Toxic Substances
Washington DC 20460
EPA 560/6-79-008
April 1979
Toxic Substances
METABOLISM SUMMARIES OF SELECTED
HALOGENATED ORGANIC COMPOUNDS
IN HUMAN AND ENVIRONMENTAL MEDIA,
A LITERATURE SURVEY
-------
Metabolism Summaries of Selected
Halogenated Organic Compounds
in Human and Environmental Media,
A Literature Survey
Randall D. Huffman
Christine M. Latanich
Thomas K. Collins
James A. Caldwell
Jeffrey D. Wiese
Contract No. 68-01-4116, Task #19
June, 1979
Joseph J. Breen - Task Manager
Cindy Stroup - Contract Project Officer
Prepared for:
Survey and Analysis Division
Office of Program Integration and Information
Office of Toxic Substances
US Environmental Protection Agnecy
Washington, DC 20460
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NOTICE
This report has been reviewed by the Office of Toxic Substances, EPA, and
approved for publication. 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
endorsement or recommendation for use.
11
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TABLE OF CONTENTS
INTRODUCTION
METABOLISM REPORTS
Benzyl Bromide 1
Bromobenzene 2
Bromoform ~>
Bromopropylbenzene 9
Carbon tetrachloride 10
o-Chlorobenzaldehyde 14
Chlorobenzene 15
Chloroform 18
Chloronaphthalene 21
Chloronitrobenzene 23
Chloroprene 27
Chlorotoluene (benzyl chloride) 29
Dichlorobenzene 31
1,2-Dichloroethane 34
1,1-Dichloroethylene (vinylidene chloride) 37
1,2-Dichloroethylene 43
1,2-Dichloropropane 45
Hexachlorobutadiene 47
Hexachloroethane 48
Methylene chloride 50
Pentachloroanisole 56
Pentachlorobenzene 58
Pentachloroethane 61
Tetrachlorobenzene 63
1,1,2,2-Tetrachloroethane 66
Tetrachloroethylene 72
Trichlorobenzene 78
1,1,1-Trichloroethane 83
1,1,2-Trichloroethane 93
Trichloroethylene 97
APPENDIX A: Summary Table of Experimental Data 108
APPENDIX B: Summary Table of the Levels of Parent 184
Halocarbon and Metabolites Identified
in Blood, Breath and Urine
REFERENCES for Summary Tables A and B 300
iii
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Introduction
The Office of Program Integration and Information's Survey and Analysis
Division is currently conducting a preliminary assessment of halogenated
organic compounds in human and environmental media. This effort was
undertaken in response to the detection and identification of numerous
halogenated hydrocarbons in the environment, notably in drinking water
supplies. Although detected levels have generally been low, several
halocarbons have entered the environment at relatively high concentrations
as a result of accidental spills or contamination of animal feed. The
reporting of halogenated pesticides in human blood, serum, and adipose
tissue further heightens concern over the potential health effects which may
be associated with a halocarbon insult.
The major thrust of this preliminary assessment is a comprehensive and
systematic analysis of selected halocarbons in man and the environment being
conducted under contract by the Research Triangle Institute (RTI).
Conceptually, the program may be partitioned into three primary levels as
depicted in Figure I-"-. This schematic flow diagram illustrates the
interlocking relationships between the environment and man and their
potential association with the incidence of disease, specifically cancer.
The three program levels in Figure 1 represent: (1) the demonstration
for man of a halocarbon dosage through environmental exposure via routes
such as air, water and food; (2) the demonstration of a body-burden in man
through the examination of urine, breath, blood, and tissues for halogenated
hydrocarbons; and (3) the demonstration of an association (i.e., a response)
between body-burden and the incidence of cancer.
To complement the RTI effort, Tracor-Jitco, Inc., under contract to the
Survey and Analysis Division, has conducted a literature survey on the
metabolism of selected halocarbons for use in evaluating the human body
burden associated with environmental exposure. Forty-nine halogenated
hydrocarbons (HHC's) were selected for this metabolism review based on the
following information (details of the HHC selection process will be included
in the report produced by RTI):
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.
Pellizzari, Edo. Preliminary Assessment of Halogenated Organic
Compounds in Man and Environmental Media. Comprehensive Monthly
Technical Progress Report No. 16 (February 1979).
IV
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INDUSTRIAL DISCHARGE
SOURCES OF HALOGENATED
HYDROCARBONS
DATA ON
SPECIFIC
INDUSTRIAL
PLANTS AND
PROCESSES
ANALYSIS OF ENVIRONMENTAL
MATRICES REPRESENTING PORTALS
OF ENTRY TO MAN
DEMOGRAPHIC,
HYDRO LOGIC,
METEOROLOGIC,
TOPOGRAPHIC
DATA
AIR
ANALYSIS
OF
ENVIRONMENTAL
SINKS
WATER
FOOD
LEVEL 1: DOSE-
l
MAN
LEVEL 2: BODY BURDEN - URINE - BLOOD - TISSUE-
BIOCHEMICAL,
PHYSIOLOGIC
PARAMETERS
LEVEL 3: RESPONSE
BACK
OR FORWARD
EXTRAPOLATION
OF
AIR/WATER
QUALITY
FORMULATION OF
HYPOTHESES
ACCOUNT FOR
LATENCY
FACTORS
EVALUATION AND
•HYPOTHESES TESTING-
CONCLUSION
MORTALITY AND
— MORBIDITY
ANALYSIS
Figure 1
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The health-related effects associated with many of these chemicals have
been studied extensively and are fairly well documented. However, the
metabolism of these compounds and the possible toxic effects of their
metabolites have yet to be clearly defined.
A thorough literature search pertinent to the metabolism of the selected
HHC's was performed and all available information collected; however, infor-
mation was found on only 30 of the 49 HHC's. The 19 compounds for which no
information was available are the following:
Bis(chloroisopropyl)ether
Bromochlorotoluene
Bromodichloroethane
Bromodichloromethane
Chiorobenzotrifluoride
Chloroprene dimer
Dibromochloromethane
Dichlorotoluene
Dibromochlorobenzaldehyde
Dichlorobutane
1,1-Dichloroethane
Dichloroheptane
Methyl dichlorophenoxyacetate
Methyl trichlorophenoxyacetate
Tetrachlorotoluene
Trichlorobutane
Trichlorohexane
Trichloropentane
Trichlorotoluene
The metabolism summaries for each of the 30 HHC's comprise Section II
of this report. Basic information on the physical properties of the
compounds is included at the beginning of each summary. Molecular and
structural formulas, the Chemical Abstracts Registry (CAS) number, accepted
synonyms, molecular weight (mol wt), boiling point (bp), and vapor pressure
(vp) are presented in the heading of each summary. The text summarizes
the available information on the uptake and retention of the compound, its
subsequent distribution and elimination patterns, the identification and
observed concentrations of metabolites, and the metabolic pathways involved.
For most of the compounds, the available information was quite limited.
In those cases, all of the information was incorporated into the reports.
Several of the compounds, however, have been extensively researched; in such
cases, the information has been summarized, but not every relevant article
cited. Special emphasis was given to those articles reporting the highest
Except where otherwise noted, this information was obtained from the
Registry of Toxic Effects of Chemical Substances, 1977, NIOSH, and the
CRC Handbook of Chemistry and Physics, 53rd and 56th ed.
vx
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observed levels of the compounds and their metabolites in humans and
experimental animals.
Appendix A of this report consists of a tabular summary of the
experimental data. Appendix B of this report consists of a tabular summary
of the levels of parent halocarbon and metabolites identified in blood,
breath, and urine. Included with this information are some of the reported
metabolic pathways for the various compounds.
Secondary information sources utilized in the literature search include:
On-Line Data Bases
Agricola
Biosis Previews
CA Condensates
CAB Abstracts
CANCERLINE
Comprehensive Dissertaion Abstracts
Excerpta Medica
NTIS
Scisearch
SSIE
TOXLINE
Abstract Journals
Biological Abstracts
Bioresearch Index
Chemical Abstracts
Excerpta Medica
FDA Clinical Experience Abstracts
Food Science and Technology Abstracts
Occupational Safety and Health Abstracts
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BENZYL BROMIDE
CH2Br
CAS: 000100390
Syn: alpha-bromotoluene
Mol. Wt.: 171.05 g/mole
bp: 201°C (at 760 mm Hg)
vp: 1.06 mm Hg (at 25°C)
In a 1958 study conducted by Bray, James and Thorpe (1), rabbits given
an aqueous benzyl bromide solution, via stomach tube, were reported to
suffer such severe anorexia that many ensuing quantitative tests proved
unreliable. Urinalysis was conducted within 24 hours of administration of
a 0.2 g/kg body weight dose. Of the original dose, 19% was recovered as
mercapturic acid and 2% as ethereal sulfate.
The authors suggested that, due to the high lability of benzyl bromide,
"considerable amounts" of the compound may be dehalogenated prior to
absorption, resulting in some benzyl alcohol formation (1).
REFERENCES
1. Bray, H.G., S.P. James and W.V. Thorpe. 1958. Metabolism of some
omega-halogenoalkylbenzenes and related alcohols in the rabbit.
Biochemistry Journal. 70: 570-9.
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BROMOBENZENE
C6H5Br
CAS: 000108861
Syn: phenyl bromide
Mol wt: 157.02 g/mole
bp: 156°C (at 760 mm Hg)
vp: 4.3 mm Hg (at 25°C)
Bromobenzene metabolism has been under investigation since the 1930's
at which time it was reported that both dogs and mice metabolize bromo-
benzene to a mercapturic acid, specifically p-bromophenylmercapturic acid
(1). Recent studies on the metabolism of bromobenzene have both confirmed
the existence of metabolites reported in earlier studies and determined the
presence of previously unknown metabolic products. Several researchers
have identified an intermediate metabolite, bromobenzene-3,4-epoxide, which
is formed by a cytochrome P-450 enzyme system within the endoplasmic retic-
ulum of the liver (2, 3, 4, 5). This intermediate is broken down to a
variety of compounds including: 3,4- and 2,3-bromocatechol (2, 11), 2-, 3-,
and 4- bromophenol (2, 3, 5, 6, 11, 12) and 2,3- and 3,4-bromophenyl-
dihydrodiol (2, 5, 11). Additionally it has been reported that up to six
percent of bromobenzene is eliminated unchanged in expired breath or feces
(6, 7).
The majority of the bromobenzene metabolites are excreted in the urine
in conjugated form (2, 5, 6, 8). Spencer and Williams (8) administered
bromobenzene to rabbits orally, and upon subsequent urine analyses noted
the presence of the conjugates mercapturic acids, glucuronides and ethereal
sulfates, in approximately a 2:3:3 ratio (accounting for 97.9% of the
dosage). They suggested that oxygen conjugation is greater than the sulfur
conjugation. This theory was supported by Williams (6) who found that 58%
of a bromobenzene dosage was excreted as o-conjugates.
Based on the results of studies in which male rats were given *^c-
bromobenzene i.p., Jollow et al. (2), suggested a detailed pathway for the
metabolism of bromobenzene (Figure 1). According to the proposed metabolic
process, bromobenzene is initially broken down to the intermediate bromo-
benzene-3,4-epoxi de.
-------
8f 8r
Epoiid* lynttotaM'
NAD* H *
Bro*noCMni*n«
Covttontty
bound to
m«cro«no4«culfl
3. 4-OihTdro«y
OH
3 4-Oihydeo-3-
hyflroiy-4-S-aarrl
cyiwmyf bromobennn*
J. 4-OihydTo-3-hYdro«y-4-S-
cyiotinyt bromobonzfm
Fig.. 1 (2).
Pathway of metabolism of bromobenzene in rats.
The epoxide intermediate is converted to 3,4-dihydro-3,4'-dihydroxy-
bromobenzene by an epoxide hydratase enzyme (5). This compound is in turn
dehydrogenated to 4-bromocatechol (2). Azouz et al. (9), found 28% of a
bromobenzene dosage administered to rabbits was excreted in urine as
4-bromocatechol (mostly in conjugated form), with peak excretion occurring
for the first two days.
Nonenzymatic rearangement of the epoxide intermediate leads to the
formation of p-bromophenol (2). Azouz (9) found small amounts of p-bromo-
phenol (2-3% of dosage) in the urine of rabbits following bromobenzene
administration. Ruzo et al. (3), reported the presence of 3- and 4-bromo-
phenol as metabolites of bromobenzene in rabbits. Bromophenol is also
formed by the alkylation of glutathione (GSH) by the epoxide intermediate
metabolite within the biliary system (2, 4). Sipes et al. (4), using rats,
determined that within 3 hours post administration 56% of dosed bromoben-
zene was present in the bile. They suggested that the bromophenol excreted
in the bile is reabsorbed from the intestine and eventually excreted in the
urine.
Bromophenylmercapturic acid was determined to be present in the urine
of rats following bromobenzene intoxication (4). Azouz et al. (9), found
the compound accounted for 22% of a bromobenzene dosage excreted in the
urine of rabbits. Gillham and Young (10) however suggest that the mercap-
turic acid conjugate is a product of the addition of HC1 during urine
analysis. Using rats subcutaneously injected with bromobenzene, they were
-------
able to isolate an acid-labile precurser of p-bromophenylmercapturic acid.
The ^authors found N-acetyl-S-(4-bromo-l,2-dihydro-2-hydroxyphenyl)-L-
cysteine to be a premercapturic acid formed in bromobenzene metabolism-
This compound was reduced to p-bromophenylmercapturic acid and p-bromophenol
upon addition of HC1 (10).
The distribution of bromobenzene metabolites in rats following admin-
istration of the chemical in a single toxic dose was determined by
Zamoaglione et al. (12). They found the metabolites bromophenylmercap-
turic acid, 4-bromophenol, bromocatechol, bromophenyl dihydrodiol and
2-bromophenol comprising 48+_5, 37+_4, 6+2, 4+1 and 4+1% of the total urinary
metabolites respectively. In a similar experiment, rats were administered
bromobenzene in a non-toxic dose, and the same metabolites were found but
in different ratios. The metabolites were present as 70+5, 18+4, 4+_2, 4+1,
and 3+1% of the total, respectively (12). Jollow et al. (2T, in studies
with rats, attributed the variation in bromophenylmercapturic acid content
to the amount of glutathione present in the liver and available for conju-
gation with the expoxide intermediate. -In the case of a toxic dose (10
mmol/kg), the glutathione became the rate-limiting factor for mercapturic
acid formation (2).
Studies to determine the mechanism of renal necrosis induced by bromo-
benzene intoxication were conducted by Reid et al. (13), and Reid (14).
Rats were administered bromobenzene intraperitoneally and 24 hours later
tissue levels were determined by GLC (Table 1) (13). Adipose tissues were
found to concentrate bromobenzene to a greater extent than the blood
plasma. The authors suggested the metabolic intermediate bromobenzene-3,
4-epoxide to be the cause of tissue damage following bromobenzene exposure
(13, 14).
Table 1 (13).
Tissue distribution of bromobenzene. Four or 24 h after administration
of bromobenzene (750 mg/kg i.p.) tissue levels were determined by GLC in
all organs except fat where the level was calculated from the specific
activity of H-bromobenzene (1 mCi/mmol)
Bromobenzene
Tissue
Plasma
Liver
Kidney
Brain
Heart
Lung
Stomach
Fat
4 h
ug/g +
34 +
282 +
235 +
206 +
146 +
142 +
132 +
5,600 +
SE
5
32
50
27
21
41
37
900
Concentration
24 h
ug/g + SE
2.1 + 0.4
10.7 + 1.2
18.9 + 4.6
7.0 + 1.4
5.0 + 1.2
6.2 + 1.0
16.8 + 6.1
400 + 150
-------
REFERENCES
1. Stekol, J.A. 1935. Metabolism of bromobenzene in growing dogs and
mice maintained on adequate diets. Proc. Soc. Exptl. Biol. Med. 33:
115-119
2. Jollow, D.J., J.R. Mitchell, N. Zampaglione and J.R. Gillette. 1974.
Bromobenzene-induced liver necrosis. Protective role of glutathione
and evidence for 3,4-bromobenzene oxide as the hepatotoxic metabo-
lite. Pharmacol. 11: 151-169.
3. Ruzo, L.O., S. Safe, and 0. Hutzinger. 1976. Metabolism of bromo-
benzene in the rabbit. J. Agric. Food Chem. 24(2): 291-293.
4. Sipes, I.G., P.L. Gigon and G. Krishna. 1974. Biliary excretion of
metabolites of bromobenzene. Biochem. Pharmacol. 23(2): 451-455.
5. Gillete, J.R. 1977. Chapter 37. Formation of reactive metabolites
of foreign compounds and their covalent binding to cellular constitu-
ents. In: Handbook of Physiology. Section 9. Reactions of Environ-
mental Agents"! pp. 577-589.
6. Williams, R.T. 1959. Chapter Eight. The metabolism of halogenated
aromatic hydrocarbons. In: Detoxication Mechanisms 2n° ed.
Chapman and Hall, Ltd., London. pp~237-277-
7. Azouz, W.M., D. V. Parke, and R. T. Williams. 1952. Fluorobenzene.
Spectrophotometric determination of the elimination of unchanged
halogenobenzenes by rabbits. A comparison of the oxidation in vivo of
fluorobenzene and of benzene. Biochem. J. 50: 702-706.
8. Spencer, B. , and R.T. Williams. 1950. The metabolism of halogeno-
benzenes. A comparison of the glucuronic acid, ethereal sulfate and
mercapturic acid conjugations of chloro-, bromo-, and iodo-benzenes
and of the o-, m- and p-chlorophenols. Biosynthesis of o-, m- and
p-chlorophenylglucuronides. Biochem. J. 47: 279-84
9. Azouz, W.M., D.V. Parke, and R.T. Williams. 1953. The determination
of catechols in urine and the formation of catechols in rabbits
receiving halogenobenzenes and other compounds. Dihydroxylation i^
vivo. Biochem. J. 55(1): 146-151.
10. Gillham, B., and L. Young. 1968. The isolation of premercapturic
acids from the urine of animals dosed with chlorobenzene and bromo-
benzene. Biochem. J. 109: 143-7
11. Jollow, D.J., and C. Smith. 1977. Chapter 4. Biochemical aspects of
toxic metabolites: formation, detoxication and covalent binding.
In: Proceedings of the International Conference on Biological
Reactions and Intermediates, pp. 42-59.
-------
12. Zampaglione, N., D.J. Jollow, J.R. Mitchell, B. Stripp, M. Hamrick and
J.R. Gillette. 1973. Role of detoxifying enzymes in bromobenzene
induced liver necrosis. J. Pharmacol. Exp. Therap. 187(1): 218-227.
13. Reid, W.D., B. Christie, B. Krishna et al. 1971. Bromobenzene metab-
olism and hepatic necrosis. Pharmacol 6: 41-55.
14. Reid, W.D. 1973. Mechanism of renal necrosis induced by bromobenzene
or chlorobenzene. Exp. Mol. Pathol. 19: 197-214.
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BROMOFORM
CHBr3 B|r
Br—C—Br
A
CAS: 000075252
Syn: tribromomethane; methenyl tribromide
Mol wt: 252.75 g/mole
bp: 149.5°C (at 760 mm Hg)
vp: 6.11 mm Hg (at 25°C)
On the basis of in vitro studies using hepatic microsomal fractions from
Long-Evans rats, Ahmed et al., suggested that bromoform is metabolized to CO
by a microsomal cytochrome P-450-dependent mixed-function oxidase system (1).
Wolf et al.(2), also studied the in vitro metabolism of bromoform using
rat hepatic microsomal fractions. The following general reaction sequence,
involving reductive metabolism to a carbene ligand, was proposed to explain
the formation of CO (2):
CX + Fe11
(FenCO) «
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References
1. Ahmed, A.E., V.L. Kubic and M.W. Anders. 1977. Metabolism of
haloforms to carbon monoxide: I. In vitro studies. Drug Metabolism
and Disposition. 5(2) :198-204.
2. Wolf, C.R., D. Mansuy, W. Nastainczyk, G. Deutschmann and V.
Ullrich. 1977. The reduction of polyhalogenated methanes by liver
microsomal cytochrome P450. Molecular Pharmacology. 13(4):698-705.
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3-BROMOPROPYLBENZENE
CH2CH2CH2Br
c9HHBr
CAS: 637-59-2
Syn: l-bromo-3-phenylpropane
Mol. wt.: 199.10 g/mole
bp: 110°C (at 12 mm Hg)
The metabolism of 3-brotnopropylbenzene in rabbits was reported by Bray
et al. (1). Rabbits were administered the compound by stomach tube as a
suspension in water in doses of 0.25g 3-bromopropylbenzene per kg. Urinary
metabolites were determined quantitatively by ether extraction, fractional
crystallization, and paper chromatography.
About 89% of the administered dose was accounted for in urine, of which
20% was ethereal sulphate and 69% was ether soluble acid. The ether sol-
uble acids included the major metabolite glucosiduronic acid and smaller
amounts of mercapturic acid and glycine conjugates. The authors suggested
that the excretion of large amounts of glucosiduronic acid and ethereal
sulphate indicate the formation of phenolic intermediates, (3-bromopropyl)-
phenol probably being the major intermediate (1).
In addition, two metabolites were identified in the unhydrolysed urine
(acidic) fraction: phenaceturic acid and N-acetyl-S-(3-phenylpropyl)-
L-cysteine. Also, phenolic metabolites were detected but not identified in
the hydrolysed urine (conjugated phenolic) fraction (1).
REFERENCE
1. Bray, H.G., S. P. James and W.V. Thorpe. 1958. Metabolism of some
omega-halogenoalkylbenzenes and related alcohols in the rabbit.
Biochem. J. 70:570-579.
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CARBON TETRACHLORIDE
Cl
c C14 CI-C —Cl
I
Cl
CAS: 000056235
Syn: methane tetrachloride; tetrachloromethane; perchloromethane
Mol wt: 153.82 g/mole
bp: 76.54°C (at 760 ram Hg)
vp: 98.9 mm Hg (at 25°C)
The metabolism of carbon tetrachloride has been studied extensively in
various animal species and two major metabolites have been determined:
chloroform (CHC^) and carbon dioxide (^2)- Lesser concentrations of
hexachloroethane (CoClg) have also been identified, and large portions
of the CCl^ are reportedly expired unchanged in the breath.
Two major theories for CCl^ detoxification are presented in the lit-
erature. In both theories the metabolism begins with dehalogenation of the
compound within the liver and, to a lesser extent, the kidney (1,2,3). One
theory attributes the dehalogenation to a non-enzymatic reaction involving
sulfhydryl compounds (1,2). As explained by Bini et al. (2), CC13 radi-
cals derived from the CC14 extract a hydrogen atom from sulphydric groups
thereby forming CHC13, or they recombine by dimerization to yield
02*215. The second theory suggests that the conversion of CC14 to its
metabolites is initiated by an hepatic enzyme system (3,4). Paul and
Rubinstein (3) found that no significant dehalogenation occured in. vitro
when liver slices were exposed to the sulfhydryl compounds glutathione and
cysteine, thereby lending support to the latter theory.
The largest portion of a CCl^. dose is expired unchanged in the breath
regardless of administrative route. Humans administered 80 ppm CC14 in a
single breath, expired 33% of the dosage unchanged within one hour (5).
Monkeys exposed to the compound in air (50 ppm for 139 to 300 minutes)
expired 40% unchanged within 1800 hours (6); and, after 18 hours rats had
expired 75% of an intra-duodenally administered CC14 dose (1 mi/kg) (3).
10
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A transitory accumulation of CC14 in the body tissues was reported by
Fowler (7). Six hours after the administration of 1 ml CCl4/kg to
rabbits, 787 ug/g was accumulated in the adipose tissue. Forty-eight hours
post-dosing the CC14 level had decreased to 45 ug/g. In related studies
with sheep (0.12 or 0.15 ml/kg, intra-ruminal), Fowler (8) found CC14
present in the bile; the maximum biliary concentration of CC14 (4-5
ug/ml ) occurred 1-3 hours after dosing and fell below one ug/ml within six
hours. Traces of CC14 were noted in sheeps' urine for up to seven days
following a 0.1 or 0.12 mL/kg intraruminal dose (8). CC14 was also evi-
dent in the blood of rabbits immediately following a 4-hour exposure to the
compound in air (9).
The majority of CHC13 formed during the metabolism of CC14 is found
in the liver and kidney. Bini, et al. (2), administered 0.1-0.5 mL CC14
directly to the stomach of rats (200 g) and 15 minutes later found 0.037 mg
CHCl3/g in the liver. The metabolite level decreased to 0.007 mg/g with-
in four hours. Similarly, in rabbits (1.5 to 3.0 kg) the maximum CHC13
concentration, following a 1.0 ml. CCl4/kg dosage administered by stomach
tube, occurred in the liver six hours after administration of the compound
(7). Significant amounts of CHC13 have also been found in the bile and
urine of test animals (8).
The presence of CHC13 in the expired air of animals exposed to CC14
has also been reported (1,3,10); yet when compared to unchanged CC14
expiration the quantity is minimal (ratios reported in dogs were between
1:1000 and 1:4000(1)).
The conversion of CC14 to C02 accounts for less than 5% of adminis-
tered CC14 (3). Paul and Rubinstein (3) found that C02 is a product of
both CC14 and CHC13 metabolism, the CHC13 to C02 reaction proceed-
ing more rapidly. These findings lead to the possibility that CHC13 may
act as an intermediate in CC14 metabolism and account for the most of
C02 produced (3).
Hexachloroethane was determined to be a minor metabolite of CC14
(2,4,7,8,11). The maximum concentration of C2Clg (16.5 ng/g) following
a 1.0 mL/kg oral dose in rabbits was found in the adipose tissue, 24 hours
after exposure (7). Bini, et al. (2), found a C2Clg concentration of
0.005 mg/g in organ homogenate 4 hours after a 0.1 to 0.5 ml dosage of
CC14 was administered to rats (200 g) via stomach tube.
Tissue concentrations of CCl4» CHC13 and C2Clg following admin-
istration by stomach tube of 1.0 ml CCl4/kg to rabbits were determined by
Fowler (7). The results, as seen in Table 1, indicate that CC14 and
C2Clg accumulate mainly in the fat while CHC13 is found to a great
extent in both the liver and fat tissues.
11
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Table I (7)
Concentrations of carbon tetrachloride (CC7,, ^g!g±s.D.\ chloroform (CffCl,, ng;g±s.o.l
and hexachloroethane (CClt.CClt. ^glg±s.o.} in rabbit tissues following admuustration of caroon
tetrachloride (1 ml.!kg)
Tissue and
sample time
6hr Fat
Liver
Kidney
Muscle
24 hr Fat
Liver
Kidney
Muscle
44 hr (Died)
Fat
Liver
Kidney
Muscle
48 hr Fat
Liver
Kidney
Muscle
No. of
rabbits
5
5
5
5
5 '
5
5
5
1
1
1
1
4"
4
4
CC1,
787 -"- 289
96=11
20=13
'21±12
96=11
7-7-M-3
6-9 = 3-9
1-3 ±0-6
23
1-1
0-5
.0-3'
3-8=0-1
0-5=0-3
0-5=0-3
CHCU
4-7±0-5
4.94-1-5
1-4=0-6
0-1=0-1
1-0-0-2
10=0-4
0-4-0-2
O-I-O-l
1-4
4-4
0-4
. Trace
0-4=0-1
0-3=0-2
0-2-0-0
0-1 ±0-1
cci3.cci3
4-1-1-1-2
.1-6-1-0-5
O-7-i- 0-2
0-3 = 0-2
4-2^1-3
2-2±l-l
0-5 ±0-2
10-0
3-1
9-2
6-8 = 2-4
1-0=0-3
Trace
Trace
REFERENCES
1. Butler, T.C. 1961. Reduction of carbon tetrachloride in vivo and
reduction of carbon tetrachloride and chloroform in vitro by tissues
and tissue constituents. J. Pharmacol. Exp. Ther. 134(3) :311-319.
2. Bini, A., G. Vecchi, G. Vivoli et al. 1975. Detection of early metab-
olites in rat liver after administration of CCl^ and
Pharmacol. Res. Commun. 7(2) : 143-149.
3. Paul, B.B. and D. Rubinstein. 1973. Metabolism of carbon tetrachlor-
ide and chloroform by the rat. J. Pharmacol. Exp. Ther. 141(2) : 141-148.
4. Hathway, D.E. 1974. Chemical, biochemical and toxicological differ-
ences between carbon tetrachloride and chloroform. Arzneim.-Forsch.
24(2):173-176.
5. Morgan, A., A. Black and D.R. Belcher. 1970. The excretion in breath
of some aliphatic halogenated hydrocarbons following administration by
inhalation. Ann. Occup. Hyg. 13:219-233.
6. McCollister, D.D., W.H. Beamer, G.J. Atchison and H. C. Spencer, 1951.
The absorption, distribution and elimination of radioactive carbon
tetrachloride by monkeys upon exposure to low vapor concentrations.
J. Pharmacol. Exptl. Ther. 102:112-124.
12
-------
7. Fowler, J.S.L. 1969. Carbon tetrachloride metabolism in the rabbit.
Brit. J. Pharmacol. 37(3):733-737.
8. Fowler, J.S.L. 1970. Carbon tetrachloride metabolism in sheep and in
Fasciola hepatica. Br. J. Pharmac. 39:599-607-
9. Moran, H.E. 1943. Determination of volatile halogenated hydrocarbons
in blood. J. Industr. Hyg. Toxicol. 25:243-248.
10. Geddes, I.C. 1971. Metabolism of volatile anesthetics. Int.
Anesthesiol. Clin. 9(3):145-169.
11. Fowler, J.S.L. 1969. A new metabolite of carbon tetrachloride. Br.
J. Pharmacol. 36(1):181P.
13
-------
CHLOROBENZALDEHYDE
C HO
CAS: 000089985
Syn: 2-chlorobenzaldehyde; ortho-chlorobenzaldehyde
Mol. Wt.: 140.57 g/mole
bp: 211.9°C (at 760 mm Hg); 84.3°C (at 10 mm Hg)
vp: 1.07 mm Hg (at 32.1°C)
In a 1973 study using both rats and cats, Leadbeater (1) found that
o-chlorobenzaldehyde is readily absorbed from both the gastrointestinal and
respiratory tracts. In vitro tests using blood samples from rats, cats and
humans gave half-lives for o-chlorobenz.aldehyde (initial concentrations of
2.65 uM) of 15, 70 and 15 seconds, respectively (1).
REFERENCES
1. Leadbeater, L. 1973. The absorption of ortho-chlorobenzylidenemalono-
nitrile (CS) by the respiratory tract. Toxicology and Applied Pharma-
cology. 25(1): 101-10.
14
-------
CHLOROBENZENE
C6H5C1
CAS: 000108907
Syn: benzene chloride; chlorbenzene; MCB; monochlorbenzene;
monochlorobenzene; phenyl chloride
Mol wt: 112.56 g/mole
bp: 132°C (at 760 mm Hg)
vp: 11.8 mm Hg (at 25°C)
In 1950, Spencer and Williams (1) studied the metabolism of chloroben-
zene in the rabbit. Three chinchilla rabbits, kept on a controlled diet
and allowed water ad libitum, were each administered 150 mg chlorobenzene/kg
via stomach tube. Upon analysis of daily urines, it was found that mercap-
turic acids, glucuronides and ethereal sulfates were excreted in roughly
equal amounts (20.4, 25.2, and 26.6% of the dosage, respectively) for a
total of 72.2% of the administered dosage. Ethereal sulfate and glucuro-
nide levels were above normal for only one day. Excretion of mercapturic
acid, however, was measurable for two days post-dosing.
In a follow-up study in which rabbits were administered 10 or 12 g of
chlorobenzene by stomach tube, Smith, et al. (2), reported results similar
to those of Spencer and Williams (1). The major metabolites found were the
ethereal sulphate and glucuronide conjugates of 4-catechol, and
p-chlorophenylmercapturic acid. Minor metabolites were reported as
p-chlorophenol and its glucuronide (about 0.5% of the dose, combined) and
3,4-dihydro-3,4-dihydroxychlorobenzene (about 0.03%).
These results were later verified by Azouz et al. (3), Williams (4),
and Parke and Williams (5). Azouz et al. (3), found that, following oral
administration of 0.5 g/kg of chlorobenzene to rabbits, 37% of the given
dose was excreted in urine as catechol derivatives and 28% was eliminated
as mercapturic acids. Chlorobenzene also formed small amounts (2-3%) of
p-chlorophenol and traces of o-chlorophenol. Williams (4) reported urinary
excretion of catechols and mercapturic acids in amounts of 27% and 25%,
respectively, from studies in which rabbits had received 0.5 g/kg chloro-
benzene orally. In addition, Azouz et al. (3), and Williams (4) reported
15
-------
that rabbits expired 27% of the oral dose (0.5 g/kg) as unchanged chloro-
benzene.
Several explanations for metabolite formations were described in the
literature. Smith et al. (2), suggested an intermediate perhydroxylation
process resulting in the formation of 3,4-dihydro-3,4-dihydroxy chloroben-
zene which then undergoes either dehydrogenation to form 4-chlorocatechol
or dehydration to form p-chlorophenol. The authors (2) concluded that
chlorobenzene undergoes oxidation more extensively than it undergoes
cysteine conjugation, and that most of the oxidized chlorobenzene appears
as 4-chlorocatechol.
Gillham and Young (6), were able to isolate an acid-labile precursor
of p-chlorophenylmercapturic acid from the urine of rats injected with
chlorobenzene. They concluded that N-acetyl-S-(4-chloro-l, 2-dihydro-2-
hydroxyphenyl)-L-cysteine was the premercapturic acid formed in chloro-
benzene metabolism and that this compound was broken down to p-chloro-
phenylmercapturic acid and chlorophenol upon the addition of HC1 during
urine analysis.
Smith et al. (7), in 1972, conducted an in-depth study of chloroben-
zene metabolism using ^C-tagged chlorobenzene. Two female Dutch rabbits
were administered 0.5 g of radioactive chlorobenzene (75.0 uci) twice daily
for four days. Urine and fecal samples were collected separately for a
7-day period, beginning with the first dosing day. The excreta were then
analyzed for metabolites, and one animal was sacrificed for tissue accumu-
lation studies.
Of the dosage, 19.6% was recovered in the urine, 2.6% in the feces and
only .005% was retained in the body tissues. In agreement with previous
studies (3,4), the authors concluded that a large percentage of the tagged
chlorobenzene was lost through respiration. Table 1 shows the major
classes of chemicals found in the urine along with metabolite distribution
(7).
As reported in earlier studies, the major metabolites of chlorobenzene
were the conjugates: ethereal sulfates, mercapturic acids and glucuro-
nides. Less than eight percent of the metabolites consisted of free state
phenols and 3,4-dihydro-3,4- dihydroxy-chlorobenzene (7)
Table 1 (7)
Distribution of radioactive metabolites in the urine of rabbits dosed
with [14C]chlorobenzene
Radioactivity % of total urinary
Metabolite (10"" d.p.m.) radioactivity
3,4-Dihydro-3,4-dihydro:cychlorobenzene
Monophenols
Dipheriols
Mercapturic acids
Ethereal sulphates
Glucuronides
Total
0-182
0-398
1-320
7-530
10-720
'10-620
31-270
0-57
2-34
4-17
23-SO
33-SS
33-57
98-83
16
-------
The authors suggested that 3,4-chlorobenzene oxide is the only initial
metabolite resulting from chlorobenzene exposure. Hydration and dehydro-
genation reactions with the oxide lead to the formation of 4-chlorocatechol,
the major diphenolic metabolite, and less frequently to 3-chlorocatechol or
chloroquinol. Catechol formation has also been attributed to the dehydro-
chlorination of 1,2-dihydro-l,2-dihydroxychlorobenzene (7).
Glutathione conjugation of the primary epoxide metabolite leads to the
formation of the premercapturic acid, N-acetyl-S-(4-chloro-l,2-dihydro-
2-hydroxy-phenyl)-L-cysteine. According to Gillham and Young (6), this
acid-labile compound is decomposed by the addition of acid, during analy-
sis, to yield p-chlorophenylmercapturic acid and monochlorophenols. Smith
et al. (7) proposed a mechamism by which all three isomers (o-, m-, and p-)
of chlorophenolmercapturic acid may be formed.
Other sources of o-, m-, and p-chlorophenol formation are believed to
exist (7). Several theories are presented by researchers; however, no
single formation process has been determined.
REFERENCES
1. Spencer, B., and R.T. Williams. 1950. The metabolism of halogeno-
benzenes. A comparison of the glucuronic acid, ethereal sulfate and
mercapturic acid conjugations of chloro-, bromoand iodo- benzenes and
of the o-, mand p-chlorophenols. Biosynthesis of o-, m- and p-chloro-
phenylglucuronides. Biochem. J. 47:279-284.
2. Smith, J.N., B. Spencer, and R.T. Williams. 1950. The metabolism of
chlorobenzene in the rabbit. Isolation of dihydrodihydroxychloro-
benzene, p-chlorophenylglucuronide, 4-chlorocatechol glucuronide and
p-chlorophenylmercapturic acid. Biochem. J. 47:284-293.
3. Azouz, W.M., D.V. Parke, and R.T. Williams. 1953. The determination
of catechols in urine, and the formation of catechols in rabbits
receiving halogenobenzenes and other compounds. Biochem. J. 55(1):
146-151.
4. Williams, R.T. 1959. Chapter 8: The metabolism of halogenated
aromatic hydrocarbons. In: Detoxication Mechanisms, 2nd ed. John
Wiley and Sons, Inc., New York. pp. 237-258.
5. Parke, D.V., and R.T. Williams. 1955. The metabolism of halogeno-
benzenes. (a) meta-dichlorobenzene. (b) further observations on the
metabolism of chlorobenzene. Biochem. J. 59:415-422.
6. Gillham, B., and L. Young. 1968. The isolation of premercapturic
acids from the urine of animals dosed with chlorobenzene and bromo-
benzene. Biochem. J. 109:143-147.
7. Smith, J.R. Lindsay, B.A.J. Shaw, and D.M. Foulkes. 1972. Mechanisms
of mammalian hydroxylation: Some novel metabolites of chlorobenzene.
Xenobiotica 2(3):215-226.
17
-------
CHLOROFORM
Cl
CHCL3 C|_C —Cl
H
CAS: 000067663
Syn: formyl trichloride; methane trichloride; methynyl
trichloride; methyl trichloride; trichloroform; trichloromethane
Mol wt: 119.38 g/mole
bp: 61.7°C (at 760 mm Hg)
vp: 173.1 mm Hg (at 25°C)
The metabolic fate of chloroform (CHC^) has been extensively stud-
ied, in part due to the past use of the compound as an anaesthetic. It has
been reported by several researchers that the major mode of excretion of
the compound and its primary metabolite, carbon dioxide (C02)> occurs
through expired air (1-8). Additional tolulene-soluble metabolites (spe-
cific makeup not determined) have been noted in expired air as well as the
presence of carbonate and bicarbonate species in the urine (1,2). Recent
studies (10, 11, 12) have revealed the presence of an intermediate metabo-
lite, phosgene (formed by microsomal oxidation of the parent compound),
which may be responsible for a portion of the C02 formed during chloro-
form metabolism.
The excretion of unchanged chloroform in expired breath has been found
to vary in different test animal species. Expiration levels of the un-
changed compound in mice, rats, and monkeys was determined by Brown et al.
(2) using C-chloroform administered orally. After 48 hours 6% of the
dose was present unchanged in the expired air of mice, 20% in rats, and 79%
in the squirrel monkey. Similar excretion results were reported by
Charlesworth (1) and Paul and Rubinstein (4). Fry et al. (3), administered
500 mg ^C-chloroform tablets to adult men and women and found up to
68.3% of the dosage was expired unchanged. Within the first eight hours
after chloroform dosing, between 17.8 and 66.6% of the dosage was expired
and by 24 hours post-dosing expired concentrations were below measurable
quantities. One hour after a single-breath dose of chloroform, Morgan et
al. (9), determined that human volunteers expired 10% of the dosage
unchanged via the lungs.
Analysis of chloroform levels in blood showed a linear relationship
between blood chloroform levels and pulmonary excretion of the compound (3).
18
-------
Varying pulmonary excretion rates of chloroform were found to exist be-
tween the males and females of test species. The males of each species
tended to retain more of the administered dosage than did the females (1)-
Additionally, Fry et al. (3), found higher retention rates in obese subjects
than in those of normal weight. These findings led to the conclusion that
the adipose tissue may act as a sink for chloroform (3).
The pulmonary expiration of the primary metabolite CC>2» like the
excretion of chloroform, varies according to the species studied. Eighty
percent of a chloroform dose administered to mice was expired in the breath
after 48 hours; 66% in rats, and 16% in monkeys (2). Fry et al. (3), deter-
mined up to 50.6% of a ^C-chloroform dose was expired as C02 i-n
humans. Maximum COo concentrations were expired between 75 and 210
minutes following administration (3).
Researchers have .concluded that the pulmonary excretion of unchanged
chloroform and the primary metabolite C02 account for the vast majority of
an administered CHC13 dose (2,3). Lesser metabolites have been found by
researchers working with various animal species; however, their presence is
minimal in comparison to the excretion of CHC13 and C02« Charlesworth
(1) administered -^C-chloroform to mice in a dosage of 60 mg/kg and found
13% of the radioactivity present as bicarbonate and carbonate in the urine.
Similar results were reported by Brown et al. (2), who found bicarbonate
and/ or carbonate and -^C-urea in the urine of rats and mice.
The biotransformation of chloroform to carbon dioxide could follow the
following reaction presented by Fry et al. (3):
CHC13 + H20 + 0 > C02 + 3HC1
The accumulation of chloroform in the adipose tissue of exposed species
leads to extensive biotransformation of the compound to C02 at that site
(3).
Recently it has been determined that phosgene (COC^) is a reactive
intermediate metabolite of chloroform, acting as a precursor to carbon
dioxide formation. The metabolite is formed during the microsomal oxida-
tion of chloroform in the liver (10,11). Due to its electrophilic nature,
phosgene reacts in the liver with nucleophiles, undergoing hydrolysis to
form C02> or reacting with nucleophilic groups to form irreversible
covalent bonds. Schematic representations of phosgene formation and
subsequent reactions are shown in Figure 1 (10).
.nicrosor.es " ' „„ /C1 + H2°
CHC1 3> Cl-C-OK Htjl > 0 C =» CO
\1 -2HC1
- covaler.C binding
Figure 1 (10) I I Co nucleophilic
groups of tissue
macror.olecules
4-carboxy-chiazolidine-2-one .
Proposed metabolism of chloroform.
19
-------
It has been suggested by some researchers that the toxic effect of
chloroform is caused by the irreversible binding of phosgene to protein
molecules within the liver and kidney (10,12).
REFERENCES
1. Charlesworth, F.A. 1976. Patterns of chloroform metabolism. Food
Cosmet. Toxicol. 14(1):59-60.
2. Brown, D.M., P.F. Langley, D. Smith and D. C. Taylor. 1974. Metabolism
of chloroform. I. The metabolism of (^C) chloroform by different
species. Xenobiotica. 4(3):151-163.
3. Fry, B.J., T. Taylor, and D.E. Hathway. 1972. Pulmonary elimination of
chloroform and its metabolites in man. Arch. Int. Pharmacodyn.
196:98-111.
4. Paul, B.B. and D. Rubinstein. 1963. Metabolism of carbon tetrachloride
and chloroform by the rat. J. Pharmacol. Exp. Ther. 141(2) : 141-148.
5. Hathway, D.E. 1974. Chemical, biochemical and toxicological differ-
ences between carbon tetrachloride and chloroform. Arzneim-Forsch.
24(2):173-176.
6. Geddes, I.C. 1972. Metabolism of volatile anaesthetics. Brit. J.
Anaesth. 44:953-960.
7. Van Dyke, R.A. 1969. On the fate of chloroform. Anesthesiol.
30(3):257-258.
8. Cohen, E.N. and N. Hood. 1969. Application of low-temperature auto-
radiography to studies of the uptake and metabolism of volatile anes-
thetics in the mouse. Anesthesiol. 30(3):306-314.
9. Morgan, A., A. Black and D.R. Belcher. 1970. The excretion in breath
of some aliphatic halogenated hydrocarbons following administration by
inhalation. Ann. Occup. Hyg. 13:219-233.
10. Mansuy, D., P. Beaune, T. Cresteil, M. Lange and J. P. Leroux. 1977.
Evidence for phosgene formation during liver microsomal oxidation of
chloroform. Biochem. Biophys. Res. Cotmnun. 79(2):513-517.
11. Pohl, L.R., B. Bhooshan, N.F. Whittaker and G. Krishna. 1977. Phos-
gene: a metabolite of chloroform. Biochem. Biophys. Res. Commun.
79(3):684-691. ~
12, Ilett, K.F., W.D. Reid, I.G. Sipes and G. Krishna. 1973. Chloroform
toxicity in mice: correlation of renal and hepatic necrosis with
covalent binding of metabolites to tissue macromolecules. Exp. Mol.
Pathol. 19:215-229.
20
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CHLORONAPHTHALENE
CiQHyCl
Mol wt: 162.62g/mole
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-chloronaphthalene
CAS: 000091587
Syn: beta-chloronaphthalene
bp: 256°C (at 760 mm Hg); 106.5°C (at 5 mm Hg)
Following administration of 1-chloronaphthalene (1 g, by stomach tube)
to male albino rabbits, Cornish and Block, 1958 (1), were able to account
for 79% of the administered compound as urinary metabolites within 4 days.
Of the administered dose, 54% was excreted as glucosiduronic acid, 13% as
mercapturic acid, 10% as ethereal sulfate and 2% as free phenolic compounds.
In a 1975 study, Ruzo et al. (2), identified the hydroxylated metabo-
lites of 1- and 2-chloronaphthalene following retrocarotid injection of the
compounds (30 mg/kg) into 10-kg pigs. Analysis of urine collected 5 hours
after dosing showed 4-chloro-l-naphthol to be the major phenolic metabolite
of 1-chloronaphthalene, and 3-chloro-2-naphthol to be the major phenolic
metabolite of 2-chloronaphthalene.
In a 1976 study, Ruzo et al. (3), found that following retrocarotid
injection (300 mg in 7.5-kg pigs), 1- and 2-chloronaphthalenes were dis-
tributed in various organs (brain, kidney, liver, lung, skeletal muscle,
psoas, heart and fat). Metabolism of the chloronaphthalenes in pigs was
found to be rapid, being virtually complete within 4 hours. Metabolites of
the chloronaphthalenes were found to be localized in the kidney, liver,
urine and bile.
21
-------
On the basis of their studies with pigs, Ruzo et al. (4), suggested
that the metabolism of 1-chloronaphthalene involves the formation of an
arene oxide intermediate. Decomposition of the intermediate to form
4-chloro-l-naphthol is accompanied by a 1,2-H shift.
Studies by Sundstrom and coworkers (5,6), on the metabolism of chloro-
naphthalenes in frogs, report findings consistent with those reported above.
References
1. Cornish, H.H. and W.D. Block. 1958. Metabolism of chlorinated naph-
thalenes. Journal of Biological Chemistry. 23(2): 583-588.
2. Ruzo, L.O., S. Safe, 0. Hutzinger, N. Platonaw and D. Jones. 1976.
Hydroxylated metabolites of chloronaphthalenes (Halowax 1031) in pig
urine. Chemosphere 3:121-123.
3. Ruzo, L.O., S. Safe, D. Jones and N. Platonaw. 1976. Uptake and
distribution of chloronaphthalenes and their metabolites in pigs.
Bulletin of Environmental Contamination and Toxicology. 16(2):233-9.
4. Ruzo, L.O., D. Jones, S. Safe and 0. Hutzinger. 1976. Metabolism of
chlorinated naphthalenes. Journal of Agriculture Chemistry and Food.
24(3):581-583.
5. Sundstrom, G., 0. Hutzinger, S. Safe, L. Ruzo and D. Jones. 1975.
Methods for the study of metabolism of toxic and persistent chemicals
in aquatic organisms as exemplified by chloronaphthalenes. Sublethal
effects of toxic chemicals on aquatic animals proceedings of the
Swedish-Netherlands Symp. p. 177-188.
6. Safe, S., D. Jones, J. Kohli, L.O. Ruzo, 0. Hutzinger and G. Sundstrom,
1976. The metabolism of chlorinated aromatic pollutants by the frog.
Can. J. Zool. 54:1818-1823.
22
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CHLORONITROBENZENE
C6H4C1N02
Mol wt: 157.56 g/mole
ortho-chloroni trob enz ene
CAS: 000088733
Syn: chloro-o-nitrobenzene;
o-chloronitrobenzene;
l-chloro-2-nitrobenzene;
2-chloro-l-nitrobenzene;
o-nitrochlorobenzene; ONCB
bp: 246°C (at 760 ram Hg)
meta-chloronitrobenzene
CAS: 000121733
Syn: chloro-m-nitrobenzene;
m-chloroni trobenz ene;
l-chloro-3-nitrobenzene;
m-ni trochlorob enz ene
bp: 235-6°C (at 760 mm Hg)
p ara-chloroni trob enz ene
CAS: 000100005
Syn: p-chloronitrobenzene;
l-chloro-4-nitrobenzene;
4-chloro-1-ni trob enz ene; p-chloroni trob enz ene
bp: 242°C (at 760 mm Hg)
Bray et al. (1), reported the metabolism of chloronitrobenzene isomers
and chloroaniline (ortho, meta, para) in the rabbit. Female rabbits (2-3
kg) were given either O.lg of o-chloroni- trobenzene, or 0.2 g of m- or
p-chloronitrobenzene, per kg body weight. The method of administration was
not stated. Feces were collected for 2 days and urine was collected daily,
usually for 2 days, until metabolites were no longer excreted. The samples
were qualitatively and quantitatively analyzed by ether extraction and
paper chromatography.
23
-------
The majority of each chloronitrobenzene compound was excreted as ether
glucuronides (19-42% of the administered dose) and ethereal sulphates
(18-24%), which represented acid-conjugated compounds of aminochlorophenols
and chloronitrophenols. Free chloroaniline was a metabolite of all 3
chloronitrobenzene isomers and accounted for 9-11% of the dose; the p-isomer
also produced a small amount (4%) of conjugated chloroaniline. Some nitro-
phenylmercapturic acid (about 7%) was formed from the o- and p-chloronitro-
benzenes. The unabsorbed material (0.3-2.8%) found in feces was completely
reduced to chloroaniline with the exception of samples from rabbits given
the p-chloronitrobenzene isomer, in which case some unchanged p-chloroni-
trobenzene was found in addition to chloroaniline. For all 3 isomers of
chloronitrobenzene, trace amounts of free phenolic metabolites were
detected. No evidence of unchanged chloronitrobenzene was found in the
urine samples. The urinary metabolites were further identified by paper
chromatography as shown in Table 1 (1).
