United States
Environmental Protection
1=1 m m Agency
EPA/690/R-06/021F
Final
8-03-2006
Provisional Peer Reviewed Toxicity Values for
4,4'-Methylenebis (2-chloroaniline)
(CASRN 101-14-4)
Superfund Health Risk Technical Support Center
National Center for Environmental Assessment
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati, OH 45268
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Acronyms and Abbreviations
bw body weight
cc cubic centimeters
CD Caesarean Delivered
CERCLA Comprehensive Environmental Response, Compensation and Liability Act
of 1980
CNS central nervous system
cu.m cubic meter
DWEL Drinking Water Equivalent Level
FEL frank-effect level
FIFRA Federal Insecticide, Fungicide, and Rodenticide Act
g grams
GI gastrointestinal
HEC human equivalent concentration
Hgb hemoglobin
i.m. intramuscular
i.p. intraperitoneal
i.v. intravenous
IRIS Integrated Risk Information System
IUR inhalation unit risk
kg kilogram
L liter
LEL lowest-effect level
LOAEL lowest-observed-adverse-effect level
LOAEL(ADJ) LOAEL adjusted to continuous exposure duration
LOAEL(HEC) LOAEL adjusted for dosimetric differences across species to a human
m meter
MCL maximum contaminant level
MCLG maximum contaminant level goal
MF modifying factor
mg milligram
mg/kg milligrams per kilogram
mg/L milligrams per liter
MRL minimal risk level
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MTD
maximum tolerated dose
MTL
median threshold limit
NAAQS
National Ambient Air Quality Standards
NOAEL
no-observed-adverse-effect level
NOAEL(ADJ)
NOAEL adjusted to continuous exposure duration
NOAEL(HEC)
NOAEL adjusted for dosimetric differences across species to a human
NOEL
no-observed-effect level
OSF
oral slope factor
p-IUR
provisional inhalation unit risk
p-OSF
provisional oral slope factor
p-RfC
provisional inhalation reference concentration
p-RfD
provisional oral reference dose
PBPK
physiologically based pharmacokinetic
PPb
parts per billion
ppm
parts per million
PPRTV
Provisional Peer Reviewed Toxicity Value
RBC
red blood cell(s)
RCRA
Resource Conservation and Recovery Act
RDDR
Regional deposited dose ratio (for the indicated lung region)
REL
relative exposure level
RfC
inhalation reference concentration
RfD
oral reference dose
RGDR
Regional gas dose ratio (for the indicated lung region)
s.c.
subcutaneous
SCE
sister chromatid exchange
SDWA
Safe Drinking Water Act
sq.cm.
square centimeters
TSCA
Toxic Substances Control Act
UF
uncertainty factor
Hg
microgram
|j,mol
micromoles
voc
volatile organic compound
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PROVISIONAL PEER REVIEWED TOXICITY VALUES FOR
4,4'-METHYLENEBIS (2-CHLOROANILINE) (CASRN 101-14-4)
Background
On December 5, 2003, the U.S. Environmental Protection Agency's (EPA's) Office of
Superfund Remediation and Technology Innovation (OSRTI) revised its hierarchy of human
health toxicity values for Superfund risk assessments, establishing the following three tiers as the
new hierarchy:
1. EPA's Integrated Risk Information System (IRIS).
2. Provisional Peer-Reviewed Toxicity Values (PPRTV) used in EPA's Superfund
Program.
3. Other (peer-reviewed) toxicity values, including:
~ Minimal Risk Levels produced by the Agency for Toxic Substances and Disease
Registry (ATSDR),
~ California Environmental Protection Agency (CalEPA) values, and
~ EPA Health Effects Assessment Summary Table (HEAST) values.
A PPRTV is defined as a toxicity value derived for use in the Superfund Program when
such a value is not available in EPA's Integrated Risk Information System (IRIS). PPRTVs are
developed according to a Standard Operating Procedure (SOP) and are derived after a review of
the relevant scientific literature using the same methods, sources of data, and Agency guidance
for value derivation generally used by the EPA IRIS Program. All provisional toxicity values
receive internal review by two EPA scientists and external peer review by three independently
selected scientific experts. PPRTVs differ from IRIS values in that PPRTVs do not receive the
multi-program consensus review provided for IRIS values. This is because IRIS values are
generally intended to be used in all EPA programs, while PPRTVs are developed specifically for
the Superfund Program.
Because science and available information evolve, PPRTVs are initially derived with a
three-year life-cycle. However, EPA Regions or the EPA Headquarters Superfund Program
sometimes request that a frequently used PPRTV be reassessed. Once an IRIS value for a
specific chemical becomes available for Agency review, the analogous PPRTV for that same
chemical is retired. It should also be noted that some PPRTV manuscripts conclude that a
PPRTV cannot be derived based on inadequate data.
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Disclaimers
Users of this document should first check to see if any IRIS values exist for the chemical
of concern before proceeding to use a PPRTV. If no IRIS value is available, staff in the regional
Superfund and RCRA program offices are advised to carefully review the information provided
in this document to ensure that the PPRTVs used are appropriate for the types of exposures and
circumstances at the Superfund site or RCRA facility in question. PPRTVs are periodically
updated; therefore, users should ensure that the values contained in the PPRTV are current at the
time of use.
It is important to remember that a provisional value alone tells very little about the
adverse effects of a chemical or the quality of evidence on which the value is based. Therefore,
users are strongly encouraged to read the entire PPRTV manuscript and understand the strengths
and limitations of the derived provisional values. PPRTVs are developed by the EPA Office of
Research and Development's National Center for Environmental Assessment, Superfund Health
Risk Technical Support Center for OSRTI. Other EPA programs or external parties who may
choose of their own initiative to use these PPRTVs are advised that Superfund resources will not
generally be used to respond to challenges of PPRTVs used in a context outside of the Superfund
Program.
Questions Regarding PPRTVs
Questions regarding the contents of the PPRTVs and their appropriate use (e.g., on
chemicals not covered, or whether chemicals have pending IRIS toxicity values) may be directed
to the EPA Office of Research and Development's National Center for Environmental
Assessment, Superfund Health Risk Technical Support Center (513-569-7300), or OSRTI.
