TECHNICAL RETORT DATA
ffteau read Instructions on the reverie txfore completing}
1. REPORT NO.
EPA/600/8-88/046
4. TITLE AND SUBTITLE
Health Effects Assessment
2.
for Mi rex
7. AUTHOR(S)
9. PERFORMING ORGANIZATION NAME AND ADDRESS
12. SPONSORING AGENCY NAME AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
3. RECIPIENT'S ACCESSION NO
PB88-179908/AS
6. REPORT DATE
6. PERFORMING ORGANIZATION CODE
8. PERFORMING ORGANIZATION REPORT N
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
13. TYPE OF REPORT AND PERIOD COVER6C
14. SPONSORING AGENCY CODE
EPA/600/22
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report summarizes and evaluates information relevant to a preliminary interim
assessment of adverse health effects associated with specific chemicals or compounds.
The Office of Emergency and Remedial Response (Superfund) uses these documents in
preparing cost-benefit analyses under Executive Order 12991 for decision-making under
CERCLA. All estimates of acceptable intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited resources
allocated to this project. The intent in these assessments is to suggest acceptable
exposure levels whenever sufficient data are available. The interim values presented
reflect the relative degree of hazard associated with exposure or risk to the
chemical(s) addressed. Whenever possible, two categories of values have been
estimated for systemic toxicants (toxicants for which cancer is not the endpoint of
concern). Thu first, RfDs or subchronic reference dose, is an estimate of an exposure
level that would not be expected to cause adverse effects when exposure occurs during
a limited time interval. The RfD is an estimate of an exposure level that would not
be expected to ciuse adverse effects when exposure occurs for a significant portion
of the lifespan.. For compounds for which there is sufficient evidence of
carcinogenicity, QI*S have been computed, if appropriate, based on oral and
inhalation data if available.
7.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.lOENTIFIERS/OPEN ENDED TERMS
c. COSATI Field/Group
. DISTRIBUTION 'STATEMENT
Public
19. SECURITY CLASS (This Report)
Unclassified
21. NO. OF PAGES
20. SECURITY CLASS (Thu patel
Unclassified
22. PRICE
EPA form 2220-1 ((!«. 4-77) PKCVIOUS COITION ) OBSOLCTC
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EPA/600/8-88/046
August, 1987
HEALTH EFFECTS ASSESSMENT
FOR MIREX
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE Oc RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
TJ,S. Environmental Protection fe
p,u-: .;. : " "-:' l'-JL-Ifc)
'2:^ -, i^aibora Street, HOOT
.-,."-.* '.L Rnr>04
-------
DISCLAIMER
This document has been reviewed 1n accordance with the U.S.
Environmental Protection Agency's peer and administrative review policies
and approved for publication. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
The report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with mlrex.
All estimates of acceptable Intakes and carcinogenic potency presented in
this document should be considered as preliminary and reflect limited re-
sources allocated to this project. Pertinent toxlcologlc and environmental
data were located through on-Hne literature searches of the TOXLINE and the
CHEMFATE/DATALOG data bases. The basic literature searched supporting this
document Is current up to May, 1986. Secondary sources of Information have
also been relied upon In the preparation of this report
The Intent 1n these assessments 1s to suggest acceptable exposure levels
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited In
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard associated with exposure or risk to the chemlcal(s) addressed.
Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer Is not the endpolnt of
concern). -The first, the AIS or acceptable Intake subchronlc, 1s an
estimate of an exposure level that would not be expected to cause adverse
effects when exposure occurs during a limited time Interval (I.e., for an
Interval that does not constitute a significant portion of the Hfespan).
This type of exposure estimate has not been extensively used or rigorously
defined, as previous risk assessment efforts have been primarily directed
toward exposures from toxicants In ambient air or water where lifetime
exposure Is assumed. Animal data used for AIS estimates generally Include
exposures with durations of 30-90 days. Subchronlc human data are rarely
available. Reported exposures are usually from chronic occupational
exposure situations or from reports of acute accidental exposure.
The AIC, acceptable Intake chronic, 1s similar In concept to the ADI
(acceptable dally Intake). It 1s an estimate of an exposure level that
would not be expected to cause adverse effects when exposure occurs for a
significant portion of the Hfespan [see U.S. EPA (1980) for a discussion of
this concept]. The AIC Is route-specific and estimates acceptable exposure
for a given route with the Implicit assumption that exposure by other routes
Is Insignificant.
Composite scores (CSs) for noncarclnogens have also been calculated
where data permitted. These values are used for ranking reportable quanti-
ties; the methodology for their development Is explained 1n U.S. EPA (1983b).
For compounds for which there Is sufficient evidence of cardnogenldty,
AIS and AIC values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980). Since cancer 1s a
process that 1s not characterized by a threshold, any exposure contributes
an Increment of risk. Consequently, derivation of AIS and AIC values would
be Inappropriate. For carcinogens, q-]*s have been computed based on oral
and Inhalation data If available.
111
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ABSTRACT
In order to place the risk assessment evaluation In proper context,
refer to the preface of this document. The preface outlines limitations
applicable to all documents of this series as well as the appropriate
Interpretation and use of the quantitative estimates presented.
