EPA/6OO/8-89/O12
March 1988
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR CHLORAL
ENVIRONMENTAL CRITERIA AND ASSESSMENT OFFICE
OFFICE OF HEALTH AND ENVIRONMENTAL ASSESSMENT
OFFICE OF RESEARCH AND DEVELOPMENT
U.S. ENVIRONMENTAL PROTECTION AGENCY
CINCINNATI, OH 45268
-------
TECHNICAL REPORT DATA
(Please read Ins true Horn on the reverse before completing)
|. REPORT NO.
EPA/600/8-89/012
3. RECIPIENT'S ACCESSION NO.
PB91-216481
|4. TITLE AND SUBTITLE
Health and Environmental Effects Document for
Chloral
5. REPORT DATE
6. PERFORMING ORGANIZATION CODE
7. AUTMOR(S)
8. 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
Health and Environmental Effects Documents (HEEDS) are prepared for the Office of
Solid Waste and Emergency Response (OSWER). This document series is intended to
support listings under the Resource Conservation and Recovery Act (RCRA) as well as
o provide health-related limits and goals for emergency and remedial actions under
he Comprehensive Environmental Response, Compensation and Liability Act (CERCLA).
Both published literature and information obtained from Agency Program Office files
are evaluated as they pertain to potential human health, aquatic life and environmen-
tal effects of hazardous waste constituents.
Several quantitative estimates are presented provided sufficient data are
available. For systemic toxicants, these include Reference Doses (RfDs) for chronic
and subchronic exposures for both the inhalation and oral exposures. In the case of
suspected carcinogens, RfDs may not be estimated. Instead, a carcinogenic potency
factor, or q^, is provided. These potency estimates are derived for both oral and
inhalation exposures where possible. In addition, unit risk estimates for air and
drinking water are presented based on inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxicity and carcinogenicity are
derived. The RQ is used to determine the quantity of a hazardous substance for
which notification is required in the event of a release as specified under CERCLA.
17.
KEY WORDS AND DOCUMENT ANALYSIS
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TERMS
c. COSATl Field/Group
. DISTRIBUTION STATEMENT
'Public
19. SECURITY CLASS (This Report)
Unclassified
21. NO. OF PAGES
77
20. SECURITY CLASS (This page)
Unclassified
22. PRICE
EPA Fern 2220-1 (R«v. 4-77) PMKVIOU* BDITION is OBSOLETE
-------
DISCLAIMER
This document has been reviewed In accordance with the U.S. Environ-
mental 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
-------
PREFACE
Health and Environmental Effects Documents (HEEOs) are prepared for the
Office of Solid Waste and Emergency Response (OSWER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and Liability Act (CERCLA). Both published literature and
Information obtained for Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for In this document
and the dates searched are Included In "Appendix: Literature Searched."
Literature search material Is current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document 1s sent to the Program Officer (OSWER).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfDs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, 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 llfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as>
previous risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfDs Is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. Instead,
a carcinogenic potency factor, or q-j* (U.S. EPA, 1980) 1s provided. These
potency estimates are derived for both oral and Inhalation exposures where
possible. In addition, unit risk estimates for air and drinking water are
presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxldty and carclno-
genlcHy are derived. The RQ Is used to determine the quantity of a hazard-
ous substance for which notification Is required In the event of a release
as specified under the Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA). These two RQs (chronic toxlclty and carclno-
genlclty) represent two of six scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxlclty, and acute mammalian toxlclty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxlclty and cancer based RQs are defined 1n U.S.
EPA, 1984 and 1986a, respectively.
111
-------
EXECUTIVE SUMMARY
Chloral (75-87-6) Is a colorless, oily liquid at room temperature with
a pungent, Irritating odor (Wlndholz, 1983). Chloral hydrate (302-17-0)
occurs In the form of transparent, colorless crystals at room temperature
and has a penetrating, slightly acrid odor (Hawley, 1981). Upon release to
water chloral will spontaneously form chloral hydrate (Wlndholz, 1983; U.S.
EPA, 1982). Montrose Chemical was the last U.S. manufacturer of chloral,
but production was discontinued when production of DDT ceased (U.S. EPA,
1986b). There are two domestic Importers for chloral and four domestic
Importers for chloral hydrate (CMR, 1986; U.S. EPA, 1986b). During 1984,
11,902 pounds of chloral was Imported Into the United States (HSDB, 1987b).
Chloral 1s used 1n the production of chloral hydrate, plastics and some'
pesticides. Including methoxychlor and DDVP (Wlndholz, 1983; U.S. EPA, 1982;
Martin and Worthing, 1977). Chloral hydrate Is used In medication as a CNS
depressant and sedative, and 1n liniments (HSDB, 1987b).
If released to the atmosphere, both chloral and chloral hydrate are
expected to exist almost entirely In the vapor form (Perry and Green, 1984;
Elsenrelch et al., 1981). Half-lives for the reaction of these compounds
with photochemlcally generated hydroxyl radicals were estimated to be 7 and
12 days, respectively. Anhydrous chloral may react with water vapor 1n the
atmosphere and form chloral hydrate. Because of Us extremely high water
solubility, chloral hydrate would be highly susceptible to removal from the
atmosphere by wet deposition. Dry deposition is probably not an Important
fate process. If released to water, chloral would react spontaneously with
water molecules to form chloral hydrate. Ihe ratio of chloral to chloral
hydrate at equilibrium would be 28,000:1 (U.S. EPA, 1982). Chloral hydrate
1v
-------
decomposes In neutral, acidic and basic solutions, and produces chloroform
and formic add by an elimination reaction catalyzed by water, OH~ and
chloralate anlon. The half-life for this reaction Is 17.5 days at pH 8 and
20°C and 1s 2 days at pH 9 and 20°C (Lukn1tsk11, 1975). Chloral hydrate 1s
not expected to volatilize significantly, bloaccumulate In aquatic organisms
or adsorb significantly to suspended solids or sediment 1n water. If
released to moist soil, chloral would probably react with soil moisture to
form chloral hydrate. Chloral hydrate Is expected to be highly mobile 1n
moist soil. Volatilization from moist soils 1s not expected to be signifi-
cant; however, both chloral and Us hydrate are expected to volatilize
fairly rapid from dry soil surfaces.
Chloral hydrate has been Identified as an aqueous chlorlnatlon product
of humlc substances and amlno acids, ubiquitous components of natural waters'
(Trehy et al.. 1986; Miller and Uden, 1983; Norwood et al., 1983; Sato et
al., 1985). Thus, chloral can occur In drinking water as a result of dis-
infection of raw water by chlorlnatlon. During the mid to late 1970s
chloral hydrate was detected 1n various drinking water supplies throughout
the United States (Keith et al., 1976; Fielding et al., 1981; Kloepfer,
1976). Disinfection of some wastewater streams by chlorlnatlon may also
result 1n the formation of chloral hydrate. Chloral hydrate has been
detected In the spent chlorlnatlon liquor from the bleaching of sulfHe pulp
and chlorinated wastewater from an extended aeration treatment plant
(Carlberg et al., 1986; Trehy et al., 1986).
Little Information was available concerning the toxlclty of chloral
hydrate to aquatic organisms. The only LC,~ for freshwater fish 1s a
value of 1720 mg/a, for golden orfe (Juhnke and Luedemann, 1978).
-------
Brlngmann and Kuehn (1980) reported that Inhibition of growth occurs at 1.6,
2.8 and 79 mg/a, for Pseudomonas putlda, Scenedesmus quadMcauda and
Entoslphon sulcatum. respectively. Studies In species of Chlamydomonas have
observed effects beginning at -0.17 g/8. (Cross and McMahon, 1976). No
data for saltwater species were found 1n the available literature.
Since chloral hydrate 1s readily absorbed from the gastrointestinal
tract and rapidly metabolized, only metabolites are detected In the blood.
Chloral hydrate 1s metabolized to TCE and TCA, with further metabolism of
TCE to TCA 1n humans and dogs (Marshall and Owens, 1954), but not In mice
(Cabana and Gessner, 1970). In humans, the amount of TCA produced 1s highly
variable, with Marshall and Owens (1954) reporting that 5-47% of an oral
dose may be metabolized to TCA. TCE 1s conjugated with glucuronlde and Is
excreted 1n the urine and bile (Harvey, 1975).
Studies of binding of TCA and TCE to plasma protein from monkeys and
humans Indicate similar levels of binding for TCE, with Increased binding of
TCA to plasma proteins from humans compared with monkeys (Peters et al.,
1975). Plasma and urine levels of TCE and TCA In humans Indicate that TCE
Is readily excreted, while the excretion of TCA 1s more prolonged.
Inhalation studies of chloral are limited to abstracts of Russian
studies (Blostov et al., 1970; Pavlova, 1975) that reported adverse effects
but did not report the frequency or duration of exposure.
Oral toxldty studies of chloral consist of a series of 90-day studies
In which mice were provided with drinking water containing chloral at 0.07
or 0.7 mg/mi (Sanders et al., 1982; Kauffmann et al., 1982; Kallman et
al., 1984). The most sensitive endpolnt of toxlclty 1n male mice was "liver"
toxldty (Sanders et al., 1982), while the most sensitive endpolnt In female
mice was 1mmunotox1c1ty (Kauffmann et al., 1982). Both effects were
v1
-------
observed at 0.07 mg/mfc, a dose of 16 mg/kg/day In males and 18 mg/kg/day
1n females. However, the biological significance of the Immune toxlclty
test results at 18 mg/kg 1s questionable. No effects on behavior were
observed 1n male mice, although body temperature was found to be depressed
at both concentrations (Kallman et al., 1984).
Chloral hydrate has been used as a sedative for humans. Adverse effects
that have been reported at therapeutic doses (0.5-2 g) Include epigastric
distress, nausea, vomiting, allergic skin reactions, eoslnophlUa, leuko-
penla and Interactions with a number of drugs (Harvey, 1975). At higher
doses, chloral hydrate has been reported to cause cardiac arrhythmias
(Bowyer and Glasser, 1980; Wiseman and Hampel, 1978).
Chloral hydrate 1s lethal to humans at a dose of -10 g (Harvey, 1975).
An oral LD5Q of 479 mg/kg has been reported 1n adult rats (Goldenthal,-
1971). Kallman et al. (1984) reported an ED of 84.5 mg chloral/kg for
disruption of a screen test 1n male mice 5 minutes after the mice were
treated by gavage with chloral hydrate.
A single dose oral study reported a dose-related Increase 1n liver
tumors In mice examined 48-92 weeks after they were treated with chloral
hydrate at 5 or 10 yg/g (R1jhs1nghan1 et al., 1986). The Increase was
statistically significant only at 10 yg/g. A nonstatlstlcally significant
Increase 1n skin tumor Incidences was observed 1n mice given 2 weekly appli-
cations of chloral hydrate followed by 18 weekly applications of croton
oil. A metabolite of chloral, trlchloroacetlc add, has Induced a
significant tumor response 1n a mouse liver bloassay. Studies of DNA
effects have reported positive results 1n mutation assays and assays of
aneuploldy Inducing activity, and chloral hydrate was found to decrease
testlcular DNA synthesis 1n an Intratestlcular Injection study using mice
(Borzelleca and Carchman, 1982). In addition, chloral shares a common
-------
metabolite (TCA) with trlchloroethylene which has been shown to be
carcinogenic 1n animal test systems.
Chloral hydrate exposure did not result 1n any changes 1n Utter
parameters or 1n any gross malformations In offspring of mice provided with
drinking water containing chloral hydrate at 0.06 or 0.6 mg chloral/ma
from 3 weeks before mating through weaning (Kallman et al., 1984). At 0.6
mg/ma, an Impairment of retention of an avoidance learning task was
observed 1n 24-day-old mice. Because pups had access to the chloral hydrate
dosing solution, It 1s not clear 1f the effect was a result of ^n utero or
postnatal exposure.
The lack of Inhalation data precluded the derivation of Inhalation RfDs.
Using the 90-day study by Sanders et al. (1982), subchronlc and chronic oral
RfDs of 1 mg/day (0.02 mg/kg/day) and 0.1 mg/day (0.002 mg/kg/day), respec-
tively, were calculated. Confidence 1n the oral RfDs Is low. An RQ for
systemic toxlclty of 1000 was calculated on the basis of liver toxlclty In
mice in the Sanders et al. (1982) study. Based on a weight of the evidence
classification of C but no quantitative evaluation, a carc1nogen1c1ty RQ of
100 was assigned.
-------
TABLE OF CONTENTS
Page
1. INTRODUCTION . 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 3
1.4. USE DATA 3
1.5. SUMMARY 5
2. ENVIRONMENTAL FATE AND TRANSPORT 6
2.1. AIR 6
2.1.1. Reaction with Hydroxyl Radicals 6
2.1.2. Reaction with Ozone 6
2.1.3. Physical Removal Processes 6
2.2. WATER 7
2.2.1. Chemical Reactions 7
2.2.2. M1crob1al Degradation 7
2.2.3. Volatilization 7
2.2.4. Adsorption 8
2.2.5. B1oaccumulat1on 8
2.3. SOIL 8
2.3.1. Hydrolysis 8
2.3.2. Adsorption 8
2.3.3. Volatilization 8
2.4. SUMMARY 9
3. EXPOSURE 10
3.1. WATER 10
3.2. SUMMARY 11
4. AQUATIC TOXICITY 13
4.1. ACUTE TOXICITY 13
4.2. CHRONIC EFFECTS 13
4.3. PLANT EFFECTS 13
4.4. SUMMARY 15
5. PHARMACOKINETCS 16
5.1. ABSORPTION 16
5.2. DISTRIBUTION 16
5.3. METABOLISM 17
5.4. EXCRETION 20
5.5. SUMMARY 22
1x
-------
TABLE OF CONTENTS (cont.)
