United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-08/005F
Final
7-14-2008
Provisional Peer Reviewed Toxicity Values for
Benzyl chloride
(CASRN 100-44-7)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

-------
Acronyms and Abbreviations
bw	body weight
cc	cubic centimeters
CD	Caesarean Delivered
CERCLA	Comprehensive Environmental Response, Compensation and
Liability Act of 1980
CNS	central nervous system
cu.m	cubic meter
DWEL	Drinking Water Equivalent Level
FEL	frank-effect level
FIFRA	Federal Insecticide, Fungicide, and Rodenticide Act
g	grams
GI	gastrointestinal
HEC	human equivalent concentration
Hgb	hemoglobin
i.m.	intramuscular
i.p.	intraperitoneal
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
i.v.	intravenous
kg	kilogram
L	liter
LEL	lowest-effect level
LOAEL	lowest-observed-adverse-effect level
LOAEL(ADJ)	LOAEL adjusted to continuous exposure duration
LOAEL(HEC)	LOAEL adjusted for dosimetric differences across species to a human
m	meter
MCL	maximum contaminant level
MCLG	maximum contaminant level goal
MF	modifying factor
mg	milligram
mg/kg	milligrams per kilogram
mg/L	milligrams per liter
MRL	minimal risk level
MTD	maximum tolerated dose
MTL	median threshold limit
NAAQS	National Ambient Air Quality Standards
NOAEL	no-ob served-adverse-effect level
NOAEL(ADJ)	NOAEL adjusted to continuous exposure duration
NOAEL(HEC)	NOAEL adjusted for dosimetric differences across species to a human
NOEL	no-ob served-effect level
OSF	oral slope factor
p-IUR	provisional inhalation unit risk
p-OSF	provisional oral slope factor
1

-------
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
ppb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
l^g
microgram
[j,mol
micromoles
voc
volatile organic compound
11

-------
7-14-2008
PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
BENZYL CHLORIDE (CASRN 100-44-7)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1.	EPA's Integrated Risk Information System (IRIS).
2.	Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3.	Other (peer-reviewed) toxicity values, including:
~	Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~	California Environmental Protection Agency (CalEPA) values, and
~	EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because new information becomes available and scientific methods improve over time,
PPRTVs are reviewed on a five-year basis and updated into the active database. Once an IRIS
value for a specific chemical becomes available for Agency review, the analogous PPRTV for
that same chemical is retired. It should also be noted that some PPRTV manuscripts conclude
that a PPRTV cannot be derived based on inadequate data.
Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
1

-------
7-14-2008
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
No RfD is available for benzyl chloride on IRIS (U.S. EPA, 2007), in the drinking water
standards and health advisories list (U.S. EPA, 2004), or in the Health Effects Assessment
Summary Table (HEAST) (U.S. EPA, 1997). The CARA list (U.S. EPA 1991, 1994a) includes a
Health and Environmental Effects Profile (HEEP) for benzyl chloride (U.S. EPA, 1986) that did
not derive an RfD. The Agency for Toxic Substances and Disease Registry (ATSDR, 2007) and
World Health Organization (WHO, 2007) have not derived any oral risk assessment values for
benzyl chloride.
No RfC is available for benzyl chloride on IRIS (U.S. EPA, 2007) or in the HEAST (U.S.
EPA, 1997). ATSDR (2007) and WHO (2007) have not derived any inhalation risk assessment
values for benzyl chloride. ACGIH (2001, 2006) has set a TLV-TWA (threshold limit
value-time-weighted average) of 1 ppm (5 mg/m3) for occupational exposure to benzyl chloride
on the basis of acute eye and nasal irritation in humans. The Occupational Safety and Health
Administration (OSHA, 2007) PEL (permissible exposure limit) for benzyl chloride is 1 ppm (5
mg/m3) for an 8-hour TWA. The National Institute of Safety and Health (NIOSH, 2007)
recommendations for benzyl chloride include an IDLH (immediately dangerous to life and
health) concentration of 10 ppm (52 mg/m3) and a REL (recommended exposure level) of 1 ppm
(5 mg/m3) as a 15-minute ceiling. The California EPA has established a chronic Reference
Exposure Level (REL) of 12 |ig/m3 for benzyl chloride to protect against respiratory effects
(CalEPA, 2005).
2

-------
7-14-2008
A carcinogenicity assessment is available for benzyl chloride on IRIS (U.S. EPA, 2007).
Benzyl chloride was assigned to cancer weight-of-evidence Group B2 (probable human
carcinogen), based on inadequate human data, sufficient evidence in animals and supporting
evidence of mutagenicity. An oral slope factor of 1.7E-01 per mg/kg-day and drinking water
unit risk of 4.9E-06 per |ig/L were derived based on dose-response data for thyroid C-cell
adenoma/carcinoma in female rats (Lijinsky, 1986). There is no quantitative estimate of
carcinogenic risk from inhalation exposure on IRIS due to inadequate data. The IRIS assessment
was verified on 03/01/89 and is based on the 1986 HEEP for benzyl chloride (U.S. EPA, 1986).
The HEAST (U.S. EPA, 1997) includes a reference to the carcinogenicity assessment on IRIS.
CalEPA (2007) derived an inhalation unit risk value of 4.9E-5 (jig/in3)"1 for benzyl
chloride from the EPA oral slope factor of 1.7E-01 per mg/kg-day (U.S. EPA, 2007) by
assuming a human breathing rate of 20 m3/day, a human body weight of 70 kg and 100%
fractional absorption after inhalation exposure. The ACGIH (2001, 2006) occupational exposure
recommendation for benzyl chloride includes an A3 notation (confirmed animal carcinogen with
unknown relevance to humans). NTP (2007) has not assessed the carcinogenicity of benzyl
chloride.
IARC (1982, 1987, 1999) assigned combined exposures to benzoyl chloride and a-
chlorinated toluenes (benzyl chloride, benzal chloride, benzotrichloride and benzoyl chloride) to
Group 2A (probably carcinogenic to humans). This classification is based on limited evidence
in humans for the carcinogenicity of a-chlorinated toluenes and benzoyl chloride, sufficient
evidence in animals for the carcinogenicity of benzyl chloride and benzotri chloride, limited
evidence in animals for the carcinogenicity of benzal chloride and inadequate evidence in
animals for the carcinogenicity of benzoyl chloride. The human data did not allow any
differential risk estimation for any of the individual chlorinated toluenes. The assessment of
limited evidence for carcinogenicity of benzyl chloride in animals was based on tumor induction
in oral, dermal and subcutaneous injection studies.
The present document does not include a cancer assessment for benzyl chloride, as one is
available on IRIS.
Literature searches were conducted from the 1960's through May 2008 for studies
relevant to the derivation of provisional toxicity values for benzyl chloride. Databases searched
include: MEDLINE (including PubMed cancer subset), TOXLINE (Special, including NTIS
subfile), BIOSIS, TSCATS/TSCATS 2, CCRIS, DART/ETIC, GENETOX, HSDB, RTECS and
Current Contents.
REVIEW OF PERTINENT DATA
Human Studies
No information was located regarding the oral toxicity or carcinogenicity of benzyl
chloride in humans.
3

-------
7-14-2008
Available information on the toxicity of inhaled benzyl chloride in humans consists of a
limited secondary report of an occupational study. In the Encyclopaedia of Occupational Health
and Safety, Mihajlova (1983) summarized noncancer health effects in workers exposed to 10
mg/m3 (1.9 ppm) of benzyl chloride. Workers complained of weakness, rapid fatigue, persistent
headaches, irritability, anorexia and insomnia. Medical examinations of the workers revealed
asthenia, dystonia of the autonomic nervous system, possible disturbances of liver function
(increased blood bilirubin, positive Takata-Ara and Weltmann tests), a reduction in the number
of leukocytes and an increased tendency to illnesses similar to colds or allergic rhinitis.
Additional relevant information, particularly the range and duration of exposure and incidences
of adverse effects, was not reported.
Several epidemiology studies investigated cancer mortality in workers occupationally
exposed to benzyl chloride and other compounds during the production of benzoyl chloride and
other chlorinated chemicals (Hagmar et al., 1986; Sakabe and Fukuda, 1977; Sakabe et al., 1976;
Sorahan and Cathcart, 1989; Sorahan et al., 1983; Wong and Morgan, 1984; Wong, 1988).
Based on assessments of these studies by EPA in the 1989 carcinogenicity assessment of benzyl
chloride on IRIS (U.S. EPA, 2007) and more recently by IARC (1999), the available human data
are inadequate for assessing the carcinogenicity of benzyl chloride alone. Study limitations
include small numbers of cancer deaths, lack of quantitative exposure data, exposure to multiple
chemicals (some of which are known carcinogens) and other confounding factors (e.g., no data
on smoking status or lung cancer occurring in smokers only).
Animal Studies
Oral Exposure
In a National Cancer Institute (NCI) subchronic rat study, groups of 10 ten-week-old
male and 10 eight-week-old female Fisher 344/N rats were given 0, 15, 30, 62, 125 or 250 mg/kg
of benzyl chloride in corn oil by gavage three times a week for 37 weeks (males) or 27 weeks
(females) (Bunner and Creasia, 1982; Lijinsky, 1986; Reuber, 1979). Rats were weighed weekly
and all survivors were necropsied and all major organs were examined histopathologically;
animals that died during treatment were not examined, and the scope of the examinations was not
specified. Parallel groups of 4 male and 4 female rats were given 0, 30 or 125 mg/kg of benzyl
chloride as above to be used for interim sacrifices at 5, 10 and 15 weeks, but results of these
sacrifices were not reported. This study was designed to determine a maximum tolerated dose
for a NCI chronic cancer bioassay in rats (Lijinsky, 1986).
Mortality occurred in 0% of males and 60% of females given 62 mg/kg-day and 100% of
both sexes at >125 mg/kg-day, as detailed in Table 1. Body weight gain was decreased in both
sexes at 62 mg/kg-day (amounts not reported, but to a statistically significant degree only in
males). Gross pathological findings were not reported. Histopathological changes were found
prominently in the squamous stomach (forestomach) and heart. Squamous stomach lesions
included hyperkeratosis in males at 15, 62 and 125 mg/kg-day and females at 30 and 62 mg/kg-
day, hyperplasia in males at 62 and 125 mg/kg-day and females at 62 mg/kg-day, and acute and
chronic gastritis in males and females at >125 mg/kg-day (Table 1). Severe acute gastritis and
ulceration was the probable cause of death in both sexes at 125 mg/kg-day. However, the
4

