United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-09/007F
Final
2-18-2009
Provisional Peer Reviewed Toxicity Values for
sec-Butyl alcohol
(CASRN 78-92-2)
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
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
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
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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
|j,mol
micromoles
voc
volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
sec-BUTYL ALCOHOL (2-BUTANOL, CASRN 78-92-2)
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
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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
sec-butyl alcohol is a high production volume (HPV) chemical also listed in the Toxic
Release Inventory (TRI). No RfD, RfC, or carcinogenicity assessment for sec-butyl alcohol
(sec-butanol, 2-butanol) is available on IRIS (U.S. EPA, 2008a), in the Health Effects
Assessment Summary Tables (HEAST; U.S. EPA, 1997), or in the Drinking Water Standards
and Health Advisory list (U.S. EPA, 2006). The IRIS RfD (consensus date 09/10/2003) for
methyl ethyl ketone (2-butanone), however, is based on a reproduction study of sec-butyl alcohol
in rats (FDRL, 1975). The Chemical Assessments and Related Activities (CARA) lists
(U.S. EPA, 1991a, 1994a) show no U.S. EPA documents for sec-butyl alcohol. The Agency for
Toxic Substances and Disease Registry (ATSDR, 2008) has not produced a Toxicological Profile
for sec-butyl alcohol. A World Health Organization (WHO, 1987) Environmental Health
Criteria document that includes sec-butyl alcohol is available, but data are inadequate to derive
an assessment. The International Agency for Research on Cancer (IARC, 2008) has not
evaluated sec-butyl alcohol for carcinogenicity. The National Toxicology Program (NTP) has
not tested the carcinogenicity of sec-butyl alcohol or included it in its 1 \x Report on Carcinogens
(NTP, 2005, 2008). The California Environmental Protection Agency (CalEPA, 2002, 2005a,
2005b) has not derived a recommended exposure limit (REL) or cancer potency factor for
sec-butyl alcohol. Occupational exposure limits are available for sec-butyl alcohol based on
acute respiratory tract and eye irritation and CNS effects; these are time-weighted-average
(TWA) limits that include an Occupational Safety and Health Administration (OSHA, 2008)
permissible exposure limit (PEL) of 150 ppm, a National Institute of Occupational Safety and
Health (NIOSH, 2005) REL of 100 ppm, and an American Conference of Governmental
Industrial Hygienists (ACGIH, 2001, 2007) threshold limit value (TLV) of 100 ppm.
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We conducted literature searches from 1960's through December 2007 for studies
relevant to the derivation of provisional toxicity values for sec-butyl alcohol. Databases
searched include MEDLINE (including cancer subset), TOXLINE (Special), BIOSIS, TSCATS
1/TSCATS 2, CCRIS, DART/ETIC, GENETOX, HSDB, RTECS, and Current Contents. A
recent review for the Joint Assessment of Commodity Chemicals (JACC) Programme of the
European Centre for Ecotoxicology and Toxicology of Chemicals (ECETOC, 2003) was also
evaluated for pertinent information. An updated literature search (through November 2008) was
conducted using PubMed.
REVIEW OF PERTINENT DATA
Pertinent data on sec-butyl alcohol are limited to an oral multigeneration reproductive
and developmental toxicity study in rats (Cox et al., 1975) and an inhalation developmental
toxicity study in rats (Nelson et al., 1989). Information on the health effects of methyl ethyl
ketone (MEK) are relevant to sec-butyl alcohol because sec-butyl alcohol is rapidly and almost
completely metabolized to MEK in orally exposed rats (see toxicokinetics section below) and the
effects of oral and inhalation exposure to sec-butyl alcohol and MEK are similar. We included
selected studies of MEK in this PPRTV document as supporting data for sec-butanol because it
is likely that effects produced by sec-butanol are caused by MEK or a subsequent metabolite
common to both chemicals. We took summaries of these selected studies from the IRIS
Summary and Toxicological Review for MEK (U.S. EPA, 2003, 2008b). The MEK studies were
not independently re-evaluated for this review.
Human Studies
Oral Exposure
No pertinent information was located regarding the effects of oral exposure to sec-butyl
alcohol or MEK in humans.
Inhalation Exposure
sec-Butanol Studies—No information was located regarding the effects of inhalation
exposure to sec-butyl alcohol in humans.
MEK Studies—Data on the effects of inhaled MEK in humans summarized here were
taken from the IRIS Summary and Toxicological Review for MEK (U.S. EPA, 2003, 2008b). As
with other small molecular weight, aliphatic, or aromatic organic chemicals used as solvents
(e.g., acetone or toluene), acute inhalation exposure to MEK vapors is expected to cause
reversible CNS depression; however, evidence for such effects in humans is limited to a single
case report (Welch et al., 1991). Data from a series of NIOSH-sponsored studies involving
acute, 4-hour exposures of volunteers (Dick et al., 1984, 1988, 1989, 1992) found no exposure
related changes in performance of psychomotor and mood tests or incidences of irritation.
Evidence that MEK may induce general solvent-like neurotoxic effects such as peripheral or
central nerve fiber degeneration in humans repeatedly exposed to MEK by inhalation consists of
a few case reports of neurological impairment in exposed workers (Seaton et al., 1992;
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Callender, 1995; Orti-Pareja et al., 1996), and one study of problematic design reporting
increased incidence of subjectively reported neurological symptoms in exposed workers
(Mitran et al., 1997; Graham, 2000). The available data provide limited and equivocal evidence
that repeated exposure to MEK in the workplace increases the hazard for persistent neurological
impairment (U.S. EPA, 2003).
Epidemiological studies of MEK-exposed workers provide no clear evidence of a cancer
hazard (Alderson and Rattan, 1980; Wen et al., 1985; Spirtas et al., 1991; Blair et al., 1998), but
the studies are generally inadequate to discern an association between MEK exposure and an
increased incidence of cancer (U.S. EPA, 2003, 2008b). These retrospective cohort studies
provide limited epidemiological evidence for bone, prostate, and certain other cancers based on a
small number of site-specific deaths and exposures that are confounded by multiple chemicals.
A case-control study examining the association between paternal exposures to several solvents
(including MEK) and childhood leukemia (Lowengart et al., 1987) is exploratory in scope and
cannot be used to reliably support the existence of any such association. Overall, the
epidemiologic evidence from which to draw conclusions about carcinogenic risks in the human
population is inconclusive. There is no clear evidence for a relationship between these cancers
and MEK exposure alone. Studies on the cancer risk of exposures to multiple solvents, including
MEK, suggest an increased cancer risk (U.S. EPA, 2003, 2008b), however, it is not possible to
attribute the increased risk to MEK.
Animal Studies
Oral Exposure
sec-Butanol Studies—The only repeat-exposure oral study of sec-butyl alcohol is a
single study, encompassing both multigenerational reproduction and developmental toxicity, by
Cox et al. (1975). In the oral RfD summary for methyl ethyl ketone (MEK) on IRIS (U.S. EPA,
2008b) and the Toxicological Review of MEK (U.S. EPA, 2003), the U.S. EPA summarized the
Cox et al. (1975) study; a U.S. EPA-sponsored peer review of this study was conducted in 2003
(U.S. EPA, 2003, Appendix A). The Cox et al. (1975) study was used as the basis of the RfD
for MEK on IRIS due to a lack of appropriate oral toxicity data for MEK and the availability of
pharmacokinetic and toxicological data supporting the use of sec-butyl alcohol as an appropriate
surrogate for MEK. A summary of the Cox et al. (1975) study, taken from the Toxicological
Review of MEK (U.S. EPA, 2003), is presented below (editorial changes added). The study
does not include statistical analyses of the results, although all collected data are fully reported.
