-------
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
-------
-------
EXECUTIVE SUMMARY
* ~ ' im
1-Chlorobutane (CAS number 109-69-3), 2-chlorobutane (CAS number
78-86-4) and t-butylchlorlde (CAS number 507-20-0) are colorless liquids at
room temperature (Hawley, 1981; Wlndholz, 1983). SRI (1987) Indicated that.
1-chlorobutane 1s currently produced by SmHhKllne Co., Palo Alto, CA, and
Union Carbide Co.. Institute, HV, and South Charleston, WV, and that
t-butylchlorlde 1s produced by Columbia Organlcs Chemical Co., Inc.,
Cassatt, SC, and United-Guardian Inc., Hauppauge, NY. Van (1986) lists
eight suppliers for 1-chlorobutane, two suppliers for 2-chlorobutane and
five suppliers for t-butylchlor1de. Available production data suggest that
1-chlorobutane and t-butylchlorlde are currently manufactured and Imported
In the United States and that 2-chlorobutane Is not currently manufactured,
but Is Imported 1n the United States. 1-Chlorobutane Is used as a solvent,
anthelmlntlc and butylatlng agent In organic synthesis. It Is also used 1n
chromatography, spectrophotometry and protein sequencing, and has potential
for use 1n polymerization of styrene (Hawley, 1981; Hlndholz, 1983; Platt
and Wallace, 1983; Kuney, 1986). 2-Chlorobutane Is used as an Intermediate
1n organic synthesis (Hawley, 1981). t-Butylchlor1de 1s used In the poly-
merization of high molecular weight polybutadlene and 1n organic synthesis
(Kuzma and Kelly, 1979; Olah and Meldar, 1980).
In the atmosphere, the monochlorobutanes are expected to react with
photochemlcally generated hydroxyl radicals. Hydroxyl reaction half-lives
of 7, 7 and 29 days have been estimated for 1-ch.lorobutane, 2-chlorobutane
and t-butylchloMde, respectively (Mill et al.. 1982; Atkinson, 1987).
Small amounts of 1- and 2-chlorobutane may be removed from the atmosphere by
wet deposition; however, any compound lost through this mechanism 1s likely
1v
-------
to reenter the atmosphere by volatilization. In water, t-butylchlorlde 1s
expected to undergo rapid chemical hydrolysis. At 25°C and neutral pH, the
hydrolytlc half-life for this compound lis estimated to be 23 seconds (Mabey
and Mill, 1978). The hydrolytlc half-life of 1- and 2-chlorobutane under
these same conditions 1s predicted to be -38 days (Jaber et al., 1984; Mabey
and Mill, 1978). The dominant removal process for 1- and 2-chlorobutane 1s
predicted to be volatilization. Using vapor pressure and water solubility
data and the method of Thomas (1982), the volatilization half-life for both
compounds from a model river 1 m deep, flowing 1 m/sec with a wind speed of
3 m/sec has been estimated to be 2.9 hours. Oxidation, photolysis, bloaccu-
mulatlon, mlcroblal degradation and adsorption to suspended solids and
•
sediments are not expected to be significant fate processes 1n water. In
moist soil, t-butylchlorlde 1s expected to chemically hydrolyze with a
half-life of <23 seconds. In moist soil, H appears that 1- and 2-chloro-
butane would be susceptible to chemical hydrolysis (half-life -38 days) and
volatilization. Oxidation of 1-chlorobutane 1n pure culture of the bacteria
Alcallgenes faecalls. Corynebacterlum sp. 7E1C, Adnetobacter sp. strain
GJ70 and Xanthobacter autotrophlcus GJ10 suggests that this compound would
also be susceptible to mlcroblal degradation In soil (Marlon and Malaney,
1963; Gerhold and Malaney. 1966; Janssen et al., 1985, 1987). 1-Butanol and
chloride Ion have been Identified as blodegradatlon products of 1-chloro-
butane (Janssen et al., 1985, 1987). Fairly rapid degradation 1s expected
to limit the Importance of leaching through soil. If released to dry soil,
the monochlorobutanes are expected to volatilize fairly rapidly.
Limited monitoring data are available for the monochlorobutanes. The
U.S. EPA STORET Data Base (U.S. EPA, 1988) contains no monitoring data for
2-chlorobutane or t-butylchlor1de. Gross analysis data for 1-chlorobutane
-------
from the U.S. EPA STORE! Data Base (U.S. EPA, 1988) Indicate that this
compound was found 1n water samples from one STORET sampling station at a
*rf " fc
concentration of 4 yg/l. 1-Chlorobutane and 2-chlorobutane have been
tentatively Identified as components of chlorinated leachate from a landfill
simulator used for the co-disposal of metal plating sludge and municipal
solid waste (Gould et al., 1983). In another study, 2-chlorobutane was
Identified 1n the gas stream generated from landfill simulators (Vogt and
Walsh, 1985).
Pertinent data regarding the effects of acute or chronic exposure of
aquatic organisms to monochlorobutanes or the effects of exposure of aquatic
plants to monochlorobutanes were not located In the available literature
*
dted 1n Appendix A.
Pertinent data regarding the pharmacoklnetlcs of 1- or 2-chlorobutane or
t-butylchlor1de were not located 1n the available literature cited In
Appendix A.
In a 14-day dose range-finding study of 1-chlorobutane, rats and mice
were treated by gavage with 1-chlorobutane 1n corn oil at doses of 0, 190,
380, 750, 1500 or 3000 mg/kg (NTP, 1986). Mortality occurred In rats and
mice at doses of >750 and >1500 mg/kg, respectively. Agresslveness, hyper-
activity, bloody discharge from the nose and mouth, and brain hemorrhages
occurred 1n rats at doses of >750 mg/kg. In mice, hyperactlvlty occurred at
3000 mg/kg.
In another dose range-finding study, rats were treated by gavage with 0,
30, 60, 120 or 500 mg/kg 1-chlorobutane for 13 weeks (NTP, 1986). Reduced
weight gain, at least 10X below control rats, occurred among males and
females at 250-500 mg/kg and at 500 mg/kg, respectively. Reduced survival
and splenic extramedullary hematopolesls occurred In males 1n the 500 mg/kg
group. Convulsions and hyperactlvlty occurred 1n male and female rats 1n
v1
-------
the 250 and 500 mg/kg groups. In another dose range-finding 'study sponsored
by the NTP (1986), mice were treated by gavage with 0. 60, 120, 500 or 1000
- ~ ~ •»
mg/kg 1-chlorobutane for 13 weeks. Convulsions and mortality occurred 1n
males and females at 1000 mg/kg.
In a chronic study, the carcinogenic potential of 1-chlorobutane was
examined 1n rats treated by gavage with 1-chlorobutane at doses of 0, 60 or
120 mg/kg for 103 weeks (NTP, 1986). Although some tumors occurred, they
were not considered to be compound-related. The authors concluded that
under the conditions of this study 1-chlorobutane was not carcinogenic.
Nonneoplastlc effects of 1-chlorobutane In rats Included hyperact1v1ty,
tremors and convulsions at 60 and 120 mg/kg and decreased weight gain,
cytoplasmlc vacuollzatlon of the adrenal cortex, nephropathy, alveolar and
brain hemorrhage, hemoslderosls and reduced survival at 120 mg/kg.
In another chronic study, mice were given gavage doses of 1-chlorobutane
at 0, 25, 500 or 1000 mg/kg for 103 weeks to assess the carcinogenic poten-
tial of 1-chlorobutane (NTP, 1986). Although some tumors occurred, they
were not considered to be compound-related. The authors concluded that
under the conditions of this study, there 1s no evidence of cardnogenldty
for 1-chlorobutane. Nonneoplastlc effects that occurred In mice at 1000
mg/kg Include the following: hyperact1v1ty, convulsions and tremors 1n
female mice; brain and lung hemorrhages 1n female mice; and decreased
survival 1n male and female mice.
In a study reported by Rudnev et al. (1979) and by Tomashevskaya and
Zholdakova (1979), 1-chlorobutane was given to rats 1n oral doses of 0,
0.02, 0.2 or 2 mg/kg for 6 months. The activities of blood alkaline
phosphatase. chollnesterase and sucdnate dehydrogenase were altered and
blood levels of Inorganic phosphate were Increased 1n rats given 2 mg/kg
1-chlorobutane.
