TECHNICAL REPORT DATA
(fltfU retd Instructions on the revent before completing}
1. REPORT NO.
EPA/600/8-88/029
3. RECIPIENT'S ACCESSION NO
PB88-179940/AS
4. TITLE AND SUBTITLE
Health Effects Assessment for 1,2-Dichloropropane
B. REPORT DATE
6. PERFORMING ORGANIZATION CODE
AUTHOR(S)
I. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
10. PROGRAM ELEMENT NO.
11. CONTRACT/GRANT NO.
12. SPONSORING AGENCY NAME AND ADDRESS
Environmental Criteria and Assessment Office
Office of Research and Development
U.S. Environmental Protection Agency
Cincinnati. OH 45268
13. TYPE OF REPORT AND PERIOD COVERED
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). The first, RfD$ 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 cause 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
18. DISTRIBUTION STATEMENT
Public
10. SECURITY CLASS (ThU Report/
Unclassified
21. NO. OF PAGES
20. SECURITY CLASS {This page)
Unclassified
22. PRICE
EPA Pwm 2220-1 («•*. 4-77) PREVIOUS COITION 11 OMOLCTC
!J
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EPA/600/8-88/029
June, 1987
HEALTH EFFECTS ASSESSMENT
FOR 1,2-DICHLOROPROPANE
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
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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
This report summarizes and evaluates Information relevant to a prelimi-
nary Interim assessment of adverse health effects associated with l,2-d1-
chloropropane. All estimates of acceptable Intakes and carcinogenic potency
presented In this document should be considered preliminary and reflect
limited resources allocated to this project. Pertinent toxicologic and
environmental data were located through on-line literature searches of the
Chemical Abstracts, TOXLINE, CANCERUNE and the CHEMFATE/DATALOG data bases.
The basic literature searched supporting this document 1s current up to May,
1986. Secondary sources of Information have also been relied upon In the
preparation of this report and represent large-scale health assessment
efforts that entail extensive peer and Agency review. The following Office
of Health and Environmental Assessment (OHEA) sources have been extensively
utilized:
U.S. EPA. 1980a. Ambient Hater Quality Criteria Document for
Dlchloropropanes and Dlchloropropenes. Prepared by the Office of
Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Water Regula-
tions and Standards, Washington, DC. EPA 440/5-80-043. NTIS
PB81-117541.
U.S. EPA. 1983a. Reportable Quantity Document for 1,2-D1chloro-
propane. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office,, Cincin-
nati, OH for the Office of Emergency and Remedial Response, Wash-
ington, DC.
U.S. EPA. 1983b. Reportable Quantity Document for Dlchloropro-
pane. Prepared by the Office of Health and Environmental Assess-
ment, Environmental Criteria and Assessment Office, Cincinnati, OH
for the Office of Emergency and Remedial Response, Washington, DC.
U.S. EPA. 1984. Drinking Water Criteria Document for 1,2-01-
chloropropane. Prepared by the Office of Health and Environmental
Assessment, Environmental Criteria and Assessment Office, Cincin-
nati, OH for the Office of Drinking Water, Washington, DC. NTIS
PB86-117850/AS.
U.S. EPA. 1985. Health and Environment Effects Profile for
Dlchloropropanes. Prepared by the Office of Health and Environ-
mental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency
Response, Washington, DC.
The Intent In these assessments 1s to suggest acceptable exposure levels
for noncardnogens and risk cancer potency estimates for carcinogens
whenever sufficient data were available. Values were not derived or larger
uncertainty factors were employed when the variable data were limited 1n
scope tending to generate conservative (I.e., protective) estimates.
Nevertheless, the Interim values presented reflect the relative degree of
hazard or risk associated with exposure to the chemlcal(s) addressed.
111
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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. Dr. Christopher DeRosa and Karen
Blackburn were the Technical Project Monitors and John Helms (Office of
Toxic Substances) was the Project Officer. The final documents 1n 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 Kim Davidson
Environmental Criteria and Assessment Office
Cincinnati, OH
v1
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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.
1,2-D1chloropane produced dose-related Increases 1n hepatic adenomas/
carcinomas In mice of both sexes given oral doses of 125 or 250 mg/kg, 5
days/week for 2 years (NTP, 1986). It was not clear 1f Increases In mammary
adenocarclnomas 1n female rats or thyroid folllcular cell tumors 1n mice
were also treatment-related. NTP (1986) noted the high background Incidence
of liver tumors In male mice, but considered the Increased hepatic tumor
response biologically significant. Adequate data for assessment of the
carcinogenic potency of 1,2-d1chloropropane by Inhalation exposure were not
found 1n the available literature.