Weanling FDRL-Wistar stock rats (30/sex/group) were given sec-butyl alcohol in
drinking water at 0, 0.3, 1 or 3% solutions and a standard laboratory ration ad
libitum (Cox et al., 1975). Weekly food consumption, fluid intakes and body
weights were examined to determine the efficiency of food utilization and to
calculate the average daily intake of sec-butyl alcohol, which was reported by the
authors for the initial 8 weeks of the study (intake was not reported for subsequent
weeks) as 0, 538, 1644, and, 5089 mg/kg-day (males) and 0, 594, 1771 and,
4571 mg/kg-day (females) for the 0, 0.3, 1, and, 3% solutions, respectively. After
8 weeks of initial exposure, F0 males and females from each exposure group were
mated to produce Fia litters, which were delivered naturally and nursed through
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21 days of lactation. FiA litters with more than eight pups were randomly culled
to eight pups per litter on day 4 after birth. Pup and dam weights were recorded
on days 4 and 21 after birth. Various indices of reproductive performance were
recorded (e.g., number of successful pregnancies, litter size, number of live pups
at birth and end of lactation). Because increased mortality and decreased body
weight occurred in the Fia litters at the 3% dose level (see below), all high-dose
parents and FiA offspring were given drinking water without sec-butanol between
days 10 and 21 of lactation and then 2% sec-butyl alcohol for the remainder of the
experimental protocol. The average daily intake in mg/kg-day at the 2% (initially
3%) exposure level was not reported by the study investigators; therefore, average
daily intakes of 3384 mg/kg-day in males and 3122 mg/kg-day in females were
estimated based on a linear regression analysis of the reported average intakes for
males and females at drinking water concentrations of 0, 0.3, 1 and 3%.
After a 2-week post-lactation period, the Fo females were remated with males of
their respective exposure groups to produce Fib litters. The Fib pregnancies of 20
pregnant rats per group were terminated on gestation day (GD) 20. Data recorded
included numbers of corpora lutea, implant sites and resorptions, number of live
and dead fetuses and the sex and weight of live fetuses. Fib fetuses were also
examined for skeletal and visceral malformations and variations.
Selected male and female Fia rats (30 of each sex per exposure group) continued
on their respective treatment protocols (0, 0.3, 1 or 2% sec-butyl alcohol) and
mated at 12 weeks of age to produce F2 litters that were delivered and nursed
through day 21 of lactation. Indices of second generation reproductive
performance were assessed, as were F2 pup weights at days 4 and 21. At day 21
of lactation, FiA adults were sacrificed. Limited hematology (six indices), blood
biochemistry (six indices) and urinary (five indices) evaluations were performed
on terminal blood and urine samples from the FiA adults. Major organs and
tissues (35 in all) from 10 male and 10 female Fia rats per exposure group were
examined histopathologically and the liver and kidneys from all 30 FiA
rats/sex/group were examined histopathologically.
At the highest exposure level (3%), net parental (F0) body-weight gain was
reduced compared with controls both in males (15%) and females (16%) during
the 8 weeks of initial exposure. No differences were found in the efficiency of
food utilization. Following birth of the first litter (Fia) of the parental generation,
various reproduction and lactation responses were measured. The study authors
reported no effects on reproductive parameters. Analysis of Fo male rat
copulatory success suggests a possible impact of 3% sec-butyl alcohol on male
reproductive performance. The incidence of male Fo rats that did not successfully
copulate with F0 females was 0% (1/30), 0.3% (2/30), 1% (0/30), and, 3% (6/30).
Data from which to determine copulatory failure were not provided for other
generations. In addition, reduced body weight gain in this high-dose group could
have contributed to copulatory success. For these reasons, the biological
significance of these data for the F0 generation males is uncertain.
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When compared to the control group, marked litter effects on pup survival and
body weight occurred in the Fia litters from the high-dose group (3%); these
included reductions in the mean number of pups/litter born alive (8.46 vs. 10.3),
the mean number of pups/litter alive before culling at 4 days (8.12 vs. 10.3), the
mean number of pups/litter alive at 21 days (6.85 vs. 7.68), the mean body
weight/pup after culling at 4 days and the mean body weight/pup at 21 days. The
high-dose mean FiA body weights at 4 and 21 days represent 22 and 39%
decreases, respectively, when compared to control values (see Table 3 on p. 15).
At the lower dose levels, the litter mean body weights were decreased relative to
control at postnatal days 4 and 21 (5 and 4% for the 0.3% group and 7 and 10%
for the 1% group, respectively), but only the change in body weight at day 21 in
the 1% group is considered to be biologically significant.
During the second pregnancy, the high-dose F0 dams receiving 2% sec-butyl
alcohol exhibited reduced weight gain (94 g) compared to control, 0.3% and 1%
dams (gains of 113, 111 and 120 g, respectively). The Fib fetuses of
high-exposure (2%) dams showed a 10% reduction in average fetal weight
compared with controls (see Table 3 on p. 15). No differences in average fetal
weight were observed at 0.3% and 1%. The difference in the mean fetal weights
of the adjusted high-dose (2%) and control groups was not statistically significant
(p > 0.05) using a t-test, but when the Fib fetal weight data were fit by linear
dose-response models, log-likelihood ratio tests indicated that mean body weights
significantly decreased with increasing dose levels.
The incidences of nidation, early fetal death and late fetal death did not appear to
be affected in the Fib litters of any exposure group compared with controls
(Cox et al., 1975). The Fib fetuses in the 2% group showed increases in skeletal
variations (missing sternebrae, wavy ribs and incomplete vertebrae ossification)
when compared with the 1% dose group. When compared with control
incidences, however, no differences were apparent. The investigators provided no
explanation for the consistently lower responses observed in the 1% (mid-dose)
group.
F2 pups from the high-dose group (2%) showed reductions in mean pup body
weight at postnatal day 4 and day 21 (see Table 3 on p. 15). Mean body weights
of F2 pups in the 0.3 and 1% groups were similar to controls at day 4 and day 21.
Although body weight reductions in the high-dose F2pups were not as great as
those observed in the high-dose FiA pups, a continued decrease in body weight
occurred in the high-dose pups at days 4 and 21 (reductions of 5% at day 4 and
13%) at day 21 when compared with F2 controls).
No exposure-related changes in hematology, blood biochemistry, urinalysis,
organ weights or increased incidence of lesions were found in the adult FiA rats
sacrificed 21 days after the F2 birth, with the exception of specific histopathologic
changes in the kidneys that were most prominent in males (Cox et al., 1975).
Microcysts in the tip of the renal papilla were reported for rats receiving 2%
sec-butanol alcohol, but not in control rats; however, the incidence was not
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reported. Slight-to-mild hydropelvis (hydronephrosis) was also observed among
control and sec-butyl alcohol-exposed rats, although no dose-related effect was
observed. Other changes included tubular cast formation and foci of tubular
degeneration and regeneration. Incidences of male Fia rats with these types of
kidney changes were 0/30, 1/30, 1/30, and, 8/30 for the control through high-dose
groups, respectively. A similar increased incidence was not observed in females.
The findings are consistent with the pattern for [several aspects] of
a2U-globulin-associated rat nephrotoxicity as described by the Risk Assessment
Forum (U.S. U.S. EPA, 1991b). Testing was not conducted, however, to
demonstrate the presence of the a2U-globulin protein.
In summary, the results of the Cox et al. (1975) study demonstrate that the
administration of sec-butyl alcohol in drinking water at concentrations as high as
3% did not affect reproductive performance in rats (with the possible exception of
male rat copulatory success), but produced maternal toxicity accompanied by
developmental effects at the highest exposure level. Decreased maternal weight
gain, decreased Fia pup survival and decreased Fia pup weights at days 4 and 21
were observed in the groups exposed to 3% sec-butyl alcohol in drinking water.