-------
7-14-2008
Table 1. Incidences of Stomach and Heart Lesions in Rats Exposed to Benzyl
Chloride by Gavage on 3 Days/Week for 27 or 37 Weeks
Dose
(mg/kg-day)
Squamous Stomach
Heart
Hyperkeratosis
Hyperplasia
Gastritis/
Ulcers3
Hyperplasia1"
Myocardial
Necrosis0
Edema
Male Rats (10/dose) (37 weeks)
0
0/10
0/10
0/10
NR
NR
NR
15
2/10
0/10
0/10
almost all rats
most ratsf
NR
30
0/9
0/9
0/9
almost all rats
most ratsf
NR
62
6/10
5/10
0/10
almost all rats
most ratsf
NR
125d
5/10
4/10
7/10k
some rats
NR
NR
250e
0/8
0/8
0/8
some rats
all rats8
NR
Female Rats (10/dose) (27 weeks)
0
1/10
0/10
0/10
NR
NR
NR
15
0/10
0/10
0/10
NR
NR
NR
30
5/10
0/10
0/10
NR
NR
NR
62h
5/10
5/10
0/10
NR
4/10
NR
1251
0/10
0/10
8/10k
NR
NR
NR
2501
0/10
0/10
2/10
NR
NR
all rats1
NR = not reported but assumed to be zero
aAcute and/or chronic gastritis, often with ulcers.
'Early lesions consisted of granulation tissue and proliferation of interstitial cells. Later lesions were
atypical (not otherwise specified) and a few resembled sarcomas. Incidences not specified.
°Focal acute myocardial necrosis.
dAll animals died within 2-3 weeks.
eAll animals died within 10 days.
fAcute myocardial necrosis was found in most rats at terminal sacrifice. Incidence not specified.
8Acute myocardial necrosis was the probable cause of death in males at 250 mg/kg-day. Incidence
not specified.
h4/10 survived 27 weeks. 1/10 developed basal cell carcinoma in situ of the squamous stomach.
'All animals died within 8 days.
'All animals died within 24 hours.
kSevere acute gastritis and ulceration was the probable cause of death in both sexes at 125 mg/kg-day.
'Edema of the heart was the probable cause of death in females at 250 mg/kg-day; incidence not
specified. Severe congestion and edema of the lungs and liver also occurred in 250 mg/kg-day
females (incidences not reported).
Source: Bunner and Creasia, 1982; Lijinsky, 1986; Reuber, 1979
5

-------
7-14-2008
incidence of forestomach lesions was sporadic across the dose groups with no clear dose-related
response. Cardiac lesions were observed in most males at all dose levels (Table 1). The earliest
cardiac lesions consisted of hyperplastic changes (granulation tissue and proliferation of
interstitial cells), and later lesions were atypical (not otherwise specified). The times at which
the early and late lesions were observed were not specified. A few of the later cardiac lesions
resembled sarcomas (incidence not reported), suggesting that some of the later cardiac lesions
might have been malignant (additional information on histology of possible malignant lesions
not reported), but the earlier lesions were considered to be noncancerous and relevant to toxicity
assessment. Additionally, focal acute myocardial necrosis occurred in most or all treated males
at >15 mg/kg-day (Table 1). The incidence of cardiac lesions in the control animals was not
reported but negative results in general were not reported. The control incidence was assumed to
be zero, as experimental protocol specified conducting histopathological examinations of all
animals. Heart lesion data were not reported for most groups of females (Table 1); the only
reported cardiac lesions in females were acute myocardial necrosis at 62 mg/kg-day and edema
at 250 mg/kg-day (Table 1); cardiac edema was the probable cause of death in the 250 mg/kg-
day females. The high-dose females also had severe congestion and edema of the lungs and
liver; histological findings in other tissues were not reported for either sex. The heart was the
most sensitive target as shown by hyperplastic and necrotic lesions in male rats at doses as low
as 15 mg/kg-day. As incidence was not reported precisely, statistical analysis was not possible.
However, the observation of lesions in "most rats" at the lowest dose is sufficient to establish a
LOAEL of 15 mg/kg-day for systemic toxicity based on cardiac lesions. A NOAEL was not
identified.
In an NCI subchronic mouse study, groups of 10 male and 10 female (C57BL/6J x
BALB/c)Fi mice were given 0, 6.3, 12.5, 25, 50 or 100 mg/kg of benzyl chloride in corn oil by
gavage 3 days/week for 26 weeks (Lijinsky, 1986). Mice were weighed weekly and all survivors
were necropsied and examined histopathologically; animals that died during treatment were not
examined and the scope of the examinations was not specified. Parallel groups of 4 male and 4
female mice were given 0, 12.5 or 50 mg/kg of benzyl chloride as above to be used for interim
sacrifices at 5,10 and 15 weeks, but results of the these sacrifices were not reported. This study
was designed to determine a maximum tolerated dose for a NCI chronic cancer bioassay
(Lijinsky, 1986). No mortality or significant decrease in body weight gain was observed in any
group. Histopathologic examinations showed effects only in the liver, consisting of hyperplasia
reported as moderate at unspecified lower dose levels, occasionally severe at 50 mg/kg-day and
frequently severe at 100 mg/kg-day. Lack of additional information on liver hyperplasia,
particularly incidence data, precludes identification of a NOAEL or LOAEL.
In the NCI chronic rat study, groups of 52 male and 52 female F344 rats were given 0, 15
or 30 mg/kg of benzyl chloride in corn oil by gavage 3 days/week for 104 weeks (Lijinsky,
1986). Surviving animals were sacrificed 3-4 weeks after the last dose. Reported endpoints
were limited to survival, body weight (measured throughout the study) and histopathology
(comprehensive examinations were performed on all animals at terminal sacrifice, as well as on
those found dead or moribund). No significant differences in survival, body weight or
incidences of non-neoplastic lesions between treated and control groups were reported.
Additional information regarding these findings, including incidence data, was not provided. No
histopathological findings were reported on microscopic examination of the stomach and heart;
6