The database for mlrex Is extensive and Includes subchronlc and chronic
toxIcHy studies, teratogenldty/reproductlve effects studies, and three
cardnogenldty studies on rats and mice. The carclnogenldty studies
provide the basis for the mlrex risk assessment; all three studies Indicated
that mlrex 1s associated with an Increased Incidence of liver tumors In rats
and mice. Results from a draft NTP (1987) bloassay report were considered
to be most useful for quantitative risk assessment. In this study, mlrex
caused a dose-related Increase In liver neoplastlc nodules and adrenal
pheochromocytomas In male F344/N rats receiving 0, 0.1, 1, 10, 25 or 50 ppm
mlrex 1n the diet for 104 weeks. Female rats exposed to the same dietary
concentrations showed dose-related Increases 1n leukemia. Control
Incidences of liver neoplastlc nodules were elevated when compared with
historical controls. In a second study with female rats using dietary
concentrations of 0, 50 or 100 ppm, the dose-related Increase in leukemia
was reproduced and a dose-related Increase In Incidence of neoplastlc
nodules was also reported.
A human carcinogenic potency estimate (q-|*J for oral exposure of 1.8
(mg/kg/day)"1 1s chosen to reflect the potency of mlrex. This value Is
based upon pooled Incidence of adrenal pheochromocytomas, neoplastlc nodules
and hepatocellular carcinomas In male rats. Data were Insufficient for
derivation of a carcinogenic potency estimate for Inhalation exposure.
1v
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ACKNOWLEDGEMENTS
The Initial draft of this report was prepared by Syracuse Research
Corporation under Contract No. 68-03-3112 for EPA's Environmental Criteria
and Assessment Office, Cincinnati, OH. Or. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents In this
series were prepared for the Office of Emergency and Remedial Response,
Washington, DC.
Scientists from the following U.S. EPA offices provided review comments
for this document series:
Environmental Criteria and Assessment Office, Cincinnati, OH
Carcinogen Assessment Group
Office of A1r Quality Planning and Standards
Office of Solid Waste
Office of Toxic Substances
Office of Drinking Water
Editorial review for the document series was provided by the following:
Judith Olsen and Erma Durden
Environmental Criteria and Assessment Office
Cincinnati, OH
Technical support services for the document series was provided by the
following:
Bette Zwayer, Jacky Bohanon and K1m Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
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TABLE OF CONTENTS
Page
1. ENVIRONMENTAL CHEMISTRY AND FATE 1
2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS 3
2.1. ORAL 3
2.2. INHALATION 3
3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS 4
3.1. SUBCHRONIC 4
3.1.1. Oral 4
3.1.2. Inhalation 4
3.2. CHRONIC 4
3.2.1. Oral 4
3.2.2. Inhalation 8
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS.
3.3.1. Oral 8
3.3.2. Inhalation 12
3.4. TOXICANT INTERACTIONS _ 12
4. CARCINOGENICITY 13
4.1. HUMAN DATA 13
4.2. BIOASSAYS 13
4.2.1. Oral 13
4.2.2. Inhalation. .... 19
4.3. OTHER RELEVANT DATA 20
4.4. WEIGHT OF EVIDENCE 20
5. REGULATORY STANDARDS AND CRITERIA 21
6. RISK ASSESSMENT 22
. 6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS) 22
6.2. ACCEPTABLE INTAKE CHRONIC (AIC) 22
6.3. CARCINOGENIC POTENCY (q-j*) 22
&.3.I. Oral 22
6.3.2. Inhalation 28
7. REFERENCES 29
APPENDIX: Summary Table for Mlrex 39
vl
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LIST OF TABLES
No. Title Page
1-1 Selected Physical and Chemical Properties and Half-Lives
for M1rex 2
3-1 Summary of Subchronlc Oral Tox1c1ty Data for M1rex 6
3-2 Summary Table for Teratogenldty and Other Reproductive
Effects 9
4-1 Summary Table for CarclnogenlcHy Studies on M1rex 14
6-1 Cancer Data Sheet for Derivation of q-j* 24
6-2 Cancer Data Sheet for Derivation of q-|* 25
6-3 Cancer Data Sheet for Derivation of q-|* 26
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LIST OF ABBREVIATIONS
AOI Acceptable dally Intake
AIC Acceptable Intake chronic
AIS Acceptable Intake subchronlc
1050 Dose lethal to 50% of recipients
NTO Maximum tolerated dose
NOEL No-observed-effect level
PCB PolychloMnated blphenyl
ppm Parts per million
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected chemical and physical properties and environmental fate of
mlrex are presented 1n Table 1-1.
Experimental evidence suggests that mlrex Is one of the most stable
organochlorIne compounds Investigated to date. It Is resistant to physical,
chemical and biological degradation (U.S. EPA, 1978). The half-life of
mlrex 1n air could not be located 1n the available literature. In the
atmosphere, mlrex 1s expected to exist primarily as adsorbed matter on
airborne partlculates because of Us low vapor pressure. Its resistance to
chemical and photochemical reactions Indicates that long distance transport
may occur before removal by dry or wet deposition. In water, mlrex 1s
expected to bloaccumulate In aquatic organisms and strongly adsorb to
suspended solids and sediments. It 1s generally agreed that mlrex 1s trans-
ported In water adsorbed to_organic partlculates. Thus, Its movement would
be expected to follow water currents. Patterns of occurrence 1n sediments
of Lake Ontario support this conclusion (EHO, 1977).