U.S. EPA (1984, 1985) calculated a human q-|* of 6.33xlO~2
(mg/kg/day)"1, based upon the hepatic tumor Incidence observed 1n male
mice. Several positive mutagenldty assays, particularly concerning
chromosomal aberrations, substantiate the weak carcinogenic potency of
1,2-d1chloropropane. The NTP draft report of 1983 was a preliminary draft
and reanalysls of carcinogenic risk values are now available (NTP, 1986).
The re-evaluated q-|* of 6.75xlO~2 (mg/kg/day)"1 based on the hepatic
tumor Incidence observed In male mice Is now considered the most appropriate
cancer risk assessment supercedlng these earlier assessments.
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Whenever possible, two categories of values have been estimated for
systemic toxicants (toxicants for which cancer 1s not the endpolnt of
concern). The first, RfD$ (formerly AIS) or subchronlc reference dose, 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
towards exposures from toxicants 1n ambient air or water where lifetime
exposure 1s assumed. Animal data used for RFD$ 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. These
values are developed for both Inhalation (RfD^j) and oral (RfD$o)
exposures.
The RfO (formerly AIC) Is similar 1n concept and addresses chronic
exposure. It 1s an estimate of an exposure level that would not be expected
to cause adverse effects when exposure occurs for a significant portion of
the llfespan [see U.S. EPA (1980b) for a d1scuss-1on of this concept]. The
RfD Is route-specific and estimates acceptable exposure for either oral
(RfDg} or Inhalation (RfDj) with the Implicit assumption that exposure
by other routes 1s Insignificant.
Composite scores (CSs) for noncardnogens have also been calculated
where data permitted. These values are used for Identifying reportable
quantities and the methodology for their development 1s explained 1n U.S.
EPA (1983).
For compounds for which there 1s sufficient evidence of cardnogenlcHy
RfD$ and RfD values are not derived. For a discussion of risk assessment
methodology for carcinogens refer to U.S. EPA (1980b). Since cancer 1s a
process that Is not characterized by a threshold, any exposure contributes
an Increment of risk. For carcinogens, q-|*s have been computed, 1f appro-
priate, based on oral and Inhalation data If available.
1v
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TABLE OF CONTENTS
1.
2.
3.
4.
5.
6.
7.
iPPE
ENVIRONMENTAL CHEMISTRY AND FATE
ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
2.2. INHALATION ...
TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. .
3.1.2. Inhalation
3.2. CHRONIC
3.2.1. Oral. ...........
3.2.2. Inhalation
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
3.4. TOXICANT INTERACTIONS. .....
CARCINOGENICITY ...... .
4.1. HUMAN DATA
4.2. BIOASSAYS
4.2.1. Oral. .
4.2.2. Inhalation. ........
4.3. OTHER RELEVANT DATA
4.4. WEIGHT OF EVIDENCE . .
REGULATORY STANDARDS AND CRITERIA .
RISK ASSESSMENT
6.1. REFERENCE DOSE (RfD) AND SUBCHRONIC REFERENCE DOSE (RfDs).
6.2. CARCINOGENIC POTENCY (q^)
6.2.1. Oral
6.2.2. Inhalation
REFERENCES
NDIX
Page
1
3
3
3
4
4
4
4
5
5
6
6
6
7
7
7
7
9
9
10
11
12
12
12
12
12
15
20
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LIST OF ABBREVIATIONS
AAOI Adjusted acceptable dally Intake
CAS Chemical Abstract Service
CNS Central nervous system
CS Composite score
DNA Deoxyrlbonuclelc add
HA Health advisory
LOEL Lowest-observed-effect level
MED Minimum effective dose
NOEL No-observed-effect level
OCT OrnHhlne carbamyl transferase
PEL Permissible exposure level
ppm Parts per million
ppt Parts per trillion
RfD Reference dose
RfDj Inhalation reference dose
RfDg Oral reference dose
RfD$ Subchronlc reference dose
RfD$j Subchronlc Inhalation reference dose
RfD$o Subchronlc oral reference dose
RNA R1bonucle1c add
RV(j Dose-rating value
RVe Effect-rating value
SCE Sister chromatld exchange
SGOT Serum glutamlc oxaloacetlc transamlnase
SGPT Serum glutamlc pyruvlc transamlnase
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LIST OF ABBREVIATIONS (cont.)
