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Allyl chloride
CASRN 107-05-1
Contents
0387
Allyl chloride; CASRN 107-05-1
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Allyl chloride
File On-Line 09/01/1990
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data
Inhalation RfC Assessment (I.B.) on-line 05/01/1995
Carcinogenicity Assessment (II.) on-line 08/01/1994
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Allyl chloride
CASRN -- 107-05-1
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Allyl chloride
CASRN -- 107-05-1
Last Revised -- 05/01/1995
The inhalation Reference Concentration (RfC) is analogous to the oral RfD and
is likewise based on the assumption that thresholds exist for certain toxic
effects such as cellular necrosis. The inhalation RfC considers toxic effects
for both the respiratory system (portal-of-entry) and for effects peripheral
to the respiratory system (extrarespiratory effects). It is expressed in
units of mg/cu.m. In general, the RfC is an estimate (with uncertainty
spanning perhaps an order of magnitude) of a daily inhalation exposure of the
human population (including sensitive subgroups) that is likely to be without
an appreciable risk of deleterious effects during a lifetime. Inhalation RfCs
were derived according to the Interim Methods for Development of Inhalation
Reference Doses (EPA/600/8-88/066F August 1989) and subsequently, according to
Methods for Derivation of Inhalation Reference Concentrations and Application
of Inhalation Dosimetry (EPA/600/8-90/066F October 1994). RfCs can also be
derived for the noncarcinogenic health effects of substances that are
carcinogens. Therefore, it is essential to refer to other sources of
information concerning the carcinogenicity of this substance. If the U.S. EPA
has evaluated this substance for potential human carcinogenicity, a summary of
that evaluation will be contained in Section II of this file.
___I.B.1. INHALATION RfC SUMMARY
Critical Effect Exposures* UF MF RfC
-------------------- --------------------------- ----- --- ---------
Functional and NOAEL: 17 mg/cu.m 3000 1 1E-3
histological peripheral NOAEL(ADJ): 3.6 mg/cu.m mg/cu.m
neurotoxicity NOAEL(HEC): 3.6 mg/cu.m
Rabbit Subchronic LOAEL: 206 mg/cu.m
Inhalation Study LOAEL(ADJ): 44 mg/cu.m
LOAEL(HEC): 44 mg/cu.m
Lu et al., 1982
*Conversion Factors: MW = 73.53. NOAEL(ADJ) = NOAEL(mg/cu.m) x 6 hours/day x
6 days/7 days = 3.6 mg/cu.m. The NOAEL(HEC) was calculated for a
gas:extrarespiratory effect assuming periodicity was attained. Since the b:a
lambda values are unknown for the experimental animal species (a) and humans
(h), a default value of 1 is used for this ratio. NOAEL(HEC) = NOAEL(ADJ) x
(b:a lambda(a)/lambda(h)) = 3.6 mg/cu.m.
___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC)
Lu, B, D. Shuwei, Y. Airu, X. YinLin, G. Taibao and C. Tao. 1982. Studies on
the toxicity of allyl chloride. Ecotoxicol. Environ. Saf. 6: 19-27.
The neurological effects of allyl chloride were studied in rabbits, cats,
and rats (Lu et al., 1982; data also reported in He et al., 1985). A group of
six male rabbits and 1 female cat were exposed to 206 mg/cu.m allyl chloride 6
hours/day, 6 days/week for 3 months (duration-adjusted concentration, 44
mg/cu.m) and an equal number of animals served as controls. Clinical
observations, body weight, hematology, urinalysis (protein, blood, cells),
liver function (SGPT), serum chemistry (total nonprotein sulfhydryls,
creatinine), electromyography (EMG, rabbits only), organ weights, and
histopathological examination including brain, spinal cord, heart, trachea,
lung, liver, kidney, spleen, adrenals, and peripheral nerves, were conducted.
Four rabbits were examined at the end of the exposure and two were used to
study recovery. EMG changes indicative of peripheral nerve damage were noted
in the rabbits at the end of the first month of exposure. Changes noted by
month 2 in all of the exposed rabbits included muscle weakness of the
extremities, lurching motion, and unsteady gait. This developed into
paralysis in three of the exposed rabbits. Relative lung and liver weights
were significantly increased in rabbits compared with controls.
