volatile halogenated organic
compounds between rat blood serum and adipose tissue using a purge/trap
procedure. International Journal of Environmental Analytical Chemistry,
8(l):55-66, 1980 by C.D. Pfaffenberger, A.J. Peoples, and H.F. Enos with
permission of Gordon and Breach Science Publishers
Cl
X
OH
I Cl
CO + HCl
t
0
Cl
HCl
n
o
H-C
,H
.Cl
Fig. 2. Possible chemical pathway for conversion of trichloroethylene
to carbon monoxide in the presence of NADPH.
Reprinted from: Conversion of trichloroethylene to carbon monoxide by
microsomal cytochrome P-450, International Symposium Microsomes and Drug
Oxidations, Proceedings, 615-621, 1976 by P.S. Traylor, W. Nastainczyk,
and V. Ulrich with permission of Pergammon Press, Inc.
56
-------
REFERENCES
Allemand H, Pessayre D, Descatoire V. et al. 1978. Metabolic activation of
trichloroethylene into a chemically reactive metabolite toxic to the liver.
J. Pharmacol. Exp. Then, 204(3): 714-734.
Artigue J, Benoit-Guyod JL, Boucherle A, et al. 1978. Determination of
urinary trichloroethylene metabolites. Bull. Trav. Soc. Pharm. (Lyon)
22(3-4):42-48.
Dalbey W, Bingham E. 1978. Metabolism of trichloroethylene by the isolated
perfused lung. Toxicol. Appl. Pharmacol. 43(2):367-378.
Droz PO, Fernandez JG. 1978. Trichloroethylene exposure. Biological
monitoring by breath and urine analyses. Br. J. Ind. Med. 35(1):35-42.
Fernandez JG, Droz PG, Humbert BE, Caperos, JR. 1977. Trichloroethylene
exposure simulation of uptake, excretion, and metabolism using a mathematical
model. Br. J. Indus. Med. 34:43-55.
Gobbato F, Mangiavacchi C. 1979. Mathematical model for the simulation of
the turnover of an industrial toxicant (solvent) subject to metabolic
transformation. G. Ital. Med. Lav. 1(2):53-60.
Ikeda M, Miyake Y, Ogata M, Ohmori S. 1980. Metabolism of trichloroethylene.
Biochem. Pharmacol. 29:2983-2992.
Monster AC. 1979. Uptake, metabolism and excretion of trichloroethylene,
1,1,1,-trichloroethane and tetrachloroethylene. Int. Arch. Occup. Environ.
Health 42:311-317.
Nomiyama H, Nomiyama K. 1979. Pathway and rate of metabolism of trichloro-
ethylene in rats and rabbits. Ind. Health 17(1):29-37.
Pfaffenberger CD, Peoples AJ, Enos HF. 1979. Distribution study of volatile
halogenated organic compounds between rat blood serum adipose tissue using a
purge/trap procedure. Int. J. Environ. Anal. Chem. 8(l):55-66.
Sato, A. 1977. Estimation of rate constants for absorption, metabolism and
excretion of trichloroethylene from analysis of urinary metabolites.
Sangyo Igaki (Jap. J. Ind. Health) 19:92-93.
Smith GF- 1978. Trichloroethylene - relationship of metabolite levels to
atmospheric concentrations: preliminary communication. J. R. Soc. Med.
71(8):591-595.
Traylor PS, Nastainczyk W, Ullrich V. 1977. Conversion of trichloroethylene
to carbon monoxide by microsomal cytochrome P-450. Microsomes Drug Oxid.,
Proc. 3rd Int. Symp. 1976 :651-621.
57
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Uehleke H, Tabarelli-Poplawski S, Bonse G, Henschler D. 1977. Spectral
evidence for 2,2,3-trichlorooxirane formation during microsomal
trichloroethylene oxidation. Arch. Toxicol. (W. Ger.) 37(2):95-105.
Vesterberg 0, Gorczak J, Krasts M. 1976. Exposure to trichloroethylene.
II. Metabolites in blood and urine. Scand. J. Work Environ. Health
2(4):212-219.
Withey JR, Collins BT. 1980. Chlorinated aliphatic hydrocarbons used in the
foods industry: the comparative pharmacokinetics of methylene chloride,
1,2-dichloroethane, chloroform and trichloroethylene after i.v. administration
in the rat. J. Environ. Pathol. Toxicol. 3(5-6):313-332.
58
-------
APPENDIX
Summary Table of Experimental Data
59
-------
Bromobenzene
Administration
Dose^ Route^ Rate Species
3 umoi bromobenzene incubated Rats
in a NADPH-generating system
with in vitro liver microsomes
(1.0-1.4 mg protein)
I.F . jnretreatment
control
50 mg/kg phenobarbitol
20 mg/kg 3-methylcholanthrene
60 mg/kg beta-naphthoflavone
Level (Time Interval)
Metabolite Blood Breath Urine
o-bromophenol
p-bromophenol
o-bromophenol
p-bromophenol
o-bromophenol
p-bromophenol
o-bromophenol
p-bromophenol
Other
(Sp_eci£y_) Ci
*
Liver micro-
somal fraction
7.1*
74.3*
64.4*
455.6*
251.4*
60.1*
169.7*
52.0*
Reference
3 iimol bromobenzene incubated
with liver microsomes
(1.0-1.4 mg protein)
I.P. pretreatment
control
20 mg/kg 3-methylcholanthrene
40 mg/kg beta-naphthoflavone
Mice
o-bromophenol
p-bromophenol
o-bromophenol
p-bromophenol
o-bromophenol
p-bromophenol
3 umol bromobenzene incubated
with liver microsomes
(1.0-1.4 mg protein)
I.P. pretreatment
control
Mice**
o-bromophenol
p-bromophenol
* specific activities Lau SS et al.
of enzymes (nmol/ 1979
min/100 mg protein)
35.8*
35.8*
105.5*
47.8*
133.5*
47.5*
60.0*
45.6*
** cytochrome P-448
noninducible strain
60
-------
Bromobenzene (Continued)
Administration
Dose , Route , Rate
50 mg/kg phenobarbital
20 mg/kg 3-methylcholanthrene
40 mg/kg beta-naphthoflavone
Species Metabolite
o-bromo phenol
p-bromophenol
o-bromophenol
p-bromophenol
o-bromophenol
p-bromophenol
Level (Time Interval) Other
Blood Breath Urine (Specify) Comments
260.0*
753.0*
51.5*
61.7*
42.0*
66.2*
Reference
Lau SS et al.
1979
(cont.)
25 ui tritium labelled
bromobenzene in solution
incubated with liver
microsomes
Rats
bromobenzene
Liver microsomes
0.864*
* rate of disappear- Wiley RA et al.
ance (nmol/mg 1979
protein/min)
1 mM final concentration
tritium labelled bromobenzene
incubated with liver
microsomes
Pr etr eatment
control
i.p. phenobarbital
bromobenzene
3.99**
37.78**
** radioactive co-
valent binding
(pmol/mg
protein/min)
61
-------
Administration
Dose , Route , Rate^
60 umol bromoform incubated
in NADPH-generating system
with liver fractions:
cytosol
(contain 5-7 mg protein)
9,000 g supernatant
(contain 5-7 mg protein)
microsome
50 umol bromoform incubated
with liver microsomes
Species Metabolite
Rats
carbon monoxide
Bromoform
Level (Time Interval)
Blood
Breath
Urine
Rats carbon monoxide
Other
^Specify) Comments
Reference
Liver fractions
0.04 nmol/
mg/min
1.43 nmol/
mg/min
1.23 nmol/
mg/min
Ahmed AE et al.