INTRODUCTION
The HEAST (U.S. EPA, 1997) includes subchronic and chronic oral RfDs of 7E-4
mg/kg-day for 4,4'-methylenebis(2-chloroaniline) (MOCA) that were based on liver and urinary
bladder effects in dogs given an average daily dose of 7.3 mg/kg-day of MOCA via gelatin
capsules for 9 years by Stula et al. (1977). An uncertainty factor of 10,000 was applied to the
LOAEL. The source of this assessment was a Health and Environmental Effects Document
(HEED) (U.S. EPA, 1990). No RfD assessment for MOCA is available on IRIS (U.S. EPA,
2005a) or in the Drinking Water Standards and Health Advisories list (U.S. EPA, 2002). Other
than the HEED discussed above, the CARA list (U.S. EPA, 1991, 1994) does not include any
relevant documents. ATSDR (1994) derived a chronic oral MRL of 0.003 mg/kg-day for
MOCA, based on a LOAEL of 10 mg/kg-day for hepatic effects (liver hyperplasia, increased
serum ALT) in the Stula et al. (1977) dog study and an uncertainty factor of 3000. ATSDR
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(1994) did not derive an acute or an intermediate duration oral MRL due to lack of data. WHO
(2002) has not assessed the toxicity of MOCA.
The HEAST (U.S. EPA, 1997) does not provide an RfC for MOCA, reporting that a
chronic inhalation RfC was considered not verifiable by the RfD/RfD Work Group (2/10/93).
U.S. EPA (1990) concluded that inhalation data were inadequate for quantitative risk assessment.
An RfC for MOCA is not available on IRIS (U.S. EPA, 2005a). ATSDR (1994) did not derive
MRLs for inhalation exposure due to the lack of suitable data. ACGIH (2001, 2002) has
established a TLV-TWA of 0.01 ppm (0.11 mg/m3) for MOCA in order to protect against
cyanosis, methemoglobinemia, adverse effects on the kidney, and cancer in the bladder and other
tissues in workers. The NIOSH (2002) REL-TWA is 0.003 mg/m3. OSHA (2002) has not
established a PEL for this chemical.
MOCA is listed on the HEAST (U.S. EPA, 1997) as a Group B2 carcinogen with an oral
slope factor of 1.3E-1 (mg/kg-day)"1 based on lung tumors in 2-year rat studies by Stula et al.
(1975) and Kommineni et al. (1978). The HEAST also reports an inhalation unit risk of 3.7E-5
(|ig/m3)"' based on route-to-route extrapolation from the oral data. The HEED (U.S. EPA, 1990)
was the source document for this assessment. A cancer assessment for MOCA is not available
on IRIS (U.S. EPA, 2005a) or in the Drinking Water Standards and Health Advisories list (U.S.
EPA, 2002). IARC (1993) classified MOCA into Group 2A,probably carcinogenic to humans,
and ACGIH (2002) put MOCA in Group A2 as a suspected human carcinogen. NTP (2002) has
not performed a cancer bioassay for MOCA.
Literature searches were conducted from 1989 to 2002 for studies relevant to the
derivation of provisional toxicity values for MOCA. The databases searched were: TOXLINE,
MEDLINE, CANCERLIT, RTECS, GENETOX, HSDB, CCRIS, TSCATS, EMIC/EMICBACK
and DART/ETICBACK. Additional literature searches were conducted by NCEA-Cincinnati
from 2002 through April 2004 using TOXLINE, MEDLINE, Chemical and Biological Abstracts
databases.
REVIEW OF PERTINENT DATA
Human Studies
Epidemiological studies of MOCA in human workers are limited. The studies have
primarily been designed to look for bladder cancer, as MOCA is structurally similar to benzidine,
which is known to produce bladder tumors in humans, and MOCA has been shown to produce
bladder tumors in animal studies.
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Linch et al. (1971) compared a group of 31 active MOCA-exposed workers at a chemical
production facility (average age of 50 years; MOCA exposure ranging from 6 months to 50
years) to 31 control workers at the plant without MOCA exposure with regard to overall health
classification, frequency and duration of absenteeism, type of illness, and urinary sediment
examination. There were no differences between active MOCA workers and controls. No
malignancies or deaths occurred in either group. The researchers further compared another group
of 178 employees who had worked with MOCA at one time, but not for at least 10 years, with
the plant population as a whole using the same endpoints. Again, no differences were found.
Two deaths due to malignancy were recorded among the 178 early exposure MOCA workers, but
in both cases, the original diagnosis (laryngeal carcinoma, carcinoma of the large bowel) and
surgery occurred prior to the earliest MOCA exposure. Continued monitoring by annual urinary
analysis and cytology revealed no cases of bladder cancer through November, 1981 among the
early exposure MOCA workers still employed by the company (workers who left the company
were not monitored for cancer incidence) (Ward et al., 1987).
Ward et al. (1988) studied the incidence of bladder cancer among workers exposed to
MOCA between 1968-1979 at a Michigan chemical plant. Exposure concentrations were not
quantified. Urine samples were submitted by 370 of the 540 eligible workers. No positive
cytology results were found. However, examination of a 28-year old worker with low-grade
intermittent hematuria found a bladder tumor. Cystoscopy was then offered to 77 workers with
atypical cells or slight hematuria in the initial screening and 83 workers whose job histories
suggested the highest exposures to MOCA. Of these, 67 agreed to have the examination, and a
bladder tumor in a second young male worker was found. Both tumors were found in men under
30 years of age who had never smoked. Tumors in both workers were small, non-invasive
papillary neoplasms that would not have been detected without systematic screening. The
prevalence of low grade tumors in asymptomatic males of this age group is not known, but the
incidence of clinically apparent tumors in men aged 25-29 is only 1 per 100,000. Although this
finding is based on only 2 cases, the researchers considered it to be consistent with the hypothesis
that MOCA induces bladder cancer in humans. A third case of a worker with papillary
transitional cell carcinoma was subsequently detected; however, that worker was excluded from
the analysis because the worker was a smoker, was exposed to MOCA for only 1.5 months, and
subsequently worked at other positions in the chemical industry that may have resulted in
exposure to other chemicals (Ward et al., 1990). This study provides only limited evidence for
an association between exposure to MOCA and bladder cancer in humans (based on only two
cases, no internal control group, exposure to other chemicals not excluded), and is not useful for
quantitative risk assessment because exposure was not quantified.
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Animal Studies
Animal studies of MOCA have been designed primarily as cancer bioassays. Studies are
available for rats, mice, and dogs.