-------
In a study reported by Vlnogradov (1979) and Riidnev et al. (1979), rats
were dosed orally with 1-chlorobutane at 0, 0.00022, 0.0022, 0.022 or 110
• -f "•
mg/kg for 30 days. Antibodies against hepatic tissues were present In rats
given doses >0.0022 mg/kg. After 30 days, an autoimmune response and an
Increase of basophU degranulatlon of the peripheral blood occurred 1n the
0.0022-110 mg/kg groups.
Wright and Schaffer (1932) observed liver and kidney lesions In dogs
given single oral doses of 0.1-10.0 cc/kg (87.5-8750 mg/kg) of 1-chloro-
butane and 0.1-0.5 cc/kg (87-435 mg/kg) of 2-chlorobutane. Gastrointestinal
Irritation was also observed In dogs given 2-chlorobutane; the effects
associated with 2-chlorobutane administration were more severe than those
associated with 1-chlorobutane. These compounds were given to parasite-
Infested dogs to assess their effectiveness as vermifuge agents. The
effects noted In dogs treated with 1-chlorobutane may not have been due to
the compound, because similar effects were also seen In controls.
Oral LD50s of 2670 mg/kg In female rats and Inhalation LC5Qs of 8000
ppm for 4 hours 1n rats have been reported for 1-chlorobutane (Smyth et al.,
1954). Tomashevskaya and Zholdakova (1979) determined LD5Q values
(unspecified route of administration) for 1-chlorobutane 1n mice, rats and
guinea pigs of 5600, 2200 and 8000 mg/kg, respectively; Rudnev et al. (1979)
reported Identical results for oral administration to rats and mice. A
dermal LD5Q of >20 rot/kg (>17,500 mg/kg) In rabbits was reported by
Smyth et al. (1954). Smyth et al. (1969) reported an oral LD5Q for
2-chlorobutane of 20 ml/kg (17,400 mg/kg) 1n rats, a dermal LD,. of 20
ml/kg (17,400 mg/kg) In rabbits and a LC5Q of 8000 ppm for 4 hours In
rats. Smyth et al. (1969) also reported necrosis of eyes and skin of
rabbits after contact with 2-chlorobutane. Eye and skin necrosis 1n rabbits
-------
and dermal Inflammation leading to ulcers and necrosis (species not
reported) have also been reported after skin and eye contact with 1-chloro-
butane (Rudnev'e~t al., 1979; Smyth et al., 1954).
The difference between the oral L050s of 2- and 1-chlorobutane suggest
that 2-chlorobutane Is more toxic than 1-chlorobutane; however, Inhalation
LD50s suggest the two compounds have comparable toxic potency. Also,
Po1r1er et al. (1975) reported the MTDs of 1- and 2-chlorobutane to be 65
and 35 mm/kg, respectively, 1n mice treated 1ntraper1toneally.
Mutagenlc effects of 1- and 2-chlorobutane and t-butylchloMde have been
studied 1n Salmonella and £. coll assays, and In bone marrow cells of rats
(Eder et al., 1980, 1982a.b; Barber et al., 1981; Barber and Donlsh, 1982;
Zelger, 1987; Zelger et al., 1987; Fluck et al., 1976; Simmon, 1981; Rudnev
et al., 1979). All of the data, except that from the reverse mutation
Salmonella studies by Simmon (1981), Indicate that 1-chlorobutane 1s non-
mutagenlc. Simmon (1981) also provided evidence 1n this assay suggesting
that 2-chlorobutane and t-butylchlor1de are mutagenlc.
Developmental effects have been reported 1n rats given oral doses of 733
mg/kg 1-chlorobutane on gestation days 1-19 (Rudnev et al., 1979; Leonskaya,
1980). Effects Included Internal hemorrhaglng 1n fetuses, Increased
embryonic mortality among the fetuses of treated dams and Increased
embryonic mortality among the fetuses of untreated dams from the second
generation of treated dams.
Cardnogenlclty data on monochlorobutanes are limited to an oral 2-year
study of 1-chlorobutane In rats and mice (NTP, 1986) and a Strain A mouse
pulmonary tumor response assay of 1- and 2-chlorobutane and t-butylchloMde
(Po1r1er et al., 1975). No evidence of carcinogenic response was found In
either study for 1-chlorobutane. However, 1-Chlorobutane Is classified as a
1x
-------
Group D compound because the data base Is considered "Inadequate" due to
deficiencies of the 2-year NTP study. 2-Chlorobutane and t-butylchlorlde
each, produced a positive tumorlgenlc response 1n the Strain A mouse
pulmonary tumor response assay; however, they are also classified as Group D
compounds: not classifiable as human carcinogens.
In a 13-week study 1n which rats were given gavage doses of 0, 30, 60,
120, 250 or 500 mg/kg 1-chlorobutane 5 days/week (NTP, 1986), convulsions
and hyperactlvlty occurred 1n males and females and reduced body weight gain
>10% below controls occurred 1n males at 250 mg/kg; this dose represents the
subchronlc LOAEL for 1-chlorobutane. No adverse effects were observed 1n
males or females at <120 mg/kg, which represents the subchronlc NOAEL for
1-chlorobutane. The corresponding oral RfD Is 0.86 mg/kg/day (l'mg/kg/day),
or 60 mg/day for a 70 kg human.
Compound-related mortality associated with hyperactlvlty, tremors and
convulsions occurred at 120 mg/kg 1n a 2-year study 1n which rats received
gavage doses of 0, 60 or 120 mg/kg on 5 days/week (NTP, 1986). No adverse
effects were observed In males and females at doses <60 mg/kg. Dose levels
representing the chronic LOAEL and NOAEL for 1-chlorobutane are 120 and 60
mg/kg, respectively. The corresponding oral RfD 1s 0.43 mg/kg/day (0.4
mg/kg/day), or 30 mg/kg/day for a 70 kg human.
A toxldty based RQ for 1-chlorobutane of 1000 was derived from the
observation of reduced survival 1n rats given gavage doses of 120 mg/kg/day
1-chlorobutane for 103 weeks (NTP. 1986).
-------
TABLE OF CONTENTS
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 1
1.4. USE DATA 4
1.5. SUMMARY 4
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. Hydrolysis ' 7
2.2.2. Oxidation 7
2.2.3. Photolysis. . • 8
2.2.4. MUroblal Degradation 8
2.2.5. Adsorption 8
2.2.6. B1oaccumulat1on . . 8
2.2.7. Volatilization 9
2.3. SOIL : . . . 9
2.3.1. Chemical Degradation. 9
2.3.2. Leaching 9*
2.3.3. Volatilization 10
2.4. SUMMARY. . 10
3. EXPOSURE 12
4. AQUATIC TOXICITY. . . 13
5. PHARMACOKINETCS 14
6. EFFECTS 15
6.1. SYSTEMIC TOXICITY . .' 15
6.1.1. Inhalation Exposure 15
6.1.2. Oral Exposure 15
6.1.3. Other Relevant Information 19
x1
-------
TABLE OF CONTENTS (cont.)
6.2.
6.3.
6.4.
6.5.
6.6.
CA'RCINOGENICITY
6.2.1. Inhalation
6.2.2. Oral
6.2.3. Other Relevant Information
MUTAGENICITY
TERATOGENICITY
OTHER REPRODUCTIVE EFFECTS
SUMMARY
EXISTING GUIDELINES AND STANDARDS
7.1.
7.2.
RISK
8.1.
8.2.
HUMAN
AQUATIC
ASSESSMENT
CARCINOGENICITY '.
8.1.1. Inhalation . . .
8.1.2. Oral
8.1.3. Other Routes .
8.1.4. Weight of Evidence.
8.1.5. Quantitative Risk Estimates
SYSTEMIC TOXICITY.