1977
Liver microsoines
145.54 nmoT/mg protein
formed
Stevens JL et al.
1979
62
-------
Bromodichloromethane
Administration
Dose, Route, Rate Species Metabolite
26 mM bromodichloromethane
incubated with liver microsome
in an NADPH-generating system carbon monoxide
0.5 mg/kg/day bromodichloro- Rats
methane, gavage, 25 days bromodichloro-
methane
chloroform
5 mg/kg/day bromodichloro-
methane, gavage, 25 days bromodichloro-
methane
chloroform
Level (Time Interval)
Blood Breath Urine
1 ug/1*
1 ug/1**
less than
1 ug/1 *
less than
1 ug/1 **
23 ug/1*
1 ug/1**
less than
1 ug/1 *
less than
1 ug/1 **
Other
(Specify) Comments
Liver microsomal
Traction
0.04 nmol/mg/min (enzymic)
0.02 nmol/mg/min (nonenzymic)
Fat *: average of 9
51 ng/g* determinations
during dosing
4 ng/g **
**: average 3 days
less than 1 and 6 days after
ng/g * dosing
less than 1
ng/g **
Fat
1,800 ng/g*
3 ng/g**
(2)
less than
1 ng/g *
less than
1 ng/g **
Reference
Ahmed AE et al.
1977
Pfaffenberger CD
et al. 1979
63
-------
Carbon Tetrachloride
Administration
Dose, Route , Rate JBpecies
i mg/kg/day carbon Rats
tetrachloride, gavage, 25 days
10 mg/kg/day carbon
tetrachloride, gavage, 25 days
10 umol carbon tetrachloride Rats
and 0.5 ml liver homogenates
incubated with:
control
1.6 mM NADH
1.6 mM NAOPH
1.6 mM NADH + NADPH *
Level (Time Interval)
Metabolite Blood Breath Urine
carbon 11 ug/1*
tetrachloride
less than
1 ug/1 **
chloroform less than
1 ug/1 *
less than
1 ug/1 **
carbon 310 ug/1*
tetrachloride
less than
1 ug/1**
chloroform 59 ug/1*
16 ug/1**
carbon dioxide
Other
(Specify) Comments Reference
Fat *',average of 9 Pfaffenberger CD
determinations et ai. 1979
1,900 ng/g* during dosing
** average 3 days
14 ng/g** and 6 days after
dosing
140 ng/g*
(1)
6 ng/g**
Fat
18,000 ng/g*
168 ng/g**
2,600 ng/g*
(1)
17 ng/g**
Shah H et al.
1979
Liver homogenates
27 nmol/g
373 nmol/g
464 nmol/g
472 nmol/g * no significant
additive effect
10 umol carbon tetrachloride
and 0.5 ml liver homogenates
incubated with:
1.6 mM NADPH
1.6 mM NADH + NADPH-
regenerating system
carbon dioxide
572 nmol/g
460 nmol/g
64
-------
Administration
Species Metabolite
Carbon Tetrachloride (Continued)
Level (Time Interval)
Other
Blood
Breath
Urine
Comments
Reference
10 umol carbon tetrachloride
and 0.5 ml liver homogenates
incubated with:
0 umol formate
1 umol formate
10 umol formate
Rats
carbon dioxide
10 umol carbon tetrachloride
and 0.5 ml liver homogenate
incubated with:
0 umol formate
10 umol formate
10 umol carbon tetrachloride
and 0.5 ml liver homogenate
incubated with:
0 mol chloroform
1 moi chloroform
10 mol chloroform
10 umol carbon tetrachloride
and 0.5 ml liver homogenate
incubated with:
0 mol chloroform
10 mol chloroform
10 umol carbon tetrachloride
and 0.5 ml liver homogenate
incubated with:
0 mM cysteine
5 mM cysteine
carbon dioxide
carbon dioxide
carbon dioxide
carbon dioxide
acid-soluble
fraction
carbon dioxide
acid-soluble
fraction
125 nmol/g
137 nmol/g
139 nmol/g
348 nmol/g
376 nmol/g
187 nmol/g
205 nmol/g
184 nmol/g
476 nmol/g
484 nmol/g
580 nmol/g
248 nmol/g
510 nmol/ml
578 nmol/ml
Shah H et al.
1979
(cont.)
65
-------
Carbon Tetrachloride (Continued)
Administration
Dose L Route L Rate Species Metabolite
1 mg/i radioactive-labeled Trout
carbon tetrachloride in 50 carbon
liters aerated de-chlorinated tetrachloride
water at 12°C for 2 hr ,
then transferred to fresh water
Level (Time Interval)
Blood Breath Urine
6.84 nmol/
ml (0 hr)
2.10 nmol/
ml (1 hr)
1.69 nmol/
ml (2 hr)
0.61 nmol/
ml (4 hr)
0.38 nmol/
ml (8 hr)
Other
(Specify)
Fat
76.60 nmol/g
(0 hr)
91.04 nmol/g
(1 hr)
99.60 nmol/g
(2 hr)
55.74 nmol/g
(4 hr)
47.66 nmol/g
(8 hr)
Comments
Reference
Statham CN et al
Half-life 1978
blood:
liver:
heart:
muscle:
gill:
brain:
skin:
spleen:
2.77 hr
38.93 hr
1.99 hr
1.71 hr
3.20 hr
2.63 hr
3.04 hr
2.29 hr
Liver
12.78 nmol/g
(0 hr)
6.14 nmol/g
(1 hr)
5.49 nmol/g
(2 hr)
5.20 nmol/g
(4 hr)
5.25 nmol/g
(8 hr)
66
-------
o-Chlorobenzaldehyde
Administration
Dose, Route , Rate
o-chlorobenzylidene
malononitrile, i.v.
Dose
9.1 mg/kg
13.7 mg/kg
18.3 mg/kg
Species Metabolite
_(Jime Interval)
Breath Urine
Other
(Specify)_
Rabbits
8.5 mg/kg (LD50/24 hr)
o-chlorobenzaldehyde, i.v.
38.8 mg/kg (LD50/24 hr)
o-chlorobenzylmalononitrile,
i.v.
424 umol/kg (LD50/24 hr)
malononitrile, i.v.
o-chlorobenzalde- 450 nmol/cc*
hyde* 140 nmol/cc
o-chlorobenzyl
malononitrile
85 nmol/cc*
37 nmol/cc
o-chlorobenzalde- 500 nmol/cc
hyde + malono-
nitrile
5300 nmol/cc
Comments
Reference
Paradowski
1979
Half-life in blood:
0.31 min
* Liver excluded
from circulation
Half-life in blood:
0.41 min
Half-life in blood:
0.38 min
Half-life in blood:
0.69 min
Half-life in blood:
67
-------
Chloronaphthalene
Administration
Dose, RouteL Rate
Species Metabolite
300 mg 1-chloronaphthalene Pigs
in solution, 2 min retrocarotid
injection
1-chloro-
naphthalene
4-chloronaphthol
Level (Time Interval)
Blood Breath Urine
5.1 ug/g
(10 min)
3.4 ug/g
(20 min)
1.8 ug/g
(40 min)
0.7 ug/g
(80 min)
0.9 ug/g
(120 min)
0.3 ug/g
(160 min)
0.3 ug/g
(200 min)
0.1 ug/g
(240 min)
L 0.1 ug/g 440.0
(160 min) ug/g
0.6 ug/g
(200 min)
0.8 ug/g
(240 min)
1.0 ug/g
(260 min)
1.3 ug/g
(300 min)
Other
(Specify) Comments
Brain
6.7 ug/g
(6 hr)
Kidney
16 . l~ug/g
(6 hr)
Liver
2.3 ug/g
(6 hr)
Lung
1.0 ug/g
(6 hr)
Heart
1.5 ug/g
(6 hr)
Psoas
5.0 ug/g
(6 hr)
Skeletal muscle
1.0 ug/g
(6 hr)
Kidney
1.4 ug/g
(6 hr)
Liver
1.0 ug/g
(6 hr)
Bile
900 ug/g
(6 hr)
Reference
Ruzo LO et al.
