United States
Environmental Protection
1=1 m m Agency
EPA/690/R-11/062F
Final
4-01-2011
Provisional Peer-Reviewed Toxicity Values for
1,1,2-Trichloroethane
(CASRN 79-00-5)
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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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Jon Reid, PhD., DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
SRC, Inc.
7502 Round Pond Road
North Syracuse, NY 13212
PRIMARY INTERNAL REVIEWERS
Harlal Choudhury, DVM, Ph.D., DABT
National Center for Environmental Assessment, Cincinnati, OH
John Stanek, Ph.D.
National Center for Environmental Assessment, Research Triangle Park, NC
This document was externally peer reviewed under contract to
Eastern Research Group, Inc.
110 Hartwell Avenue
Lexington, MA 02421-3136
Questions regarding the contents of this document may be directed to the U.S. EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center (513-569-7300)

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TABLE OF CONTENTS
COMMONLY USED ABBREVIATIONS	ii
BACKGROUND	1
HISTORY	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVS	2
INTRODUCTION	2
REVIEW 01 PERTINENT DATA	3
HUMAN STUDIES	3
ANIMAL STUDIES	3
Oral Exposure	3
Subchronic-duration Studies	3
Chronic-duration Studies	4
Reproductive/devel opmental Studi es	5
Inhalation Exposure	5
Subchronic-duration Studies	5
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC ORAL RfD
VALUES I OR 1,1,2-TRICHLOROETHANE	8
SUBCHRONIC p-RlD	8
CHRONIC p-RlD	9
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC INHALATION
RfC VALUES I OR 1,1,2-TRICHLOROETHANE	9
PROVISIONAL CARCINOGENICITY ASSESSMENT FOR
1,1,2-TRICHLOROETHANE	9
REFERENCES	10
APPENDIX A. DERIVATION OF A SCREENING VALUE FOR
1,1,2-TRICHLOROETHANE	13
APPENDIX B. DETAILS OF BENCHMARK DOSE MODELING FOR SCREENING
SUBCHRONIC p-RfC	17
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMD
benchmark dose
BMCL
benchmark concentration lower bound 95% confidence interval
BMDL
benchmark dose lower bound 95% confidence interval
HEC
human equivalent concentration
HED
human equivalent dose
IUR
inhalation unit risk
LOAEL
lowest-observed-adverse-effect level
LOAELadj
LOAEL adjusted to continuous exposure duration
LOAELhec
LOAEL adjusted for dosimetric differences across species to a human
NOAEL
no-ob served-adverse-effect level
NOAELadj
NOAEL adjusted to continuous exposure duration
NOAELrec
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 reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
POD
point of departure
RfC
reference concentration (inhalation)
RfD
reference dose (oral)
UF
uncertainty factor
UFa
animal-to-human uncertainty factor
UFC
composite uncertainty factor
UFd
incomplete-to-complete database uncertainty factor
UFh
interhuman uncertainty factor
UFl
LOAEL-to-NOAEL uncertainty factor
UFS
subchronic-to-chronic uncertainty factor
WOE
weight of evidence
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PROVISIONAL PEER-REVIEWED TOXICITY VALUES FOR
1,1,2-TRICHLOROETHANE (CASRN 79-00-5)
BACKGROUND
HISTORY
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA) 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 (PPRTVs) 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 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 multiprogram 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 5-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 documents 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 Resource Conservation and Recovery Act (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.
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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 document 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 IRIS database (U.S. EPA, 2010a) lists an RfD of 4 x 10 3 mg/kg-day for
1,1,2-trichloroethane (verified 1988) based on aNOAEL of 3.9 mg/kg-day for serum chemistry
changes indicative of hepatotoxicity in female mice exposed to the chemical in the drinking
water for 90 days (Sanders et al., 1985; White et al., 1985) and a composite uncertainty factor
(UFC) of 1000 (10 each for use of a sub chronic-duration study, extrapolation from mice to
humans, and protection of sensitive individuals). This RfD is also included on the Drinking
Water Standards and Health Advisories list (U.S. EPA, 2006); the source is a Drinking Water
Health Advisory document (U.S. EPA, 1989). The Chemical Assessments and Related
Activities (CARA) list (U.S. EPA, 1991, 1994a) also includes a Health Effects Assessment for
1,1,2-Trichloroethane (U.S. EPA, 1984) that does not, however, incorporate a noncancer toxicity
assessment. The HEAST (U.S. EPA, 2010b) refers to IRIS for the RfD and lists a subchronic
RfD of 4 x 10~2 mg/kg-day based on the same NOAEL—but with the UFC reduced to 100
without the 10-fold factor for extrapolation to a chronic duration. ATSDR (1989) derived an
intermediate oral minimal risk level (MRL) (analogous to a subchronic RfD) of
4 x 10 2 mg/kg-day by the same method. The World Health Organization (WHO, 2008) has not
evaluated the toxicity of 1,1,2-trichloroethane.
An RfC for 1,1,2-trichloroethane is not available on the IRIS (U.S. EPA, 2010a) database
or on the HEAST (U.S. EPA, 2010b). ATSDR (1989) declined to derive MRLs for inhalation
exposure to 1,1,2-trichloroethane. The American Conference of Governmental Industrial
Hygienists (ACGIH, 2001, 2007), the National Institute for Occupational Safety and Health
(NIOSH, 2008), and the Occupational Safety and Health Administration (OSHA, 2008) all list
time-weighted average (TWA) occupational exposure levels of 10 ppm (55 mg/m3) for
1,1,2-trichloroethane to protect against central nervous system depression, eye and upper
respiratory tract irritation, and liver damage.
IRIS includes a cancer assessment for 1,1,2-trichloroethane (verified 7-23-86) in which
the chemical was assigned to cancer weight-of-evidence (WOE) Group C (Possible Human
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Carcinogen) and both an oral slope factor (OSF; 5.7 x 10 2 per mg/kg-day) and an inhalation
unit risk (IUR; 1.6 x io~5 per |ig/m3) were derived based on an increased incidence of
hepatocellular carcinoma in B6C3Fi mice administered the test material by gavage for 78 weeks
(National Cancer Institute [NCI], 1978). The International Agency for Research on Cancer
(IARC, 1991, 1999) classified 1,1,2-trichloroethane as Group 3 (Unclassifiable) with respect to
carcinogenicity in humans based on no human data and limited evidence of carcinogenicity in
animals (hepatocellular neoplasms and adrenal pheochromocytomas in male and female B6C3Fi
mice in the NCI, 1978 study). 1,1,2-Trichloroethane is not included in the National Toxicology
Program (NTP, 2005) 11th Report on Carcinogens.
Literature searches were conducted on sources published from 1960 through
September 2010 for studies relevant to the derivation of provisional toxicity values for
1,1,2-trichloroethane. Databases searched include MEDLINE, TOXLINE (Special), BIOSIS,
TSCATS 1/TSCATS 2, CCRIS, DART/ETIC, GENETOX, HSDB, RTECS, and Current
Contents (last 6 months). An Organisation for Economic Co-operation and Development
Screening Information Data Set (OECD SIDS) submission on 1,1,2-trichloroethane from the
Japanese Ministry of Foreign Affairs (1999) was also reviewed for relevant data.