STEL Short-term exposed level
TLV Threshold limit value
TWA Time-weighted average
1x
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1. ENVIRONMENTAL CHEMISTRY AND FATE
Selected chemical and physical properties and environmental fate of
l,2-d1chloropropane are presented In Table 1-1.
In the atmosphere, 1,2-d1chloropropane should occur mostly 1n the vapor
phase and appears to be susceptible to oxidation by HO radical (U.S. EPA,
1985). The atmospheric half-life listed 1n Table 1-1 was calculated using a
reaction rate constant of <4.4xlO~13 cmVmolecule-sec at 23°C (Atkinson,
1985) and a HO radical concentration of S.OxlO5 molecules/cm3 (U.S. EPA,
1986a). -In water and soil, volatilization appears to be the major mechanism
In determining the fate of 1,2-d1chloropropane. The aquatic half-life
listed In Table 1-1 was calculated using the U.S. EPA EXAMS computer simula-
tion and a measured Henry's Law constant of 0.00231 atm-m3/mol. Bloaccu-
mulatlon 1n aquatic organisms and adsorption to sediments by 1,2-d1chloro-
propane should not be significant (U.S. EPA, 1985).
The soil half-life listed 1n Table 1-1 1s based on a study examining the
volatility of 14C-2-labeled 1,2-d1chloropropane from a sandy loam son
under simulated conditions. Ten days after application, <1X of the original
radlolabel remained 1n the soil, which corresponds to a half-life of <2
days. Low adsorption to soil and monitoring data Indicate that l,2-d1-
chloropropane Is highly mobile In soil and may leach Into groundwater (U.S.
EPA, 1985).
0077h -1- 10/09/86
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TABLE 1-1
Chemical and Physical Properties and Environmental Fate
of T,2-Q1chloropropane
Property
Value
Reference
CAS number:
Chemical name:
Molecular weight:
Vapor pressure:
Water solubility:
Log octanol/water
partition coefficient:
B1oconcentrat1on factor:
Soil adsorption
coefficient:
Half-lives In
A1r:
Water:
Soil:
78-87-5
halogenated aliphatic
hydrocarbon
112.99
42 mm Hg at 20°C
50 mm Hg at 25°C
2700 mg/l at 20°C
2.02-2.28 (estimated)
-10, carp (CypMnus carplo)
27-51
-23 days
1.6 days (river),estimated
1.7 days (pond), estimated
10 days (eutrophlc lake),
estimated
11 days (ollgotrophlc lake),
estimated
<2 days
U.S. EPA, 1985
U.S. EPA, 1985
U.S. EPA, 1985
U.S. EPA, 1985
Kawasaki, 1980
U.S. EPA, 1985
Atkinson, 1985
U.S. EPA, 1985
U.S. EPA, 1985
U.S. EPA, 1985
U.S. EPA, 1985
U.S. EPA, 1985
0077h
-2-
10/09/86
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2. ABSORPTION FACTORS IN HUMANS AND EXPERIMENTAL ANIMALS
2.1. ORAL
Data regarding the absorption of 1,2-d1ch1oropropane after oral adminis-
tration In humans could not be located 1n the available literature
Male rats given a single oral 0.88 mg dose of 1,2-d1chloro(1-l4C)-
propane (8.5 yd) excreted 5.0% of the administered radioactivity 1n the
feces after 24 hours and 6.8% after 96 hours (Hutson et al., 1971). Females
excreted 3.8% of the administered radioactivity 1n the feces after 24 hours
and 4.9% after 96 hours. The Investigators observed that 80-90% of the
administered radioactivity was eliminated by all routes within 24 hours of
dosing. These results Indicate that 1,2-d1chloropropane Is extensively and
rapidly absorbed after oral administration.
2.2. INHALATION
Pertinent data regarding the absorption of 1,2-d1chloropropane after
Inhalation exposure 1n either humans or experimental animals could not be
located In the available literature.
0077h -3- 08/19/86
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3. TOXICITY IN HUMANS AND EXPERIMENTAL ANIMALS
3.1. SUBCHRONIC
3.1.1. Oral. NTP (1986) conducted a 13-week gavage study using groups of
10 male and 10 female F344/N rats and 10 male and 10 female B6C3F1 mice.
1,2-D1chloropropane (99.4X pure) In corn oil was given 5 days/week at 0, 60,
125, 250, 500 or 1000 mg/kg to rats and at 0, 30, 60, 125, 250 or 500 mg/kg
to mice. All treated male and female rats at 1000 mg/kg/day and 5/10 males
treated with 500 mg/kg/day died before the end of the study. Hepatic
changes, Including centrllobular congestion, necrosis and fatty changes,
predominated In the 1000 mg/kg/day rats. No treatment-related effects were
observed In rats given <250 mg/kg/day. In mice given <500 mg/kg/day, there
were no effects on hlstopathology and Isolated Instances of mortality were
not treatment-related.
