United States
kS^laMIjk Environmental Protection
^J^iniiil m11 Agency
EPA/690/R-11/010F
Final
12-19-2011
Provisional Peer-Reviewed Toxicity Values for
Benzotrichloride
(CASRN 98-07-7)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268

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AUTHORS, CONTRIBUTORS, AND REVIEWERS
CHEMICAL MANAGER
Harlal Choudhury, DVM, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
DRAFT DOCUMENT PREPARED BY
ICF International
9300 Lee Highway
Fairfax, VA 22031
PRIMARY INTERNAL REVIEWERS
Dan D. Petersen, PhD, DABT
National Center for Environmental Assessment, Cincinnati, OH
Paul G. Reinhart, PhD, DABT
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	iv
BACKGROUND	1
DISCLAIMERS	1
QUESTIONS REGARDING PPRTVS	 1
INTRODUCTION	2
REVIEW OF POTENTIALLY RELEVANT DATA (CANCER AND NONCANCER)	4
HUMAN STUDIES	11
Oral and Inhalation Exposure	11
ANIMAL STUDIES	12
Oral Exposure	12
Short-term Study	12
Chronic-duration Studies	13
Chronic-duration Carcinogenicity Studies	13
Developmental and Reproductive Studies	14
Inhalation Exposure	15
Short-term Study	15
Chronic-duration Studies	16
Chronic-duration Carcinogenicity Studies	16
Developmental and Reproductive Studies	17
Other Exposures	17
OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)	18
DERIVATION 01 PROVISIONAL VALUES	22
DERIVATION OF ORAL REFERENCE DOSES	23
Derivation of Subchronic p-RfD	23
Derivation of Chronic p-RfD	25
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS	25
Derivation of Subchronic p-RfC	25
Derivation of Chronic p-RfC	26
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR	26
DERIVATION OF PROVISIONAL CANCER VALUES	26
Derivation of a p-OSF	26
Derivation of a p-IUR	26
APPENDIX A. DERIVATION OF A SCREENING SUBCHRONIC p-RfC	27
APPENDIX B. DATA TABLES	31
APPENDIX C. BMC MODELING OUTPUTS FOR BENZOTRICHLORIDE	35
APPENDIX D. REFERENCES	58
in
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COMMONLY USED ABBREVIATIONS
BMC
benchmark concentration
BMCL
benchmark concentration lower bound 95% confidence interval
BMD
benchmark dose
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
NOAELhec
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
POD
point of departure
p-OSF
provisional oral slope factor
p-RfC
provisional reference concentration (inhalation)
p-RfD
provisional reference dose (oral)
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
BENZOTRICHLORIDE (CASRN 98-07-7)
BACKGROUND
A Provisional Peer-Reviewed Toxicity Value (PPRTV) is defined as a toxicity value
derived for use in the Superfund Program. PPRTVs are derived after a review of the relevant
scientific literature using established Agency guidance on human health toxicity value
derivations. All PPRTV assessments receive internal review by a standing panel of National
Center for Environment Assessment (NCEA) scientists and an independent external peer review
by three scientific experts.
The purpose of this document is to provide support for the hazard and dose-response
assessment pertaining to chronic and subchronic exposures to substances of concern, to present
the major conclusions reached in the hazard identification and derivation of the PPRTVs, and to
characterize the overall confidence in these conclusions and toxicity values. It is not intended to
be a comprehensive treatise on the chemical or toxicological nature of this substance.
The PPRTV review process provides needed toxicity values in a quick turnaround
timeframe while maintaining scientific quality. PPRTV assessments are updated approximately
on a 5-year cycle for new data or methodologies that might impact the toxicity values or
characterization of potential for adverse human health effects and are revised as appropriate. It is
important to utilize the PPRTV database (http://hhpprtv.ornl.gov) to obtain the current
information available. When a final Integrated Risk Information System (IRIS) assessment is
made publicly available on the Internet (www.epa.gov/iris), the respective PPRTVs are removed
from the database.
DISCLAIMERS
The PPRTV document provides toxicity values and information about the adverse effects
of the chemical and the evidence on which the value is based, including the strengths and
limitations of the data. All users are advised to review the information provided in this
document to ensure that the PPRTV used is appropriate for the types of exposures and
circumstances at the site in question and the risk management decision that would be supported
by the risk assessment.
Other U.S. Environmental Protection Agency (EPA) programs or external parties who
may choose to use PPRTVs are advised that Superfund resources will not generally be used to
respond to challenges, if any, of PPRTVs used in a context outside of the Superfund program.
QUESTIONS REGARDING PPRTVS
Questions regarding the contents and appropriate use of this PPRTV assessment should
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).
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INTRODUCTION
Benzotrichloride, or a,a,a-trichlorotoluene, is extensively used as an intermediate in the
manufacture of benzoyl chloride-substituted benzophenones and in the preparation of dyes and
pigments, ultraviolet stabilizers, and other derivatives (IARC, 1982; NTP, 2005). In addition,
benzotrichloride is also used in the manufacture of benzotrifluoride, hydroxybenzophenone,
antiseptics, and antimicrobial agents (NTP, 2005). Benzotrichloride is an unstable chemical and
hydrolyzes rapidly to benzoic acid and hydrochloric acid in the presence of moisture (U.S. EPA,
1982). The empirical formula for benzotrichloride is C7H5CI13 (see Figure 1). A table of
physicochemical properties is provided below (see Table 1). In this document, unless otherwise
noted, "statistical significant" denotes ap< 0.05.
CI-
CI
CI
^ //
Figure 1. Benzotrichloride
Table 1. Physicochemical Properties Table
Benzotrichloride3 (CASRN 98-07-7)
Property (unit)
Value
Boiling point (°C)
220.8
Melting point (°C)
-5.0
Density (g/cm3 at 20°C)
1.3756
Vapor pressure (Pa at 25°C)
55.15
pH (unitless)
Not available
Solubility in water (mg/L at 5°C)
53
Relative vapor density (air =1)
6.77
Molecular weight (g/mol)
195.48
Octanol/water partition coefficient (unitless)
2.92
aValues from Hazardous Substances Data Bank (HSDB), 2005.
No chronic oral reference dose (RfD) or chronic reference concentration (RfC) for
benzotrichloride is included in the IRIS database (U.S. EPA, 2009b) or on the Drinking Water
Standards and Health Advisories List (U.S. EPA, 2006). The HEAST does not list an RfD or
RfC value, but it lists the EPA IRIS as a reference (U.S. EPA, 2009b). CalEPA (2008a,b) has
not derived toxicity values for exposure to benzotrichloride; however, CalEPA (1994) reports
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_2
two No Significant Risk Levels for benzotrichloride: (1) 5.0 x 10 [j,g/day (oral) based on the
cancer potency value calculated by the EPA, and (2) 2.0 x 10 4 (j,g/day (inhalation) determined in
a draft review that is undergoing external review. The CARA list (U.S. EPA, 1994a) includes a
Health and Environmental Effects Profile (HEEP) for benzotrichloride (U.S. EPA, 1986). The
toxicity of benzotrichloride has not been reviewed by ATSDR (2008) or the World Health
Organization (WHO, 2010). An occupational exposure short-term exposure level (STEL) ceiling
value of 0.1 ppm with a skin notation has been derived by the American Conference of
Governmental Industrial Hygienists (ACGIH, 2009) as reported in the Hazardous Substances
Data Bank (HSDB, 2005). The National Institute of Occupational Safety and Health (NIOSH,
2003) has not issued threshold limit values (TLVs), and the Occupational Safety and Health
Administration (OSHA, 1998) has not set occupational exposure limits for benzotrichloride.
The HEAST (U.S. EPA, 2009a) does not list cancer slope factors or unit risk values for
benzotrichloride but instead cites the IRIS database (U.S. EPA, 2009b), which classifies
benzotrichloride as Category B2 (Probable Human Carcinogen) based on inadequate human
data and sufficient evidence of carcinogenicity in animals, including significantly increased
incidence of benign and malignant tumors at multiple sites in one strain of female mice treated
orally, dermally, and by inhalation. Additionally, evidence of mutagenicity was observed in
several test systems (U.S. EPA, 1986). An oral slope factor (OSF) of 1.3 x 101 per mg/kg-day
and a drinking water unit risk of 3.6 x 10 4 per [j,g/L were derived in the IRIS cancer assessment
using the linearized multistage procedure as the extrapolation method. Benzotrichloride is
included in the NTP's 11th Report on Carcinogens (NTP, 2005) and is categorized as
"Reasonably Anticipated to be a Human CarcinogenThe NTP assessment is based on
sufficient evidence of animal carcinogenicity, including squamous cell carcinomas of the
forestomach, skin, and lungs; adenocarcinomas of the lungs; and upper digestive tract tumors
(NTP, 2005). The International Agency for Research on Cancer (IARC, 2000) has classified
combined exposures to alpha-chlorinated toluenes (including benzotrichloride) as Probably
Carcinogenic to Humans (Group 2A). A comprehensive review of toxicological studies of
benzotrichloride published through July 2006 was conducted by EPA (2009b), but no new health
effects data were identified that would directly affect the revision of the existing carcinogenicity
assessment for benzotrichloride.
Literature searches were conducted on sources published from 1900 through
October 2010 for studies relevant to the derivation of provisional toxicity values for
benzotrichloride, CASRN 98-07-7. Searches were conducted using EPA's Health and
Environmental Research Online (HERO) evergreen database of scientific literature. HERO
searches the following databases: AGRICOLA; American Chemical Society; BioOne; Cochrane
Library; DOE: Energy Information Administration, Information Bridge, and Energy Citations
Database; EBSCO: Academic Search Complete; GeoRef Preview; GPO: Government Printing
Office; Informaworld; IngentaConnect; J-STAGE: Japan Science & Technology; JSTOR:
Mathematics & Statistics and Life Sciences; NSCEP/NEPIS (EPA publications available through
the National Service Center for Environmental Publications [NSCEP] and National
Environmental Publications Internet Site [NEPIS] database); PubMed: MEDLINE and
CANCERLIT databases; SAGE; Science Direct; Scirus; Scitopia; SpringerLink; TOXNET
(Toxicology Data Network): ANEUPL, CCRIS, ChemlDplus, CIS, CRISP, DART, EMIC,
EPIDEM, ETICBACK, FEDRIP, GENE-TOX, HAPAB, HEEP, HMTC, HSDB, IRIS, ITER,
LactMed, Multi-Database Search, NIOSH, NTIS, PESTAB, PPBIB, RISKLINE, TRI; and
TSCATS; Virtual Health Library; Web of Science (searches Current Content database among
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others); World Health Organization; and Worldwide Science. The following databases outside
of HERO were also searched for information that could support the derivation of provisional risk
assessment values: ACGM, AT SDR, CalEPA, EPA IRIS, EPA HEAST, EPA HEEP, EPA OW,
EPA TSCATS/TSCATS2, NIOSH, NTP, OSHA, and RTECS.
REVIEW OF POTENTIALLY RELEVANT DATA
(CANCER AND NONCANCER)
Table 2 provides summaries of the potentially relevant toxicity studies. Entries for the
principal studies are bolded and identified by the marking "PS."
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Table 2. Summary of Potentially Relevant Data for Benzotrichloride (CASRN 98-07-7)
Category
Number of Male/Female
Species, Study Type, and
Duration
Dosimetry13
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes3
Human
1. Oral (mg/kg-day)b
None
2. Inhalation (mg/m3)b
Carcinogenic
163 exposed and
790 unexposed workers (sex
not specified); workers were
exposed to a mixture of
chlorinated toluenes versus
benzotrichloride alone, only
workers exposed for at least
6 months were considered;
exposures occurred between
1923-1945, 1946-1960,
and 1961-1970
Exposure not
measured
Standardized Mortality Ratios
(SMRs) were calculated using
mortality rates for the general
population as comparison; SMRs
were elevated in the exposed group
for all causes, all cancers, digestive
system cancers, and respiratory
system cancers; Using life tables,
cancer mortality was significantly
increased only in exposed workers
who were first employed before 1951.
None
identified
Not
estimated
None
identified
Sorahan et al.
(1983)

Carcinogenic
951 male workers employed
between 1977 to 1984;
workers were exposed to a
mixture of chlorinated
toluenes versus
benzotrichloride alone;
study is a follow up the
study performed in 1983;
follow-up period was 1977
to 1984
Exposure not
measured
The standardized mortality ratios
(SMRs) for all causes, all cancers,
and all noncancers in workers
exposed to mixtures of chlorinated
toluenes (including benzotrichloride)
were 138, 163, and 129, respectively
compared to the general population of
England and Wales; significant
excess mortality for lung cancer and
Hodgkin's disease, with SMRs of 180
and 714; relative risks for deaths from
lung cancer were elevated for
exposure to benzotrichloride and
other chlorinated toluenes, but the
association was not statistically
significant.
None
identified
Not
estimated
None
identified
Sorahan and
Cathcart
(1989)

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Table 2. Summary of Potentially Relevant Data for Benzotrichloride (CASRN 98-07-7)
Category
Number of Male/Female
Species, Study Type, and
Duration
Dosimetry13
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes3
Carcinogenic
697 male workers at a
chlorination plant (exposed
to benzotrichloride,
benzylchloride, benzoyl
chloride, and other related
chemicals); mortality was
observed from 1943 to 1982
Exposure not
measured
For the cohort as a whole, no
statistically significant excess
mortality was reported; however,
authors state that based on animal
data, as well as other epidemiologic
studies, together with the internal
consistency of analysis by length of
employment, there may be an
association between the chlorination
process of toluene at the plant and an
increased risk of respiratory cancer.
None
identified
Not
estimated
None
identified
Wong (1988)

