United States
Environmental Protection
Agency
Health Effects Research
Laboratory
Research Triangle Park NC 27711
Research and Development
EPA-600/S1 -85-001 Feb. 1985
Project Summary
Investigation of the
Metabolism of Chlorinated
Hydrocarbons in Subhuman
Species
Carl C. Smith, Steven T. Cragg, Geraldine F. Wolfe, and Walter W. Weigel
The metabolic fate and pharmacoki-
netics of four common contaminants of
chlorinated drinking water were studied
in rats and rhesus monkeys. Rats ex-
creted single oral or intravenous (i.v.)
doses of 1,2,4-trichlorobenzene (TCB)
primarily in the urine and feces; tissue
levels were highest in the fat, kidneys,
and liver. In monkeys, excretion of TCB
following single oral or i.v. doses was
slower than in rats, and fecal excretion
was less important. In a subchronic
toxicity study with monkeys, TCB was
toxic at daily doses of 90 mg/kg body
weight or more and was lethal at 174
mg/kg. TCB at 90-174 mg/kg in-
creased hepatic enzyme activity in
monkeys, and these increases correlated
well with changes in urinary chlorgu-
anide metabolite profiles. In rats, the
toxicity of single oral doses of TCB was
decreased by pretreatment with pheno-
barbital and increased by pretreatment.
with 3-methylcholanthrene.
In rats, bromodichloromethane(BDC)
tended to accumulate in fat, especially
after i.v. administration. BDC given to
monkeys both i.v. and orally was ex-
creted primarily via the lung, with
metabolism probably accounting for
about 5% of the dose.
In monkeys receiving single i.v. or
oral doses of bis(2-chloroisopropyl)
ether (BCIE), no more than one-third of
the dose was recovered in the urine and
feces. Repeated 30-mg/kg oral doses
of BCIE to monkeys had toxic effects;
again, the lungs appeared to be an
important route of elimination. Monkeys
excreted single oral doses of bis(2-
chloroethyl) ether (BCEE) primarily in
the urine.
This Project Summary was developed
by EPA's Health Effects Research Labo-
ratory, Research Triangle Park, NC, to
announce key findings of the research
project that is fully documented in a
separate report of the same title (see
Project Report ordering information at
back).
Introduction
Rats and monkeys were used to study
the metabolic fate and pharmacokinetics
of four common halogenated organic
contaminants of chlorinated drinking
water: 1,2,4-trichlorobenzene (TCB); bro-
modichloromethane (BDC); bis(2-chloro-
isopropyl) ether (BCIE); and bis(2-chloro-
ethyl) ether (BCEE). Emphasis was on the
use of rhesus monkeys, because there is
evidence that, in general, monkeys are
more similar to man in their metabolism
of compounds than are other common
laboratory animals. The purpose of these
studies was to provide data useful in
judging the potential toxicity of these
contaminants to man.
Procedure
Studies with
1,2,4-Trichlorobenzene
Excretion and tissue distribution of TCB
following single oral or intravenous (i.v.)
doses were measured in young male
Charles River albino rats. The treatment
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solution contained 2.0 mg (0.45 fjC\
14C)1,2,4-TCB per ml of waterethanol:
Emulphor® (8:1:1, v/v/v). Rats (four per
treatment) were given this solution in an
oral dose of 10 mg/kg. Treatment groups
were sacrificed at 3,6,12,24,48,72, and
96 h post-treatment. Urine and feces
were collected at 24-h intervals or at
necropsy. The following tissues were
analyzed for total 14C activity by liquid
scintillation counting: whole blood, plas-
ma, liver, spleen, kidneys, lungs, heart,
testes, brain, fat, muscle, and (together
with their contents) stomach, small intes-
tine, cecum, and large intestine.
Excretion and blood levels of TCB
following single oral or i.v. doses (10
mg/kg b.w.) were measured in young
adult female rhesus monkeys (two per
treatment). Blood samples were taken
before treatment and at 1, 2, 4, 6, 8, 12,
24, 48, 72, and 96 h post-treatment.
Urine samples were collected at 6,8,12,
24,48, 72, and 96 h post-treatment, and
feces samples were collected at 24-h
intervals.
