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Annual report : National Institute of Environmental Health Sciences (Volume 1985) online

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the methyl group of 2- creso1 • Unlike the feces, the bile contained mostly neta-
bolites with trace amounts )f TOCP detected at only 12 and 24 nr following
application. o-Cresyl dihydrogen ohosphate and di-o- cresyl hydrogen phosphate
were the prevaTant metabolites in the bile at all time points. Di-o-cresyl
hydrogen ohosphate and _o-cresyl dihydrogen phosphate were the major netabolites
in the plasma while dihydroxymethyl TOCP was present in trace amounts. An
appreciable amount of saligenin cycl ic-o-tolyl phosphate, which is believed to
be the active neurotoxic metabolite, was detected in the plasma.

SIGNIFICANCE TO BIOMEDICAL RESEARCH AND THE PROGRAM OF THE INSTITUTE : 2,5-HD
is believed to be the ultimate neurotoxic metabolite of the industrial neuro-
toxic solvents n-hexane and methyl -n-butyl ketone. These chemicals have been
widely jsed in Various industries, Therefore potential for human exposure is
high. Since these chemicals have been shown to cause neurotoxicity in humans
as ■''e 11 as in laboratory animals, it -/as of interest to determine the fate )f
the active metabolite in the highly sensitive spec'es '.chicken) and the less
sensitive species (rats). The objective of this work has been to determine
which species, rat or chicken, serves as the best model for human exoosure. It
was also of interest to determine the pharmacokinetics and disposition of this
neurotoxic metabolite in various species.

TOCP as well as many other organophosphorus compounds are known to cause a
toxic condition described as organophosphorus induced delayed neurotoxicity
(OPIDN). Some animal species (e.g., chickens, cats and humans) are sensitive
while others (e.g. rats and mice) are not. This study was initiated to
investigate the pharmacokinetics and metabolism of TOCP as a model compound
for OPIDN in sensitive and insensitive species. This may give us a better
understanding of the mechanism by which this group of organophosphorus compounds
cause their effect and thus help in protecting man and his domestic animals
from the toxic effect of these chemicals.

PUBLICATIONS

Nomeir, A. A. and Abou-Donia, M. B. : Analysis of 2 _nexarie anfl related
chemicals by capillary gas chromatograohy and high-performance liquid chroma-
tography. Anal . Biochem. In press.

Nomeir, A. A. and Abou-Donia, M. B. : Studies on the metabolism of the neuro-
toxic tri-o- cresyl phosphate I - synthesis and identification by infrared,
proton nucTear magnetic resonance and mass spectrometry of five of its
metabolites. Toxicology . In press.

Nomeir, A. and Abou-Donia, M.B.: Studies on the metabolism of the neurotoxic
tri-o-cresyl phospohate II - distribution, excretion and metabolism in male
cats - after a single dermal application. Toxicology . In press.

Abou-Donia, M. B. and Nomeir, A. A.: The role of pharmacokinetics and metabolism
in species sensitivity to neurotoxic agents. Fundam . Appl . Toxicol . In press.



954



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT



PROJECT NUMBER



Z01 ES 21059-01 STB



PERIOD COVERED

October 1. 1984 to September 30. 1985



TITLE OF PROJECT \B0 characters or less Title must fit on one line between the borders )

Gastric Toxicity of Acrylic Acid Esters



-> ; i!NC;PAL INVESTIGATOR (List other orotessionai personnel belov. the Principal Investigator (Name title laboratory, md institute affiliation)



PI : Rurhan I . Ghanayem
H. B. Matthews



Staff Fellow TRTP, NIEHS
Research Chemist TRTP, NIEHS



COOPERATING UNITS (if any)



Chemical Pathology branch. TRTP. NIEHS

LAB/BRANCH

Systemic Toxicology Branch



SECTION

Chemical Disposition



INSTITUTE AND LOCATION

NTFHS, NTH, Rpsparrh -ianglp Park, NC 27709



TOTAL MAN-YEARS

0_6_



PROFESSIONAL



OTHER



0.0



CHECK APPROPRIATE BOX(ES)

□ (a) Human subjects

□ (a1) Minors

□ (a2) Interviews



□ .(b) Human tissues



fj (c) Neither



SUMMARY OF WORK (Use standard unreduced type Do not exceed the space provided )