Mlrex will exist predominantly 1n the sediments of surface water,
adsorbed to partlculate matter or dissolved 1n aliphatic materials (NAS/NRC,
1978).
Bomberger et al. (1983) reported that mlrex does not leach Into the soil
profile and H volatilizes slowly. Since the compound Is strongly adsorbed
to soil and remains on the surface, a major loss from terrestrial systems 1s
expected to be erosion and transport Into surface waters. Its estimated
half-life In soil Is >12 years (NAS/NRC, 1978).
0094h -1- 04/25/87
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TABLE 1-1
Selected Physical and Chemical Properties and Half-Lives for Mlrex
Property
Value
Reference
CAS number:
Chemical class:
Molecular weight:
Vapor pressure at 25°C:
Hater solubility at 22°C:
Log octanol/water
partition coefflcTent:
Bloconcentratlon factor:
Log soil adsorption
coefficient:
Environmental half-life:
Half-life 1n Soil
2385-85-5
organochlorlne
pesticide
545.5
3xlO~7 mm Hg
0.07 ng/8.
6.89
18,200 fathead
minnow (Plmephales
promelas)
5.38
5-12 years
>12 years
IARC, 1979
Relnbold et al., 1979
VeHh et al., 1979
Velth et al., 1979
Relnbold et al., 1979
NAS/NRC, 1978
NAS/NRC, 1978
NA = Not available
0094h
-2-
04/25/87
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Mehendale et al. (1972) administered oral doses of 6 mg/kg to rats and
found that -60% of the dose was recovered 1n feces within 48 hours, probably
representing unabsorbed mlrex. After this, excretion leveled off, suggest-
ing that once absorbed mlrex 1s readily stored and poorly excreted.
Iv1e et al. (1974) fed rats diets containing 0.3, 3 or 30 ppm mlrex for
up to 16 months and reported that mlrex was rapidly absorbed and retained 1n
tissues In a dose-related manner. Mlrex concentrations 1n tissues steadily
Increased during exposure and no plateau was reached. One half or less of
the dose was eliminated after 10 months.
Other authors have reported data Indicating mlrex absorption >50%.
Gibson et al. (1972) gave rats single oral doses of 0.2 mg/kg radlolabeled
mlrex 1n corn oil, and found that 18% of the total radioactivity was elimi-
nated 1n 7 days, with fecal elimination 1n the first 48 hours accounting for
2% of the total elimination. Chambers et al. (1982) gave rats single oral
doses of 38 ug mlrex. Fecal elimination 1n the first 2 days was 21-29% of
the total dose and probably represented unabsorbed mlrex. Total fecal
elimination 1n 2 weeks was 25-31% of the total dose. Urinary elimination
was <1% In 2 weeks. These data Indicate a mlrex absorption rate of 70-80%.
Byrd et al. (1982) used pharmacoklnetlc data from oral and Intravenous
studies to construct a pharmacoklnetlc model for mlrex In rats. This model
Indicated that average absorption of a 1 mg/kg oral dose was 69%.
2.2. INHALATION
Pertinent data regarding respiratory absorption of mlrex could not be
located 1n the available literature.
0094h -3- 04/25/87
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. There were several studies available concerning the sub-
chronic oral tox1c1ty of mlrex In laboratory animals. Most of these are
summarized 1n Table 3-1. The most common effects of subchronlc mlrex
Intoxication were weight loss and Increased relative liver weight and
reproductive failure (NAS/NRC, 1978).
Because of Us highly bloaccumulatlve nature, very low doses of mlrex
can be toxic 1n extended exposures. Hayes (1967) proposed a "chronldty
factor," defined as the single dose LD-g divided by the 90 dose LD5Q, to
reflect cumulative effects of toxicants. Galnes and Klmbrough (1970)
reported a single dose LD. of 365 mg/kg and a 90 dose L0,-n of 6
mg/kg/day. The resulting chronldty factor of 60.8 was the highest factor
reported for any pesticide, Including DOT (5.6) and dleldrln (12.8) (U.S.
EPA, 1980).
3.1.2. Inhalation. Pertinent data concerning subchronlc toxlclty of
Inhaled mlrex could not be located 1n the available literature.
3.2. CHRONIC
3.2.1. Oral. Monitoring data Indicate that humans are exposed to mlrex
through consumption of seafood, fish, game and mammals as well as mothers
milk (NAS/NRC, 1978); however, toxic effects In humans have not been report-
ed. Since mlrex 1s strongly bloaccumulated and very slowly eliminated,
prolonged low level exposures may lead to significant body burdens. In
general, for chemicals exhibiting these characteristics, stressful condi-
tions such as weight loss or Illness, resulting In depletion of fat reserves
may result 1n mobilization and redistribution of mlrex, possibly leading to
toxic concentrations 1n the brain, liver or kidney (Geyer et al., 1980).