Subchronic oral TCB toxicity was
studied in rhesus monkeys. Initial dose
levels were 1, 5, and 25 mg/kg b.w. (five
monkeys per treatment). When after one
month these doses had not caused weight
loss, changes in clinical chemistry anal-
yses, or changes in urinary chlorguanide
metabolite profiles, an additional dose
level of 125 mg/kg was added. Of five
monkeys receiving this dose for a month,
one died after 15 days, one showed
temporary weight loss, and the remaining
three showed no signs or symptoms of
TCB toxicity. Therefore, after the second
month of the study, the 5- and 25-mg/kg
groups were divided in half and assigned
to two new dose levels, 90 and 174
mg/kg; the original control group was
continued. Weights and blood samples
were taken weekly. Urinary profiles of
chlorguanide metabolites were measured
monthly. After 12 weeks or at death,
animals were necropsied, and liver slices
were frozen for enzyme assays (described
below).
The chlorguanide metabolite profile
test, developed in this laboratory, is based
on the principle that the^activity of mixed
function oxidases (MFO) in the liver (the
P-450 system) can be estimated from the
profile of urinary metabolites of a com-
pound metabolized primarily by this
system. Chlorguanide (CG) is oxidized by
P-448 to chlorguanide triazine (CGT) and
by P-450 to p-chlorophenyl biguanide
(PBG). Parent CG is also excreted. Thus,
the urinary concentrations of CGT and
PBG can be used to estimate the relative
activities of P-448 and P-450 in the liver.
The relative activity of each monoxyge-
nase component can be measured by
comparing urinary levels of CGT and PBG
metabolites with levels of CG. We have
developed colorimetric and microbiologi-
cal methods for measuring CG, CGT, PBG
(after conversion to CGT), and total CG
metabolites. Through the use of radio-
labelled CG, a method for separating CG
and its metabolites using thin-layer
chromatography (TLC) was developed. In
the TCB subchronic toxicity study, CG,
CGT, and PBG were extracted and sepa-
rated from a two-day urine pool obtained
following a single oral dose of chlorgua-
nide hydrochloride(10 mg/kg b.w.), and
the radioactivity for each of the CG
metabolites was determined by liquid
scintillation counting.
Microsomal suspensions of monkey
liver samples were assayed for rates of
MFO (P-448 and P-450) activity, via N-
demethylation of aminopyrine and benz-
phetamine and hydroxylation of zoxazol-
amine and aniline.
In a study of the effects of MFO inducers
on the acute toxicity of TCB, groups of
four rats were pretreated with phenobar-
bital (in water, 75 mg/kg for 4 days),
Aroclor®* 1254 (in corn oil, 50 mg/kg.for
5 days), 3-methylcholanthrene(3-MC)(in
corn oil, 20 mg/kg for 2 days), water (2
ml/kg for 4 days), or corn oil (2 ml/kg for 5
days). TCB was administered 24 h after
the last pretreatment, in a single oral
dose of either 800 or 1000 mg/kg. Rats
were weighed daily until sacrifice 6 days
after dosing with TCB.
Studies with
Bromodichloromethane
In a pilot study of bromodichlorome-
thane tissue distribution, male Charles
River albino rats (two per treatment)
received 14C-BDC i.v. at 10 mg/kg or
orally at 20 mg/kg, with a specific activity
of 448 dpm//ug of BDC. Rats were sacri-
ficed at 3 and 6 h post-treatment. Urine
was collected until the animals were
sacrificed, and tissues were analyzed as
described above.
In a "crossover" study of BDC blood
levels, excretion, and tissue distribution,
two female rhesus monkeys received oral
or i.v. doses of 14C-BDC(10 mg/kg). One
animal received an i.v. dose initially and
•Mention of trade names or commercial products
does not constitute endorsement or recommenda-
tion for use.
oral doses 9 and 82 days later; the oth<
received an oral dose initially and i.
doses 9 and 82 days later. Blood sample
were taken before treatment and at 2, <
6,8,12, 24, and 48 h after the two initii
doses. Urine and feces samples were als
collected at 4,12,24, and 48 h. Followin
the final dose, blood samples were take
at 1, 2, 4, 6, 8, 12, and 24 h. Urine an
feces samples were collected over th
24-h period. After 24 h, the monkey
were necropsied, and tissue levels of14
were determined.
Studies with
Bis(2-chloroisopropyl) Ether
Blood levels, excretion, and tissu
distribution of 14C-BCIE were determine
in female rhesus monkeys followin
single oral or i.v. doses (30 mg/kg) with
specific activity of 88.68 dpm///g. On
animal in each treatment group wa
sacrificed after 4 h, and one additions
orally dosed animal was sacrificed after i
h. Blood samples were collected at 1,2,4
and 6 h, urine samples at 4 and 6 h, an
feces samples when available. The re
maining two animals in each treatmen
group were sacrificed after 168 h. Blooi
samples were taken before treatment, a
2, 4, 6, 8, 12, and 24 h post-treatment
and daily thereafter. Urine samples wen
collected at 4,6,8,12, and 24 h and dail<
thereafter. Feces samples were collectei
daily.