8.2.1. Inhalation Exposure . . .
8.2.2. Oral Exposure . . >
Page
23
23
23
26
27
..... 29
29
29
33
33
33
34
34
34
34
34
34
35
35
. . » ' '. . 35
35
9. REPORTABLE QUANTITIES ...... ........ . ....... 39
9.1. BASED ON SYSTEMIC TOXICITY ..... . .......... 39
9.2. BASED ON CARCINOGENICITY ................. 39
10. REFERENCES .......... .................. 43
APPENDIX A: LITERATURE SEARCHED .................... 52
APPENDIX B: SUMMARY TABLE FOR MONOCHLOROBUTANES ............ 55
-------
LIST OF TABLES
No. Title Page
1-1 Synonyms, Structure and CAS Registry Numbers of
Selected Monochlorobutanes 2
1-2 Some Physical Properties of Selected Monochlorobutanes. ... 3
6-1 Oral L05Q Values for 1- and 2-Chlorobutane 21
6-2 Inhalation Lethal Concentration Summary for 1- and
2-Chlorobutane Using the Rat 22
6-3 MutagenlcHy Data for Monochlorobutanes 28
9-1 Oral Toxlclty Summary for 1-Chlorobutane 40
9-2 1-Chlorobutane: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 41
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LIST OF ABBREVIATIONS
BCF .__._ B1oconcentrat1on factor
CAS Chemical Abstract Service
COD Chemical oxygen demand
CS Composite score
OOC Dissolved organic carbon
DNA Deoxyr1bonude1c add
Koc Soil sorptlon coefficient standardized
with respect to organic carbon
Kow Octanol/water partition coefficient
LC5Q Concentration lethal to 50% of recipients
LD50 Dose lethal to 50% of Recipients
MED Minimum effective dose
MTD Maximum tolerated dose
WOAEL No-observed-adverse-effect level
ppm Parts per million
RfD Reference dose .
RQ Reportable quantity
RV
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
* rf " •• .
The synonyms, structures and CAS Registry numbers for the three mono-
chlorobutane Isomers are provided In Table 1-1. Each of the monochloro-
butanes have a molecular weight of 92.57 and an empirical formula of
C4H9C1.
1.2. PHYSICAL AND CHEMICAL PROPERTIES
The selected monochlorobutanes are colorless liquids at room temperature
that are mlsdble with alcohol and ether {Hawley, 1981; Wlndholz, 1983).
2-Chlorobutane 1s reported to have a pleasant ethereal odor (Wlndholz,
1983). Selected physical properties are listed 1n Table 1-2.
1.3. PRODUCTION DATA
1-Chlorobutane 1s prepared from butyl alcohol by heating with hydro-
chloric add and anhydrous zinc dlchloMde. and 2-chlorobutane 1s prepared
from sec-butyl alcohol by heating with hydrochloric acid and anhydrous zinc
dlchloMde (Wlndholz, 1983). t-ButylchloMde 1s prepared by shaking t-butyl
alcohol with concentrated hydrochloric add and then distilling (Wlndholz,
1983). SRI (1987) lists no manufacturers for 2-chlorobutane, but lists the
following manufacturers for the other monochlorobutane Isomers:
1-Chlorobutane: SmlthKllne Beckman Corp., Palo Alto, CA
Union Carb'lde, Institute, WV
Union Carb'lde, South Charleston, WV
t-Butylchlor1de: Columbia OrganVcs, Cassatt, SC
United-Guardian, Hauppauge, NY
Van (1986) listed the following companies as suppliers of monochlorobutanes:
1-chlorobutane - Aldrlch Chemical, Austin Chemical, Chemical Dynamics, F1lo
Chemical. Nachem, P-S Chemicals, Union Carbide, VaHchem Products; 2-chloro-
butane - Fllo Chemical, Wall Chemical; t-butylchlorlde - Aldrlch Chemical,
0120d -1- 05/27/88
-------
to
o
o.
TABLE 1-1
Synonyns. Structure and GAS Registry Numbers of Selected Honochlorobutanes
Compound
Synonyms*
Structure
CAS Registry Number
1-Chlorobutane
2-Chlorobutane
t-Butylchlorlde
n-butylchlortde;
n-propylcarblnyl chloride;
butyl chloride
sec-butylchlorlde;
2-chloro-3-roethylpropane
2-chloro-2-methylpropane;
2-chlorolsobutane;
trtmethylchlororoethane
C1-CH2-CH2-CH2-CH3
Cl
I
CH3-CH-CH2-CH3
CH3 '
I
CH3-C-C1
CH3
109-69-3
78-86-4
507-20-0
*U1ndholz, 1983
o
\
rv>
CD
CD
-------
o
o
I
CO
i
TABLE 1-2
Some Physical Properties of Selected Honochlorobutanes
Property
1-Chlorobutane
2-Chlorobutane
t-Butylchlorlde
Melting point. *C
Boiling point. *C
Vapor pressure
Water solubility
Log Kow
Density
Flashpoint (closed cup). °C
Air conversion factors at 20°C
-123. la
78.43a
80 on Hg (20°C)b
102 ran Hg (25'C)a
1100 rog/i (20°C)a
0.885? {20°C)a
-28a
1 ppm = 0.26 rog/m»
1 mg/n* = 3.848 ppm
-113.3 (racen»1c)a
-140.5 (active)3
68.25 (act1ve)a
151.6 ran Hga (25°C)
1000 rog/l (25°C)a
2.52e
0.8732 (raceralc. 2Q°C)a
0.8950 (active. 0°)a
-29a
•
1 ppro =0.26 mg/ma
1 rag/ra8 = 3.848 ppro
-25.4a
50.7a
294.8 mm Hg (25°C)a
930 rag/l (25°C)C
2.39e
0.8420 (20°C)a
-5a
1 ppm =0.26 mg/ma
1 mg/m3 = 3.848 ppm
aR1dd1ck et al.. 1986
*>Boubl1ck et al.. 1984
CU.S. EPA. 1987a
dHansch and Leo. 1985
eU.S. EPA. 1987b
CD
00
-------
Eastern Chemical, F1lo Chemical, H. Shattuck Chemical, Wall Chemical. It
can be Inferred from this Information that 1-chlorobutane and t-butyl-
chloHde are currently manufactured and Imported In the United States and
that 2-chlorobutane 1s not currently manufactured 1n the United States, but
1s Imported. Importation and production data for recent years were not
located In the available literature cited 1n Appendix A.
1.4. USE DATA
1-Chlorobutane 1s used as a solvent, anthelm1nt1c and butylatlng agent
In organic synthesis, e.g., In the manufacture of butyl cellulose. It Is
used 1n chromatography, spectrophotometry and protein sequencing, and has
potential for use In the polymerization of styrene (Hawley, 1981; Ulndholz,
1983; Platt and Wallace, 1983; Kuney, 1986). 2-Chlorobutane Is used as an
Intermediate 1n organic synthesis (Hawley, 1981). t-ButylchloMde 1s used
1n the polymerization of high molecular weight polybutadlene and In organic
synthesis (Kuzma and Kelly, 1979; Olah and Meldar, 1980).
1.5. SUMMARY
1-Chlorobutane -(CAS number 109-69-3). 2-chlorobutane (CAS number
78.86-4} and t-butylchlor1de (CAS number 507-20-0) are colorless liquids at
room temperature (Hawley, 1981; Wlndholz. 1983). SRI (1987) Indicated that
1-chlorobutane Is currently produced by SmlthKHne Co., Palo Alto, CA, and
Union Carbide Co., Institute, WV, and South Charleston, WV, and that
t-butylchlorlde 1s produced by Columbia Organic Chemical Co., Inc., Cassatt.
SC, and United-Guardian Inc., Hauppauge, NY. Van (1986) lists eight
suppliers for 1-chlorobutane, two suppliers for 2-chlorobutane and five
suppliers for t-butylchlorlde. Available production data suggest that
1-chlorobutane and t-butylchloMde are currently manufactured and Imported
In the United States and that 2-chlorobutane Is not currently manufactured,
0120d -4- 07/20/88
-------
but Is Imported In the United States. Chlorobutane Is used as a solvent,
anthelmlntic and butylatlng agent In organic synthesis. It 1s also used 1n
- w - ^
chromatography, spectrophotometry and protein sequencing, and has potential
for use 1n polymerization of styrene (Hawley, 1981; Wlndholz, 1983; Platt
and Wallace, 1983; Kuney, 1986). 2-Chlorobutane Is used as an Intermediate
1n organic synthesis (Hawley, 1981). t-ButylchloHde 1s used In the poly-
merization of high molecular weight polybutadlene and In organic synthesis
(Kuzma and Kelly. 1979; Olah and Meldar, 1980).
