2-CHL0R0-1,3-BUTADIENE
(CHLOROPRENE)
HAZARD PROFILE
Prepared by:
Karen Blackburn
Dipak Basu
Stephen J. Bosch
Center for Chemical Hazard Assessment
Syracuse Research Corporation
Merrill Lane
Syracuse, MY 13210
Contract Mo. 68-03-3082
Prepared for:
Environmental Criteria and Assessment Office
U.S. Environmental Protection .Agency
26 West St. Clair Street
Cincinnati, OH 45268
Project Officer: Dr. Michael Dourson
September 29, 1982
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EXECUTIVE SUMMARY
5-Chlora-1,3-butadiene ( chloroprene) Is a colorless, volatile liquid. In
1976, the estimated United States production of chloroprene was 164 million kg .
Virtually all chloroprene is used in the manufacture of synthetic rubber. Very
little information is available in the literature pertaining to the fate and
transport processes of chloroprene in the environment. In ttje atmosphere,
probably the most important fate-determining process of this chemical is its
reaction with ozone. The atmospheric half-life for this reaction has been
estimated to be 2 hours. For lack of monitoring data, the human intake of this
chemical from drinking water, foods, and skin exposure cannot be estimated.
Until mora ambient air monitoring data are available, it is impossible to
estimate the human intake of chloroprene through inhalation.
Chloroprene has been shown to be mutagenic in bacterial systems and
experimental animals in vivo, and a lactogenic Jjl ^ oo cm pafclona&ly ~ exposed humana.
There are some epidemiological data which indicate that occupational exposure to
chloroprene may be linked to increased incidence of lung and skin cancer;
however, all the studies had major methodological deficiencies.
Repeated exposure to chloroprene results in central nervous system, cardio-
vascular, and reproductive abnormalities. Acute effects of chloroprene exposure
include central nervous system depression, lung injury, liver and kidney damage,
Irritation of the skin and mucous membranes, respiratory difficulties,
dermatitis, and alopecia.
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An ADI of 0.0184 mg/kg/day has been estimated for inhalation exposures based
upon tbe National Institute for Occupational Safety and Health's (NIQSH)
recommended 15-minute ceiling concentration for work-place exposures of 1 ppm
chloroprene.
Pertinent data regarding the aquatic toxicity of chloroprene were not
located in the available literature.
ill
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1. HTRODDCTIOH
2-Chloro-1,3-butadiene (chloroprene) is a colorless, mobile, volatile
liquid (Johnson, 1979)* Chloroprene is manufactured in a three step process:
1) chlorination of 1,3-butadiene to form 1,^-dichloro-2-butene, 2? isomerization
to 1,2»dichloro-3-butane, and 3) dehydrochlorination with caustic soda to form
2-chloro-1,3-butadiene»
CAS Registry Number:
Formula:
Molecular Weight:
Melting Point:
Boiling Point:
Density:
Flash Point:
Vapor Pressure:
Solubility:
In 1976, two United States companies produced an estimated 164 million kg of
chloroprene, and the total world production in 1977 was estimated at 300 million
kg (IARC, 1979).
Virtually all chloroprene is polymerized to form polychloroprene, a syn-
thetic rubber used for wire and cable covers, gaskets, automotive parts, ad-
hesives, caulks, flaae-resJLatant cushioning, and other applications requiring
chemical, oil, and weather resistance or high gum strength (Johnson, 1979).
126-99-8
CftHgCl
38.5*1 (Johnson, 1979)
-130#C (Johnson, 1979)
59.* (Johnson,, 1979)
0.958$ (Johnson, 1979)
-20°C (JLSTM, open cup) (Johnson, 1979)
215.^ m at 25*C (Patty, 198D
<17% (Johnson, 1979)
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2. ENVIRONMENTAL PATE AND TRANSPORT PROCESSES
Very little information la available In the literature pertaining to the
fate and transport processes of ohloroprene in the environment. Ho information
was found regarding the microbial biodegradability of ohloroprene in the aquatic
environment or in soils, la the atmosphere, chloropreae is very slightly
reactive towards RO^* radicals. The half-life for this reaction has been esti-
mated to be 2.2 years (Brown et al., 1975). The chemical is more reactive
towards atmospheric 0H« radicals and 0^. The half-lives for these reactions have
been estimated to be 21 hours and 2 hours, respectively (Brown et al., 1975) .
The reaction of chloroprene with 0^ is expected to yield 2-chloroacrolein as the
product (Brown et al., 1975). The persistence data for chloroprene with regard
to volatilization and chemloal reactions in the aquatic phase could sot be found
in the available literature.
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3. EXPOSURE
3.1. WATER
Although chloroprene or its isomer has been detected at = 1 ppb level in the
Ohio River near Cannelton, Indiana and Houston Ship Channel near Pasadena
Gardens, Texas, (Swing et al., 1977), its detection in any drinking water has
not been reported.
3.2. FOOD
The U.S. Food and Drug Administration (FDA) permits the use of chloroprene
as a component of adhesives that are intended for use in food packaging
{IARC, 1979). However, no data indicating its level in foods could be found.
3.3. AIB
During 19T3» the airborne concentrations of chloroprene in a United States
chloroprene polymerization plant were found to range from 50 to 5000 mg/m^ in the
make-up area, from 440 to 24,300 mg/m^ in the reactor area, from 10 to 1500 og/rn^
in the monomer recovery area, and from 400 to 900 mg/m^ in the latex area
(IARC, 1979). In 1977, mean airborne concentrations of chloroprene of up to
¦a
0.72 mg/nr were reported in a roll building area in a metal fabricating plant
where polychloroprene was applied extensively to metal cylinders prior to
vulcanization (IARC, 1979). It has been estimated that *2500 to 3000 workers in
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the United States are currently exposed to chloroprene during its manufacture and
polymerization (XAflC, 1979).