The acute gastric toxicity of acrylic acid esters was studied in F 344 male
rats . Gavage administration of a single dose of ethyl acrylate (EtAc) or
methyl acrylate (MeAc) caused dose- and time-dependent mucosal and submucosal
edema and vacuolization of the tunica muscularis in the forestomach and sub-
mucosal edema in the glandular stomach. Equivalent sc or ip doses of EtAc did
not produce similar gastric lesions. Structure-toxi ci ty relationships
revealed that MeAc was a more potent gastric toxin than EtAc , while acrylic acid
and n-butyl acrylate were without effects. Gavage administration of equimolar
doses of the saturated analoges of acrylic acid esters (methyl propionate or
ethyl propionate) as well as methacrylic acid esters w ere without gastric toxi-
city. The gastric toxicity of acrylic acid esters was found to be dependent
upon both acrylate ester concentration in dose vehicle and the lipophi 1 icity of
the dose vehicle (corn oil vs water). Gavage administration of 14 consecutive
daily doses of EtAc produced no lesions in the glandular stomach, which indica-
tes that prolonged insult with EtAc resulted in adaptation of the glandular
stomach. On the other hand, similar treatment with EtAc caused a dose-dependent
mucosal edema associated with vesicles, mucosal hyperplasia and hyperkeratosi s,
submucosal edema and inflammation, vacuolization of tunica muscularis and muco-
sal erosions or ulcers.



955



PHS 6040 (Rev 1/84)



GPO 91 4-8IB



Z01 ES 21059-01 STB



PROJECT DESCRIPTION

METHODS EMPLOYED : This work applied gravimetric techniques for the evaluation
of gastric edema as well as histopathologic techniques for the evaluation and
characterization of gastric edema and other gastric lesions.

MAJOR BINDINGS AND PROPOSED COURSE : Methyl acrylate and ethyl acrylate caused
profound forestomach toxicity in F344 male rats. Structure-toxici ty relation-
ship studies revealed - 1) Methyl acrylate is more potent that EtAc, while acry-
lic acid and n-butyl acrylate were without effects, 2) The structural
requirements for acrylic acid esters to cause gastric lesions include an intact
ester molecule, a double bond, snd no substitution at carbon number 2. Addi-
tional studies indicated that gastric toxicity may be attributed to the intact
ester mi le or to metabolite(s) other than products of carboxylesterase-
mediated hydrolysis ''acrylic acid and alcohol) and that gastric toxicity is
dependent upon both acrylate ester concentration in dose vehicle and the
1 ipophi 1 icity of the dose vehicle (corn oil vs. water). Glandular stomach
lesions observed after 1,2 or 4 daily gavage doses of 200 mg/kg of EtAc to F344
male rats include submucosal edema and inflammation. These lesions were not
observed following 14 daily gavage doses. Therefore, it appears as if the glan-
dular stomach became resistant to repeat EtAc gavage exposure with no apparent
gastric alterations observed after 14 daily gavage exposures. On the other
hand, forestomach lesions observed after 1,2 or 4 daily gavage doses of 200
mg/kg of EtAc to F344 rats include mucosal edema and inflammation, vacuolization
of tunica muscularis and mucosal erosions or ulcers. The forestomach adapted to
the continuous insult by the development of a dose-dependent inflammation,
hyperplasia and hyperkeratosis after 14 daily gavage doses of EtAc. The nature
of this adaptation and the mechanisms involved in their induction by EtAc are
currently being investigated.

SIGNIFICANCE TO BIOMEDICAL RESEARCH AND THE PROGRAM OF THE INSTITUTE : Acrylic
acid esters are widely used in the production of polymers and copolymers for
use in the preparation of latex paints, textiles, paper coating and specialty
plastics. In a recent study conducted by the NTP, chronic administration of
EtAc in corn oil by gavage resulted in a compound-related increase in the inci-
dences of hyperkeratosis, inflammation and hyperplasia of the forestomach in
the 13-week and 2-year studies. In the 2-year studies, EtAc caused squamous
cell papillomas and squamous cell carcinomas of the forestomach of both sexes of
F344 rats and B6C3F1 mice. The present studies provide a greater insight into
the mechanism of the chronic toxicity of EtAc, valuable information about the
structure toxicity relationships of all acrylic acid esters, and indicate a role
of metabolic activation in the acute gastric toxicity caused by these important
industrial chemicals.

PUBLICATIONS

Ghanayem, B. I., Maronpot, R. R. and Matthews, H. B. (1985) Ethyl acrylate-
induced gastric toxicity I. Effect of single and repetitive dosing. Toxicol.
Appl. Pharmacol. (In press).