-------
7-14-2008
thus, there is no indication that chronic exposure results in the development of the non-neoplastic
forestomach and cardiac lesions observed in the subchronic exposure study (Bunner and Creasia,
1982). There was no discussion of the discrepancies between the subchronic and chronic studies.
Neoplastic effects included squamous cell tumors of the forestomach in three high-dose males
(two with carcinoma, one with papilloma) and statistically significantly increased incidences of
thyroid C-cell adenoma/carcinoma in high-dose females (4/52, 8/51 and 14/52 for the control,
low- and high-dose). A NOAEL of 30 mg/kg-day, the highest dose tested, was identified for
chronic toxicity, but the NOAEL is equivocal due to the incomplete reporting of the non-
neoplastic findings.
In the NCI chronic mouse study, groups of 52 male and 52 female (C57BL/6J x
BALB/c)Fi mice were given 0, 50 or 100 mg/kg of benzyl chloride in corn oil by gavage 3
days/week for 104 weeks (Lijinsky, 1986). Surviving animals were sacrificed 3-4 weeks after
the last dose. Reported endpoints were limited to survival, body weight (measured throughout
the study) and histopathology (comprehensive examinations were performed on all animals at
terminal sacrifice, as well as on those found dead or moribund). Treatment with benzyl chloride
had no effect on survival or body weight compared to controls. Incidences of several types of
tumors were significantly increased in high-dose mice, including forestomach
carcinoma/papilloma in males (0/51, 4/52 and 32/52 for control, low- and high-dose) and
females (0/52, 5/50, 19/51), hemangioma/hemangiosarcoma in males (0/52, 0/52, 5/52) and lung
alveolar-bronchiolar adenoma/carcinoma in females (1/51, 2/51, 6/51). Epithelial hyperplasia
occurred in the stomachs of mice without stomach tumors, but incidences and effect levels were
not reported. There were no statistically significant increases in incidences of other
nonneoplastic lesions (additional information not reported). A lack of additional information on
the stomach hyperplasia, particularly incidence data, precludes identification of a NOAEL or
LOAEL.
Developmental toxicity was evaluated in groups of 17 female New Zealand albino rabbits
that were given 0, 10 or 30 mg/kg-day of benzyl chloride in gelatin capsules on gestation days
(GD) 6-18 (Monsanto Co., 1977a). Maternal body weight, mortality and behavioral reactions
were assessed through GD 29, at which time the does were sacrificed, implantations and
resorptions assessed, and fetuses examined for viability, body weight and external abnormalities.
Subsequently, fetal viability in a 37°C incubator was monitored for 24 hours by observing
respiratory and paw movements hourly for 7 hours and at hour 24 and then all offspring were
examined for internal and skeletal abnormalities. Benzyl chloride exposure had no effect on any
of the endpoints, indicating that this study identified a NOAEL of 30 mg/kg-day, but no LOAEL
for maternal and developmental toxicity in rabbits.
Developmental toxicity was evaluated in groups of 8 female Sprague-Dawley rats that
were given 0, 50 or 100 mg/kg-day of benzyl chloride in corn oil by gavage on GD 6-15 and
sacrificed on GD 20 (Skowronski and Abdel-Rahman, 1986). Maternal endpoints included body
weight, signs of toxicity and survival. Developmental endpoints included numbers of
implantations, resorptions, live and dead fetuses and fetal weight, length, gender, external
abnormalities, skeletal abnormalities (half of each litter) and visceral abnormalities (remaining
half of each litter). No maternal effects were observed. The only statistically significant
(p<0.05) developmental effect was a 10% reduction in mean fetal length in the high-dose group;
7

-------
7-14-2008
crown-to-rump lengths (mean ± SE) were 4.0 ± 0.1, 3.9 ±0.1 and 3.6 ± 0.1 cm at 0, 50 and 100
mg/kg-day, respectively. No major skeletal or visceral abnormalities were observed, although
incidences of minor sternebral anomalies (e.g., small, slanted and incompletely ossified
sternebrae) were slightly increased (not statistically significant or clearly dose-related) in treated
fetuses. This study identified a NOAEL of 100 mg/kg-day and no LOAEL for maternal toxicity
and a NOAEL of 50 mg/kg-day and a LOAEL of 100 mg/kg-day for developmental toxicity
(minor fetotoxicity manifested as slightly reduced crown-rump length) in rats.
Inhalation Exposure
Groups of 10 male Swiss OFi mice were exposed to benzyl chloride vapor at mean
measured concentrations of 22 + 4.2 ppm or 46 + 8.8 ppm (114 or 238 mg/m3) for 6 hours/day,
5 days/week for 4, 9 or 14 days (Zissu, 1995). The targeted concentrations were 17 and 51 ppm,
which were the RD50 and 3 x RD50, respectively. RD50 is the concentration at which breathing
rate in Swiss mice is decreased by 50% during a 15-minute exposure due to upper respiratory
tract sensory irritation (trigeminal nerve stimulation in the nasal mucosa). Groups of five control
mice were exposed to filtered air for each benzyl chloride group. Histological examinations
were performed on the nasal passages, trachea and lungs. Histology of nonrespiratory tract
tissues and other endpoints were not evaluated. The 46 ppm exposure level induced lesions in
the nasal anterior respiratory epithelium (rhinitis, metaplasia, necrosis) and olfactory epithelium
in the dorsal meatus (extensive loss of sensory epithelium with damage to sustentacular cells).
The nasal lesions were collectively graded as severe, very severe and severe after 4, 9 and 14
days of exposure, respectively. No histological changes in the trachea or lungs were observed.
The 22 ppm exposure level is considered to be a NOAEL because the sensory irritant response
(decreased breathing rate) was not accompanied by any histopathological changes in the upper or
lower respiratory tract and the relevance of the mouse RD50 test for evaluating respiratory tract
irritation in humans is unclear (Bos et al., 1991, 2002). Based on the induction of nasal lesions,
this study identified a NOAEL of 22 ppm and LOAEL of 46 ppm for short-term exposure in
mice.
Histopathology results are available for a study in which groups of 16 male and 16
female rats (strain not reported) were exposed to an aerosol (uncharacterized) of benzyl chloride
at 0, 4.2, 17.6, 45.2 or 167 mg/m3 (0, 0.8, 3.4, 8.7 or 38.0 ppm) for 4 weeks (Rohm and Haas
Co., 1988). The hours/day and days/week of exposure were not indicated and a report of the
complete study was not located. Histology evaluations were limited to the nasal cavity including
turbinates, larynx, trachea, lungs and thoracic lymph nodes in 10 rats/sex at 0 and 38 ppm and to
the nasal turbinates only in the remaining 6 rats/sex at 0 ppm and in all 16 rats/sex at 8.7 ppm.
Findings included nasal turbinate lesions in all examined rats at 38 ppm; the mucosa of the
anterior nasal turbinates exhibited hyperplasia and non-keratinizing squamous metaplasia, rarely
with necrosis or inflammatory cell infiltration. There were no exposure-related histopathological
changes in the nasal cavity/turbinates at 8.7 ppm, or in the other parts of the respiratory tract or
thoracic lymph nodes at 8.7 or 38 ppm. The limited available information indicates that short-
term exposure to 38 ppm caused nasal lesions in rats, but identification of a useful NOAEL or
LOAEL is precluded by the incomplete exposure information.
8

-------
7-14-2008
Groups of 5 male and 5 female albino rats were exposed to benzyl chloride vapor in mean
analytical concentrations of 0, 14.4, 50.7 or 143.6 ppm (0, 75, 263, or 744 mg/m3) for 6
hours/day, 5 days/week for 2 weeks (Monsanto Co., 1977b). Endpoints examined were clinical
signs, mortality, body weight and gross pathology. Hypoactivity and ptosis reportedly occurred
in rats in all three exposure groups (incidence data not reported), but not in unexposed controls.
Effects observed at >50.7 ppm included salivation, ruffed fur, dyspnea, nasal discharge and
weakness (incidences not reported), as well as body weight loss. At 143.6 ppm, rats exhibited
tremors and ataxia (incidences not reported) and 2/5 males and 4/5 females died during the
second week of exposure. At necropsy, lungs of the 143.6 ppm rats did not collapse when the
thoraxes were opened; as noted in another study by these investigators (Monsanto Co., 1977b),
this effect is consistent with pulmonary edema. No other effects of exposure were reported.
Evaluation of this study is complicated by the small numbers of animals and poorly reported
data. The small number of rats and unreported incidence data preclude classifying the low (14.4
ppm) exposure concentration as a NOAEL or LOAEL, although 50.7 ppm is a clear adverse
effect level based on multiple clinical signs, including nasal discharge and dyspnea.
Groups of 10 male and 10 female Sprague-Dawley rats, 10 male Duncan-Hartley guinea
pigs and 10 male Syrian Golden hamsters were exposed to benzyl chloride vapor concentrations
of 0, 12, 35 or 102 ppm (0, 60, 180 or 530 mg/m3) for 6 hours/day, 5 days/week for 5 weeks (24
exposure days) (Monsanto Co., 1983). Endpoints evaluated in all species included clinical signs,
mortality, body weight and gross pathology. Histopathologic examinations were conducted only
in guinea pigs and limited to the lungs in two animals per group from the control, mid- and high-
level groups.
In the rat 5-week study, exposure-related adverse effects were observed only at the
highest exposure level (102 ppm) (Monsanto Co., 1983). All high-level male and female rats
had symptoms of respiratory difficulties (sneezing and congested breathing) during exposure and
two high-exposure males additionally experienced rapid or shallow breathing, but no clinical
signs were observed in the low- and mid-level groups. No eye irritation or other exposure-
related clinical signs or gross lesions were observed in any group. Body weight gain was
significantly reduced in high-level males throughout the study (final weight was 20.6% lower
than controls, p<0.01) and in high-level females at week 1 and weeks 3-5 (final weight was
13.9% lower than controls, p<0.01), but low- and mid-level group body weights were
comparable to controls. This study identified a NOAEL of 35 ppm and LOAEL of 102 ppm in
rats based on respiratory symptoms and decreased body weight gain.
In the guinea pig 5-week study, clinical signs that included labored breathing, sneezing,
eye irritation, lacrimation and wetness around the nose and mouth and/or chest and feet occurred
in all animals at 102 ppm (Monsanto Co., 1983). There were no clear exposure-related clinical
signs at lower concentrations or significant changes in body weight at any exposure level. At
necropsy, incidences of gross lesions were increased in the lungs in the mid- and high-
concentration groups; these pulmonary effects consisted of edematous changes and
hemorrhage(s) in the affected animals (Table 2). In afflicted animals, the lungs failed to collapse
and, when incised, released a thin watery clear or off-white fluid; these effects were tentatively
attributed to diffuse mild pulmonary edema. Lungs from two affected animals from each of the
mid- and high-concentration groups and lungs from two animals in the control group were
9