0094h -4- ' 04/25/87
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Carclnogenlclty was the primary focus of the three animal studies
Involving chronic exposure to mlrex. Therefore, these studies are discussed
1n more detail 1n Chapter 4.
In reviewing data from the Ulland et al. (1973) chronic study, Reuber
(1977) reported that rats exposed to diets containing 50 or 100 ppm mlrex
for 2 years had severe liver and kidney necrosis and chronic nephritis.
The NTP (1987) conducted a chronic bloassay with F344/N rats to deter-
mine possible carc1nogen1c1ty of mlrex (see Chapter 4). Groups of 52 F344/N
rats of each sex were fed diets containing 0, 0.1, 1.0, 10, 25 or 50 ppm
mlrex for 104 weeks and sacrificed 8-10 weeks later. During the first 6
months of the 2-year study, because of good survival and absence of observ-
able toxic effects In female rats, additional groups (termed second study)
of 52 F344/N female rats were started at dietary concentrations of 0, 50 and
100 ppm mlrex.
Mean body weights of male rats that received 25 or 50 ppm mlrex were
5-18X lower than those of the controls throughout most of the study; mean
body weights of female rats that received 50-100 ppm mlrex were 4-18% lower
than those of the controls after week 40. (Feed consumption by dosed male
rats was 83-91% that of controls, and that by dosed female rats vas 86-99%
that of controls. At the end of the study, the survival of male rats that
received 25 or 50 ppm mlrex was lower than that of controls (controls,
44/52; 25 ppm, 19/52; 50 ppm, 15/52).
The most notable effects were observed 1n the livers of both male and
female rats. Fatty metamorphosis, cytomegaly, anglectasls (males only) and
necrosis of the liver were observed at Increased Incidence In dosed rats. A
significant Increase 1n the Incidence of hyperplasla of the transitional
epithelium of the kidney pelvis was also observed In male rats (controls,
0/51; 0.1 ppm, 2/51; 1 ppm, 2/52; 10 ppm, 5/52; 25 ppm, 14/51; 50 ppm, 9/52).
0094h " -7- 04/25/87
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3.2.2. Inhalation. Chronic Inhalation experiments with mlrex could not
be located 1n the available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.3.1. Oral. There are several studies available concerning possible
teratogenlc and reproductive effects of mlrex. These are summarized In
Table 3-2. Mlrex has been found to cause abnormalities Including scollosls,
cleft palate, cataracts and heart defects (NAS/NRC, 1978). Maternal toxlc-
1ty and reduced survival of offspring were also evident 1n some of these
studies. Reproductive effects of mlrex Include reductions In fertility and
litter size, decreased birth weight and reduced survival of offspring.
Fetal edema Is commonly reported 1n mlrex reproductive studies (Buelke-
Sam et al., 1983; Byrd et al., 1980; Chernoff et al., 1979a; Kavlock et a!.,
1982). Disruption of maternal blood flow appears to be the mechanism under-
lying this and possibly other observed reproductive and teratogenlc effects
of mlrex. Buelke-Sam et al. (1983) found that maternal visceral blood flow,
particularly uterine and conceptus blood flow, was markedly reduced In
mlrex-treated rats. These authors proposed that the resulting hypoxla
during organogenesls was responsible for reduced fetal weights, fetal edema
and prenatal death, as well as toxic effects on maternal organs.
Mlrex also causes cardiac defects, Including dysrhythmlas, 1n fetal and
newborn rats (Grabowskl, 1982, 1983a,b; Grabowskl and Payne, 1980). This
appears to be the most sensitive effect of mlrex 1n reproductive studies,
with no NOEL determined In studies 1n which doses as low as 0.1 mg/kg/day
for 6-8 days during organogenesls or organ development were used (Grabowskl,
1983a,b). These effects were not accompanied by obvious abnormalities.
Some of the dysrhythmlas were transient and benign, but others were fatal.
0094h " -8- 04/25/87
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A third commonly reported effect of mlrex 1n reproductlon/teratogenldty
studies Is formation of cataracts In offspring (Chernoff et al., 1976,
1979b; Chu et al., 1981; Galnes and Klmbrough, 1970; Grabowskl, 1982; Rogers
et al., 1984; Rogers and Grabowskl, 1984). Cataract formation has been
Induced by both prenatal and perinatal exposure to mlrex.
3.3.2. Inhalation. Reports of teratogenlclty or reproductive effect
studies with mlrex by Inhalation exposure could not be located 1n the
available literature.
3.4. TOXICANT INTERACTIONS
There were several studies available concerning the effects of mlrex on
the tox1c1ty of other compounds. Mlrex reportedly had no effect on the
hepatotoxldty caused by chloroform (Bell and Mehendale, 1985; Clanflone et
al., 1979, 1980; Curtis and Mehendale, 1980; Curtis et al., 1979, 1981;
Hewett et al., 1978). Abraham et al. (1974) fed mice diets containing PCBs
or mlrex or both, and found that the most severe toxic effects occurred In
mice receiving a combination of PCB and mlrex; however, 1t was not reported
1-f the effects appeared to be additive or synerglstlc.