6.
7.
8.
•
9.
EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures
6.1.2. Oral Exposures
6.1.3. Other Relevant Information
6.2. CARCINOGENICITY
6.2.1. Inhalation
6.2.2. Oral
6.2.3. Other Relevant Information
6.3. MUTAGENICITY . . .
6.4. TERATOGENICITY
6.5. OTHER REPRODUCTIVE EFFECTS
6.6. SUMMARY
EXISTING GUIDELINES AND STANDARDS
RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation
8.1.2. Oral
8.1.3. Other Routes
8.1.4. Weight of Evidence
8.1.5. Quantitative Risk Estimates
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure
8.2.2. Oral Exposure
REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
9.2. BASED ON CARCINOGENICITY
iu. ncr cncnuCd
APPENDIX A: LITERATURE SEARCHED
APPENDIX B: SUMMARY TABLE FOR CHLORAL
Paqe
23
23
23
23
25
28
28
29
29
31
35
36
36
39
40
40
40
40
40
40
41
41
41
41
44
44
47
50
62
65
-------
LIST OF TABLES
No. Title Page
1-1 Selected Physical Properties for Chloral and Chloral
Hydrate 2
1-2 1977 Production Data for Chloral and Chloral Hydrate 4
4-1 Effects of Chloral Hydrate on Four Species of Chlamydomonas . 14
5-1 Mean Cumulative Urinary Excretion (% of Dose) of Chloral
Hydrate Metabolites by Five Male Rhesus Monkeys Receiving
500 mg Chloral Hydrate/kg and by Six Male Squirrel Monkeys
Receiving 150 mg Chloral Hydrate/kg per os_ 21
6-1 Acute Oral Lethality Data of Chloral Hydrate 27
6-2 Hlstologlcal Classification of Hepatic Nodules and
Their Distribution 1n C57BLxC3HFl Male Mice Sacrificed
Between Weeks 48 and 92 After a Single Intragastrlc
Dose of Chloral Hydrate 30
6-3 Genotox1c1ty of Chloral and Chloral Hydrate 32
9-1 Tox1c1ty Summary for Chloral (>99% Parity) Administered
to Mice 1n Drinking Water 45
9-2 Composite Scores for Chloral from Oral Mouse Studies 46
9-3 Chloral: Minimum Effective Dose (MED) and Reportable
Quantity (RQ) 48
x1
-------
LIST OF ABBREVIATIONS
BCF Bloconcentratlon factor
bw Body weight
CAS Chemical Abstract Service
CNS Central nervous system
CS Composite score
DMA Deoxyrlbonuclelc add
ED5 Dose effective to 50% of recipients
GC Gas chromatography
IR Infra red
K Soil sorptlon coefficient
oc v
K Octanol/water partition coefficient
ow
LC5Q Concentration lethal to 50% of recipients
LD5Q Dose lethal to 50% of recipients
LD,Q Lowest lethal dose
LDH Lactate dehydrogenase
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
MS Mass spectrometry
NADPH N1cot1nam1de adenlne dlnucleotlde phosphate (reduced form)
NOAEL No-observed-adversed-effect level
NOEL No-observed-effect level
ppm Parts per million
RBC Red blood cell
RfD Reference dose
RQ Reportable quantity
RV Dose-rating value
RV Effect-rating value
SGOT Serum glutamlc oxaloacetlc transamlnase
SGPT Serum glutamlc pyruvlc transamlnase
TCE Trlchloroethanol
TCE-G Trlchloroethanol glucuronlde
TCA TMchloroacetlc acid
TWA Time-weighted average
-------
1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
Chloral 1s also known as tMchloroacetaldehyde. Chloral hydrate 1s also
known as trlchloroacetaldehyde monohydrate and 2,2,2-tr1chloro-l,1-ethane-
dlol (Wlndholz, 1983). The structure, molecular weight, empirical formula
and CAS Registry number for chloral and chloral hydrate are given below.
Chloral Chloral hydrate
Cl 0 C10H
I // II
Cl-C-C Cl-C-CH
I \ II
Cl H C10H
Molecular weight: 147.22 165.23
Empirical formula: C2HC130 C2H3C1302
CAS Registry number: 75-87-6 302-17-0
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Chloral Is a colorless, oily liquid at room temperature and has a
pungent Irritating odor (Wlndholz, 1983). Chloral hydrate exists as trans-
parent, colorless crystals at room temperature. The hydrate has an
aromatic, penetrating, slightly acrid odor and a slightly bitter, sharp
taste (Hawley, 1981). Upon release to water, chloral will spontaneously
form choral hydrate (Wlndholz, 1983; U.S. EPA, 1982). Selected physical
properties for these compounds are listed In Table 1-1. Chloral 1s soluble
In ether and Is soluble In alcohol, forming chloral alcoholate (Wlndholz,
1983). Chloral hydrate Is highly soluble In alcohol, chloroform, ether,
carbon dlsulflde and olive oil; 1t 1s freely soluble 1n acetone and methyl
ethyl ketone; and 1t Is moderately or sparingly soluble 1n turpentine,
petroleum ether, carbon tetrachlorlde, benzene and toluene (Wlndholz, 1983).
0085d -1- 01/28/88
-------
TABLE 1-1
Selected Physical Properties for Chloral and Chloral Hydrate
Property
Melting point:
Boiling point:
Vapor pressure
at 25°C:
Water solubility
at 25°C:
Log Kow:
Specific gravity,
25/4°C:
Refractive Index,
nB°:
Chloral
-57.7°C
97.8°C
51 mm Hg
exists In
hydrated
form In
water*
exists 1n
hydrated
form 1n
water*
1.505
1.45572
Chloral hydrate
57°C
98°C (with
dissociation to
chloral and water)
16 mm Hg
8.25x10* mg/8.
0.99
NA
NA
Reference
Wlndholz, 1983
Wlndholz, 1983
Perry and
Green, 1984
Seldell, 1941
Hansch and
Leo, 1985
Wlndholz, 1983
Wlndholz, 1983
*See value for chloral hydrate
NA = riot available
0085d
-2-
01/13/88
-------
PRODUCTION DATA
Chloral can be prepared by two methods: by direct chlorlnatlon of
either acetaldehyde or paraldehyde 1n the presence of antimony chloride or
by chlorlnatlon of ethyl alcohol followed by treatment with concentrated
sulfurlc acid and then distillation (HSOB, 1987a; Wlndholz, 1983). Chloral
hydrate 1s prepared by addition of water to anhydrous chloral (Wlndholz,
1983).
Production data regarding chloral and chloral hydrate from the U.S. EPA
TSCA Production file are provided 1n Table 1-2. Montrose Chemical was the
last U.S. manufacturer of chloral, but production was discontinued when pro-
duction of DDT ceased (U.S. EPA, 1986b). There are two domestic Importers
for chloral: R.W. Greef and Co. and Lobel Chemical Corp., and four domestic
Importers for chloral hydrate: Centerchem., Ceres Chemical Co., N1pa
Laboratories and Spectrum Chemical Manufacturing Corp. (CMR, 1986; U.S. EPA,
1986b). During 1984, 11,902 pounds of chloral hydrate were Imported Into
the United States (HSDB, 1987b).
1.4. USE DATA
Chloral 1s used In the production of chloral hydrate, plastics and some
pesticides, Including methoxychlor and DDVP (Wlndholz, 1983; U.S. EPA, 1982;
Martin and Worthing, 1977). Chloral also has been used In the production of
DDT and has potential for use In the production of trlchloroacetlc acid
(Frelter, 1978; U.S. EPA, 1982). Chloral hydrate Is used In medication as a
CNS depressant and sedative, and 1n liniments (HSDB, 1987b). Chloral
hydrate has also been used as an Intermediate In the production of dlchloro-
acetlc acid and DDT (HSDB, 1987b; Mitchell, 1980).
0085d -3- 01/28/88
-------
TABLE 1-2
1977 Production Data for Chloral and Chloral Hydrate3
Compound
Company/Location
Production/Import Volume
(million pounds)
Chloral
Chloral hydrate
Diamond Shamrock
Houston, TX
Montrose Chemical of California
Henderson, NV
Texas Eastman
Longvlew, TX
Continental Oil Co.
Westlake, LA
confidential
Diamond Shamrock
Houston, TX
Centerchem Inc.
New York, NY (Importer)
JCD Group Inc.
New York, NY (Importer)
1.0-10
confidential
1.0-10
(site limited use)
1.0-10
0.10-1.0
1.0-10
0.01-0.10
aSource: U.S. EPA, 1977
DTh1s company Imported chloral hydrate 1n previous years.
0085d
-4-
01/13/88
-------
1.5. SUMMARY
Chloral (75-87-6) 1s a colorless, oily liquid at room temperature with
a pungent, Irritating odor (Wlndholz, 1983). Chloral hydrate (302-17-0)
occurs 1n the form of transparent, colorless crystals at room temperature
and has a penetrating, slightly acrid odor (Hawley, 1981). Upon release to
water chloral will spontaneously form chloral hydrate (Wlndholz, 1983; U.S.
EPA, 1982). Montrose Chemical was the last U.S. manufacturer of chloral,
but production was discontinued when production of DDT ceased (U.S. EPA,
1986b). There are two domestic Importers for chloral and four domestic
Importers for chloral hydrate (CMR, 1986; U.S. EPA, 19865). During 1984,
11,902 pounds of chloral was Imported Into the United States (HSDB, 1987b).
Chloral Is used In the production of chloral hydrate, plastics and some
pesticides, Including methoxychlor and DDVP (Wlndholz, 1983; U.S. EPA, 1982;'
Martin and Worthing, 1977). Chloral hydrate Is used 1n medication as a CNS
depressant and sedative, and 1n liniments (HSDB, 1987b).
0085d -5- 01/28/88
-------
2. ENVIRONMENTAL FATE AND TRANSPORT
Limited data regarding the environmental fate and transport of chloral
and chloral hydrate were located 1n the available literature. When
possible, predictions concerning environmental fate and transport of this
compound were based on physical properties or molecular structure.
2.1. AIR
These compounds are expected to exist almost entirely In the vapor phase
In the atmosphere (Perry and Green, 1984; Elsenrelch et al., 1981) because
of the relatively high vapor pressure of chloral (51 mm Hg at 25°C) and
chloral hydrate (16 mm Hg at 25°C).
2.1.1. Reaction with Hydroxyl Radicals. Using the method of Atkinson
(1985), the rate constants for the reaction of chloral and chloral hydrate'
with photochemically generated hydroxyl radicals In the atmosphere at 25°C
were estimated to be 2.3xlO~12 and 1.3xKT12 cm3/molecule-sec, respec-
tively. Assuming an ambient hydroxyl radical concentration of 5.0xl05
molecules/cm3 (Atkinson, 1985), the respective HO- reaction half-lives
for chloral and chloral hydrate were determined to be ~7 and 12 days. Ohta
and M1zoguch1 (1980) Investigated the photooxldatlon products of chloral 1n
a glass cell using IR absorption spectroscopy. Major products were
determined to be HC1, CO, C02 and COC1?. Ihe photooxldatlon was a chain
reaction and the chain carrier was chlorine; however, the wavelength of
"Jlriht ncoH \ n +f{^£ St"(J" "3 S PCt rS^CTtjCj.
2.1.2. Reaction with Ozone. Chloral and chloral hydrate will not react
with ozone molecules 1n the atmosphere (U.S. EPA, 1987a).
2.1.3. Physical Removal Processes. Given Us high water solubility,
chloral hydrate would be highly susceptible to removal from the atmosphere
0085d -6- 01/28/88
-------
by wet deposition. Anhydrous chloral may react with water vapor In the
atmosphere to form chloral hydrate and subsequently be removed from the
atmosphere by wet deposition. Dry deposition Is probably not an Important
fate process for these compounds since both chloral and chloral hydrate are
expected to exist almost entirely 1n the vapor phase 1n the atmosphere.
2.2. WATER
2.2.1. Chemical Reactions. Chloral reacts spontaneously with water to
form chloral hydrate. The ratio of chloral hydrate to chloral at equilibrium
Is 28,000:1 (U.S. EPA, 1982). Although chloral Itself 1s stable, Us
aqueous solutions are not (Luknltskll, 1975). Chloral hydrate decomposes In
neutral, addle and basic solutions. The Initial step In the decomposition
of chloral hydrate can be described by the following elimination reaction:
OH-
CC13CH(OH)2 > CC13H * HCOO-
Th1s reaction Is catalyzed by water, OH~ and chloralate anlon. The half-
life for this reaction Is reported to be 17.5 days at pH 8 and 20°C and 4
days at pH 9 and 20°C (Luknltskll, 1975). Large decreases In pH of aqueous
solutions have been found to occur over time as the result of CCK-group
destruction with HC1 formation (Luknltskll, 1975).
2.2.2. M1crob1al Degradation. Pertinent data regarding the mlcroblal
degradation of chloral hydrate were not located 1n the available literature
cited 1n the Appendix.
2.2.3. Volatilization. Keith et al. (1976) determined that chloral
hydrate Is so highly polar that 1t does not appreciably strip out of aqueous
solution even at elevated temperatures. Henry's Law constant for chloral
hydrate was estimated to be lx!0~10 atm-mVmol at 25°C using the group
0085d -7- 01/13/88
-------
contribution method of H1ne and Mookerjee (1975). This value Indicates that
volatilization from all bodies of water would not be significant (Lyman et
al., 1982).
2.2.4. Adsorption. Pertinent data regarding the adsorption of chloral
hydrate to suspended solids and sediments 1n water were not located,
although the relatively high water solubility and low K suggest that
adsorption 1s not likely.