To test the effect of multiple oral doses
14C-BCIE (30 mg/kg) was given daily foi
three consecutive days to three femaU
rhesus monkeys. One animal receivec
only two doses, because of the severity o
toxic effects. One of the other two animal:
vomited an undetermined portion of tht
second dose. Blood samples were taker
before treatment and at 1,2,4,8, and 24
h post-treatment on days 1,2, and 3, daily
on days 4-10, and for one monkey also or
days 13,15, and 17. Urine samples were
collected at 12 and 24 h on day 1 and daily
thereafter. Feces were collected when-
ever available during days 1 -3, and 12
and 24 h on day 4, and daily thereafter.
Study with
Bis(2-chloroethyl) Ether
Two female rhesus monkeys received
single 10-mg/kg oral doses of 14C-BCEE
with a specific activity of 106.27 dpm/A/g
of BCEE. Urine samples were collected at
6, 12, 24, 36, 48, 72, and 96 h post-
treatment, and feces samples daily for 4
days.
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Results and Discussion
Excretion and Tissue
Distribution of TCB in Rats
Although single oral and i.v. doses of
"C-TCB to rats produced similar meta-
bolic patterns, tissue levels were higher
after i.v. administration. Following single
oral doses to rats, excretion of TCB and its
metabolites was approximately 95%
complete at 24 h post-treatment and
complete at 48 h. Mean urinary excretion
at 96 h was 85.1 %, and mean excretion in
the f eces was 14.9%. Approximately 96%
of the administered UC was accounted
for in the urine, feces, and analyzed
tissues after 12 h, and all of the dose was
accounted for after 24 h. Following single
i.v. doses, excretion was approximately
85% complete at 24 h and 95% complete
at 48 h. At 96 h, mean urinary excretion
was 83.2% of the dose, and mean excre-
tion in the feces was 12.4%.
In orally dosed rats, the highest tissue
levels were observed at 3 h. Outside of
the gastrointestinal (Gl) tract, 14C levels
were highest in the kidney, liver, plasma,
and fat. At 24 h, very little 14C was in the
stomach; about 3.5% of the dose was in
the rest of the Gl tract, and all other
tissues accounted for about 1% of the
dose. Some radioactivity persisted in the
fat, kidneys, and liver for at least 96 h
after single oral doses. Following i.v.
administration, maximum tissue levels
occurred at 3 or 6 h post-treatment; levels
were much higher in the fat than in any
other tissue analyzed (51.6 /jg/g at 3 h).
Prominent radioactivity in the intestines
at 3 h indicated biliary excretion of TCB or
its metabolites and probable enterohe-
patic circulation. At 24 h, 14C levels
exceeded 1 yug/g in the fat, liver, and
kidneys; at 96 h, radioactivity was still
appreciable in these tissues.
Pharmacokinetic Study of
TCB in Monkeys
Following a single i.v. dose of 14C-TCB
at 10 mg/kg, 14C levels in blood declined
very rapidly, from an estimated zero-time
level of about 112//g/ml to 2.0-2.9//g/ml
at 1 h post-treatment. In the one monkey
observed for 96 h, blood levels declined
gradually to 0.2 //g/ml. Peak blood levels
for orally treated monkeys were 3.0/*g/ml
at 1 h and 2.3 //g/ml at 2 h. For both
routes, plasma levels were slightly higher
than blood levels through about 2 h post-
treatment.
Urinary excretion following i.v. admin-
istration accounted for about 22% of the
dose at 24 h and 38% at 96 h. Following
oral administration, urinary excretion
levels were 36.7% and 39.8% at 24 h and
56.7% and 73.1 % at 96 h. It appears that
following i.v. dosing, TCB was rapidly
deposited in the fat, then slowly mobilized
and metabolized by the liver, whereas
following oral dosing, it was transported
first to the liver, where it was more rapidly
metabolized before entering the systemic
circulation. Fecal excretion was insignifi-
cant for both routes, accounting for less
than 4% of the dose. The low level of fecal
radioactivity following i.v. treatment pro-
vides indirect evidence that enterohepatic
circulation of TCB and its metabolites was
less in the monkey than in the rat.