Animal
1. Oral (mg/kg-day)b
Short term
10M/10F, Sprague-Dawley
rat, diet 7 d/wk, 4 wks
0,0.046, 0.46, 4.6,
46
Investigators did not observe
clinical signs of toxicity and no
mortality occurred during the
study period; significant changes in
SDH levels noted in males treated
with benzotrichloride at doses
greater than 0.046 mg/kg-day;
liver, kidney, and thyroid
considered to be target organs,
though morphological effects were
mild even at high doses. Males
more susceptible than females to
toxic effects of benzotrichloride.
0.046
0.048
(based on
significant
changes in
serum
SDH
levels in
males)
0.46
Chu et al.
(1984)
PS
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Table 2. Summary of Potentially Relevant Data for Benzotrichloride (CASRN 98-07-7)
Category
Number of Male/Female
Species, Study Type, and
Duration
Dosimetry13
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes3
Carcinogenic
200 Female ICR mouse,
gavage, 40 per dose group,
2 d/wk, 25 wks
0,0.41, 1.62,6.57,
26.57
Dose-dependent increase in mortality;
the primary causes of mortality were
lymphosarcoma and stomach cancer.
There was a statistically significant
positive trend in incidence of tumors
of the forestomach, lung, and
hematopoietic system.
0.41
Not
estimated
1.62
Hooker
Chemical
Company
(1980)
IRIS,
U.S. EPA
(1990)
Developmental
Female rat, gavage,
Gestation Days 6 through
15, 10 days; number of
animals not specified
0, 12.5, 25, 50
All dosages reduced mean fetal
weight. Reduced number of fetuses
per litter at all treated doses;
additionally, skeletal anomalies were
noted (doses not specified).
Histological alterations in the
maternal thyroid gland, bone marrow,
kidney, and liver were also noted
(doses not specified).
None
identified
Not
estimated
12.5
Ruddick et al.
(1982); this
study is only
available in
abstract form;
hence,
complete
study details
are
unavailable

Reproductive
None
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Table 2. Summary of Potentially Relevant Data for Benzotrichloride (CASRN 98-07-7)
Category
Number of Male/Female
Species, Study Type, and
Duration
Dosimetry13
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes3
2. Inhalation (mg/m3)b
Short-term
10M/10F Sprague-Dawley
albino rat, 6 hr/d, 5 d/wk,
4 wks
0,0.91,8.61,82.1
(extrarespiratory
effects)
0,1.77,16.77,160
(respiratory
effects)
All animals in the high exposure
group died prior to termination of
the study; animals in the mid-dose
group exhibited statistically
significant reduced body weight
compared to the control group; a
dose-response trend was observed
in absolute and relative organ
weights of both males and females;
absolute weights of spleen, liver,
kidneys, adrenals, and pituitary
were significantly reduced in males
in the mid-dose group. In females,
absolute liver, heart, and lungs and
trachea weights were significantly
reduced compared to males in the
mid-dose group; relative
organ-weight analyses indicated
statistically significant, dose-related
changes in the lungs and trachea,
adrenals, thyroid, and brain of both
male and female rats; these findings
were corroborated by the
morphological alterations in the
lung, trachea and nasal turbinates.
1.77
(based on
respiratory
effects)
1.36
(based on
changes in
relative
brain
weight in
males)
16.77
(based on
respiratory
effects)
Levin (1981)
PS
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Table 2. Summary of Potentially Relevant Data for Benzotrichloride (CASRN 98-07-7)
Category
Number of Male/Female
Species, Study Type, and
Duration
Dosimetry13
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes3
Carcinogenic
Male Sprague-Dawley rat,
number not specified,
6 hr/d, 5 d/wk, 1-6 mos
3.083
After 6 mos of exposure, squamous
metaplasia or hyperplasia of upper
respiratory tract, and papillomas in
the nasal cavity; later observation also
revealed malignant tumors in the skin
and the external ear duct (incidence
rates not provided in the abstract).
None
identified
Not
estimated
None
identified
Koshi and
Fukuda
(1986); this
study is only
available in
abstract form;
hence,
complete
study details
are
unavailable

Carcinogenic
Female ICR mouse, number
of animals not specified,
inhalation exposure,
30 mins twice a wk for
5 mos
0.323
Moderate adenoid hyperplasia was
recorded in part of the trachea and
major bronchi of mice that died at
2 mos after study initiation;
paraleukemia and leukemia were
noted in animals that died after 5 mos;
all exposed animals also exhibited
hypertrophy of the thymus, lymph
nodes, and spleen which suggested
metastasis to other organs; study
authors reported pulmonary tumors in
all animals; dermal lesions included
squamous cell carcinomas and
papillomas.
None
identified
Not
estimated
None
identified
Takemoto
etal. (1978)

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Table 2. Summary of Potentially Relevant Data for Benzotrichloride (CASRN 98-07-7)
Category
Number of Male/Female
Species, Study Type, and
Duration
Dosimetry13
Critical Effects
NOAELb
BMDL/
BMCLb
LOAELb
Reference
(Comments)
Notes3
Carcinogenic
Female ICR mouse, number
of animals not specified,
inhalation exposure,
30 mins twice a wk for
12 mos
0.076
Adenomas were seen in mice dying
9 mos after exposure and benign
adenomas were seen at 12 mos (per
author these animals died during
treatment course); leukemoid lesions
occurred after 12 mos; cancerous
lesions were found in all lungs
examined (malignant
adenocarcinoma, adenoma, or
adenoid proliferation); 90% of those
sacrificed at 15 mos had cancerous
lesions of the lung.
None
identified
Not
estimated
None
identified
Yoshimura et
al. (1979)