0094h -12- 04/25/87
-------
4. CARCINOGENICITY
4.1. HUMAN DATA
The only ep1dem1olog1cal study available of cancer Incidence 1n relation
to mlrex exposure was that concerning residents of the Love Canal area 1n
New York. There was no evidence of higher cancer rates associated with
residence In this area (Janerlch et a!., 1981).
4.2. BIOASSAYS
4.2.1. Oral. Relevant data from three chronic oral carc1nogen1c1ty
bloassays 1n animals are summarized In Table 4-1.
Innes et al. (1969) tested an unspecified commercial mlrex formulation
In two hybrid strains of mice, (C57Bl/6xC3H/AnF)Fl and (C57Bl/6xAKR)Fl.
Treated mice (18/sex/straln) Initially received gavage doses of 10 mg/kg/day
on days 7-28 of age, then received a diet containing 26 ppm mlrex for 18
months, approximating the MTD. All treated mice died before 18 months.
Tumor1gen1c1ty was evaluated by the authors based on magnitude of relative
risk, comparing tumor Incidence In treated mice with controls. A separate
analysis using the Mantel-Haenszel procedure was performed for hepatomas,
pulmonary tumors, lymphomas and total mice with tumors. Mlrex caused a
significant (p<0.01) Increase 1n hepatomas In both strains of treated mice
(29/65; 65 of 72 animals were necropsled) compared with controls (14/338).
The hepatoma classification Included both hepatomas and carcinomas. Six
known carcinogens (urethan, amltrol, aramlte, dlhydrosafrole, Isosafrole and
safrole) were used as positive controls In this study and were clearly
tumorlgenlc. By comparison with the average response of the seven positive
controls (number of mice with hepatomas), mlrex had a relative risk of 0.945
across both strains and sexes, meaning that mlrex possessed -95X of the
carcinogenic potency of the known carcinogens tested In this study (Innes et
0094h -13- 04/25/87
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al., 1969). The female mice of both strains, when compared with female
positive controls of the respective strains, had relative risks for
hepatomas of 1.07 and 2.9 for the (C57B1/6 x C3H/Anf) Fl and (C57B1/6 x AKR)
Fl, respectively, while the males had relative risks for hepatomas of 0.38
and 0.7, respectively.
Ulland et al. (1973, 1977) fed groups of 26 male and 26 female Charles
River CD rats diets containing mlrex (99% purity) at concentrations of 50
and 100 ppm for 18 months. Untreated controls and positive controls treated
with a known carcinogen (2-AAF) were also Included. There was a treatment-
related decrease In survival. In the original evaluation, mlrex was report-
ed not to be carcinogenic; however, a reevaluatlon using guidelines for the
classification of liver tumors developed at an NCI workshop Indicated that
mlrex was carcinogenic (Ulland et al., 1973). A summary of this controversy
was presented by Ulland et al. (1977). Major points from their discussion
are summarized below.
The test animals showed a wide spectrum of neoplasms which, except for
liver lesions, showed little correlation with mlrex dosage. Therefore, the
relationship between mlrex exposure and the development of lesions at other
sites could not be established. There was a high Incidence of tumors,
regardless of sex or dose, but no statistically significant differences were
noted except for tumors of the liver (neoplastlc nodules). One carcinoma
was detected 1n the low-dose group, five 1n the high-dose group and none In
the control group. The difference 1n this parameter between test animals
and controls was not significantly different. Only the observation of seven
neoplastlc nodules of the liver 1n the high-dose (100 ppm) male rats was
significant at p<0.05. The authors did state, however, that this type of
neoplastlc nodule has been shown to progress to hepatocellular carcinoma 1n
0094h " -17- 04/25/87
-------
studies of other carcinogens. In addition, the absence of neoplastlc
nodules among controls and the fact that this type of lesion 1s character-
istic of early response to known carcinogens also suggests carcinogenic
activity. According to the authors, to call such nodules merely hyper-
plastic belles their neoplastlc nature and malignant potent1.il.
In the NTP (1987) cardnogenldty bloassay, currently available 1n draft
form, groups of 52 F344/N rats of each sex were fed diets containing 0, 0.1,
1.0, 10, 25 or 50 ppm mlrex for 104 weeks and sacrificed 8-10 weeks later.
During the first 6 months of the 2-year study, because of good survival and
the absence of observable toxic effects In female rats, additional groups
(termed second study) of 52 F344/N female rats were started at dietary
concentrations of 0, 50 and 100 ppm mlrex. The average amount of mlrex
consumed per day 1n the first studies was -0.007, 0.07, 0.7, 1.9 and 3.8 mg
mlrex/kg bw, respectively, for the 0.1, 1, 10, 25 and 50 ppm groups of male
and female rats. For the second study In female rats the feed consumption
data are Incomplete; however, based on the feed consumption data for the
first study 1n female rats, average estimated mlrex doses would have been
3.8 and 7.7 mg/kg for the 50 and 100 ppm groups, respectively.
