EPA 560/6-76-023 V
HEALTH AND ENVIRONMENTAL IMPACTS
TASK 1
VINYLIDENE CHLORIDE
OCTOBER 1976
FINAL REPORT
NMENTAL PROTECTION AGENCY
ICE OF TOXIC SUBSTANCES
WASHINGTON, D.C.
-------
EPA-560/6-76-023
HEALTH AND ENVIRONMENTAL IMPACTS
Task 1
VINYLIDENE CHLORIDE
October 1976
Final Report
Contract 68-01-4116
EPA Project Officer
William Coniglio
Environmental Protection Agency
Office of Toxic Substances
Washington, D.C. 20460
-------
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 indorsement or
recommendation for use.
-------
Table of Contents
Page
Summary 1
Tabular Summary 6
Introduction 11
Scope 12
Information Sources 12
Review of the Literature 13
Appendix A. Factors to be Identified 49
Appendix B. Sources Used in Vinylidene Chloride Search 51
Bibliography 52
-------
Summary
Virtually no information is available on the absorption and metabolism
of vinjrlidene chloride. Its oral and inhalation toxicity, however, indicates
that it is readily absorbed from the gastrointestinal and respiratory
tracts. Its fate following absorption has not yet been elucidated.
As: indicated by the tabular summary, the metabolic effects of vinyli-
dene chloride have received little study. It has been demonstrated, however,
that vinylidene chloride affects the activity of several enzymes, notably
hepatic glucose-6-phosphatase and serum alanine alpha-ketoglutarate trans-
aminase. The extent of the effect on these enzymes is modified by prior or
concurrent administration of enzyme inducing or inhibiting compounds such as
phenobarbital and 3-methylcholanthrene.
The acute toxicity of vinylidene chloride has received considerable
attention, but the results reported have been highly inconsistent. Four-
hour inhalation LC 's for rats ranging from 600 ppm (27) to 15,000 ppm
(25) have been reported. The lethal concentration has been found to vary
greatly with the dietary condition (fed or fasted) and the hepatic glutathione
content, which shows significant variations in a diurnal rhythm.
The pathological effects induced by vinylidene chloride are presented in
Figures 14 and 15. With each effect is listed the lowest dosage level at
which it: was observed, the period of exposure, the period of observation
(in parentheses), if longer than the period of exposure, and the bibliographic
reference number. Information from reports which observed the effect at
higher doses is listed in the footnotes.
The minimum effective concentration of vinylidene chloride has not been
clearly established. In 1971, the American Council of Government Industrial
Hygienists (3) set the TLV at 10 ppm. In 1972, the Manufacturing Chemists
3
Association (36) established a TLV of 5 mg/m (approx. 1.25 ppm). However,
Prendergast (42) observed toxic effects in animals exposed to vinylidene
3
chloride at 101 mg/m (26 ppm) for 90 days, and doubtful effects were
observed at 20 mg/m (5 ppm).
-------
Several studies have shown vinylidene chloride to be mutagenic to
S. typhimurium and E. coli. This effect, however, was attributed to a
metabolite of vinylidene chloride.
Tumors have allegedly been induced in rats by inhalation of high con-
centrations of vinylidene chloride (53), but no reports to date have sub-
stantiated this allegation.
Very little information relevant to the epidemiology of vinylidene
chloride has been reported. The reports made to date have involved cases where
vinylidene chloride was only one of several, or many, chemicals to which
the subjects were exposed. In no case was it possible to draw definite
conclusions about vinylidene chloride.
Several studies have been performed, under simulated environmental con-
ditions, to elucidate the environmental fate of vinylidene chloride. Possible
mechanisms of reaction and reaction products have been suggested and an atmospheric
half-life of 2.1 hours has been calculated. No information is available on the
effects of vinylidene chloride on the environment/ecosystems, and the information
available on monitoring and exposure levels is negligible.
-------
monkey
dog
rabbit
damage (hlnrnlnelrnl) (48 ppm;90 d; A2)
liver damage (histological) (48 ppm; 90 d; 42)
11
weight lQ8SXJ- (15 ppm: 90 d: 42)
mortality'1" (5 ppm; 90 d; 42)
|lung damage (histological) (48 ppm; 90 d; 42)
i
(liver damage (histological) (48 ppm; 90 d; 42)
weight loss (5 ppm; 90 d; 42)
|lung damage (histological) (48 ppm; 90 d; 42)
weight loss" (25 ppm; 90 d; 42_)
elevated serum glutamic-pyruvic transaminase (48 ppm; 90 d; 42)
. guinea pig
[elevated liver alkaline phosphatase (48 ppm; 90 d; 42)
I
o
rat
I lung damage (histological) (48 ppm; 90 d; 42)
mortality7 (5 ppm; 90 d; 42.)
[irritation of eye and upper respiratory tract (200 ppm; 6 hr/d. 5 d/wk, 4 wk; 15)
elevated serum glutamic-pyruvic transaminase (48 ppm; 90 d; 42)
I elevated liver alkaline phosphatase (48 ppm; 90 d; 42)
lung damage (histological) (48 ppm; 90 d; 42)
kidney damage (histological) (48 ppm; 90 d; 42)
I liver damage (histological) (48 ppm; 90 d; 42)
[retarded weight gain (5 ppm; 90 d;
^mortality (5 ppm; 90 d; 42)
-------
1 1
1
human ' '
1 1 |
i i
|CNS depression (4000 ppm; 23)
i
1 irritation 'of eye and upper respiratory tract (25 ppm; 23)
1 \
1 !
cat 1 I mortality (506 ppm; 2 hr; 45)
i 1
1 1 | irritation of eye and upper respiratory tract (253 ppm; 2 hr; 45)
,
. I
raDBlt ' ' | reduced reflex strength (253 ppm; 40 min; 45)
- - ; I i
I 1
P. 8uinea P18 1 1 mortality"* (1265 ppm; 2 hr (36 hr) ; 45)
w i I I
(D .
1 '
iS i
8 ' ' i
c 1
i i
decreased liver glucose-6-phosphatase (2270 ppm; 1 hr; 10)
i i
ncreased serum glutamic oxalacetic transaminase (1440 ppm; 1 hr; 24)
i i
rat ' (increased serum alpha-ketoglutarate transaminase (200 ppm; 4 hr; 24)
. . '
1 ' 1 e
1 ' '
i
levated serum glutamic-pyruvic transaminase (1440 ppm; 1 hr; 10)
, i
liver damage (histological) (200 ppm; 4 hr; 31)
1 ' i
. mortality
mouse 1 |
i i
(600 ppm; 4 hr (24 hr) ; 27)
1 t
1 CNS depression (11,400 ppm; 2 hr; 45)
i 1
1 ' mortality1 (127 ppm; 2 hr (7 d) ; 45)
1 1 i
1 1
10
1. 253 ppm; 2 hr (24 hr); 45_
3800 ppm; 2 hr (24 hr); «.
2. 4900 ppm; 4 hr (14 d); £7
6150 ppm; 4 hr (14 d); 4J
15,000 ppm; 4 hr (24 hr); 2T_
32,000 ppm; 4 hr (14 d); 11
3. 2000 ppm; 4 hr; 25_
4. 2024 ppm; 2 hr (24 hr); 45
100 1000
Vinylidene Chloride Concentration (ppm)
42
10,000
5. 15 ppm; 90 d; 42_
48 ppm; 90 d; 42
500 ppm; 6 hr/d, 5 d/wk, 4 wk; 15
500 ppm; 6 hr/d, 5 d/wk, 4 wk; 15
90 d; 4£
.. n; 6 hr/d, 5 d/wk
6. 500 ppm; 6 hr/d, 5 d/wk
7. 15 ppm; 90 d; 42_
26 ppm; 90 d; 42
48 ppm; 90 d; 42
8. 100 ppm; 8 hr/d, 5 d/wk; 6 wk; 42
100,000
9. 25 ppm; 90 d; 42^
48 ppm; 90 d; «_
10. 26 ppm; 90 d;
zo ppm; yu a; a/
48 ppm; 90 d; 42^
11. 26 ppm; 90 d; 42^
48 ppm; 90 d; 42_
100 ppm; 8 hr/d, 5 d/wk, 6 wk; 42_
Figure 14. Effects Induced by Vinylidene Chloride-inhalation
-------
I M
H-
! 9
: OQ
mortality (LD5Q) (1510 mg/kg; 32)
depressed hepatic bile flow (610 mg/kg; 19)
*j liver damage (histological) (610 mg/kg; 19)
prolonged hexobarbital sleeping time (400 mg/kg; 26)
increased hepatic triglycerides (400 mg/kg; 29)
Increased plasma alanine transaminase (300 mg/kg; 32)
increased liver tyrosine transaminase (300 mg/kg; 32)
g
s
J
prolonged pentobarbital sleeping time (200 mg/kg; 24, also 400 mg/kg; 26)
increased serum alpha-ketoglutarate transaminase (200 mg/kg; 29)
increased liver alkaline phosphatase (100 mg/kg; 32)
increased plasma alkaline phosphatase (100 mg/kg; 32)
decreased liver glucose-6-phosphatase (100 mg/kg; 24 and 32)
200 400 600 800 1000 1200 1400 1600 1800 2000 2200 2400
Vinylidene Chloride Dose (mg/kg)
Figure 15. Effects induced by Vinylidene Chloride - p.o. and i.p.*
-------
Tabular Summary
The following table is a graphic representation of the information
available on the health and environmental impacts of vinylidene chloride.
The information has been organized by the various subfields given in Appen-
dix: A. The route of administration of vinylidene chloride, the species of
animal employed and the reference of each study are presented. In the case
of human studies, the number of subjects, if it was specified, is included
When one of these categories of information was not ^tated in the article,
the letters n.s. are used to so indicate.
All studies reasonably applicable to a given subfield are included
therein. Thus, while this table gives no indication of the quality of the
information reported, it does give an excellent indication of the quantity
of information available in each category.
-------
I.
A.
1.
2.
3.
4.
HEALTH IMPACT
lexicological Data
Absorption, excretion, topical
transport, and distribution . , n .
* inhalation
in vitro
Metabolic effects
Pharmacology oral
oral
oral
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
in vitro
Biochemical parameters oral*
oral*
oral
oral
oral
oral
i.p.
inhalation
inhalation
inhalation
inhalation
inhalation
mouse
rat
rat liver
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat liver
mouse
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
38 Meyer 1959
27 Jaeger 1974
7 Bonse 1975
32 Jenkins 1972
29 Jaeger 1973
26 Jaeger 1973
10 Carlson 1972
27 Jaeger 1974
48 Siletchnik 1974
44 Reynolds 1975
31 Jaeger 1975
28 Jaeger 1975
24 Jaeger 1975
27 Jaeger 1974
49 Sporn 1970
49 Sporn 1970
32 Jenkins 1972
29 Jaeger 1973
26 Jaeger 1973
30 Jaeger 1973
19 Harms 1976
42 Prendergast 1967
10 Carlson 1972
25 Jaeger 1973
27 Jaeger 1974
44 Reynolds 1975
* A copolymer of vinylidene chloride was used.
-------
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
in vitro
in vitro
in vitro
5. Acute, subacute, and oral*
chronic toxicity
oral
oral
oral*
i.v.*
topical
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
rat
rat
rat
guinea pig
rabbit
dog
monkey
rat liver
rat liver
rat spleen
rat
rat
rat
dog
rabbit
rabbit
mouse
rat
rat
rat
rat
rat
rat
rat
rat
rat
rat
guinea pig
guinea pig
rabbit
rabbit
cat
dog
31 Jaeger 1975
28 Jaeger 1975
24 Jaeger 1975
42 Prendergast 1967
42 Prendergast 1967
42 Prendergast 1967
42 Prendergast 1967
27 Jaeger 1974
7 Bonse 1975
46 Shmuter 1976
51 Wilson 1954
32 Jenkins 1972
30 Jaeger 1973
51 Wilson 1954
39 Miyasaki 1959
45 Rylova 1953
45 Rylova 1953
11 Carpenter 1949
42 Prendergast 1967
15 Gage 1970
47 Siegel 1971
10 Carlson 1972
25 Jaeger 1973
30 Jaeger 1973
27 Jaeger 1974
44 Reynolds 1975
31 Jaeger 1975
45 Rylova 1953 '
42 Prendergast 1967
45 Rylova 1953
42 Prendergast 1967
45 Rylova 1953
42 Prendergast 1967
* A copolymer of vinylidene chloride was used.
7a
-------
inhalation
inhalation
inhalation
in vitro*
monkey
human
n.s.