The main metabolic processes responsible for chloronitrobenzene degra-
dation in the rabbit were reduction and hydroxylation. Figure 1 represents
the metabolism of chloronitrobenzene and chloroaniline isomers (1).
Evidence supporting the formation of chloroaniline from o- and
p-chloronitrobenzene was reported by Renshaw & Ashcroft (2). An incidence
of toxic symptoms in chemical plant workers due to inhalation of chloroni-
trobenzene vapors led to suggestion that the compound may be reduced by
hemoglobin to amidochlorobenzene (chloroaniline). Reduction may occur in
the lungs, body tissues, or liver cells.
Table 1 (1). Urinary metabolites of rabbits exposed to 0.1 g/kg o-chloronitro-
benzene or 0.2 g/kg m- or p-chloronitrobenzene. Metabolites were
identified by paper chromatographic analysis of 4 types of urine
extracts. Compounds in parenetheses were present in trace
amounts.
ortho-chloronitrobenzene
N-acetyl-S-(2-nitrophenyl)-
L-cysteine
2-amino-3-chlorophenol
(3-amino-2-chlorophenol)
3-amino-4-chlorophenol
4-amino-4-chloropheno1
o-chloroaniline
(2-chloro-3-nitrophenol)
(3-chloro-2-nitrophenol)
3-chloro-4-nitrophenol
4-chloro-3-nitrophenol
meta-chloronitrobenzene para-chloronitrobenzene
2-amino-4-chlorophenol
4-amino-2-chlorophenol
m-chloroaniline
2-chloro-4-nitrophenol
N-acetyl(-S-(4-nitro-
phenol)-L-cysteine
2-amino-5-chlorophenol
p-chloroaniline
(2-chloro-5-nitrophenol)
24
-------
I) o-chloronitrobenzene
IV) o-chloroaniline
V
II) m-chlcronitrobenzene
V) m-chloroaniline
NR,
OH
III) p-chloronitrobenzene
VI) p-chloroaniline
Fig. 1 (1). Phenolic metabolites excreted (free or conjugated) in urine by
the rabbit after dosage with o-, m- and p- chloronitrobenzene
and o-, m- and p-chloroaniline. Broken arrows point to meta-
bolites excreted only in very small amounts. (Although only a
small amount of 4-chloro-3-nitrophenol was excreted following
administration of o-chloronitrobenzene, it is likely that a much
greater amount was formed and reduced to 3-amino-4-chlorophenol
before it was excreted.)
25
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REFERENCES
1. Bray, E.G., Sybil P- James, and W.V. Thorpe. 1956. The metabolism of
the monochloronitrobenzenes in the rabbit. Biochem. J. 64: 38-44.
2. Renshaw, A. and G.V. Ashcroft. 1926. Four cases of poisoning by
mononitrochlorobenzene and one by acetanilide, occurring in a chemical
works: with an explanation of the toxic symptoms produced. J. Ind.
Hyg. 8(2):67-73.
26
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CHLOROPRENE
Cl
C4H5C1 C = CH2
H
CAS: 000126998
Syn: chlorobutadiene; 2-chlorobuta-l,3-diene; 2-chloro-l,3-butadiene
Mol wt: 88.54 g/mole
bp: 59.4°C (at 760 mm Hg)
vp: 275 mm Hg (at 30°C)
Based on a review of the recent literature, Bardodej (1) suggests that
chloroprene is metabolized by hepatic mixed-function oxidases, which
catalyze the epoxidation of the compound. The author indicated that the
carcinogenicity of chloroprene may be attributed to an epoxide of the
compound.
Jaeger et al. (2), studied the effects of chloroprene on serum alanine-
ketoglutarate transaminase (AKT) activity in rats. Adult male Holtzman
rats (250-350 g) were used for inhalation experiments. After exposure to
various concentrations (ranging from 500 ppm to approximately 10,000 ppm)
of chloroprene in air, the rats were sacrificed and the blood was collected
for determination of serum enzyme activity.
Results showed that AKT activity in rats varied with the time of day at
which the rats were exposed to chloroprene (concentration was not specified
for this experiment). This effect was related to the circardian rhythm of
hepatic glutathione (GSH) concentrations observed in a previous experiment
with non-exposed rats. In addition, fasted rats had overall lower GSH
levels than normal-diet fed rats. It was concluded that when rats were
exposed to chloroprene at times of lowered GSH concentration, the level of
serum AKT activity increased and the toxic effect of chloroprene was
potentiated.
27
-------
A dose-response relationship for serum AKT activity was also observed.
Furthermore, rats which were fasted prior to chloroprene exposure showed
increased levels of AKT activity at all concentrations tested; rats which
were fed before exposure were not affected at chloroprene levels of 500,
1,000 and 2,000 ppm. The authors concluded that fasted rats were more
susceptible than fed rats to the toxic effects of chloroprene.
REFERENCES
1. Bardodej, Z. 1976. Metabolic studies and the evaluation of genetic
risk from the viewpoint of industrial toxicology- Mutation Research.
41: 7-14.
2. Jaeger, R.J., R.B. Conolly, E.S. Reynolds, and S.D. Murphy. 1975.
Biochemical toxicology of unsaturated halogenated monomers. Environ.
Hlth. Perspect. 11: 121-128.
28
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CHLOROTOLUENE
CyHyCl
Mol wt: 126.59g/mole
alpha - chlorotoluene
CAS: 000100447
Syn: benzyl chloride; chloromethyl benzene;
tolyl chloride; chlorophenyl methane
bp: 179.3°C (at 760 mm Hg); 66°C (at 11 mm Hg)
vp: 1.3 mm Hg (at 25°C)
CH,
p - chlorotoluene
CAS: 000106434
Syn: p-tolyl chloride; 4-chloro-l-methyl benzene
bp: 162°C (at 760 mm Hg); 44°C (at 10 mm Hg)
vp: 3.5 mm Hg (at 25°C)
On the basis of a series of tests using rats, Knight and Young (1) con-
cluded that, unlike many other simple halocarbon compounds, chlorotoluene
is converted in vivo directly to a mercapturic acid metabolite, benzylmer-
capturic acid,~~without the intermediate formation of a premercapturic acid.
29
-------
Bray et al. (2, 3, 4), after studying the metabolism of chlorotoluene
in rats, rabbits and guinea pigs, proposed a 3-stage process for the
formation of mercapturic acid:
1. the conjugation of the precursor with glutathione;
2. the hydrolysis of the glutathione conjugate by glutathionase
to an S-substituted cysteine, glycine and glutatnic acid;
3. the acetylatian of the S-substituted cysteine to mercapturic
acid.
In addition to mercapturic acid metabolites, Bray et al. (2), also
isolated benzoic and hippuric acid metabolites from the urine of rabbits
treated with chlorotoluene. The authors suggested that these metabolites
are formed via the intermediate formation of benzyl alcohols.
REFERENCES
1. Knight, R.H. and L. Young. 1958. Biochemical studies of toxic
agents: 11. The occurrence of premercapturic acids. Biochem. Journ.
70(0:111-119.
2. Bray, H.G., S.P- James, and W.V. Thorpe. 1958. Metabolism of some
w-halogenoalkylbenzenes and related alcohols in the rabbit. Biochem.
Journ. 70:570-579.
3. Bray, H.G., T.S. Franklin, and S.P- James. 1959. The formation of
mercapturic acids: 3. N-acetylation of S-substituted cysteines in the
rabbit, rat and guinea pig. Biochem. Journ. 73:465-473.
4. Bray, H.G., W.V. Thorpe, and O.K. Vallance. 1952. The liberation of
chloride ions from organic chlorocompounds by tissue extracts.
Biochem. Journ. 51:193-201.
30
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DICHLOROBENZENE
C6H4C12
Mol wt: 147.01 g/raole
ortho-di chlorob enz ene
CAS: 000095501
Syn: o-dichlorobenzene; 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: 541-73-1
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)
In a 1923 study of the fate of ortho- and meta-dichlorobenzene in dogs,
Hele and Callaw (1) found that the administration of the compounds led to a
corresponding rise of neutral sulfur in the urine. The authors suggested
that such a rise indicates the presence of a mercapturic acid in the excre-
ted urine; the specific constitution of the metabolite was not determined.
Azouz et al. (2,3,4), studied the metabolism of o- and p-dichloroben-
zenes in chinchilla rabbits. The compounds were administered to the
rabbits via stomach tube in doses of 0.5 g/kg. The ortho compound was
suspended in water and the para isomer was administered as 25% (w/v)
31
-------
solution in olive oil. Urine samples were collected daily and analyzed for
metabolites using chromatographic methods. The major metabolite of
o-dichlorobenzene was identified as 3,4-dichlorophenol, which represented
about 30% of the dose administered. Minor metabolites were 2,3-dichloro-
phenol (9% of dose) and 3,4- and 4,5-dichlorocatechols (4% of dose). These
compounds were excreted as o-conjugates with glucuronic and sulphuric
acids. 3,4-Dichlorophenyl-mercapturic acid was also identified as a minor
(5% of dose) metabolite. The metabolism of p-dichlorobenzene resulted in
the excretion of conjugated 2,5-dichlorophenol (35% of dose) and
2,5-dichloroquinol (6% of dose). No catechol or mercapturic acid was
formed. The excretion of o-dichlorobenzene metabolites peaked on the first
day following administration and was completed by day 5 or 6. With
p-dichlorobenzene, excretion of the metabolites peaked on the second day
and was still appreciable on day 6 (4).
In a follow-up study, Parke and Williams (5) reported on the metabolism
of the dichlorobenzene isomers, with special reference to the meta-isomer.
Following oral administration of 0.5 g/kg of dichlorobenzene isomers to
rabbits, six classes of compounds were determined to be metabolites of the
dichlorobenzenes. These metabolites are listed in Table 1, along with
their percentage of the administered dosage.
Upon further analysis of m-dichlorobenzene metabolism it was found that
20% of the dose was excreted as 2,4-dichlorophenol, while 3,5-dichlorophe-
nol, 3,5-dichlorocatechol and 2,4-dichlorophenyl mercapturic acid were minor
metabolites. Only half of the dose was accounted for. The excretion of
the metabolites, as conjugates with glucuronic and sulphuric acids, reached
a maximum on the first day after dosing and was complete within 5 days.
In an occupational study by Pagnotto and Walkley (6), a good correlation
was found between the average air concentration of p-dichlorobenzene and
the urinary excretion of dichlorophenol. Exposed workers showed rapid
excretion of the metabolite, beginning shortly after exposure and peaking
at the end of the work shift. Dichlorophenol excretion dropped off rapidly
after terminiation of exposure, but was complete only after several days.
Table 1 (5).
i'j-crrtwn of tnelabolittJi of dichloroitenzenti In/ rni/bite
frd WM 0-5 g./kg. body wt. Results «re c*|>resMci »« percentage of fed do.vs.
Uichlornljcnzcne
Meubolit* ortho m,~ ^7
Cjlucuronide 4K 3ti 3(i
hthcrr*] suJphnte ;>! -, 2~
Mercapturic acid 5 jj y
Total conjugal** 74 .-, 03
MononheaoU 31) .1.-, 35
Giu-chols 4 ~3 U
Quioola It u ca. 6
Period of excretion Bf
-------
REFERENCES
1. Hele, T.S. and E.H. Callow. 1923. The fate of some halogen deriva-
tives of benzene and of benzene in the animal body. Proc. Physiol.
Soc. J. Physiol. 57: xliii.
2. Azouz, W.M., D.V. Parke and R.T. Williams. 1953. Studies in detoxi-
cation. 51. The determination of catechols in urine, and the
formation of catechols in rabbits receiving halogenobenzenes and other
compounds. Dihydroxylation in vivo. Biochem. J. 55(1): 146-151.
3. Azouz, W.M., D.V. Parke and R.T. Williams. 1954. The metabolism of
dichlorobenzenes. Biochem. J. 57(2): xii.
4. Azouz, W.M., D.V. Parke and R.T. Willliams. 1955. Studies in detoxi-
cation. 62. The metabolism of halogenobenzenes. ortho and para-
Dichlorobenzenes. Biochem. J. 59: 410-415.
5. Parke, D.V. and R.T. Williams. 1955. Studies in detoxication. 63.
The metabolism of halogenobenzenes. (a) meta-Dichlorobenzene. (b)
Further observations on the metabolism of chlorobenzene. Biochem. J.
59: 415-422.
6. Pagnotto, L.D. and J.E. Walkley. 1965. Urinary dichlorophenol as an
index of para-dichlorobenzene exposure. Am. Ind. Hyg. Assoc. J. 26:
137-142.
33
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1,2-DICHLOROETHANE
Cl Cl
C2H4C12 H —C—C—H
H H
CAS: 000107062
Syn: sytn-dichloroethane;
alpha,beta-dichloroethane; dichloroethylene;
EDC; ethane dichloride; ethylene
chloride; ethylene dichloride; glycol
dichloride
Mol wt: 98.96 g/mole
bp: 83.47°C (at 760 mm Hg)
vp: 76.2 mm Hg (at 25°C)
In vivo studies on 1,2-dichloroethane metabolism in the mouse were
reportedBy" Yliner (1). Female albino mice were given an intraperitoneal
injection of 0.05, 0.10, 0.14, or 0.17g of ^C-labelled 1,2-dichloro-
ethane per kg body wt., as a 10% solution in olive oil. Volatile
metabolites, urine, and feces were collected every 24 hours for 3 days.
Whole body homogenates were analyzed for remaining radioactivity at the end
of the 3-day period. Radioactivity was measured by liquid scintillation
and metabolites were identified by paper chromatography.
Analyses showed that the radioactivity was rapidly excreted, over 90%
being eliminated in 24 hours at each dose level. The levels of activity in
each constituent, depending on the dose, ranged as follows:
10-42% expired unchanged
12-15% expired as CC>2
51-73% detected in urine
0-0.6% found in feces contaminated with urine
0.6-1.3% remained in whole-body homogenate
34
-------
The urinary metabolites excreted in 24-hours were further analyzed by
isotope dilution techniques and the relative amount of each was expressed
as a percentage of the total urinary radioactivity. Three major metabo-
lites in urine were identified as chloroacetic acid (6-23%), S-carboxy-
methylcysteine (44-46% free and 0.05-5% conjugated), and thiodiacetic acid
(33-34%). Small amounts of 2-chloroethanol (0.0-0.8%) and S,S'-ethylene-
bis-cysteine (0.7-1.0%) were also detected. No oxalic acid was found. A
minor portion of the radioactivity may be attributed to S-(Beta-hydroxy-
ethyl)-cysteine and its mercapturic acid. The author proposed that 1,2-di-
chloroethane metabolism proceeds primarily via formation of chloroacetic
acid. The metabolic processes may involve enzymatic dehalogenation of
1,2-dichloroethane and its intermediates (1).
In vitro experiments were also conducted in an effort to determine
whether the metabolite S,S'-ethylene-bis-cysteine is formed by enzymatic
reaction. 1,2-Dichloroethane and L-cysteine hydrochloride interacted in
alkaline solution (pH 7.4) at 37°, resulting in the formation of the
thrioether S,S'-ethylene-bis-cysteine. No non-enzymatic reaction was
observed. From the in vitro results it was suggested that S,S'-ethylene-
bis-cysteine is probably formed enzymatically in. vivo by the reaction of
1,2-dichloroethane and glutathione (1).
Similar data regarding the production of thioethers from the reaction
of 1,2-dichloroethane with protein were reported by Morrison and Munro (2).
I_n vitro experiments were conducted in which fish solids (freeze-dried cod
filets) were refluxed with 10 volumes of 1,2-dichloroethane for 0.5 to 16
hours in order to determine the effects of the compound on the amino acids
of fish protein. Analysis of the resulting acid hydrolysates and enzymatic
hydrolysates indicated the destruction of cystine and histidine, and inter-
ference with the enzymatic release of methionine, histidine, and cystine.
The authors suggested that the reactions involved alkylation by 1,2-di-
chloroethane of the sulfhydryl groups of protein, resulting in the produc-
tion of thioether compounds such as S,S'-ethylene-bis-cysteine. To demon-
strate the proposed alkylation process, S,S'-ethylene-bis-cysteine was
synthesized by refluxing 10 g of L-cysteine (in 100 ml of 0.2M
with 25 ml of 1,2-dichloroethane.
Nachtomi et al. (3), reported the urinary metabolites of 1,2-dichloro-
ethane in the rat. Rats were treated by stomach tube with 100 mg of 1,2-
dichloroethane in a soybean oil solution. Urine was collected for 24 hours
and analyzed by paper chromatography and paper electrophoresis. The major
metabolite was identified as S-(Beta-hydroxyethyl) mercapturic acid.
Traces of S-(Beta-hydroxyethyl)cysteine were also detected.
Heppel et al. (4), suggested that 1,2-dichloroethane may be detoxified
in rats by reaction with sulfur-containing compounds. Young male rats
(33.3 - 46.1 g) were subjected to single or multiple 4-hour exposures to
1,000 ppm of 1,2-dichloroethane in air. Diets were supplemented with
various sulfur-containing compounds including inorganic salts, amino acids,
and organic S-compounds. Mortality and toxicity were recorded. It was
35
-------
shown that the toxicity of 1,2-dichloroethane in rats was reduced by the
following compounds: L-cystine and DL-methionine (amino acids), thiourea,
thiouracil, 2-thiobarbituric acid, B,B'-dithiodiproprionic acid, L-cysteine
hydrochloride, and thiolactic acid (only when administered i.p.). The
authors noted that all the compounds listed can supply sulfhydryl groups
for detoxifying 1,2-dichloroethane.
REFERENCES
1. Yllner, S. 1971. Metabolism of 1,2-dichloroethane-1^C in the mouse.
Acta pharmacol. et toxicol. 30:257-265.
2. Morrison, A.B. and I.C. Munro. 1965. Factors influencing the
nutritional value of fish flour. IV. Reaction between
1,2-dichloroethane and protein. Can. J. Biochem. 43:33-40.
3. Nachtomi, E., E. Alumot and A. Bondi. 1966. The metabolism of
ethylene dibromide in the rat. I. Identification of detoxification
products in urine. Israel J. Chem. 4:239-246.
4. Heppel, Leon A., V.T. Porterfield and N.E. Sharpless. 1947.
Toxicology of 1,2-dichloroethane (ethylene dichloride). IV. Its
detoxication by L-cystine, DL-methionine and certain other sulfur
containing compounds. J. Pharmacol. Exp. Therap. 91:385-394.
36
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1,1-DICHLOROETHYLENE
Cl H
C2H2C12 \ = C
/ \
Cl H
CAS:
Syn: 1,1-DCE; 1 , 1-dichloroethene;
vinylidene chloride;
vinylidine chloride
Mol wt: 96.94
bp: 37°C(at 760 mm Hg)
vp: 633.7 mm Hg (at 25°C)
Prior to 1975, little information was available on the metabolism of
1,1-dichloroethylene (1,1-DCE; vinylidene chloride). Recently, however, it
has been established that 1,1-DCE undergoes extensive, rapid metabolism.
Most of an administered dose of 1,1-DCE is excreted unchanged through the
lungs or as polar metabolites in urine. The metabolic products in urine
include two major metabolites, thiodiglycollic acid and N-acetyl-S-
cysteinyl-acetyl derivative, as well as chloroacetic acid, dithioglycollic
acid, thioglycollic acid, and N-acetyl-S-(2-carboxymethyl)cysteine. The
metabolic process involves oxidation of 1,1-DCE to the epoxide, structural
rearrangement of the epoxide to form chloroacetic acid (a major intermedi-
ate), and subsequent conjugation of chloroacetic acid with glutathione to
yield the final metabolites. 1,1-DCE is metabolized primarily in the liver
and is glutathione-dependent.
Reichert and Werner (1) determined the metabolic fate of (^C) 1,1-DCE
in rats after administration of a single oral dose of 0.5 or 50 mg per kg
body weight. Analysis of radioactivity for 72 hours after administration
showed that with the 0.5 mg/kg dose, about 0.9% was expired as unchanged
1,1-DCE, 23% was expired as CC^j and 52% was eliminated in urine. At
the 50 mg/kg level, the proportions of C-activity were 20% unchanged
1,1-DCE, 6% C02> and 36% urinary radioactivity. Residual activity in
the body after 72 hours amounted to 2-4% of the administered dose, and was
located primarily in the liver, with minimal radioactivity present in other
tissues. Similar data were reported by McKenna et al. (2), based on studies
in which rats, fasted or fed, were given an oral dose of 1 or 50 mg of
,1-DCE per kg body weight or were subjected to inhalation exposures
37
-------
of 10 or 200 ppm of (14C)1,1-DCE for 6 hours. Elimination of 14C-
activity was followed for 72 hours and the results, indicating the percent-
age of the dose that was metabolized, were reported as follows: with 10
ppm or 1 mg/kg, 97-99% was metabolized; with 50 mg/kg, 60-75%; and at 200
ppm, 92-96% was metabolized. The authors concluded that the fate of 1,1-DCE
in the rat was dependent on both the dose and the route of administration.
The identities and proportions of 1,1-DCE metabolites in mice and rats
were reported by Jones and Hathway (3). Metabolite determinations were made
by scintillation, thin-layer and gas chromatography. and mass spectrometry
for 3 days after oral administration of 50 mg of (^C) 1,1-DCE per kg body
weight. The results are presented in Table 1. Mice metabolized over 20%
more of the oral dose than did rats, which corresponded directly to the
greater activity of cytochrome P-450 in mice.
A comprehensive metabolic scheme for 1,1-dichloroethylene in mammals
was postulated by Jones and Hathway (3) as shown in Figure 1.
The first step in 1,1-DCE metabolism is the formation of the corres-
ponding epoxide (3,4,5,6,7,8). 1,1-Dichloroethylene epoxide is highly
unstable and short-lived, and has only recently been synthesized (5,6).
Table 1 (3).
Relative proportion of ( C) excretory products after oral
administration of 50 mg/kg of (l-^C)DCE to rodents (observations 3
days after dosing)
Excretory products
Unchanged DCE pulmonary
C02 excretion
Chloroacetic acid
Thiodiglycollic acid
Thioglycollic acid
Dithioglycollic acid
Thioglycollyloxalic acid
N-Acetyl-S-cysteinyl acetyl derivative
N-Acetyl-S-(2-carboxymethyl)cysteine
Urea
* Alderley Park strains.
14
C expressed as % of dose
Mice*
6
3
0
3
5
23
3
50
4
3
Rats*
28
3.5
1
22
3
5
2
28
0
3.5
38
-------
The epoxide then undergoes rearrangement, primarily by the migration of
one Cl atom and the loss of the other Cl atom, to yield chloroacetyl chlor-
ide (3,5,6,7) which is subsequently hydrolyzed to chloroacetic acid (7). A
minor amount of chloroacetic acid may also be formed from 1,1-dichlorogly-
col, which is an intermediate derived from rearrangement of 1,1-DCE epoxide
by hydrogen migration (7). The major and minor pathways of chloroacetic
acid formation from 1,1-DCE are shown in Figure 2 (7).
One of the major urinary metabolites, the N-acetyl-S-cysteinyl acetyl
derivative, is probably formed from the reaction of 1,1-DCE epoxide with
glutathione, catalyzed by glutathione S-epoxide transferase (3,8).
The other main metabolite, thiodiglycollic acid, is formed from chloro-
acetic acid (3,8) through a series of degradative reactions, catalyzed by
glutathione S-acyl transferase (8). Furthermore, thiodiglycollic acid was
shown to undergo hydrolysis in vivo by the action of beta-thionase, produc-
ing the metabolites thioglycollic acid and dithioglycollic acid (3).
According to Hathway (8), the end products CC>2 and urea may be formed
by the action of epoxide transferase on 1,1-DCE epoxide, or by the
metabolism of chloroacetic acid.
Another possible metabolite of 1,1-DCE may be monochlorocitric acid,
which Jaeger (9) suggests might be a conversion product of chloroacetic
acid, based on the observation of increased hepatic citric acid concentra-
tions in rats following inhalation exposure to 250 ppm of 1,1-DCE.
The extent of 1,1-DCE metabolism is glutathione-dependent, according to
studies by McKenna et al. (2), in which fasted rats, with correspondingly
lower hepatic glutathione levels, metabolized less (92%) of an inhaled dose
of 1,1-DCE (200 ppm) than did fed rats (96% metabolized). Also, identifi-
cation of the major urinary metabolites as thiodiglycollic acid and
N-acetyl-S-cysteinyl acetyl derivative indicated the metabolism of 1,1-DCE
via glutathione conjugation. Similarly, Jaeger et al. (10) concluded that
glutathione was an important site of 1,1-DCE detoxification based on the
results of earlier experiments (11) with rats, both in_ vivo and in isolated
perfused rat liver. In general, therefore, researchers agree that 1,1-DCE
is metabolized in the liver and is dependent on hepatic glutathione for
detoxification.
39
-------
H.C=CCl.
(a)
RC—CHCH,SCH.CR'
II I 'II
O NH O
Ac
HO:CCHCH,SCH,CO,H
NH,
'"
008,00,8
(b)
CO(NH,),
HO,CCHCH,SCH.CO.H
OH
S(CH.CO,H), (g)
HSCH.CO,H (h)
J
), (j)
Fig. 1 (3). Metabolic pathway for vinylidene chloride in mammals.
a) 1,1-dichloroethylene
b) chloroacetic acid
c) S-chlorocarbonylmethylcysteinyl-
glutathione
d) S-carboxymethylcysteinylglutathione
e) N-acetyl-S-cysteinyl acetyl derivative
f) S-carboxymethylcysteine
g) thiodiglycollic acid
h) thioglycollic acid
j) dithioglycollic acid
40
-------
(a)
CLC-CH, (d) (f)
T -I -»aOC — CH.C1— HOOC — CH3CI
C1:C — CH, Lx"^
_ V J^CUC^-
rcic
I
L O
H
— >C10C-CH:CI->HOOC-CH..C1
OH onJ
a) 1,1-dichloroethylene
b) 1,1-dichloroethylene epoxide
c) 1,1-dichloroglycol
d) chloroacetyl chloride
e) dichloroacetaldehyde
f) chloroacetic acid
Fig. 2 (7). Metabolism of 1,1-DCE to monochloroacetic acid
41
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REFERENCES
1. Reichert, D. and H.W. Werner. 1978. Disposition and metabolism of
(14C)l,l-dichloroethylene after single oral administration in rats.
Naunyn-Schmiedebergs Arch. Pharmacol. V302, S. p. R22. Abstract no.
87-
2. McKenna, M.J., J.A. Zempel, E.O. Madrid and P.J. Gehring. 1977. The
fate of ( C) vinylidene chloride following inhalation exposure and
oral administration in rats. Toxicol. Appl. Pharmacol. 41(1): p.
218. Abstract no. 206.
3. Jones, B.K. and D.E. Hathway- 1978. Differences in metabolism of
vinylidene chloride between mice and rats. Br. J. Cancer. 37:
411-417.
4. Reichert, D. and N. Bashti. 1976. Metabolism and disposition of
1,1-dichoroethylene in the isolated blood-perfused liver of the rat.
Naunyn-Schmiedeburg's Arch. Pharmacol. 293 (Suppl.) p. R64. Abstract
no. 255.
5. Greim, H., G. Bonse, Z. Radwan, D. Reichert and D. Henschler. 1975.
Mutagenicity in vitro and potential carcinogenicity of chlorinated
ethylenes as a function of metabolic oxirane formation. Biochem.
Pharmacol. 24(21): 2013-2017.
6. Henschler, D. and G. Bonse. 1977. Metabolic activation of chlorinated
ethylenes: dependence of mutagenic effect on electrophilic reactivity
of the metabolically formed epoxides. Arch.
Toxicol. 39: 7-12.
7. Leibman, K.C. and E. Ortiz. 1977. Metabolism of halogenated
ethylenes. Environ. Hlth. Perspect. 21: 91-97.
8. Hathway, D.E. 1977. Comparative mammalian metabolism of vinyl
chloride and vinylidene chloride in relation to oncogenic potential.
Environ. Hlth. Perspect. 21: 55-59.
9. Jaeger, R.J. 1977. Effect of 1,1-dichloroethylene exposure on hepatic
mitochondria. Res. Commun. Chem. Pathol. Pharmacol. 18(1): 83-94.
10. Jaeger, R.J., R.B. Conolly, E.S. Reynolds, and S.D. Murphy. 1975.
Biochemical toxicology of unsaturated halogenated monomers. Environ.
Hlth. Perspect. 11: 121-128.
11. Jaeger, R.J., R.B. Conolly and S.D. Murphy. 1974. Effect of 18 hr
fast and glutathione depletion on 1,1-dichloroethylene-induced
hepatotoxicity and lethality in rats. Exper. Molec. Pathol. 20:
187-198.
42
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1,2- DICHLOROETHYLENE
Mol wt: 96.94 g/mole
cis-1,2-dichloroethylene
(J
,/ \
Cl Cl
CAS: 000156592 N _
Syn: cis-dichloroethylene; H
cis-1 , 2-dichloroethene
bp: 60.3°C (at 760 mm Hg)
vp: 176.6 mm Hg (at 25°C)
trans-1,2-dichloroethylene
CI H
CAS: 000540590 ^ _ c
Syn: trans-acetylene dichloride; H Cl
trans-dichloroethylene
bp: 47.5°C (at approx. 1 atm)
vp: 275.6 mm Hg (at 25°C)
Experimental data are limited regarding the metabolism of cis- and
trans-1,2-dichloroethylene (1,2-DCE). However, several authors have postu-
lated metabolic pathways for the compound by analogy to the metabolism of
related compounds such as trichloroethylene.
The first step in 1,2-DCE metabolism is probably the formation of
1,2-dichloroethylene epoxide. The epoxide then undergoes rearrangement to
yield another intermediate, dichloroacetaldehyde. Finally, the metabolic
end products include chlorinated alcohol and acid compounds (1,2,3).
Leibman and Ortiz (1) proposed a metabolic scheme for 1,2-DCE as shown
in Figure 1, based partly on the results of metabolism tests with isolated
rat liver microsomal systems, and partly by analogy to the metabolism of
other chlorinated ethylenes. The authors indicated that the metabolism of
1,2-DCE proceeds primarily via dichloroacetaldehyde. The aldehyde is pro-
duced mainly by rearrangement of the epoxide, involving migration of a
chlorine atom from one carbon atom to the other. A similar chlorine-
migration rearrangement may occur, to a lesser extent, with the dichloro-
ethylene glycol (formed from hydration of the epoxide). Rearrangement of
1,2-DCE epoxide with migration of a hydrogen atom may yield monochloro-
acetyl chloride and ultimately produce monochloroacetic acid. Dichloro-
acetaldehyde and monochloroacetic acid were not identified in significant
43
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quantities as end-product metabolites of 1,2-DCE by Leibman and Ortiz (1),
however the authors suggest that the compounds are involved in the metabolic
scheme.
ciCH.- COO— C1CH,— COOH
Fig. 1 (1). A proposed metabolic pathway of 1,2-dichloroethylene.
a) 1,2-dichloroethylene
b) 1,2-dichloroethylene epoxide
c) 1,2-dichloroglycol
d) dichloroacetaldehyde
e) monochloroacetyl chloride
f) 2,2-dichloro-l,l-ethanediol
g) monochloroacetic acid
Bonse et al. (3), reported the production of small amounts of dichloro-
acetic acid and dichloroethanol from rat liver preparations after perfusion
with 55 nmol of cis- or trans-1,2-DCE per ml. After a review of the Bonse
et al. study (3), Leibman and Ortiz (1) suggested that the identification
of dichloroacetic acid and dichloroethanol as metabolites of 1,2-DCE prob-
ably indicates the formation of dichloroacetaldehyde as an intermediate.
REFERENCES
1. Leibman, K..C. and E. Ortiz. 1977. Metabolism of haolgenated ethylenes.
Environ. Hlth. Perspect. 21: 91-97.
2. Henschler, D. and G. Bonse. 1977. Metabolic activation of chlorinated
ethylenes: dependence of mutagenic effect on electrophilic reactivity
of the metabolically formed epoxides. Arch. Toxicol. 39: 7-12.
3. Bonse, G., T. Urban, D. Reichert and D. Henschler. 1975. Chemical
reactivity, metabolic oxirane formation and biological reactivity of
chlorinated ethylenes in the isolated perfused rat liver preparation.
Biochem. Pharmacol. 24(19): 1829-1834.
44
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1,2-DICHLOROPROPANE
Cl Cl H
C3H6C12 H-C-C-C-H
H H H
CAS: 000078875
Syn: alpha,beta-dichloropropane; propyiene chloride;
propylene dichloride; alpha,beta-propylene dichloride
Mol wt: 112.99 g/mole
bp: 96-37°C (at 760 mm Hg)
vp: 50.8 mm Hg (at 25°C)
Inhalation studies were conducted by Heppel et al. (1), in which blood
levels of 1,2-dichloropropane were determined in rabbits and dogs. Rabbits
(size, sex and number not specified) were exposed to constant concentra-
tions of 2,200 or 1,500 ppm of dichloropropane in air for 7 hours per day
for 5 days. Respective blood levels of 1.5 to 2.9 mg and 0.6 to 1.1 mg of
dichloropropane per 100 cc of blood were found. Three dogs (size and sex
not specified) were exposed to 1,000 ppm of dichloropropane for 7 hours,
resulting in average blood levels of 1.3, 1.5 and 1.6 mg per 100 cc.
In related tests, Heppel et al. (1), concluded that rats, mice and
guinea pigs excreted an unidentified pigment-producing substance in urine
after exposure to dichloropropane vapors.
Hutson et al. (2), reported the rates and routes of 1,2-dichloropropane
excretion in rats. In one experiment, 6 adult male and 6 adult female rats
(Carworth Farm E strain) were administered, by stomach tube, one dose of
0.88 mg (8.5 uCi) of l,2-dichloro(l-^C)propane in 0.5 ml arachis oil.
The excretion of radioactivity in urine and feces was then measured by
scintillation at 24-hour intervals for 96 hours. After 96 hours the recov-
ery of radioactivity by scintillation was also determined from the skin,
alimentary tract and remaining carcass. Results of the experiment showed
that radioactivity was excreted very rapidly, primarily in the urine.
About 50.2% of the administered dose was excreted in urine in the first 24
hours. In decreasing order, less radioactivity was recovered from the
feces, carcass, skin, and gut.
45
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In a second experiment (2), the respiratory excretion of the compound
was analyzed. A single oral dose of 1.07 rag (10.3 uc) of 1,2-dichloro-
(l-^C)propane was given to each of 5 female rats which were housed
together in a compartmented chamber. Air was drawn through the chamber at
the rate of 650 ml/min. and then collected in sodium hydroxide traps.
Radioassays measured the amount of (^C) carbon dioxide and other vola-
tile radioactivity in the exhaled air.
Results of the respiration tests indicated that a large amount of
radioactivity, 23.1% of the oral dose, was exhaled as volatile chlorinated
hydrocarbon, probably as unchanged dichloropropane. In addition, 19.3% of
the dose was expelled as C^C) carbon dioxide, indicating that extensive
metabolism of dichloropropane also occurred. The radioactive substances
recovered in the tests were not identified in the report (2).
REFERENCES
1. Heppel, L.A., P. A. Neal, B. Highman, and V.T. Porterfield. 1946.
Toxicology of 1,2-dichloropropane (propylene dichloride). I. Studies
on effects of daily inhalations. J. Ind. Hyg. Toxcicol. 28(1): 1-8.
2. Hutson, D.H., J.A. Moss, and B.A. Pickering. 1971. The excretion and
retention of components of the soil fumigant D-D and their metabolites
in the rat. Food Cosmet. Toxicol. 9(5): 677-80.
46
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HEXACHLOROBUTADIENE
Cl Cl
\ /
/C=C\ Cl
Cl C=C/
ci Xci
CAS: 000087683
Syn : HCBD
Mol. Wt. : 264.79 g/mole
bp: 210 - 220°C
vp: 22 nm Hg (at 100°C)
In a 1963 report, Murzakaev et al. (1), stated that the polychloro-
butanes C^E^Cl^ and C^H^Clg are intermediate products in the
metabolism of hexachlorobutadiene.
Gul'ko and Dranovskaya (2), utilizing a pulsed polarographic method,
determined that mice fed hexachlorobutadiene (5 mg/kg) retained the follow-
ing organ levels of the parent compound: liver, 17.4 and 28.8 ug, respec-
tively, 1 and 2 hours after administration; brain, 14.5, 59.2 and 11.4 ug
after 3, 24 and 96 hours, respectively.
REFERENCES
1. Murzakaev, F.G. 1963. Some data on the toxicity of a new insecticide,
hexachlorobutadiene, and its intermediate metabolic products. Farmakol
i Tokaikol. 26(6): 750-753.
2. Gul'ko, A.G. and L.M. Dranovskaya. 1967. Determination of hexachloro-
butadiene in biological substrates by a pulsed polarographic method.
Vop. Gig. Toksikol. Pestits., Tr. Nauch. Sess. Akad. Med. Nauk SSSR.
79-81.
47
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HEXACHLOROETHANE
Cl Cl
C2C1& CI —C—C—Cl
I I
Cl Cl
CAS: 000067721
Syn: Carbon hexachloride; ethane hexachloride; 1,1,1,2,2,2-hexachloro-
ethane'; perchloroethane
Mol wt: 236.74 g/mole
bp: 186°C (at 777 mm Hg)
vp: 1.2 mm Hg (at 32.7°C)
Hexachloroethane (HCE) metabolism in rabbits was reported by Jondorf et
al. (1). ^C-Labelled hexachloroethane was fed to rabbits in doses of
0.5 g/kg. The results showed that HCE was metabolized very slowly. In
three days, 57, of the radioactivity was detected in urine, 14% to 24% was
measured in expired air, and the remainder was assumed to be located in the
rabbit tissues and intestinal tract. Identification and concentrations of
the urinary metabolites, shown as averages for three experiments, were
reported as follows:
trichloroethanol, 1.3%
trichloroacetic acid, 1.3%
dichloroacetic acid, 0.8%
monochloroacetic acid (highly toxic), 0.7%
dichloroethanol, 0.4%
oxalic acid, 0.1%
The metabolites found in expired air included C02> hexachloroethane,
tetrachloroethylene and 1,1,2,2-tetrachloroethane.
48
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The metabolism of HCE by sheep was studied by Fowler (2) in a series of
experiments. Following oral administration of 0.5 g HCE/kg to the sheep,
samples of venous blood, urine, feces, bile and various tissue were taken
periodically. Tetrachloroethylene (TCE) and pentachloroethane (PCE) were
identified as the main metabolites. In the first experiment, blood levels
of HCE, TCE and PCE peaked at 24 hours, at 10-28 ug/ml , 0.6-1.1 ug/ml, and
0.15-0.50 ug/ml, respectively. In a second experiment it was determined
that most of the urinary and fecal excretion of HCE and its metabolites
occurred within 24 hours. Greater amounts of each compound were eliminated
in feces than in urine, as shown in Table 1. Results of a third experiment
showed that the concentration of HCE in the bile was 8-10 times greater
than the blood level. Analysis of tissue samples indicated that low levels
of HCE and its metabolites were widely distributed throughout the animal.
Table 1. Total (ug) 24-hr excretion of HCE, TCE, and PCE in urine and
feces of 2 anaesthetized sheep after oral administration of 0.5 g HCE/kg.
Metabolite concentration (ug)
hexachloroethane
tetrachloroethylene
pentachloroethane
In vitro experiments were also conducted by Fowler (2), using fresh
liver slices in olive oil emulsion and 18 or 54 mg HCE/L. The tissue
homogenates were incubated at 37°C for 4 hours. Both TCE and PCE were
liberated during incubation. When the tests were repeated with liver
slices heated for 5 minutes at 70°C prior to incubation, the two metabo-
lites were liberated in much smaller amounts. The results indicated that
the metabolism of HCE was an enzymatic process involving at least two
enzymes, both of which were present in the liver.
REFERENCES
1. Jondorf, W.R., D.V. Parke and R.T. Williams. 1957. The metabolism of
(^C)-hexachloroethane. Biochem. J. 65: 14p-15p.
2. Fowler, J.S.L. 1969. Some hepatotoxic actions of hexachloroethane and
its metabolites in sheep. Brit. J. Pharmacol. 35(3): 530-542.
49
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METHYLENE CHLORIDE
Cl
CH2C12 H-C-CI
I
H
CAS: 000075092
Syn: methane dichloride; dichloromethane;
methylene bichloride; methylene
chloride; methylene dichloride
Mol wt: 84.93 g/mole
bp: 40°C (at 760 mm Hg)
vp: 430.4 mm Hg (at 25°C)
The major metabolites of methylene chloride (CH2Cl2J dichloro-
methane) reported in the literature are carbon monoxide, carbon dioxide,
and an unknown acid metabolite (1,2). No evidence was found to support the
actual incorporation of methylene chloride into cellular constituents.
Several experimenters (3,4) have reported data that indicated formalde-
hyde (CH20) as a metabolite of methylene chloride. However, DiVencenzo
and Hamilton (1) studied the fate of ^C-labeled methylene chloride in-
jected intraperitoneally in rats and suggested that the changes in CH20
levels found in serum and tissue were physiologically induced; no evidence
was found to support the conversion of CH2Cl2 to C^O in vivo.
Early investigations of the metabolism of methylene chloride suggested
that it may be metabolized to carbon monoxide (5,6,7). Stewart et al.
(5,6), exposed eleven volunteers to methylene chloride vapor in concentra-
tions of 500 to 1,000 ppm for 1 or 2 hours. They found that the concentra-
tion of carbon monoxide (CO), in the form of carboxyhemoglobin (COHb), was
increased in the blood of the subjects.
Kubic et al. (8), found that intraperitoneal administration of dihalo-
methane elevated carboxyhemoglobin in the blood of rats. In the same
experiment the authors administered ^C-dichloromethane to rats intra-
peritoneally at a dose of 3 mmol/kg. The infrared spectra of the blood of
these rats showed the presence of the absorption band characteristic of
^C-carbon monoxide. The authors considered this conclusive evidence
that dichloromethane is metabolized to carbon monoxide in the rat. Other
studies of dichloromethane metabolism in rats (1,2,9) using radioactive-
labeled methylene chloride report findings consistent with those of Kubic
et al. (8).
50
-------
Several experimenters (9,10) have observed a maximum saturation of COHb
in the blood after exposure to dichlorome thane. Hogan et al. (10) exposed
rats to 400 ppm dichloromethane, resulting in a 7% COHb level in the blood
of the rats. Exposure levels as high as 2300 ppm caused no further increase
in the 7% COHb level although the maximum COHb level persisted for a longer
period at the higher doses. Similarly, Miller et al. (9) found that a dose
of 3.0 mmol/kg injected intraperitoneally in rats yielded a maximum level
of COHb blood saturation of about 6%.
Kubic and Anders (11) found that dihalomethanes are metabolized to
carbon monoxide by hepatic microsomal fractions in the presence of NADPH
and oxygen. An increased rate of conversion of dibromomethane to CO was
correlated with increased microsomal cytochrome P-450 content, indicating a
cytochrome P-450-dependent mixed oxidase system. Hogan et al. (10)
reported similar findings using dichloromethane.
DiVencenzo and Hamilton (1) studied the disposition of (C) methyl-
ene chloride injected intraperitoneally in rats. Each rat received from
11.7 to 21.6 uCi of radioactivity in doses from 412 to 930 mg of
l^C^C^ per kg body weight. After two hours, 75% of the radio-
activity was exhaled.
After 24 hours a total of 98% of the initial dose was exhaled. Urinary
radioactivity accounted for about 1% of the dose at 24 hours. Fecal radio-
activity was less than 0.1% at 24 hours (Table 1).
Of the radioactivity collected from the breath, unchanged
i^CE2c^-2 accounted for 98.8% of breath radioactivity at 2 hours, 96.1
at 8 hours, and 93% at 24 hours. At 24 hours, less than 7% of the
radioactive dose was in the form of metabolites: 2% was converted to
^CO, 3% was converted to 1^C02> and 12 was an unknown compound
(Table 2). According to the authors, CO may be an intermediate in the
formation of C02 (!)•
51
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Table 1 (1). Dissemination of radioactivity in rats treated
intraperitoneally with (14C)methylene chloride3
Experimental Duration
Breath
Urine
Feces
Carcass
Chamber washings
Total
2 hrb
77.9, 93.2
0.01
0.01
3.09 + 0.99
0.12 + 0.08
88.8
N
2
4
4
4
4
8 hr
98.6, 96.8
0.01
0.01
2.06, 2.42
0.41, 0.15
100.2
N
2
2
2
2
2
24 hrb
98.2
1.06 + 0.15
0.07 + 0.01
1.53 + 0.12
0.07 + 0.04
100.9
N
1
5
5
3
5
a ( C)Methylene chloride was administered i.p. in doses ranging from
412-930 mg/kg. Values are expressed as percent of dose.
b Mean + SE
52
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Table 2 (1). Radioactive compounds detected in rat breath following the
intraperitoneal administration of (l^C)methylene chloride3
Experimental Duration
Compound 2 hr N 8 hr N 24 hr N
CH2CL2 77.0, 92.Ob 2 95.3, 92.6b 2 91.50 1
C02 0.44, 0.65 2 1.44, 1.61 2 3.04 1
CO 0.14, 0.14 2 1.16, 1.69 2 2.15 1
Unknown 0.34, 0.46 2 0.74, 0.86 2 1.49 1
f- Expressed as percentage of the original dose.
Individual values for each experimental animal.
DiVencenzo and Hamilton (1) found the amount of radioactivity in the
rat tissues to be relatively low, less than 2% of the dose after 24 hours.
The liver, kidneys, and adrenal glands had the highest amount, although the
radioactivity was generally widespread in the rat tissues. No metabolites
other than CO, C02» and an unknown compound were found in the
breath, blood or tissues.
Rodkey and Collison (2), using a closed rebreathing system, exposed
rats to 0.2 mmol of ^Cl^C^ vapor per kg for 15 hours. Expired
^CO and ^COo accounted for 76% of the radioactivity given. They
found no accumulation of radioactivity in the tissues at these low doses.
In a study of the metabolism of ^C-labelled methylene chloride in
rats, Carlsson and Hultengren (12) found that immediately after exposure to
1,935 mg of ^CH2Cl2 per m^ of inspiratory air, adipose tissue
contained the highest level per gram of tissue (Figure 1). In the follow-
up study (6 hours after exposure) it was found that radioactive carbon
decreased very rapidly in the adipose tissue and the brain tissue. Levels
in other tissues (liver, kidney, and adrenals) declined at slower rates.
53
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yg CH Cl /g tissue
75
50
liver
kidneys
adrenals
25
time after
exposure
adipose tissue
hours
Figure 1. Accumulation of methylene chloride (ug CH Cl /g tissue) and
its metabolites in organs and tissues during the 6-h
follow-up after exposure to methylene chloride in
inspiratory air. (Redrawn from 12)
54
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REFERENCES
1. DiVincenzo, G.D. and M.L. Hamilton. 1975. Fate and disposition of
C^C) methylene chloride in the rat. Toxicol. Appl. Pharmacol.
32(2): 385-393. -
2. Rodkey, F.L. and H.A. Collison. 1977. Biological oxidation of
( C) methylene chloride to carbon monoxide and carbon dioxide by
rat. Toxicol. Appl. Pharmacol. 40(1): 33-38.
3. Heppel, L.A. and V.T. Porterfield. 1948. Enzymatic dehalogenation
of certain brominated and chlorinated compounds. J. Biol. Chem.
176: 763-769. -
4. Ahmed, A.E., M.W. Anders. 1976. Metabolism of dihalome thanes to
formaldehyde and inorganic halide. I. In vitro studies. Drug
Metab. Dispos. 4(4): 357-361.
5. Stewart, R.D., T.N. Fisher, M.J. Hosko, J.E. Peterson, E.D. Baretta
and H.C. Dodd. 1972. Carboxyhemoglobin elevation after exposure to
dichlorome thane. Science. 176(Apr 21): 295-296.
6. Stewart, R.D., T.N. Fisher, M.J. Hosko, J.E. Peterson, E.D. Baretta
and H.C. Dodd. 1972. Experimental human exposure to methylene
chloride. Arch. Environ. Health. 25(5): 342-348.
7. Ratney, R.S., D.H. Wegman and H.B. Elkins. 1974. In vivo conver-
sion of methylene chloride to carbon monoxide. Arch. Environ.
Health. 28(4): 223-226.
8. Kubic, V.L., M.W. Anders, R.R. Engel, C.H. Barlow, and W.S. Caughey.
1974. Metabolism of dihalomethanes to carbon monoxide I. In vivo
studies. Drug Metab. Dispos. 2(1): 53-57
9. Miller, V.L., R.R. Engel and M.W. Anders. 1973. In vivo metabolism
of dihalomethanes to carbon monoxide (CO). Pharmacologis t . 15(2):
190. Abstract no. 184
10. Hogan, G.K., R.G. Smith, and H.H. Cornish. 1976. Studies on the
micro- somal conversion of dichloromethane to carbon monoxide.
Toxicol. Appl. Pharmacol. 37(1): 112. Abstract no. 49.
11. Kubic, V.L. and M.W. Anders. 1975. Metabolism of dihalomethanes to
carbon monoxide. II. In_ vitro studies. Drug Metab. Dispos.
3(2): 104-112.
12. Carlsson, A. and M. Hultengren. 1975. Exposure to methylene
chloride. III. Metabolism of ^C-labelled methylene chloride in
rat. Scand. J. Work. Environ. Health. 1(2): 104-108.
55
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PENTACHLOROANISOLE
CAS: 1825-21-4
Syn: pentachloromethoxybenzene; 2,3,4,5,6-pentachloroanisole;
methyl pentachlorophenate
Mol. wt.: 280.34 g/mole
The uptake, metabolism, and elimination of pentachloroanisole (PCA)
in rainbow trout was reported by Glickman et al.(l). PCA uptake was
studied in fish (8-10 g) exposed to 0.024 mg of (1^C)PCA per liter of
water for a total of 12 hours. Samples of blood and tissues (liver,
muscle, and fat) were collected periodically during exposure for analysis
of PCA concentrations. From the data collected it was determined that PCA
was rapidly taken up from water and was especially concentrated in adipose
tissue. The concentration of PCA in adipose tissue reached a level equal
to 4,000 times the initial PCA concentration in water.
In the elimination tests, fish were exposed for 12 hours to
( C)PCA (0.024 mg/L) and then removed to fresh water. The analysis of
samples taken daily for 7 days showed very long retention of PCA in the
blood and tissues. The half-life of PCA was calculated for the samples and
expressed in terms of days as follows: fat tissue, 23.4; liver, 6.9;
muscle, 6.3; and blood, 6.3. The long retention times were attributed to
high lipid solubility of PCA.