2.2.5. Bloaccumulatlon. Pertinent data regarding the bloaccumulatlon of
chloral hydrate In aquatic organisms were not located. A BCF of 5 was
estimated for this compound using a linear regression equation based on a
measured log K of 0.99. This BCF value and the extremely high water
solubility of chloral hydrate suggest that this compound would not bloaccu-
mulate significantly 1n aquatic organisms.
2.3. SOIL
2.3.1. Hydratlon. If released to moist soil, anhydrous chloral would
probably react with soil moisture to form chloral hydrate.
2.3.2. Adsorption. A K of 75 was estimated for chloral hydrate using
the molecular topology and quantitative structure-activity relationship
analysis of Sabljlc (1984); a K of 82 was estimated using a linear
regression equation based on a log K of 0.99 (Hansch and Leo, 1985;
Lyman et al., 1982). These K values suggest that chloral hydrate would
be highly mobile 1n soil and may leach Into groundwater (Swann et al., 1983).
2.3.3. Vclatmzat*GJi. Because of the relatively low value of Henry:s
Law constant for chloral hydrate (lxlO~10 atm-ma/mol at 25°C), this com-
pound 1s not expected to volatilize significantly from moist soil surfaces.
The relatively high vapor pressures of chloral and chloral hydrate suggest,
however, that these compounds would volatilize fairly rapidly from dry soil
surfaces.
0085d -8- 01/13/88
-------
2.4. SUMMARY
If released to the atmosphere, both chloral and chloral hydrate are
expected to exist almost entirely In the vapor form (Perry and Green, 1984;
E1senre1ch et al., 1981). Half-lives for the reaction of these compounds
with photochemlcally generated hydroxyl radicals were estimated to be 7 and
12 days, respectively. Anhydrous chloral may react with water vapor 1n the
atmosphere and form chloral hydrate. Because of Us extremely high water
solubility, chloral hydrate would be highly susceptible to removal from the
atmosphere by wet deposition. Dry deposition Is probably not an Important
fate process. If released to water, chloral would react spontaneously with
water molecules to form chloral hydrate. The ratio of chloral to chloral
hydrate at equilibrium would be 28,000:1 (U.S. EPA, 1982). Chloral hydrate
decomposes 1n neutral, acidic and basic solutions, producing chloroform and'
formic add by an elimination reaction catalyzed by water, OH~ and chlor-
alate anlon. The half-life for this reaction 1s 17.5 days at pH 8 and 20°C
and 1s 2 days at pH 9 and 20°C (Lukn1tsk11, 1975). Chloral hydrate 1s not
expected to volatilize significantly, bloaccumulate 1n aquatic organisms or
adsorb significantly to suspended solids or sediment In water. If released
to moist soil, chloral would probably react with soil moisture to form
chloral hydrate. Chloral hydrate 1s expected to be highly mobile 1n moist
soil. Volatilization from moist soils 1s not expected to be significant;
however, both chloral and Us hydrate are expected to volatilize fairly
rapid from dry soil surfaces.
0085d -9- 01/28/88
-------
3. EXPOSURE
HonltoMng data were not available to Indicate that the general popu-
lation 1s exposed to chloral or Its hydrate by Inhalation, Ingestlon of
contaminated food or dermal contact. Limited monitoring data are available
on chloral hydrate 1n drinking water.
3.1. WATER
Chloral hydrate has been Identified as a product of aqueous chlorlnatlon,
of humlc substances at pH 4-9 and amlno adds at pH 7-8 (Trehy et al., 1986;
MUler and Uden, 1983; Norwood et al., 1983; Sato et al., 1985). Humlc
substances and amlno adds are ubiquitous constituents of natural waters.
Thus, chloral hydrate can occur 1n drinking water as a result of disinfec-
tion of raw water by chlorlnatlon. During the 1975 National Organlcs
Reconalssance Study (NORS) chloral hydrate was Identified In drinking water
supplies from 6 out of 10 cities. Locations at which samples were taken and
the corresponding concentrations of chloral hydrate are as follows:
Cincinnati, OH, 2.0 yg/8.; Philadelphia, PA, 5.0 wg/i; Seattle, WA,
3.5 iig/l; Grand Forks, ND, 0.01 jig/H; New York CHy, 0.02 yg/a;
Terrebonne Parish, LA, 1.0 yg/l; Miami, FL, not detected; Ottumwa, IA,
not detected; Lawrence, MA, not detected; and Tucson, AZ, not detected
(Keith et al., 1976). Chloral hydrate was not Identified 1n any of the NORS
samples analyzed by the Inert gas stripping technique referred to as
Volatile Organlcs Analysis (Keith et al.f 1976). Keith et al. (1976)
determined that because of the high polarity of chloral hydrate, Volatile
Organlcs Analysis 1s not a suitable technique for Isolating and concentrat-
ing chloral hydrate before analysis by GC or GC/MS. Consequently, data
0085d -10- 01/28/88
-------
provided In the NORS may be Incomplete. Chloral hydrate was also qualita-
tively Identified In finished drinking waters from 1 out of 14 cities
sampled throughout the United States between 1977 and 1979 and the finished
drinking water supply of Kansas City, Kansas between 1973 and 1975 (Fielding
et a!., 1981; Kloepfer, 1976). Although these data suggest that there may
be widespread distribution of chloral hydrate In drinking waters, statis-
tical confirmation of this distribution Is not possible because of the lack
of sufficient monitoring data.
Disinfection of some wastewater streams by chlorlnatlon may also cause
the formation of chloral hydrate. Chloral hydrate has been Identified 1n
the spent chlorlnatlon liquor from the bleaching of sulflte pulp at high and
low I1gn1n content. Concentrations of chloral corresponded to <0.1 and
0.5/g per ton of pulp processed, respectively (Carlberg et a!., 1986).'
Samples of chlorinated wastewater from an extended aeration treatment plant
collected on 2 days were found to contain 20-38 vq/9. chloral hydrate
(Trehy et al.t 1986).
3.2. SUMHARY
Chloral hydrate has been Identified as an aqueous chlorlnatlon product
of humlc substances and ami no adds, ubiquitous components of natural waters
(Trehy et al., 1986; MUler and Uden, 1983; Norwood et al., 1983; Sato et
a!., 1985). Thus, chloral can occur 1n drinking water as a result of
disinfection of raw water by chlorlnatlon. During the mid to late 1970s
chloral hydrate was detected 1n various drinking water supplies throughout
the United States (Keith et al., 1976; Fielding et al.. 1981; Kloepfer,
1976). Disinfection of some wastewater streams by chlorlnatlon may also
result In the formation of chloral hydrate. Chloral hydrate has been
0085d -11- 01/13/88
-------
detected 1n the spent chlorlnatlon liquor from the bleaching of sulfHe pulp
and chlorinated wastewater from an extended aeration treatment plant
(Carlberg et al.. 1986; Trehy et a!., 1986).
0085d -12- 01/13/88
-------
4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
Juhnke and Luedemann (1978) reported a 48-hour LC5Q value of 1720 mg
chloral hydrate/a, for golden orfe, Leudscus idus melanotus. under static
conditions. Brlngmann and Kuehn (1980) found that chloral hydrate at 1.6
and 79 mg/8. resulted in a >3% decrease In growth 1n cultures of the
bacteria, Pseudomonas putida, and the protozoan, Entoslphon sulcatum.
respectively. The bacteria were exposed to chloral hydrate for 16 hours,
while the protozoa were exposed for 72 hours.
No effects were observed In trout, blueglll or lamprey larvae exposed to
chloral hydrate at 0.1 or 1.0 ppm for 24 hours (Applegate et al., 1957).
4.2. CHRONIC EFFECTS
Pertinent data regarding effects of chronic chloral hydrate exposure in
aquatic organisms were not located In the available literature cited 1n
Appendix A.
4.3. PLANT EFFECTS
A chloral hydrate concentration of 2.8 mg/l resulted In a >3% decrease
in growth of cultures of the algae, Scenedesmus quadricauda. exposed for 7
days (Brlngmann and Kuehn, 1980). Lewin et al. (1982) found that chloral
hydrate Inhibited the motility of four species of the flagellated green
algae, Chlamydomonas. grown in cultures without Inducing death or flagellar
autonomy (Table 4-1). The results Indicated that C. dysosmos was most
sensitive in the test for immobilization, while C. moewussi (-) died at the
lowest concentration.
Cross and McHahon (1976) added chloral hydrate to cultures of Chlamydo-
monas relnhardi and observed the breakdown of polysomes and inhibition of
protein synthesis at chloral hydrate concentrations of >10 mM (0.17 g/l).
0085d -13- 01/13/88
-------
TABLE 4-1
Effects of Chloral Hydrate on Four Species of Chlamydomonas3
Species
Lowest Concentration
Resulting 1n 100%
Immobilization
(mM)
aSource: Lewln et a!., 1982
bMat1ng types
Highest Concentration
Permitting Survival
for 5 minutes
(mM)
c.
c.
c.
c.
moewussll (Ob
relnhardtll ( + )b
dysosmos
monolca
60 (9.9 g/a)
60
60
60
30 (4.9 g/l)
120
120 (19.8
60
120
125 (20.1
120
500* (8.3
g/D
g/O
0085d
-14-
01/13/88
-------
Because significant levels of the chloral hydrate metabolites, TCA and TCE
were not found In the cultures, the Investigators concluded that chloral
hydrate Hself produced the observed effects.
4.4. SUHMARY
Little Information was available concerning the toxldty of chloral
hydrate to aquatic organisms. The only LC™ for freshwater fish Is a
value of 1720 mg/9. for golden orfe (Juhnke and Luedemann, 1978).
BMngmann and Kuehn (1980) reported that Inhibition of growth occurs at 1.6,
2.8 and 79 mg/8. for Pseudomonas putlda. Scenedesmus quadrlcauda and
Entoslphon sulcatum. respectively. Studies 1n species of Chlamydomonas have
observed effects beginning at -0.17 q/i (Cross and McMahon, 1976). No
data for saltwater species were found In the available literature.
0085d -15- 01/13/88
-------
5. PHARMACOKINETICS
5.1. ABSORPTION
Quantitative data concerning the absorption of choral hydrate from the
gastrointestinal and respiratory tracts were not located. The appearance of
chloral hydrate metabolites In the plasma of humans and dogs 5-10 minutes
following an oral dose Indicated that 1t was readily absorbed from the
gastrointestinal tract (Marshall and Owens, 1954). Because chloral hydrate
1s metabolized quickly, 1t 1s not usually found 1n the blood.
5.2. DISTRIBUTION
Data regarding tissue distribution of chloral hydrate and Us metabo-
lites were not located. Using equilibrium dialysis, Peters et al. (1975)
examined the plasma protein binding of chloral hydrate metabolites 1n plasma
from rhesus monkeys, squirrel monkeys and man. The results Indicated
similar levels of binding for TCE, with 19, 24 and 25% binding 1n rhesus
monkeys, squirrel monkeys and man, respectively. Results of TCA binding
Indicated levels of 69 and 64% binding for rhesus and squirrel monkeys,
respectively, 1n contrast to ~85X for man.
Sellers et al. (1978) found that after seven men were given single oral
doses of chloral hydrate at 15 mg/kg, peak plasma TCE concentrations of
8.5+1.5 mg/8, were reached 1n <2 hours. 1CA accumulated 1n the plasma
during the 24 hours after dosing. Mean serum half-lives of TCE and TCA were
estimated at 8 and 75 hours, respectively. In another study by Sellers et
al / *1 Q "I Q \ 4 k\ A f amst «• A t* «*r\ cnl-»^o/*^r \^tt* r t\ /•» I w o »\ /\i» a 1 r\f\cotf, / 1 C m*i /!/ n \ ft £
i* \ i .f f w / » «. itC ^QiiiC j C » Ci» ^MMjC.vv-> «*. t v
-------
5.3. METABOLISM
The metabolism of chloral 1s presented In Figure 5-1. Chloral 1s
rapidly reduced to trlchloroethanol (TCE). In vitro studies have shown that
chloral 1s an effective substrate for the cytosollc, NADH requiring enzyme,
alcohol dehydrogenase. In addition, 1n rat liver cytosol two additional
NADPH-dependant enzymes have been demonstrated (U.S. EPA, 1985a). Ln vitro
studies also Indicate that chloral can be reduced by human red blood cells
(Sellers et al., 1972).
As reviewed by U.S. EPA (1985a), the origin of the plasma and urinary
metabolite trlchloroacetlc acid (TCA) Is lass clear. Acetaldehyde
dehydrogenase had been proposed as a likely candidate for this oxidation
reaction; however, chloral hydrate has been reported not to be a substrate
for human acetaldehyde dehydrogenase. A chloral hydrate dehydrogenase has'
been reported 1n the rabbit. An aldehyde dehydrogenase prepared from rat
liver mitochondria has been shown to convert chloral to TCA. While the
liver appears to be the primary metabolic site, other tissues such as lung,
brain and RBCs may be Involved.
In 18 humans given a constant dally oral dose of chloral hydrate at
1-6 g for 5-20 days, Marshall and Owens (1954) estimated that 5-47% of the
dose was oxidized to TCA. These values, estimated from the amount of TCA
excreted 1n the urine, were minimum values according to the authors.
Results of a single dose study showed that as much as 87% of chloral hydrate
1s metabolized to TCA 1n humans. In dogs, Marshall and Owens (1954)
estimated that >26% of an oral dose of chloral hydrate was oxidized to TCA.