REVIEW OF PERTINENT DATA
HUMAN STUDIES
No relevant data were located regarding the toxicity of 1,1,2-trichloroethane to humans
following oral or inhalation exposure.
ANIMAL STUDIES
Oral Exposure
Subchronic-duration Studies
Groups of male and female CD-I mice (16/sex/group) were exposed to
1,1,2-trichloroethane in the drinking water for 90 days at concentrations of 20, 200, or
2000 mg/L, which the study authors equated to dosages of 0, 4.4, 46, and 305 mg/kg-day for
males and 0, 3.9, 44, and 384 mg/kg-day for females (White et al., 1985; Sanders et al., 1985).
Groups of 24 mice of each sex served as controls. Endpoints assessed included water
consumption, body weight, selected organ weights, hematology, serum chemistry, hepatic
microsomal activity, and humoral and cell-mediated immune status. Body-weight gain over the
90-day study was significantly reduced by 35% in high-dose males and corresponded with a
significant 35-40% decrease in water consumption in this group. Terminal body weight was
reduced 10% in the high-dose males compared with controls. There was no effect on body
weight or water consumption in males of other dose groups or in females. Hematological
findings, highlighted by slight (5—6%) statistically significant reductions in hemoglobin and
hematocrit in high-dose females, were generally unremarkable. Serum enzyme changes of note
included significant increases in cholesterol in high-dose males and females (30—35%), alkaline
phosphatase (ALP) in high-dose males (60%) and females of all dose groups (20-40%, not
increasing with dose), aspartate aminotransferase (AST or SGOT) in females of all dose groups
(30-40%), not increasing with dose), and alanine aminotransferase (ALT or SGPT) in high-dose
females (63%). Liver glutathione was significantly reduced by 16% in mid-dose males and 28%
in high-dose males. In females, liver glutathione was not reduced and was actually significantly
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increased in the high-dose group. Assays for microsomal enzyme activity showed no evidence
of enzyme induction in males or females; there were significant decreases in cytochrome P-450
levels and aniline hydroxylase activity in mid- and high-dose females. Both absolute and
relative liver weights were significantly increased by approximately 30% in high-dose females;
other organ-weight changes in females were unremarkable. Organ-weight changes in males
were secondary to the effect on body weight. Immunological evaluations revealed no effects on
cell-mediated immunity (delayed-type hypersensitivity and popliteal lymph node proliferation
responses to sheep red blood cells), but humoral immune status was depressed, as indicated by
significant dose-related decreases in hemagglutination titers in mid- and high-dose males and
females, and significantly decreased spleen lymphocyte responsiveness to the B-cell mitogen
lipopolysaccharide in high-dose females. Macrophage function was significantly decreased in
high-dose males, as indicated by the ability of peritoneal macrophages to phagocytize sheep red
blood cells.
In this study (White et al., 1985; Sanders et al., 1985), the high-dose of
305-384 mg/kg-day produced reduced body-weight gain secondary to reduced water
consumption in male mice, and mild toxicity to the liver in mice of both sexes, as indicated by
increases in serum cholesterol in males and females, ALP in males, ALT in females, and liver
weight in females (without evidence of hepatic microsomal enzyme induction). Smaller
increases in ALP and AST in female mice of all dose groups did not increase with dose and are
not considered to be related to treatment. Binding with glutathione is a detoxification pathway
for 1,1,2-trichloroethane (ATSDR, 1989). As the dose of such a chemical increases, more
glutathione is used to detoxify the chemical, and glutathione stored in the liver can become
depleted. Toxic effects may become evident when the functional reserve capacity of the liver is
exceeded. Depletion of liver glutathione, then, is not a toxic effect itself, but a biochemical
change that can serve as a marker for toxicity. The data from male mice in this study suggest
that toxic effects on the liver can occur with -30% depletion of liver glutathione (as in the
high-dose group). The absence of evidence for any hepatotoxic effects in mid-dose male mice
suggests that the 16% depletion of glutathione in this group is within the functional reserve
capacity of the mouse liver for this chemical. Therefore, the 16% decrease in glutathione levels
is not an adverse effect by itself, nor is it evidence that an adverse effect will be produced at this
dose level. (It is not clear how to interpret the increase in glutathione levels in high-dose
females.) Effects on microsomal enzyme activity reported in mid- and high-dose females are
also considered to be biochemical changes that are not clearly adverse. Immunotoxicity assays
found some results suggesting suppression of immune function by 1,1,2-trichloroethane in the
mid- and high-dose groups, although not all of the tests produced consistent results. In
conclusion, this study authors identified a NOAEL of 3.9 mg/kg-day and a LOAEL of
44 mg/kg-day based on hepatic and immunological effects. The study was limited by the
relatively large number of sporadic and inconsistent findings and failure to evaluate
histopathology.
Chronic-duration Studies
In a chronic-duration cancer bioassay by NCI (1978), rats and mice were administered
1,1,2-trichloroethane by gavage in corn oil for 78 weeks. Groups of Osborne-Mendel rats
(50/sex/group) initially received doses of 30 or 70 mg/kg-day, 5 days/week. At Week 20, doses
were increased to 50 and 100 mg/kg-day, respectively. Groups of B6C3Fi mice (50/sex/group)
were initially given 150 or 300 mg/kg-day, 5 days/week. At Week 20, the doses were increased
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to 200 and 400 mg/kg-day, respectively. Untreated and vehicle controls (20/sex/species/group)
were included. No treatment-related nonneoplastic lesions were reported in any groups of rats or
mice. Both sexes of mice had dose-related increases in incidence of hepatocellular carcinoma;
these results are the basis for the verified WOE classification and the OSF and the IUR that
appear on the IRIS database (U.S. EPA, 2010a).
Reproductive/developmental Studies
In a developmental toxicity screen, groups of 30 pregnant female ICR/SIM mice were
treated with 0 or 350 mg/kg-day of 1,1,2-trichloroethane by gavage in corn oil on Days 8-12 of
gestation and allowed to litter (Seidenberg et al., 1986). A total of three dams died in the treated
group versus none in the controls. It is not clear whether these deaths were due to chemical
toxicity. Body-weight gain in the dams did not differ between the two groups. There were a
total of 30 litters in the control group and 25 litters in the treated group, with no resorbed litters.
There were no effects on pup survival or body weight, monitored up to Postnatal Day (PND) 3.
This study found no evidence for developmental toxicity by 1,1,2-trichloroethane at
350 mg/kg-day.
Inhalation Exposure
Subchronic-duration Studies
Groups of 8-week-old Fischer 344 CDF (F344) Crl:BR rats (10/sex/group) were exposed
by whole-body inhalation to 0 (filtered air), 15, 40, or 100 ppm of 1,1,2-trichloroethane
(99.55% pure) vapor (measured concentrations) 6 hours/day, 5 days/week, for 13 weeks
(minimum of 65 exposures) in an unpublished study (WIL Research Laboratories, 2002).