1976
68
-------
Chloronaphthalene (Continued)
Administration
Dose, Route, Rate Species Metabolite
300 mg 2-chloronaphthalene
in solution, 2 min retrocarotid 2-chloro-
injection naphthalene
3-chloro-2-
naphthol
Level (Time Interval)
Blood Breath Urine
6.2 ug/g
(10 min)
3.8 ug/g
(20 min)
1.9 ug/g
(40 min)
1.0 ug/g
(80 min)
1.0 ug/g
(120 min)
0.6 ug/g
(160 min)
0.2 ug/g
(200 min)
0.2 ug/g
(240 min)
0.1 ug/g
(260 min)
0.2 ug/g 60.0 ug/g
(200 min) (6 hr)
0.5 ug/g
(240 min)
0.8 ug/g
(260 min)
1.0 ug/g
(300 min)
Other
(Specify) Comments
Brain
21.4 ug/g
(6 hr)
Kidney
14.4 ug/g
(6 hr)
Fat
0.6 ug/g
(6 hr)
Liver
5.2 ug/g
(6 hr)
Lung
H78 uq/g
(6 hr)
Heart
4.5 ug/g
(6 hr)
Psoas
4.5 ug/g
(6 hr)
Skeletal muscle
2.2 ug/g
(6 hr)
Kidney
0.6 ug/g
(6 hr)
Liver
0.7 ug/g
(6 hr)
Bile
260.0 ug/g
(6 hr)
Reference
Ruzo LO et al.
1976
(cont.)
69
-------
Chloronaphthalene (Continued)
Administration Level (Time Interval) Other
Dosei_,Routj3 L_Rate_ ^J|C.ie_s__ Metabolite Blood Breath Urine. (Specify) ^J^WDSPA3. Reference^
400 mg/kg 1,2-dichloro- Rats 5,6-dichloro-l,2- identified Secours V et al.
naphthalene, single oral dihydroxy-1,2-
dihydronaphthalene
(glucuronide conju-
gate)
400 mg/kg 2,7-dichloro- 7-chloro-2-naphthol identified
naphthalene, single oral (free + conjugated)
400 mg/kg 2,6-dichloro- 6-chloro-2-naphthol identified
naphthalene, single oral (free + conjugated)
2,6-dichloronaphthol identified
70
-------
Chloroform
Administration
Dose, Route, Rate
26 mM chloroform incubated
with liver microsome in an
NADPH-generating system
1.75 nmol radioactive
labelled chloroform,
sacrificed 3 hr after
administration
. Species Metabolite
Rats
carbon monoxide
Mice
Level
Jlopjd
(Time Interval) ___
Breath. Urine
Other
Comments
Reference
0.5 mg/kg/day chloroform,
gavage, 25 days
Rats
5 mg/kg/day chloroform,
gavage, 25 days
L_ive_r micro-
somar~fraction
0.00 nmoiTmg/0.03
nmol/mg/min (enzymic)
min (nonenzymic)
Ahmed AE et al.
1977
Liver*
MP: 101
ML: 129
EP: 115
EL: 154
CP: 234
Kidney*
MP: 117
ML : 211
EP: 191
EL: 165
CP: 75
Fat
chloroform 12 ug/1* 99 ng/g*
7 ug/1** 5 ng/g**
Fat
chloroform 69 ug/1* 12,000 ng/g*
8 ug/1** 2 ng/g**
(2)
Kluwe WM 1979
MP: mitochondria
protein
ML: mitochondria
lipid
EP: endoplasmic
reticulum protein
EL: endoplasmic
reticulum lipid
CP: cytosolic
protein
* specific activity
in dpm/mg
*: average of 9 Pfaffenberger CD
determinations et al. 1979
during dosing
**: average 3
days and 6 days
after dosing
71
-------
Chloroform (Continued)
Administration
OP.3-.6 L _RjrLute_L Rate
Level (Time Interval)
~~
Other
__
Jlet_abol_i_te Blood ~~reati ____ Urine _______ (J^e^ifj^)__ _ Comments
liver microsomes from i.p.
phenobarbital pretreated rats
incubated in an atmosphere
of air with:
1 mM chloroform, 1 mM
cysteine
1 mM chloroform, 2 mM
cysteine
Rats
phosgene
Pohl LR et al.
1978
Liver
microsome
1.98 nmol/mg
protein/10
min
4.38 nmol/mg
protein/10
min
1 mM deuterium labelled
chloroform, 2 mM cysteine
2.29 nmol/mg
protein/10 min
1 mM chloroform
incubated with liver microsomes
from i.p. phenobarbital (80
mg/kg) pretreated rats
Rats
(MC)
chloroform
1 mM (14C)chloroform 2 mM
cysteine incubated with
liver microsomes from i.p.
phenobarbital (80 mg/kg)
pretreated rats
chloroform
2-oxothiazolidine-
4-carboxylic acid
1 mM chloroform, 2 mM liver
microsomes from i.p. pheno-
barbital (80 mg/kg) pretreated
rats incubated in an
(180)02 atmosphere
phosgene
Liver
microsome
binding
2178 pmole/mg
protein/10
min
Liver
microsome
protein
binding
1032 pmol/mg
protein/10
min
identified
Pohl LR et al.
1977
identified
72
-------
Administration
Dose, Route, Rate
Species Metabolite
Dibromochloromethane
Level
Blood
-- Interval)
Breath Urine
26 mM dibromochloromethane
incubated with liver microsomes
in an NAOPH-generating system
Rats
carbon monoxide
Other
Comments
Reference
Liver microsomal
Traction
0.42 nmol/
mg/min (enzymic)
0.03 nmol/mg/min (nonenzymic)
Ahmed AE et al.
1977
73
-------
Dichlorobenzene
Administration
Dose, Route, Rate _
1000 ppm (14C)p-dichloro-
benzene, inhalation, 3 hr/day,
10 days
Species
ro- Rats
hr/day,
Level (Time Interval)
Metabolite Blood Breath Urine
p-dichlorobenzene 0.2% 73.0%
(0-24 hr)
19.8%
(24-48 hr)
3.4%
(48-72 hr)
0.8%
(72-96 hr)
0.4%
(96-120 hr)
97.4%
(total)
Other
(Specify)
Feces
2.5%
(0-24 hr)
less than
0.1%
(24-120 hr)
2.5%
(total)
Bile
4875%*
Comments
time intervals
after dosing ceased
Reference
Hawkins DR
1980
* rats with cannulated
bile ducts
2,5-dichloropheny1
sulfate
2,4-dichlorophenyl
glucuronide
unknown
et al.