In an early study from the German literature (Grundmann and Steinhoff, 1970; Steinhoff
and Grundmann, 1971), groups of 25 Wistar rats of each sex were given a low protein diet
containing 0 or 0.1% (1000 ppm) of MOCA for 500 days. The cumulative dose in the treated
groups was estimated by the researchers at 27 g/kg, corresponding to an average daily dose of 54
mg/kg-day. After 500 days, all rats received untreated diet for the remainder of their lives. The
average survival time was reduced in treated rats (565 and 535 days in males and females,
respectively) compared with controls (730 days). Among treated rats, 23 males and 20 females
died with tumors. Liver tumors (hepatomas) were observed in 22/25 treated males and 18/25
treated females compared with 0/25 in controls of both sexes (p<0.001 by Fisher exact test).
Lung tumors (mainly carcinomas) were observed in 8/25 treated males (p=0.002 by Fisher exact
test) and 5/25 treated females (p=0.025 by Fisher exact test) compared with 0/25 in controls of
both sexes. Statistical analysis of these results was performed by IARC (1993). Two mammary
adenomas were also observed in treated females.
Stula et al. (1975), exposed groups of 50 male and 50 female Charles River CD rats to 0
or 1000 ppm (50 mg/kg-day, assuming a rat consumes a daily amount of food equal to 5% of its
body weight) of MOCA (95% pure) added to a standard diet (23% protein) for up to 2 years. Six
rats from each group were sacrificed after one year for interim evaluation. Terminal sacrifice for
a group was performed when only six animals remained alive in that group. All rats placed on
the study were necropsied, and 30 tissues from each rat were microscopically examined. Tumor
incidence was evaluated using the chi-square test (p<0.05). Survival appeared to be reduced in
treated rats; 50% survival was reached after 581 days in treated males and females, compared
with 626 and 677 days in control males and females, respectively. Body weight and food
consumption were not reported (and may not have been measured). The results of the interim
sacrifice were not reported separately, although it was mentioned that adenomatosis, a
preneoplastic or early neoplastic lesion in the lung that progressed to adenocarcinoma, was seen
as early as one year on test. At terminal sacrifice, examination of the lung showed statistically
significant increased incidences of adenomatosis in males (14/44 vs 1/44 in controls) and females
(11/44 vs 1/44 in controls) and adenocarcinoma in males (21/44 vs 0/44) and females (27/44 vs
0/44). Related findings that were not statistically significant, but are noteworthy because of their
rarity, were squamous cell carcinomas in 1 treated male and 1 treated female, and pleural cavity
biphasic tumors (similar to mesotheliomas) in 4 treated males and 2 treated females. Neither of
these tumors were seen in controls. Focal pleural and/or pericardial hyperplasia was typically
seen adjacent to lung adenocarcinomas. The only other noteworthy findings occurred in the
liver. Liver tumors were found in treated male (3/44 hepatocellular adenoma, 3/44 hepatocellular
carcinoma) and female (2/44 hepatocellular adenoma, 3/44 hepatocellular carcinoma) rats, but
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not in controls of either sex. The differences from controls were not statistically significant,
however. The neoplastic lesions in the liver were accompanied by hepatocytomegaly, fatty
change, necrosis, bile duct proliferation, and fibrosis, although no details were provided
regarding the incidence or severity of the nonneoplastic lesions.
As part of the same study, Stula et al (1975) exposed 25 additional rats per sex to 0 or
1000 ppm (50 mg/kg-day, as above) of MOCA (95% pure) in a protein restricted diet (7%
protein). Four animals of each sex from the control and treated groups were sacrificed after one
year of treatment; those animals were not included in the analysis of tumor incidence. The low
protein diet caused a reduction in survival compared with the standard diet, so that the test was
ended after 16 months. Survival appeared to be slightly lower in the MOCA treated group (50%
survival at 432 and 438 days in males and females, respectively) than in controls (50% survival
at 476 and 483 days in males and females, respectively). The development of lung tumors was
similar to the standard diet study, with statistically significant increases in adenomatosis in males
(8/21 vs 1/21 in controls) and females (14/21 vs 1/21 in controls) and adenocarcinoma in males
(5/21 vs 0/21 in controls) and females (6/21 vs 0/21 in controls), and a pleural cavity biphasic
tumor in 1 treated male (and no controls). In the liver, the nonneoplastic lesions were similar to
those seen in the standard diet study. However, the incidences of hepatocellular adenomas (5/21)
and carcinomas (11/21) in male rats were statistically significantly increased (0/21 in controls).
Lower incidences of these tumors were found in treated females (2/21 adenoma, 1/21
carcinoma). In females, there was a statistically significant increase in the incidence of
mammary adenocarcinoma (6/21 vs 0/21 in controls), corresponding to a significant decrease in
mammary fibroadenoma (1/21 vs 7/21 in controls).
Kommineni et al. (1978) exposed male Sprague-Dawley rats (50 - 100 per dose) to
industrial grade MOCA (unspecified purity) in protein sufficient diets (27% protein) at 0, 250,
500, or 1000 ppm, or in protein restricted diets (8% protein) at 0, 125, 250, or 500 ppm for 18
months, followed by a 6-month recovery period. Based on the assumption that a rat consumes a
daily amount of food equal to 5% of its body weight, low-, mid-, and high-dose rats received
approximately 12.5, 25, and 50 mg/kg-day in the protein sufficient dose group and 6.25, 12.5,
and 25 mg/kg-day in the protein restricted groups. The following parameters were evaluated:
survival, food consumption, body weight, size and location of palpable masses, selected
hematology parameters (hematocrit and hemoglobin; 10 rats per dose on 5 occasions over 72
weeks), and urinalysis (volume, specific gravity, and urine MOCA concentration were
determined on 4 occasions over 52 weeks). All rats that died before the conclusion of the study
were autopsied, and all survivors at the end of the study were sacrificed and autopsied. Gross
lesions and major organs (lungs, liver, kidney, spleen, pancreas, adrenals, pituitary, thyroid,
urinary bladder, brain, and gross lesions) were examined microscopically.