01?0d -S- 07/20/88
-------
2. ENVIRONMENTAL FATE AND TRANSPORT
2.1. AIR
Because of their relatively high vapor pressures (ranging from 102-298
mm Hg at 25°C), the monochlorobutanes are expected to exist almost entirely
In the vapor phase 1n the atmosphere (E1senre1ch et al., 1981).
2.1.1. Reaction with Hydroxyl Radicals. The rate constant for reaction
of 2-chlorobutane with photochemlcally generated hydroxyl radicals In air
was experimentally determined to be 2.3xlO"12 cm3-molecule/sec at 25°C
(Mill et al., 1982). Given an average ambient hydroxyl radical concentra-
tion of 5.0x10* molecules/cm3 (Atkinson, 1987), the reaction half-life
for 2-chlorobutane was estimated to be 7 days. Using the method of Atkinson
•
(1987), the rate constant and half-life for reaction of 1-chlorobutane with
photochemlcally generated hydroxyl radicals 1n the atmosphere was also
estimated to be 7 days. Using the same method, the rate constant for
reaction of t-butylchlor1de with photochemlcally generated hydroxyl radicals
1n the atmosphere was estimated to be 5.6xlO~13 cm3/molecule-sec at
25°C, which corresponds to a half-life of 29 days.
2.1.2. Reaction with Ozone. The monochlorobutanes are not susceptible to
reaction with ozone molecules Tn the atmosphere (U.S. EPA, 1987c).
2.1.3. Physical Removal Processes. Based on the water solubility data
provided In Table 1-2, It appears that small amounts of 1- and 2-chloro-
butane may be removed from the atmosphere by wet deposition; however, any
compound lost through washout 1s likely to reenter the atmosphere by
volatilization. The significance of physical removal of t-butylchlor1de
from the atmosphere cannot be predicted from the available Information.
0120d -6- 05/27/88
-------
2.2. HATER
2.2.1. Hydrolysis. The half-life for chemical hydrolysis of t-butyl-
• -^ *»
chloride at 25°C and neutral pH was estimated to be 23 seconds based on a
reaction rate constant of 3.02xlO'2 sec'* (Mabey and Mill, 1978).
Experimental data regarding chemical hydrolysis of 1- and 2-chlorobutane
were not located In the available literature; however, the hydrolytlc
half-life for these compounds 1s expected to be analogous to that of ethyl
chloride, which 1s structurally slmHlar to these compounds (Jaber et al.,
1984). The reaction rate constant for chemical hydrolysis of ethylchloMde
at 25°C and neutral pH has been measured to be 2.1xlO~7 sec'1, which
corresponds to a hydrolytlc half-life of 38 days (Mabey and Mill, 1978).
•
2.2.2. Oxidation. The rate constant for the reaction of 1-chlorobutane
with photochemically generated hydroxyl radicals 1n water was experimentally
determined to be 3x10" i/mol-sec (Zepp et al., 1987). Assuming an average
ambient hydroxyl radical concentration of ~10~17 mol/i near the surface
of natural sunlit water, the reaction half-life for 1-chlorobutane was
estimated to be -1 year (Mill et al., 1980). This value suggests that under
typical conditions reaction with photochemlcally generated hydroxyl radicals
would not be an Important fate process. Even Vn situations where the
hydroxyl radical concentration 1s relatively high (during summer In shallow.
clear water bodies, especially streams or ponds with Inputs from ground-
waters or other sources with high ratios of nitrate to DOC), reaction with
photochemically generated hydroxyl radicals 1s not expected to be an
Important fate process because of the rapid loss of 1- and 2-chlorobutane by
/
volatilization.
0120d -7- 07/20/88
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2.2.3. Photolysis. Photolysis of the monochlorobutanes Is not expected
to be an environmentally relevant fate process because these compounds have
••"""»
no chromophores that would absorb UV light 1n the environmentally signifi-
cant range (\ >290 nm) (Jaber et al., 1984).
2.2.4. N1crob1al Degradation. Incubation of 1- and 2-chlorobutane, at an
Initial concentration equivalent to 2.5 mg/i COD, 1n an activated sludge
Inoculum under aerobic conditions resulted 1n 9.6 and 4.8X COD removal,
respectively. In 1.4 days (Okey and Bogan, 1965). Pure cultures of the
bacteria Alcallqenes faecal Is. Corynebacterlum sp. 7E1C, Adnetobacter sp.
strain GJ70 and Xanthobacter autotrophlcus GJ10 were found capable of
oxidizing 1-chlorobutane (Marlon and Halaney, 1963; Gerhold and Malaney,
•
1966; Janssen et al., 1985, 1987). Adnetobacter and X. autotrophlcus
degraded 1-chlorobutane to 1-butanol and chloride 1on (Janssen et al., 1985,
1987).
2.2.5. Adsorption. Rapid chemical hydrolysis of t-butylchlorlde suggests
that this compound would not persist long enough In water for adsorption to
suspended solids and sediments to be a significant fate process. Estimated
K values of 102 and 107 for 1- and 2-chlorobutane, respectively, suggest
that adsorption to supended solids and sediments would not be an Important
fate process (Section 2.3.2.).
2.2.6. B1oaccumu1at1on. Rapid chemical hydrolysis of t-butylchloMde
under environmental conditions suggests that this compound would not persist
long enough In water to bloaccumulate In aquatic organisms. Based on the
water solubilities listed 1n Table 1-2, BCFs of 12 and 13 were estimated for
1- and 2-chlorobutane, respectively, using the following equation (Bysshe,
1982): log BCF = 2.791 - 0.564 log S. These BCF values suggest that 1- and
2-chlorobutane would not bloaccumulate significantly 1n aquatic organisms.
0120d -8- 05/27/88
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2.2.7. Volatilization. Rapid chemical hydrolysis of t-butylchlorlde
under environmental conditions suggests that this compound would not persist
• ~ ' •>
long enough In water for volatilization to be a significant fate process.
Henry's Law. constants of 8.9xlO~3 atm-mVmol at 20°C for 1-chlorobutane
and 1.9xlO~a atm-mVmol at 25°C for 2-chlorobutane were estimated using
the water solubility and vapor pressure data provided In Table 1-2. These
values of Henry's Law constant Indicate that these compounds are extremely
volatile and should evaporate rapidly from all bodies of water (Thomas.
1982). Using these Henry's Law constant values and the method of Thomas
(1982) the volatilization half-life from a model river 1 m deep, flowing 1
m/sec with a wind speed of 3 m/sec was estimated to be 2.9 hours for both
•
1- and 2-chlorobutane.
2.3. SOIL
2.3.1. Chemical Degradation. The monochlorobutanes are expected to
chemically hydrolyze In moist soil at rates that are equal to or greater
than those found 1n water. Based on Information available regarding
chemical degradation of the monochlorobutanes In water, t-butylchlor1de 1s
expected to have a hydrolytlc half-life of <23 seconds at neutral pH; the
hydrolytlc half-life of 1- and 2-chlorobutane 1s expected to be -38 days at
neutral pH (see Section 2.2.1.).
2.3.2. Leaching. Rapid chemical hydrolysis of t-butylchlorlde under
environmental conditions suggests that this compound would not persist long
enough 1n soil for significant leaching to occur. Based on the water
solubilities listed In Table 1-2, KQC values of 102 and 107 have been
estimated for 1- and 2-chlorobutane, respectively, using the following
equation (Lyman et al., 1982): log KQC » -0.557 log S * 4.277 where S 1s
1n ymol/i. These K values suggest that these compounds would be
0120d -9- 07/20/88
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highly mobile In soil (Swann et al., 1983); however, fairly rapid degrada-
tion 1s expected to limit the significance of leaching.