Duration-adjusted concentrations in mg/m3 were 0, 14.6, 39.0, and 97.5 mg/m3 (e.g.,
15 ppm x 5.46 mg/m3 per ppm x 6/24 hours x 5/7 days = 14.6 mg/m3). Rats were observed
daily; detailed clinical examinations and body-weight and food consumption measurements were
performed weekly. Ophthalmic examinations were made before exposure and near study
termination. Hematology and serum chemistry variables were assessed prior to study
termination. Comprehensive necropsies were conducted for all animals. Organ weights were
evaluated for adrenals, brain, epididymides, heart, kidneys, liver, lungs, ovaries, spleen, testes,
thymus, and thyroids/parathyroids. Comprehensive microscopic evaluations were made for all
control and high-dose rats, as well as for larynx, kidneys, liver, lungs, nasal tissues, trachea, and
gross lesions from all animals in the 15- and 40-ppm test groups. In the only notable deviation
from the test protocol, on Day 56 of the study, control rats were inadvertently exposed to
15 ppm, and the 15-ppm group rats were inadvertently placed in the control chamber for the
6-hour exposure period.
There was no dose-related effect on mortality, and no clinical signs related to treatment
were observed (WIL Research Laboratories, 2002). A female rat in the 15-ppm group was
sacrificed in extremis on Day 30 of the study with red discharge around the eyes, decreased
defecation, and impaired use of hind limbs; however, the study authors did consider these effects
to be related to treatment because they occurred in a low-dose rat, and no similar observations
were made in any of the rats exposed to higher concentrations. No other mortality or sacrifices
in extremis occurred. Other than a small, transitory decrease in body weight (-6%) and food
consumption in high-dose females at the end of the first week of the study, the data showed no
time- or dose-related adverse effects on body weight or food consumption. Ophthalmology was
unaffected. The data showed no treatment-related effects on hematological variables. The only
statistically significant effects on serum chemistry were slight increases in mean cholesterol in
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mid- and high-dose females (+15-16%) and high-dose males (+19%) and a slight decrease in
mean glucose in high-dose females (—14%). The data showed no treatment-related findings with
regard to organ weights. Gross necropsy results were unremarkable. Histopathological
evaluations showed hepatocellular vacuolation in 3/10 females each in the 15- and 40-ppm
treatment groups and in 5/10 males and 10/10 females in the 100-ppm treatment groups. The
control incidences (and low- and mid-dose male incidences) were not reported but presumably
were 0/10. Vacuolation was characterized by focal-to-multifocal distribution of small vacuoles
in the cytoplasm of hepatocytes. No special staining techniques were used to identify the
material in the vacuoles, but the researchers considered the morphology of the vacuoles to be
consistent with lipid accumulation. The severity of vacuolation was graded as minimal in all
dose groups, with no change in severity with dose. There were no other microscopic findings in
hepatocytes. Lesions of the olfactory epithelium, including vacuolation/microcyst formation,
atrophy, and respiratory epithelial metaplasia, were found predominantly in the 40- and 100-ppm
treatment groups. More detailed discussions of these lesions and associated incidence data are
presented in Table 1. There were no other treatment-related histopathological findings in
exposed rats.
Hepatocellular vacuolation and increased serum cholesterol were both observed in
mid-dose females and high-dose males and females. Both observations are consistent with
changes in lipid handling in the liver. However, vacuolation was of minimal severity in all
groups, and cholesterol increases were likewise small in all groups. There were no indications of
more clearly adverse changes in the liver by gross or histopathological examination,
organ-weight measurement, or serum chemistry (e.g., ALP, ALT, AST) at any exposure level
tested. Given the minimal nature of the observed liver changes and lack of progression to more
clearly adverse effects with increasing exposure level, the observed liver changes are not
considered to be toxicologically significant. The study authors reached the same conclusion. In
contrast, the nasal lesions represent a spectrum of effects ranging from vacuolation/microcyst
formation at all exposure levels to more clearly adverse effects such as atrophy at 40 ppm and
metaplasia at 100 ppm. The researchers considered vacuolation/microcyst formation in the
olfactory epithelium to be "probably degenerative in nature." Because the incidence of
vacuolation/microcysts in the 15-ppm group was low and the more clearly adverse lesions were
found only at 40 ppm and above, the study authors characterized the low-exposure concentration
of 15 ppm as a NOAEL. A LOAEL of 40 ppm (LOAELadj = 39.0 mg/m3) and a NOAEL of
15 ppm (NOAELadj = 14.6 mg/m3) are identified for this study based on nasal lesions in the
olfactory epithelium of exposed rats.
In an unpublished study by Dow Chemical Company (briefly summarized by ACGIH,
2001; ATSDR, 1989; U.S. EPA, 1984), unspecified numbers of male and female rats, guinea
pigs, and rabbits were exposed to 1,1,2-trichloroethane vapors at a concentration of 15 ppm,
7 hours/day, 5 days/week, for 6 months. No treatment-related adverse effects were noted
regarding growth, mortality, organ weight, hematology, or clinical chemistry. Nor were there
indications of treatment-related histopathologic changes. Female rats exposed to a
1,1,2-trichloroethane vapor concentration of 30 ppm, 7 hours/day, for 16 days, had minor fatty
changes and cloudy swelling in the liver, but male rats appeared unaffected. The secondary
accounts of these unpublished studies do not provide sufficient detail to provide a basis for an
RfC for 1,1,2-trichloroethane.
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Table 1. Incidence of Lesions in the Olfactory Epithelium in Rats Exposed by
Inhalation to l,l?2-Trichloroethanea

Concentration (ppm)
Endpoint/Sex
0
15
40
100
Male
Vacuolation/microcystsb
1/10
2/10°
6/10°
10/10cd
Atrophy®
0/10
0/10
6/10c,d
7/10c'd
Metaplasiaf
0/10
1/108
l/10c
3/10°
Female
Vacuolation/microcystsb
1/10
4/10°
4/10°
8/10cd
Atrophy®
0/10
0/10
7/10c'd
10/10cd
Metaplasiaf
0/10
0/10
l/10c
5/10cd
"WIL Research Laboratories, 2002; incidence represents number of individuals affected/number examined; six
sections (levels) were examined for each animal; no further details for the section levels were described in the
report.
bSmall focal-to-multifocal vacuoles or microcysts primarily concentrated in the epithelium of the nasal septum in the
dorsal medial meatus (Section Levels 2-5, except in low-concentration groups). Vacuoles were generally devoid
of material with occasional eosinophilic globular material.
"Highlighted by study authors as "test article-related" based on details of examined sections (six/rat) and dose
response.
Statistically significant difference from control (p < 0.05) by Fisher's Exact test performed for this review.
"Thinning of olfactory epithelium due primarily to reduced thickness of nuclear cell layer; minimal-to-mild severity
in Section Levels 3, 4, and 5; focal in distribution; affecting primarily the epithelium of the nasal septum in the
dorsal medial meatus. The mechanism of cell loss was not obvious.
fFocal areas of metaplastic change from olfactory to respiratory epithelium; Section Levels 4 and 5.