Metabolism experiments were conducted with rainbow trout (50-100 g)
exposed to 0.05 mg (14C)PCA/L at 12°C for 24 hours. After exposure,
the bile, liver, and muscle tissues were collected for determination of
metabolites. Analysis revealed only PCA in muscle tissue, PCA plus a more
polar substance in liver tissue, and a polar metabolite in bile which was
identified as glucoronide-conjugated pentachlorophenol (PCP). Through
further experimentation the authors concluded that the PCP detected in bile
was formed in vivo by demethylation of PCA.
56
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Based on their results, Glickman et al.(l), suggested two explana-
tions of the route and rate of PCA elimination from rainbow trout. First,
biliary excretion of the compound may be controlled by the rate of PCA
demethylation to PCP, which is then conjugated with glucoronic acid and
excreted. Secondly, the transfer of PCA from the tissues to the metabolic
and excretory sites (liver, kidney, and gills) may be the overall factor
influencing PCA elimination.
REFERENCE
1. Glickman, A. H., C.N. Statham, A. Wu, and J.J. Lech. 1977. Studies
on the uptake, metabolism, and disposition of pentachlorophenol and
pentachloroanisole in rainbow trout. Toxicol. Appl. Pharmacol.
41:649-658.
57
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PENTACHLOROBENZENE
C6HC15
CAS: 000608935
SYN: quintachlorobenzene;
1,2,3,4,5-pentachlorobenzene
Mol. Wt.: 250.34
bp: 277 (at 760 mm Hg)
vp: 1.04 mm Hg (at 98.6°C)
Parke and Williams (1) reported that pentachlorobenzene is only slightly
altered in vivo by rabbits. Urinary excretion of metabolites by the rabbit
plays a"minor role in bodily elimination of pentachlorobenzene, accounting
for not more than 1% of a 0.5 mg/kg dose. Three to four days following
gavage administration, 60% of the dose was isolated in the gut contents and
tissues. Additionally, 10-20% of the dose was deteted in expired air as
lesser chlorinated benzenes.
Kolhi et al. (2), reported that analysis of urine and feces obtained
from rabbits (4-5 kg) for 10 days following ip administration of penta-
chlorobenzene (300 mg), revealed the presence of pentachlorophenol (1% of
dose), 2,3,4,5-tetrachlorophenol (1% of dose) and a trace amount of bound
metabolites. The presence of urinary dechlorination products led Kolhi et
al. (2), to propose that the oxidation and accompanying dechlorination-
hydroxylation of pentachlorobenzene may be associated with an arene oxide
intermediate.
Following daily oral dosing of pentachlorobenzene (8 mg/kg) to male
rats (250 g) for 19 days, Engst et al. (3), identified the following metab-
olites :
A. Urine:
1) 2,3,4,5-tetrachlorophenol and pentachlorophenol, identified as
the main metabolites
2) pentachlorobenzene, 2,3,4,6-tetrachlorophenol and/or 2,3,5,6-
tetrachlorophenol, present in free form
3) 2,4,6-trichlorophenol and 1,2,3,4-tetrachlorophenol, present in
small amounts
58
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B. Faces:
pentachlorobenzene, tetrachlorobenzene and trichlorobenzene
C. Kidneys and blood:
pentachlorophenol and 2,3,4,5-tetrachlorophenol
D. Liver:
pentachlorobenzene and 1,3,5-trichlorobenzene.
Leber et al. (4), reported in 1977 the results of a metabolism study in
which rhesus monkeys were given ^C-labelled pentachlorobenzene (20
mg/animal). Up to 22% of the dose was isolated from the feces and urine
during the first 6 days following dosing. Feces were found to contain the
parent compound while the radioactive compounds in the urine were identi-
fied as two isomers of tetrachlorophenol. The authors concluded that pen-
tachlorobenzene exhibits a prolonged retention time in the rhesus monkey
(4).
Following a single ip injection of pentachlorobenzene (403 uM/kg) to
female rats, Koss and Koransky (5) analyzed the urine and feces collected
for 4 days to identify the metabolic products. Almost complete biodegrada-
tion of the pentachlorobenzene was observed; the major portion of the dose
was excreted in the urine and feces as hydrophilic metabolites, including
pentachlorophenol (9%), 2,3,4,5-tetrachlorophenol, tetrahydroquinone, a
hydroxylated chlorothiocompound, and trace amounts of another tetrachloro-
phenol isomer. These compounds were also identified in the tissues of the
treated rats.
59
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REFERENCES
1. Parke, D.V. and R.T. Williams. 1960. Studies in detoxification. 81.
The metabolism of halogenobenzenes: (a) penta- and hexa-chloroben-
zenes. (b) Further observations on 1:3:5-trichlorobenzene. Biochem.
£._ 74: 5-9.
2. Kolhi, J., D. Jones and S. Safe. 1976. The metabolism of higher
chlorinated benzene isomers. Can. J. Biochem. 54(3): 203-8.
3. Engst, R., R.M. Macholz, M. Kujawa, H.-J. Lewerenz and R. Plass.
1976. The metabolism of lindane and its metabolites
gamma-2,3,4,5,6-penta- chlorocyclohexane, pentachlorobenzene, and
pentachlorophenol in rats and the pathways of lindane metabolism.
Journ. Env. Sci. Hlth. Bll(2): 95-117-
4. Leber, A.P., R.I. Freudenthal, R.L. Baron and A. Curley. 1977. Phar-
macokinetics and metabolism of pentachlorobenzene in rhesus monkeys.
Tox. App. Pharm. 41(1): 215. Abstract no. 199.
5. Koss, G. and W. Koransky. 1978. Pentachlorophenol in different
species of vertebrates after administration of hexachlorobenzene and
pentachlorobenzene. Env. Sci. Res. 12: 131-7.
60
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PENTACHLOROETHANE
Cl Cl
C2HC15 I I
Cl—C—C—H
I !
Cl Cl
CAS: 000076017
Syn: ethane pentachloride
Mol wt: 202.30 g/mole
bp: 162°c (at 760 mm Hg)
vp: 4.5 mm Hg (at 25°c)
The metabolism of pentachloroethane (PCE) in mice was studied exten-
sively by Yllner (1). Female albino mice were injected subcutaneously with
20 uL of PCE and were sustained on a 5% glucose solution during the studies.
Urine, feces, and expired air were collected for 4 days. Quantitative
determinations of PCE metabolites were made by gas and paper chromatography.
About 80% of the administered dose of PCE was accounted for in 4 days.
The greatest excretion of metabolites occurred in the first 24 hours after
injection. In order of predominance, the metabolites were identified as
PCE (unchanged), trichloroethanol, trichloroacetic acid, tetrachloro-
ethylene, and trichloroethylene. Fowler (2) also identified tetrachloro-
ethylene as a metabolite of PCE given orally to sheep. The results of
Yllner's studies (1) indicated that hydrolysis of the carbon-to-chlorine
bond was the major and most rapid reaction in PCE metabolism. Hydrolysis
of C-C1 bonds apparently yielded chloral, an important intermediate in the
formation of trichloroethanol by reduction and trichloroacetic acid by
oxidation. The metabolites trichloroethylene and tetrachloroethylene were
probably formed by direct removal of chlorine and hydrochloric acid,
respectively, from chloral.
In more recent studies, Yllner (3) confirmed his preliminary data on
the metabolism of PCE in mice. PCE (1.1 - 1.8 g/kg) was injected subcuta-
neously in mice and excretion was monitored for 3 days. Specific quantita-
tive determinations of the metabolites showed that about 1/3 (12 - 51%) of
the injected dose was expired unchanged. The levels of other metabolites
were reported as follows:
61
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trichloroethanol 16-32% in urine
trichloroacetic acid 9-18% in urine
trichloroethylene 2-16% in expired air
tetrachloroethylene 3-9% in expired air.
In addition to the above mentioned pathway of PCE metabolism, Yllner
(3) suggested that at least part of the urinary metabolites (trichloro-
ethanol and trichloroacetic acid) were probably formed via trichloro-
ethylene and its metabolite, chloral hydrate.
REFERENCES
1. Yllner, S., 1963. The metabolism of pentachloroethane and unsymmetric
tetrachloroethane. Proc. XIV. Int. Congr. Occupat. Health. Madrid.
825-827.
2. Fowler, J.S.L., 1969. Some hepatotoxic actions of hexachloroethane and
its metabolites in sheep. Brit. J. Pharmacol. 35(3):530-542.
3. Yllner, S., 1971. Metabolism of pentachloroethane in the mouse. Acta
pharmacol. et toxicol. 29(5-6):481-489.
62
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TETRACHLOROBENZENE
C6H2C14
Mol wt: 215.88g/mole
1,2,3,4-tetrachlorobenzene
CAS: 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: 000634662
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: 243-6°C (at 760 mm Hg)
vp: 0.1 mmHg (at 25°C)
In a study reported in 1958, Jondorf and colleagues (1) examined the
metabolism of the three isomeric forms of tetrachlorobenzene in doe chin-
chilla rabbits. Each experimental rabbit received a daily dose (0.3 or
0.5 g/kg), via gavage administration, of one of the isomeric tetrachloro-
benzenes. Expired air, urine and feces were collected daily for spectro-
photometric and chromatographic determination of parent compound and metab-
olite concentrations. At the end of 6 days, some of the experimental
63
-------
rabbits were sacrificed for tissue and organ analysis. Results of the
tests are presented in Tables 1-4 (1).
Table 1 . Elimination of unchanged tetrachlorobenzenes in the expired air of rabbits
receiving these compounds orally
Percentage of dose in expired air
Tetra-
cliloroD6HZ6n.c
fed
1:2:3:4-
1:2:3:5-
1:2:4:5-
Days after dosing
jJOSG
0-5
0-3
0-5
0-3
0-5
1
1-9
0-8
2-1
0-9
1-2
o
2-'"1
1-7
2-1
3-2
0-2
3
1-6
6-7
1-2
9-8
0-2
4
0-2
—
2-9
—
—
5 Total
— 5-9
g.o
2-6 10-9
— 13-9
— 1-6
Table 2. Tetrachlorobenzenes in tissues
Dose, 0-5 g./kg. orally. Babbits were killed 6 days after dosing.
Percentage of dose found unchanged in
Tetracblorobenzene
fed
1:2:3:4-
1:2:3:5-
1:2:4:5-
Liver
0-1
<0-5
0-1
Brain
—
<0-2
<0-1
Skin
2
5
10
Depot
fat
5
11
25
Gut
contents
0-5
1-4
6'2
Best of
body
2-0
5-2
6-4
1
Total
10
23
4S
Table 3. Urinary excretion of the metabolites of tetrachlorobenzenes
Dose, 0-5 g./kg. orally. Figures given are mean values with ranges in parentheses and the number of experiment
indicated by superior figures.
Percentage of dose excreted as
Tetrachlorobenzene
administered
1:2:3:4-
1:2:3:5-
1:2:4:5-
* Without collars, 5-5 (2-8)'; with collars, to prevent coprophagy, 0 (4-10)a.
t Without collars, 2 (
1-3 (0-9, 1-6)J
Total
43 (38, 4S)!
5 (4, tip
2-2 (1-1, S-:)'
Phenols
Tetrachlorobenzene
fed
1:2:3:4-
1:2:3:5-
1:2:4:5-
Tetrachloro-
phenola
43
5
2
Other
phenols
<1
5
5
Unchanged tetrachlorobenzone in
Faeces
5
14
16
Tissues
10
23
48
Breath
8
12
2
Other chloro-
benzenes in
breath
o
9
10
Total
Iji
tia
sJ
As shown in the tables, metabolism of the tetrachlorobenzenes proceeded
fairly slowly. In 6 days 43% of 1,2,3,4-tetrachlorobenzene was oxidized to
2,3,4,5-tetrachlorophenol, 5% of 1,2,3,5-tetrachlorobenzene was oxidized to
2,3,4,6-tetrachlorophenol, and 2% of 1,2,4,5-tetrachlorobenzene was oxi-
dized to 2,3,5,6-tetrachlorophenol. Two to 15% of the administered com-
pounds was dechlorinated and excreted in the expired air and urine as less
64
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chlorinated benzenes, while the reminder was excreted or retained in the
tissues unchanged (1).
Kohli et al. (2), also studied the metabolism of tetrachlorobenzenes in
rabbits. In addition to those isolated by Jondorf et al. (1), the phenolic
metabolites of 1,2,3,4-tetrachlorobenzene were found to contain 2,3,4,6-
tetrachlorophenol, and 2,3,4,5- and 2,3,5,6-tetrachlorophenol for 1,2,3,5-
tetrachlorobenzene (2). They suggested that the conversion to tetrachloro-
phenols involves the formation of arena oxide intermediates, as shown in
the following diagram.
CI
CI
Metabolism of isomeric tetrachlorobenzenes
References
Jondorf, W.R., D.V. Parke and R.T. Williams. 1958.
fication. 76. The metabolism of halogenobenzenes.
and 1:2:4:5-tetrachlorobenzenes. Biochem. J. 69(2)
Studies in detoxi-
1:2:3:4-, 1:2:3:5-
181-189.
Kolhi, J., D. Jones and S. Safe. 1976. The metabolism of higher
chlorinated benzene isomers. Can. J. Biochem. 54(3): 203-8.
65
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1,1,2,2-TETRACHLOROETHANE
Cl Cl
C2H2C14 H__C_C_H
I I
Cl Cl
CAS: 000079345
Syn: acetylene tetrachloride; dichloro-2,2-dichloroethane;
tetrachloroethane; sym-tetrachloroethane; TCE.
Mol wt: 167.84 g/mole
bp: 760°C (at 146.5 mm Hg)
vp: 6.4 mm Hg (at 25°C)
The literature on 1,1,2,2-tetrachloroethane (tetrachloroethane) metab-
olism is limited with regard to biotransformation in humans. However,
Yllner (1) conducted a comprehensive study of tetrachloroethane metabolism
in the mouse. Also, a thorough review of the available literature is
included in the NIOSH criteria document on occupational exposure to
1,1,2,2-tetrachloroethane (2).
The retention and elimination of tetrachloroethane and other halogen-
ated hydrocarbons by humans was studied by Morgan et al. (3). Subjects
were administered about 2.5 mg of -^Cl-labelled 1,1,2,2-tetrachloroethane
in a single-breath inhalation exposure, in which each subject held the
vapor in his lungs for 20 seconds to maximize pulmonary absorption. From
analysis of "el-activity in expired breath immediately after exposure,
it was determined that approximately 97% of the tetrachlorethane was
retained in the lungs. The elimination of "d-activity in expired air
was then measured for 1 hour. Results showed that only 3.3% of the retain-
ed tetrachloroethane was exhaled in one hour, indicating a low rate of pul-
monary elimination for the compound (2,3). In addition, a urine sample was
taken 1 hour after administration of the hydrocarbon and measurement of the
radioactivity demonstrated that tetrachloroethane had a relatively high
urinary excretion rate (equivalent to 0.015% per minute) compared to the
other hydrocarbons tested (3).
66
-------
Morgan et al. (3), also performed in vitro tests to determine the par-
tition coefficients (Kp) of 1,1,2,2-tetrachloroethane between blood and
air and between serum and sir. Samples of 2 ml of venous blood or serum
were equilibrated with 1 ml of tetrachloroethane for 5 minutes at 40°C.
The KD values, defined as the concentration in liquid/ concentration in
gas, were reported as 72.6 (blood/air) and 78.2 (serum/air). The authors
suggested that the high KD values for tetrachloroethane represented the
compound's solubility in blood and serum lipids, which would account for
its high level of retention in the lungs (2,3).
The pattern of elimination, identification of metabolites, and prob-
able metabolic pathways were reported by Yllner (1) in an extensive study
of 1,1,2,2-tetrachoroethane metabolism in the mouse. Mice were injected
intraperitoneally with 0.21-0.32 g of ^C-labelled tetrachloroethane
(0.51 uCi/mg) per kg of body weight, and the elimination of radioactivity
was measured by liquid scintillation spectrometry for 3 days. Metabolites
in urine and expired air were determined by gas or paper chromatography and
isotope dilution analysis (1,2).
The results showed that the metabolism of 1,1,2,2-tetrachloroethane in
the mouse was fairly rapid and complete, 60-70% of the dose being excreted
in 24 hours. In 3 days, about 50% of the administered dose was oxidized
and expired as ^C02- Less than 4% was expired unchanged, 28% was
excreted in urine, less than 1% was detected in feces contaminated with
urine, and 16% of the dose remained in the animal tissues (1,2).
Analysis of the expired air revealed the presence of minute quantities
of trichloroethylene and tetrachloroethylene in addition to C02 and
unchanged tetrachloroethane. In the first 24 hours, tri- and tetrachloro-
ethylene were expired in amounts equal to about 0.2 - 0.4% of the injected
dose of 1,1,2,2-tetrachloroethane (1).
The urinary metabolites excreted in 24 hours were identified and
expressed as percentages of urinary radioactivity as shown in Table 1 (1).
67
-------
% of urinary activity
a
Mean Range
Dichloroacetic acid
Trichloroacetic acid
Trichloroethanol
Oxalic acid
Glyoxylic acid
Urea
27<7)
4(4)
10(5)
7(7)
0.9(4)
2(2)
20-34
2-8
3-15
5-10
0.4-1.4
2-3
3 The figures in brackets denote the number of animals examined.
Table 1 (1). Isotope dilution analysis of urinary metabolites from
14
mice receiving 1,1,2,2-tetrachloroethane C. Dose
0.16' - 0.32g/kg. Percentage of urinary activity
excreted in 24 hours.
Ikeda and Ohtsuji (4) also reported low levels of the urinary metabo-
lites trichloracetic acid and trichloroethanol in rats, following exposure
to 1,1,2,2-tetrachloroethane. Two studies were conducted, and urinary con-
centrations of total trichloro-compounds (TTC), trichloroacetic acid (TCA),
and trichloroethanol (TCE) were determined for each by a modification of
the Fujiwara color reaction method. In the first experiment, rats were
exposed to 200 ppm of tetrachloroethane for 8 hours. Urine was collected
for 48 hours and the concentrations of TTC, TCA, and TCE were determined to
be 8.2, 1.7, and 6.5 mg/kg of body weight, respectively. The second test
involved intraperitoneal injection in rats of 2.78 mmol of tetrachloro-
ethane per kg body weight. In the first 48 hours after injection, urinary
metabolite concentrations were reported to be 2.1 mg/kg TTC, 1.3 mg/kg TCA,
and 0.8 mg/kg TCE. In the next 48-hour period the respective metabolite
levels were 0.3, 0.3, and an immeasurable amount. The authors pointed out
that among tetrachloroethane and the other compounds tested (trichloro- and
tetrachloro-deriviatives of ethane and ethylene), variations in the quanti-
ties of metabolites eliminated were related to the vapor pressure of the
test compounds. Furthermore, it was stated that the rate of elimination is
determined in part by the compound's degree of stability, or tendency to
undergo biotransformation (2,4).
68
-------
Yllner (1) proposed a scheme for the metabolism of 1,1,2,2-tetra-
chloroethane, shown in Figure 1, based on the study of tetrachloroethane
metabolism in the mouse. The major pathway probably involves hydrolytic
cleavage of the two carbon-chlorine bonds to form dichloroacetaldehyde
hydrate, which is then oxidized to the major intermediate metabolite,
dichloroacetic acid. Dichloroacetic acid, not a stable end product, under-
goes further biotransformation, probably via hydrolytic dehalogenation, to
produce the urinary metabolite glyoxylic acid (1,2). The degradation of
1,1,2,2-tetrachloroethane to glyoxylic acid was substantiated by the detec-
tion of C02 and oxalic acid, which are glyoxylate metabolites, in mice
exposed to tetrachloroethane (1). The production of glycine, another end
product of glyoxylic acid, was demonstrated by the excretion of large
amounts of hippuric acid from mice following simultaneous injections of
^C-tetrachloroethane and sodium benzoate (1,2).
A second metabolic pathway was described in which a minor amount of
1,1,2,2-tetrachloroethane is probably dechlorinated by a non-enzymic reac-
tion to form trichloroethylene, the precursor to the urinary metabolites
trichloroacetic acid and trichloroethanol (1,2).
Third, a very small amount of 1,1,2,2-tetrachloroethane probably
undergoes oxidation to tetrachloroethylene, which the author suggested
would contribute slightly to the production of the urinary end products
oxalic acid and trichloroacetic acid, based on the results of an earlier
study (Yllner, S., 1961, Nature, 191: 820) on the metabolism of tetra-
chloroethylene (1,2).
69
-------
CC!2 : CHCI •< CHC!2 CHCIj'
[CC!3CHO]
CC!2 : CC!2
, / \ X i
CC13CH2OH CCI3COOH HOOC COOH
•> [CHC!2CHO]
CHCI2 COOH
CHO COOH
T
CO2+ [HCOOH]
CH2 NH2 COOH
a) trichloroethylene
b) tetrachloroethane
c) dichloroacetaldehyde
d) trichloroacetaldehyde
e) tetrachloroethylene
f) dichloroacetic acid
g) trichloroethanol
h) trichloroacetic acid
i) oxalic acid
j) glycine acid
k) glyceine
Fig. 1. Proposed metabolic pathways of 1,1,2,2-tetrachoroethane.
bracketed compounds were not isolated. From the NIOSH criteria
document on occupational exposure to 1,1,2,2-tetrachloroethane (2)
as adapted from Yllner (1).
The
70
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REFERENCES
1. Yllner, S. 1971. Metabolism of 1,l,2,2-tetrachloroethane-14C in the
mouse. Acta pharmacol et toxicol. 29: 499-512.
2. NIOSH, 1976. Criteria for a recommended standard ... occupational
exposure to 1,1,2,2-tetrachloroethane. U.S. Dept. H.E.W. Publication
no. 77-121: pp. 27-29, 61-64.
3. Morgan, A., A. Black and D.R. Belcher. 1970. The excretion in breath
of some aliphatic halogenated hydrocarbons following administration by
inhalation. Ann. Occup. Hyg. 13: 219-233.
4. Ikeda, M. and H. Ohtsuji. 1972. A comparative study of the excretion
of Fujiwara reaction-positive substances in urine of humans and rodents
given trichloroor tetrachloro-derivatives of ethane and ethylene. Br.
J. Ind. Med. 29: 99-104
71
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TETRACHLOROETHYLENE
Cl Cl
\ /
C2ClA C = C
/ \
ci ci
CAS: 000127184
Syn: carbon bichloride; carbon dichloride;
ethylene Cetrachloride; perchloroethylene;
tetrachloroethylene ; tetrachloroethene ;
1,1,2, 2- tetrachloroethylene
Mol wt: 165.83 g/mole
bp: 121°C (at 760 mm Hg)
vp: 18.0 mm Hg (at 25°C)
Various researchers have reported on the metabolites of tetrachloro-
ethylene. Much of what has been reported is contradictory. The conflict-
ing data involves the identification of metabolites found in the urine.
Researchers of the metabolism of tetrachloroethylene in animals and humans
agree that trichloroacetic acid is a metabolite in the urine. Daniel (1),
Bonse et al. (2), Leibman and Ortiz (3), and Hake et al. (4) report that
trichloroacetic acid is the only metabolite of tetrachloroethylene found in
the urine. Several experimenters have found oxalic acid as a metabolite in
the urine (5,6). Ikeda et al. (7,8) found trichloroethanol. Ogata et al.
(9) found an unknown chlorinated hydrocarbon that gave trichloroacetic acid
upon oxidation but could not identify it as trichloroethanol. One research-
er (6) reported ethylene glycol as the most prevalent metabolite.
Yllner (5) exposed mice to ^C-tetrachloroethylene vapor (1.3 mg/gm
body weight). Using chromatographic, autoradiographic and isotope-dilution
methods, he found the following: 52% of the total urinary 1^C-activity
was identified as trichloroacetic acid, oxalic acid accounted for 11%, and
dichloroacetic acid was found in trace amounts. No trichloroethanol was
found. Yllner was unable to extract 18% of the urinary ^C-activity. To
account for the trichloroacetic acid he proposed the formation of an epox-
ide intermediate as one metabolic pathway. The epoxide then undergoes
rearrangement to form trichloroacetic chloride, as shown:
cci2 = cci2 ->• ci2c — -cci + ci3c — coci -»• ci3c — COOH
72
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Daniel (1), studying the distribution of 36Cl-tetrachloroethylene
radioactivity fed to rats, detected trichloroacetic acid and inorganic
chloride as the only metabolites of tetrachloroethylene in urine. He found
an equimolar ratio between trichloroacetic acid and chloride ion. There-
fore, little if any oxalic acid could have been present. Daniel (1)
suggested that the metabolism of tetrachloroethylene may involve the
following series of reactions:
/O
cci2=cci2 + ci2c—-cci2 + ci3c —coci -> ci3ccooH + ci
In this proposed pathway, the acid chloride is rapidly hydrolized to
trichloroacetic acid. Neither trichloroethanol or oxalic acid are formed.
Ikeda and Ohtsuji (7) exposed rats to tetrachloroethylene vapor at a
concentration of 200 ppm for 8 hours and collected the urine for 48 hours
from the start of exposure. They determined the metabolites colori-
metrically by the Fujiwara reaction and found trichloroacetic acid and
trichloroethanol as the urinary metabolites of tetrachloroethylene. In the
same report Ikeda and Ohtsuji (7) found that male workers exposed to 20-70
ppm and 200-400 ppm tetrachloroethylene excreted both trichloroethanol and
trichloroacetic acid in the urine. In order to 'determine the effects of
different routes of administration on the urinary metabolites Ikeda and
Ohtsuji (7) injected tetrachloroethylene intraperitoneally into rats and
mice. The urine was collected for 48 hours after injection. They found
little or no trichloroethanol excreted in the urine of the rats and mice.
Ogata et al. (9-) exposed human male volunteers to 87 ppm tetrachloro-
ethylene for 3 hours, collecting the urine frequently for up to 100 hours
after the start of exposure. Two trichloro-compounds were determined, tri-
chloroacetic acid and an unknown compound which gave trichloroacetic acid
upon oxidation by chromium oxide. Ogata et al. (9) could not detect the
absorption maximum of trichloroethanol after treating with beta-glucuroni-
dase, so the unknown chlorinated hydrocarbon could not be shown to be tri-
chloroethanol.
Dmitrieva (6) reported that ethylene glycol was the most prevalent
urinary metabolite in rats following acute and chronic exposure to tetra-
chloroethylene. Trichloroacetic acid and oxalic acid were also found.
Bonse et al. (2), studying oxirane formation and biological reactivity
of chlorinated ethylenes, found that in isolated perfused rat livers, tri-
chloroacetic acid was the only metabolite of tetrachloroethylene. Ten to
15% of the total uptake of tetrachloroethylene was found as trichloroacetic
acid in the circulating perfuse, and 3 to 5% of the total uptake was found
as trichloroacetic acid bound to the liver tissue and extractable only
after acid hydrolysis. The authors proposed the following mechanism based
on their findings:
73
-------
Cic===cci2 - ci/—cci2 -> cci3- coci
H S04
CC13— COOH ^ 1 CC13— COR
Enzyme
Catalysed
R = (eg. OH, SH, NH?)
The authors postulated that trichloroacetyl chloride reacted with cell con-
stituents resulting in acylation (2).
In a review of the literature, Liebman and Ortiz (3) proposed that
tetrachloroethylene is metabolized to tetrachloroethylene oxide by mixed
function oxidation followed by hydration of the epoxide, forming a glycol.
Due to the symmetry of the epoxide and the glycol, rearrangement of either
would yield only one product, trichloroacetyl chloride, which is hydrolyzed
to trichloroacetic acid.
Whether the different metabolites are due to differences in experimen-
tal procedure or method of analysis is not fully explored in the litera-
ture. Daniel (1) stated that some of the conflicting observations may be
due to the different routes of administration employed. Ikeda and Ohtsuji
(7) suggested that the differences may be due to duration and intensity of
exposure. Leibman and Ortiz (3), in a review of the metabolism of halogen-
ated ethylenes, suggest that in those studies (7,8) using the Fujiwara
colorimetric reaction, it was assumed that trichloroethanol was that part
of the total trichloro compounds not identified as trichloroacetic acid.
Ogata et al. (9), using this method, could not prove that trichloroethanol
was part of the total trichloro compounds.
Studies on the fate of tetrachloroethylene in rats and humans indicate
that the greater part of the dose (by inhalation, ingestion, or intraperi-
toneal injection) is expired via the lungs (1,5,9,10,11). Daniel (1) fed
rats 1.75 uCi 36Cl-tetrachloroethylene and found that 97.9% of the orig-
inal dose was expired in 48 hours. None of the metabolites of tetrachloro-
ethylene were found in the expired air. -^Cl-Tetrachloroethylene was
expired by the rats unchanged. Approximately 2% of the radioactivity was
excreted in the urine in 18 days. Of this, trichloroacetic acid in the
urine made up 0.6% of the original radioactivity.
74
-------
Yllner (5) exposed mice to ^C-tetrachloroethylene vapor (1.3 mg/gm
body weight) in sealed flasks. Seventy percent of the solvent was absorbed.
In four days about 90% of the absorbed ^C-activity was excreted: 70% of
the absorbed ^C-activity was found in expired air, 20% in the urine, and
less than 0.5% in the feces. After exposure of human volunteers to 87 ppm
for 3 hours, Ogata et al. (9), found that 1.8% of the inhaled amount was
excreted by the kidney as trichloroacetic acid. Other researchers (10,12)
have observed that only a small portion of the solvent accumulated in the
body, while most of the solvent was rapidly absorbed and excreted via the
lungs. Bolanowska and Golacka (13) reported results contrary to this view
and stated that very little tetrachloroethylene is metabolized in man.
Ikeda and Ohtsuji (7), in experiments on the excretion of metabolites
in rat urine, found 5.3 mg/kg body weight of trichloroacetic acid and 3.2
mg/kg body weight of trichloroethanol after exposing rats to 200 ppm tetra-
chloroethylene for 8 hours. Ikeda and Ohtsuji (7) found 4-20 mg/kg body
weight of trichloroethanol and 4-35 mg/kg body weight of trichloroacetic
acid in the urine of workers occupationally exposed to 20 - 70 ppm tetra-
chloroethylene. In workers exposed to 200 - 400 ppm tetrachloroethylene,
21 to 100 mg/L of trichloroethanol and 32 - 97 mg/L of trichloroacetic acid
were found in the urine. In order to evaluate the effect of different
routes of administration, Ikeda and Ohtsuji (7) injected rats with 2.78
mmol/kg body weight of tetrachloroethylene intraperitoneally. After col-
lecting the urine for 48 hours, analysis showed the accumulation of 5.5
mg/kg body weight trichloroacetic acid and little or no trichloroethanol.
Ikeda et al. (8) found that urinary metabolite levels in man and rats
increased until atmospheric concentrations of tetrachloroethylene reached
50 - 100 ppm; little increase was observed at higher concentrations.
Results indicate that the capacity of human subjects to metabolize tetra-
chloroethylene is limited even at relatively low concentrations.
Experimenters have shown that the metabolites of tetrachloroethylene
are very slowly excreted (10,12,14). Wolff (12) detected 1 ppm of tetra-
chloroethylene in the breath of humans 14 days after the subjects were
exposed to a concentration of 100 ppm tetrachloroethylene (7 hours/day, 5
days). They found a respiratory half-life of 3 days for tetrachloroethyl-
ene. Ikeda and Imamura (10) reported a urinary half-life of 144 hours, and
calculated a respiratory half-life of 65 hours (occupational exposure) from
the data of Stewart et al. (11).
Lastly, tetrachloroethylene has been shown to accumulate in body
tissues. Savolainen et al. (15) exposed rats to 200 ppm tetrachloroethyl-
ene for 6 hours per day for 4 days. Seventeen hours after the fourth day
exposure, they found a marked accumulation of the solvent in the perirenal
fat (622.2 nmol/g), as well as accumulations in the cerebrum (18.4 nmol/g)
and cerebellum (13.1 nmol/g). After 6 hours additional exposure on the
fifth day, 1724.8 nmol/g of tetrachloroethylene was found in the perirenal
fat. Significant accumulations of tetrachloroethylene were also detected
in the brain (cerebrum, 142.5 nmol/g; cerebelllum, 92,3 nmol/g) after 6
hours exposure on the fifth day.
75
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REFERENCES
1. Daniel, J.W. 1963. The metabolism of 36Cl-labelled trichloroethyl-
ene and tetrachloroethylene in the rat. Biochem. Pharmacol. 12:
795-802.
2. Bonse, G., T. Urban, D. Reichert and D. Henschler. 1975. Chemical
reactivity, metabolic oxirane formation and biological reactivity of
chlorinated ethylenes in the isolated perfused rat liver preparation.
Biochem. Pharmacol. 24(19): 1829-1834.
3. Leibman, K.C. and E. Ortiz. 1977. Metabolism of halogenated ethyl-
enes. Environ. Hlth. Perspect. 21: 91-97.
4. Hake, C.L., R.D. Stewart, A. Wu and S.A. Graff. 1976. Experimental
human exposures to perchloroethylene: I. Absorption and excretion.
Toxicol. Appl. Pharmacol. 37(1): 175. Abstract no. 200.
5. Yllner, S. 1961. Urinary metabolites of -^C-tetrachloroethylene in
mice. Nature. 191: 820.
6. Dmitrieva, N.V. 1967- Tetrachloroethylene metabolism. Gig. Tr.
Prof. Zabol. 11(1): 54-56. Chem. Abs. 66: 93533b.
7. Ikeda, M. and H. Ohtsuji. 1972. A comparative study of the excretion
of Fujiwara reaction-positive substances in urine of humans and
rodents given trichloroor tetrachloro-derivatives of ethane and
ethylene. Brit. J. Ind. Med. 29(1): 99-104.
8. Ikeda, M., H. Ohtsuji, T. Imamura and Y. Komoike. 1972. Urinary
excretion of total trichloro - compounds, trichloroethanol, and tri-
chloroacetic acid as a measure of exposure to trichloroethylene and
tetrachloroethylene. Brit. J. Ind. Med. 29(3): 328-333.
9. Ogata, M., Y. Takatsuka, K. Tomokuni, and K. Muroi. 1971. Excretion
of organic chlorine compounds in the urine of persons exposed to
vapours of trichloroethylene and tetrachloroethylene. Brit. J. Ind.
Med. 28(4): 386-391.
10. Ikeda, M. and T. Imamura. 1973. Biological half-life of trichloro-
ethylene and tetrachloroethylene in human subjects. Int. Arch.
Arbeitsmed. 31(3): 209-224.
11. Stewart, R.D., E.D. Baretta and H.C. Dodd. 1970. Experimental human
exposure to tetrachloroethylene. Arch. Environ. Hlth. 20: 224-229.
12. Wolff, M.S. 1976. Evidence for existence in human tissues of mono-
mers for plastics and rubber manufacture. Environ. Health. Perspect.
17: 183-187.
76
-------
13. Bolanowska, W. and J. Golacka. 1972. Inhalation and excretion of
tetrachloroethylene in humans under experimental conditions. Med.
Pracy 23(2): 109-119. Excerpta Medica. 35(3): Abstract 1163.
14. Ikeda, M. 1977. Metabolism of trichloroethylene and tetrachloro-
ethylene in human subjects. Environ. Hlth. Perspect. 21: 239-245.
15. Savolainen, H., P- Pfaffli, M. Tengen and H. Vainio. 1977. Biochem-
ical and behavioural effects of inhalation exposure to tetrachloro-
ethylene and dichlormethane. J. Neuropathol. Exp. Neurol. 36(6):
941-949.
77
-------
TRICHLOROBENZENE
C6H3C13
Mol. Wt: 181.45 g/mole
1,2,3-Trichlorobenzene
CAS: 000087616
SYN: vic-trichlorobenzene
1,2,6-trichlorobenzene
bp: 2180009 (at 760 mm Hg)
vp: .99 mm Hg (at 40°C)
1,2,4-Tr i ch1orob enz ene
CAS: 000120821
SYN: unsym-trichlorobenzene
bp: 213.5°C (at 760 mm Hg); 84.8°C 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)
Jondorf et al., in reports published in 1954 (1) and 1955 (2), identi-
fied the major urinary metabolites of the isomeric trichlorobenzenes in the
rabbit as trichlorophenols, predominantly conjugated with glucuronic acid
and ethereal sulfate. 1,2,3-Trichlorobenzene was found to generate 2,3,4-
trichlorophenol as its major metabolite, with lesser quantities of 3,4,5-
trichlorophenol and 3,4,5-trichlorocatechol. 1,2,4-Trichlorobenzene gave
rise to 2,4,5- and 2,3,5-trichlorophenol, together with small amounts of
3,4,6-trichlorocatechol. 1,3,5-Trichlorobenzene, the least readily meta-
bolized isomer, was found to generate only one phenolic metabolite, identi-
fied as 2,4,6-trichlorophenol. Trace amounts of mercapturic acids were de-
tected from 1,2,3- and 1,2,4-trichlorobenzene and were identified by the
same authors (2,3) as 3,4,5-trichlorophenylmercapturic acid, and 2,3,5- and
2,4,5-trichlorophenylmercapturic acids, respectively. Results and
78
-------
a schematic representation of metabolites identified by Jondorf et al. (2)>
are presented in Table 1 and Figure 1.
Table 1 (2). Quantitative excretion of metabolites of the
isomeric trichlorobenzenes.
[>.->se fed, 0-5 g./kg. wt. of rabbit. Figures refer to percentage of rlo«e excreted during 5
-------
(Ill)
Cl ... „ Cl ...
Major H. x-3,5-trichlorobenzene by rabbits and found that, in 9 days, approximately
10% of the dose administered (0.5 g/kg, oral) was excreted in the urine as
2,4,6- trichlorophenol. 4-Chlorophenol and 4-chlorocatechol were identi-
fied as minor urinary metabolites. The major portion of the administered
dose was recovered unchanged; 19% was found in the gut contents, 13% in the
feces, 32% in the body tissues, and 12% in expired air, 8 days afer dosing
(4).
80
-------
In 1976, Kolhi, et al. (5), reported a study of the metabolism of the
isomeric trichlorobenzenes in the rabbit. Analysis was performed on urine
and feces collected for 10 days following intraperitoneal administration of
the trichlorobenzene isomers (300 mg/rabbit; ave. wt. 4-5 kg). Qualitative
results were similar to those obtained in previous studies. However,
evidence was provided for the presence, as metabolites, of 2,3,6- and
2,3,5-trichlorophenols from 1,2,3- and 1,3,5-trichlorobenzenes, res-
pectively.
Kohli et al. (5), postulated the intermediacy of an arene oxide in
phenolic metabolite production from the isomeric trichlorobenzenes. A
schematic representation of tri.chlorobenzene metabolism, showing the arene
oxide intermediates, is presented in Figure 3 (5).
Fig. 3. Metabolism of isomeric trichlorobenzenes
81
-------
REFERENCES
1954. The metabolism of
J. 58(4): xxxv-xxxvi.
1. Jondorf, W.R., D.V. Parke and R.T. Williams.
the isomeric trichlorobenzenes. Biochem.
Abstract.
2. Jondorf, W.R., D.V. Parke and R.T. Williams. 1955. Studies in detoxi-
cation: 66. The metabolism of halogenobenzenes. 1:2:3-, 1:2:4- and
1:3:5-trichlorobenzenes. Biochem. J. 61(3): 512-20.
3. Jondorf, W.R., D.V. Parke and R.T. Williams. 1955. The structure of
the mercapturic acids formed in rabbits from trichlorobenzenes.
Biochem. J. 60(1): vii-viii. Abstract.
4. Parke, D.V. and R.T. Williams. 1960. Studies in detoxication: 81.
The metabolism of halogenobenzenes: (a) penta- and hexa-chloro-
benzenes. (b) Further observations on 1:3:5-trichlorobenzene.
Biochem. J. 74: 5-9.
5. Kohli, J., D. Jones and S. Safe. 1976. The metabolism of higher
chlorinated benzene isomers. Can. J. Biochem. 54(3): 203-8.
82
-------
1,1,1-TRICHLOROETHANE
Cl H
I I
G2H3cl3 Cl —C—C—H
I I
C! H
CAS: 000071556
Syn: methylchloroform; MC; alpha-trichloroethane
Mol wt: 133.41
bp: 74.1°C (at 760 mm Hg)
vp: 121.3 mm Hg (at 25°C)
The rapid and almost complete pulmonary excretion of 1,1,1-trichloro-
ethane, or methyl chloroform (MC) from the rat was demonstrated by Hake et
al. (1). Young adult rats (170-183 gm) were injected intraperitoneally
with 700 mg of 1,1, l-trichloroethane-l-C^ per kg. Urine, feces and ex-
pired air were collected for 25 hours, after which samples of blood,
various organs (liver, intestines, spleen, kidneys, heart, lungs, and
brain), retroperitoneal fat, skin, and muscle tissue were removed for
carbon-14 assay. Radioactivity was measured with a liquid scintillation
spectrometer and metabolites were identified by paper chromatography.
According to the data, 98.7% of the administered dose was excreted
through the lungs as unchanged 1,1,1-trichloroethane-l-C^ and about 0.5%
of the dose was excreted as C^02« Much of the remaining radioactivity
was detected in the urine as the glucuronide of 2,2,2-trichloro-
ethanol-2-C , possibly formed by hydroxylation and conjugation of the
parent compound. Very little carbon-14 activity was retained in the rat.
Analysis of the organs and tissues showed no activity in the spleen, trace
amounts in the liver, intestines, kidneys, heart, lung, brain, muscle, and
hair, and less than 0.05% of the dose in the blood, fat, and feces each.
The skin contained 0.08 - 0.12% of the dose of radioactivity, at least 90%
of which was attributed to unchanged 1,1,1-trichloroethane-l-C (1).
83
-------
Ikeda and Ohtsuji (2) studied the urinary metabolism of methylchloro-
form in the rat. Inhalation experiments were conducted in which
Wistar-strain rats (70 g) were exposed to 200 ppm of MC in air for 8
hours. Urine was collected for 48 hours after the start of the exposure
and analyzed colorimetrically by the Fujiwara reaction method to determine
the amounts of trichloroethanol (TCE) and trichloroacetic acid (TCA).
Very small amounts were detected: 3.1 and 0.5 mg/kg body weight of TCE and
TCA, respectively. Similar results were obtained when rats were injected
intraperitoneally with 2.78 mmol of MC per kg. Metabolite levels in urine
after 48 hours represented the excretion of 3.5 mg TCE
and 0.5 mg TCA/kg body weight. Metabolite excretion during the second
48-hour period amounted to an immeasurable amount of TCE and 0.3 mg
TCA/kg. The authors noted that the detection of very low levels of urinary
metabolites was consistent with the observation of Hake et al. (1), that
1,1,1-trichloroethane is almost entirely eliminated through the lungs while
only a small amount is metabolized and excreted in urine.
Eben and Kimmerle (3) confirmed the findings of Hake et al. (1), and
Ikeda and Ohtsuji (2) and furthermore reported that the amounts of urinary
metabolites and MC (in expired air) were both time-dependent and
dose-dependent. Acute and subchronic inhalation tests were conducted with
male Wistar rats. In the acute exposure studies, rats were subjected to a
single exposure of about 221 or 443 ppm of MC in air for 4 hours. Urine
was collected daily for 3 or 4 days for gas-chromatographic analysis of TCE
and TCA. Also, in several cases the concentration of MC in expired air was
measured hourly up to 11 hours after exposure.
Results showed that in each case most of the total TCE in urine was ex-
creted within 24 hours. The total amounts of TCE excreted from rats ex-
posed to 221 ppm and 443 ppm MC were 126.2 ug and 206.5 ug, respectively,
during the first day, and 7.5 and 8.6 ug, respectively, during the second
day. The metabolite TCA was eliminated in much smaller quantities and at a
more consistent rate, as follows: 3.2 ug (from the 221 ppm exposure) and
9.5 ug (443 ppm exposure) during the first day, and 8.1 and 10.6 ug, res-
pectively, during the second day. The hourly measurements of MC in expired
air indicated that MC content decreased exponentially with time. MC levels
also varied with the dose administered. At the 221 ppm exposure level, ex-
pired air contained 2.488 mg MC in the 1st hour and only 0.050 mg MC in the
8th hour; at the 443 ppm exposure, the values were 5.719 mg and 0.098 mg MC
during the 1st and 8th hours, respectively (3).
In the subchronic experiments, rats were exposed to 204 ppm MC for 8
hours per day, 5 days per week, for 14 weeks. Urinary excretion of TCE and
TCA was measured after the daily exposure. Blood concentrations of MC and
TCE were determined immediately after exposure, periodically
throughout the 14 weeks. After 14 weeks, samples of the fat, brain, heart,
liver, kidneys and spleen were analyzed for MC accumulation (3).
It was found that urinary TCA excretion was relatively constant during
the entire experiment, ranging between 12 and 20 ug per consecutive 24-hour
periods. Urinary TCE levels increased from about 93 ug in the first week
to about 435 ug in the tenth, after which the levels decreased slightly.
84
-------
Blood concentrations of MC and TCE were nearly constant; MC measured 0.677
to 1.000 ug/mL blood and TCE ranged form 0.059 to 0.88 ug/mL. The analyzed
tissue samples showed no accumulation of MC.
Human inhalation exposure studies have shown results similar to the
data obtained from experiments with rodents. The rapid pulmonary excretion
of MC by humans was reported by Morgan et al. (4). The subjects were
administered about 5 mg of ^Cl methylchloroform in a single inhalation
exposure and the expired air was analyzed for 1 hour by gamma-ray scintil-
lation spectrometry. A total of 44% of the inhaled dose was excreted in
the breath in one hour,
Astrand et al. (5), measured the concentration of methyl chloroform in
alveolar air, arterial blood, and venous blood of 12 men in an inhalation
study designed to simulate exposure to MC during light occupational work.
Test variables included exposure to methylchloroform at 250 or 350 ppm in
air, at rest or during light exercise (50, 100, or 150 W as measured on a
bicycle ergometer), with or without 4% C02 added to inspiratory air to
increase alveolar ventilation. Each exposure period was 30 minutes.
Breath and blood samples were taken during and after exposure for gas
chromatographic determination of MC content. The methylchloroform levels
measured at the end of the exposure period are shown in Tables 1 and 2. In
addition, results showed that MC levels in air and blood increased rapidly,
usually leveling off after 20 to 30 minutes during exposure. After level-
ing off, there was no increase in MC concentration in air or arterial blood
proportional to increased ventilation or circulation. The venous blood
levels of MC rose at about the same rate as arterial blood levels. MC con-
centrations in expired air, venous blood, and arterial blood all dropped
rapidly after exposure.
85
-------
Table 1 (5). Arterial and venous blood concentrations at rest
and exercise during exposure to 250 ppm and 350 ppm of methylchloroform.
All data are derived from individual values at the end of each exposure
period. Mean values and standard deviation are given except when
n 3, the mean and extreme values are given.
No. of
subjects
Arterial
blood cone.
ppm
Venous
blood cone.
ppm
Arterio-venous
difference
ppm
250 ppm
at
50
100
150
rest
watt
watt
watt
12
9
4
4
3.
4.
5.
5.
0
5
2
5
+ 0.
+ 0.
+ 0.
+ 0.
2
2
2
3
1.4
3.1
3.5
4.4
+ 0
+ 0
+ 0
+ 0
.2
.4
.8
.4
1.6
1.4
1.7
1.1
+ 0.2
+ 0.3
+ 0.8
+ 0.3
350 ppm
at
50
rest
watt
5
5
5.
7.
0
2
+ 0.
+ 0.
5
4
3.0
4.0
+ 0
5.5
- 6
.6
.6
2.0
0.4
+ 0.4
1.9
- 3.3
250 ppm
at
at
4 ;
50
4 /
rest
rest +
I C02
watt +
I C02
3
3
3
1.
3.
3.
2
9
0
2
.2
- 2.
3.3
- 3.
3.9
- 4.
5
9
5
1
0.5
0.9
1.4
.0
- 1
1.2
- 1
1.9
- 2
.2
.3
.3
1
1.0
1.7
0.9
.2
- 1.4
2.2
- 2.6
2.0
- 2.6
86
-------
Table 2. Alveolar air concentrations for 12 male subjects, at rest and
during exercise, exposed to 250 ppm and 350 ppm of methylchloroform in
air. VA = alveolar ventilation per unit of time (dead space estimated at
150 cnH for all subjects).
VA Alveolar
0 ppm
at rest
250 ppm
at rest
50 watt
100 watt
150 watt
350 ppm
at rest
50 watt
No. of
sub j.
8
12
9
4
4
5
5
BTPS
L/min
8.9 +
6.6 +
22.5 +
36.9 T
59.5 +
6.6 +
21.8 +
1.3*
0.4
1.9
2.4
4.8
0.7
1.1
cone.
ppm
-
125 +
168 +
210 +
207 +
179 +
239 +
6
7
4
14
13
17
250 ppm
at rest
at rest +
4 % C02
50 watt +
4 % C02
3
3
3
6.3
5.1 - 7.0
17.8
14.0 - 22.7
38.2
32.1 - 46.6
128
110 - 139
176
164 - 182
201
188 - 216
* measurement made after 5-10 min.
In another human exposure study, Stewart et al. (6), reported the
methylchloroform concentrations in expired air and the levels of urinary
metabolites TCE and TCA in 11 male subjects (31-62 yrs. old) exposed to 500
ppm methylchloroform in air for 6.5 - 7 hours per day for 5 days. The MC
concentration in alveolar air decreased exponentially after the exposure
period and was readily detected for a period of 10 days by infrared
techniques. In some cases, methylchloroform was detected by gas
chromatography as long as one month after exposure. A slight cumulative
effect of MC concentration in alveolar air was observed corresponding to
repeated exposures over the 5 day period. A leveling-off, or equilibrium,
was reached between the 3r" and 4"1 days.
87
-------
Results of the urinalyses are given in Table 3. The levels of TCE
showed a progressive increase during the 5-day exposure period. TCE was
still detected in urine 5 days after the final exposure but none was
detected 12 days after exposure. TCA concentrations, however, did not
increase much above the normal range (6).
Table 3 (6). Urinary excretion of TCA and TCE in five subjects
during and following vapor exposure to methyl chloroform
Control value
(mean and
range)
Methyl chloroform, 500 ppm
seven hrs/day for five days
TCA,
mg/24 hr
14.2 (8.0 - 22.8)
TCE,
mg/24 hr
less than 1.0
1st exposure day
2nd exposure day
3rd exposure day
4th exposure day
6th day following
last exposure
12th day following
last exposure
7.5 (2.6
10.9 (8.2
12.3 (5.6
14.1 (7.8
10.5
19.3)
27.0)
19.2)
18.0 (13.0 - 26.0)
17.5 (8.0 - 22.0)
20.1 (7.9 - 49.0)
30.1 (14.8 - 66.5)
29.3 (19.1 - 51.0)
46.6 (23.4 - 93.6)
7.0 (1.0 - 14.9)
less than 1.0
A study of the long-term occupational exposure of men to MC in air was
reported by Seki et al. (7). Concentrations of the urinary metabolites,
TCE and TCA, and total trichloro-compounds (TTC) were measured in males
(23-53 years old) who had been exposed to methyl chloroform at 4, 25, or 53
ppm for 8 hrs/day, 5.5 days/week, for at least 5 years. Urinalyses were
made daily for 1 week. The data, summarized in Table 4, indicated linear
relationships between the concentration of MC in inhaled air and the levels
of TTC, TCE, and TCA in urine. The biological half-life of methylchloro-
form, based on the decrease in urinary total trichlorocompounds, was
calculated as about 8.7 hours.