••*•"•
2.3.3. Volatilization. The relatively high vapor pressures of the
monochlorobutanes (ranging from 102-298 mm Hg at 25°C) suggest that these
compounds would volatilize fairly rapidly from dry soil surfaces. Evapora-
tion of 1- and 2-chlorobutane from moist soils may also be significant since
these compounds do not tend to adsorb to soil and appear to evaporate
rapidly from water (see Sections 2.2.7. and 2.3.2.).
2.4. SUMMARY
In the atmosphere, the monochlorobutanes are expected to react with
photochemically generated hydroxyl radicals. Hydroxyl reaction half-lives
•
of 7, 7 and 29 days have been estimated for 1-chlorobutane, 2-chlorobutane
and t-butylchloMde, respectively (Mill et al., 1982; Atkinson, 1987).
Small amounts of 1- and 2-chlorobutane may be removed from the atmosphere by
wet deposition; however, any compound lost through this mechanism 1s likely
to reenter the atmosphere by volatilization. In water, t-butylchlor1de 1s
expected to undergo rapid chemical hydrolysis. At 25°C and neutral pH, the
hydrolytlc half-life for this compound 1s estimated to be 23 seconds (Mabey
and Mill, 1978). The hydrolytlc half-life of 1- and 2-chlorobutane under
these same conditions 1s predicted to be ~38 days (Jaber et al., 1984; Mabey
and Mill, 1978). The dominant removal process for 1- and 2-chlorobutane 1s
predicted to be volatilization. Using vapor pressure and water solubility
data and the method of Thomas (1982). the volatilization half-life for both
compounds frooi a model river 1 m deep, flowing 1 m/sec with a wind speed of
3 m/sec has been estimated to be 2.9 hours. Oxidation, photolysis,
bloaccumulatlon, microblal degradation and adsorption to suspended solids
and sediments are not expected to be significant fate processes 1n water.
0120d -10- 07/20/88
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In moist soil, t-butylchlorlde Is expected to chemically hydrolyze with a
half-life of <23 seconds. In moist soil, H appears that 1- and 2-chloro-
• ~ " «»
butane would be susceptible to chemical hydrolysis (half-life -38 days) and
volatilization. Oxidation of 1-chlorobutane 1n pure culture of the
bacteria AlcaHgenes faecalls. Corynebacterlum sp. 7E1C, Adnetobacter sp.
strain GJ70 and Xanthobacter autotrophlcus GJ10 suggests that this compound
would also be susceptible to mlcroblal degradation 1n soil (Marlon and
Malaney, 1963; Gerhold and Malaney, 1!366; Janssen et al., 1985, 1987).
1-Butanol and chloride 1on have been Identified as blodegradatlon products
of 1-chlorobutane (Janssen et al., 1985, 1987). Fairly rapid degradation Is
expected to limit the Importance of leaching through soil. If released to
*
dry soil, the monochlorobutanes are expected to volatilize fairly rapidly.
0120d -11- 05/27/88
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3. EXPOSURE
- •*" "^
Limited monitoring data are available for the monochlorobutanes. The
U.S. EPA STORE! Data Base (U.S. EPA, 1988) contains no monitoring data for
2-chlorobutane or t-butylchlor1de. Gross analysis data for 1-chlorobutane
from the U.S. EPA STORET Data Base (U.S. EPA, 1988) Indicate that this
compound was found 1n water samples from one STORET sampling station at a
concentration of 4 pg/1. 1-Chlorobutane and 2-chlorobutane have been
tentatively Identified as components of chlorinated leachate from a landfill
simulator used for the co-disposal of metal plating sludge and municipal
solid waste (Gould et al., 1983). In another study, 2-chlorobutane was
•
Identified 1n the gas stream generated from landfill simulators (Vogt and
Walsh, 1985).
0120d -12- 05/27/88
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4. AQUATIC TOXICITY
Pertinent data regarding the effects of acute or chronic exposure of
aquatic organisms to monochlorobutanes or the effects of exposure of aquatic
plants to monochlorobutanes were not located 1n the available literature
cited 1n Appendix A.
0120d -13- 05/27/88
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5. PHARMACOKINETICS
Pertinent data regarding the pharmacoklnetlcs of 1- or 2-chlorobutane or
t-butylchloMde were not located 1n the available literature cited 1n
Appendix A.
0120d -14- 05/27/88
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
• •*" " •»
6.1.1. Inhalation Exposure. Pertinent data regarding systemic toxldty
from Inhalation exposure to monochlorobutanes were not located In the
available literature cited In Appendix A.
6.1.2. Oral Exposure.
6.1.2.1. SUBCHRONIC EXPOSURE — In a dose range-finding study
sponsored by the NTP (1986), groups of 10 male and 10 female B6C3F1 mice
were given 0, 60, 120, 250, 500 or 1000 mg/kg of 1-chlorobutane and 10 male
and 10 female F344/N rats were given 0, 30, 60, 120, 250 or 500 mg/kg of
1-chlorobutane. Each group was treated by gavage with pure 1-chlorobutane
(99.5%) In corn oil, 5 days/week for 13 weeks. Animals were weighed weekly,
and extensive hlstologlcal examinations were performed.
A number of gavage accidents occurred during the studies using mice (two
vehicle control females, a male and female In the 60 mg/kg groups, a female
In the 120 mg/kg group and .two females In the 1000 mg/k-g group). In the
1000 mg/kg group, convulsions and death occurred In two female mice. No
other compound-related clinical signs of" hlstopathologlcal effects were
reported for mice. In rats, 6/10 males 1n the 500 mg/kg group died
prematurely and three deaths were due to gavage accidents. Survival was
100% 1n all other groups of rats. A dose-related decrease 1n weight gain
occurred 1n male and female rats; males 1n the 250 and 500 mg/kg groups had
final weights that were 11 and 20% less than control weights, respectively,
and females 1n the 500 mg/kg group had weights that were 10% lower than the
female control weights. Convulsions and hyperactlvlty occurred 1n 5/10 male
and 2/10 female rats 1n the 250 mg/kg group, and 1n 9/10 males and 8/10
0120d -15- 07/22/88
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females In the 500 mg/kg group. •Extramedullary hematopolesls of the spleen
occurred 1n 3/10 male rats 1n the 500 mg/kg group and In 0/10 rats In the
. w • ^
control groups.
A Soviet study Inadequately reported by Rudnev et al. (1979) and by
Tomashevskaya and Zholdakova (1979) examined the toxic effects of subchronlc
oral administration of 1-chlorobutane In- rats. In this study, groups of 15
rats were dosed with 0, 0.02. 0.2 or 2 mg/kg 1-chlorobutane In oil for 6
months. The frequency of administration was not stated 1n the translation.
At 2 mg/kg, the activities of blood alkaline phosphatase, chollnesterase and
sucdnate dehydrogenase were altered, and higher blood levels of Inorganic
phosphate were observed. At 0.02 and 0.2 mg/kg, no statistically s1gn1f1-
•
cant differences were observed In treated animals.
In a Soviet study reported by Rudnev et al. (1979), groups of 10 rats
were given dally oral doses of 0, 0.00022, 0.0022, 0.022 or 110 mg/kg
1-chlorobutane 1n sunflower oil for 30 days. A dose-related Increase 1n the
litre of antibodies to liver tissue was observed, being highest -In the 110
mg/kg group and absent In the 0.00022 mg/kg group. A significant Increase
In the degree of basophll degranuTatlon 1n the peripheral blood was reported
for rats In groups treated with doses >0.0022 mg/kg, and persisted until 8
weeks after treatment when the study was discontinued. After 30 days, a
dose-related Increase In antibody sensUlzatlon and an Increased autoimmune
patch formation 1n the peripheral blood occurred 1n rats given 0.0022, 0.022
and 110 mg/kg 1-chlorobutane. This study appears to be a reprint of a
Soviet study by Vlnogradov (1979), which reported .that oral doses of 0.0022
mg/kg 1-chlorobutane given to rats for 30 days were "autosensltlzlng."
Pertinent data regarding the effects of subchronlc oral exposure to
2-chlorobutane and t-butylchlor1de were not located 1n the available
literature dted In Appendix A.
