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Benzyl chloride
CASRN 100-44-7
Contents
0393
Benzyl chloride; CASRN 100-44-7
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 Benzyl chloride
File On-Line 08/01/1989
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) no data
Inhalation RfC Assessment (I.B.) message 07/01/1995
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 -- Benzyl chloride
CASRN -- 100-44-7
Primary Synonym -- Chloromethylbenzene
Not available at this time.
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Benzyl chloride
CASRN -- 100-44-7
Primary Synonym -- Chloromethylbenzene
The health effects data for benzyl chloride were reviewed by the U.S. EPA
RfD/RfC Work Group and determined to be inadequate for derivation of an
inhalation RfC. The verification status of this chemical is currently not
verifiable. There are currently no EPA documents available for this chemical.
Agency Work Group Review -- 11/07/1991
EPA Contacts:
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 -- Benzyl chloride
CASRN -- 100-44-7
Primary Synonym -- Chloromethylbenzene
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 -- B2; probable human carcinogen
Basis -- Based on inadequate human data and sufficient evidence of
carcinogenicity in animals; namely significantly increased incidences of
benign and malignant tumors at multiple sites in both sexes of mice and a
significant increase in thyroid tumors in female rats. There was evidence of
mutagenicity in a variety of test systems.
___II.A.2. HUMAN CARCINOGENICITY DATA
Inadequate. Studies have shown that occupational exposure to the process
of benzoyl chloride production, in which benzyl chloride is a minor reaction
by-product, may increase the risk of cancer-induced mortality. The available
human data for benzyl chloride alone are considered inadequate because the
studies included small numbers of cancer deaths and were based on exposure to
mixtures of chlorinated compounds. In addition, data on cigarette smoking
were incomplete.
Sakabe et al. (1976) reported three cancer deaths among 41 workers
employed in a benzoyl chloride production plant in Japan between 1954 and
1972. Two of the deaths were from lung cancer, both in smokers who were in
their forties. The third cancer death was from maxillary malignant lymphoma
in a 50 year-old worker with and unspecified smoking status. The fourth
cancer case, diagnosed as squamous cell carcinoma of the lung, was identified
in a nonsmoker still living in 1973. These four workers were employed in
benzoyl chloride production from 6 to 15 years. The number of deaths from
lung cancer (2) was significantly higher than the number expected (0.06),
based on the Japanese national rate for death from lung cancer in males.
In addition to benzyl chloride, these workers were exposed to
benzotrichloride, benzoyl chloride, toluene, chlorine gas, hydrogen chloride,
benzal chloride, other chlorinated toluenes and polymerized products from the
process. The authors considered it unlikely that the four cases of cancer
were produced by exposure to benzyl chloride because this was a very minor
reaction product in the production process.
In a subsequent case report, two lung cancer deaths were identified among
workers engaged in benzoyl peroxide and benzoyl chloride production at another
plant, in which the total number of workers ranged from 13 in 1952 to 40 in
1963 (Sakabe and Fukuda, 1977). The two individuals, one of whom was a
smoker, were in their forties and had worked in benzoyl chloride production
for 6 to 18 years. The number of deaths expected among these workers was not
reported.
Sorahan et al. (1983) carried out a study of cancer mortality among 953
workers at a British factory engaged in production of chlorinated toluenes.
As in the Japanese plants, there was exposure to toluene (the starting
material), benzotrichloride and benzoyl chloride (the major reaction
products), as well as to benzyl chloride, benzal chloride and other materials.
The cohort of exposed workers consisted of 163 males employed for at least six
months between 1961 and 1970. Some of these individuals started employment as
early as 1923. Of the 10 deaths from cancer (25 total deaths) reported in
this group, 5 were due to digestive system cancers and 5 to respiratory
cancers, compared with the expected values of 1.24 and 1.78, respectively.