Histopathological examination of the rabbits revealed degeneration of
peripheral nerve fibers consistent with the abnormal clinical and EMG
findings. Other changes observed in the rabbits included dilation of
sinusoids and vacuolar degeneration in the liver, congestion or cloudy
swelling and fatty degeneration of the epithelium of the renal convoluted
tubules, and thickening of the alveolar septa in the lungs. The exposed cat
exhibited only muscle weakness and unsteady gait toward the end of the
exposure period. No other treatment-related effects were observed in the
parameters measured.
Rabbits (n=6, 5 male and 1 female) and 10 male rats were exposed to 17
mg/cu.m allyl chloride 6 hours/day, 6 days/week for 5 months (duration-
adjusted concentration is 3.6 mg/cu.m) (Lu et al., 1982; data also reported in
He et al., 1985). An equal number served as controls. The exposure protocol
and analyses performed at the end of exposure were essentially identical to
the exposure to 206 mg/cu.m. No data are presented regarding the results of
this experiment but it is stated that no evidence of adverse treatment-related
effects was found after exposure to 17 mg/cu.m. This study identifies a NOAEL
for neurological effects of 17 mg/cu.m [NOAEL(HEC) = 3.6 mg/cu.m for
extrarespiratory effects assuming periodicity is attained and using the
default value of 1 for b:a lambda(a)/lambda(h)].
___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC)
UF -- Two uncertainty factors of 10 each are used for protection of sensitive
human subpopulations and for extrapolation from a subchronic study. An
additional factor of 10 is applied due to data base deficiencies including
lack of adequate developmental and reproductive toxicity data. A factor of 3
is applied for uncertainty in the extrapolation from laboratory animal to
humans.
MF -- None
___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC)
Chronic toxic polyneuropathy in humans associated with allyl chloride
exposure was first reported in 17 Chinese women employed in the manufacture of
sodium allyl sulfonate who were also exposed to sodium sulfite (He et al.,
1980). The exposure levels were not specified and the women were exposed for
durations that ranged from 7 months to 5 years. Physical and neurological
examinations, electromyography (EMG), nerve conduction measurements, and
rheography of the extremities were conducted. Laboratory determinations
conducted on some or all of the subjects included routine blood and urine
tests, liver function tests (SGPT, thymol turbidity, and thymol flocculation),
blood glucose, electrolytes, nonprotein nitrogen, erythrocyte sedimentation
rate, PSP (phenosulfulfonthalein clearance) test, EKG, EEG, and BMR (basal
metabolic rate). Clinical signs of polyneuropathy were observed in 17 cases,
including impairment of pain and touch sensation, decreased vibration
sensation, slightly decreased posture sensation, weakened muscle strength,
loss of ankle reflex, decreased skin temperature, hyperhydrosis of the hands
and feet, and tenderness of the calf. Electromyographs indicated the presence
of neuropathy in 8 of 13 cases. Nerve conduction velocity in the tibial and
peroneal nerves was slowed in seven cases, and in five of these cases, motor
nerve distal latencies were also prolonged in both nerves. Rheographic
abnormalities were also observed in 14 of 15 patients. Liver function and
other laboratory findings were normal.
After the discovery of polyneuropathy associated with allyl chloride
exposure, He et al. (1985) conducted an epidemiological study of sodium allyl
sulfonate workers in two different factories (data also reported in He and
Zhang, 1985). Twenty-six workers in factory A were exposed to 2.6-6650
mg/cu.m allyl chloride for 2.5 months to 6 years. The exposure is reported as
138 mg/cu.m with a standard deviation of 12 based on 68 area samples (He,
1991). No information is available regarding location, duration, or timing of
samples. Workers (n=27) in factory B were exposed to 0.2-25.13 mg/cu.m allyl
chloride for 1 to 4.5 years based on only 10 area samples (He, 1991; no mean
concentration or other sampling details provided). The reference group
consisted of 50 healthy adults with an age range similar to that of the
exposed groups (He, 1991). No other information is available for comparison
of the exposed and control groups. Physical and neurological examinations,
visual acuity, visual field detection, rheography of the extremities,
electrocardiography, electromyography (EMG), and nerve conduction measurements
were conducted. Laboratory determinations conducted on some or all of the
subjects included routine blood and urine tests, liver function tests (SGPT,
thymol turbidity, and thymol flocculation), blood glucose, electrolytes,
nonprotein nitrogen, erythrocyte sedimentation rate, PSP test, EEG, and BMR.
All factory A workers experienced lacrimation and sneezing when first exposed.