Chloroprene concentration in air in the immediate vicinity of a polyehloro-
prene rubber plant in Russia was 28.5 At distances of 500 and 7000 meters
away from the plant, the chloroprene concentrations were 0.73 and 0.2
respectively (IARC, 1979) . The ambient air concentration of chloroprene in
Baton Rouge, Louisiana was monitored by Hughes et al. (1980) and no chloroprene
could be detected.- However, Hartov et al. (1560) monitored the ambient air
throughout Hew Jersey and found that chloroprene was ubiquitous throughout the
state at concentrations <1 ppb»
3.4. DERMAL
Pertinent data regarding the dermal exposure to chloroprene were not
located in the available literature.
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M. PHARMACOKINETICS
Although the metabolism of chloroprene has not been thoroughly Investi-
gated, It has been hypothesized that 'chloroprene is metabolized in a manner
similar to vinyl chloride (Haley, 1978). This implies that chloroprene would be
first metabolized to a reactive epoxide intermediate via hepatic mixed function
oxidases. This intermediate could then give rise to an aldehyde or undergo
conjugation with glutathione. Limited available data support this hypothesis.
It has been shown in vitro that chloroprene forms peroxides, taking up oxygen in
positions 1 and 2. Bartsch et al. (1976) have shown that mitagenicity in
Salmonella is appreciably enhanced by addition of a hepatic microsomal fraction,
suggesting formation of a reactive intermediate.
The involvement of glutathione has been somewhat more thoroughly studied.
Summer and Greia { 1980} have shown that following a single oral dose of chloro-
prene C100 or 200 ag/kg) , there is a rapid decrease in hepatic GSH. Hepatic GSH
was decreased to 55 and 39>, respectively, of the control value 3 hours post-
treatment. In Cophen A-50 pretreatad animals, the decrease was 57 and 55?,
respectively. In isolated hepatocytea, cellular GSR decreased to 50% of control
levels within 15 minutes of addition of 3 «M chloroprene. Oral dosing with
chloroprene resulted in a dose-related increase in urinary excretion of
thioethers (presumably GSH-oonjugates and mercaptic acids) In the urine. At high
doses, a decline in excretion was observed, possibly due to GSH depletion.
Jaeger et al. (1975) found that fasted rata were more sensitive to inhala-
tion effects of chloroprene, both as indicated by lethality and as shown by
increases in serum alanine a ketoglutarate transaminase (ART) (an Indicator of
hepatotoxicity) . Bats were exposed for 4 hours to 500, 1000, 2000, or 10,000 ppm
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abloroprww. A-t concentrations <10,000 ppa, effects on serum Aid and survival
were sean oaly ic fasted rats. These authors present evidence ttoat tije reported
riiffarenoes la toxicity are related to hapatic glutathione levels.
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5. EFFECTS
5.K CARCINOGENICITY
5.1.1. Human Studies. Khachatrian (1972a) reported data on akin cancer inci-
dence in chloroprene workers. Exposure concentrations were not reported. Cases
were followed from 1956 to 1970. Incidence rates are reported for ehloroprene
workers, chemical workers, noil-chemical workers and non-industrial workers
(Table 5-1). IAflC (7979) notes that this study failed to distinguish prevalent
from incident oases, failed to document completeness of case reporting among the
exposure groups, failed to adjust for age and aex, and failed to control for the
effects of smoking and exposure to other toxicants. In addition, absence of
histological information on all types of reported caneera is stressed as a
serious limitation.
In a simultaneous study, Khachatrian (1972b) reported the incidence of lung
cancer in chloroprene workers (Table 5-2), also from the period of 1956 to 1970.
Of the 87 lung cancer cases, 16 were identified in former chromium workers.
Again, exposure levels were not reported. Seventy-six percent of the workers
with lung cancer had chronic bronchitis, had tuberculosis, and 4.5$ had
pneumonia; 66% of the workers with lung cancer smoked. HXOSH (1977) notes that
the methods used for cancer diagnosis were not specified, and that there were
inconsistencies between data reported in the text versus the tables. In addi-
tion, NIOSH (1977) notes that a panel of Soviet experts las determined that there
were methodological errors that could lead to incorrect conclusions. IABC (1979)
emphasizes that the limitations associated with the skin cancer study also apply
to the lung cancer study.
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TABLE 5-1
Sic in Cancer Incidence*
-Vuaifcer of
Joti Category ladlviduala $ Affected
Chloroprene workers 684 3.0
(average age 59-6, average
employni«ot 9,5 years}
Chloroprene derivative workers 2250 1.69
(average age 59.1, average
ftaployment 3.7 yeara 1
Chemical workers Jtf8o 0.67
(average age 64.4, average
years employment 13,%)
Non-chamieal workers 8755 O.ii
(average age 68.9, average
years employment 15.4}
Non-induatrial workers 8520 0.13
(average age 72.05, average
ys&rs saigioymetit 16.3}
«Sourae: HIOSH, 1977
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TABLE 5-2
Lung Cancer Incidence*
Job Category
Chloroprene workers
(average age 44.5, average
years of .employment 8.7)
Chemical workers
(average age 54.9, average
years of employment 10.3)
Non-chemical workers
(average age 59.3, average
years of employment 14.9)
Non-induatrial workers
(average age 60.2, average
years of employment 13.5)
Number of
Individuals % Affected
2934 1.24
4780 0.46
6045 0.8
6220 0.064
•Source: NIOSH, 1977
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Pell (1976) examined cancer mortality in two populations of chloroprene
workers. One population (234 aen) were first exposed between 1931 and 1918;
these individuals were followed from 1956 to 1974. The second population
(1576 men) were first exposed between 1942 and 1957, and were followed from 1957
to 1974. The number of lung cancer deaths did not differ from expected; the
risks of digestive cancer, and lymphatic and hematopoietic cancer were slightly
elevated in the second cohort (19 versus 13*3 expected, respectively, and
7 versus 4.5 expected, respectively). There were eight lung cancer cases among
maintenance mechanics in the second cohort (40% of total lung cancers), although
maintenance mechanics accounted for only 17% of the population. These workers
would be expected to have a high exposure to chloroprene. IARC (1979) notes the
following limitations in this study: retired, disabled, and former workers were
not uniformly included; smoking and exposure to other toxicants were not con-
sidered; exposure concentrations are lacking; data on cell types of the cancers
were not reported; and the second cohort was not followed for an adequate latency
period. Skin eaneer--ineMfcncte",'ttiEsrnot considered.