3.1.2. Inhalation. Sldorenko et al. (1979) continuously exposed male
rats to 1.5 or 9 mg/m3 1,2-d1chloropropane for 86 days. There were no
apparent effects on body weights or limited hematologlca'l parameters.
Effects on the CNS, evaluated by a change In "total threshold Indicator"
(not otherwise defined), were observed only at termination at 9 mg/m3.
Changes (probably elevation) 1n blood chollnesterase activity were noted at
9 mg/m3 after 25 days of exposure. Other changes of questionable biologi-
cal significance reported for rats at 9 mg/m3 Included ultrastructural
changes 1n the lungs, slightly decreased RNA content and Increased DNA
content (evidence of Increased ploldy) In the liver, and slightly Increased
liver enzyme activities (not specified).
Heppel et al. (1948) found few changes In rats, guinea pigs or dogs
exposed 7 hours/day, 5 days/week for -28 weeks to 400 ppm (1840 mg/m3)
1,2-d1chloropropane; C57 mice exposed under the same conditions all died
within 12 sessions and nearly all exposed C3H mice died within 37 sessions.
0077h -4- 02/18/87
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Histologies"), examination of the mice revealed congestion, fatty degeneration
of the livers and kidneys, and centMlobular necrosis.
In a 13-week Inhalation study using rats, mice and rabbits, groups of 10
rats/sex and 10 mice/sex were exposed to 0, 15, 50 or 100 ppm (0, 69, 230 or
691 mg/m3) 1,2-d1chloropropane 6 hours/day, 5 days/week (Dow Chemical Co.,
1985). Groups of seven rabbits/sex were exposed to 0, 150, 500 or 1000 ppm
(0, 691, 2300 or 4600 mg/m3) 1,2-d1chloropropane 6 hours/day, 5 days/week.
H1stolog1cal examination of nasal tissue revealed a slight to very slight
degeneration of olfactory tissues 1n rats exposed to 50 and 150 ppm. This
effect was also observed 1n some (number not specified) male rabbits exposed
at 1000 ppm, but was not observed In mice. Rats exposed to 50 and 150 ppm
had slight respiratory epithelial hyperplasla also, and hyperplasla was
observed 1n a few (number not specified) rats exposed to 15 ppm l,2-d1-
chloropropane.
Anemia (determined by blood test) was considered a dose-related effect
for male rabbits at all dose levels, and for female rabbits at the 500 and
1000 ppm dose levels. Upon examination of blood smears and hlstopathology
of bone marrow, the anemia appeared to be regenerative. Anemia was not
observed 1n rats or mice. Further details of this study were not provided
1n the preliminary report.
3.2. CHRONIC
3.2.1. Oral. NTP (1986) orally administered 0, 125 or 250 mg/kg 1,2-dl-
chloropropane, 5 days/week, to groups of 50 female rats and 50 male and 50
female mice, and 0, 62 or 125 mg/kg, 5 days/week, to groups of 50 male rats
for 103 weeks. Male and female rats had dose-related decreases 1n body
weight gain; a depression of terminal body weight >10% was noted 1n high-
dose males and females. The mortality rate among high-dose female rats was
0077h -5- 02/18/87
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greatly accelerated, but survival 1n low-dose females and male rats was
unaffected. Treatment-related nonneoplastlc changes 1n rats Included
mammary gland hyperplasla (low-dose females), fod of hepatic clear cell
changes and hepatocellular necrosis (high-dose females). Treatment with
either dose significantly decreased survival 1n female mice. Hepatocyto-
megaly and hepatic necrosis occurred 1n a dose-related manner 1n males.
Forestomach acanthosls occurred at a slightly Increased Incidence In high-
dose males and both treated groups of females and suppuratlve Inflammation
(particularly of the reproductive organs) occurred more frequently In
treated females that died before the end of the study, compared with
controls.
3.2.2. Inhalation. Pertinent data regarding the toxldty of l,2-d1-
chloropropane after chronic Inhalation exposure could not be located 1n the
available literature.
3.3. TERATOGENICITY AND OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding the teratogenldty of oral or Inhalation
exposure to 1,2-d1chloropropane could not be located 1n the available
literature. Shalpak (1976) observed that exposure to 9 mg/m3, for an
unspecified duration, Impaired spermatogenesls 1n rats.