Muller et al. (1974) treated three male volunteers with a single oral
dose of chloral hydrate at 15 mg/kg, and determined levels of TCE (free and
glucuronlde) and TCA 1n the urine for up to 168 hours after dosing. The
0085d -17- 03/10/88
-------
MITOCHONDRIA
CYTOSOL
NAD*
ALDEHYDE
DEHYDROGENASE
C CI3 COOH
rrcA]
CHLORAL
C CI3 CHO
CYTOSOL
NADH
ALCOHOL
DEHYDROGENASE
NADPH
ALDEHYDE
REDUCTASE
MICROSOMES
NADPH. 02
C 03 CH2OH
rrcEj
GLUCURONYL
TRANSFERASE
C CI3 CH20 C€H906
(TCE-GLUCURONIDE1
FIGURE 5-1
Metabolism of Chloral Hydrate
Source: Ikeda et al.. 1980; U.S. EPA. 1985a
0085d
-18-
01/13/88
-------
level of TCE 1n the urine accounted for -23% of the dose, while the level of
TCA accounted for -24% of the dose.
In a study of chloral hydrate metabolism (Cabana and Gessner, 1970),
male Swiss Webster mice were treated with an Intraperltoneal Injection of
the compound at 500 mg/kg. Of the administered dose, 56% was reduced to
TCE, 11% was oxidized to TCA, with -9.6% not metabolized. These values are
based on analysis of whole body homogenates at up to 360 minutes after
dosing. Following Injection of mice with TCE, TCA was not detected.
Peters et al. (1975) studied the metabolism of chloral hydrate In rhesus
and squirrel monkeys treated by stomach tube with a single dose that
resulted In similar sedative effects. Four male rhesus monkeys received
doses of chloral hydrate at 500 mg/kg and six male squirrel monkeys were
treated at 150 mg/kg. Plasma levels of TCE, TCE-G and TCA were determined'
2, 4 and 7.5 hours after dosing. Chloral hydrate was not detected In the
plasma from any monkey. At 2 hours after dosing, plasma levels of TCE, the
active metabolite, were markedly lower In the squirrel monkey, but concen-
trations of TCE-G were 2-fold higher, Indicating that the squirrel monkey
has a greater capacity to detoxify TCE by glucuronlde conjugation. The
total levels of TCE and TCE-G 1n squirrel and rhesus monkeys were 103 and
136 ymol/100 ml, respectively. TCA was detected 1n the plasma of both
species of monkeys, but at levels below TCE concentrations, Indicating that
the oxidation of chloral hydrate to TCA may be a less significant pathway.
Because recovery of chloral hydrate metabolites was lower 1n the urine of
squirrel monkeys compared with rhesus monkeys, the authors suggested that
squirrel monkeys may be capable of forming a TCA conjugate that was not
measured.
0085d -19- 03/10/88
-------
5.4. EXCRETION
In a comparative study where dogs and humans were treated orally with
chloral hydrate, Marshall and Owens (1954) found that the dog excreted 0.83%
of the total TCE 1n the urine as free TCE, with remaining TCE excreted as
the glucuronlde conjugate. In humans, 4.6% of the TCE 1n the urine was
free-TCE. Renal excretion of free and conjugated TCE accounted for 16-35%
of a 16.5 mg/kg dose of chloral hydrate given to six volunteers.
Muller et al. (1974) found that urinary TCE and TCA accounted for 47% of
a single oral dose of 15 mg chloral hydrate/kg given to three volunteers.
The determination of metabolite levels for up to 168 hours after dosing
revealed that TCE levels In the urine peaked at 24 hours after dosing, while
peak TCA levels were found at 48 hours. TCE was not detected 1n the urine
120 hours after dosing, while TCA was still detected 168 hours after dosing.
Sellers et al. (1978) collected urine from seven men for 36 hours after
they received single oral doses of chloral hydrate at 15 mg/kg. After 6, 18
and 36 hours, 7.1, 10.5 and 24.1% of the dose was recovered as TCE, TCE-G
and TCA. During the collection period, the proportion of TCA steadily
Increased.
Urinary excretion data for chloral hydrate metabolites In rhesus and
squirrel monkeys are presented 1n Table 5-1. The monkeys were given single
oral doses of chloral hydrate that resulted 1n a similar sedative effect.
As Indicated 1n Table 5-1, 76.1% of the dose administered to rhesus monkeys
was recovered 1n the urine, while only 46.2% was recovered In urine from
squirrel monkeys. Feces were not examined for metabolites.
Hobara et al. (1986) examined the biliary excretion of chloral hydrate
and Us metabolites 1n anesthetized dogs given single Intravenous Injections
at 25 mg/kg. Analysis of bile samples taken at half-hour Intervals for 2
hours showed that 19.2% of the dose was excreted 1n the bile, with 95.2% of
0085d -20- 03/10/88
-------
TABLE 5-1
Mean Cumulative Urinary Excretion (% of Dose) of Chloral Hydrate
Metabolites by Five Male Rhesus Monkeys Receiving 500 mg
Chloral Hydrate/kg and by Six Male Squirrel Monkeys Receiving
150 mg Chloral Hydrate/kg per os^*
MetabolHe(s)
Time After
Administration
(hours)
Rhesus Monkeys
Mean
Squirrel Monkeys
Mean
TCE
TCE-G
TCA
Total metabolites
24
60
24
60
24
60
24
60
0.51
0.53
70.22
71.1
3.73
4.47
74.57
76.1
0.36
0.36
44.14
45.2
0.19
0.5
44.79
46.2
*Source: Peters et a!., 1975
0085d
-21-
01/13/88
-------
the biliary excretion In the form of conjugated TCE, 3% as chloral hydrate,
1% as free TCE and 0.8X as TCA.
5.5. SUMMARY
Since chloral hydrate 1s readily absorbed from the gastrointestinal
tract and rapidly metabolized, only metabolites are detected 1n the blood.
Chloral hydrate Is metabolized to TCE and TCA, with further metabolism of
TCE to TCA 1n humans and dogs (Marshall and Owens, 1954), but not 1n mice
(Cabana and Gessner, 1970). In humans, the amount of TCA produced Is highly
variable; Marshall and Owens (1954) reported that 5-87% of an oral dose may
be metabolized to TCA. TCE 1s conjugated with glucuronlde and Is excreted
1n the urine and bile (Harvey, 1975).
Studies of binding of TCA and TCE to plasma protein from monkeys and
humans Indicate similar levels of binding for TCE, with Increased binding of
TCA to plasma proteins from humans compared to monkeys (Peters et al.,
1975). Plasma and urine levels of TCE and TCA 1n humans Indicate that TCE
Is readily excreted, while the excretion of TCA 1s more prolonged.
0085d -22- 03/10/88
-------
6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures. The only Inhalation data available were
abstracts of two Russian studies. Blostov et al. (1970) exposed mice to
chloral at 0.06 mg/8, (60 mg/m3) and reported depressed growth rate,
leukocytosls, decreased A/G ratio and changes In arterial blood pressure and
CNS responses. In a study by Pavlova (1975), rats and rabbits exposed to
chloral at 0.1 mg/8. (100 mg/m3) developed altered CNS functions,
Impaired "antitoxic and enzyme-synthesizing" functions of the liver and
morphological changes In the blood cells. These studies did not report
either the frequency or duration of exposure.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC — Sanders et al. (1982) treated groups of 140"
CD-I mice/sex (4 weeks old at start of study) with chloral hydrate 1n the
drinking water at 0.07 or 0.7 mg/ma. for 90 days. Groups of 260 mice/sex
provided with delonlzed water served as controls. Body weight and fluid
consumption was determined twice weekly for 48 mice/sex for the control
group and 32 mice/sex In the treatment groups. Based on these data, the TWA
chloral hydrate Intake was 18 and 173 mg/kg/day for females and 16 and 160
mg/kg/day for males at 0.07 and 0.7 mg/ma,, respectively. Male mice showed
a dose-dependent Increase 1n body weight. This effect was confirmed by
Increased final body weights observed 1n mice used for gross pathology
(n=15-21). A similar effect on growth rate was not observed In females,
except body weights were Increased compared with controls In female mice
used for gross pathology (n=13-22) at 0.7 mg/ma. A significant (p<0.05)
Increase In both relative and absolute liver weight 1n males at both concen-
trations was observed. Lung and brain weights were slightly decreased 1n
males, but the effect was not dose-related. Serum and liver chemistries,
0085d -23- 01/28/88
-------
which were examined In 4-8 mlce/sex/group, provided further evidence that
the liver Is the target of chloral toxldty. In male mice, an Increase In
serum SGOT and LOH {but not SGPT) activity was observed. These Increases
were significant (p<0.05) 1n high-dose males. Hepatic mlcrosomal amlno-
pyrlne N-demethylase and aniline hydroxylase activity and cytochrome b5
content were significantly Increased (p<0.05) 1n males at both doses.
Hepatic P-450 content was not Increased. In females at 0.7 mg/mt, aniline
hydroxylase activity was Increased, while liver nonproteln sulfhydryl and
cytochrome b5 levels were decreased. No dose-related changes In hemato-
loglcal, coagulation or urlnalysls parameters were noted In either sex.
Hlstopathologlcal examinations were not performed.
Kauffmann et al. (1982) reported on the Immunologlcal status of 12 mice/
sex from the exposure groups described In the Sanders et al. (1982) study.'
Humoral Immunity, assessed by measuring the production of antibody-forming
cells, hemagglutlnatlon tlters and spleen cell response to Upopolysaccha-
rlde from Salmonella typhosa. showed no significant changes 1n male mice.
In female mice, the number of antibody-forming cells (AFC) produced against
sheep RBCs was depressed significantly on day 4 after Immunization at both
concentrations when expressed as AFC/spleen, but only at the high dose when
expressed as AFC/106 cells. Other measures of humoral Immunity, hemag-
glutlnatlon tHers and spleen cell response to Upopolysaccharlde were not
affected In females. Cell-mediated Immunity, measured by a delayed hyper-
sensitivity to sheep RBC did not show a significant dose-related response IP.
either male or female mice. The Investigators concluded that the Immune
system was the most sensitive endpolnt 1n female mice, with effects
occurring at 0.07 mg/mi (18 mg/kg/day). The liver was the most sensitive
endpolnt In male mice, with effects also occurring at 0.07 mg/mi (16
mg/kg/day) (Sanders et al., 1982).
0085d -24- 01/28/88
-------
Kallman et al. (1984) exposed groups of 24 male CD-I mice (~5 weeks old)
to chloral hydrate In the drinking water for 90 days at the same doses and
1n the same manner as described for the Sanders et al. (1982) study. Each
test group was divided Into 2 squads of 12 mice that were subjected to
different batteries of behavioral evaluations. Measurements completed on
mice from squad 1 Included weekly body weights, activity measurements during
exposure, screen testing 24 hours after the last exposure day (91) and
swimming endurance on day 92. In squad 2 mice, biweekly food consumption
and rectal temperature on exposure days 45 and 91 were measured. Forepaw
grip strength and response to olfactory and pain stimuli were measured In
squad 2 mice on day 91, while passive avoidance learning (I.e., learning to
avoid an electric shock) was examined on days 91 and 92. The results of the
study did not show significant changes 1n any of the behavioral parameters.1
Body weights (squad 1) were significantly (p<0.05) reduced In both dose
groups between weeks 5 and 7, but were similar to control levels by the end
of the exposure period. Food Intake was not affected by chloral treatment
(squad 2). Body temperature was significantly (p<0.05) reduced In mice
treated at 160 mg/kg/day at both day 45 and day 91 but was reduced signifi-
cantly only on day 91 1n mice treated at 16 mg/kg/day.
6.1.2.2. CHRONIC — Pertinent data regarding the toxldty of chloral
following chronic oral Intake were not located In the available literature
cited In Appendix A.
6.1.3. Other Relevant Information. Chloral hydrate was Introduced as a
therapeutic agent 1n 1869. The compound was used as a hypnotic until well
Into the 20th century, and 1t Is still used as a sedative 1n humans (Sanders
et al., 1982). Chloral .hydrate 1s Irritating to the skin and mucous
membranes. Death 1n humans occurs at an oral dose of -10 g, although death
0085d -25- 01/28/88
-------
has been reported at a dose of 4 g and Individuals have survived oral doses
of 30 g (Harvey, 1975). The recommended oral dose for the relief of
Insomnia In adults 1s 500 mg to 1 g, with some Individuals requiring doses
as high as 2 g. The therapeutic blood level for TCE, the active metabolite,
1s 10-15 vg/ma. (Rumack and Peterson, 1980). Treatment with chloral
hydrate causes an excessive contraction of the pupil of the eye (Hecht,
1978), and habitual use can result 1n the development of tolerance and
addiction. Adverse side effects of chloral hydrate treatment at recommended
doses Include epigastric distress, nausea, vomiting, allergic skin
reactions, eoslnophllla and leukopenla. At higher doses, chloral hydrate
can cause objects to appear smaller than they are (Hecht, 1978), and the
compound has been reported to cause cardiac arrhythmia (Bowyer and Glasser,
1980; Wiseman and Hampel, 1978). In reviewing 12 cases of chloral hydrate
poisoning, Wiseman and Hampel (1978) found no correlation between plasma TCE
concentrations 24 hours after Ingestlon and cardiac effects.
Additional adverse reactions of chloral hydrate treatment Include Inter-
actions with a number of drugs. In man, chloral hydrate accelerates the
rate of metabolic disposition of the anticoagulants, dlcumarol and warfarin
with a potentially fatal outcome (Harvey, 1975). Because the metabolite,
TCA, displaces addle drugs from plasma proteins, chloral hydrate has the
potential of Interacting with many drugs. The potentlatlon of effects
following co-administration of chloral hydrate and alcohol has long been
known. This pctcr.t'.atlcr, occurs because ethanol accelerates the reduction
of chloral hydrate to the active TCE metabolite (Harvey, 1975).