8Not considered by study authors to be related to exposure; associated with inflammation within the nasal cavity
and, therefore, interpreted to be spontaneous in origin.
A single male dog and 24 Sprague-Dawley rats (12/sex) were exposed to
1,1,2-trichloroethane at a target vapor concentration of 100 ppm (mean measured concentration
of 84 ppm), 7 hours/day (on alternate days), for up to 6 months (Mellon Institute, 1947).
Air-exposed animals (1 dog and 12 rats/sex) served as controls. Endemic lung infection in the
entire rat colony resulted in high mortality among treated and control rats (57 and 62%,
respectively) during the study and rendered it unusable for determining the toxicity of
1,1,2-trichloroethane. The treated dog exhibited a 13.2% decrease in body-weight gain relative
to the control dog, but no obvious treatment-related effects on hematology or clinical chemistry,
and no pathological signs. Inclusion of only a single treated dog is an obvious limitation of this
study.
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DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR 1,1,2-TRICHLOROETHANE
SUBCHRONIC p-RfD
The sub chronic-duration mouse study (White et al., 1985; Sanders et al., 1985) identified
the liver and immune systems as sensitive targets of 1,1,2-trichloroethane toxicity. A NOAEL of
3.9 mg/kg-day and a LOAEL of 44 mg/kg-day were defined by a WOE for hepatotoxicity
(significant increases in serum cholesterol in high-dose males and females, ALP in high-dose
males, ALT in high-dose females, and liver weight [without evidence of enzyme induction] in
high-dose females) and depressed immune status (significant dose-related decreases in
hemagglutination titers in mid- and high-dose males and females, spleen lymphocyte
responsiveness to the B-cell mitogen lipopolysaccharide in high-dose females, and macrophage
function in high-dose males). Because the toxic effects were identified as the WOE of a number
of different specific endpoints and it is unclear to what extent the individual immunological
assays can be considered reliable markers of immunotoxicity, benchmark dose (BMD) modeling
of individual test results was not performed. There is support for the liver as a sensitive target
for 1,1,2-trichloroethane from acute and injection studies (ATSDR, 1989). The chronic-duration
NCI (1978) study observed hepatocellular carcinomas in mice, which also supports the liver as a
target for 1,1,2-trichloroethane. This study did not report noncancer lesions in the liver, but the
study was conducted primarily as a cancer bioassay, and the extent of the evaluation for
noncancer lesions is unclear. The Seidenberg et al. (1986) study, although only a screen,
suggests that the developing fetus is not a critical target for 1,1,2-trichloroethane toxicity.
A subchronic p-RfD is derived by applying a UFC of 1000 to the NOAEL of
3.9 mg/kg-day as follows:
Subchronic p-RfD = NOAEL ^ UFC
= 3.9 mg/kg-day ^ 1000
= 0.004 or 4 x 10~3 mg/kg-day
The UFC of 1000 is composed of the following:
•	A UFa of 10 for interspecies extrapolation was applied to account for potential
pharmacokinetic and pharmacodynamic differences between mice and humans.
•	A UFh of 10 for intraspecies differences was applied to account for potentially
susceptible individuals in the absence of information on the variability of
response in humans.
•	A UFd of 10 was applied to account for deficiencies in the database. The
database includes limited subchronic-duration, chronic-duration, and
developmental toxicity studies. The database lacks complete systemic toxicity
data (most notably, histopathology), a complete developmental toxicity study, and
a multigeneration reproduction study.
Confidence in the critical study is low to medium. The study included an adequate
number of mice of each sex and an adequate number of dose groups and identified both a
NOAEL and a LOAEL. The study was limited by a relatively large number of sporadic and
inconsistent findings, and failure to perform histopathological examination. Confidence in the
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database is low due to the lack of reproductive testing, limited developmental toxicity testing,
and absence of other adequate chronic- or subchronic-duration systemic toxicity studies. Overall
confidence in the subchronic p-RfD is low.
CHRONIC p-RfD
A verified (1988) RfD of 4 x 10 3 mg/kg-day for 1,1,2-trichloroethane is posted on the
IRIS database (U.S. EPA, 2010a). The RfD is based on a LOAEL of 44 mg/kg-day and a
NOAEL of 3.9 mg/kg-day in mice in the 90-day drinking water study (Sanders et al., 1985;
White et al., 1985) and a UFC of 1000 (10 each for use of a subchronic-duration study,
extrapolation from mice to humans, and protection of sensitive individuals). A UFD was not
included, as this RfD was derived before application of a UFD became standard practice.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR 1,1,2-TRICHLOROETHANE
No subchronic or chronic p-RfC can be derived for the following reason: the only
suitable study for deriving RfC values is a nonpeer-reviewed rat study by WIL Research
Laboratories (2002). A screening subchronic and chronic p-RfC are developed in Appendix A.
Please see the attached Appendix A for details.
PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR 1,1,2-TRICHLOROETHANE
IRIS (U.S. EPA, 2010a) posts a cancer assessment for 1,1,2-trichloroethane (verified
7-23-86) that assigns a cancer WOE Group C (Possible Human Carcinogen); this classification
is based on statistically significant increases in hepatocellular carcinoma in B6C3Fi mice and
pheochromocytomas in female B6C3Fi mice (NCI, 1978). IRIS posts an OSF
(5.7 x 10~2 per mg/kg-day) and an IUR (1.6 x io~5 per |ig/m3); both are based on an increased
incidence of hepatocellular carcinoma in B6C3Fi mice administered the test material by gavage
for 78 weeks (NCI, 1978).
Recently, a PBPK model for 1,1,2-trichloroethane in rats and mice was developed (The
Sapphire Group, 2003) based on previous work (Gargas and Andersen, 1989) and new
experimental studies (Poet et al., 2003). The model was applied for route-to-route extrapolation
of the NCI (1978) cancer data from oral-to-inhalation exposure (The Sapphire Group, 2004).
The model predicted that the 195-mg/kg-day (5 days/week) cancer LOAEL in mice in the NCI
(1978) study was equivalent to a continuous inhalation exposure concentration of 27 ppm in
female mice.
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of the threshold limit values for chemical substances. 7th Edition. Cincinnati, OH: ACGIH.
ACGIH (American Conference of Governmental Industrial Hygienists). (2007) Threshold limit
values for chemical substances and physical agents and biological exposure indices. Cincinnati,
OH: ACGIH.
ATSDR (Agency for Toxic Substances and Disease Registry). (1989) Toxicological profile for
1,1,2-Trichloroethane. U.S. Department of Health and Human Services, Public Health Service,
Atlanta, GA. Available online at http://www.atsdr.cdc.gov/toxprofiles/tpl48.pdf.
Gargas, ML; Andersen, ME. (1989) Determining kinetic constants of chlorinated ethane
metabolism in the rat from rates of exhalation. Toxicol ApplPharmacol 99(2):344-353.
IARC (International Agency for Research on Cancer). (1991) 1,1,2-Trichaloroethane (group 3).
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Compounds; Cobalt and Cobalt Compounds. Summary of data and evaluation. IARC
Monographs on the Evaluation of Carcinogenic Risks to Humans, Vol 52. Lyon: IARC, pp. 337.