-------
7-14-2008
Table 2. Incidence of pulmonary effects in guinea pigs exposed to benzyl chloride by
inhalation for 5 weeks (6 hours per day, 5 days per week)
Nominal exposure level
in ppm (mg/m3)
0
12 (60)
35 (80)
102 (530)
edema
0/10 a
1/10
5/10
5/10
hemorrhage
1/10
0/10
3/10
2/10
a number affected/number exposed
Source: Monsanto Co., 1983
examined for histopathology. The most prominent exposure-related microscopic lesion was
diffuse distension of the alveoli with thinning of the bordering interstitium. Small foci of
pulmonary emphysema and very mild edema were observed occasionally at the high
concentration, but the edema was considered by the investigators to be of insufficient severity to
have caused the gross lesion. The smooth muscle surrounding bronchioles and bronchi was
moderately thickened. The lungs of the single low-exposure level animal showing gross
pulmonary signs were not examined microscopically. According to the investigators, the results
of this study suggest that 12 ppm was a no effect level and that exposure to >35 ppm initiated
changes in pulmonary tissues, because the gross edematous changes were substantiated by
histological findings of mild pulmonary edema and more marked alveolar distention, and the
finding of gross edema in one animal at 12 ppm may not be related to treatment. This study
identified a NOAEL of 12 ppm based on gross lung lesions (histology not evaluated at this
concentration) and a LOAEL of 35 ppm based on gross and microscopic lung lesions, in guinea
pigs.
In the hamster 5-week study, exposure-related adverse effects were observed only at 102
ppm (Monsanto Co., 1983). Effects included clinical signs of irritation (sneezing and eye
irritation) in all animals and significantly reduced body weight gain during weeks 2-5 (final
weight was 16.3% lower than controls, p<0.01). The most prominent gross lesion apparent at
necropsy was abnormal discoloration/pigmentation of the liver, which appeared to be exposure-
related; incidences were 2/10, 4/10, 6/10 and 7/10 at 0, 12, 35 and 102 ppm, respectively. The
significance of this finding is uncertain because histological examinations were not performed;
the researchers considered the lesion to be an artifact of experimental procedures (incomplete
exsanguination at necropsy). Gross lung congestion was observed in a few animals but was not
clearly exposure-related; incidences were 0/10, 1/10, 0/10 and 2/10 at 0, 12, 35 and 102 ppm,
respectively. This study identified a NOAEL of 35 ppm and a LOAEL of 102 ppm in hamsters,
based on clinical signs of nasal and eye irritation and decreased body weight gain.
Groups of 30 male and 30 female Sprague-Dawley rats and 30 male Hartley guinea pigs
were exposed to mean analytical benzyl chloride vapor concentrations of 0, 0.005, 0.062 or
0.148 mg/L (5, 62 or 148 mg/m3; 1.0, 12.0 or 28.6 ppm) for 6 hours/day, 5 days/week for 14
weeks (10 animals/group) or 27 weeks (20 animals/group) (Monsanto Co., 1984). Endpoints
evaluated throughout the study included clinical signs and body weight. Endpoints evaluated at
weeks 14 and 28 included hematology (erythrocyte count, total and differential white blood cell
counts, hemoglobin, hematocrit, mean corpuscular volume, mean corpuscular hemoglobin and
10

-------
7-14-2008
mean corpuscular hemoglobin concentration), serum chemistry (alkaline phosphatase, serum
glutamic pyruvic transaminase, total bilirubin, blood urea nitrogen, total protein, potassium and
sodium), urine indices (volume, specific gravity, total protein, glucose, pH presence of blood,
color and gross appearance), selected organ weights (liver, kidney, adrenal, brain, heart, spleen,
pituitary and testis) and gross pathology. Histological examinations were performed on 10
animals/sex/species from the control and high-exposure (28.6 ppm) groups at 27 weeks; due to a
lack of compound-related histopathology in these animals, tissue examinations were not
performed in the low- and mid-exposure groups at 27 weeks or for any of the animals sacrificed
at 14 weeks. The histological examinations included the organs that were weighed, as well as
nasal turbinates, trachea, lung, esophagus, stomach, small and large intestines, pancreas, prostate,
uterus, ovary, thyroids, parathyroids, aorta, bone, bone marrow, mesenteric lymph nodes, urinary
bladder, skeletal muscle, skin, eyes and gross lesions.
In rats, exposure to benzyl chloride had no effect on clinical signs, survival, body weight,
serum chemistry or urinalysis (Monsanto Co., 1984). The only statistically significant (p<0.05)
hematological effect was a slight reduction in mean corpuscular volume (MCV) in female rats at
>12 ppm at week 14 only; MCV was 1.0, 2.9 and 3.0% lower than controls at 1.0, 12.0 and 28.6
ppm, respectively. The small (3.0%) decrease in MCV is not considered clinically significant.
Uterine hydrometra at an incidence of 0/10, 0/10, 1/10 and 2/10 for the 0, 5, 60 and 148 mg/m3
exposure groups, respectively, were reported for the scheduled interim sacrifice at 14 weeks.
Statistical significance was not reported, presumably being greater than the p = 0.05 criterion.
However, a Cochran-Armitage lack-of-trend test performed by the U.S. EPA obtained statistical
significance at the p = 0.03 level. At terminal sacrifice, uterine hydrometra also were evident at
an incidence of 0/20, 2/19, 1/20 and 2/19 for the 0, 5, 60 and 148 mg/m3 exposure groups,
respectively. The Cochran-Armitage lack-of-trend test was suggestive of a trend (p = 0.15). The
clinical significance of these findings is uncertain. Other effects included organ weight changes
at week 27, but with no exposure-related gross pathology or histopathology. Statistically
significant changes in organ weights included increased absolute and relative spleen weights in
females at 28.6 ppm (14 and 18% higher than controls, respectively), increased relative left
kidney weight in females at 28.6 ppm (21% higher than controls; relative weight of right kidney
was increased but not statistically significant), decreased relative heart weight in males at >1.0
ppm (~10%> lower than controls at all levels) and decreased absolute heart weight in males at
28.6 ppm (11% lower than controls). The high exposure concentration of 28.6 ppm (148 mg/m3)
is a LOAEL for rats in this study based on the changes in spleen, kidney and heart weights,
although somewhat equivocal due to the absence of gross or microscopic pathology or serum
chemistry changes.
In guinea pigs, exposure to benzyl chloride had no effect on clinical signs, survival, body
weight, serum chemistry or urinalysis (Monsanto Co., 1984). The only statistically significant
(p<0.05) hematological effect was a slight reduction in MCV in low- and high-exposure guinea
pigs at week 27; MCV was 2.5, 1.5 and 5.5% lower than controls at 1.0, 12.0 and 28.6 ppm,
respectively. The decreases in MCV are not considered clinically significant due to the small
(<5.5%) magnitudes and lack of other hematological effects. Absolute and relative kidney
weights were increased at 28.6 ppm, but the differences were only statistically significant
(p<0.05) for the left kidney (-10% less than controls for both absolute and relative weights); no
gross or histopahtological lesions were reported. An increased incidence of grossly observable
11

-------
7-14-2008
liver lesions was evident at the highest exposure level. Necrotic areas in the liver were reported
at an incidence of 1/20, 0/18, 0/20 and 3/19 for the 0, 5, 60 and 148 mg/m3 exposure groups,
respectively. Abnormal pigmentation was present in 2/20, 1/18, 1/20 and 4/19 for the 0, 5, 60
and 148 mg/m3 exposure groups, respectively. Statistical significance was not reported,
presumably being greater than the p = 0.05 criterion. However, comparing the high-exposure
level necrosis response to the combined response for the three lower exposure groups, statistical
significance is obtained (p = 0.030) by the Fisher's exact test. A Cochran-Armitage lack-of-trend
test yields a p-value of 0.083 level for liver necrosis. For liver pigmentation, the Fisher's exact
test (p = 0.10) and Cochran-Armitage lack-of-trend test (p = 0.16) were only suggestive of an
effect. Absolute and relative liver weights also were increased in treated animals compared to
controls, with relative weights increased by about 10% in the two highest exposure groups for
males (p < 0.01). Microscopic examination of tissues at terminal sacrifice was performed on only
10 animals of each sex for only the control and high-dose groups. There was no significant
difference in the incidence of liver necrosis between control (2/10) and high-dose (3/10) males.
Taken together, the observations are suggestive of adverse liver effects at the high exposure level
(148 mg/m3). Accordingly, the exposure level of 148 mg/m3 is designated as a LOAEL for liver
effects in guinea pigs in this 27-week study.
Other Studies
Acute Inhalation Exposure - Acute exposure to benzyl chloride vapor can produce
irritation of the eyes and upper respiratory tract in humans. The following dose-response
information on inhalation of benzyl chloride vapor, apparently based on limited information, was
reported in the NIOSH (1978) criteria document for benzyl chloride and summarized by ACGIH
(2001) as follows: exposure to 1.5 ppm for 5 minutes resulted in slight conjunctivitis; 8 ppm was
the threshold for eye irritation in a 10-second exposure trial and a single breath of air containing
35 ppm caused nasal irritation.
Changes in neuromuscular excitability were observed in mice during a 3-minute
"behavioral despair" swimming test conducted during a 4-hour exposure to 12-22 ppm benzyl
chloride (De Ceaurriz et al., 1983).
Dermal and Parenteral Exposure - The carcinogenicity of benzyl chloride has been
tested in dermal, subcutaneous and intraperitoneal studies in animals (Ashby et al., 1982;
Coombs, 1982a,b; Fukuda et al., 1981). These studies were evaluated by EPA in the 1989
carcinogenicity assessment for benzyl chloride on IRIS (U.S. EPA, 2007); newer cancer studies
were not located. As indicated in the IRIS summaries of these studies, which are reproduced
below, there is limited evidence for benzyl chloride-induced skin carcinomas in mice following
dermal exposure and injection site sarcomas in rats following subcutaneous injection.
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 |iL
benzyl chloride 3 times/week for 4 weeks, followed by 2 times/week until termination at 40
weeks. In the second study, 2.3 |iL benzyl chloride was diluted to a final volume of 25 |iL with
benzene and applied to the skin of 7-week-old mice 2 times/week for 50 weeks. There were 2/20
12