Acute oral lethality data 1n animals are presented 1n Table 6-1. The
lowest LD5Q was observed 1n rats, with a value of 285 mg/kg In 1- to
2-day-old rats, and an LD5Q of 479 mg/kg In adult rats (Goldenthal, 1971).
0085d -26- 01/28/88
-------
TABLE 6-1
Acute Oral Lethality Data of Chloral Hydrate
Species
Result
(mg/kg)
Reference
Mouse, female
Mouse, male
Rat, adult
Rat, 1-2 days old
Rabbit
Dog
Cat
LD50 1265
LD50 1442
L050 479
LD50 285
LDLO 100°
LDLO 100°
LDLO
Sanders et al., 1982
Sanders et al., 1982
Goldenthal, 1971
Goldenthal, 1971
Adams, 1943
Adams, 1943
Adams, 1943
0085d
-27-
01/28/88
-------
In a range-finding study (Sanders et al., 1982), groups of 60 male CD-I
mice were treated by gavage with chloral hydrate at 0, 14.4 or 144 mg
chloral/kg for 14 consecutive days. Treatment-related deaths were not
observed and body weights of treated mice were similar to controls. Organ
weight measurements, completed on 11-12 mice/group, showed that liver
weights were Increased by 1854 and spleen weights were decreased by 27% In
the 144 mg/kg group compared with controls. These changes were significant
at p<0.05. Similar but not significant changes 1n organ weights were
observed at 14.4 mg/kg. No changes were noted In hematologlcal parameters,
coagulation values, SGPT activity or blood urea nitrogen levels (measured In
10-12 mice/group). Although LDH activity was significantly (p<0.05)
depressed compared with controls, the authors stated that this effect was
difficult to Interpret because most reported abnormalities result In-
elevated LDH levels. Kauffmann et al. (1982) studied the Immunologlcal
status of these mice. No significant (p<0.05) changes were noted 1n spleen
weight, spleen antibody-forming cells or delayed type hypersens1t1v1ty
response to sheep RBC.
Kallman et al. (1984) determined an ED™ of 84.5 mg chloral/kg for
disruption of a motor coordination test (screen test) 1n male CD-I mice 5
minutes after the mice were treated by gavage with a single dose of chloral
hydrate. In male CD-I mice treated by gavage with chloral hydrate for 14
days at 0, 14.4 or 144.4 mg chloral/kg/day, no effects on body weight or on
a battery of behavioral tests (locomotor activity, screen test, sw'iffifimiu
endurance) were observed (Kallman et al., 1984).
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carclnogenlclty of
chloral following Inhalation exposure were not located 1n the available
literature cited In Appendix A.
0085d -28- 01/28/88
-------
6.2.2. Oral. R1jhs1nghan1 et al. (1986) treated 15-day-old male
C57BLxC3HFl mice by gavage with a single dose of chloral hydrate In dis-
tilled water at 0 (35 mice), 5 (25 mice) or 10 yg/g (20 mice) body weight.
Twenty-four hours after dosing, 6-10 mice In each group were sacrificed, and
the mltotlc Index of liver cells was determined (Section 6.3.). The remain-
Ing mice were sacrificed when moribund or were killed at Intervals up to 92
weeks after treatment. The livers of these mice were fixed and examined
hlstologlcally. No hepatic nodules were observed 1n mice sacrificed before
48 weeks. In mice sacrificed between weeks 48 and 92, relative liver
weights were Increased at 10 yg/g compared with controls. Examination of
the livers revealed a significant (p<0.05) Increase 1n the number of mice
with hepatic nodules In mice treated at 10 yg/g. The tumor Incidences and
the types of tumors found are presented 1n Table 6-2. As shown In Table'
6-2, tumors In the treatment groups tended to appear earlier than 1n
controls. The authors stated that their results Indicated that the carcino-
genic potency of chloral hydrate should be Investigated further.
6.2.3. Other Relevant Information. Roe and Salaman (1955) studied the
ability of chloral hydrate to Initiate skin tumors 1n mice. Groups of 20 S
strain male mice were given 2 weekly skin applications of chloral hydrate 1n
acetone for a total dose of 24 or 225 mg. The chloral hydrate treatment was
followed by 18 skin applications of 3 ma of a 0.5% croton oil solution.
The croton oil treatment began 3 days after the first chloral hydrate appli-
cation. A group of 20 mice receiving 18 croton oil applications served as
controls. The described treatment resulted 1n a nonstatlstlcally signifi-
cant Increase 1n skin tumors, with 4/17 and 4/20 mice with skin tumors 1n
the low- and high-dose groups, respectively, compared with 1/20 control mice
with tumors.
0085d -29- 01/28/88
-------
TABLE 6-2
g Hlstologlcal Classification of Hepatic Nodules and Their Distribution
» In C57BLxC3HFl Hale Mice Sacrificed Between Weeks 48 and 92
°- After a Single Intragastrlc Dose of Chloral Hydrate3
CO
o
I
Histology of Hepatic Nodulesb
Dose of Chloral Hydrate No. of Mice
(vg/9 bw) No. of Nice
0.00 2/19
5 3/9
10 6/8
with Nodules/
Examined (%)
(10.5)
(33.3)
|75)<
QUALITY OF
Hyperplastlc Adenoma tous
0 0
1 (88)c 1 (60)
0 3 (48, 67, 78)
EVIDENCE
Trabecular
Carcinoma
2 (89, 89)
1 (78)
3 (60, 78. 88)
Strengths of study: Controls were used; the compound was administered dally.
Weaknesses of study: Inadequate numbers of mice of one sex were used; mice were treated with a single
dose; mice were examined 48-92 weeks after dosing.
Overall adequacy: Inadequate
aSource: Rljhslnghanl et al., 1986
bNodules were categorized on the basis of the most advanced lesion In the nodule.
o cF1gures 'n parentheses represent the Interval In weeks between the administration of chloral hydrate
" and sacrifice.
o
oo dThe difference In the Incidence of nodules between the groups given 10 ug/g of chloral hydrate and
00 distilled water Is significant (p<0.05).
-------
TCA, which 1s a metabolite of both trlchloroethylene and chloral, has
been shown to be related to an Increased Incidence 1n liver carcinomas 1n
mice exposed to TCA 1n their drinking water (Herren-Freund, 1986). These
data are evaluated more fully In U.S. EPA (1987c).
6.3. MUTAGENICITY
The genotoxlclty data for chloral and chloral hydrate are presented In
Table 6-3. Both chloral and chloral hydrate have tested positive for
mutation In Salmonella typhlmurlum. both with and without activation
(Waskell, 1978; B1gnam1 et al., 1980; Bruce and Heddle, 1979). Positive
results for mutation have also been reported for chloral hydrate (but not
chloral) In Streptomyces coellcolor. and both chloral and the hydrate have
tested positive for mutation In Asperglllus nldulans (B1gnam1 et al., 1980).
Studies of mutation and mltotlc gene conversion In Saccharomyces cerevlslae-
have found negative results for mutation with positive results for gene
conversion (Bronzettl et al., 1984). Chloral hydrate has been evaluated for
Us ability to produce aneuploldy In several test systems.
Aneuploldy tests 1n A. nldulans have consistently shown positive results
(Singh and Slnha, 1976; Crebelll et al., 1985; Kafer, 1986), and chloral
hydrate has been shown to Induce aneuploldy 1n S>. cerevlslae (Sora and
Carbone, 1987). In an in vivo study of chloral hydrate, an Increa-se 1n
nondlsjunctlon of sperm from mice treated by an 1ntraper1toneal Injection
has been reported (Russo et al., 1984). According to Russo et al. (1984),
who reviewed studies 1n grasshopper spermatocytes (RIs, 1949) and 1n
Pleurodeles walt111 eggs (Senteln and Ated, 1974), the target of chloral
hydrate 1s the mltotlc spindle. It appears to block spindle elongation.
Additional studies using mammals have not been conclusive. Cassldy and
Boshell (1980) did not find any effects on mitosis 1n the basal cells of the
tongue or adnar cells of the parotid gland from rats given a single
0085d -31- 03/10/88
-------
TABLE 6-3
Genotoxlclty of Chloral and Chloral Hydrate
0
0
00
en
0.
CO
1
01/13/88
Assay
Reverse
mutation
Reverse and
forward
mutation
Forward
mutation
Reverse
mutation,
mltotlc gene
conversion
Indicator
Organism
Salmonella
tynhlmurlum
TA1535. TA1537
TA98. TAIOO
S. typhlmurltai
TAIOO. TA98,
TA1535. his G
S. typhlmurlun
TAIOO. TA1535
S. typhlnurlum
TAIOO. TA1535
Strt'ptomyces
coellcolor
S. coellcolor
A3(2')
Asperglllus
nldullans 35
A. nldullans 35
Saccharomyces
cerevlslae D7
Compound
and/or Purity
chloral hydrate
chloral hydrate/
recrystalllzed
chloral
chloral hydrate
chloral
chloral hydrate
chloral
chloral hydrate
chloral hydrate
Application
plate Incorpo-
ration
plate Incorpo-
ration
plate Incorpo-
ration and
spot test
plate Incorpo-
ration and
spot test
plate Incorpo-
ration and
spot test
plate Incorpo-
ration and
spot test
plate Incorpo-
ration and
spot test
plate Incorpo-
ration and
spot test
suspension test
Concentration
or Dose
0.05-5000
yg/plate
10 mg/plate
0.25-1
iil/plate
1-5 mg/plate
10-40
pi/plate
2-10 mg/plate
1-20
nt/plate
1-10
mg/plate
5-20 mH
Activating Response
System
fS-9 {
+S-9 weakly t
In TAIOO.
- In TA98.
TA1535 and
his G
»S-9 t In TAIOO
- In TA1535
vS-9 t In TAIOO
^ In TA1535
none
none weakly t
none weakly *
none weakly «•
+S-9 - mutation
i gene con-
version
Comment
NC
Chloral hydrate resulted
In 0.00145 r ever tan ts/mol
compared with 0.06 rever-
tants/mol for the {»)
control dlethyl sulfate
Number of revertants
greater without S-9
NC
NC
Ueakly «• for both
forward and reverse
mutations
NC
NC
A dose-related Increase
In gene conversion was
observed only with
metabolic activation
Reference
Bruce and
Heddle. 1979
Uaskell, 1978
Blgnaml
et al.. 1980
Blgnaml
et al.. 1980
Blgnaml
et al.. 1980
Blgnaml
et al.. 1980
Blgnaml
et al.. 1980
Blgnaml
et al.. 1980
Bronzettt
et al.. 1984
-------
TABLE 6-3 (cont.)
00
un
i
Oi
Oft
CB
OS
Assay
Reverse
mutation,
mltotlc gene
conversion
Induced
aneuploldy
Sex-linked
recessive
lethal
Effects on
mitosis In
basal cells
of tongue
and aclnar
cells of
parotid gland
Ntcronucleus,
sperm abnor-
malities
Indicator
Organism
S. cerevlslae 07
S. cerevlslae
A. nldulans
dtplold
A. nldulans
35yl7
A. nldulans
Drosophlla
melanoqaster
rats, 8 weeks
old
C57Bl/6y C3H/He
mice
Compound
and/or Purity
chloral hydrate
chloral hydrate/
99X
chloral hydrate
chloral hydrate/
99X
chloral hydrate/
lab grade
chloral hydrate/
99X
chloral hydrate
chloral hydrate
,
Application Concentration Activating Response
or Oose System
host-mediated 500 mg/kg NA - mutation
assay, mice were «• gene con-
treated orally version
dissolved In 1-2S mH none *
sporulatlon
media
plate Incorpo- 0.001-0.04 N none *
ration
plate Incorpo- 5, 10 raft none «•
ratlon
•In liquid" 5-40 mH none +
feeding 5500 ppm NA equivocal
feeding,
Injection 10.000 ppm - Injection
Injected 200 mg/kg NA
(specific route
not stated)
Intraperltoneal 0-2500 mg/kg NA
Injections, 5
dally doses
Comment
f results were observed
In the tester strain
recovered from the lungs
but not the liver or
kidney
Sporulatlon was Inhib-
ited and a net Increase
of dlplold and dlsomlc
clones was observed
An Increased number of
haplolds was observed
Chloral hydrate Induced
haplold and nondtsjunt-
t tonal dlplold somatic
segregants
Chloral hydrate Induced
polyploldy
X lethal In files fed
chloral hydrate was
0.13 compared with
0.04-0.05 In controls
and those Injected with
chloral hydrate
3 rats/group (- control,
«• control, treatment
group)
Nlcronucleus studies
were conducted 4 hours
after the last Injec-
tion; sperm were exam-
ined 35 days after the
last Injection
Reference
Bronzettl
et al.. 1984
Sora and
Carbone, 1987
Singh and
Slnha, 1976
Crebellt
et al., 1985
Kafer. 1986
Yoon et al..
1985
Cassldy and
Boshell, 1980
Bruce and
Neddie. 1979
-------
TABLE 6-3 (cont.)