Most of the workers in factory A reported neurological signs that included
muscle weakness, paresthesia, numbness and cramping pain of the extremities,
sensory impairment in the glove-stocking distribution, and reduced ankle
reflexes. EMG revealed abnormalities in 53% of the workers studied in factory
A. Significant decreases in motor nerve conduction velocity and increased
motor distal latency were observed in workers from factory A and B compared to
a reference group. Results are reported for five to nine factory A workers
and all factory B workers. The same neurological signs were present in the
factory B workers, but to a lesser degree. Cramping was reported much less in
these workers. However, evidence of mild neuropathy was revealed by EMG in 13
of 27 factory B workers. Although He et al. (1985) identify the peripheral
nervous system as a sensitive target in humans, inadequate exposure
characterization precludes the use of this study as the basis for derivation
of the RfC. Because of the small number of samples and the use of area samples
without further characterization of proximity of workers and sampling
locations, the available data are not considered to be adequate to
quantitatively characterize the exposure of these subjects.
The effects of occupational exposure to allyl chloride were studied in 45
male and 15 female workers in an allyl chloride manufacturing plant who were
exposed to concentrations of allyl chloride ranging from 1-113 ppm for 16
months (Hausler and Lenich, 1968 as reported in NIOSH, 1976). No information
was given regarding the sampling and analytical method or the number and
location of samples. Medical examinations were conducted on the workers,
including urinalyses and liver function tests (thymol, cadmium, and serum
bilirubin tests, in addition to LDH, SGOT, SGPT, sorbose dehydrogenase, and
glutamic acid dehydrogenase determinations). Clinical examinations revealed
only the presence of a garlic-like odor of the body and exhaled breath in 20
of the workers. Urinalyses revealed traces of protein, a few erythrocytes,
epithelial cells, and leukocytes in the urine of two workers, and urobilinogen
levels were slightly elevated in five workers. Liver function tests showed 5
subjects with SGOT above 45 U and 25 with SGPT above 17 U. Actual values were
not provided for this or other measurements. The plant was subsequently
redesigned and exposure to allyl chloride was generally 1 ppm or less, with
the exception of the pumproom, where the concentration was 15-36 ppm. After 6
months of exposure to these lower levels, the workers reported to have
abnormal liver findings had normal liver and urine tests, but the data are not
presented to support this conclusion. Although the authors claim that the
liver function tests indicate the presence of early liver damage due to allyl
chloride, the absence of pre-exposure control values, inadequate exposure
characterization, and poor reporting of results preclude consideration of this
study as the basis for derivation of the RfC.
Quast et al. (1982a) exposed Fisher 344 rats and B6C3F1 mice
(n=10/sex/concentration) to 0, 1, 3, 10, and 20 ppm allyl chloride (0, 3, 9,
30, and 60 mg/cu.m, respectively) 6 hours/day, 5 days/week for up to 3 months
(duration-adjusted concentrations are 0, 0.54, 1.6, 5.4, and 11 mg/cu.m,
respectively) with an interim sacrifice at 1 month. Clinical observations
were conducted, and body weights, hematology, urinalysis, clinical chemistry,
organ weights, gross pathology, and histopathological evaluations of several
organs (including the lungs and two sections of the nasal turbinates) were
done. No treatment-related changes in any of the parameters evaluated were
noted in either species. Elevated SGPT and SGOT values in the 20-ppm male
mice sacrificed at 1 month were accompanied by microscopic changes in the
liver described as multifocal acute coagulation necrosis accompanied by
glycogen depletion. The lesions were not observed in the male mice after 3
months of exposure, and they were not observed in the female mice or rats of
either sex.