Survival was reduced in all treated groups in a dose-related manner (Kommineni et al.,
1978). Mean survival times for the control, low-, mid-, and high-dose groups were 89, 87, 80,
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and 65 weeks, respectively, in the protein-adequate study (statistically significantly reduced in
the mid- and high-dose groups) and 87, 81, 79, and 77 weeks, respectively, in the protein-
deficient study (statistically significantly reduced in the high-dose group). In general, body
weights of protein-deficient rats were lower than those of protein-adequate rats. In both studies,
body weights of high-dose rats were reduced compared to their respective controls, starting at
approximately 20 weeks and continuing throughout the study. Body weights of rats in the other
groups were generally similar to controls. Food consumption in all treated groups at all time
periods was generally within 11% of control values. Hematocrit and hemoglobin values showed
slight decreases relative to controls in the high-dose groups in both the protein-adequate and
protein-deficient studies, but were within historical control ranges. Noncancer lesions observed
during the microscopic examinations were not reported. Increased incidences of pulmonary
adenomas and adenocarcinomas, mammary adenocarcinomas, Zymbal gland carcinomas, and
hepatocellular carcinomas were observed in animals exposed to MOCA in either of the diets
compared with controls (Table 1). Increased incidences of these tumors were attributed to
MOCA exposure. Metastasis of these neoplasms to other organs, such as kidneys, pituitary
gland, and pancreas, was also noted.
Russfield et al. (1975) exposed male Charles River CD-I (Sprague-Dawley-derived) rats
(25 per dose) and male and female Charles River CD-I (HaM/ICR-derived) mice (25 per sex and
dose) to MOCA (hydrochloride salt), 98% pure in the diet at 0, 500 or 1000 ppm (rats), or 0,
1000 or 2000 ppm (mice) for 18 months. Dietary concentrations (ppm) were converted to
mg/kg-day by assuming that a rat consumes a daily amount of food equal to 5% of its body
weight and a mouse consumes a daily amount of food equal to 15% of its body weight.
Therefore, low- and high-dose rats were estimated to receive 25 and 50 mg/kg-day, respectively,
of the hydrochloride salt (21.5 and 43.0 mg/kg-day, respectively, of MOCA), and low- and high-
dose mice were estimated to receive 150 and 300 mg/kg-day, respectively, of the hydrochloride
salt (129.5 and 259 mg/kg-day, respectively, of MOCA). Surviving animals were maintained on
untreated diet for an additional 6 months after treatment. The following parameters were
evaluated: clinical signs of toxicity (daily), body weight (unspecified intervals), food
consumption (first 20-25 weeks), gross pathology (animals that survived >6 months or killed in
extremis), and microscopic pathology of the lung, liver, spleen, kidney, adrenal, heart, bladder,
stomach, intestines, unspecified reproductive organs, gross lesions, and (in rats) pituitary.
Tumor incidence was statistically evaluated using the Fisher exact test.
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Table 1. Tumor Incidence in Male Rats Exposed to MOCA in the Diet for 18 Months Followed by a
6-Month Recovery Period (Kommineni et al., 1978)
Tumor
Protein-Adequate Diet
Protein-Restricted Diet
Dose Group
(ppm)
Incidence
(%)
Dose Group
(ppm)
Incidence
Lung,
0
0/100
(0)
0
0/100
(0)
adenocarcinoma
250
14/100
(14) ***
125
3/100
(3)
500
20/75
(27)***
250
7/75
(9) **
1000
31/50
(62) ***
500
8/50
(16) ***
Lung, all tumors
0
1/100
(1)
0
0/100
(0)
(adenocarcinoma,
250
23/100
(23) ***
125
6/100
(6) **
adenoma, epidermoid
500
28/75
(37)***
250
11/75
(15)***
carcinoma)
1000
35/50
(70)***
500
13/50
(26)***
Mammary,
0
1/100
a)
0
0/100
(0)
adenocarcinoma
250
5/100
(5)
125
1/100
(1)
500
8/75
(11) **
250
3/75
(4)
1000
14/50
(28) ***
500
3/50
(6) *
Zymbal gland,
0
1/100
(1)
0
0/100
(0)
carcinoma
250
8/100
(8) *
125
0/100
(0)
500
5/75
(V)
250
4/75
(5) *
1000
11/50
(22) ***
500
6/50
(12) ***
Liver, hepatocellular
0
0/100
(0)
0
0/100
(0)
carcinoma
250
3/100
(3)
125
0/100
(0)
500
3/75
(4)
250
0/75
(0)
1000
18/50
(36) ***
500
9/50
(18) ***
Hemangio sarcoma
0
2/100
(2)
0
1/100
(1)
250
4/100
(4)
125
2/100
(2)
500
3/75
(4)
250
4/75
(5)
1000
0/50
(0)
500
4/50
(8) *
Total Neoplasms1
0
250
500
1000
58/100 (58)
80/100 (80) ***
61/75 (81)***
48/50 (96) ***
0
125
250
500
37/100 (37)
34/100 (34)
40/75 (53) *
36/50 (72) ***
* Significantly different from controls (p<0.05)
** Significantly different from controls (p<0.01)
*** Significantly different from controls (p<0.001)
1 Includes rats with multiple neoplasms and neoplasms in other organs
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At 18 months, survival in treated rats (80%) was slightly less than controls (96%), while
at 20-22 months, survival was 55% in all groups (Russfield et al, 1975). Food consumption
during the first 20-25 weeks of the study was similar in treated and control rats, but body weights
at the end of the 18-month treatment period were reduced by about 100 g (13%) in the high-dose
group and 50 g {1.5%) in the low-dose group. Body weights remained depressed throughout the
6-month recovery period. The study authors reported that no striking differences were seen in
the incidence or intensity of gross or microscopic nonneoplastic lesions (data not shown). No
statistically significant increases in tumor incidence were seen in treated rats, but there was some
evidence for a tumorigenic effect from small increases in lung tumors (particularly adenomatosis,
characterized as a metaplastic transformation of alveolar cells) and liver tumors (described as
hepatomas) (Table 2). In mice, the high dose produced an increase in early mortality in females
(data not shown). The low dose had no effect on survival in mice, and neither dose had any
effect on food consumption or body weight in the mice. Incidence and intensity of nonneoplastic
lesions were similar in treated and control mice (data not shown). There was a statistically
significant increase in the incidence of liver tumors (hepatomas) in female mice of both dose
groups (Table 2). Hepatomas were not increased in male mice. Slight increases in the
incidences of vascular tumors (primarily subcutaneous hemangiomas and hemangiosarcomas) in
both male and female mice were not statistically significant and were within the range of
historical controls.