Assay
Testlcular
DNA synthesis
Nondlsjunc-
tlon In sperm
Nilotic
Index
Indicator
Organism
mice, 3-Y
rale*. ICR Swiss
Webster
nice (C57Bl/Cncx
C3H/Cnc) Fj
C57HLxC3HFl
mice1
Compound
and/or Purity
chloral hydrate
chloral hydrate
chloral hydrate/
99X
chloral hydrate/
laboratory grade
Application
oral
Intratestlcular
Injection
Intraperltoneal
Injection
oral, single
dose
Concentration Activating Response
or Dose System
SO mg/kg NA
10-900 mg/kg NA * at doses
>75 mg/kg
82.7. 165.4. NA * at each
413.5 mg/kg dose and
cell stage -
the Index of
hyperhaploldy
was greater
than controls
5 or 10 t>g/g NA Increased
mltotlc
Index of
liver cells -
significantly
Increased
only at 5 jig/g
Comment Reference
A decrease In DNA syn- Seller, 1977
thesis was not observed
At 75 mg/kg, DNA syn- Borzelleca and
thesis was 30X of con- Carchman, 1982
trol; at 300 mg/kg, DNA
synthesis was 3X of
control
Nice treated at high Russo et al..
dose remained under 1984
anesthesia for -5 hours;
mice sacrificed at 5,
12. 21 or 42 days after
treatment
Nltotfc Indices were Rljhslnghanl
determined 24 hours et al., 1986
after mice were treated
NA = Not applicable; NC = no comment
00
CO
-------
Injection of chloral hydrate. An Increase In the mltotlc Index of liver
cells was observed 1n mice given a single oral dose of chloral hydrate
(R1jhs1nghan1 et al., 1986).
6.4. TERATOGENICITY
In a study by Kallman et al. (1984), female CD-I mice were provided with
drinking water containing chloral at 0, 0.06 or 0.6 mg/ml for 3 weeks
before mating, during gestation and until the pups were weaned. Five
Utters were studied at each concentration. Measurement of water Intake
during gestation Indicated that chloral Intake was 21.3 and 204.8 mg/kg/day
for the 0.06 and 0.6 mg/ml groups, respectively. No effects were noted on
#
the total Utter weight, number of pups delivered, gestation length, the
number of stillborn pups, gross pup malformations or maternal weight gain.
However, It 1s clear that a maximal tolerated dose was not tested. In'
addition, evaluation for skeletal defects or soft tissue defects not other
than those apparent during gross examination was not conducted. On the day
of birth (day 0), the litters were culled to eight pups. During the pre-
weanlng period, drinking solutions were available to the pups. Behavioral
testing of pups was conducted from days 1-17, with a screen test completed
on day. 17, and passive avoidance learning tested on days 23 and 24. No
effects were noted on the following behaviors: righting reflex, forellmb
placing, forepaw grasping, rooting reflex, eye opening, auditory startle,
bar holding, cliff drop and screen test. Results of a passive avoidance
learning test showed a significant Impairment of retention of the task In
mice exposed to 0.6 rug/ma peMnatally. Because the preweanlng mice had
access to the chloral hydrate containing drinking water, It Is not clear If
the observed behavioral .effect was a result of in utero or postnatal
exposure. No effects on passive avoidance learning were observed at
0.06 dig/ml.
0085d -35- 03/10/88
-------
6.5. OTHER REPRODUCTIVE EFFECTS
Sperm abnormalities were not observed 1n groups of eight mice given 5
dally 1ntraper1toneal Injections of chloral hydrate at up to 2500 mg/kg
(Bruce and Heddle, 1979). The sperm were examined 35 days after the last
Injection.
Borzelleca and Carchman (1982) treated male ICR Swiss albino mice with
Intratestlcular Injections of chloral hydrate at 10-900 mg/kg, followed by
an Intratestlcular Injection of trltlated thymldlne 3.5 hours later. After
0.5 hours, the mice were sacrificed, and the amount of newly synthesized DNA
was determined. The results Indicated that doses >75 mg/kg caused a signif-
icant Inhibition of DNA synthesis, with synthesis 3054 of control values at
75 mg/kg and 3% of control values at 300 mg/kg. Seller (1977) found no
effects on testlcular DNA synthesis In mice treated orally with chloral'
hydrate.
6.6. SUMMARY
Inhalation studies of chloral are limited to abstracts of Russian
studies (Blostov et al., 1970; Pavlova, 1975) that reported adverse effects
but did not report the frequency or duration of exposure.
Oral toxlclty studies of chloral consist of a series of 90-day studies
1n which mice were provided with drinking water containing chloral at 0.07
or 0.7 mg/ml (Sanders et al., 1982; Kauffmann et al., 1982; Kallman et
al., 1984). The most sensitive endpo^nt of toxlclty In male mice was liver
toxlclty (Sanders et al.j 1982), yhlle ihs most sensitive endpoint In female
mice was 1mmunotox1c1ty (Kauffmann et al., 1982). Both effects were
observed at 0.07 mg/mt, a dose of 16 mq/kg/day In males and 18 mg/kg/day
1n females. No effects on behavior were observed In male mice, although
body temperature was found to be depressed at both concentrations (Kallman
et al., 1984).
0085d -36- 01/13/88
-------
Chloral hydrate has been used as a sedative for humans. Adverse effects
that have been reported at therapeutic doses (0.5-2 g) Include epigastric
distress, nausea, vomiting, allergic skin reactions, eoslnophllla, leuko-
penla and Interactions with a number of drugs (Harvey, 1975). At higher
doses, chloral hydrate has been reported to cause cardiac arrhythmias
(Bowyer and Glasser, 1980; Wiseman and Hampel, 1978).
Chloral hydrate Is lethal to humans at a dose of -10 g (Harvey, 1975).
An oral ID™ of 479 mg/kg has been reported In adult rats (Goldenthal,
1971). Kallman et al. (1984) reported an E05Q of 84.5 mg chloral/kg for
disruption of a screen test In male mice 5 minutes after the mice were
treated by gavage with chloral hydrate.
A single dose oral study reported a dose-related Increase In liver
tumors 1n mice examined 48-92 weeks after they were treated with chloral
hydrate at 5 or 10 yg/g (R1jhslnghanl et al., 1986). The Increase was
statistically significant only at 10 yg/g. A nonstatlstlcally significant
Increase In skin tumor Incidences was observed 1n mice given 2 weekly appli-
cations of chloral hydrate followed by 18 weekly applications of croton oil.
Studies of DNA effects have reported positive results 1n mutation assays and
assays of aneuploldlzlng activity, and chloral hydrate was found to decrease
testlcular DNA synthesis In an Intratestlcular Injection study using mice
(Borzelleca and Carchman, 1982).
Chloral hydrate exposure did not result In any changes In Utter
parameters or 1n any gross malformations \n offspring of mice provided with
drinking water containing chloral hydrate at 0.06 or 0.6 mg chloral/ml
from 3 weeks before mating through weaning (Kallman et al., 1984). At 0.6
mg/mi, an Impairment of retention of an avoidance learning task was
0085d -37- 01/28/88
-------
observed In 24-day-old mice. Because pups had access to the chloral hydrate
dosing solution, H Is not clear 1f the effect was a result of Iji utero or
postnatal exposure.
0085d -38- 01/13/88
-------
7. EXISTING GUIDELINES AND STANDARDS
U.S. EPA (1987b) has proposed an RQ of 5000 for chloral. No other
pertinent guidelines and standards, Including EPA ambient water and air
quality criteria, drinking water standards, FAO/WHO ADIs, EPA or FDA toler-
ances for raw agricultural commodities or foods, and ACGIH, NIOSH or OSHA
occupational exposure limits were located In the available literature as
cited 1n Appendix A.
0085d -39- 01/28/88
-------
8. RISK ASSESSNENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the carclnogenlclty of
chloral following Inhalation exposure were not located 1n the available
literature cited In Appendix A.
8.1.2. Oral. In a study by R1jhs1nghan1 et al. (1986). a dose-related
Increase 1n liver tumor Incidence was observed 1n mice sacrificed 48-92
weeks after being given a single gavage dose of chloral hydrate at 0, 5 or
10 vg/g. Liver tumors were significantly (p<0.05) Increased only at
10 yg/g.
8.1.3. Other Routes. In a 2-stage skin carclnogenlclty study, Roe and
Salaman (1955) found a nonsignificant Increase In skin tumors 1n mice given
2 weekly treatments of chloral hydrate, followed by 18 weekly applications'
of croton oil.
8.1.4. Weight of Evidence. There are no human data Indicating that
chloral 1s a carcinogen. The R1jhs1nghan1 et al. (1986) mouse bloassay
study 1s Inadequate for quantitative assessment. Mice were treated only
once and few mice were at risk for tumor development. Despite these
limitations, the R1jhs1nghan1 et al. (1986) gavage study In mice provides
limited evidence that chloral may be a carcinogen. In this study, high-dose
animals showed a significant Increase In numbers of hepatic nodules and 2/3
carcinomas occurred much earlier than the two carcinomas In the control
group. Positive results In mt;t3gen4,c*ty assays also suggest the presence of
genotoxlc activity which may be consistent with carcinogenic mechanisms. In
addition, TCA, a metabolite of chloral, has been shown to be carcinogenic
(Herren-Freund, 1986). Chloral and TCA are the metabolites suggested to be
Involved In the carclnogenlclty of trlchloroethylene (U.S. EPA, 1987c).
Using the EPA Guidelines for Carcinogen Risk Assessment, the positive
0085d -40- 03/10/88
-------
albeit less than Ideal bloassay response In male mice together with
Indications of genotoxldty and knowledge of metabolites which are by
bloassay shown to be carcinogenic, combined with a lack of chronic human
data places chloral In weight of evidence Group C.
8.1.5. Quantitative Risk Estimates. The only positive carclnogenlclty
study of chloral available Is the single dose study by R1Jhs1nghan1 et al.
(1986). This study has too many limitations to support a reasonable
derivation of a carcinogenic potency estimate as discussed 1n Section
8.1.4. An examination of the Herren-Freund (1986) dose-response data 1n the
mouse liver together with the R1jhs1nghan1 (1986) mouse liver responses and
approximations with percent TCA produced as a metabolite of chloral might
yield a basis for quantitative assessment. This analysis, however, 1s
outside of the scope of this document.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposures. Lack of data concerning the toxldty of
chloral hydrate following Inhalation exposure precludes the derivation of
subchronlc and chronic Inhalation RfDs.
8.2.2. Oral Exposures.
8.2.2.1. LESS THAN LIFETIME EXPOSURES — The data concerning the sub-
chronic oral toxldty of chloral are limited to a series of 90-day studies
1n which mice were provided with drinking water containing chloral hydrate
at 0, 0.07 or 0.7 mg/ma (Sanders et al., 1982; Kauffmann et al., 1982;
Kallman et al., 1984). Measurement of water Intake Indicated that male mice
consumed averages of 16 or 160 mg chloral hydrate/kg/day and female mice
consumed an average of 18 or 173 mg chloral hydrate/kg/day. Female mice
were not studied In the Kallman et al. (1984) 90-day study. In the Sanders
et al. (1982) study, a significant dose-related Increase 1n relative liver
0085d -41- 03/10/88
-------
weights was observed In male but not female mice. Serum S60T and LDH activ-
ity were significantly Increased 1n high-dose males, and Increased mlcro-
somal cytochrome b5 content and amlnopyrlne N-demethylase and aniline
hydroxylase activities were significantly Increased 1n males at both doses.
In high-dose females, aniline hydroxylase activity was Increased, while
liver nonproteln sulfhydryl and cytochrome b5 levels were decreased. No
significant changes were noted In low-dose females.
Kauffmann et al. (1982) studied the Immune status of mice treated with
chloral hydrate. The only significant effect noted was a significant
depression 1n the number of antibody-forming cells (AFC) produced against
sheep RBC on day 4 after Immunization 1n female mice at both concentrations.
However, this reflects data expressed as AFC/spleen when results were
expressed as AFC/106 cells only the high dose was significantly dif-
ferent than controls. Other measures of humoral Immunity were not affected.
The authors did state that the AFC test was the most sensitive Indicator.
Kallman et al. (1984) did not observe any effects on the behavior of
male mice treated with chloral hydrate In the drinking water. Body tempera-
ture was significantly reduced on days 45 and 91 at 160 mg/kg/day and on day
91 at 16 mg/kg/day. In a behavioral teratology study (Kallman et al.,
1984), no effects were noted 1n mice from dams treated at 21.3 mg chloral/
kg/day from 3 weeks before mating through weaning, while passive avoidance
learning was significantly affected 1n mice from dams treated at 204.8
mg/kg/day.
The results of these studies Indicate that the liver 1s the most sensi-
tive target of chloral toxlclty In male mice, while the Immune system may be
the most sensitive endpolnt In female mice. Liver effects In male mice
provided with drinking water containing chloral hydrate at 0.07 mg chloral
hydrate/ml, resulted 1n the lowest LOAEL of 16 mg/kg/day. While Increases
0085d -42- 03/10/88
-------
1n "liver weight and associated Increases In enzyme activity are not
necessarily Indicative of an adverse effect, the absence of confirmatory
hlstopathologlcal data makes It difficult to rule out an adverse effect.
This dose Is well below the dose of 204.8 mg/kg/day that resulted In
behavioral effects 1n mice exposed jm utero and postnatally.
A subchronlc oral RfD of 0.02 mg chloral hydrate/kg/day or 1 mg/day for
a 70 kg human, may be derived from the lowest LOAEL of 16 mg chloral/kg/day
by dividing the LOAEL by an uncertainty factor of 1000, 10 to extrapolate
from animals to humans, 10 to estimate a NOEL from a LOAEL and 10 to protect
sensitive Individuals. While this document Is Intended to develop an RfD
for chloral per se, 1t Is not considered appropriate to convert the dose to
an equivalent chloral concentration. Since chloral rapidly Is converted to
chloral hydrate 1n an aqueous environment, expression of the dose as chloral'
hydrate 1s considered appropriate.
Confidence In this RfD Is low. The limited studies available did not
Identify a PEL, NOAEL or NOEL. The effects observed were marginal and
hlstopathologlcal examinations were not completed. In addition, the metabo-
lism of chloral 1s known to differ between mice and humans.
8.2.2.2. CHRONIC EXPOSURES — Chronic oral studies of chloral were
not available. A chronic oral RfD of 0.002 mg chloral hydrate/kg/day or 0.1
mg/day for a 70 kg human can be derived by dividing the subchronlc oral RfD
by an additional uncertainty factor of 10 to extrapolate from subchronlc
exposure.