In a follow-up study, Quast et al. (1982b) exposed 25 male and female
Fisher 344 rats and 25 male and female B6C3F1 mice to 0, 50, 100, or 250 ppm
allyl chloride (0, 150, 301, and 752 mg/cu.m) 6 hours/day, 5 days/week for 90
days (duration-adjusted concentrations are 0, 27, 54, and 134 mg/cu.m,
respectively) with an interim sacrifice at 30 days. Clinical observations
were conducted, and body weights, hematology (10 animals/group), urinalysis
(10 animals/group), clinical chemistry, organ weights, gross pathology, and
histopathological evaluations of several organs (including the lungs) were
performed. No treatment-related effects on mortality, clinical observations,
body weight, urinalysis, hematology, clinical chemistry, or organ weights were
noted in either species. The absolute and relative liver weights were
increased in the male rats exposed to 100 and 250 ppm allyl chloride and in
all exposed female rats. There were no accompanying changes in serum liver
enzyme activity or microscopic appearance of the liver, so the biological
significance of the liver weight change is not clear. The livers of the male
and female mice exposed to 250 ppm allyl chloride showed increased glycogen in
the periportal hepatocytes with variable staining of the centrilobular
hepatocytes without degeneration or necrosis. The toxicological significance
of this effect is not clear. These results do not corroborate the finding of
liver effects in the interim sacrifice at 20 ppm in Quast et al. (1982a). No
exposure-related changes in the lungs were noted in rats or mice. The only
microscopic effect considered to be related to allyl chloride exposure was
observed in the kidneys of both male and female rats exposed to 100 and 250
ppm allyl chloride. The animals exposed to 100 ppm exhibited a slight
increase in the cytoplasmic granularity and eosinophilic staining of the
cortical epithelial cells when compared with the control rats. These changes
were also observed in the 250-ppm animals as well as an increase in the number
of tubules showing focal collapse and atrophy. This study identifies a NOAEL
at 50 ppm for kidney effects [NOAEL(HEC) = 27 mg/cu.m].
Torkelson et al. (1959) exposed 5 rats/sex, 4 male guinea pigs, and 1
female rabbit to 8 ppm (24 mg/cu.m) allyl chloride 7 hours/day, 5 days/week
for 35 days, with equal numbers of animals as controls. No clinical signs of
toxicity were evident in these animals, nor did they exhibit any reductions in
weight gain compared with the control animals. Histopathological examination
of the liver in all three species revealed dilation of the sinusoids, cloudy
swelling, and focal necrosis. The kidneys of all three species were found to
have changes in the glomeruli, necrosis of the epithelium of the convoluted
tubules, and proliferation of the interstitial tissues. These changes were
reported to have occurred in all animals, but results in controls were not
described. These findings contradict the reports of Quast et al. (1982a,b)
who found kidney effects and questionable liver effects only at much higher
concentrations. There is no obvious explanation for the difference between
the two studies. In a second experiment, Torkelson et al. (1959) exposed 24
rats, 3 rabbits, 9 guinea pigs, and 1 dog of each sex to 3 ppm allyl chloride
(9 mg/cu.m) 7 hours/day, 5 days/week for 6 months (duration-adjusted value is
1.88 mg/cu.m). Untreated controls were included for each species. The
animals were split into two groups: one group was killed immediately after
the last exposure, and the other group was held for an additional 2 months to
observe recovery from any adverse effects that may have occurred. No changes
related to treatment were observed in any of the animals exposed to 3 ppm
allyl chloride with regard to mortality, behavior, gross appearance, final
body weight, or clinical or hematological parameters. The only
histopathological change observed was slight central lobular degeneration in
the livers of the female rats. The effect was not observed in the control
groups, any other species, or in the female rats allowed to recover for 2
months. The small number of animals, poor reporting of results, and
contradiction of these findings by better designed studies rule out the use of
this study as the basis for the RfC.
Effects in the respiratory tract have been reported in animals exposed to
high concentrations of allyl chloride. Lu et al. (1982) found marked
congestion, hemorrhage, and edema on post-mortem examination after 2-hour
exposures in a study designed to identify the LC50. Individual exposure
levels are not reported, but the 2-hour LC50 values for mouse, rat and guinea
pig are 11,500, 11,800, and 6000 mg/cu.m, respectively. Nielson and Bakbo
(1985) studied sensory irritation in mice exposed to 1100-3770 ppm allyl
chloride for 10-30 minutes. The RD50 (concentration causing a 50% decrease in
respiratory rate) was identified as 2330 pm (7000 mg/cu.m) in mice. No
decrease in respiratory rate was observed when mice were exposed to 3770 ppm
via a tracheal cannula, indicating that the effect occurs by upper respiratory
tract irritation and not irritation in the thoracic region. Lack of effects
in the respiratory system at much lower concentrations in the Quast et al.
(1982a,b) studies indicate the lower sensitivity of the respiratory tract
effects compared with neurotoxic and renal effects.
Renal toxicity and neurotoxicity have also been observed in animals
exposed to allyl chloride by oral and subcutaneous administration. He et al.
