FINAL DRAFT
United States trAfl nu /uii?
Environmental Protection « I ,I««
Agency March, 1988
Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR CHLORAL
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
»
NOTICE
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DISCLAIMER
This report Is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEDs) are prepared for the
Office of Solid Haste and Emergency Response (OSUER). This document series
1s 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 1s 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 (OSUER}.
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, Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval I.e., for an Interval that
does not constitute a significant portion of the Hfespan. This type of
exposure estimate has not been extensively used, or rigorously defined as
previous risk assessment efforts have 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 cardno-
genlclty are derived. The RQ 1s used to determine the quantity of a hazard-
ous substance for which notification 1s 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-
genldty) represent two of six scores developed (the remaining four reflect
IgnltabllUy, reactivity, aquatic toxlclty, and acute mammalian toxldty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxlclty and cancer based RQs are defined In U.S.
EPA. 1984 and 1986a. respectively.
111
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EXECUTIVE SUMMARY
Chloral (75-87-6) Is a colorless, oily liquid at room temperature with
a pungent, Irritating odor (Ulndholz. 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 (Mlndholz, 1983; U.S.
EPA, 1982). Montrose Chemical was the last U.S. manufacturer of chloral,
but production was discontinued when production of DOT 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 (HSOB, 1987b).
Chloral Is used In the production of chloral hydrate, plastics and some
pesticides. Including methoxychlor and DOVP (Ulndholz, 1983; U.S. EPA, 1982;
Martin and Worthing, 1977). Chloral hydrate Is used 1n medication as a 'CMS
depressant and sedative, and In 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 photochemically 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 Its 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
1v
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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 Is 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 Is not expected to be signifi-
cant; however, both chloral and Us hydrate are expected to volatilize
falirly rapid from dry soil surfaces.
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; 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 In 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 sulflte pulp
and chlorinated wastewater from an extended aeration treatment plant
(Carlberg et al., 1986; Trehy et al., 1986).
Little Information was available concerning the toxldty of chloral
hydrate to aquatic organisms. The only LC5Q for freshwater fish 1s a
value of 1720 mg/l for golden orfe (Juhnke and Luedemann, 1978).
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BMngmann and Kuehn (I960) reported that Inhibition of growth occurs at 1.6,
2.8 and 79 mg/l for Pseudomonas putIda. Scenedesmus quadrlcauda and
Entoslphon sulcatum. respectively. Studies In species of Chlamydomonas have
observed effects beginning at -0.17 g/l (Cross and McMahon, 1976). No
data for saltwater species were found In 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 Is 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 Is 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 In 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 Is 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 tox1c1ty 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; Kail man et
al., 1984). The most sensitive endpolnt of toxlclty In male mice was liver
toxlclty (Sanders et al., 1982), while the most sensitive endpolnt In female
mice was Immunotoxlclty (Kauffmann et al., 1982). Both effects were
vl
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observed at 0.07 mg/rai, a dose of 16 mg/kg/day In males and 18 mg/kg/day
In females. However, the biological significance of the Immune toxldty
test results at 18 mg/kg Is questionable. No effects on behavior were
observed 1n male mice, although body temperature was found to be depressed
at both concentrations (Kallman et a1.t 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 In liver
tumors 1n 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 In skin tumor Incidences was observed In 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 In a mouse liver bloassay. Studies of ONA
effects have reported positive results In mutation assays and assays of
aneuploldy Inducing activity, and chloral hydrate was found to decrease
testlcular DNA synthesis 1n an 1ntratest1cular injection study using mice
(Borzelleca and Carchman, 1982). In addition, chloral shares a common
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metabolite (TCA) with trlchloroethylene which has been shown to be
carcinogenic 1n animal test systems.
- Chloral hydrate exposure did not result In any changes In Utter
parameters or In any gross malformations 1n 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 (Kailman et al., 1984). At 0.6
mg/mi, an Impairment of retention of an avoidance learning task was
observed In 24-day-old mice. Because pups had access to the chloral hydrate
dosing solution. 1t Is not clear If the effect was a result of Vn 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 In the oral RfOs Is low. An RQ for
systemic toxlclty of 1000 was calculated on the basis of liver toxldty In
mice In the Sanders et al. (1982) study. Based on a weight of the evidence
classification of C but no quantitative evaluation, a carclnogenlclty RQ of
100 was assigned.
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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. HATER 7
2.2.1. Chemical Reactions 7
2.2.2. Mlcroblal 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
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TABLE OF CONTENTS (cont.)
Page
6. EFFECTS 23
6.1. SYSTEMIC TOXICITY 23
6.1.1. Inhalation Exposures 23
6.1.2. Oral Exposures 23
6.1.3. Other Relevant Information 25
6.2. CARCINOGENICITY 28
6.2.1. Inhalation 28
6.2.2. Oral 29
6.2.3. Other Relevant Information 29
6.3. MUTAGENICITY 31
6.4. TERATOGENICITY 35
6.5. OTHER REPRODUCTIVE EFFECTS ..... 36
6.6. SUMMARY 36
7. EXISTING GUIDELINES AND STANDARDS 39
8. RISK ASSESSMENT 40
8.1. CARCINOGENICITY 40
8.1.1. Inhalation 40
8.1.2. Oral. . . 40
8.1.3. Other Routes. . 40
8.1.4. Height of Evidence 40
8.1.5. Quantitative Risk Estimates 41
8.2. SYSTEMIC TOXICITY 41
8.2.1. Inhalation Exposure 41
8.2.2. Oral Exposure 41
9. REPORTABLE QUANTITIES 44
9.1. BASED ON SYSTEMIC TOXICITY 44
9.2. BASED ON CARCINOGENICITY 47
10. REFERENCES 50
APPENDIX A: LITERATURE SEARCHED 62
APPENDIX B: SUMMARY TABLE FOR CHLORAL 65
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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 Hale Rhesus Monkeys Receiving
500 mg Chloral Hydrate/kg and by Six Male Squirrel Monkeys
Receiving 150 mg Chloral Hydrate/kg per p_s 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 Genotoxlclty of Chloral and Chloral Hydrate 32
9-1 Toxlclty 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
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LIST OF ABBREVIATIONS
BCF B1oconcentrat1on factor
bw Body weight
CAS Chemical Abstract Service
CNS Central nervous system
CS Composite score
DNA OeoxyHbonuclelc add
ED5Q Dose effective to 50% of recipients
GC Gas chromatography
IR Infra red
K Soil sorptlon coefficient
oc
KW Octanol/water partition coefficient
LC5Q Concentration lethal to 50% of recipients
LD50 Dose lethal to 50% of recipients
LD, - Lowest lethal dose
LDH Lactate dehydrogenase
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
NS 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
RVd Dose-rating value
RVg 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
xll
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUNBER
Chloral 1s also known as trlchloroacetaldehyde. Chloral hydrate Is also
known as trlchloroacetaldehyde monohydrate and 2,2,2-tr1ch1oro-l,l-ethane-
dlol {Ulndholz, 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: CpHC^O 02^0130
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 1n Table 1-1. Chloral Is soluble
In ether and Is soluble 1n alcohol, forming chloral alcoholate (Ulndholz.