-------
Table 4 (7). Concentrations of metabolites in urine samples from
workers exposed to methylchloroform at various concentrations
for 8 hrs/day, 5.5 days/week, occupational exposure.
Metabolite concentrations*
Cone, of MC mg/L
in inhaled air
(ppm)
4.3
24.6
53.4
No. of
subjects
10
26
10
TTC
2.0
8.2
13.9
TCE
1.2
5.5
9.9
TCA
0.6
2.4
3.6
* Values represent geometric means.
Although it has been established that almost all of an inhaled dose of
methylchloroform is eliminated through the lungs and an additional portion
of the dose is excreted as urinary metabolites, recent studies have shown
that very small amounts of the parent compound, (methylchloroform) also
accumulate in body tissues. The bioconcentration of methylchloroform in
the perirenal fat, brain, liver, lung and blood of the rat was studied by
Savolainen et al. (8). Adult male Sprague-Dawley rats were exposed to 20
umol/L (500 ppm) of MC in air for 6 hrs/day for 4 days. Gas-liquid chroraa-
tograph analyses were made on the 5 day, 17 hours after the last
exposure period.
According to the results, methylchloroform accumulated primarily in the
perirenal fat (16.9 nmol/g) while smaller amounts were detected in the
organ tissues and blood (0.08 to 0.17 nmol/g). Additional exposure periods
of 2,3,4, or 6 hours on day 5 increased the concentrations of MC in tissues
and blood as shown (8):
Methylchloroform concentration in tissues
(nmol/g) after 4 days exposure (8)
17 hours after immediately after 2-6
final exposure hours additional exposure on
5th day
Perirenal fat
Cerebrum
Cerebullum
Lungs
Liver
Blood
16.9
0.15
0.17
0.17
0.15
0.08
183.5
12.2
13.2
7.9
14.7
8.5
- 276.0
- 15.6
- 21.3
- 11.7
- 21.3
- 13.1
89.
-------
In a more extensive inhalation study, Holmberg et al. (9), reported the
distribution of methylchloroform in the blood, liver, kidneys, and brain
tissues of mice exposed to various air concentrations of MC for different
periods of exposure. Male albino mice (NMRI strain, weighing 25 - 30 g)
were subjected to concentrations of 10 ppm to 10,000 ppm of MC for 0.5 to
24 hours. Blood and organ tissues were analyzed by gas chromatography. In
general, concentrations of methylchloroform were usually highest in the
liver and lowest in the blood. After exposure to 100 ppm MC for 0.5 to 24
hours, the levels of MC ranged as follows: 3.5 to 14.0 ug MC per g of
tissue (wet weight) in the liver, 3.0 to 8.1 ug/g in blood, 4.3 to 10.0
ug/g in the kidneys, and 4.4 to 9.2 ug/g in the brain tissues. Methyl-
chloroform concentrations resulting from other exposure times and dose
levels are given in Table 5.
90
-------
Table 5 (9). Concentrations of methylchloroform in mouse tissues at different inspiratory
air concentrations and exposure durations: means and standard deviations. Number of animals
indicated in parentheses. Concentrations in ug of methylchloroform per gram of tissue (wet weight),
Exposure
Time (h)
10 ppm
3
6
24
100 ppm
0.5
1
2
3
4
4.5
5
6
16
24
1,000 ppm
0.5
1
3
4.5
6
5,000 ppm
0.5
1
3
10,000 ppm
0.5
3
6
Blood
0.15 +
0.47 +
0.60 +
3.0 +
4.8 +
4.2 +
4.5 +
8.1 +
5.6 +
6.2 +
6.0 +
5.8 +
6.3 +
31 +
38 +
41 +
48 +
36 +
103 +
144 +
165 +
251 +
204 +
404 +
0.07
0.20
0.16
1.0
1.5
1.5
1.0
1.2
1.2
0.9
2.1
1.6
3.0
24
6
22
5
16
23
46
25
93
31
158
(7)
(5)
(4)
(9)
(8)
(8)
(9)
(8)
(8)
(8)
(9)
(4)
(9)
(15)
(8)
(17)
(8)
(8)
(8)
(8)
(8)
(9)
(4)
(3)
Liver
0.43 +
1.2 +
1.5 +
3.5 +
5.7 +
4.8 +
6.6 +
11.4 +
12.6 +
9.0 +
9.6 +
14.0 +
12.2 +
63 +
68 +
114 +
118 +
107 +
316 +
444 +
754 +
824 +
1250 +
1429 +
0.15
0.3
0.3
1.3
2.5
2.3
1.2
2.0
2.2
4.5
2.1
6.8
4.6
31
10
68
10
38
16
118
226
482
409
418
(10)
(5)
(5)
(8)
(8)
(8)
(9)
(8)
(8)
(8)
(9)
(4)
(9)
(14)
(8)
(17)
(8)
(10)
(8)
(8)
(8)
(8)
(4)
(5)
Kidney
0.30 +
1.0 +
1.1 +
4.3 +
7.7 +
4.7 +
5.3 +
10.0 +
6.0 +
8.0 +
8.6 +
8.3 +
5.9 +
48 +
44 +
65 +
51 +
60 +
189 +
256 +
153 +
315 +
498 +
752 +
0.14
0.2
0.2
1.1
7.3
1.2
1.6
1.4
0.8
2.0
1.8
5.0
2.2
13
9
29
7
16
52
65
27
71
114
251
(10)
(5)
(5)
(9)
(8)
(8)
(8)
(8)
(7)
(8)
(9)
(4)
(9)
(14)
(8)
(18)
(8)
(10)
(8)
(8)
(8)
(8)
(5)
(5)
Brain
0.21 +
0.6 +
0.8 +
4.4 +
5.7 +
4.4 +
6.0 +
9.2 +
6.7 +
6.8 +
6.8 +
6.0 +
6.2 +
36 +
43 +
53 +
59 +
57 +
178 +
246 +
156 +
361 +
554 +
739 +
0.1
0.2
0.1
1.3
1.4
1.3
0.9
0.9
0.9
1.7
0.9
0.7
1.3
7
8
12
6
17
18
54
24
70
76
170
1 (10)
(5)
(5)
(9)
(8)
(8)
(9)
(8)
(8)
(8)
(9)
(4)
(9)
(14)
(8)
(18)
(8)
(9)
(8)
(8)
(8)
(8)
(5)
(5)
-------
REFERENCES
1. Hake, C.L., T.B. Waggoner, D.N. Robertson and V.K. Rowe. 1960. The
metabolism of 1,1,1-trichloroethane by the rat. Arch. Environ.
Hlth. 1(23):101-105.
2. Ikeda, M. and H. Ohtsuji. 1972. A comparative study of the excre-
tion of Fujiwara reaction-positive substances in urine of humans and
rodents given trichloro- or tetrachloro-derivatives of ethane and
ethylene. Brit. J. Ind. Med. 29(1): 99-104.
3. Eben, A. and G. Kimmerle. 1974. Metabolism, excretion and toxi-
cology of methylchloroform in actue and subacute exposed rats. Arch.
Toxikol. 31: 233-242.
4. Morgan, A., A. Black and D.R. Belcher. 1970. The excretion in
breath of some aliphatic halogenated hydrocarbons following adminis-
tration by inhalation. Ann. Occup. Hyg. 13(4): 219-233.
5. Astrand, I., A. Kilbom, I. Wahlberg and P. Ovrum. 1973. Methyl-
chloroform exposure: I. Concentration in alveolar air and blood at
rest and during exercise. Work-environ.- hlth. 10:69-81
6. Stewart, R.D., H.H. Gay, A.W. Schaffer, D.S. Erley, and V.K. Rowe.
1969. Experimental human exposure to methyl chloroform vapor. Arch.
Environ. Hlth. 19: 467-472.
7. Seki, Y., Y. Urashima, H. Aikawa, H. Matsumura, Y. Ichikawa, F.
Hiratsuka, Y. Yoshioka, S. Shimbo, and M. Ikeda. 1975. Trichloro-
compounds in the urine of humans exposed to methyl chloroform at
sub-threshold levels. Int. Arch. Arbeitsmed. 34(1): 39-49.
8. Savolainen, H., P- Pfaffli, M. Tengen, and H. Vainio. 1977. Tri-
chloroethylene and 1,1,1-trichloroethane: effects on brain and liver
after five days intermittent inhalation. Arch. Toxicol. 38:
229-237.
9. Holmberg, B., I. Jakobson, and K. Sigvardsson. 1977. A study on the
distribution of methylchloroform and n-octane in the mouse during and
after inhalation. Scand. j. work environ, and health 3: 43-52.
92
-------
1,1,2-TRICHLOROETHANE
Cl H
C2H3Cl3 I I
H-C-C-CI
I I
Cl H
CAS: 000079005
Syn: ethane trichloride; beta-trichloroethane;
1,1,2-trichlorethane; vinyl trichloride
Mol wt: 133.41 g/mole
bp: 113.77°C (at 760 nm Hg)
vp: 23.16 nm Hg (at 25°C)
A comprehensive investigation by Yllner et. al. (1), indicated that
1,1,2-trichloroethane is extensively metabolized, primarily through the
formation of chloroacetic acid. Female albino mice were injected intraper-
itoneally with 0.1 to 0.2 g/kg doses of Ijl^-trichloroethane-l^-^C
(0.38 uCi/mg) and the elimination of radioactivity in urine, feces, and
expired air was measured by liquid scintillation techniques for 3 days.
Over 90% (range 82-98%) of the administered dose of radiation was elimi-
nated in the first 24 hours, primarily in the urine. Total levels of
carbon-14 activity eliminated in 3 days were reported as follows:
73-87% of the dose excreted in urine
0.1-2% detected in feces contaminated with urine
16-22% eliminated through the lungs
1-3% residual radioactivity found in whole-body homogenates taken
at the end of the test period
Further analyses of the expired air by isotope dilution methods showed that
about 3/5 of the radioactivity content was attributable to carbon dioxide
and the remaining 2/5 to unchanged trichloroethane. The major urinary
metabolites were determined by paper chromatography and isotope dilution
analysis as shown:
93
-------
chloroacetic acid, 6-31% of urinary radioactivity
S-carboxymethylcysteine, 29-46% free and 3-10% conjugated
thiodiacetic acid, 38-42%
In addition, analysis revealed small quantities of glycollic acid,
2,2-dichloroethanol, oxalic acid, 2,2,2-trichloroethanol, and trichloro-
acetic acid. The close similarity of urinary metabolites obtained from
1,1,2-trichloroethane with those obtained from chloroacetic acid adminis-
tered to mice in a previous experiment indicates that the metabolism of
1,1,2-trichloroethane occurs primarily via chloroacetic acid. Figure 1
represents the proposed metabolic pathway of 1,1,2-trichloroethane (1).
Ikeda and Ohtsuji (2) also reported the urinary excretion of very small
quantities of trichloroacetic acid (TCA) and trichloroethanol (TCE) by rats
exposed to 1,1,2-trichloroethane. In one inhalation experiment, male and
female Wistar rats (70 g) were subjected to 200 ppm of 1,1,2-trichloro-
ethane in air for 8 hours. Urine was collected for 48 hours from the
beginning of the exposure, and determination of the metabolites by the
Fujiwara color reaction indicated the excretion of 0.3 mg TCA/kg body
weight and 0.3 mg TCE/kg. A second experiment in which rats were injected
intraperitone- ally with 2.78 mmol of 1,1,2-trichloroethane per kg body
weight resulted in the excretion of similar quantities of the metabolites;
after the first 48 hours, metabolite excretion was determined to be 0.4 mg
TCA/kg and 0.2 mg TCE/kg. Urine collected during an additional 48-hour
period indicated excretion of another 0.3 mg TCA/kg and an immeasurable
amount of TCE. The authors explained that the low levels of urinary
metabolites may be attri- buted to the difficulty of the chemical
transformation (the shifting of one Cl atom from one carbon atom to the
other) required to form TCA or TCE from 1,1,2-trichloroethane. Also, it
was noted that the estimates made by the Fujiwara reaction may include
metabolites other than TCA and TCE.
94
-------
I
I
e *
CHO-CH-Cl - - - - - CIIO.CH -SO
t
g
III
h
a) 2,2-dichloroethanol
b) 1,1,2-trichloroethane
c) S-(2,2-dichloroethyl)-glutathione
d) chloroacetaldehyde
e) S-formylmethylglutathione
f) chloroacetic acid
g) S-carboxymethylglutathione
h) S-carboxymethylcysteine
i) thiodiacetic acid
The full arrows indicate the suggested routes
and the dotted arrows the alternatives.
Fig. 1(1). Metabolic fate of 1,1,2-trichloroethane.
Morgan et. al. (3), conducted a human inhalation study which
demonstrated that 1,1,2-trichloroethane has a low rate of pulmonary
elimination. The subjects were administered about 5 mg of 38-C1 labelled
1,1,2-trichloro- ethane in a single inhaled breath and radioactivity in the
expired air was measured by gamma-ray scintillation spectrometry for 1 hour
after expo- sure. A total of 2.9% of the administered dose was excreted in
the breath in 1 hour. The authors suggested an explanation for the low
rate of 1,1,2- trichloroethane excretion as a function of the compound's
partition coeffi- cients and diffusion rates. Measurements of partition
coefficients for 1,1,2-trichloroethane between blood and air (44.2) and
serum and air (37.1) at 40°C may indicate high solubility of the compound
in blood lipids; however, high partition coefficients also represent slower
diffusion across the alveolar membranes and consequently indicate a slower
rate of 1,1,2-trichloroethane removed from the lungs during expiration.
95
-------
REFERENCES
1. Yllner, S. Metabolism of 1,1,2-trichloroethane-l,2-14C in the mouse.
Acta pharmacol. et toxicol. 1971. 30:248-256.
2. Ikeda, M. and H. Ohtsuji. 1972. A comparative study of the excretion
of Fujiwara reaction-positive substances in urine of humans and rodents
given trichloro- or tetrachloro-derivatives of ethane and ethylene
Brit. J. Ind. Med. 29(1):99-104.
3. Morgan, A., A. Black and D.R. Belcher. 1970. Excretion in breath of
some aliphatic halogenated hydrocarbons following administration by
inhalation. Ann. Occup. Hyg. 13(4):219-233.
96
-------
TRICHLOROETHYLENE
a c.
C2HC13 C = C
-------
absorbed by humans after exposure to various concentrations of TCE (54 to
390 ppm, for 160 minutes to 8 hours) ranges from 36% to 78% of the
inspired TCE, with most reported values approaching 60% (2,3,4,5,6,7,
8,9). It has been demonstrated by Monster et al. (10), that the respira-
tory retention of TCE is proportional to the concentration in inspiratory
air. The addition of work during exposure causes a further increase in
the absorption of TCE (10,11).
After absorption, TCE is rapidly eliminated from the blood as shown in
Figure 1, based on the human inhalation studies by Monster et al. (10).
Subjects were exposed to 70 or 140 ppm TCE in air, with or without the
addition of exercise (100 W on a bicycle ergometer), for 4 hours. It was
found that the concentration of TCE in blood decreased greatly in the
first few minutes after the exposure period, then declined at a much
slower rate.
According to Fabre and Truhaut (1952, Br. J. Ind. Med., 9:39-43) as
reported by Waters et al. (1), the transport of TCE(whichis highly solu-
ble in fat) in blood may be facilitated by the lipids in erythrocyte
membranes. In inhalation experiments with rats exposed to 10 mg TCE/liter
of air, 41.3 mg% TCE was detected in blood cellular components as compared
to 2.5 mg% TCE found in blood plasma.
TCE is eliminated from the blood partly via pulmonary expiration.
Daniel (12) determined that, after rats were given a single oral dose of
4.0, 7.5 or 8.6 uCi of 56C1-TCE, as much as 72-85% of the dose was
exhaled as unchanged TCE. In humans, however, a relatively small amount,
about 7-25%, of the TCE absorbed by inhalation is expired unchanged
(2,6,7,10,11). Furthermore, Nomiyama and Nomiyama (13) reported that
women expired less TCE than did men. In general, the expiration of TCE
decreases exponentially (6,10,13,14,15). The rate constant for pulmonary
elimination of TCE in humans has been calculated as k:0.14 hour"1 (6).
Monster et al. (10), reported that trichloroethanol, in the expired breath
of humans after exposure to TCE, also decreased exponentially. Ikeda (16)
calculated the respiratory half-life of TCE to be about 25 hours, based on
data from Stewart et al. (14), and Stewart et al. (1970, Arch. Environ.
Hlth., 20:224). "
Most of the TCE which has been absorbed into the body undergoes exten-
sive metabolism and is eliminated in urine. Soucek and Vlachova (3) con-
ducted a thorough study of the excretion of urinary TCE metabolites in
humans. The subjects were exposed to known TCE concentrations (500-850 ug
TCE per liter of air) for 5 hours. Urine was collected continuously
during the exposure period and for 3 days after exposure, and subsequent
samples were taken daily for analysis until metabolites could no longer be
detected. The primary metabolite, trichloroethanol, accounted for a total
of about 50% of the absorbed TCE. Trichloroethanol appeared in the urine
soon after the start of the exposure and its concentration increased
rapidly until a maximum level was reached a few hours after the end of the
exposure period. The level of trichloroethanol in urine then decreased at
two successive exponential rates: initially the concentration dropped at
a fast rate for 3-4 days and then decreased at a slower rate for 7-9
days. Trichloroethanol was excreted for an average of 350 hours. The
second major urinary metabolite, trichloroacetic acid (TCA), was detected
98
-------
TCE
0.001 -
X 70 ppm
A 70 ppm with workload
-f- 140 ppm
140 ppm with workload
0.0001 _
0.00001 _
post-exposure
Figure 1. Trichloroethylene concentrations in human blood (as
fraction of dose/liter whole blood) after 4 hours inhalation
exposure to 70 or 140 ppm TCE, at rest or with work (two ^-hour
periods of exercise, 100 W, on a bicycle ergotneter during exposure).
Data points were calculated by dividing individual concentrations
(mg/1) by individual dose (mg). The figure represents the means
of four subjects under each exposure condition. Redrawn from
Monster et al. (10).
99
-------
in amounts equal to about 19% of the TCE dose. TCA in urine was found
immediately after the beginning of TCE inhalation. The concentration of
TCA then increased slowly, peaked at 24-48 hours, and decreased exponen-
tially in two phases. The average total excretion time for TCA was 387
hours. In addition, a diurnal variation was observed in the amount of TCA
excreted; a daily maximum level of TCA occurred at 1:00 p.m. each day.
Excretion of a third urinary metabolite, monochloroacetic acid (MCA),
accounted for 4% of the inhaled TCE. Starting a few minutes after the
beginning of TCE inhalation, the MCA concentration increased rapidly,
reached a maximum level at the end of the exposure, and then declined at
an exponential rate. The period of MCA excretion was about 112 hours.
Altogether, a total of 73% of the TCE absorbed by inhalation was excreted
in urine in the form of monochloroacetic acid, trichloroacetic acid, and
trichloroethanol, in a ratio of 1:5:12 by quantity.
Similar results were obtained from human inhalation studies by
Bartonicek (8) in which 8 subjects were exposed to 1,042 ug of TCE per
liter of air for 5 hours. Urine was analyzed daily for 3 weeks. The
author reported that an average of 45.4% of the inhaled TCE was excreted
as trichloroethanol and 31.9% as trichloroacetic acid. The value for the
ratio of TCA/trichloroethanol excretion was about 1.44, compared to the
ratio of 2.4 found by Soucek and Vlachova (3). Other researchers have
determined TCA/trichloroethanol ratios of 1.99 and 1.84, as cited by
Bartonicek (8).
Several authors have also reported experimental data comparable to
Bartonicek (8) and Soucek and Vlachova (3) demonstrating that humans
excrete nearly twice as much trichloroethanol (32.7-68.8% of absorbed TCE)
as trichloroacetic acid (17.7-43.9%) after inhalation of various concen-
trations of TCE (54-390 ppm) for up to 8 hours (2,6,17,18).
It has been well established from the literature that trichloroacetic
acid is excreted in urine at a much slower rate and for a longer time than
trichloroethanol, and that the total amount of trichloroethanol excreted
is greater than the amount of TCA. A similar time course of trichloro-
ethanol and TCA urinary elimination has been reported from long-term
studies of repeated inhalation exposures or occupational exposure of
humans to trichloroethylene (15,17,19,20). An example of the elimination
pattern, similar to that described by Bartonicek (8), is shown in Figure 2
(15). Muller and Spassowski (19) described the pattern of elimination in
terms of a reverse ration by determining that the trichloroethanol-to-TCA
ratio decreases from 10 to 1-2, over day 1 to day 5
of the exposure.
Researchers have concluded that the concentrations of trichloroethanol
and trichloroacetic acid in human urine are proportional to the environ-
mental concentration of TCE, based on the results of occupational exposure
studies (16,17,21) . Ikeda (16) and Ikeda et al. (21), reported a linear
correlation between TCE in air and metabolite levels in urine. Examples of
the relationship are given in Table 1. It was noted that the urinary con-
centration of TCA deviated from the linear regression line when the TCE
concentration in air exceeded 50 ppm (16,21). Ikeda (16) also used the
data from occupational exposure studies to calculate a mean urinary
half-life of 41 hours for TCE in humans.
100
-------
2 3 4 5 "6"" 78
Days after tte beginning of th« exposure
10
Fig 2. Urinary trichloroethanol (TCE) and trichloroacetic acid
(TCA)-excretion (24-h specimens) during and after repeated exposure (on 5
successive days, 4 h/day) to a TCE concentration of 48.0 ^ 3 ppm (mean of
4 subjects). TCE.
TCA. (From Ref. 15).
Other species have been shown to metabolize TCE to the same major
metabolites (TCA and trichloroethanol) found in humans. The amounts of
metabolites excreted vary widely among species. A comprehensive review
of the literature regarding TCE metabolism in experimental animals was
published in 1970 by the Joint FAO/WHO Expert Committee on Food Additives
(22). Dogs reportedly excreted 5-8% of retained TCE as TCA and 15-20% as
trichloroethanol for up to 4 days following exposure. After inhalation
of TCE, rats excreted 4% of the dose as TCA. The lungs and spleen were
probably the major metabolic sites. Following oral administration of
TCE, rats excreted 3% as TCA and 15% as trichloroethanol. In another
Table 1(21).
Metabolite concentrations in urine samples from workers
exposed trichloroethylene at various concentrations for 8
hrs/day, 6 days/week.
Trichloroethylene
(ppm)
No. of Workers
TTC
(a)
Metabolite concentration
(mg/liter)
Trichloroethanol TCA
10
25
50
60
120
6
4
5
5
4
60.5
164.3
418.9
468.0
915.3
42.0
77.3
267.3
307.9
681.8
17.6
77.2
146.6
155.4
230.1
(a'TTC represents total trichloro-compounds.
101
-------
case, rats were given 3^C1-TCE by gavage and of the 15% excreted in
urine, 1-5% was detected as TCA and 10-15% as trichloroethanol (12,22).
Rabbits and guinea pigs showed the presence of TCA in urine after TCE
exposure (22). In experiments with calves fed 3 or 12 g of TCE daily for
4 or 5 days, urinalyses showed the excretion of about 1% as TCA, 13-25% as
trichloroethanol, and traces of TCE (22,23).
Although it has been shown in the literature that almost all of the
TCE which is absorbed into the human body is eventually eliminated in the
urine or expired air, Bartonicek (8) reported that small amounts of TCE
metabolites may also be excreted in feces, sweat, and saliva. Samples of
each were collected and analyzed on the third day after human subjects had
been exposed to 1,042 ug TCE/liter of air for 5 hours. From the results
it was determined that 8.4% of the TCE dose was present as both metabo-
lites in the feces; sweat contained 0.15-0.35 mg TCA/100 ml and 0.10-1.92
mg trichloroethanol/100 ml; and saliva contained 0.10-0.15 mg TCA/100 ml
and 0.09-0.32 mg trichloroethanol/100 ml. The author stated that despite
the fact that the metabolite levels were very low in feces, sweat, and
saliva, the data may be significant in partially explaining the fate of
trichloroethylene that is absorbed but not accounted for in urine or
expired air.
Several studies have been reported regarding blood levels of
trichloroethylene metabolites (8,15,20,24). In one such study, Muller et
al. (24) reported maximum levels of 50 ug TCA/ml of blood and 2.3 ug
trichloroethanol (non-glucuronic fraction) per ml of blood when human sub-
jects were exposed to 50 ppm TCE for 6 hours per day for 5 days. The
significant accumulations of TCA may be attributed to a high plasma pro-
tein binding rate (90-86% for 10-50 ug TCA/ml). The authors also noted
that the pattern of elimination of TCA and trichloroethanol from the blood
parallels the course of urinary elimination of TCE metabolites. Muller et
al. (24) also determined the half-lives of TCA and trichloroethanol in
blood at 100 hours and 12 hours, respectively. Levels of TCA persisted in
blood for over two weeks after exposure to TCE (24).
In the results of similar sub-acute inhalation experiments, Kimmerle
and Eben (15) reported concentrations of trichloroethanol in human blood
higher than the levels reported by Muller et al. (24). Data obtained from
humans exposed to 48 ppm of TCE for 4 hours per day for 5 days are sum-
marized in Table 2 (15).
Table 2 (15). Concentrations of trichloroethanol in the blood of 8
humans exposed to 48 ppm of TCE for 4 hours/day, for 5
days. Figures represent ranges of the maximum
concentrations found on each day. Concentrations are
expressed in ug/mL.
Days of Trichloroethanol Days after Trichloroethanol
exposure concentration(12:00 noon) exposure concentration(8;00 a.m.)
1
2
3
4
5
1.275 -
0.567 -
2.010 -
1.565 -
1.974 -
2.849
1.296
2.530
2.580
2.870
1
2
3
7
0.510
0.179
n.d.*
0-0.
- 2.110
- 0.507
- 0.272
030
102
-------
Kimmerle and Eben (15) also conducted an acute exposure experiment in
which human subjects were exposed to 40 or 44 ppm of TCE for 4 hours. The
blood levels of trichloroethanol at the end of the inhalation ranged from
0.706 to 1.776 ug/ml blood. At 96 hours after the start of exposure, less
than 0.123 ug/ml was detected.
Ertle et al. (20), reported data comparable to Muller et al. (24), and
Kimmerle and Eben (15). Humans were exposed to 50 ppm constant, 250 ppm
(for 12 min./hr.), or 100 ppm constant TCE concentrations for 6 hours per
day for 5 days. Results showed a day-to-day accumulation of trichloro-
ethanol in the blood. Maximum trichloroethanol concentrations attained
for each of the three exposure levels were 2.0, 2.5, and 5.0 ug/ml,
respectively.
Bartonicek (8) measured the concentration of TCA in separate fractions
of plasma and red blood cells of humans (exposed to 1043 ug TCE/L air, 5
hrs). The mean values, obtained on the third day after exposure, were
reported as follows: plasma, 2.4 mg/100 ml plasma; red blood cells, 0.5
mg/100 ml red cell mass.
TCE that is absorbed but not metabolized (and excreted) immediately
may be retained in adipose tissues (1). According to Fabre and Truhaut
(1952, Br. J. Ind. Med. 9:39-43) as reported by Waters et al. (1), analy-
sis of various tissues of the guinea pig following inhalation exposure to
TCE revealed that TCE and TCA accumulated in most tissues, but concentra-
tions were consistently highest in the fat tissue. Following chronic
inhalation of 6-9 mg TCE/liter of air (4-5 hrs/day, 5-23 days), the con-
centration of trichloroethylene in fat was found to be 3.1 - 3.9 mg/100 g
fresh tissue, and the concentrations of trichloroacetic acid in fat ranged
up to 4.4 rag/100 g tissue. Levels of TCA were higher than TCE in all
tissues.
A comprehensive scheme for the metabolism of TCE, based on a review of
the literature, was proposed by Waters et al. (1), as shown in Figure 2.
The first step in TCE metabolism is the formation of chloral hydrate via
trichlorethylene oxide or trichlorethylene glycol (1). Spectral evidence
for the formation of the TCE epoxide has been demonstrated in vitro by
Uehleke et al. (25). The oxide intermediate is very unstable, rearranging
spontaneously to trichloroacetalolehkyde and subsequently to chloral
hydrate (1). In general, the intramolecular rearrangement of TCE to
chloral hydrate involves chlorine migration and is mediated by a micro-
somal NADPH/02 - dependent reaction occuring primarily in the liver (1).
Chloral hydrate formation was reported jtn vitro (26,27) and in human
blood plasma (28). According to the Waters et al. (1), review, chloral
hydrate is also a short-lived intermediate, having a biological half-life
of less than 30 minutes in humans, 10 minutes in dogs, and 10-20 minutes
in mice. The compound is rapidly metabolized, undergoing either, a)
oxidation to trichloroacetic acid by the action of chloral hydrate dehy-
drogenase (NAD coenzyme) or b) reduction to trichloroethanol by liver
alcohol dehydrogenase (NADH coenzyme). Trichloroethanol is usually
excreted in urine as a conjugate of glucuronic acid; conjugation takes
place primarily in the liver (1). As described earlier, Soucek and
Vlachova (3) determined the presence of small amounts of monochloroacetic
acid as another final metabolite of trichloroethylene.
103
-------
cfl
THICHLCROtTHYLENE
HIXEo FUNCTION OXIDASES
TRICHLOROETHYLENE
GLYCOL
Cl Cl
CI-C-C-H
V
TRICHLOROETHYLENE
OXIDE
OH-
Cl OH
INTRAMOLECULAR REARRANGEMENT PRODUCT
I
TRICHLOROACETALOEHYOE
Hrof?OLr$IS
Cl *OH
I i
Cl —C - C -H
I
I
ALCOHOL 0£HrOKOC£NAS£/NAOH
Cl H ^
I I
CI-C-C-OH
I
I
UOP
Cl H
TRICHLOROETHANOL
t
•*^ Cl OH ^^
CHLORAL HYDRATE
Mix£D FUNCTION
OXIOASCS
Cl H
C,_C-C-0-CSH0B
TRICHLOROETHANOL
GLUCUHONlOE
CHLORAL
f 3EHfCROGEK&Si /NAD
0
TRICHLOHOACETIC ACIO
Figure 3. Proposed intermediary metabolism of TCE (1)
104
-------
REFERENCES
1 Waters, E.M., H.B. Gertsner and J.E. Huff. 1977. Trichloroethylene.
I. An overview. J. Toxicol. Environ. Hlth. 2:671-707.
2. Fernandez, J.G., B.E. Humbert, P.O. Droz and J.R. Caperos. 1975.
Trichloroethylene exposure. Percentage studies of absorption,
excretion and metabolism by human subjects. Arch. Mai. Prof.
36(7-8):397-407.
3. Soucek, B. and D. Vlachova. 1960. Excretion of trichloroethylene
metabolites in human urine. Brit. J. Med. 17:60-64.
4. Soucek, B. and D. Vlachova. 1959. Metabolites of trichloroethylene
excreted in the urine in man. Pracovni Lekarstvi 11:457-61. Chem.
Abst. 54:19975f.
5. Soucek, B., J. Teisinger and E. Pavelkova. 1952. Absorption and
elimination of trichlorethylene in man. Pracovni Lekartsvi 4:31-41.
Chem. Abst. 49:4181e.
6. Nomiyama, K. and H. Nomiyama. 1971. Metabolism of trichloroethylene
in human: sex difference in urinary excretion of trichloroacetic acid
and trichloroethanol. Int. Arch. Arbeitsmed. 28(l):37-48.
7. Nomiyama, K. and H. Nomiyama. 1977. Dose-response relationship for
trichloroethylene in man. Int.'Arch. Occup. Environ. Hlth. 39:237-248.
8. Bartonicek, V. 1962. Metabolism and excretion of trichloroethylene
after inhalation by human subjects. Brit. J. Industr. Med.
19(2):134-141.
9. NIOSH. 1973. Criteria for a recommended standard ... occupational
exposure to trichloroethylene. Dept. of H.E.W.
10. Monster, A.C., G. Boersma, and W.C. Duba. 1976. Pharmacokinetics of
trichloroethylene in volunteers, influence of workload and exposure
concentration. Int. Arch. Occup. Environ. Hlth. 38:87-102.
11. Astrand, I. 1975. Uptake of solvents in the blood and tissues of
man. A review. Scand. j. work environ, and health. 1:199-218.
12. Daniel, J.W. 1963. The metabolism of 36Cl-labelled
trichloroethylene and tetrachloroethylene in the rat. Biochem.
Pharmacol. 12(8):795-802.
13. Nomiyama, K. and H. Nomiyama. 1974. Respiratory elimination of
organic solvents in man. Benzene, toluene, n-hexane,
trichloroethylene, acetone, ethyl acetate and ethyl alcohol. Int.
Arch. Arbeitsmed. 32:85-91.
105
-------
14. 'Stewart, R.D., H.C. Dodd, H.H. Gay and D.S. Erley. 1970. Experi-
mental human exposure to trichloroethylene. Arch. Environ. Health.
20(1):64-71.
15. Kimmerle, G. and A. Eben. 1973. Metabolism, excretion and toxi-
cology of trichloroethylene after inhalation. 2. Experimental human
exposure. Arch. Toxicol. 30(2):127-138.
16. Ikeda, M. 1977. Metabolism of trichloroethylene and tetrachloro-
ethylene in human subjects. Environ. Hlth. Perspect. 21:239-245.
17. Ogata, M., Y. Takatsuka and T. Katsumara. 1971. Excretion of
organic chlorine compounds in the urine of persons exposed to vapours
of trichloroethylene and tetrachloroethylene. Brit. J. Ind. Med.
28(4):386-391.
18. Bartonicek, V. and J. Teisinger. 1962. Effect of tetraethyl thiuram
disulphide (disulfiram) on metabolism of trichloroethylene in man.
Brit. J. Ind. Med. 19:216-221.
19. Muller, G. and M. Spassowski. 1973. Pharmacokinetics of
trichloroethylene metabolites in man. Naunyn. Schmied. Arch. Pharm.
277/Sup. (R48). Abstract.
20. Ertle, T., D. Henschler, G. Muller, and M. Spassowski. 1972.
Metabolism of trichloroethylene in man. I. The significance of
trichloroethanol in long-term exposure conditions. Arch. Toxicol.
29, 171-188.
21. Ikeda, M., H. Ohtsuji, T. Imamura and Y. Komoike. 1972. Urinary
excretion of total trichloro-compounds, trichloroethanol, and
trichloroacetic acid as a measure of exposure to trichloroethylene
and tetrachloroethylene. Br. J. Ind. Med. 29:328-333.
22. FAO/WHO. 1970. Toxicological evaluation of some extraction solvents
and certain other substances. 14th report of the Joint FAO/WHO
Expert Committee on Food Additivies, FAO Nutrition Meetings Report
Series No. 48A. p. 121-128.
23. Seto, T.A. and M.O. Schultze. 1955. Metabolism of trichloroethylene
in the bovine. Proc. Soc. Exptl. Biol. Med. 90:314-316.
24. Muller, G., M. Spassowski and D. Henschler. 1972. Trichloroethylene
exposure and trichloroethylene metabolites in urine and blood. Arch^
Toxicol. 29(4):335-340.
25. Uehleke, H. , S. Poplawski, G. Bonse and D. Henschler. 1977.
Spectral evidence for 2,2,3-trichloro-oxirane formation during
microsomal trichloroethylene oxidation. Xenobiotica 7(1/2):94-95.
Abstract.
106
-------
26. Leibman, K.C. 1966. Metabolism of trichloroethylene in liver
microsomes. I. Characteristics of the reaction. Mol. Pharmacol.
l(3):239-246.
27. Bonse, G., T. Urban, D. Reichert and D. Henschler. 1975. Chemical
reactivity, metabolic oxirane formation, and biological reactivity of
chlorinated ethylenes in the isolated perfused rat liver
preparation. Biochem. Pharmacol. 24(19):1829-1834.
28. Cole, W.J., R.G. Mitchell, R.F. Salamonsen. 1975. Isolation,
characterization and quantitation of chloral hydrate as a transient
metabolite of trichloroethylene in man using electron capture gas
chromatography and mass fragmentography. J. Pharm. Pharmacol.
27(167-171).
107
-------
APPENDIX A
Summary Table
of
Experimental Data
108
-------
INTRODUCTION
The following table summarizes the experimental data reported in the
literature on the 30 halogenated hydrocarbon compounds discussed in the
preceding section. Although the table was intended to accompany the
metabolism chapters, a bibliography (pages 300-309) has been included in
order that the table may be used as a separate indexed reference.
The information under each compound is listed, by corresponding
author(s), in the same order as it was discussed in the metabolism chapters.
Included are the experimental species and the rate (or dose) and methods of
administration, followed by the name of the metabolite its observed
concentration expressed as a percentage of the administered dose of the
parent compound (unless otherwise indicated), the medium (urine, expired
air, blood, feces, or tissues) in which the metabolite was measured, and the
reference. Additional data and details of the experimental method may be
obtained from the original reference.
109
-------
Rate and Route
Compound Species of administration
Benzyl Bromide rabbit 0.2 g/kg, by
stomach tube
Benzyl Chloride rabbit 0.2 g/kg, by
stomach tube
guinea pig unspecified
rat unspecified
Bromobenzene rabbit 0.5 g/kg, oral dose
rabbit 0.5 g/kg, stomach
tube
rabbit 210 mg/kg, via
stomach tube
Compound
mercapturic acid
ethereal sulfate
mercapturic acid
glycine conjugate
(benzoic or phenyl-
acetic)
glucosiduronic acid
(mainly phenols)
unconjugated acids
(benzoic or
phenylacetic)
mercapturic acid
mercapturic acid
bromobenzene
(unchanged)
bromobenzene
(unchanged)
total conjugates
glucuronide
ethereal sulfate
mercapturic acid
Metabolites
Percent of
dose
19%
2%
49%
(37-67)
(24 hrs)
20%
(12-16)
(24 hrs)
0.4%
(0-5)
(24 hrs)
17%
(24 hrs)
4%
27%
6%
(1-2 days)
6.3%
97.9%
40.2%
36.8%
20.9%
Site Ref.
urine A-l
urine A-l
urine B-l
urine
urine
urine
urine B-2
urine
expired C-l
air
expired C-2
air
urine C-3
urine
urine
urine
-------
Compound Species
Bromobenzene rabbit
(continued)
rabbit
(a) figure shown is rabbit
percent yield of
metabolite ob-
tained by
extraction and
purification of
the ether ex- rat
tracts of
hydrolyzed
rabbit urine.
rat
Rate and Route
of administration
0.5 g/kg, oral dose
0.5 mg/kg, via
stomach tube
50 mg/kg, i.p.
injection
10.0 mmol/kg, i.p.
injection
0.05 mmol/kg, i.v.
injection
Compound
total 0- conjugates
mercapturic acid
mono phenols
catechols
4-bromocatechol
bromophenylmercapturic
acid
4-bromo phenol
3-bromophenol
bromophenylmercapturic
acid
4-bromo phenol
bromocatechol
\
bromophenyldihydrodiol
2-bromo phenol
bromophenylmercap-
turic acid
Metabolites
Percent of
dose
58%
(1-2 days)
25%
(1-2 days)
2-3%
(1-2 days)
28%
(1-2 days)
28.2%
(4 days)
22%
1.2%<*>
(10 days)
i.o%(a)
(10 days)
48%
(48 hrs)
37%
(48 hrs)
6%
(48 hrs)
4%
(48 hrs)
3%
(48 hrs)
70%
(48 hrs)
Site Ref.
urine C-l
urine
urine
urine
urine C-4
urine
urine C-5
urine
urine C-6
urine
urine
urine
urine
urine C-6
-------
Metabolites
Compound
Rate and Route
Species of administration
Compound
Percent of
dose
Site
Ref.
Bromobenzene
(continued)
rat
rat
rat
0.05 mmol/kg, i.v.
injection
dosage not stated;
i.p. injection
288 umol 14C-
b romob enz ene
4-bromopheno1
bromocatecho1
bromophenyldihydrodiol
2-bromophenol
4-bromophenol
2-bromophenol
3,4-bromocatechol
2,3-bromocatechol
3,4-bromophenyldi-
hydradiol
2,3-bromophenyIdi-
hydrodiol
total urinary
metabolites
mercapturic acids
18%
(48 hrs)
4%
(48 hrs)
4%
(48 hrs)
3%
(48 hrs)
40%
(48 hrs)
4%
(48 hrs)
4%
(48 hrs)
trace
(48 hrs)
3%
(48 hrs)
trace
(48 hrs)
23 umol
(4 hrs)
63 umol
(8 hrs)
240 umol
(24 hrs)
15.1 umol
(4 hrs)
urne
urne
urine
urine
urine
urine
urine
urine
urine
urine
urine
C-6
C-7
C-8
urine
-------
Compound
Rate and Route
Species of administration
Compound
Metabolites
Percent of
dose
Site
Ref.
Bromobenzene
(continued)
rat
rat
rat
288 umol C
bromobenzene
20 mg/kg ^c-
bromobenzene, i.v.
injection
750 mg/kg, i.p.
injection
mercapturic acids
phenolic metabolites
bromobenzene
metabolites
(unspecified)
bromobenzene
41.2 umol
(8 hrs)
141.6 umol
(24 hrs)
5.5 umol
(4 hrs)
15.1 umol
(8 hrs)
64.7 umol
(24 hrs)
11%
(initial
30 min.)
urne
(2nd 30 min.)
56%
(3 hrs,
cumulative)
80%
(3 hrs,
cumulative)
5,600 ug/g
(4 hrs)
400 ug/g
(24 hrs)
132 ug/g
(4 hrs)
urne
stomach
C-8
bile C-9
bile
bile
bile
plus
urine
adipose C-8
tissue
16.8 ug/g
-------
Compound
Rate and Route
Species of administration
Compound
Metabolites
Percent of
dose
Site
Ref,
Bromobenzene
(continued)
rat
750 mg/kg, i.p.
injection
bromobenzene
60 umol bromoform
added to incubation
mixture; incubated
at 37°C for 15 min.
235 ug/g
(4 hrs)
18.9 ug/g
(24 hrs)
282 ug/g
(4 hrs)
10.7 ug/g
(24 hrs)
206 ug/g
(4 hrs)
7.0 ug/g
(4 hrs)
146 ug/g
(4 hrs)
5.0 ug/g
(24 hrs)
142 ug/g
(4 hrs)
6.2 ug/g
(24 hrs)
34 ug/g
(4 hrs)
2.1 ug/g
(24 hrs)
kidney C-8
liver
brain
heart
lung
plasma
Bromoform
rat liver
microsomal
fractions
carbon monoxide
100%
in vitro D-l
-------
Rate and Route
Compound Species of administration
3-Bromopropylbenzene rabbit 0.25 g/kg, by
stomach tube
Carbon tetrachloride human 80 ppm ^carbon
tetrachloride, via
single breath
inhalation
monkey 46 ppm ^carbon
tetrachloride,
inhalation for
344 minutes
rat 1.0 mL ^carbon
tetrachloride/ kg,
intraduodenal
rabbit 1 ml /kg, via
stomach tube
Compound
ethereal sulphate
ether soluble acid
(primarily glucosid-
uronic acid; also
mercapturic acid
and glycine
conjugates)
N-acetyl-S-(3-phenyl-
propyl )-L-cysteine
phenaceturic acid
phenolic metabolites
(unspecified)
^carbon tetrachloride
(unchanged)
^carbon tetrachloride
(unchanged)
•^carbon tetrachloride
(unchanged)
carbon tetrachloride
(unchanged)
Metabolites
Percent of
dose
20%
69%
unspecified
amount
unspecified
amount
unspecified
amount
33%
(1 hr)
40%
(1800 hrs)
85%
(18 hrs)
787 ug/g
(6 hrs)
96 ug/g
(24 hrs)
Site Ref.
urine E-l
urine
unhydrolysed
urine (acidic)
unhydrolysed
urine (acidic)
hydrolysed urine
(conjugated
phenolic)
expired F-l
breath
expired F-2
breath
expired F-3
breath
fat F-4
tissue
-------
Metabolites
Compound
Rate and Route
Species of administration
Compound
Percent of
dose
Site
Ref.
Carbon tetrachloride
(continued)
rabbit
sheep
sheep
1 ml/kg, via
stomach tube
0.12 ml/kg,
directly to rumen
0.15 ml/kg,
directly to rumen
carbon tetrachloride,
unchanged
carbon tetrachloride
carbon tetrachloride
45 ug/g fat F-4
(48 hrs) tissue
96 ug/g liver
(6 hrs)
7.7 ug/g
(24 hrs)
3.8 ug/g
(48 hrs)
398 ug, total bile F-5
(6 hrs)
433 ug, total
(day 1)
7 ug, total
(day 2)
trace-6 ug,
total per day
(day 3-7)
438 ug, total bile F-5
(6 hrs)
543 ug, total
(day 1)
9 ug, total
(day 2)
nil-8 ug,
total per day
(day 3-7)
-------
Compound Species
Carbon tetrachloride rabbit
(continued)
Rate and Route
of administration
1.0 ml /kg via
stomach tube
Compound
carbon tetrachloride
(unchanged)
Metabolites
Percent of
dose Site Ref.
37 ug/g bile F-5
(6 hrs)
7.8 ug/g
(24 hrs)
1.1 ug/g
(48 hrs)
sheep
sheep
rabbit
0.1 mg/kg,
directly to rumen
carbon tetrachloride
0.12 ml/kg,
directly to rumen
carbon tetrachloride
110 ppm, inhalation
(4 hrs)
carbon tetrachloride
19.2 ug, total urine
(day 1)
5.9 ug, total
(day 2)
4.6 ug, total
(day 3)
trace-1.3 ug,
total per day
(day 4-7)
1.2 ug, total urine
(day 1)
1.0 ug, total
(day 2)
0.7 ug, total
(day 3)
trace-0.7 ug,
total per day
(day 4-7)
trace
(at end of
exposure)
blood
F-5
F-5
F-6
-------
Metabolites
Compound
Rate and Route
Species of administration
Compound
Percent of
dose
Site
Ref.
Carbon tetrachloride
(continued)
rabbit
rat
rabbit
225 ppm, inhalation
(4 hrs)
carbon tetrachloride
345 ppm, inhalation carbon tetrachloride
(4 hrs)
600 ppm, inhalation
(4 hrs)
0.1-0.5 ml, via
stomach tube
carbon tetrachloride
chloroform
1 ml/kg, via
stomach tube
chloroform
0.2 mg/100 mL blood
blood
(at end of
exposure)
0.6 mg/100 mL blood
blood
(at end of
exposure)
0.4 mg/100 mL blood
blood
0.037 mg/g
(15 min.)
0.027 mg/g
(30 min.)
0.007 mg/g
(240 min.)
4.7 ug/g
(6 hrs)
1.0 ug/g
(24 hrs)
0.4 ug/g
(48 hrs)
4.9 ug/g
(6 hrs)
1.0 ug/g
(24 hrs)
liver
fat
tissue
liver
F-6
F-6
F-6
F-7
F-4
-------
Metabolites
Rate and Route
Compound Species of administration Compound
Carbon tetrachloride rabbit 1.0 ml /kg, via chloroform
(continued) stomach tube
rabbit 1.0 mL/kg, via chloroform
stomach tube
Percent of
dose Site Ref.
0.8 ug/g liver F-4
(48 hrs)
0.50 ug/g bile F-5
(6 hrs)
0.14 ug/g
(24 hrs)
0.45 ug/g
(48 hrs)
sheep
sheep
0.1 ml/kg,
directly to rumen
0.12 ml/kg,
directly to rumen
chloroform
chloroform
3.7 ug/, total urine
(day 1)
2.0 ug, total
(day 2)
1.8 ug, total
(day 3)
trace-0.8 ug
total per day
(day 4-7)
6.6 ug, total urine
(day 1)
3.3 ug, total
(day 2)
2.2 ug, total
(day 3)
trace-2.0 ug,
total per day
(day 4-7)
F-5
F-5
-------
Compound
Species
Rate and Route
of administration
Compound
Metabolites
Percent of
dose
Site
Ref,
Carbon tetrachloride
(continued)
sheep
0.12mL/kg,
directly to rumen
chloroform
0 ug, total
(6 hrs)
241 ug, total
(day 1)
122 ug, total
(day 2)
0-95 ug,
total per day
(day 3-7)
bile
F-5
sheep
KJ
o
dog
rat
monkey
0.15 ml/kg,
directly to rumen
chloroform
5 ml/hr, inhalation
(3 hrs)
1.0 ml
tetrachloride/kg,
intraduodenal
46 ppm ^carbon
tetrachloride,
inhalation for
344 minutes
chloroform
•^carbon dioxide
l^carbon dioxide
0 ug, total
(6 hrs)
210 ug, total
(day 1)
126 ug, total
(day 2)
nil-120 ug,
total per day
(day 3-7)
0.1-0.5 mg,
total
(2 hrs)
1%
(18 hrs)
11%
(1800 hrs)
bile
F-5
expired
air
expired
breath
expired
breath
F-8
F-2
-------
Compound
Rate and Route
Species of administration
Compound
Metabolites
Percent of
dose
Site
Ref,
Carbon tetrachloride rabbit
(continued)
1 ml/kg, via
stomach tube
hexach1oroe thane
rat
rabbit
0.1-0.5 ml, via
stomach tube
1.0 ml/kg, via
stomach tube
hexachloroethane
hexachloroethane
4.1 ng/g
(6 hrs)
16.5 ng/g
(24 hrs)
6.8 ng/g
(48 hrs)
1.6 ng/g
(6 hrs)
4.2 ng/g
(24 hrs)
1.0 ng/g
(48 hrs)
0.005 mg/g
(240 min.)
trace
(6 hrs)
5.5 ng/g
(24 hrs)
fat
F-4
liver
liver
bile
F-7
F-5
trace
(48 hrs)
-------
Metabolites
Rate and Route
Compound Species of administration Compound
o-Chlorobenzaldehyde cat 2.65 uM unchanged
in vitro blood tests
man 2.65 uM unchanged
in vitro blood tests
rat 2.65 uM unchanged
in vitro blood tests
Chlorobenzene rabbit 150 mg/kg, via urinary metabolites,
stomach tube total
glucuronide
ethereal sulfate
mercapturic acid
rabbit 10 or 12 g chloro- 4-chlorocatechol
benzene, via stomach (ethereal sulphate
tube and glucuronide
conjugates )
p-chlorophenyl-
mercapturic acid
p- chloro phenol and
p- chloro phenol-
glucuronide
3 , 4-dihydro~3 ,4-
dihydroxychloro-
Percent of
dose Site Ref.