At the next lower dose (1%) in this same generation, only reductions in Fia pup
weights (7 to 10% at days 4 and 21) were observed; however, no similar
reductions in body weight were observed in subsequent generations at the 1%
dose level. The following effects were noted at the 2% level (the adjusted
high-dose level administered following Fia postnatal day 21): decreased maternal
body-weight gain during the second pregnancy of the F0 dams, decreased Fib fetal
weights when pregnancy was terminated at gestation day 20, and decreased F2
pup weights at postnatal days 4 and 21. Developmental endpoints were not
affected at the 0.3% sec-butyl alcohol exposure levels in any of the generations,
sec-butanol treatment produced an increase in the incidence of kidney lesions in
high-dose male rats (Fia generation) that were exposed from gestation through
12 weeks after birth, mating and gestation and lactation of the F2 generation; no
other treatment-related histopathologic lesions were observed in adult rats. Thus,
Cox et al. (1975) identified a LOAEL of 3122 mg/kg-day (2% solution) and a
NOAEL of 1771 mg/kg-day (1% solution) based on decreased Fib fetal weights
and decreased Fia and F2 pup body weights. The maternal LOAEL in this study
was 3122 mg/kg-day (2% solution) based on decreased weight gain and the
NOAEL was 1771 mg/kg-day (1% solution, (p. 35-39).
MEK Studies—Studies of repeat-dose oral exposures to MEK that might be relevant to
sec-butanol have not been conducted (U.S. EPA 2003, 2008b).
Inhalation Exposure
sec-Butyl Alcohol Studies—Developmental toxicity was evaluated in groups of
15-16 female Sprague-Dawley rats that were exposed to sec-butyl alcohol at target
concentrations of 0, 3500, 5000, or 7000 ppm for 7 hours/day on GDs 1-19 (Nelson et al., 1989).
Continuous infrared monitoring showed that mean measured concentrations were essentially the
same as the target concentrations. The maternal animals were evaluated for clinical signs
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(presumed daily), food and water intake (weekly), and body weight (GDs 0-7, 14, and 20); the
animals were sacrificed on GD 20 for uterine and fetal examinations. Developmental endpoints
included numbers of corpora lutea, resorptions and live fetuses, fetal body weight and sex, and
external (all fetuses), skeletal (one-half of fetuses), and visceral (the other half of fetuses)
malformations and variations. An exposure of 7000 ppm produced narcosis in all maternal
animals and the animals did not recover completely between exposures. At 5000 ppm, the
animals were partially narcotized with impaired locomotor activity. At 3500 ppm the animals
were not visibly affected. Maternal body weights were not reported, but maternal body-weight
gain and food consumption were statistically significantly reduced at > 3500 ppm. At 3500,
5000, and 7000 ppm, body-weight gain at the end of the study was approximately 27, 23, and,
77% lower than controls (as estimated from graphed data), and overall mean food consumption
was approximately 11, 14, and, 29% lower than controls. Fetal body weight was significantly
reduced at > 5000 ppm; at 3500, 5000, and, 7000 ppm, mean weight was 6.5, 16.1, and, 54.8%
lower than controls in male fetuses and 6.1, 18.2, and, 54.5% lower than controls in female
fetuses (see Table 1). Other developmental toxicity only occurred at 7000 ppm; these effects
consisted of significantly increased resorptions/litter, decreased live fetuses/litter, and increased
number of fetuses with skeletal variations. The skeletal variations were described as typical of
fetotoxicity, particularly reduced ossification (additional details not reported). This study
identifies a LOAEL of 3500 ppm and no NOAEL for maternal toxicity based on reduced body-
weight gain and food consumption. A NOAEL of 3500 ppm and LOAEL of 5000 ppm were
identified for developmental toxicity based on reduced fetal body weight.
Table 1. Key Maternal and Fetal Effects in Rats Exposed to sec-Butyl Alcohol by
Inhalation for 7 hours/day on Gestation Days l-19a
Endpoint
0 ppm
3500 ppm
5000 ppm
7000 ppm
Resorptions/litter
1.5 ± 1.3b
1.6 ± 1.4
1.5 ±0.9
3.8 ± 2.2°
Live fetuses/litter
14 ±2
15 ± 2
14 ±3
10 ± 3°
Fetal weight, female (g)d
3.1 ±0.22
2.9 ±0.20
2.6 ± 0.23°
1.4 ± 0.18°
Fetal weight, male (g)d
3.3 ±0.23
3.1 ±0.22
2.7 ± 0.25°
1.5 ± 0.12°
aNelsonetal., 1989
bMean values ± standard deviations
Significantly different from control (p < 0.05)
dNot reported whether based on individual or litter weights
MEK Studies—Developmental toxicity, subchronic toxicity, and neurotoxicity studies
showed that developmental toxicity is the most sensitive toxicologically relevant effect of
inhalation exposure to MEK. Summaries of these studies, taken from the IRIS RfC summary for
MEK (U.S. EPA, 2008b), are presented below (editorial changes added).
Deacon et al. (1981) exposed groups of 26, 19, 19 and 18 Sprague-Dawley dams
to nominal MEK concentrations of 0, 400, 1000 or 3000 ppm, respectively
(7 hours/day on GD 6-15). Results from the study were also reported by Dow
Chemical Corporation (1979). Average measured MEK concentrations were 412,
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1002 and, 3005 ppm. Dams exposed to 3005 ppm MEK exhibited maternal
toxicity that was demonstrated by a slight decrease in weight gain (326 g for
3005 ppm group vs. 351 g for control;p < 0.05 at GD 16) and increased water
consumption on days 15-17 (82 mL/day for 3005 ppm group vs. 69 mL/day for
control; p < 0.05 at GD 16) (Dow Chemical Corporation, 1979). None of the
exposure levels produced statistically significant effects on the incidence of
pregnancy or resorptions, the average number of implantations or live fetuses per
dam, or fetal weight and length. No statistically significant differences in the
incidences of external or soft-tissue alterations were observed in the exposed
groups when compared with the control. A statistically significant difference in
the incidence of litters with extra ribs was observed in the 3005 ppm exposure
group when compared with the controls. The incidence of extra ribs was 2/26 for
control litters versus 0/19, 0/19, and, 6/18 for 412, 1002, and, 3005 ppm litters,
respectively. Thus, this study found maternal toxicity (decreased weight gain)
and fetal toxicity (increased incidence of skeletal variations) at 3005 ppm
(LOAEL) but not at 412 or 1002 ppm (NOAEL).
Schwetz et al. (1991) exposed groups of 10 virgin Swiss CD-I mice and 33 sperm
plug-positive (GD 0) females to mean MEK concentrations of 0, 398 ± 9,
1010 ± 28 or 3020 ± 79 ppm by inhalation for 7 hours/day on GD 6-15. Dams
were then sacrificed on GD 18. Results from this study were also reported by
Mast et al. (1989) and NTP (1990). At these exposure concentrations (0, 398,
1010 or 3020 ppm), the number of gravid/mated mice were 26/33, 23/33, 26/33,
and, 28/33, respectively. A slight concentration-related increase in liver-to-body-
weight ratio (approximately 7% over control at 3020 ppm) was observed in the
dams. Only two statistically significant developmental effects were observed:
(1) a decrease in mean fetal weight (per litter) at 3020 ppm for males (5%
decrease compared with controls) and for male and female fetuses combined (4%
decrease compared with controls) and (2) a positive trend for increasing incidence
of fetuses (total) with misaligned sternebrae with increasing exposure level
(incidences were 31/310, 27/260, 49/291, and, 58/323 for the control through
3020 ppm exposure groups). No increase in the incidence of intrauterine death
was observed in any of the exposed groups and no statistically significant
increases in the incidence of malformations occurred. Developmental and
maternal effect levels were established at 3020 ppm for a small, but statistically
significant, decrease in fetal weight among males, increased incidence of
misaligned sternebrae and an increase in maternal liver-to-body-weight ratio.
Cavender et al. (1983) exposed male and female Fischer 344 rats (15/sex/group)
in a whole body dynamic airflow chamber to MEK 6 hours/day, 5 days/week, for
90 days. The reported TWA exposure concentrations (by gas-liquid
chromatography) of MEK were 0, 1254, 2518, or, 5041 ppm. Results of the study
are also reported in Toxigenics (1981). At the study termination,
10 animals/sex/group were subject to routine gross pathology and histopathology.