956



5



701 ES 21059-01 STB



Ghanayem, 3. I., Maronpot, R. R. and Matthews, H. S. (1985) Ethyl acrylate-
induced gastric toxicity II. Structure-toxicity relationships and mechanism.
Toxicol. Appl. Pharmacol. (In press).



957



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT



PROJECT NUMBER

Z01 ES 21060-01 STB



PERIOD COVERED

October 1, 1984 to September 30, 1985



TITLE OF PROJECT (80 characters or less Title must tit on one line between the borders )

Ethyl Aery! ate Metabolism and the Metabolic Basis of Gastric Toxicity

PRINCIPAL INVESTIGATOR (List other orotessional personnel below the Principal Investigator I (Name, title, laboratory, and institute attiliauoni



PI



Burhan I. Ghanayem
H. B. Matthews



Staff Fellow T RTP, NIEHS
Research Chemist TRTP, NIEHS



COOPERATING UNITS (it any)



LAB/BRANCH

Systemi : Toxicol ' '■•inch



SECTION

Chemical Disposition



INSTITUTE AND LOCATION

NIEHS, MIH, Research Triangle Park, N C 27709






TOTAL MAN-YEARS

0.3



PROFESSIONAL

0.3



OTHER



0.0



CHECK APPROPRIATE BOX(ES)

□ (a) Human subjects
] (al) Minors
. (a2) Interviews



(b) Human tissues (c) Neither



SUMMARY OF WORK (Use standard unreduced type Do not exceed the space provided I



The absorption, distribution, covalent b inding and excretion of 2, 3-^C-ethyl

EtAC was readily absorbed,



rats.



acrylate (EtAc) was studied in F344 male

distributed to all tissues, metabolized and excreted mainly in the expired air

as 14 C-C02 ( s 70% of the dose in 24 hours)

tJAireLeJ Tn the urine in \ hours as me re a



acid. Approximately i% of the administer
hours. The highest concentrations of rad
liver and kidneys respectively. Chemical
liver revealed that a -najor portion of th



1 iver wa s covalent! y boun'd to the protein
Twen ty - four hours after treatment, there
lent protein binding in the liver, while
mach. Mo significant binding to nucleic
1 iver.



3-5' of the adm inistered dose was
pturic acids of EtAC and acrylic
ed dose were excreted in the bile in 6
ioactivity fie re found in the stomach,
fractionation of the forestomach and
e radioactivity in the stomach and



fraction at 4" hours after treatment.



was a significant decline in EtAc cova-
there was no such decline in the sto-
acids was found in the stomach or the



953



PHS 6040 (Rev 1/84)



GPO 91 4-91 8



Z01 ES 21060-01 STB

PROJECT DESCRIPTION

METHODS EMPLOYED : This work utilized 14 C-labeled EtAc in order to quantitate
absorption, distribution, metabolism and clearance of EtAc in F344 male rats.
Tissue distribution was qtiantitated using a tissue oxidizer and scintillation
counting techniques. Covalent binding of EtAc to chemical fractions of tissues
(lipids, proteins and nucleic acids) was performed by a series of extractions
and centrifugations. Urine was analyzed by high performance liquid chroma-
tography for EtAc metabolites.

MAJOR FINDINGS AND PROPOSED COURSE : EtAc was readily absorbed from the stomach
[- 90% of the dose in 4 hours) of F344 male rats, distributed to all tissues
examined, and rapidly excreted in the expired air and in the urine. EtAc did
not bind to nucleic acids but did bind covalently to the protein of the Foresto-
mach and liver. The covalently bound radioactivity in the liver proteins
declined significantly between \ and 24 hours while no significant decline was
seen in the covalent binding of EtAc derived radioactivity forestonach proteins.
The major urinary metabolites of EtAc were the mercapturic acids of EtAc and
acrylic acid.

SIGNIFICANCE TO BIOMEDICAL RESEARCH AND THE PROGRAM OF THE INSTITUTE :

Ethyl acrylate is a major industrial chemical (250 million pounds/yr) which has
been identified as a potential carcinogen in a recent NTP bioassay. The present
investigation is designated to determine the fate of EtAc in the intact ani-
mal. This study identifies possible mechanisms of EtAc toxicity under con-
ditions of the NTP bioassay and provides data which will facilitate extrapolation
of NTP chronic toxicity results to human exposure conditions. These results can
be used to develop a risk/benefit ratio for EtAc and identify those exposure con-
ditions which are most likely to threaten human health.