51.5%*
54%
(24 hr)
34%
(24 hr)
10%
(24 hr)
250 mg/kg/day
benzene, oral, up to 10 days
p-dichlorobenzene
1.0%
87.0%
(0-24 hr)
7.5%
(24-48 hr)
2.5%
(48-72 hr)
0.1%
(72-96 hr)
less than
0.1%
(96-120 hr)
97.1%
(total)
Feces
1.9%
(0-24 hr)
0.1%
(24-48 hr)
less than 0.1%
(48-120 hr)
2.0%
(total)
Bile
63.0%*
74
-------
Dichlorobenzene (Continued)
Administration
Dose^ Route , Rate Species
250 mg/kg/day ^ ^ •'p-dichloro-
benzene, subcutaneous, up
to 10 days
Metabolite
2 , 5-dichloropheny 1
sulfate
2 ,4-dichlorophenyl
glucuronide
unknown
p-dichlorobenzene
Level (Time Interval)
Blood Breath Urine
28.1%*
46%
(0-24 hr)
33%
(0-24 hr)
10%
(0-24 hr)
6.4% 41.0%
(0-24 hr)
23.5%
(24-48 hr)
13.5%
(48-72 hr)
7.8%
(72-96 hr)
4.7%
(96-120 hr)
90.5%
(total)
54.0%*
Other
(Specify) Comments Reference
Hawkins OR et al.
1980
(cont. )
Feces
0.1%
(0-24 hr)
0.9%
(24-48 hr)
0.9%
(48-72 hr)
0.6%
(72-96 hr)
0.6%
(96-120 hr)
3.1%
(total)
Bile
4670%*
2.63 mg/m p-dichlorobenzene
in Tokyo ambient air
2,5-dichlorophenyl
sulphate
2,4-dichlorophenyl
glucuronide
unknown
Pigeons* p-dichlorobenzene
Humans
53%
(0-24 hr)
31%
(0-24 hr)
~J(V
(0-24 hr)
*from environment
Morita M et al.
1978
1.88 ppm
75
-------
Administration
Dose, Route, Rate Species Metabolite
750 mg/kg 1,2-dichloroethane,
single oral
Rats
chloroethanol
1,2-Dichloroethane
Level (Time Interval)
Other
Blood
Breath Urine
5.6 ug/ml
(1 hr)
67.8 ug/ml
(4 hr)
37.6 ug/ml
(12 hr)
14.1 ug/ml
(24 hr)
8.2 ug/ml
(48 hr)
ITeILt?
Liver
0.5 ug/g
(12 hr)
13.5 ug/g
(24 hr)
13.0 ug/g
(48 hr)
Kokarovtseva MG
et al. 1978
255 umol 1,2-dichloroethane
incubated with 6 mg cytosol
protein, 30 umol GSH, 50 umol
phosphate buffer
Rats
ethylene
15 mg/kg 1,2-dichloroethane,
i.v.
Rats
1,2-dichloro-
ethane
Liver
10.3 pmol/
min/mg
Kidney
5.2 pmol/
min/mg
Livesey JC et al.
1979
Fat*
24.92 ug/g
* peak concentration
Maximal accumulation
in fat: 32.5 min
Withey JR et al.
1980
Elimination half-
life in fat: 78 min
76
-------
1,1-Dichloroethylene
Administration
Dose , Route L Rate
(2-14C)l,l-dichloroethylene
Intragastric dose
500 ug/kg
350 mg/kg
I . V . dose
500 ug/kg
Level (Time Interval)
Species Metabolite Blood Breath
Rats
1,1-dichloro- 0.6%
ethylene (0-24 hr)
0.06%
(24-48 hr)
0.08%
(48-72 hr)
0.7%
(total)
carbon dioxide 3.9%
(0-24 hr)
0.5%
(24-48 hr)
0.5%
(48-72 hr)
4.8%
(total)
1,1-dichloro- 62.4%
ethylene (0-24 hr)
4.8%
(24-48 hr)
0.1%
(48-72 hr)
67.3%
(total)
carbon dioxide 0.3%
(0-24 hr)
0.4%
(24-48 hr)
0.3%
(48-72 hr)
1.0%
(total)
1,1-dichloroethylene 80%
(0-24 hr)
0%
(24-48 hr)
0%
(48-72 hr)
80%
(total)
Urine
71.3%
(0-24 hr)
5.3%
(24-48 hr)
3.6%
(48-72 hr)
80.2%
(total)
17.6%
(0-24 hr)
10.0%
24-48 hr)
1.9%
(48-72 hr)
29.5%
(total)
14.4%
(0-24 hr)
0.7%
(24-48 hr)
0%
(48-72 hr)
15.0%
(total)
Other
(Specify)
Feces
5.1%
(0-24 hr)
2.7%
(24-48 hr)
0.6%
(48-72 hr)
8.3%
(total)
Feces
0.4%
(0-24 hr)
0.5%
(24-48 hr)
0.4%
(48-72 hr)
1.3%
(total)
Feces
0.3%
(0-24 hr)
0.1%
(24-48 hr)
0%
(48-72 hr)
0.4%
(total)
Comments
percentages of
administered dose
Reference
Jones BK et al.
1978
77
-------
1,1-Dichloroethylene (Continued)
Administration
I.P. dose
500 ug/kg
350 ug/kg
Level (Time Interval)
Metabolite
carbon dioxide
1,1-dichloro-
ethylene
carbon dioxide
1,1-dichloro-
ethylene
carbon dioxide
Blood Breath
3.5%
(0-24 hr)
0%
(24-48 hr)
0%
(48-72 hr)
3.5%
(total)
11.4%
(0-24 hr)
0.2%
(24-48 hr)
0.1%
(48-72 hr)
11.7%
(total)
2.6%
(0-24 hr)
0.5%
(24-48 hr)
0.5%
(48-72 hr)
3.6%
(total)
90.5%
(0-24 hr)
0.6%
(24-48 hr)
0%
(48-72 hr)
91.1%
(total)
0.7%
(0-24 hr)
0.5%
(24-48 hr)
0.1%
(48-72 hr)
1.3%
(total)
Urine
65.8%
(0-24 hr)
2.0%
(24-48 hr)
1.2%
(48-72 hr)
69.0%
(total)
7.1%
(0-24 hr)
0.3%
(24-48 hr)
0.3%
(48-72 hr)
7.7%
(total)
Other
(Specify)
Feces
14.2%
(0-24 hr)
1.6%
(24-48 hr)
0.4%
(48-72 hr)
16.2%
(total)
Feces
0.5%
(0-24 hr)
0.1%
(24-48 hr)
0.1%
(48-72 hr)
0.7%
(total)
Comments
Reference
Jones BK et al.
1978
(cont.)