Available online at http://monographs.iarc.fr/ENG/Monographs/vol52/volume52.pdf.
IARC (International Agency for Research on Cancer). (1999) 1,1,2-Trichloroethane (group 3).
In: Re-evaluation of Some Organic Chemicals, Hydrazine and Hydrogen peroxide. Summary of
Data and Evaluation. IARC Monographs on the Evaluation of Carcinogenic Risks to Humans,
Vol 71. Lyon: IARC, pp. 1153.
Japan Ministry of Foreign Affairs. (1999) 1,1,2-Trichloroethane. OECD/SIDS (Organisation
for economic co-operation and development/Screening information data set) submission. United
Nations Environmental Programme Publications. Available online at
http://www.inchem.org/documents/sids/sids/79005.pdf.
Mellon Institute. (1947) Repeated exposure of rats and dogs to vapors of eight chlorinated
hydrocarbons. TSCA 8d Submission. Fiche # OTS0515559. Submitting organization: Union
Carbide Corporation.
NCI (National Cancer Institute). (1978) Bioassay of 1,1,2-Trichloroethane for possible
carcinogenicity. CAS# 79-00-5. NCI-GC-TR-74. U.S. Department of Health, Education and
Welfare, Public Health Service, Bethesda, MD. Available online at
http://ntp.niehs.nih.gov/ntp/htdocs/LT rpts/tr074.pdf.
NIOSH (National Institute for Occupational Safety and Health). (2008) NIOSH pocket guide to
chemical hazards. Available online at http://www.cdc.gov/niosh/npg/.
NTP (National Toxicology Program). (2005) 11th Report on Carcinogens. U.S. Department of
Health and Human Services, Public Health Service, National Institutes of Health, Research
Triangle Park, NC. Available online at http://ntp-server.niehs.nih.gov/index.cfm?obiectid=
32BA9724-F1F6-975E-7FCE50709CB4C932.
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OSHA (Occupational Safety and Health Administration). (2008) Table Z-l limits for air
contaminants: occupational safety and health standards, subpart Z, toxic and hazardous
substances. U.S. Department of Labor, Washington, DC. OSHA Standard 1910.1000.
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http://63.234.227.130/pls/oshaweb/owadisp.show document?p table=STANDARDS&
p id=9992.
Poet, TS; Curry, TL; Luders, TM; et al. (2003) Pharmacokinetics of 1,1,2-trichloroethane in
rats and mice. Battelle Project No. 41608. June 10, 2003. Amended Final Report. (Cited in The
Sapphire Group, 2004).
Sanders, VM; White, KL, Jr; Shopp, GM; et al. (1985) Humoral and cell-mediated immune
status of mice exposed to 1,1,2-trichloroethane. Drug Chem Tox 8(5):357-372.
Seidenberg, JM; Anderson, DG; Becker, RA. (1986) Validation of an in vivo developmental
toxicity screen in the mouse. Teratog CarcinogMutagen 6(5):361-374.
The Sapphire Group. (2003) Physiologically based pharmacokinetic model development,
simulations, and sensitivity analysis for repeated exposure to 1,1,2-trichloroethane. Revised
final report. July 7, 2003, Dayton, OH. (Cited in The Sapphire Group, 2004).
The Sapphire Group. (2004) Route-to-route extrapolation of 1,1,2-trichloroethane studies from
the oral route to inhalation using physiologically based pharmacokinetic models: carcinogenicity.
January 19, 2004, Dayton, Ohio.
U.S. EPA (Environmental Protection Agency). (1984) Health effects assessment for
1,1,2-trichloroethane. Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste and
Emergency Response, Washington, DC. EPA 540/1-86/045.
U.S. (Environmental Protection Agency). 1989. Drinking water health advisory for
1,1,2-trichloroethane. Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking Water,
Washington, DC. EPA/820/K-89/105.
U.S. (Environmental Protection Agency). 1991. Chemical assessments and related activities
(CARA). Office of Health and Environmental Assessment, Washington, DC.
U.S. EPA (Environmental Protection Agency). 1994a. Chemical assessments and related
activities (CARA). Office of Health and Environmental Assessment, Washington, DC.
EPA/600/R-94/904. Available online at
nepis.epa.gov/Exe/ZvPURL.cgi?Dockev=60001G8L.txt.
U.S. EPA (Environmental Protection Agency). 1994b. Methods for derivation of inhalation
reference concentrations (rfcs) and application of inhalation dosimetry. U.S. Environmental
Protection Agency, Office of Research and Development, Office of Health and Environmental
Assessment, Washington, DC, EPA/600/8-90/066F. Available online at
http://cfpub.epa. gov/ncea/cfm/recordisplav.cfm?deid=71993.
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U.S. EPA (Environmental Protection Agency). (2000) Benchmark dose technical guidance
document. External Review Draft. EPA/630/R-00/001. Available online at
http://www.epa.gov/nceawwwl/pdfs/bmds/BMD-External 10 13 2000.pdf.
U.S. EPA (Environmental Protection Agency). (2006) 2006 Edition of the drinking water
standards and health advisories. Office of Water, Washington, DC. EPA 822-R-06-013.
Washington, DC. Available online at
http://www.epa.gov/waterscience/drinking/standards/dwstandards.pdf.
U.S. EPA (Environmental Protection Agency). (2010a) Integrated Risk Information System
(IRIS). Office of Research and Development, National Center for Environmental Assessment,
Washington, DC. Available online at http J/www, epa. gov/iri s/.
U.S. EPA (Environmental Protection Agency). (2010b) 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. EPA/540/R-97/036. NTIS PB97-921199. Available
online at nepis.epa.gov/Exe/ZyPURL.cgi?Dockev=2000Q0GZ.txt.
White, KL, Jr; Sanders, VM; Barnes, W; et al. (1985) Toxicology of 1,1,2-trichloroethane in
the mouse. Drug Chem Tox 8(5):333—355.
WHO (World Health Organization). (2008) Online catalogs for the Environmental Health
Criteria Series. Available online at http://www.who.int/ipcs/publications/ehc/ehc alphabetical/
en/index.html.
WIL Research Laboratories. (2002) A 90-day inhalation study of 1,1,2-trichloroethane
(1,1,2-TCE) in rats (with satellite groups for pharmacokinetic evaluations in rats and mice).
Final Report. WIL-417002.
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APPENDIX A. DERIVATION OF A SCREENING VALUE FOR
1,1,2-TRICHLOROETHANE
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
subchronic or chronic p-RfC for 1,1,2-trichloroethane. However, information is available for
this chemical which, although insufficient to support derivation of a provisional toxicity value,
under current guidelines, may be of limited use to risk assessors. In such cases, the Superfund
Health Risk Technical Support Center summarizes available information in an Appendix and
develops a "screening value." Appendices receive the same level of internal and external
scientific peer review as the PPRTV documents to ensure their appropriateness within the
limitations detailed in the document. Users of screening toxicity values in an appendix to a
PPRTV assessment should understand that there is considerably more uncertainty associated
with the derivation of an appendix screening toxicity value than for a value presented in the body
of the assessment. Questions or concerns about the appropriate use of screening values should
be directed to the Superfund Health Risk Technical Support Center.