Special neurohistopathological studies were conducted on the medulla and the
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sciatic and tibial nerves of the remaining five male and female rats from each
group.
Cavender et al. (1983) reported no deaths during the 90-day study. Transient,
statistically significant depressions in body weight gain compared to the control
were seen in high dose (5041 ppm) male and female rats early in the study. There
were no treatment-related effects on food consumption or in the ophthalmological
studies in any MEK-exposed rats. The evaluation of neurological function (i.e.,
assessments of posture, gait, facial muscular tone or symmetry and four
neuromuscular reflexes) revealed no abnormalities (Toxigenics, 1981). At all
exposure concentrations, female rats exhibited statistically significant (p < 0.05)
dose-dependent increases in absolute liver weight when compared to controls,
which were unaccompanied by any histopathology. Other statistically significant
differences in organ weights included decreased brain weights (absolute and
relative) and spleen weights (absolute) in 5041 ppm females and increased
relative kidney weights in 5041 ppm males and females. Differences in the serum
chemistry values for female rats in the 5041 ppm exposure group included
significant increases in serum potassium, alkaline phosphatase and glucose and a
significant decrease in SGPT (ALT) activity when compared to controls. No
differences in serum chemistry between MEK-exposed males and control animals
were observed. The only statistically significant differences in hematology
parameters were higher mean corpuscular hemoglobin in 5041 ppm male and
female rats and higher mean corpuscular hemoglobin concentration in 5041 ppm
females. The findings corresponded to a slight, but not significant, decrease in the
number of red blood cells. With the exception of larger urine quantity in
5041 ppm males, no urinalysis parameters were significantly different in
MEK-exposed rats when compared with controls. (None of these changes are
considered toxicologically significant).
Routine gross and histopathological examinations and the special neuropathology
studies revealed no lesions that could be attributed to MEK exposure
(Cavender et al., 1983). Thus, while the increase in absolute liver weights and
mildly altered serum enzyme activities in high-dose female rats indicated possible
liver damage, no histopathological lesions in the liver were observed. The authors
stated that the response may have been the result of a physiological adaptation
mechanism. While the decrease in brain weight in the 5041 ppm females (9%
compared to controls) indicated possible effects of MEK on brain tissue, no
histopathological lesions of the brain were observed.
Minimal-to-mild lesions in the upper or lower respiratory tract were noted in all
control and MEK-exposed rats and were coded as chronic respiratory disease
consisting of "multifocal accumulation of lymphoid cells in the bronchial wall
and peribronchial tissues with occasional polymorphonuclear cells (eosinophils)
in the perivascular areas of small veins" (Toxigenics, 1981). Because the
bronchial epithelium remained intact and exudates were not present in bronchial
lumens, the lesions were considered insignificant pathologically. In addition, the
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authors reported an increased prevalence of nasal inflammation (including
submucosal lymphocytic infiltration and luminal exudate) across control and all
exposure groups. There was no difference in the character or severity of lesions
among the control and three treatment groups. While the authors suggested that
the pulmonary lesions were secondary to mycoplasma infection, no infectious
agent was cultured to verify this etiology. Since there is no indication that
respiratory lesions are related to MEK exposure, the results confound the outcome
of the study with regard to lesions of the upper respiratory tract.
In summary, review of the Cavender et al. (1983) findings reveals effects remote
to the respiratory tract in the 5041 ppm animals that are of uncertain biological
significance, including: reduced body-weight gain, statistically significant
increases in relative liver weight (males and females) and altered serum liver
enzymes (females) and decreased brain weight (females). As noted previously,
reported liver effects are more likely indicative of a physiological adaptive
response than toxicity. The finding of decreased brain weight observed in female
rats raises concerns, but is difficult to interpret. Generally, with a brain weight
reduction of 5%, one might expect evidence of corresponding pathology;
however, no treatment-related brain pathology was observed in this study. The
reduction in brain weight relative to controls observed in only one sex also raises
questions about the relevance of the finding. Thus, while the reduction in brain
weight at 5041 ppm is noteworthy, its biological significance is uncertain.
Animal studies provide no convincing evidence that exposure to MEK alone
causes persistent neurotoxic effects (U.S. EPA, 2003, 2008b). Saida et al. (1976)
found no evidence of peripheral neuropathy (as indicated by paralysis) following
continuous exposure of 12 Sprague-Dawley rats to 1125 ppm MEK for
16-55 days. Cavender et al. (1983) found no neurological effects in special
neuropathological studies of the medulla and sciatic and tibial nerves of rats
exposed to MEK at concentrations up to 5041 ppm for 90 days. Takeuchi et al.
(1983) exposed male Wistar rats (8 per group) to 200 ppm MEK 12 hours/day for
24 weeks and found no evidence of a persistent effect on motor or mixed nerve
conduction velocity, distal motor nerve latency or histopathological lesions of tail
nerves. Couri et al. (1974) exposed four cats, four rats, five mice and an unknown
number of chickens to 1500 ppm MEK 24 hours/day, 7 days/week, for 7-9 weeks
with no apparent adverse neurologic effects.
The range of toxic effects in animals resulting from inhalation exposure to MEK
indicates that developmental effects are the most sensitive, toxicologically
relevant endpoint. Inhalation exposure of experimental animals to approximately
3000 ppm MEK (7 hours/day) during gestation resulted in developmental effects
(Schwetz et al., 1991; Deacon et al., 1981). (p. 41)
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Other Studies
Toxicokinetics
The IRIS document for MEK summarizes the toxicokinetics of sec-butyl alcohol. In
brief, Traiger and Bruckner (1976) reported the determination of a half-life of 2.5 hours for the
elimination of sec-butanol from blood of rats administered an oral dose of 2.2 ml/kg (equivalent
to 1.77 g/kg). One hour after administration, a maximal blood level of 800 mg sec-butanol/1 was
reached; the MEK level at that time point was 430 mg/1 rising to a maximum of 1,050 mg/1 at
4 hours after administration of the alcohol. Based on this and other data, Dietz et al. (1981)
established that approximately 96% of an administered oral dose of 2-butanol is oxidized in vivo
to MEK within 16 hours of oral administration. A physiologically based pharmacokinetic model
(PBPK model) reported by Dietz et al. (1981) reported that no significant difference in the area
under the curve (AUC) of MEK blood concentration was observed after oral dosing of rats with
either 1776 mg/kg sec-butanol or 1,690 mg/kg MEK (10,899 ± 842 or 9868 ± 566 mg-hour/liter,
respectively). Peak concentrations of MEK and its downstream metabolites were similar whether
MEK or sec-butanol were administered (Dietz et al., 1981), with a shift of approximately 4 hours
to reach peak concentrations when MEK was administered:
Table 2. Peak Blood Concentrations Following sec-Butanol or MEK
Administration of
Administration of
1776 mg/kg sec-butanol
1690 mg/kg MEK
MEK 0.78 mg/ml at 8 hr
0.95 mg/ml at 4 hr
3H-2B 0.04 mg/ml at 12 hr
0.027 mg/ml at 8 hr
2,3-BD 0.21 mg/ml at 18 hr
0.26 mg/ml at 18 hr
The Dietz et al. (1981) paper provides further support for the rapid conversion of orally
administered 2-butanol to MEK as ultimately, sec-butanol and MEK are metabolized to the same
intermediates (3H-2B and 2,3-BD).