1983). Chloral hydrate Is highly soluble In alcohol, chloroform, ether.
carbon dlsulflde and olive oil; It 1s freely soluble In acetone and methyl
ethyl ketone; and 1t Is moderately or sparingly soluble In turpentine,
petroleum ether, carbon tetrachlorlde, benzene and toluene (Ulndholz. 1983).
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TABLE 1-1
Selected Physical Properties for Chloral and Chloral Hydrate
Property
Melting point:
Boiling point:
Vapor pressure
at 25°C:
Uater solubility
at 25°C:
Log Kow:
Specific gravity,
25/4°C:
Refractive Index,
Chloral
-57.7°C
97.8"C
51 mm Hg
exists In
hydrated
form In
water*
exists 1n
hydrated
form In
water*
1.505
1.45572
Chloral hydrate
57°C
98°C (with
dissociation to
chloral and water)
16 mm Hg
8.25x10* rog/l
0.99
NA
NA
Reference
: Ulndholz, 1983
Ulndholz, 1983
Perry and
Green, 1984
Seldell. 1941
Hansch and
Leo, 1985
Ulndholz, 1983
Ulndholz, 1983
*See value for chloral hydrate
NA . Not available
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1.3. PRODUCTION DATA .
Chloral can be prepared by two methods: by direct chloHnatlon of
either acetaldehyde or paraldehyde 1n the presence of antimony chloride or
by chlorlnatlon of ethyl alcohol followed by treatment with concentrated
sulfuMc acid and then distillation (HSDB, 1987a; Wlndholz, 1983). Chloral
hydrate Is 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 In Table 1-2. Montrose Chemical was the
last U.S. manufacturer of chloral, but production was discontinued when pro-
duction of DOT ceased (U.S. EPA, 19865). There are two domestic Importers
for chloral: R.U. Greef and Co. and Lobel Chemical Corp., and four domestic
Importers for chloral hydrate: Centerchem., Ceres Chemical Co., Nlpa
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, 19875).
1.4. USE DATA
Chloral Is 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 also has been used In the production of
DDT and has potential for use In the production of tMchloroacetlc add
(Frelter, 1978; U.S. EPA, 1982). Chloral hydrate Is used In medication as a
CNS depressant and sedative, and In liniments (HSDB, 19875). Chloral
hydrate has also been used as an Intermediate 1n the production of dlchloro-
acetlc acid and DDT (HSDB. 19875; Mitchell. 1980).
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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
Hontrose Chemical of California
Henderson, NV
Texas Eastman
longvlew, TX
Continental Oil Co.
Uestlake, 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
none^
aSource: U.S. EPA. 1977
bTh1s company Imported chloral hydrate 1n previous years.
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1.5. 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,
19865). There are two domestic Importers for chloral and four domestic
Importers for chloral hydrate (CMR, 1986; U.S. EPA. 1986D). 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 1s used In medication as a CNS
depressant and sedative, and 1n liniments (HSDB, 1987D).
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2. ENVIRONMENTAL FATE AND TRANSPORT
Limited data regarding the environmental fate and transport of chloral
and chloral hydrate were located In 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 1n the atmosphere at 25°C
were estimated to be 2.3xlO~12 and 1.3xlO~12 cm3/molecule-sec, respec-
tively. Assuming an ambient hydroxyl radical concentration of 5.0x10*
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 In
a glass cell using IR absorption spectroscopy. Major products were
determined to be HC1. CO. CO, and COC12. The photooxldatlon was a chain
reaction and the chain carrier was chlorine; however, the wavelength of
light used In this study was not reported.
2.1.2. Reaction with Ozone. Chloral and chloral hydrate will not react
with ozone molecules In 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
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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 Is stable. Us
aqueous solutions are not (Luknltskll, 1975). Chloral hydrate decomposes In
neutral, acidic 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-
Thts 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 1n pH of aqueous
solutions have been found to occur over time as the result of CCU-group
destruction with HC1 formation (Luknltskll, 1975).
2.2.2. M1crob1al Degradation. Pertinent data regarding the microblal
degradation of chloral hydrate were not located In the available literature
cited In the Appendix.
2.2.3. Volatilization. Keith et al. (1976) determined that chloral
hydrate Is so highly polar that H does not appreciably strip out of aqueous
solution even at elevated temperatures. Henry's Law constant for chloral
hydrate was estimated to be lxlO~10 atm-mVmol at 25°C using the group
0085d -7- 01/13/88
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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. B1oaccumu1at1on. 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 SablJIc (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 KQC values suggest that chloral hydrate would
be highly mobile 1n soil and may leach Into groundwater (Swann et al., 1983).
2.3.3. Volatilization. Because of the relatively low value of Henry's
Law constant for chloral hydrate (Ix10~10 atm-mVmol at 25°C), this com-
pound Is 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
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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;
E1:>enre1ch et al., 1981). Half-lives for the reaction of these compounds
with photochemically 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 Its extremely high water
solubility, chloral hydrate would be highly susceptible to removal from the
atmosphere by wet deposition. Dry deposition 1s 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, addle and basic solutions, producing chloroform and
formic acid by an elimination reaction catalyzed by water, OH~ and chlor-
alate anlon. The* half-life for this reaction Is 17.5 days at pH 8 and 20°C
and Is 2 days at pH 9 and 20°C (Lukn1tsk11, 1975). Chloral hydrate Is 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 Is not expected to be significant;
however, both chloral and Its hydrate are expected to volatilize fairly
rapid from dry soil surfaces.