3.4. TOXICANT INTERACTIONS
Drew et al. (1978) found that simultaneous Inhalation exposure to
1,2-d1chloropropane and tMchloropropane synerg1st1cally Increased SGPT
levels and had additive effects on SCOT and OCT levels, 24 hours after
exposure; however, effects of this combination on each enzyme were antago-
nistic at 48 hours. U.S. EPA (1984) concluded that, overall, the compounds
did not act In a synerglstlc manner.
0077h -6- 02/18/87
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4. CARCINOGENICITY
4.1. HUMAN DATA
Pertinent data regarding oral or Inhalation exposure In humans and
resultant cardnogenldty could not be located 1n the available literature.
4.2. BIOASSAYS
4.2.1. Oral. The only available cardnogenesls bloassay of 1,2-d1ch1oro-
propane Is provided as a final report by the NTP (1986) (see Section
3.2.1.). Male rats treated by gavage with 62 or 125 mg/kg, 5 days/week for
103 weeks had significantly Increased Incidence of any tumor type. Treated
female rats had significantly Increased Incidences of mammary adenocarcl-
nomas (0 mg/kg, 1/50; 125 mg/kg, 2/50; 250 mg/kg, 5/50); although not
significantly different at p=0.05 when compared with the Incidence 1n
controls by the Fischer exact test, the Incidences were statistically
significant for dose-related trends by the life table and Incidental tumor
tests. NTP (1986) considered the mammary tumor response 1n female rats to
be equivocal evidence for Us carcinogenic potential.
Incidence data for treatment-related Increases 1n hepatic adenoma and
carcinomas combined 1n mice are shown 1n Table 4-1. Significant dose-
related trends for these tumor types were observed 1n both sexes, and the
tumor response was significantly elevated at 250 mg/kg 1n both sexes.
Significant dose-related trends for Hver adenomas 1n males and females were
also found (data not shown). NTP (1986) observed nonsignificant trends In
the Incidences of liver carcinomas 1n both males (0 mg/kg, 11/50; 125 mg/kg,
17/49; 250 mg/kg, 16/50) and females (0 mg/kg, 1/50; 125 mg/kg, 3/50; 250
mg/kg, 4/50). The Investigators noted the high historical background rate
of hepatic tumors 1n male B6C3F1 mice and the genetic heterogeneity of the
parent (C3H) strain, but concluded that the findings were of biological
significance.
0077h -7- 02/18/87
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TABLE 4-1
Hepatic Adenoma/Carcinoma Incidence In B6C3F1 Mice
Orally Administered 1,2-01chloropropane (>99.4% pure)
1n Corn Oil for 103 Weeks3
Sex
M
F
Doseb
(mg/kg)
0
125
250
0
125
250
Tumor Incidence
18/50
26/49
33/50
2/50
8/50
9/50
aSource: NTP, 1986
bAdm1n1stered by gavage 5 times/week
0077h
-8-
02/18/87
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Thyroid folUcular cell tumors (adenomas and carcinomas) occurred In
5/46 high-dose female mice; control Incidences for these tumor types were
1/48. NTP (1986) was uncertain that these tumors were treatment-related,
but noted that Incidence 1n female mice may have been underestimated because
of the early mortality that occurred In this group.
4.2.2. Inhalation. Pertinent data regarding tumor development after
chronic Inhalation exposure to 1,2-d1chloropropane could not be located 1n
the available literature. Heppel et al. (1948) reported that thirty-seven
4- to 7-hour exposure sessions to 1,2-d1chloropropane Induced multiple
hepatomas In mice. In this experiment, 80 C3H mice were exposed for 4-7
hours dally, 5 days/week to 400 ppm (1840 mg/m3). Survival was poor and
the cause of death apparently was related to severe liver necrosis. Only
three mice survived the exposures and a subsequent 7-month observation
period, and they had multiple hepatomas similar to those Induced by known
hepatocardnogens. Apparently, controls were not Included In this
experiment.
4.3. OTHER RELEVANT DATA
Several researchers (NTP, 1986; Haworth et al., 1983; Principe et al.,
1981) found that 1,2-d1chloropropane was marg1nally-to-strongly mutagenlc 1n
Salmonella typhlmuMum strains TA100 and TA1535. The extent of genotoxldty
was consistently diminished by addition of an S-9 mlcrosomal fraction.
