A V-QII United States
Environmental Protection
M % Agency
EPA/690/R-05/01 OF
Final
10-04-2005
Provisional Peer Reviewed Toxicity Values for
1 -Chlorobutane
(CASRN 109-69-3)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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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
i.v.	intravenous
IRIS	Integrated Risk Information System
IUR	inhalation unit risk
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
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MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-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-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
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
Hg
microgram
|imol
micromoles
VOC
volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
1-CHLOROBUTANE (CASRN 109-69-3)
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 science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions (or the EPA HQ Superfund Program) sometimes
request that a frequently used PPRTV be reassessed. 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.
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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
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
The HE AST (U.S. EPA, 1997) lists a chronic oral RfD of 4E-1 mg/kg-day for 1-
chlorobutane, based on a duration-adjusted NOAEL of 43 mg/kg-day for increased mortality, and
effects on the central nervous and hematologic systems in a 2-year bioassay in rats (NTP, 1986)
and an uncertainty factor of 100. The subchronic RfD of 9E-1 is based on a duration-adjusted
NOAEL of 86 mg/kg-day for decreased body weight gain, changes in hematopoiesis, and central
nervous system effects in a 13-week study in rats (NTP, 1986) and an uncertainty factor of 100.
The source document for both of these RfDs was a Health and Environmental Effects Document
(HEED) for Monochlorobutanes (U.S. EPA, 1988). IRIS (U.S. EPA, 2005a) does not list an RfD
for 1-chlorobutane, and this chemical is not included in the Drinking Water Standards and Health
Advisories List (U.S. EPA, 2002). In addition to the Health and Environmental Effects
Document (HEED) (U.S. EPA, 1988), the Chemical Assessments and Related Activities
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(CARA) list (U.S. EPA, 1991, 1994) reports a Health and Environmental Effects Profile (HEEP)
for Monochlorobutanes (U.S. EPA, 1983). ATSDR (2003) has not published a Toxicological
Profile for 1-chlorobutane, and no Environmental Health Criteria Document is available (WHO,
2003).
No RfC for 1-chlorobutane is listed in the HEED (U.S. EPA, 1988), HEAST (U.S. EPA,
1997) or IRIS (U.S. EPA, 2005a). ACGIH (2003), NIOSH (2003), and OSHA (2003) have not
developed occupational exposure limits for 1-chlorobutane.
1-Chlorobutane is categorized in cancer weight-of-evidence group D (not classifiable as
to human carcinogenicity) in the HEED (U.S. EPA, 1988). The HEAST (1997) does not report
the carcinogenicity assessment for 1-chlorobutane, but the group D classification is included on
IRIS (U.S. EPA, 2005a). IARC (2003) has not evaluated the carcinogenicity of 1-chlorobutane.
NTP (1986) has conducted a 2-year carcinogenicity bioassay of 1-chlorobutane in mice and rats,
and reported no evidence of carcinogenicity in males or females of either species.
Literature searches were conducted from 1987 through October, 2003 for studies relevant
to the derivation of provisional toxicity values for 1-chlorobutane. Databases searched included:
TOXLINE (supplemented with BIOSIS andNTIS updates), MEDLINE, TSCATS, RTECS,
CCRIS, DART, EMIC/EMICBACK, HSDB, GENETOX, and CANCERLIT.
REVIEW OF PERTINENT DATA
Human Studies
Studies examining the toxicity or carcinogenicity of 1-chlorobutane in humans were not
located.
Animal Studies
In a dose range-finding study sponsored by the National Toxicology Program (NTP,
1986), groups of 10 male and 10 female F344/N rats were given 0, 30, 60, 120, 250, or 500
mg/kg of 1-chlorobutane and groups of 10 male and 10 female B6C3F1 mice were given 0, 60,
120, 250, 500, or 1000 mg/kg of 1-chlorobutane. Each group was treated by gavage with pure
compound in corn oil, 5 days/week for 13 weeks. The animals were observed for clinical signs
two times per day; moribund animals were killed. For the NTP studies summarized here, if
convulsions occurred, they were generally observed at the time of gavage dosing, although this
was not clearly specified. Animals were weighed weekly, and extensive histological
examinations were performed.