Developmental
None
Reproductive
None
aIRIS = utilized by IRIS, citation; PS = Principal study.
bDosimetry conversion equations: Oral: NOAELAm = NOAEL x Food Consumption per Day x (1 -f- Body Weight) x (Days Dosed ^ Total Days); Inhalation:
NOAELadj = NOAEL x (Hours per Day ^ 4) x (Days Dosed ^ Total Days); Noncancer oral data are only adjusted for continuous exposure; NOAEL, BMDL/BMCL and
LOAEL values are converted to human equivalent dose (HED in mg/kg-day) or human equivalent concentration (HEC in mg/m3); Equation for HEC conversion:
HEC = NOAELadj x RGDR.
°Not reported by the study author but determined from data.
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HUMAN STUDIES
Oral and Inhalation Exposure
No published studies investigating the effects of subchronic- or chronic-duration oral
exposure to benzotrichloride in humans have been identified. The effects of inhalation exposure
of humans to mixtures of chlorinated toluenes including benzotri chloride have been investigated
in three epidemiological/occupational studies (Sorahan et al., 1983; Sorahan and Cathcart, 1989;
Wong, 1988).
Sorahan et al. (1983) and Sorahan and Cathcart (1989) conducted two studies: the first
being a retrospective study of a cohort of 953 people (sex not specified) employed in a chemical
factory manufacturing chlorinated toluenes (CT) and the second being a follow-up study to the
1983 cohort. The population in the first study consisted of employees with up to 24 years of
exposure with an additional criterion for inclusion in the study being a minimum of 6 months of
employment. Employees exposed to chlorinated toluenes from 1923-1945, 1946-1960, and
1961-1970 were included in the study. The study authors compared mortality in 163 exposed
employees to 790 employees who were not exposed. The second study included a period of
follow-up spanning from 1977 to 1984 for 951 of the original 953 workers.
The study made comparisons using two standard populations in the 1983 study. The first
approach used mortality rates in England and Wales as an external standard, while the second
approach used regression models in life tables (RMLT) as the internal standard. The study
authors used Standardized Mortality Ratio (SMR) and RMLT to analyze the mortality among
workers exposed to CT. In the 1989 study, in addition to the SMR data, Sorahan and Cathcart
performed a "nested case-control" to gather more detailed information on likely occupational
risks. SMR results from the 1983 study indicated a statistically significant (p < 0.01) difference
in cancer mortality between the group exposed to CT and cancer mortality in the rest of England
and Wales. Similarly, for the combined group (with and without CT exposure), mortality from
all cancers was significantly elevated (p < 0.05) compared to cancer mortality in all of England
and Wales. Results from the 1989 study also indicated a statistically significant (p < 0.05)
difference in lung cancer mortality between the CT-exposed group and the rest of England and
Wales. In the 1983 study, RMLT results indicated that the null hypothesis (i.e., CT exposure has
no effect on cancer mortality) was rejected at the 5%-level. Though all cancers in the
CT-exposed group were of the respiratory and digestive systems, their association with CT
exposure failed to reach statistical significance when tumor types were considered individually.
The study authors did not find statistically significant relationships between CT exposure and
cancer mortality or that of any other cause. The study authors drew these conclusions after
controlling for employment entry cohort and age at entry to the study. Using a "nested case
control" approach in the 1989 study, the study authors stated that results did not show convincing
evidence of occupational involvement, though there was a positive nonsignificant effect for
benzotrichloride exposure that was not due to confounding effects of smoking, based on
available smoking data. However, based on the incidence of cancers in both studies, the study
authors concluded that though the results may be biased, there is evidence of increased cancer
mortality, but not from other causes, among the group exposed to CTs. The study authors also
stated that based on results of other toxicological studies on benzotrichloride, it is reasonable to
assume that benzotrichloride may be a potential human carcinogen. Because these studies
involved exposures to a mixture of chlorinated toluenes and the study authors did not report
exposure levels to benzotrichloride, a NOAEL or a LOAEL is not identified.
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Wong (1988) conducted a "historical prospective" (retrospective) mortality study on
697 males employed at a chlorination plant manufacturing benzotrichloride, benzyl chloride,
benzoyl chloride, and other related chemicals between 1943 and 1982. Females were not
included in the study because the number of females potentially exposed to chlorinated toluenes
was low (n = 43). A majority of the study cohort was potentially exposed to benzyl chloride,
benzoyl chloride, and other related chemicals. The study reported SMRs computed based on
comparisons to age- and gender-specific death rates for the U.S. population. The study authors
reported 47 deaths in the entire cohort during the observation period spanning from 1943 to
1982. When compared to the U.S. mortality rates of 46.9, the SMR was 100. Ten of the
47 deaths were attributed to malignant neoplasms, with 8.2 predicted. The study reported that
seven deaths were a result of respiratory cancer compared to 2.8 expected. The SMR for
respiratory cancer was 246 with a borderline statistical significance (and a lower 95% confidence
limit of 99). Seventeen deaths were attributed to diseases of the circulatory system with a SMR
of 96, which was not statistically significant. The study authors conducted analyses based on
race, job subcohort, chemical-specific analysis, length of employment, and latency, and
concluded that there was a statistically significant increase in lung cancer mortality among male
employees with 15 or more years of employment (two deaths in workers employed <15 years
and five deaths in workers employed >15 years). However, five workers out of the total seven
lung cancer deaths were known smokers, and the study authors could not determine whether the
observed lung cancer mortality excess was due to exposure to chlorinated toluenes, smoking, or
other causes. Based on the study results and toxicity observed in animal data, the study authors
concluded that there may be an association between exposure to chlorinated toluenes and an
increased risk of respiratory cancer. Because the study involved exposures to a mixture of
chlorinated toluenes and exposure doses and did not report data specific to benzotrichloride
exposure levels, a NOAEL or a LOAEL is not identified from this study.
ANIMAL STUDIES
Oral Exposure
The effects of oral exposure of animals to benzotrichloride have been evaluated in
short-term (Chu et al., 1984), developmental toxicity (Ruddick et al., 1982, presented only as an
abstract), and chronic-duration carcinogenicity studies (Published studies investigating the
reproductive effects of benzotrichloride in animals have not been identified.
Short-term Study
The study by Chu et al. (1984) is selected as the principal study for deriving the
subchronic p-RfD. Chu et al. (1984) conducted a 28-day feeding study in rats. Groups of
10 male and 10 female Sprague-Dawley rats per group were fed diets containing 0, 0.5, 5.0, 50,
or 500 ppm (0, 0.046, 0.46, 4.6, and 46 mg/kg-day) of benzotrichloride (purity = 98%) dissolved
in corn oil via the diet daily, for 7 days a week, for 4 weeks. The control groups were fed a diet
containing 4%-corn oil only. The study authors recorded body weights and food consumption
weekly and made clinical observations daily. At study termination, all animals were euthanized,
and gross examinations were performed at necropsy. The study authors analyzed hepatic mixed
function oxidase activity and serum enzyme levels along with various hematological parameters
including hemoglobin concentration (Hgb), packed cell volume, total and differential leukocyte
counts, mean corpuscular volume (MCV), mean corpuscular hemoglobin concentration
(MCHC), and mean corpuscular hemoglobin (MCH). At necropsy, the study authors examined
the liver, brain, heart, spleen, and kidney for gross lesions. Statistical analyses were carried out
using a one-way multiple analyses of variance and Duncan's multiple range tests. No clinical
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signs, mortality, or gross changes were observed in any of the treated animals. Significant
(p < 0.05) increases in serum sorbitol dehydrogenase (SDH) activity were noted in male rats
treated with 0.46-, 4.6-, and 46-mg.kg-day benzotrichloride compared to the concurrent control
group. The study did not provide SDH levels at the 0.046-mg/kg-day dose level; thus, it raises
uncertainty in dose response. Benzotrichloride exposure was also associated with elevated
lactate dehydrogenase (LDH) activity at the 46-mg/kg-day dose (control: 1336 ± 309; 500 ppm:
1646 ± 163). Hematological parameters and bone marrow (no information is presented
indicating whether this was assessed histopathologically) were not affected as a result of
exposure to benzotrichloride. Histopathological changes were noted in the liver, kidney, and the
thyroid gland. The study authors stated that the morphological changes in these organs were
mild even at the highest administered dose of benzotrichloride and that male rats were more
susceptible to these changes than females (incidence data for these morphological changes were
not provided in the study report). However, the study authors also reported that the histological
changes produced by benzotrichloride became progressively more severe and occurred with
greater frequency as dose levels increased. Because the study does not present dose-specific
incidence data, a dose-response trend in these histological changes is not estimated. The study
summary does not present dose-specific incidence data on morphological changes in various
organs. Architectural changes in the liver consisted of mild regular and irregular lobular
patterns. Hepatocytes exhibited mild anisokaryosis associated with pyknosis, and occasional
necrotic hepatocytes were also noted. In addition, cytoplasmic vacuolation and increased
eosinophilia were also seen in the portal areas of the hepatic lobule (dose-dependent data not
presented). In the kidney, mild but significant (significance level and dose not reported) changes
consisting of accumulation of eosinophilic intracytoplasmic inclusions in the epithelium of
proximal tubules that were associated with focal-glomerular adhesions and interstitial scarring
due to spontaneous aging process were noted. Histological alternations in the thyroid were mild
in nature and consisted of a reduction in follicular size and colloid density. The study authors
stated that the significant increase in serum SDH activity in male rats treated with
benzotrichloride was consistent with the morphological changes observed in the liver because
changes in SDH levels indicate liver injury. Though the study authors state that there were
statistically significant increases in SDH activities in animals treated with benzotrichloride, the
significance level at the lowest administered dose of 0.5 ppm could not be confirmed because
SDH levels for this dose group were not provided in the study summary. Significant SDH
changes at doses as low as 5 ppm along with morphological changes observed in the liver
constitute liver injury. Based on these results, a LOAEL of 0.46 mg/kg-day is identified for
statistically significant (p < 0.05) changes in SDH levels along with morphological changes in
the liver in male and female Sprague-Dawley rats. A NOAEL of 0.046 mg/kg-day is identified
in this study.
Chronic-duration Studies
Studies investigating the chronic-duration noncancer toxicity of benzotrichloride via oral
exposure have not been located.
Chronic-duration Carcinogenicity Studies
Fukuda et al. (1993) and Hooker Chemical Company (1980) conducted a 25-week
carcinogenicity study in ICR-Specific Pathogen Free (SPF) mice. Groups of 40 female ICR-SPF
mice were treated with 0.0315, 0.125, 0.5, or 2 |iL (0.41, 1.62, 6.57, and 26.57 mg/kgbody
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weight-day1) of benzotrichloride (purity not provided) dissolved in 0.1-ml sesame oil, twice a
week, for 25 weeks via gastric intubation. Though the use of a control group is not specifically
mentioned in the study report, the results table provides information regarding tumor incidence
in the control animals (n = 40). Eighteen months after study initiation, animals were sacrificed,
autopsied, and examined histopathologically. Changes in body weights and clinical
observations, if performed, were not reported in the study. Mortality increased with dose and
occurred earlier in higher dose groups. The study authors recorded 50% mortality at 16.5 and
6.5 months, respectively, in animals treated with 6.57 and 26.57 mg/kg-day of benzotri chloride
twice per week. The study authors stated that tumors developed earlier in animals treated with
either 6.57 or 26.57 mg/kg-day of benzotri chloride compared to animals treated with a lower
dose of the chemical, strengthening the evidence for a dose-response relationship for the
observed tumors (see Appendix B, Table B. 1). A tumor type that appeared early was thymoma,
which appeared within 6 months in 18% (7/38) and 5% (2/40) of animals treated with 26.57 and
6.57 mg/kg-day of benzotri chloride, respectively. The most frequently seen tumor was
squamous cell carcinoma of the forestomach; incidence for squamous cell carcinomas and
papillomas of the forestomach was 66% in animals treated with 26.57 mg/kg-day of
benzotrichloride at 12 months and 58% in animals treated with 6.57 mg/kg-day of
benzotrichloride at 18 months. In contrast, incidences of forestomach cancer in the 1.62 and
0.41 mg/kg-day dose groups, and the controls at 18 months were 5% (2/39), 0% (0/39), and
0% (0/39), respectively. Metastases were also noted but only for lymphogenous or
hematogenous tumor types. In contrast to forestomach cancers, no glandular stomach tumors
were noted. However, low incidences of atypical hyperplasia and hyperplastic metaplasia of the
glandular mucosa were noted. Besides squamous cell carcinomas, the other most-frequently
seen tumors were adenocarcinoma and adenomas of the lung. The study authors found lung
tumors in over 60 of animals in the three highest dose groups at the end of the study. The
authors also reported less-frequently occurring tumors of the exocrine glands such as sweat
glands, salivary glands, and lacrimal ducts in 7% (10/150) animals treated with 0.41, 1.62, 6.57,
and 26.57 mg/kg of benzotrichloride along with one instance of endothelioma of vessels
supplying the liver. Cancers of the hematopoietic system were also common in animals dosed
with 6.57 or 26.57 mg/kg-day of benzotrichloride (1/39, 2/39, 1/39, 3/40, and 8/38 in the control
and the four treatment groups, respectively). Based on these results, the study authors concluded
that benzotrichloride is not only a local carcinogen (causing cancers in the forestomach) but also
a systemic carcinogen (causing cancers in the lung, thymus, hematopoietic system, and hepatic
vascular system).
Developmental and Reproductive Studies
No studies investigating the reproductive effects of benzotrichloride via oral exposure
have been identified. Ruddick et al. (1982; in abstract form only) administered benzotrichloride
to pregnant rats (number of animals not specified) on Gestation Days (GDs) 6 through 15 via
gavage at doses of 0, 12.5, 25, or 50 mg/kg-day. Maternal-weight gain, changes in organs,
hematology, residue analysis (details not provided in the abstract), microscopic examination, and
15 biochemical parameters were used to evaluate maternal toxicity. The study authors measured
teratogenicity by examining litter size, fetal weight, deciduoma, skeleton and visceral
parameters, residue analysis, and microscopic examination of fetuses. A significant (p < 0.05)
' Dose (mg/kg-BW-day) = Dose (ill) x Density of the chemical fg) x 1 x l x 1000 mgx2
Day x ml x 1000 jxl x Animal Body Weight (kg) x g x7
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decrease in maternal-weight gain was noted in dams receiving 25- or 50 mg/kg-day
benzotrichloride. The highest dose—50 mg/kg-day—increased the number of resorption sites
and reduced the number of fetuses per litter. A decrease in mean fetal weight was noted at all
three dose levels of benzotrichloride compared to the control group. The number of skeletal
anomalies was most evident in pups exposed to benzotrichloride (dose-specific information not
provided). Histological changes were evident in the maternal thyroid gland, bone marrow,
kidney, and the liver. Significant (significance level not provided) changes were observed in
some clinical and hematological parameters along with changes in organ weights in animals (no
data on whether these changes were noted in the dams or pups) treated with 50 mg/kg-day
benzotrichloride. These results were available only in abstract form. Based on the results
presented here, a LOAEL of 12.5 mg/kg-day is derived for benzotrichloride based on decreased
mean fetal weight. A NOAEL cannot be determined from this study.
Inhalation Exposure
The effects of inhalation exposure of animals to benzotrichloride have been evaluated in
short-term (Levin, 1981) and chronic-duration carcinogenicity studies (Yoshimura et al., 1979;
Takemoto et al., 1978; Koshi and Fukuda, 1986). Published studies investigating reproductive
and developmental effects of benzotrichloride in animals via inhalation exposure have not been
identified.
Short-term Study
The study by Levin (1981) is selected as the principal study for deriving the
subchronic p-RfC. The International Research and Development Corporation (IRDC),
Mattawan, Michigan (1981; unpublished study) conducted a 4-week inhalation study on
benzotrichloride using rats. Groups of 10 male and 10 female Sprague-Dawley albino rats per
group were exposed 6 hours/day, 5 days/week, for 4 weeks to clean filtered air or 5.1, 48.2, or
-3
460 |ig/L (mg/m ) of benzotrichloride (purity = 96.4%) vapor. Body weights were determined
prior to study initiation and once every week thereafter until study termination. The study
authors noted signs of toxicity once every week and checked animals for mortality twice per day
prior to benzotrichloride exposure and again after each exposure until study termination. At
study termination, various serum biochemical, hematological, and urine analyses were
conducted. In addition, the study authors determined absolute and relative organ weights and
conducted histopathological evaluations after animal sacrifice. Animals that died or were
sacrificed in extremis prior to study termination were evaluated using the same methods, except
body and organ weights were not measured. Marked dyspnea, nasal and ocular discharge, and
gasping were noted in animals exposed to 460 mg/m3 benzotrichloride during Week 1 of the
study. In contrast, only mild dyspnea was observed in animals exposed to 48.2 mg/m
benzotrichloride. All animals exposed to 460 mg/m3 of benzotrichloride either died or were
-3
sacrificed in extremis by the seventh day of the study. One female treated with 48.2 mg/m of
benzotrichloride died prior to final sacrifice. None of the other animals died during the study
"3
period. Body weights for both male and female rats treated with 48.2 mg/m benzotrichloride
were statistically significantly (p < 0.05) lower when compared to the corresponding control
-3
group (see Appendix B, Table B.2). In contrast, animals treated with 5.1 mg/m of
benzotrichloride exhibited no apparent difference in body weights from the control group.
Examination of hematological, biochemical, and urine analyses data indicated no
compound-related changes. Absolute organ weight analysis indicated statistically significant
(p < 0.01) changes in the spleen (males), liver (males and females), kidney (males), and heart
(females) of animals dosed with 48.2 mg/m3 benzotrichloride compared to the control group (see
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Appendix B, Table B.3). Relative organ weight analyses indicated statistically significant
changes in the lungs and trachea (p < 0.01; apparently excised as a unit and weighed together),
adrenals (p < 0.05), thyroid, and brain (p < 0.01) of both male and female rats (see Appendix B,
Table B.4). The study authors suggest that the changes in relative brain weights may be related
to the effect of benzotrichloride on body weight rather than a direct effect on organs.
Histopathological examination revealed treatment-related morphological alterations in
"3
the lung, trachea, and nasal turbinates in male and female rats treated with 48.2- and 460-mg/m
benzotrichloride. Lesions in the lung included infiltrates of acute inflammatory cells,
ulcerations, and desquamation of the superficial epithelial cells of the main bronchial stem and
bronchioles of all sections. The severity of these lesions was reported to be comparable in both
"3
the 48.2- and 460-mg/m dose groups. Lesions in the nasal turbinates and the trachea included
focal-to-diffuse and slight-to-moderate infiltrations of the acute inflammatory cells along with
squamous metaplasia of the superficial epithelial cells that lined the tissues. These lesions were
not noted in the low-dose males and females. Hepatocellular necrosis/necrotic foci were noted in
the livers of some of the treated animals but not in the control group. The study authors stated
that such lesions are common spontaneous findings in rats and were not considered to be
treatment related. Based on the results presented above, a LOAEL of 48.2 mg/m is identified
for statistically significant (p < 0.01) changes in relative adrenal and thyroid weights in males,
and relative lungs and trachea weight in male and female rats, which is corroborated by the
morphological alterations in the lung, trachea, and nasal turbinates. ANOAEL of 5.1 mg/m3 is
identified in this study.
Chronic-duration Studies
No studies investigating the effects of chronic-duration systemic toxicity of
benzotrichloride in animals via inhalation exposure have been identified.
Chronic-duration Carcinogenicity Studies
Koshi and Fukuda (1986) conducted a 6-month carcinogenicity study in rats along with
1- and 3-month studies. Groups (number not specified) of male Sprague-Dawley rats were
exposed to benzotrichloride (purity not specified) at 1 ppm in air for 6 hours/day, 5 days/week,
for 1, 3, or 6 months. The corresponding average daily concentration was 3.083 mg/m . Details
of this study are limited as the study is available only as an abstract; therefore the details of the
control group are not reported. Neoplastic changes were not noted in the 1- and 3-month
exposure groups. However, in the 6-month exposure group with an observation period of
5 months, malignant and benign tumors were observed in the respiratory system as well as in the
skin and external ear duct. Additionally, at the end of the 6-month exposure period, squamous
metaplasia or hyperplasia of the upper respiratory tract, and papillomas in the nasal cavity were
recorded. These results suggest that inhalation exposure to 1 ppm benzotrichloride is
carcinogenic to male Sprague-Dawley rats.
Takemoto et al. (1978) conducted a 5-month study in ICR mice. A group of (number of
animals not clearly specified) ICR female mice were exposed to average air concentrations of
6.8 ppm benzotrichloride (purity not specified) vapors for 30 minutes, twice weekly, for
5 months. The equivalent average continuous concentration over the study period was
0.323 mg/m3. The study summary does not discuss the use of a control group. At the end of
5 months of exposure, the animals were observed without exposure for an additional 1 or
5 months and sacrificed and autopsied 6 and 10 months after study initiation. All animals,
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including animals that died during the study period, received histopathological examination.
Moderate adenoid hyperplasia was recorded in the tracheas and major bronchi of mice that died
within 2 months of study initiation. In the majority of animals that died by the end of the
5-month exposure period, epithelial proliferation of the trachea, bronchus, and bronchiole were
manifested as mild-to-intermediate adenoid proliferation. In animals that died by the fifth
month, 50% (6/12) had paraleukemia and leukemia, whereas only 10% (2/20) of animals that
died after 5 months of the study exhibited incidence of leukemia. All animals also exhibited
hypertrophy of the thymus, lymph nodes, and spleen, which suggested tumor metastasis to other
organs. All animals (n = 8) that survived the 10-month observation period exhibited adenoid
proliferation of the trachea and intrapulmonary bronchial epithelia, whereas two animals
exhibited papillomas of the intrapulmonary bronchi. Additionally, the study authors reported
pulmonary tumors in all eight animals sacrificed at the end of the 10-month observation period.
Dermal lesions included squamous cell carcinomas in three animals, and papillomas in four
animals. Mild keratocyte proliferation in the stomach was also noted in several animals (number
not specified) along with inflammatory damages in the spleen. These results suggest that
benzotrichloride is carcinogenic to female ICR mice via the inhalation exposure route.
Yoshimura et al. (1979) conducted a 12-month carcinogenicity study of benzotrichloride
in ICR mice. A group of ICR-JCL female mice (number of animals not clearly specified) were
exposed to 1.6-ppm benzotrichloride (purity not specified) vapors for 30 minutes, twice weekly,
o
for 12 months at room temperature and at 50 C. The corresponding average continuous
concentration was 0.076 mg/m over the course of the study period. The use of a control group
is not discussed in the study summary. At the end of 12 months of exposure, the animals were
observed without further exposure and sacrificed and autopsied 12 and 15 months after study
initiation. All animals, including animals that died during the study period, received
histopathological examination. The authors reported incidence of cancerous lesions in mice as
early as 9 months after study initiation. Among the animals that died by 12 months, some
exhibited mild adenoid proliferation in the bronchial epithelia (3/4), while others exhibited
benign adenoma (3/4). In animals exposed to benzotrichloride at 50°C, the incidence of
leukemoid lesions was 11% (4/37). All 10 animals sacrificed and autopsied at the end of the
12-month exposure period exhibited epithelial proliferation of the trachea, bronchus, and
terminal bronchiole along with localized squamous epithelialization. Cancerous lesions were
also noted in all examined lungs. All animals that were sacrificed at 15 months exhibited
proliferation of the tracheal and terminal bronchiolar epithelia. When compared to animals
sacrificed and observed at the end of 12 months, the 15 month-group exhibited more advanced
squamous epithelial proliferation as well as epithelial keratinization. The study authors also
reported skin lesions that included papillomas and epidermoid carcinomas. Examination of other
organs indicated evidence of keratinization of the gastric mucosa. These results suggest that
benzotrichloride is carcinogenic to female ICR-JCL mice via the inhalation exposure route.
Developmental and Reproductive Studies
No studies investigating the developmental and reproductive toxicity of benzotrichloride
in animals via inhalation exposure have been identified.
Other Exposures
No studies investigating benzotrichloride toxicity in humans or animals by other
exposure pathways have been identified.
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OTHER DATA (SHORT-TERM TESTS, OTHER EXAMINATIONS)
Little information is available on the toxicokinetics of benzotrichloride. Available
studies (U.S. EPA, 1986; Yu and Nietschmann, 1980) indicate that benzotri chloride is rapidly
and extensively absorbed from the gastrointestinal tract of rats and efficiently eliminated in the
urine (90%) and feces (10%) 48 hours after a single oral dose of radiolabeled benzotri chloride
(data regarding specific carbon labeling is not provided). The elimination half-life of 14C was
estimated to be about 22 hours. Total radiocarbon in tissues was 1.5% of the dose after 72 hours
with fat, liver, and kidney exhibiting higher residue levels compared to other tissues and muscle
exhibiting the lowest residue levels. Excretion of benzotri chloride seemed to follow first-order
kinetics with rapid distribution in the body followed by elimination of 90% of the dose in urine
with the remaining 10% being eliminated in the feces. Yu and Nietchsmann (1980) reported that
benzotrichloride was rapidly metabolized via hydrolysis (data regarding hydrolysis via enzyme
interaction are not provided) to form benzoic acid, which was further metabolized to hippuric
acid following conjugation with glycine.
The genotoxicity of benzotrichloride has been evaluated in various studies using in vitro
and in vivo test systems (Khudoley et al., 1987; Yasuo et al., 1978; Zeiger et al.,1988; You et al.,
1986; Koshi and Fukuda, 1986). These test results indicate that benzotrichloride has mutagenic
(with metabolic activation) and clastogenic activity.
Table 3 summarizes the results of the toxicokinetics and genotoxicity studies of
benzotrichloride.
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Table 3. Other Studies for Benzotrichloride (CASRN 98-07-7)
Tests
Materials and Methods
Results
Conclusions
References
Toxicokinetic
Eight groups of 4-wk-old
Sprague-Dawley albino rats
(2-3 rats/group, M or F) were
administered one oral dose (40 mg/kg)
of 14C-benzotrichloride in corn oil.
Urine and feces samples were
collected at 24 (Groups 2 and 3), 48
(Group 4), and 72 (Groups 5, 6, 7, and
8) hrs after dosing. Group 1 samples
were collected after 8 hrs, when these
animals were sacrificed.
Benzotrichloride was rapidly absorbed by the
gastrointestinal tract and eliminated well by the urine
(90%) and feces (10%) after 48 hrs. A half-life for
absorption was estimated at 3 hrs; the half-life for
elimination from blood was 22 hrs and about 14 hrs for
elimination from tissues (kidney, liver, muscle, fat,
brain, heart, spleen, gonads, uterus, lung, and blood).
Radiocarbon residue in tissues was low, with only about
1.5% left in the body after 72 hrs. Distribution data
indicated that residue was highest in fat, followed by the
liver and kidney. No parent compound was detected in
the urine; authors suggested that the benzotrichloride
was hydrolyzed to benzoic acid, which then was
conjugated with glycine to form hippuric acid, which
was the predominate metabolite detected in urine.
Benzotrichloride was rapidly and
efficiently absorbed by the
gastrointestinal tract. However,
based on the data, authors
concluded that benzotrichloride
should not be accumulative or
persistent in mammals.
Yu and
Nietschmann
(1980);
U.S. EPA
(1986)
Genotoxicity
Ames mutagenicity assay was used to
test mutagenic potential of a number
of compounds, including
benzotrichloride. Salmonella
typhimurium strains TA98, TA100,
TA1538, TA1530, TA1535, TA1537,
TA97, and TA102 were metabolically
activated with S-9 from
Aroclor-treated rats to test for
mutagenicity.
Data showed that the benzotrichloride was mutagenic in
strains TA98, TA100, and TA1538 (the frequency of
mutations were more than spontaneous background by
2~5 fold), but not in strains TA1530, TA1535, TA1537,
TA97, or TA102.
Benzotrichloride was one of 126
compounds assayed; results for the
group of compounds including
benzotrichloride mirrored other
available data. No specific
conclusions were drawn by the
authors regarding benzotrichloride
despite findings of mutagenicity in
some strains.
Khudoley et
al. (1987)
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Table 3. Other Studies for Benzotrichloride (CASRN 98-07-7)
Tests
Materials and Methods
Results
Conclusions
References
Genotoxicity
Ames mutagenicity assay was used to
test for mutagenic potential.
Salmonella typhimurium strains TA97,
TA98, TA100, TA1535, and TA1537
were used with activation by S-9
fractions of Aroclor 1254-induced,
male Sprague-Dawley rat and male
Syrian hamster livers.
In the TA100 strain, benzotrichloride was mutagenic
without activation, with activation of Aroclor
1254-hamster liver S-9, and with Aroclor 1254-induced
rat liver S-9. In the TA98 strain, two tests without
activation yielded negative and questionable results,
respectively. In two tests (from two different
laboratories) TA98 mutagenicity tests with Aroclor
1254-hamster liver S-9 results were positive or
questionable. Both tests using TA98 with Aroclor
1254-induced rat liver S-9 were positive.
The authors concluded that
benzotrichloride is mutagenic in
bacterial test strains.
Zeiger et al.
(1988)
Genotoxicity
and
Mutagenicity
Benzotrichloride and three other
compounds were tested for
mutagenicity in vitro by rec-assay (for
DNA damage) using Bacillus subtilis,
reversion assays (for gene mutations)
using E. coli WP2, and Ames
Salmonella TA strains with and
without metabolic activation.
Benzotrichloride was positive in the rec-assay.
However, benzotrichloride required metabolic activation
in several of the Salmonella and E. coli strains before
showing mutagenic response. Benzotrichloride was
highly mutagenic in the reversion assays for WP2 her,
TA100, TA98, and TA1535 when metabolically
activated. E. coli B/r WP2 try (hcr+) was not as sensitive
to the mutagenicity of benzotrichloride as WP2 try her.
Benzotrichloride was positive in
the rec-assay without S-9; however,
it did require metabolic activation
to induce mutation. The
requirement of activation in only
some of these assays may be
related to differences in the
permeability of cell membranes
and/or to the differences in
metabolic systems of B. subtilis,
E. coli or S. typhimurium.
Yasuo et al.
(1978)