HeLa cells
42 Prendergast 1967
45 Rylova 1953
23 Irish 1962
5 Bando 1973
6. Sensitization from
repeated doses
7. Teratogenicity and
mutagenicity
11. Synergisms
in vitro S. typhimurium 37 McCann 1975
in vitro E. coli K12 17 Greim 1975
in vitro S. typhimurium 6 Bartsch 1975
8. Carcinogenicity
9. Dose-response
relationships
10. Behavioral effects
oral
oral
S.C.*
inhalation
oral
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
inhalation
rat
dog
rat
rat
rat
mouse
rat
rat
rat
rat
rabbit
human
22 Hushon 1976
22 Hushon 1976
40 Oppenheimer 1955
53 Anon. 1975
32 Jenkins 1972
45 Rylova 1953
11 Carpenter 1949
47 Siegel 1971
30 Jaeger 1973
27 Jaeger 1974
45 Rylova 1953
45 Rylova 1953
B. Epidemiological Data
1. Occupational exposure
studies
inhalation* human(2) 8 Broser 1970
inhalation human(98) 33 Kramer 1972
* A copolymer of vinylidene chloride was used.
-------
inhalation human(4) 52 Anon. 1974
2. Environmental incidents, topical human(1) 42 Osbourn 1973
poisonings, and case
histories
3. Clinical and subclinical inhalation human(98) 33 Kramer 1972
manifestations
4. Statistical or risk-
composition studies
5. Other controlled studies
II. ENVIRONMENTAL IMPACT
A. Environmental Fate
1. Chemical and biochemical 13 Billing 1976
reactions in the environment u Dming 19?5
16 Gay 1976
20 Heicklen 1975
2. Transport in soils,
aquatic systems and biota
B. Environmental/Ecosystem Effects
1. Fish and other aquatic
organisms
2. Birds
3. Mammals of economic importance
4. Other terrestrial organisms
5. Atmosphere and/or climate
6. Manmade structures
-------
III. Monitoring Data and Exposure Levels
A. Human exposure profile
inhalation
inhalation
inhalation
4 Anderson 1963
2 Altman 1966
22 Hushon 1976
B. Exposure of other organisms
C. Monitoring data
10
-------
Introduction
Vinylidene chloride (1,1-dichloroethylene; 1,1-dichloroethene; 1,1-DCE)
was first reported, as a "strange new fluid," in 1838, but was regarded
only as a laboratory curiosity until the late 1920's when its tendency
toward polymerization was discovered. It began to find extensive commercial
use in the 1940's, and its use has continued to grow to the extent that
an estimated 265 million pounds were produced in the U.S. in 1974.
The bulk of the vinylidene chloride produced in this country is
used in two applications: (1) the production of methyl chloroform;
and (2) the formation, with other monomers, of a polymer. Because of its
good barrier properties, the polymer is used to fabricate packaging films
and is applied as a coating to other packaging materials. The polymer is
also used in the production of flame-resistant fibers and is applied as a
coating to impart flame resistance to textiles, carpets, non-wovens and paper.
Human exposure and environmental contamination are inevitable results
of the widespread use of vinylidene chloride. It is important, therefore,
that the risks and liabilities involved are fully understood. To this
end, a number of investigations into the health and environmental impacts of
vinylidene chloride have been performed over the past thirty years. It
is the objective of this report to compile and review those investigations
and, specifically, to identify any aspects of human or environmental
toxicology of vinylidene chloride of which the current knowledge is
inadequate.
11
-------
Research Request No. 1 of EPA Contract No. 68-01-4116 authorized
Tracer Jitco to (1) search the domestic and foreign literature for infor-
mation on health and environmental impacts of vinylidene chloride, and
(2) prepare a final report consisting, at a minimum, of a summary of the
information derived from the literature search, with appropriate biblio-
graphic references. An outline of factors to be identified was provided
by the EPA, and is reproduced as Appendix A.
Information Sources
The secondary journals and on-line data bases employed in the literature
search on vinylidene chloride are presented in Appendix B. In addition to
those information sources, a large number of standard handbooks and desk
references were searched. Furthermore, the bibliography of each article
selected was scanned for relevant citations.
12
-------
Review of the Literature
The earliest reference to vinylidene chloride toxicity appeared in
a 1945 review of the toxicology of plastics, in which A.G. Cranch stated,
with no supporting evidence, that vinylidene chloride is "essentially
inert physiologically" (12).
In 1945, Reinhardt reported, without details, that experimental
studies on laboratory animals indicated that the vapor toxicity of vinylidine
chloride is of the same order as that of ethylene dichloride (43) .
In a study reported in 1949, groups of six male or female Sherman
albino rats, weighing 100-150 g. each, were used by Carpenter, et al. , to
measure the acute vapor toxicity of 96 chemical compounds. Each group of
animals was exposed to a given concentration of a chemical for a period
of 4 hours and then observed for 14 days. Chemical concentrations were
increased by a factor of 2 until a concentration was reached which killed
2,3 or 4 of 6 rats within the observation period. Autopsies were performed
on all of the rats to assure that they did not die of extraneous infection.
The concentration of vinylidene chloride which was found to kill 2-4
of 6 rats was 32,000 ppm (11).
In an article published in 1953, M.L. Rylova reported on studies on
the toxicity of technical grade vinylidene chloride that had been per-
formed using white mice, guinea pigs, rabbits, cats and humans
Acute toxicity was tested by exposure of mice for two hours to
vinylidene chloride vapors in a concentration of 0.5 to 45 mg/1. A
narcotic effect, indicated by a lateral position of 2 out of 12 mice,
was observed only at the highest concentration. Exposure at the lowest
concentration was lethal for 6 out of 24 mice, death occurring during the
first week after exposure. At a concentration of 1 mg/1, 9 of 24 mice suc-
cumbed during the first 24 hours. In most cases, autopsy disclosed no
visible changes. The 24-hour LC for a 2-hour exposure was determined to be
15 mg/1. The author noted that earlier tests with the same sample of
13
-------
vinylidene chloride showed a lower toxicity. It was suggested that the
increase may have resulted from the formation of more toxic admixtures
during standing (45).
In inhalation tests with guinea pigs, 2-hour exposure to 5 mg/1 killed
1 of 3 animals after 36 hours, while 8 mg/1 killed 3 of 3 within 24 hours.
Death was caused by respiratory paralysis, and autopsy disclosed a con-
gestive hyperemia of the laryngeal and pulmonary mucosae (45).
During a period of 3.1 to 4 months, one female and two male rab-
bits were exposed 5-7 times for 2-hours at intervals ranging from 8 to
37 days to increasing concentrations (2-30 mg/1) of vinylidene chloride
vapors. The female died after 5 exposures (the last at 20 mg/1), while
the males survived 7 exposures (the last at 30 mg/1). At autopsy the
nasal mucosa of the female was covered with pus, the laryngeal mucosa
exhibited a sharp hemorrhage and the larynx cavity contained a foamy
liquid; the lungs were congested, hemorrhagic and edematous; the liver
was congested and hypertrophied (45).
To determine the mimimum effective concentration of vinylidene
chloride vapors, Rylova measured the changes in the rate of development
of muscular stress and of reflex strength of 7 rabbits during inhalation
of vinylidene chloride for 40 minutes. The average minimum effective
concentration was found to be 1 mg/1 (45).
Application of liquid vinylidene chloride for 5 minutes to the
shaved abdominal skin of rabbits was observed to cause a slight,
transient erythema. Following a 10-minute exposure, the erythema lasted about
1 hour. A rabbit ear concha placed in liquid vinylidene chloride for 1
minute developed an inflammatory edema (45).
Two-hour exposure of cats to vinylidene chloride vapors in a con-
centration of 1 mg/1 resulted in only a slight irritation of the eye and
nose mucosae. At 2 mg/1, the vapors produced a state of strong excitation
14
-------
in 2 of 3 cats. One hour following exposure (2 mg/1) of the cats, a male,
exhibited an unsteady gait, labored breathing and finally respiratory
failure. Autopsy revealed the presence of an edematous fluid in the
tracheal cavity, tracheal hyperemia, and pulmonary edema. A female
cat which died a few hours after exposure to 2 mg/1 showed only a slight
hyperemia of the upper trachea. Autopsy of cats exposed to 6 mg/1 for 2
hours disclosed a slight pulmonary edema, hemorrhages and foci of pneumonia (45)
In tests on human subjects, Rylova found the threshold of vinylidene
chloride vapor for irritating action on the mucosae of the eye and upper
respiratory tract to be 0.1 mg/1. The odor perception threshold was found
to be 0.2 mg/1. The author suggested that the irritating effects may have
been the result of decomposition products, such as formaldehyde and HC1 (45).
Rylova noted that in the presence of air, vinylidene chloride forms
explosive peroxide compounds which decompose slowly to give formaldehyde,
phosgene and HC1 (45).
In a test of the chronic toxicity of a copolymer of vinyl and vinylidene
chloride, Seeler, et al., (cited by Wilson and McCormick, 1954) found
that rats fed a diet containing 5% vinyl and vinylidene chloride copolymer
for 2 years showed no toxic effects. Two dogs fed a diet containing
5% of the copolymer were also without evidence of toxic effects (51).
In 1955, Oppenheimer, et al., studied the carcinogenicity of a number
of polymers by inserting, s.c., in Wistar rats, small squares of circles
(1.5 cm wide) of film, one on each side of the abdominal wall just ventral
to the fascia. One of the films used was Saran, a copolymer of vinyl
chloride and vinylidene chloride. The first effect of the film was its
encapsulation in a sac or pocket of connective tissue. This encapsulation
was evident within 2-3 weeks after implantation, and was found in all-
animals except those in which a tumor was induced. In most cases, the
tumors induced were fibrosarcomas and were located entirely in the subcutaneous
layers. Saran induced tumors in 5 of 42 rats, with a latent period of 390
to 847 days (40).
15
-------
A 1959 report by K. Miyasaki described an experiment in which rabbits
were injected i.v. with copolymerization products of vinyl chloride and
vinylidene chloride (EV) (no details given) according to the following
schedule:
1% EV 1 cc/kg, daily for 2 weeks: 9 rabbits
5% EV 1 cc/kg, daily for 2 weeks: 5 rabbits
1% EV 1 cc/kg, daily for 3 months: 9 rabbits
Throughout the experiment, all of the rabbits were healthy and maintained
their normal body weight. Blood tests showed a reduction in red blood
cell count, hemoglobin, hematocrit, erythrocyte resistance and whole
blood specific gravity. The white blood cell count, color index, coagulation
time, bleeding time and plasma specific gravity showed no significant
changes. At autopsy the spleen and bone marrow appeared white, and the
spleen swollen. Histological examination of the rabbits treated for
3 months revealed the cells belonging to the reticulo-endothelial system
of the spleen, bone marrow, liver, lymphatic tissue, and lungs to be
extremely hypertropic (39).
In a 1959 study, Meyer and Kerk tested the abdominal skin of mice
for percutaneous permeability of 37 aliphatic compounds. The compounds
were applied on a surface of 2.2 sq. cm. and their permeability measured
as the time required to show the appearance of an eserine effect on the
striated muscles. Dichloroethylene (isomer not specified) took 28 minutes.
For comparison, time for some of the other compounds are shown below (38).
Methanol - n-Octanol (prim) 29
Ethanol - n-Octanol (sec) 49
n-Propanol - n-Nonylalcohol 64
i-Propanol - n-Decylalcohol 43
n-Butanol 73 Methyl glycol
i-Butanol 64 Ethyl glycol
n-Pentanol 43 1,2-Propylene glycol
i-Amylalcohol 47 1,3-Butylene glycol
n-Hexanol 21 Carbitol
n-Heptanol 26 Hexamethylene glycol
16
-------
Glycerin - Tetrabromoethane
Hexane - Trichloroethylene 20
Trichloromethane - Tetrachloroethylene 23
Dlbromoethane - Allyl bromide 12
Dichloroethane - n-Allyl chloride 28
D. Irish, 1962, discussed the toxicity of vinylidene chloride based
on an unpublished report by the Biochemical Research Laboratory of the Dow
Chemical Company. This 1962 report stated that vapor exposure (animal
not stated; apparently human) of 4000 ppm vinylidene chloride results in
central nervous system depression and the associated symptoms of drunkeness,
with the development of unconsciousness during continued exposure. With
an exposure of short duration complete recovery from the anesthetic
effect is expected. The maximum single exposure in animals which could
be tolerated without injuries was above 1000 ppm for up to 1 hour and 200
ppm for up to 8 hours (23).
Chronic vapor exposure, 5 days a week, 8 hours a day, for several
months resulted in some kidney and liver injuries in animals (species
not: specified) at concentrations of 100 and 50 ppm. Minimal liver and
kidney injuries resulted even at 25 ppm. Vapor exposure studies on carbon
tetrachloride resulted in similiar findings. Studies on laboratory animals
indicate that the quantitative vapor toxicity of vinylidene chloride is
slightly greater than that of ethylene dichloride and slightly less than
that of carbon tetrachloride (23, 35).
Eye contact studies showed that inhibited vinylidene chloride was
moderately irritating to the eyes, causing pain, conjunctival irritation
and some transient corneal injury, although permanent damage was rare.
A high concentration of the phenolic inhibitor itself, however, caused
serious and permanent eye injury (23).
The inhibitor content of liquid vinylidene chloride was held partially
responsible for the skin irritation that develops after only a few minutes
of direct contact to the skin (23).