In male rats, there was a- dose-relate<3 Increase In hepatocellular
neoplastlc nodules (controls, 3/52; 0.1 ppm, 5/52; 1 ppm, 5/52; 10 ppm,
14/52; 25 ppm, 15/52; 50 ppm, 26/52) and the 10, 25 and 50 ppm groups were
significantly greater than controls. In female rats (second study), the
Incidence of-hepatocellular neoplastlc nodules was dose-related and. signifi-
cantly greater than controls (controls, 2/52; 50 ppm, 23/52; 100 ppm, 30/52).
0094h -18- 04/25/87
-------
In the first female rat study the control Incidence rate was elevated as
compared with both historical controls and the control group females 1n the
second study, precluding pooling of the data from the first and second study
for hepatocellular neoplastlc nodules. In addition, any potential compound-
related Incidence rate could have been obscured by the elevated control
Incidence rate 1n the first study.
The Incidence of pheochromocytomas/mallgnant pheochromocytomas
(combined) of the adrenal gland occurred with a positive trend (p<0.001,
Cochran-ArmHage test) In male rats (controls, 10/51; 0.1 ppm, 7/52; 1 ppm,
13/52; 10 ppm, 12/52; 25 ppm, 18/51; 50 ppm, 20/51). The Incidences In the
25 and 50 ppm male rats were significantly greater than controls (p<0.005,
Fischer Exact test). In addition, there was a positive trend with dose for
transitional cell paplllomas of the kidney 1n male rats. However, In the
draft report the authors expressed reservations concerning the biological
significance and ability of this tumor type to progress.
In both the first and second studies In female rats, the Incidence of
mononuclear cell leukemia showed a dose-related Increase (first study:
controls, 8/52; 0.1 ppm, 8/52; 1 ppm, 11/52; 10 ppm, 14/52; 25 ppm, 18/52;
50 ppm, 18/52; second study: controls, 6/52; 50 ppm, 9/52; 100 ppm, 14/52).
When the data from both studies are combined, the Incidences are signifi-
cantly Increased 1n the 10, 25, 50 and 100 ppm groups.
The authors concluded that mlrex Is clearly carcinogenic In both male
and female F344/N rats as Indicated by marked Increased Incidences of benign
neoplastlc nodules of the liver 1n both males and females, as well as
Incidences of mononuclear cell leukemia 1n females and Increased- Incidences
of pheochromocytomas of the adrenal gland In male';.
4.2.2. Inhalation. Carclnogenldty bloassays In which mlrex was adminis-
tered by Inhalation could not be located 1n the available literature.
0094h -19- 04/30/87
-------
4.3. OTHER RELEVANT DATA
Abraham et al. (1983) examined ploldy patterns In livers of male
Sprague-Oawley rats receiving 100 ppm mlrex In the diet for 13 months. The
distribution of dlplold and tetraplold nuclei In nodular (e.g., adenomas and
carcinomas) and nonnodular areas was analyzed. Mlrex disturbed the usual
distribution of nodular areas within the ploldy. classes, selectively
reducing the number of tetraplold cells. This effect Is consistent with the
nature of liver tumors 1n rats, the greatest effect occurlng In hepato-
cellular carcinomas.
There 1s relatively little Information available concerning mutagenldty
of mlrex. Hallet et al. (1978), Schoeny et al. (1979) and NTP (1987) found
that mlrex was not mutagenlc to five strains of Salmonella typhlmurlum 1n
standard Ames tests with or without mammalian activating systems. H1rex did
not Induce either sister chromatld exchanges or chromosomal aberrations 1n
Chinese hamster ovary cells In the presence or absence of a mammalian
activating system.
4.4. WEIGHT OF EVIDENCE
IARC (1979) reviewed the available evidence concerning mlrex cardno-
genlcHy and concluded that there was "sufficient evidence that mlrex Is
carcinogenic In mice and rats." Human data were Inadequate for evaluation,
and IARC (1979) concluded that 1t would be reasonable to regard mlrex as 1f
It presented a carcinogenic risk for humans. Using the U.S. EPA (1986)
guidelines, mlrex would be classified In EPA Group B2, probable human
carcinogen, on the basis of sufficient evidence from animal studies
(multiple experiments In different species) and Inadequate evidence from
human studies.
0094h -20- 07/30/87
-------
5. REGULATORY STANDARDS AND CRITERIA
The following tolerances for residues of mlrex on raw agricultural
commodities have been established (Code of Federal Regulations, 1982; U.S.
EPA, 1983a): 0.1 ppm (negligible residue) In the fat of meat from cattle,
goats, hogs, horses and sheep; 0.1 ppm 1n milk fat, reflecting negligible
residues In milk; 0.1 ppm (negligible residue) In eggs; 0.01 ppm (negligible
residue) In or on all raw agricultural commodities, exclusive of those
mentioned above.
U.S. EPA (1976) recommended a water quality criterion of 0.001 yg/l
for the protection of aquatic life. This value was derived by applying a
safety factor of 0.01 to the lowest concentration affecting several species
of aquatic crustaceans.
0094h -21- 04/25/87
-------
6. RISK ASSESSMENT
6.1. ACCEPTABLE INTAKE SUBCHRONIC (AIS)
Because of Its carclnogenldty, no oral or Inhalation AIS values can be
calculated for mirex.