Benzotrichloride was tested using
alkaline elution to measure DNA
strand breaks in human bronchial
epithelial cells. Cells were labeled by
incubation for 3 days in medium
containing 0.1 |iCi/ml of [3H]
thymidine. The cells were treated
with BTC or benzo(a)pyrene for 1 hr
(0.1—1 |ig). washed, suspended, and
impinged onto polycarbonate filters
for detection of DNA strand breaks.
Benzotrichloride induced DNA strand breaks at all
concentrations and was 3-4 times more active than
benzo(a)pyrene.
The data indicate that
benzotrichloride is a strong inducer
of DNA strand breaks in human
precursor cells for lung cancer.
You et al.
(1986)
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Table 3. Other Studies for Benzotrichloride (CASRN 98-07-7)
Tests
Materials and Methods
Results
Conclusions
References
Clastogenicity
Male Sprague-Dawley rats were
exposed via inhalation to 1 ppm of
benzotrichloride for 6 hrs a day,
5	days a wk, over a period of 1, 3, or
6	mos.
There was a small but significant increase for all
exposure periods (1,3, and 6 mos) in chromosomal
aberrations in bone marrow cells, particularly chromatid
gaps. There was a significantly higher occurrence of
sister-chromatid exchanges in peripheral blood
lymphocytes in each exposure group when compared to
controls. Chromosomal aberrations in peripheral blood
lymphocytes were similar to controls for the 1-mo
exposure, but aberrant metaphases were significantly
higher for the 6-mo exposure group.
Results suggest clastogenic effects
occurred over all exposure periods.
However, authors concluded that
the individual responses did not
always correlate well with these
effects.
Koshi and
Fukuda (1986)
(Abstract)
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DERIVATION OF PROVISIONAL VALUES
Table 4 below summarizes the noncancer reference values. Table 5 summarizes the
cancer values. The toxicity values have been converted to HED/HEC units. IRIS data are
included in the table if available.
Table 4. Summary of Reference Values for Benzotrichloride (CASRN 98-07-7)
Toxicity Type
(Units)
Species/Sex
Critical Effect
p-Reference
Value
POD
Method
POD
UFC
Principal
Study
Subchronic
p-RfD
(mg/kg-day)
Sprague-
Dawley rat;
M/F
Significantly increased
SDH levels beginning
at the 0.046 mg/kg-day
dose group
accompanied by
morphological changes
in the liver, kidney, and
thyroid
5 x 10~5
BMDL
0.048
1000
Chu et al.
(1984)
Chronic p-RfD
(mg/kg-day)
None
None
None
None
None
None
None
Screening
Subchronic
p-RfC (mg/m3)
Albino Rat
(strain not
specified);
M/F
Significant (p < 0.01)
changes in relative
lungs and trachea
weight and
morphological
alterations in the lung,
trachea, and nasal
turbinates
5 x 10~3
BMCL
1.36
300
Levin
(1981)
Chronic p-RfC
(mg/m3)
None
None
None
None
None
None
None
Table 5. Summary of Cancer Values for Benzotrichloride (CASRN 98-07-7)
Toxicity Type"
Species/Sex
Tumor Type
Cancer Value
Principal Study
OSF
(IRIS, 1990)
ICR-JCL
Mouse/F
Squamous cell carcinoma in
the forestomach;
adenocarcinoma and
adenoma in the lung;
lymphosarcoma of the
thymus, lymphatic leukemia
in the hematopoietic system
1.3 x 101 (mg/kg-day) 1
Hooker Chemical
Company (1980)
p-IUR
None
None
None
None
"All the reference values obtained from IRIS are indicated with the latest review date.
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DERIVATION OF ORAL REFERENCE DOSES
Derivation of Subchronic p-RfD
The study by Chu et al. (1984) is selected as the principal study for deriving the
subchronic p-RfD. This study is a 28 day study and is the only available study for this purpose.
Administered dose levels in this study were: control, 0.5, 5.0, 50.0, and 500.0 ppm (0, 0.046,
0.46, 4.6, and 46 mg/kg-day). The critical endpoints reported are changes in liver SDH levels
commensurate with morphological changes reported (as occurring but not quantified) in the liver
of male and female Sprague-Dawley rats. Changes in SDH levels were reported as statistically
significant (p < 0.05) beginning at the 5.0 ppm dose level. However, no data was presented for
the 0.5 ppm level. This study is in a peer-reviewed journal publication and the study follows
standards of study design and performance. Supporting studies are Fukuda et al. (1993) and
Ruddick et al. (1982). Fukuda reported increased incidence of tumors in the forestomach as well
as lung, thymus, hematopoietic system, and hepatic vascular system at doses of 1.62 mg/kg-day.
Ruddick reported that the high dose of 50 mg/kg-day increased the number of resorption sites
and reduced number of fetuses per litter and decrease in mean fetal weight at 12.5, 25, or
50 mg/kg-day. Details are provided in the "Review of Potentially Relevant Data" section of this
report. These levels are higher than those of effects at low doses in the principal study
(Chu et al., 1984).
Since no data for SDH or other effects were reported for the 0.5 ppm level, this point
could not be considered in a BMD analysis; i.e., the point was ignored. The remaining points,
0.0, 5.0, 50.0, and 500.0 ppm were subjected to BMD analysis (see Figure C.l). The data
(extracted from the paper) are shown in Table 6.
Table 6. Data Extracted from Chu et al. (1984)
Treatment Level (ppm)
Treatment Level (mg/kg-day)
Serum SDH (mlU/ml) & SD
Control
0.0
19 ± 4.8
5.0
0.46
32 ± 8.9*
50
4.6
38 ± 15*
500
46
29 ± 12*
* Significant p > 0,05
Modeling failed for all models for the database which included the 500 ppm level. After
dropping this level, an exponential model with nonhomogeneous variance is the best fit of the
data. A change in one standard deviation from the control mean is the appropriate default
approach for the determination of the POD since expected normal ranges are unknown. Since
only two dose levels could be modeled, using the non-homogeneous variance causes loss of one
degree of freedom. Hence the model failed Test 6a (Degrees of Freedom = 0) as indicated in
Appendix C. However, visual inspection of the fitted curve and observation that the scaled
residuals were small (<2.0) provides justification for accepting the model, regardless. The BMD
and BMDLisd is 0.12 and 0.048, respectively. See Appendix C for BMD information.
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Adjusted doses for Continuous Exposure:
The study authors report that "growth rate and food consumption were not affected by
treatment," and "body weight and food consumption were determined weekly..However, the
food consumption values were not reported. The dose conversion from ppm in diet to
mg/kg-day; 0.0, 0.5, 5.0, 50, and 500 ppm to 0.0, 0.046, 0.46, 4.6, and 46 mg/kg-day is
calculated as follows. The conversion is based on a food consumption of 0.0215 kg/day (males
and females). This food consumption value (0.0215 kg food/day) can be compared to the default
food factor (subchronic for Sprague-Dawley rats) of 0.023 kg food /day for male and 0.020 for
female (U.S. EPA, 1988). The dosimetric conversion is as follows, using 0.5 ppm as an
example:
Dose adj = Dose(ppm) x (food consumption/BW) x 1 (dose is continuous)
0.5 ppm (mg/kg food) x (0.0215 kg food/day ^ 0.2355 kg bw)
= 0.046 mg/kg-day
The adjusted doses were modeled and a BMDLisd of 0.048 mg/kg-day for increased serum SDH
in males was chosen as the POD.
Subchronic p-RfD = BMDLisd UFC
= 0.048 mg/kg-day 1000
= 5 x 10~5 mg/kg-day
Tables 7 and 8 summarize the associated uncertainty factors and confidence descriptors.
Table 7. Uncertainty Factors for Subchronic p-RfD
for Benzotrichloride (CASRN 98-07-7)
UF
Value
Justification
ufa
10
A UFa of 10 is applied for interspecies extrapolation to account for potential toxicokinetic
and toxicodynamic differences between rats and humans. There are no data to determine
whether humans are more or less sensitive than rats used in Chu et al. (1984) to liver
effects of benzotrichloride.
ufd
10
The only study that is available is the Chu et al. (1984) study. No other studies of longer
duration examining a full suite of effects are available. The database includes an abstract
of a developmental study via the oral exposure route but no multigeneration reproduction
studies. As such, there is a need for developmental and multigeneration reproductive
toxicity studies via the oral route. The results of the available developmental study
indicate that the lowest administered dose exhibited a decrease in mean fetal body
weights. Additionally, skeletal anomalies, resorption sites, and reduced number of fetuses
per litter were also reported at higher doses in the studies indicating a compound-related
developmental effect. Additional studies are needed for confirming these developmental
effects. As such, an UF of 10 is applied.
UFh
10
A UFh of 10 is applied for intraspecies differences to account for potentially susceptible
individuals in the absence of definitive information on the variability of response in
humans.
ufl
1
A UFl of 1 is applied because the POD has been developed using a BMDL.
UFS
1
A UFS of 1 is applied because the principal study (Chu et al., 1984) is a subchronic study.
UFC
<3000
1000