17
-------
Because vinylidene chloride has a high vapor pressure, the Dow study
suggested a maximum possible concentration of 25 ppm in the work atmosphere.
(8 hour per day, 5 days a week). Persons prone to kidney or liver disease,
or who are excessive users of alcohol, should be forbidden to work even in
areas mildly contaminated with vinylidene chloride (23, 35).
In 1963, A. Osbourn reported a case in which Saran wrap, a copolymer
of vinylidene chloride and vinyl chloride, was implicated as the causitive agent
of contact dermatitis of the body of a 30-year-old white male. The patient
was given a steroid cream to treat an area of localized psoriasis, and was
instructed to cover the area with Saran wrap for two to three hour periods
every evening. The psoriasis improved, but the patient developed an
inflammed, swollen, vesicular and exudative dermatitis on the area covered
by Saran wrap (41) .
Anderson and Saunders* 1963, of Lockheed Missiles and Space Company,
identified contaminants in the atmospheres of the manned Mercury spacecraft.
Vinylidene chloride, one of the contaminants, was believed to have originated
as one of several impurities in a batch of contaminated breathing oxygen.
The authors reported a value of 0-2 ppm as a probable minimum concentration
which would have ensued had all the recovered contaminants been dispersed
in the free volume of the cabin at one time (4).
Altman and Dittmer, 1966, reported that 2 ppm is the highest con-
centration of the vinylidene chloride normally found in the atmospheres of
nuclear submarines (2).
Using rats, guinea pigs, dogs, rabbits and monkeys, Prendergast et al.,
1967, studied the inhalation toxicity of vinylidene chloride. Animals were
subjected to 2 types of studies: repeated, daily, 8-hour exposures, 5 days/
week, for 6 weeks and continuous 90-day exposures. The animals were exposed
to concentrations of 395, 189, 101, 61 and 20 mg/m (42).
18
-------
3
Repeated exposure to 395 mg/m (100 ppm) did not result in a single
animal death (out of a total 38) or visible signs of toxicity. However, the
rabbits and monkeys were observed to have lost weight; autopsy revealed
normal organs; however, one rat had a gelatinous material on the kidney
and bloody urine in the bladder. Pneumonitis and congested lungs were
found in an occasional rat or guinea pig. Guinea pig serum urea nitrogen
concentration was 23+3 mg/100 ml, which favorably compared with 24+5
mg/100 ml obtained from control animals (42).
3
At continuous exposure to 189 mg/m , 7 out of 15 guinea pigs died in
the beginning (day 4-day 9) of the experiment and 3 out of 9 monkeys died
on days 26, 60 and 64. Surviving animals exhibited no visible signs of
toxicity. Dogs and monkeys lost weight, while the rats gained less than
the controls. Gross examination revealed mottled livers in many animals.
Histopathologic examination of liver sections from dogs, monkeys and
rats revealed morphologic changes which consisted of fatty metamorphosis,
focal necrosis, hemosiderin deposition, lymphocytic infiltration, bile
duct proliferation, fibrosis and pseudo-lobule formation. These changes
were most severe in dogs. Kidney sections from all rats showed nuclear
hypertrophy of tubular epithelium. Nonspecific inflammatory changes in the
lungs of a majority of animals were also observed. One adrenal gland from a
dog; contained a cortical adenoma composed of cells of the zona glomerulosa
type. The hepatic changes observed in dogs, monkeys and rats and the
renal changes in rats were considered to be a direct result of the exposure.
Liver alkaline phosphatase activity in surviving rats and guinea pigs was
elevated, in comparision to control animals; serum glutamic-pyruvic trans-
aminase activity was also elevated in rats and guinea pigs, but was more
noticeable in guinea pigs. Although 2 rats had elevated liver lipid con-
tents of 34.4 and 20.0%, the average value did agree well with the control
animals (42).
3
Continuous exposure of 101 mg/m did not result in visible toxic signs
in the surviving animals, although 3 out of 15 guinea pigs died between day
3 and 6 of the experiment and 2 out of 3 monkeys died on days 39 and 47.
19
-------
Loss in body weight was observed for rabbits, monkeys and dogs. Gross
examination revealed white or bluish-grey spots and nodules on several
guinea pig and rat lungs. Nonspecific inflammatory changes were noted
in the lungs of all animals upon histopathologic study, but no changes
were observed that could be attributed to the exposure. Guinea pig
serum urea nitrogen concentration of 24 + 3 mg/100 ml favorably compared with
the control value of 24 + 5 mg/100 ml (42).
Three out of 15 guinea pigs died on day 3 and 4 of the experiment when
3
continually exposed to 61 mg/m , although visible signs of toxicity were
not apparent in surviving animals. Weight loss was observed in monkeys,
and the rats gained less than the controls. Gross examination revealed
mottled livers and/or spleens in several animals of all species. Non-
specific inflammatory changes, most marked in the lungs, and less so in
the liver and kidneys, were observed in all species. These changes were not
considered by the authors to have been induced by the exposure. Rat and
guinea pig serum urea nitrogen levels of 20+4 and 26+3 mg/100 ml,
respectively were not dissimiliar to the control values of 20 + 4 and
24+5 mg/100 ml, respectively (42).
3
Average continuous exposure of 20 mg/m resulted in the death of 2
out: of 45 rats, 2 out of 45 guinea pigs, and 1 out of 21 monkeys, with no
visible toxic signs in the survivors. Weight loss was observed in dogs,
while the rats gained less than the controls animals. Mottled livers
were observed in about one-third of all animals upon gross examination.
Histopathologic examination revealed nonspecific inflammatory changes in
the lungs of all species and in the livers and kidneys of monkeys. None
of the pathologic changes noted were considered by the authors to have been
caused by the exposure. Urea nitrogen concentrations in rat and guinea pig
sera compared favorably with controls. In both rats and guinea pigs, liver
lipid values fell within control limits (42).
According to Vallaud, et al., (cited by Lefaux, 1968), D. Matruchot
regards vinylidene chloride to be slightly narcotic and highly toxic,
20
-------
resulting in death, accompanied by convulsions and spasms, in minutes or
hours (34).
Since 1959 health specialists in the U.S.S.R. have fixed a maximum concen-
o
tration of 50 mg/m for vinylidene chloride (34).
The inhalation toxicity of vinylidene chloride on rats was reported by
Gage in 1970. Groups of 4 F and 4 M rats, weighing 200 g each, were exposed
to an atmospheric concentration of 500 ppm or 200 ppm for periods of 6
hours, 5 days a week for up to 4 weeks. The rats exposed to 500 ppm of
vinylidene chloride experienced nose irritation and retarded weight gain;
histological examination at autopsy revealed liver cell degeneration. Rats
exposed to 200 ppm of vinylidene chloride experienced slight nose irritation
and histological examination at autopsy revealed normal organs (15).
In 1970, Broser, Henschler and Hopf reported the clinical findings in
2 patients with poisoning subsequent to handling an aqueous dispersion of
vinylidene chloride copolymers. Within 8 to 30 hours of the exposure,
both patients developed sensory disturbances in the trigeminal area of the
face, mouth and tongue, spreading later on to the 2nd, or 2nd and 3rd
cervical segments. One patient exhibited motor weakness of the jaw
muscles, the lateral recti muscles of the eyes and of the tongue muscles.
Electromyographic evaluation of the trigemino-facial reflexes revealed
the functional disorder to involve mainly the interneuronal system (8).
In another report (Henschler, 1970) on the same case, the same
authors concluded that the cause of the poisoning was monochloroacetylene
and/or dichloroacetylene, both of which were present as highly toxic gas
contaminants in the initial vinylidene chloride product or developed .from
contaminants (tetrachloroethane, trichloroethylene) during production
or storage (21).
Sporn, et al., 1970, studied the effects of oral administration of
oil and aqueous extracts of a vinylidene chloride copolymer on 60 mice and
32 white rats. The extracts were obtained by 3 months contact of the
solvents with the polymer. Neither 1 ml of either extract, nor 4 repeated
21
-------
doses of 10-fold concentrations influenced the viability of the animals or
their body or organ weights. The aqueous extract, administered as 50%
of the drinking water for 60 days, induced a slight decrease (13-17%) in
aldolase, glutamic oxalacetic transaminase, succinoxidase, and acid
and alkaline phosphatase activities, without influencing the blood picture,
succindehydrogenase activity and the ascorbic acid content of the adrenals.
The oil extract, administered as 8% of the food, had no apparent effect.
The adverse effects induced by the aqueous extract were attributed to the
presence of chlorhydrine in the polymer (49).
In a study published in 1971, Siegel, et al., determined the LC of
vinylidene chloride using male NRMR : 0 (SD) Sprague-Dawley derived rats.
The animals were exposed to vinylidene chloride vapors for 4 hours and
then observed for 2 weeks. At 4900 ppm, 1 of 16 rats died, and at 6150 ppm,
7 of 16 died. From this data, the LC _ was estimated to be 6350 ppm (47).
In 1971, the American Conference of Government Industrial Hygienists
set the threshold limit value for vinylidene chloride, for an 8-hour
working exposure, at 10 ppm (3).
A 1972 report by Aleksandrowicz, et al., described the results of a
study to test the possibility of using a vinyl chloride-vinylidene chloride
copolymer in the surgical therapy of aneurisms of brain blood vessels. In
7 rabbits, weighing 3.5 to 5.5 kg, the copolymer was applied on the vascular
mucosa of the brain and on the vascular nerve-bundle. This was covered
with a layer of an epoxy resin to add strength. The animals were sacrificed
30, 60 and 90 days after treatment. Microscopic examination of the coated
tissues disclosed no serious damage (1).
Using adult Holtzman rats weighing 200 to 470 g, Jenkins, et al., 1972,
studied the biochemical effects of vinylidene chloride. The time-response
and dose-response relationships of p.o. vinylidene chloride administration
to enzyme activities are shown in Figure 1 and Table 1. Vinylidene chloride
induced a decrease in liver glucose-6-phosphatase (G-6-Pase) activity and
increased activities in liver alkaline phosphatase (AP) and tyrosine
22
-------
transaminase (IT) and in plasma alkaline phosphatase and alanine transaminase
(AT), all of which were dose-related. In a comparison of these responses
between male and female rats, it was found that females exhibited a greater
response in G-6-Pase and liver AP then males. Similar tests with CC1. and
1,2-dichloroethylene demonstrated that vinylidene chloride is more potent
than either of those chemicals (32).
The effect of phenobarbital (PB) on vinylidene chloride toxicity was
tested in rats which had received daily i.p. injections of 50 mg/kg of
sodium phenobarbital for 5 days prior to administration of vinylidene
chloride. When measured 20 hour after vinylidene chloride administration,
PB pretreatment resulted in reduced effects on liver AP and TT and plasma
AT activities. In contrast, PB pretreatment increased the effect of
CC1, on these parameters (32).
To test the effect of adrenalectomy on vinylidene chloride, Jenkins,
et al., determined the LDsn of vinylidene chloride, and for comparison
CC1,, in adrenalectomized and sham-operated rats (18-hour fasted), the
results are presented in Table 2 (32).
Using male Sprague-Dawley derived rats, Carlson and Fuller (1972),
investigated the effects of prior i.p. administration of phenobarbital (PB),
3-iaethylcholanthrene (3-MC), 2-diethylaminoethyl-2,2-diphenyl valerate
hydrochloride (SKF 525A), and 2,4-dichloro-6-phenylphenoxyethyl-diethylamine
hydrochloride (Lilly 18947) on the inhalation toxicity of vinylidene chloride.
PB is an enzyme inducing agent which is known to potentiate CC1, toxicity;
3-MC is an enzyme inducer which protects aginst CC1, hepatotoxicity; SKF
525A and Lilly 18947 inhibit microsomal enzyme metabolism and protect
against CC1, damage. PB was administered in doses of 50 mg/kg for four
days, 3-MC in doses of 40 mg/kg for 2 days, SKF 525A in a single dose of
50 mg/kg and Lilly 18947 in a single dose of 30 mg/kg. Controls were
injected with corn oil or saline. Exposures to vinylidene chloride were
made 24 hours after the last dose of PB, 48 hours after the last dose
of 3-MC and 30 minutes after dosage with SKF 525A and Lilly 18947.
23
-------
2000
1000
700
900
300
o
K
O
u
u.
O
100
60
40
,A
t« LIVEN ALKALINE PMOSPMATASE
II LIVED TYNOSINC TRANSAMINASE
4 1 LIVER aLUCOSE-«-PHOSPHATASC
0 PLASMA ALANINE TRANSAMINASE
PLASMA ALKALINE PHOSPNATASE
0 20 40 60 60 100 120 140
HOURS AFTER ORAL ADMINISTRATION OF
CH2CCI2 (500 nig/Kg)
Fio. I. Biochemical time-response to po administration of 1,1-dichloroethylene tcr male rats. Each
point represents the mean percent of control obtained from a group of 3 rats based on the mean value
for 3 control rats sacrificed at the same time. The ranges of control means for the time points studied
were: liver AP, 0.34-0.41; liver TT, 10.1-19.1; liver G-6-Pase, 20.8-30.6; plasma AT, 0.08-0.16;
plasma AP, 0.28-0.58 (/ig product formed/hr/mg or ml).