The subchronic-duration inhalation study conducted with rats by WIL Research
Laboratories (2002) is the only study suitable for use in the derivation of p-RfC values. Both
systemic and respiratory effects were observed. Systemic effects included hepatocellular
vacuolation and increased serum cholesterol in mid-dose females and high-dose males and
females, suggesting a possible treatment-related effect on lipid metabolism. However, these
changes were minimal in all affected groups, and there were no more clearly adverse liver effects
at any exposure level. This differs from the oral data, where increases in serum cholesterol were
larger and accompanied by increases in liver weight and serum enzymes indicative of liver
damage (ALP, ALT). The liver changes observed following inhalation exposure were not
considered to be toxicologically significant. The observed respiratory effects comprised lesions
of the olfactory epithelium of the nasal turbinates, ranging from vacuolation/microcyst formation
(characterized by the researchers as "probably degenerative in nature") to atrophy and respiratory
epithelial metaplasia. A low incidence of vacuolation/microcyst formation was the only effect at
15 ppm; more clearly adverse lesions (atrophy, metaplasia) and higher incidences of
vacuolation/microcysts were seen at >40 ppm. A LOAEL of 40 ppm (LOAELadj = 39.0 mg/m3)
and a NOAEL of 15 ppm (NOAELadj = 14.6 mg/m3) were identified for this study on this basis.
The data sets for nasal lesions (vacuolation/microcysts, atrophy, metaplasia) from WIL
Research Laboratories (2002) were all subjected to BMD modeling to determine a point of
departure (POD) for the derivation of p-RfC values. Vacuolation/microcyst formation was
included as a sensitive indicator of nasal effects. Although not necessarily adverse by itself, it
was considered to be "probably degenerative" by the study authors and occurred in the key study
as part of a spectrum of lesions of the olfactory epithelium including more clearly adverse
effects. Benchmark dose modeling software (BMDS; version 2.0) was used to run models for
each of the data sets shown in Table 1. A benchmark response of 10% was used, as
recommended by EPA (2000) for quantal data. Details of the model-fitting procedure and output
are presented in Appendix B. All data sets were successfully modeled. BMD and benchmark
dose lower bound 95% confidence interval (BMDL) values from the best fitting model for each
data set are shown in Table A. 1. The lowest BMDL values were obtained for
vacuolation/microcyst formation in males and females and atrophy in males, all of which were
within approximately 1 mg/m3 of each other (3.9-5.0 mg/m3).
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Table A.l. BMD Modeling Results from Best Fitting Models for Lesions in the Nasal
Olfactory Epithelium of Ratsa
Endpoint
BMDioadj
(mg/m3)
BMDLioadj
(mg/m3)
Vacuolation/microcysts in males
13.7
3.9
Vacuolation/microcysts in females
7.4
4.4
Atrophy in males
7.9
5.0
Atrophy in females
32.9
14.3
Metaplasia in males
25.7
11.8
Metaplasia in females
38.7
16.1
aWIL Research Laboratories, 2002; values are duration-adjusted concentrations.
Based on the values shown in Table A.l, the BMDLioadj of 3.9 mg/m3 for
vacuolation/microcysts in male rats is the lowest value, and as such, is used for the POD in
deriving screening subchronic and chronic p-RfC values for 1,1,2-trichloroethane. Given that
1,1,2-trichloroethane induced portal-of-entry nasal lesions, the following dosimetric adjustments
were made to convert the BMDLioadj value for rodents to a human equivalent concentration
(HEC) (U.S. EPA, 1994b). A Regional Gas Deposition Ratio (RGDR) of 0.13 was calculated as
follows (Equation 4-18 and default variables from U.S. EPA, 1994b):
RGDRet = (Vf/SAftU =0.13
(Ve/SAet)ii uman
Where:	Ve	= Minute volume (L/min)
= 0.137 L/min for male F344 rats (based on default body
wt of 180 mg in a subchronic-duration study) and
13.8 L/min for humans
SAet	= Surface area of the extrathoracic region (cm2)
= 15 cm2 for rats, 200 cm2 for humans
The BMDLhec of 0.51 mg/m3 was subsequently derived as
BMDLiohec ~ RGDRet x BMDLioadj
= 0.13x3.9
= 0.51 mg/m3
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SCREENING SUBCHRONIC p-RfC
To derive the screening subchronic p-RfC for 1,1,2-trichloroethane, a UFC of 300 was
applied to the BMDLiohec, as follows:
Screening subchronic p-RfC = BMDLiohec ^ UFc
= 0.51 mg/m3 - 300
= 2 x 10~3 mg/m3
The UFC of 300 is composed of the following:
•	A UFa of 3 (10°5) was applied to account for interspecies extrapolation
(toxicodynamic portion only) because a dosimetric adjustment was made.
•	A UFh of 10 for intraspecies differences was applied to account for potentially
susceptible individuals in the absence of information on the variability of
response in humans.
•	A UFd of 10 for database uncertainty was applied. The database for
1,1,2-trichloroethane contains only one adequate sub chronic-duration inhalation
study. There are no supporting systemic toxicity studies or developmental or
reproductive toxicity studies.
Confidence in the critical study is medium. The study included an adequate number of
rats of each sex and an adequate number of dose groups, examined comprehensive endpoints,
identified both a NOAEL and a LOAEL, and was well reported (sufficient to support BMD
modeling). The study has not been peer reviewed, however. Confidence in the database is low
due to the lack of reproductive and developmental toxicity testing and the absence of supporting
subchronic- or chronic-duration systemic toxicity studies. Overall confidence in the screening
subchronic p-RfC is low.
SCREENING CHRONIC p-RfC
To derive the screening chronic p-RfC for 1,1,2-trichloroethane, a UFcof 3000 was
applied to the BMDLiohec, as follows:
Screening chronic p-RfC = BMDLiohec ^ UFc
= 0.51 mg/m3-3000
= 2 x 10~4 mg/m3
The UFC of 3000 is composed of the following:
•	A UFa of 3 (10°5) was applied to account for interspecies extrapolation
(toxicodynamic portion only) because a dosimetric adjustment was made.
•	A UFh of 10 for intraspecies differences was applied to account for potentially
susceptible individuals in the absence of information on the variability of
response in humans.
•	A UFS of 10 was applied for using a subchronic-duration study to approximate
chronic-duration exposure.
•	A UFD of 10 for database uncertainty was applied. The database for
1,1,2-trichloroethane contains only one adequate subchronic-duration inhalation
study. There are no chronic-duration, developmental, or reproductive toxicity
studies.
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As discussed for the screening subchronic p-RfC, confidence in the principal study is
medium, and confidence in the database and screening chronic p-RfC are low.
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APPENDIX B. DETAILS OF BENCHMARK DOSE MODELING
FOR SCREENING SUBCHRONIC p-RfC
MODEL-FITTING PROCEDURE FOR DICHOTOMOUS DATA
The model-fitting procedure for dichotomous data is as follows. All available
dichotomous models in the EPA benchmark dose modeling software are fit to the incidence data
using the extra risk option. The multistage model is run for all polynomial degrees up to n - 1
(where n is the number of dose groups including control); the lowest degree polynomial
providing adequate fit is used for comparison with the other models, per EPA (2000) guidance.