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Table 8. Confidence Descriptor for Subchronic p-RfD for Benzotrichloride
Confidence Categories
Designation3
Discussion
Confidence in study
L
Confidence in the key study is low. Although
appropriate endpoints were evaluated in sufficient
number of animals, the exposure duration is short.
SDH values in the lowest dose administered
(0.046 mg/kg-day) were not reported. Though
morphological changes in the liver, kidney, and the
thyroid gland were noted, incidences of these
occurrences in animals were also not reported.
Additionally, though the authors state that there
were statistically significant increases in SDH
activities in animals treated with benzotrichloride,
significance level at the lowest administered dose of
0.046 mg/kg-day could not be confirmed because
SDH levels for this dose group were not provided in
the study summary.
Confidence in database
L
The database includes one chronic-duration
carcinogenicity study in rats (Fukuda et al., 1993).
One developmental toxicity study (Ruddick et al.,
1982) in the form of an abstract was available.
However, a two-generation reproduction study via
the oral route was not available.
Confidence in subchronic p-RfCb
L
The overall confidence in the subchronic p-RfD for
benzotrichloride is low because there are data gaps
in the principal study as outlined in the "Review of
Potentially Relevant Data" section.
"L = Low, M = Medium, H = High.
''The overall confidence cannot be greater than lowest entry in table.
Derivation of Chronic p-RfD
No published studies investigating the noncancer effects of chronic-duration oral
exposure to benzotrichloride in humans or animals have been identified. A short-duration
(28-day) study (Chu et al., 1984) is available. In addition, a developmental toxicity study
(Ruddick et al., 1982) is available but was reported in abstract form only. The 28-day study
would require additional UF of 10 for duration which could result in a composite UF of 10,000.
Therefore, the derivation of a chronic oral toxicity value is precluded. A screening chronic
p-RfD was not derived due to the combination of the large composite UF and the short duration
(28 days) of the available study (Chu et al., 1984).
DERIVATION OF INHALATION REFERENCE CONCENTRATIONS
Derivation of Subchronic p-RfC
No subchronic RfC is presented here because the selected study, although well designed
and managed, is unpublished. For this reason a screening value is presented in this document
that may be useful in certain instances. Please see the attached Appendix A for details.
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Derivation of Chronic p-RfC
No published studies investigating the effects of chronic-duration inhalation exposure to
benzotrichloride in humans or animals have been identified. Lack of data precludes the
derivation of a chronic inhalation toxicity value.
CANCER WEIGHT-OF-EVIDENCE DESCRIPTOR
IRIS (U.S. EPA, 1990) provides a WOE Descriptor of B2; probable human carcinogen.
DERIVATION OF PROVISIONAL CANCER VALUES
Derivation of a p-OSF
IRIS (U.S. EPA, 1990) provides an OSF of 1.3 x 101 per mg/kg-day.
Derivation of a p-IUR
IRIS (U.S. EPA, 1990) did not develop an IUR. The available inhalation studies were
evaluated and are all of less than chronic duration. Accordingly, lack of quantitative information
from chronic-duration inhalation studies precludes derivation of a p-IUR.
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APPENDIX A. DERIVATION OF A SCREENING SUBCHRONIC p-RfC
For reasons noted in the main PPRTV document, it is inappropriate to derive provisional
toxicity values for benzotrichloride. 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 study by Levin (1981, unpublished) is selected as the principal study for the
derivation of a screening subchronic p-RfC value. The critical endpoints are statistically
significant (p < 0.01) changes in relative lungs and trachea weights that are corroborated with
morphological alterations in the lung, trachea, and nasal turbinates in males and females and
significant (p < 0.01) changes in relative adrenal and thyroid weights in males and females. This
study was submitted to the EPA, Office of Pesticides and Toxic Substances (as stated in the
cover letter of the study) by Velsicol Chemical Corporation, follows GLP guidelines, and seems
to follow the standards of study design and performance with the number of animals,
examination of potential toxicity endpoints, and presentation of results. Details are provided in
the "Review of Potentially Relevant Data" section.
Justification
Available information regarding the effects of chlorinated toluenes including
benzotrichloride by inhalation in humans is limited to three occupational exposure studies
(Sorahan and Cathcart, 1989; Sorahan et al., 1983; Wong,1988). Besides cancer mortality, none
of these studies provide information regarding systemic toxicity effects. Subchronic- and
chronic-duration studies investigating systemic toxicity of benzotrichloride in animals via
inhalation have not been identified. The only short-term study that is identified pertaining to the
toxicity of inhaled benzotrichloride is the Levin (1981) study. This study is well conducted, and
the authors state that GLP protocols were followed. Additionally, the study authors also
examined several other endpoints, including hematological, biochemical, and urine analysis.
Also, the study authors observed animals for mortality, appearance, and behavior after every
exposure and once a week, respectively. Because no other short-term, subchronic-duration, or
chronic-duration systemic toxicity inhalation studies have been identified, the 4-week inhalation
study in Sprague-Dawley rats by Levin (1981) is selected as the principal study for the derivation
of a subchronic p-RfC.
Derivation of Screening Subchronic p-RfC
Because both respiratory and extrarespiratory effects were noted in treated animals,
dosimetric adjustments using equations for extrarespiratory and respiratory effects are presented
below.
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Extrarespiratory Effects
To determine the POD for the derivation of the subchronic p-RfC for relative changes in
brain and adrenals weight, exposure concentrations were converted to Human Equivalent
Concentration (HEC) using dosimetric adjustments for inhalation for extrarespiratory effects as
specified in the RfC guidelines (U.S. EPA, 1994b).
"3
NOAELhec, ExResp = (Dose in mg/m ) x (continuous adjustment) x
(blood - gas partition coefficient)
= 5.1 mg/m x (6 - 24) x (5 - 7) x (1)2 = 5.1 x 0.860
= 0.91 mg/m3
Respiratory Effects
To determine the POD for the derivation of subchronic p-RfC for relative changes in
lungs and trachea weight that were corroborated with morphological alterations in the lung,
trachea, and nasal turbinates in males and females, exposure concentrations were converted to
HECs (changes in relative lungs and trachea weight as well as morphological alterations in the
lung, trachea, and nasal turbinates) using the dosimetric adjustments for inhalation for respiratory
effects as specified in the RfC guidelines (U.S. EPA, 1994b).
NOAELhec, Resp = (Dose in mg/m ) x (continuous adjustment) x RGDR*
= 5.1 mg/m3 x (6-24) x (5-7) x 1.9
= 1.77 mg/m3
*RGDR = [(Ve/SA*)a-(Ve/SA*)h]
*SA = Total surface area
RGDR = [(0.2464591 m3/day/0.34375 m2) - (20 m3/day/54.34 m2)]
RGDR = 1.9480126
Default values for VE human and animal and SA human and animal obtained from U.S. EPA (1994b).
HECs for extrarespiratory effects are lower than respiratory. Therefore, only
extrarespiratory effects were modeled.
All of the BMCLisd predicted values in Table A. 1 are greater than the study NOAEL of
0.91 mg/m3. Since the study NOAEL is correlated to study design and only identifies a lower
point for no effects while the BMCL utilizes additional data from the study to predict a NOAEL,
the lowest BMCLisd is used as a POD. The relative brain weight in male rats, being the lowest,
is selected for use in the derivation of the p-RfC.
POD	= (BMCLisd, extrarespiratory) x 1 (modeling was done
with duration adjusted inputs) x (blood partition
coefficient)
= 1.36 mg/m3 x 1
POD (BMCL Adjusted, hec) = 1.36 mg/m3
A screening subchronic p-RfC is developed as follows:
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Screening Subchronic p-RfC = BMCL Adjusted, hec ^ UFc
= 1.36 mg/m3300
= 5 x 10~3 mg/m3
Tables A.2 and A.3, respectively, summarize the UFs and the confidence descriptor for
the screening subchronic p-RfC.
Table A.l. BMC Modeling Summary
Effect"
BMCLisd
Relative weight changes in adrenals in female rats (Table C.l)
3.37
Relative weight changes in adrenals in male rats (Table C.2)
2.27
Relative weight changes in brain in female rats (Table C.3)
4.92
Relative weight changes in brain in male rats (Table C.4)
1.36
Relative weight changes in thyroid in female rats (Table C.5)
5.89
Relative weight changes in thyroid in male rats (Table C.6)
3.60
aSee tables indicated.
Table A.2. Uncertainty Factors for Screening Subchronic p-RfC for Benzotrichloride
UF
Value
Justification
ufa
3
A UFa of 3 is applied for animal-to-human extrapolation to account for the
toxicodynamic portion of the UFA because the toxicokinetic portion (10°5) has
been addressed in dosimetric conversions.
ufd
10
Other than the principal study, there are no other inhalation studies available.
There is an the oral developmental study available in abstract format only
indicating that the lowest administered dose exhibited a decrease in mean fetal
body weights. Additionally, the study authors reported skeletal anomalies,
resorption sites, and reduced number of fetuses per litter at higher doses in the
study, indicating a compound related developmental effect.
UFh
10
A UFh of 10 is applied for intraspecies differences to account for potentially
susceptible individuals in the absence of definitive information on the variability
of response in humans.
ufl
1
A UFl of 1 is applied because the POD has been developed using a BMCL.
UFS
1
A UFS of 1 is applied because the principal study (Levin, 1981) is of subchronic
duration.
UFC
<3000
300

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Table A.3. Confidence Descriptor for Screening Subchronic p-RfC for Benzotrichloride
Confidence Categories
Designation3
Discussion
Confidence in Study
L
Confidence in the key study is low. Although the
study evaluated appropriate endpoints in an
adequate number of animals, the exposure duration
is short.
Confidence in Database
L
The database includes three chronic-duration
carcinogenicity studies in rats and mice (Koshi and
Fukuda, 1986; Takemoto et al., 1978; Yoshimura et
al., 1979).
No developmental toxicity studies and no
two-generation reproduction studies are available
via the inhalation route.
Confidence in Screening
Subchronic p-RfCb
L
The overall confidence in the subchronic p-RfC for
benzotrichloride is low.
aL = Low, M = Medium, H = High.
bThe overall confidence cannot be greater than lowest entry in table.
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APPENDIX B. DATA TABLES
Table B.l. Cancer Incidence in Mice Exposed to Benzotrichloride
via Gastric Intubation for 25 Weeks"
Dose
Group
(jil/day)
No. of Mice With
Tumors/
No. of Effective
Mice (%)
No. of Mice With Tumors
Forestomach
Lung
Hematopoietic
System (%)
Others
(%)
SCC
PA
(%)
ADC
AD
(%)