TABLE 1
DOSE-RESPONSE RELATIONSHIPS OF BIOCHEMICAL PARAMETERS AT TIME OF MAXIMUM EFFECT
AFTER ORAL ADMINISTRATION OF I.I-DICHLOROETHYLENE TO MALE RATS
Liver glucose-6-phosphatase
Liver alkaline phosphatase
Liver tyrosine transaminase
Plasma alkaline phosphatase
Plasma alanine transaminase
Hours
46
22
22
46
46
100 mg/kg
80 ±5'-*
194±37»
96 ±16
110±15
68 ±20
Dose
300 mg/kg
53 ±26
468 ± 48*
380±60»
150 ±34
150 ±35'
500 mg/kg
42±3»
774 ± 77"
1070 ±119"
450 ± 46*
1868 ±202"
All values are expressed as mean percent ± SE of controls given an equal volume of corn oil.
Each dose group consisted of 3-6 rats. Control values were: liver G-6-Pase, 25.3 ± 1.0; liver AP,
0.34 ±0.03; liver TT, 12.9 ±1.2; plasma AP, 0.10 ±0.01; plasma AT, 0.38 ±0.05 (jig product
formed/hr/mg or ml).
* Significantly different from next lower dose, p < 0.05.
TABLE 2
ORAL LD50 OF I,I-DICHLOROETHYLENE AND CCI4 IN ADRENALECTOMIZED AND SHAM-
OPERATED MALE RATS
Operation
Adrenalectomy
Sham
Time*
(hr)
24
96
24
96
LD50 (mg/kg)
1,1-DCE
84(64-111)"
81 (70-94)
1550(1520-1581)
1510(1445-1578)
ecu
3260 (3070-3460)
3200 (2870-3348)
>7975
3250(2928-3608)
Values in parentheses are 95 % confidence limits.
* Indicates time after administration of test compounds for LD50 calculation.
24
-------
Hepatotoxicity was assessed by measuring serum glutamic oxalacetic (SCOT)
a.nd serum glutamic pyruvic (SGPT) transaminases and liver glucose-6-
phosphatase (G-6-P). The lungs of the test animals were excised and
weighed. Results of the tests are shown in Tables 3-7. All four of the
compounds tested increased vinylidene chloride lethality. However, there
was no increase in hepatotoxicity as evidenced by SCOT, SGPT or G-6-P, nor
was any lung damage apparent through gross observation or weighing
of the lungs (10).
C. Kramer and J. Mutchler, of the Dow Chemical Company, 1972,
offered a technique of evaluating industrial exposure effects on a group
of exposed workmen which would account for individual levels of exposure,
rather than depending on a collective comparison with a control population.
In the example given, a group of 98 workmen were exposed to vinyl chloride
and vinylidene chloride; the vinyl chloride concentrations were higher than
those of vinylidene chloride, due to the larger quantities of vinyl chloride
used and its greater volatility. In more recent measurements of this study,
infrared and gas, chromatographic techniques have established that the vinyl
chloride concentrations average 10 ppm, whereas almost all the vinylidene
chloride concentrations amount to less than 5 ppm, and are most often
detectable only in trace amounts (33).
Comparison of 95 parameters of the history, physical examination and
laboratory work of the exposed workmen with those of a control group revealed
no basic differences between the two populations with regard to general
health nor the appearance of any significant disease as a result of work
exposure (33). ~~
Kramer and Mutchler concluded that repeated exposure to vinyl chloride
at TWA (time-weighted average) levels of 300 ppm or above for a working.
lifetime, together with a very low level of vinylidene chloride may
result in minor changes in certain physiologic and clinical laboratory
parameters. Some impairment in liver function tests was implied, although
no overt clinical disease was observed in any of the individuals studied (33)
25
-------
.TABLE 3
Fffect of 3 MC or PB Pretrcatment on 1, 1 -Dichloroethylene Lethality
1, 1-Dichloroethylone
(ppm for 1 hr)
20,000
32,500
Deaths
Control
0/4
0/3
in 24 Hours
PB 3MC
3/4 4/4
4/4 4/4
TABLE 4
Effect of PB and 3 MC on 1, 1 -Dichloroothylene (1440 ppm for 1 hr)
Hepatotoxicity 24 Hr Following IrJialation
Treatment
Saline
Saline
- Air
- Dichloroethylene
PB - Dichloroethylene
3MC -
Dichloroethylene
SGPT
6 t
18 t
41 t
10 1
1.6a
6.0
0.8
2 . (>
SOOT
17 t
31 1
44 t
40 1
0.
7.
16.
"5.
8
5
3
6
Reitman-Frankel Units.
s
TABLE 5
Effect of PB and 3 MC on 1, 1-Dich)oro«'thylcne Inhalation-Induced
Changes in Liver Glucose;-6-Pho-uphatase Activity
Pretfeatnu-nt
Corn oil
Corn oil
3MC
Saline
Saline
PB
1, 1 -Dichloroethylcuc
(ppm)
0
2270
2270
0 '
2990
'2990
Glucose -6-Phosphatase
16.8 1 1.21 ..
12. 9 1 0.64b
14.4 t 0.83
14.9 t 0.99
13. !S ± 0.31
13.5 1 1. 17
umoles
P < 0.05.
measured 48 hr after inhalation.
26
-------
TABLE 6
Effect of SKF 525A and Lilly 189-47 on Survival Time During Inhalation
of 1, 1-Dii-hloroelhylene
1, l-Dichloroethylene Survival Time (min)
(ppm) Control SKF 525A Lilly 18947
42,000 90 i 11.8 48 t 10. 3* , --
53,000 S3 1 14.5 -- 32 t 4. 1*
aP < 0.05.
TABLE 7
Lungs Weights Following 1 Hr Exposure to 1. l-Dichloroethylene
Pre- 1,1-Dichloro
treatment ethylene (pprr
Saline
Saline
PB
Corn oil
Corn oil
3 MC
aNumbf: r
0
3590
3590
0
3270
3270
of animals.
Lung
»)
4.
4.
5.
8.
5.
ft.
Wet Wt. 3
T,unL'
Body Wt. x 1U
76
54
05
25
65
26
to.
to.
t n.
±2.
to.
to.
76
35
79
16
25
57
(4)a
(4)
(4)
(4)
(4)
(4) ,
1.
1.
1.
1.
1.
1.
Dry
Wt
Body Wt.
25
14
02
57
14
36
to.
to.
to.
io.
to.
to.
25
C8
90
36
06
13
x 10-
(2)
(2)
(3)
(4)
(4)
(4)
27
-------
The 1972 threshold limit value (TLV) for vinylidene chloride, established
3
by the Manufacturing Chemists Association, is 5 mg/m (36).
In an effort to elucidate the mechanism of vinylidene chloride toxicity
Jaeger, et al., 1973, compared the effects of vinylidene chloride with those
of CC1., for which the mechanism of toxicity has been extensively studied.
The parameters studied were glucose-6-phosphatase (G-6-Pase) and serum
alanine-alpha-ketoglutarate transaminase (SAKT) activities, pentobarbital
sleeping time (PST), liver triglyceride content, malonyldialdehyde formation
in vitro, and conjugated diene levels in endoplasmic reticulum lipid.
The tests were performed on male Holtzman rats, 250-350 g, to which vinylidene
chloride and CC1, were administered by gavage. Results of the tests are
presented in Figures 2-9. Vinylidene chloride administration resulted in
decreased hepatic G-6-Pase, increased SAKT and liver triglycerides, and
prolongation of PST. Little or no effect on hepatic lipoperoxidation was
induced by vinylidene chloride, as evidenced by unchanged or reduced
levels of malonyldialdehyde and conjugated dienes. The authors concluded
that they found no evidence of a mechanistic similiarity between the
hepatotoxicities of vinylidene chloride and CC1, (25).
The correlation between diurnal variation of hepatic glutathione (GSH)
concentration and vinylidene chloride inhalation toxicity in rats was dis-
cussed in a 1973 paper by Jaeger, et al. In tests on male Holtzman rats
weighing 250-350 g, the hepatic GSH concentration was found to vary as
shown in Figure 10. To test the effects of this variation, two groups of
rats were exposed to 2,000 ppm vinylidene chloride, one group between 10 a.m.
and 2 p.m. and the other between 10 p.m. and 2 a.m. Serum alanine
alpha-ketoglutarate transaminase (SAKT) activity was measured 23 hours after
the end of exposure or at death. The 10 a.m. to 2 p.m. exposure caused
only a slight increase in SAKT and no lethality, while the 10 p.m. to 2 a.m.
exposure resulted in a marked increase in SAKT, and death in 2 of 5 rats.
The animals which died exhibited bloody ascites, while those that survived
showed no apparent signs of liver injury. The authors discussed the significance
of these findings for industrial hygiene (25).
28
-------
|O7) (5)
1
o eo
§ eo
o
U40
20
sooo
4000
3000
O
u
1000
o too 200 400 too
IJ-BCHLOROETHYLENE DOSE (mg/k«)
Fio. 2 Dose-response effect of 1,1-DCE on total hepatic G6Pase and SAKT. Rats, fasted and dosed
as described in Methods, were sacrificed at 24 hr. In this and subsequent figures, an asterisk indicates
significantly different from control at p < 0.05. The number in parentheses represents the number of
animals used in each experiment. Control values for total liver G6Pase were 88.2 ± 1.5 mg Pi/hr/100 g
body weight and for SAKT 0.28 ± 0.01 mg pyruvate/ml serum/hr.
240
200-
!|60.
Id
*" 120
e
Z
g 80
_i
(A
40
o
if}
(II)
(3)
(38) (5)
-*-
ft
T|
Tl
f|
0 100 200 400 800
1,1-OICHLOROETHYLENE DOSE
(mg/Kg)
FKJ. S Dose-response effect of 1,1-DCE on pentobarbital sleeping time"(PST). The same rats used
in Fig. 1 were used for these experiments. PST was determined between 20 and.24 hr.
8
£
£
(9
K
0
£
U
X
<
^J
H
^.^
H
§ SO
uj
,. 40
0
oi 30
5^
I20'
~" 0-
(13)
«^r
I_^^**t *
^^*-*""^ 1
\"^"^
0 100 200 400
(10)
f.
800
1,1-DICHLOROETHYLENE DOSE (mg/kg)
Fio4 -Dose-response effect of 1,1-DCE on total heptatic triglycerides, 24 hr after dosing. The values
plotted are corrected for changes in liver to body weight ratio. The unconnected data were also signifi-
cantly elevated at 400 and 800 mg/kg of 1,1 -DCE (8.2 ± 0.7 mg triglyceride/g wet tissue weight in controls
versus 11.1 ± 1.0 and 13.0 ± 1.0 for the two higher doses of 1,1-DCE).
29
-------
I.
(13)
3000
4000
3000
O
cc
o
u
2000 £
1000
CO
048 16 24
HOURS AFTER IJ-DICHLOROETHYLENE
(400mg/kg)
Flo. 5 time-response effect of 1,1-DCE on total hepatic G6Paseand SAKT activity. All rats were
fasted 28 hr before sacrifice. Values for control animals that had been given corn oil at various times
before sacrifice were the same as in Fig. 1. There was no difference due to different times of corn oil
treatment, and values for all control animals were pooled.
200
£ 160-
> 120
w
40
(5)
(9)
(38)
(10)
rfi
(ii)
rtf
CONTROL 2-4 4-8 12-16 20-24
HOURS AFTER 1,1-DICHLOROETHYLENE
(400 ma/Kg)
Fio. 6.Time-response effect of 1,1-DCE on pentobarbital sleeping time (PST). The rats described
in Fig. 4 were given pentobarbital sodium, 30 mg/kg ip, 2-4 hr before sacrifice and the PST was
determined.
0.50
5 0.40J
in
0.30
V)
O 0.10
Q.
O
(n-6)
Sjtl CCI4
60
75
90
INCUBATION TIME (min)
Fio. 7r Effect of CC14 and 1,1-DCE on in vitro lipid peroxidation. Whole liver homogenates from 6
male, nonfasted rats were treated with 5^1 of either 1,1-DCE or CCI4. All values of ODM3om are
corrected for the blank tissue absorption.
30
-------
0.70
0.60
5 oso
trt
> 0.40
55
5 0.30-j
o 0.20
a.
o
0.10
CCI4
2.5 ml/Kg
(10)
CORN OIL
CONTROL
(10)
60 75 90
INCUBATION TIME (mln)
FJO. 8effect of in vivo treatment with 1,1-DCE or CCU on in vitro lipid peroxidation. Rats were
fasted overnight and dosed the following morning with corn oil (2.5 ml/kg), 1,1-DCE (1 ml/kg) or
CC1« (2.5 ml/kg). One hour after dosing, the animals were sacrificed, and the liver homogenates were
prepared. The experimental procedure was identical to the experiment in Fig. 6 except that exogenous
addition of the chlorinated hydrocarbons was omitted.