5.1.2. Experimental Animals. Ponomarkov and Tomatis (1980) administered
100 mg/kg chloroprene in olive oil to BDIV rats. A single dose was given to
pregnant dams (24 animals) by stomach tube on day 17 of gestation. Progeny
(81 males, 64 females) were treated weekly from weaning with 50 mg/kg chloro-
prene for 120 weeks. Fourteen pregnant dams receiving 0.3 ^ olive oil'on day 17
of gestation served as controls. Of their offspring, 53 males and 53 females
received weekly doses of 0.3 olive oil from weaning for 120 weeks. After
120 weeks of treatment, all surviving animals were autopsied. All "major" inter-
nal organs, in addition to those which showed gross abnormalities, were examined
histologically. No differences in survival or body weights were found between
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treated animals and controls. Animals receiving chloroprene that died within the
first 23 to 35 weeks showed severe congestion of the lungs and kidneys. In some
of the animals autopsied following 80 to 90 weeks of treatment, severe liver
necrosis was observed. The incidence of tumors in chloroprene treated rats was
the same as that observed in vehicle treated controls.
Zil'fyan et al. (1975, 1977) administered 200 mg/kg chloroprene in sun-
flower oil by gavage. Rats were dosed 2 times/week for 25 weeks. Forty rats
survived for 2 years. Tumors related to treatment were not observed.
The same group (Zil'fyan et al.f 1975, 1977) applied chloroprene,
9,10-dimethyl-1,2-benzanthracene (DMBA), or both to the shaved skin of mice. A
50% solution of chloroprene in benzene was applied 2 times/week for 25 weeks to
100 mice. A 0.1% solution of DMBA in benzene was applied using the same exposure
regimen (80 mice). In addition, 50 applications of the 50% chloroprene solution
were combined with five applications of 0.01$ DMBA (80 mice). Of the mice
treated with 0.1% DMBA, 92% developed skin oaroinomas. Skin tumors were not
found in the other two groups.
In another segment of this group's evaluation (Zil'fyan et al., 1977), 100
rats received 200 mg/kg chloroprene intratracheally. Five doses were given at
20-day intervals. Gross and microscopic evaluation of the lungs of animals that
died or were sacrificed 6 or 14 months after exposure did not reveal any tumors.
Zil'fyan et al. (1977) administered 10 subcutaneous injections of
400 mg/kg chloroprene in sunflower oil to 110 rats, and an additional 100 rats
received 50 injections of 200 mg/kg. In the first group, 88 animals survived
>6 months, and, in t.ie second group, there were 46 survivors. No local sarcomas
were reported in either group within the 2-year observation period. Of 60 rats
injected with a single dose of 0.5 mg DMBA, 50 survived to the appearance of the
first tumor (3*5 months), and 32 developed local sarcomas. An additional group
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of animals received 5 og DMBA as well as 50 injections of 200 mg/kg chloroprene;
42 rats survived until appearance of the first tumor (4 months), and 24 developed
local sarcomas.
ACGIH (1980) cite unpublished data which indicate a lack of carcinogenic
effect in rats or hamsters exposed to 50 ppm chloroprene for 2 years or
18 months. Growth retardation was noted. Exposure to 10 ppm did not result in
any observable adverse effects.
5.2. MUTAGENICITY
5.2.1. Human Studies. Katosova (1973) reported a significant elevation in
incidence of chromosome aberrations in blood cells from 18 workers exposed to an
average concentration of 18 mg/m^ chloroprene. Workers were exposed from 2 to 10
years. A frequency of 4.7$ aberrations and 3.7$ gaps was reported for the
chloroprene exposed group, as compared to 0.652 and 1.14%, respectively, in a
group of nine non-chloroprene exposed auto workers. TheBa...waa.v»e*.
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to 2 mg/m^ methyl methacrylate. The incidence of chromatid breaks was 16.8%, and
the incidence of chromosome breaks was 16.9$.
Gu (1981) found that the rate of sister chromatid exchange (SCE) in lympho-
cytes from chloroprene exposed workers was not signficantly different from con-
trols, nor did chloroprene induce SCE in vitro.
5.2.2. In Vivo Tests with Experimental Animals. The number of dominant lethal
mutations was increased when rats were exposed to 0.14 mg/m^ chloroprene for
2.5 months, but not following exposure to 0.057 mg/m^. In mice, exposure for
2 months to chloroprene concentrations of 3*5 and 1.85 mg/m^ increased the num-
ber of dominant lethal mutations. Exposure to concentrations of 0.05, 0.064,
0.13, and 0.32 had no significant effect. Chromosome aberrations in bone marrow
•were elevated in mice exposed to 0.13, 0.32, 1.85, or 3.5 mg/m^ chloroprene for
2 months, but not in groups exposed to 0.064 or 0.054 mg/m^ (Sanotskii, 1976).
5.2.3* Other Systems. Drosophlla were fed four different concentrations of
chloroprene. A dose effect relationship for recessive lethal mutations could not
be established. The author pooled the data for all dose levels and found that
these pooled data showed a higher incidence of recessive lethal mutations than
controls (Vogel, 1979).
Bartsch et al. (1976) reported that chloroprene is mutagenic to Salmonella
typhlmurium TA100. Mutagenicity is increased by the addition of a microsomal
fraction from mouse liver. Mouse kidney also increased mutagenicity, but was
only 50$ as effective as liver. Phenobarbitone pretreatment of animals increased
the mutagenic response for both organs. Human liver was active, but neither
mouse nor human lung showed an effect.