1,2-01chloropropane has not been shown to have any direct alkylatlng
activity, while the metabolite 1,2-epoxypropane has been shown to be an
alkylatlng agent (Jones and Gibson, 1980). The role of metabolite activa-
tion In 1,2-d1chloropropane toxlclty 1s not clear. Principe et al. (1981)
also found that 1,2-dlchloropropane Induced forward mutations In Asperqlllus
nldulans. but It was Ineffective In Inducing somatic segregation 1n the same
0077h -9- 02/18/87
-------
species (CrebelH et al., 1984). 1,2-D1ch1oropropane was associated with
SCE and chromosomal aberrations 1n Chinese hamster ovary cells (HIP, 1986),
and Oragusanu and Goldstein (1975) demonstrated chromosomal aberrations In
bone marrow cells from 1,2-d1chloropropane-treated rats. Woodruff et al.
(1985) observed that 1,2-d1chloropropane did not cause sex-Hnked recessive
lethality In DrosophUa melanoqaster.
4.4. WEIGHT OF EVIDENCE
The evidence for the cardnogenlcity of 1,2-dlchloropropane 1s both
direct and Indirect. From animal bloassays there Is significantly Increased
liver tumor Incidence (adenomas and carcinomas combined) In male and female
B6C3F1 mice. In male F344 rats there Is no significant response while In
female rats there 1s an elevated trend response In mammary gland adeno-
cardnomas with a negative trend 1n Incidence of fIbroadenomas. Thyroid
folUcular cell adenomas and carcinomas were significantly Increased In
high-dose female mice but not 1n low-dose females. Taken together the liver
tumor response provides limited to borderline sufficient evidence of
cardnogenlcity with the mammary and thyroid responses being supportive of
possible carcinogenic potential. Indirectly, the evidence of mutagenlc
activity; the probability that metabolites of 1,2-d1chloropropane are
formed, one being 1,2-epoxypropane which Is an alkylatlng agent, and the
structural similarity of 1,2-d1chloropropane to other chemicals that are
carcinogenic 1n rats and mice (DBCP, 1,2-dlchloroethane, 1,2-
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5. REGULATORY STANDARDS AND- CRITERIA '
Because of the limitations of the available data base, U.S. EPA (1980a)
did not derive a satisfactory ambient water quality criterion for l,2-d1-
chloropropane, using conventional methodology. The Agency cited a 30-day
study by Kurysheva and Ekshtat (1975), In which oral doses of 14.4 mg/kg/day
to rats produced changes In serum enzyme levels, for derivation of provi-
sional water criteria. Application of an uncertainty factor of 1000 to this
LOEL and use of standard assumptions (70 kg human body weight, 0.0065 kg/day
fish consumption, and a bloconcentratlon factor of 4.11) resulted In a water
level of 483 yg/l.
ACGIH (1985) adopted a TLV-THA of 75 ppm (-350 mg/m3) and a 15-mlnute
STEL of 110 ppm (-510 mg/m3) for 1,2-d1chloropropane. ACGIH (1986) stated
that the TLV-THA was based upon the Heppel et al. (1946, 1948) studies, but
recommended that H be reconsidered because the TLVs for other hepatotoxlc
halogenated compounds have recently been reduced.
U.S. EPA (1984) considered toxlcologkal data Insufficient for calcula-
tion of a 1-day or 10-day child or adult HA, or a lifetime AADI. Alterna-
tively, the Agency suggested a 7-day level of 0.3 mg/i, based upon the
limited toxlclty data of Ekshtat et al. (1975), until more adequate data
were available.
0077h -11- 10/09/86
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6. RIS.K ASSESSMENT
6.1. REFERENCE DOSE (RfD) AND SUBCHRONIC REFERENCE DOSE
Because oral 1,2-d1chloropropane Induced Increases 1n liver tumor
Incidence In mice (NTP, 1986), It would be Inappropriate to derive RfD or
RfDc values for either the oral or the Inhalation route.