50% (half-life) blood G-l
(70 sec.)
50% (half-life) blood
(15 sec.)
50% (half-life) blood
(15 sec.)
72.2% urine H-l
25.2%
26.6%
20.4%
major metabolite urine H-2
(2 days)
major metabolite urine
(2 days)
0.5% urine
(2 days)
0.03% urine
(2 days)
benzene
rabbit
0.5 g chloro-
benzene/kg, oral
catechol
derivatives
37%
urine
H-3
-------
Rate and Route
Compound Species of administration
Chlorobenzene rabbit 0.5 g chloro-
(continued) benzene/kg, oral
rabbit 0.5 g chloro-
benzene/kg, oral
rabbit 0.5 g chloro-
benzene/kg, oral
rabbit 0.5 g chloro-
benzene/kg, oral
rabbit 0.5 g 14C-chloro-
benzene, orally,
twice daily for
four days
Compound
mercapturic acids
p-chlorophenol
o-chloro phenol
catechols
mercapturic acids
chlorobenzene
(unchanged)
chlorobenzene
(unchanged)
14C-activity
Metabolites
Percent of
dose
28%
2-3%
trace
27%
27%
27%
27%
19.6%
2.6%
0.005%
Site Ref.
urine
urine
urine
urine H-4
urine
expired G-3
air
expired G-4
air
urine G-5
feces
body
tissues
(a) urinary metabo-
lites are expressed
as percentage of
urinary
urinary metabolites^3'
3,4-dihydro-3,4- 0.57%(a)
dihydroxy-chlorobenzene
mono phenols
diphenols
mercapturic acids
ethereal sulphates
glucuronides
urine
-------
Rate and Route
Compound Species of administration
Chloroform mouse 60 mg/kg, orally
rat 60 mg/kg, orally
(a) combined with
toluene soluble
metabolites
monkey 60mg/kg, orally
mouse 60 mg/kg, oral dose,
daily for 5 days
rat (60 mg/kg, oral dose,
daily for 5 days)
monkey 60 mg/kg, oral dose,
daily for 5 days
(b) range of adults, human ^ ' 500 mg/orally
18 to 50 years (male)
old, weighing
60 to 80 kg.
Compound
CO 2
bicarbonate/ carbonate
CO 2
chloroform' a'
CO 2
CO 2
chloroform,
(unchanged)
CO 2
chloroform,
unchanged
CO 2
chloroform,
unchanged
chloroform,
unchanged
CO2
Metabolites
Percent of
dose
80%
(24 hrs)
13%
(24 hrs)
66%
(24 hrs)
20%
(24 hrs)
18%
(24 hrs)
80%
(48 hrs)
6%
(48 hrs)
66%
(48 hrs)
20%
(48 hrs)
16%
(48 hrs)
79%
(48 hrs)
17.8-66.6%
(8 hrs)
50.6%
(8 hrs)
Site
expired
breath
urine
expired
breath
expired
breath
expired
breath
expired
breath
expired
breath
expired
breath
expired
breath
expired
breath
expired
breath
expired
air
expired
air
Ref .
1-1
1-1
1-1
1-2
1-2
1-2
1-3
-------
N>
Ul
Compound Species
Chloroform (female)^)
(continued)
human
1-C1
Chloronaphthalene male albino
rabbits
(approx.
2 kilos in
weight)
Rate and Route
of administration Compound
500 mg/orally chloroform,
unchanged
CO 2
5 mg, single breath chloroform
inhalation
napthalene isomer
1 g/rabbit, by ethereal sulfate
stomach tube
mercapturic acids
glucuronic acid
free phenolic
compounds
Metabolites
Percent of
dose
25.6-40.4%
(8 hrs)
48 . 5%
(8 hrs)
10%
10.1%
(4 days)
13.1%
(4 days)
53.7%
(4 days)
2%
(4 days)
Site Ref.
expired 1-3
air
expired
air
expired 1-4
air
urine J-l
urine
urine
urine
1-C1 naphthalene isomer
Yorkshire
pig (avg.
7.5 kg in
weight)
300 mg/pig, 1-C1 naphthalene
retrocarotid
administration
6.7 ug/g
(6 hours)
16.1 ug/g
(6 hours)
2.3 ug/g
(6 hours)
1.0 ug/g
(6 hours)
1.0 ug/g
(6 hours)
5.0 ug/g
(6 hours)
1.5 ug/g
(6 hours)
brain J-2
kidney
liver
skeletal
muscles
lung
psoas
heart
-------
ISi
ON
Metabolites
Rate and Route Percent of
Compound Species of administration Compound dose
Chloronaphthalene 1-C1 naphthalene isomer
(cont.) (cont.)
Yorkshire 300 rag/pig, 4-C1 naphthol 1.4 ug/g
pig (avg. retrocarotid (6 hours)
7.5 kg in administration 1.0 ug/g
weight) (6 hours)
440 ug/g
(6 hours
900 ug/g
(6 hours)
2-C1 napthalene isomer
Yorkshire 300 ing/pig, 2-C1 naphthalene 21.4 ug/g
pig (avg. retrocarotic (6 hours)
7.5 kg in administration 14.4 ug/g
weight) (6 hours)
5.2 ug/g
(6 hours)
2.2 ug/g
(6 hours)
0.8 ug/g
(6 hours)
4.5 ug/g
(6 hours)
4.5 ug/g
(6 hours)
0.6 ug/g
(6 hours)
3-Cl-2-naphthol 0.6 ug/g
(6 hours)
0.7 ug/g
(6 hours)
60 ug/g
(6 hours)
260 ug/g
(6 hours)
Site Ref.
kidney J-2
liver
urine
bile
brain
kidney
liver
skeletal muscle
lung
psoas
heart
fat
kidney
liver
urine
bile
-------
Compound
Rate and Route
Species of administration
Metabolites
Compound
Percent of
dose
Site
Ref.
Chloronitrobenzene
isomers
rabbit
(a) method of adminis-
tration not reported
(b) See summary
report for
identification
of aminochloro-
phenols and
chloronitro-
phenols
(c) This amount was
considered in-
significant since
it was within
the normal range
of mercapturic
acid levels in
urine.
rabbit
ortho-isomer,
0.1 g/kg
meta-isomer,
0.2
ether glucuronides
ethereal sulphates^5)
(aminochlorophenols and
chloronitrophenols)
free chloroaniline
nitrophenylmercapturic
acid
free phenolics
ether glucuronide
ethereal sulphates^")
free chloroaniline
nitrophenylmercapturic
acid
free phenolics
42%
24%
0.3%
7%
urine
urine
urine
feces
urine
K-l
K-l
trace amounts urine
33% urine
18% urine
11% urine
0.6% feces
1%'°) urine
trace amounts urine
K-l
-------
K>
CO
Compound Species
Chloronitrobenzene rabbit
isomers
(continued)
(d) Measured by
colorimetry.
A lower value
(3%) was obtained
by modified
Stekol method.
See Ref. B-l for
details .
Chloroprene human
(a) Metabolism
information was
based on
author's review
of chloroprene
toxicity reports.
No experimental
data was
reported.
Metabolites
Rate and Route Percent of
of administration Compound dose Site Ref.
para-isomer. ether glucuronide 19% urine K-l
0.2 g/kg (a)
ethereal sulphates 'k) 21% urine
free chloroaniline 9% urine
small amount feces
conjugated chloroaniline 4% urine
nitrophenylmercapturic 7%^ ' urine
acid
free phenolics trace amount urine
p-chloronitrobenzene , small amount feces
unchanged
(a) an epoxide^3' (a) liver L-l
Chlorotoluene - See Benzyl chloride
-------
Metabolites
Rate and Route
Compound Species of administration Compound
Dichlorobenzene rabbit 0.5 g/kg, via glucuronide
stomach tube
(o-isomer) ethereal sulfate
mercapturic acid
mono phenols
catechols
quinols
(m-isomer) glucuronide
ethereal sulfate
mercapturic acid
mono phenols
catechols
quinols
(p-isomer) glucuronide
ethereal sulfate
mercapturic acid
monophenols
catechols
quinols
rabbit 0.5 g/kg. via 3,4-dichlorophenol
stomach tube
(o-isomer) 2,3-dichlorophenol
dose
48%
21%
5%
39%
4%
0%
36%
7%
11%
25%
3%
0
36%
27%
0%
35%
0%
6%
30%
9%
Percent of
Site Ref.
urine M-l
urine
urine
urine
urine
urine
urine M-l
urine
urine
urine
urine
urine
urine M-l
urine
urine
urine
urine
urine
urine M-2
urine
-------
Compound Species
Dichlorobenzene rabbits
(continued)
rabbit
rabbit
1,2- Dichloroethane mouse
(a) figures represent
percentage of
Rate and Route
of administration
0.5 g/kg, via
stomach tube
(o-isomer )
0.5 g/kg, via
stomach tube
(m-isomer )
0.5 g/kg, via
stomach tube
0.05, 0.10. 0.14 or
0.17 g/kg 14C-1,2-
dichloroethane,i.p.
injection
Compound
3,4- and 4,5-dichloro-
catechols
3 , 4-dichlorophenyl-
mercapturic acid
2 , 4-dichl orophenol
3, 5-dichlorophenol
3, 5-dichlorocatechol
2,4-dichlorophenol-
mercapturic acid
2, 5-dichlorophenol
2,5-dichloroquinol
14C-l,2-dichloro-
ethane , unchanged
14C02
l^C-activity
urinary
chloroacetic acid
Metabolites
Percent of
dose
4%
5%
20%
minor amount
minor amount
minor amount
35%
6%
10-42%
(3 days)
12-15%
(3 days)
0-0.6%
(3 days)
0.6-1.3%
(3 days)
51-73%
(total, 3
days)
6_23%(a)
(3 days)
Site
urine
urine
urine
urine
urine
urine
urine
urine
expired
breath
expired
breath
feces con-
taminated
with urine
whole-body
homogenate
urine
urine
Ref .
M-2
M-l
M-2
N-l
-------
Compound Species
1,2- Dichloroethane mouse
(continued)
rat
(b) exact amounts
were not reported
1 , 1-Dichloroethylene rat
(vinylidene
chloride ;1,1-DCE)
rat
Rate and Route
of administration
0.05, 0.10. 0.14 or
0.17 g/kg 14C-1,2-
dichloroethane,i.p.
injection
0.05-0.17 g/kg,
14C-l,2-dichloro-
ethane, i.p.
injection
100 mg, stomach tube
0.5 mg (14C)-
1,1-DCE per kg,
oral dose
50 mg (14C)
1,1-DCE per kg,
Compound
S-carboxymethyl-
cysteine free
conjugated
thiodiacetic acid
2-chloroethanol
S , S ' -ethylene-bis-
cysteine
S-(beta-hydroxyethyl)
mercapturic acid
S-(beta-hydroxyethyl)
cysteine
(14C) 1,1-DCE
(unchanged)
14C02
14C-activity
(primarily thiodi-
glycollic acid)
(14C) 1,1-DCE
(unchanged)
Metabolites
Percent of
dose
44-46%(a)
(3 days)
0.5-5%(a)
(3 days)
33-34%(a>
(3 days)
0.0-0.8%(a>
(3 days)
0.7-1.0%(a>
( 3 days )
major
metabolitetb'
trace
x _ v
amount s *• " '
0.9%
(72 hrs)
23%
(72 hrs)
52%
(72 hrs)
2-4%
(72 hrs)
20%
(72 hrs)
Site Ref.
urine N-l
urine
urine
urine
urine
urine N-2
urine
expired 0-1
breath
expired
breath
urine
liver and
other
tissues
expired 0-1
breath
oral dose
-------
Compound Species
1 , 1-Dichloroethylene rat
(vinylidene
chloride )
(continued )
rat
(a) represents rat
metabolized (fasted or
1,1-DCE; fed)
metabolites
were not
identified
(b) primarily
eliminated in
urine
Rate and Route
of administration Compound
50 mg (14C) - 14C02
1,1-DCE per kg,
oral dose)
14C-activity
(primarily thiodi-
glycollic acid)
0.5 or 50 mg (14C)- residual 14C-activity
1,1-DCE per kg,
oral dose
1 mg (14C)1,1-DCE 14C-activity(a)
per kg, oral dose
50 mg (14C) - 14C activity
-------
OJ
UJ
Metabolites
Rate and Route
Compound Species of administration Compound
1,1-Dichloroethylene mouse 50 mg (^C) (^C) 1,1-DCE
(vinylidene 1,1-DCE per kg, unchanged
chloride) oral dose
(continued) l^COo
chloroacetic acid
thiodiglycollic acid
thioglycollic acid
dithioglycollic acid
thioglycollyloxalic acid
N-acetyl-S-cysteinyl
acetyl derivative
N-acetyl-S-(2-carboxy-
methyl)cysteine
urea
rat 50 mg (14C)- ( 14C)1, 1-DCE,
1,1-DCE per kg, unchanged
oral dose
l^COo
Percent of
dose
6%
3%
0
3%
5%
23%
3%
50%
4%
3%
28%
3.5%
Site Ref.
expired 0-3
air
expired
air
urine
urine
urine
urine
urine
urine
urine
urine
expired 0-3
air
expired
air
chloroacetic acid 1%
thiodiglycollic acid 22%
urine
urine
-------
Metabolites
LO
1,
Compound Species
1-Dichloroethylene (rat)
(vinylidene
chloride)
(continued)
Rate and Route
of administration
(50 mg (14C)
1,1 -DCE per kg,
oral dose)
Compound
thioglycollic acid
dithioglycollic acid
thioglycollyloxalic
Percent of
dose
3%
5%
2%
Site
urine
urine
urine
Ref .
(0-3)
acid
N-acetyl-S-cysteinyl 28%
acetyl derivative
N-acetyl-S-(2-carboxy- 0
methyl)cysteine
urea 3.5%
(b) total uptake of
trans-l,2-DCE
was about
10 nmol/ml
urine
urine
urine
1 ,2-Dichloroethylene rat liver
cis-isomer
(a) total uptake of
cis-l,2-DCE was
about 25 nmol/ml
trans-isomer rat liver
55 nmol/ml of
homogenate, by
perfusion
55 nmol/mL of
homogenate, by
perfusion
dichloroacetic acid 1-3% of in vitro P-l
total
uptake'3^
dichloroethanol 8-10% of in vitro
total
uptake^3'
dichloroacetic acid 0.5-1% of in vitro P-l
and dichloroethanol total
uptake^)
-------
Compound
Species
Rate and Route
of administration
Compound
Metabolites
Percent of
dose Site Ref.
1,2-Dichloropropane rabbit
rabbit
dog
(a) Present in urine,
but not identi-
fied or quanti-
tated
rat, mouse,
guinea pig
Ul
rat
(b) probably un-
changed 1,2—di-
propane
rat
1,500 ppm in air
(7 hrs per day for
5 days)
2,200 ppm in air
(7 hrs per day for
5 days)
1,000 ppm in air
(7 hrs per day for
5 days)
dichloropropane
vapors (concentra-
tion not specified)
dichloropropane
dichloropropane
dichloropropane
pigment-producing
substance*'3'
0.88 mg (8.5 uCi) of radioactive substance
l,2-dichloro(l-14C)- (unidentified)
propane in 0.5 ml
arachis oil, single
dose, via stomach tube
1.07 mg (10.3 uCi)
of 1.2-dichloro-
(1-1^C) propane,
single oral dose
volatile chlorinated
hydrocarbon
14
C02
0.6-1.1 mg/
100 cc blood
1.5-2.9 mg/
100 cc blood
1.3-1.6 rag/
100 cc blood
(a)
50.2%
(24 hrs)
4.9-6.9%
(96 hrs)
3.2-4.1%
(96 hrs)
1.4-1.7%
(96 hrs)
0.5%
(96 hrs)
23.1%
19.3%
blood
blood
blood
urine
Q-l
Q-l
Q-l
urine
feces
carcass
skin
gut
expired
air
expired
air
Q-2
Q-2
-------
Compound
Hexachlorobutadiene
Species
albino
mice, white
rats ,
guinea pigs
Rate and Route
of administration
unspecified
Compound
hexachlorobutane
Metabolites
Percent of
dose
unspecified
Site Ref.
unspeci- R-l
fied
unspecified
pentachlorobutane
unspecified
unspeci- R-l
fied
mice
oral
(5 mg/kg)
hexachlorobu t ad i ene
hexachlorobutadiene
17.4 ug
(1 hour)
28.8 ug
(2 hours)
14.5 ug
(3 hours)
liver
brain
R-2
59.2 ug
(24 hours)
11.4 ug
(96 hours)
rabbit 0.5 g of 14C-hexa-
chloroethane per kg
body wt., in diet
Hexachloroethane
trichloroethanol
trichloroacetic acid
dichloroacetic acid
monochloroacetic acid
(highly toxic)
dichloroethanol
oxalic acid
1.3%
(3 days)
1.3%
(3 days)
0.8%
(3 days)
0.7%
(3 days)
0.4%
(3 days)
0.1%
(3 days)
urine
urine
urine
urine
urine
urine
S-l
-------
CO
Metabolites
Rate and Route
Compound Species of administration Compound
Hexachloroe thane
(continued)
rabbit 0.5 g of ^C-hexa- volatile metabolites
chloroethane per kg (included CC>2»
body wt . , in diet ^2^6
tetrachloroethylene and
1,1,2, 2-te trachloro-
ethane)
(a) sheep #1-10 sheep^3' 0.5 g/kg, single hexachloroethane
oral dose
tetrachloroethylene
pentachloroethane
(b) sheep #11 and 12. sheep^") 0.5 g/kg, single hexachloroethane
96-hr metabolite oral dose
levels were very
low or nil; see
Table 2 in
ref. M-2
tetrachloroethylene
pentachloroethane
Percent of
dose
14-24%
(3 days)
10-28 ug/ml
(24 hrs)
0.6-1.1 ug/mi
(24 hrs)
0.15-0.50
ug/ml
(24 hrs)
780-1260 ug
(24 hrs)
50-70 ug
(24 hrs)
854-1300 ug
(24 hrs)
25-29 ug
(24 hrs)
trace-468 ug
(24 hrs)
20-25 ug
(24 hrs)
Site Ref.
expired S-l
air
blood S-2
blood
blood
feces S-2
urine
feces
urine
feces
urine
-------
Compound
Rate and Route
Species of administration
Compound
Metabolites
Percent of
dose
Site
Ref.
Hexachloroethane
(continued)
(c) Sheep #27 and
28, anaesthetized.
See Table 3,
ref. M-2 for
additional
details
0.5 g/kg,
single oral dose
hexachloroethane
sheep
(c)
0.5 g/kg,
single oral dose
hexachloroethane
tetrachloroethylene
1.7-2.2 ug/g
(4 hrs)
0.2 ug/g
(6 hrs)
trace-1.1
ug/g
(8.5 hrs)
trace-0.04
ug/g
(8.5 hrs)
trace-0.2
ug/g
(8.5 hrs)
0.3-0.5 ug/g
(4 hrs)
0.2-0.4 ug/g
(6 hrs)
0.6-2.1 ug/g
(8.5 hrs)
trace-0.5
ug/g
(8.5 hrs)
trace-2.8
ug/g
(8.5 hrs)
bile S-2
blood
fat
muscle
brain, S-2
kidney
and liver
bile
blood
fat
muscle
brain,
kidney
and liver
-------
OJ
VO
Rate and Route
Compound Species of administration
Hexach 1 or oe thane
(continued)
sheep(c) .5 g/kg
single oral dose
sheep(c) 0.5 g/kg,
single oral dose
fresh 18 mg/1 added to
liver emulsion
slices, in
olive oil
emulsion,
37°C
heated 18 mg/1 added to
liver emulsion
slices (5
min. ,
70°C),
in olive
oil emulsion
Compound
pent ach lor oe thane
pentachloroethane
hexachloroethane
tetrachloroethylene
pentachloroethane
hexachloroethane
tetrachloroethylene
pentachloroethane
Metabolites
Percent of
dose
0-trace
(4 hrs)
0-trace
(6 hrs)
0-0.02 ug/g
(8.5 hrs)
trace-0.01
ug/g(8.5 hrs)
trace-0.02
ug/g
(8.5 hrs)
13.3 ug/g
(4 hrs)
9.1 ug/g
(4 hrs)
0.76 ug/g
(4 hrs)
50.8 ug/g
(4 hrs)
.
2.4 ug/g
(4 hrs)
1.74 ug/g
(4 hrs)
Site Ref.
bile S-2
blood
fat
muscle
brain,
kidney
and liver
in vitro S-2
in vitro
in vitro
in vitro S-2
in vitro
in vitro
-------
o
Compound
Hexachloroethane
(continued)
Methylene chloride
(a) represents l^C-
methylene chloride
and metabolites
(b) figures represent
individual values
for each
experimental
Species
fresh
liver
slices in
olive oil
emulsion,
37°C
heated
liver
slices (5
min,
70°C),
in olive
oil
emulsion
rat
Rate and Route
of administration Compound
54 mg/L added to hexachloroethane
emulsion
tetrachloroethylene
pent achloroe thane
54 mg/1 added to hexachloroethane
emulsion
tetrachloroethylene
pent achloroe thane
412-930 mg (14C)- 14C-activity (a)
methylene
chloride/kg,
intr a peritoneal
injection
Metabolites
Percent of
dose Site
56.4 ug/g in vitro
(4 hrs)
56.4 ug/g in vitro
(4 hrs)
0.95 ug/g in vitro
(4 hrs)
20.2 ug/g in vitro
(4 hrs)
0.36 ug/g in vitro
(4 hrs)
0.12 ug/g in vitro
(4 hrs)
77.9, 93.2(b> breath
(2 hrs)
98.6, 96.8(b>
(8 hrs)
98.2
(24 hrs)
3.09 carcass
(2 hrs)
2.06, 2.42^b^
(8 hrs)
Ref .
S-2
S-2
T-l
animal
-------
Compound
Rate and Route
Species of administration
Compound
Metabolites
Percent of
dose
Site
Ref.
Methylene chloride
(continued)
rat
412-930 mg(14C)-
methylene
chloride/kg,
intraperitoneal
injection
1.53
(24 hrs)
less than
0.01 (2 hrs
and 8 hrs)
carcass
urine and
feces
T-l
(b) figures represent
individual values
for each
experimental
anima1
rat
412-930 mg
(^Cj-methylene
chloride/kg
intraperitoneal
injection
methylene chloride
carbon dioxide
1.06
(24 hrs)
.07
(24 hrs)
urine
feces
77.0, 92.0(b) breath
(2 hrs)
95.3, 92.6
(8 hrs)
91.50
(24 hrs)
0.44, 0.65(b) breath
(2 hrs)
1.44, 1
(8 hrs)
3.04
(24 hrs)
T-l
-------
Compound
Species
Rate and Route
of administration
Compound
Metabolites
Percent of
dose
Site
Ref
Methylene chloride
(continued)
(b) figures represent
individual values
for each
experimental
animal
(c) dpm x 1CH g
tissue, wet
weight
rat
412-930 mg(14C)-
methylene
chloride/kg,
intraperitoneal
injection
carbon monoxide
14
^activity
(unidentified
compound)
- activity
0.14, 0.14
(2 hrs)
40.4, 40.2
(8 hrs)
18.3
-------
Metabolites
UJ
Compound
Species
Rate and Route
of administration
Compound
Percent of
dose
Site
Ref .
Methylene chloride
(continued)
(b) figures represent
individual values
for each
experimental
animal
(c) dpra x 103 g
tissue, wet
weight
rat
412-930 mg (14C)-
methylene
chloride/kg,
intraperitoneal
injection
^C-activity
7.4
(24 hrs)
16.2 (c>
(2 hrs)
adrenal
glands
15.4, 15.3 (b»c)
(8 hr)
8.7
(2 hrs)
fat
T-l
10.8, 36.5 (b'c)
(8 hrs)
3.3 <0
(24 hrs)
-------
Compound
Rate and Route
Species of administration
Compound
Metabolites
Percent of
dose
Site
Ref.
Methylene chloride
(continued)
(c) dpm x 103 g
tissue, wet
weight
rat
rat
human
412-930 mg (14C)-
methylene
chloride/kg,
intraperitoneal
injection
0.2 mmol/kg 14C-
methylene chloride,
inhalation (8 hours),
closed rebreathing
system
213 ppm methylene
chloride inhalation
(60 min)
carbon monoxide
carbon dioxide
carboxyhemoglobin
(COHb)
2.2-3.8 (b»c)
(2 hrs)
2.1-7.8
(8 hrs)
2.1-5.5
(24 hrs)
47%
(c)
(c)
lung,
heart,
brain,
stomach,
small &
large
intestines
breath
T-l
T-2
29%
1.5%
COHb
saturation
(after 30 min
of exposure)
1.75%
COHb
saturation
(after 60 min
of exposure)
2.4%
COHb
saturation
(3 hrs
after
exposure)
breath
blood
T-3
-------
Compound
Species
Rate and Route
of administration
Compound
Metabolites
Percent of
dose Site Ref.
Methylene chloride
(continued)
human
human
rat
986 ppm, inhalation
(2 hrs)
carboxyhemoglobin
(COHb)
180-200 ppm, carboxyhemoglobin
workroom air (8 hrs) (COHb)
3.0 mraol/kg,
intraperitoneal
injection
carboxyhemoglobin
(COHb)
10% blood blood T-3
COHb
saturation
1 hr
post-
exposure
9% COHb blood T-4
blood
saturation
(after 8 hrs
exposure)
6% maximum blood T-5
saturation
(after 2-2.5
hrs)
rat 440 ppm,
inhalation exposure
(3 hr)
Pentachloroanisole rainbow 0.024 mg^^C
(PCA) trout PCA/L water, at
12°C for
12 hrs.
carboxyhemoglobin
(COHb)
pentachloroanisole
7% maximum blood
saturation
approx. fat
80 ug/g
(after 12 hrs
exposure)
approx. liver
3 ug/g
(after
12 hrs
exposure)
T-6
U-l
-------
Compound
Species
Rate and Route
of administration
Compound
Metabolites
Percent of
dose Site Ref.
Pentachloroanisole
(PCA)
(continued)
rainbow
trout
0.024 mg 14C
PCA/L water, at
12°C for
12 hours
pentachloroanisole
rainbow
trout
0.05 mg14C
PCA/L water, at
12°C for
24 hrs
pentachlorophenol
glucuronide
approx.
2 ug/g
(after
12 hrs
exposure)
approx.
1 ug/g
(after
12 hrs
exposure)
10 ug/g
muscle
U-l
(a) dose (0.5 mg/kg)
was administered
by subcutaneous
injection
other phenols
0.2%
(4 days)
0.7%(a)
(10 days)
1%
(3 and
4 days )
(10 days)
blood
bile
U-l
Pentachlorobenzene
rabbit
0.5 mg/kg, by
stomach tube
tri- or penta-
ch 1 or o phenol
0.2%
(3 days)
urine V-l
urine
-------
Compound
Rate and Route
Species of administration
Compound
Metabolites
Percent of
dose
Site
Ref.
Pentachlorobenzene
(continued)
(a) dose (0.5 mg/kg)
was administered
by subcutaneous
injection
rabbit
0.5 mg/kg, by
stomach tube
pentachlorobenzene,
unchanged
other chloro-
hydrocarbons
pentachlorobenzene
pentachlorobenzene
pentachlorobenzene
0
(3 and 4
days)
0(a)
(10 days)
9%
(3 days)
21%
(4 days)
(10 days)
5%
(3 days)
5%
(4 days)
(10 days)
45%
(3 days)
31%
(4 days)
(10 days)
(3 days)
5%
(4 days)
expired
air
V-l
expired
air
f eces
gut
contents
gut
contents
V-l
pelt
pelt
-------
Metabolites
Compound
Rate and Route
Species of administration
Compound
Percent of
dose
Site
Ref.
Pentachlorobenzene
(continued)
(a) dose (0.5 rag/kg)
was administered
by subcutaneous
injection
rabbit
0.5 mg/kg, by
stomach tube
pentachlorobenzene
pentachlorobenzene
00
(b) results obtained
from a preview
article, the
study manuscript
is in publication
preparation
rat
unspecified
unchanged*- '
pentachlorophenol'"'
47%(a>
(10 days)
15%
(3 days)
9%
(4 days)
(10 days)
6%
(3 days)
5.5%
(4 days)
I0(a)
(10 days)
3%
9%
pelt V-l
depot fat
rest of
body
total
excretion
products
(urine
plus
feces)
total
excretion
products
(urine
plus
feces)
V-2
-------
Metabolites
Compound
Rate and Route
Species of administration
Compound
Percent of
dose
Site
Ref.
Pentachlorobenzene
(continued)
rat
unspecified
tetrachlorophenol^k) unspecified
total
excretion
products
(urine
plus
feces)
V-2
tetrachloro-
hydroquinone
unspecified
a hydroxylated
chlorothio-
compound
unspecified
total
excretion
products
(urine
plus
feces)
total
excretion
products
(urine
plus
feces)
Pentachloroethane
mouse
20 uL, injected
subcutaneously
pentachloroethane
(unchanged)
tetrachloroethylene
trichloroethanol
trichloroacetic acid
approx. 29%
(24 hrs)
approx. 4%
(24 hrs)
approx. 12%
(24 hrs)
approx. 5%
(24 hrs)
urine,
feces,
and
expired
air
combined
same as
above
same as
above
s ame a s
above
W-l
-------
Ul
o
Metabolites
Rate and Route
Compound Species of administration Compound
Pentachloroethane (mouse) (20 ul , injected trichloroethylene
(continued) subcutaneously)
(a) amount was not
quantitated, but
appeared to be a
little less than
the amount of
tetrachloro-
ethylene.
sheep 0.3 ml /kg, pentachloroethane
single oral dose
tetrachloroethylene
mouse 1.1—1.8 g/kg, pentachloroethane
injected sub- (unchanged)
cutaneously
trichloroethanol
trichloroacetic acid
trichloroethylene
tetrachloroethylene
Percent of
dose
less than
5% (a)
(24 hrs)
approx. 10~"
g/ml of
plasma
(day 3)
less than 10~5
g/ml of
plasma
(day 3)
12-51%
(3 days)
16-32%
(3 days)
9-18%
(3 days)
2-16%
(3 days)
3-9%
(3 days)
Site Ref.
(urine, (W-l)
feces ,
and
expired
air
combined)
venous W-2
blood
venous
blood
expired W-3
air
urine
urine
expired
air
expired
air
-------
Rate and Route
Compound Species of administration
Tetrachlorobenzene 1,2,3, 4-isomer
rabbit 300 mg/ rabbit (male,
4-5 kg), by ip
injection
rabbit .5 g/kg (chinchilla
doe), by stomach
Compound
2,3,4,5-tetra-
chlorophenol
2,3,4,6-tetra-
chloro phenol
tetrachloro-
phenols
Metabolites
Percent of
dose Site Ref.
20% urine X-l
(10 days)
2% urine
(10 days)
43% urine X-2
(6 days)
tube
(2,3,4,5-tetra-
chlorophenol)
other phenols
1,2,3,4-tetrachloro-
benzene, unchanged
other chloro-
benzenes
1,2,3,4-tetrachloro-
benzene, unchanged
less than 1%
(6 days)
(6 days)
2%
(2 days)
5%
(6 days)
10%, total
(6 days)
0.1%
2%
5%
0.5%
urine
expired
air
expired
air
f eces
tissues
liver
skin
depot
fat
gu t c on-
tents
-------
Metabolites
Rate and Route
Compound Species of administration Compound
Tetrachlorobenzene rabbit (1 ,2,3,4-isomer) 1,2,3,4-tetrachloro-
(continued) (continued) benzene, unchanged
1 , 2,3,5-isomer
rabbit 300 rag/rabbit (male, 2,3,4,5-tetra-
4~5 kg), by ip chloro phenol
injection
2,3,5,6-tetra-
chlorophenol
2,3,4,6-tetra-
chlorophenol
rabbit .5 g/kg (chinchilla tetrachloro-
doe), by stomach phenols (pre-
tube dominant ly
2,3,4,6-tetra-
chlorophneol)
other phenols
1,2,3,5-tetrachloro-
benzene, unchanged
other chloro-
benzenes
1,2,3,5- tetrachloro-
benzene, unchanged
Percent of
dose
2.0%
3%
(10 days)
2%
(10 days)
1.5%
(10 days)
S7
J/o
(6 days)
5%
(6 days)
12%
(6 days)
9%
(6 days)
14%
(6 days)
23%
(6 days)
Site Ref.
rest of X-2
body
urine X-l
urine
urine
urine X-2
urine
expired
air
expired
air
faces
tissues
-------
U)
Rate and Route
Compound Species of administration
Tetrachlorobenzene (1,2,3, 5-isomer )
(continued) (continued)
rabbit .5 g/kg (chinchilla
doe), by stomach
tube
1 ,2, 4, 5-isomer
rabbit 300 rag/rabbit (male,
4-5 kg), by ip
injection
rabbit .5 g/kg (chinchilla
doe), by stomach
tube
Compound
1,2,3, 5-tetrachloro-
benzene, unchanged
2,3,5,6-tetrachloro-
phenol
tetrachloro phenols
other phenols
1, 2,4,5- tetrachloro-
benzene, unchanged
other chloro-
benzenes
1 ,2,4,5-tetrachloro-
benzene, unchanged
1,2,4,5-tetrachloro-
benzene, unchanged
Metabolites
Percent of
dose
0.5%
0.2%
5%
11%
1.4%
5.2%
2%
2%
(6 days)
5%
(6 days)
2%
(6 days)
10%
(6 days)
16%
(6 days)
48%
(6 days)
Site Ref.
liver X-2
brain
skin
Depot
fat
Gut con-
tents
rest of
body
urine X-2
urine X-l
urine
expired
air
expired
air
f eces
tissues
-------
Metabolites
Rate and Route
Compound Species of administration Compound
Tetrachlorobenzene rabbit 1 ,2,4,5-isomer 1,2,4,5-tetrachloro-
(continued) .5 g/kg (chinchilla benzene, unchanged
doe), by stomach
tube
1,1,2,2-Tetrachloro- human 2.5 mg ^8cj__ 38ci_act£v£ty
ethane tetrachloroethane,
single breath
inhalation
mouse 0.21-0.32 g 14C- 14C02
tetrachloroethane
per kg body wt . ,
intraperitoneal ^C- tetrachloroethane
injection (unchanged)
l^C-activity
Percent of
dose
0.1%
0.1%
10%
25%
6.2%
6.4%
3.3%
(1 hr)
50%
(3 days)
4%
(3 days)
28%
(3 days)
less than 1%
(3 days)
16%
(3 days)
Site Ref.
liver X-l
brain
skin
Depot
fat
Gut con-
tents
rest of
body
expired Y-l
air
expired Y-2
air
expired
air
urine
feces
contaminated
with urine
whole
body
homogenate
-------
C ompouud
Rate and Route
Species of administration
Compound
Metabolites
Percent of
dose
Site
Ref.
1,1,2,2-Tetrachloro-
ethane
(continued)
mouse
(a) figures express
metabolites as
percentage of
urinary
radioactivity
Ul
On
mouse
rat
0.16-0.32 g
l^C-tetrachloro-
ethane per kg
body wt.
0.16-0.32 g
^C-tetrachloro-
ethane per kg body
weight
200 ppm, inhalation
exposure (8 hrs)
trichloroethylene
tetrachloroethylene
dichloroacetic acid
trichloroethanol
oxalic acid
trichloroacetic acid
urea
glyoxylic acid
total trichloro-
compounds
trichloroacetic acid
trichloroethanol
0.2-0.4%
(24 hrs)
0.2-0.4%
(24 hrs)
27%(a>
(24 hrs)
(24 hrs)
(24 hrs)
(24 hrs)
2%(a>
(24 hrs)
0.9%(a)
(24 hrs)
8.2 mg/kg
(48 hrs)
1.7 mg/kg
(48 hrs)
6.5 mg/kg
(48 hrs)
expired
air
expired
air
urine
urine
urne
urine
urine
urne
urne
urne
Y-2
Y-2
Y-3
-------
Compound
Rate and Route
Species of administration
Compound
Metabolites
Percent of
dose
Site
Ref.
1,1,2,2-Tetrachloro-
ethane
(continued)
Ul
o\
rat
200 ppm, inhalation
exposure (8 hrs)
total trichloro-
compounds
rat
2.78 mmol tetra-
chloroethane per
kg body wt
(equivalent to
467 mg/kg(b))
trichloroacetic acid
trichloroethanol
(b) conversion of
2.78 mmol to
467 rag/kg was
reported in
NIOSH criteria
document on
occupational
exposure to
1,1,2,2-tetra-
chloroethane
2.1 rag/kg urine
(48 hrs)
0.3 mg/kg
(2nd 48-hr
period)
1.3 mg/kg urine
(48 hrs)
0.3 mg/kg
(2nd 48-hr
period)
0.8 mg/kg urine
(48 hrs)
immeasureable
amount
(2nd 48-hr
period)
Y-3
Y-3
-------
Compound Species
Tetrachloroethylene rat
Rate and Route
of administration
1.75 uCi 36C1-
tetrachloroethylene
Compound
3"Cl-radioactivity
Metabolites
Percent of
dose
97.9%
(48 hrs)
Site Ref.
expired Z-l
air
rat liver
(b) absorbed radio-
activity was
equivalent to
70% of the dose
mouse
(a) represents
percentage of
urinary
radioactivity
mouse
administered by
stomach tube
180 ppm vapor
1.3 mg/g
body weight
(vapor, 2 hrs)
trichloroacetic acid
trichloroacetic acid
(bound to liver tissue)
l^C-radioactivity
trichloroacetic acid
oxalic acid
dichloroacetic acid
2.1% urine
(18 days;
urinary
radioactivity
consisted of
trichloroacetic
acid (0.6% of
original dose)
and inorganic
chloride)
10-15%
3-5%
90% of
absorbed
activity
20% of
absorbed
activity
(b)
(b)
less than
0.5% of
absorbed
activity^'
in
vitro
in
vitro
expired
air
urine
feces
Z-2
Z-3
urine
trace
amounts (a)
-------
Rate and Route
Compound Species of administration
Tetrachloroethylene rat 200 ppm,
(continued) inhalation exposure
(8 hrs)
rats 2. 78 mmol/kg
body wt . ,
intraperitoneal
injection
^ (a) single animal mouse 2.78 mmol/kg
00 results body wt . ,
intraperitoneal
injection
human 20-70 ppm,
occupational
exposure
human 200-400 ppm,
occupational
exposure
human 87 ppm inhalation
Compound
trichloroacetic acid
trichloroethanol
trichloroacetic acid
trichloroethanol
trichloroacetic acid
trichloroethanol
trichloroacetic acid
trichloroethanol
trichloroacetic acid
trichloroethanol
trichloroacetic acid
Metabolites
Percent of
dose Site
5.3 mg/kg urine
body weight
(48 hrs)
3.2 mg/kg urine
body weight
(48 hrs)
5.5 mg/kg urine
body weight
(48 hrs)
0.08 mg/kg urine
body weight
(48 hrs)
23.7. 22.9 urine
tng/L^a)
0.1, 0.4 urine
mgA/a)
4-35 mg/L urine
4-20 mg/L urine
32-97 mg/L urine
21-100 mg/L urine
1.8% of urine
Ref .
Z-4
Z-4
Z-4
Z-4
Z-4
Z-5
(3 hrs)
retained
tetrachloro-
ethylene
(67 hrs)
-------
Compound
Tetrachloroethylene
(continued)
Species
human
human
(male)
human
(female)
Rate and Route
of administration
87 ppm inhalation
(3 hrs)
30-100 ppm,
inhalation
(8 hrs/day,
5 days/week,
occupational
exposure)
10-20 ppm vapor
(8 hrs/day,
5 days /week,
Compound
unknown chloride
total trichlorocompounds
total trichlorocompounds
Metabolites
Percent of
dose Site Ref.
1.0% of urine Z-5
retained
tetrachloro-
ethylene
(67 hrs)
123.3 hrs urine Z-6
biological
half-life
190.1 hrs urine
biological
half-life
Ul
VO
human
occupational
exposure)
100 ppm inhalation
7 hrs/day, 5 days
rat
200 ppm
6 hrs/day, 4 days
tetrachloroethylene
tetrachloroethylene
tetrachloroethylene
1 ppm
(14 days after
exposure)
3 days
expirational
half-life
622.2
nmol/g
(17 hrs after
last exposure)
18.4 nmol/g
(17 hrs after
exposure)
13.1 nmol/g
(17 hrs after
exposure)
breath
breath
perirenal
fat
cerebrum
cerebellum
Z-7
Z-8
-------
Metabolites
Compound
Rate and Route
Species of administration
Compound
Percent of
dose
Site
Ref.
Tetrachloroethylene
(continued)
rat
200 ppm 6 hrs/day,
5 days
tetrachloroethylene
1724.8 nmol/g
after 5th
day/6 hrs
exposure
142.5 nmol/g
after 5th
day/6 hrs
exposure
92.3 nraol/g
after 5th
day/6 hrs
exposure
perirenal
fat
cerebrum
Z-8
cerebellum
Trichlorobenzene
rabbit
1,2,3-isomer
0.5 g/kg, by
stomach tube;
superior numbers
indicate the
number of trials
glucuronide
ethereal sulfate
total trichlorophenols
mercapturic acid
(2,3,4-trichloro-
phenylmercap-
turic acid)
50%3
(46-55%)
(5 days)
12%3
(9-13%)
(5 days)
78%4
(64-89%)
(5 days)
0.3%3
(0.2-0.5%)
(5 days)
urine
urine
urine
urine
AA-1
-------
Metabolites
Compound
Rate and Route
Species of administration
Compound
Percent of
dose
Site
Ref.
Trichlorobenzene
(continued)
rabbit
rabbit
1,2,4-isomer
0.5 g/kg, by
stomach tube
superior numbers
indicate the number
of trials
1,3,5-isomer
0.5 g/kg, by
stomach tube;
superior numbers
indicate the number
of trials
glucuronide
ethereal sulfate
total phenols
mercapturic acid
(2,3,5- and
2,4,5-trichloro-
phenylmercap-
turic acids)
glucuronide
ethereal sulfate
total phenols
mercapturic
acid
27%3
(18-33%)
(5 days)
(10-12%)
(5 days)
42%3
(33-51%)
(5 days)
0.3%3
(0.2-0.5%)
(5 days)
(16-23%)
(5 days)
3%5
(1-5%)
(5 days)
(7-13%)
(5 days)
urine
urine
urine
AA-1
urine
urine
urine
urine
AA-1
(5 days)
-------
Metabolites
Compound
Rate and Route
Species of administration
Compound
Percent of
dose
Site
Ref.
Trichlorobenzene
(continued)
rabbit
rabbit
1,3,5-isomer
1.5 g/rabbit
(unspecified
weight)
0.5 g/kg, by
stomach tube
1,3,5-trichloro-
benzene
trichloro-
phenol
other phenols
(including
4-chlorophenol and
4-chlorocatechol)
1,3,5-trichloro-
benzene, unchanged
other chloro-
hydrocarbons
1,3,5-trichloro-
benzene, unchanged
9%
(2 days)
(8 days)
10%
(9 days)
(8 days)
4%
(9 days)
12%
(8 days)
8.5%
(9 days)
0.6%
(8 days)
1.5%
(9 days)
13%
(8 days)
1.5%
(9 days)
23%
(8 days)
18%
(9 days)
feces
urine
AA-1
AA-2
urine
expired
air
expired AA-2
air
feces
feces
gut
contents
-------
Metabolites
Compound
Rate and Route
Species of administration
Compound
Percent of
dose
Site
Ref.
Trichlorobenzene
(continued)
rabbit
1, 3,5-isomer
0.5 g/kg, by
stomach tube
1,3,5-trichloro-
benzene, unchanged
5%
(8 days)
5%
(9 days)
(8 days)
4.5%
(9 days)
22%
(8 days)
20%
(9 days)
pelt,
including
subcutaneous
fat
depot
fat
AA-2
rest of
body
1,1,1-Trichloroethane rat
700 mg
1,1,1-trichlor-
ethane-1-C14
per kg, injected
intraperitoneally
1,1,1-trichloroethane-
unchanged
98.7%
(25 hrs)
expired
air
AB-1
l^C-activity,
primarily
2,2,2-trichloro-
ethanol-2-
C^glucuronide
0.5%
(25 hrs)
0.85%
(25 hrs)
expired
air
urine
-------
Metabolites
Compound
Species
Rate and Route
of administration
Compound
Percent of
dose
Site
Ref.
1,1,1-Trichloroethane
(continued)
rat
rat
700 mg
1,1,1-trichlor-
ethane-1-C14
per kg, injected
intraperitoneally
200 ppm, inhalation
(8 hrs)
2.78 mmol/kg body
weight, intraperi-
toneal injection
^C-activity, at least
90% unchanged
1,1,1-trichloro-
ethane 1-1-C14
l^C-activity
l^C-activity
trichloroethanol
trichloroacetic acid
trichloroethanol
0.08-0.12%
(25 hrs)
0.02%
(25 hrs)
0.02%
(25 hrs)
0.03%
(25 hrs)
trace
amounts
3.1 mg/kg
body
(48 hrs)
0.5 mg/kg
body weight
(48 hrs)
3.5 mg/kg
body weight
(48 hrs)
skin
AA-2
blood
fat
feces
liver,
intestines,
kidneys,
heart,
lung,
brain,
muscle,
and hair
urine AB-2
urine
urine AB-2
-------
Metabolites
Compound
Rate and Route
Species of administration
Compound
Percent of
dose
Site
Ref.
1,1,1-Trichloroethane rat
rat
CTv
Ul
rat
2.78 mmol/kg body trichloroethanol
221 ppm, inhalation
(4 hrs)
221 ppm, inhalation
(4 hrs)
trichloroacetic acid
trichloroethanol
trichloracetic acid
1,1,1-trichloroethane
immeasurable
amount
(2nd 48 hr
period)
0.5 mg/kg
body weight
(48 hrs)
0.3 mg/kg
body weight
(2nd 48 hr
period)
126.2 ug,
total
(24 hrs)
7.5 ug,
total
(2nd 24 hr
period)
3.2 ug,
total
(24 hrs)
8.1 ug,
total
(2nd 24-hr
period)
2.488 mg
(1st hr
post-
exposure)
urine
urine
AB-3
urine
AB-3
expired
air
-------
Metabolites
Compound
Rate and Route
Species of administration
Compound
Percent of
dose
Site
Ref.
1,1,1-Trichloroethane rat
(continued)
rat
221 ppm, inhalation 1,1,1-trichloroethane
443 ppm, inhalation trichloroethanol
(4 hrs)
0.050 mg
(8th hr
post-
exposure)
206.5 ug,
total
(24 hrs)
expired
air
urine
AB-3
AB-3
trichloroacetic acid
8.5 ug
(2nd 24 hr
period
9.5 ug
(24 hrs)
urine
443 ppm, inhalation 1,1,1-trichloroethane
(4 hrs)
204 ppm, inhalation
(8 hrs/day,
5 days/week, for
14 weeks)
trichloroethanol
10.6 ug
(2nd 24 hr
period)
5.719 mg
(1st hr
post-
exposure)
0.098 mg
(8th hr
post-
exposure)
93 ug/24 hrs
(1st week)
435 ug/24 hrs
(10th week)
expired
air
urine
urine
AB-3
AB-3
-------
Rate and Route
Compound Species of administration
1, 1, 1-Trichloroethane rat 204 ppm, inhalation
(continued) (8 hrs/day,
5 days/week, for
14 weeks)
human 5 rag 38C1-1,1,1-
trichloroethane ,
Compound
trichloroethanol
trichloroacetic acid
1,1, 1-trichloroethane
-^el-radioactivity
Metabolites
Percent of
dose Site Ref.
0.059-0.88 blood
ug/ml
(determined
periodically,
14 weeks)
12-20 ug/ urine
24 hrs
(weekly)
0.677-1.000 blood
ug/ml
(determined
periodically,
14 weeks)
44% expired AB-4
(1 hr) air
human
human
inhalation (single
breath)
250 ppm, inhalation
(30 minutes per
exposure, at rest
and with consecutive
work loads of
50, 100, and 150 W)
1,1,1-trichloroethane
3.0 ppm
(at rest)
4.5 ppm
(50 W)
5.2 ppm
(100 W)
5.5 ppm
(150 W)
1.4 ppm
(at rest)
arterial
blood
AB-5
venous
blood
-------
Metabolites
Compound
Species
Rate and Route
of administration
Compound
Percent of
dose
Site
Ref.
1,1,1-Trichloroethane
(continued)
human
1,1,1-Trichloroethane
3.1 ppm
(50 W)
venous
blood
AB-5
3.5 ppm
(100 W)
4.4 ppm
(150 W)
125 ppm
(at rest)
alveolar
air
168 ppm
(50 W)
cr>
oo
210 ppm
(100 W)
human
350 ppm, inhalation
(30 minutes per
exposure, at rest
and with 50 W work-
load)
1,1,1-trichloroethane
207 ppm
(150 W)
5.0 ppm
(at rest)
7.2 ppm
(50 W)
arterial
blood
AB-5
3.0 ppm
(at rest)
venous
blood
5.5 ppm
(50 W)
179 ppm
(at rest)
alveolar
air
-------
C ompound S pec i e s
1, 1 , 1-Trichloroe thane human
(continued)
Metabolites
Rate and Route Percent of
of administration Compound dose
350 ppm, inhalation 1, 1 , 1-trichloroethane 239 ppm
(30 minutes per (50 W)
exposure; at rest,
at rest plus 4%
C02, and 50 W
workload plus 4%
C02)
Site Ref.
arterial AB-5
blood
human
250 ppm, inhalation
(30 minutes per
exposure; at rest,
at rest plus 4%
C02, and 50 W
workload plus 4%
C02)
250 ppm, inhalation
(30 minutes per
exposure; at rest,
at rest plus 4%
C02, and 50 W
workload plus 4%
C02
1,1,1-trichloroethanol
1,1,1-trichloroethanol
2.2 ppm
(at rest)
3.3 ppm
(at rest
plus 4% C02)
3.9 ppm
(50 W plus
4% C02)
1.0 ppm
(at rest)
1.2 ppm
(at rest plus
4% C02)
1.9 ppm
(50 W plus
4% C02)
128 ppm
(at rest
176 ppm
(at rest
plus 4% (C02)
201 ppm
(50 W
plus 4% C02)
arterial
blood
venous
blood
alveolar
air
AB-5
-------
Compound
Species
Rate and Route
of administration
Compound
Metabolites
Percent of
dose
Site
Ref.