CONTROL (17)
I.I-OCE
4 10 20
HOURS AFTER DOSING
Fio. 6 Effect of CCU and 1,1-DCE on microsomal conjugated dienes. Rats, fasted 20-28 hr before
sacrifice, were dosed with corn oil, 1,1-DCE or CCI* as described for Fig. 7. At the indicated times after
dosing, the animals were sacrificed (1-2 PM), their livers were removed, and conjugated dienes were
measured as described in methods. The results shown in this figure represent the weight-corrected
amounts expressed as a percentage of pooled control values (0.21 ± 0.01 OD243nm/IOO g body weight).
z
o
9.0
SH
a: x
£ ^8.0
ijj Ul
0 *
z 70
o >
°§
uj CD 6.0
§-
^ o
H 2 5;0
1 ^
3 6 4.0
o
t
';
i
\;\
Fed - «
Fast - »
n = 3/poinl
*
4 7 10 I 4 7 10 I 4 7 10 I 4 7 10 I 4"
''» AM PM AM
CLOCK TIML (tOSTi
t Day I f Day 2 t Day }
F'igur,. ]_Q
OIURNAL VAKJATION Of HEPATIC GLUT ATM IQiJE CONCRMT^flTloN TM
31
-------
In tests using male Holtzman rats, 225-325 g, Jaeger and Murphy, 1973
found that vinylidene chloride (400 mg/kg, p.o.) prolonged pentobarbital
sleeping time between 2 and 4 hours after administration. Liver
injury, as measured by glucose-6-phosphatase depression was not detected
at this time, and hexobarbital sleeping time was not affected. At 17 to 22
hours after dosing, both pentobarbital and hexobarbital sleeping times were
prolonged, and hepatic injury was apparent. The authors suggested that
orally administered vinylidene chloride affects the absorption or distribution
of pentobarbital. The metabolism of pentobarbital did not appear
to be affected, since the rate of its disappearance was determined to be
similar in vinylidene chloride-treated and control rats (26).
In a brief communication published in 1973, Jaegar, et al., reported
that following a single oral dose (400 mg/kg) of vinylidene chloride, both
adrenalectomized (ADX) and sham rats had similar 24-hour mortalities. The
ADX rats, however, exhibited an apparent decrease in hepatic injury as
measured by serum AKT elevation and the degree of bloody ascites
and hemorrhagic congestion. Corticosterone treatment, which significantly
elevated serum and AKT liver activity in ADX rats, resulted in a slight
decrease of lethal effects of vinylidene chloride in both ADX and sham
rats. Prolonged (45 hour) fasting potentiated hepatic injury as measured
by the 4-hour elevation of serum AKT. Glucose (25% ad lib) provided some
protection against lethality in ADX rats. When vinylidene chloride was
administered by inhalation for 4 hours, the LC for fed rats was estimated
to be between 10,000 and 15,000 ppm, while the LC,-0 for fasted rats was
between 500 and 2500 ppm (30).
In 1973, Bando and Rosenbaum reported that when HeLa cell cultures,
in tubes, were covered with Saran Wrap, a copolymer of vinyl and vinylidene
chlorides, no cytotoxicity was induced. However, when the plastic wrap was
cut to fit inside plastic petri dishes and the HeLa cell suspension
cultured thereupon, extensive degeneration was observed at 72 hours, but
not before, in the cells overlaid on the Saran (5).
32
-------
In a 1974 report, Jaeger, et al., related findings on the effects
of fasting and glutathione depletion on vinylidene chloride toxicity.
Male Holtzman rats weighing between 250 and 400 g were used in the experiments.
By exposing fed rats to vinylidene chloride vapors for 4 hours and then
observing them for 24 hours, the LC5Q was determined to be 15,000
ppm. Similar treatment of rats that had been fasted for 18 hours prior
to exposured yielded an LC-_ of 600 ppm. The minimum lethal concentrations
for the fed and fasted rats were 10,000 and 200 ppm, respectively. Deter-
mination of the 24-hour serum alanine-alpha-ketoglutarate transaminase
(AKT) activity after a 4-hour vinylidene chloride inhalation exposure
disclosed a dose-related increase which was much greater in fasted than in
fed rats. Reversal of the feeding schedule (refeeding fasted rats or fasting
fed rats) 2 hours prior to vinylidene chloride exposure did not alter the
toxic effects. Analysis of blood and liver samples from vinylidene chloride
treated rats demonstrated that altered distribution of the compound cannot
account for the difference in sensitivity between fed and fasted animals (27).
Jaeger, et al., also performed in vitro experiments on perfused rat
livers to determine if vinylidene chloride-induced hepatotoxicity results
from a direct effect, on the liver. The perfused livers were exposed to a
concentration of 20,000 ppm vinylidene chloride in the gas phase. After
3 hours the livers of fed rats showed no change in weight or perfusate AKT.
The livers of fasted rats, however, began to appear grossly damaged within
2 hours, becoming pale and swollen, with decreased flow. At the end of
3 hours both their weight and the perfusate AKT had increased markedly. In
experiments to determine a biochemical difference between fed and fasted rats
which could account for the difference in sensitivity to vinylidene chloride,
alanine, sodium oleate and glucose were added to the perfusate without
effect. Exposure of fed animals to cold stress and epinephrine prior to
vinylidene chloride exposure also failed to effect the sensitivity (27).
Measurement of hepatic glutathione (GSH) concentration revealed a
significant reduction in fasted rats, compared to fed rats. Vinylidene
chloride exposure caused a reduction of hepatic GSH in both fed and
33
-------
fasted rats. The degree of reduction, however, did not correlate with
hepatic injury. To test the possibility that GSH depletion causes
enhanced sensitivity to vinylidene chloride, Jaeger, et al., pretreated
fed rats with diethylmaleate (DEM) (0.25 ml/kg, i.p.), a compound which
depletes hepatic GSH but is not known to cause liver injury. Upon exposure
to vinylidene chloride at 1000 ppm for 4 hours, the DEM-treated rats
showed a 42-fold elevation of serum AKT, while vehicle-treated rats showed
only a 3.8-fold increase. The DEM-treated rats exhibited bloody ascites
and hemorrhagic liver enlargement. One of these rats died at 5 hours, although
the vinylidene chloride concentration was well below the minimum lethal
concentration (10,000 ppm) for fed rats (27).
To further test the hypothesis that depletion of hepatic GSH is
responsible for the alteration of sensitivity to vinylidene chloride, the
in vitro effect of DEM was tested in the isolated rat liver system.
The addition of DEM (25 mcl) to the perfusate of vinylidene chloride-
treated livers from fed rats resulted in an increase of perfusate AKT
comparable to that seen in the perfused livers from fasted rats (27).
In a 1974 article, Siletchnik and Carlson reported the results of experi-
ments on the cardiac sensitizing effects of vinylidene chloride, and its
enhancement by phenobarbital (PB) pretreatment. The test animals were
male Charles River albino rats weighing between 250 and 400 g. The animals
were lightly sedated with 25 mg/kg sodium pentobarbital i.p. and restrained
in a supine position. The animals were placed in an air chamber and
injected with epinephrine at a dose of 4 meg/kg. The rats were then exposed
to 25,600 ppm vinylidene chloride for 10 minutes or more and the dose of
epinephrine titrated to determine the minimum concentration necessary to
produce arrhythmias or demonstrate a difference between pairs of animals.
The effect of PB pretreatment was studied in pairs of rats, one of which
was pretreated with PB 50 mg/kg i.p. for 4 days (controls received saline)
and exposed to vinylidene chloride 24 hours after the last dose (48).
Exposure to vinylidene chloride alone caused progressive sinus
bradycardia accompanied by arrythmias which took the form of AV-block,
34
-------
multiple continuous premature ventricular contractions and ventricular
fibrillation. The dose of epinephrine necessary to elicit cardiac
arrhythmias in vinylidene chloride-exposed rats was as low as 0.5 meg/kg,
while doses of 4 meg/kg failed to elicit arrhythmias in the air-exposed
rats. The dose of epinephrine necessary to elicit arrhythmias in
vinylidene chloride-exposed rats was time-dependent, as shown in Figure 11.
The data in Table 8 indicates that PB pretreatment enhances the ability
of vinylidene chloride, thereby hastening the amount of cardiotoxic
metabolite formed (48).
The death of 4 workers in a B.F. Goodrich PVC plant prompted labor
unions, in 1974, to demand emergency controls on the occupational exposure
to vinyl chloride or other chemicals involved in its production or use.
The 4 workers had average exposures of some 19 years to vinyl chloride
and 10 years to vinylidene chloride, with variable exposures to such
chemicals as vinyl acetate, methyl aerylate, ethyl aerylate, methanol,
and chlorinated solvents. Death was attributed to angiosarcoma of the
liver, a disease so rare that NIOSH believes that it causes only 20 to 30
deaths a year throughout the U.S. (52).
A 1975 report by Reynolds, et al., examined the role of the mixed
function oxidase system (MFOS) in the acute toxic responses of animals to
vinylidene chloride. Differential induction of MFOS components was
achieved by treating 200 g male Sprague-Dawley rats with 400 mcM/kg doses
of phenobarbital (PBT), 3-methylcholanthrene (3-MC), hexachlorobenzene
(HCB), spironolactone (SNL), or prenenolone-16-alpha-carbonitrile (PCN)
or 150-300 mcM/kg doses of Arochlor 1254 (1254) by gavage once daily for
7 days. On the 8th day the animals were exposed to 200 ppm vinylidene
chloride in the atmosphere for 4 hours, and sacrificed 2 hours thereafter (44)
Vinylidene chloride exposure resulted in extensive liver injury, which
occurred earlier and was more extensive in fasted than in fed rats. In
fasted rats, parenchymal cell injury, characterized by retraction of cell
borders and the formation of pericellular lacunae became apparent within
2 hours of the onset of exposure. Such cells showed loss of perinuclear
35
-------
8.0-
S1
?
u
± 700 ppm. (8) Continuous premature ventricular contractions.
(') PB injected 50mg/kg i.p. for 4 days. (') Spontaneous, no epinephrine injected.
36
-------
chromatin and clumping and coalescence of perinuclear chromatin into
temporary cresentic deposits of electron-opaque material against the nuclear
envelope. Mitochondria appeared swollen, with ruptured outer membranes.
Following vinylidene chloride exposure, the zone of injured midzonal
parenchymal cells became confluent, forming a prominent midzonal stripe
of necrosis; hemorrhagic centrolobular necrosis rapidly ensued, becoming
readily apparent within 6 hours. Necrosis was minimized by PBT and abolished
by 1254 pretreatment; HCB, 3-MC, SNL and PCN were without effect. In
contrast, PBT, 1254 and HCB potentiated the hepatotoxic action of vinyl chloride
monomer (VCM; 5,000 ppm, 6 hour). Liver glutathione content was decreased
and serum alanine alpha-ketoglutarate transaminase activity, an
indicator of hepatic injury, greatly increased by vinylidene chloride
exposure in all rats except those pretreated with 1254. The authors found
a strong correlation between the degree of injury induced by vinylidene
chloride, or VCM, and mean total microsomal cytochrome P-450 content (44).
The histological changes induced in the livers of adult male Holtzman rats,
250-350 g, by exposure to 200 ppm atmospheric vinylidene chloride for 4 hours
were described in a 1975 report by Jaeger, et al. Within 2 hours after
exposure, massive midzonal hepatic necrosis with hepatic thrombosis
and chromatolysis were apparent in the livers of fasted, but not fed, rats.
Subsequently, the central portion of the lobule collapsed, accompanied by
congestion, ascites and an increased hematocrit. Early changes were observed
in the nucleus, mitochondria and plasma membrane, indicating that these
organelles are primarily affected by vinylidene chloride (31).
The results of an investigation of the interaction of acetone and
vinylidene chloride are shown in Table 9. A 2-hour exposure to 10,000 ppm
acetone either prior to or concurrent with vinylidene chloride exposure
(2,,000 ppm, 4 hours) resulted in a significant increase in serum AKT
activity at 6 hours in fed rats (31).
37
-------
Table 9 Effect of acetone exposure on the serum ART
response to inhaled 1,1-DCE in fed rats.*
Serum AKT, mg pyruvate/
N ml-hrb
6 hr 24 hr
Air + l.l-DCE 10 0.37±0.05 0.43±0.03
Acetone before 1,1-DCE 5 1.10±0.20<* 1.39±0.34°
Acetone with 1,1-DCE 5 1.02±0.41« 0.54±0.15
Fasted rats 3 13.45±1.92
(5)' (4)' (1.22-23.58)"
SKF-525A* 0.60 ±0.08 18.34
(5)' (2)' (9.10+27.68)"
II Saline 0.32±0.04 17.72±1.47b
(5) (3)- (2 died)
Cysteine* 0.75±0.09: 2.43±0 75d' '«
(5) (5)
Numbers in parentheses indicate number of animals in
groups N.
b p <0.05 when compared to fed rats.