Drevon and Kuroki (1979) found chloroprene was not mutagenic when tested
using 779 Chinese hamster cells. Markovits et al. ( 1977) found that chloroprene
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induced transformation in cultured hamster lung cells. Menezes et al. ( 1979)
also found that chloroprene induced transformation in hamster lung cells. In
addition, they demonstrated that when hamsters were innoculated intraoccularly
with these transformed cells, malignant fibrosarcomas developed.
5.3. TERATOGENICITY
Culik et al. (1978) exposed pregnant rats to chloroprene via inhalation.
Daily exposures were of 4 hours duration and exposure concentrations were 0, 1,
10, and 25 ppm chloroprene. Two studies were conducted. In the first,
50 dams/group were exposed on days 1 through 12 of gestation and sacrificed on
day 17 in order to evaluate the embryotoxic potential of chloroprene. In the
second, 25 dams/group were exposed on days 3 through 20 of gestation and sacri-
ficed on day 21 to evaluate the teratogenic potential of chloroprene. No effects
on embryonic or fetal survival, incidence of soft tissue, or skeletal defects
were demonstrated. These data are at odds with other investigators. In this
study, the investigators attempted to limit exposure to chloroprene per se.
Chloroprene readily polymerizes when exposed to light and heat, and may oxidize
to form peroxides as well as other reaction products, some of which may be more
toxic than chloroprene. The authors hypothesize that this may account for the
differences between their data and those of other Investigators.
Salnikova (1968) evaluated the embryotoxic effects of inhaled combinations
of chloroprene and ammonia. The method of generating the vapors and the identity
of contaminants were not discussed. The concentration of chloroprene was
14.4 mg/m^ and the concentration of ammonia was 4.8 mg/m^. Thirteen mice and 11
rats were exposed to this mixture for 4 hours/day for the first 18 or 19 days of
gestation, respectively. An ammonia control group exposed to 58 mg/a? was
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Included (10 mice, 7 rats), and a negative control group exposed to air alone (11
mice, 9 rats) was also included. A group exposed solely to chloroprene was not
included. Dams were evaluated on day 17 for changes in body weight, hemoglobin,
and red and white cell counts. No differences from controls were reported. On
the last day of exposure, dams were autopsied and the following variables
evaluated: liver weight, kidney weight, urinary albumin and chloride, number of
corpora lutea, sites of implantation, post-implantation deaths, and the number
of live fetuses and their weights. Pre-implantation deaths were defined as the
difference between the number of corpora lutea and the number of implantation
sites. The kidney weights of both mice and rats were greater than controls
(PsO.01 and 0.05, respectively). Liver weights in mice were also increased
(PsO.01). In mice, the number of post-implantation deaths was significantly
elevated (P< 0.001); rats were not affected. Incidence of rat fetuses with
hematomas or cyanoses was elevated in the exposed group, but not significantly
(P > 0.05). The mean number of normal rat fetuses/litter was decreased by 52%
CP < 0.0,1). The criteria for determining normal fetuses were not specified.
Whether these effects might be attributable to a synergistic effect of ammonia
and chloroprene is unclear. In addition, the amounts of oxidized chloroprene and
other contaminants were not determined.
Salnikova and Fomenko (1973) exposed pregnant rats (22 to 30/group) to
chloroprene vi^ inhalation. Rats were exposed 4 hours/day to 1.11, 0.83, 0.17,
0.36, or 0.016 ppm chloroprene (purity not specified). The experiments were done
at three different times, each with a concurrent control group (number not
specified) . Embryonic and fetal deaths were monitored. Fetuses were evaluated
for the following: liver weight, femoral and fibular diaphysls lengths, and
disturbances in vascular permeability. Two-month-old offspring from treated
dams were examined for: urinary proteins, cholinesterase (tissue not speci-
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fied), oxygen requirement, serum sulfhydryl content, urinary hippuric acid after
benzoate loading, weight gain, and weight ratios of brain, lungs, liver, and
kidneys. In dams exposed to 0.83 or 1.11 ppm chloroprene, embryonic deaths were
significantly increased (P < 0.01 and P < 0.05, respectively). Exposure to 1 ppm
chloroprenfe resulted in depressed fetal body weight (P < 0.001). Disturbances
in vascular permeability and decreases in the lengths of the tibia and the fibula
were also reported for exposure to 1 ppm chloroprene. Mortality in pups from
dams exposed to 0.17 and 0.036 ppm chloroprene was significantly increased
during the first 3 weeks postpartum (P=0.05 and P < 0.02, respectively). A clear
dose response was not seen in any of the physiological parameters measured in
these offspring. Reporting of these data was variable and incomplete. NIOSH
(1977) felt that interpretation of these data was not possible. -
Apoiani (1970) examined the effect of chloroprene on pregnant rats housed at
various distances from a chloroprene plant. The number of rats and length of
exposure were not specified. In-plant chloroprene concentrations were reported
to be as high as 61 ppm (Group 1). Mean chloroprene concentrations at distances"
from the plant of 500 meters (Group 2) , 1500 meters (Group 3) , and 7000 meters
(Group 4) were 0.2, 0.14, and 0.05 ppm, respectively. Group 4 was used as the
control. The authors noted increased fetal mortality (no specific data given),
and reductions in placental weight. In Group 1, weights of fetal livers on
day 20 of gestation were lower and length of gestation was lengthened. An
increase in prenatal and neonatal deaths was also noted in this group. A
non-dose related decrease in placental weights was noted for all exposed groups.
Salnikova and Fomenko (1973) studied the embryotoxic and teratogenic
effeots of chloroprene following both oral and inhalation exposures. Eight to 15
dams/group were evaluated. Six groups were given daily oral doses of 0.5 mg/kg.
Each group was exposed for 2 oonsecutive days during gestation, through day 14
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(i.e., day 3 and 4, day 5 and 6, etc.). One group was dosed every day from day 1
through 14. An unexposed control group was included. Eight additional groups
were exposed to 1.1 ppm chloroprene via inhalation, also for 2-day periods
through day 18. The number of hours/exposure was not specified. All dams were
sacrificed on day 20 of gestation. In the group of rats exposed to oral chloro-
prene for 14 consecutive days, embryonic deaths were significantly elevated
(P < 0.001). The number of embryonic and fetal deaths was also elevated in
groups exposed on days 3 and 4.and on days 11 and 12 of gestation. All fetuses
from the group exposed for 14 days showed hydrocephalus and internal bleeding.