OOSSd -9- 01/28/88
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3. EXPOSURE
Monitoring data were not available to Indicate that the general popu-
lation Is exposed to chloral or Its hydrate by Inhalation, 1ngest1on of
contaminated food or dermal contact. Limited monitoring data are available
on chloral hydrate In drinking water.
3.1. WATER
Chloral hydrate has been Identified as a product of aqueous chlorlnatlon
of humlc substances at pH 4-9 and ami no adds at pH 7-8 (Trehy et al., 1986;
Miller and Uden, 1983; Norwood et al., 1983; Sato et al., 1985). Humlc
substances and ami no acids 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 vg/l; Philadelphia, PA, 5.0 »g/t; Seattle, WA,
3.5 yg/l; Grand Forks, NO, 0.01 yg/l; New York City, 0.02 yg/l;
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 In any of the NORS
samples analyzed by the Inert gas stripping technique referred to as
Volatile Organlcs Analysis (Keith et al., 1976). Keith et al. (1976)
determined that because of the high polarity of chloral hydrate. Volatile
Organlcs Analysis Is 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
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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 CUy, Kansas between 1973 and 1975 (Fielding
et al., 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 1s 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 In
the spent chlorlnatlon liquor from the bleaching of sulflte pulp at high and
low Hgnln content. Concentrations of chloral corresponded to <0.1 and
0.5/g per ton of pulp processed, respectively (Carlberg et al., 1986).
Samples of chlorinated wastewater from an extended aeration treatment plant
collected on '2 days were found to contain 20-38 yg/i chloral hydrate
(Trehy et al., 1986).
3.2. SUMMARY
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; Miller and Uden, 1983; Norwood et al., 1983; Sato et
al., 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
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detected 1n the spent chlorlnatlon liquor from the bleaching of sulfUe pulp
and chlorinated wastewater from an extended aeration treatment plant
(Carlberg et a!., 1986; Trehy et al., 1986).
0085d .12- 01/13/88
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4. AQUATIC TOXICITY
4.1. ACUTE TOXICITY
Juhnke and Luedemann (1978) reported a 48-hour LC5Q value of 1720 mg
chloral hydrate/l for golden orfe, Leudscus 1dus melanotus. under static
conditions. Brlngmann and Kuehn (1980) found that chloral hydrate at 1.6
and 79 mg/i resulted 1n a >3% decrease In growth In cultures of the
bacteria, Pseudomonas outIda, 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 1n
aquatic organisms were not located 1n the available literature cited 1n
Appendix A.
,4.3.. PLANT EFFECTS
A chloral hydrate concentration of 2.8 mg/i resulted 1n a >3X decrease
1n growth of cultures of the algae, Scenedesmus quadrlcauda. exposed for 7
days (Brlngmann and Kuehn, 1980). Lewln et al. (1982) found that chloral
hydrate Inhibited the motlllty of four species of the flagellated green
algae, Chlamvdomonas. grown In cultures without Inducing death or flagellar
autonomy (Table 4-1). The results Indicated that C_. dvsosmos was most
sensitive In the test for Immobilization, while C. moewussl (-) died at the
lowest concentration.
Cross and HcNahon (1976) added chloral hydrate to cultures of Chlamydo-
monas relnhardl and observed the breakdown of polysomes and Inhibition of
protein synthesis at chloral hydrate concentrations of >10 md (0.17 g/l).
0085d -13- 01/13/88
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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 Mb
(-)
re1nhardt11 (+)b
(-)
dysosmos
monolca
60 (9.9 g/l)
60
60
60
. 30 (4.9 g/l)
120
120 (19.8
60
120
125 (20.1
120
500* (8.3
g/D
g/D
g/i)
0085d
-14-
01/13/88
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Because significant levels of the chloral hydrate metabolites, TCA and TCE
were not found 1n the cultures, the Investigators concluded that chloral
hydrate Itself produced the observed effects.
4.4. SUMMARY
Little Information was available concerning the toxldty of chloral
hydrate to aquatic organisms. The only LC5Q for freshwater fish Is a
value of 1720 mg/i 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/l for Pseudomonas putlda. Scenedesmus quadMcauda and
Entoslphon sulcatum. respectively. Studies In species of Chlamydomonas have
observed effects beginning at -0.17 g/i (Cross and McMahon, 1976). No
data for saltwater species were found In the available literature.
0085d -15- 01/13/88
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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 H was readily absorbed from the
gastrointestinal tract (Marshall and Owens, 1954). Because chloral hydrate
1s metabolized quickly, 1t Is 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 25X binding 1n rhesus
monkeys, squirrel monkeys and man, respectively. Results'of TCA binding
Indicated levels of 69 and 64X binding, for rhesus and squirrel monkeys,
respectively, 1n contrast to ~85% 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/i were reached In <2 hours. TCA accumulated 1n the plasma
during the 24 hours after dosing. Hean serum half-lives of TCE and TCA were
estimated at 8 and 75 hours, respectively. In another study by Sellers et
al. (1978), the same seven subjects were given oral doses (15 mg/kg) of
chloral hydrate each night for 8 nights. At the end of the dosing period,
mean plasma TCA concentrations were 82.3 mg/i, Indicating that TCA tends
to accumulate In the plasma.
0085d -16- 01/13/88
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5.3. METABOLISM
The metabolism of chloral 1s presented 1n Figure 5-1. Chloral Is
rapidly reduced to tMchloroethanol (TCE). .In vitro studies have shown that
chloral Is an effective substrate for the cytosollc, NAOH requiring enzyme,
alcohol dehydrogenase. In addition, In rat liver cytosol two additional
NADPH-dependant enzymes have been demonstrated (U.S. EPA, 1985a). In. 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) 1s less 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 >26X of an oral dose of chloral hydrate was oxidized to TCA.