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In rats, 6/10 males in the 500 mg/kg group died prematurely (NTP, 1986). Because of
increased irritability of rats at the higher doses, dosing by gavage became extremely difficult;
three deaths were due to gavage accidents. Survival was 100% in all other groups of rats. A
dose-related decrease in weight gain occurred in male and female rats; males in the 250 and
500 mg/kg groups had final weights that were 11 and 20% lower than control weights,
respectively, and females in the 500 mg/kg group had weights that were 10% lower than the
female control weights. Convulsions occurred in 5/10 male and 2/10 female rats in the 250
mg/kg group, and in 9/10 males and 8/10 females in the 500 mg/kg group. Extramedullary
hematopoiesis of the spleen occurred in 3/10 male rats in the 500 mg/kg group and in 0/10 rats in
the control groups; the severity was mild in two rats and moderate in the third. No other
compound-related clinical signs or histopathological effects were reported for rats.
A number of gavage accidents occurred during the studies using mice (two vehicle
control females, a male and female in the 60 mg/kg groups, a female in the 120 mg/kg group, and
two females in the 1000 mg/kg group); these accidents were attributed to technician error, rather
than any compound-related difficulties (NTP, 1986). No treatment-related changes in body
weight were seen in male or female rats of any group. In the 1000 mg/kg group, convulsions
occurred in two female mice. No other compound-related clinical signs or histopathological
effects were reported for mice.
NTP (1986) also conducted a 2- year toxicology and carcinogenesis study of
1-chlorobutane in male and female F-344/N rats and B6C3F1 mice. In the rat study, groups of 50
animals/sex/group were given 0, 60, or 120 mg/kg of 1-chlorobutane (99.5% pure) in corn oil by
gavage 5 days/week for 103 weeks. Animals were observed twice daily, and clinical signs were
recorded once per week. Body weights were recorded once per week for the first 12 weeks of the
study and once per month thereafter. A necropsy was performed on all animals, including those
found dead, unless they were excessively autolyzed or cannibalized. Examinations for grossly
visible lesions were performed on all major organs, and pathology was performed on 28 organs,
as well as any noticeable gross masses. Sentinel rats were found to have antibodies to the Sendai
and RC viruses, but the impact of the presence of these viruses on the reliability of the study
results is not known.
Survival was significantly reduced in high-dose male (17/50 treated vs. 40/50 vehicle
control) and female rats (11/50 vs. 35/50), relative to controls; these deaths were considered to be
compound-related, and not due to errors in gavage (NTP, 1986). The study authors expressed a
concern about decreased study sensitivity, in terms of detecting carcinogenesis, resulting from
the mortality in the high dose group. Many dosed rats had tremors and convulsions after being
gavaged; the study authors suggested a link between animals that showed convulsions and those
that died, although supporting incidence data were not provided. Mean body weights of treated
and control rats were comparable throughout the study; a slight decrease (3%) in body weight
throughout the study in high-dose male rats was not considered to be a treatment-related effect.
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Nephropathy occurred in female rats, but did not occur in a dose-related manner and was not
accompanied by other evidence indicating that it was a compound-related adverse effect.
Cytoplasmic vacuolization of the adrenal occurred in a dose-related manner in male rats;
although this effect indicates a build-up of fatty deposits, the toxicological significance of this
effect is not clear. Lung alveolar and brain hemorrhage, lymphoid depletion of the spleen,
splenic hemosiderosis, and multiple organ congestion occurred in a dose-related manner in male
and female rats; in most cases, the differences were only significant at the highest exposure level.
Generally, these effects were restricted to rats that died during the study; the study authors
suggested that many of these lesions were consistent with rats dying suddenly during
convulsions. The incidence of each of these effects was significant when compared with control
groups at a dose level of 120 mg/kg, but not at 60 mg/kg.