78
-------
1,1-Dichloroethylene (Continued)
Administration
Dose , Route , Rate Species
350 mg/kg (l14C)l,l-dichloro-
ethylene, intragastric
350 mg/kg (l14C-)-l,l-dichloro-
ethylene, intragastric
Rat equipped with biliary
fistula
0.5 mg/kg (14C) 1,1-dichloro- Rats
ethylene, single oral
50 rag/kg (14C)l,l-dichloro-
ethylene, single oral
0.5 mg/kg (14C)l,l-dichloro- Rats
ethylene, stomach tube
Level (Time Interval) Other
Metabolite Blood
1,1-dichloro-
ethylene
thiodiglycollic acid
N-acetyl-S-cysteinyl-
acetyl derivative
dithioglycollic acid
thioglycollic acid
chloroacetic acid
urea
S-(carboxymethyl)-
cysteine
1 , 1-dichloroethylene
1,1-dichloro-
ethylene
(unchanged)
carbon dioxide
1, 1-dichloro-
ethylene
(unchanged)
carbon dioxide
1,1-dichloro-
ethylene
(unchanged)
Breath Urine (Specify)
0%
(0-3 hr)
2.9%
(3-6 hr)
15.8%
(6-24 hr)
3.1%
(24-48 hr)
37. OK
48.03;
5.0%
3.0%
3.0%
0.5%
0%
Bile
0% 0.9%
(0-3 hr) (0-3 hr)
0.2% 2.1%
(3-6 hr) (3-6 hr)
6.5% 5.9%
(6-24 hr) (6-24 hr)
2.4% 2.4%
(24-48 hr) (24-48 hr)
0.9% 52%
23%
20% 36%
6%
Fecal
1.26% 43.55% 15774%
(0-72 hr) (0-72 hr) (0-72 hr)
Comments Reference
percentage of Jones BK et al.
administered 1978
radioactivity (cont.)
percentage of Reichert D et al.
administered 1978
radioactivity
percentage of Reichert D 1979
administered
radioactivity
79
-------
1,1-Dichloroethylene (Continued)
Administration
Dose, Route, Rate
5.0 mg/kg (14C)l,l-dichloro-
ethylene, stomach tube
50 mg/kg (14C)1,1-dichloro-
ethylene, stomach tube
Species Metabolite
carbon dioxide
1,1-dichloro-
ethylene
(unchanged)
carbon dioxide
1 , 1-dichloro-
ethylene
(unchanged)
carbon dioxide
Level (Time Interval)
Blood Breath Urine
13.64%
(0-72 hr)
9. 70S! 53.883;
(0-72 hr) (0-72 hr)
11.35%
(0-72 hr)
16.47% 42.11%
(0-72 hr) (0-72 hr)
6.13%
(0-72 hr)
Other
(Specify)
Fecal
14.54%
(0-72 hr)
Fecal
7 .65/o
(0-72 hr)
Comments Reference
Reichert D 1979
(cont . )
Main urinary
metabolites identified
thiodiglycolic acid
N-acetyl-S-(2-
carboxymethyl)
cysteine and
methylthio-acetyl-
aminoethanol
80
-------
Administration
Dose , Route, Rate
1,2-Dichloropropane
Level (Time Interval)
Species Metabolite Bill"! _§.1l££Lth. Urine
Other
(Specify)
Comments
Reference
20 rag/kg 1,2-dichloropropane,
oral, 4 days
Rats
N~acetyl-S-(2-
hydroxypropyl)
cysteine
N-acetyl-S-(2,3-
dihydroxypropyl)-
cysteine
beta-chlorolactate
25-35JS
identified
identified
Jones AR et al.
1980
100 mg/kg 1,2-dichloroethane,
single i.p.
1,2-dichloro-
propane
(unchanged)
5$
(0-3 hr)
CO'
(9-18 hr)
81
-------
Hexachlorobenzene
Administration
Dose L Route, Rate
1.42 mM 14C-hexachloro-
benzene/kg, i.p.
no occupational exposure to
chlorinated hydrocarbons
polyvinyl chloride plant
workers
magnesium plant workers
technical grade pentachloro-
phenol (20 mg/kg/day for day
1-42; 15 mg/kg/day for day
43-160), oral (diet)
Technical grade
pentachlorophenol in dose
0%
10%
35K
100%
Species Metabolite
Level (Time Interval)
Blood Breath Urine
Rats
hexachlorobenzene IK
(0-4 wk)
pentachlorophenol 28%
(0-4 wk)
pentachlorothiophenol 46%
(0-4 wk)
tetrachlorohydroquinone 17%
(0-4 wk)
tetrachlorothiophenol 1%
(0-4 wk)
Humans hexachlorobenzene
(9)
(9) hexachlorobenzene
(17) hexachlorobenzene
Heifers
(12)
1.04 ppb
1.54 ppb
29.61 ppb
0.16 ppb
(day 160)
0.25 ppb
(day 160)
0.46 ppb
(day 160)
0.77 ppb
(day 160)
Other
(Specify) Comments Reference
Feces percentage of Koss G et al.
695 radioactivity 1978
(0-4 wk)
16%
(0-4 wk)
9%
(0-4 wk)
0%
(0-4 wk)
0%
(0-4 wk)
numbers of Lunde C et al.
subjects in 1977
parentheses
hexachlorobenzene Parker CE et al.
is a contaminant 1980
300 mg/kg hexachlorobenzene, Rats
oral
2,4,5-trichloro-
phenol
identified
Renner G et al. 1977
82
-------
Hexachlorobenzene (Continued)
Administration
110 ug -^C-hexachlorobenzene ,
oral (diet), up to 550 days
Species Metabolite
Monkeys
hexachlorobenzene
pentachlorobenzene
pentachlorophenol
pentachloro-
-benzene, hexa-
chlorobenzene,
and tetrachloro-
benzene
Level (Time Interval) __
lood Breath Urine
50-75?;
25-50SJ
Other
Comments
Reference
Feces
99%
approx. 1%
trace
Rozman K et al.
1978
300 ppm technical grade
pentachloronitrobenzene
(impurities: 0.21 ppm
pentachlorobenzene, 0.6 ppm
2,3,4-tetrachloronitrobenzene,
4.5 ppm hexachlorobenzene),
oral (diet), 16 weeks
Hens
hexachlorobenzene 0.403 ppm
Fat
1978 ppm
Bile-gall
bladder
17.50 ppm
Liver
7.47 ppm
Egg yolk
7.95 ppm
Egg white
0.032" ppm
Breast muscle
0.334 ppm
Excreta
not detect-
able
Half-life: 90 days
Simon GS et al.
1979
1.3 uCi C-hexachlorobenzene,
i.v.
Rats
12.9 uCi 14C-hexachloro-
benzene, i.v.
Monkeys
hexachlorobenzene
hexachlorobenzene
0.2$
1.6%
(6 yr)
Feces
Feces
28.21S
(1 yr)
percentage of
administered dose
Yanc
197E
RSH et al.