Confidence 1n this RfD Is low because 1t Is based on a 90-day mouse
study that did not define a NOEL or NOAEL and did not Include hlstopatho-
loglcal examinations. In addition, there are no supporting studies, and 1t
1s known that the metabolism of chloral In mice Is different from that 1n
humans.
0085d -43- 03/10/88
-------
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEHIC TOXICITY
The toxlclty of chloral was discussed In Chapter 6. The only data
suitable for the derivation of an RQ are the drinking water studies, which
are summarized In Table 9-1. In the study by Sanders et al. (1982), effects
on the liver were observed 1n male mice treated with chloral hydrate In the
drinking water at a dose of 16 mg chloral/kg/day for 90 days. In female
mice treated at 173 mg/kg/day for 90 days, Immune system effects were ob-
served (Kauffmann et al., 1982). Kallman et al. (1984) found an Impairment
In retention of a passive avoidance task In the offspring of mice treated
with chloral hydrate In the drinking water at 204.8 mg chloral/kg/day from 3
weeks before mating through weaning. Because the offspring and dams had
access to the drinking water containing chloral, 1t 1s not clear If the
observed effect was a result of pre- or postnatal exposure.
The derivations of CS and RQ values are presented In Table 9-2.
Possible developmental behavioral effects In mice (an RV of 9) were (
observed at a human MED of 1078 mg/day, which corresponds to an RV. of 1
(Kallman et al., 1984). Multiplying the RVg by the RVd, a CS of 7 Is
calculated. This value Is not adjusted for duration because the entire
period of gestation and neonatal development was encompassed by the exposure
protocol. Other portions of this study Illustrated that behavioral effects
were not seen 1n adult animals at similar exposures. Higher CS values are
calculated from the 90-day drinking water study. The liver effects 1n male
mice (Sanders et al., 1982) and the Immune system effects 1n female mice
(Kauffmann et al., 1982) occurred at human MEDs of 8.8 and 87, respectively,
which correspond to RV^s of 4.1 and 2.6. The liver effort? in male ™1ce
0085d -44- 01/29/88
-------
o
00
tn
Q.
tn
i
TABLE 9-1
Toxlclty Summary for Chloral (>99X Purity) Administered to Hlce In Drinking Mater
Number
Sex at Start
N 140 total
N 11
F 12
f 5
Average
Weight
(kg)
0.034b
0.031b
0.026b
0.03d
Exposure
0.07 mg/t drinking
water for 90 days
0.7 mg/fc drinking
water for 90 days
0.07 mg/t drinking
water for 90 days
0.60 rag/ml drinking
water 3 weeks before
mating through weaning
Transformed Equivalent
Animal Dose Human Dose
(mg/kg/day) (mg/kg/day)
16C 1.26
160C 12.1
173C 12.4
204. 8C 15.4
Response
Increased liver weights. SGOT and
LDH. Increased hepatic mlcrosomal
amlnopyrlne N-demethylase and
aniline hydroxylase activity
Increased liver weights, and
Increases In serum SGOT and LDH,
Increased hepatic mlcrosomal
amlnopyrlne N-demethylase and
aniline hydroxylase activity
Decrease In the number of antibody-
forming cells per 10* cells
Impairment In retention of a passive
avoidance task In offspring
Reference
Sanders
et al.. 1982
Sanders
et al.. 1982
Kauffmann
et al.. 1982
Kallman
et al.. 1984
Calculated by multiplying the animal transformed dose by the cube root of the ratio of the animal body weight to the reference human body
weight (70 kg).
Estimated from growth curves In the study
C0osage estimated by Investigators
••Reference mouse body weight (U.S. EPA. 1985c)
VD
CD
00
-------
o
o
00
tn
Q.
1
£
1
o
\
rv>
TABLE 9-2
Composite Scores for Chloral from Oral Studies In Mice
Chronic
Animal Dose Human MED* Rvd Effect RVe CS RQ
(mg/kg/day) (mg/day)
16 8.82* 4.1 Liver toxlclty - Increased 4 16.4 1000
weight, enzyme Induction
160 85.4 ?.6 Increases In serum SGOT 6 15.6 100
and LDH
18 8/* ?.6 Decrease In the number of 5 13 1000
antibody-forming cells
204.8 1078 1 Behavioral changes in off- 7 7 1000
spring
*The dose was divided by an uncertainty factor of 10 to approximate chronic exposure.
Reference
Sanders
et al., 1982
Sanders
et al., 1982
Kauffman
et al., 1982
Kail man
et al.. 1984
CO
CO
-------
correspond to an RV of 4, and the Immune system effects to an RV of
" C
5. The severity of the "liver effects was Increased at the high dose In male
mice at this dose level (160 mg/kg/day), the associates MED Is 85.4. The
Increases In the serum enzymes SGUT and LDN suggests cellular necrosis
resulting 1n an RV of 6. Mut1ply1ng by the RV of 26 results 1n a CS
of 15.6 which also corresponds to an RQ of 1000.
The CS of 16.4 derived from the Hver effects In male mice observed 1n
the 90-day study (Sanders et al., 1982) corresponding to an RQ of 1000 1s
selected to represent the toxlclty of chloral and Is presented In Table 9-3.
9.2. BASED ON CARCINOGENICITY
R1jhs1nghan1 et al. (1986) found a dose-related significant Increase In
liver tumor Incidence 1n mice sacrificed 48-92 weeks after being given a
single gavage dose of chloral hydrate at 0, 5 or 10 ^g/g. In a study by
Roe and Salaman (1955), a nonsignificant Increase 1n skin tumors 1n mice was
observed 1n a 2-stage carclnogenldty study.
There are no human data Indicating that chloral 1s a carcinogen. The
R1jhs1nghan1 et al. (1986) mouse bloassay study Is Inadequate for
quantitative assessment. Mice were treated only once and few mice were at
risk for tumor development. Despite these limitations, the R1jhs1nghan1 et
al. (1986) gavage study 1n mice provides limited evidence that chloral may
be a carcinogen. In this study, high-dose animals showed a significant
Increase 1n numbers of hepatic nodules and 2/3 carcinomas occurred much
earlier than the two carcinomas 1n the control group. Positive results 1n
mutagenlclty assays also suggest the presence of genotoxlc activity which
may be consistent with carcinogenic mechanisms. In addition, TCA, a
metabolite of chloral, has been shown to be carcinogenic (Henen-Feund,
1986). Chloral and TCA are the metabolites suggested to be Involved 1n the
carclnogenldty of tMchloroethylene (U.S. EPA, 1987c). Using the EPA
0085d -47- 03/10/88
-------
TABLE 9-3
Chloral
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 8.82 mg/day
Effect: liver tox1c1ty - decreased liver weight and enzyme
Induction
Reference: Sanders et al., 1982
RVd: 4.1
RVe: 4
Composite Score: 16.4
RQ: 1000
*Equ1valent human dose
0085d -48- 01/28/88
-------
Guidelines for Carcinogen Risk Assessment, the positive albeit less than
Ideal bloassay response In male mice together with Indications of
genotoxldty and knowledge of metabolites which are by bloassay shown to be
carcinogenic, combined with a lack of chronic human data places chloral 1n
weight of evidence Group C. Because the best available data are Inadequate
to calculate a potency factor, chloral 1s assigned a Potency Group of 2.
Chloral, with an EPA Group of C and a Potency Group of 2, corresponds to a
Hazard Ranking of LOW, which Is assigned an RQ of 100.
0085d -49- 03/10/88
-------
10. REFERENCES
Adams, W.L. 1943. The comparative tox1c1ty of chloral alcoholate and
chloral hydrate. J. Pharmacol. Exp. Therap. 78: 340-345.
Applegate, V.C., J.H. Howell, A.E. Hall, Jr. and M.A. Smith. 1957.
Toxlclty of 4346 Chemicals to Larval Lampreys and Fishes. Spec. Scl. Rep.
F1sh. No. 207, Fish W1ldl. Serv., USDI, Washington, DC. p. 46.
Atkinson, R. 1985. Kinetics and mechanisms of the gas phase reactions of
the hydroxyl radical with organic compounds under atmospheric conditions.
Chem. Rev. 85: 185-193.
Blgnaml, M., G. Contl, R. CrebelH, et al. 1980. Mutagenlclty of halo-
genated aliphatic hydrocarbons 1n Salmonella typh1mur1um, Streptomyces
coellcolor and Asperglllus nldulans. Chem. B1ol. Interact. 30(1): 9-23.
Blostov, A.N., Y.S. Rotenberg and V.G. Mulentova. 1970. lexicological
evaluation of chloral 1n the process of Us liberation during spraying and
pouring of polyurethane foams. G1g. Tr. Prof. Zabol. 14(16)L: 26-29.
(CHed In U.S. EPA, 1985a)
Scrzcllaca, J.P. and R.A. Carchman. 1382. Effects of selected organic
drinking water contaminants on male reproduction. NTIS PB82-259847. 149 p.
Bowyer, K. and S.P. Glasser. 1980. Chloral hydrate overdose and cardiac
arrhythmias. Chest. 77(2): 232-235.
0085d -50- 03/10/88
-------
BMngmann, G. and R. Kuehn. 1980. Comparison of the toxlclty thresholds of
water pollutants to bacteria, algae, and protozoa In the cell multiplication
Inhibition test. Water Res. 14(3): 231-241.
Bronzettl, G., A. Gain, C. Corsl, et al. 1984. Genetic and biochemical
Investigation on chloral hydrate In vitro and In vivo. Mutat. Res. 141(1):
19-22.
Bruce, W.R. and J.A. Heddle. 1979. The mutagenlc activity of 61 agents as
determined by the mlcronucleus, Salmonella, and sperm abnormality assays.
Can. J. Genet. Cytol. 21(3): 319-333.
Cabana, B.E. and P.K. Gessner. 1970. The kinetics of chloral hydrate'
metabolism In mice and the effect thereon of ethanol. J. Pharmacol. Exp.
Ther. 174(2): 260-275.
Carlberg, G.E., H. Drangsholt and N. Gjos. 1986. Identification of chlori-
nated compounds In the spent chlorlnatlon liquor from differently treated
sulphite pulps with special emphasis on mutagenlc compounds. Sc1. Total
Environ. 48: 157-167.
Cassldy, D.J. and 3.L. Boshell. 1980. An In vivo study of the action of
chloral hydrate on mitosis. Anat. Rec. 196: 235.
CMR (Chemical Marketing Reporter). 1986. OPD Chemical Buyers Directory,
74th Annual ed., H. Van, Ed. Schnell Publishing Co., New York, NY. p. 220.
0085d -51- 03/10/88
-------
CrebelH, R., G. Contl, L. Contl and A. Carere. 1985. MutagenlcHy of
trlchloroethylene, trlchloroethanol and chloral hydrate In Asperqlllus
nldulans. Mutat. Res. 155: 105-111.
Cross, J. and 0. McMahon. 1976. Chloral hydrate causes breakdown of poly-
somes In Chlamydomonas relnhardl In vivo. J. B1ol. Chem. 251(9): 2637-2643.
E1senre1ch, S.J., B.B. Looney and J.D. Thornton. 1981. Airborne organic
contaminants of the Great Lakes ecosystem. Environ. Scl. Technol. 15(1):
30-38.
Fielding, M., T.M. Gibson, H.A. James, K. McLoughUn and C.P. Steel. 1981.
Organic mlcropollutants 1n drinking water. TR-159. Medmenham, Eng. Water
Res. Cent. 47 p.
Frelter, E.R. 1978. Acetic acid derivatives (halogenated). In: K1rk-
Othmer Encyclopedia of Chemical Technology, 3rd ed., Vol. 1, M. Grayson and
D. Eckroth, Ed. John Wiley and Sons, New York. p. 174.
Goldenthal, E.I. 1971. A compilation of IQ^Q values 1n newborn and adult
animals. Toxlcol. Appl. Pharmacol. 18: 185-207.
Hansch, C. ar.d A.3. Leo. 1985. KeclCherc Project Issue Me. 26. Pomona
College, Claremont, CA.
Harvey, S.C. 1975. Hypnotics and sedatives: Miscellaneous agents. In: The
Pharmacological Basis of Therapeutics, A.S. Goodman and A. Gllman, Ed.
p. 124-129.
0085d -52- 03/10/88
-------
Hawley, G.G. 1981. The Condensed Chemical Dictionary, 10th ed. Van
Nostrand Relnhold Co., New York. p. 228.
Hecht, A. 1978. Drug effects on the eye. FDA Consum. 12: 14-15.
Herren-Freund, S.L., M.A. Pereura, G. Olsen and A.B. DeAngelo. 1986. The
cardnogenlclty of tMchloroethylene and Us metabolites (trlchloroacetlc
add, dlchloroacetlc add) 1n mouse liver. Proc. Am. Assoc. Cancer. Res.
27: 91.
H1ne, J. and P.K. Mookerjee. 1975. The Intrinsic hydrophlUc character of
organic compounds. Correlations 1n terms of structural contributions. J.
Org. Chem. 40(3): 292-298.
Hobara, T., H. Kobayashl, T. Kawamoto, et al. 1986. Biliary excretion of
tMchloroethylene and Its metabolites In dogs. Toxlcol. Lett. 32: 119-122.
HSDB (Hazardous Substance Data Base). 1987a. Report No. 2557. National
Library of Medicine. On-L1ne. CAS No. 75-87-6.
HSDB (Hazardous Substance Data Base). 1987b. Report No. 222. National
Library of Medicine. On-Llne. CAS No. 302-17-0.