The standardized mortality ratio for each of these sites was significantly
higher than expected, based on mortality rates for England and Wales. A
survival analysis using the Cox Proportional Hazard Model, adjusted for age at
entry to the survey and the time period when employment began, was also
conducted. This analysis showed a statistically significant association
between estimated cumulative exposure and deaths from cancer at all sites (but
not for digestive or respiratory cancers individually) for persons first
employed before 1951. The association was not significant for all entry
cohorts combined. Interpretation of this study is limited by several factors
including possible bias in assignment of exposure categories, exposure to
multiple compounds and lack of data on smoking.
A retrospective mortality study was reported on a cohort of 697 male
workers who were exposed to benzyl chloride, benzoyl chloride and
benzotrichloride at a chlorination plant in Tennessee (Wong and Morgan, 1984).
The length of employment at the plant ranged from 1 year to >35 years. Seven
deaths from respiratory cancer were found in the total cohort compared with
2.84 deaths expected, based on U.S. mortality rates for males. Five of these
deaths occurred in workers employed for at least 15 years. This was
significantly greater than the 1.32 deaths expected for this subgroup. The
results of this study were confounded by exposures to several chemicals and
lack of data on smoking.
In summary, because of small sample sizes, lack of data on cigarette
smoking and the fact that exposure was to a mixture of halogenated
intermediates, the available human data are insufficient to determine the
potential carcinogenicity of benzyl chloride.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Sufficient. In a NCI carcinogenicity bioassay (Lijinsky, 1986), Fischer
F344 rats (52/sex/dose) and B6C3F1 mice (52/sex/dose) were administered benzyl
chloride in corn oil by gavage 3 times/week for 104 weeks. They were
sacrificed for comprehensive histological analysis 3 to 4 weeks after the last
dose. Rats received either 0, 15, or 30 mg/kg per dose; mice received either
0, 50, or 100 mg/kg per dose. No significant differences in survival were
seen between treated and control groups. In rats, the only statistically
significant increase in tumor incidence attributed to treatment was thyroid C-
cell adenoma/carcinoma in the female high-dose group (4/52, 8/51, 14/52 for
low, medium and high doses, respectively). In male mice, statistically
significant increases in the following tumor incidences were observed:
hemangioma/hemangiosarcoma in the high-dose group (0/52, 0/52, 5/52) hepatic
carcinoma/adenoma in the low-dose group (17/52, 28/52, 20/51) forestomach
carcinoma in the high-dose group (0/51, 2/52, 8/52), and forestomach
carcinoma/papilloma in the high-dose group (0/51, 4/52, 32/52). In female
mice, a statistically significant increase in the incidence of forestomach
carcinoma/papilloma was reported (0/52, 5/50, 19/51). Also, a slightly
increased incidence of lung alveolar-bronchiolar adenoma/carcinoma (1/52,
2/51, 6/51) was observed in the high-dose group of female mice.
Fukuda et al. (1981) conducted two skin-painting studies on specific-
pathogen-free ICR mice, using benzyl chloride dissolved in benzene. Benzene-
only controls were included for vehicle comparison. In the first study, no
tumors were observed in 11 mice treated with 10 uL benzyl chloride 3
times/week for 4 weeks, followed by 2 times/week until termination at 40
weeks. In the second study, 2.3 uL benzyl chloride was diluted to a final
volume of 25 uL with benzene and applied to the skin of 7-week-old mice 2
times/week for 50 weeks. Two of 20 control animals developed lung adenomas,
while 5/20 treated mice developed tumors, including 2 lung adenomas and 3 skin
carcinomas. Two of the skin carcinomas metastasized to the primary lymphatic
organs, liver, or kidneys. Although these tumor incidences are not
statistically significantly greater than controls, the authors considered
benzyl chloride to be a weak carcinogen when applied topically. The short
duration of the studies limited their sensitivity.