Fat
approx. 0.3 ug
eq/g
83
-------
Administration
Dose LJtoute^ jtete
Species Metabolite
Hexachlorobenzene (Continued)
Level (Time Interval)
Blood Breath Urine
Other
(Specify) Comments ^Reference
24.7 uCi 14C-hexachloro-
benzene, i.v.
hexachlorobenzene
1.8SJ
(100 day)
26.2 uCi 14C-hexachloro-
benzene, i.v.
hexachlorobenzene
Fat
S: 430.5 ng/g
(1 yr)
0: 397.8 ng/g
(1 yr) S:
Bone marrow 0:
372.6 ng/g~
(1 yr)
Feces
(100 day)
Fat
S: 3170.3 ng/g
(100 day)
0: 2899.1 ng/g
(100 day)
Adrenal gland
367.5 ng/g
(100 day)
Feces
1.1% 8.8%
(3 mo) (6 mo)
Fat
~5T~1829.8 ng/g
(6 mo)
0: 1789.9 ng/g
(6 mo)
Bone marrow
1637.8~ng7g~
(6 mo)
Adrenal ^glancl
328.7 ngAf
(6 mo)
Yang RSH et al,
1978
(cont.)
subcutaneous fat
omental fat
84
-------
Administration
Dose, Route, Rate
Species Metabolite
Hexachloroethane
Level (Time Interval) Other
Blood Breath jy.riQ
-------
Administration
0.025 mCi/mmol
14
C)-
Spj3c_ies_
Rats
Metabolite
Methylene Chloride
Level (Time Interval)
Blood EJreath Urine
Other
Comments Reference
methylene chloride incubated
with liver microsomes
Pretreatmen t
control
50 mg/kg phenobarbital i.p.
methylene chloride
2,600 mg/m methylene
chloride (750 ppm),
inhalation, 1 hr while
exercising at a rate of
50 W on a bicycle ergometer
Humans
(12 male) methylene chloride
Liver
microsome*
lipid: 0.27
protein: 0.14
lipid: 1.97
protein: 0.57
covalent binding
to microsome (nmol
bound/mg protein
or lipid/min)
Anders MV et al.
1977
* mean concentration
10.2 mg/kg
(1 hr)
8.4 mg/kg
(4 hr)
Engstrom J et al.
1977
methylene chloride, closed
rebreathing system
Dose (umol/kg)
82
100
122
793
Rats
carbon monoxide*
0.2 mmoi/kg methylene chloride Rats
(.75 uCi/kg), closed rebreath-
ing system, sacrificed after
7 hr
carbon monoxide
carbon dioxide
46.9%
28.9%
Concen tratipn in
closed system
0.46 (4 hr)**
0.48 (4 hr)**
0.48 (4 hr)**
0.18 (4 hr)**
Rodkey FL et al.
1977a
* per mole methylene
chloride administered
**moles CO produced per
mole of methylene
chloride given
Rodkey FL et al.
1977b
86
-------
Pentachloroanisole
Administration
Dose, RouteLJRate_
Species^
0.024 mg/1 ^C-pentachloro-
anisole, 12 hr, transferred to
fresh water
0.024 mg/1 14C-pentachloro-
anisole, 24 hr, transferred to
fresh water
Rainbow
Trout
Metabolite
Level (Time Interval)
Blood
Breath
Urine
pentachloroanisole
pentachlorophenol
Other
_(S£e£if_yJ_
Comments
Reference
Elimination half-
Tffe
Glickman AH et al.
1977
liver: 6.9 days
fat: 23.4 days
muscle: 6.3 days
blood: 6.3 days
Elimination half-
liver: 9.8 hr
fat: 23.7 hr
muscle: 6.9 hr
0.05 mg/1 14C-pentachloro-
anisole, 12 hr
0.05 mg/1, ^C-pentachloro-
anisole 12 hr after being in
1 mg/1 24 hr
20 rag/kg ^C-pentachloro-
anisole, single i.p.
Mice
pentachlorphenol-
glucuronide
pentachlorophenol
pentachloroanisole
pentachlorophenol-
glucuronide
pentachlorophenol
pentachloroanisole
Bile
2~5T~ng (83S)
6 ng (2«)
47 ng (15%)
Bile
85~ng (42%)
10 ng (5%)
107 ng (53%)
pentachlorophenol
(free)
tetrahydroquinone
2S
175
Feces
US-
Elimination half-
Tife
blood:
urine:
feces:
5.6 hr
5.6 hr
8.0 hr
liver: 19.3 hr
muscle: 6.1 hr
adipose: 7.0 hr
skin: 6.2 hr
Vodnick MJ et al.
1980
87
-------
Pentachlorobenzene
Administration
Dose, Route, Rate
403 uM pentachlorobenzene,
i.p.
__Sp_eciej3
Rats
Metabolite
Level (Time Interval)
Blood Breath Urine
Other
_(•>£?.<: i_fy_)__ ___Q9.(5!n.?n.t.l5. RBfjsrenc_e
pentachlorobenzene
(unchanged)
pentachlorophenol
Urine & Feces Other metabolites
Koss G et al.
1978
chlorophenol
tetrachlorohydro
quinone
hydroxylated
chlorothio compound
tetrachlorophenol
isomer
20 mg pentachlorobenzene,
single oral
no occupational exposure
to chlorinated hydrocarbons
Monkeys
Humans
(9)
pentachlorobenzene
pentachlorobenzene *
Urine & Feces
22%
(0-6 days)
metabolites
identified in
urine: 2 isomers
of tetrachlorophenol
number of subjects
in parentheses
Leber AP et al.
1977
Lunde G et al.
1977
polyvinyl chloride plant
workers
magnesium plant workers
(9)
(17)
* no data
0.15 ppb
300 ppm technical grade
pentachloronitrobenzene*
oral (diet), 16 weeks
* contains 0.21 ppm penta-
chlorobenzene, 0.6 ppm
tetrachlorobenzene,
4.5 ppm hexachlorobenzene
Hens
pentachlorobenzene 0.013 ppm
Fat
1.32 ppm
Bile-gall
bladder
1.46 ppm
Liver
Q.2TS ppm
Egg yolk
0.355ppm
white
Simon GS et al.
1979
88
-------
Pentachlorobenzene (Continued)
Administration Level (Time Interval) _ Other
_
Dose , Route , Rate __________ Species Metabolite _______ Blood _ §r ea th __ !^yi§ ____ (SESliCX.! _____ Comments _____________ Reference
Breast muscle Simon GS et al.
' 1979
(cont.)
Excreta
0.01? ppm
89
-------
Administration
Dose ^ Rqute_L_Rat_e
5 mg/kg/day 1,2,4,5-
tetrachlorobenzene, oral
(diet), 2 yr
Species
Beagle
Dogs
Tetrachlorobenzene
Level (Time Interval) Other
_Met_abqlite_ Blood ""Breath'""IFine CS&eciTyJ Comments Reference
tetrachlorobenzene
tetrachlorobenzene
in Norway fjord
Fish
Uptake rate
constants
blood: very large
fat: very large
Elimination rate
constants
EToodT~~6.64 x 10~3/day
fat: 6.01 x lO^/day
Half-life
blood: IDA days
fat: 111 days
Braun WH et al.
tetrachlorobenzene
Fat
0.08-1.4 ppm
Ofstad EB et al.
1918
90
-------
Administration
Dose, Route, Rate
3.3 uM tetrachloroethylene
incubated with hepatic
microsome
Additions
None
200 mM SKF525A
2.33 mM metyrapone
C0:02 (80:20)
Tetrachloroethylene
Level (Time Interval)
Species Metabolite Blood Breath Urine
Other
(Specify)_
Comments
Reference
Rats
tetrachloro-
ethylene
trichloroacetate
tetrachloro-
ethylene
trichloroacetate
tetrachloro-
ethylene
trichloroactate
tetrachloro-
ethylene
tr ichloroacetate
eels in 50 ppm tetrachloro-
ethylene solution for 3 days;
their flesh removed and
homogenized with water
(20.5 ppm tetrachloroethylene);
10 ml/kg homogenized solution,
oral
Rats
tetrachloro-
ethylene
24.8 ng/g
(3 hr)
19.6 ng/g
(6 hr)
13.1 ng/g
(12 hr)
11.5 ng/g
(20 hr)
Spectral
binding to
cytochrome
P-450
100%
100%
67%
20%
25%
not determined
25%
Costa AK et al.