Stula et al. (1977) administered MOCA (90% pure) in gelatin capsules at 100 mg/day to 6
female purebred beagle dogs, 3 days per week for 6 weeks and then 5 days per week thereafter
for up to 9 years. The average dose per treatment was 10.3 mg/kg and the average daily dose was
7.3 mg/kg-day, calculated from data provided by the investigators. Six control dogs received no
treatment. Body weights were determined weekly. Hematology (erythrocyte count, hemoglobin
concentration, hematocrit, total leukocyte count, and differential leukocyte), clinical chemistry
(glucose, urea nitrogen, cholesterol, alkaline phosphatase, alanine aminotransferase (ALT), total
protein, albumin-globulin ratio, and gamma-glutamyl transpeptidase), and urinalysis (volume,
pH, appearance, osmolality, protein, sugar, blood, acetone, urobilinogen, bilirubin, and
microscopic examination of the sediment [in addition to a yearly urine sediment cytology
examination]) evaluations were performed throughout the study (approximately every 3 to 12
months). After approximately 8 to 9 years of treatment, surviving dogs were sacrificed by
electrocution and necropsied. Twenty-seven tissues and all gross lesions were microscopically
examined. There were no apparent treatment-related effects on mortality (1 treated dog died after
3.4 years on study due to natural causes unrelated to MOCA ingestion) or body weights. Mean
serum ALT was statistically significantly increased by over 2-fold in the treated dogs (a control
dog that had consistently high ALT measurements throughout the study, later found to be
associated with marked cholangiofibrosis of the liver in this individual, was excluded from this
analysis). After 7 years on study, urine sediment changes (increased erythrocytes, leukocytes,
epithelial cells - some with abnormalities) suggested development of tumors in the genitourinary
tract in treated dogs. Subsequent examinations revealed that 4 of the 5 treated dogs surviving 8-9
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Table 2. Tumor Incidence in Male and Female Test Animals Exposed to MOCA Hydrochloride Salt in the
Diet for 18 Months (Russfield et al., 1975)"
Incidence (%)
Tumor
0 ppm
500 ppm
1000 ppm
2000 ppm
Male Rats
Lung, Adenomatosis
0/22 (0)
3/22 (14)
4/19 (21)
n/a
Lung, Adenoma
1/22 (4)
1/22 (4)
1/19 (5)
n/a
Lung, Adenocarcinoma
0/22 (0)
1/22 (4)
1/19 (5)
n/a
Liver, Hepatoma
0/22 (0)
1/22 (4)
4/19 (21)
n/a
Male Mice
Liver, Hepatoma
3/18 (17)
n/a
3/13 (23)
4/20 (20)
Vascular, Hemangioma
0/18 (0)
n/a
2/13 (15)
5/20 (25)
Vascular, Hemangiosarcoma
0/18 (0)
n/a
1/13 (8)
3/20 (15)
Female Mice
Liver, Hepatoma
0/20 (0)
n/a
9/21 (43) **
7/14 (50) **
Vascular, Hemangioma
1/20 (5)
n/a
0/21 (0)
4/14 (29)
Vascular, Hemangio sarcoma
0/20 (0)
n/a
0/21 (0)
2/14 (14)
a Concentration of the HC1 salt is reported in this table
** Significantly greater than controls (p<0.01)
n/a = not applicable
10
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years had papillary transitional cell carcinomas of the urinary bladder, a statistically significant
increase over the 0/6 incidence of this tumor in controls. The other treated dog had a combined
transitional cell carcinoma and adenocarcinoma of the urethra. Follicular cystitis (slight in
severity), seen in the bladders of all treated dogs that survived 8-9 years, was often found
adjacent to a tumor. This lesion was not seen in control dogs. Nodular hyperplasia of the liver
was observed in 3/5 treated dogs that survived 8-9 years, which was a statistically significant
increase over controls (0/6).
No studies evaluating the toxicity of MOCA via inhalation exposure are available.
Other Studies
MOCA has been extensively tested for genotoxicity. Results have been summarized by
U.S. EPA (1990), ATSDR (1994), and IARC (1993). MOCA was generally positive in tests for
reverse mutation in Salmonella typhimurium TA98 and TA100 with metabolic activation, but not
without activation or in other tester strains. Results were mixed for reverse mutation in
Escherichia coli with activation and negative without. Tests for prophage induction in E. coli
(with activation) and differential toxicity in Bacillus subtilus (with or without activation) were
positive. In the yeast Saccharomyces cerevisiae, MOCA produced positive results in an assay for
aneuploidy (without activation), but mixed or negative results in assays for gene conversion,
reverse mutation, and homozygosis. In vitro tests in mammalian cells were positive for forward
mutation in mouse lymphoma cells (with activation, but not without), unscheduled DNA
synthesis in rat, mouse, and hamster primary hepatocytes (without activation), single strand DNA
breaks in hamster and human lung embryonic cells (without activation), DNA adduct formation
in dog and human bladder explant culture (without activation), and cell transformation in
BALB/c 3T3 mouse cells, RLV/Fischer rat embryo cells, and Syrian hamster kidney BAK cells
(with or without activation). Results were equivocal or negative for sister chromatid exchange or
chromosomal aberrations in Chinese hamster ovary cells and human leukocytes in vitro (with or
without activation). In vivo assays for mutations in Drosophila melanogaster, micro nucleus
formation in mice, and covalent binding to DNA in rat lung, liver, and kidney were all positive.
These results show that MOCA is a genetic toxicant with a broad range of activity. The
requirement for activation in most in vitro assays suggests that a metabolite is the proximate
genetic toxicant.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
ORAL RfD VALUES FOR 4,4'-METHYLENEBIS(2-CHLOROANILINE)
Limited human studies found no noncancer effects attributable to MOCA, but were
primarily interested in cancer effects. Animal studies for MOCA were designed primarily as
cancer studies, but observations regarding nonneoplastic effects were reported in some of them.
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For example, the liver was identified as a target of MOCA toxicity in chronically exposed rats
and dogs. Stula et al. (1975) reported nonneoplastic liver lesions, including hepatocytomegaly,
fatty change, necrosis, bile duct proliferation, and fibrosis, in male and female Charles River CD
rats fed a diet containing 1000 ppm (50 mg/kg-day) of MOCA for up to two years. Liver tumors
were also seen in some rats in the treated group. Details regarding the incidence and severity of
the nonneoplastic lesions were not reported. The wording of the paper suggests that the liver
lesions accompanied the liver tumors, but it is not clear whether they were also seen in animals
without tumors. The researchers reported that occurrence of nonneoplastic liver lesions was
similar in a second experiment using a protein-restricted diet, although liver tumor incidence in
male rats was significantly increased under these conditions.