Efforts to assess the potency of benzyl chloride as a carcinogen and skin
tumor initiator provided predominantly negative results. Coombs (1982a)
applied 1.0 mg benzyl chloride in toluene to the backs of 40 T.O. (Swiss-
Webster derived Theiler's Original) mice, followed by twice weekly treatments
of croton oil in toluene for 10 months. While 8/19 positive controls treated
with 0.4 mg benzo[a]pyrene developed skin tumors, none (0/37) of the benzyl
chloride-treated mice did. In a second initiation-promotion test, Coombs
(1982b) topically applied 10, 100, or 1000 ug benzyl chloride in acetone,
followed by twice weekly applications of the promotor 12-O-tetra-'3-decanoyl-
phorbol-'3-acetate. At the end of 11 weeks, all of the positive controls
treated with (7,12-dimethylbenz[a]anthracene) had skin tumors, whereas at 6
months (approximately 12 weeks later), only 20% of the mice treated with
benzyl chloride showed similar changes. Ashby et al. (1982) topically treated
groups of 20 Swiss mice with 100 ug benzyl chloride in toluene twice weekly.
After 7.5 months, none of the treated mice had skin tumors compared with 18/20
of the positive controls treated with benzo[a]pyrene.
Druckrey et al. (1970) administered benzyl chloride in peanut oil via
weekly subcutaneous injection to BD-strain rats for 51 weeks. Local sarcomas
were produced in 3/14 rats given 40 mg/kg/week and in 6/8 rats given 80
mg/kg/week. The average induction time was 500 days and metastases to the
lung occurred in the high-dose group only.
Groups of 20 strain A/H mice were injected intraperitoneally over a 24-
week period with benzyl chloride in tricaprylin (total doses of 4.7, 11.8, or
15.8 mmol/kg). No differences in pulmonary adenoma formation between treated
and vehicle control mice were observed (Poirier et al., 1975).
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Benzyl chloride was weakly mutagenic to Salmonella typhimurium strain
TA100 and Eschericia coli WP2 uvr A(p), which are sensitive to the induction
of point mutations (Venitt, 1982). It was also positive for genotoxicity in
repair-deficient strains (Fluck et al., 1976; Rosenkranz and Leifer, 1980).
Parry and Wilcox (1982) reported that benzyl chloride affects the replication
and repair mechanisms in fungi. In Drosophila melanogaster, benzyl chloride
was found to induce somatic mutations more readily than sex-linked alterations
(Fahmy and Fahmy, 1982). In mammalian cultured cells, benzyl chloride was
slightly mutagenic to DNA excision-repair deficient strains of CHO cells (Hoy
et al., 1984), but was generally ineffective in increasing unscheduled DNA
synthesis (Mitchell, 1976; Booth et al., 1983). Scott and Topham (1982)
concluded that benzyl chloride was generally not mutagenic in in vivo
mammalian systems, including the mouse micronucleus and sperm head abnormality
tests.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
___II.B.1. SUMMARY OF RISK ESTIMATES
Oral Slope Factor -- 1.7E-1 per (mg/kg)/day
Drinking Water Unit Risk -- 4.9E-6 per ug/L
Extrapolation Method -- Linearized multistage procedure, extra risk
Drinking Water Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- -------------
E-4 (1 in 10,000) 2E+1 ug/L
E-5 (1 in 100,000) 2 ug/L
E-6 (1 in 1,000,000) 2E-1 ug/L
___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
Tumor Type -- thyroid, C-cell adenoma/carcinoma
Test Animals -- rat/Fischer 344, female
Route -- gavage, corn oil
Reference -- Lijinsky, 1986
Administered Dose Human Equivalent Tumor
(mg/kg, 3 times/week) Dose (mg/kg)/day Incidence
--------------------- ---------------- ---------
0 0 4/52
15 1.06 8/51
30 2.12 14/52
___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
The human equivalent doses were calculated by multiplying the experimental
dose by 3 days/7 days and by 104 weeks/107.5 weeks. Because body weight gain
data were not provided, a reference weight of 0.35 kg for rats was assumed.