MQIler 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
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MITOCHONDRIA
CYTOSOL
NAD*
ALDEHYDE
DEHYDROGENASE
rrcAj
CHLORAL
C CI3 CHO
CYTOSOL
NADH
ALCOHOL
DEHYDROGENASE
NADPH
ALDEHYDE
REDUCTASE
MICROSOMES
NADPH, 02
C Ct3 CH20H
rrcEi
GLUCURONYL
TRANSFERASE
C O3 CH2O CtHgOe
rrCE-GLUCURONIOEl
FIGURE 5-1
Metabolism of Chloral Hydrate
Source: Ikeda et al.. 1980; U.S. EPA. 1985a
OOSSd
-18-
01/13/88
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level of TCE In the urine accounted for -23% of the dose, while the level of
TCA accounted for ~24X 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, 56X was reduced to
TCii, 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 1n 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 1n 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 In squirrel and rhesus monkeys were 103 and
136 ymol/100 mi, 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 In 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
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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 In the urine as free TCE, with remaining TCE excreted as
the glucuronlde conjugate. In humans, 4.6% of the TCE In 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.
MQller 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 1n 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 In 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 Its metabolites In 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 In the bile, with 95.2% of
0085d -20- 03/10/88
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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_*
Time After Rhesus Monkeys Squirrel Monkeys
MetabolUe(s) Administration Mean Mean
(hours)
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 al.t 1975
0085d -21- 01/13/88
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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 Is readily absorbed from the gastrointestinal
tract and rapidly metabolized, only metabolites are detected In the blood.
Chloral hydrate Is metabolized to TCE and TCA, with further metabolism of
TCE to TCA In 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 Is more prolonged.
0085d -22- 03/10/88
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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/l (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/l (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/mi 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/mi, respectively. Hale mice showed
a dose-dependent Increase In 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/mi. A significant (p<0.05)
Increase In both relative and absolute liver weight In males at both concen-
trations was observed. Lung and brain weights were slightly decreased In
males, but the effect was not dose-related. Serum and liver chemistries,
0085d -23- 01/28/88
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which were examined In 4-8 ra1ce/sex/group, provided further evidence that
the liver Is the target of chloral toxlclty. In male mice, an Increase In
serum SGOT and LDH (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) In 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.
H1stopatholog1cal 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, hemagglutlnation tlters and spleen cell response to Upopolysaccha-
rlde from Salmonella tvohosa. 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/10* cells. Other measures of humoral Immunity, hemag-
glutlnatlon tlters 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 In
either male or female mice. The Investigators concluded that the Immune
system was the most sensitive endpolnt In 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/ml (16
mg/kg/day) (Sanders et al., 1982).
0085d -24- 01/28/88
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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
In 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.
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 fntake 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 In mice treated at 16 mg/kg/day.
6.1.2.2. CHRONIC — Pertinent data regarding the toxlclty of chloral
following chronic oral Intake were not located 1n the available literature
cited 1n Appendix A.
6.1.3. Other Relevant Information. Chloral hydrate was Introduced as a
therapeutic agent In 1869. The compound was used as a hypnotic until well
Into the 20th century, and 1t Is still used as a sedative In humans (Sanders
et al.. 1982). Chloral hydrate 1s Irritating to the skin and mucous
membranes. Death In humans occurs at an oral dose of "10 g, although death
0085d -25- 01/28/88
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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 1n 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 yg/ml (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 In 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 potentlatlon occurs because ethanol accelerates the reduction
of chloral hydrate to the active TCE metabolite (Harvey. 1975).
Acute oral lethality data In animals are presented In Table 6-1. The
lowest ID., was observed In rats, with a value of 285 mg/kg In 1- to
2-day-old rats, and an L05Q of 479 mg/kg In adult rats (Goldenthal. 1971).
0085d -26- 01/28/88
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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
LD50 479
L050 285
LOLO 1000
LOLO 1000
LDLO 400
Sanders et al., 1982
Sanders et al., 1982
Goldenthal. 1971
Goldenthal, 1971
Adams, 1943
Adams, 1943
Adams, 1943
0085d
-27-
01/28/88
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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 18X 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 1n 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 In spleen
weight, spleen antibody-forming cells or delayed type hypersens1t1v1ty
response to sheep RBC.
Kail man et al. (1984) determined an ED5Q of 84.5 mg chloral/kg for
disruption of a motor coordination test (screen test) In 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, swimming
endurance) were observed (Kailman et al.. 1984).
6.2. CARCIN06ENICITY
6.2.1. Inhalation. Pertinent data regarding the carc1nogen1c1ty of
chloral following Inhalation exposure were not located In the available
literature cited In Appendix A.
0085d -28- 01/28/88
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6.2.2. Oral. Rljhslnghanl et al. (1986) treated 15-day-old male
C57BLxC3HF1 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 In the number of mice
with hepatic nodules 1n mice treated at 10 yg/g. The tumor Incidences and
the types of tumors found are presented 1n Table 6-2. As shown 1n Table
6-2, tumors In the treatment groups tended to appear earlier than In
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 In
acetone for a total dose of 24 or 225 mg. The chloral hydrate treatment was
followed by 18 skin applications of 3 ml of a 0.5X 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 In skin tumors, with 4/17 and 4/20 mice with skin tumors In
the low- and high-dose groups, respectively, compared with 1/20 control mice
with tumors.
0085d -29- 01/28/88
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TABLE 6-2
g Hlstologlcal Classification of Hepatic Nodules and Their Distribution
« In C57BLxC3HFl Hale Nice Sacrificed Between Weeks 48 and 92
°- After a Single Intragastrtc Dose of Chloral Hydrate9
CO
o
I
Histology of Hepatic Nodulesb
Dose of Chloral Hydrate
(vg/g bw)
0.00
5
10
No. of Nice with Nodules/
No. of Mice Examined (*)
2/19 (10.5)
3/9 (33.3)
6/8 (75)d
QUALIIY OF
. Hyperplastlc Adenoroatous
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
DNodules were categorized on the basis of the most advanced lesion In the nodule.
o cF1gures In parentheses represent the Interval In weeks between the administration of chloral hydrate
N? and sacrifice.
__i
o
GO dThe difference In the Incidence of nodules between the groups given 10 pg/g of chloral hydrate and
00 distilled water Is significant (p<0.05).