Pheochromocytomas of the adrenal gland were significantly increased in the low-dose
female rats (1/50, vehicle control; 6/50, low-dose; and 1/49, high-dose) (NTP, 1986). The
incidence of medullary hyperplasia, an expected preneoplastic observation associated with these
tumors (observed in 3/50 vehicle controls; 7/50 low-dose females; and 4/49 high-dose females)
did not suggest a dose-related neoplastic relationship. The incidence of pheochromocytomas was
low, not dose-related, and not seen in male rats. Furthermore, pheochromocytomas are
late-developing tumors and they were not considered by the study authors to be treatment related.
Thus, NTP concluded that there was no evidence of carcinogenicity of 1-chlorobutane for male
and female rats under the conditions of these studies. It was noted, however, that the
chemical-induced mortality in high-dose rats suggests that toxic levels were reached and might
have reduced the sensitivity of the study for determining carcinogenicity.
In the mouse portion of the study, groups of 50 male and female B6C3F1 mice were
gavaged with 1-chlorobutane (99.5% pure) in corn oil at 0, 500, or 1000 mg/kg-day, 5 days/week
for 103 weeks (NTP, 1986). Because of high treatment-related mortality, all mice dosed at 1000
mg/kg-day were sacrificed in the 45th week and a second study with additional groups of 50
mice/sex was started at 0 and 250 mg/kg-day. Animals were observed twice daily, and clinical
signs were recorded once per week. Body weights were recorded once per week for the first 12
weeks of the study and once per month thereafter. A necropsy was performed on all animals,
including those found dead, unless they were excessively autolyzed or cannibalized.
Examinations for grossly visible lesions were performed on all major organs, and pathology was
performed on 29 organs, as well as any noticeable gross masses. Sendai virus was present in
some female mice in the first study, but not in the second. In addition, mouse hepatitis virus
(MHV) was detected in both groups of mouse control animals, but the impact of the presence of
these viruses on the reliability of the study results is not known.
Survival (54-64%) was comparable for vehicle controls and 500-mg/kg-day groups in the
first study, and also for vehicle controls and 250-mg/kg-day groups in the second study (50-72%)
(NTP, 1986). The 1000-mg/kg-day male mice showed lower (~10%>) mean body weights,
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compared with vehicle controls, after week 36; body weights for other groups were comparable
to controls. Compound-related signs included convulsions, primarily in high-dose (1000 mg/kg-
day) mice. As with rats, animals dying early often showed hemorrhage of the brain and/or lung.
Both control and treated female mice developed suppurative inflammation, with some evidence
of Klebsiella pneumoniae infection, but the incidence was not elevated by dose. No other effects
on noncarcinogenic endpoints were reported in mice.
An increased incidence of alveolar/bronchiolar adenomas or carcinomas (combined) (as
evaluated by the Incidental Tumor Test) was observed in females in the 500 mg/kg group (9/50)
compared with its vehicle controls (3/50), and no effect was seen in the 250 mg/kg group (8/50
treated vs. 6/50 vehicle control)(NTP, 1986). The incidence of these tumors was not statistically
significantly elevated when treated groups were compared with pooled vehicle control groups
(9/100) from the first and second part of the study. In addition, the lack of hyperplasia in females
and the negative trend seen in males suggest that these marginal effects were not
treatment-related. A statistically significantly increased incidence of hepatocellular adenomas or
carcinomas (combined) was observed in females in the 500 mg/kg group (8/50 vs. 3/50) but not
in the 250 mg/kg group (9/50 vs. 7/50). When compared with pooled vehicle controls from the
two studies, however, the incidence was not statistically significantly elevated. In the first study,
there was an increased incidence (not statistically significant) of hemangiosarcomas in males
(1/50, control; 3/50, 500 mg/kg-day; 4/50, 1000 mg/kg-day), but such an increase was not
observed in males in the second study (4/50 control vs. 2/50 at 250 mg/kg); the increase was not
statistically significant when treated animals were compared with pooled vehicle controls. Since
the incidences of hepatocellular adenomas and carcinomas in females were highly variable
between the vehicle controls in the two studies (2-16%) and there were no dose-related effects in
male mice, these tumors in female mice were not considered treatment-related. The
hemangiosarcomas in male mice were also not considered to be compound-related, as the
incidence in the vehicle controls was highly variable (2-8%) and the incidence in the first study
was lower than the NTP historical incidence (4%). NTP concluded that there was no evidence of
carcinogenicity of 1-chlorobutane for male and female mice under the conditions of these studies.