(1981) administered allyl chloride in arachis oil by gavage to mice at doses
of 300 or 500 mg/kg 3 times a week for 2-17 weeks. Clinical signs of
neurotoxicity observed in animals treated with 500 mg/kg within the first
month included hind limb weakness, hunching of the back, and a sprawling gait,
but no paralysis. Mice dosed with 300 mg/kg allyl chloride developed some
hind limb weakness by the third month of treatment. Light and electron
microscopy revealed that animals exhibiting clinical signs of neurotoxicity
also had definite peripheral nerve fiber degeneration. Nerve damage was also
found in animals that were asymptomatic. Degeneration of the axons was seen
in many peripheral nerves and roots, and tended to be more severe in the
distal portions and in motor rather than sensory nerves. Degenerated fibers
were also found in the dorsal, ventral, and lateral columns of the spinal
cord. The kidneys were examined by light microscopy in 10 exposed and 4
control animals, and large foci of inflammatory cells including lymphocytes
and plasma cells were seen in 7 of these animals. The liver appeared
unaffected in the treated animals. He et al. (1980) treated 6 rabbits with 50
mg/kg allyl chloride subcutaneously 3 times in 1 week followed by 100 mg/kg,
3 times/week for 38-80 days. A peripheral neuropathy with EMG abnormalities
developed in all treated animals at 5-6 weeks of treatment. Hunched posture
in rats treated by gavage with 55 or 75 mg/kg/day and incoordination in male
mice surviving to 48 weeks of gavage treatment with 200 mg/kg/day were reported
in the NCI (1978) study. Detailed examination of the peripheral nerves
was not performed.
John et al. (1983) exposed pregnant Sprague-Dawley rats to 0, 30, or 300
ppm (0, 90, or 270 mg/cu.m) 7 hours/day on days 6-15 of gestation and New
Zealand rabbits to the same concentrations on days 6-18 of gestation. Maternal
body weight and food and water consumption were recorded until the uterine
contents were removed and examined on gestational day 21 (rats) or 29
(rabbits). Maternal liver weights, and the number and position of live, dead
or resorbed fetuses were recorded. After being weighed and measured, fetuses
were examined for external malformations, cleft palate, soft tissue and
cranial alterations (1/3 were examined), and skeletal malformations.
Maternal toxicity was evident in both species at the high dose based on
reduced weight gain on the first few days of exposure, increases in liver
weight (both species) and increased kidney weight (rats only). The data
showing the extent of these effects was not presented. There was no evidence
of a significant treatment-related effect on corpora lutea, implantation, live
fetuses/litter, or incidence of resorptions in either species. A slight delay
in skeletal development was seen in the rat fetuses from the 300-ppm group,
but no other developmental effects were seen in either species.
Hardin et al. (1987) reported a screening developmental study in which
pregnant CD-1 mice were dosed by gavage with 500 mg/kg/day on days 6-13 of
gestation. Parameters evaluated as a screen for developmental toxicity were
litter size, birth weight, and neonatal survival to postnatal day 3. Under
this protocol, no effects on developing fetuses were observed. This study is
compromised by the occurrence of 50% maternal mortality, and the evaluation of
a samll number of litters. A developmental study in which rats were dosed
intraperitoneally with 80 mg/kg on days 1-15 of gestation showed an increase
in fetal resorptions, craniofacial defects, and edema (Hardin et al., 1981).
___I.B.5. CONFIDENCE IN THE INHALATION RfC
Study -- Low
Data Base -- Low
RfC -- Low
The confidence in the principal study is low because it used a small
number of animals and reported detailed results for only the higher
concentration with poor reporting of results for the NOAEL exposure. The
confidence in the data base is low because there is conflicting information on
possible liver effects and no data on reproductive toxicity and because
chronic animal studies are lacking. Low confidence in the RfC follows.
___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC
Source Document -- This assessment is not presented in any existing U.S. EPA
document.
Other EPA Documentation -- U.S. EPA, 1986
Agency Work Group Review -- 12/19/1990
Verification Date -- 12/19/1990
___I.B.7. EPA CONTACTS (INHALATION RfC)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Allyl chloride
CASRN -- 107-05-1
Last Revised -- 08/01/1994
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- C; possible human carcinogen
Basis -- Classification is based on a low (but biologically important)
incidence of forestomach tumors in female mice and positive results in a
variety of genetic toxicity tests. Allyl chloride is an alkylating agent and
structurally related to probable human carcinogens.
___II.A.2. HUMAN CARCINOGENICITY DATA
None.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Limited. The results from a chronic gavage study, a short-term lung
adenoma bioassay, and a skin painting study are suggestive of carcinogenicity,
but interpretation is limited by inadequacies in the data.