-------
TCA, which Is a metabolite of both trlchloroethylene and chloral, has
been shown to be related to an Increased Incidence In liver carcinomas In
mice exposed to TCA In their drinking water (Herren-Freund, 1986). These
data are evaluated more fully 1n U.S. EPA (1987c).
6.3. MUTA6ENICITY
The genotoxldty data for chloral and chloral hydrate are presented In
Table 6-3. Both chloral and chloral hydrate have tested positive for
mutation In Salmonella typh1mur1um. both with and without activation
(Maskell. 1978; B1gnam1 et al.. 1980; Bruce and Neddie. 1979). Positive
results for mutation have also been reported for chloral hydrate (but not
chloral) 1n Streptomvces coellcolor. and both chloral and the hydrate have
tested positive for mutation 1n Asperglllus nldulans (B1gnam1 et al., 1980).
Studies of mutation and mltotlc gene conversion 1n Saccharomvces 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 1n several test .systems.
Aneuploldy tests In 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 In S. cerevlslae (Sora and
Carbone, 1987). In an in vivo study of chloral hydrate, an Increase 1n
nondlsjunctlon of sperm from mice treated by an Intraperltoneal Injection
has been reported (Russo et al., 1984). According to Russo et al. (1984),
who reviewed studies 1n grasshopper spermatocytes (R1s. 1949) and 1n
Pleurodeles wait!11 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 aclnar cells of the parotid gland from rats given a single
0085d -31- 03/10/88
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TABLE 6-3
Genotoxtctty of Chloral and Chloral Hydrate
o
o
in
°- Assay
Reverse
•utatlon
L»
1 Reverse and
forward
autatlon
Forward
autatlon
Reverse
autatlon,
altotlc gene
o conversion
Indicator
Organlsa
Salaonella
typhlaurlua
TA1535. TA1537
1A98. TA100
S. typhlaurlua
TA100. TA98.
TA1535. his 6
S. typhlaurlua
TA100. TA1S35
S. typhlaurlua
TA100. TA1535
Streptoayces
coellcolor
A3|2)
S. coellcolor
A3(2)
Asperglllus
nldullans 35
A. nldullans 35
Saccharoayces
cerevlslae 07
Coapound
and/or Purity
chloral hydrate
chloral hydrate/
recrys tall lied
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
iig/plate
10 ag/plate
0.25-1
vl/plate
US Bg/plate
10-40
nt/plate
2-10 ag/plate
1-20
nl/plate
1-10
ag/plate
5-20 «M
Activating Response
Systea
±S-9 t
»S-9 weakly {
In TA100.
- In TA98.
TA1535 and
his 6
»S-9 t In TA100
- In TA1535
»S-9 t In TA100
- In TA1535
none
none weakly *
none weakly »
none weakly »
tS-9 - autatlon
i gene con-
version
Coanent
NC
Chloral hydrate resulted
In 0.00145 revertants/aol
coapared with 0.06 rever-
tants/aol for the (O
control dlethyl sulfate
Number of revertants
greater without S-9
NC
NC
weakly «• 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
Blgnaat
et al.. 1980
Btgnaal
et al.. 1980
Blgnaal
et al.. 1980
Btgnaal
et al.. 1980
Blgnaal
et al.. 1980
Blgnaal
et al.. 1980
Broniettl
et al.. 1984
-------
TABJ.E 6-3 (cont.)
Assay
Reverse
autatlon,
•ttotlc gene
conversion
Induced
aneuploldy
Indicator
Organ 1 SB
J. cerevisiae 07
£• cerevisiae
A,, nldulans
dlplold
A., nldulans
35y17
Co-pound
and/or Purity
chloral hydrate
chloral hydrate/
99X
chloral hydrate
chloral hydrate/
99X
Application Concent rat ten
or Dose
host-Mediated 500 ag/kg
assay, alee were
treated orally
dissolved In l-?5 afl
sporulatlon
aedla
plate Incorpo- 0,001-0.04 H
ration
plate Incorpo- 5. 10 aM
ration
Activating Response Conaeni
Systea
NA - au tat Ion «• results were observed
» gene con- In the tester strain
version recovered froa the lungs
but not the liver or
kidney
none » Sporulatlon was Inhib-
ited and a net Increase
of dlplold and dt sonic
clones was observed
none » An Increased number of
haplolds was observed
none » Chloral hydrate Induced
haplotd and nondlsjunt-
Reference
Bronzettt
et al.. 1984
Sora and
Carbone. 1987
t
Singh and
Slnha. 1976
Crebelll
et al.. 1985
Sex-linked
recessive
lethal
Effects on
altosis In
basal cells
of tongue
and acinar
cells of
parotid gland
Nlcronucleus,
spera abnor-
aalitles
A. nldulans
Orosophila
aelanogaster
rats. 8 weeks
old
chloral hydrate/
lab grade
chloral hydrate/
99%
chloral hydrate
C57Bl/6y C3H/He
alee
chloral hydrate
•In liquid"
feeding
Injection
Injected
(specific route
not stated)
Intraperltoneal
Injections. S
dally doses
tlonal diplold somatic
segregants
5-40 an none » Chloral hydrate Induced Kflfer, 1986
polyploldy
5500 ppa NA equivocal * lethal In files fed Voon et al..
feeding. chloral hydrate was 1985
10.000 ppa - Injection 0.13 coapared with
0.04-0.05 In controls
and those Injected with
chloral hydrate
200 ag/kg NA - 3 rats/group (- control. Cassldy and
* control, treataent Boshell. 1980
group)
0-2500 ag/kg NA - Hlcronucleus studies Bruce and
were conducted 4 hours Heddle, 1979
after the last Injec-
tion; spera were exaa-
Ined 35 days after the
last Injection
-------
TABLE 6-3 (cont.)
00
in
a.