Mutagenicity
sec-Butanol Studies—The mutagenicity of sec-butyl alcohol has been tested in bacteria,
yeast and mammalian cells with negative results. In bacteria, sec-butyl alcohol does not induce
reverse mutation in Salmonella typhimurium TA 1535, TA 1537, TA1538, TA98, or, TA100, or
Escherichia coli WP2 uvr A pKM 101 in the presence or absence of metabolic activation (rat
liver S9 fraction) (Brooks et al., 1988; Shell Oil Company, 1986). In yeast, sec-butanol does not
induce mitotic gene conversions in Saccharomyces cerevisiae JD1 in the presence or absence of
rat liver S9 metabolic activation (Brooks et al., 1988; Shell Oil Company, 1986). In mammalian
cells, sec-butyl alcohol does not cause chromosome damage in cultured Chinese hamster ovary
cells in the presence or absence of rat liver S9 metabolic activation (Brooks et al., 1988; Shell
Oil Company, 1986).
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MEK Studies—As reported in the IRIS summary for MEK (U.S. EPA, 2008b):
MEK has not exhibited mutagenic activity in a number of conventional short-term
test systems. In vitro tests showed that MEK is not genotoxic in the Salmonella
(Ames) assay (with or without metabolic activation), the L5178/TK+/" mouse
lymphoma assay, or the BALB/3T3 cell transformation assay and did not induce
unscheduled DNA synthesis in rat primary hepatocytes or chromosome
aberrations or sister chromatid exchange (Florin et al., 1980; Douglas et al., 1980;
O'Donoghue et al., 1988; NTP, undated; Zeiger et al., 1992). No induction of
micronuclei was found in the erythrocytes of mice (O'Donoghue et al., 1988) or
hamsters (WHO, 1992) after intraperitoneal injection with MEK. The only
evidence of mutagenicity was mitotic chromosome loss at a high concentration in
a study on aneuploidy in the diploid D61, M strain of the yeast Saccharomyces
cerevisiae (Zimmerman et al., 1985); the relevance of this positive result to
humans is unknown. In general, studies of MEK yielded little or no evidence of
mutagenicity. Structure Activity Relationships (SAR) analysis suggests that
MEK is unlikely to be carcinogenic based on the absence of any structural alerts
indicative of carcinogenic potential (Woo et al., 2002).
No cancer bioassay is available from which to assess the carcinogenic potential of
MEK in experimental animals by the oral or inhalation routes. In a skin
carcinogenesis study, groups of 10-15 male C3H/He mice received dermal
applications of 50 mg of a solution containing 17, 25, or, 29% MEK and one or
more other solvents (dodecylbenzene, benzyl disulfide, phenylbenzothiophene
and/or decalin) twice a week for 1 year (Horton et al., 1965). A single skin tumor
developed in 1/10 mice treated for 27 weeks with the solution containing 29%
MEK, and in 1/15 mice treated with the solution containing 17% MEK. This
study is an inadequate test of MEK carcinogenicity because of concomitant
exposure to chemicals that are expected to accelerate the rate of skin tumor
formation, (p. 47).
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL p-RfD VALUES FOR sec-BUTYL ALCOHOL
Studies of MEK are relevant to derivation of toxicity values for sec-butyl alcohol because
pharmacokinetic and toxicological data indicate that effects produced by sec-butyl alcohol are
likely caused by MEK or a subsequent metabolite common to both chemicals. As summarized in
the Toxicological Review of MEK (U.S. EPA, 2003), supporting pharmacokinetic findings in
rats include
(1) orally administered sec-butyl alcohol was almost completely (96%) converted
to MEK and its metabolites within 16 hours, (2) peak MEK blood concentrations
occurred at similar times after the administration of 1776 mg/kg (0.024 mol/kg)
sec-butyl alcohol (7-8 hours) and 1690 mg/kg (0.023 mol/kg) MEK (4-5 hours),
and (3) common metabolites (3-hydroxy-2-butanone and 2,3-butanediol) were
formed and eliminated with similar kinetics after the administration of sec-butyl
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alcohol or MEK (Traiger and Bruckner, 1976; Dietz et al., 1981). Comparable
pharmacokinetic data for sec-butyl alcohol and MEK in humans are not available;
however, evidence for conversion of sec-butyl alcohol to MEK in humans
supports the assumption that rats and humans metabolize sec-butyl alcohol
similarly, (p. 10).
Toxicological findings supporting the relevance of MEK to sec-butyl alcohol include
(1) fetal weight deficits were critical effects in studies of rats
(Schwetz et al., 1974; Deacon et al., 1981) and mice (Schwetz et al., 1991)
exposed to MEK by inhalation during gestation, in the two-generation
reproductive and developmental toxicity study in rats exposed to sec-butyl
alcohol in drinking water (Cox et al., 1975), and in the study of rats
exposed to sec-butyl alcohol by inhalation during gestation (Nelson et al.,
1989) and (2) the relationships between air concentrations and the degree
of fetal weight changes were consistent for MEK and sec-butyl alcohol.
(p. 60).
Oral RfD
The oral toxicity database for sec-butyl alcohol consists of a two-generation reproductive
and developmental toxicity study in rats (Cox et al., 1975). No relevant oral MEK studies are
available. Effects identified in the two-generation study include decreased pup survival and
decreased neonatal body weight in Fia pups whose parents were exposed to 3% sec-butyl alcohol
in drinking water before mating through day 10 of lactation. Decreased body weights, with no
effect on survival, were observed in Fib fetuses and Fia and F2 pups that were exposed to 2%
sec-butyl alcohol in drinking water. In adult rats, exposure to 3% sec-butyl alcohol in drinking
water for 8 weeks caused reduced weight gain in Fo males and females. Fi animals exposed to
sec-butyl alcohol in drinking water at concentrations up to 2% for 12 weeks after birth and
through mating, gestation, and lactation of F2 litters were subject to hematology, blood
biochemistry, urinalysis, organ weight, gross pathology, and histopathology evaluations. No
exposure-related changes were found with the exception of specific histopathologic changes of
the kidney in male rats exposed to 2% sec-butyl alcohol. Changes were consistent with the
pattern of several aspects of a2U-globulin-associated rat nephrotoxicity; however, testing needed
to demonstrate the presence of a2U-globulin was not conducted. Therefore, the relevance of this
finding to humans is uncertain. This study (Cox et al., 1975) identifies a LOAEL of
3122 mg/kg-day (2% solution) and aNOAEL of 1771 mg/kg-day (1% solution) based on the
decreases in fetal weight and pup body weight. The finding of developmental toxicity as the
most sensitive toxicologically relevant endpoint in rats exposed orally to sec-butyl alcohol is
consistent with similar findings in inhalation developmental toxicity studies of sec-butyl alcohol
(Nelson et al., 1989) and MEK (Schwetz et al., 1974, 1991; Deacon et al., 1981)
(U.S. EPA 2003, 2008b).
The Cox et al. (1975) study of sec-butyl alcohol is the principal study used to derive the
RfD for MEK that is on IRIS (U.S. EPA, 2008b). The derivation of the MEK RfD used
benchmark dose (BMD) analysis of the fetal and pup body weight data to obtain an LED05 value
for sec-butyl alcohol that was molar adjusted to account for differences in the molecular weights
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of sec-butyl alcohol and MEK. The unadjusted LED05 value can be used to derive subchronic
and chronic RfDs for sec-butyl alcohol. Calculation of the unadjusted LED05 value for sec-butyl
alcohol, as reported in the IRIS summary for MEK (editorial changes added), is presented below.
Fetal body weight data from the Fib generation and day 4 and 21 pup weights from the
Fia and F2 generations (Table 3) were analyzed by benchmark dose modeling. Decreased
Fia pup survival observed in the highest dose group (i.e., 3% solution) is likely to have
confounded the effects on body weight. Therefore, these data were not included in the
modeling. Models for continuous data (linear, polynomial or power), either with a
constant variance or with variance as a power function of the mean value (using an
additional model parameter), were fit to the data using U.S. EPA's Benchmark Dose
Software (BMDS version 1.3.1). The software was used to calculate potential points of
departure for deriving the RfD by estimating the effective dose at a specified level of
response (EDX) and its 95% lower bound (LEDX). In the case of pup or fetal body weight,
there is no specific decrement that is generally regarded as indicative of an adverse
response. Consequently, for each generation, a 5% decrease in the mean pup or fetus
body weight per litter (compared with the control mean) was selected as the benchmark
response because it was a response rate that fell within the range of experimental dose
levels used in the Cox et al. (1975) study, (p. 64).