-------
7-14-2008
control animals that 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.
Ashby et al. (1982) topically treated groups of 20 Swiss mice with 100 |ig 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.
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 |ig benzyl chloride
in acetone, followed by twice weekly applications of the promotor 12-0-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.
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).
Genotoxicity - Genotoxicity studies of benzyl chloride were evaluated by EPA in the
1989 carcinogenicity assessment of benzyl chloride on IRIS (U.S. EPA, 2007) and more recently
by IARC (1999). These evaluations indicate that benzyl chloride induced DNA damage and
mutagenicity in bacteria; sister chromatid exchanges, chromosomal aberrations, mutations, and
DNA strand breaks in cultured rodent cells; and DNA breaks, but not chromosomal aberrations,
in cultured human cells. Conflicting results were reported for induction of sister chromatid
exchanges in cultured human cells and negative results were reported for induction of
micronuclei and sperm head abnormalities in mice in vivo.
13

-------
7-14-2008
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR BENZYL CHLORIDE
Subchronic p-RfD
Information relevant to provisional subchronic RfD derivation is available from
subchronic toxicity studies in rats and mice (Bunner and Creasia, 1982; Lijinsky, 1986; Reuber,
1979) and developmental toxicity studies in rats and rabbits (Monsanto Co., 1977a; Skowronski
and Abdel-Rahman, 1986).
In the subchronic study in rats, doses ranging from 15-250 mg/kg-day were administered
by gavage 3 days/week for up to 27 weeks (females) or 37 weeks (males) (Bunner and Creasia,
1982; Lijinsky, 1986; Reuber, 1979). Heart lesions (hyperplastic changes and myocardial
necrosis) occurring in males at >15 mg/kg-day were established as the basis for the LOAEL.
Although quantitative incidence was not reported, the fact that most male rats were affected at
the lowest dose adequately defines a subchronic LOAEL of 15 mg/kg-day for cardiac lesions. A
NOAEL was not established.
The observed cardiac effects are rare in rats and were not observed in the chronic study
using the same strain of rats (Lijinsky, 1986), which suggests that the effects may not be a result
of benzyl chloride exposure. There is no explanation of the discrepancy in the chronic study
report. There is no evidence of microbial involvement in the elicitation of these effects and no
reference to a specific pathogenic origin for these effects could be found in the literature. There
was an apparent dose-related increase in the incidence and severity of the lesions, however. In
addition, similar effects have been induced in rats treated with isoproterenol (Pearl and Balazs,
1967), although there is no substantive structural similarity between benzyl chloride and
isoproterenol. Therefore, other than the absence of these effects in the chronic study, there is no
reason to reject them as the basis for the pRfD.
In the subchronic study in mice, doses ranging from 6.3-100 mg/kg-day were
administered by gavage 3 days/week for up to 26 weeks (Lijinsky, 1986). Liver hyperplasia was
the only reported effect, but effect levels and incidences were not specified, precluding
identification of a NOAEL or LOAEL in the mice.
The developmental toxicity study in rabbits (Monsanto Co., 1977a) administered benzyl
chloride by capsule on GD 6-18 and identified a NOAEL of 30 mg/kg-day, but no LOAEL, for
maternal and developmental toxicity. The developmental study in rats (Skowronski and Abdel-
Rahman, 1986) used gavage administration on GD 6-15 and identified a NOAEL of 100 mg/kg-
day, but no LOAEL, for maternal toxicity and a NOAEL of 50 mg/kg-day and a LOAEL of 100
mg/kg-day for developmental toxicity (minor fetotoxicity manifested as slightly reduced crown-
rump length). Although no maternal toxicity was observed at 100 mg/kg-day, this NOAEL is in
the range of doses that increased mortality in the subchronic rat study and is considerably higher
than the 15 mg/kg-day subchronic LOAEL for cardiac lesions.
The 15 mg/kg-day LOAEL for cardiac lesions in male rats (Bunner and Creasia, 1982)
was used to derive the subchronic p-RfD; use of benchmark dose analysis was precluded by
14

-------
7-14-2008
unreported quantitative incidence data. The LOAEL was first adjusted for intermittent exposure,
as follows:
Adjusted LOAEL (LOAELadj) = LOAEL x (days/week)
= 15 mg/kg-day x (3 days/7 days)
= 6.4 mg/kg-day
The LOAELadj of 6.4 mg/kg-day was divided by a composite uncertainty factor of 3000
to derive a subchronic p-RfD of 2E-03 mg/kg-day, as follows:
Subchronic p-RfD = LOAELadj ^ UF
= 6.4 mg/kg-day ^ 3000
= 0.002 or 2E-3 mg/kg-day
The uncertainty factor (UF) of 3000 was composed of the following:
A full default UF of 10 was applied for interspecies extrapolation to account for
potential pharmacodynamic and pharmacokinetic differences between rats and
humans.
A full default 10-fold UF for intraspecies differences was used to account for
potentially susceptible individuals in the absence of quantitative information or
information on the variability of response in humans.
A full default UF of 10 was applied for use of a LOAEL. A NOAEL was not
identified.
A partial UF of 3 (10°5) was included for database insufficiencies due to the
limited supporting data available and lack of a multi-generation reproduction
study.
Confidence in the key subchronic toxicity study in rats is low. This study used a wide
range of dose levels and included comprehensive histological examinations, but hematology,
clinical chemistry and urinalysis were not evaluated. This study is further limited by incomplete
reporting of nonneoplastic lesions, particularly a lack of quantitative incidence data for the
critical effect (cardiac lesions). In addition, cardiac lesions are rare in rats and were not seen in
the chronic study (Lijinsky, 1986). Confidence in the database is low. A subchronic study is
available in a second species (mouse), but the design is the same as the rat study and reporting
inadequacies preclude identification of effect levels. Adequate developmental toxicity studies
are available in two species (rats and rabbits), but reproductive toxicity has not been evaluated.
Low confidence in the subchronic p-RfD results.
Chronic p-RfD
Limited information on the chronic oral toxicity of benzyl chloride is available from
carcinogenicity studies in which rats and mice were treated by gavage 3 days/week for 104
weeks (Lijinsky, 1986). In the rat study, it was reported that exposure to 15 or 30 mg/kg-day did
not cause any significantly increased incidences of non-neoplastic lesions, implying that 30
mg/kg-day was a chronic NOAEL. This NOAEL is equivocal and not useful for RfD derivation
15

-------
7-14-2008
because additional information on non-neoplastic effects, including incidence data and a
discussion of results, was lacking. Thus, the chronic exposure study did not provide evidence of
the heart and stomach lesions observed in the subchronic rat study (Bunner and Creasia, 1982;
Lijinsky, 1986; Reuber, 1979) for which there was no explanation (see previous section). The
chronic study in mice used dose levels of 50 and 100 mg/kg-day and found significantly
increased incidences of tumors, particularly forestomach carcinomas and papillomas, at 100
mg/kg-day. Nonneoplastic lesions in mice were limited to stomach epithelial hyperplasia in
animals without stomach tumors, but unreported effect levels and incidence data preclude
identification of a NOAEL or LOAEL. Although it is possible that 50 mg/kg-day was a chronic
LOAEL for stomach hyperplasia in mice, this dose is higher than the subchronic LOAELs for
stomach and heart lesions in rats (30 and 15 mg/kg-day, respectively).
Because reporting limitations preclude identification of an unequivocal NOAEL or
LOAEL for chronic toxicity, the subchronic p-RfD provided the best basis for deriving a chronic
p-RfD. An uncertainty factor of 1 was applied to the subchronic p-RfD to extrapolate from
subchronic to chronic duration because the apparent lack of cardiac lesions in the chronic rat
study suggests that a longer exposure duration may not have an effect on the LOAEL. The
chronic p-RfD of 2E-3 mg/kg-day is derived as follows:
Chronic p-RfD = Subchronic p-RfD UF
= 0.002 mg/kg-day ^ 1
= 0.002 or 2E-3 mg/kg-day
Confidence in the subchronic toxicity study used to derive the chronic p-RfD is low, as
discussed in the subchronic p-RfD derivation. The database includes chronic toxicity studies in
two species and adequate developmental toxicity studies in two species. Confidence in the
database is low because the chronic studies, primarily designed as carcinogenicity bioassays,
provided incomplete reporting of noncancer endpoints. Reproductive toxicity studies have not
been conducted. The chronic study (Lijinsky, 1986), however, did conduct histopathology on all
major organs following NCI study protocol. Although negative findings were not explicit, it
seems highly unlikely that cardiac effects so evident in the subchronic study could have been
overlooked in the chronic study. Low confidence in the chronic p-RfD results.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR BENZYL CHLORIDE
Subchronic p-RfC
The subchronic inhalation toxicity of benzyl chloride has been tested in intermittent
exposure (6 hours/day, 5 days/week) studies of rats, guinea pigs and hamsters exposed to 12, 35
or 102 ppm vapor for 5 weeks (Monsanto Co., 1983) and rats and guinea pigs exposed to 1, 12 or
28.6 ppm vapor for 27 weeks (Monsanto Co., 1984). Endpoints in the 5-week studies were
limited to clinical signs, mortality, body weight and gross pathology in all species, and lung
histology in a small number of guinea pigs (2/sex/dose). The 27-week studies additionally
included comprehensive histology examinations (including nasal turbinates, trachea and lung)
16