Using the data from Lijinsky (1986), slope factors were derived for the
incidence of forestomach papilloma and carcinoma in male mice [5.6E-2 per
(mg/kg)/day] and in female mice [1.2E-1 per (mg/kg)/day]. The rat C-cell
adenoma/carcinoma data were used because they resulted in the highest slope
factor.
The unit risk should not be used if the water concentration exceeds 2E+3
ug/L, since above this concentration the slope factor may differ from that
stated.
___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL)
A sufficent number of animals were used for analysis of late-developing
tumors. Benzyl chloride was administered by a relevant route of exposure at
two doses in both sexes of two species for the animals' lifespan.
Histological examination was comprehensive. Slope factors derived from tumor
data at another site in another species were within a factor of 3.
__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
The 1986 Health and Environmental Effects Profile for Benzyl Chloride has
received Agency review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 03/01/1989
Verification Date -- 03/01/1989
___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 -- Benzyl chloride
CASRN -- 100-44-7
Primary Synonym -- Chloromethylbenzene
Last Revised -- 07/01/1993
__VI.A. ORAL RfD REFERENCES
None
__VI.B. INHALATION RfD REFERENCES
None available
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Ashby, J., C. Gaunt and M. Robinson. 1982. Carcinogenicity bioassay of 4-
chloromethyl biphenyl (4CMB), 4-hydroxymethyl (4HMB) and benzyl chloride (BC)
on mouse skin. Interim 7-month report. Mutat. Res. 100(1-4): 399-401.
Booth, S.C., A.J. Mould, A. Shaw and R.C. Garner. 1983. The biological
activity of 4-chloromethylbiphenyl, benzyl chloride and 4-
hydroxymethylbiphenyl in four short-term tests for carcinogencity. A report
of an individual study in the U.K.E.M.S. genotoxicity trial 1981. Mutat. Res.
119(2): 121-133.
Coombs, M.M. 1982a. Attempts to initiate skin tumors in mice in the 2-stage
system using 4-chloromethylbiphenyl (4CMB), 4-hydroxymethyl-biphenyl (4HMB),
and benzyl chloride (BC). Report of the experiment at 10 months. Mutat. Res.
100: 403-405.
Coombs, M.M. 1982b. The UKEMS Genotoxicity Trial: A summary of the assays
for skin tumor induction in mice, the subcutaneous implant test and the
sebaceous gland suppression test. Mutat. Res. 100: 407-409.
Druckrey, H., H. Kruse, R. Preussmann, S. Ivankovic and C. Landschuetz. 1970.
Cancerogenic alkylating substances. III. Alkyl-halogenides, -sulfates, -
sulfonates and strained heterocyclic compounds. Z. Krebsforsch. 74(3): 241-
273.
Fahmy, M.J. and O.G. Fahmy. 1982. Genetic activities of 4- chloromethyl-
biphenyl, the 4-hydroxy derivative and benzyl chloride in the soma and germ
line of Drosophila melanogaster. Mutat. Res. 100(1-4): 339-344.
Fluck, E.R., L.A. Poirier and H.W. Ruelius. 1976. Evaluation of a DNA
polymerase-deficient mutant of E. coli for the rapid detection of carcinogens.
Chem. Biol. Interact. 15 : 219-231.
Fukuda, K., H. Matsushita, H. Sakabe and K. Takemoto. 1981. Carcinogenicity
of benzyl chloride, benzal chloride, benzotrichloride and benzoyl chloride in
mice by skin application. Gann. 72(5): 655-664.
Hoy, C.A., E.P. Salazar and L.H. Thompson. 1984. Rapid detection of DNA-
damaging agents using repair-deficient CHO cells. Mutat. Res. 130(5): 321-
332.
Lijinsky, W. 1986. Chronic bioassay of benzyl chloride in F344 rats and
(C57BL/6J x BALB/c)F1 mice. J. Natl. Cancer Inst. 76(6): 1231-1236.
Mitchell, A.D. 1976. Potential Prescreens for Chemical Carcinogens:
Unscheduled DNA Synthesis. Task 2. Final Report. 70 p.