1,1,1-Trichloroethane human
(continued)
human
500 ppm, inhalation
(6.5 7 hrs/day,
5 days)
trichloroethanol
trichloroacetic acid
500 ppm, inhalation
6.5 7 hrs/day,
5 days
trichloroacetic acid
20.1 mg/24 hrs urine
(1st day)
30.1 mg/24 hrs
(2nd day)
29.3 mg/24 hrs
(3rd day)
46.6 mg/24 hrs
(4th day)
7.0 mg/24 hrs
AB-6
(6th
day
after last
exposure)
less than
1.0 mg/24 hrs
(12th
day
urine
after last
exposure)
7.5 mg/24 hrs
(1st day)
10.9 mg/24 hrs
(2nd day)
12.3 mg/24 hrs urine
3rd day)
14.1 mg/24 hrs
(4th day)
18.0 mg/24 hrs
(6th day
after last
exposure)
AB-6
-------
Metabolites
Compound
Rate and Route
Species of administration
Compound
Percent of
dose
Site
Ref.
1,1,1-Trichloroethane
(continued)
human
human
human
human
rat
500 ppm, inhalation
6.5 7 hrs/day,
5 days
4.3 ppm, inhalation
(8 hrs/day, 5.5
days/week, at least
5 years)
24.6 ppm, inhalation
(8 hrs/day, 5.5
days/week, at least
5 years)
53.4 ppm, inhalation
(8 hrs/day, 5 1/2
days/week, at least
5 years)
20 umol/L (500 ppm),
inhalation
(6 hrs/day, 4 days)
trichloroacetic acid
total trichloro-
compounds
tr ich1oroe thano1
trichloroacetic acid
total trichloro-
compounds
trichloroethano1
trichloroacetic acid
total trichloro-
compounds
tr i chloroe thano1
trichloroacetic acid
1,1,1-trichloroethane
17.5 mg/24 hrs urine
12th day)
after last
exposure)
2.0 mg/L
1.2 mg/L
0.6 mg/L
8.2 mg/L
5.5 mg/L
2.4 mg/L
13.9 mg/L
9.9 mg/L
3.6 mg/L
urine
urine
urine
urine
urine
urine
urine
urine
urine
AB-6
AB-7
AB-7
AB-7
16.9 nmol/g perirenal AB-8
(17 hrs after fat
last exposure)
183.5-276.0
nmol/g
(immediately
after
additional
2-6 hrs
exposure)
-------
1,
Compound Species
1 , 1-Trichloroethane rat
(continued)
Rate and Route
of administration
20 umol/L (500 ppm),
inhalation
(6 hrs/day, 4 days)
Compound
1, 1 ,1-trichloroethane
Metabolites
Percent of
dose Site
0.08-0.17 brain,
nmol/g liver,
(17 hrs after lung,
last exposure) blood
(each)
Ref .
AB-8
7.9-21.3
nmol/g
(immediately
after 2-6 hrs
additional
exposure)
(a)
1,1
(a)
additonal mouse*-3'
exposure data
are given in
Table 6 of
summary report
on 1,1, 1-Tri-
chloroethane
, 2-Trichloroethane mouse
about 3/5 of the
expired
l^C-activity
was 14C025
2/5 was unchanged
1,1,2-trichloro-
ethane
100 ppm, inhalation 1, 1 , 1-trichloroethane
(0.5-24 hrs)
0.1-0.2 g of l^C-activity
14C-l,l,2-tri-
chloroethane per
kg, injected
intraperitoneally
3.5-14.0 ug/g
3.0-8.1 ug/g
4.3-10.0 ug/g
4.4-9.2 ug/g
16-22%(a>
(3 days)
0.1-2%
(3 days)
1-3%
(3 days)
liver AB-9
blood
kidneys
brain
expired AC-1
air
feces
contami-
nated
with
urine
whole-
body
hemogenate
-------
Compound
Rate and Route
Species of administration
Metabolites
Compound
Percent of
dose
Site
Ref.
1,1,2-Trichloroethane
(continued)
(b) figures represent
percentage of
urinary
radioactivity
mouse
mouse
rat
0.1-0.2 g of
14C-l,l,2-tri-
ethane per kg,
injected
intraperitoneally
200 ppm, inhalation
(8 hrs)
l^C-activity, urinary
chloroacetic acid
S-carboxymethyl-
cysetine
thiodiacetic acid
oxalic acid
2,2-dichloro-
ethanol^
2,2,2-trichloro-
trichloroacetic
acid
(3 days)
0.3-0.5%(b)
(3 days)
0.9-2.1%
(3 days)
0.2% (mean)
(3 days)
1.4-2.3%
(3 days)
0.3 mg/kg
body weight
(48 hrs after
exposure)
urne
AC-1
urne
AC-2
-------
Metabolites
Compound
Rate and Route
Species of administration
Compound
Percent of
dose
Site
Ref.
1,1,2-Trichloroethane
(continued)
rat
rat
200 ppm, inhalation
(8 hrs)
2.78 mmol/kg
body weight,
injected intra-
peritoneally
tr i chloroe thano1
trichloroacetic acid
trichloroethanol
0.3 mg/kg urine
body weight
(48 hrs after
exposure)
0.4 mg/kg urine
body weight
(48 hrs)
0.3 mg/kg
body weight
(2nd 48 hr
period)
0.2 mg/kg urine
body weight
(48 hrs)
AC-2
human
about 5mg
38Cl-l,l,2-tri-
chloroethane,
inhaled in single
breath
38ci-radioactivity
immeasurable
amount
(2nd 48 hr
period)
2.9%
(1 hr)
expired
breath
AC-3
Trichloroethylene
(TCE)
rat
10 mg/L air,
inhalation
(exposure period
not stated)
trichloroethylene
41.3 mg%
2.5 mg%
blood
cellular
compon-
ents
blood
plasma
AD-1
-------
Metabolites
Rate and Route
Compound Species of administration
Trichloroethylene
(TCE)
(continued) rat 4.0. 7.5, or 8.6 uCi
of ^6C1-TCE
human 54 or 97 ppm,
inhalation (8 hrs)
human 250-380 ppm,
inhalation
(160 min.)
human 27, 81, or 201 ppm,
inhalation
(4 hrs)
human 70 or 140 ppm, with
or without 100 W
workload; inhalation
(4 hrs)
human 0.537 or 1.074 ppm,
inhalation, at rest
Compound
trichloroethylene
(unchanged)
trichloroethylene
(unchanged)
trichloroethylene
(unchanged)
trichloroethylene
(unchanged)
trichloroethylene
(unchanged)
trichloroethylene
Percent of
dose
72-85%
8%
of retained
TCE
16%
or retained
TCE
13-19%
of retained
TCE
10%
(of retained
TCE)
25% of
inspired TCE
Site
expired
air
expired
air
expired
air
expired
air
expired
air
expired
air
Ref .
AD- 2
AD- 3
AD-4
AD- 5
AD-6
AD- 7
human
(30 min)
inhalation, con-
centration not
reported
trichloroethylene
concentration
27.7% of expired
retained TCE, air
men
18.6% of expired
retained TCE, air
women
AD-8
-------
Compound
Rate and Route
Species of administration
Compound
Metabolites
Percent of
dose
Site
Ref.
Trichloroethylene
(TCE)
(continued)
human
500-850 ug/L air,
inhalation (5 hrs)
trichloroethanol
trichloroacetic acid
monochloroacetic
acid
human
1,042 ug/L air,
inhalation (5 hrs)
human
54 or 97 ppm,
inhalation (8 hrs)
trichloroethanol
trichloroacetic acid
trichloroethanol
50%, total
amount
excreted
(350 hrs,
average)
19%, total
amount
excreted
(387 hrs,
average)
4%, total
amount
excreted
(112 hrs,
average)
45.4%
(total,
3 weeks)
31.9%
(total,
3 weeks)
32.7%
(several
weeks)
urine
AD-9
urine
urine
urine
urine
urine
AD-10
AD-3
-------
Rate and Route
Compound Species of administration
Trichloroethylene
(TCE)
(continued) human 54 or 97 ppm,
inhalation (8 hrs)
human 250-380 ppm,
inhalation
(160 min)
human 170 ppm inhalation
(3 hrs)
human 170 ppm, inhalation
(7 hrs with a 1-hr
break)
human 1 mg/L air,
inhalation (5 hrs)
Compound
trichloroacetic acid
trichloroethanol
trichloroacetic acid
trichloroethanol
trichloroacetic acid
trichloroethanol
trichloroacetic acid
trichloroethanol
trichloroacetic acid
Metabolites
Percent of
dose Site Ref.
17.7% urine
(several
weeks)
42.7-48.6% urine AD-4
of retained
TCE (6 days)
32.6-43.9% urine
or retained
TCE (6 days)
53.1% urine AD-11
(100 hrs)
21.9% urine
(100 hrs)
44% urine AD-11
(100 hrs)
18.1% urine
(100 hrs)
46.1% urine AD- 12
(16 or 21
days)
30.1% urine
(16 or 21
days)
-------
Compound
Rate and Route
Species of administration
Compound
Metabolites
Percent of
dose
Site
Ref.
Trichloroethylene
(TCE)
(continued)
(a) exposure was
8 hrs/day, 6
days/week,
occupational
exposure.
Additional data
are available
from Ref. AD-13.
(b) Metabolite
levels represent
mean values
obtained from
sample urinalyses.
human
10, 25, 50, 60, or
120 ppm,
inhalation^3'
total trichloro-
compounds
trichloroethanol
60.5 mg/L
(10 ppm
exposure)
164.3 mg/L
(25 ppm
exposure)
418.9 mg/L
(50 ppm
exposure)
468.0 mg/L
(60 ppm
exposure)
915.3 mg/L
(120 ppm
exposure)
42.0 mg/L
(10 ppm
exposure)
77.3 mg/L
(25 ppm
exposure)
267.3 mg/L
(50 ppm
exposure)
307.9 mg/L
(60 ppm
exposure)
urine
urine
urine
urine
urine
urine
urine
urine
urine
AD-13
-------
Compound Species
Trichloroethylene (human)
(TCE)
(continued)
(a) exposure was 8
hrs/day, 6 days/
week, occupa-
tional exposure.
additional data
are available
from Ref. AD-13.
Metabolites
Rate and Route Percent of
of administration Compound dose Site Ref.
(10, 25, 50, 60, or (trichloroethanol) 681.8 mg/L (urine) (AD-13)
120 ppm, (120 ppm
inhalation) ^a' exposure)
trichloroacetic acid 17.6 mg/L urine
(10 ppm
exposure)
77.2 mg/L urine
(25 ppm
exposure)
146.6 mg/L urine
(50 ppm
exposure)
155.4 mg/L urine
(60 ppm
exposure)
230.1 mg/L urine
(120 ppm
exposure)
dog
dose and method
not stated
rat
inhalation; dose
not stated
trichloroethanol
trichloroacetic acid
trichloroacetic acid
15-20% of urine AD-14
absorbed TCE
(4 days)
5-8% of urine
absorbed TCE
(4 days)
4% of inhaled urine AD-14
amount of TCE
-------
Compound Species
Trichloroethylene rat
(TCE)
(continued)
rat
calf
human
Rate and Route
of administration
oral administration,
dose not stated
38C1-TCE,
not stated
gavage
3 or 12 g,
(daily, 4
1,042 ug/L
dose
, by
oral
or 5 days)
air,
Compound
trichloroethanol
trichloroacetic acid
trichloroethanol
trichloroacetic acid
trichloroethylene
trichloroethanol
trichloroacetic acid
trichloroethanol and
Metabolites
Percent of
dose
• 15%
3%
10-15%
1-5%
trace
amounts
13-25%
1%
8.4%
Site
urine
urine
urine
urine
urine
urine
urine
f eces
Ref.
AD-14
AD 2
and
AD-14
AD-14
and
AD- 15
AD- 10
inhalation (5 hrs)
trichloroacetic acid
trichloroacetic acid
trichloroethanol
(3rd day
post-exposure)
0.15-0.35 sweat
mg/100 ml
(3rd day
post-exposure)
0.10-0.15 saliva
mg/100 m).
(3rd day
post-exposure)
0.10-1.92 sweat
mg/100 ml
(3rd day
post-exposure)
0.09-0.32 saliva
mg/100 ml
(3rd day
post—exposure)
-------
Compound
Rate and Route
Species of administration
Compound
Metabolites
Percent of
dose
Site
Ref.
Trichloroethylene
(TCE)
(continued)
human
human
50 ppm, inhalation
(6 hrs/day, 5 days)
48 ppm, inhalation
(4 hrs/day, 5 days)
00
tr i chloroe thano1
trichloroacetic acid
trichloroethanol
2.3 ug/ml
50 ug/ml
1.28-2.85
ug/mL
(jst day of
exposure)
0.57-1.30
ug/ml
(2nd day)
2.01-2.53
ug/ml
(3rd day)
1.57-2.58
ug/ml
(4th day)
1.97-2.87
ug/ml
(5th day)
0.51-2.11
ug/ml (1st
day post-ex-
posure)
0.18-0.51
ug/ml (2nd
day post-ex-
posure)
blood
blood
blood
AD-16
AD-17
-------
Compound
Trichloroethylene
(TCE)
(continued)
Rate and Route
Species of administration
human 48 ppm, inhalation
(4 hrs/day, 5 days
Compound
trichloroethanol
Metabolites
Percent of
dose Site
0.03-0.27 blood
ug/ml
(3rd day
post-exposure)
Ref .
AD- 17
human
00
to
human
human
human
40 or 44 ppm,
inhalation
(4 hrs)
trichloroethanol
50 ppm, inhalation
(6 hrs/day, 5 days)
trichloroethanol
250 ppm (12 min/hr), trichloroethanol
inhalation (6 hr/day,
5 days)
100 ppm (constant), trichloroethanol
inhalation (6 hr/day,
5 days)
0.03 blood
ug/ml-
(7th day
post-exposure)
0.706-1.776 blood AD-17
ug/ml
(at end of
exposure)
less than
0.03-0.123
ug/mL
(96 hrs after
start of
exposure)
2.0 ug/ml blood AD-18
(maximum
level
attained)
2.5 ug/ml blood AD-18
(maximum
level
attained)
5.0 ug/ml blood AD-18
(maximum
level
attained)
-------
Compound
Rate and Route
Species of administration
Compound
Metabolites
Percent of
dose
Site
Ref.
Trichloroethylene
(TCE)
(continued)
(b) further
information on
the levels of
TCE in fat and
other tissues is
given in Table 7
of Ref. AD-1.
human
guinea
pig(b)
1042 ug/L air,
inhalation (5 hrs)
trichloroacetic acid
6-9 mg/L air,
chronic inhalation
(4-5 hrs/day,
5-23 days)
trichloroethylene
trichloroacetic acid
00
2.4 mg/100 ml plasma AD-10
(3rd day
post-exposure)
0.5 mg/100 ml red blood
of red cell cells
mass
(3rd day
post-exposure)
3.1-3.9 fat AD-1
mg/100 g
fresh tissue
up to 4.4 fat
mg/100 g
fresh tissue
-------
APPENDIX B
Summary Table
of
The Levels of Parent Halocarbon and Metabolites
Identified in Blood, Breath, and Urine
184
-------
INTRODUCTION
After completion of the text and summary table (Appendix A) it was
determined that the metabolism data could be presented in a more useful
manner for those interested in exposure monitoring. Appendix B was designed
as a reference table for this purpose. It includes the reported levels of
30 halogenated hydrocarbon compounds and their metabolites found in
physiological media (i.e., blood, breath, and urine) that can be readily
monitored. Wherever possible, a proposed metabolic pathway reported in the
literature is presented along with the tabular data for each compound.
Since the data is taken from Appendix A, the reference numbers of
Appendix B correspond to the original references found in Appendix A.
Additional data and details of experimental methods may be obtained from the
original references.
185
-------
BENZYL BROMIDE
CHOH
benzyl bromide v^ benzyl alsohol
v
:x .
Based on findings of Bray et al., (A-l)
mercapturic acid
ethereal sulphate
Breath
Parent compound: No data
Half-life of parent compound: No data
Metabolites: No data
Half-life of metabolite: No data
Metabolite conjugates:
mercapturic acid
ethereal sulphate
Urine Blood
No data No data
No data No data
No data No data
No data No data
19%
(24 hrs)
2%
(24 hrs)
Comments Ref.
rabbit, 0.2 g/kg, via stomach tube A-l
rabbit, 0.2 g/kg, via stomach tube A-l
-------
BENZYL CHLORIDE (CHLOROTOLUENE)
,
J
n?v1 r>>i1 r-vv-t A^
conjugation
with
glutathlone
glutathionase
V
/
hydrolysis
oo
S-substituted cysteine,
glycine and glutamic acid
acetylation
mercapturic
acid
Proposed pathway for the formation of mercapturic acid Bray et al., (B-2)
Breath
Urine
Blood
Comments
Ref.
Parent compound: No data
Half-life of parent compound: No data
Metaboli tes:
benzoic or phenyl-
acetic acids (unconjugated)
Metabolite conjugates:
mercapturic acid
No data
No data
17%
(24 hrs)
49%
(36-67%)
(24 hrs)
4%
27%
No data
No data
rabbit, 0.2 g/kg, by stomach tube B-l
rabbit, 0.2 g/kg, by stomach tube B-l
guinea pig, rate and route
unspecified
rat, rate and route unspecified
B-2
B-2
-------
Benzyl chloride (ChlorotolueneMcontinued)
Breath
Urine
Blood
Comments
Ref.
Metabolite conjugates: (cont.)
glycine conjugate
(benzoic or phenylacetic)
glucosiduronic acid
(mainly phenols)
20%
(12-16)
(24 hrs)
0.4%
(0-5)
24 hrs
rabbit, 0.2 g/kg, by stomach tube B-l
rabbit, 0.2 g/kg, by stomach tube B-l
00
oo
-------
ROMOBENZENE
Proposed:metabolic pathway (Jollow et al., 1974, Pharmacol. 11: 151-169)
(a)
(c)
Br
Epoxide synthetase
(Microsomes) s?- ^t ^
ss- TV Nonenzymatic
NADPH +
GSH
Transferase \Hydrase
I Rearrangement \
nonenzymatic "v
(f)
Ac Cys S H
(d)
GS H
Acetyi-
transferase
(g)
H
Cys S H
(e)
(h)
Covalently
bound to
raacromolecules
Br
H
OH H
OH
(a) Bromobenzene
(b) Bromobenzene epoxide
(c) p-Bromophenol
(d) 3,4-Dihydro-3-hydroxy-4-
(. S-glutathionyl bromobenzei
(e) 3,4-Dihydro-3,4-dihydroxy-
broraobenzene
(f) 3,4-Dihydro-3-hydroxy-4-S-
acetyl cysteinyl bromobenzen
(g) 3,4-Dihydro-3-hydroxy-4-S-
cysteinyl bromobenzene
(b) 3,4-Dihydroxy bromobenzene
-------
Bromobenzene (continued)
Breath
Urine
Blood
Comments
Ref.
Parent compound:
Half-life of parent compound;
Metabolic half-life:
9.8 min., whole body
homogenate
9.3 min., plasma
9.5 min., liver
Metaboli tes:
monophenols
(uncharacterized)
4-bromopheno1
(1-2 days)
6.3%
No data
(a)figure shown is percent yield
of metabolite obtained by ex-
traction and purification of
the ether extracts of
hydrolyzed rabbit urine
3—bromopheno1
No data
2-3%
(1-2 days)
40%
(48 hrs)
37%
(48 hrs)
18%
(48 hrs)
1.2% (a)
(10 days)
1.0% (a)
(10 days)
No data
rabbit, 0.5 g/kg, oral dose C-l
rabbit, 0.5 g/kg, stomach tube C-2
rat, 10 umol^C-bromobenzene, i .v. C-6
rat, 10 umol l^C-bromobenzene, i.v. C-6
rat, 10 umol l^C-bromobenzene, i.v. C-6
rat, 10 umol l^C-bromobenzene, i.v. C-6
rabbit, 0.5 g/kg, oral dose C-l
rat, dosage not stated, i.p. C-7
injection
rat, 10.0 mmol/kg, i.p. injection C-6
rat, 0.05 mmol/kg, i.v. injection C-6
rabbit, 50 mg/kg, i.p. injection
rabbit, 50 mg/kg, i.p. injection
C-5
C-5
-------
Bromobenzene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
2-bromophenol
bromophenyldihydrodiol
3-4-bromophenyldihydrodiol
2-3-bromophenyldihydrodiol
bromocatechols
(uncharacteri zed)
4%
(48 hrs)
3%
(48 hrs)
3%
(48 hrs)
4%
(48 hrs)
4%
(48 hrs)
3%
(48 hrs)
trace
(48 hrs)
28%
(1-2 days)
6%
(48 hrs)
4%
(48 hrs)
rat, dosage not stated, i.p. C-7
injection
rat, 0.05 mmol/kg, i.v. injection C-6
rat, 10.0 mmol/kg, i.p. injection C-6
rat, 10.0 mmol/kg, i.p. injection C-6
rat, 0.05 mmol/kg, i.v. injection C-6
rat, dosage not stated, i.p.
injection
rat, dosage not stated, i.p.
injection
rabbit, 0.5 g/kg, oral dose
C-7
C-7
C-l
rat, 10.0 mmol/kg, i.p. injection C-6
rat, 0.05 mmol/kg, i.v. injection C-6
-------
Bromobenzene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
3,4-bromocatechol
2,3-bromocatechol
Metabolite conjugates:
total o-conjugates
total conjugates
glucuroni de
ethereal sulphate
mercapturic acid
bromophenylmercapturic acid
4%
(48 hrs)
trace
(48 hrs)
58%
(1-2 days)
97.9%
40.2%
36.8%
20.9%
25%
(1-2 days)
70%
(48 hrs)
48%
(48 hrs)
rat, dosage not stated, i.p.
injection C-7
rat, dosage not stated, i.p.
injection C-7
rabbit, 0.5 g/kg, oral dose C-l
rabbit, 210 mg/kg, via stomach tube C-3
rabbit, 210 mg/kg, via stomach tube C-3
rabbit, 210 mg/kg, via stomach tube C-3
rabbit, 210 mg/kg, via stomach tube C-3
rabbit, 0.5 g/kg, oral dose C-l
rat, 0.05 mmol/kg, i.v. injection C-6
rat, 10.0 mmol/kg, i.v. injection C-6
22%
rabbit, 0.5 mg/kg, via stomach tube C-4
-------
BROMOFORM
No data were available regarding bromoform metabolites in breath, urine or blood. The following metabolic scheme
represents the reduction of bromoform to carbon monoxide, based on in vitro studies (D-l).
P-450 mixed function
Br oxidase
Br - C - Br CO
i- H carbon monoxide
w bromoform
-------
3-BROMOPROPYLBENZENE
3-bromopropylbenzene
\
phenolic
intermediates
(3-bromopropyl)
phenol probably
being the major
intermediate
ethereal sulphate
ether soluble acid
glucosiduronic acid
mercapturic acid
glycine conjugates
VO
-P-
Based on findings reported by Bray et al., (E-l)
Breath
Urine
Blood
Comments
Metabolites:
total urinary metabolites
Ref.
Parent compound:
Half-life of parent co
No data
mpound: No data
No data
No data
No data
No data
89%
rabbit, 0.25 g/kg, via stomach tube E-l
-------
3-Bromopropylbenzene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolite conjugates:
ethereal sulphate
ether soluble acid
(primarily glucosiduronic acid;
also mercapturic acid and glycine
conjugates)
phenaceturic acid
N-acetyl-S-(3-phenyl
propyl)-L-cysteine
VO
Ul
phenoli cs
(uncharacteri zed)
20%
69%
unspecified
amount
unspecified
amount
unspecified
amount
rabbit, 0.25 g/kg, via stomach tube E-l
rabbit, 0.25 g/kg, via stomach tube E-l
rabbit, 0.25 g/kg, via stomach tube E-l
rabbit, 0.25 g/kg, via stomach tube E-l
rabbit, 0.25 g/kg, via stomach tube E-l
-------
CARBON TETRACHLORIDE
Cl
i
Cl - C - Cl
I
Cl
carbon tetrachloride
dehalogenation
~> > >
Cl -
Cl
C+
i
Cl
/
chloroform carbon
dioxide
- cci
hexachloroethane
Based on findings of Paul and Rubinsteins, (F-2)
Breath
Urine
Blood
Comments
Ref.
Parent compound:
33%
(1 hr)
40%
(1800 hrs)
85%
(18 hrs)
19.2 ug total
(day 1)
5.9 ug total
(day 2)
human, 80 ppm ^carbon tetra- F-3
chloride, single breath inhalation
monkey, 46 ppm l^carbon tetra- F-4
chloride, inhalation for 344 minutes
rat, 1.0 ml l^carbon tetra-
chloride /kg, intraduodenal
sheep, 0.1 mg/kg, intra-ruminal
sheep, 0.1 mg/kg, intra-ruminal
F-2
F-6
F-6
-------
Carbon tetrachloride (continued)
Breath
Urine
Blood
Comments
Ref.
'arent compound (cont.)
4.6 ug total
(day 3)
trace-1.3 ug
(day 4-7)
1.2 ug total
(day 1)
1.0 ug total
(day 2)
0.7 ug total
(day 3)
trace-0.7 ug
(day 4-7)
trace (at end
of exposure)
0.2 rag/100 ml
blood (at end
of exposure)
0.6 mg/100 ml
blood (at end
of exposure)
0.4 mg/100 ml
blood (at end
of exposure)
sheep, 0.1 rag/kg, intra-ruminal
F-6
sheep, 0.1 mg/kg, intra-ruminal F-6
sheep, 0.12 mg/kg, intra-ruminal F-6
sheep, 0.12 mg/kg, intra-ruminal F-6
sheep, 0.12 mg/kg, intra-ruminal F-6
sheep, 0.12 mg/kg, intra-ruminal F-6
rabbit, 110 ppm, inhalation, 4 hrs F-7
rabbit, 225 ppm, inhalation, 4 hrs F-7
rabbit, 345 ppm, inhalation, 4 hrs F-7
rabbit, 600 ppm, inhalation, 4 hrs F-7
Half-life of parent compound: No data
No data
No data
-------
Carbon tetrachloride (continued)
Breath
Urine
Blood
Comments
Ref.
Metaboli tes:
l^C-carbon dioxide
chloroform
oo
11%
(1800 hrs)
1%
(18 hrs)
3.7 ug total
(day 1)
2.0 ug total
(day 2)
1.8 ug total
(day 3)
trace-0.8 ug
(day 4-7)
6.6 ug total
(day 1)
1.0 ug total
(day 2)
0.7 ug total
(day 3)
trace-0.7 ug
total (day 4-7)
monkey, 46 ppm ^carbon tetrachloride,
inhalation, 344 minutes F-4
rat, 1.0 ml l^carbon tetra-
chloride/kg, intraduodenal
sheep, 0.1 mg/kg, intra-ruminal
F-2
F-6
sheep, 0.1 mg/kg, intra-ruminal F-6
sheep, 0.1 mg/kg, intra-ruminal F-6
sheep, 0.1 mg/kg, intra-ruminal F-6
sheep, 0.12 mg/kg, intra-ruminal F-6
sheep, 0.12 mg/kg, intra-ruminal F-6
sheep, 0.12 mg/kg, intra-ruminal F-6
sheep, 0.12 mg/kg, intra-ruminal F-6
-------
Carbon tetrachloride (continued)
Breath Urine Blood Comments Ref.
letabolite conjugates: No data No data No data
VD
-------
o-CHLOROBENZALDEHYDE
C HO
o-chlorobenzaldehyde
Breath Urine
Parent Compound: No data No data
ro Half-life of parent compound:
o
Metabolites: No data No data
Metabolite conjugates: No data No data
Blood
No
15
70
15
No
No
data
seconds
seconds
seconds
data
data
Comments Ref.
human, 2.65 uM, in vitro blood tests G-l
cat, 2.65 uM, in vitro blood tests G-l
rat, 2.65 uM, in vitro blood tests G-l
-------
CHLOROBENZENE
Cl
Cl
+protein(SH)?> -2H
or H- proteinS,,
chlorobenzene
Cl
S
H
SCH?CH(NH2)COOH
acetylation
+2H20
-protein(SH).
Cl
SCH2CH(NHAc)COOH
Cl
OH
Cl
HOH
Cl
-2H
HOH
OH
OH
p-chlorophenol
3,4-dihydro-3,4-dihydroxy-
chlorobenzene
4-chlorocatechol
Proposed by Smith et al., 1950 (H-2)
-------
Chlorobenzene (continued)
Breath
Parent compound: 27%
Half-life of parent compound: No data
Metaboli tes:
l^C-acti vi ty
total urinary metabolites
glucuronide
(a) expressed as percentage
of urinary ^C-activity
(19.6% of total 14C-
K> chlorobenzene dose)
o
r-o
ethereal sulphate
mercapturic acid
p-chlorophenylmercapturi c
aci d
Urine Blood
No data No data
19.6%
72.2%
25.2%
33.57%(a)
26.6%
33.88%(a)
20.4%
23.80%(a)
28%
27%
major
metaboli te
(2 days)
Comments
rabbi t ,
rabbi t ,
orally,
rabbi t ,
rabbit,
rabbi t ,
orally
rabbi t ,
rabbi t ,
orally,
rabbi t ,
rabbi t ,
orally,
rabbit,
rabbit ,
rabbit ,
stomach
0.5 g/kg, oral
0.5 g l^C-chlorobenzene,
twice daily for 4 days
150 mg/kg, via stomach tube
150 mg/kg, via stomach tube
0.5 g l^C-chlorobenzene,
twice daily for 4 days
150 mg/kg, via stomach tube
0.5 g l^C-chlorobenzene,
twice daily for 4 days
150 mg/kg, via stomach tube
0.5 g ^C-chlorobenzene ,
twice daily for 4 days
0.5 g/kg, oral
0.5 g/kg, oral
10 or 12 g total dose, via
tube
Ref .
H-3
H-5
H-l
H-l
H-5
H-l
H-5
H-l
H-5
H-3
H-4
H-2
catechols
27%
rabbit, 0.5 g/kg, oral
H-4
-------
Chlorobenzene (continued)
Breath
Urine
Blood
Comments
Ref.
O
OO
Metabolites (cont.)
catechol derivatives
(uncharac teri zed)
4-chlorocatechol
(ethereal sulphate
and glucuronide conjugates)
monophenols
(uncharacterized)
p-chlorophenol
o-chlorophenol
p-chlorophenol and
p-chlorophenol glucuronide
di phenols
3,4-dihydro-3,4-
dihychoxychlorobenzene
37%
major
metabolite
(2 days)
2.84%(a)
2-3%
trace
0.5%
(2 days)
4.17%(a)
0.57%(a)
0.03%
(2 days)
rabbit, 0.5 g/kg, oral H-3
rabbit, 10 or 12 g total dose, H-2
via stomach tube
rabbit, 0.5 g ^C-chlorobenzene, H-5
orally, twice daily for 4 days
rabbit, 0.5 g/kg, oral H-3
rabbit, 0.5 g/kg, oral H-3
rabbit, 10 or 12 g total dose, via H-2
stomach tube
rabbit, 0.5 g ^^C-chlorobenzene, H-5
orally, twice daily for 4 days
rabbit, 0.5 g i^C-chlorobenzene, H-5
orally, twice daily for 4 days
rabbit, 10 or 12 g total dose, via H-2
stomach tube
-------
CHLOROFORM
CHC1,
chloroform
raicrosoraes
NADPH, 02
Cl
Cl-C-OH
Cl
trichloromethanol
-HC1
-) 0=C,
phosgene
'Cl
- 2IIC1
carbon
dioxide
ro
o
Proposed metabolism,
Mansuy et al., 1977
Biochem. Biophys. Res. Commun. 79(2):513-517.
0
+ cys/
1H — COOH
,NH
covalent binding
to nucleophilic
groups of tissue
macromolecules
4-carboxy-thiazolidine-2-one.
Breath
Urine
Blood
Comments
Ref.
Parent compound:
17.8-66.6%
(8 hrs)
human, 4 males, 500 mg, oral
1-3
-------
Chloroform (continued)
Breath
Urine
Blood
Comments
Ref.
arent compound (cont.)
NJ
O
(a) chloroform combined with
toluene-soluble metabolites
Half-life of parent compound:
Metaboli tes:
carbon dioxide
25.6-40.4%
(8 hrs)
10%
78%
20%
20%(a)
(24 hrs)
6%
No data
50.6%
(8 hrs)
48.5%
(8 hrs)
18%
(24 hrs)
16%
No data
No data
human, 4 females, 500 mg, oral
human, 5 mg single breath
inhalation
monkey, 60 mg/kg, oral dose
daily for 5 days
rat, 60 mg/kg, oral dose
daily for 5 days
rat, 60 mg/kg, oral
mouse, 60 mg/kg, oral dose,
daily for 5 days
human, 4 males, 500 mg, oral
human, 4 females, 500 mg, oral
monkey, 60 mg/kg, oral
1-3
1-4
1-2
1-2
1-1
1-2
1-3
1-3
1-1
monkey, 60 mg/kg, oral dose, daily 1-2
for 5 days
Metabolite conjugates:
No data
No data
No data
-------
Chloroform (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
bi carbonate/carbonate
compounds
66%
(24 hrs)
80%
(24 hrs)
13%
(24 hrs)
rat, 60 mg/kg, oral dose, daily
for 5 days
mouse, 60 mg/kg, oral
mouse, 60 mg/kg, oral
1-2
1-1
1-1
ro
o
-------
CHLORONAPHTHALENE
Based on findings of Ruzo et al. 1976. J. Agr Chem and Food 24(3): 581-3.
arene
oxide
1,2-H
shift
s
/
1-chloronaphthalene
4-chloro-l-naphthol
2-chloronaphthalene
3-chloro-2-napthol
Breath
Urine
Blood
Comments
Ref.
Parent compound:
1-C1 naphthalene
Ni
o
5.1 ug/g after
10 min.
3.4 ug/g after
20 min.
pig, 300 mg dose of 1--
chloronaphthalene, 7.5 kg
pig, retrocarotid administration
J-2
1.8 ug/g
40 min.
after
0.7 ug/g
80 min.
after
0.9 ug/g
120 min.
after
0.3 ug/g
160 min.
after
0.3 ug/g
200 min.
after
0.1 ug/g
240 min.
after
-------
Chloronaphthalene (continued)
Breath
Urine
Blood
Comments
Ref.
Parent compound (cont.)
2-C1 naphthalene
CO
O
OO
6.2 ug/g after
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.
after
after
after
after
after
after
after
after
pig, 300 mg dose of 2-
chloronaphthalene, 7.5 kg pig,
retrocarotial administration
J-2
Half-life of parent compound:
Metaboli tes:
4-C1 naphthol
No data
No data
No data
400 ug/g
(6 hrs after
admi nistrati on)
Yorkshire pig, 300 mg of 1-C1
naphthalene isomer, 7.5 kg pig,
retrocarotid administration
J-2
-------
Chloronaphthalene (continued)
Breath
Urine
Blood
Comments
Ref.
letabolites (cont.)
4-C1 naphthol
K3
O
0.1 ug/g after
160 min.
0.6 ug/g after
200 min.
0.8 ug/g after
240 min.
1.0 ug/g after
260 min.
1.3 ug/g after
300 min.
free phenolic compounds
3-Cl-2-naphthal
2%
(4 days)
60 ug/g
(6 hrs after
admini strati on)
0.2 ug/g after
200 min.
0.5 ug/g after
240 min.
0.8 ug/g after
260 min.
Yorkshire pig, 300 mg of 1-C1
naphthalene isomer, 7.5 kg pig,
retrocarotid administration
(J-2)
male albino rabbit, 1 g per rabbit,
by stomach tube
Yorkshire pig, 300 mg of 2-C1
naphthalene isomer, 7.5 kg pig,
retrocarotid administration
J-l
J-2
1.0 ug/g after
300 min.
-------
Chloronaphthalene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolite conjugates of
1-chloronaphthlene:
ethereal sulfate
mercapturic acids
glucuronic acid
10.1%
(4 days)
13.1%
(4 days)
53.7%
(4 days)
male albino rabbits, 1 g/rabbit,
by stomach tube. The rabbits weighed
approximately 2 kg. Expressed as
percentage of original dose
J-l
-------
CHLORONITROBENZENE
Cl
HO
4-chloro-3-nitrophenol
NO,,
Cl
Cl
3-amino-4-chlorophenol
Cl
OH
V \
o-chloronitrobenzene
3-chloro-4-nitrophenol / 4-amino-3-chlorophenol
Cl
\
o-chloroaniline
\
\
^V
HO
Proposed metabolism of o-chloronitrobenzene,
Bray et al., 1956 (K-l)
Cl
\
3-chloro-2-nitrophenol 2-amino-3-chlorophenol
N0
NH,
Cl
OH
\
Cl
OH
2-chloro-3-nitrophenol 3-amino-2-chlorophenol
-------
CHLORONITROBENZENE
Ki
1—>
NO
NO,
Cl
\
p-chloronitrobenzene
NH,
Cl
p-chloroaniline
\
\
NO,
'OH
Cl
NH,
OH
Cl
2-amino-5-chlorophenol
Proposed metabolism of p-chloronltrobenzene,
Bray et al., 1956 (K-l)
2-chloro-5-nitrophenol
-------
CHLORONITROBENZENE
0,
Cl
V
~7
Cl
OH
NO,
OH
2-chloro-4-nitrophenol 4-amino-2-chlorophenol
Cl
CO
m-chloronitrobenzene
Proposed metabolism of m-chloronltrobenzene,
Bray et al., 1956 (K-l)
NH,
NH,
HO
m-chloroaniline
2-amino-4-chlorophenol
-------
Chloronitrobenzene (continued)
Breath
Urine
Blood
Comments
Ref.
Parent compound:
Half-life of parent compound:
Metabolites of
o-chloronitro-
benzene isomer:
free chloroaniline
free phenolics
Metabolites of
m-chloronitrobenzene
isomer:
free chloroaniline
free phenolics
Metabolites of
p-Chloronitrobenzene
i somer:
free chloroaniline
free phenolics
No data
No data
Not detected No data
No data No data
9%
trace amounts
11%
trace amounts
9%
trace amounts
rabbit, 0.1 g/kg. Expressed as
percent of dose.
rabbit, 0.1 g/kg. Expressed as
percent of dose.
rabbit, 0.2 g/kg. Expressed as
percent of dose.
rabbit, 0.2 g/kg. Expressed as
percent of dose.
rabbit, 0.2 g/kg. Expressed as
percent of dose.
rabbit, 0.2 g/kg. Expressed as
percent of dose.
K-l
K-l
K-l
K-l
K-l
K-l
-------
Chloronitrobenzene (continued)
Breath
Urine
Blood
Comments
Ref.
etabolite conjugates of
o-chloroni trobenzene
isomer:
ether glucuronide
ethereal sulphates
(aminochlorophenols and
chloroni trophenols)
ni trophenylmercapturi c
acid
Metabolite conjugates of
^ m-chloronitrobenzene
1/1 isomer:
ether glucuronide
ethereal sulphates
(aminochlorophenols and
chloroni trophenols)
ni trophenylmercapturi c
acid
Metabolite conjugates of
p-chloroni trobenzene
isomer:
ether glucuronide
ethereal sulphate
(aminochlorophenols and
chloroni trophenols)
42%
24%
33%
18%
19%
21%
rabbit, 0.1 g/kg. Expressed as
percent of dose.
rabbit, 0.1 g/kg. Expressed as
percent of dose.
rabbit, 0.1 g/kg. Expressed as
percent of dose.
rabbit, 0.2 g/kg. Expressed as
percent of dose.
rabbit, 0.2 g/kg. Expressed as
percent of dose.
rabbit, 0.2 g/kg. Expressed as
percent of dose.
rabbit, 0.2 g/kg. Expressed as
percent of dose.
rabbit, 0.2 g/kg. Expressed as
percent of dose.
K-l
K-l
K-l
K-l
K-l
K-l
K-l
K-l
-------
Chloronitrobenzene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolite conjugates of
p-chloronitrobenzene
i somer (cont.)
conjugated chloroaniline
ni trophenylmercapturic
acid (colorimetic
method)
ni trophenyltnercapturi c
acid (modified
Stekol method)
4%
7%
3%
rabbit, 0.2 g/kg. Expressed as
percent of dose.
rabbit, 0.2 g/kg. Expressed as
percent of dose.
rabbit, 0.2 g/kg. Expressed as
percent of dose.
K-l
K-l
K-l
-------
CHLOROPRENE
Cl
hepatic mixed-function oxidases
-^ epoxidation
chloroprene
Based on findings of Bardodej, (L-l)
Parent compound:
Half-life of parent compound:
Metaboli tes:
Metabolite conjugates:
Breath
No data
No data
No data
No data
Urine
No data
No data
No data
No data
Blood Comments Ref.
No data
No data
No data
No data
-------
CHLOROTOLUENE - SEE BENZYL CHLORIDE p. 187
00
-------
DICHLOROBENZENE
Cl
o-dichlorobenzene
\
H
H OH
1,2-dihydro-4,5-dichloro-
benzene-1,2-diol
3,4-dichlorophenol
ei
OH
2,3-dichlorophenol
Gl
1,2-dihydro-3,4-dichloro-
benzene-1,2-diol
OH
Proposed metabolism of
o-dichlorobenzene,
Parke and Williams, 1955
(M-3)
3,4-dichlorocatechol
-------
DICHLOROBENZENE
M
M
O
p-dichlorobenzene
1,4-dihydro-2,5-dichloro-
benzene-1,4-diol
possible direct
hydroxylation
Proposed metabolism of
p-dichlorobenzene,
Parke and Williams, 1955 (M-3)
Cl Cl
2,5-dichlorophenol 2,5-dichloroquinol
-------
DICHLOROBENZENE
m-dichlorobenzene
ro
ro
•1,2-dihydro-3,5-dichJloro
benzene-1,2-diol
Proposed metabolism of
m-dichlorobenzene,
Parke and Wiilliams, 1955 (M-3)
possible direct
hydroxylation
OH
2,4-dichlorophenol
3,5-dichloro-
phenol
OH
3,5-dichlorocatecho]
-------
Dichlorobenzene (continued)
Breath
Urine
Blood
Comments
Ret.
Parent compound:
Half-life of parent compound:
Metabolites of
o-isomer :
di chlorocatechol
catechols
quinols
mono phenols
Metabolites of
m-isomer :
catechols
quinols
mono phenols
Metabolites of
p-isomer :
catechols
quinols
mono phenols
No data No data No
No data No data No
7.8%
4%
4%
0%
39%
4%
3%
0%
25%
0%
0%
6%
35%
data
data
rabbit ,
rabbi t ,
rabbit ,
rabbit ,
rabbi t ,
rabbi t ,
rabbi t ,
rabbi t ,
rabbi t ,
rabbi t ,
rabbi t ,
rabbi t ,
rabbi t ,
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
5
5
5
5
5
5
5
5
5
5
5
5
5
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
via stomach
via stomach
via stomach
via stomach
via stomach
via stomach
via stomach
via stomach
via stomach
via stomach
via stomach
via stomach
via stomach
tube
tube
tube
tube
tube
tube
tube
tube
tube
tube
tube
tube
tube
M-l
M-2
M-3
M-3
M-3
M-2
M-3
M-3
M-3
M-2
M-3
M-3
M-3
-------
Dichlorobenzene (continued)
Metabolite conjugates of
p-isomer:
Breath
Urine
Blood
Comments
Ref.
Metabolite conjugates of
o-isomer :
glucuronides 48%
48%
ethereal sulfates 21%
21%
mercapturic acid 5%
5%
Metabolite conjugates of
ro m-isomer:
NJ
glucuronides 31%
36%
ethereal sulfates 11%
7%
mercapturic acid 9%
11%
rabbi
rabbi
rabbi
rabbi
rabbi
rabbi
rabbi
rabbi
rabbi
rabbi
rabbi
rabbi
t,
t,
t,
t,
t,
t,
t,
t,
t,
t,
t,
t,
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
0.
5
5
5
5
5
5
5
5
5
5
5
5
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
g/kg,
via
via
via
via
via
via
via
via
via
via
vi a
via
stomach
stomach
stomach
stomach
stomach
stomach
stomach
stomach
stomach
stomach
stomach
stomach
tube
tube
tube
tube
tube
tube
tube
tube
tube
tube
tube
tube
M-2
M-3
M-2
M-3
M-2
M-3
M-2
M-3
M-2
M-3
M-2
M-3
glucuroni des
37%
rabbit, 0.5 g/kg, via stomach tube M-2
-------
Dichlorobenzene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolite conjugates
of p-isomer (cont.)
(glucuronides, cont.)
ethereal sulfate
mercapturic acid
36%
27%
27%
0%
0%
rabbit, 0.5 g/kg, via stomach tube M-3
rabbit, 0.5 g/kg, via stomach tube M-2
rabbit, 0.5 g/kg, via stomach tube M-3
rabbit, 0.5 g/kg, via stomach tube M-2
rabbit, 0.5 g/kg, via stomach tube M-3
-------
1,2-DICHLOROETHANE
Proposed metabolic pathway of 1,2-dichloroethane,
Yllner, 1979 (N-l)
CH2C1-CH2C1
CH2C1-CH2OH
1,2-dichloroethane chloroethanol
CH C1COOH —
chloroacetic acid
reaction with
glutathione
S-carboxymethylcysteine
(free and conjugated)
thiodiacetic acid
S,S'-ethylene-bis-cysteine
S-(beta-hydroxyethyl)-cysteine
S- (beta-hydroxyethyl)'-cysteine
mercapturic acid
Breath
Urine
Blood
Comments
Ref .
Parent compound:
l^C- 1 , 2-di chloroethane
Half-life of parent compound;
Metaboli tes:
10-42%
of dose
(3 days)
No data
12-15%
of dose
(3 days)
chloroacetic acid
(a) figure represents the
percentage of total radio-
activity in urine, rather
than percentage of dose.
Total 14-C urinary activity was
51-73% of dose.
No data
No data
6-23%(a)
(3 days)
mouse. 0.05, 0.10, 0.14 and 0.17
g/kg *^C-1 , 2-di chloroethane ,
i.p.
mouse. 0.05, 0.10, 0.14 and 0.17
g/kg l^C-1,2-dichloroethane,
i.p.
mouse. 0.05, 0.10, 0.14 and 0.17
g/kg l^C-1,2-dichloroethane,
i.p.
N-l
N-l
N-l
-------
1,2-DICHLOROETHANE (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
free S-carboxymethylcysteine
thiodiacetic acid
2-chloroethanol
Metabolite conjugates:
S-carboxymethylcysteine
S,S'-ethylene-bis-
cysteine
S-(beta-hydroxyethyl
mercapturic acid
S-(beta-hydroxyethyl
cysteine
ty
44-46%(a)
(3 days)
33-34%(a)
(3 days)
0.0-0.8%(a)
(3 days)
0.5-5%(a)
(3 days)
0.7-1.0%(a)
(3 days)
major
metaboli te
trace amounts
51-73%
(total for
3 days)
mouse. 0.05, 0.10, 0.14 and 0.17 N-l
g/kg l^C-1,2-dichloroethane,
i.p.
mouse. 0.05, 0.10, 0.14 and 0.17 N-l
g/kg l^C-1,2-dichloroethane,
i.p.
mouse. 0.05, 0.10, 0.14 and 0.17 N-l
g/kg l^C-1,2-dichloroethane,
i.p.
mouse. 0.05, 0.10, 0.14 and 0.17 N-l
g/kg l^C-1,2-dichloroethane,
i .p.
mouse. 0.05, 0.10, 0.14 and 0.17 N-l
g/kg l^C-1,2-dichloroethane,
i.p.
rat, 100 mg, stomach tube N-2
rat, 100 mg, stomach tube N-2
mouse, 0.05, 0.10, 0.14 or 0.17 N-l
g/kg I'+C-l, 2-di chloroethane, i.p.
-------
1,1-DICHLOROETHYLENE
(VINYLIDENE CHLORIDE)
RC—CHCH,SCH.CR' HCXCCHCH.SCH^COjH
NH,
O NH O
Ac
le)
I
(f)
;HO,CCHCHISCH.CO.H
\ C
OH
I
StCH-CO.H), fg)
I
HSCH^O.H (h)
CICH.CO.H
(b)
HOH.C—CO,H
CO(NH,).
a) 1,1- dichloroethylene
b) chloroacetic acid
c) S-chlorocarbonylmethyleysteinyl-
glutathione
d) S-carboxyraethylcysteinylglutathione
e) N-acetyl-S-cysteinyl acetyl derivative
f) S-carboxymethylcysCeine
g) thiodiglycollic acid
h) thioglycollic acid
j) dithioglycollic acid
(SCH.CO^), (j)
Metabolic pathway for vinylidene chloride in mammals- From Ref. 0-3
-------
1,1-DICHLOROETHYLENE
(VINYLIDENE CHLORIDE)
Breath
Urine
Blood
Comments
Ref.
Parent compound:
unchanged 1,1-DCE
28%
20%
(72 hrs)
0.9%
(72 hrs)
6%
rat, 50 mg (14C)1,1-DCE per kg, 0-3
oral
rat, 50 mg (14C)1,1-DCE per kg, 0-1
oral
rat, 0.5 mg (14C) 1,1-DCE per kg, 0-1
oral
mouse, 50 mg (14C) 1,1-DCE per kg, 0-3
oral
-activity
(a) total elimination;
oo primarily urinary
(b) primarily thiodigly-
collic acid
97-99%(a)
(72 hrs post-
exposure)
92%(a)
(72 hrs post-
exposure)
96Z(a)
(72 hrs post-
exposure)
97-99%(a)
(72 hrs)
60-75%(a)
(72 hrs)
52%(b)
(72 hrs)
36%(b)
(72 hrs)
rat, lOppm (14C) 1,1-DCE,
inhalation, 6 hrs
0-2
fasted rat, 200ppm (14C) 1,1-DCE, 0-2
inhalation, 6 hrs
fed rat, 200ppm ( 14C) 1 , 1-DCE , 0-2
inhalation, 6 hrs
rat, I mg (14C)1,1-DCE per kg, 0-2
oral dose
rat, 50 mg (14C)1,1-DCE per kg, 0-2
oral dose
rat, 0.5 mg (14C)l,1-DCE per kg, 0-1
oral dose
rat, 50 mg (14C)1,1-DCE per kg, 0-1
oral dose
-------
I,l-DICHLOROETHYLENE
(VINYLIDENE CHLORIDE) (continued)
Breath
Urine
Blood
Comments
Ref.