Additionally, Kavlock et al. (1995) determined that the 5% benchmark response level for fetal
weight was essentially comparable to the no-statistical-significance-of-trend dose (a surrogate for
the NOAEL) for a series of developmental toxicity studies conducted by the National
Toxicology Program.
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Table 3. Body Weight (Litter Means and Standard Deviation) for Fia and F2 Neonatal
Rats and FiB Fetuses Exposed to sec-Butyl Alcohol"
Endpoint (generation)
Control
0.3%
(594 mg/kg-day1*)
1%
(1771 mg/kg-day")
2%
(3122 mg/kg-dayc)
Fia pup body weight, day 4
10.7 ± 1.1
(n = 29)
10.2 ± 1.3
(n = 27)
10.0 ± 1.3
(n = 30)
NAd
Fia pup body weight, day 21
49.0 ±3.8
(n = 28)
47.0 ±3.9
(n = 27)
44.0 ±4.8
(n = 30)
NAd
Fib fetal weight, GD 20
4.1 ± 1.5
(n = 29)
4.2 ±0.7
(n = 27)
4.4 ± 1.0
(n = 30)
3.7 ± 1.0
(n = 29)
F2 pup body weight, day 4
10.0 ± 1.4
(n = 28)
9.7 ± 1.6
(n = 28)
9.6 ±2.3
(n = 27)
9.5 ± 1.6
(n = 24)
F2pup body weight, day 21
40.0 ±6.1
(n = 27)
39.0 ±7.8
(n = 28)
39.0 ±9.4
(n = 25)
35.0 ±4.7
(n = 23)
aMean body weights and associated standard deviations were calculated from individual litter means in Appendix
II of the Cox et al. (1975) report.
bAverage daily intake of sec-butyl alcohol as reported by the authors.
Calculated based on a linear regression analysis of the reported average intakes and drinking water concentrations
of sec-butyl alcohol.
dHigh-dose FiA pups were exposed to 3% sec-butyl alcohol (4571 mg/kg-day). These were not included in the
modeling due to possibly confounding mortality.
Table 4 summarizes the ED05 and LED05 values calculated from the various data
sets from the study.
Table 4. Benchmark Doses for Developmental Effects in Various Generations of Rats
Exposed to sec-Butyl Alcohol and Potential Points of Departure for the RfDa
Endpoint
ED05b
(mg/kg-day)
LED05b
(mg/kg-day)
Fia pup body weight, day 4°
1387
803
Fia pup body weight, day 21°
878
657
F ib fetal weight, GD 20
2198
1046
F2 pup body weight, day 4
3471
1347
F2 pup body weight, day 21
2056
901
aU.S. EPA, 2003; 2008b
bED05 = Benchmark dose associated with a 5% decrease in litter mean pup or fetus body weight (compared with
control mean).
LED05 = 95% lower confidence limit on the ED05.
°The data for the high-dose group (3%) were not included in the modeling due to possibly confounding mortality.
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LED05 values from the data sets are within 2-fold of each other, suggesting that all
of the modeling results are equally plausible. The lowest point of departure,
based on the decreased pup body weight at postnatal day 21 in the FiA generation
(LED05 = 657 mg/kg-day), was selected for deriving the RfD as the most health
protective value."
Subchronic p-RfD
Derivation of the subchronic RfD for sec-butyl alcohol involves dividing the LED05 of
657 mg/kg-day by an UF of 300. The subchronic p-RfD of 2E+0 mg/kg-day is calculated as
follows:
Subchronic p-RfD = LED05 ^ UF
= 657 mg/kg-day 300
= 2 or 2E+0 mg/kg-day
The composite UF of 300 includes component UFs of 10 for extrapolation from rats to humans,
10 for human variability, and 3 for database insufficiencies, as explained below.
•	A 10-fold UF is used to account for laboratory animal-to-human interspecies
differences. No information is available on the toxicity of sec-butyl alcohol or
MEK in humans exposed by the oral route. No other information is available to
assess possible differences between animals and humans in pharmacokinetic and
pharmacodynamic responses to sec-butyl alcohol. Rat and human PBPK models
for oral exposure to sec-butyl alcohol could potentially be used to decrease
pharmacokinetic uncertainty in extrapolating from rats to humans, but such
models are not currently available.
•	A 10-fold UF for intraspecies differences is used to account for potentially
susceptible human subpopulations because information on the variability in
response of humans to sec-butyl alcohol exposure is not available.
•	A partial uncertainty factor of 3 (10°5) is used to account for deficiencies in the
available sec-butyl alcohol database. The oral database comprises a
two-generation reproductive and developmental toxicity study (Cox et al., 1975)
wherein rats were exposed to sec-butyl alcohol for 14-18 weeks. The study
includes evaluations of food and water intake, body weight, hematology, clinical
chemistry, urinalysis, and gross and microscopic pathology in the parental
animals. However, supporting data from a second study or species are not
available, and, as noted in the Toxicological Review of MEK (U.S. EPA, 2003),
The Cox et al. (1975) study protocol, although consistent with U.S. Food and
Drug Administration (FDA) guidelines available at the time that the study was
conducted, did not include the evaluation of certain parameters routinely
measured in studies of more current design. Deficiencies included: lack of
measurements of estrous cyclicity, sperm parameters, weights of uterus,
epididymides, seminal vesicles and brain and less than complete clinical
chemistry/hematology and histopathology. Water consumption was recorded in
Fo and F ia rats prior to mating, but not during gestation and lactation.
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Consequently, more accurate measures of offspring exposure could not be
developed. Statistical analyses were not performed by study investigators. In
addition, changes in the drinking water concentration of high-dose animals during
the last 2 weeks of Fo lactation of Fia litters from 3% to 0% and then to 2%
sec-butyl alcohol introduces some uncertainty in the exposure of high-dose
animals.
As stated in the IRIS summary for MEK (U.S. EPA, 2008b),
An uncertainty factor for extrapolation from a LOAEL to a NOAEL was not
necessary because BMD modeling was used to determine the point of departure.
The dose corresponding to a 5% decrease in pup weight, relative to control, was
selected as the point of departure. There is no specific decrement in fetal/pup
weight that is generally recognized as indicative of an adverse effect. Further,
there were no other effects in the range of the LED05 of 657 mg/kg-day.
Therefore, no further adjustments were considered for identifying a level of oral
exposure to sec-butyl alcohol associated with a minimal level of risk.
Consistent with U.S. EPA practice (U.S. EPA, 1991c), an UF was not used to
account for extrapolation from less-than-subchronic results because
developmental toxicity (decreased pup body weight following in utero and
neonatal exposure) was used as the critical effect. The developmental period is
recognized as a susceptible lifestage where exposure during certain time windows
of development are more relevant to the induction of developmental effects than
lifetime exposure.
The overall confidence in this RfD assessment is medium-to-low. As stated in the IRIS
summary for MEK (U.S. EPA, 2008b):
Confidence in the principal study is medium-to-low. The multigeneration
reproduction and developmental drinking water toxicity study of sec-butyl alcohol
defined a critical effect that is corroborated by inhalation exposure developmental
toxicity studies for sec-butyl alcohol and MEK. The principal study examined
appropriate reproductive, developmental and systemic toxicity endpoints in an
adequate number of rats exposed to control conditions or three dose levels and
identified NOAELs and LOAELs for maternal and developmental toxicity and a
NOAEL for reproductive toxicity. Lowering the drinking water concentration of
sec-butyl alcohol in the high-dose group from 3% to 2%, however, confounds the
ability to discern the dose level responsible for the observed developmental
effects. Furthermore, certain parameters routinely evaluated in studies of more
current design (e.g., estrous cyclicity, sperm parameters and uterine weight) were
not measured in Cox et al. (1975).