Assay
Indicator
Organise
CiMpound
and/or Purity
Application
Concentration
or Dose
Activating
System
Response
Coonent
Reference
Testlcular alee. 3-V
DMA synthesis
chloral hydrate oral
50 «g/kg
•Ice. ICR Swiss chloral hydrate Intratestlcular 10-900 *g/kg
Webster Injection
NA A decrease In ONA syn-
thesis was not observed
NA » at doses At 75 ag/kg. DMA syn-
>75 og/kg thesis was 30X of con-
trol; at 300 ng/kg. DMA
synthesis was 3X of
control
Seller. 1977
Borzelleca and
Carchnan. 1982
Nondtsjunc- alee (C57Bl/Cncx
tlon In sperm C3H/Cnc) fj
Nttotlc C57BLxC3HM
Index alee
chloral hydrate/
99X
chloral hydrate/
laboratory grade
Intraperttoneal 82.7, 165.4. NA
Injection 413.5 mg/kg
oral, single 5 or 10 *g/g NA
dose
f
* at each
dose and
cell stage -
the Index of
hyperhaploldy
was greater
than controls
Increased
•Itotlc
Index of
liver cells -
significantly
'Increased
only at 5 ng/g
Nice treated at high Russo et al..
dose remained under 1984
anesthesia for -5 hours;
•Ice sacrificed at 5.
12. 21 or 42 days after
treatment
Nilotic Indices were Rljhslnghanl
determined 24 hours et al.. 1986
after nice were treated
NA - Not applicable; NC - no c
C3
CO
eo
-------
Injection of chloral hydrate. An Increase In the mltotlc Index of liver
cells was observed In mice given a single oral dose of chloral hydrate
(R1Jhs1nghan1 et al., 1986).
6.4. TERATOGEHICITY
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/mi 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/mi groups, respectively. No effects were noted on
the total litter weight, number of pups delivered, gestation length, the
number of stillborn pups, gross pup malformations or maternal weight gain.
However, 1t 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 mg/ml perlnatally. Because the preweanlng mice had
access to the chloral hydrate containing drinking water. It 1s not clear 1f
the observed behavioral effect was a result of \n utero or postnatal
exposure. No effects on passive avoidance learning were observed at
0.06 mg/mi.
0085d -35- 03/10/88
-------
6.5. OTHER REPRODUCTIVE EFFECTS
Sperm abnormalities were not observed In groups of eight mice given 5
dally 1ntraper1toneal Injections of chloral hydrate at up to 2500 mg/kg
(Bruce and Meddle, 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 Initiated 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 30X of control values at
75 mg/kg and 3X 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
In which mice were provided with drinking water containing chloral at 0.07
or 0.7 rag/mi (Sanders et al., 1982; Kauffmann et al., 1982; Kallman et
al., 1984). The most sensitive endpolnt of toxlclty In male mice was liver
toxlclty (Sanders et al., 1982), while the most sensitive endpolnt In female
mice was Immunotoxldty (Kauffmann et al., 1982). Both effects were
observed at 0.07 mg/mi, a dose of 16 mg/kg/day In males and 18 mg/kg/day
In 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, eoslnophHla, 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 LD5Q of 479 mg/kg has been reported 1n 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 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 In 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 1n an Intratestlcular Injection study using mice
(Borzelleca and Carchman, 1982).
Chloral hydrate exposure did not result 1n any changes In litter
parameters or 1n any gross malformations 1n 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 1n 24-day-old mice. Because pups had access to the chloral hydrate
dosing solution, 1t Is not clear 1f the effect was a result of Jyn 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 ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the cardnogenlclty 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 In 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 v9/g.
8.1.3. Other Routes. In a 2-stage "Skin cardnogenlclty study, Roe and
Salaman (1955) found a nonsignificant Increase 1n skin tumors In 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 Is 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 Rljhslnghanl 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 In numbers of hepatic nodules and 2/3
carcinomas occurred much earlier than the two carcinomas In the control
group. Positive results In mutagenldty 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 cardnogenlclty of tHchloroethylene (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 1n male mice together with
Indications of genotoxlclty 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 cardnogenlcUy
study of chloral available Is the single dose study by Rljhslnghanl et al.
(1986). This study has too many limitations to support a reasonable
derivation of a carcinogenic potency estimate as discussed In Section
8.1.4. An examination of the Herren-Freund (1986) dose-response data In 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, Is
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 RfOs.
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/mi (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 SGOT and LDH activ-
ity were significantly Increased In 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/10* 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.
Kail roan et al. (1984) did not observe any effects on the behavior of
« . • • . • a « w .
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 In mice from dams treated at 204.8
mg/kg/day.
The results of these studies Indicate that the liver is the most sensi-
tive target of chloral toxldty In male mice, while the Immune system may be
the most sensitive endpolnt 1n female mice. Liver effects In male mice
provided with drinking water containing chloral hydrate at 0.07 mg chloral
hydrate/mi, resulted In the lowest LOAEL of 16 mg/kg/day. While Increases
0085d -42- 03/10/88
-------
In liver weight and associated Increases 1n enzyme activity are not
necessarily Indicative of an adverse effect, the absence of confirmatory
hlstopathologlcal data makes 1t 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 In mice exposed Vn 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. It 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 Is considered appropriate.
Confidence 1n this RfD 1s 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 In this RfD 1s low because It 1s 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 It
Is known that the metabolism of chloral 1n mice Is different from that In
humans.
0085d -43- 03/10/88
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
The toxldty 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 1n 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 Is not clear 1f 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 1n 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 1s
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 In adult animals at similar exposures. Higher CS values are
calculated from the 90-day drinking water study. The liver effects In male
mice (Sanders et al., 1982) and the Immune system effects In female mice
(Kauffmann et al., 1982) occurred at human MEDs of 8.8 and 87, respectively,
which correspond to RVds of 4.1 and 2.6. The liver effects 1n male mice
0085d -44- 01/29/88
-------
o
00
tn
Number Average
Sex at Start Height
(kg)
N 140 total 0.034°
H 11 0.031°
£
i
F 12 0.026°
F 5 0.03d
TABLE 9-1
Toxic 1 ty Summary for Chloral (>99* Purity) Administered
Transformed • Equivalent
Exposure Animal Dose Human Dose
(mg/kg/day) (mg/kg/day)
0.07 mg/t drinking 16C 1.26
water for 90 days
0.7 mg/t drinking 16QC 12.1
water for 90 days
0.07 mg/t drinking 173C 12.4
water for 90 days
0.60 mg/mt drinking 204. 8C 15.4
water 3 weeks before
mating through weaning
to Nice In Drinking Hater
Response
Increased liver weights. SCOT and
LOH. Increased hepatic mtcrosomal
amlnopyrlne N-demethylase and
aniline hydroxylase activity
Increased liver weights, and
Increases In serum SGOT and LDH,
Increased hepatic mlcrosoaal
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)
-------
00
in
TABLE 9-2
Composite Scores for Chloral from Oral Studies In Nice
1
1
0
V.