Half-life of parent compound:
lite
CO 2
Metaboli tes:
14
^Metabolite conjugates:
chloroacetic acid
dithioglycollic acid
N-acetyl-S-(2-carboxy-
methyl) cysteine
N-acetyl-S-cysteinyl
acetyl derivative
thiodigylcollic acid
No data
23%
(72 hrs)
(72 hrs)
3%
3.5%
No data
1%
23%
5%
4%
50%
28%
3%
No data
rat, 0.5 mg (14C)1,1-DCE per kg, 0-1
oral dose
rat, 50 mg (14C)1,1-DCE per kg, 0-1
oral dose
mouse, 50 mg (14C)l,l-DCE per kg, 0-3
oral dose
rat, 50 mg (14C)1,1-DCE per kg, 0-3
oral dose
rat, 50 mg (14C)1,1-DCE per kg, 0-3
oral dose
mouse, 50 mg (14C)1,1-DCE per kg, 0-3
oral dose
rat, 50 mg (14C)1,1-DCE per kg, 0-3
oral dose
rat, 50 mg (14C)l,l-DCE per kg, 0-3
oral dose
mouse, 50 mg (14C)1,1-DCE per kg, 0-3
oral dose
rat, 50 mg (14C)1,1-DCE per kg, 0-3
oral dose
mouse, 50 mg (14C)1,1-DGE per kg, 0-3
oral dose
-------
1,l-DICHLOROETHYLENE
(VINYLIDENE CHLORIDE) (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolite conjugates (cont.)
(thiodiglycollic acid, cont.)
22%
rat, 50 mg (14C)1,1-DGE per kg,
oral dose
0-3
thioglycollic acid
K3
OJ
o
thioglycollyloxalic acid
urea
5%
3%
3%
2%
3%
3.5%
mouse, 50 mg (14C)l,l-DCE per kg, 0-3
oral dose
rat, 0.5 mg (14C)1,1-DCE per kg, 0-3
oral dose
mouse, 50 mg (14C)1,1-DCE per kg, 0-3
oral dose
rat, 50 mg (14C)1,1-DCE per kg, 0-3
oral dose
mouse, .50 mg (14C)l,l-DCE per kg, 0-3
oral dose
rat, 50 mg (14C)1,1-DCE per kg, 0-3
oral dose
-------
1,2-DICHLOROETHYLENE
Proposed metabolic pathway (by analogy to the metabolism of related compounds such as trichloroethylene)
K3
CO
CI-CH —CHO
g
CICH-- COC1—-C1CH,— COOH
r
Cl.CH —CH(OH),
A proposed metabolic pathway of 1,2-dichloroethylene.
a) 1,2-dichloroethylene
b) 1,2—dichloroethylene epoxide
c) 1,2-dichloroglycol
d) dichloroacetaldehyde
e) monochloroacetyl chloride
f) 2,2-dichloro-l,1-ethanediol
g) monochloroacetic acid
No information was available on the distribution of 1,2-dichloroethylene
in breath, urine, or blood. An i_n vi tro study using rat liver homogenates
reported small amounts of dichloroacetic acid and dichloroethanol after
perfusion with cis or trans 1,2-DCE (P-l).
-------
1,2-DICHLOROPROPANE
C, C, H
C-C-C-H
A A A
Breath
Urine
Blood
Comments
Ref.
LO
CO
Parent compound:
di chloropropane 0.6-1.1 mg/100
cc blood
1.5-2.9 mg/100
cc blood
1.3-1.6 mg/100
cc blood
volatile chlorinated 23.1%
rabbit, 1,500 ppm in air, 7 hrs/
day for 5 days
rabbit, 2,200 ppm in air, 7 hrs/
day for 5 days
dog, 1,000 ppm in air, 7 hrs/
day for 5 days
rat, 1.07 mg (10.3 uCi ) of 1,2-
Q-l
Q-l
Q-l
Q-2
hydrocarbons, probably
unchanged 1,2-dichloro
propane
Half-life of parent compound:
Metaboli tes:
, . . ,
dichloro-(l-l^C)propane, single
oral dose
14
CO 2
radioactive substances
No data
19.3%
No data
No data
50.2%
pigment-producing substance
present, but
not i denti fied
or quantitated
rat, 1.07 mg (10.3 uCi) of 1,2- Q-2
dichloro-( l-^C)propane, single
dose, by stomach tube
rat, 0.88 mg (8.5 uCi) of 1,2- Q-2
di ch 1 or o-(l-^C) propane,
in 0.5 ml arachis oil, single
oral dose
rat, mouse, and guinea pig; dichloro- Q-l
propane vapors, concentration
not stated
Metabolite conjugates:
No data
No data
No data
-------
HEXACHLOROBUTADIENE
Based on findings of Murzakaev., (R-l)
\
C = C
Cl'
\
Cl
C =C
\
Cl Cl
hexachlorobutadiene
polychlorobutanes
C.H-Clc and C.H.C1,
455 446
Breath
Urine
Blood
Comments
Ref.
Parent compound:
Half-life of parent compound:
Metaboli tes:
pentachlorobutane
Metabolite conjugates:
No
No
No
No
data
data
data
data
No
No
No
No
data
data
data
data
No
No
No
No
data
data
data
data
-------
HEXACHLOROETHANE
Cl Cl
I I
Cl —C —C—Cl
I i
Cl Cl
hexachloroethane
No data were available on the metabolic pathway of hexachloroethane.
LO
-P-
Breath
Urine
Blood
Comments
Ref.
Parent compound:
hexachloroethane
Half-life of parent compound:
Metaboli tes:
tri chloroethanol
No data
50-70 ug/ml
(24 hours)
No data
1.3%
(3 days)
10-28 ug/ml
(24 hours)
0.2 ug/g
(6 hrs)
No data
sheep, 0.5 g/kg, single oral dose S-2
sheep (anaesthetized) 0.5 g/kg,
single oral dose
rabbit, 0.5 g of 14Ohexachloro-
ethane/kg body wt., in diet
S-2
S-l
-------
HEXACHLOROETHANE (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
tr i chloroaceti c acid
di chloroaceti c acid
monochloroaceti c acid
di chloroethanol
oxalic acid
N>
OJ
Ul
volatile metabolites 14-24%
(includes CC>2» C2C^6>
tetrachloroethylene and
1,1, 2,2-tetrachloroethane)
tetrachloroethylene
pen t achl or oe thane
1.3%
(3 days)
0.8%
(3 days)
0.7%
(3 days)
0.4%
(3 days)
0.1%
(3 days)
25-29 ug
(24 hrs)
20-25 ug
(24 hrs)
rabbit, 0.5 g of ^C-hexachloro-
ethane/kg body wt . , in diet
rabbit, 0.5 g of ^C-hexachloro-
ethane/kg body wt . , in diet
rabbit, 0.5 g of ^C-hexachloro-
ethane/kg body wt., in diet
rabbit, 0.5 g of 14C-hexachloro-
ethane/kg body wt . , in diet
rabbit, 0.5 g of ^C-hexachloro-
ethane/kg body wt., in diet
rabbit, 0.5 g of 14C-hexachloro-
ethane/kg body wt . , in diet
0.6-1.1 ug/ml sheep, 0.5 g/kg, single oral dose
(24 hrs)
0.2-0.4 ug/ml sheep, 0.5 g/kg, single oral dose
(6 hrs)
0.06-0.5 ug/ml sheep, 0.5 g/kg, single oral dose
(24 hrs)
0 - trace sheep, 0.5 g/kg, single oral dose
(6 hrs)
S-l
S-l
S-l
S-l
S-l
S-l
S-2
S-2
S-2
S-2
Metabolite conjugates:
No data
No data
No data
-------
METHYLENE CHLORIDE
Based on findings of Kubic and Anders. 1975. Metabolism of dihalomethanes
to carbon monoxide II. Drug Metab. Dispos. 3(2): 104-112.
Cl
I
H-C-CI
I
H
P450 mixed-function oxidases
NADPH, 0_
—y co
carbon monoxide
methylene chloride
Breath
Urine
Blood
Comments
Ref.
Parent compound:
methylene chloride
Half-life for elimination
of CO'Hb after methylene
chloride exposure
77.0%, 92.0%
(2 hrs)
95.3%, 92.6%
(8 hrs)
91.50%
(24 hrs)
13 hrs,
rat, 412-930 mg/kg, i.p. Expressed T-l
as percentage of original dose.
These are values for individual ex-
perimental animals.
rat, 412-930 mg/kg, i.p. Expressed T-l
as percentage of original dose.
These are values for individual ex-
perimental animals.
rat, 412-930 mg/kg, i.p. Expressed T-l
as percentage of original dose.
These are values for individual ex-
perimental animals.
human, 8 hrs exposure to 180 ppm T-4
methylene chloride
-------
Methylene chloride (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites:
(C^)carbon dioxide
carbon dioxide
(C. ^)carbon monoxide
0.44%, 0.65%
(2 hrs)
1.44%, 1.61
(8 hrs)
3.04%
(24 hrs)
29%
0.14%, 0.14%
(2 hrs)
rat, 412-930 mg/kg, i.p. Expressed as T-l
percentage of original dose. These
are values for individual experimental
animals.
rat, 412-930 mg/kg, i.p. Expressed as T-l
percentage of original dose. These
are values for individual experimental
animals.
rat, 412-930 mg/kg, i.p. Expressed as T-l
percentage of original dose. These
are values for individual experimental
animals.
rat, 0.2 mmol/kg ^C-methylene
chloride inhalation (8 hrs), closed
rebreathing system
T-2
rat, 412-930 mg/kg, i.p. Expressed as T-l
percentage of original dose. These
are values for individual experimental
animals
1.16%, 1.69%
(8 hrs)
rat, 412-930 mg/kg, i.p. Expressed as T-l
percentage of original dose. These
are values for individual experimental
animals
2.15%
(24 hrs)
rat, 412-930 mg/kg, i.p. Expressed as T-l
percentage of original dose. These
are values for individual experimental
animals
-------
Methytene chloride (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont)
carbon monoxide
47%
Lo
00
carbon monoxide as
carboxyhemoglobin (COHb)
1.5%
Hb saturation
after 30 min.
exposure
1.75% Hb
saturation after
60 min.
exposure
2.4% Hb
saturation 3 hrs
after exposure
10.1% Hb
saturation 1
hr post exposure
9% Hb
saturati on
rat, 0.2 mmol/kg 14C-methylene T-2
chloride inhalation (8 hrs),
closed rebreathing system
human, 213 ppm methylene chloride T-3
inhalation (60 min)
human, 213 ppm methylene chloride T-3
inhalation (60 min)
human, 986 ppm methylene chloride T-3
inhalation (2 hrs)
human, 180 ppm, workroom air (8 hrs) T-4
6% maximum
Hb saturation
7% maximum
Hb saturation
rat, 3.0 mmol/kg i.p. (after 2-2.5 T-5
hrs)
rat, 440 ppm inhalation exposure
(3 hrs)
T-6
-------
Methylene chloride (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(1^C)-unidentified
compound
'(l4C)-activity
representing parent
compound and metabolites
0.34%, 0.46%
(2 hrs)
0.74%, 0.86%
(8 hrs)
1.49%
(24 hrs)
75%
(2 hrs)
98%
(24 hrs)
1.0%
(24 hrs)
rat, 412-930 mg/kg i.p. Expressed T-l
as percentage of original dose.
These are values for individual
experimental animals.
rat, 412-930 mg/kg i.p. Expressed T-l
as percentage of original dose.
These are values for individual
experimental animals.
rat, 412-930 mg/kg i.p. Expressed T-l
as percentage of original dose.
These are values for individual
experimental animals.
rat, 412-930 mg/kg methylene T-l
chloride, i.p. Expressed as per-
centage of orginial dose.
rat, 412-930 mg/kg methylene T-l
chloride, i.p. Expressed as per-
centage of orginial dose.
rat, 412-930 mg/kg methylene T-l
chloride, i.p. Expressed as per-
centage of orginial dose.
Metabolite conjugates:
No data
No data
No data
-------
PENTACHLOROANISOLE (PGA)
OCH-
Cl
pentachloroanisole
demethylation
Breath
Urine
Blood
pentachlorophenol
Comments
Based on findings of
Glickman et al., (U-l)
Ref.
Parent Compound:
Half-life of parent compound:
)
Metaboli tes:
Metabolite conjugates:
No data
No data
No data
No data
approx. 1 ug/g
(12 hrs)
6.3 days
No data
No data
rainbow trout, 0.024 mg 1ZfC
PGA/L H20 at 12°C for 12 hrs
rainbow trout, 0.024 mg 14C
PGA/L H20 at 12°C for 12 hrs
U-l
U-l
-------
PENTACHLOROBENZENE
oxidation
arena
oxide
dechlorination-
hydroxylation
dechlorination
products
Metabolism of pentachlorobenzene, based on studies by Kohli et al., 1976
(Can. J. Biochem.. 54(3): 203-208).
Breath
Urine
Blood
Comments
Ref.
Parent Compound:
3% total
excretion
products
(urine + feces)
chinchilla doe, 0.5 mg/kg, by V-l
stomach tube
chinchilla doe, 0.5 mg/kg, by
subcutaneous injection
rat, rate and route of administration V-2
unspeci fied
Half-life of parent compound: No data
No data
No data
-------
Pentachlorobenzene (continued)
Breath
Urine
Blood
Comments
Ref.
Metaboli tes:
pentachlorophenol
tetrachlorophenol
tetrachlorohydroquinone
alpha-hydroxylated
chlorothio compound
tri- or penta- chlorophenol
other phenols
other chlorohydrocarbons
(3 days)
21%
(4 days)
9% total
excreti on
products
(urine + feces)
unspeci fied
amount
unspecifi ed
amount
unspecified
amount
0.2%
(3 days)
0.2%
(4 days)
0.7%
(7 days)
1%
(3 and 4 days)
1%
(10 days)
rat, rate and route of administration V-2
unspeci fi ed
rat, rate and route of administration V-2
unspeci fi ed
rat, rate and route of administration V-2
unspeci fi ed
rat, rate and route of administration V-2
unspeci fi ed
chinchilla doe, 0.5 mg/kg, by stomach V-l
tube
chinchilla doe, 0.5 mg/kg, by stomach V-l
tube
chinchilla doe, 0.5 mg/kg, by
subcutaneous injection
V-l
chinchilla doe, 0.5 mg/kg, by stomach V-l
tube
chinchilla doe, 0.5 mg/kg, by
subcutaneous injection
V-l
chinchilla doe, 0.5 mg/kg, by stomach V-l
tube
chinchilla doe, 0.5 mg/kg, by
stomach tube
V-l
-------
Pentachlorobenzene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(other chlorohydrocarbons,
cont.)
Metabolite conjugates:
2%
(10 days)
No data
No data
No data
chinchilla doe, 0.5 mg/kg, by
subcutaneous injection
V-l
-P-
LO
-------
PENTACHLOROETHANE
CC10 : CHC1
71 2
trichloroethylene
cci3
pentac
\
cci2
CHC1?
hloroethane
-HC1
/
: CC12
-HCL ^
+H20
\
tetrachloroethylene
CC1,
chloral
red
ox
/
X
trichloroethanol
CC1 COOH
trichloroacetic acid
Metabolism of pentachloroethane, from Yllner, 1963 (W-l)
Breath
Urine
Blood
Comments
Ref.
Parent compound:
present
present
12-51%
(3 days)
greater than
10~6 g/ml of
of plasma (3
days), venous
blood
unchanged pentachloroethane in the W-l
urine, feces and expired air account-
ed for approx. 30% (24 hrs) of the
20 ul dose injected subcutaneously
in mice
sheep, 0.3 ml/kg single oral dose W-2
mouse, 1.1-1.8 g/kg injected
subcutaneously
W-3
-------
Pentachloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Half-life of parent compound:
Metaboli tes:
tetrachloroethylene
No data
present
No data
present
No data
greater than
10~6 g/ml of
of plasma (3
days), venous
blood
fo
-p-
01
tri chloroethanol
3-9%
(3 days)
present
trichloroacetic acid
present
present
16-32%
(3 days)
present
9-18%
(3 days)
tetrachloroethylene in the urine, W-l
feces and expired air accounted
for 5% (24 hrs) of the 20 ul dose
injected subcutaneously in mice
sheep, 0.3 ml/kg single oral dose W-2
mouse, 1.1-1.8 g/kg injected W-3
subcutaneously
tetrachloroethanol in the urine, W-l
feces and expired air accounted
for 10% (24 hrs) of the 20 ul dose
injected subcutaneously in mice
mouse, 1.1-1.8 g/kg injected W-3
subcutaneously
trichloroacetic acid in the urine, W-l
feces and expired air accounted
for 5% (24 hrs) of the 20 ul dose
injected subcutaneously in mice
mouse, 1.1-1.8 g/kg injected W-3
subcutaneously
-------
Pentachloroethane (continued)
Breath
Urine
Blood
Comments
Ref .
Metabolites (cont.)
tri chloroethylene
present
present
2-16%
(3 days)
trichloroethylene in the urine, W-l
feces and expired air accounted
for less than 5% (24 hrs) of the
20 ul dose injected subcutaneously
in mice. The amount was not
quantitated, but appeared to be
less than the amount of
tetrachloroethylene eliminated.
mouse, 1.1-1.8 g/kg injected W-3
subcutaneously
Metabolite conjugates:
No data
No data
No data
-------
TET RACHLORO BENZENE
K>
-P-
~-J
tetrachlorobenzene
tetrachlorobenzene
•tetrachlorobenzene
•tetrachlorobenzene oxide
•tetrachlorobenzene oxide
•tetrachlorobenzene oxide
•tetrachlorobenzene oxide
•tetrachlorophenol
•tetrachlorophenol
•tetrachlorophenol
Proposed metabolism of tetrachlorobenzene
isomers, from Kohli et al., 1976 (X-l)
I)
II)
III)
IV)
v)
VI)
VII)
VIII)
IX)
X)
1
1
1
2
1
2
2
2
2
2
,2
,2
,2
,3
,3
,3
,3
,3
,3
,3
,3
,3
,3
,4
,4
,4
,5
,4
,4
,5
,4-
,5-
,5-
,5-
,5-
,6-
,6-
,6-
,5-
,6-
Breath
Urine
Blood
Comments
Ref.
Parent Compound:
1,2,3,4-isomer 8%
(6
1 ,2,4 , 5-isomer 2%
(6
I, 2, 3, 5-isomer 12%
(6
days )
days)
days)
chinchilla
by stomach
chinchilla
by stomach
chinchi lla
by stomach
doe rabbits,
tube
doe rabbi ts ,
tube
doe rabbits,
tube
0.5 g/kg
0.5 g/kg
0.5 g/kg
X-2
X-2
X-2
-------
Tetrachlorobenzene (continued)
Breath
Urine
Blood
Comments
Ref.
Half-life of parent compound: No data
Metabolites of the
1,2,3,4-isomer:
2,3,4,5-tetrachloro-
phenol
other phenols
mercapturic acid
other chlorobenzenes
Metabolites of the
1,2,3, 5-isomer:
2,3,4,5-tetrachloro-
phenol
2,3,5,6-tetrachloro-
phenol
2,3,4 ,6-tetrachloro-
phenol
tetrach1orophenols
(predominantly 2,3,4,6-
tetrachlorophenol
No data
20%
(10 days)
437.
(6 days)
less than \%
(6 days)
less than 1%
(6 days)
2%
(2 days)
3%
(10 days)
2%
(10 days)
1.5%
(10 days)
(6 days)
No data
male rabbits, 300 mg/rabbit (4-5 kg), X-l
by i.p. injection
chinchilla doe rabbits, 0.5 g/kg, X-2
by stomach tube
chinchilla doe rabbits, 0.5 g/kg, by X-2
stomach tube
chinchilla doe rabbits, 0.5 g/kg, by X-2
stomach tube
chinchilla doe rabbits, 0.5 g/kg, by X-2
stomach tube
male rabbits, 300 mg/rabbit (4-5 kg), X-l
by i.p. injection
male rabbits, 300 mg/rabbit (4-5 kg), X-l
by i.p. injection
male rabbits, 300 mg/rabbit (4-5 kg), X-l
by i.p. injection
chinchilla doe rabbits, 0.5 g/kg, X-2
by stomach tube
-------
Tetrachlorobenzene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites of the
1,2,3,5-isomer (cont.)
other phenols
other chlorobenzenes
Metabolites of the
1,2,4,5-isomer:
tetrach1orophenols
j
s
D
other phenols
other chlorobenzenes
(6 days)
10%
(6 days)
5%
(6 days)
2%
(6 days)
5%
(6 days)
chinchilla doe rabbits, 0.5 g/kg,
by stomach tube
chinchilla doe rabbits, 0.5 g/kg,
by stomach tube
chinchilla doe rabbits, 0.5 g/kg
by stomach tube
chinchilla doe rabbits, 0.5 g/kg
by stomach tube
chinchilla doe rabbits, 0.5 g/kg
by stomach tube
X-2
X-2
X-2
X-2
X-2
Metabolite conjugates:
No data
No data
No data
-------
1,1,2,2-TETRACHLOROETHANE
Adapted from the findings of Yllner, (Y-3)
Ul
O
CC12 : CHCI
|CCI3 CHOJ
CHCI2 CHCI2-
. I
CCI2 : CC!2
/ \ X I
[CHCI2 CHOJ
CHCI2 COOH
• I
CCI3 CH2 OH CCI3 COOH HOOC COOH 4 CHO COOH .
T
CO2+.(HCOOH]
CH2NH2COOH
CO-
a~) trichloroethylene
b) tetrachloroethane
c) dichloroacetaldehyde
d) trichloroacetaldehyde
e) tetrachloroethylene
f) dichloroacetic acid
g) trichloroethanol
h) trichloroacetic acid
i) oxalic acid
j) glycine acid
k) glyceine
Parent compound:
l^C-tetrachloroethane
Metaboli tes:
Breath
4%
(3 days)
Urine
Blood
Comments
Ref.
mouse, 0.21-0.32 g
tetrachloroethane per kg body wt,
i .p. inject! on
Y-3
50%
(3 days)
mouse, 0.21-0.32 g 14C-
tetrachloroethane per kg body wt ,
i .p. injection
Y-3
-------
1,1,2,2-Tetrachloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
dichloroacetic acid
trichloroethanol
oxalic acid
trichloroacetic acid
27% of
urinary
activi ty
(24 hrs)
10% of
urinary
activity
(24 hrs)
8.2 mg/kg
(48 hrs)
0.8 mg/kg
(48 hrs)
trace
(96 hrs)
7% of urinary
activi ty
(24 hrs)
4% of urinary
activi ty
(24 hrs)
1.7 mg/kg
(48 hrs)
1.3 mg/kg
(48 hrs)
0.3 mg/kg
(96 hrs)
mouse, 0.16-0.32 g 14C-tetrachloro- Y-3
ethane per kg body wt, i.p. injection
mouse, 0.16-0.32 g ^C-tetrachloro- Y-3
ethane per kg body wt, i.p. injectir
ion
rat, 200 ppm, inhalation exposure
(8 hrs)
Y-4
rat, 2.78 mmol/kg body wt, (equiva- Y-4
lent to 467 mg/kg), i.p. injection
rat, 2.78 mmol/kg body wt, (equiva- Y-4
lent to 467 mg/kg), i.p. injection
mouse, 0.16-0.32 g 14C-tetrachloro Y-3
ethane per kg body wt, i.p. injection
mouse, 0.16-0.32 g ^C-tetrachloro Y-3
ethane per kg body wt, i.p. injection
rat, 200 ppm, inhalation exposure Y-4
(8 hrs)
rat, 2.78 mmol/kg body wt, (equiva- Y-4
lent to 467 mg/kg), i.p. injection
rat, 2.78 mmol/kg body wt, (equiva- Y-4
lent to 467 mg/kg), i.p. injection
-------
1,1,2,2-Tetrachloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
Ln
N>
urea
glyoxylic acid
chlorinated hydrocarbons
-C activity
38Cl-activity
2% of
uri nary
activi ty
(24 hrs)
0.9% of
urinary
activi ty
(24 hrs)
0.5 mg/L
of urine
0.5 mg/L
of urine
28%
(3 days)
3.3%
(1 hr)
of retained
radioactivi ty
mouse, 0.16-0.32 g 14C-tetrachloro- Y-3
ethane per kg body wt, i.p. injection
mouse, 0.16-0.32 g 14o tetrachloro- Y-3
ethane per kg body wt, i.p. injection
dog, (dose not stated) inhalation ex- Y-2
posure (1 hr/day, up to 20 days)
rat, rabbit, and guinea pig (dose not Y-2
stated), subcutaneous injection
mouse, 0.21-0.32 g 14C-tetrachloro- Y-3
ethane per kg body wt, i.p. injection
human, 2.5 mg 38Cl-tetrachloro- Y-3
ethane inhaled; 97% of the dose was
retained in the lungs
Metabolite conjugates:
No data
No data
No data
-------
TETRACHLOROETHYLENE
Proposed metabolism ol TetrachloroeLhylene. Bonse et al., (Z-2)
ci2c
Tetrachloroethylene
trichloroacetic
acid
CC1_ -> CCI,— COC1
CCI — COOH
COR
c atalysed
R = (eg. OH, SH, NH2)
Breath
Urine
Blood
Comments
Ref.
[^Parent compound:
1 ppm
14 days
after
exposure
97.9%
(48 hrs)
Half-life of parent compound: 3 days
Half-life of metabolites:
total trichloro
compounds
65 hrs
144 hrs
123.3 hrs
human, 100 ppm inhalation 7 hrs/
day, 5 days
rat, 1.75 uCi, administered by
stomach tube. Expressed as per-
centage of original dose.
human, 100 ppm inhalation 7 hr/
day, 5 days
human, occupational exposure
Z-7
Z-l
Z-7
Z-6
human (male), 30-100 ppm, inhalation Z-6
8 hrs/day, 5 days/week, occupational
exposure
-------
Tetrachloroethylene (Conti nued)
Breath
Urine
Blood
Comments
Ref.
Half-life of metabolites (cont.)
(total trichloro
compounds, cont.)
Metaboli tes:
trichloroacetic acid
Ul
-p-
tr i ch1or oe thano1
190.1 hrs
52%
5.3 mg/kg
body wt
(48 hrs)
5.5 mg/kg
body wt
(48 hrs)
4-35 mg/L
32-97 mg/L
1.8% of
retained
tetrachloro-
ethylene
(67 hrs)
3.2 mg/kg
body wt.
(48 hrs)
human (female), 10-20 ppm, inhalation Z-6
8 hrs/day, 5 days/week, occupational
exposure
mouse, 1.3 mg/g body wt, vapor,2 hrs, Z-3
exposure. Figure represents per-
centage of urinary radioactivity.
Urinary radioactivity was 20% of
absorbed activity.
rat, 200 ppm inhalation exposure,
8 hrs
rat, 2.78 mmol/kg body wt, i.p.
human, 20-70 ppm, daily,
intermittent occupational
exposure
human, 200-400 ppm daily,
intermitten occupational
exposure
human, 87 ppm, inhalation
exposure, 3 hrs
rat, 200 ppm, inhalation
exposure, 8 hrs
Z-4
Z-4
Z-4
Z-4
Z-5
Z-4
-------
Tetrachloroethylene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroethanol, cont.)
oxalic acid
01
t_n
dichloroacetic acid
unknown chloride
36Cl-activity
representing parent
compound and/or metabolites
97. <
(48
hrs)
0.08 mg/kg
body wt
(48 hrs)
4-20 mg/L
21-100 mg/L
11%
trace
amount
1.0% of
retained
tetrachloro-
ethylene
(67 hrs)
2.1%
(48 hrs)
rat, 2.78 mmol/kg body wt i.p.
human, 20-70 ppm, daily,
intermittent occupational
exposure
human, 200-400 ppm, daily,
intermittent occupational
exposure
mouse, 1.3 mg/g body wt, vapor,
2 hrs exposure. Figure represents
percentage of urinary radioactivity.
Urinary activity was 20% of
absorbed activity.
mouse, 1.3 mg/g body wt, vapor,
2 hrs exposure. Figure represents
percentage of urinary radioactivity.
Urinary activity was 20% of absorbed
activi ty.
human, 87 ppm inhalation exposure,
3 hrs
Z-4
Z-4
Z-4
Z-3
Z-3
Z-5
rat, 1.75 uCi, administered by
stomach tube
Z-l
-------
Tetrachloroethylene (continued)
Breath
Urine
Blood
Comments
Ref .
Metabolites (cont.)
l^C activity representing 70%
parent compound and/or of absorbed
metabolites activity
20% of absorb-
ed activity
mouse, 1.3 mg/g body wt
inhalation, 2 hrs
Z-3
Metabolite conjugates:
No data
No data
No data
-------
TRT CHLOROBENZENE
-trichlorobenzene
-trichlorobenzene
•trichlorobenzene
-trichlorobenzene oxide
•trichlorobenzene oxide
•trichlorobenzene oxide
•trichlorobenzene oxide
•trichlorobenzene oxide
•trichloropbenol
•trichlorophenol
•trichlorophenol
•trichlorophenol
trichlorophenol
•trichlorophenol
Metabolism of trichlorobenzene isomers
based studies by Kohli et a I., 1976
(AA-2).
I)
II)
III)
IV)
V)
VI)
VII)
VIII)
IX)
X)
XI)
YT T \
•A.J, .L J
XIII)
XIV)
1,2,3-
1,3,5-
1,2,4-
2,3,4-
3,4,5-
1,3,5-
2,3,5-
2,4,5-
2,3,6-
2,3,4-
3,4,5-
2,4,6-
2,3,5-
2,4,5-
Breath
Urine
Blood
Comments
Ref.
1,2,3 isomer
Parent compound:
Half-life of parent compound:
Metaboli tes:
tri chlorophenols
(primarily 2,3,4-trichloro-
phenol; smaller amounts
of 3,4,5-trichlorophenol
and 3,4,5-trichlorocatechol )
2,3,4-tri ch1orophenol
No data
No data
No data
No data
78%
(5 days)
No data
No data
(10 days)
rabbit, 0.5 g/kg, by
stomach tube
AA-l
rabbit, 300 mg, i.p.
AA-2
-------
Trichlorobenzene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
2, 3 , 6-tr i ch 1 or o phenol
3 ,4, 5-tr i chlorophenyl
acetate
Metabolite conjugates:
glucuroni de
ethereal sulphate
ui 2, 3 ,4-tri chlorophenyl-
oo ...
mercapturic acid
1%
(10 days)
2%
(10 days)
50%
(5 days)
12%
(5 days)
0.3%
(5 days)
rabbi t ,
rabbi t ,
300 mg, i.p.
300 mg, i.p.
rabbit, 0.5 g/kg,
by stomach tube
rabbi t ,
stomach
rabbi t ,
stomach
0.5 g/kg by
tube
0.5 g/kg, by
tube
AA-2
AA-2
AA-1
AA-1
AA-1
-------
Trichlorobenzene (continued)
Breath
Urine
Blood
Comments
Ref.
1,2,4 isotner
Parent compound:
Half-life of parent compound:
Metaboli tes:
tri chlorophenols
(2,4,5- and 2,3,5-
trichloropheno1, plus
small amounts of 3,4,6-
trichlorocatechol)
2,4,5-tr i ch1oro pheno1
2,3,5-trichloro pheno1
Metabolite conjugates:
glucuronide
ethereal sulphate
mercapturic acids
(2,3,5- and 2,4,5-
trichlorophenyl mercap-
turic acids)
Ui
No data
No data
No data
No data
42%
(5 days)
5%
(10 days)
(10 days)
27%
(5 days)
11%
(5 days)
0.3%
(5 days)
No data
No data
rabbit, 0.5 g/kg, by
stomach tube
rabbit, 300 mg, i.p.
rabbit, 300 mg, i.p.
rabbit, 0.5 g/kg, by
stomach tube
rabbit, 0.5 g/kg, by
stomach tube
rabbit, 0.5 g/kg, by
stomach tube
AA-1
AA-2
AA-2
AA-1
AA-1
AA-1
-------
Trichlorobenzene (continued)
Breath
Urine
Blood
Comments
Ref.
1,3,5 i somer:
Parent compound:
Half-life of parent compound:
Metaboli tes:
2,4 ,6-tri ch1orophenol
ro
ON
o
other phenols
(4-chlorophenol and
4-chlorocatechol)
monochlorobenzene
Metabolite conjugates:
glucuronide
ethereal sulphate
mercapturic acid
12%
(8 days)
8.5%
(9 days)
No data
No data
3%
(8 days)
10%
(9 days)
1%
(8 days)
4%
(9 days)
1%
(8 or 9 days)
20%
(5 days)
(5 days)
0
No data
rabbit, 0.5 g/kg,
by stomach tube
rabbit, 0.5 g/kg,
by stomach tube
rabbit, 0.5 g/kg,
by stomach tube
rabbit, 0;5 g/kg,
by stomach tube
rabbit, 0.5 g/kg,
by stomach tube
rabbit, 0.5 g/kg,
by stomach tube
rabbit, 0.5 g/kg,
by stomach tube
rabbit, 0.5 g/kg,
by stomach tube
rabbit, 0.5 g/kg,
by stomach tube
rabbit, 0.5 g/kg,
by stomach tube
rabbit, 0.5 g/kg,
by stomach tube
AA-3
AA-3
AA-1
AA-3
AA-3
AA-3
AA-3
AA-3
AA-1
AA-1
AA-1
-------
1,1,I-TRICHLOROETHANE
oxidation
\
Cl
trichloroethanol
. C13COCOOH
'rrichloroacetic acid
Proposed formation of urinary metabolites of 1,1,1-trichloroethane, from Ikeda and
Ohtsuji, 1972 (AB-2)
Breath
Urine
Blood
Comments
Ref.
Parent compound:
(a) alveolar air
concentration of
1,1,l-trichloroethane
125 ppm (a)
(at rest)
168 ppm (a)
(50 W)
human, 250 ppm exposure, 30 min. per AB-5
exposure, at rest and with consecutive
work loads of 50, 100, and 150 W as
measured on a bicycle ergometer
human, 250 ppm exposure, 30 min. per AB-5
exposure, at rest and with consecutive
work loads of 50, 100, and 150 W as
measured on a bicycle ergometer
-------
1,1,1-Trich1 oroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Parent compound (cont.)
210 ppm (a)
(100 W)
27 ppm (a)
(150 W)
3.0 ppm
arterial blood
(at rest)
4.5 ppm
arterial blood
(50 W)
5.2 ppm
arterial blood
(100 W)
5.5 ppm
arterial blood
(150 W)
human, 250 ppm exposure, 30 min. per AB-5
exposure, at rest and with consecutive
work loads of 50, 100, and 150 W as
measured on a bicycle ergometer
human, 250 ppm exposure, 30 min. per AB-5
exposure, at rest and with consecutive
work loads of 50, 100, and 150 W as
measured on a bicycle ergometer
human, 250 ppm exposure, 30 min. per AB-5
exposure, at rest and with consecutive
work loads of 50, 100, and 150 W as
measured on a bicycle ergometer
human, 250 ppm exposure, 30 min. per AB-5
exposure, at rest and with consecutive
work loads of 50, 100, and 150 W as
measured on a bicycle ergometer
human, 250 ppm exposure, 30 min. per AB-5
exposure, at rest and with consecutive
work loads of 50, 100, and 150 W as
measured on a bicycle ergometer
human, 250 ppm exposure, 30 min. per AB-5
exposure, at rest and with consecutive
work loads of 50, 100, and 150 W as
measured on a bicycle ergometer
-------
1,1,1-Tri chloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Parent compound (cont.)
K3
o>
u>
179 ppm,
alveolar air
(at rest)
239 ppm,
alveolar air
(50 W)
1.4 ppm,
venous blood
(at rest)
3.1 ppm,
venous blood
(50 W)
3.5 ppm,
venous blood
(100 W)
4.4 ppm,
venous blood
(150 W)
human, 250 ppm exposure, 30 min. per AB-5
exposure, at rest and with consecutive
work loads of 50, 100, and 150 W as
measured on a bicycle ergometer
human, 250 ppm exposure, 30 min. per AB-5
exposure, at rest and with consecutive
work loads of 50, 100, and 150 W as
measured on a bicycle ergometer
human, 250 ppm exposure, 30 min. per AB-5
exposure, at rest and with consecutive
work loads of 50, 100, and 150 W as
measured on a bicycle ergometer
human, 250 ppm exposure, 30 min. per AB-5
exposure, at rest and with consecutive
work loads of 50, 100, and 150 W as
measured on a bicycle ergometer
human, 350 ppm exposure, 30 min. per AB-5
exposure, at rest and with 50 W
work load as measured on a bicycle
ergometer
human, 350 ppm exposure, 30 min. per AB-5
exposure, at rest and with 50 W
work load as measured on a bicycle
ergometer
-------
1,1 ,1-Tri chloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Parent compound (cont.)
CTv
-C-
128 ppm,
alveolar air
(at rest)
176 ppm,
alveolar air
(at rest
plus 4%
C02)
201 ppm,
alveolar air
(50 W
plus 4%
C02)
5.0 ppm,
arterial blood
(at rest)
7.2 ppm,
arterial blood
(50 W)
3.0 ppm,
venous blood
(at rest)
4.0 ppm
venous blood
(50 W)
human, 350 ppm exposure, 30 min. per AB-5
exposure, at rest and with 50 W work
load as measured on a bicycle
ergometer
human, 350 ppm exposure, 30 min. per AB-5
exposure, at rest and with 50 W work
load as measured on a bicycle
ergometer
human, 350 ppm exposure, 30 min. per AB-5
exposure, at rest and with 50 W work
load as measured on a bicycle
ergometer
human, 350 ppm exposure, 30 min. per AB-5
exposure, at rest and with 50 W work
load as measured on a bicycle
ergometer
human, 250 ppm exposure, 30 min. per AB-5
exposure; at rest, at rest plus 4%
C02, and 50 W workload plus 4%
CO 2
human, 250 ppm exposure, 30 min. per AB-5
exposure; at rest, at rest plus 4%
C02, and 50 W workload plus 4%
CO 2
human, 250 ppm exposure, 30 min. per AB-5
exposure; at rest, at rest plus 4%
CO2, and 50 W workload plus 4%
CO 2
-------
1,1,1-Trichloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Parent compound (cont.)
ON
Ln
2. 2 ppm,
arterial blood
(at rest)
3.3 ppm,
arterial blood
(at rest plus
4% C02)
3.9 ppm,
arterial blood
(50 W plus
4% C02)
1.0 ppm,
venous blood
(at rest)
1.2 ppm,
venous blood
(at rest plus
4% C02)
1.9 ppm,
venous blood
(50 W plus
4% C02)
human, 250 ppm exposure, 30 min. per AB-5
exposure; at rest, at rest plus 4%
CC>2, and 50 W workload plus 4%
CO 2
human, 250 ppm exposure, 30 min. per AB-5
exposure; at rest, at rest plus 4%
C02, and 50 W workload plus 4%
CO 2
human, 250 ppm exposure, 30 min. per AB-5
exposure; at rest, at rest plus 4%
COo, and 50 W workload plus 4%
human, 250 ppm exposure, 30 min. per AB-5
exposure; at rest, at rest plus 4%
CC>2, and 50 W workload plus 4%
CO 2
human, 250 ppm exposure, 30 min. per AB-5
exposure; at rest, at rest plus 4%
C02, and 50 W workload plus 4%
CO 2
human, 250 ppm exposure, 30 min. per AB-5
exposure; at rest, at rest plus 4%
C02, and 50 W workload plus 4%
CO 2
-------
1,1,1-Trichloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Parent compound (cont.)
CTv
Os
98.7%
(25 hrs)
2.488 mg
(1st hr)
1.156 mg
(2nd hr)
0.589 mg
(3rd hr)
0.309 mg
(4th hr)
0.191 mg
(5th hr)
0.117 mg
(6th hr)
0.073 mg
(7th hr)
0.050 mg
(8th hr)
rat. 700 mg 1,1,1-trichloroethane- AB-1
1-C^ per kg, i .p.
rat, 221 ppm, inhalation exposure AB-3
(4 hrs); expired air level of
parent compound measured hourly
rat, 221 ppm, inhalation exposure AB-3
(4 hrs); expired air level of
parent compound measured hourly
rat, 221 ppm, inhalation exposure AB-3
(4 hrs); expired air level of
parent compound measured hourly
rat, 221 ppm, inhalation exposure AB-3
(4 hrs); expired air level of
parent compound measured hourly
rat, 221 ppm, inhalation exposure AB-3
(4 hrs); expired air level of
parent compound measured hourly
rat, 221 ppm, inhalation exposure AB-3
(4 hrs); expired air level of
parent compound measured hourly
rat, 221 ppm, inhalation exposure AB-3
(4 hrs); expired air level of
parent compound measured hourly
rat, 221 ppm, inhalation exposure AB-3
(4 hrs); expired air level of
parent compound measured hourly
-------
1,1,1-Trichloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Parent compound (cont.)
NJ
ON
5.719 mg
(1st hr)
3.350 mg
(2nd hr)
1.539 mg
(3rd hr)
0.793 mg
(4th hr)
0.441 mg
(5th hr)
0.259 mg
(6th hr)
0.154 mg
(7th hr)
0.098 mg
(8th hr)
rat, 443 ppm, inhalation exposure AB-3
(4 hrs); expired air level of
parent compound measured hourly
rat, 443 ppm, inhalation exposure AB-3
(4 hrs); expired air level of
parent compound measured hourly
rat, 443 ppm, inhalation exposure AB-3
(4 hrs); expired air level of
parent compound measured hourly
rat, 443 ppm, inhalation exposure AB-3
(4 hrs); expired air level of
parent compound measured hourly
rat, 443 ppm, inhalation exposure AB-3
(4 hrs); expired air level of
parent compound measured hourly
rat, 443 ppm, inhalation exposure AB-3
(4 hrs); expired air level of
parent compound measured hourly
rat, 443 ppm, inhalation exposure AB-3
(4 hrs); expired air level of
parent compound measured hourly
rat, 443 ppm, inhalation exposure AB-3
(4 hrs); expired air level of
parent compound measured hourly
-------
1,1,l-Trichloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Parent compound (cont.)
ro
-------
1,1,1-Trichloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Parent compound (cont.)
4.5 ug/g
(3 hrs)
8.1 ug/g
(4 hrs)
5.6 ug/g
(4.5 hrs)
6.2 ug/g
(5 hrs)
6.0 ug/g
(6 hrs)
5.8 ug/g
(16 hrs)
6.3 ug/g
(24 hrs)
31 ug/g
(0.5 hr
exposure)
38 ug/g
(1 hr exposure)
41 ug/g
(3 hrs exposure)
48 ug/g
(4.5 hrs
exposure)
36 ug/g
(6 hrs exposure)
mouse, 100 ppm inhalation exposure
for various exposure periods
mouse, 100 ppm inhalation exposure
for various exposure periods
mouse, 100 ppm inhalation exposure
for various exposure periods
mouse, 100 ppm inhalation exposure
for various exposure periods
mouse, 100 ppm inhalation exposure
for various exposure periods
mouse, 100 ppm inhalation exposure
for various exposure periods
mouse, 100 ppm inhalation exposure
for various exposure periods
mouse, 1000 ppm inhalation exposure
for 0.5, 1, 3, 4.5, or 6 hours
mouse, 1000 ppm inhalation exposure
for 0.5, 1, 3, 4.5, or 6 hours
mouse, 1000 ppm inhalation exposure
for 0.5, I, 3, 4.5, or 6 hours
mouse, 1000 ppm inhalation exposure
for 0.5, 1, 3, 4.5, or 6 hours
mouse, 1000 ppm inhalation exposure
for 0.5, 1, 3, 4.5, or 6 hours
AB-9
AB-9
AB-9
AB-9
AB-9
AB-9
AB-9
AB-9
AB-9
AB-9
AB-9
AB-9
-------
1,1,l-Trichloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Parent compound (cont.)
Half-life of parent compound:
Metaboli tes:
8.7 hrs
(average)
14
CO 2
trichloroethanol
0.5%
(25 hrs)
103 ug/g
(0.5 hr
exposure)
144 ug/g
(1 hr
exposure)
165 ug/g
(3 hrs
exposure)
251 ug/g
(0.5 hr
exposure)
204 ug/g
(3 hrs
exposure)
404 ug/g
(6 hrs
exposure)
20.1 mg/24 hrs
(1st day)
3O.1 mg/24 hrs
(2nd day)
mouse, 5,000 ppm inhalation
exposure, for 0.5, 1, or 3 hours
mouse, 5,000 ppm inhalation
exposure, for 0.5, 1, or 3 hours
mouse, 5,000 ppm inhalation
exposure, for 0.5, 1, or 3 hours
mouse, 10,000 inhalation exposure
for 0.5, 3, or 6 hours
mouse, 10,000 inhalation exposure
for 0.5, 3, or 6 hours
mouse, 10,000 inhalation exposure
for 0.5, 3, or 6 hours
human, occupational inhalation
exposure to 4, 25, 28, or 53 ppm,
for 8 hrs/day, 5-1/2 days/week,
for at least 5 years (average)
rat, 700 mg 1,1,1-trichloroethane-
1-C *^ per kg, i.p.
human, 500 ppm inhalation exposure
6 1/2-7 hrs/day, 5 days
human, 5OO ppm inhalation exposure
6 1/2—7 hirs/day, 5 days
AB-9
AB-9
AB-9
AB-9
AB-9
AB-9
AB-7
AB-1
AB-6
AB—6
-------
1,1,1-Trichloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroethanol, cont.)
29.3 mg/24 hrs
(3rd day)
46.6 mg/24 hrs
(4th day)
7.0 mg/24 hrs
(6th day
after last
exposure)
less than 1.0
mg/24 hrs
(12th day after
last exposure)
1.2 mg/L
(4.3 ppm
exposure)
5.5 mg/L
(24.6 ppm ex-
posure)
9.9 mg/L
(53.4 ppm ex-
posure)
human, 500 ppm inhalation exposure
6 1/2-7 hrs/day, 5 days
human, 500 ppm inhalation exposure
6 1/2-7 hrs/day, 5 days
human, 500 ppm inhalation exposure
6 1/2-7 hrs/day, 5 days
human, 500 ppm inhalation exposure
6 1/2-7 hrs/day, 5 days
AB-6
AB-6
AB-6
AB-6
human, occupational inhalation ex- AB-7
posure to 4.3, 24.6, or 53.4 ppm for
8 hrs/day, 5 1/2 days/week, for at
least 5 years
human, occupational inhalation ex- AB-7
posure to 4.3, 24.6, or 53.4 ppm for
8 hrs/day, 5 1/2 days/week, for at
least 5 years
human, occupational inhalation ex- AB-7
posure to 4.3, 24.6, or 53.4 ppm for
8 hrs/day, 5 1/2 days/week, for at
least 5 years
-------
1,1,1-Trichloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroethanol, cont.)
ho
-J
IS3
3. 1 mg/kg
(48 hrs)
3.5 mg/kg
(48 hrs)
126.2 ug
(24 hrs)
7.5 ug
(2nd 24-hr
peri od)
206.5 ug
(24 hrs)
8.6 ug
(2nd 24-hr
peri od)
0.088 ug/ml
(week 1)
0.063 ug/ml
(week 2)
rat, 200 ppm inhalation exposure AB-2
8 hours
rat, 2.78 mmol/kg, i.p. AB-2
rat, 221 ppm inhalation exposure AB-3
4 hours
rat, 221 ppm inhalation exposure, AB-3
4 hours
rat, 443 ppm inhalation exposure,
4 hrs
rat, 443 ppm inhalation exposure,
4 hrs
rat, chronic inhalation exposure,
204 ppm for 8 hrs/day, 5 days/week
for 14 weeks; trichloroethanol in
blood measured periodically during
exposure at 1,2,4 and 9 weeks
rat, chronic inhalation exposure,
204 ppm for 8 hrs/day, 5 days/week
for 14 weeks; trichloroethanol in
blood measured periodically during
exposure at 1,2,4 and 9 weeks
AB-3
AB-3
AB-3
AB-3
-------
1,1,1-Trichloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroethanol, cont.)
—I
CO
93.0 ug/24 hrs
(week 1)
222.9 ug/24 hrs
(week 2)
189.8 ug/24 hrs
(week 3)
216.3 ug/24 hrs
(week 4)
0.059 ug/ml rat, chronic inhalation exposure, AB-3
(week 4) 204 ppm for 8 hrs/day, 5 days/week
for 14 weeks; trichloroethanol in
blood measured periodically during
exposure at 1,2,4 and 9 weeks
0.071 ug/ml rat, chronic inhalation exposure, AB-3
(week 9) 204 ppm for 8 hrs/day, 5 days/week
for 14 weeks; trichloroethanol in
blood measured periodically during
exposure at 1,2,4 and 9 weeks
rat, chronic inhalation exposure, AB-3
204 ppm for 8 hrs/day, 5 days/week
for 14 weeks, trichloroethanol in
urine measured weekly
rat, chronic inhalation exposure, AB-3
204 ppm for 8 hrs/day, 5 days/week
for 14 weeks, trichloroethanol in
urine measured weekly
rat, chronic inhalation exposure, AB-3
204 ppm for 8 hrs/day, 5 days/week
for 14 weeks, trichloroethanol in
urine measured weekly
rat, chronic inhalation exposure, AB-3
204 ppm for 8 hrs/day, 5 days/week
for 14 weeks, trichloroethanol in
urine measured weekly
-------
1,1,l-Trichloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroethanol, cont.)
254.5 ug/24 hrs
(week 5)
194.1 ug/24 hrs
(week 6)
302.8 ug/24 hrs
(week 7)
339.0 ug/24 hrs
(week 8)
383.9 ug/24 hrs
(week 9)
435.1 ug/24 hrs
(week 10)
rat, chronic inhalation exposure, AB-3
204 ppm for 8 hrs/day, 5 days/week
for 14 weeks, trichloroethanol in
urine measured weekly
rat, chronic inhalation exposure, AB-3
204 ppm for 8 hrs/day, 5 days/week
for 14 weeks, trichloroethanol in
urine measured weekly
rat, chronic inhalation exposure, AB-3
204 ppm for 8 hrs/day, 5 days/week
for 14 weeks, trichloroethanol in
urine measured weekly
rat, chronic inhalation exposure, AB-3
204 ppm for 8 hrs/day, 5 days/week
for 14 weeks, trichloroethanol in
urine measured weekly
rat, chronic inhalation exposure, AB-3
204 ppm for 8 hrs/day, 5 days/week
for 14 weeks, trichloroethanol in
urine measured weekly
rat, chronic inhalation exposure, AB-3
204 ppm for 8 hrs/day, 5 days/week
for 14 weeks, trichloroethanol in
urine measured weekly
-------
1,1,1-Trichloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites, (cont.)