Embryonic and fetal deaths were elevated in litters from dams exposed via inhala-
tion on days 1 and 2, 3 and 4, 9 and 10, 11 and 12, and continuously on days 1
through 20. An increase in hydrocephalus with cerebral herniation was seen in
litters of dams exposed after day 5 of gestation, with the highest frequency in
litters from dams exposed on days 5 and 6.
It is impossible to evaluate the significance of the Soviet teratology
studies. Data on the purity of the compound to which the animals were exposed
are lacking. In view of the purported differences in toxioity of pure chloro-
prene versus oxidation products, this becomes a serious problem. Incomplete
reporting of experimental methodology and data creates other problems, espec-
ially since primary effects noted included embryo and fetal toxicity as opposed
to frank terata. Data on maternal toxicity were not reported in many instances.
The non-specific effects noted in the embryos and fetuses could have been a
consequence of maternal toxicity. In addition, the negative teratology study of
Culik et al. (1978) does not clearly indicate whether the highest dose employed
was olose to the maximum tolerated dose (MTD). As teratogenic effects may occur
within a very narrow exposure window, this could also be a problem. In con-
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elusion, insufficient .data are available to adequately assess the teratogenic
potential of chloroprene.
5.4. OTHER REPRODUCTIVE EFFECTS
5.4.1. Hunan Studies. Sanotskii (1976) reported disturbances in spermato-
genesis in chloroprene workers after 6 to 10 years of exposure, and morphological
sperm abnormalities after 11 years of exposure. He also reported an increase in
spontaneous abortions in wives of these workers 3 times the incidence in the
general population. Chloroprene concentrations within the plant ranged from 1 to
•a
7 mg/nr, with ammonia being the most frequently encountered agent to which the
workers were exposed.
5.4.2. Animal Studies, von Oettingen et al. (1936) noted regressive changes
in the spermatic epithelium or seminiferous tubules in rats exposed to a mean
chloroprene concentration of 0.2 ag/l (0.1 to 0.35 mg/fc) via inhalation. Two
rats and four mice were exposed continuously for 35 days, two rats and three mice
for 74 days, and four rats and four mice for 91 days. The testicular changes
were noted in each of the groups of rats; similar effects were not seen in mice.
Rats, mice, and cats autopsied following lethal subcutaneous doses also showed
pathological changes in the testes. Rats autopsied following lethal oral doses
showed testicular pathology. The same kinds of effects were noted in rats
exposed dermally to chloroprene. In this study segment, 0.5 oc of ohloroprene
was rubbed into the skin daily for 1 week. The animals were rested for 2 weeks,
the hair removed, and 1.5 cc of chloroprene applied to the skin daily. Seven
rats were treated for 55 days, and one for 49 days. At autopsy, the testes
showed degeneration and calcification.
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Male rats exposed to ctaloroprene by skin painting (amount not specified) for
33 or 44 days were mated to untreated females (6 males/group). In males treated
for 34 days, breeding was delayed. Half of the animals exposed for 44 days
failed to reproduce within 97 days. Male rats were exposed via inhalation to the
following concentrations (mg/Jl): 0.434 (2 rats), 1.074 ( 1 rat), 1.088 (3 rats),
1.095 ( 1 rat), 2.223 ( 1 rat), 6.035 ( 12 rats), 8.421 (2 rats), 10.0 (3 rats),
16.983 (3 rats), and 22.419 (1 rat). All exposures were of 8 hours duration.
Only 6 of these 19 animals successfully impregnated females, and in .three of
these, mating was delayed. The response was not dose dependent. All of six
control males mated successfully. In similar experiments with mice, the same
kinds of effects were reported.
Male rats exposed to chloroprene at a concentration of 1.69 mg/m^ for*
4.5 months showed a reduction in the number of normal spermatogonia, an increase
in the number of dead spermatozoa, a decreased period of sperm motility, and an
increase in sensitivity to sperm inactivation in acid media. Exposure to
in..similar but less severe effects. Exposure to 0.051 mg/m^
caused no changes in spermatogenesis (Sanotskii, 1976).
Culik et al. (1978) evaluated the effects of inhalation exposure on male
reproductive function, in which 5 rats/dose were exposed to 0 or 25 ppm chloro-
prene 4 hours/day for 22 days. After the final exposure, each male was caged
with three unexposed females. The males remained with the females for 7 days,
after which they were transferred to a new group of females. This was repeated
for 8 weeks. Litters of pups from these matings were evaluated for number of
pups and body weight of pups at weaning. The percentage of successful matings,
the percentage of pups surviving until 4 days postpartum, and the percentage of
pups surviving until weaning were also monitored. No treatment related effects
were found.
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In mice, exposure to 35 mg/m^ for 2 months (eight animals) resulted in an
increase in the number of "tubules with disquamating germinal epithelium."
Exposure to'0.32 mg/m^ (seven animals) had no effect on testicular morphology. A
control group of eight animals was included. No effects on spermatogenesis were
noted in mice (Sanotskii, 1976).
Pregnant rats were more sensitive to inhalation of 4 mg/m^ chloroprene
(duration not specified) than were non-pregnant animals. Pregnant animals
showed inhibition of spontaneous locomotor activity, an increase in urinary
hippuric acid after sodium benzoate administration, hypoproteinemia, an increase
in oxygen consumption, reduced weight gain, and an increase in weight coeffi-
cients of brain, lungs, liver, and kidneys. Non-pregnant animals showed a
reduction in activity without the other effects. Exposure of pregnant animals to
0.6 mg/m^ resulted in hypoproteinemia; exposure to 0.013 mg/m^ had no effect on
pregnant rats (Sanotskii, 1976).