j
6.2. CARCINOGENIC POTENCY (q^)
6.2.1. Oral. U.S. EPA (1985) derived q *s for Increased lifetime rtsk
1n humans from hepatic adenoma/carcinoma data from both male and female mice
based on a 1983 draft of the aforementioned 1986 NTP study. The data used
In the derivation of these q,*s have now been revised 1n the final NTP
draft and these data are shown 1n Tables 6-1 and 6-2. The linearized multi-
stage model adopted by the U.S. EPA (1980b) was used to estimate the excess
risk to humans associated with oral exposure to 1,2-d1chloropropane. The
human q *s derived are 6.75xlO"2 (mg/kg/day)"1 and 2.19xlO~2
(mg/kg/day)'1 from data on the males
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TABLE 6-1
Derivation of q-]* for 1,2-D1chloropropane
Reference: NTP, 1986
Specles/straln/sex: mouse, B6C3F1, male
Route/vehicle: gavage, corn oil
Length of exposure (le) = 103 weeks
Length of experiment (Le) = 105-107 weeks
Llfespan of animal (L) = 105-107 weeks
Body weight = 0.04 kg (measured)
Tumor site and type: liver, adenoma or carcinoma
Experimental Doses
or Exposures
(mg/kg/day, 5 days/week)
0
125
250
Transformed Dose
(mg/kg/day)
0
86.8
173.5
Incidence
No. Responding/No. Tested
18/50
26/50
33/50
Unadjusted q-j* from study = 5.60428xlO~3 (mg/kg/day)~r
Human q-)* = 6.753556xlO~2 (mg/kg/day)'1
0077h -13- 02/18/87
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TABLE 6-2
Derivation of q-|* for 1,2-D1ch1oropropane
Reference: NTP, 1986
Specles/straln/sex: mouse, B6C3F1, female
Route/vehicle: gavage, corn oil
Length of exposure (le) = 103 weeks
Length of experiment (Le) = 105-107 weeks
Llfespan of animal (L) = 105-107 weeks
Body weight = 0.038 kg (measured)
Tumor site and type: liver, adenoma or carcinoma
Experimental Doses
or Exposures
(mg/kg/day, 5 days/week)
0
125
250
Transformed Dose
(mg/kg/day)
0
86.8
173.5
Incidence
No. Responding/No.
2/50
8/50
9/50
Tested
Unadjusted q-|* from study = 1.78892xlO"3 (mg/kg/day)'1
Human q-|* = 2.19296xlO~2 (mg/kg/day)'1
0077h -14- 02/18/87
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7. REFERENCES
AC6IH (American Conference of Governmental Hyglenlsts). 1985. Threshold
Limit Values for Chemical Substances 1n the Work Environment Intended
Changes for 1985-1986. Cincinnati, OH. p. 28.
ACGIH (American Conference of Governmental Hyglenlsts). 1986. Documenta-
tion of the Threshold Limit Values and Biological Exposure Indices, 5th ed.
Cincinnati, OH. p. 501.
Atkinson, R. 1985. Kinetics and mechanisms of the gas phase reactions of
the hydroxyl radical with organic compounds under atmospheric conditions.
Chem. Rev. 85: 69-201.
CrebelH, R., G. Contl, L. Contl and A. Carere. 1984. Induction of somatic
segregation by halogenated aliphatic hydrocarbons In Asperqlllus nldulans.
Mutat. Res. 138(1): 33-38.
Dow Chemical Company. 1985. Data generated from a 13-week Inhalation study
on l,2-d1chloropropane with attachments. U.S. EPA/OPTS Public File.
Microfiche #OTS 0000399-0.
Dragusanu, S. and I. Goldstein. 1975. Structural and numerical changes of
chromosomes In experimental Intoxication with dlchloropropane. Rev. Ig.
Bacterial. Vlrusol. Parazltol. Epldemlol. PneumofHzlol. Ig. 24: 37.
(Cited In U.S. EPA, 1980a, 1985)
0077h -15- 10/09/86
-------
Drew, R., J. Patel and F. Lin. 1978. Changes In serum enzymes In rats
after Inhalation of organic solvents singly and 1n combination. Toxlcol.
Appl. Pharmacol. 45: 809-819.
Ekshtat, B.Y., N.G. Kurysheva, V.N. Fedyanlna and M.N. Pavlenko. 1975.
Study of the cumulative properties of substances at different activity
levels. Uch. Zap. Mosk. Nauchno. Isslend. Inst. G. 22: 46. (Cited In U.S.
EPA, 1980a, 1984)
Haworth, S., T. Lawlor, K. Mortelmans, H. Speck and E. Zelger. 1983.
Salmonella mutagenlclty testing of 250 chemicals. Environ. Mutagen. Suppl.
1: 3-142. (Cited In U.S. EPA, 1985)
Heppel, L.A., P.A. Meal, B. Hlghman and V.T. Potterfleld. 1946. Toxicology
of 1,2-d1chloropropane. I. Studies on effects of dally Inhalation. J. Ind.
Hyg. Toxlcol. 28: 1.