Subchronic Toxicity of
TCB in Monkeys
Toxic effects of TCB were observed in
monkeys at all three dose levels. At 174
mg/kg, all four monkeys lost weight
rapidly, and two died after three weeks of
treatment. Treatment of the two surviving
monkeys was discontinued on day 25, at
which time the monkeys showed weak-
ness and tremors. After treatment was
discontinued, both monkeys began to gain
weight; however, one died during the
sixth week, apparently of acute gastric
dilatation due to overeating.
At the two lower doses, weight loss
was variable. At 125 mg/kg, three mon-
keys lost weight rapidly during the first
two weeks of treatment; one of these
animals died on day 16, and the other two
stabilized and then gained weight rapidly
during the remainder of the treatment
period. The fourth monkey showed a
gradual weight gain over the treatment
period, with only a slight weight loss
during weeks 7-8. At 90 mg/kg, one
monkey rapidly lost 2.5 kg during the first
4 weeks, then stabilized and gained
weight. The weight of a second monkey
remained relatively stable throughout the
period, though it declined slightly over the
last 4 weeks of treatment. The two
remaining monkeys at 90 mg/kg showed
moderate weight loss throughout the first
6-7 weeks. One of these monkeys then
gained weight rapidly during weeks 8-10.
The other died in'the seventh week;
however, the absence of definitive toxic
manifestations before death or at necrop-
sy suggests that the death may not have
been drug related. A possible explanation
for stabilization and weight gain following
initial weight loss is that the animals
responded by developing hepatic MFO
induction, thus reducing the effective
dose through increased metabolism of
TCB.
Hematocrit tended to decline gradually
in all TCB treatment groups, with subse-
quent increases after 5-7 weeks in the
monkeys receiving 90 and 125 mg/kg. In
the one surviving high-dose monkey
withdrawn from treatment, hematocrit
returned to the pretreatment value by the
end of the study.
Ratios of liver weight to body weight (at
sacrifice) were significantly higher in the
monkeys receiving TCB at 125 and 174
mg/kg than in the untreated controls.
The effect was less in the high-dose
group, all of whose members either died
or were withdrawn from treatment after 3
weeks. This ratio was also elevated in the
90-mg/kg monkey that died after 7
weeks, though not in the other animals at
that dose.
Comparison of chlorguanide metabolite
profiles between treatment groups and
the control group appeared to indicate a
significant decrease in percent CG in the
urine, a significant increase in percent
PBG, and no change in percent CGT
following treatment with TCB for 30 days.
However, large individual variation in
baseline (pretreatment) profiles gave rise
to large baseline differences among the
groups, especially in percent CG and
percent CGT. Comparison of the mean
change in the parameters (the post-
treatment value minus the baseline value
for each group) indicated that percent CG
decreased significantly in the 125 mg/kg
group and percent PBG increased signifi-
cantly in all three treatment groups. CGT
tended to decrease in all groups; this
decrease was statistically significant
when post-treatment values for the 90-
and 174-mg/kg groups were compared
with their own baseline values, but not
when change in CGT was compared
between each treatment group and the
control group. After 60 days' treatment,
the 90-mg/kg and 125-mg/kg groups
showed stabilization or partial reversal of
all changes in CG metabolite profile.
In Vitro Enzyme Assays of
Monkey Livers
Enzyme activity (as nanomoles per
minute per gram liver) was significantly
increased against all four substrates.
Mean increases over control values for
the 90- and 125-mg/kg groups ranged
from about 185% to 260%. The 174-
mg/kg dose also increased activity against
all four substrates, but interpretation of
the results is complicated by the general
toxicity of the dose and the cessation of
treatment after 3 weeks. MFO activity
was similarly increased in the 90- and
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125-mg/kg groups. Enzyme activities
were positively correlated with urinary
levels of PBG and were not significantly
correlated with urinary levels of CGT.
Inhibition and Potentiation of the
Hepatotoxicity of TCB in Rats
Following pretreatment with Aroclor,
two rats receiving TCB at 1000 mg/kg
died within 24 h after TCB administration,
and one receiving TCB at 800 mg/kg died
after 4 days. One rat induced with 3-MC
and given TCB at 1000 mg/kg died after 3
days. All other rats survived the observa-
tion period. Rats pretreated with Aroclor
or 3-MC lost more weight than did the
vehicle control rats, but rats pretreated
with phenobarbital lost less weight than
the controls. Weight loss reached a
maximum on days 3-4; all surviving rats
then began to gain weight. The most
severe liver damage occurred in the
groups that had lost the most weight; rats
pretreated with phenobarbital showed
less liver damage than did the controls.