-------
7-14-2008
and hematology, clinical chemistry and urinalysis evaluations in both species. Short-term studies
of respiratory tract histopathology were conducted in mice exposed to 22 or 46 ppm vapor for 6
hours/day, 5 days/week for 4-14 days (Zissu, 1995) and rats exposed to 8.7 or 38 ppm (as an
aerosol) for 4 weeks (hours/day and days/week of exposure not reported; aerosol not
characterized) (Rohm and Haas Co., 1988). The study results and adjusted and human-
equivalent NOAELs and LOAELs are shown in Table 3.
Table 3. Benzyl Chloride Inhalation Toxicity Studies in Rodents
Species
(study)
Exposure
duration
NOAELa
LOAEL
NOAELADJb
LOAELadj
RGDRC
(region)
NOAELnix''
LOAELhec
Mouse
2 weeks
114 (22)
20.4
0.97
19.7
(Zissu, 1995)
(maximum)
238 (46)
42.5
(ET)
41.0
Rat
2 weeks
none

2.59

(Monsanto 1977b)

75 (14.4)
13.4
(PU)
34.7
Rat
5 weeks
180 (35)
32.1
2.59
83.0
(Monsanto 1983)

530(102)
94.6
(PU)
245
Guinea pig
5 weeks
60 (12)
10.7
0.335
3.58
(Monsanto 1983)

180 (35)
32.1
(PU)
10.8
Hamster
5 weeks
180 (35)
32.1
0.339
10.9
(Monsanto 1983)

530(102)
94.6
(PU)
32.1
Rat
27 weeks
148 (28.6)
26.4
2.59
68.4
(Monsanto 1984)

None

(PU)

Guinea pig
27 weeks
148 (28.6)
26.4
0.525
13.9
(Monsanto 1984)

None

(PU)

a nominal (unadjusted exposure) in mg/m3 (ppm)
b adjusted for exposure schedule (mg/m3)
0 regional gas dose ratio for region indicated (based on default body weights)
d N(L)OAELadj x RGDR(mg/m3)
No adverse effects occurred at any exposure concentration tested in the 27-week studies
yielding a NOAEL of 28.6 ppm in guinea pigs and rats. Effects on the respiratory tract and
decreased body weight occurred at higher concentrations in the 5-week studies, which identified
a NOAEL of 12 ppm and LOAEL of 35 ppm in guinea pigs based on gross and microscopic lung
lesions, a NOAEL of 35 ppm and LOAEL of 102 ppm in rats based on respiratory clinical signs
(sneezing and congested breathing) and decreased body weight gain, and a NOAEL of 35 ppm
and LOAEL of 102 ppm in hamsters based on signs of nasal irritation (sneezing), eye irritation
and decreased body weight gain. No clinical signs or other effects were observed in the guinea
pigs exposed to 35 ppm (the LOAEL for lung lesions); clinical signs of respiratory tract and eye
irritation (sneezing, labored breathing, nose/mouth wetness, eye irritation and lacrimation)
occurred at 102 ppm, the same concentration causing similar clinical signs in rats and hamsters.
However, no gross lung lesions (lung histology not evaluated) were observed in rats or hamsters,
even at the concentration causing clinical signs (102 ppm). Results of the 5-week studies
indicate that the respiratory tract was a target in all three species, with the guinea pig more
sensitive to benzyl chloride-induced effects than rats and hamsters; lung lesions were identified
as the critical effect in guinea pigs.
17

-------
7-14-2008
As indicated above, respiratory effects in the 5-week studies included clinical signs of
nasal irritation in guinea pigs, rats and hamsters at 102 ppm, but not at 35 ppm, the LOAEL for
gross lung lesions in guinea pigs. However, clinical signs may not be as sensitive as
histopathological changes for defining the NOAEL and LOAEL for benzyl chloride effects to the
upper respiratory tract. Data from the 5-week studies do not provide clarification on this issue,
since nasal histopathology was not evaluated. The 27-week study (Monsanto Co., 1984)
identified a NOAEL of 28.6 ppm for both clinical signs and nasal (and lung) histopathology in
guinea pigs and rats, but there is some uncertainty regarding the lack of nasal lesions, because it
is not known if the nasal tissue sectioning practices are adequate by current standards and nasal
histology was not examined in lower exposure groups (<12 ppm). Short-term studies (Rohm and
Haas Co., 1988; Zissu, 1995) found nasal lesions in rats and mice at concentrations similar to the
5-week LOAEL for gross lung pathology in guinea pigs (35 ppm). Exposure to 38 ppm (as an
aerosol) for 4 weeks caused mucosal lesions (hyperplasia and non-keratizing squamous
metaplasia) in the anterior nasal turbinates in rats (Rohm and Haas Co., 1988); however,
comparison of LOAEL values from the 4- and 5-week studies is compromised by unreported
daily exposure duration, use of an uncharacterized aerosol, and lack of lung pathology evaluation
in the 4-week study. In mice, exposure to 46 ppm for 6 hours/day, 5 days/week for 4-14 days
caused nasal lesions graded as severe or very severe, in the anterior respiratory epithelium
(rhinitis, metaplasia, necrosis) and olfactory epithelium in the dorsal meatus (extensive loss of
sensory epithelium with damage to sustentacular cells), but no histopathology in the trachea or
lungs (Zissu, 1995). No nasal lesions were observed in the mice at 17 ppm, although nasal
irritation apparently occurred because this level was the acute RD50 [i.e., concentration at which
respiratory rate in Swiss mice is decreased by 50% during a 15-minute exposure due to sensory
irritation (trigeminal nerve stimulation) in the nasal mucosa]. However, 17 ppm was classified
as a NOAEL for nasal irritation because there was no upper or lower respiratory tract
histopathology at this concentration and the relevance of the mouse RD50 test for evaluating
respiratory tract irritation in humans is unclear (Bos et al., 1991, 2002). The short-term studies
indicate that nasal effects are an additional sensitive respiratory endpoint for benzyl chloride, but
do not provide a suitable basis for RfC derivation because adverse nasal effects (histopathology)
did not occur in mice or rats at concentrations below the 5-week NOAEL of 35 ppm for lung
lesions in guinea pigs.
Benchmark Concentration (BMC) modeling was performed for the two endpoints
defining the LOAEL in the Monsanto Co. (1983) 5-week inhalation study on guinea pigs. The
two endpoints were pulmonary edema and pulmonary hemorrhage (see Table 2). All the
dichotomous models in BMDS, version 1.4.1 (U.S. EPA, 2008), were fit to the nominal exposure
concentrations (in mg/m3) for each endpoint for estimation of a BMCLio. None of the models
provided an adequate fit to the pulmonary hemorrhage data. The model fits to the pulmonary
edema data are shown in Table 4. Several of the models fit adequately to the pulmonary edema
endpoint. Unconstrained model fits for the two-parameter models resulted in slope or power
parameters less than one, with BMCLio estimates several orders of magnitude below the BMD.
The log-logistic model provides the best fit on the basis of the lowest AIC; it also provides the
lowest BMCLio. The log-logistic BMCLio of 19.58 mg/m3 corresponds to a BMCLrec of 1.17
mg/m3 after adusting for exposure regimen (6 hours per day, 5 days per week) and multiplying
by the RGDR of 0.335.
18

-------
7-14-2008
Table 4. Benchmark Concentration modeling results for pulmonary edema endpoint in
guinea pigs exposed to benzyl chloride by inhalation for 5 weeks