Goodness-of-fit is assessed by the % test. Models with a % goodness-of-fit/?-value >0.1 are
considered to have adequate fit. Scaled residuals near the benchmark response, as well as visual
inspection of the graphs associated with each model run, are also considered in evaluating the
adequacy of fit. When several models provide adequate fit to the data (% p > 0.1, scaled
residuals <2.0, visual inspection validates adequacy of fit), models are compared using the
Akaike Information Criterion (AIC). The model with the lowest AIC is considered to provide
the best fit to the data. When several models have the same AIC, the model resulting in the
lowest benchmark dose lower bound 95% confidence interval (BMDL) is selected. In
accordance with EPA (2000) guidance, benchmark doses (BMDs) and BMDLs associated with
an extra risk of 10% are calculated for all models.
MODEL-FITTING RESULTS FOR INCIDENCE OF METAPLASIA OF OLFACTORY
RESPIRATORY EPITHELIUM IN MALE RATS (WIL Research Laboratories, 2002)
All models provide adequate fit (see Table B-l). The log-logistic model has the lowest
AIC value, and is, therefore, chosen as the best fitting model for this data set (see Figure B-l).
Table B-l. Model Predictions for Incidence of Metaplasia of
Olfactory Epithelium in Male Ratsa
Model
Degrees
of
Freedom
x2
x2
Goodness-of-Fit
/7-Value
AIC
BMDioadj
(mg/m3)
BMDLioadj
(mg/m3)
Gamma (power > 1)
3
0.54
0.9093
27.6909
27.9939
14.4868
Logistic
2
0.79
0.6735
30.3402
54.7621
34.9704
Log-logistic (slope > 1)
3
0.46
0.9286
27.6441
25.7126
11.7901
Log-probit (slope >1)
2
1.03
0.5970
30.5384
48.7572
24.3648
Multistage (degree = 1, betas > 0)
3
0.54
0.9093
27.6909
27.9939
14.4868
Multistage (degree = 2, betas > 0)
3
0.54
0.9093
27.6909
27.9939
14.4868
Multistage (degree = 3, betas > 0)
3
0.54
0.9093
27.6909
27.9939
14.4868
Probit
2
0.78
0.6767
30.2872
51.3098
32.3413
Weibull (power > 1)
3
0.54
0.9093
27.6909
27.9939
14.4868
Quantal Linear
3
0.54
0.9093
27.6909
27.9939
14.4868
aWIL Research Laboratories, 2002
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Log-Logistic Model with 0.95 Confidence Level
0.7
Log-Logistic
0.6
0.5
0.4
0.3
0.2
0.1
0
BMDL
BMD
0
20
40
60
80
100
Dose
15:19 07/16 2008
Figure B-l. Best Fitting Model for Nasal Metaplasia in Male Rats
(WIL Research Laboratories, 2002)
Dose is duration-adjusted and in units of mg/m3.
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MODEL-FITTING RESULTS FOR INCIDENCE OF METAPLASIA OF OLFACTORY
EPITHELIUM IN FEMALE RATS (WIL Research Laboratories, 2002)
All models provide adequate fit to the data (see Table B-2). On the basis of the lowest
AIC, the 2-degree multistage model (see Figure B-2) has the best fit.
Table B-2. Model Predictions for Incidence of Metaplasia of
Olfactory Respiratory Epithelium in Female Ratsa
Model
Degrees
of
Freedom
x2
x2
Goodness- of-Fit
/7-Value
AIC
BMDioadj
(mg/m3)
BMDLioadj
(mg/m3)
Gamma (power >1)
2
0.09
0.9559
24.5114
41.7446
16.8434
Logistic
2
0.61
0.7379
25.1976
52.9053
33.7445
Log-logistic (slope > 1)
2
0.10
0.9509
24.5346
41.6801
17.2468
Log-probit (slope >1)
2
0.04
0.9812
24.4297
40.03
21.3577
Multistage (degree = 1, betas > 0)
3
1.74
0.6284
24.8265
21.5612
11.7056
Multistage (degree = 2, betas > 0)
3
0.16
0.9842
22.6709
38.6873
16.1186
Multistage (degree = 3, betas > 0)
2
2
0.9302
24.614
42.5194
16.2985
Probit
2
0.44
0.8036
24.9647
49.168
31.234
Weibull (power > 1)
2
0.13
0.9345
24.5847
42.6364
16.4894
Quantal Linear
3
1.74
0.6284
24.8265
21.5611
11.7056
"WIL Research Laboratories, 2002
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Multistage Model with 0.95 Confidence Level
Multistage
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
BMDL
BMD
0
20
40
60
80
100
Dose
15:10 07/16 2008
Figure B-2. Best Fitting Model for Nasal Metaplasia in Female Rats
(WIL Research Laboratories, 2002)
Dose is duration-adjusted and in units of mg/m3.
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MODEL-FITTING RESULTS FOR INCIDENCE OF VACUOLATION/MICROCYSTS
IN NASAL OLFACTORY EPITHELIUM IN MALE RATS (WIL Research Laboratories,
2002)
All models provide adequate fit (see Table B-3). The 2-degree multistage model (see
Figure B-3) yields the lowest AIC value and, therefore, is chosen as the best fitting model for this
data set.
Table B-3. Model Predictions for Incidence of Vacuolation/Microcysts
in Nasal Olfactory Epithelium in Male Ratsa
Model
Degrees
of
Freedom
x2
x2
Goodness-of-Fit
/7-Value
AIC
BMDioadj
(mg/m3)
BMDLioadj
(mg/m3)
Gamma (power > 1)
1
0.19
0.6618
36.2229
17.3851
4.2487
Logistic
2
0.14
0.9323
34.1886
11.5423
7.21718
Log-logistic (slope >1)
2
0.39
0.8219
34.3686
34.2933
7.13212
Log-probit (slope >1)
1
0.39
0.5312
36.3686
31.1043
7.14513
Multistage (degree = 1, betas > 0)
2
2.14
0.3431
37.0322
4.2804
2.69705
Multistage (degree = 2, betas > 0)
2
0.06
0.9727
34.0681
13.6836
3.92139
Multistage (degree = 3, betas > 0)
1
0.00
0.9803
35.9711
13.6079
3.69657
Probit
2
0.10
0.9523
34.0951
10.6275
6.87619
Weibull (power > 1)
1
0.04
0.8429
36.0214
15.6032
4.43506
Quantal Linear
2
2.14
0.3430
37.0322
4.28032
2.69705
aWIL Research Laboratories, 2002
21
1,1,2-Trichloroethane

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FINAL
4-1-2011
Multistage Model with 0.95 Confidence Level
Multistage
1
0.8
0.6
0.4
0.2
0
BMDL
BMD
0
20
40
60
80
100
Dose
14:35 07/16 2008
Figure B-3. Best Fitting Model for Vacuolation/Microcysts in Nasal Olfactory Epithelium
in Male Rats (WIL Research Laboratories, 2002)
Dose is duration-adjusted and in units of mg/m3.