959



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT



PROJECT NUMBER



Z01 ES 21070-02 STB



PERIOD COVERED

October 1, 1984 to September 30, 1985



TITLE OF PROJECT (80 characters or less Title must fit on one line between the borders )

TCDD Teratogenicity: Modulation in Mixtures



PRINCIPAL INVESTIGATOR (List other professional oersonnel below the Principal Investigator I (Name, title, laboratory, and institute affiliation}



PI: Linda S. Birnbaum



Research Microbiologist



TRTP NIEHS



Others: James C. Lamb Research Biologist
James D. McKinney Research Chemist
Martha Harris Head Technician
Robert M. Pratt Research Biologist



TRTP


NIEHS


LMB


NIEHS


TRTP


NIEHS


LRDT


NIEHS



COOPERATING UNITS (it any)



LAB/BRANCH



Systemic Toxicology Branch



SECTION



Chemical Disposition



INSTITUTE AND LOCATION



NIEHS. NIH. Research Triangle Park, NC 2709



t



TOTAL MAN-YEARS



2^3_



PROFESSIONAL

IL8_



OTHER

1.5



CHECK APPROPRIATE BOXlESI

□ (a) Human subjects
3 (a1) Minors
] (a2) Interviews



□ (b) Human tissues



[E (c) Neither



SUMMARY OF WORK fUse standard unreduced type Do not exceed the space provided )



TCDD (dioxin, 2
chemicals known
its most freque
nephrosis chara
sensitivity of
interaction of
Such chemicals
nyls , hormones
TCDD toxicity a
nistic hypothes



,3,7,8-tetrachlorodibenzo-jj-dioxin) is one of the most toxic
to man. Progressive weight loss and thymic atrophy are two of
nt toxic symptoms. The induction of cleft palate and hydro -
cterize the teratogenic response of mice to TCDD. Because of the
this response, we decided to use teratogenicity to measure the
TCDD and other compounds with which it occurs in the environment,
include polychlori nated di benzofurans , polychlorinated biophe -
such as thyroxi ns and hydrocortisone , and drugs. The effects on
re dependent upon chemical structure and may support a mecha -
is of TCDD toxicity.



960



PHS 6040 (Rev 1/84)



GPO 91 4-9I6



PROJECT 'DESCRIPTION

METHODS EMPLOYED: Female C57BL/6N (36) mice are mated overnight with proven
breeder male 3b mice. The presence of a vaginal plug defines gestation day 0.
The pregnant mice are treated orally once a day on days 10-13 with the com-
pounds of interest. On day 13, the dams are sacrificed, and the fetuses exa-
mined for cleft palate and kidney anomalies.

MAJOR FINDINGS AND PROPOSED COURSE : Hydronephrosis (HN) is the most sensitive
teratogenic response to TCTJD and related compounds in sensitive strains of mice.
At doses where cleft palate incidence is 0-10%, all the fetuses have affected
kidneys. A dose of 1 g/kg/day on gestation dsys 10-13 results in approximately
20% HN and no cleft palate. At 3 g/kg, the incidence of HN is essentially 100%
while the cleft palate incidence is 5-3%. As the dose of TCDD is raised to 4,5,
or 6 g/kg/day, the incidence of cleft palate is approximately 40%, 50-70%, and
30-100%. This very steep dose response is also observed wi th "CDF and other
related compounds.

The nature of the teratogenic interaction between TCDD and TCDF was shown to be
additive. One g of TCDD is approximately equal to 30 g of TCDF in the cleft
palate assay. The interaction between TCDD and 2,3,4,5,3' ,4'-hexachlorobiphenyl
(HCB), a relatively non- toxic, mixed inducer, PCB, is also additive.
Combination of 20 mg/kg HCB and 3 g/kg TCDD resulted in 40% cleft palate. While
20mg/kg HCB by itself failed to cause cleft palate, it did cause a low incidence
of HN. Higher doses of HCB did produce cleft palate: 60 mg/kg caused about 8%
cleft palate. Thus 1 g of TCDD is approximately equal to 20 mg of HCB.