5.5. CHRONIC AND SUBACUTE TOXICITY
5.5.1. Effects in Humans. Avakian et al. ( 1960) reported on the health of 273
workers with 7 to 13 years of industrial chloroprene exposure (air concentrations
not reported). Disorders of the cardiovascular system were the problems of
primary concern. Fifteen percent of the workers noted heaviness in the chest,
18? had slow pulse, 199 had fast pulse, 6.79 showed signs of cardiac neurosis,
and 15 to 30$ were hypotensive. Capillary permeability was found to be increased
in the majority"of the workers. Of 96 workers examined, 27$ liad decreased heart
rates, 33$ showed indications of myocardial dystrophy, and 15$ showed athero-
sclerosis of the cardiao vessels. The control group (number not specific) showed
a 7.3$ incidence of myocardial dystrophy and 4.8$ atherosclerosis. Follow-up
5-14
-------
examinations showed an Increase to 39.2$ of the workers showing signs of myocar-
dial dystrophy and 39.2% cardiac neurosis.
Mikaelian and Frangullan ( 1965) reported that chloroprene depressed immune
function in exposed workers. Kechek and Semerdzhian <1972) reported an increase
in the (3-globulin fraction and a decrease in the -y-globulin fraction of serum
from chloroprene-exposed workers (air concentration not reported).
Mkhitarian (1960 a,b) studied chloroprene workers from 1950 to 1954; 114
workers were included. Five different professions with varying degrees of chlor-
oprene exposure were identified (actual exposure not reported); 25 workers had
>10 years of exposure, 20 for 5 to 10 years, and 33 to 37 for <5 years. Blood
samples were tested for: glucose, cholesterol, total protein, albumin, total
globulins, glutathione, fibrinogen, carbonic anhydrase, catalase, calcium
chloride, and reserve alkalinity. Blood pressure was also measured. The follow-
ing effects were reported: hypoglycemia, hypocholinesteremia, decreased
carbonic anhydrase activity, decreased reserve alkalinity, hypotension, and de-
creased blood clotting. Control data were not presented and statistical analyses
were not performed.
Mnatsakanian and Mushegian (1964) studied porphyrin metabolism in children
attending schools at various distances from a chloroprene plant. Schools were
located at distances of 100, 500, and 700 meters from the plant, and air chloro-
prene concentrations were 0.08 to 0.13, 0.07 to 0.12, and 0.04 to 0.05, respec-
tively. Urinary total coproporphyrin was measured in 42 children from the first
school, 99 from the second, and 105 from the third. Mean coproporphyrin levels
were 6.36, 5.51, and 4.11 pg, respectively. NI0SH (19T7) points out that all of
these values fall well within normal values reported for children.
Mnatsakanian (1966) also measured urinary 17-ketosteroids as an indicator
of adrenal function using the same groups of children. The control group had a
5-15
-------
mean value of 0.73 mg. Air chloroprene concentrations of 0.07 to 0.12 and 0.08
to 0.13 corresponded to urinary 17-ketosteroid excretion values of 0.0919 and
1.021 mg, respectively. NI0SH (1977) notes that both of these values are within
the normal range for children.
Volkova et al. (1976) examined 65 chloroprene exposed workers; 43 had
<5 years of exposure and 15 had worked from 10 to 20 years. Air chloroprene
concentrations varied from 0.8 to 1.95 ppm. Workers complained of fatigue,
headache, and chest pain; 47$ of the women reported menstrual disorders (10$ in
control population, total number not specified). There was concomittant ex-
posure to other substances.
Gasparian and Arutiunian (1965) did electroencephalograph^ examinations of
70 chloroprene production workers. Twenty non-exposed individuals were used as
controls. Workers were primarily those with 5 to 15 years of exposure. The
three most common types of EEG abnormalities were deflections of low voltage and
frequency, deflections or low frequenoy but long duration (A-type), and incon-
sistent wave patterns with alternating a, 8, and A activities and occasional
spikes. When the 'exposed workers were subjected to a flashing light, 82.8$
responded, while 17.2$ failed to respond; 100$ of the control group responded.
Of the exposed group, 78.6$ did not synchronize with the frequency of a visual
stimulus, while only 25$ of the controls failed to synchronize. NI0SH (1977)
notes that the original paper did not report many important experimental details.
Gooch and Hawn (1981) studied several groups of workers employed in a
ohloroprene plant. Workers were assigned to groups of currently exposed, pre-
viously exposed, and never exposed. Each job category was then rated as having a
potential for high, moderate, low, or varied exposure. Each worker had been
subjected to a physical examination upon initial employment, and annually there-
after. The following serum evaluations were done: calcium, phosphorus, glucose,
5-16
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blood urea nitrogen, uric acid, cholesterol, total protein, albumin, total bili-
rubin, alkaline phosphatase, lactic dehydrogenase, and serum glutamic oxaloace-
tic transaminase. Whole blood was evaluated for white and differential cell
counts, red blood cell count, hemoglobin, and hematocrit.
The currently-exposed study group consisted of 336 workers, the not cur-
rently exposed group consisted of 227 workers, and the never-exposed group
consisted of 283 workers. The never-exposed group consisted of plant workers
with job categories in which direct exposure to chloroprene was not anticipated
and this group was used as the control group for comparisons with the other two
groups. Measurements of air chloroprene concentrations were not done, and it is
uncertain how much indirect exposure these individuals might have had. In the
currently-exposed group, 76- workers were selected for paired comparisons of test
results before and after exposure to chloroprene. Why this procedure was not
done with a larger percentage of the currently-exposed group is not clear. Mean
ages were comparable for the three groups. Sex composition varied; the
currently-exposed group was 3 • 3 Vfettale, ttfe not currently exposed group was 3 • 1 %
female, and the never-exposed group was 13-2% female. In the currently exposed
group, 176 individuals had been exposed for <1 year, 80 for 1 to 5 years, 17 for 6
to 10 years, and 63 for >10 years.