Poirier et al. (1975) gave groups of 10 male and 10 female strain A/Heston mice a total of
24 i.p. injections (3 injections/week for 8 weeks) of 13, 32, or 65 mmol/kg (1194, 3000, or 6017
mg/kg) of 1-chlorobutane in tricaprylin. Untreated and tricaprylin-treated mice were used as
negative controls, and urethane-treated mice were used as positive controls. Mice were
sacrificed 24 weeks after the first injection. Survival at termination of the study was >90%. No
statistically significant increase in the average number of lung tumors per mouse occurred in
mice given 1-chlorobutane. This assay scores only lung tumors and is considered to be a
short-term in vivo screening test.
Two studies from the Soviet literature were located, but did not provide sufficient
information to allow independent evaluation. In one study, groups of 15 rats were dosed orally
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with 0, 0.02, 0.2, or 2 mg/kg of 1-chlorobutane in oil for 6 months (Tomashevskaya and
Zholdakova, 1979). The frequency of administration was not stated in the translation. At 2
mg/kg, the activities of blood alkaline phosphatase, cholinesterase, and succinate dehydrogenase
were altered, and higher blood levels of inorganic phosphate were observed. At 0.02 and 0.2
mg/kg, no statistically significant differences were observed in treated animals. In a second
study, groups of 10 rats were given daily oral doses of 0, 0.00022, 0.0022, 0.022, or 110 mg/kg
of 1-chlorobutane in sunflower oil for 30 days (Rudnev et al., 1979). A dose-related increase in
the titre of antibodies to liver tissue was observed (numerical data not reported), being highest in
the 110 mg/kg group and absent in the 0.00022 mg/kg group. A significant increase in the
degree of basophil degranulation in the peripheral blood was reported for rats in groups treated
with doses > 0.0022 mg/kg, and persisted until 8 weeks after treatment when the study was
discontinued. After 30 days, a dose-related increase in antibody sensitization and an increased
autoimmune patch formation in the peripheral blood occurred in rats given 0.0022, 0.022, or 110
mg/kg of 1-chlorobutane.
Other Studies
When tested in the Salmonella!microsomal assay, 1-chlorobutane was nonmutagenic in
strains TA98, TA100, TA1535, and TA1537 with and without the addition of hepatic
homogenates (Eder et al., 1980, 1982a,b; Barber et al., 1981; Barber and Donish, 1982; Zeiger,
1987, 1990; Zeiger et al., 1987; NTP, 1986). In contrast, Simmon (1981) reported positive
results in strain TA100 in the absence of hepatic homogenates; however, no control data were
provided. Negative results were obtained in an assay of DNA damage assay in Escherichia coli
(Fluck et al., 1976). 1-Chlorobutane was negative for DNA double-strand break induction in the
alkaline elution assay in rat hepatocytes (Storer et al., 1996). 1-Chlorobutane has given mixed
(Myhr et al., 1990) or positive (NTP, 1986) results in the mouse lymphoma L5178Y assay in the
absence of S9, but was negative in the presence of S9 (Myhr et al., 1990). Negative results were
obtained, both with and without S9, in chromosomal aberration tests in Chinese hamster ovary
cells and rat bone marrow cells (Anderson et al., 1990; NTP, 1986; Rudnev et al., 1979), and in
tests for sister chromatid exchange in Chinese hamster ovary cells (Anderson et al., 1990; NTP,
1986).
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR 1-CHLOROBUTANE
Subchronic p-RfD
Only one adequate evaluation of the subchronic toxicity of 1-chlorobutane was located in
the literature. NTP (1986) reported that rats exposed to 250 mg/kg-day or greater for 13 weeks
showed significant, dose-related decreases in body weight, as well as convulsions.
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Extramedullary hematopoiesis of the spleen was noted in male rats exposed to 500 mg/kg-day.