Other studies in rats and mice (Kommineni et al., 1978; Ruchfield et al., 1975) treated
with 12.5 to 50 mg/kg-day of MOCA in the diet for 18 months did not provide any evaluation of
non-neoplastic effects. Both of these studies included a 6-month recovery period after treatment,
which would have made detection of nonneoplastic lesions difficult, as treatment-related lesions
might have been repaired and/or obscured by age-related changes during this time. The 9-year
dog study found an over 2-fold increase in mean serum ALT in treated dogs versus controls, and
a statistically significant increase in nodular hyperplasia of the liver in the treated dogs (3/5,
versus 0/6 in controls). No liver tumors were found in the dogs. The average daily dose of
MOCA in the treated dogs was 7.3 mg/kg-day. These studies establish that the liver is a sensitive
target of toxicity for MOCA. The lowest dose known to produce an effect on the liver is 7.3
mg/kg-day in the 9-year dog study. A NOAEL has not been established.
A provisional chronic RfD of 0.002 mg/kg-day (2E-3) can be derived for MOCA from
the dog LOAEL of 7.3 mg/kg-day by applying an uncertainty factor of 3000 (10 for use of a
LOAEL, 10 to extrapolate from dogs to humans, 10 to protect sensitive individuals, and 3 for
database deficiencies, including lack of reproductive or developmental toxicity studies), as
follows:
p-RfD = LOAEL - UF
= 7.3 mg/kg-day-^ 3000
= 0.002 mg/kg-day or 2E-3 mg/kg-day
In the absence of any subchronic oral data, the chronic p-RfD of 0.002 mg/kg-day can be
adopted as a protective estimate of the subchronic p-RfD, leading to a provisional subchronic
RfD of 0.002 mg/kg-day for MOCA.
Confidence in the key study is low. The study included only a small number of dogs of
one sex, and only one dose level was tested. Confidence in the database is low; as reproductive
and developmental toxicity have not been studied, and systemic toxicity data are available only
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from studies designed primarily as cancer bioassays that failed to identify a NOAEL. Low
confidence in the subchronic and chronic p-RfD values follows.
DERIVATION OF PROVISIONAL SUBCHRONIC AND CHRONIC
INHALATION RfC VALUES FOR 4,4'-METHYLENEBIS(2-CHLOROANILINE)
Limited human studies found no noncancer effects attributable to MOCA, but were
primarily interested in cancer effects. No animal data regarding the toxicity of MOCA following
subchronic or chronic inhalation exposure are available. Therefore, derivation of subchronic and
chronic p-RfC values for MOCA is precluded.
DERIVATION OF A PROVISIONAL CARCINOGENICITY ASSESSMENT
FOR 4,4'-METHYLENEBIS(2-CHLOROANILINE) (MOCA)
Weight-of-Evidence Classification
Human data are not adequate for carcinogenicity evaluation of MOCA, although there is
suggestive evidence that MOCA may produce bladder tumors in humans. Animal data have
consistently shown that MOCA is carcinogenic in all laboratory animal species evaluated (rats,
mice, and dogs). Tumor production has occurred at the lowest dose evaluated in all species, and
the available data suggest that MOCA is comprehensively genotoxic. According to the 2005
Cancer Guidelines, the descriptor "Likely to be carcinogenic to humans" is appropriate for
MOCA. This descriptor is applied when "...the weight of the evidence is adequate to
demonstrate carcinogenic potential to humans but does not reach the weight of evidence for the
descriptor "Carcinogenic to Humans". MOCA satisfies at least two of the illustrative examples
described under this category including, "...an agent demonstrating a plausible (but not definitely
causal) association between human exposure and cancer..." and "... an agent that has tested
positive in animal experiments in more than one species, sex, strain, or exposure route, with or
without evidence of carcinogenicity in humans". Suggestive epidemiologic evidence is available
and MOCA has tested positive in rats, mice, and dogs in adequate studies. IARC classified
MOCA as "probably carcinogenic to humans."
Quantitative Estimates of Carcinogenic Risk
Dose-response modeling for MOCA was conducted on data from the studies of
Kommineni et al. (1978) in male rats (protein-adequate study only) and Russfield et al. (1975) in
female mice. Each of these studies included multiple dose levels and reported statistically
significant increases in at least one tumor type. Both were adequate cancer bioassays, although
group sizes were small in the Russfield et al. (1975) study. While it is technically possible to
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model the results of a single-dose study (e.g., the rat study of Stula et al., 1975 or the dog study
of Stula et al., 1977), such studies provide little information about the shape of the dose-response
curve, limiting their utility for dose-response modeling.
A weight of evidence evaluation supports a determination that MOCA is carcinogenic by
a mutagenic MOA. Determination of the mode of action of carcinogens is addressed in Section 5
of the 2005 Cancer Supplementary Guidance (U.S. EPA, 2005b) as follows: "Determinations of
chemicals that are operating by a mutagenic mode of action entails evaluation of test results for
genotoxic endpoints, metabolic profiles, physio chemical properties, and structure-activity
relationships (Waters et al., 1999)." These factors are considered below:
Genetic endpoints: As described in the previous section entitled "Other Studies" short term tests
results provide ample evidence for mutagenicity (heritable genetic damage). Positive tests
include bacteria (Ames test), yeast, in vitro mammalian cells for forward mutation in mouse
lymphoma cells, unscheduled DNA synthesis in rat, mouse and hamster primary hepatocytes,
single strand DNA breaks in hamster and human lung embryonic cells, DNA adduct formation in
dog and human bladder explant culture, and cell transformation BALB/c 3T3 mouse cells,
RLV/Fisher rat embryo cells, and Syrian hamster kidney BK cells. In vivo assays in Drosophila
melanogaster, micro nucleus in mice and covalent binding to DNA in rat lung, liver and kidney
were also positive. Metabolic activation was required in many tests indicating a metabolite is
necessary for the action. Other mechanisms of carcinogenesis are possible in addition to
mutagenesis, e.g. mitogenesis, inhibition of cell death, cytotoxicity with reparative cell
proliferation, immune suppression, interference with repair enzymes or genes, oxidative damage,
etc.
Metabolic profiles: Metabolic activation was required in many of the genotoxicity tests,
indicating that a metabolite, rather than the parent compound, is the proximate carcinogen. There
is no data to support a unique metabolic profile in humans.