Thyroid hormones seem to potentiate the teratogenicity of TCDD. Both T3 and T4
(thyroxine) enhance the induction of cleft palate. T3 is five times more potent
than T4. Treatment of pregnant mice with 250 g T3/kg and 3 g/kg TCDD
increased the incidence of cleft palate five times over that seen with TCDD
alone. Thyroid hormones themselves did not cause hydronephrosis or dioxin-like
cleft palate.

Hydrocortisone (HC), an adrenal glucocorticord, can also cause cleft palate.
However, the mechanism of HC-induced cleft palate involves generalized growth
retardation as opposed to the failure of programmed cell death involved in
dioxin-induced cleft palate. When doses which are at the threshold for cleft
palate induction, when given alone, i.e. 3 g/kg TCDD and 25 mg/kg HC, are given
in combination, all the fetuses are affected. This suggests a potent synergism.
However, morphometry of the palatal shelves late on gestation day 14 reveal that
in the combination- treated fetuses, the shelves look HC-like, not dioxin-like.
The mechanism of these interactions is under investigation.

The ability of chemicals to antagonize TCDD toxicity will also be studied. Such
compounds include thyroid antagonists, ^3, and certain anti- inflammatory drugs
2,4,6-tri iodophenol , a potential thyroid antagonist, had no effect on the TCDD
induction of cleft palate.

The nature of the interaction with other xenobiotics with which TCDD is found in
the environment will also be examined.

961



Z01 ES 21070-02 STB



SIGNIFICANCE TO BIOMEDICAL RESEARCH AND THE PROGRAM OF THE INSTITUTE : TCDD is an
extremely toxic chemical of jreat environmental concern. It is round in :om-
bination with many other chemicals. The toxicity of such mixtures needs to he
studied in an organized manner for predictive purposes and to help elucidate the
mechanism of its toxicity.

PUBLICATIONS:

Birnbaum, L.S., Weber, H., Harris, M.W., Lamb, J.C., and McKinney, J.D.: Toxic
interaction of specific polychlorinated biphenyls and 2,3,7,8-tetrachlorodi-
^enzo-o-dioxi n: Increased incidence of cleft palate in nice. Toxico l . Appl .
Pharmacol. 77 : I 1-302, 1985.

Weber, ' J ., Maris, '•'. W., Haseman, J.K., and "inhaum, L. S.: Teratogenic poten .

of 2,3,7,3-tetrachlorodibenzn-p-dioxin (TCDD), , , ,8-tetrac'nloro i

(TCDF), and TC -" IF combinations in C57Bh/6N mice. Tox. Letts. (In press.



962



DEPARTMENT OF HEALTH AND HUMAN SERVICES - PUBLIC HEALTH SERVICE
NOTICE OF INTRAMURAL RESEARCH PROJECT



PROJECT NUMBER



Z01 ES 21075-02 STB



PERIOD COVERED

October 1, 1984 to September 30, 1985



TITLE OF PROJECT (SO characters or less Title must tit on one line between the borders )

Xenobiotic Metabolism



PRINCIPAL INVESTIGATOR (List other professional personnel below the Principal Investigator I (Name, title, laboratory, and institute affiliation)

PI: Leo T. Burka Research Chemist TRTP NIEHS



Others: Burhan I. Ghanayem
C. P. Kool
Richard Smith



Staff Fellow
Research Chemist
Staff Fellow



TRTP NIEHS
TRTP NIEHS
TRTP NIEHS



COOPERATING UNITS (it any)



LAB/BRANCH

Systemic Toxicology Branch



SECTION

Chemical Disposition



INSTITUTE AND LOCATION

NIEHS. NIH. Research Triangle Park. NC 27709



TOTAL MAN-YEARS

UL



PROFESSIONAL

0.9



OTHER



0.8



CHECK APPROPRIATE BOX(ES)

□ (a) Human subjects

□ (a1) Minors

□ (a2) Interviews



□ (b) Human tissues



(c) Neither



SUMMARY OF WORK (Use standard unreduced type Do not exceed the space provided )

Four compounds either being tested or being considered for testing by the NTP
were investigated. Two major urinary metabol i tes of 1 ,2 -di hydro- 2,2,4 -tri-
me thylquinol i ne were identified as the 0-sulfate conjugate of 1 ,2-di hydro-S-
hy droxy -2,2, 4-tri me thy lquinoline . The chemical disposition and to some extent

of l-chloro-2-methylpropene and 3-chloro-2-methylpropene
The most noteworthy observation in these studies is that



the coval
were inve
about 33%
in the fi
found to
that the
quercetin



ent binding
sti gated,
of the dos
rst 6 hr.
be N-acetyl



natural ly-c
in vivo.



e of l-chloro-2-methy 1 propene is exhaled, unmetabol ized,
The major urinary metabolite of 3-chloro-2-methy Ipropene was
-S- (2-methylprop-2-enyl )-!_- cysteine . It was demonstrated
ccurring flavone, kaempferol , was hydroxylated to give



963



PHS 6040 (Rev 1/84)



GPO 91 4-91!