After adjustment of the data for age differences, no statistically signifi-
cant effects CP < 0.05) were found when biochemical parameters for the three
groups were compared. In the group of 76 workers which served as their own
controls, significant differences were found between baseline and post-exposure
values of cholesterol, glucose, and LDfl. The authors indicated that values both
before and after exposure were within "normal" ranges, and attributed the
apparent effects to intrapersonal variability, rather than to chloroprene expo-
sure. It is impossible to evaluate this study in reference to other occupational
5-17
-------
exposure evaluations which suggest effects in workers, since exposure data are
not reported.
5.5.2. Effects In Experimental Animals. Rats exposed to chloroprene via inhala-
tion (1.69 for 1.5 months showed an increase in the ¦'summation index*
I method not specified), a decrease in the synthesis of Mppurie acid from sodium
benzoate, and an inhibition of gas exchange. Exposure to chloroprene concentra-
tions of 0.51 or 0.051 mg/&3 had no effect on these parameters. Using the same
indicators, mice exposed to 35. 1.95, 0-32, 0.13, 0.06^4, and 0.054 mg/m^ showed
no adverse effects. Apparently, mice were exposed for only 2 months
(Sauotflkii, 1976)*
Clary et al. (1979) exposed rats to air concent rations of 39, )51, or
625 ppm chloroprene, and haeaters to 35. 162, or 5?0 ?pa chloroprene for 4 .
Animals were axposed 5 hours/day, 5 days/week. Tan aaimals/sex/doae were used,
with an equal size control group. In both rats and hamsters exposed to the
highest levels, eye irritation, restlessness, lethargy, nasal discharge, acid
orange-colored urine were noted. Hair loss was observed in female rats at the
high and mid-exposura concentrations. Exposure-related growth retardation was
observed. Food consumption was decreased in rats of both sexes during the early
pert of the study (not monitored in hamsters). In rats, no deaths were observed
at the low dose; at the mid-dose, three males died during the course of the study
(two after the first week, one ifter the second); and at the highest exposure
level, five vales and three feaales died during the course of the study. In
hamsters, there were no deaths at the low dose; one male and three females died
during the course of the mid-dose exposure; and at the highest exposure concen-
tration, all animals died within the first week. There were no deaths in the
control groups. After 4 weeks of exposure, blood samples were evaluated for
5-16
-------
hemoglobin, packed cell volume, erythrocytes, and white blood cells. No treat-
ment related effects were seen. In addition to body weight, weights of heart,
kidney, liver, spleen, brain, thyroid, and adrenals were recorded. In rats of
both sexes, body weights were significantly depressed at all exposure levels. No
differences were seen in heart or spleen weights. In females, kidney weights
were elevated at both the mid and high doses; brain weights were increased at all
dose levels; lung, thyroid, and adrenal weights were increased at the high dose.
In male rats, heart weights were unaffected; liver weights were depressed at the
low and mid-dose and elevated at the high dose; spleen weights were decreased at
all dose levels; brain weights were higher in all treated groups; lung weights
were elevated at the highest exposure level; and adrenal weights were increased
in all exposed groups.
Nystrom (1948) exposed 10 rats to an air chloroprene concentration of
56 ppm, every day for 8/hours/day for 5 months. There were no deaths, nor
changes in body weight, red cell counts, leukooyte counts, or hemoglobin levels.
"Inconsiderable" changes were observed at autopsy.
Asmangulian and Badalian (1971) exposed rats (number unspecified) to daily
oral doses of 15 mg/kg for 5 months. No deaths were reported and no information
on other indicators of toxicity was presented.
5.6. ACUTE TOXICITY
5.6.1. Effects in Humans. The effects of acute exposure to high concentrations
of chloroprene include central nervous system depression, lung injury, liver and
kidney damage, irritation of the skin and mucous membranes, respiratory diffi-
culties, dermatitis, and alopecia (IARC, 1979).
5-19
-------
Roubal ( 1942) reported the following effects in workers from the
Czechoslovakia chloroprene rubber industry: hair loss, chest pressure, rapid
pulse, severe fatigue, conjunctivitis, necrosis of the corneal epithelium, and
albumin in the urine.
Nystrom (1948) reported the results of medical evaluation of Swedish chlor-
oprene workers. Experimental exposure of human subjects to 973 ppm chloroprene
resulted in nausea and giddiness after 15 minutes in resting subjects,and 5 to
10 minutes in subjects performing light work. Pilot plant workers exposed to
459 ppm chloroprene were anemic. In the main plant, chloroprene concentrations
ranged from 56 to >334 ppm. Workers developed extreme fatigue and severe chest
pains after 1 month of work. They also reported personality changes including
irritability. Contact deAnatitis and hair loss were also reported. Liver,
kidney, and-lung function tests, and electrocardiograms were normal.
Lejhancova (1967) evaluated six women exposed to chloroprene. Chloroprene
concentrations ranged from 61 to 292 mg/m^. The women reported headaches,
nausea, and severe fatigue, as well as hair loss.
Paulet and Malasses (1969) reported a high frequency of chemical burns in
workers employed in a French polychloroprene plant. Conjunctivitis, hair loss,
and sexual impotency were also reported.
5.6.2. Effects in Experimental Animals. von Oettingen et al. (1936)
evaluated the pathological consequences of single oral lethal doses of chloro-
prene in rats. Doses varied from 0.2 to 0.8 mil chloroprene. None of the three
animals dosed with 0.2 mil chloroprene died; 100% of the animals dosed with 0.8 mil
chloroprene (four animals) died, with time of death varying from 6 hours to
10 days after dosing. A dose of 0.3 m£ (five animals) resulted in 40$ mortality
within 4 days. Animals showed Inflammation of the mucous membranes,
5-20
-------
particularly of the eyes and nose, and Irritation of the gastrointestinal tract.
At autopsy, the lungs were hyperemia, showing edema and hemorrhagic areas. The
liver, spleen, and kidneys were hyperemia and the livers frequently enlarged.