6.2. ACCEPTABLE INTAKE CHRONIC (AIC)
Because of Us cardnogenlcHy, no oral or Inhalation AIC values can be
calculated for mirex.
6.3. CARCINOGENIC POTENCY (q^)
6.3.1. Oral. Although there are no ep1dem1olog1cal studies available
that are useful for assessing carcinogenic risk of mirex to humans, there
are three animal studies available that Indicate that mirex 1s carcinogenic
(Innes et al.t 1969; inland et al., 1973, 1977; NTP, 1987).
Innes et al. (1969) found that mirex (26 ppm diet) caused a significant
Increase 1n hepatomas In male and female strain (C5781/6xAKR)Fl mice
(p<0.01) and \n male strain (C57Bl/6xC3H/Anf)F1 mice (p<0.05).
lllland et al. (1977) reported that mirex caused a significant Increase
(p<0.05) In neoplastlc nodules of the liver In male Charles River CO rats
exposed to 80-100 ppm diet for 18 months. They noted that progression of
these nodules to hepatocellular carcinomas was highly probable and
therefore, these data are suggestive of mirex carclnogenlclty.
Reporting Inadequacies (both studies) and the. controversy, over tumor
classification (inland, 1973, 1977), combined with only a single dose level
and high mortality In the Innes et al. (1969) study, make these evaluations
less than optimum for quantitative risk assessment.
A draft report of an NTP study riot subject to these deficiencies Is also
available (NTP, 1987). In this study groups of 52 rats/sev/dose were fed
diets containing 0, 0.1, 1.0, 10, 25 or 50 ppm mirex for 104 weeks and
0094h -22- 04/25/87
-------
sacrificed 8-10 weeks later. An additional study with female rats was
Included 1n which 5"2 female rats/dose were exposed through their diet to 0,
50 or 100 ppm mlrex (second study).
In this NTP study,. Incidences of neoplastlc liver nodules were Increased
In both male and female- rats, without Increases 1n hepatocellular carcinoma.
Liver nodules are generally assumed to have the potential to progress to
malignancy. In the first female rat study, concurrent control Incidence of
nodules was significantly elevated compared with both historic controls and
concurrent controls from the second study.
The Incidence of pheochromocytomas or combined pheochromocytomas and
malignant pheochromocytomas of the adrenal gland showed a positive dose
trend In males with the 25 and 50 ppm dose groups being significantly
different from controls In palrwlse comparisons.
Mononuclear cell leukemia showed positive dose-related trends 1n both
studies with female rats. Palrwlse comparisons showed that the 25 and 50
ppm groups were significantly different from the concurrent control 1n the
first study and the 100 ppm group was elevated compared with the second
study concurrent control. Since the control groups did not differ signifi-
cantly, the data were pooled by NTP and an analysis of the pooled data Indi-
cated that the 10, 25, 50 and 100 ppm groups were significantly different
from controls.
Potency estimates arid associated parameters were developed using Global
82 (Howe and Crump, 1982) and are shown 1n Tables 6-1, 6-2 and 6-3. The
cancer guidelines (U.S. EPA, 1986) suggest that In order to obtain a total
estimate of carcinogenic risk animals with one or more tumor sites or types,
of those types showing a significantly elevated Incidence In response to
009th -23- 04/25/87
-------
TABLE 6-1
Cancer Data Sheet for Derivation of q-|*
Reference: NTP, 1987
Compound: mlrex
Species, strain, sex: rats, Fischer F344/N, male
Route/vehicle: oral, diet
Length of exposure (le) = 104 weeks
Length of experiment (Le) = 104 weeks
Llfespan of animal (L) = 104 weeks
Body weight = 0.35 kg (estimated from graphic data provided by Investigators)
Tumor site and type: liver neoplastlc nodule, hepatocellular carcinoma,
adrenal pheochromocytoma and malignant pheochromocytoma
Route, Vehicle; oral, diet
Experimental
Doses or Exposures
(ppm)
0
0.1
1
10 ,:.