Also at 500 mg/kg-day, a number of rats died (some directly due to the chemical and some by
gavage error related to increased irritability of the animals). In mice, convulsions were seen only
at 1000 mg/kg-day. In support of the neurological findings in the subchronic study, clinical signs
and histopathological lesions indicative of a gross neurological effect were also observed in the
subsequent chronic rat and mouse studies. In the subchronic rat study, no effects were reported
at 120 mg/kg-day or below. There is some uncertainty associated with this finding, however,
because systematic tests for sensitive neurological endpoints were not conducted. This is an
important issue for this chemical, since gross neurological effects were among the most sensitive
effects observed in the study.
Because both changes in body weight and appearance of convulsions were associated
with exposure to 250 mg/kg-day, the lowest dose at which effects occurred in the subchronic rat
study, both endpoints were modeled using U.S. EPA's Benchmark Dose Software, version 1.3.2.
Models suitable for continuous variables were applied to the body weight data shown in Table 1.
For convulsions, models suitable for dichotomous variables were applied to data for the
incidence of rats that experienced one or more convulsions at any time of the study (see Table 1).
A 10% change from control values was used as the benchmark response in either case (U.S.
EPA, 1996, 2000). Results were based on extra risk. As males appeared to be most sensitive for
both endpoints, only male data were modeled. Results from the various model types are
presented in Table 2.
As can be seen from Table 2, the continuous models did not result in adequate model fits
for the body weight data using the recommended value of p>0.1 (U.S. EPA, 1996, 2000). All of
the dichotomous models produced adequate fits (p>0.1) to the convulsion incidence data. The
best fitting model, as determined by Akaike's Information Criteria (AIC), is the Gamma model.
The Gamma model estimated a BMDL of 97 mg/kg-day and BMD of 156 mg/kg-day. In
accordance with U.S. EPA (2000) guidance, the BMDL of 97 mg/kg-day was used as the point of
departure for derivation of the subchronic p-RfD.
Table 1. Data from the Subchronic NTP (1986) Rat Study Used for BMD Modeling
Dose Group
0
30
60
120
N
10
10
10
10
Final Body Weight
Mean
299
300
290
285
Standard Deviation
4
5
4
3
Number of Animals
With Convulsions
0
0
0
0
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250	10	265	4	5
500
10
240
10

9
Table 2.
BMD Modeling Results for 1-Chlorobutane Based on the Subchronic NTP (1986) Rat Study
Endpoint
Model
LED10
ED10
P-Value
AIC
Body Weight
Linear
231
244
<0.05
-
Body Weight
Polynomial
186
211
<0.05
-
Body Weight
Power
231
244
<0.05
-
Body Weight
Hill
68
89
<0.05
-
Convulsions
Gamma
97
156
.8928
25.82
Convulsions
Quantal-Quadratic
88
111
.8429
25.93
Convulsions
Weibull
86
144
.7634
26.91
Convulsions
Probit
108
161
.5318
28.03
Convulsions
Logistic
112
163
.4475
28.53
Convulsions
Multi-Stage
84
150
.5268
29.18
Convulsions
Quantal-Linear
31
47
.1702
34.82
The BMDL was duration adjusted as follows:
5days!-week
BMDL = BMDL x —f—	-
Idays / wssk
-97x%
= 69 mg/kg-day
To the duration-adjusted BMDL of 69 mg/kg-day, an uncertainty factor of 1000 (10 for
animal to human extrapolation, 10 for intrahuman variability, and 10 for inadequacies in the
database), was applied to give the provisional subchronic RfD of 0.07 mg/kg-day. A full
uncertainty factor of 10 was applied for database uncertainties due to the lack of reproductive and
developmental data and a lack of evaluation of sensitive neurologic effects in the principal study.
subchronic p-RfD = LED10 UF
= 69 mg/kg-day ^ 1000
= 0.07 or 7E-2 mg/kg-day
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Confidence in the principal study is low-to-medium. The study was an adequate,
subchronic study in both sexes of two rodent species that clearly identified a NOAEL and
LOAEL; however, reporting of the results was limited (lack of numerical data for many
evaluated endpoints), and the study did not adequately evaluate neurological endpoints, which
appear to be an important target for 1-chlorobutane. Confidence in the database is low; the only
adequate supporting data for the principal subchronic study come from the chronic study
described in the same report. Low confidence in the provisional subchronic RfD results.