Groups of Osborne-Mendel rats and B6C3F1 mice (50 animals/sex/dose) were
administered technical grade allyl chloride in corn oil by gavage, 5
times/week for 78 weeks (NCI, 1978). Twenty animals/sex/group served as
vehicle controls and untreated controls for each species. As the material was
highly toxic, the initial doses were adjusted downward. Final TWAs for the
low- and high-dose groups over the 78-week dosing period were as follows: 57
and 77 mg/kg/day for male rats; 55 and 73 mg/kg/day for female rats; 172 and
199 mg/kg/day for male mice; and 129 and 258 mg/kg/day for female mice. Rats
were observed for an additional 30-33 weeks and mice for an additional 14
weeks after the dosing period. Mortality in the high-dose groups of rats
(both sexes) and male mice was very high; fifty percent mortality in these
groups was reached in 14-38 weeks. Adequate numbers of animals survived in
all low-dose groups and in the high-dose female mice to evaluate the risk from
late-developing tumors. In rats, no statistically significant increases in
tumor incidence at any sites were observed.
In mice of both sexes, proliferative nonneoplastic lesions of the stomach
were observed. In female mice, squamous cell papillomas and carcinomas of the
forestomach were observed in 0/39 control (19 vehicle and 20 untreated), 3/47
low-dose (2 carcinomas), and 3/45 high-dose animals (all papillomas).
Sufficient numbers of high-dose females survived to evaluate risk from late
developing tumors. In male mice, squamous cell carcinomas of the forestomach
occurred in 0/29 (17 vehicle and 12 untreated) control, 2/36 low-dose, and
0/10 high-dose animals (only 10 high-dose males survived past 52 weeks). The
incidence of these tumors was not significantly greater than that in the
concurrent controls at either dose level for either sex. The combined
incidence in females, however, was significantly increased at both doses
relative to historical vehicle controls (1/180 female mice with squamous cell
papilloma or carcinoma of the forestomach). The incidence of carcinomas in
the low-dose males was also significantly elevated compared with historical
controls (1/180). The time period during which the historical control data
were collected was not specified. Because the stomach tumors were considered
to be a rare tumor type, and because the proliferative lesions could represent
an early stage in the neoplastic process, the findings were interpreted by the
authors to be strongly suggestive of carcinogenicity in mice. The Data
Evaluation/Risk Assessment Subgroup of the Clearinghouse on Environmental
Carcinogens reviewed the NCI bioassay. The reviewers considered this study
inadequate for drawing any conclusion about the carcinogenicity of allyl
chloride because of the poor survival in the high dose groups.
Male and female Strain A/St mice (10/sex/group) were given intraperitoneal
injections of allyl chloride (unkown purity) in tricaprylin 3 times/week for 8
weeks, for total doses of 1.2, 2.9, and 5.9 g/kg (Theiss et al., 1979). After
24 weeks from beginning of the exposure, the mice were sacrificed and their
lungs examined for gross lesions (adenomas). The average numbers of adenomas
per mouse (20 animals/group, both sexes combined) were 0.19, 0.60, 0.50, and
0.60 in the vehicle control, low-, medium- and high-dose groups, respectively.
The average in the high-dose group was reported as significantly increased
relative to the vehicle controls by either the Student's t test or the chi-
square test, but not both. While the results may indicate carcinogenic
activity, the statistical analyses were not well reported, and there was no
indication of a dose-related increase in tumor multiplicity.
Van Duuren et al. (1979) tested allyl chloride (of unknown purity) in skin
painting experiments with female Ha:ICR Swiss mice (30 mice/dose, housed 6
mice/cage). Allyl chloride in acetone, administered 3 times/week (31 or 94
mg/mouse) for 63-85 weeks did not induce skin tumors. Lung and stomach
papillomas were observed in both dose groups: 14 lung and 3 stomach papillomas
in the low-dose group and 12 lung and 3 stomach papillomas in the high-dose
group. One adenocarcinoma of the glandular stomach was reported in the high-
dose group. The authors indicated that these incidences were not
significantly elevated compared with vehicle or nontreated controls (control
incidence not reported). A single application of allyl chloride to Ha:ICR
Swiss mice (94 mg/mouse) followed by repeated applications of phorbol
myristate acetate resulted in an accelerated onset and a statistically
significant increase in skin tumor incidence (10 total papillomas/7 tumor-
bearing animals, control incidence not reported).