' Values in parentheses are ranges.
" 50 mg/kg, IP.
, 500 mg/kg, IP.
1 p<0.05 when compared to saline control rats.
p<0.05 when compared to fed saline pretreated rats.
i
To further test the interaction between vinylidene chloride and VCM,
rats were exposed to 10,600 ppm VCM for 5 hours prior to a 4 hour exposure
to 2000 ppm vinylidene chloride. As shown in Table 11, VCM, which depleted
38
-------
liver GSH, significantly enhanced vinylidene chloride hepatotoxicity,
as evidenced by increased serum AKT and SDH activities (31).
Table 11 Effort of prior VCM exposure on serum AKT+
SDH after 1,1-DCE exposure in fed rats.
Exposure conditions
Unexposed controls
Air + 1,1-DCE
VCM (5hr) + l.l-CDE
N
50
5
5
Serum
AKT, mg
pyruvate/
ml-hr'
0.20-0.40
0.38±0.01
(0.35-0.43)
3.77±1.39b
(0.94-8.22)
Serum
SDH,
units/ml
serum-
min*
. 5-10
6.2±1.0
(4.4-10.0)
548±190b
(42-1178)
Values in parentheses are ranges.
b p<0.05 compared to animals also given 1,1-DCE but
previously exposed to air. See text for details.
The results of a further study by Jaeger, et al., 1975, on the interaction
of vinylidene chloride (DCE) and vinyl chloride monomer (VCM) are presented
in Table 12. Adult male Holtzman rats were used in this study. The
combined exposure to VCM and vinylidene chloride in molar ratios of 5:1
arid 3:1 resulted in complete protection; at an equimolar ratio, protection
was not complete. Measurement of serum sorbitol dehydrogenase, another
index of hepatotoxicity, confirmed the protective action of VCM (28).
Table 12 -Effect of a 4-hr VCM and/or DCE Exposure on Serum AKT Activity
In Fed or Fasted Rats (Killed) at or Before 6 hr
Atmosphere Concentration,
ppm
VCM
DCE
Fed
Serum AKT Activity.
mg pyruvata/ml/hr
(N = 5) Fasted
0.2-0.40*
1.122 ±46
1,056 ±68
671 ±116
201 ±12
12.093 ±929
205 ±7
195^15
210±9
190 ±7
1. 981) ±76
1.971 ±50
0.80 ±35
0.21 ± .03
0.21 ± .01
0.24 ±.05
0.22 ± .01
. 0.21 ± .01
0.24 ± .01
- 160B±8.95t
0.16 ±.02
0.21 ± .02
' ' 2.00 ±1.43*
9.73±2.45t9
0.18 ± .03
* Control range, see footnote Table 2. >
t P <.05 when compared to air control. 1
$ Two rats In this group had severe liver Injury while the other three were normal.
5 These rats were killed in extremis before 6 hr. :
39
-------
In a recent (1975) communication, R.J. Jaeger briefly reported on a
series of experiments to determine the interaction between vinyl chloride
monomer (VCM) and vinylidene chloride. Exposure of fasted rats to 0.02%
(v/v) atmospheric vinylidene chloride for 4 hours produced a 50-fold
increase in serum alanine alpha-ketoglurate transaminase (SAKT)
activity at 2 hours after the end of exposure. Exposure to 0.1% VCM
was without effect on SAKT. When 0.02% vinylidene chloride and 0.1%
VCM were administered to fasted rats simultaneously for 4 hours, there was
a complete lack of injury in the rats killed 2 hours later. Thus, VCM
prevented vinylidene chloride injury. This protection was concentration
dependent, and was still apparent at a 1:1 molar ratio (24).
The findings of a study by Bonse, et al.^ on the uptake and metabolism
of chlorinated ethylenes in relation to their acute liver toxicity were
reported in an article published in 1975. Livers of female Wistar rats, 170-
230 g, were exposed to the test chemicals by adding the chemicals as
vapors to the carbogen, a 5% CCL and 95% 0,- mixture, used for oxygenating
blood in the perfusion. Results of the tests are shown in Table 13. Vinyli-
dene chloride was readily taken up by the system and resulted in increased
hepatic enzyme activities. No metabolites of vinylidene chloride were
determined (7).
In a 1975 review of the literature on vinylidene chloride, T.J.
Haley postulated the biotransformation pathway for vinylidene chloride
presented in Figure 12 (18).
Van Each and Van Logten, 1975, suggested that the presence of the
double bond in vinylidene chloride could lead to free radical formation
during metabolism, with the resultant product acting as an alkylating
agent (50).
Vinylidene chloride was tested for mutagenicity by McCann et al., 1975,
using the Salmonella/microsome test. Petri plates containing several
specially constructed mutants of Salmonella typhimuriun (to which homogenates
of rat or human liver had been added to provide metabolic conversion of
40
-------
Table 13 Comparative metabolism of chlorinated ethylenes in .the i|olated perfused
rat liver under equimolar substrate concentrations (55.0-2.5 nmol/ml) .
Each value represents the mean of 3 to 5 experiments.
Compound
(cone, gas-"
phase ppm)
Cl% ,CI
,C=C,
Cl Cl
H ,CI
e=c
/ \
Cl Cl
H . H
c=c
Cl Cl
Hx Cl
c = cx
Cl H
Cl H
V f
/c c
cr H
Uptake8'
(nmol/ml)
* .
=
1 " . ) |
±a.
[-,.., .^... |
' 20 40
i i i i
Solubilityb)
in liver
tissue (%)
41 ± 5
4 i 1
-> + i
3-1
6 i 2
4.
1 - 0.5
Metabolitesb)
(%)
CCl-jCOOH 1O-15
(perfusate)
CC13COOH 3-5
(bound -in tissue)
CC1,CHO 2-4
CCl^COOH 15 -2O
CC13CH2OHC) 65-75
CHC12COOH 1-3
CHCl-CH.OH 8-1O
CHC12COOH
0.5-1
CHC12CH2OH
3)
Enzyme a<
lactate/
pyruvate
O1 6O1 18O'
7.3 7.4 7.9
t ± t
2.2 2.2 2.4
7.9 7.9 8.0
+ + +
2.5 2.5 2.5
8.0 7.1 17.4
+ + +
2.5 2.2 4.0
7.4 6.7 12.3
+ +. +
2.2 2.1 3.O
7.4 6.6 11.7
+ + +
2.3 2.2 2.9
:tivities (perfusate
GPT
(mU/ml-g live
O1 60' 12O' ISO1
1.9 2.2 2.2 2.4
+ + + +
0.6 0.8 O.8 O.8
2.0 2.1 2.1 2.1
+ + + +
O.8 O.8 0.8 O.8
1.8 2.0 7.7 23.0
+ + + +
0.8 0.8 3.O 4.5
1.4 1.5 1.5 3.6
+ + + +
0.4 O.6 O.6 1.2
1.2 1.4 1.4 4.0
+ + + +
0.3 0.3 0.3 O.8
)
GOT
r-\
O' 60' 120' 18O'
1.8 1.9 2.2 2.2
+ -t- + +
0.6 O.8 O.8 0.8
1.9 1.9 2.2 2.3
+ + + +
3.8 O.8 O.8 O.9
I. 8 2.O 5.2 14. O
+ + + +
).8 O.8 2.O 3.5
L.9 2.4 3.1 5.4
!± i ± ±
D.8 0.8 1.0 1.4
1.2 1.4 2.3 4.6
i-
+ + + +
.3 0.3 0.8 1.0
a)
b)
c)
d)
uptake (at 6O -min), conditions: perfusate flow 1.0 - O.O5 ml/min-g liver"1.
all values as percent of total uptake.
total = free (5%) and conjugated (95%) forms.
not determined.
-------
i n m
ChC = CHa - ^ ClaC^CH - ^ ChCH - CHO
Vinylidene Chloride <>' Dichloroacetyl-
Diehloroethyleneoxide aldehyde
IS I
H
glutathione '
ClaC -CH + GSH - =-r - -. - ^ ChC - C-OH
V/ epoxytransf erase i |
0 H SO
sn
ChCH - CHOH
S-CH2-CH-COOH
NH Dichloroacetic Acid
COCH3
Mercapturic Acid Derivative
FIG. 12 Postulated biotransformation of vinyliclene chloride by
hepatic mixed function oxidases.
the chemical to an active form) were exposed to an atmosphere of vinylidene
chloride (concentration and duration not specified) . By counting the
number of histidine revertants per plate, it was found that vinylidene
chloride is weakly mutagenic. Upon testing 174 carcinogens, the authors
reported that this test method shows a high (90%) correlation between
mutagenicity and carcinogenicity (37) .
To study the mutagenicity of vinylidene chloride, Greim, et al.,
1975, employed a metabolizing in vitro system with E coli K 12. Cultures
of this bioauxotrophic strain were suspended for 2 hours in an incubate
containing mouse liver microsomal enzymes, an NADPH-generating system
arid 2.5 mM vinylidene chloride. A mutation rate of slightly more than
twice the spontaneous rate was detected in the arginine genes . Other
genes tested showed little or no mutation. When the tests were performed
without the addition of microsomal enzymes, no mutagenic activity was
observed. This indicates that it is not vinylidene chloride itself but
a metabolite that is the mutagenic agent (17) .
42
-------
Using the histidine-auxotroph strains of Salmonella typhlmurium TA1530
and TA100, Bartsch, et al., 1975, examined the tissue-mediated mutagenicity
of vinylidene chloride. Incubates containing the baceria, an NADPH-
generating system and mouse or rat liver, kidney or lung fractions were
exposed to vinylidene chloride vapor in a desiccator at atmospheric con-
centrations of 0.2, 2 or 20% for up to 4 hours. The concentrations of
vinylidene chloride in the aqueous phase after 2 hours of exposure to 0.2,
2 and 20% in the air were 0.33, 3.3 and 33 mM, respectively. Results of
the tests are shown in Figure 13 and Table 14. The mutagenic response of
both strains increased after exposure to up to 2% vinylidene chloride.
The authors suggested that the lower mutagenic response observed with
20% vinylidene chloride may have resulted from an inhibitory action of the
compound or its metabolites on the microsomal enzymes responsible for its
metabolic activation. A linear increase, with time, in mutagenic response
was observed when TA100 strain was exposed to 2% vinylidene chloride for
periods of up to 4 hours. Ommission of the NADPH-generating system from
the incubate resulted in a complete absence of mutagenic response (6).
In further studies, Bartsch, et al., found that pretreatment of
female BD-VI rats with phenobarbitone (0.1% in the drinking water for 7
days) increased the mutagenic effect of exposure to 2% vinylidene chloride
in air on S. typhimurium; pretreatment with pregnenolone-16alpha-carbonitrile
(50 mg/kg, 5 times orally at 12 hour intervals) or aminoacetonitrile (500
mg/kg, single s.c. dose, 24 hours before the assay) or the addition of
N-acetyl-cysteine and N-acetyl methionine (12 mcM of each per ml soft
agar layer) resulted in a reduction of mutagenic response (6).
Prof. P.L. Viola of Regina Elena Institute for Cancer Research, in Rome,
has reported (1975) that vinylidene chloride may be carcinogenic to rats
in high concentrations via inhalation. Viola allegedly has found tumors
in animals exposed to the chemical (53).
The Dow Chemical Corporation has stated (1975) that the average exposure
of a production facility employee to vinylidene chloride monomer rarely
if ever reaches the TLV of 10 ppm (7).
43
-------
~i
8
9
10
11
12
13
14
15
16
17
18
Yes
Yes
No
No
Yes
Yes
OF- 1 mousey No
No
Yes
Yes
No
No
No
No
No
BDV1 rat ? No
No
No
+ 500
-) )
Liver -f 330
16
-f- 147
- 31
Kidnev + 67
20
4- 34
5
Lung 4- 21
- 6
-.- 95
Lner - 0
+ 18
Kidney - IS
.+ y
Lung - 9
-23
-10
-49
.i; 4
'15
: 7
-t
3
4
: 4
5
. 9
7
: 4
; -»
T
:' 7
150
5
100
5
45
9
20
6
10
1
6
>
30
0
5
5
3
3
20% VDC in air
his* Reljim
revertanis activm
per plate 5
330
7
435
1
173
17
i25-
16
48 ;
10
37
14 :
77-
: 29
- 5
46
' 1
:: 5
, T
- 5
- \ .
5
. 1
3
: 8
S
-> ' ->
16 i 2
21 4
11 2
12 : f.
7J
2
100
0
40
4
11
*
II
I
i
3
18
0
4
S
)
3
'Assays carried out as described in Fig. I.
fEqulvalent to 38 nig wet tissue per plate.
JNADP' (2.0 umol per plate) and glucose-d-phosphate (2.5 umol per plate).
tjMeun values ' s.c. from 1-4 experiments, each using pooled tissues from 4 mice or 3 rats. The number of spontaneous mutations per
(49 ; 2) ha:, been subducted from each value.