1980
Liver
160.0 ng/g
(3 hr)
55.5 ng/g
(6 hr)
23.3 ng/g
(12 hr)
18.5 ng/g
(20 hr)
Adipose
tissue
104.3 ng/g
(3 hr)
248.2 ng/g
(6 hr)
141.8 ng/g
(12 hr)
55.9 ng/g
(20 hr)
Miyake Y 1978
Half-life
blood : 16 hr
liver : 5 hr
adipose
tissues : 6 hr
91
-------
Tetrachloroethylene (Continued)
Administration
Dose,_Routej Rate Species
70 ppm tetrachloroethylene, Humans
inhalation, 4 hr (4-6)
1 mg/kg tetrachloroethylene, Rats
oral gavage, sacrificed
after 72 hr
500 mg/kg tetrachloroethylene,
oral gavage, sacrificed after
72 hr
Level (Time Interval)
Metabolite Blood Breath Urine
tetrachloroethylene 95%
trichloroacetic acid
carbon dioxide 0.04
umol eq
(2.5%)
tetrachloro- 1.05 0.24
ethylene umol eq umol eq
(71.5%) (16.5%)
carbon dioxide 3.44
umol eq
(0.558)
tetrachloro- 667.31 34.48
ethylene umol eq umol eq
(89.9%) (4.6%)
Other
(Specify) Comments Reference
Kidney Miyake Y 1978
25.9 ng/g (cont. )
(3 hr)
35.1 ng/g
(6 hr)
42.1 ng/g
(12 hr)
114.1 ng/g
(20 hr)
Muscle
28.3 ng/g
(3 hr)
22.4 ng/g
(6 hr)
19.3 ng/g
(12 hr)
13.2 ng/g
(20 hr)
Monster AC 1979
Pegg DG et al.
1979
Feces
0.09
umol eq
(6.2%)
Carcass
umol eq
(3.3%)
Feces
29.08
umol eq
(3.9%)
92
-------
Tetrachloroethylene (Continued)
Administration
Dose, Route, Rate Species Metabolite Blood Bi
10 ppm tetrachloroethylene,
inhalation, 72 hr
carbon dioxide
tetrachloro-
ethylene
Level
Blood
(Time Interval)
Breath
0.32
umol eq
(3.6%)
6.08
umol eq
(68.1%)
Urine
1.66
umol eq
(18.730
Other
(Sp_ecify_)
Carcass
8.5 umol
(1.2%)
Feces
0.46
umol eq
(5.2%)
Carcass
0.38 umol
(4.3%)
eq
eq
Comments
Reference
Pegg DG et al.
1979
(cont.)
600 ppm tetrachloroethylene,
inhalation, 72 hr
carbon dioxide
tetrachloro-
ethylene
3.25
umol eq
(0.7%)
412.38
umol eq
(88%)
27.40
umol eq
(6.0%)
Feces
14.24
umol eq
(3.1%)
Carcass
10.07 ~
umol eq
(2.2%)
93
-------
Administration
Dqse_u Rjjute , Rate
Species Metabolite
0.018 mg/1 (14C)-1,2,4-
trichlorobenzene, 8 hr static
exposure; transferred to fresh
flowing water
Trout
14
-C label
1,2 ,4-Trichlorobenzene
Level (Time Interval)
Blood Breath Urine
33*
Other
(Specify)
Comments
Reference
Liver
102*
Muscle
51*
Bile
104^240*
* maximal ratio:
tissue
water
Elimination half-
lives Tiar days 1-2
blood: 0.02 days
liver: 0.4 days
muscle: 0.4 days
Melancon MJ et al.
1980
0.020 mg/1 (14C)-l,2-4-trichloro-
benzene, continuous flow, 35
days; transferred to fresh
flowing water
14
-C label
84*
Liver
389*
Bile
500-1400*
Muscle
89*
Elimination half-
1ives for days 4-36
IfveF:~5STay s
muscle: 47 days
blood: less than 1 day
0.40 mg/1 (14C)-1,2,4-
trichlorobenzene, 24 hr
0.24 mg/1 (14C)-
1,2,4-trichlorobenzene, 24 hr
14
-C label
5.8 ug/ml
14
-C label
1.3 ug/ml
Bile
38.2 ug/g
Muscle
9.6 ug/g
Liver
19.3 ug/g
Bile
6.8 ug/g
Muscle
2.5 ug/g
Liver
4.0 ug/g
Kidney
1.8 ug/g
Plasma
1.4 ug/g
94
-------
1,2,4-Trichlorobenzene (Continued)
Administration
Dose, Route, Rate
0.20 mg/1 (14C)-1,2,4-
trichlorobenzene, 24 hr
1 mmol/kg/day
(14C)-1,2,4-trichlorobenzene,
oral, 7 days
Level (Time Interval) Other
Species Metabolite Blood Breath Urine (Specify) Comments
Carp Bile
i4-C label 2.8 ug/ml 18.1 ug/g
Muscle
2.2 ug/g
Liver
11.3 ug/g
Kidney
7.6 ug/g
Plasma
3.0 ug/g
Rats Feces post exposure
3, 14-C label 72% 4S amount
Reference
Melancon MJ et al.
1980
(cont.)
Smith E et al.
1980
(day 1-15) (day 1-8)
Abdominal
fat"
2033 dpm/g
(day 1)
642 dpm/g
(day 6)
342 dpm/g
(day 11)
408 dpm/g
(day 16)
Liver
1075 dpm/g
(day 1)
442 dpm/g
(day 6)
308 dpm/g
(day 11)
317 dpm/g
(day 16)
Adrenal gland
754 dpm/g
(day 1)
246 dpm/g
(day 6)
6,660,000 dpm total
95
-------
1 ,2 ,4-Trichlorobenzene (Continued)
Administration Level (Time Interval) ___ Other
Dose^ Route , Rate __________ Spec ies Met abol i te ________ B.L°_od ____ Breatli ___ Urine ___ ^Specify) __^omments
Muscle Smith E et al.
400 dpm/g 1980
(day 1) (cont.)
Kidney
1471 dpm/g
(day 1)
404 dpm/g
(day 6)
Heart
438 dpm
(day 1)
Spleen
404 dpm
(day 1)
96
-------
Administration
Dose, RouteL Rate
Species
Metabolite
1,1, 1-Trichloroethane
Level (Time Interval)
Blood Breath
70 ppm 1,1,1-trichloroethane, Humans
inhalation, 4 hr (6)
Other
( Speci f y )
trichloroethanol
trichloroacetic acid
trichloroethane
(unchanged)
80%
less than
2%
less than
2%
Comments
Reference
half life in blood:
10-12 hr
half life in blood:
80-100 hr
half life for
adipose saturation:
25 hr
blood/gas partition
coefficient = 5
Monster AC 1979
97
-------
Trichloroethylene
Administration
L JLoH.li?. L _Rate.
Species
Metabolite
Level (Time Interval)
Blood Breath" Urine
100 umol
14
ethylene, i.
after 4 hr
-C trichloro-
sacrif iced
Rats
tricoloroethylene
100 umol 14-C trichloro-
ehtylene i.p. to phenobarbital
pretreated
trichloroethylene
5 umol -C trichloro-
ethylene incubated under air
with microsomes from 125 mg
of liver and an NADPH
generating system
Pretreatment
control
10 mg/kg phenobarbital i.