Mice were exposed to chloroprene via inhalation for 1 hour to 1 to 33 mg/l
chloroprene. A concentration of 1 mg/A did not result in any fatalities in nine
animals. All concentrations £3 mg/fi, resulted in 100$ mortality at varying time
intervals after exposures. The lungs showed edema, emphysema, and hemorrhagic
areas. In addition, the liver, spleen, and kidneys were hyperemic
(von Oettingen, 1936)-
Table 5-3 presents acute toxicity data for chloroprene.
5-21
-------
TABLE 5-3
Acute Toxicity of Chrloroprene*
Exposure Exposure
Concentration Species Duration Effect
or Dose
2300 mg/m^
mouse
2 hr
LC50
•a
3000 mg/nr
mouse
1 hr
LC50
600 mg/m^
mouse
8 hr
LC50
3400 mg/m^
rabbit
8 hr
LC50
1300 mg/m^
cat
8 hr
r-
o
o
3 mg/kg
mouse
1 sc
dose
LD50
25 mg/kg
rat
1 oral
dose
LD50
260 mg/kg
mouse
1 oral
dose
LD50
•Source: Sanotskii, 1976
hr = hours; sc = subcutaneous
5-22
-------
6. AQUATIC TOXICITY
6.1. ACUTE
Pertinent data regarding the acute effects of ctaloroprene toxicity were not
located in the available literature.
6.2. CHRONIC
Pertinent data regarding the chronic effects of chloroprene toxicity were
not located in the available literature.
6.3. PLANT EFFECTS
Pertinent data regarding the plant effects of chloroprene were not located
in the available literature.
6.4. RESIDUE
Pertinent data regarding residue >f chloroprene were not located in the
available literature.
6.5. OTHER RELEVANT INFORMATION
Pertinent data regarding other relevant information on chloroprene were not
located in the available literature.
-------
7. EXISTING GUIDELINES AND STANDARDS
The ACGIH recommended Threshold Limit Value (TLV) is 10 ppm (ACGIH, 1980).
This recommendation is based primarily upon an unpublished study showing growth
retardation in rats and hamsters exposed to 50 ppm chloroprene via inhalation for
2 years or 18 months, and upon "minimal" toxicity observed in rats and hamsters
following 4-week inhalation exposures to 39 Ppm chloroprene.
NIOSH ( 1977) recommends a 15-minute ceiling concentration of 1 ppm as a
workplace standard. This lower recommended limit reflects consideration of
Soviet animal and epidemiological data showing mutagenic and reproductive
effects following low level exposures.
Other occupational exposure recommendations include: West Germany, 10 ppm;
Sweden, 25 ppm; Romania, 8 ppm; East Germany, 3 ppm; and Russia, 0.6 ppm
(ACGIH, 1980).
7-1
-------
8. APPROACHES TO CRITERION DERIVATION
The available data, both human and animal, indicate that mutagenicity, as
indicated by chromosomal aberrations, dominant lethal mutations (in animals),
and an increase in spontaneous abortions (human), as well as adverse effects on
male reproductive capacity, are the most sensitive indicators of chloroprene
toxicity (Table 8-1). Soviet workers have demonstrated these effects in experi-
mental animals at very low levels. Interpretation of these data are difficult.
Workers in other countries have demonstrated similar effects only at much higher
doses. The Soviet studies do not report experimental methodology, especially in
terms of the purity of the compound administered, in adequate detail. Since
there are indications that oxidation products of chloroprene may be much more
toxic than the monomer per se, this becomes a serious consideration. The epi-
demiological studies are bracketed with the same concern. In addition, although
chromosomal aberrations certainly generate concern, their ultimate significance
in terms of the consequences to exposed individuals and subsequent generations
remains unclear. Animal data do indicate that chloroprene is a potential mutagen
to germ cells as well as somatic cells. Available data are inadequate to assess
the potential carcinogenicity of chloroprene.
NIOSH ( 1977) took all of these factors into consideration when an occupa-
tional exposure limit of 3*6 mg/nr was suggested. For the purposes of this
assessment, it is recommended that the NIOSH ( 1977) guideline be used as a
starting point for development of a criterion level. Assuming an 8-hour breath-
ing volume of 10 m^, an absorption efficiency of 50*, and spreading exposure out
over 7 days, the calculated intake would be:
3.6 mg/m^ x 10 m^ x 0.5 x 5/7 s 12.86 mg/day.
8-1
-------
TABLE 8-1
Summary of In Vivo Mutagenicity and Reproductive Effects
Species Route Concentration Effect
human
inhalation
18 mg/m^
Chromoscme aberrations
human
inhalation
6 mg/m^
Chromosome aberrations
human
inhalation
1-7 mg/m^
Chromosome aberrations
human
inhalation
2-2.2 mg/m^
Chromosome aberrations
mouse
inhalation
1.85 mg/m^
Dominant lethal
mutations
rat
inhalation
0.14 mg/m^
Dominant lethal
mutations
mouse
inhalation
0.13 mg/rn^
Chromosome aberrations
rat
inhalation
¦a
90 mg/nr
Pregnant females exposed;
no effect on offspring
rat
inhalation
•a
3.0 mg/nr
Embryotoxio
rat
oral
0.5 mg/kg
Embryotoxio, teratogenic
rat
inhalation
3.98 mg/m^
Embryotoxio, teratogenic
human
inhalation
1-7 mg/m^
Effects on spermatogones^
and sperm morphology;
increase in spontaneous
abortions
rat
inhalation
200 mg/m^
Abnormal testicular
morphology
mouse
inhalt tion
0.32 mg/m^
Abormal testicular
morphology
rat
inhalation
3
0.15 mg/m
Decreased sperm
viability, motility
rat
inhalation
90 mg/m^
Males were exposed; no
effects on reproductive
performance were
observed
8-2
-------
applying an uncertainty factor of 1<1, In order to protect potentially snore
sensitive segments of the general population, results in a suggested acceptable
daily intajce (AM) of 1.29 ®g/
-------
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