0120d -16- 07/20/88
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6.1.2.2. CHRONIC EXPOSURE -- In a 2-year study of the systemic
effects of 1-chlorobutane (NTP, 1986), groups of 50 male and 50 female
F344/N rats were treated by gavage with 99.5X pure 1-chTorobutane 1n corn
oil, at doses of 0, 60 or 120 mg/kg, 5 days/week for 103 weeks. Clinical
signs and body weight were monitored throughout the study, and at necropsy,
grossly vlsable lesions were examined and comprehensive hlstologlcal
examinations were performed.
Hyperact1v1ty, tremors and convulsions were noted In many rats after
treatment, but no Incidence data were provided for these effects. The
"Discussion and Conclusions" section of the report associated these effects
with rats that died during the study. Also, sentinel rats were found to
* . .
have antibodies to the Sendal and RC viruses. (The Impact of the presence
of these viruses on the reliability of the results of this study Is
unknown.) Cytoplasmlc vacuollzatlon of the adrenal cortex occurred 1n 5/50,
10/50 and 20/50 male rats 1n the 0, 60 and 120 mg/kg groups, respectively.
Cytoplasmlc vacuollzatlon did not occur at an Increased Incidence In female
rats (4/50, 5/50 and 3/49 for females In the 0, 60 and 120 mg/kg groups,
respectively). Although this effect Indicates a build-up of fatty deposits,
the toxlcologlcal significance of this effect 1s unclear.
Lung alveolar and brain hemorrhage, lymphold depletion and hemoslderosls
occurred 1n a dose-related manner 1n male and female rats that died during
the study. Brain hemorrhage was also observed 1n one male rat 1n the
high-dose group at termination. In the 0, 60 and 120 mg/kg groups: lung
hemorrhages occurred 1n 0/50, 2/50 and 19/50 male rats and In 0/50, 1/50 and
26/50 female rats, respectively; brain hemorrhages occurred 1n 2/49, 4/50
and 18/49 males and In 1/50, 1/50 and 25/50 females, respectively; lymphold
depletion of the spleen occurred 1n 1/50, 1/50 and 15/50 males and 1/50,
0120d -17- 07/20/88
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1/50 and 24/50 females, respectively; and hemoslderosls occurred In 6/50,
3/50 and 16/50 males and 3/50, 3/50 and 27/50 females, respectively. Organ
• ••' " «»
congestion also occurred 1n 2/50, 6/50 and 15/50 male rats and 0/50, 1/50
and 28/50 female rats 1n the 0, 60 and 120 mg/kg groups, respectively.
Nephropathy, without any toxicologlcally significant lesions, was observed
In 13/50, 25/50 and 20/50 female rats at 0, 60 and 120 mg/kg, respectively.
Dose-related mortality occurred In both sexes of rats and was statistically
significant at the high dose (p<0.001). Mortality rates In the 0, 60 and
120 mg/kg groups were 10/50, 18/50 and 33/50 for male rats and 15/50, 12/50
and 39/50 for female rats, respectively. Slightly reduced body weights were
also observed throughout the study 1n high-dose male rats. This weight
•
reduction was not considered to be compound-related.
In a 2-year study of 1-chlorobutane, NTP (1986) treated groups of 50
male and 50 female B6C3F1 mice by gavage with 99.5X pure 1-chlorobutane 1n
corn oil at doses of 0, 500 or 1000 mg/kg, 5 days/week for 103 weeks.
Because of a high death rate 1n females at 1000 mg/kg/day group, a second
series of 2-year studies was started 13 months after Initiation of the first
study with additional groups of 50 male and 50 female mice given either 0 or
250 mg/kg 1-chlorobutane. The experimental design and duration of this
second study were Identical to the original study. Clinical signs and body
weight were monitored throughout the study, and at necropsy, grossly vlsable
lesions were examined and comprehensive histologlcal examinations were
performed.
Hyperactlvlty, tremors and convulsions occurred In mice after treatment,
and brain and lung hemorrhages were observed 1n females 1n the 1000 mg/kg
dose group that died prematurely. Mortality rates 1n the control and 500
mg/kg groups were 17/50 and 23/50 for male and 21/50 and 18/50 for female
0120d -18- 07/20/88
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mice, respectively. In the 1000 mg/kg group, 50X of the female mice were
dead by exposure week 25; this group of females was terminated at week 45.
Statistically significant mortality (p<0.001) was observed 1n high-dose
group male mice; only 10 male mice survived to study completion. There were
no compound-related effects on survival 1in the 250 and 500 mg/kg groups. No
significant' association between hlstologlcal effects and exposure to 250 or
500 mg/kg of 1-chlorobutane was observed 1n treated mice.
Pertinent data regarding the effects of chronic oral exposure to
2-chlorobutane and t-butylchlor1de were not located 1n the available
literature dted In Appendix A.
6.1.3. Other Relevant Information. In a 14-day study conducted by NTP
*
(1986), groups of five male and five female F344/N rats and equal numbers of
B6C3F1 mice were treated by gavage with 0, 190, 380, 750, 1500 or 3000 mg/kg
1-chlorobutane In corn oil. All male and female rats 1n the 1500 and 3000
mg/kg groups died, and 3/5 male and 1/5 female rats died 1n the 750 mg/kg
group. Agresslveness, hyperactlvlty, bloody discharge from the nose and
mouth, and brain hemorrhages occurred In rats given >750 mg/kg 1-chloro-
butane. All mice In the 3000 mg/kg group died, and 3/5 male and 2/5 female
mice In the 1500 mg/kg group died. Hyperactlvlty was observed 1n mice In
the 1500 and 3000 mg/kg groups, and convulsions occurred 1n 2/10 males In
the 3000 mg/kg group.
Wright and Schaffer (1932) studied the antlhelmlntic properties and
acute toxic effects of single doses of 0.1-10.0 cc/kg (87.5-8750 mg/kg)
1-chlorobutane and 0.1-0.5 cc/kg (87-435 mg/kg) 2-chlorobutane 1n 21 and 10
parasite-Infested dogs, respectively. The route of administration of these
compounds 1s assumed to be oral gavage, based on the administration of other
chemicals reported 1n this study. Hlstologlcal examination revealed cloudy
0120d -19- 07/20/88
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swelling, slight fatty Infiltration and passive congestion with blUrubln
deposits 1n the livers of dogs given 1-chlorobutane. Also, slight fatty
Infiltration and cloudy swelling of the kidneys were observed. The acute
toxic effects of 2-chlorobutane were more marked. Gross observations
Included yellow discoloration of the liver, congestion of the liver and
k-1dneys and Inflammation of the gastrointestinal tract. H1stolog1cal exami-
nation of the liver revealed passive congestion, cloudy swelling, fatty
changes, which 1s evidence of Imminent liver necrosis. Similar examination
of the kidney revealed passive congestion and parenchymous degeneration.
The authors reported that, based on control data, the hepatic effects
observed In dogs given 1-chlorobutane, may not be compound-related; however,
•
the authors Indicated that the effects observed In dogs treated with
2-chlorobutane are probably compound-related. Although 2-chlorobutane
appears to be more toxic than 1-chlorobutane, 1t Is unclear whether adequate
numbers of dogs were examined to justify a comparison of the toxlclty
associated with 1- and 2-chlorobutane (U.S. EPA, 1983).
Oral LD_Q values and lethal concentrations for 1- and 2-chlorobutane
are summarized 1n Tables 6-1 and 6-2. For 1-chlorobutane, Smyth et al.
(1954) determined a 14-day dermal LD5Q of >20 ml/kg (17,500 mg/kg) In
rabbits and a 14-day oral LD5Q of 2670 mg/kg 1n rats. Smyth et al. (1954)
also determined a 4-hour lethal concentration for 1-chlorobutane of 8000 ppm
1n rats. Tomashevskaya and Zholdakova (1979) determined LD5Q values
(unspecified route of administration) for 1-chlorobutane 1n mice, rats and
guinea pigs of 5600, 2200 and 8000 mg/kg, respectively; Rudnev et al. 0979)
reported Identical results for oral administration to rats and mice. Smyth
et al. (1954) reported that eye and skin contact with 1-chlorobutane Induces
necrosis In rabbits, and Rudnev et al. (1984) reported that 1-chlorobutane
Induces dermal Inflammation which progresses to ulcers and necrosis.