0
4/39 (10)
0
0
0
1
1
5
1(3)
lb
0.0315
10/39 (26)
0
0
0
1
6
18
2(5)
2C
0.125
30/39 (77)*
2
0
5
9
17
67*
1(3)
3d
0.5
39/40 (98)*
21
2
Ui
OO
*
16
19
OO
00
*
3(8)
5e
2.0
36/38 (95)*
24
1
66*
10
14
63*
8 (21)*
4f
aValues obtained from Fukuda et al. (1993)
fibrosarcoma of the uterus
°One hemangioendothelioma of the liver and one adenoma of the Harderian gland
dOne adenocarcinoma of the salivary gland, and one adenocarcinoma and adenoma of the mammary gland
eOne squamous cell carcinoma of the esophagus, one carcinosarcoma and one adenocarcinoma of the salivary gland,
and one adenocarcinoma and adenoma of the mammary gland
fOne adenoma of the salivary gland, one adenosquamous carcinoma, one adenocarcinoma, and one adenoma of the
mammary gland
Statistically significantly different from the control (p < 0.01) (Fisher's exact probability test)
SCC = Squamous cell carcinoma; PA = Papilloma; ADC = Adenocarcinoma; AD = Adenoma
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Table B.2. Group Mean Body Weight in Rats Treated with Benzotrichloride via Inhalation Exposure11
Dose
Group
(ppm)
PreExposure
Body Weight
(g)
Body Weight (g)
Week 1
Week 2
Week 3
Week 4
Body Weight
(% Change
Compared to
Control)
% Change
Compared
to
Preexposure
Body Weight
(% Change
Compared to
Control)
% Change
Compared
to
Preexposure
Body Weight
(% Change
Compared to
Control)
% Change
Compared
to
Preexposure
Body Weight
(% Change
Compared to
Control)
% Change
Compared
to
Preexposure
Males
0
212 ± 5.6
272 ± 11.3
28%
315 ± 17.3
49%
350 ± 18.9
65%
379 ±20.3
79%
5.1
212 ±4.9
270 ± 15.2
(-0.7%)
27%
317 ± 19.7
(0.63%)
50%
352 ±25.5
(0.57%)
66%
379 ±32.5
(0%)
79%
48.2
211 ±4.2
241 ±4.8*
(-11%)
14%
255 ± 14.6*
(-19%)
21%
272 ± 12.8*
(-22%)
29%
286 ± 17.9*
(-25%)
36%
460.0b
213 ±8.3
150
(-45%)
-30%
NA
NA
NA
NA
NA
NA
Females
0
161 ± 8.9
193 ± 13.5
15%
210 ± 11.2
35%
225 ± 15.7
40%
238 ± 15.4
48%
5.1
162 ± 8.2
193 ±9.8
(0%)
15%
215 ± 13.1
(2.4%)
33%
229 ± 17.8
(1.7%)
41%
243 ± 19.3
(2.1%)
50%
48.2
163 ±5.9
179 ± 8.0*
(-7%)
10%
>k>k
189 ± 10.7
(-10%)
16%
>k>k
198± 14.7
(-12%)
21%
>k>k
203 ± 19.7
(-14.7%)
25%
460.0b
160 ±5.6
105 ±3.5**
(-46%)
-34%
NA
NA
NA
NA
NA
NA
"Values obtained from Levin (1981) and presented as mean body weight in grams ± standard deviation
bAll animals in this dose group either died or were killed in extremis by the seventh day of the study
*p < 0.05, **p < 0.01
NA = Not applicable
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Table B.3. Results of Absolute Organ Weights in Rats Exposed to Benzotrichloride via Inhalation for 4 Weeks"
Dose
Group
(Hg/L)
No. of
Animals
Absolute Organ Weight
(% Change Compared to Control)
Spleen (g)
Liver (g)
Kidney (g)
Heart (g)
Lungs/Trachea (g)
Adrenals (mg)
Pituitary (g)
Males
0
10
0.69 ±0.094
9.88 ± 1.162
2.57 ±0.169
1.34 ±0.174
1.40 ±0.149
57 ±5.7
12 ± 1.1
5.1
10
0.74 ±0.164
(7)
9.72 ± 1.001
(-1.6)
2.51 ±0.308
(-2.3)
1.37 ±0.284
(2.2)
1.43 ±0.172
(2.1)
53 ±5.4
("7)
11 ±2.3
(-8.3)
48.2
10
0.48 ± 0.082**
(-30)
7.37 ±0.561**
(-25)
2.00 ±0.137**
(-22)
1.03 ±0.096
(-23)
1.53 ±0.137
(9.3)
50 ±7.0*
(-12.3)
9 ± 1.3**
(-25)
Females
0
10
0.49 ±0.128
6.47 ±0.456
1.64 ± 0.137
0.86 ±0.080
1.10 ± 0.130
62 ±4.8
12 ± 1.2
5.1
10
0.53 ±0.092
(8.2)
6.58 ±0.626
(1.7)
1.67 ±0.208
(1.8)
0.89 ±0.144
(3.5)
1.22 ±0.228
(11)
66 ±6.0
(6.5)
13 ±2.1
(8.3)
48.2
9
0.43 ± 0.074
(-12)
5.49 ±0.401**
(-15)
1.48 ±0.098
(-9.8)
0.74 ±0.100**
(-14)
1.36 ±0.183**
(24)
64 ± 5.3
(3.2)
11 ±2.0
(-8.33)
aValues obtained from Levin (1981) and presented as mean ± standard deviation
*p < 0.05, ** p < 0.01
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Table B.4. Results of Relative Organ Weights in Rats Exposed to Benzotrichloride via
Inhalation for 4 Weeks"
Dose Group
(Hg/L)
No. of
Animals
Relative Organ Weight (g)
(% Change Compared to Control)
Lungs/Trachea
Brain
Adrenals
Thyroid
Males
0
10
0.40 ±0.04
0.57 ±0.04
0.016 ±0.001
0.0060 ±0.0010
5.1
10
0.42 ±0.03
(5)
0.57 ±0.03
(0)
0.016 ±0.002
(0)
0.0059 ±0.0006
(-1.7)
48.2
9
0.60 ± 0.08**
(50)
0.75 ±0.06**
(32)
0.019 ±0.003*
(19)
0.0074 ±0.0012**
(23.3)
Females
0
10
0.51 ±0.034
0.88 ±0.078
0.029 ±0.0035
0.0076 ±0.0017
5.1
10
0.56 ±0.091
(9.8)
0.84 ±0.043
(-4.5)
0.030 ±0.0031
(3.4)
0.0072 ±0.0016
(-5.3)
48.2
9
0.75 ± 0.067**
(39.2)
1.00 ±0.066**
(13.6)
0.035 ±0.0039**
(20.7)
0.0086 ±0.0018
(13.2)
aValues obtained from Levin (1981) are presented as percentage of body weight ± standard deviation; study
authors do not provide information on whether preexposure body weights, or body weights after 4 weeks of
exposure were used to determine the relative organ weights
*p < 0.05, ** p < 0.01
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APPENDIX C. BMC MODELING OUTPUTS FOR BENZOTRICHLORIDE
Exponential Model 4 with 0.95 Confidence Level
Exponential
50
45
40
35
30
25
20
15
BMD
0
1
2
3
4
dose
16:32 12/20 2010
Chu et al., 1984: Output for selected model; Exponential (SDH)
Exponential Model. (Version: 1.61; Date: 7/24/2009)
Input Data File: C:\USEPA\BMDS21\Data\Trichlorotoluene\exp_Trichlorotoluene-
lastdose_chlorotoluene-exponcv-l.(d)
Gnuplot Plotting File:
Mon Dec 20 16:32:53 2010
BMDS Model Run
The form of the response function by Model:
Model 2
Model 3
Model 4
Model 5
Y[dose]	= a	*	exp{sign *	b * dose}
Y[dose]	= a	*	exp{sign *	(b * dose)Ad}
Y[dose]	= a	*	[c-(c-l) *	exp{-b * dose}]
Y[dose]	= a	*	[c-(c-l) *	exp{-(b * dose)Ad}]
Note: Y[dose] is the median response for exposure
sign = +1 for increasing trend in data;
sign = -1 for decreasing trend.
dose;
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Model 2 is nested within Models 3 and 4.
Model 3 is nested within Model 5.
Model 4 is nested within Model 5.
Dependent variable = Mean
Independent variable = Dose
Data are assumed to be distributed: normally
Variance Model: exp(lnalpha +rho *ln(Y[dose]))
The variance is to be modeled as Var(i) = exp(lalpha + log(mean(i)) * rho)
Total number of dose groups = 3
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
MLE solution provided: Exact
Initial Parameter Values
Variable
lnalpha
rho
a
b
c
d
Model 4
-5.98576
3.07359
18.05
0.547585
2.21053
1
Parameter Estimates
Variable
lnalpha
rho
Model 4
-6.20098
3.11033