Relative mulagenic activity was expressed by taking (he value obtained in experiment 3 as 100.
44
-------
To estimate the persistance of low-molecular-weight chlorinated hydrocarbons
in natural water bodies, Billing, et al., 1975, carried out laboratory studies
on evaporation and reaction rates at the 1-ppm level in water under ambient con-
ditions. Vinylidene chloride evaporated to the extent of 50% in 22 minutes and
90% in 89 minutes when stirred in water at 25°C. The hydrolytic-oxidative reaction
half-life of vinylidene chloride was not determined, but that for related
chlorinated hydrocarbons was 6-18 months. The authors concluded that
1 ppm concentrations of low-molecular-weight chlorinated hydrocarbons would not
persist in agitated natural water bodies due to evaporation (14).
To derive information on the atmospheric degradation of halogenated compounds,
Gay, el: al., 1976, studied the photooxidation of chlorinated ethylenes in air
in the presence of nitrogen dioxide with ultraviolet light. At a concentration
of 4.85 ppm, in the presence of 2.26 ppm NCL, vinylidene chloride was found to
decompose rapidly (83% in 140 min). The reaction products identified were
formic acid, hydrochloric acid, carbon monoxide, formaldehyde, ozone, phosgene,
chloroacetyl chloride, formyl chloride and nitric acid. Possible reaction
mechanisms were discussed (16).
On the basis of laboratory studies on photolysis rates under simulated atmospheric
conditions (100 ppm vinylidene chloride with 5 ppm N0?; 27°C), Dilling, et al.,
1976, calculated the half-life of atmospheric vinylidene chloride to be 2.1 hours (13).
The gas-phase room-temperature oxidation of haloethylenes was reviewed by
Heicklen, et al., in 1975. Tests have been performed on five types of oxidation:
(1) chlorine atom initiation, (2) Hg 6(3P) sensitization, (3) reaction with 0(3P),
(4) reaction with 0( P) in the presence of 0 , and (5) reaction with 0 (20).
The Cl-atom initiated and Hg 6( P) sensitized oxidations of vinylidene chloride
proceed by a long-chain free radical process. Reaction with 0( **) results in
double-bond cleavage. Ozonolysis proceeds by a chain oxidation, carried by a di-
radical mechanism, but is inhibited in the presence of 0_ (20).
The authors concluded that chloroolefins in the atmosphere will generate
chlorine atoms and oxidize in a chain process. For vinylidene chloride, the
relative imporatnce of C=C cleavage, excited molecule and rearrangement pro-
cesses were calculated to be 31:55:14, respectively (20).
45
-------
Sweden has set its exposure level for vinylidene chloride at a
recommended 1 ppm, with a maximum of 5 ppm weighted average for 15 minute
periods (22).
Local hemolysis tests on rat spleen samples in gel, performed by
L.Shmuter in 1976, demonstrated that dichloroethylene (isomer not specified)
at a concentration of 25 mg/1 stimulates, while 5 mg/1 inhibits, the
formation of cells producing antibodies to typhoid antigen, as well as the
plasmocytic reaction of the spleen following immunization of the 0-
aiitigen from Sal. typhi (46).
Harms, et al., 1976, reported on the action of chlorinated hydrocarbons
on bile duct-pancreatic fluid in laboratory rats. Male Sprague-Dawley rats
were treated with 0.5 ml/kg vinylidene chloride i.p., in 4 volumes of corn
oil one day before testing; this dose approximated the LD-,.. The first test
3
consisted of a retrograde intrabiliary injection of H-inulin followed by
a 6-minute period of occlusion, holding the H-inulin solution in the biliary
tree* then collecting and analyzing each drop of bile. Dilution of the
3
K-inulin content in the drops from the distant portion of the biliary
tree was accomplished by increased excretion of bile duct-pancreatic fluid
into the duct system during the 6-minute occlusion period. Recovery of
this retrogradely inject inulin was not significantly different from
controls, so a double cannulation method was utilized (19).
The second method consisted of cannulating the common bile duct at
the proximal bifurcation to collect hepatic bile and distally at the duodenum
to collect bile duct-pancreatic fluid. Pretreatment with vinylidene chloride
brought about a marginal depression in hepatic bile flow, but significantly
increased bile duct-pancreatic fluid flow at the same time. Histopathologic
examinations indicated that one out of 5 rats had liver necrosis, the
remaining ones showed slight congestion. Only mild nonspecific interstitial
inflammation and congestion were noted in the pancreas and common bile duct (19),
3
Recovery in hepatic bile of H-ouabain administered intravenously 1
hour earlier was marginally depressed in vinylidene chloride treated rats (19).
46
-------
In a current investigation sponsored by the Manufacturing Chemists
Association in cooperation with Dow Chemical Corporation, the following projects
are being conducted:
1. A toxicological study on the effects of vinylidene chloride included
in the drinking water of rats for 90 days and two years.
2. A toxicological study of vinylidene chloride in peanut oil fed to
dogs for 90 days.
3. A 90 day and two year vapor inhalation study of vinylidene chloride
on rats.
4. A study of the effects of maternally inhaled or ingested vinylidene
chloride on rat and rabbit embryonal and fetal development.
5. A study of absorption, distribution, metabolism and excretion
of ingested and inhaled vinylidene chloride in rats.
To date, only the first two 90 day studies have been completed, and those
showed no evidence of carcinogenicity of vinylidene chloride (22).
The teratogenicity of vinylidene chloride is currently being studied by
Midwest: Research Institute under contract to the EPA office of Toxic Substances.
A report is expected by January 1977 (9).
Vinylidene chloride is produced by only 3 plants in the U.S. - PPG,
Lake Charles, La.; Dow Chemical, Freeport, Texas and Plaquemine, La. Production
losses from these plants are estimated to release 3.355 million pounds of
vinylidene chloride into the environment annually (See Table 15). An additional
709,400 pounds are estimated to be released during polymer synthesis and pro-
cessing (See Table 16) (22).
47
-------
TABLE 15?
EMISSIONS OF VINYLIDENE CHLORIDE
Producer
PPG
Dow Chemical
Location
Lake Charles, La.
Freeport Texas
Plaquemine, La.
TOTAL
Total annual emmisions (Ibs/yr)
2,920,000*
175,000**
289,000
146,000
3,355,000*
610,000**
Xmg /m Enmlsslon in Ibs/lOOlbe
VDC monomer
3.06 1.72 - 1.67
.1 83 ' .10
.3 03
.51 - .48
.1 53
*Emissions using an existing control technology.
**Emissions reflecting new control technology at PPG plant by late 1975.
TABLE 16
ESTIMATED ANNUAL EMISSIONS OF VINYLIDENE CHLORIDE IN THE U.S.A.
A. Monomer Synthesis
B. Polymer Synthesis
Total
1. Latex for Burner Coatings
2. Latex for Miscellaneous Coatings
3. Synthetic Fibres
4. Coating Resin for Cellophane
5. Extrusion Resin (Emulsion)
6. Extrusion Resin (Suspension)
C. Fabrication Polymer Processing
Total
1. Coating Cellophane
2. Coating Plastics, Paper and Glassine
3. Extrusion
4. Miscellaneous Coating
TOTAL
Ibs/yr
3,355,000*
611,000**
679 ,000
120,000
150,000
160,000
182,000
27,000
40,000
30,400
1,600
16,400
400
12,000
4,064,000 Ibs/yr.
*Emissions using an existing control technology.
**Emissions reflecting new control technology at PPG plant by late
1975' 48
-------
Appendix A. Factors to be Identified
Research Request No. 1
Contract No. 68-01-4116
Information to be derived in the literature search shall
include:
I. Health Impact
A. Toxicological data.
1. Absorption/ excretion, transport, and
distribution.
2. Metabolic effects.
3. Pharmacology.
4. Biochemical descriptions of effects on
organs, cells, enzyme systems, and nucleic
acids and proteins.
5. Acute, subacute, and chronic toxicity.
6. Sensitization from repeated doses.
7. Teratogenicity and mutagenicity.
. 8. Carcinogenicity.
9. Dose-response relationships.
10. Behavioral effects.
11. Synergisms and related interactive effects
with other chemicals.
B. Epidemiological data.
1. Occupational exposure studies.
*
2. Environmental incidents, poisonings, and
case histories.
3. Clinical and subclinical manifestations.
4. Statistical or risk-comparison studies.
5. Other controlled studies.
49
-------
Appendix A. Factors to be Identified (continued)
II. Environmental Impact.
A. Environmental fate.
1. Chemical and biochemical reactions,
including degradation and chemical inter-
conversion, in the environment.
2. Transport in soils, aquatic systems,
and biota.
B. Environmental/ecosystem effects
1. Fish and other aquatic organisms.
2. Birds.
3. Mammals of economic importance.
4. Other terrestrial organisms.
[Note: To the extent, these impacts should
be related to the categories under I, A, above.]
5. Atmosphere and/or climate.
6. Manmade structures.
III. Monitoring Data and Exposure Levels.
A. Human exposure profile, defined in geographic
terms, if necessary.
B. Exposure of other organisms, and assessment of
degree of risk.
C. Monitoring data.
N.B. It is recognized that all of these subjects may not
be presented in the literature. This listing reflects
information needed, but a determination of nonavail-
ability is also important. The contractor should
notify the Project Officer of gaps in the literature,
as soon as the determination has been made.
50
-------
Appendix B. Sources Used in Vinylidene Chloride Search
Secondary Journals (1950-present)
Air Pollution Abstracts
Biological Abstracts
Bioresearch Index
Chemical Abstracts (1907-present)
Chemische Zentralblatt
Current Contents (1976 only)
Excerpta Medica
Pharm and Toxicol
Public Hlth., Soc. Med. and Hygiene
Occup. Hlth. and Ind. Med.
Devel. Biol. and Teratol.
FDA Clinical Experience Abstracts
Index Medicus
Industrial Hygiene Digest
Pollution Abstracts
Referativnyi Zhurnal
On-line Data Bases
CAIN
CANCERLINE
ENVIRONLINE
MEDLINE
NTIS
SCISEARCH
TOXLINE
51
-------
Bibliography
1. Aleksandrowicz, R., W. Mazurowski, J. Wislawski, J. Lozinski and
K. Gralinska. 1972. Influence of polymers used for reinforcing
of blood vessels on tissues of test animals. Polimery Med.,
2(1):77-81.
2. Altman, P.L., D.S. Dittmer. 1966. Environmental Biology. Federation
of American Societies for Experimental Biology, Bethesda, Md.,
pp. 326, 328.
3. American Conference of Governmental Industrial Hygienists. Documentation
of the Threshold Limit Values for Substances in Workroom Air.
Cincinnati, Ohio, pp. 351-352, 1971.
4. Anderson, W.L. and R.A. Saunders. 1963. Evolution of materials in the
closed system. Symposium on Toxicity in the Closed Ecological
System (M. Honma and H.J. Crosby, eds.), Lockheed Missiles and
Space Co., Palo Alto, California, pp. 9-18.
5. Bando, B.M. and M.J. Rosenbaum. 1973. Toxicity to HeLa cells mediated by
plastic wraps. Lab. Pract., 22:26.
6. Bartsch, H., C. Malaveille, R. Montesano, L. Tomatis. 1975. Nature
(London), 255(5510):641-3.
7. Bonse, G., T. Urban, D. Reichert, 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):1829-34.
8. Broser, F. 1970. Irreversible lesions of the trigeminal nerve caused
by chlorinated acetylenes in two patients. Deut. Z. Nervenheilk,
197(2):163-170.
9. Brunner, p.: Personal Communication
10. Carlson, G.P. and G.C. Fuller. 1972. Interaction of Modifiers of hepatic micro-
somal drug metabolism and the inhalation toxicity of 1,1-
dichloroethylene. Res. Commun. Chem. Pathol. Pharmacol., 4(3):553-560.
11. Carpenter, C.P., H.F. Smyth, Jr. and U.C. Pozzani. 1949. The assay'of
acute vapor toxicity, and the grading and interpretation of results
on ninety-six chemical compounds. J. Ind. Hyg. Toxicol., 31:343-6.
12. Cranch, A.G. 1945. Toxicity of some of the newer plastics. Industrial
Medicine, 15(2):168-170.
13. Billing, W.L., C.J. Bredeweg and N.R. Tefertiller. 1976. Simulated
atmospheric photodecomposition rates of methylene chloride, 1,1,1-
trichloroethane, trichloroethylene, tetrachloroethylene and
other compounds. Environ. Sci. Technol. 10(4):351-356.
52
-------
14. Dilling, W.D., N.B. Tefertiller and G.J. Kallos. 1975. Evaporation
rates and reactivities of methylene chloride, chloroform,
1,1,1-trichloroethane, trichloroethylene, tetrachloroethylene
and other chlorinated compounds in dilute aqueous solutions.
Environ. Sci. Technol. 9(9):833-838.