Model
p-value
AIC
BMCioa
BMCL io
log-logistic (constrained)13
0.63
37.93
38.12
19.58
multi-stagec
0.40
38.93
54.06
33.75
gamma (constrained)11
0.40
38.93
54.06
33.75
log-probit (constrained)
0.21
40.25
79.87
52.54
log-logistic (unconstrained)
0.45
39.84
28.32
4.1 x 10"5
a mg/m3
b for all constrained models, slope or power parameters hit lower bound of 1
0 2nd order model fit; only 1st order parameter was significant
d constrained gamma (and Weibull) models reduce to lst-order multistage and provide identical fits
Source: Monsanto Co., 1983
The BMCLio of 19.58 mg/m for lung lesions in guinea pigs in the 5-week study
(Monsanto Co., 1983) was used to calculate a subchronic p-RfC. The BMCL was first duration
adjusted for intermittent exposure (6 hours/day, 5 days/week), as follows:
BMCLadj = BMCL x (hours/day) x (days/week)
= 19.58 mg/m3 x (6 hours/24hours) x (5 days/7 days)
= 3.50 mg/m3
Benzyl chloride exhibited its toxic effects in the lungs and, because of its reactivity, is
treated as a Category 1 gas for purposes of calculating the p-RfC (U.S. EPA, 1994b). Benzyl
chloride's reactivity is demonstrated by the nature of the respiratory effects previously described
and by its rapid hydrolysis in water (U.S. EPA, 1986); no significant accumulation of benzyl
chloride in blood is expected that would lower the rate of absorption over time. The human
equivalent concentration (HEC) for a Category 1 gas with effects in the lungs is calculated by
multiplying the duration-adjusted BMCL by the regional gas dose ratio in the pulmonary region
(RGDRpu) (U.S. EPA, 1994b). Using values for guinea pigs and humans, an RGDRPU of 0.335
was determined using the following equation:
RGDRpu =

(0 -
xZalv

e
SAT3 \
Ve
(Dosepu)A _
ySApu ;
\
V

(.Dosepu)H
f 0 \
^¦alv

f
VE

V SApjj y
H
e
V
J
SAgj \
V„
SA%t
H
where:
A and H = subscripts for animal (guinea pig) and human values
Dosepu	= Dose in pulmonary region
Qaiv	= Alveolar ventilation rates, in cmVmin
131 cm3/min for guinea pig
9246 cm3/min for human
19

-------
7-14-2008
SAEt
SApu
SAtb
Surface area of pulmonary region in m2
0.9 m2 for guinea pig
54 m2 for human
Surface area of tracheobronchial region in cm2
200 cm2 for guinea pig
3200 cm2 for human
Surface area of extrathoracic region in cm2
30 cm2 for guinea pig
200 cm2 for human
Minute volume in cm3/min
195 cmVmin for guinea pig
13,800 cm3/min for human
The alveolar ventilation rates were calculated as 67% of the minute volumes according to
U.S. EPA (1988). The regional surface areas for guinea pigs and humans and the minute
volume for humans were taken from U.S. EPA (1994b). The minute volume for guinea pigs
was calculated using the time-weighted average body weight in the Monsanto Co. (1984)
study, 0.425 kg and the intercept and coefficient values provided in Table 4-6 of U.S. EPA
(1994b) for the algorithm:
The BMCLrec is then calculated from the BMCLadj and RGDRPU, as follows:
BMCLhec = BMCLadj x RGDRpu
= 3.50 mg/m3 x 0.335
= 1.17 mg/m3
A subchronic p-RfC of 0.004 mg/m3 was derived by dividing the BMCLrec of 1.17
mg/m3 by a composite uncertainty factor (UF) of 300, as follows:
The composite uncertainty factor of 300 is composed of the following:
A full default 10-fold UF for intraspecies differences is used to account for
potentially susceptible individuals in the absence of information on the variability
of response in humans. Individuals with pre-existing respiratory disorders, such
as asthmas or emphysema may be more susceptible to inhaled benzyl chloride.
In (VE)
In (VE)
Ve
b0 + bi [ln(BW)]
-1.191 +0.516 [ln(0.425)]
195 cm3/min
Subchronic p-RfC = NOAELrec ^ UF
= 1.17 mg/m3 -300
= 0.004 or 4E-3 mg/m3
20

-------
7-14-2008
A partial UF of 3 (10°5) is applied for interspecies extrapolation to account for
potential pharmacodynamic differences between guinea pigs and humans.
Converting the rat data to human equivalent concentrations by the dosimetric
equations accounts for pharmacokinetic differences between guinea pigs and
humans; thus, it was not necessary to use the default UF of 10 for interspecies
extrapolation.
A full default UF of 10 is included for database insufficiencies. Supporting
systemic toxicity data are limited and the database lacks reproductive and
developmental toxicity studies by the inhalation route.
Confidence in the key study is low. The 5-week study in guinea pigs was well-designed
as a short-term range-finding study, but used few animals and did not conduct histopathological
examinations. In addition, the pulmonary effects were not observed in the longer-term 27-week
study. The 27-week study in guinea pigs was well-designed, used adequate numbers of animals,
a wide variety of endpoints (including comprehensive histopathological examinations) and
appropriate controls. However, histopathological examinations were limited to 10 animals in the
control and high-dose groups and possibly insufficient for nasal tissues, and the (equivocal)
LOAEL was much higher than the short-term LOAEL in the 5-week study. Confidence in the
database is low-to-medium because a companion 27-week study in a second species (rat) has the
same limitations as the 27-week guinea pig study and 5-week studies in rats and hamsters lack
histopathological evaluations. Subchronic studies with adequate nasal histopathology
assessments are needed to corroborate the sensitive nasal effects observed in short-term studies
in rats and mice, and reproductive and developmental toxicity studies have not been conducted
(although developmental toxicity has been tested following oral exposure). Low confidence in
the subchronic p-RfC results.
Chronic p-RfC
No chronic inhalation toxicity studies of benzyl chloride have been conducted, indicating
that the subchronic BMCLrec provides the best basis for deriving a chronic p-RfC. An
additional UF of 3 (10°5) is applied to extrapolate from subchronic to chronic exposure, making
the composite UF equal to 1000. A partial UF is used for duration extrapolation because the data
suggest that exposure duration may not be a main determinant for lung effects and the 27-week
duration of the supporting guinea pig study is closer to chronic exposure than a standard 90-day
subchronic study. Application of the composite UF yields a chronic p-RfC of 0.001 mg/m3, as
follows:
Chronic p-RfC = NOAELrec - UF
1.17 mg/m3-1000
= 0.001 or 1E-3 mg/m3
Confidence in the 5-week study used to derive the subchronic p-RfC is medium, as
discussed for subchronic p-RfC derivation. Confidence in the database is low due to the lack of
chronic inhalation data and for the reasons discussed for the subchronic p-RfC, including
uncertainty in the adequacy of nasal toxicity assessment and lack of reproductive and
developmental toxicity data.
21

-------
7-14-2008
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR
BENZYL CHLORIDE
No oral cancer values were developed since an OSF exists on IRIS (U.S. EPA, 2007).
No inhalation values were developed because of a lack of data.
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2001. Documentation
of the threshold limit values for chemical substances. 7th Edition. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hygienists). 2006. Threshold limit
values for chemical substances and physical agents and biological exposure indices. Cincinnati,
OH.
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(l-4):399-401.
ATSDR (Agency for Toxic Substances and Disease Registry). 2007. Toxicological Profile
Information Sheet. U.S. Department of Health and Human Services, Public Health Service.
Available at http://www.atsdr.cdc.gov/toxpro2.html.
Bos, P.M., A. Zwart, P.G. Reuzel et al. 1991. Evaluation of the sensory irritation test for the
assessment of occupational health risk. Crit. Rev. Toxicol. 21(6):423-450.
Bos, P.M., M. Busschers and J.H. Arts. 2002. Evaluation of the sensory irritation test (Alarie
test) for the assessment of respiratory tract irritation. J. Occup. Environ. Med. 44(10):968-976.
Bunner, B.L. and D.A. Creasia. 1982. Toxicity, tissue distribution, and excretion of benzyl
chloride in the rat. J. Toxicol. Environ. Health. 10:837-846.
CalEPA (California Environmental Protection Agency). 2007. Benzyl Chloride. Air Toxic Hot
Spots Program Risk Assessment Guidelines, part II. Technical Support Document Describing
Available Cancer Potency Factors. Office of Environmental Health Hazard Assessment.
December 2002. Available at http://www.oehha.ca.gov/air/hot spots/pdf/TSDNov2002.pdf.
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.
22