a

19.0972

b

2.02513

c

2.03987

d

1
NC = No
Convergence



Table of Stats From Input
Data
Dose
N Obs Mean

Obs Std Dev
0
10 19

4.8
0.46
10 32

8.9
4.6
10 38

15

Estimated Values
of
Interest
Dose
Est Mean Est
Std
Scaled Residual
0
19.1 4.
422
-0.06952
0.46
31.13 9.
455
0.29
4.6
38.95
13.4
-0.2252
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Other models for which	likelihoods are calculated:
Model A1:	Yij	= Mu(i) + e(ij)
Var{e(ij)}	= SigmaA2
Model A2 :	Yij	= Mu(i) + e(ij)
Var{e(ij)}	= Sigma(i)^2
Model A3:	Yij	= Mu(i) + e(ij)
Var{e(ij)}	= exp(lalpha + log(mean(i)) * rho)
Model R:	Yij	= Mu + e(i)
Var{e(ij)}	= Sigma^2
Likelihoods of Interest
Model	Log(likelihood)	DF	AIC
A1	-83.80127	4	175.6025
A2	-78.04677	6	168.0935
A3	-78.28222	5	166.5644
R	-91.22702	2	186.454
4	-78.28222	5	166.5644
Additive constant for all log-likelihoods =	-27.57. This constant added to the
above values gives the log-likelihood including the term that does not
depend on the model parameters.
Explanation of Tests
Test 1: Does response and/or variances differ among Dose levels? (A2 vs. R)
Test 2: Are Variances Homogeneous? (A2 vs. Al)
Test 3: Are variances adeguately modeled? (A2 vs. A3)
Test 6a: Does Model 4 fit the data? (A3 vs 4)
Test
Test 1
Test 2
Test 3
Test 6a
Tests of Interest
-2*log(Likelihood Ratio)
26.36
11.51
0. 4709
5.684e-014
D. F.
4
2
1
0
p-value
< 0.0001
0. 003168
0. 4926
N/A
The p-value for Test 1 is less than .05. There appears to be a
difference between response and/or variances among the dose
levels, it seems appropriate to model the data.
The p-value for Test 2 is less than .1. A non-homogeneous
variance model appears to be appropriate.
The p-value for Test 3 is greater than .1. The modeled
variance appears to be appropriate here.
Degrees of freedom for Test 6a are less than or egual to 0.
The Chi-Sguare test for fit is not valid.
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Benchmark Dose Computations:
Specified Effect = 1.000000
Risk Type = Estimated standard deviations from control
Confidence Level = 0.950000
BMD =	0.124376
BMDL = 0.0477324
Levin, 1981: Relative Weight Changes in Adrenals in Female Rats
Table C.l. Model Predictions for Relative Weight Changes in Adrenals in Female Rats"
Model
Homogeneity
Variance
/7-Value
Goodness-of-Fit
p-\alueb
AIC for
Fitted
Model
bmc1sd
(mg/m3)
bmcl1sd
(mg/m3)
Conclusions
Linear
(constant
variance)
0.790
0.796
-296.10
4.89
3.37
Lowest AIC
Lowest BMCL
Polynomial
(constant
variance)
0.790
0.796
-296.10
4.89
3.37
Lowest AIC
Lowest BMCL
Maximum order beta = 0
(32 =0
Power
(constant
variance)
0.790
0.796
-296.10
4.89
3.37
Lowest AIC
Lowest BMCL
hit bound (power =1)
"Levin, 1981
bValues <0.10 fail to meet conventional goodness-of-fit criteria
AIC = Akaike's Information Criteria; BMC = benchmark concentration; BMCL lower confidence limit (95%) on the
benchmark concentration
Output for selected model: Linear
Levin, 1981: Relative Weight Changes in Adrenals in Female Rats
Polynomial Model. (Version: 2.13; Date: 04/08/2008)
Input Data File: C:\l\Levin_l98l_Adrenals_F_Linear_2.(d)
Gnuplot Plotting File: C:\l\Levin_1981_Adrenals_F_Linear_2.plt
Mon May 03 22:13:09 2010
[add notes here]
The form of the response function is:
Y[dose] = beta_0 + beta_l*dose + beta_2*doseA2 + ...
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Dependent variable = Mean
Independent variable = Dose
rho is set to 0
Signs of the polynomial coefficients are not restricted
A constant variance model is fit
Total number of dose groups = 3
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
alpha = 1.224 69e-005
rho =	0 Specified
beta_0 = 0.0291803
beta 1 = 0.000678636
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -rho
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
alpha	beta_0	beta_l
alpha 1	1.3e-0 0 9	2.6e-GlG
beta_0 1.3e-0 0 9	1	-0.62
beta 1 2.6e-010	-0.62	1
Parameter Estimates
95.0% Wald Confidence Interval
Variable	Estimate	Std. Err.	Lower Conf. Limit Upper Conf. Limit
alpha	l.lGG54e-GG5	2.89Q15e-GQ6	5.34G78e-QG6	1.667e-GG5
beta_0	0.0291802	0.000784162	0.0276433	0.0307171
beta 1	0.000 67 8 92 4	0.000162535	0.000360361	0.0009 97 487
Table of Data and Estimated Values of Interest
Dose	N Obs Mean	Est Mean Obs Std Dev Est Std Dev Scaled Res.
0 10	0.029	0.0292	0.0035	0.00332	-0.172
0.9107 10	0.03	0.0298	0.0031	0.00332	0.192
8.607	9	0.035	0.035	0.0039	0.00332	-0.0214
Model Descriptions for likelihoods calculated
Model A1:	Yij	= Mu(i) + e(ij)
Var{e(ij)}	= SigmaA2
Model A2:	Yij	= Mu(i) + e(ij)
Var{e(ij)}	= Sigma(i)A2
Model A3:	Yij	= Mu(i) + e(ij)
Var{e(ij)}	= SigmaA2
Model A3 uses any fixed variance parameters that
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were specified by the user
Model R:	Yi = Mu + e(i)
Var{e(i)} = SigmaA2
Likelihoods of Interest
Model	Log (likelihood) # Pararn's	AIC
A1	151.081809	4	-294.163619
A2	151.318092	6	-290.636184
A3	151.081809	4	-294.163619
fitted	151.048341	3	-296.096682
R	144.218266	2	-284.436532
Test
1:
Test
2:
Test
3:
Test
4 :
(Note:
Explanation of Tests
Do responses and/or variances differ among Dose levels?
(A2 vs. R)
Are Variances Homogeneous? (A1 vs A2)
Are variances adequately modeled? (A2 vs. A3)
Does the Model for the Mean Fit? (A3 vs. fitted)
When rho=0 the results of Test 3 and Test 2 will be the same.)
Tests of Interest
Test	-2*log(Likelihood Ratio)	Test df	p-value
Test 1	14.1997	4	0.006684
Test 2	0.472566	2	0.7896
Test 3	0.472566	2	0.7896
Test 4	0.0669367	1	0.7959
The p-value for Test 1 is less than .05. There appears to be a
difference between response and/or variances among the dose levels
It seems appropriate to model the data
The p-value for Test 2 is greater than .1. A homogeneous variance
model appears to be appropriate here
The p-value for Test 3 is greater than .1. The modeled variance appears
to be appropriate here
The p-value for Test 4 is greater than .1. The model chosen seems
to adequately describe the data
Benchmark Dose Computation
Specified effect =	1
Risk Type =	Estimated standard deviations from the control mean
Confidence level =	0.95
BMC =	4.88 631
BMCL =	3.36777
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Linear Model with 0.95 Confidence Level
Linear
0.038
0.036
0.034
0.032
0.03
0.028
0.026
BMDL
BMD
0
1
2
3
4
5
6
7
8
9
dose
22:13 05/03 2010
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Levin, 1981: Relative Weight Changes in Adrenals in Female Rats
Levin, 1981: Relative Weight Changes in Adrenals in Male Rats
Table C.2. Model Predictions for Relative Weight Changes in Adrenals in Male Rats"
Model
Homogeneity
Variance
p-Value
Goodness-of-Fit
p-Valueb
AIC for
Fitted
Model
8*0
Is
bmcl1sd
(mg/m3)
Conclusions
Power
(nonconstant
variance)
0.006
NA
125388.30
-999.00
-999.00
Invalid BMC
Invalid BMCL
p-score 4 < 0.1
Poor variance model
Linear
(nonconstant
variance)
0.006
0.615
-340.03
3.88
2.27
Lowest AIC
Lowest BMCL
Poor variance
model
Polynomial
(nonconstant
variance)
0.006
0.615
-340.03
3.88
2.27
Lowest AIC
Lowest BMCL
Poor variance
model
Maximum order
beta = 0
P2 =0
"Levin, 1981
bValues <0.10 fail to meet conventional goodness-of-fit criteria
AIC = Akaike's Information Criteria; BMC = benchmark concentration; BMCL lower confidence limit (95%) on
the benchmark concentration
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Output for selected model: Linear
Levin, 1981: Relative Weight Changes in Adrenals in Male Rats
Polynomial Model. (Version: 2.13; Date: 04/08/2008)
Input Data File: C:\l\Levin_l98l_Adrenals_M_Linear_l.(d)
Gnuplot Plotting File: C:\l\Levin_1981_Adrenals_M_Linear_l.plt
Mon May 03 22:04:40 2010
[add notes here]
The form of the response function is:
Y[dose] = beta_0 + beta_l*dose + beta_2*doseA2 + ...
Dependent variable = Mean
Independent variable = Dose
Signs of the polynomial coefficients are not restricted
The variance is to be modeled as Var(i) = exp(lalpha + log(mean(i)) * rho)
Total number of dose groups = 3
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
lalpha =	-12.2751
rho =	0
beta_0 = 0.0158432
beta 1 = 0.000364611
Asymptotic Correlation Matrix of Parameter Estimates
lalpha	rho	beta_0	beta_l
lalpha	1	1	0.062	-0.12
rho	1	1	0.062	-0.12
beta_0	0.062	0.062	1	-0.44
beta 1	-0.12	-0.12	-0.44	1
Parameter Estimates
95.0% Wald Confidence Interval
Variable
lalpha
rho
beta_0
beta 1
Estimate
22.0711
8.50195
0.0158586
0.000357602
Std. Err.
14.1123
3.45995
0.000339921
0.000116287
Lower Conf. Limit
-5.58851
1.72057
0.0151924
0.000129684
Upper Conf. Limit
49.7308
15.2833
0.0165248
0.000585521
Table of Data and Estimated Values of Interest
Dose	N Obs Mean	Est Mean Obs Std Dev Est Std Dev Scaled Res.
0 10	0.016	0.0159	0.001	0.00139	0.322
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0.9107 10	0.016	0.0162	0.002	0.00151	-0.385
8.607 10	0.019	0.0189	0.003	0.00295	0.0681
Model Descriptions for likelihoods calculated
Model A1:	Yij = Mu(i) + e(ij)
Var{e(ij)} = SigmaA2
Model A2 :	Yij = Mu(i) + e(ij)
Var{e(ij)} = Sigma(i)A2
Model A3:	Yij = Mu(i) + e(ij)
Var{e(ij)} = exp(lalpha + rho*ln(Mu(i)))
Model A3 uses any fixed variance parameters that
were specified by the user
Model R:	Yi = Mu + e(i)
Var{e(i)} = SigmaA2
Likelihoods of Interest
Model	Log(likelihood) # Param's	AIC
A1	170.706390	4	-333.412781
A2	175.895471	6	-339.790943
A3	174.141539	5	-338.283079
fitted	174.014936	4	-340.029872
R	164.864419	2	-325.728838
Test
1:
Test
2:
Test
3:
Test
4 :
Explanation of Tests
Do responses and/or variances differ among Dose levels?
(A2 vs. R)
Are Variances Homogeneous? (A1 vs A2)
Are variances adequately modeled? (A2 vs. A3)
Does the Model for the Mean Fit? (A3 vs. fitted)
(Note: When rho=0 the results of Test 3 and Test 2 will be the same.)
Tests of Interest
Test -2*log(Likelihood Ratio) Test df	p-value
Test 1	22.0621	4	0.0001948
Test 2	10.3782	2	0.005577
Test 3	3.50786	1	0.06108
Test 4	0.253206	1	0.6148
The p-value for Test 1 is less than .05. There appears to be a
difference between response and/or variances among the dose levels
It seems appropriate to model the data
The p-value for Test 2 is less than .1. A non-homogeneous variance
model appears to be appropriate
The p-value for Test 3 is less than .1. You may want to consider a
different variance model
The p-value for Test 4 is greater than .1. The model chosen seems
to adequately describe the data
Benchmark Dose Computation
Specified effect =	1
Risk Type	=	Estimated standard deviations from the control mean
Confidence level =	0.95
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BMC
3.87848
BMCL
2.27453
FINAL
12-19-2011
Linear Model with 0.95 Confidence Level
0.021
0.02
0.019
0.018
0.017
0.016
0.015
0.014
22:04 05/03 2010
Linear
BMDL
BMD
4 5
dose
Levin, 1981: Relative Weight Changes in Adrenals in Male Rats
Levin, 1981: Relative Weight Changes in Brain in Female Rats
Table C.3. Model Predictions for Relative Weight Changes in Brain in Female Rats"
Model
Homogeneity
Variance
p-Value
Goodness-of-Fit
p-Valueb
AIC for
Fitted
Model
BMC1SD
(mg/m3)
BMCL1SD
(mg/m3)
Conclusions
Linear
(constant
variance)
0.185
0.048
-123.76
3.91
2.82
p-score 4 < 0.1
Power
(constant
variance)
0.185
NA
-123.56
7.88
3.20
p-score 4 < 0.1
Polynomial
(constant
variance)
0.185
0.132
-125.40
5.76
4.92
Lowest AIC
Lowest BMCL
"Levin, 1981
bValues <0.10 fail to meet conventional goodness-of-fit criteria
AIC = Akaike's Information Criteria; BMC = benchmark concentration; BMCL lower confidence limit (95%) on
the benchmark concentration
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Output for selected model: Polynomial
Levin, 1981: Relative Weight Changes in Brain in Female Rats
Polynomial Model. (Version: 2.13; Date: 04/08/2008)
Input Data File: C:\l\Levin_1981_Brain_F_Poly_2.(d)
Gnuplot Plotting File: C:\l\Levin_1981_Brain_F_Poly_2.pit
Mon May 03 22:14:34 2010
[add notes here]
The form of the response function is:
Y[dose] = beta_0 + beta_l*dose + beta_2*doseA2 + ...
Dependent variable = Mean
Independent variable = Dose
rho is set to 0
The polynomial coefficients are restricted to be positive
A constant variance model is fit
Total number of dose groups = 3
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
alpha = 0.00408635
rho =	0 Specified
beta_G =	0.88
beta_l =	0
beta 2 =	0
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -rho -beta_l
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
alpha	beta_0	beta_2
alpha 1 -4.5e-GG9	-I.9e-G1G
beta_0 -4.5e-009	1	-0.56
beta 2 -1.9e-010	-0.56	1
Parameter Estimates
Variable
alpha
beta_0
beta_l
beta 2
Estimate
0.00396162
0.859331
.877 62e-024
0.00189536
Std. Err.
0.00104037
0.0141536
NA
0.000342935
95.0% Wald Confidence Interval
Lower Conf. Limit Upper Conf. Limit
0.00192253	0.00600071
0.83159	0.887072
0.001
0.0025675
NA - Indicates that this parameter has hit a bound
implied by some inequality constraint and thus
has no standard error.
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Table of Data and Estimated Values of Interest
Dose	N Obs Mean	Est Mean Obs Std Dev Est Std Dev Scaled Res.
Model A1:	Yij = Mu(i) + e(ij)
Var{e(ij)} = SigmaA2
Model A2 :	Yij = Mu(i) +e(ij)
Var{e(ij)} = Sigma(i)A2
Model A3:	Yij = Mu(i) +e(ij)
Var{e(ij)} = SigmaA2
Model A3 uses any fixed variance parameters that
were specified by the user
Model R:	Yi = Mu + e(i)
Var{e(i)} = SigmaA2
0 10	0.88	0.859	0.078	0.0629	1.04
0.9107 10	0.84	0.861	0.043	0.0629	-1.05
8.607	9	1	1	0.066	0.0629	0.0124
Model Descriptions for likelihoods calculated
Likelihoods of Interest
Model	Log(likelihood) # Param's	AIC
A1	66.834899	4	-125.669797
A2	68.522550	6	-125.045100
A3	66.834899	4	-125.669797
fitted	65.700977	3	-125.401955
R	55.268815	2	-106.537629
Explanation of Tests
Test 1:
Test 2
Test 3
Test 4
(Note:
Do responses and/or variances differ among Dose levels?
(A2 vs. R)
Are Variances Homogeneous? (A1 vs A2)
Are variances adequately modeled? (A2 vs. A3)
Does the Model for the Mean Fit? (A3 vs. fitted)
When rho=0 the results of Test 3 and Test 2 will be the same.)
Tests of Interest
Test
-2*log(Likelihood Ratio) Test df
p-value
Test 1
Test 2
Test 3
Test 4
26.5075
3.3753
3.3753
2.26784
<.0001
0 . 185
0 . 185
0.1321
The p-value for Test 1 is less than .05. There appears to be a
difference between response and/or variances among the dose levels
It seems appropriate to model the data
The p-value for Test 2 is greater than .1.
model appears to be appropriate here
A homogeneous variance
The p-value for Test 3 is greater than .1. The modeled variance appears
to be appropriate here
The p-value for Test 4 is greater than .1. The model chosen seems
to adequately describe the data
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Benchmark Dose Computation
Specified effect =	1
Risk Type =	Estimated standard deviations from the control mean
Confidence level =	0.95
BMC =	5.76266
BMCL =	4.92272
Polynomial Model with 0.95 Confidence Level
Polynomial
1.05
0.95
0.9
0.85
BMDL
BMD
0
1
2
3
4
5
6
7
8
9
dose
22:14 05/03 2010
Levin, 1981: Relative Weight Changes in Brain in Female Rats
Levin, 1981: Relative Weight Changes in Brain in Male Rats
Table C.4. Model Predictions for Relative Weight Changes in Brain in Male Rats3
Model
Homogeneity
Variance
p-Value
Goodness-of-Fit
p-Valueb
AIC for
Fitted
Model
BMC1SD
(mg/m3)
bmcl1sd
(mg/m3)
Conclusions
Linear
(nonconstant variance)
0.089
0.154
-153.11
1.60
1.19
Lowest BMCL
Polynomial
(nonconstant
variance)
0.089
0.782
-155.06
3.70
1.36
Lowest AIC
pi =0
Power
(nonconstant variance)
0.089
NA
-153.12
7.13
1.37
/?-score 4 < 0.1
BMC/BMCL ratio > 3
aLevin 1981
bValues <0.10 fail to meet conventional goodness-of-fit criteria
AIC = Akaike's Information Criteria; BMC = benchmark concentration; BMCL lower confidence limit (95%) on the
benchmark concentration
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Output for selected model: Polynomial
Levin, 1981: Relative Weight Changes in Brain in Male Rats
Polynomial Model. (Version: 2.13; Date: 04/08/2008)
Input Data File: C:\l\Levin_1981_Brain_M_Poly_l.(d)
Gnuplot Plotting File: C:\l\Levin_1981_Brain_M_Poly_l.pit
Mon May 03 22:02:33 2010
[add notes here]
The form of the response function is:
Y[dose] = beta_0 + beta_l*dose + beta_2*doseA2 + ...
Dependent variable = Mean
Independent variable = Dose
The polynomial coefficients are restricted to be positive
The variance is to be modeled as Var(i) = exp(lalpha + log(mean(i)) * rho)
Total number of dose groups = 3
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
lalpha =	-6.19808
rho =	0
beta_G =	0.57
beta_l =	0
beta 2 = 0.00271731
Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -beta_l
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
lalpha	rho	beta_0	beta_2
lalpha 1	0.96	le-005	-0.00024
rho 0.96	1	-8.7e-GG6	-0.00021
beta_0 le-005	-8.7e-006	1	-0.4
beta 2 -0.00024	-0.00021	-0.4	1
Parameter Estimates
95.0% Wald Confidence Interval
Variable Estimate Std. Err.	Lower Conf. Limit	Upper Conf. Limit
lalpha -4.63533 0.971828	-6.54008	-2.73059
rho 3.82488 1.99069	-0.076796	7.72656
beta_0 0.569001 0.00756025	0.554183	0.583818
beta_l 0 NA
beta_2 0.00244278 0.000264367	0.00192463	0.00296093
NA - Indicates that this parameter has hit a bound
implied by some inequality constraint and thus
49
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has no standard error.
Table of Data and Estimated Values of Interest
Dose	N Obs Mean	Est Mean Obs Std Dev Est Std Dev Scaled Res.
0 10	0.57	0.569	0.04	0.0335	0.0943
0.9107 10	0.57	0.571	0.03	0.0337	-0.0962
8.607 10	0.75	0.75	0.06	0.0568	0.00206
Model Descriptions for likelihoods calculated
Model A1:	Yij = Mu(i) + e(ij)
Var{e(ij)} = SigmaA2
Model A2:	Yij = Mu(i) +e(ij)
Var{e(ij)} = Sigma(i)A2
Model A3:	Yij = Mu(i) +e(ij)
Var{e(ij)} = exp(lalpha + rho*ln(Mu(i)))
Model A3 uses any fixed variance parameters that
were specified by the user
Model R:	Yi = Mu + e(i)
Var{e(i)} = SigmaA2
Likelihoods of Interest
Model	Log(likelihood)	# Param's	AIC
A1	79.551590	4	-151.103179
A2	81.968852	6	-151.937704
A3	81.570537	5	-153.141074
fitted	81.532234	4	-155.064468
R	55.608044	2	-107.216087
Explanation of Tests
Test
1:
Test
2:
Test
3:
Test
4 :
(Note:
Do responses and/or variances differ among Dose levels?
(A2 vs. R)
Are Variances Homogeneous? (A1 vs A2)
Are variances adequately modeled? (A2 vs. A3)
Does the Model for the Mean Fit? (A3 vs. fitted)
When rho=0 the results of Test 3 and Test 2 will be the same.)
Tests of Interest
Test	-2*log(Likelihood Ratio)	Test df	p-value
Test 1	52.7216	4	<.0001
Test 2	4.83452	2	0.08917
Test 3	0.79663	1	0.3721
Test 4	0.0766067	1	0.7819
The p-value for Test 1 is less than .05. There appears to be a
difference between response and/or variances among the dose levels
It seems appropriate to model the data
The p-value for Test 2 is less than .1. A non-homogeneous variance
model appears to be appropriate
The p-value for Test 3 is greater than .1. The modeled variance appears
to be appropriate here
The p-value for Test 4 is greater than .1. The model chosen seems
50
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to adequately describe the data
Benchmark Dose Computation
Specified effect =	1
Risk Type =	Estimated standard deviations from the control mean
Confidence level =	0.95
BMC =	3.70353
BMCL =	1.3 60 67
Polynomial Model with 0.95 Confidence Level
Polynomial
8
0.75
0.7
0.65
0.6
0.55
BMDL
BMD
0
1
2
3
4
5
6
7
8
9
dose
22:02 05/03 2010
Levin, 1981: Relative Weight Changes in Brain in Male Rats
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Levin, 1981: Relative Weight Changes in Thyroid in Female Rats
Table C.5. Model Predictions for Relative Weight Changes in Thyroid in Female Rats"
Model
Homogeneity
Variance p-Value
Goodness-of-Fit
p-Valueb
AIC for
Fitted Model
bmc1sd
(mg/m3)
bmcl1sd
(mg/m3)
Conclusions
Linear
(constant variance)
0.943
0.462
-337.56
11.48
5.89
Lowest BMCL
Power
(constant variance)
0.943
NA
-335.80
8.90
6.02
p-score 4 < 0.1
Polynomial
(constant variance)
0.943
0.566
-337.78
9.98
7.20
Lowest AIC
"Levin, 1981
Values <0.10 fail to meet conventional goodness-of-fit criteria
AIC = Akaike's Information Criteria; BMC = benchmark concentration; BMCL lower confidence limit (95%) on the
benchmark concentration
Output for selected model: Polynomial
Levin, 1981: Relative Weight Changes in Thyroid in Female Rats
Polynomial Model. (Version: 2.13; Date: 04/08/2008)
Input Data File: C:\l\Levin_1981_Thyroids_F_Poly_2.(d)
Gnuplot Plotting File: C:\l\Levin_1981_Thyroids_F_Poly_2.pit
Mon May 03 22:12:00 2010
[add notes here]
The form of the response function is:
Y[dose] = beta_0 + beta_l*dose + beta_2*doseA2 + ...
Dependent variable = Mean
Independent variable = Dose
rho is set to 0
The polynomial coefficients are restricted to be positive
A constant variance model is fit
Total number of dose groups = 3
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
alpha = 2.88346e-006
rho =	0 Specified
beta_G =	0.007 6
beta_l =	0
beta 2 =	0
Asymptotic Correlation Matrix of Parameter Estimates
52
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( *** The model parameter(s) -rho -beta_l
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
alpha	beta_0	beta_2
alpha 1	5e-010	-9.5e-012
beta_0 5e-010	1	-0.56
beta 2 -9.5e-012	-0.56	1
Parameter Estimates
95.0% Wald Confidence Interval
Variable Estimate Std. Err.	Lower Conf. Limit	Upper Conf. Limit
alpha 2.61465e-006 6.86641e-007	1.26886e-006	3.96044e-006
beta_0 0.00739443 0.000363612	0.00668176	0.0081071
beta_l 2.03355e-025 NA
beta~2 1.62389e-005 8.81012e-006	-1.02863e-006	3.35064e-005
NA - Indicates that this parameter has hit a bound
implied by some inequality constraint and thus
has no standard error.
Table of Data and Estimated Values of Interest
Dose	N Obs Mean	Est Mean Obs Std Dev Est Std Dev Scaled Res.
0 10	0.0076	0.00739	0.0017	0.00162	0.402
0.9107 10	0.0072	0.00741	0.0016	0.00162	-0.407
8.607	9	0.0086	0.0086	0.0018	0.00162	0.0048
Model Descriptions for likelihoods calculated
Model A1:	Yij = Mu(i) + e(ij)
Var{e(ij)} = SigmaA2
Model A2:	Yij = Mu(i) +e(ij)
Var{e(ij)} = Sigma(i)A2
Model A3:	Yij = Mu(i) +e(ij)
Var{e(ij)} = SigmaA2
Model A3 uses any fixed variance parameters that
were specified by the user
Model R:	Yi = Mu + e(i)
Var{e(i)} = SigmaA2
Likelihoods of Interest
Model	Log(likelihood) # Param's	AIC
A1	172.052916	4	-336.105832
A2	172.112133	6	-332.224266
A3	172.052916	4	-336.105832
fitted	171.888511	3	-337.777023
R	170.282159	2	-336.564317
Explanation of Tests
Test 1: Do responses and/or variances differ among Dose levels?
(A2 vs. R)
53
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Test 2:	Are Variances Homogeneous? (A1 vs A2)
Test 3:	Are variances adequately modeled? (A2 vs. A3)
Test 4:	Does the Model for the Mean Fit? (A3 vs. fitted)
(Note:	When rho=0 the results of Test 3 and Test 2 will be the same.)
Tests of Interest
Test	-2*log(Likelihood Ratio)	Test df	p-value
Test 1	3.65995	4	0.454
Test 2	0.118434	2	0.9425
Test 3	0.118434	2	0.9425
Test 4	0.32881	1	0.5664
The p-value for Test 1 is greater than .05. There may not be a
diffence between responses and/or variances among the dose levels
Modelling the data with a dose/response curve may not be appropriate
The p-value for Test 2 is greater than .1. A homogeneous variance
model appears to be appropriate here
The p-value for Test 3 is greater than .1. The modeled variance appears
to be appropriate here
The p-value for Test 4 is greater than .1. The model chosen seems
to adequately describe the data
Benchmark Dose Computation
Specified effect =	1
Risk Type =	Estimated standard deviations from the control mean
Confidence level =	0.95
BMC =	9.97 87 3
BMCL =	7.20419
Polynomial Model with 0.95 Confidence Level
Polynomial
0.01
0.0095
0.009
0.0085
0.008
0.0075
0.007
0.0065
0.006
BMDL
BMD
0
2
4
6
8
10
dose
22:12 05/03 2010
Levin, 1981: Relative Weight Changes in Thyroid in Female Rats
54
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Levin, 1981: Relative Weight Changes in Thyroid in Male Rats
Table C.6. Model Predictions for Relative Weight Changes in Thyroid in Male Rats"