15. Gage, J.C. 1970. Subacute inhalation toxicity of 109 industrial
chemicals. Brit. J. Ind. Med., 27(1):1-18.
16. Gay, B.W., Jr., P.L. Hanst, J.J. Bufalini and R.C. Noonan. 1976.
Atmospheric oxidation of chlorinated ethylenes. Environ. Sci.
Technol. 10(1):58-67.
17> 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., 24:2013-2017.
18. Haley, T.J. 1975. Vinylidene Chloride: A Review of the Literature.
Clinical Toxicology, 8(6):633.
19. Harms, M.S., R.E. Peterson, J.M. Fujimoto and C.P. Erwin. 1976.
Increased "bile duct-pancreatic fluid" flow in chlorinated hydro-
carbon-treated rats. Toxicol. Appl. Pharmacol., 35(l):41-9.
20. Heicklen, J.P., E. Sanhueza, E.G. Hisatsune, R.K.M. Jayanty, R.
Simonaitis, L.A. Hull, C.W. Blume and E. Mathias. 1975.
Oxidation of Halocarbons. EPA-650/3-75-008.
21. Henschler, D., F. Broser and H.C. Hopf. 1970. "Polyneuritis cranialis:
following poisoning with chlorinated acetylenes while handling
vinylidene copolymers. Arch Toxikol, 26(l):62-75.
22. Hushon, J. and M. Kornreich. 1976. Air Pollution Assessment of
Vinylidene Chloride. U.S. Environmental Protection Agency Report.
23. D. Irish. 1972. Industrial Hygiene and Toxicology, Vol. II. F.A. Patty,
ed., Wiley (Interscience), New York, pp. 1305-1307.
24. Jaeger, R.J. 1975. Vinyl chloride monomer. Hepatotoxicity and
interaction with 1,1-dichloroethylene. Ann. N.Y. Acad. Sci., 246:
150-1.
25. Jaeger, R.J., R.B. Conolly and S.D. Murphy. 1973. Diurnal variation
of hepatic glutathione concentration and its correlation with 1,1-
dichloroethylene inhalation toxicity in rats. Res. Commun. Chem.
Pathol. Pharmacol., 6(2):465-71.
26. Jaeger, R.J. and S.D. Murphy. 1973. Alterations of barbiturate action
following 1,1-dichloroethylene, corticosterone, or acrolein. Arch.
Int. Pharmacodyn. Ther., 205(2]1:281-92.
53
-------
27. Jaeger, R.J., R.B. Conolly and S.D. Murphy. 1974. Effect of 18 hr fast
and glutathione depletion of 1,1-dichloroethylene-induced hepato-
toxicity and lethality in rats. Exp. Mol. Pathol., 20(2):187-98.
28. Jaeger, R.J., R.B. Conolly and S.D. Murphy. 1975. Short-term inhalation
toxicity of halogenated hydrocarbons. Effects on fasting rats.
Arch. Environ. Health, 30(1):26-31.
29. Jaeger, R.J., M.J. Trabulus and S.D. Murphy. 1973. Biochemical effects
of 1,1-dichloroethylene in rats. Dissociation of its hepatotoxicity
from a lipoperoxidative mechanism. Toxicol. Appl. Pharmacol.
24(3):457-67.
30. Jaeger, R.J., M.J. Trabulus and S.D. Murphy. 1973. The interaction of
adrenalectomy,partial adrenal replacement therapy and starvation
with hepatotoxicity and lethality after 1,1-dichloroethylene intoxi-
cation. Toxicol. Appl. Pharmacol., 25(3):491.
31. Jaeger, R.J., R.B. Conolly, E.S. Reynolds and S.D. Murphy. 1975.
Biochemical toxicology of unsaturated halogenated monomers.
Environ. Health Perspect, 11:121-8.
32. Jenkins, L.J., Jr., M.J. Trabulus and S.D. Murphy. 1972. Biochemical
effects of 1,1-dichloroethylene in rats. Comparison with carbon
tetrachloride and 1,2-dichloroethylene. Toxicol. Appl. Pharmacol.,
23(3):501-10.
33. Kramer, C.G. and J.E. Mutchler. 1972. The correlation of clinical and
environmental measurements for workers exposed to vinyl chloride.
Am. Ind. Hyg. Assoc. J., 33(1):19-30.
34. Lefaux, R. Industrial toxicology of monomers and various metals.
Practical Toxicology of Plastics. Chemical Rubber Company, Cleveland,
Ohio, pp. 66-153.
35. Leonard, E.G. 1971. High Polymers. XXIV. Vinyl and Diene Monomers.
Part 3. Wiley-Interscience, New York, pp. 1255-1289.
36. Manufacturing Chemists Association. Guide for Safety in the Chemical
Laboratory, 2nd ed., Appendix 4, Van Nostrand-Reinhold, New York,
p. 441. .
37. McCann, J., E. Choi, E. Yamasaki and B.N. Ames. 1975. Detection of
carcinogens in the Salmonella/Microsome Test: Assay of 300 chemicals.
Proc. Natl. Acad. Sci. U.S.A., 72:5135-5139.
38. Meyer, Fr. and L. Kerk. 1959. Permeability of the skin to some aliphatic
carrier substances. Arch, exptl. Pathol. Pharmakol., 235:267-79.
39. Miyasaki, K. Experimental studies on the reticulo-endothelial system
by intravenous injection of high molecular synthetic vinyl compounds
in rabbits. Acta Pathologica Japonica, 9(1):109-131.
54
-------
40. Oppenheimer, B.S., E.T. Oppenheimer, I. Danishefsley, A.P. Stout and
F.R. Eirich. 1955. Further studies of polymers as carcinogenic
agents in animals. Cancer Res. 15:333-40.
41. Osbourn, R.A. Contact dermatitis caused by saran wrap. Journal of the
American Medical Association, 188(13):141.
42. Prendergast, J.A., R.A. Jones, L.J. Jenkins, Jr. and J. Siegel. 1967.
Effects on experimental animals of long-term inhalation of trichloro-
ethylene, carbon tetrachloride, 1,1,1-trichloroethane, dichlorodi-
fluoromethane, and 1,1-dichloroethylene. Toxicol. Appl. Pharmacol.,
10(2):270-89.
43. Reinhardt, R.C. 1947. Handling vinylidene chloride. Chem. Eng. News,
25:2136.
44. Reynolds, E.S., M.T. Moslen, S. Szabo, R.J. Jaeger and S.D. Murphy.
1975. Hepatotoxicity of vinyl chloride and 1,1-dichloroethylene.
Role of mixed function oxidase system. Am. J. Pathol., 81(1):
219-36.
45. Rylova, M.L. 1953. Toxicity of 1,1-ethene dichloride. Farmakol. i
Toksikol., 16(1):47-50.
46. Shmuter, L.M. 1976. Influence of acute and chronic poisoning with
dichloroethylene on thekinetics of antibody-forming cells and the
plasmocytic reaction in the spleen of rats in immunization with the
0-antigen of Sal. typhi. Farmakol. Toksikol., 39(l):104-8.
47. Siegel, J., R.A. Jones, R.A. Coon and J.P. Lyon. 1971. Effects on
experimental animals of acute, repeated, and continuous inhalation
exposures to dichloroacetylene mixtures. Toxicol. Appl. Pharmacol.
18(1):168-174.
48. Siletchnik, L.M. and G.P. Carlson. 1974. Cardiac sensitizing effects
of 1,1-dichloroethylene. Enhancement by phenobarbital pretreatment.
Arch. Int. Pharmacodyn. Ther. 210(2):359-64.
49. Sporn, A., A. Cirstea, D. Ilean, L.D. Ghizelea and L. Stoenescu. 1970.
Contributions to investigations on the toxicity of vinylidene
chloride polymer extracts. Igiena (Bucharest), 19:587.
50. Van Esch, G.J. and M.J. Van Logten. 1975.' Vinyl chloride: A report of
a European assessment. Toxicology, 4:1.
51. Wilson, R.H. and W.E. McCormick. 1954. Toxicology of plastics.
Plastomers and monomers. Ind. Med. and Surg., 23:479-86.
52. Anon. 1974. Battle lines drawn on vinyl chloride issue. Chem. Eng.
News, 52(8):16.
53. Anon. 1975. Health hazards of monomers probed. C&E News, 53(3):8.
55
-------
TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
1. REPORT MO.
EPA 560/6-76-023
2.
3. RECIPIENT'S ACCESSION NO.
4. TITLE AND SUBTITLE
Health and Environmental Impacts:
Vinylidene Chloride
Task 1,
5. REPORT DATE
October 1976
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
Randall D. Huffman
Purna Desai-Greenaway
8. PERFORMING ORGANIZATION REPORT NO
9. PERFORMING ORGANIZATION NAME AND ADDRESS
Tracer Jitco, Inc.
1776 East Jefferson Street
Rockville, Maryland 20852
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
68-01-4116, Task 1
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 CODE
16. SUPPLEMENTARY NOTES
16. ABSTRACT
A comprehensive survey of the world literature was conducted to pre-
pare this report on the health and environmental impacts of vinylidene chloride.
The available information indicates that vinylidene chloride may have significant
health effects, but the information shows inconsistencies and is insufficient
for the formulation of conclusions. Very little information is available oh the
environmental impacts of vinylidene chloride.
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TERMS
c. COSATI Field/Group
Vinylidene Chloride
1,1-Dich.loroethylene
Health Effects
Environmental Impacts
8. DISTRIBUTION STATEMENT
Release Unlimited
19. SECURITY CLASS (This Report)
Unclassified
21. NO. OF PAGES
55
20. SECURITY CLASS (Thispage)
Unclassified
22. PRICE
EPA Form 2220-1 (9-73)
-------
INSTRUCTIONS
1. REPORT NUMBER
Insert the EPA report number as it appears on the cover of the"publication.
2. LEAVE BLANK
3. RECIPIENTS ACCESSION NUMBER
Reserved for use by each report recipient.
4. TITLE AND SUBTITLE
Title should indicate clearly and briefly the subject coverage of the report, and be displayed prominently. Set subtitle, if used, in smaller
type or otherwise subordinate it to main title. When a report is prepared in more than one volume, repeat the primary title, add volume
number and include subtitle for the specific title.
5. REPORT DATE
Each report shall carry a date indicating at least month and year. Indicate the basis on which it was selected (e.g., date of issue, date of
approval, date of preparation, etc.j.
6. PERFORMING ORGANIZATION CODE
Leave blank.
7. AUTHOR(S)
Give name(s) in conventional order (John R. Doe, J. Robert Doe, etc.). List author's affiliation if it differs from the performing organi-
zation.
8. PERFORMING ORGANIZATION REPORT NUMBER
Insert if performing organization wishes to assign this number.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
Give name, street, city, state, and ZIP code. List no more than two levels of an organizational hirearchy.
10. PROGRAM ELEMENT NUMBER
Use the program element number under which the report was prepared. Subordinate numbers may be included in parentheses.
11. CONTRACT/GRANT NUMBER.
Insert contract or grant number under which report was prepared.
12. SPONSORING AGENCY NAME AND ADDRESS
Include ZIP code.
13. TYPE OF REPORT AND PERIOD COVERED
Indicate interim final, etc., and if applicable, dates covered.
14. SPONSORING AGENCY CODE
Leave blank.
15. SUPPLEMENTARY NOTES
Enter information not included elsewhere but useful, such as: Prepared in cooperation with, Translation of, Presented at conference of,
To be published in, Supersedes, Supplements, etc.
16. ABSTRACT
Include a brief (200 words or less) factual summary of the most significant information contained in the report. If the report contains a
significant bibliography or literature survey, mention it here.
17. KEY WORDS AND DOCUMENT ANALYSIS
(a) DESCRIPTORS - Select from the Thesaurus of Engineering and Scientific Terms the proper authorized terms that identify the major
concept of the research and are sufficiently specific and precise to be used as index entries for cataloging.
(b) IDENTIFIERS AND OPEN-ENDED TERMS - Use identifiers for project names, code names, equipment designators, etc. Use open-
ended terms written in descriptor form for those subjects for which no descriptor exists.
(c) COSATI FIELD GROUP - Field and group assignments are to be taken from the 1965 COSATI Subject Category List. Since the ma-
jority of documents are multidisciplinary in nature, the Primary Field/Group assignment(s) will be specific discipline, area of human
endeavor, or type of physical object. The application(s) will be cross-referenced with secondary Field/Group assignments that will follow
the primary posting(s).
18. DISTRIBUTION STATEMENT
Denote reusability to the public or limitation for reasons other than security for example "Release Unlimited." Cite any availability to
the public, with address and price. '
19. &20. SECURITY CLASSIFICATION
DO NOT submit classified reports to the National Technical Information service.
21. NUMBER OF PAGES
Insert the total number of pages, including this one and unnumbered pages, but exclude distribution list, if any.
22. PRICE
Insert the price set by the National Technical Information Service or the Government Printing Office, if known.
EPA Form 2220-1 (9-73) (Reverse)
------- |