Thus, phenobarbital decreased and 3-MC
increased the toxicity of single oral doses
of TCB in rats, probably through changes
in hepatotoxicity.
Pharmacokinetic Studies on
BDC in Rats
When 14C-BDC was given to rats i.v.,
accumulation in fat accounted for more
than 50% of the dose recovered in the
tissues. Elevated levels were also ob-
served in the liver, blood, plasma, kidneys,
and lungs. Small amounts of 14C in the Gl
tract suggested that the compound was
excreted in the bile. The distribution
pattern was very different following oral
administration: the compound was slow
to leave the stomach, levels in fat were
lower than observed following i.v. admin-
istration (6.9 vs. 24.4 fjg/g at 3 h), and
levels in the liver were higher (9.0 vs. 3.7
fjg/g at 3 h). The tissues accounted for
much less of the dose at 3 h when BDC
was given orally (8.6% vs. 25.5% after i.v.
administration); recovery in the urine was
higher.
Pharmacokinetics of'
BDC in Monkeys
Following i.v. administration of UC-
BDC to monkeys, blood levels fell rapidly
for the first 8 h and more gradually for the
next 40 h (from about 2 fjg/g at 1 h to
0.2-0.4 fjg/Q at 48 h). Blood levels were
more variable following oral dosing, peak-
ing at 4 h and declining in a pattern
similar to that seen following i.v. admin-
istration. Urinary excretion of 14C account-
ed for no more than about 6% of the dose
and was generally between 2 and 3%,
regardless of the route of administration.
Fecal excretion was 0.2-1.65% of the
dose. Little BDC appeared to be sequester-
ed in any tissue; levels were highest in
the bile, cecum, and liver by both routes,
and were slightly higher following oral
administration. BDC appeared to be ex-
creted primarily via the lung. Metabolism
of BDC probably accounted for no more
than about 5% of the dose.
Pharmacokinetics of
BCIE in Monkeys
Following a single i.v. dose of 1*C-BCIE,
blood levels dropped rapidly, from an
estimated zero-time level of about 330
jug/gto2-hvaluesof24.3-32.7//g/gand
12-h values of 8.4 fjg/g. Over the next 6
days, the levels declined gradually to
about 2.5 fjg/g. During the first 5 days,
plasma UC levels were slightly higher
than values for whole blood. Monkeys
receiving BCIE orally had peak values 2-4
h after administration, ranging from
21.8-26.1 A/g/g. The pattern of decline in
blood levels was similar to that observed
following i.v. administration; levels after
7 days were 1.2 and 1.9 fjg/g. Plasma and
blood levels were similar. Monkeys re-
ceiving BCIE i.v. excreted 28.6% and
34.8% of the dose in the urine; about half
of this amount was eliminated in 4 h.
After oral administration, urinary excre-
tion was 24% and 30.1% of the dose;
about half was eliminated by 8 h. Fecal
excretion was 1.2% and 6% of the i.v.
dose and 1.6% and 1.9% of the oral dose.
Thus, no more than one-third of the dose
administered by either route was recover-
ed in the urine and feces. The only organs
showing significant levels of 14C from
BCIE after 7 days were the liver and
kidneys. Fat also showed some sequester-
ing activity, and there appeared to be
some biliary excretion of BCIE or its
metabolites.
Multiple Dose Study of
BCIE in Monkeys
Two monkeys receiving three daily oral
doses of 14C-BCIE developed edema and
subdural hemorrhage in the tissues
around the eyes, while the third monkey
showed no ocular reaction to treatment.
All three monkeys lost weight. Weight
loss was greatest in the animals with
ocular symptoms, and these animals also
had decreased urine flow. One of the
monkeys exhibiting toxic symptoms also
had exhibited glucosuria and hypergly-
cemia before treatment began, and was
not given a third dose of BCIE. The other
monkey with toxic symptoms began men-
struation on the fifth day of the study, 14
days earlier than expected.
Peak blood levels of BCIE generally
occurred at 2 h post-treatment; 2-h values
ranged from 17.2-34 /Lig/ml. Levels drop-
ped rapidly during the next 6 h and more
slowly through the remainder of the 24-h
period. Residual radioactivity increased
with repeated doses; 24-h values ranged
from 5.0-8.9 //g/ml after the first dose,
7.8-10.5 //g/ml after the second, and 8.3-
14.9 fjg/m\ after the third. Plasma levels
of BCIE were consistently higher than
blood levels. The slopes of the dieaway
curves for both blood and plasma levels
appeared flatter on day 3 than previously.