Chronic p-RfD
The only available chronic data on the toxicity of 1-chlorobutane are the data from the
NTP (1986) 2-year bioassay. This study identified a NOAEL of 60 mg/kg-day and LOAEL of
120 mg/kg-day in rats for convulsions and tremors, lung and brain hemorrhage, splenic lymphoid
depletion and hemosiderosis, multiple organ congestion, and increased mortality in both sexes of
rats. The study authors suggest that many of the observed lesions may be related to the
convulsions seen following exposure; however, data specifically correlating these effects with
animals that showed convulsions or animals that died prior to study termination are not available.
Convulsions were also observed (at higher doses) in the chronic mouse study and subchronic rat
and mouse studies. There is some uncertainty associated with the NOAEL of 60 mg/kg-day
because systematic tests for sensitive neurological endpoints were not conducted. This is an
important issue for this chemical, since gross neurological effects were the most sensitive effects
observed in the study. Benchmark dose modeling (U.S. EPA, 1996, 2000) was considered for
analysis of the chronic rat data, but was not applied because the available data are insufficient to
adequately describe the dose-response function (the data from the study identify only one effect
level). As such, modeling the data would not reduce the uncertainty regarding identification of
the point of departure. As the data are not amenable to Benchmark Dose analysis, a
NOAEL/LOAEL approach was adopted.
The NOAEL of 60 mg/kg-day was duration-adjusted as follows:
„„ , „T	5days /
NOAELrAnn = NOAEL x			
!• J	7 days/week
= 60 >' yl'
= 43 mgjkg - day
To the duration-adjusted NOAEL of 43 mg/kg-day, an uncertainty factor of 1000 (10 for
animal to human extrapolation, 10 for intrahuman variability, and 10 for inadequacies in the
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database, including a lack of evaluation of reproductive, developmental, and sensitive
neurological effects) was applied to give the provisional chronic RfD of 0.04 mg/kg-day.
p-RfD	= NOAEL - UF
= 43 mg/kg-day-^ 1000
= 0.04 or 4E-2 mg/kg-day
Confidence in the principal study is low-to-medium. The study was an adequate, lifetime
study in both sexes of two rodent species that clearly identified a NOAEL and LOAEL; however,
the likely presence of the Sendai and RC viruses in the rats somewhat confounds study
interpretation, the study's ability to identify chronic effects may have been affected by study
mortality, and the study's ability to describe the dose-response function of 1-chlorobutane is
limited by the fact that only one effect level was identified. Confidence in the database is low;
the only adequate supporting data for the principal chronic study come from the subchronic study
described in the same report. Low confidence in the provisional chronic RfD results.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR 1-CHLOROBUTANE
In the absence of subchronic or chronic data on the inhalation toxicity of 1-chlorobutane
in humans or animals, derivation of provisional subchronic or chronic RfC values is precluded.
DERIVATION OF A PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR 1-CHLOROBUTANE
NTP (1986) examined the effects of 2-year gavage exposure to 1-chlorobutane on male
and female F344/N rats (doses of 60 or 120 mg/kg for 5 days/week) and B6C3F1 mice (doses of
250 or 500 mg/kg for 5 days/week). Despite exceeding the MTD, as evidenced by increased
high-dose mortality, no consistent evidence of dose-related tumor formation was reported in
either sex of either species. The study authors noted that toxicity in high-dose rats, particularly
females, reduced the sensitivity of the study for determining carcinogenicity. In a short-term
assay screening assay, Poirier et al. (1975) reported that administration of 24 intraperitoneal
injections (3/week) to mice at levels of 1194, 3000, or 6017 mg/kg did not result in an increase in
the average number of lung tumors per mouse. The overwhelming majority of available tests of
mutagenicity, DNA reactivity, and clastogenicity of 1-chlorobutane in bacteria and mammalian
cells have been negative. Under the guidelines (U.S. EPA 2005b), the data are inadequate for an
assessment of human carcinogenic potential of 1-chlorobutane based on negative results in tests
of two non-human species (one of which - in rats - had reduced sensitivity due to high mortality
in the high-dose group) and evidence of a lack of genotoxicity.