Ikeda, M., Y. Mlyake, M. Ogata and S. Ohmorl. 1980. Metabolism of tr1-
chloroethylene. Blochem. Pharmacol. 29: 2983-2992. (Cited In U.S. EPA,
1985a)
0085d -53- 03/10/88
-------
Juhnke, I. and 0. Luedemann. 1978. Results of the study of 200 chemical
compounds on acute fish toxlclty using the Golden Orfe test. Z. Wasser
Abwasser Forsch. 11{5): 161-164.
Kafer, E. 1986. Tests which distinguish Induced crossing-over and
aneuploldy from secondary segregation 1n Asperqlllus treated with chloral
hydrate or gamma-rays. Mutat. Res. 164(3): 145-166.
Kallman, M.J., G.L. Kaempf and R.L. Balster. 1984. Behavioral toxldty of
chloral In mice: an approach to evaluation. Neurobehav. Toxlcol. Teratol.
6(2): 137-146.
Kauffmann, B.M., K.L. White, Jr., V.M. Sanders, et al. 1982. Humoral and'
cell-mediated Immune status 1n mice exposed to chloral hydrate. Environ.
Health Perspect. 44: 147-151.
Keith, L.H., A.W. Garrison, F.R. Allen, et al. 1976. Identification of
organic compounds In drinking water from thirteen United States cities. In:
Ident. Anal. Organic Pollut. Water, L.H. Keith, Ed. Ann Arbor Press, Ann
Arbor, MI. p. 329-373.
Kleopfer, R.O. 1976. Analysis of drinking water for organic compounds.
In: Identif, Anal, Org. Pollut. Hater, L.H. Keith, Ed. Ann Arbor Press, Ann
Arbor, MI. p. 399-416.
Lewln, R.A., T.H. Lee and L.S. Fang. 1982. Effects of various agents on
flagellar activity, flagellar autotomy and cell viability 1n four species of
Chlamydomonas (chlorophyta: volvocales). Symp. Soc. Exp. Blol. 35: 421-437.
0085d -54- 03/10/88
-------
Lukn1tsk11, F.I. 1975. The chemistry of chloral. Chem. Rev. 75(3):
259-289.
Lyman, W.J., W.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. McGraw Hill Book Co., New York. p. 4-9, 5-5,
15-16.
Marshall, E.K., Jr. and A.H. Owens, Jr. 1954. Absorption, excretion and
metabolic fate of chloral hydrate and trlchloroethanol. Bull. Johns Hopkins
Hosp. 95: 1-18.
Martin, H. and C.R. Worthing, Ed. 1977. Pesticide Manual, 5th ed. British
Crop Protection Council, p. 149, 182, 352.
Miller, J.W. and P.C. Uden. 1983. Characterization of nonvolatile aqueous
chlorlnatlon products of humlc substances. Environ. Sc1. Technol. 17(3):
150-157.
Mitchell, T.F. 1980. Glue. In: K1rk-0thmer Encyclopedia of Chemical
Technology, 3rd ed., Vol. II, M. Grayson and D. Eckroth, Ed. John Wiley and
Sons, New York. p. 913.
Muller, G., M. Spassovskl and D. Henschler. 1974. Metabolism of trlchloro-
ethylene In man. II. Pharmacoklnetlcs of metabolites. Arch. Toxlcol.
32(4): 283-295.
0085d -55- 03/10/88
-------
Norwood, D.L., J.D. Johnson, R.F. Chrlstman and D.S. MUllngton. 1983.
ChloMnatlon products from aquatic humlc material at neutral pH. Water
Chlorlnatlon: Environ. Impact Health Eff. 4(1): 191-200.
Ohta, T. and I. Mlzoguchl. 1980. Photoox1dat1on of chloral 1n air.
Tokyo-Torltsu E1se1 Kenkyusho Kenkyu Nempo. 31: 238-243. (CA 95:85356e)
Pavlova, L.P. 1975. lexicological characteristics of trlchloroacetalde-
hyde. Tr. Azerb. Nauchno-Issled. Inst. G1g. Tr. Prof. Zabol. 10: 99-105.
(CA 87:194996u)
Perry, R.H. and D. Green. 1984. Perry's Chemical Handbook. Physical and
Chemical Data. McGraw Hill, 6th edition, New York, NY. p. 3-52.
Peters, J.H., G.R. Gordon and S.A. Ferguson. 1975. Chloral hydrate and
meperldlne: Response and metabolism 1n squirrel and rhesus monkeys.
Toxlcol. Appl. Pharmacol. 31(2): 290-301.
R1jhs1nghan1, K.S., C. Abrahams, M.A. Swerdlow, K.V. Rao and T. Ghose.
1986. Induction of neoplastlc lesions In the livers of C57BL x C3HF1 mice
by chloral hydrate. Cancer Detect Prev. 9(3-4): 279-288.
R1^. H» 1949' Ths ana^hase wovernent of chronsosornss IP. ths snsrfT52tocv/tss cf
the grasshopper. Blol. Bull. 96: 90-106. (CUed In Russo et a!., 1984)
0085d -56- 03/10/88
-------
Roe, F.J.C. and M.H. Salaman. 1955. Further studies on Incomplete carclno-
genesls: Trlethylene melamlne (T.E.M.) 1,2-benzanthracene and B-prop1olac-
tone, as Initiators of skin tumour formation In the mouse. Br. J. Cancer.
9: 177-203.
Rumack, B.H. and R.G. Peterson. 1980. Clinical toxicology. .In: Casarett
and Doull's Toxicology, The Basic Science of Poisons, J. Doull, C.P.
Klaassen and M.O. Amdur, Ed. Macmlllan Publishing Co., Inc., New York.
p. 677, 694.
Russo, A., F. Pacchlerottl and P. Metalll. 1984. Nond1sjunct1on Induced In
mouse spermatogenesls by chloral hydrate, a metabolite of tMchloroethylene.
Environ. Mutagen. 6(5): 695-703.
Sabljlc, A. 1984. Predictions of the nature and strength of soil sorptlon
of organic pollutants by molecular topology. J. Agrlc. Food Chem. 32:
243-246.
Sanders, V.M., B.M. Kauffmann, K.L. White, Jr. 1982. Toxicology of chloral
hydrate In the mouse. Environ. Health Perspect. 44: 173-146.
Sato, T., M. Mukalda, Y. Ose, H. Nagase and T. Ishlkawa. 1985. Mutagen-
1c1ty of chlorinated products from son humlc substances. Scl. Total
Environ. 46: 229-241.
Seldell, A. 1941. Solubilities of Organic Compounds. D. Van Norstrand Co.
Inc., New York, NY. p. 92-93.
0085d -57- 03/10/88
-------
Seller, J.P. 1977. Inhibition of testlcular DNA synthesis by chemical
mutagens and carcinogens. Preliminary results In the validation of a novel
short-term test. Hutat. Res. 46: 305-310.
Sellers, E.M., M. Lang, J. Koch-Wesser, E. LeBlanc and H. Kalant. 1972.
Interactions of chloral hydrate and ethanol In man: I. Metabolism. Cl1n.
Pharmacol. Therap. 13: 37. (Cited 1n Sellers et al., 1978)
Sellers, E.M., M. Lang-Sellers and J. Koch-Weser. 1978. Comparative
metabolism of chloral hydrate and tMclorfos. J. CUn. Pharmacol. 18:
457-461.
Senteln, P. and Y. Ated. 1974. Action de Thydrate de chloral sur les
mitoses de segmentation de Toeuf de Pleurodele. Etude cytologlque et
ultrastructurale. Chromosoma. 45: 215-244. (Cited In Russo et al., 1984)
Singh, M. and U. S1nha. 1976. Chloral hydrate Induced haploldlzatlon In
Asperqlllus nldulans. Experlentla. 32: 1144-1145.
Sora, S. and M.L. Agostlnl Carbone. 1987. Chloral hydrate, methylmercury
hydroxide and ethldlum bromide affect chromosomal segregation during melosls
of Saccharomyces cerevlslae. Mutat. Res. 190(1): 13-17.
Swann, R.L., D.A. Laskowskl, P.J. McCall, K. Vander Kuy and H.J. Dlshburger.
1983. A rapid method for the estimation of the environmental parameters
octanol/water partition coefficient, soil sorptlon constant, water to air
ratio and water solubility. Res. Rev. 85: 17-28.
0085d -58- 03/10/88
-------
Tabakoff, B., C. Vugrlndc, R. Anderson and S.G.A. Allvlsatos. 1974.
Reduction chloral hydrate to tMchloroethanol In brain extracts. Blochem.
Pharmacol. 23(2): 455-460.
Trehy, M.L., R.A. Yost and C.J. Miles. 1986. ChloMnatlon byproducts of
amlno acids In natural waters. Environ. Sc1. Technol. 20: 1117-1122.
U.S. EPA. 1977. Computer print-out of non-confidential production data
from TSCA Inventory. OPTS, CID, U.S. EPA, Washington, DC.
U.S. EPA. 1980. Guidelines and Methodology Used 1n the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Criteria
Documents. Federal Register. 45:(231): 49347-49357.
U.S. EPA. 1982. Chemical Hazard Information Profile Draft Report: TM-
chloroacetaldehyde. March 31, 1982. U.S. EPA, Office of Toxic Substances.
U.S. EPA 1984. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Tox1c1ty 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, Wash-
ington, DC.
U.S. EPA. 1985a. Health Assessment Document for TMchloroethylene. Final
Draft. Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH, Research Triangle Park, NC.
EPA 600/8-82-006F. NTIS PB 85-249696. p. 4-41, 4-67.
0085d -59- 03/10/88
-------
U.S. EPA. 19855. Reference Values for Risk Assessment. Prepared by the
Office of Health and Environmental Assessment, Environmental Criteria and
Assessment Office, Cincinnati, OH for the Office of Solid Waste, Washington,
DC.
U.S. EPA. 1986a. Methodology for Evaluating Potential Carc1nogen1c1ty 1n
Support of Reportable Quantity Adjustments Pursuant to CERCLA Section 102.
Prepared by the Office of Health and Environmental Assessment, Carcinogen
Assessment Group, for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986b. The verification of the production of 56 chemicals.
Contract No. 68-02-4209. Office of Toxic Substances, Washington, DC.
U.S. EPA. 1986c. Guidelines for Carcinogen Risk Assessment. Federal
Register. 51(185): 33992-34003.
U.S. EPA. 1987a. Graphical Exposure Modeling System (GEMS). Fate of
Atmospheric Pollutants (FAP). Office of Toxic Substances, Washington, DC.
U.S. EPA. 1987b. Hazardous Substances; Reportable Quantity Adjustments;
Proposed Rules. 40 CFR Parts 117 and 302. Federal Register. 52(50):
8140-8186.
U.S. EPA. 1987c. Addendum to the Health Assessment Document for
TMchloroethylene. EPA 600/8-82/006FA.
0085d -60- 03/10/88
-------
Waskell, L. 1978. A study of the mutagenlclty of anesthetics and their
metabolites. Mutat. Res. 57(2): 141-153.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co., Inc.,
Rahway, NJ. p. 288, 1376.
Wiseman, H.M. and G. Hampel. 1978. Cardiac arrhythmias due to chloral
hydrate poisoning. Br. Med. J. 2: 960.
Yoon, 3.S., J.M. Mason, R. Valencia, R.C. Woodruff and S. Zlmmerlng. 1985.
Chemical mutagenesls testing In Drosophlla. IV. Results of 45 coded
compounds tested for the National Toxicology Program. Environ. Mutagen.
7(3): 349-367.
0085d -61- 03/10/88
-------
APPENDIX A
LITERATURE SEARCHED
This HEED 1s based on data Identified by computerized literature
searches of the following:
CHEMLINE
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXLIT
TOXLIT 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
CAS ONLINE (Chemistry and Aquatic)
HSDB
These searches were conducted 1n October 1987, and the following secondary
sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1987. TLVs: Threshold Limit Values for Chemical Substances 1n the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
NY
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 28. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene 3nd Toxicology t 3rd rev. ed.. Vol. 2C. -Dohn miey 3Pd
^ NY. p. 3817-5112.'
0085d -62- 03/10/88
-------
Grayson. M. and D. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
EPA 600/6-84-010. NTIS PB84-243906. SRI International, Menlo
Park, CA.
NTP (National Toxicology Program). 1987. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, I.N. 1984. Dangerous Properties of Industrial Materials, 6th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1987. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call 1n
Programs. Registration Standards and the Data Call 1n Programs.
Office of Pesticide Programs, Washington, DC.
USITC (U.S. International Trade Commission). 1986. Synthetic
Organic Chemicals. U.S. Production and Sales, 1985, USITC Publ.
1892, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
0085d -63- 03/10/88
-------
In addition, approximately 30 compendia of aquatic toxldty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxldty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0085d -64- 03/10/88
-------
o
CO
tn
Q.
Summary Table for Chloral
Species
Inhalation Exposure
Subchronlc ID
Chronic ID
Oral Exposure
Subchronlc mouse,
male
Chronic mouse,
male
REPORTABLE QUANTITIES
Based on chronic toxlclty:
Based on carclnogenlclty:
Exposure
ID
ID
0.07 mg/ma In the
drinking water for
90 days
(16 mg/kg/day)
0.07 mg/mfc In the
drinking water for
90 days
(16 mg/kg/day)
1000 pounds
100 pounds
Effect RfD or qi* Reference
ID ID ID
ID ID ID
Increase In relative liver 1 mg/day Sanders
weights. Increase In serum et al.,
SGOT and LDH activity
Increase In relative liver 0.1 mg/day Sanders
weights, Increase In serum et al.,
SGOT and LDH activity
Sanders
et al..
Sanders
et al.,
1982
1982
1982
1982
00
00
ID = Insufficient data
------- |