30 mg/kg CoCl2 s.c.
Other
Muscle*
3.1 nmol/g
Liver*
117 nmol/g
Cornmen t_s
* amount bound to
tissue proteins
Re fereruie
Allemand H et al.
1978
Muscle*
4.1 nmol/kg
Liver*
171 nmol/kg
trichloroethylene
Liver microsomes
7.7**
53.7**
5.5**
** amount (nmol/g
liver/15 min)
irreversibly bound
to microsome
proteins
30-45 ppm trichloroethylene,
isolated lung perfusion, 3.5 hr
Rats
tricoloroethanol
2.0 ug/g
of lung
1.17 ug/g
of lung
trichloroethylene
blood/air partition
coefficient was 26
for rats, 2 for
guinea pigs
Dalbey W et al.
1978
Guinea
Pigs
trichloroethanol
trichloroacetic
acid
Lung
4.64 ug/g
of lung
87.5%
(200 min)
12.5%
(200 min)
98
-------
Trichloroethylene (Continued)
Administration
Species Metabolite
Blood
Level (Time Interval)
Breath" UrTnes
30-45 ppm trichloroethylene,
isolated lung perfusion;
75 mg/kg i.p. phenobarbital
pretreatment
Rats
tricoloroethanol
trichloroacetic
3.44 ug/g
of lung
Other
(Specify)
Lung
Comments
Reference
(140 min)
6.1%
(140 min)
Dalbey W et al.
1978
(cont.)
30-45 ppm trichloroethylene,
isolated lung perfusion;
35 ul ethanol added 5 min
after respiration initiation
trichloroethanol
2.28 ug/g
of lung
(140 min)
50 ppm trichloroethylene,
intermittent inhalation
exposure during 8 hr/day work
Humans
(6 males)
200 ppm trichloroethylene,
intermittent inhalation
during 8 hr/day work
Humans
(6 females)
70 ppm trichloroethylene, Humans
inhalation at rest, 4 hr (6)
trichloroethylene
trichloroethanol
trichloroacetic
acid
10SS
43$
21K
Biological half-life
in urine
trichlorocompounds:
50.7 hr
trichloroethanol:
42.7 hr
trichloroacetic acid:
57.6 hr
Biological half-life
in urine
trichlorocompounds:
26.1 hr
trichloroethanol:
15.3 hr
trichloroacetic: acid
39.7 hr
Ikeda M 1977
Half-life in blood
trichloroethanol:
10-12 hr
trichloroacetic acid:
80-100 hr
Monster AC 1979
99
-------
Trichloroethylene (Continued)
Administration
Dose L Route , Rate Species
10 mg trichloroethylene, Rats
single i.p. injection
0.5 g trichloroethylene, Rabbits
single i.p. injection
Metabolite
trichloroethanol
trichloroacetic
acid
total trichloro-
compounds
Blood Breath
trichloroethanol
trichloroacetic acid
total trichloro compounds
1 mg/kg/day trichloroethylene, Rats
gavage, 25 days
10 mg/kg day/trichloroethylene,
gavage, 25 days
trichloroethylene
chloroform
trichloroethylene
chloroform
1 ug/1*
1 ug/1**
1600 ug/1*
28 ug/1**
1 ug/1*
6 ug/1**
9300 ug/1*
60 ug/1**
Urine
3.18 mg
(0-3 day)
0.26 mg
(0-3 day)
3.73 mg
(0-3 day)
157.2 mg
(0-4 day)
0.9 mg
(0-4 day)
172.7 mg
(0-4 day)
(SpecifyJ Comments Reference
Nomiyama H et al.
1979
Fat *: average of 9 Pfaffenberger
280 ng/g* determinations CD 1979
**: average
1 ng/g** 3 days and 6 days after
dosing
100 ng/g*
6 ng/g**
Fat
20,000 ng/g*
1 ng/g**
480 ng/g*
(1)
less than
1 ng/g **
100
-------
Trichloroethylene (Continued)
dministration
e(te
Metabolite
Level (Time Interval)
richloroethylene,
ontinuous inhalation
26
26
40
35
39
aecies
Humans
(2)
Volunteer trichloroacetic
#1 acid
Volunteer
n
Blood
Breath
Urine
54 mg/1
51 mg/1
61 mg/1
97 mg/1
67 mg/1
92 mg/1
Other
(Specify)
Comments
Reference
ratio of tri-
chloroethylene
retained to tri-
chloroacetic acid
excreted per day was
approximately 1:0.1
Smith CF 1978
100-200 ppm
tr ichloroethylene,
inhalation at rest
and at work
Average uptake
Group I: H5%
Group II: 44%
Group III: 42%
Humans
Group I
trichloroacetic
acid
trichloroethanol
Group II
Group III
trichloroacetic
acid
trichloroethanol
trichloroacetic
acid
trichloroethanol
0.4 mg/kg
(30 min)
0.7 mg/kg
(30 min)
0.6 mg/kg
(30 min)
0.8 mg/kg
(30 min)
0.7 mg/kg
(30 min)
1.4 mg/kg
(30 min)
3.0 umol
(0-5 hr)
135 umol
(0-5 hr)
9 umol
(0-5 hr)
235 umol
(0-5 hr)
4 umol
(0-5 hr)
344 umol
(0-5 hr)
Vesterberg 0 et al.
1976
101
-------
:EFORT
NO
a. T.tie snri G^bt t:<
Metabolism Summaries of Selected Halogenated Organic Compounds
in Human and Environmental Media, A Literature Survey, Second
JJpda_te_ __ _ __ ____________ _ __ __. _____
7 Author(5i
Halpin, Verna_j_Mey_eri Daniel; Lowe_, Eugene W. ________
I S. r=erformirr Organization Name and Address
| Tracor Jitco, Inc.
j 1776 E. Jefferson Street
! Rockvile, MD 20852
3. Recipient's Access or,
_ 560/7-82-0_03
5. Report Date
August, 1982
i 8. Pen'orming Organization Rept. No
10. Project/Task/WorK Unrt No
! 11. Contract(C) or GranUG1 No.
! (o 68-01-6021
12. Sponsoring Organization Name and Addres
U.S. EPA/OTS (TS-793)
401 M Street, S.W.
Washington, D.C. 20460
13. Type of Report & penod Covered
Literature Survey
1978 - 1980
15. Supplementary Notes
16. Abstract (Limit: 200 words)
This report is the second update of the original EPA report "Metabolism Summaries of
Selected Halogenated Organic Compounds in Human and Environmental Media, Literature
Survey" (EPA-560/6-79-008).
This report updates available data from 1978 - 1980 on 23 halogenated hydrocarbons
(HHC's) identified as environmental pollutants and potential health hazards, including
two chemicals not covered in the earlier reports. Included is information on the uptake
and retention of the compounds, their subsequent distribution and elimination patterns,
the identification and observed concentrations of metabolites, and the metabolic pathways
involved. This report includes, as an appendix, a tabular summary of the experimental
data reported.
17. Document Analysis a. Descriptors
b. Identitiers/Open-Ended Terms
i.. COSATI Field/Group
1^. Availability Statement
19. Security Class (This Report)
20. Security Class (This Page)
21. No. of Pages
! no
! 22. Pncp
ANSI-Z3S.18:
See Instructions on Reverse
OPTIONAL FORW 272 (4-77!
iFormerly NTIS-35)
'-...T3r1mrnt of Commerce
------- |