Homogeneity
Variance
Goodness-of-Fit
AIC for
Fitted
bmc1sd
bmcl1sd

Model
p-Value
p-Valueb
Model
(mg/m3)
(mg/m3)
Conclusions
Linear
0.105
0.818
-385.29
5.27
3.60
Lowest AIC
(constant variance)





Lowest BMCL
Power
0.105
NA
-381.64
8.16
3.68
p-score 4 < 0.1
(constant variance)






Polynomial
0.105
0.777
-383.62
6.83
5.66

(constant variance)






"Levin, 1981
Values <0.10 fail to meet conventional goodness-of-fit criteria
AIC = Akaike's Information Criteria; BMC = benchmark concentration; BMCL lower confidence limit (95%) on
the benchmark concentration
Output for selected model: Linear
Levin, 1981: Relative Weight Changes in Thyroid in Male Rats
Polynomial Model. (Version: 2.13; Date: 04/08/2008)
Input Data File: C:\l\Levin_1981_Thyroids_M_Linear_2.(d)
Gnuplot Plotting File: C:\l\Levin_1981_Thyroids_M_Linear_2.pit
Mon May 03 22:10:52 2010
[add notes here]
The form of the response function is:
Y[dose] = beta_0 + beta_l*dose + beta_2*dose/x2 + ...
Dependent variable = Mean
Independent variable = Dose
rho is set to 0
Signs of the polynomial coefficients are not restricted
A constant variance model is fit
Total number of dose groups = 3
Total number of records with missing values = 0
Maximum number of iterations = 250
Relative Function Convergence has been set to: le-008
Parameter Convergence has been set to: le-008
Default Initial Parameter Values
alpha = 9.33333e-007
rho =	0 Specified
beta_G = 0.00587747
beta 1 = 0.00017521
! ! ! Warning: optimum may not have been found. ! ! !
!!! You may want to try choosing different initial values.
55
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Asymptotic Correlation Matrix of Parameter Estimates
( *** The model parameter(s) -alpha -rho
have been estimated at a boundary point, or have been specified by the user,
and do not appear in the correlation matrix )
beta_0	beta_l
beta_0	1	-0.63
beta 1	-0.63	1
Parameter Estimates
95.0% Wald Confidence Interval
Variable	Estimate	Std. Err.	Lower Conf. Limit Upper Conf. Limit
alpha	8.51334e-007	NA
beta_0	0.00587747	0.00021804	0.00545012	0.00630482
beta_l	0.00017521	4.36342e-005	8.96887e-005	0.000260732
NA - Indicates that this parameter has hit a bound
implied by some inequality constraint and thus
has no standard error.
Table of Data and Estimated Values of Interest
Dose	N Obs Mean	Est Mean Obs Std Dev Est Std Dev Scaled Res.
0 10	0.006	0.00588	0.001	0.000923	0.42
0.9107 10	0.0059	0.00604	0.0006	0.000923	-0.47
8.607 10	0.0074	0.00739	0.0012	0.000923	0.0497
Model Descriptions for likelihoods calculated
Model A1:	Yij = Mu(i) + e(ij)
Var{e(ij)} = SigmaA2
Model A2:	Yij = Mu(i) +e(ij)
Var{e(ij)} = Sigma(i)A2
Model A3:	Yij = Mu(i) +e(ij)
Var{e(ij)} = SigmaA2
Model A3 uses any fixed variance parameters that
were specified by the user
Model R:	Yi = Mu + e(i)
Var{e(i)} = SigmaA2
Likelihoods of Interest
Model	Log(likelihood) # Param's	AIC
A1	194.847959	4	-381.695918
A2	197.098107	6	-382.196214
A3	194.847959	4	-381.695918
fitted	194.646919	2	-385.293839
R	188.194979	2	-372.389959
Explanation of Tests
Test 1: Do responses and/or variances differ among Dose levels?
(A2 vs. R)
Test 2: Are Variances Homogeneous? (A1 vs A2)
56
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Test 3: Are variances adequately modeled? (A2 vs. A3)
Test 4: Does the Model for the Mean Fit? (A3 vs. fitted)
(Note: When rho=0 the results of Test 3 and Test 2 will be the same.)
Tests of Interest
Test	-2*log(Likelihood Ratio)	Test df	p-value
Test 1	17.8063	4	0.001346
Test 2	4.5003	2	0.1054
Test 3	4.5003	2	0.1054
Test 4	0.402079	2	0.8179
The p-value for Test 1 is less than .05. There appears to be a
difference between response and/or variances among the dose levels
It seems appropriate to model the data
The p-value for Test 2 is greater than .1. A homogeneous variance
model appears to be appropriate here
The p-value for Test 3 is greater than .1. The modeled variance appears
to be appropriate here
The p-value for Test 4 is greater than .1. The model chosen seems
to adequately describe the data
Benchmark Dose Computation
Specified effect =	1
Risk Type =	Estimated standard deviations from the control mean
Confidence level =	0.95
BMC =	5.2 6 612
BMCL =	3.5 9 958
Linear Model with 0.95 Confidence Level
0.0085
Linear
0.008
0.0075
0.007
0.0065
0.006
0.0055
BMDL
BMD
0.005
0
1
2
3
4
5
6
7
8
9
dose
22:10 05/03 2010
Levin, 1981: Relative Weight Changes in Thyroid in Male Rats
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