0120d -20- 07/20/88
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TABLE (>-l
Oral 1050 Values for 1- and 2-Chlorobutane
Compound
1-Chlorobutane
Species
rat
LD50
(mg/kg)
2,670*
2,200
Reference
Smyth et al., 1954
Rudnev et al., 1979;
mouse
guinea pig
2-Chlorobutane rat
5,600
8,000
17,400
Tomashevskaya and
Zholdakova, 1979
Rudnev et al., 1979;
Tomashevskaya and
Zholdakova, 1979
Tomashevskaya and
Zholdakova, 1979
Smyth et al., 1969
0120d
-21-
07/20/88
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TABLE 6-2
Inhalation Lethal Concentration Summary for 1- and 2-Chlorobutane
Using the Rat
Compound
Concentration/
Duration
Mortality
Reference
1-Chlorobutane
2-Chlorobutane
8000 ppm/4 hours
8000 ppm/4 hours
2/6
3/6
Smyth et al.,
1954
Smyth et al.,
1969
0120d
-22-
05/27/88
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For 2-chlorobutane, an oral ID™ 1n rats of 20 ml/kg (17,400 mg/kg),
a dermal LD-. In rabbits of 20 mi/kg (17,400 mg/kg) and a lethal concen-
• •» " •
tratlon 1n rats of 8000 ppm for 4 hours were reported by Smyth et al.
(1969). In this study, 2-chlorobutane Induced necrosis on the skin and eyes
of rabbits (Smyth et al., 1969).
The difference between the oral LD5Qs of 2-chlorobutane and 1-chloro-
butane suggests that 2-chlorobutane Is more toxic than 1-chlorobutane In
rats; however, Inhalation LD,Qs suggest that the two compounds have
comparable toxic potency. Also, Po1r1er et al. (1975) reported MTDs for
IntrapeHtoneal administration of 1-chlorobutane and 2-chlorobutane of 65
and 35 mmoles In mice, respectively.
•
Selan and Evans (1987) reported that acute oral administration of 0.1
ml/kg (87.5 mg/kg) 1-chlorobutane 1n corn oil Induced a significant
dose-related Inhibition of hepatic triglycerlde secretion Into the blood
serum of male rats and mice. In. vitro Inhibition by 1-chlorobutane of
triglycerlde secretion 1n Isolated rat hepatocytes was'also reported. Using
an in vitro Upld free, soluble enzyme system, Law et al. (1985) demon-
strated Iji vitro Inhibition of a-chymotryps1n by 1- and 2-chlorobutane.
Other relevant Information regarding t-butylchlor1de were not located 1n
the available literature dted In Appendix A.
6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carclnogenlclty of
Inhaled 1- and 2-chlorobutane and t-butylchlor1de were not located 1n the
available literature cited In Appendix A.
6.2.2. Oral. In a 2-year study of the carcinogenic effects of 1-chloro-
butane (NtP, 1986), groups of 50 male and 50 female F344/N rats were treated
by gavage with 99.55C pure 1-chlorobutane In corn oil at doses of 0, 60 or
0120d -23- 07/20/88
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120 mg/kg, 5 days/week for 103 weeks. Clinical signs were recorded weekly
and body weights were determined weekly for the first 12 weeks of the study
- - "•
and monthly thereafter. At necropsy, grossly visible lesions were examined
and comprehensive hlstologlcal examinations were performed.
Survival 1n the high-dose groups was significantly reduced; however, the
authors felt survival throughout the study was adequate for proper analysis
of the carcinogenic potential of 1-chlorobutane. Also, sentinel rats were
found to have antibodies to the Sendal and RC viruses. The Impact of the
presence of these viruses on the reliability of the results of this study
are unknown.
NTP (1986) concluded that there was no evidence that 1-chlorobutane was
carcinogenic In rats 1n this study, although three tumor types were
observed. Pheochromocytomas of the adrenal medulla were observed 1n 0/50,
6/50 and 1/49 female rats at 0, 60 and 120 mg/kg, respectively, and 1
control female had a malignant pheochromocytoma. Although the Incidence of
pheochromocytonia alone and p'heochromocty'oma combined with malignant
pheochromocytoma 1n the low-dose group was significantly greater than In
controls, the authors noted that the Incidence was not dose-related and that
the Incidence of medullary hyperplasla (3/50. 7/50 and 4/49 at 0, 60 and 120
mg/kg, respectively), an expected preneoplastlc observation associated with
these tumors, did not suggest a neoplastlc phenomenon 1n progress. Further-
more, pheochromocytomas are late developing tumors, and none were observed
In the 11 high-dose females that survived 2 years.
Pancreatic adnar cell adenomas also occurred 1n 4/50, 9/50 and 5/48
male rats at 0, 60 and 120 mg/kg. Although the test for positive trend was
significant, the Incidence was clearly not dose-related and the Incidence 1n
either treated group was not significantly greater than the Incidence In
0120d -24- 07/20/88
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controls. A transitional cell papllloma of the urinary bladder was observed
In one male at 60 mg/kg and 1n one female at 120 mg/kg; the Incidence of
- w * ^
this tumor In historical controls 1s very low, 0% In male rats and 0.3% 1n
female rats 1n NTP-sponsored bloassays. The significance of this tumor 1n
this experiment 1s not known.
In another 2-year study of the carcinogenic effects of 1-chlorobutane
(NTP, 1986), groups of 50 male and 50 female B6C3F1 mice were treated by
gavage with 99.5X pure 1-chlorobutane In. corn oil at doses of 0, 500 and
1000 mg/kg, 5 days/week for 103 weeks. After 13 months, additional groups
of equal numbers of mice were started at 0 or 250 mg/kg 1-chlorobutane
because of a high death rate 1n the 1000 mg/kg group. The experimental
•
design of this study was Identical to the first study. Clinical signs were
recorded weekly and body weights were determined weekly for the first 12
weeks of the study and monthly thereafter. At necropsy, grossly vlsable
lesions were examined and comprehensive histologlcal examinations were
performed.
Among female mice In the 0 and 500 mg/kg groups, the Incidence of
alveolar and broncheolar adenomas and carcinomas was 3/50 and 9/50, respec-
tively. The Incidence at 500 mg/kg was marginally significant compared with
controls (p=0.028. Incidental tumor test). The Incidence of alveolar and
broncheolar tumors was 9/100, 8/50 and 9/50 for the combined control groups
and the 250 and 500 mg/kg/day. groups,, respectively. The Incidence 1n
treated groups was not significantly different from controls. Hepatocellu-
lar adenomas or carcinomas (combined) occurred at a marginally significantly
Increased Incidence (p°0.04) In female mice from the 500 mg/kg group
compared with concurrent controls, but not when compared with combined
controls. The Incidence of hepatocellular adenomas or carcinomas 1n the
0120d -25- 07/20/88
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control group from the second study exceeded that of 500 mg/kg females 1n
the first study. Hemanglosarcomas occurred 1n 1/50, 3/50 and 4/50 male mice
. rf - ^
1n the first study at 0, 500 and 1000 mg/kg groups, respectively; the
Incidence 1n the 1000 mg/kg group was marginally significant (p=0.04). In
the control and 250 mg/kg groups from the second study, the occurrence of
hemanglosarcomas was 4/50 and 2/50, respectively.
Although hepatocellular adenomas or carcinomas and hemanglosarcomas
occurred at marginally significant Incidences 1n female mice, comparisons of
the Incidence of these tumors with combined control groups (from the two
mouse experiments) or historical data suggested that these Incidences were
not significant. In addition, lack of a dose-response relationship or
absence of positive trends of occurrence of these tumors led the authors to
conclude that there was no evidence of carcinogenic potential for 1-chloro-
butane 1n mice 1n these studies.
. Pertinent data regarding the carcinogenic effects from oral exposure to
2-chlorobutane and t-butylchlor1de were not located 1n the available
literature cited 1n Appendix A.