Confidence in the database is medium-to-low. The Cox et al. (1975) study includes investigation
of systemic toxicity endpoints, as well as reproductive and developmental toxicity.
Developmental effects were identified as the most sensitive endpoints. Similar developmental
effects were reported following inhalation exposure to both sec-butyl alcohol and MEK,
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providing support for the Cox et al. (1975) findings. However, the absence of oral data in a
second study or species precludes any higher level of database confidence. Reflecting the
medium-to-low confidence in the principal study and medium-to-low confidence in the database,
confidence in the subchronic p-RfD is medium-to-low.
Chronic p-RfD
Chronic toxicity testing of sec-butyl alcohol has not been conducted, indicating that the
subchronic RfD of 2 mg/kg-day provides the only basis for deriving a chronic RfD. No UF is
applied to the subchronic p-RfD to extrapolate from subchronic-to-chronic duration because
developmental toxicity is the critical effect. Consistent with U.S. EPA practice, the
developmental period is recognized as a susceptible lifestage where exposure during certain time
windows of development are more relevant to the induction of developmental effects than
lifetime exposure. Therefore, the chronic p-RfD is 2E+0 mg/kg-day, the same value as the
subchronic p-RfD.
Confidence in the subchronic toxicity study used to derive the chronic p-RfD is
medium-to-low as discussed in the subchronic p-RfD derivation. Confidence in the database is
low due to the lack of chronic data and for the reasons discussed in the subchronic p-RfD
derivation. Low confidence in the chronic p-RfD results.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC INHALATION
p-RfC VALUES FOR sec-BUTYL ALCOHOL
Inhalation RfC
The inhalation toxicity database for sec-butyl alcohol is limited to a single developmental
toxicity study in rats (Nelson et al., 1989). In this study, rats were exposed to sec-butyl alcohol
at concentrations of 0, 3500, 5000, or 7000 ppm for 7 hours/day on GDs 1-19. Maternal effects
include reduced food consumption and body-weight gain at > 3500 ppm and narcosis at
> 5000 ppm. Developmental effects include reduced fetal body weight at > 5000 ppm and
increased resorptions, decreased live fetuses, and increased skeletal variations at 7000 ppm. No
NOAEL and a LOAEL of 3500 ppm were identified for maternal toxicity based on reduced
body-weight gain. A NOAEL of 3500 ppm and LOAEL of 5000 ppm were identified for
developmental toxicity based on reduced fetal body weight.
The reduced fetal body weight provides an adequate basis for RfC derivation because
supporting MEK data indicate that developmental toxicity is likely to be a critical effect of sec-
butyl alcohol. As discussed previously, data from rats suggest that almost all of an oral dose of
sec-butyl alcohol is rapidly converted to MEK, indicating the plausibility that effects produced
by sec-butyl alcohol and MEK are caused by MEK or a subsequent metabolite common to both
chemicals. This plausibility is supported by the consistency of the finding of developmental
toxicity in rats exposed to sec-butyl alcohol by inhalation (Nelson et al., 1989) with similar
findings in inhalation developmental toxicity studies of MEK in rats and mice (Deacon et al.,
1981; Schwetz et al., 1974, 1991) and in the oral 2-generation reproductive and developmental
toxicity study of sec-butyl alcohol in rats (Cox et al., 1975). Critical effects in all of these
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studies include fetal weight deficits, and the relationships between air concentrations and the
degree of fetal weight changes are consistent for sec-butyl alcohol and MEK (U.S. EPA, 2003).
There is no clear evidence for other systemic effects resulting from inhalation exposure to
MEK (U.S. EPA, 2003). A subchronic inhalation study of MEK found no persistent
body-weight changes, gross behavioral changes, or histological changes in major tissues and
organs in rats exposed 6 hours/day, 5 days/week, for 90 days to concentrations as high as
5041 ppm (Cavender et al., 1983). Some changes in organ weight (including increased liver
weight and decreased brain weight) and clinical pathology parameters were observed; however,
these were not supported by histological changes. No central or peripheral neural histopathology
occurred in this study and other studies of shorter duration provide no convincing evidence that
repeated exposure to MEK, by itself, is capable of producing nerve degeneration or other
persistent neurological effects (Couri et al., 1974; Saida et al., 1976; Takeuchi et al., 1983). The
inhalation developmental toxicity studies found that repeated exposure of rats and mice to MEK
at approximately 3000 ppm (highest tested levels) produced no overt neurological effects in the
dams (Schwetz et al., 1974, 1991; Deacon et al., 1981) and narcosis only occurred at > 5000 ppm
in the maternal rats exposed to sec-butyl alcohol (Nelson et al., 1989). The available data also
provide no evidence for upper respiratory tract irritation or other portal-of-entry effects following
inhalation exposure to MEK at concentrations up to 6000 ppm (U.S. EPA, 2003).
As summarized above, developmental toxicity is a likely critical effect of inhaled
sec-butanol because (1) effects produced by sec-butyl alcohol and MEK are probably caused by
MEK or a subsequent metabolite common to both and (2) developmental toxicity is a
documented critical effect of inhaled MEK as well as ingested sec-butyl alcohol.
Subchronic p-RfC
The NOAEL of 3500 ppm (10,605 mg/m3) for reduced fetal body weight in rats
(Nelson et al., 1989) is used to derive the subchronic p-RfC. The lack of specificity regarding
sample size precludes BMD analysis of the fetal body-weight data.
The RfC is intended to apply to continuous lifetime exposures to humans (U.S. EPA,
1994b). Because the RfC values are often derived from studies using intermittent and
less-than-lifetime exposures, U.S. EPA has established guidance (U.S. EPA, 1994b) for adjusting
the exposures to an appropriate human equivalent via a simple concentration (C) x time (t)
relationship (e.g., 8 hours @ 300 ppm = 24 hours @ 100 ppm). For developmental studies, the
Guidelines for Developmental Toxicity Risk Assessment (U.S. EPA, 1991c) and the Reproductive
Toxicity Risk Assessment Guidelines (U.S. EPA, 1996) note that peak exposure may be a more
relevant exposure metric for short half-life compounds because the toxic effects may be due to
absolute concentration at a specific critical period during fetal development. Some more recent
studies suggest that area under the curve (AUC), the assumption underlying the C x t
relationship, may be a more appropriate metric for some developmental toxicants than peak
exposure. The latter has been demonstrated for certain agents with a short half-life in the body
(U.S. EPA, 2002). In consideration of this information, U.S. EPA recommends that adjusted
continuous exposures be used for inhalation developmental toxicity studies as for other health
effects from inhalation exposure (U.S. EPA, 2002).
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Duration adjustment is appropriate as the more health-protective procedure, unless there
are pharmacokinetic data suggesting that the adjustment to a continuous exposure equivalent is
inappropriate, or mode of action information suggests that a susceptible period of development is
specifically targeted (which would suggest that the peak dose may represent the effective dose).
In applying these considerations to sec-butyl alcohol, the critical effect is nonspecific
developmental toxicity (reduced fetal body weight), which suggests that duration adjustment
may be appropriate. Alternatively, the available pharmacokinetic data (oral) indicate that
sec-butanol is rapidly absorbed and metabolized, suggesting that duration adjustment may be less
appropriate than peak exposure. Overall, the available pharmacokinetic and mechanism of
action data for sec-butyl alcohol do not provide sufficient evidence to support the use of either
peak exposure level or AUC as the most appropriate metric for internal effective dose. Thus, it
is appropriate to apply a health-protective duration adjustment to time-weight the intermittent
exposures used in the principal study. The NOAEL of 3500 ppm (10,605 mg/m3) for reduced
fetal body weight in rats exposed to sec-butyl alcohol for 7 hours/day on days 1-19 of gestation
(Nelson et al., 1989) is adjusted from intermittent to continuous exposure as follows:
NOAELadj = 10,605 mg/m3 x 7 hours/24 hours
= 3093 mg/m3
Derivation of the p-RfC next involves converting the duration-adjusted rat NOAEL to a
human equivalent concentration (HEC). The U.S. EPA (1994b) procedure for calculating a HEC
for an extrarespiratory effect from a vapor is to multiply the duration-adjusted NOAEL by the
ratio of animal-to-human blood:air partition coefficients, as follows:
NOAELhec = NOAEL adj x (Hb/g)A/(Hb/g)H
= 3093 mg/m3 x 1
= 3093 mg/m3
where,
(Hb/g)A/(Hb/g)H = rat-to-human blood:air partition coefficient ratio
= default ratio of 1 because Hb/g values for sec-butyl alcohol were
not located.