22
1,1,2-Trichloroethane

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FINAL
4-1-2011
MODEL-FITTING RESULTS FOR INCIDENCE OF VACUOLATION/MICROCYSTS
IN NASAL OLFACTORY EPITHELIUM IN FEMALE RATS (WIL Research
Laboratories, 2002)
All models provide adequate fit (see Table B-4). The gamma, 1-degree multistage,
2-degree multistage, Weibull, and quantal linear models provide identical fit and the lowest AIC;
the BMDL value from these models is chosen to represent the data set. The gamma model is
representative of these models (see Figure B-4).
Table B-4. Model Predictions for Incidence of Vacuolation/Microcysts in Nasal
Olfactory Epithelium in Female Ratsa
Model
Degrees
of
Freedom
x2
x2
Goodness-of-Fit
/7-Value
AIC
BMDioadj
(mg/m3)
BMDL10adj
(mg/m3)
Gamma (power > 1)
2
1.06
0.5900
48.4574
7.38404
4.36516
Logistic
2
1.47
0.4793
48.9266
15.4579
10.1475
Log-logistic (slope >1)
1
1.17
0.2788
50.6072
5.37071
2.20114
Log-probit (slope >1)
2
1.81
0.4038
49.1768
13.6485
7.50422
Multistage (degree = 1, betas > 0)
2
1.06
0.5900
48.4574
7.38404
4.36516
Multistage (degree = 2, betas > 0)
2
1.06
0.5900
48.4574
7.38404
4.36516
Multistage (degree = 3, betas > 0)
1
1.04
0.3067
50.442
7.95963
4.37088
Probit
2
1.44
0.4871
48.8872
14.9474
10.2404
Weibull (power > 1)
2
1.06
0.5900
48.4574
7.38405
4.36516
Quantal Linear
2
1.06
0.5900
48.4574
7.38404
4.36516
aWIL Research Laboratories, 2002
23
1,1,2-Trichloroethane

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FINAL
4-1-2011
Gamma Multi-Hit Model with 0.95 Confidence Level
Gamma Multi-Hit
1
0.8
0.6
0.4
0.2
0
BMDL
BMD
0
20
40
60
80
100
Dose
14:52 07/16 2008
Figure B-4. Representative Best Fitting Model for Vacuolation/Microcysts in Nasal
Olfactory Epithelium in Female Rats (WIL Research Laboratories, 2002)
Dose is duration-adjusted and in units of mg/m3
24
1,1,2-Trichloroethane

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FINAL
4-1-2011
MODEL-FITTING RESULTS FOR INCIDENCE OF ATROPHY OF NASAL
OLFACTORY EPITHELIUM IN MALE RATS (WIL Research Laboratories, 2002)
All but the probit and logistic models provide adequate fit (see Table B-5). The 1-degree
multistage and quantal linear models have the lowest AIC values and provide identical fit to the
data; the BMDL value from these models is chosen to represent the data set. The quantal linear
model is representative of these models (see Figure B-5).
Table B-5. Model Predictions for Incidence of Atrophy of Nasal Olfactory Epithelium
in Male Ratsa
Model
Degrees
of
Freedom
x2
x2
Goodness-of-Fit
/7-Value
AIC
BMDioadj
(mg/m3)
BMDLioadj
(mg/m3)
Gamma (power >1)
2
3.94
0.1398
34.5264
14.0015
5.29409
Logistic
2
7.91
0.0192
39.0046
NAb
NA
Log-logistic (slope >1)
2
3.21
0.2008
33.7213
15.1826
4.36048
Log-probit (slope >1)
2
3.11
0.2111
33.4581
16.4607
9.09944
Multistage (degree = 1, betas > 0)
3
3.75
0.2900
33.1399
7.86439
5.03062
Multistage (degree = 2, betas > 0)
2
3.88
0.1436
35.111
8.72496
5.04195
Multistage (degree = 3, betas > 0
2
3.88
0.1436
35.111
8.72496
5.04195
Probit
2
7.76
0.0206
38.5262
NA
NA
Weibull (power > 1)
2
3.94
0.1392
34.7729
11.9249
5.182
Quantal Linear
3
3.75
0.2901
33.1399
7.86432
5.03062
aWIL Research Laboratories, 2002
l:'NA = Not Applicable; model does not provide adequate fit
25
1,1,2-Trichloroethane

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FINAL
4-1-2011
Quantal Linear
BMDL
Quantal Linear Model with 0.95 Confidence Level
0	20	40	60	80	100
Dose
13:49 07/16 2008
Figure B-5. Representative Best Fitting Model for Atrophy of Nasal Olfactory Epithelium
in Male Rats (WIL Research Laboratories, 2002)
Dose is duration-adjusted and in units of mg/m3.
26
1,1,2-Trichloroethane

-------
FINAL
4-1-2011
MODEL-FITTING RESULTS FOR INCIDENCE OF ATROPHY OF NASAL
OLFACTORY EPITHELIUM IN FEMALE RATS (WIL Research Laboratories, 2002)
All but the Weibull model provide adequate fit (see Table B-6). The log-logistic model
has the lowest AIC value (see Figure B-6).
Table B-6. Model Predictions for Incidence of Atrophy of Nasal Olfactory Epithelium
in Female Ratsa
Model
Degrees
of
Freedom
x2
x2
Goodness-of-Fit
/7-Value
AIC
BMDioadj
(mg/m3)
BMDLioadj
(mg/m3)
Gamma (power >1)
3
0.01
0.9998
14.2324
25.07
13.3745
Logistic
2
0.00
1.0000
16.2173
35.2969
15.2877
Log-logistic (slope > 1)
3
0.00
1.0000
14.2173
32.9312
14.2601
Log-probit (slope >1)
2
0.00
1.0000
16.2173
29.2977
13.9644
Multistage (degree = 1, betas > 0)
3
5.61
0.1320
23.607
4.25009
2.72382
Multistage (degree = 2, betas > 0)
3
1.74
0.6274
17.2572
12.838
6.59393
Multistage (degree = 3, betas > 0)
3
0.65
0.8860
15.4208
17.8769
8.99183
Probit
2
0.00
1.0000
16.2173
31.9657
14.261
Weibull (power > 1)
Model does not run
Quantal Linear
3
5.61
0.1320
23.607
4.25009
2.72382
" WIL Research Laboratories, 2002
27
1,1,2-Trichloroethane

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FINAL
4-1-2011
Log-Logistic Model with 0.95 Confidence Level
1
0.8
T3
0
1	06
y=
<
£=
O
-4—1
o
£ 0.4
LL
0.2
0
0	20	40	60	80	100
Dose
14:18 07/16 2008
Figure B-6. Best Fitting Model for Atrophy of Nasal Olfactory Epithelium in Female Rats
(WIL Research Laboratories, 2002)
Dose is duration-adjusted and in units of mg/m3.
Log-Logistic
BMDL
BMD
28
1,1,2-Trichloroethane

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