Physiochemical properties: There are no properties that would suggest significant differences in
absorption, distribution, elimination in humans vs. non-human animals to the extent that the
proximate carcinogen would not be available at the target organ(s).
Structure-activity analyses in a weight of evidence approach: MOCA is structurally similar to
benzidine, a known human bladder carcinogen. Benzidine is known to produce various tumor
types at multiple sites in animal species exposed by several routes and is positive in Ames test,
mouse lymphoma, DNA damage assays, sister chromatid exchange, and micronucleus formation.
The structural and toxicological similarity of MOCA to benzidine supports selection of a
mutagenic MOA for the carcinogenic action of MOCA. This p-SF for MOCA is based on lung
tumors, however, mammary, zymbal gland, liver tumors, and hemangiosarcomas and also
bladder cancer were observed in supporting studies. According to the 2005 Cancer Guidelines,
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concordance of tumor sites is not required for supporting evidence. The lung tumors provide the
most sensitive endpoint in these studies.
The mode of action evidence for MOCA is analyzed under the mode of action framework
in EPA's 2005 Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a, Section 2.4.3).
1. MOA sufficiently supported in animals? The studies clearly show carcinogenesis in
animals; short term testing clearly indicates a mutagenic mode of action in several cell
types and tests, as indicated earlier.
2. MOA relevant to humans? MOCA is a systemic mutagen in test animals;
Epidemiologic investigations are suggestive; a QSAR surrogate, benzidine, is
carcinogenic to humans, likely by a mutagenic endpoint.
3. Susceptible lifestages or populations? This is discussed in the following pages in
relation to the Supplemental Guidance for Assessing Susceptibility from Early-Life
Exposure to Carcinogens (Supplemental Guidance) (U.S. EPA, 2005b).
The hypothesis that MOCA carcinogenicity has a mutagenic mode of action is presumed to apply
to all tumor types.
Dose response modeling was performed based on statistically significant tumors in the
Kommineni et al. (1978) and Russfield et al. (1975) studies: lung adenocarcinomas and
combined tumors, mammary adenocarcinomas, Zymbal gland carcinomas, and liver
hepatocellular carcinomas in male rats (Table 3) and liver hepatomas in female mice (Table 4).
The derivations used the U.S. EPA (2005) guidelines for cancer risk assessment. Since a
mutagenic mode of action is appropriate for MOCA-induced tumors, the BMD multistage model
was used for dose-response modeling. Background incidence was included as extra risk. In
accordance with the 2005 Cancer guidelines, the BMDL10 (95th percentile lower bound on dose
estimated to produce a 10% increase in tumor incidence over background) was estimated using
the U.S. EPA (1996, 2000) benchmark dose methodology, and a linear extrapolation to the origin
was performed by dividing the BMDL10 into 0.1 (10%). The values based directly on the oral
animal tumor data are adjusted to human values by correcting for differences in body weight
between humans and rodents. U.S. EPA uses a cross-species scaling factor of body weight raised
to the % power (U.S. EPA, 2005). Adjustment from animal to human slope factor is performed
by multiplying the animal value by the ratio of human to animal body weight raised to the %
power and by multiplying this product by the ratio of life span of animal to duration of the
experiment raised to the 3rd power. The latter term reduces to 1 for both of the studies being
modeled since the 2-year duration of the studies (including the 6 month observation period) is
equal to the reference life span of 24 months in rodents. The short exposure duration in both of
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these studies (18 out of 24 months) is taken into account in calculation of the average daily doses
used in the modeling exercises.
Data for each tumor grouping are shown in Tables 3,4 and 5. Slope factors estimated as
0.1/BMDL10 were very similar for each tumor grouping. The highest estimate of human cancer
risk was based on the combined incidence of lung tumors (adenoma, adenocarcinoma,
epidermoid carcinoma) in male rats (human 0.1/BMDL10 = 0.10 per mg/kg-day, 1E-1 per
mg/kg-day) (rounded from 9.95E-2 - Table 3). Successively lower estimates, all within one
order of magnitude of the high risk estimate, were derived from lung adenocarcinomas in male
rats, liver hepatomas in female mice, mammary adenocarcinomas in male rats, Zymbal gland
adenocarcinomas in male rats, and liver hepatocellular carcinomas in male rats. Figures (1-6)
demonstrating the model fits are included at the end of this document.
EPA has concluded, by a weight of evidence evaluation, that MOCA is carcinogenic by a
mutagenic mode of action. According to the Supplemental Guidance for Assessing Susceptibility
from Early-Life Exposure to Carcinogens (Supplemental Guidance) (U.S. EPA, 2005b) those
exposed to carcinogens with a mutagenic mode of action are assumed to have increased early-life
susceptibility. Data for MOCA are not sufficient to develop separate risk estimates for childhood
exposure. The oral slope factor of 1E-1 per mg/kg-day, calculated from data from adult
exposure, does not reflect presumed early-life susceptibility for this chemical and age-dependent
adjustment factors (ADAFs) should be applied to this slope factor when assessing cancer risks.
Example evaluations of cancer risks based on age at exposure are given in Section 6 of the
Supplemental Guidance which establishes ADAFs for three specific age groups. The current
ADAFs and their age groupings are 10 for <2 years, 3 for 2 to <16 years, and 1 for 16 years and
above (U.S. EPA, 2005b). The 10-fold and 3-fold adjustments in slope factor are to be combined
with age-specific exposure estimates when estimating cancer risks from early life (<16 years age)
exposure to MOCA. These ADAFs and their age groups were derived from the 2005
Supplemental Guidance, and they maybe revised over time. The most current information on
the application of ADAFs for cancer risk assessment can be found at
www.epa.gov/cancerguidelines/. In estimating risk, EPA recommends using age-specific values
for both exposure and cancer potency; for MOCA, age-specific values for cancer potency are
calculated using the appropriate ADAFs. A cancer risk is derived for each age group, and these
are summed across age groups to obtain the total risk for the exposure period of interest (see
Section 6 of the Supplemental Guidance).
The oral slope factor, calculated from adult exposure, is derived from the BMDL10, the
95% lower bound on the exposure associated with an 10% extra cancer risk, by dividing the risk
(as a fraction) by the BMDL10, and represents an upper bound risk estimate for continuous
lifetime exposure without consideration of increased early-life susceptibility due to MOCA's
mutagenic mode of action:
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The slope of the linear extrapolation from the central estimate, human BMD10 is
0.1/(14.37 mg/kg-day) = 7E-3 per mg/kg-day. The BMD10 for humans was calculated
from the BMD10 for animals according to the same procedure for conversion of the
BMDL10 for animals to humans.