Z01 ES 21075-02 STB a



PROJECT DESCRIPTION



METHODS EMPLOYES : Metabolites were identified in biological samples using a
high performance liquid chromatograph (HPLC) equipped with a variable wave-
length UV detector and a radioactive flow detector. The chemical structures of
the metabolites were determined either by isolation using a preparative HPLC
column followed by nuclear magnetic resonance (NMR) and/or mass spectrometry
(MS) or by coelution on HPLC with an authentic sample. In some cases the meta-
bolite was chemically synthesized as further proof of structure. Chemical
disposition studies were carried out in glass metabolism cages; tissue radioac-
tivity was determined by oxidation to CO2 and liquids instillation counting.

MAJOR C INDING AND PROPOSED COURSE :

a) Major urinary netabol ites of l,2-dihydro-2,2,4-trimethyl quinol ine (TMQ)

in the rat - Two TMQ metabolites comprising 50 and 30 percent of the total
urinary radioactivity were isolated and purified using a reversed phase
comparative HPLC column with ammonium acetate buffer (Ph5)-acetoni trile as
the eluent. The NMR spectra of the metabolites were obtained at 300 MHz in
deuterium oxide. Exact mass determinations were obtained by FAB MS/MS. The
spectral data were most consistent with the major metabolite being either a
5_ or 7-oxygenated derivative of TMQ. The metabolite was conclusively iden-
tified as the 0-sulfate conjugate of l,2-dihydro-6-hydroxy-2,2,4-trimethyl-
quinoline by chemical synthesis. p-Anisidine was condensed with acetone using M
iodine as a catalyst to give l,2-(Jihydro-6-methoxy-2,2,4 trimethyl quinol ine. •
The methoxy grouD was converted to the free phenol using boron tribromide and
the phenol was subsequently converted to the 0-sulfate by reaction with
sulfur trioxide-oyridine complex. The HPLC retention time, UV spectrum and
NMR spectrum of the synthetic product was identical to the isolated compound.
The NMR and mass spectra of the second metabolite were consistent with a
mono-0-sul fate conjugate of 1, 2-dihydro-l,6-dihydroxy-2, 2, 4-trimethyl quinol ine.
The sulfate group is probably on the phenol oxygen rather than the N-oxide,
but this cannot be shown conclusively by the spectra alone. Attempted pre-
paration of the fi-0-sul fate-N-hydroxy compound by chemical oxidation was
unsuccessful .

b) Chemical disposition studies on chloromethyl propenes - The tissue distribu-
tion and excretion profiles of [ 14 C]-3-chloro-2 methyl propene (DVMC) and
[14c]-i-chloro-2-methyl propene (MAC) were determined at a single time
point (6 hr) and at one oral dose (150 mg/kg, corn oil) in male rats. In
both cases the highest tissue concentration of radioactivity was found in
the kidney forestomach and large intestine. A major part of the dose was
excreted in 6 hr - 35?. of MAC, mostly in the urine (21%) and 57% of DMVC
volatiles predominantly as expired volatiles (34%). The DMVC volatiles were
trapped on activated carbon filters, analyzed by HPLC, and found to be 96%
DMVC and 4% of a second, less polar compound that was not MAC.

There were four major urinary metabolites of MAC. The predominant one
(70-80% of the total) was identified by its nmr spectrum as a mercapturic
acid conjugate, N-acetyl-S-(2-methyl prop-2-enyl )-L-cysteine. The identity f
was substantiated by chemical synthesis from N-acetyl-L-cysteine and MAC in
aqueous sodium bicarbonate.

964



Z01 ES 21075-0 2 STB



There were five major urinary netabolites of DMVC. The predominant one
(35-40% of the total radioactivity) was investigated. It. is a very polar



Online LibraryNational Institute of Environmental Health ScienceAnnual report : National Institute of Environmental Health Sciences (Volume 1985) → online text (page 92 of 114)