25
50
Transformed Dose3
(mg/kg/day)
0
0.007
0.07
0.7
1.8
3.8
Incidence
No. Responding/No. Tested
16/52
11/52
17/52
23/52
27/51°
35/52
aEst1mated by the authors
DAdrenal not examined In one rat that did not have hepatocellular neo-
plastlc nodule or hepatocellular carcinoma
Unadjusted q-|* from study = 3.0895188X10'1 (mg/kg/day)"i
Human q-|* = 1.8068 (mg/kg/day)'1
0094h -24- . 04/25/87
-------
TABLE 6-2
Cancer Data Sheet for Derivation of q-j*
Reference: MTP, 1987
Compound: ml rex.,
Species, strain, sex: rats, Fischer F344/N, female
Route/vehicle: oral, diet
Length of exposure (le) = 104 weeks
Length of experiment {Le) = 104 weeks
Llfespan of animal (L) = 104 weeks
Body weight = 0.24 kg (estimated from graphic data provided by Investigators)
Tumor site and type: liver neoplastlc nodule, hepatocellular carcinoma
and leukemia
Route, Vehicle: oral, diet
Experimental
Doses or Exposures
(ppm)
0
Q.I
1
10
25
50
Transformed Dose*
(mg/kg/day)
0
0.007
0.08
0.7
2.0
3.9
Incidence
No. Responding/No. Tested
17/52
13/52
13/52
18/52
22/52
21/52
^Estimated by the authors
Unadjusted q-j* from study = 1.1854367xlO~i (mg/kg/day)'1
Human q-|* = 7.8615X10'1 (mg/kg/day)'1
0094h
-25-
04/25/87
-------
TABLE 6-3
Cancer Data Sheet for Derivation of q-|*
Reference: NTP, 1987
Compound: mlrex
Species, strain, sex: rats, Fischer F344/N, female, study #2
Route/vehicle: oral, diet
Length of exposure (le) = 104 weeks
Length of experiment (Le) = 104 weeks
Llfespan of anl.iwl (L) « 104 weeks
Body weight = 0.22 kg {estimated from graphic data provided by Investigators)
Tumor site and type: liver neoplastlc nodule, hepatocellular carcinoma
and leukemia
Route, Vehicle: oral, diet
Experimental
Doses or Exposures
(ppm)
0
50
100
Transformed Doset
(mgAg/day)
0
3.9
7.7
Incidence
No. Responding/No. Tested
7/52
25/52
37/52
^Estimated by the authors
Unadjusted q-]* from study = !<9918064xlO~1 (mg/kg/day)'1
Human q-j* = 1.2235 (mg/kg/day)"1
0094h -26- 04/25/87
-------
treatment, should be pooled and the pooled estimates utilized for extrapola-
tion. The guidelines also state that benign and malignant tumors should be
combined unless the benign tumors are not considered to have the potential
to progress to the associated malignancy.
Pooled counts were developed using the Individual animal data appended
to the NTP (1987) report. For male rats any animal having a diagnosed Hver
neoplastlc nodule, hepatocellular carcinoma, adrenal pheochromocytoma or
malignant pheochromocytoma was counted. For female rats for each study, any
animal showing a diagnosed hepatic neoplastlc nodule, hepatocellular
carcinoma or leukemia was counted. The resulting human q,*s were 1.8, 0.8
and 1.2 (mg/kg/day)'1 for the males, first study females and second study
females, respectively.
The estimate of 1.8 (mg/kg/day)'1 Is chosen to represent the carcino-
genic potency of mlrex. It should be noted that the potency estimate
Includes benign tumor counts for two endpolnts (liver and adrenal) based on
their presumed potential to progress. It should also be noted that this
estimate does not take Into consideration the Increased mortality rate seen
1n the two highest dose groups. This Increase In Intercurrent mortality
could have resulted 1n fewer animals 1n these groups surviving to develop
tumors. While the 1986 cancer guidelines suggest correction for Inter-
current mortality, this correction cannot be performed without access to
Individual animal data on mortality. While NTP provides estimates of tumor
Incidence that take mortality Into account, these estimates are for Indi-
vidual tumor sites rather than the pooled site estimates suggested by the
guidelines. Potencies could be estimated based upon summed site-specific
estimates; however, this would overestimate risk when animals exhibited more
than one tumor type. With the high tumor Incidences observed 1n this study
this consideration could result 1n a significant overestlmatlon of potency.
0094h . -27- 04/25/87
-------
For purposes of comparison, these summed estimates were calculated for
male rats. Summed q.*s for Individual sites corrected for mortality
showed only a 3-fold Increase over the pooled estimates. This small
Increase In the context of the high tumor Incidence and error Introduced by
counting the same animal twice suggests that Intercurrent mortality In this
study had only a small affect on tumor Incidence.
Review of the CBI file for mlrex did not reveal any Information that
would affect this risk assessment.
6.3.2. Inhalation. There were no Inhalation carc1nogen1c1ty data
available for mlrex, and therefore, no carcinogenic risk assessment can be
performed.
0094h -28- 04/25/87
-------
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Abston, P.A. and J.D. Yarbrough. 1976. The ]n_ vivo effect of mlrex on
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0094h -30- 04/25/87
-------
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0094h -31- 04/25/87
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0094h -32- 04/25/87
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Gibson, J.R., G.W. Iv1e and H.W. Dorough. 1972. Fate of mlrex and Us
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Grabowskl, C.T. 1982. Functional testing for the effects of very low doses
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Grabowskl, C.T. and D.B. Payne. 1980. An electrocardiograph^ study of
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1167-1178.
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0094h . -38- 04/30/87
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APPENDIX
Summary Table for M1rex*
Route
Species/
Strain/Sex
Experimental
Exposure/Dose
Effect
Oral
rat/
F344/N
male
0, 0.1, 1, 10,
25, or 50 ppm
In the diet
liver neo-
plastlc
nodules,
adrenal
pheochromo-
cytomas
1.8
(mg/kg/day)'1
*Source: NTP, 1987
U.S.
-bection Agency
ome -w
*, Library 15PL-J.O)
Dearborn Street, Room 16/0
6°604
0094h
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