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10-04-2005
REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 2003. Threshold Limit
Values for Chemical Substances and Physical Agents and Biological Exposure Indices. ACGIH,
Cincinnati, OH.
Anderson, B.E., E. Zeiger, M.D. Shelby et al. 1990. Chromosome Aberration and Sister
Chromatid Exchange Test Results with 42 Chemicals. Environ. Mol. Mutagen Suppl. 0(18): 55-
137.
ATSDR (Agency for Toxic Substances and Disease Registry). 2003. Internet HazDat-
Toxicological Profile Query. Online, http://www.alsdr.cdc.gov/toxpro2.html
Barber, E.D. and W.H. Donish. 1982. An exposure system for quantitative measurements of the
microbial mutagenicity of volatile liquids. Environ. Sci. Res. 25: 1-18.
Barber, E.D., W.H. Donish and K.R. Mueller. 1981. A procedure for the quantitative
measurement of the mutagenicity of volatile liquids in the Ames Salmonella typhimurium
mammalian/microsome assay. Mutat. Res. 90(1): 31-34.
Eder, E., T. Neudecker, D. Lutz and D. Henschler. 1980. Mutagenic potential of allyl and allylic
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mutagenic properties. Biochem. Pharmacol. 29:993-998.
Eder, E., D. Henschler and T. Neudecker. 1982a. Mutagenic properties of allylic and
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831-848.
Eder, E., T. Neudecker, D. Lutz and D. Henschler. 1982b. Correlation of alkylating and
mutagenic activities of allyl and allylic compounds: Standard alkylation test vs. kinetic
investigation. Chem. Biol. Interact. 38:303- 315.
Fluck, E.R., L.A. Poirier and H.W. Ruelius. 1976. Evaluation of a DNA polymerase-deficient
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IARC (International Agency for Research on Cancer). 2003. Search IARC Monographs.
Online. http://l 93.51.164.11/cgi/iHound/Chem/iH Chem Frames.html
Myhr, B., D. McGregor, L. Bowers et al. 1990. Mouse lymphoma cell mutation assay results
with 41 compounds. Environ. Mol. Mutagen. 16(Suppl 18): 138-167.
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NIOSH (National Institute for Occupational Safety and Health). 2003. Online NIOSH Pocket
Guide to Chemical Hazards. Index by CASRN. Online.
http://www.cdc.gov/niosh/npg/npgdcas.html
NTP (National Toxicology Program). 1986. Toxicology and carcinogenesis studies of n-butyl
chloride in F344/N rats and B6C3F1 mice (gavage studies). CAS No. 109-69-3. NTP-TR-312.
198 p.
OSHA (Occupational Safety and Health Administration). 2003. OSHA Standard 1910.1000
Table Z-l. Part Z, Toxic and Hazardous Substances. Online.
http://www.osha-slc.gov/OshStd data/1910 1000 TABLE Z-l.html
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.
Rudnev, M.I., L.A. Tomashevskaya, G.I. Vinogradov et al. 1979. Hygienic substantiation of the
permissible concentration of benzyl and butyl chlorides in water. Gig. Sanit. 3:11-15. (Rus.)
Simmon, V.F. 1981. Applications of the Salmonella/microsome assay. In: Short-term Tests
Chemical Carcinogens, H. Stich and R. San, Ed. Springer- Verlag, New York. p. 120-126.
Storer, R.D., T.W. McKelvey, A.R. Kraynak et al. 1996. Revalidation of the in vitro alkaline
elution/rat hepatocyte assay for DNA damage: Improved criteria for assessment of cytotoxicity
and genotoxicity and results for 81 compounds. Mutat. Res. 368(2): 59-101.
Tomashevskaya, L.A. and Z.I. Zholdakova. 1979. Characteristics of the Toxic Effect of Butyl
Chloride as a Pollutant of Chemical Industry Waste Water. Vrach. Delo. 7: 105-107. (Cited in
U.S. EPA, 1988)
U.S. EPA. 1983. Health and Environmental Effects Profile for Monochlorobutanes. 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,
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U.S. EPA. 1988. Health and Environmental Effects Document for Chlorobutanes. 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. 1991. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. April.