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Ally chloride is an alkylating agent. Mutagenicity assays of allyl
chloride in Salmonella typhimurium have been generally positive with or
without metabolic activation (for example, Bignami et al., 1980), but have
greatly decreased activity in the presence of an exogenous activating system
(Eder et al., 1980). It produced gene conversion in Saccharomyces cervesiae
but no mutations in Aspergillus nidulans or chromosome aberrations in rat
liver cells (Bignami et al, 1980). Allyl chloride at a concentration of 1 mM
induced unscheduled DNA synthesis in HeLa cells (Schiffman et al., 1983).
Allyl chloride epoxide is epichlorohydrin, a nasal carcinogen for rats by
inhalation and a probable human carcinogen, although the likelihood of
formation of this metabolite is unknown. Allyl chloride is structurally
similar to dibromochloropropane, a probable human carcinogen.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1986, 1979
The 1986 Health and Environmental Effects Profile received OHEA review. The
Preliminary Risk Assessment is an internal EPA document.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 11/12/1986, 02/24/1988, 04/05/1989
Verification Date -- 04/05/1989
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- Allyl chloride
CASRN -- 107-05-1
Last Revised -- 05/01/1995
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfD REFERENCES
Hardin, B.D., G.P. Bond, M.R. Sikov, F.D. Andrew, R.P. Beliles and R.W.
Niemeier. 1981. Testing of selected workplace chemicals for teratogenic
potential. Scand. J. Work Environ. Health. 7: 66-75.
Hardin, B.D., R.L. Shuler, J.R. Burg, et al. 1987. Evaluation of 60
chemicals in a preliminary developmental toxicity test. Teratogen.
Carcinogen. Mutagen. 7: 29-48.
Hausler, M. and R. Lenich. 1968. Effect of chronic occupational allyl
chloride exposure. Arch. Toxicol. (Berl.) 23: 209-214.
He, F. and S.L. Zhang. 1985. Effects of allyl chloride on occupationally
exposed subjects. Scand. J. Work Environ. Health. 11(Suppl 4): 43-45.
He, F., D. Shen, Y. Guo and B. Lu. 1980. Toxic polyneuropathy due to chronic
allyl chloride intoxication: A clinical and experimental study. Chin. Med.
J. 93(3): 177-182. (Eng. ed.)
He, F., J.M. Jacobs and F. Scaravilli. 1981. The pathology of allyl chloride
neurotoxicity in mice. Acta Neuropathol. 55(2): 125-133.
He, F., B. Lu, S. Zhang, S. Dong, A. Yu and B. Wang. 1985. Chronic allyl
chloride poisoning. An epidemiology, clinical, toxicological and
neuropathological study. G. Ital. Med. Lav. 7(1): 5-15.
He, F. 1991. Institute Occupational Medicine, Chinese Academy of
Preventative Medicine/WHO Collaborating Centre Occupational Health, Beijing,
China. Letter to Daniel Guth, U.S. EPA, Research Triangle Park, NC.
September 16.
John, J.A., T.S. Gushow, J.A. Ayres, T.R. Hanley Jr., J.F. Quast and K.S. Rao.
1983. Teratologic evaluation of inhaled epichlorohydrin and allyl chloride in
rats and rabbits. Fund. Appl. Toxicol. 3: 437-42.
Lu, B., D. Shuwei, Y. Airu, X. YinLin, G. Taibao and C. Tao. 1982. Studies
on the toxicity of allyl chloride. Ecotoxicol. Environ. Saf. 6: 19-27.
NCI (National Cancer Institute). 1978. Bioassay of allyl chloride for
possible carcinogenicity. CAS No. 107-05-1. NCI-CG-TR-73. DHEW Publ. No.
(NIH) 78-1323.
Nielson, G.D. and J.C. Bakbo. 1985. Sensory irritating effects of allyl
halides and a role for hydrogen bonding as a likely feature at the receptor
site. Acta Pharmacol. Toxicol. 57: 106-16.
NIOSH (National Institute for Occupational Safety and Health). 1976. Criteria
for a recommended standard...Occupational exposure to allyl chloride. U.S.
DHEW, PHS, CDC, Rockville, MD. HEW Publ. No. (NIOSH) 76-204.
Quast, J.F., J.W. Henck, D.J. Schuetz and M.J. McKenna. 1982a. Allyl
chloride - Subchronic Studies. IA - 90-day inhalation study in laboratory
rodents (CDF-Fisher 344 rats and B6C3F1 mice). OTS Document #FYI-AX-0782-
0199.