(trichloroethanol, cont.)
fO
^J
Ln
trichloroacetic acid
305.7 ug/24 hrs
(week 11)
291.7 ug/24 hrs
(week 12)
372.2 ug/24 hrs
(week 13)
362.2 ug/24 hrs
(week 14)
7.5 mg/24 hrs
(1st day)
10.9 mg/24 hrs
(2nd day)
12.3 mg/24 hrs
(3rd day)
14.1 mg/24 hrs
(4th day)
AB-3
AB-3
rat, chronic inhalation exposure, AB-3
204 ppm for 8 hrs/day, 5 days/week
for 14 weeks, trichloroethanol in
urine measured weekly
rat, chronic inhalation exposure,
204 ppm for 8 hrs/day, 5 days/week
for 14 weeks, trichloroethanol in
urine measured weekly
rat, chronic inhalation exposure,
204 ppm for 8 hrs/day, 5 days/week
for 14 weeks, trichloroethanol in
urine measured weekly
rat, chronic inhalation exposure,
204 ppm for 8 hrs/day, 5 days/week
for 14 weeks, trichloroethanol in
urine measured weekly
human, 500 ppm, inhalation exposure, AB-6
6 1/2-7 hrs/day, 5 days
human, 500 ppm, inhalation exposure, AB-6
6 1/2-7 hrs/day, 5 days
human, 500 ppm, inhalation exposure, AB-6
6 1/2-7 hrs/day, 5 days
human, 500 ppm, inhalation exposure, AB-6
6 1/2-7 hrs/day, 5 days
AB-3
-------
1,1,1-Trichloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroacetic acid, cont.)
18.0 mg/24 hrs
(6th day after
last exposure)
17.5 mg/24 hrs
(12th day
after last
exposure
0.6 mg/L
(4.3 ppm
exposure)
2.4 mg/L
(24.6 ppm
exposure)
3.6 mg/L
(53.4 ppm
exposure)
0.5 mg/kg
body wt
(48 hrs)
0.5 mg/kg
body wt
(48 hrs)
human, 500 ppm, inhalation exposure, AB-6
6 1/2-7 hrs/day, 5 days
human, 500 ppm, inhalation exposure, AB-6
6 1/2-7 hrs/day, 5 days
human, occupational inhalation ex- AB-7
posure to 4.3, 24.6, or 53.4 ppm for
8 hrs/day, 5 1/2 days/week, for at
least 5 years
human, occupational inhalation ex- AB-7
posure to 4.3, 24.6, or 53.4 ppm for
8 hrs/day, 5 1/2 days/week, for at
least 5 years
human, occupational inhalation ex- AB-7
posure to 4.3, 24.6, or 53.4 ppm for
8 hrs/day, 5 1/2 days/week, for at
least 5 years
rat, 200 ppm inhalation exposure, 8 AB-2
hours
rat, 2.78 mmol/kg, i.p.
AB-2
-------
1,1,1-Tri chloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroacetic acid, cont.)
0.3 mg/kg
body wt
(2nd 48-)
hr period)
3.2 ug
(24 hrs)
8.1 ug
(2nd 24-)
hr period)
9.5 ug
(24 hrs)
10.6 ug
(2nd 24-
hr period)
7.5 ug
(3rd 24-
hr period)
12-20 ug
(daily
average)
rat, 2.78 mmol/kg, i.p.
AB-2
rat, 221 ppm inhalation exposure, AB-3
4 hrs
rat, 221 ppm inhalation exposure, AB-3
4 hrs
rat, 443 ppm inhalation exposure, AB-3
4 hours
rat, 443 ppm inhalation exposure, AB-3
4 hours
rat, 443 ppm inhalation exposure, AB-3
4 hours
rat, 204 ppm inhalation exposure, AB-3
8 hrs/day, 5 days/week, for
14 weeks
-------
1,1,1-Trichloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolite conjugates:
^C-acti vi ty ,
primar i ly
2 , 2 , 2- tricolor oethanol
-2-cM glucuronide
Other:
vity
i^C-activity
44%
0.85%
(24 hrs)
0.02%
(25 hrs)
rat, 700 mg 1,1,1-trichloroethane
per kg, i.p.
AB-1
human, 5 mg ^°C1-1,1,1-trichloro- AB-4
ethane, inhalation (single breath)
rat. 700 mg 1,1,1-trichloroethane- AB-1
l-C^ per kg, i.p.
NJ
-~J
00
-------
1,1,2-TRICHLOROETHANE
e *
JOC.CII^CI
1 -''
IIOOC-CH-SG
a) 2,2-dichloroethanol
b) 1 , 1 ,2-trichloroethane
c) S-(2,2-dichloroethyl)-glutathione
d) chloroacetaldehyde
e) S-fonnylmethylglutathione
f) chloroacetic acid
g) S-carboxymethylglutathione
h) S-carboxymethylcysteine
i) thiodiacetic acid
The full arrows indicate the suggested routes
and the dotted arrows the alternatives.
Metabolic fate of 1 , 1 ,2-trichloroethane. (From ref. AC-1)
Breath
Urine
Blood
Comments
Ref.
Parent compound:
Half-life of parent compound:
Metaboli tes:
approx. 6.4-
8.8%
(3 days)
No data
approx. 9.6-
13.2%
(3 days)
No data
No data
mouse, 0.1-0.2 g 14C-1,1,2-
trichlo-roethane per kg, i.p.
mouse, 0.1-0.2 g 14C-1,1,2-
trichloroethane per kg, i.p.
AC-1
AC-1
-------
1,1,2-Trichloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
tri chloroethanol
00
o
2,2,2-trichloroethanol
2,2,-dichloroethanol
0.3 mg/kg
body wt
(48 hrs from
start of ex-
posure)
0.2 mg/kg
body wt
(48 hrs from
start of
exposure)
trace
48-hr
peri od
(2nd
0.2% of total
urinary
radiocati vi ty ;
equivalent to
about 0.16% of
14C- 1,1,2-
tri chloroethane dose
(3 days)
1.4% of total
uri nary
radiocativi ty ;
equivalent to
about 1.12% of
14C- 1,1,2-
tri chloroethane dose
(3 days)
rat, 200 ppm inhalation exposure,
8 hours
rat, 2.78 mmol/kg, i.p.
AC-2
AC-2
rat, 2.78 mmol/kg, i.p.
mouse, 0.1-0.2 g of 1
trichloroethane, i.p.
AC-2
AC-1
mouse, 0.1-0.2 g of ^C-1,1,2-
trichloroethane, i.p.
AC-1
-------
1,1,2-Trichloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
trichloroacetic acid
chloroacetic acid
0.3 mg/kg
body wt
(48 hrs
from
start of
exposure)
0.4 mg/kg
body wt
(48 hrs)
0.3 mg/kg
body wt
(2nd 48-
hr period)
1.9% of total
urinary radio-
activity; equiv-
alent to about
1.52% of 14C-
l, 1,2-trichloro-
ethane dose
(3 days)
16.% of total
urinary radio-
activity; equiv-
alent to about
12.78% of l^C-
l, 1,2-trichloro-
ethane dose
(3 days)
rat, 200 ppm inhalation exposure,
8 hours
AC-2
rat, 2.78 mmol/kg, i.p.
rat, 2.78 mmol/kg, i.p.
mouse, 0.1-0.2 g of 14C-1,1,2-
trichloroethane, i.p.
AC-2
AC-2
AC-1
mouse, 0.1-0.2 g of 1
trichloroethane, i.p.
AC-1
-------
I,1,2-Trichloroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
S-carboxymethylcysteine
conjugated S-carboxy-
methyleysteine
thiodiacetic acid
oxalic acid
38.% of total
urinary radio-
activity; equiv-
alent to about
30.36% of 14C-
l ,1,2-trichloro-
ethane dose
(3 days)
5.% of total
urinary radio-
activity; equiv-
alent to about
4.0% of 14C-
1,1,2-trichloro-
ethane dose
(3 days)
40% of total
urinary radio-
activity; equiv-
alent to about
31.96% of 14C-
1,1,2-trichloro-
ethane dose
(3 days)
0.4% of total
urinary radio-
activity; equiv-
alent to about
0.32% of 14C-
1,1,2-trichloro-
ethane dose
(3 days)
mouse, 0.1-0.2 g of 14C-1,1,2-
trichloroethane, i.p.
i.p.
mouse, 0.1-0.2 g of 14C-1,1,2-
trichloroethane, i.p.
mouse, 0.1-0.2 g of 14C-1,1,2-
trichloroethane, i.p.
AC-1
mouse, 0.1-0.2 g of 14C-1,1,2- AC-1
trichloroethane,
AC-1
AC-1
-------
1,1,2-Tri ch1oroethane (continued)
Breath
Urine
Blood
Comments
Ref.
Other:
radioactivity
2.9%
(1 hr)
human, about 5 mg of 38C1-1,1,2-
trichloroethane, inhaled in a single
breath
AC-3
ro
CO
-------
TRICHLOROETHYLENE
(TCE)
TSICHLOROETHYLENE
GLYCOL
TR1CHLCROETHYLENE
'M6L UIKtO f'JNCJlOH 0.IVOJ5f5
I
I
CI-C-C-H
\ /
o
TSICHLOROETHYLENE
OXIDE
INTRAMOLECULAR REARRANGEMENT PHOOUCT
*
CI
THlCHLOROACifALOEHYOE
HfO.fOl.rSIS
Proposed intermediary
metabolism of TCE. (AD-1)
CO
-p-
ALCOHOL D£HrO»OaEHAS£ /N1OH
CI H ^^
I I
CI-C -C-OM
I I
CI M
TRICHLOROE THANOL
I I
CI-C - C -H
I I
-^ CI OH ^
CHLORAL HYDRATE
vixCD FUNCTION
onojsfs
UOP OLUCufOnri. TftiNSfERASE
CI H
d-c-C-O-C^O,. TRICHLOROETHANOL
1 1
CI H
GLUCUflONtOE
TaiCHLORO^CEIlC
Breath
Urine
Blood
Comments
Ref .
Parent compound:
27.7/4 of
retained TCE
human, male, inhalation exposure,
concentration of TCE not stated
AD-8
18.6% of
retained TCE
human, female, inhalation exposure, AD-8
concentration of TCE not stated
25.% of
inhaled TCE
concentration
human, 0.537 or 1.074 ppm inhalation, AD-7
for 30 min., at rest
19.% of
retained TCE
human, male, 27 ppm inhalation
exposure, 4 hours
AD-5
16.% of
retained TCE
human, male, 81 ppm inhalation
exposure, 4 hours
AD-5
-------
Trichloroethylene (continued)
Breath
Urine
Blood
Comments
Ref.
Parent compound (cont.)
00
U1
13.% of
retained TCE
19.2% of
retained TCE
12.7% of
retained TCE
10% of
retained TCE
8% of
retained TCE
72.1%
82.3%
84.!
41.3 mg%
(in blood
cellular
components)
human, male, 201 ppm inhalation AD-5
exposure, 4 hours
human, male, 320 ppm inhalation AD-4
exposure, 160 min
human, female, 320 ppm inhalation AD-4
exposure, 160 min
human, male, 70 or 140 ppm inhalation AD-6
exposure, with or without 100 W
workload, for 4 hours
human, male, 54 or 97 ppm AD-3
inhalation exposure, 8 hours
rat, 4.0 uCi of 38Cl-trichloro- AD-2
ethylene, by stomach tube
rat, 7.5 uCi of 38Cl-trichloro- AD-2
ethylene, by stomach tube
rat, 8.6 uCi of 38Cl-trichloro- AD-2
ethylene, by stomach tube
rat, 10 mg/L, inhalation (exposure AD-1
period not stated)
-------
Trichloroethylene (continued)
Breath
Urine
Blood
Comments
Ref.
Parent compound (cont.)
Half-life of parent compound:
Metaboli tes:
tri chloroethanol
No data
2.5 mg% in
blood plasma
trace amount
No data
50% total
amount excret-
ed (350 hrs,
avg.)
45.4%
(3 weeks)
32.7%
(several
weeks)
48.6% of
of retained
TCE (6 days)
42.7% of
of retained
TCE (6 days)
53.1%
(100 hrs)
No data
rat, 10 mg/L, inhalation (exposure
period not stated)
calf, 3 or 12 g, oral dose, daily
for 4 or 5 days
AD-1
AD-14
and
AD-15
humans, male and female, 500-850
ug/L inhalation exposure for
5 hours
humans, male and female, 1042 ug/L
inhalation exposure for 8 hours
AD-9
AD-10
human, male, 54 or 97 ppm inhalation AD-3
exposure for 8 hours
human, male, 250-380 ppm inhalation AD-4
exposure, 160 minutes
human, female, 250-380 ppm inhalation AD-4
exposure, 160 minutes
human, male, 170 ppm inhalation
exposure for 3 hours
AD-11
-------
Trichloroethylene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroethanol, cont.)
r-o
00
44%
(100 hrs)
46.1%
(16 or 21
days)
25.1 mg/L
(3 ppm
exposure)
24.9 mg/L
(5 ppm
exposure)
42.0 mg/L
(10 ppm
exposure)
77.3 mg/L
(25 ppm
exposure)
220.3 mg/L
(40 ppm
exposure)
human, male, 170 ppm inhalation
exposure for 7 hours (with a
1-hour break)
human, female, 1 mg/L inhalation
exposure for 5 hours
human, male, occupational exposure
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified
in parentheses
human, male, occupational exposure
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified
in parentheses
human, male, occupational exposure
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified
in parentheses
human, male, occupational exposure
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified
in parentheses
human, male, occupational exposure
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified
in parentheses
AD-11
AD-12
AD-13
AD-13
AD-13
AD-13
AD-13
-------
Trichloroethylene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroethanol, cont.)
00
00
256.7 mg/L
(45 ppra
exposure)
267.3 mg/L
(50 ppm
exposure)
307.7 mg/L
(60 ppm
exposure)
681.8 mg/L
(120 ppm
exposure)
973.1 mg/L
(175 ppm
exposure)
1.7 ug/ml
(1st exposure
day)
2.1 ug/ml
(2nd exposure
day)
human, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified
in parentheses
human, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified
in parentheses
human, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified
in parentheses
human, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified
in parentheses
human, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified
in parentheses
human, male, 50 ppm inhalation AD-16
exposure, 6 hrs/day for 5
days. Trichloroethanol level
was measured daily, nonglucuronized
fraction only. Figures represent
maximum levels attained.
human, male, 50 ppm inhalation AD-16
exposure, 6 hrs/day for 5
days. Trichloroethanol level
was measured daily, nonglucuronized
fraction only. Figures represent
-------
Trichloroethylene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroethanol, cont.)
NJ
00
VO
2.2 ug/ml
(3rd exposure
day)
2.3 ug/ml
(4th exposure
day)
2.3 ug/ml
(5th exposure
day)
1.28-2.85 ug/ml
(1st exposure
day)
1.44-2.91 ug/ml
(2nd exposure
day)
human, male, 50 ppm inhalation
exposure, 6 hrs/day for 5
days. Trichloroethanol level
was measured daily, nonglucuronized
fraction only. Figures represent
maximum levels attained.
human, male, 50 ppm inhalation
exposure, 6 hrs/day for 5
days. Trichloroethanol level
was measured daily, nonglucuronized
fraction only. Figures represent
maximum levels attained.
human, male, 50 ppm inhalation
exposure, 6 hrs/day for 5
days. Trichloroethanol level
was measured daily, nonglucuronized
fraction only. Figures represent
maximum levels attained.
AD-16
AD-16
AD-16
AD-17
humans, male and female, 48 ppm
inhalation exposure, 4 hrs/day
for 5 days. Blood levels of Trichloroethanol
were determined daily during
and after exposure.
humans, male and female, 48 ppm AD-17
inhalation exposure, 4 hrs/day
for 5 days. Blood levels of trichloroethanol
were determined daily during
and after exposure.
-------
Trichloroethylene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroethanol, cont.)
2.01-2.53 ug/ml
(3rd exposure
day)
1.57-2.58 ug/ml
(4th exposure
day)
1.97-2.87 ug/ml
(5th exposure
day)
0.51-2.11 ug/ml
(1st day post-
exposure )
0.18-0.51 ug/ml
(2nd day post-
exposure)
humans, male and female, 48 ppm AD-17
inhalation exposure, 4 hrs/day
for 5 days. Blood levels of trichloroethanol
were determined daily during
and after exposure.
humans, male and female, 48 ppm AD-17
inhalation exposure, 4 hrs/day
for 5 days. Blood levels of trichloroethanol
were determined daily during
and after exposure.
humans, male and female, 48 ppm AD-17
inhalation exposure, 4 hrs/day
for 5 days. Blood levels of trichloroethanol
were determined daily during
and after exposure.
humans, male and female, 48 ppm AD-17
inhalation exposure, 4 hrs/day
for 5 days. Blood levels of trichloroethanol
were determined daily during
and after exposure.
humans, male and female, 48 ppm AD-17
inhalation exposure, 4 hrs/day
for 5 days. Blood levels of trichloroethanol
were determined daily during
and after exposure.
-------
Trichloroethylene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroethanol, cont.)
0.03-0.27 ug/ml
(3rd day post-
exposure )
0.05-0.14 ug/ml
(4th day post-
exposure)
0.03-0.08 ug/ml
(5th day post-
exposure)
0.05 ug/ml
(6th day post-
exposure)
0.03 ug/ml
(7th day post-
exposure )
0.71-1.78 ug/ml
(immediately
after exposure)
humans, male and female, 48 ppm AD-17
inhalation exposure, 4 hrs/day
for 5 days. Blood levels of trichloroethanol
were determined daily during
and after exposure.
humans, male and female, 48 ppm AD-17
inhalation exposure, 4 hrs/day
for 5 days. Blood levels of trichloroethanol
were determined daily during
and after exposure.
humans, male and female, 48 ppm AD-17
inhalation exposure, 4 hrs/day
for 5 days. Blood levels of trichloroethanol
were determined daily during
and after exposure.
humans, male and female, 48 ppm AD-17
inhalation exposure, 4 hrs/day
for 5 days. Blood levels of trichloroethanol
were determined daily during
and after exposure.
humans, male and female, 48 ppm AD-17
inhalation exposure, 4 hrs/day
for 5 days. Blood levels of trichloroethanol
were determined daily during
and after exposure.
human, female, 40 or 44 ppm
inhalation exposure. Refer to
reference AD-17 for additional
details and data.
AD-17
-------
Trichloroethylene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroethanol, cont.)
0.47-0.70 ug/mL
(24 hrs from
start of
exposure)
less than 0.12
ug/ml (96 hrs
from start of
exposure)
0.78-1.32 ug/ml
(immediately
after expsoure)
0.24-0.55
ug/ml
(24 hrs from
start of
exposure)
trace (96 hrs
from
start of
exposure)
2.0 ug/ml
(maximum
level attained
during exposure)
human, female, 40 or 44 ppm
inhalation exposure. Refer to
reference AD-17 for additional
details and data.
human, female, 40 or 44 ppm
inhalation exposure. Refer to
reference AD-17 for additional
details and data.
human, male, 40 or 44 ppm
inhalation exposure. Refer to
reference AD-17 for additional
details and data.
human, male, 40 or 44 ppm
inhalation exposure. Refer to
reference AD-17 for additional
details and data.
human, male, 40 or 44 ppm
inhalation exposure. Refer to
reference AD-17 for additional
details and data.
human, male, 50 ppm inhalation
exposure, 6 hours/day, 5 days
2.5 ug/mL human, male, inhalation
(maximum exposure, 12 mins/hrs, 6 hrs/
level attained day 5 days
during exposure)
AD-17
AD-17
AD-17
AD-17
AD-17
AD-18
AD-18
-------
Trichloroethylene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroethanol, cont.)
VO
OJ
trichloracetic acid
15-20%
(4 days)
15%
10-15%
13-25%
19%, total
amount ex-
creted (387
hrs, avg.)
31.9%
(3 weeks)
17.7%
(several
weeks)
32.6%
(6 days)
43.9%
(6 days)
5.0 ug/ml human, male, 100 ppm inhalation AD-18
(maximum level exposure, 6 hrs/day, 5 days
attained during
exposure)
dog, dose and method not stated
rat, oral administration, dose
not stated
rat, 38C1_TCE> dose not stated;
administered by stomach tube
calf, 3 or 12 g, oral, daily for
4 or 5 days
humans, male and female, 500-850
ug/L inhalation exposure for
8 hours
AD-14
AD-14
AD-14
AD-14
and
AD-15
AD-9
humans, male and female, AD-10
1042 ug/L inhalation exposure
for 8 hours
humans, male, 54 or 97 ppm AD-3
inhalation exposure for 8 hours
humans, male, 250-380 ppm inhalation AD-4
exposure, 160 minutes
humans, female, 250-380 ppm
inhalation exposure, 160 minutes
AD-4
-------
Trichloroethylene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroacetic acid, cont.)
21.9%
(100 hrs)
18.1%
(100 hrs)
30.1%
(16 or 21
days)
12.7 mg/L
(3 ppm
exposure)
20.2 mg/L
(5 ppm
exposure)
17.6 mg/L
(10 ppm
exposure)
77.2 mg/L
(25 ppm
exposure)
humans, male, 170 ppm inhalation AD-11
exposure for 3 hours
humans, male, 170 ppm inhalation AD-11
exposure for 7 hours (with a
1-hour break)
humans, female, 1 mg/L AD-12
inhalation exposure for 5 hours
humans, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
humans, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
humans, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
humans, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
-------
Trichloroethylene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroacetic acid, cont.)
90.6 mg/L
(40 ppm
exposure)
138.4 mg/L
(45 ppm
exposure)
146.4 mg/L
(50 ppm
exposure)
155.4 mg/L
(60 ppm
exposure)
230.1 mg/L
(120 ppm
exposure)
235.8 mg/L
(175 ppm
exposure)
humans, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
humans, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
humans, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
humans, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
humans, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
humans, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
-------
Trichloroethylene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroacetic acid, cont.)
17 ug/ml
(1st exposure
day)
30 ug/ml
(2nd exposure
day)
38 ug/ml
(3rd exj-v.sure
day)
45 ug/ml
(4th exposure
day)
52 ug/ml
(5th exposure
day)
2.4 mg/100 ml
of plasma
(3rd day
post-exposure)
0.5 mg/100 ml
of red cell
mass (3rd day
post-exposure)
humans, male, 50 ppm inhalation AD-16
exposure, 6 hours/day for 5 days.
Figures represent maximum levels
attained daily in plasma.
humans, male, 50 ppm inhalation AD-16
exposure, 6 hours/day for 5 days.
Figures represent maximum levels
attained daily in plasma.
hunians, male, 50 ppm inhalation AD-16
exposure, 6 hours/day for 5 days.
Figures represent maximum levels
attained daily in plasma.
humans, male, 50 ppm inhalation AD-16
exposure, 6 hours/day for 5 days.
Figures represent maximum levels
attained daily in plasma.
humans, male, 50 ppm inhalation AD-16
exposure, 6 hours/day for 5 days.
Figures represent maximum levels
attained daily in plasma.
humans, male and female, AD-20
1042 ug/L inhalation exposure
for 5 hours
humans, male and female, AD-20
1042 ug/L inhalation exposure
for 5 hours
-------
Trichloroethylene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(trichloroacetic acid, cont.)
monochloroacetic acid
total trichloro-compounds
5-8%
(4 days)
4%
1%
4%,
total amount
excreted (112
hrs. av g. )
39.4 mg/L
(3 ppm
exposure)
45.6 mg/L
(5 ppm
exposure)
60.5 mg/L
(10 ppm
exposure)
dog, dose and method not stated
rat, inhalation exposure, dose not
stated
calf, 3 or 12 g, oral dose, daily
for 4 or 5 days
humans, male and female, 500-850
ug/L inhalation exposure for 8
hours
humans, male, occupational exposure
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
humans, male, occupational exposure
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
humans, male, occupational exposure
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
AD-14
AD-14
AD-14
and
AD-15
AD-9
AD-13
AD-13
AD-13
-------
Trichloroethylene (continued)
Breath
Urine
Blood
Comments
Ref.
Metabolites (cont.)
(total trichloro-compounds,
cont.)
ho
*£>
00
164.3 mg/L
(25 ppm
exposure)
324.9 mg/L
(40 ppm
exposure)
399.0 mg/L
(45 ppm
exposure)
418.9 mg/L
(50 ppm
exposure)
468.0 mg/L
(60 ppm
exposure)
915.3 mg/L
(120 ppm
exposure)
humans, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
humans, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
humans, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
humans, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
humans, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
humans, male, occupational exposure AD-13
(8 hrs/day, 6 days/week) to various
concentrations of TCE, specified in
parentheses
-------
Trichloroethylene (continued)
Breath
Urine
Blood
Comments
Ref.
Half-life of metabolites:
tr i ch1oroe thano1
trichloroacetic acid
monochloroacetic acid
24 hours
in 1st phase
of excretion
(first 3-4 days)
40 hours
in 2nd phase
of excretion
(second 7-9 days)
50 hours
in 1st phase
of excretion
(first 5 days)
70 hours
in 2nd phase
of excretion
(second 14 days)
15 hours
(total period
of excretion
was 112 hours,
avg. )
humans, male and female, 500-850 AD-9
ug/L inhalation exposure for
8 hours
humans, male and female, 500-850 AD-9
ug/L inhalation exposure for
8 hours
humans, male and female, 500-850 AD-9
ug/L inhalation exposure for
8 hours
humans, male and female, 500-850 AD-9
ug/L inhalation exposure for
8 hours
humans, male and female, 500-850 AD-9
ug/L inhalation exposure for
8 hours
Metabolite conjugates:
No data
No data
No data
-------
References for Appendix
A and B
300
-------
REFERENCES
A-l. Bray, H.G., S.P. James and W.V. Thorpe. 1958. Metabolism of some
omega-halogenoalkyl benzenes and related alcohols in the rabbit.
Biochem. J. 70: 570-579.
B-l. Bray, H.G., S.P. James, and W.V. Thorpe. 1958. Metabolism of some
w-halogenoalkylbenzenes and related alcohols in the rabbit.
Biochem. J. 70: 570-579.
B-2. Bray, H.G., T.S. Franklin, and S.P. James. 1959. The formation of
mercapturic acids: 3. N-acetylation of S-substituted cysteines in
the rabbit, rat and guinea pig. Biochem. J. 73: 465-473.
C-l. Williams, R.T. 1959. Chap. 8. The metabolism of halogenated
aromatic hydrocarbons. In: Detoxication Mechanisms. 2nd ed.
Chapman and Hall, Ltd. London, pp. 237-277.
C-2. Azouz, W.M., D.V. Parke and R.T. Williams. 1952. Fluorobenzene.
Spectrophotometric determination of the elimination of unchanged
halobenzenes by rabbits. A comparison of the oxidation in vivo of
fluorobenzene and of benzene. Biochem. J. 50: 702-706.
C-3. Spencer, B. and R.T. Williams. 1950. Metabolism of halogenoben-
zenes. A comparison of the glucuronic acid, ethereal sulfate and
mercapturic acid conjugations of chloro-, bromo- and iodobenzenes
and of the o-, m- and p-chlorophenols. Biosynthesis of o-, m- and
p-chlorophenylglucuronides. Biochem J. 47: 279-84.
C-4. Azouz, W.M., D.V. Parke and R.T. Williams. 1953. The determination
of catechols in urine and the formation of catechols in rabbits
receiving halogenobenzenes and other compounds. Dihydroxylation in
vivo. Biochem J. 55(1): 146-51.
C-5. Ruzo, L.O., S. Safe, and 0. Hutzinger. 1976. Metabolism of bromo-
benzene in the rabbit. J. Agric. Food Chem. 24(2): 291-293.
C-6. Zampaglione, N., D.J. Jollow, J.R.. Mitchell, B. Stripp, M. Hamrick
and J.R. Gillette. 1973. Role of detoxifying enzymes in bromo-
benzene-induced liver necrosis. J. Pharmacol Exp. Therap. 187(1):
218-227.
C-7. Jollow, D.J., and C. Smith. 1977. Chapter 4. Biochemical aspects
of toxic metabolites: formation, detoxication and covalent bind-
ing. In: Proceedings of the International Conference on Biological
Reactions and Intermediates, pp. 42-59.
C-8. Reid, W.P., B. Christie, G. Krishina, J.R. Mitchell, J. Moskowitz
and B.B. Brodie. 1971. Bromobenzene metabolism and hepatic
necrosis. Pharmacol. 6: 41-55.
301
-------
C-9 Sipes, I.G., P.L. Gigon and G. Krishna. 1974. Biliary excretion of
metabolites of b romob enz ene . Biochem. Pharmacol. 23(2): 451-455.
D-l Ahmed, A.E., V.L. Kubic and M.W. Anders. 1977. Metabolism of halo-
forms to carbon monoxide: I. In vitro studies. Drug Metabolism
and Disposition. 5(2): 198-204.
E-l. Bray, H.G., S.P. James and W.V. Thorpe. 1958. Metabolism of some
omega-halogenoalkylbenzenes and related alcohols in the rabbit.
Biochem. J. 70: 570-579.
F-l. Morgan, A., A. Black and D.R. Belcher. 1970. The excretion in
breath of some aliphatic halogenated hydrocarbons following adminis-
tration by inhalation. Ann. Occup. Hyg. 13: 219-233.
F-2. McCollister, D.D., W.H. Beamer, G.J. Atchison and H.C. Spencer.
1951. The absorption, distribution and elimination of radioactive
carbon tetrachloride by monkeys upon exposure to low vapor concen-
trations. J. Pharmacol. Exptl. Ther. 102: 112-124.
F-3. Paul, B.B. and D. Rubinstein. 1963. Metabolism of carbon tetra-
chloride and chloroform by the rat. J. Pharmacol. Exp. Ther.
141(2): 141-148.
F-4. Fowler, J.S.L. 1969. Carbon tetrachloride metabolism in the
rabbit. Brit. J. Pharmacol. 37(3): 733-7.
F-5. Fowler, J.S.L. 1970. Carbon tetrachloride metabolism in sheep and
in Fasicola hepatica. Br. J. Pharmac. 39: 599-607.
F-6. Moran, H.E. 1943. Determination of volatile halogenated hydrocar-
bons in blood. J. Industr. Hyg. Toxicol. 25(6): 243-248.
F-7. Bini, A., G. Vecchi, G. Vivoli, V. Vannini and C. Cessi. 1975.
Detection of early metabolites in rat liver after administration of
and CBrC^. Pharmacol. Res. Commun. 7(2): 143-149.
F-8. Butler, T.C. 1961. Reduction of carbon tetrachloride rn vivo and
reduction of carbon tetrachloride and chloroform in vitro by tissues
and tissue constituents. J. Pharmacol. Exp. Ther. 134(3) : 311-319.
G-l. Leadbeater, L. 1973. The absorption of ortho-chlorobenzylidene-
malononitrile (CS) by the respiratory tract. Toxicology and Applied
Pharmacology. 25(1): 101-10.
H-l. Spencer, B. and R.T. Williams. 1950. The metabolism of halogeno-
benzenes. A comparison of the glucuronic acid, ethereal sulfate and
mercapturic acid conjugations of chloro-, bromo- and iodo-benzenes
and of the o-, m- and p-chlorophenols. Biosynthesis of o-, m- and
p-chlorophenylglucuronides. Biochem J. 47: 279-284.
302
-------
H-2. Smith, J.N., B. Spencer, and R.T. Williams. 1950. The metabolism
of chlorobenzene in the rabbit. Isolation of dihydrodihydroxy-
chlorobenzene, p-chlorophenylglucuronide, 4-chlorocatechol glucuro-
nide and p-chlorophenylmercapturic acid. Biochem. J. 47: 284-293.
H-3. Azouz, W.M., D.V. Parke and R.T. Williams. 1953. The determination
of catechols in urine and the formation of catechols in rabbits
receiving halogenobenzenes and other compounds. Biochem. J.
55(1): 146-151.
H-4. Williams, R.T. 1959. Chapter 8: The metabolism of halogenated
aromatic hydrocarbons. In: Detoxication Mechanisms, 2nd ed. John
Wiley and Sons, Inc., New York.
1-1. Charlesworth, F.A. 1976. Patterns of chloroform metabolism. Food
Cosmet. Toxicol. 14(1): 59-60.
1-2. Brown, D.M., P.P. Langley, D. Smity et al. 1974. Metabolism of
chloroform - I. Metabolism of ^C-chloroform by different
species. Xenobiotica 4(3): 151-163.
1-3. Fry, B.J., T. Taylor and D.E. Hathway. 1972. Pulmonary elimination
of chloroform and its metabolites in man. Arch. Int. Pharmacodyn
196: 98-111.
1-4. Morgan, A., A. Black and D.R. Belcher. 1970. The excretion in
breath of some aliphatic halogenated hydrocarbons following adminis-
tration by inhalation. Ann. Occup. Hyg. 13: 219-233.
J-l. Cornish, H.H. and W.D. Block. 1958. Metabolism of chlorinated
naphthalenes. Journal of Biological Chemistry. 23(2): 583-8.
J-2. Ruzo, L.O., S. Safe, D. Jones and N. Platonaw. 1976. Uptake and
distribution of chloronaphthalenes and their metabolities in pigs.
Bulletin of Environmental Contamination and Toxicology. 16(2):
233-9.
K-l. Bray, H.G., S.P- James and W.V. Thorpe. 1956. Metabolism of the
monochloronitrobenzenes in the rabbit. Biochem. J. 64: 38-44.
L-l. Bardodej, Z. 1976. Metabolic studies and the evaluation of genetic
risk from the viewpoint of industrial toxicology. Mutation
Research. 41: 7-14.
M-l. Parke, D.V. and R.T. Williams. 1955. The metabolism of halogeno-
benzenes. (a) meta-Dichlorobenzene. (b) Further observations on
the metabolism of chlorobenzene. Biochem. J. 59: 415-422.
M-2. Azouz, W.M., D.V. Parke and R.T. Williams. 1955. The metabolism of
halogenobenzenes. ortho and para-Dichlorobenzenes. Biochem. J.
59: 410-415.
303
-------
N-l. Yllner, S. 1971. Metabolism of 1,2-dichloroethane-14C in the
mouse. Acta pharmacol. et toxicol. 30: 257-265.
N-2. Nachtomi, E., E. Alumot and A. Bondi. 1966. The metabolism of
ethylene dibromide in the rat. I. Identification of detoxification
products in urine. Israel J. Chem. 4: 239-246.
0-1. Reichert, D. and H.W. Werner. 1978. Disposition and metabolism of
(l^C)l,1-dichloroethylene after single oral administration in
rats. Naunyn-Schmiedebergs Arch. Pharmacol. V302, S. p. R22.
Abstract no. 87.
0-2. McKenna, M.J., J.A. Zempel, E.O. Madrid and P.J. Gehring. 1977.
The fate of (^C) vinylidene chloride following inhalation expos-
ure and oral administration in rats. Toxicol. Appl. Pharmacol.
41(1): p. 218. Abstract no. 206.
0-3. Jones, B.K. and D.E. Hathway. 1978. Differences in metabolism of
vinylidene chloride between mice and rats. Br. J. Cancer. 37:
411-417.
P-l. Bonse, G., T. Urban, D. Reichert and D. Henschler. 1975. Chemical
reactivity, metabolic oxirane formation and biological reactivity of
chlorinated ethylenes in the isolated perfused rat liver prepara-
tion. Biochem. Pharmacol. 24(19): 1829-1834.
Q-l. Heppel, L.A., P.A. Neal, B. Highman and V.T. Porterfield. 1946.
Toxicology of 1,2-dichloropropane (propylene dichloride). I.
Studies on effects of daily inhalations. J. Indus. Hyg. Toxicol.
28(1): 1-8.
Q-2. Hutson, D.H., J.A. Moss and B.A. Pickering. 1971. The excretion
and retention of components of the soil fumigant D-D and their
metabolites in the rat. Food Cosmet. Toxicol. 9(5): 677-680.
R-l. Murzakaev, F.G. 1963. Some data on the toxicity of a new insecti-
cide, hexachlorobutadiene, and its intermediate metabolic products.
Formakol i Toksikol. 26(6): 750-753.
R-2. Gul'ko, A.G. and L.M. Dranovskaya. 1967. Determination of hexa-
chlorobutadiene in biological substrates by a pulsed polarographic
method. Vop. Gig. Toksikol. Restits., Tr. Nauch. Sess. Akad. Med.
Nauk SSSR~:79-81.
S-l.
S-2.
T-l.
Jondorf, W.R., D.V. Parke and R.T. Williams.
hexachloroethane. Biochem. J. 65: 14p-15p.
1957- Metabolism of
Fowler, J.S.L. 1969. Some hepatotoxic actions of hexachloroethane
and its metabolites in sheep. Brit. J. Pharmacol. 35(3): 530-542.
DiVencenzo, G.D., M.L. Hamilton. 1975. Fate and disposition of
(l^C) methylene chloride in the rat. Toxicol. Appl. Pharmacol.
32(2): 385-393.
304
-------
T-2. Rodkey, F.L. and H.A. Collison. 1977. Biological oxidation of
(1*C) methylene chloride to carbon monoxide and carbon dioxide by
the rat. Toxicol. Appl. Pharmacol. 40(1): 33-38.
T-3. Stewart, R.D., T.N. Fisher, M.J. Hosko, J.E. Peterson, E.D. Baretta
and H.C. Dodd. 1972. Carboxyhemoglobin elevation after exposure to
dichloromethane. Science. 176(Apr21): 295-296.
T-4. Ratney, R.S., D.H. Wegman and H.B. Elkins. 1974. In vivo conver-
sion of methylene chloride to carbon monoxide. Arch. Environ
Health. 28(4): 223-226.
T-5. Miller, V.L., R.R. Engel and W.M. Anders. 1973. In vivo metabolism
of dihalomethanes to carbon monoxide (CO). Pharmacologist. 15(2):
190. Abstract no. 184.
T-6. Hogan, G.K., R.G. Smith and H.H. Cornish. 1976. Studies on the
microsomal conversion of dichloromethane to carbon monoxide.
Toxicol. Appl. Pharmacol. 37(1): 112. Abstract no. 49.
U-l. Glickman, A.H., C.N. Statham, A. Wu and J.J. Lech. 1977- Studies
on the uptake, metabolism, and disposition of pentachlorophenol and
petachloroanisole in rainbow trout. Toxicol. Appl. Pharmacol. 41:
649-658.
V-l. Parke, D.V. and R.T. Williams. 1960. Studies in detoxification.
81. The metabolism of halogenobenzenes: (a) penta- and hexachloro-
benzenes. (b) Further observations on 1:3:5-trichlorobenzene.
Biochem. J. 74: 5-9.
V-2. Koss, G. and W. Koransky. 1978. Pentachlorophenol in different
species of vertebrates after administration of hexachlorobenzene and
pentachlorobenzene. Env. Sci. Res. 12: 131-7.
W-l. Yllner, S. 1963. The metabolism of pentachloroethane and unsym-
metric tetrachloroethane. Proc. XIV. Int. Congr. Occupat. Health.
Madrid. 825-827.
W-2. Fowler, J.S.L. 1969. Some hepatotoxic actions of hexachloroethane
and its metabolites in sheep. Brit. J. Pharmacol. 35(3): 530-542.
W-3. Yllner, S. 1971. Metabolism of pentachloroethane in the mouse.
Acta pharmacol. et toxicol. 29(5-6): 481-489.
X-l. Kolhi, J., D. Jones and S. Safe. 1976. The metabolism of the
higher chlorinated benzene isomers. Can. Journ. Biochem. 54(3):
203-8.
X-2. Jondorf, W.R., D.V. Parke and R.T. Williams. 1958. Studies in
detoxification. 76: The metabolism of halogenobenzenes. 1:2:3:4-,
1:2:3:5- and 1:2:4:5-tetrachlorobenzenes. Biochem. Journ. 69(2):
181-9.
305
-------
Y-l. Morgan, A., A. Black and D.R. Belcher. 1970. The excretion in
breath of some aliphatic halogenated hydrocarbons following adminis-
tration by inhalation. Ann. Occup. Hyg. 33: 219-233.
Y-2. Yllner, S. 1971. Metabolism of 1,l,2,2-tetrachloroethane-14C in
the mouse. Acta pharmacol. et toxicol. 29: 499-512.
Y-3. Ikeda, M. and H. Ohtsuji. 1972. A comparative study of the excre-
tion of Fujiwara reaction-positive substances in urine of humans and
rodents given trichloro- or tetrachloro-derivatives of ethane and
ethylene. Br. J. Ind. Med. 29: 99-104.
Z-l. Daniel, J.W. 1963. The metabolism of 36Cl-labelled trichloro-
ethylene and tetrachloroethylene in the rat. Biochem. Pharmacol.
12: 795-802.
1-1. Bonse, G., T. Urban, D. Reichert and D. Henschler. 1975. Chemical
reactivity, metabolic oxerane formation, and biological reactivity
of chlorinated ethylenes in the isolated perfused rat liver prepara-
tion. Biochem. Pharmacol. 24(19): 1829-1834.
Z-3. Yllner, S. 1961. Urinary metabolites of l^C-tetrachloroethylene
in mice. Nature. 191: 820.
Z-4. Ikeda, M., and H. Ohtsuji. 1972. A comparative study of the excre-
tion of Fujiwara reaction - positive substances in urine of humans
and rodents given trichloro- or tetrachloro-derivatives of ethane
and ethylene. Brit. J. Ind. Med. 29(1): 99-104.
Z-5. Ogata, M., Y. Takatsuka, K. Tomokuni and K. Muroi. 1971. Excretion
of organic chlorine compounds in the urine of persons exposed to
vapours of trichloroethylene and tetrachloroethylene. Brit. J. Ind.
Med. 28(4): 386-391.
Z-6. Ikeda, M. and T. Imamura. 1973. Biological half-life of trichloro-
ethylene and tetrachloroethylene in human subjects. Int. Arch.
Arbeitsmed. 31(3): 209-224.
Z-7. Wolff, M.S. 1976. Evidence for existence in human tissues of
monomers for plastics and rubber manufacture. Environ. Health.
Perspect. 17: 183-187.
Z-8. Savolainen, H., P- Pfaffli, M. Tengen and H. Vainio. 1977. Bio-
chemical and behavioral effects of inhalation exposure to tetra-
chloroethylelne and dichlormethane. J. Neuropathol. Exp. Neurol.
36(6): 941-949. ~~
AA-1. Jondorf, W.R., D.V. Parke and R.T. Williams. 1955. Studies in
detoxification: 66. The metabolism of halogenobenzenes. 1:2:3-,
1:2:4- and 1:3:5-trichlorobenzenes. Biochem. J. 61(3): 512-520.
306
-------
AA-2. Parke, D.V. and R.T. Williams. 1960. Studies in detoxication:
81. The metabolism of halogenobenzenes: (a) penta- and hexachloro-
benzenes. (b) Further observations on 1:3:5-trichlorobenzene.
Biochem. J. 74: 5-9.
AB-1. Hake, C.L., T.B. Waggoner, D.N. Robertson and V.K. Rowe. 1960. The
metabolism of 1,1,1-trichloroethane by the rat. Arch. Environ.
Hlth. 1(23): 101-105.
AB-2. Ikeda, M. and H. Ohtsuji. 1972. A comparative study of the excre-
tion of Fujiwara reaction-positive substances in urine of humans and
rodents given trichloro- or tetrachloro-derivatives of ethane and
ethylene. Brit. J. Ind. Med. 29(1): 99-104.
AB-3. Eben, A. and G. Kimmerle. 1974. Metabolism, excretion and toxi-
cology of methylchloroform in acute and subacute exposed rats.
Arch. Toxicol. 31: 233-242.
AB-4. Morgan, A., A. Black and D.R. Belcher. 1970. The excretion in
breath of some aliphatic halogenated hydrocarbons following admin-
istration by inhalation. Ann. Occup. Hyg. 13(4): 219-233.
AB-5. Astrand, I., A. Kilbom, I. Wahlberg and P. Ovrum. 1973. Methyl-
chloroform exposure: I. Concentration in alveolar air and blood
at rest and during exercise. Work-environ.-h1th. 10: 69-81.
AB-6. Stewart, R.D., H.H. Gay, A.W. Schaffer, D.S. Erley and V.K. Rowe.
1969. Experimental human exposure to methylchloroform vapor. Arch.
Environ. Hlth. 19: 467-472.
AB-7. Seki, Y., Y. Urashima, H. Aikawa, H. Matsumura, Y. Ichikawa, F.
Hiratsuka, Y. Yoskioka, S. Shimbo and M. Ikeda. 1975. Trichloro-
compounds in the urine of humans exposed to methylchloroform at
sub-threshold levels. Int. Arch. Arbeitsmed. 34(1): 39-49.
AB-8. Savolainen, H., P- Pfaffli, M. Tengen and H. Vainio. 1977. Tri-
chloroethylene and 1,1,1-trichloroethane: effects on brain and
liver after five days intermittent inhalation. Arch. Toxicol. 38:
229-237.
AB-9. Holmberg, B., I. Jakobson and K. Sigvardsson. 1977. A study on the
distribution of methylchloroform and n-octane in the mouse during
and after inhalation. Scand. j. work environ, and health 3: 43-52.
AC-1. Yllner, S. 1971. Metabolism of 1,1,2-trichloroethane-l,2~1^C in
the mouse. Acta pharmacol. et toxicol. 30: 248-256.
AC-2. Ikeda, M. and H. Ohtsuji. 1972. A comparative study of the excre-
tion of Fujiwara reaction-positive substances in urine of humans and
rodents given trichloro- or tetrachloro-derivatives of ethane and
ethylene. Brit. J. Ind. Med. 29(1): 99-104.
307
-------
AC-3. Morgan, A., A. Black and D.R. Belcher. 1970. Excretion in breath
of some aliphatic halogenated hydrocarbons following administration
by inhalation. Ann. Occup. Hyg. 13(4): 219-233.
AD-1. Waters, E.M., H.B. Gertsner and J.E. Huff. 1977- Trichloroethyl-
ene. I. An overview. J. Toxicol. Environ. Hlth. 2: 671-707.
AD-2. Daniel, J.W. 1963. The metabolism of 36Cl-labelled trichloro-
ethylene and tetrachloroethylene in the rat. Biochem. Pharmacol.
12(8): 795-802.
AD-3. Fernandez, J.G., B.E. Humbert, P.O. Droz and J.R. Caperos. 1975.
Trichloroethylene exposure. Percentage studies of absorption,
excretion and metabolism by human subjects. Arch. Mai. Prof.
36(7-8): 397-407.
AD-4. Nomiyama, K. and H. Nomiyama. 1971. Metabolism of trichloro-
ethylene in humans sex difference in urinary excretion of trichloro-
acetic acid and trichloroethanol. Int. Arch. Arbeitsmed. 28(1):
37-48.
AD-5. Nomiyama, K. and H. Nomiyana. 1977. Dose-response relationship for
trichloroethylene in man. Int. Arch. Occup. Environ. Hlth. 39:
237-248.
AD-6. Monster, A.C. G. Boersema and W.C. Duka. 1976. Pharmacokinetics of
trichloroethylene in volunteers, influence of workload and exposure
concentration. Int. Arch. Occup. Environ. Hlth. 38: 87-102.
AD-7. Astrand, I. 1975. Uptake of solvents in the blood and tissues of
man. A review. Scand. j. Work. Environ, and Health. 1: 199-218.
AD-8. Nomiyama, K. and H. Nomiyama. 1974. Respiratory elimination of
organic solvents in man. Benzene, toluene, n-hexane, trichloro-
ethylene, acetone, ethyl acetate and ethly alcohol. Int. Arch.
Arbeitsemd. 32: 85-91.
AD-9. Soucek, B. and D. Vlachova. 1960. Excretion of trichloroethylene
metabolites in human urine. Brit. J. Med. 17: 60-64.
AD-10. Bartonicek, V. 1962. Metabolism and excretion of trichloreo-
ethylene after inhalation by human subjects. Brit. J. Indus. Med.
19(2): 134-141.
AD-11. Ogata, M., Y. Takatsuka and T. Katsumaro. 1971. Excretion of
organic chlorine compounds in the urine of persons exposed to
vapours of trichloroethylene and tetrachloroethylene. Brit. J. Ind.
Med. 28(4): 386-391.
AD-12. Bartonicek, V. and J. Teisinger. 1962. Effect of tetraethyl
thiuram disulphide (disulfiram) on metabolism of trichloroethylene
in man. Brit. J. Ind. Med. 19: 216-221.
308
-------
AD-13. Ikeda, M., H. Ohtsuji, T. Imaniura and Y. Komoike. 1972. Urinary
excretion of total trichloro-cotnpounds, trichloroethanol, and
trichloroacetric acid as a measure of exposure to trichloroethylene
and tetrachloroethylene. Br. J. Ind. Med. 29: 328-333.
AD-14. FAO/WHO. 1970. Toxicological evaluation of some extraction
solvents and certain other substances. 14^ report of the Joint
FAO/WHO Expert Committee on Food Additives, FAO Nutrition Meetings
Report Series No. 48A. pp. 121-128.
AD-15. Seto, T.A. and M.O. Schultze. 1975. Metabolixm of trichloro-
ethylene in the borine. Proc. Soc. Exptl. Biol. Med. 90: 314-316.
AD-16. Muller, G., M. Spassowski and D. Henschler. 1972. Trichloro-
ethylene exposure and trichloroethylene metabolites in urine and
blood. Arch. Toxicol. 29(4): 335-340.
AD-17. Kimmerle, G. and A. Eben. 1973. Metabolism, excretion and toxi-
cology of trichloroethylene after inhalation. 2. Experimental
human exposure. Arch. Toxicol. 30(2): 127-138.
AD-18. Ertle, T., D. Henschler, G. Muller and M. Spassowski. 1972.
Metabolism of trichloroethylene in man. I. The significance of
trichloroethanol in long-term exposure conditions. Arch. Toxicol.
29: 171-188.
309
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TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
1. REPORT NO.
2.
3. RECIPIENT'S ACCESSIOf*NO.
4. TITLE AND SUBTITLE
Metabolism Summaries of Selected Halogenated Organic
Compounds in Human and Environmental Media, A Literature
Survey
5. REPORT DATE
June, 1979
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
R. Huffman, C. Latanich, T. Collins, J. Caldwell,
J. Wiese
8. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND AOOHESS
Tracor Jitco
1776 E. Jefferson St.
Rockville, MD 20852
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
68-01-4116, Research
Request 19
12. SPONSORING AGENCY NAME AND ADDRESS
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, D.C. 20460
13. TYPE OF REPORT AND PERIOD COVERED
Final
14. SPONSORING AGENCY COOE
IS. SUPPLEMENTARY NOTES
16. ABSTRACT
In response to growing concern about halogenated hydrocarbons (HHC's) identified
as environmental pollutants and potential health hazards, the Office of Program
Integration and Information's Monitoring Division is currently conducting a
preliminary assessment of HHC's in man and environmental media. This report, which
represents an initial effort in the program, is a summary of the available information
on the metabolism of 49 selected HHC's. It includes 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. The report includes, as an appendix, a tabulary summary of the
experimental data reported.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
Metabolism
Metabolites
Metabolic pathways
Halogenated hydrocarbons
Halocarbons
3. DISTRIBUTION STATEMENT
19. SECURITY CLASS (This Report)
21. NO OF PAGES
309
20. SECURITY CLASS (This page)
22. PRICE
EPA Form 2220-1 (9-73)
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