The slope factor for MOCA should not be used with exposures exceeding the point of departure
(BMDL10) 1 mg/kg-day, because above this level the fitted dose-response model better
characterizes what is known about the carcinogenicity of MOCA. For exposures greater than the
BMDL10, contact the Superfund Technical Support Center. Additionally, age-dependent
adjustment factors (ADAFs) should be applied to this slope factor when assessing cancer risks to
individuals <16 years old as discussed above (U.S. EPA, 2005).
There are no suitable human or animal carcinogenicity data from which to derive a
provisional inhalation unit risk for MOCA.
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Table 3. BMD10, BMDL Values Based on Lung, Mammary, Zymbal Gland, and Liver Tumor Incidences in Male Rats (Kommineniet al., 1978)
Tumor
0
Average Daily Dose (mg/kg-day)1
9.4 18.8
37.5
rat
BMD10
rat
BMDL10
rat2
0.1 /BMDL! 0
Human3
0.1 /BMDL! 0
OSF
Lung (adenoma, epidermoid
carcinoma, adenocarcinoma)
1/100
23/100
28/75
35/50
4.45
3.25
3.08E-2
9.95E-2
Lung (adenocarcinoma)
0/100
14/100
20/75
31/50
7.45
5.01
1.96E-2
6.34E-2
Mammary (adenocarcinoma)
1/100
5/100
8/75
14/50
18.70
12.83
7.80E-3
2.52E-2
Zymbal gland (adenocarcinoma)
1/100
8/100
5/75
11/50
19.66
13.32
5.96E-3
2.43E-2
Liver (hepatocellular carcinoma)
0/100
3/100
3/75
18/50
20.03
16.78
6.42E-3
1.93E-2
'Rats were exposed to dietary levels of 0, 250, 500, or 1000 ppm of MOCA for 18 months and observed for an additional 6 months. Doses of 0, 12.5, 25, and 50 mg/kg-day
were estimated by assuming that a rat consumes 5% of his body weight per day. These doses were expanded to continuous exposure by multiplying by 18/24 months.
2Rat BMDL10 values were calculated (extra risk, background estimated in model) from the lowest-degree polynomial model that gave an adequate fit (chi-square goodness-of-
fit statistic p value >0.05), as per the U.S. EPA (1996) Benchmark Dose Technical Guidance Document. Models with more than 2 parameters were not considered for
selection (degrees of freedom = # dose groups -2 = 4-2 = 2).
3Human value calculated as: rat value ( 0.1/BMDL10) x (Whlm / W„,)1/4 x (L / Le)3 where Whlm = 70 kg (human reference body weight), Wra, = 0.64 kg (TWA male rat body
weight for the lowest affected dose group during the 18 month exposure), L = 24 months (rat life span), Le = 24 months (duration of experiment)
18
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Table 4. BMD10, BMDL Values Based on Liver Tumor Incidence in Female Mice (Russfield et al., 1975)
Tumor
0
Dose (mg/kg-day)
97
194
mouse mouse2 mouse
BMD10 BMDL10 0.1/BMDL10
mg/kg-day mg/kg-day mg/kg-day
0.1/BMDL! 03
(mg/kg-day)1
OSF
human
Liver (hepatoma)
0/20
9/21
7/14
23.09
15.58
6.42E-3
4.28E-2
'Mice were exposed to dietary levels of 0, 1000, or 2000 ppm of MOCA hydrochloride salt for 18 months and observed for an additional 6 months. Doses of 0, 129.5, and 259
mg/kg-day were estimated by assuming that a mouse consumes 15% of his body weight per day and adjusting for MOCA content of the administered material based on
molecular weight. These doses were expanded to continuous exposure by multiplying by 18/24 months.
2Mouse BMDL10 calculated (extra risk, background estimated in model) from the lowest-degree polynomial model that gave an adequate fit (chi-square goodness-of-fit
statistic p value >0.05), as per the U.S. EPA (1996) Benchmark Dose Technical Guidance Document. A 2-degree polynomial model was chosen.
3Human value 0.1/BMDL10) calculated as: mouse value ( 0.1/BMDL10) x (Whum / Wmollse)1/4 x (L / Le)3 where Whum = 70 kg (human reference body weight), Wmollse = 0.0353 kg
(U.S. EPA, 1988 reference value), L = 24 months (rat life span), Le = 24 months (duration of experiment)
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Table 5. BMD results
Tumor Groups
BMD10 (animal)
mg/kg-day
BMDL10 (animal)
mg/kg-day
0.1/BMDL10 (animal)
(mg/kg-day)1
Probability
human 0.1/BMDL10
(mg/kg-day)1
OSF
Rat Lung: adenoma, epidermoid carcinoma,
adenocarc inoma
4.47
3.25
3.08E-2
0.528
9.95E-2
Rat Lung: adenocarcinoma
7.45
5.10
1.96E-2
0.875
6.34E-2
Mouse Liver
23.09
15.58
6.42E-2
0.637
4.28E-2
Rat Mammary
18.70
12.73
7.80E-2
0.920
2..52E-2
Rat Zymbal
19.66
13.32
7.50E-3
0.139
2.43E-2
Rat Liver
20.03
16.77
5.96E-3
0.390
1.93E-2
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Multistage Model with 0.95 Confidence Lavsl
dase
14:01 09/26 2005
Figure 1: Lung: adenoma, epidermoid carcinoma, adenocarcinoma (units in abscissa are
mg/kg-day)
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Multistage Model with 0.95 Confidence Level
D 5 10 15 3D 25 30 3E 4D
dose
13:51 C0,® 2005
Figure 2: Lung (adenocarcinoma) (units in abscissa are mg/kg-day)
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Multistage Modal with D.95 Confidence Level
c
o
tj
'E
10 15 20 25 3D
dose
35 40
13:55 IM33 2DDE
Figure 3: Mammary (adenocarcinoma) (units in abscissa are mg/kg-day)
23
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Multistage Model with Q.95 Confidence Level
dDSE
13:57 09^6 2015
Figure 4: Zymbal Gland (units in abscissa are mg/kg-day)
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0.5
0.4
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Multistage Model Vvith 0.95 Confidence Level
dose
14:01 09/36 200E
Figure 6: Liver, Hepatoma (Russfeld et al., 1975) (units in abscissa are mg/kg-day)
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