The NOAELhec of 3093 mg/m3 is divided by a composite UF of 100 to derive a
•j
subchronic p-RfC of 3E+1 mg/m , as follows:
Subchronic p-RfC = NOAELhec UF
= 3093 mg/m3 - 100
= 30 or 3E+1 mg/m3
The composite UF of 100 includes component factors of 3 for interspecies extrapolation, 10 for
human variability, and 3 for database insufficiencies, as explained below.
• A partial UF of 3 (10°5) is used for interspecies extrapolation. This UF comprises
two areas of uncertainty: pharmacokinetics and pharmacodynamics. In this
assessment the pharmacokinetic component is addressed by the dosimetric
adjustment (i.e., calculation of the HEC according to the procedures in the RfC
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methodology (U.S. EPA, 1994b). Consequently, only the pharmacodynamic area
of uncertainty remains as a partial factor for interspecies extrapolation.
•	A 10-fold UF for intraspecies differences is used to account for potentially
susceptible individuals within the human population because information on the
variability in response of humans to sec-butyl alcohol or MEK exposure is not
available.
•	A partial UF of 3 (10°5) is used to account for database deficiencies. The
inhalation database for sec-butyl alcohol is limited to a single developmental
toxicity study in rats (Nelson et al., 1989), although supporting inhalation data on
MEK provide minimum database requirements for RfC derivation. The MEK
inhalation database includes a 90-day toxicity study in rats (Cavender et al., 1983)
and developmental toxicity studies in rats and mice (Deacon et al., 1981;
Schwetz et al., 1991). An inhalation multigeneration reproductive toxicity study
of MEK is lacking, although this database deficiency is partially addressed by the
oral 2-generation study of sec-butyl alcohol in rats (Cox et al., 1975).
Neurotoxicity is adequately addressed by the subchronic inhalation study
(Cavender et al., 1983), which includes examinations for both neurological
function and for central nervous system lesions with special neuropathological
procedures, but the MEK database lacks a developmental neurotoxicity study.
Consistent with U.S. EPA practice (U.S. EPA, 1991c), an UF is not used to account for
extrapolation from less-than-subchronic results because developmental toxicity resulting from a
narrow period of exposure (GD 1-19) is used as the critical effect. The developmental period is
recognized as a susceptible lifestage where exposure during certain time windows of
development are more relevant to the induction of developmental effects than lifetime exposure.
Confidence in the principal study is medium. The principal study examines appropriate
developmental toxicity endpoints in an adequate number of rats exposed to control conditions or
three exposure levels and identified aNOAEL and LOAEL for developmental toxicity and a
LOAEL for maternal toxicity, but a NOAEL for maternal toxicity is not identified and the data
for the critical effect (fetal body weight) is incompletely reported (precluding BMD analysis).
Confidence in the database is medium-to-low. The inhalation developmental toxicity study of
sec-butyl alcohol defined a critical effect that is corroborated by inhalation developmental
toxicity studies for MEK and an oral multigeneration reproductive and developmental toxicity
study for sec-butyl alcohol. Although similar developmental effects were reported following
oral exposure to sec-butyl alcohol and by inhalation exposure to MEK, the absence of any
subchronic inhalation data for sec-butyl alcohol precludes any higher level of database
confidence. Reflecting the medium confidence in the principal study and medium-to-low
confidence in the database, confidence in the subchronic p-RfC is medium-to-low.
Chronic p-RfC
Chronic toxicity testing of sec-butyl alcohol (or MEK) has not been conducted, indicating
"3
that the subchronic p-RfC of 30 mg/m provides the only basis for deriving a chronic RfC. No
UF is applied to the subchronic RfC to extrapolate from subchronic-to-chronic duration because
developmental toxicity is the critical effect. Consistent with U.S. EPA practice, the
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developmental period is recognized as a susceptible lifestage where exposure during certain time
windows of development are more relevant to the induction of developmental effects than
lifetime exposure. Therefore, the chronic p-RfC is 3E+1 mg/m3—the same value as the
sub chronic RfC.
Confidence in the developmental toxicity study used to derive the chronic p-RfC is
medium as discussed in the subchronic RfC derivation. Confidence in the database is low due to
the lack of chronic data and for the reasons discussed in the subchronic p-RfC derivation. Low
confidence in the chronic p-RfC follows.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR sec-BUTYL ALCOHOL
There are no human or animal carcinogenicity data for sec-butyl alcohol.
As stated in the Toxicological Review of MEK (U.S. EPA, 2003),
Epidemiological studies of MEK-exposed workers provide no clear evidence of a
cancer hazard (Alderson and Rattan, 1980; Wen et al., 1985; Spirtas et al., 1991;
Blair et al., 1998), but the studies are generally inadequate to discern an
association between MEK exposure and an increased incidence of cancer...
Overall, the epidemiologic evidence from which to draw conclusions about
carcinogenic risks of MEK in the human population is inconclusive. Although
there is some suggestion of increased risk for certain cancers (including bone and
prostate) involving multiple solvent exposures that include MEK, there is no clear
evidence for a relationship between these cancers and MEK exposure alone.
(p. 23)
The only information on the carcinogenicity of MEK in animals is a dermal application
study that is an inadequate test of MEK's potential carcinogenicity due to concomitant exposure
to chemicals that are expected to accelerate the rate of skin tumor formation
(Horton et al., 1965). SAR analysis suggests that MEK is unlikely to be carcinogenic based on
the absence of any structural alerts indicative of carcinogenic potential (Woo et al., 2002).
The mutagenicity of sec-butanol has been tested in bacteria, yeast, and mammalian cells
with negative results. When tested in vitro with and without metabolic activation, sec-butyl
alcohol did not induce reverse mutations in Salmonella typhimurium or Escherichia coli, mitotic
gene conversions in Saccharomyces cerevisiae or chromosome damage in Chinese hamster
ovary cells (Brooks et al., 1988; Shell Oil Company, 1986).
The preponderance of studies of MEK yielded no evidence of mutagenicity. As stated in
the IRIS summary for MEK (U.S. EPA, 2008b),
In vitro tests showed that MEK was not genotoxic in Salmonella typhimurium
(with or without metabolic activation), the L5178/TK+/" mouse lymphoma assay
or the B ALB/3T3 cell transformation assay and did not induce unscheduled DNA
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synthesis in rat primary hepatocytes or chromosome aberrations or sister
chromatid exchange (Florin et al., 1980; Douglas et al., 1980; O'Donoghue et al.,
1988; NTP, undated; Zeiger et al., 1992). Micronuclei were not induced in the
erythrocytes of mice (O'Donoghue et al., 1988) or hamsters (WHO, 1992) after
intraperitoneal injection with MEK. The only evidence of genotoxicity was
mitotic chromosome loss at a high concentration in a study on aneuploidy in the
diploid D61, M strain of the yeast Saccharomyces cerevisiae (Zimmerman et al.,
1985); the relevance of this positive result to humans is unknown, (p. 48)
In accordance with current U.S. EPA cancer guidelines (U.S. EPA, 2005), the available
data are inadequate for an assessment of human carcinogenic potential of sec-butanol.
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