ro
Chronic
Animal Dose Human HED*
(mg/kg/day) (mg/day)
16 8.82*
160 85.4
18 87*
204.8 1078
*The dose was divided by an
.i
RVd Effect RVe CS RQ
4.1 Liver toxtclty -.Increased 4 16.4 1000
weight, enzyme Induction
2.6 Increases In serum SCOT 6 15.6 100
and LDH
2.6 Decrease In the number of 5 13 1000
antibody-forming rails
1 Behavioral changes In off- 7 7 1000
spring
uncertainty factor of 10 to approximate chronic exposure.
Reference
Sanders
et al..
Sanders
et al..
Kauffman
et al..
Kail roan
et al..
1982
1982
1982
1984
CD
oa
-------
correspond to an RV of 4, and the Immune system effects to an RV of
5. The severity of the liver effects was Increased at the high dose 1n male
mice at this dose level (160 mg/kg/day), the associates MED 1s 85.4. The
Increases In the serum enzymes SGUT and LON suggests cellular necrosis
resulting In an RV of 6. Mut1ply1ng by the RVd 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 liver effects 1n 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 1n Table 9-3.
9.2. BASED ON CARCINOGENICITY
Rljhslnghanl et al. (1986) found a dose-related significant Increase In
liver tumor Incidence In mice sacrificed 48-92 weeks after being given a
single gavage dose of chloral hydrate at 0, 5 or 10 yg/g. In a study by
Roe and Salaman (1955), a nonsignificant Increase In skin tumors In 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 In 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 trlchloroethylene (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 toxldty - decreased liver weight and enzyme
Induction
Reference: Sanders et a!., 1982
RVe: . . . ff : 4. f
Composite Score: 16.4
RQ: 1000
*Equ1va1ent human dose
0085d -48- 01/28/88
-------
Guidelines for Carcinogen Risk Assessment, the positive albeit less than
Ideal bloassay response 1n male mice together with Indications of
genotox1c1ty 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 LOU, which 1s assigned an RQ of 100.
0085d -49- 03/10/88
-------
10. REFERENCES
Adams, W.L. 1943. The comparative toxlclty 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, F1sh Ulldl. 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. Nutagenlclty of halo-
genated aliphatic hydrocarbons In Salmonella tvphlmurlum. Streptomyces
coellcolor and Asperqlllus nldulans. Chem. Blol. Interact. 30(1): 9-23.
Blostov, A.N., Y.S. Rotenberg and V.G. Mulentova. 1970. Toxlcologlcal
evaluation of chloral 1n the process of Us liberation during spraying and
pouring of polyurethane foams. Gig. Tr. Prof. Zabol. 14(16)L: 26-29.
(Cited In U.S. EPA. 1985a)
Borzelleca, J.F. and R.A. Carchman. 1982. 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 1n 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 Ijn vivo. Hutat. Res. 141(1):
19-22.
Bruce, U.R. and J.A. Meddle. 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 1n mice and the effect thereon of ethanol. J. Pharmacol. Exp.
Ther. 174(2): .260-275.
Carlberg, G.E., H. Orangsholt and N. GJos. 1986. Identification of chlori-
nated compounds 1n 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 J.L. Boshell. 1980. An In vivo study of the action of
chloral hydrate on mitosis. Anat. Rec. 196: 235.
CMR (Chemical Marketing Reporter). 1986. OPO 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 Asperglllus
nldulans. Mutat. Res. 155: 105-111.
Cross, J. and D. McMahon. 1976. Chloral hydrate causes breakdown of poly-
somes In Chlarovdomonas relnhardl 1n vivo. J. B1ol. Chera. 251(9): 2637-2643.
Elsenrelch, 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. McLoughlln and C.P. Steel. 1981.
Organic mlcropollutants 1n drinking water. TR-159. Hedmenham, Eng. Hater
Res. Cent. 47 p.
frelter, E.R..... 19,7.8.. Acetic,, acid derivatives (halogenated). In: Klrk-
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 LD5Q values 1n newborn and adult
animals. Toxlcol. Appl. Pharmacol. 18: 185-207.
Hansch, C. and A.J. Leo. 1985. MedChem Project Issue No. 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. Oilman, 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: H-15.
Herren-Freund, S.L., M.A. Pereura, G. Olsen and A.B. DeAngelo. 1986. The
carclnogenlclty of trlchloroethylene and Us metabolites (trlchloroacetlc
acid, dlchloroacetlc acid) 1n mouse Hver. 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
trlchloroethylene and Its metabolites 1n dogs. Toxlcol. Lett. 32: 119-122.
HSDB (Hazardous Substance Data Base). 1987a. Report No. 2557. National
Library of Medicine. On-Line. CAS No. 75-87-6.
HSDB (Hazardous Substance Data Base). 1987b. Report No. 222. National
Library of Medicine. On-L1ne. CAS No. 302-17-0.
Ikeda, M., Y. Mlyake, M. Ogata and S. Ohmorl. 1980. Metabolism of trl-
chloroethylene. Blochem. Pharmacol. 29: 2983-2992. (Cited 1n 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 toxldty using the Golden Orfe test. Z. Wasser
Abwasser Forsch. 11(5): 161-164.
Kifer, 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 toxlclty of
chloral 1n mice: an approach to evaluation. Neurobehav. Toxlcol. Teratol.
6(2): 137-146.
Kauffmann, B.H., K.L. White. Jr., V.H. 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.y. Garrison. F.R. Allen, et al. 1976. Identification of
organic compounds In drinking water from thirteen United States cities. Ln:
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: Identlf. Anal. Org. Pollut. Water, 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 In four species of
Chlamvdomonas (chlorophyta: volvocales). Symp. Soc. Exp. B1ol. 35: 421-437.