-------
7-14-2008
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.
De Ceaurriz, J., J.P. Desiles, P. Bonnet et al. 1983. Concentration-dependent behavioral
changes in mice following short-term inhalation exposure to various industrial solvents. Toxicol.
Appl. Pharmacol. 67:383-389.
Druckrey, H., H. Kruse, R. Preussmann et al. 1970. Cancerogenic alkylating substances. III.
Alkyl-halogenides, -sulfates, - sulfonates and strained heterocyclic compounds. Z. Krebsforsch.
74(3):241- 273.
Fukuda, K., H. Matsushita, H. Sakabe et al. 1981. Carcinogenicity of benzyl chloride, benzal
chloride, benzotrichloride and benzoyl chloride in mice by skin application. Gann. 72(5):655-
664.
Hagmar, L., T. Bellander, V. Englander et al. 1986. Mortality and cancer morbidity among
workers in a chemical factory. Scand. J. Work Environ. Health 12: 545-551.
IARC (International Agency for Research on Cancer). 1982. IARC Monographs on the
Evaluation of the Carcinogenic Risk of Chemicals to Humans. Some Industrial Chemicals and
Dyestuffs. Benzyl Chloride. 29:49-63. Lyon, France.
IARC (International Agency for Research on Cancer). 1987. IARC Monographs on the
Evaluation of the Carcinogenic Risk of Chemicals to Humans. Overall Evaluations of
Carcinogenicity: An Updating of IARC Monographs Volumes 1 to 42. a-Chlorinated Toluenes.
Supplement 7: 148-149. Lyon, France.
IARC (International Agency for Research on Cancer). 1999. IARC Monographs on the
Evaluation of the Carcinogenic Risk of Chemicals to Humans. Re-evaluation of some Organic
Chemicals, Hydrazine and Hydrogen Peroxide (Part Two). a-Chlorinated Toluenes and Benzyl
Chloride. 71:453-477. Lyon, France.
Lijinsky, W. 1986. Chronic bioassay of benzyl chloride in F344 rats and (C57BL/6J x
BALB/c)Fi mice. J. Natl. Cancer Inst. 76:1231-1236.
Mihajlova, T.V. 1983. Benzyl chloride. In: Encyclopaedia of Occupational Health and Safety,
3rd (revised) ed., L. Parmeggiani, Ed. 1:262. International Labor Office, Geneva, Switzerland.
Monsanto Co. 1977a. Teratogenic study with benzyl chloride in albino rabbits with cover letter
dated 05/11/94. Study performed by Industrial Bio-test Laboratories, Inc. TSCA Section 8D
submission. OTS0557183.
Monsanto Co. 1977b. Two-week pilot vapor inhalation toxicity study with benzyl chloride in
albino rats with cover letter dated 05/11/94. Study performed by Industrial Bio-test
Laboratories, Inc. TSCA Section 8D submission. OTS0557182.
23

-------
7-14-2008
Monsanto Co. 1983. Initial Submission: 4-Week inhalation toxicity study of benzyl chloride to
male and female rats, male guinea pigs and male hamsters. ML-79-049. Study performed by
Monsanto Company, Environmental Health Laboratory. TSCA Section 8ECP submission.
OTS0538499.
Monsanto Co. 1984. Twenty-seven week inhalation toxicity of benzyl chloride vapor to male
and female rats and male guinea pigs with cover letter dated 05/11/94. Study performed by
Monsanto Company, Environmental Health Laboratory. TSCA Section 8D submission.
OTS0557187.
NIOSH (National Institue for Occupational Safety and Health). 1978. Criteria for a
Recommended Standard Occupational Exposure to Benzyl Chloride. DHEW (NIOSH),
Cincinnati, OH. Publ. No. 78-182.
NIOSH (National Institute for Occupational Safety and Health). 2007. NIOSH Pocket Guide to
Chemical Hazards. Available at http://www.cdc.gov/niosh/npg/.
NTP (National Toxicology Program). 2007. 11th Report on Carcinogens. Available at
http://ntp.niehs.nih.gov/index.cfm?obiectid=32BA9724-FlF6-975E-7FCE50709CB4C932.
OSHA (Occupational Safety and Health Administration). 2007. OSHA Standard 1910.1000
Table Z-l. Part Z, Toxic and Hazardous Substances. Available at
http://www.osha.gov/pls/oshaweb/owadisp.show document?p table=STANDARDS&p id=999
2.
Pearl, W and T. Balazs. 1967. Survival of stressed rats following experimental cardiac necrosis.
Experientia. 23:138-139.
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.
Reuber, M.D. 1979. Memorandum from Dr. Melvin D. Reuber (Head, Pathology Section) to
Dr. William Lijinsky (Director, Chemical Carcinogenesis Program) regarding the pathology
report on benzyl chloride in rats - subchronic study. Frederick Cancer Res. Cen. August 21.
Rohm and Haas Co. 1988. Initial submission: Benzyl chloride: Four-week inhalation toxicity
study in rats with cover letter dated 9/22/92. Study performed by Ray Brown, Research
Pathology Services, Inc. TSCA Section 8ECP submission. OTS0546511.
Skowronski, G. and M.S. Abdel-Rahman. 1986. Teratogenicity of benzyl chloride in the rat. J.
Toxicol. Environ. Health. 17:51-56.
Sakabe, H. and K. Fukuda. 1977. An updating report on cancer among benzoyl chloride
manufacturing workers. Ind. Health. 15:173-174.
24

-------
7-14-2008
Sakabe, H., H. Matsushita and S. Koshi. 1976. Cancer among benzoyl chloride manufacturing
workers. Ann. NY Acad. Sci. 271:67-70.
Sorahan, T. and M. Cathcart. 1989. Lung cancer mortality among workers in a factory
manufacturing chlorinated toluenes: 1961-84. Brit. J. Ind. Med. 46:425-427.
Sorahan, T., J.A.H. Waterhouse, M.A. Cooke et al. 1983. A mortality study of workers in a
factory manufacturing chlorinated toluenes. Ann. Occup. Hyg. 27:173-182.
U.S. EPA. 1986. Health and Environmental Effects Profile (HEEP) 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.
U.S. EPA. 1988. Recommendations for and Documentation of Biological Values for Use
in Risk Assessment. 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/600/6-87/008. NTIS PB88-
179874/AS.
U.S. EPA. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
U.S. EPA. 1994a. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1994b. Methods for Derivation of Inhalation Reference Concentrations and
Application of Inhalation Dosimetry. Office of Research and Development, Washington, DC.
EPA/600/8-90/066F.
U.S. EPA. 1997. Health Effects Assessment Summary Tables. FY-1997 Update. Prepared by
the Office of Research and Development, National Center for Environmental Assessment,
Cincinnati OH for the Office of Emergency and Remedial Response, Washington, DC. July.
EPA/540/R-97/036. NTIS PB97-921199.
U.S. EPA. 2006. 2006 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. EPA 822-R-06-013. Washington, DC. Available at
http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf
U.S. EPA. 2007. Integrated Risk Information System (IRIS). Online. Office of Research and
Development, National Center for Environmental Assessment, Washington, DC.
http://www.epa.gov/iris
U.S. EPA. 2008. Benchmark Dose Software (version 1.4.1). National Center for Environmental
Assessment, Washington, DC. Available at http://www.epa.gov/ncea/bmds/progreg.html
25

-------
7-14-2008
WHO (World Health Organization). 2007. Online catalogs for the Environmental Health
Criteria Series. Available at http://www.inchem.org/pages/ehc.html
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.
Wong, O. 1988. A cohort mortality study of employees exposed to chlorinated chemicals. Am.
J. Ind. Med. 14:417-431.
Zissu, D. 1995. Histopathological changes in the respiratory tract of mice exposed to ten
families of airborne chemicals. J. Appl. Toxicol. 15(3):207-213.
26

-------
7-14-2008
APPENDIX A. Benchmark Concentration Modeling for Pulmonary Edema in Guinea Pigs
Exposed to Benzyl Chloride by Inhalation for 5 Weeks (Monsanto Co., 1983)
Lung edema
5 week Guinea pig inhalation study (Monsanto, 1983)
Logistic Model. (Version: 2.9; Date: 02/20/2007)
Input Data File: C:\BMDS\DATA\BENZYL_CHORIDE_RFD.(d)
Gnuplot Plotting File: C:\BMDS\DATA\BENZYL_CHORIDE_RFD.plt
Thu Jan 24 14:18:19 2008
BMDS MODEL RUN
The form of the probability function is:
P[response] = background+(l-background)/[l+EXP(-intercept-slope*Log(dose))]
Dependent variable = edema
Independent variable = d
Slope parameter is restricted as slope >= 1
Total number of observations = 4
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
User has chosen the log transformed model
Default Initial Parameter Values
background = 0
intercept = -5.97847
slope = 1.01144
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -background -slope
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
intercept
intercept	1
27

-------
7-14-2008
Parameter Estimates
Variable	Estimate
background	0
intercept	-5.83799
slope	1
95.0% Wald Confidence Interval
Std. Err. Lower Conf. Limit Upper Conf. Limit
*
*
*
*
*
*
- Indicates that this value is not calculated.
*
*
*
Analysis of Deviance Table
Model Log(likelihood) #Param's Deviance Testd.f. P-value
Full model -17.1138 4
Fitted model -17.9641 1 1.70074 3 0.6368
Reduced model -23.5268 1 12.826 3 0.005029
AIC:
37.9283
Goodness of Fit
Scaled
Dose Est.Prob. Expected Observed Size Residual
0.0000
0.0000
0.000
0
10
0.000
60.0000
0.1489
1.489
1
10
-0.434
180.0000
0.3441
3.441
5
10
1.038
530.0000
0.6070
6.070
5
10
-0.693
ChiA2 = 1.75 d.f. = 3
P-value = 0.6269
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 38.121
BMDL = 19.5754
28

-------