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U.S. EPA. 1994. Chemical Assessments and Related Activities (CARA). Office of Health and
Environmental Assessment, Washington, DC. December.
U.S. EPA. 1996. Benchmark Dose Technical Guidance Document. Draft Report. Risk
Assessment Forum, National Center for Environmental Assessment, Washington, DC.
EPA/600/P-96/002A.
U.S. EPA. 1997. Health Effects Assessment Summary Tables (HEAST). 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. 2000. Benchmark Dose Technical Guidance Document. Draft Report. Risk
Assessment Forum, National Center for Environmental Assessment, Washington, DC.
EPA/63 0/R-00/001.
U.S. EPA. 2002. 2002 Edition of the Drinking Water Standards and Health Advisories. Office
of Water, Washington, DC. Summer, 2002. EPA 822-R-02-038. Online.
http://www.epa. gov/waterscience/drinking/standards/dwstandards .pdf
U.S. EPA. 2005a. Integrated Risk Information System (IRIS). Office of Research and
Development. National Center for Environmental Assessment, Washington, DC. Online.
http://www.epa. gov/ iris/
U.S. EPA. 2005b. Guidelines for Carcinogen Risk Assessment. Office of Research and
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Criteria Series. Online, http://www.who.int/dsa/cat97/zehcl.htm
Zeiger, E. 1987. Carcinogenicity of mutagens: Predictive capability of the Salmonella
mutagenesis assay for rodent carcinogenicity. Cancer Res. 47(5): 1287-1296.
Zeiger, E., B. Anderson, S. Haworth et al. 1987. Salmonella mutagenicity tests: III. Results
from the testing of 255 chemicals. Environ. Mutagen. 9(9): 1-109.
Zeiger, E. 1990. Mutagenicity of 42 Chemicals in Salmonella. Environ. Mol. Mutagen.
16(Suppl 18): 32-54.
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APPENDIX A - RESULTS OF BENCHMARK DOSE ANALYSIS
Gamma Multi-Hit Model with 0.95 Confidence Level
dose
1 1:23 10/24 2003
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$Revision: 2.1 $ $Date: 2000/02/26 03:37:57 $
Input Data File: C:\BMDS\UNSAVED1.(d)
Gnuplot Plotting File: C:\BMDS\UNSAVED1 .pit
Fri Oct 24 11:23:00 2003
BMDS MODEL RUN
The form of the probability function is:
P[response]= background+(l-background)*CumGamma[slope*dose,power],
where CumGammaQ is the cummulative Gamma distribution function
Dependent variable = convulsions
Independent variable = COLUMN!
Power parameter is restricted as power >=1
Total number of observations = 6
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
Default Initial (and Specified) Parameter Values
Background = 0.0454545
Slope = 0.0115921
Power = 3.39562
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -Background
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
Slope Power
Slope 1 0.97
Power 0.97
1
Parameter Estimates
Variable
Background
Slope
Power
0.0202592
6.00738
Estimate
0
0.0112356
3.13899
Std. Err.
NA
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NA - Indicates that this parameter has hit a bound
implied by some inequality constraint and thus
has no standard error.
Analysis of Deviance Table
Model Log(likelihood) Deviance Test DF
Full model -10.1823
Fitted model -10.909 1.45348 4
Reduced model -32.5964 44.8281 5
P-value
0.8348
<.0001
AIC:
25.8181
Goodness of Fit
Scaled
Dose Est.Prob. Expected Observed Size Residual
0.0000
0.0000
0.000
0
10
0
30.0000
0.0000
0.000
0
10
-0.02024
60.0000
0.0016
0.016
0
10
-0.1258
120.0000
0.0373
0.373
0
10
-0.6223
250.0000
0.3942
3.942
5
10
0.6847
500.0000
0.9373
9.373
9
10
-0.4868
Chi-square =
1.11 DF = 4
P-value = 0.8928
Benchmark Dose Computation
Specified effect = 0.1
Risk Type = Extra risk
Confidence level = 0.95
BMD = 155.846
BMDL = 97.1323
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