Quast, J.F., J.W. Henck, D.J. Schuetz, D.A. Dittenber and M.J. McKenna. 1982b.
Allyl chloride - Subchronic studies. IB - Results of an inhalation 4-day
probe and 90-day subchronic study in laboratory rodents. OTS Document #FYI-
AX-0782-0199.
Torkelson, T.R., M.A. Wolf, F. Oyen and V.K. Rowe. 1959. Vapor toxicity of
allyl chloride as determined on laboratory animals. Am. Ind. Hyg. Assoc. J.
20: 217-223.
U.S. EPA. 1986. Health and Environmental Effects Profile for Allyl Chloride.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste
and Emergency Response, Washington, DC. EPA/600/X-86/198.
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Bignami, M., G. Conti, L. Conti, R. Crebelli, F. Misuraca, A.M. Puglia, R.
Randazzo, G. Sciandrello and A. Carere. 1980. Mutagenicity of halogenated
aliphatic hydrocarbons in salmonella typhimurium, Streptomyces coelicolor and
Aspergillus nidulans. Chem.-Biol. Interaction. 30(1): 9-23.
Eder, E., T. Neudecker, D. Lutz and D. Henschler. 1980. Mutagenic potential
of allyl and allylic compounds: Structure-activity relationship as determined
by alkylating and direct in vitro mutagenic properties. Biochem. Pharmacol.
29(3): 993-998.
NCI (National Cancer Institute). 1978. Bioassay of Allyl Chloride for
Possible Carcinogenicity. Carcinogenesis Technical Report Series.
NCI-CG-TR-73. PB-287516.
Schiffmann, D., E. Eder, T. Neudecker and D. Henschler. 1983. Induction of
unscheduled DNA synthesis in HeLa cells by allylic compounds. Cancer
Letters. 20(3) 263-269.
Theiss, J.C., M.B. Shimkin and L.A. Poirer. 1979. Induction of pulmonary
adenomas in strain A mice by SUBSTituted organohalides. Cancer Res. 39:
391-395.
U.S. EPA. 1979. The Carcinogen Assessment Group's Preliminary Risk
Assessment on Allyl Chloride. Type 1-Air Program.
U.S. EPA. 1986. Health and Environmental Effects Profile for Allyl
Chloride. Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH. ECAO-Cin-P186.
Van Duuren, B.L., B.M Goldschmidt, G. Loewengart, A.C. Smith, S. Melchionne,
I. Seldman and D. Roth. 1979. Carcinogenicity of halogenated olefinic and
aliphatic hydrocarbons in mice. J. Natl. Cancer Inst. 63(6): 1433-1439.
_VII. REVISION HISTORY
Substance Name -- Allyl chloride
CASRN -- 107-05-1
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
09/01/1990 II. Carcinogen assessment on-line
09/01/1990 VI. Bibliography on-line
01/01/1991 I.B. Inhalation RfC now under review
08/01/1991 VI.C. Eder et al. 1980 reference volume corrected
12/01/1991 I.B. Inhalation RfC on-line
12/01/1991 VI.B. Inhalation RfC references added
01/01/1992 IV. Regulatory Action section on-line
05/01/1995 I.B. Principal study author name corrected
05/01/1995 VI.B. Author name corrected
VIII. SYNONYMS
Substance Name -- Allyl chloride
CASRN -- 107-05-1
Last Revised -- 09/01/1990
107-05-1
ALLILE (CLORURO DI) [ITALIAN]
ALLYLCHLORID [GERMAN]
ALLYL CHLORIDE
ALLYLE (CHLORURE D') [FRENCH]
P-AMINOPROPIOFENON [CZECH]
CHLORALLYLENE
3-CHLOROPRENE
1-CHLORO-2-PROPENE
3-CHLOROPROPENE-1
1-CHLORO PROPENE-2
3-CHLOROPROPENE
3-CHLORO-1-PROPENE
3-CHLOROPROPYLENE
ALPHA-CHLOROPROPYLENE
3-CHLORPROPEN [GERMAN]
CHLORURE D'ALLYLE [FRENCH]
CLORURO DE ALILO [SPANISH]
HSDB 178
NCI-C04615
NSC 20939
1-PROPENE, 3-CHLORO-
PROPENE, 3-CHLORO-
2-PROPENYL CHLORIDE
UN 1100
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0387.HTM
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