The monkey exhibiting the most severe
toxic symptoms also had (after the second
dose) the highest peak blood concentra-
tion observed in the study (34 /yg/ml vs.
16.5 and 23.0 ;ug/ml in the other two
monkeys, one of which had vomited part
of this dose).
Urinary excretion of 14C was variable.
Only 30-45% of the dose was accounted
for in the urine and feces (no more than
4% in the feces), suggesting that the
lungs were an important route of elimina-
tion of this compound.
Pharmacokinetic Study of
BCEE in Monkeys
Two monkeys given 14C-BCEE orally
excreted about 43% of the dose in the
urine in 24 h post-treatment. One monkey
had excreted about 17% of the dose by 6 h
and about 30% by 12 h, while the other
monkey had excreted only 26.5 ml of
urine by 12 h, accounting for only 0.003%
of the administered dose. At 72 h, re-
coveries were 53.3% and 63.4%. Very
little radioactivity was recovered in the
feces (1.10% and 1.63% of the dose
through 96 h). The monkey with reduced
urine flow also showed hemorrhagic
darkening below the eyes, reduced food
consumption, and ketones in the urine,
and began menstruation at 24 h after
dosing.
Conclusions and
Recommendations
In rats, single oral doses of TCB were
excreted in the urine (85%) and feces
(15%). Tissue levels were highest in the
fat, kidneys, and liver. After i.v. admin-
istration, fat TCB levels were higher, and
excretion was slower. In monkeys, excre-
tion of TCB was slower than in rats, and
fecal excretion was less important. In
4
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subchronic studies with monkeys, TCB
had toxic effects at daily doses of 90
mg/kg body weight or more and was
lethal in about 25 days at 174 mg/kg.
TCB at 90-174 mg/kg increased liver
enzyme activity in monkeys. It is sug-
gested that the effect of TCB on hepatic
enzymes be tested in humans. Hepatic
enzyme induction results correlated well
with effects on chlorguanide metabolite
profiles, suggesting that the GC metabo-
lite profile test merits further trial as an in
vivo assay for hepatic drug-metabolizing
enzymes in humans. The toxicity of single
oral doses of TCB in rats was decreased
by pretreatment with phenobarbital and
increased by pretreatment with 3-MC;
these results were unexpected, and it is
suggested that the experiment be re-
peated.
BDC given to rats i.v. accumulated in
the fat; oral administration resulted in
lower levels in fat and higher revels in the
liver. In monkeys, BDC was excreted
primarily via the lung, with metabolism
probably accounting for no more than
about 5% of the dose. Additional studies
are needed to measure the chronic toxicity
of BDC in rats and monkeys and to char-
acterize the urinary metabolites.
When BCIE was given to monkeys
either i.v. or orally, no more than one-
third of the dose was recovered in the
urine and feces. BCIE persisted longest in
the liver, kidneys, and fat. Repeated 30-
mg/kg doses of BCIE to monkeys caused
toxic effects, including periocular irrita-
tion. Only 30-45% of the dose was
accounted for in the urine and feces,
suggesting that the lungs were an im-
portant route of elimination. Single oral
doses of BCEE were excreted primarily in
the urine (53-63% of the dose at 72 h);
toxic signs were seen at 10 mg/kg in one
of the two monkeys tested. The present
studies suggest that BCIE and BCEE may
affect the menstrual cycle in monkeys;
this possible effect should be tested. More
extensive metabolic and chronic toxicity
studies are needed to determine whether
renal and periorbital toxic effects are due
to these compounds or to metabolites.
Car 1C. Smith. Steven T. Cragg, GeraldineF. Wolfe, and Walter W. We/gel are with
University of Cincinnati, Cincinnati, OH 45267.
Robert Lingg is the EPA Project Officer (see below).
The complete report, entitled "Investigation of the Metabolism of Chlorinated
Hydrocarbons in Subhuman Species," (Order No. PB 85-152 387/AS; Cost:
$14.50, subject to change) will be available only from:
National Technical Information Service
5285 Port Royal Road
Springfield. VA 22161
Telephone: 703-487-4650
The EPA Project Officer can be contacted at:
Health Effects Research Laboratory
U.S. Environmental Protection Agency
Research Triangle Park, NC 27711
*USGPO: 1985-559-111/10787
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United States Center for Environmental Research
Environmental Protection Information
Agency Cincinnati OH 45268
Official Business
Penalty for Private Use $300
OC00329 PS
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