Parry, J.M. and P. Wilcox. 1982. The genetic toxicology in fungi of 4-
chloromethylbiphenyl (4CMB), 4-hydroxymethylbiphenyl (4HMB) and benzyl
chloride (BC). Survey of the results of the U.K.E.M.S. collaborative
genotoxicity trial 1981. Mutat. Res. 100(1-4): 185-200.
Poirier, L.A., G.D. Stoner and M.B. Shimkin. 1975. Bioassay of alkyl halides
and nucleotide base analogs by pulmonary tumor response in strain A mice.
Cancer Res. 35(6): 1411-1415.
Rosenkranz, H.S. and Z. Leifer. 1980. Determining the DNA-modifying activity
of chemicals using DNA polymerase-deficient Escherichia coli. Chem. Mutat.
Prin. Methods Detection. 6: 109-147.
Sakabe, H. and K. Fukuda. 1977. An updating report on cancer among benzoyl
chloride manufacturing workers. Ind. Health. 15(3-4): 173-174.
Sakabe, H., H. Matsushita and S. Koshi. 1976. Cancer among benzoyl chloride
manufacturing workers. Ann. NY. Acad. Sci. 271: 67-70.
Scott, K. and J.C. Topham. 1982. Sperm head abnormality test. Mutat. Res.
100: 345-350.
Sorahan, T., J.A.H. Waterhouse, M.A. Cooke, E.M.B. Smith, J.R. Jackson and L.
Temkin. 1983. A mortality study of workers in a factory manufacturing
chlorinated toluenes. Ann. Occup. Hyg. 27(2): 173-182.
U.S. EPA. 1986. Health and Environmental Effects Profile for Benzyl
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.
Venitt, S. 1982. U.K.E.M.S. Collaborative Genotoxicity Trial. Bacterial
mutation test of 4-chloromethylbiphenyl, 4-hydroxymethyl-biphenyl and benzyl
chloride; analysis of data from 17 laboratories. Mutat. Res. 100: 91-109.
Wong, O. and R.W. Morgan. 1984. Final Report. A Cohort Mortality Study of
Employees at the Velsicol Chattanooga Plant. 1943-1982. Prepared for
Velsicol Chemical Corp. by Environmental Health Associates, Inc. TSCA 8e
submission 8EHQ-0884-0522, 88-8400657.
_VII. REVISION HISTORY
Substance Name -- Benzyl chloride
CASRN -- 100-44-7
Primary Synonym -- Chloromethylbenzene
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
08/01/1989 II. Carcinogen summary on-line
08/01/1989 VI. Bibliography on-line
01/01/1990 II.A.2. Text edited
01/01/1990 II.A.3. Text edited
02/01/1990 V. Supplementary data on-line
12/01/1991 I.B. Inhalation RfC now under review
01/01/1992 I.B. Inhalation RfC message on-line
01/01/1992 VI.B. Inhalation RfC references: none available
01/01/1992 IV. Regulatory Action section on-line
07/01/1992 II.A.2. Minor text revision
07/01/1993 VI.C. References alphabetized correctly
07/01/1995 I.B. Primary contact changed
VIII. SYNONYMS
Substance Name -- Benzyl chloride
CASRN -- 100-44-7
Primary Synonym -- Chloromethylbenzene
Last Revised -- 08/01/1989
100-44-7
BENZENE, (CHLOROMETHYL)-
BENZILE (CLORURO DI) (Italian)
BENZYL CHLORIDE
BENZYLE (CHLORURE DE) (French)
BENZYLCHLORID (German)
CHLOROMETHYLBENZENE
CHLOROPHENYLMETHANE
alpha-CHLOROTOLUENE
omega-CHLOROTOLUENE
alpha-CHLORTOLUOL (German)
CHLORURE DE BENZYLE (French)
NCI-C06360
RCRA WASTE NUMBER P028
TOLUENE, alpha-CHLORO-
TOLYL CHLORIDE
UN 1738
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0393.HTM
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