Heppel, L.A., B. Hlghman and E.Y. Peake. 1948. Toxicology of 1,2-dlchloro-
propane. IV. Effects of repeated exposure to a low concentration of the
vapor. J. Ind. Hyg. Toxlcol. 30: 189.
Hutson, D.H., J.A. Moss and B.A. Pickering. 1971. Excretion and retention
of components of the soil fumlgant 0-D and their metabolites In the rat.
Food Cosmet. Toxlcol. 9(5): 677-680.
Jones, A. and J. Gibson. 1980. 1,2-D1chloropropane metabolism and fate 1n
the rat. Xenoblotlca. 10(11): 835-346.
0077h -16- 02/18/87
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Kawasaki, M. 1980. Experiences with the test scheme under the chemical
control law of Japan. .An approach to structure-activity correlations.
Ecotoxlcol. Environ. Safety. 4: 444-454.
Kurysheva, N.G. and B.Y. Ekshtat. 1975. Effects of 1,3-d1chloropropylene
and 1,2-d1chloropropane on the functional state of the liver 1n animal
experiments. Uch. Zap. Mosk. Nauchno-Issled. Inst. Gig. 22: 89-92. [CA
86(17):115725h] (Cited 1n U.S. EPA, 1980a)
NTP (National Toxicology Program). 1986. NTP Technical Report on the
Carclnogenesls Studies of 1,2-01chloropropane (Propylene DIchloMde). (CAS
No. 78-87-5). In F344/N rats and B6C3F1 mice (gavage studies). NTP-82-092,
NIH Publ. No. 84-2519, NTP TR 263. U.S. DHHS, PHS, NIH. August, 1986.
Draft.
Principe, P., E. Dogl1ott1, M. B1gnam1, et al. 1981. MutagenlcHy of chem-
icals of Industrial and agricultural relevance 1n Salmonella. Streptomyces
and Asperqlllus. J. Sc1. Food Agrlc. 32(8): 826-832.
Shalpak, V.M. 1976. Biological effect of chlorinated hydrocarbon on
animals following their Inhalation. Sb. Tr., Nauchno-Issled. Inst. G1g. Gr.
Profzabol. T1fl1s. 15: 194-196. (CA 89:18050p) (Cited 1n U.S. EPA, 1985)
Sldorenko, G.I., V.R. Tsulaya, T.I. Bonashevskaya and V.M. Shalpak. 1979.
Study of the combined action of a group of chlorine derivatives of hydro-
carbons entering the organism by Inhalation. Environ. Health Perspect. 30:
13-18.
0077h -17- 02/18/87
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U.S. EPA. 1980a. Ambient Water Quality Criteria Document for Dlchloropro-
panes and Dlchloropropenes. Prepared by the Office of Health and Environ-
mental Assessment, Environmental Criteria and Assessment Office, Cincinnati,
OH for the Office of Hater Regulations and Standards, U.S. EPA, Washington,
DC. EPA 440/5-80-043. NTIS PB81-117541.
U.S. EPA. 1980b. Guidelines and Methodology Used In the Preparation of
Health Effects Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45(231): 79347-79357.
U.S. EPA. 1983. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxldty Data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1984. Drinking Water Criteria Document for 1,2-D1chloropropane.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Drinking
Water, Washington, DC. NTIS PB86-117850/AS.
U.S. EPA. 1985. Health and Environment Effects Profile for Dlchloropro-
panes. Prepared by the Office of Health and Environmental Assessment,
Environmental Criteria and Assessment Office, Cincinnati, OH for the Office
of Solid Waste and Emergency Response, Washington, DC.
0077h -18- 02/18/87
-------
U.S. EPA. 1986a. Graphical Exposure Modeling System (GEMS). Fate of
Atmospheric Pollutants (FAP). Office of Toxic Substances, U.S. EPA,
Washington, DC.
U.S. EPA. 1986b. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
Woodruff, R.C., J.M. Mason, R. Valencia and S. Zlmmerlng. 1985. Chemical
mutagenesls testing 1n DrosophHa. V. Results of 53 coded compounds tested
for the national toxicology program. Environ. Mutagen. 7(5): 677-702.
0077h -19- 02/18/87
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APPENDIX
.Summary Table for 1,2-D1chloropropane*
Route Species
Experimental
Dose
(mg/kg/day)
Effect
or Unit Risk
Oral
mouse
Q, 125, 250,
5 days/week
for 103 weeks
dose-related
Increases 1n
hepatic
adenomas/
carcinomas
6.75xlO~2
(mg/kg/dayr1
'Source: NTP, 1986
0077h
-20-
02/18/87
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