0085d -54- 03/10/88
-------
Luknltskll, F.I. 1975. The chemistry of chloral. Chero. Rev. 75(3):
259-289.
Lynian, H.J., W.F. Reehl and D.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. McGraw H111 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
ch1or1nat1pn 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 HI ley and
Sons, New York. p. 913.
MOller. G., M. Spassovskl and 0. Henschler. 1974. Metabolism of tMchloro-
ethylene In man. II. Pharmacok1net1cs of metabolites. Arch. Toxlcol.
32(4): 283-295.
0085d -55- 03/10/88
-------
Norwood, O.L., J.D. Johnson, R.F. Chrlstraan and D.S. M1111ngton. 1983.
Chlorlnatlon 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 In air.
Tokyo-TorHsu E1se1 Kenkyusho Kenkyu Nempo. 31: 238-243. (CA 95:85356e)
Pavlova, L.P. 1975. Tox1colog1cal characteristics of trlchloroacetalde-
hyde. Tr. Azerb. Nauchno-Issled. Inst. Gig. 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 H111. 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, H.A. Swerdlow, K.V. Rao and T. Ghose.
1986. Induction of neoplastlc lesions 1n the livers of C57BL x C3HF1 mice
by chloral hydrate. Cancer Detect Prev. 9(3-4): 279-288.
R1s, H. 1949. The anaphase movement of chromosomes In the spermatocytes of
the grasshopper. B1o1. Bull. 96: 90-106. (Cited In Russo et al.. 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 1n the mouse. Br. J. Cancer.
9: 177-203.
Rumack, B.H. and R.G. Peterson. 1980. Clinical toxicology. In.: Casarett
and Ooull's Toxicology, The Basic Science of Poisons, J. Doull, C.P.
Klaassen and M.O. Amdur, Ed. Hacmlllan Publishing Co., Inc., New York.
p. 677, 694..
Russo, A., F. Pacchlerottl and P. HetalH. 1984. Nondlsjunctlon Induced 1n
mouse spermatogenesls by chloral hydrate, a metabolite of trlchloroethylene.
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. HhHe, Jr. 1982. Toxicology of chloral
hydrate 1n the mouse. Environ. Health Perspect. 44: 173-146.
Sato, T., H. Mukalda. Y. Ose, H. Nagase and T. Ishlkawa. 1985. Hutagen-
1c1ty of chlorinated products from soil 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 1n the validation of a novel
short-term test. Mutat. Res. 46: 305-310.
Sellers, E.M., N. Lang, J. Koch-Messer, E. LeBlanc and H. Kalant. 1972.
Interactions of chloral hydrate and ethanol 1n man: I. Metabolism. Cl1n.
Pharmacol. Therap. 13: 37. (Cited 1n Sellers et al., 1978}
Sellers, E.M., H. Lang-Sellers and 0. Koch-Weser. 1978. Comparative
metabolism of chloral hydrate and trlclorfos. J. Clln. Pharmacol. 18:
457-461.
Senteln, P. and Y. Ated. 1974. Action de 1'hydrate de chloral sur les
mitoses de segmentation de 1'oeuf de Pleurodele. Etude cytologlque et
ultrastructurale. Chromosoma. 45: 215-244. (Cited In Russo et al., 1984)
*•„'., • "
Singh, N. and U. Slnha. 1976. Chloral hydrate Induced haploldlzatlon In
Asperqlllus nldulans. Exper1ent1a. 32: 1144-1145.
Sora, S. and N.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.3. 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
-------
Talbakoff, B., C. Vugrlndc, R. Anderson and S.G.A. A11v1satos. 1974.
Reduction chloral hydrate to trlchloroethanol \n brain extracts. Blochem.
Pharmacol. 23(2): 455-460.
Trehy, M.L., R.A. Yost and C.J. Miles. 1986. Chlorlnatlon byproducts of
amlno adds 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, CIO, U.S. EPA, Washington, OC.
U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Mater Criteria
Documents. Federal Register. 45:(231): 49347-49357.
U.S. EPA. 1982. Chemical Hazard Information Profile Draft Report: Tr1-
f • . - . •
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 Toxlclty Data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Haste and Emergency Response, Wash-
ington, DC.
U.S. EPA. 1985a. Health Assessment Document for Trlchloroethylene. 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. 1985b. 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 Carc1nogen1cUy In
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): 33992r34003.
U.S. EPA. 1987a. Graphical Exposure Modeling System (GENS). 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
THchloroethylene. EPA 600/8-82/006FA.
0085d -60- 03/10/88
-------
Haskell. L. 1978. A study of the mutagenldty of anesthetics and their
metabolites. Mutat. Res. 57(2): 141-153.
Wlndholz, H., 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. Ned. 0. 2: 960.
Yoon, J.S., J.M. Mason. R. Valencia. R.C. Woodruff and S. Z1mmer1ng. 1985.
Chemical mutagenesls testing 1n Drosophlla. IV. Results of 45 coded
compounds tested for the National Toxicology Program. Environ. Mutagen.
7(3): 349-367.
0085d -61- 03/10/88
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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 Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
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
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton. Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2B. John Wiley and
Sons, NY. p. 2879-3816.
Clayton, G.D. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed.. Vol. 2C. John Wiley and
Sons, NY. p. 3817-5112.
0085d -62- 03/10/88
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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. MHO, Lyons, France.
Jaber, H.M., M.R. Mabey. A.T. Lieu. T.M. 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 1n the Special Review
Program. Registration Standards Program and the Data Call 1n
Programs. Registration Standards and the Data Call In 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
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In addition, approximately 30 compendia of aquatic toxlclty 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 Toxlclty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior. Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
HcKee, 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
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eo
en
APPENDIX B
Summary Table.for Chloral
o
CJ
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 rog/mi In the
drinking water for
90 days
(16 rag/kg/day)
0.07 rag/ma In the
drinking water for
90 days
(16 mg/kg/day)
1000 pounds
100 pounds
Effect RfD or q-|* Reference
ID ID ID
ID ID ID
Increase In relative liver 1 mg/day Sanders
weights. Increase In serum et al.t
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
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