6.2.3. Other Relevant Information. Polrler et al. (1975) examined the
pulmonary tumor response of strain A/Heston mice to 1-chlorobutane,
2-chlorobutane and t-butylchlor1de. Groups of 10 male and 10 female mice
received a total of 24 1ntraper1toneal Injections (3 Injections/week) of
either 65. 32.4 or 12.9.mmol/kg (6018, 3000 or 1194 mg/kg) 1-chlorobutane or
t-butylch1or1de or 13 IntraperUoneal Injections of 35, 17.5 or 7 mmol/kg
(3240, 1620 or 648 mg/kg) 2-chlorobutane 1n trlcaprylln. Doses 1n the high,
middle and low groups corresponded to 100, 50 and 20% of the MTD, respec-
tively. Untreated and trlcapryHn-treated mice were used as negative
controls and urethane-treated mice were used as positive controls. The mice
0120d -26- 07/20/88
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were sacrificed 24 weeks after the first Injection. t-Butylchlor1de Induced
a dose-related Increase 1n the number of lung tumors/mouse that was slight,
••""*•
but statistically significant at the 32.4 mmol/kg dose level (p<0.05).
2-Chlorobutane Induced a dose-related Increase In the number of lung
tumors/mouse that was statistically significant at the 35 mmol/kg dose level
(p<0.05). No statistically significant Increase 1n the number of tumors/
mouse occurred 1n mice given 1-chlorobutane. Further, 100% of the mice
given urethane (positive controls) developed tumors and the average number
of tumors/mouse Increased In a dose-related manner. 2-Chlorobutane and
t-butylchlorlde may be considered to be positive 1n the strain A/Heston
mouse lung .tumor assay.
6.3. HUTAGENICITY
Results of mutagen1c1ty assays conducted with 1- and 2-chlorobutane and
t-butylchlor1de are summarized In Table 6-3. In most reverse mutation
assays, using various strains of Salmonella typhlmuMum. t-butylchlorlde and
1-clilorobutane were not found to be mutagenlc (Eder et al., 1980, 1982a,b;
Barber et al., 1981; Barber and Donlsh, 1982; Zelger, 1987; Zelger et al.,
1987). A Soviet study by Rudnev et al. (1979) found 1-chlorobutane to be
negative 1n a chromosomal aberration test In rat bone marrow cells. The
route of administration 1n this study was not Indicated. Pluck et al.
(1976) reported that 1-chlorobutane was negative 1n a DNA damage assay In E_.
coll; however, apparently only one dose was tested and no system was 1n
place to contain the volatile vapors of 1-chlorobutane.
'The only positive results 1n the Salmonella reverse mutation assay were
reported by Simmon (1981), who Implied that 1- and 2-chlorobutane and
t-butylchlorlde were mutagenlc; however, control data were not provided, and
1t 1s not clear why these were the only positive results reported.
0120d -27- 07/20/88
-------
TABIE 6-3
ro
0
O.
1
rs)
CO
I
09/23/88
HutagenlcUy Data for Nonochlorobutane
Assay
Reverse
•utatlon
Reverse
•utatlon
Reverse
•utallon
Reverse
•utatlon
Reverse
•utatlon
Reverse
•utatlon
Reverse
•utatlon
Reverse
•ulatlon
Reverse
•utatlon
Chromosomal
aberration
OKA dawage
Indicator
Or 9411 1 im
Salmonella
typhtwirluM TA100
S. typhlMurluM
TA100
S. typhlaurluM
TA100
S. typhlMurliiM
TA100. TA1535.
1A1537. TA9B
S. typhlMurtiiM
1A153S. TA98.
1A100
S. typhlMurluM
1A100
S. typhlMurluM
S. typhlMurluM
1A100
S. typhlMurtuM
TA100
bone Marrow cell
tscherlchla co_U
CoMpound/
Purity
1-chlorobutane/
NR
1 -chlorobutane/
100X
1 -chlorobutane/
10W
1 -ehlorobulane/
99. W
1 -chlorobutane/
99. W
1 -chlorobutane/
MR
2 -chlorobutane/
NR
t-butylchlortde/
NR
t-butylchlorlde/
NR
1 -chlorobutane/
NR
1 -chlorobutane/
NR
Application
NR
liquid
suspens Ion
liquid
suspension
pretncubatlon
vapor eiposure
vapor exposure
vapor exposure
NR
vapor exposure
dally oral
administration
to rats for
6 Months
In vitro
Concentration
or Dose
NR
0.1-10 vt/2 M
NR
10-666 i>g/Plate
1.9-32.7 nN/plate
2 Ml/desiccator
4 tit/destccatrfr
NR
1 i>i/deslccator
110. 0.022 and
0.0022 Mg/kg
26 Ml
Activating Response Reference
Systen
»S-9 = Eder el al.'.
I982a
»S-9 - Eder et al..
19BO
»S 9 = Eder et al..
1982b
»S-9 = Zelger et al.,
1987; Zetger.
1987
»S-9 ~ Barber et al..
1981; Barber
and Donlsh.
19B2
none » Slnraon. 1981
none * Simon. 1981
»S-9 = Eder et al..
1982a
none > Slonwn. 1981
NA - Rudnev et al..
1979
none - Fluck et al. .
1976
NR =. Not reported
-------
6.4. TERATOGENICITY
In a study reported by Rudnev et al. (1979) and Leonskaya et al. (1980),
4 groups of 20 Hlstar rats received oral doses of 0, 0.02, 110 or 733
mg/kg/day 1-chlorobutane 1n sunflower oil on days 1-19 of gestation.
Compared with controls, a slightly Increased Incidence of Internal organ
hemorrhage occurred among the fetuses of rats given 733 mg/kg/day, and a
statistically significant Increase 1n embryonic mortality occurred among
rats given 733 mg/kg/day. In a 2-generat1on teratogenlclty study by
Leonskaya (1980), significantly Increased embryonic mortality occurred among
pregnant rats that were offspring of dams given 733 mg/kg 1-chlorobutane on
gestation days 1-19.
6.5. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding other reproductive effects of 1- and 2-chloro-
butane and t-butylchlorlde were not located In the available literature
dted In Appendix A. The 2-generat1on study by Leonskaya (1980), discussed
1n Section 6.4., did not examine the reproductive effects of 1-chlorobutane.
6.6. SUMMARY
In a 14-day dose range-finding study of 1-chlorobutane, rats and mice
were treated by gavage with 1-chlorobutane In corn oil at doses of 0, 190,
380, 750, 1500 or 3000 mg/kg (NTP, 1986). Mortality occurred 1n rats and
mice at doses of >750 and >1500 mg/kg, respectively. Agresslveness, hyper-
actlvlty, bloody discharge from the nose and mouth, and brain hemorrhages
occurred In rats at doses of >750 mg/kg. In mice, hyperactlvHy occurred at
1500 and 3000 mg/kg.
In another dose range-finding study, rats were treated by gavage with 0,
30, 60, 120 or 500 mg/kg 1-chlorobutane for 13 weeks (NTP, 1986). Reduced
weight gain, at least 10% below control rats, occurred among males and
0120d -29- 07/20/88
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females at 250-500 mg/kg and at 500 mg/kg, respectively. Reduced survival
and splenic extramedullary hematopolesls occurred In males 1n the 500 mg/kg
•rf " *.
group. Convulsions and hyperactlvlty occurred 1n male and female rats 1n
the 250 and 500 mg/kg groups. In another dose range-finding study sponsored
by the NTP (1986), mice were treated by gavage with 0, 60, 120, 500 or 1000
mg/kg 1-chlorobutane for 13 weeks. Convulsions and mortality occurred 1n
males and females at 1000 mg/kg.
In a chronic study, the carcinogenic potential of 1-chlorobutane was
examined In rats treated by gavage with 1-chlorobutane at doses of 0, 60 or
120 mg/kg for 103 weeks (NTP, 1986). Although some tumors occurred, they
were not considered to be compound-related. The authors concluded that
•
under the conditions of this study 1-chlorobutane was not carcinogenic.
Nonneoplastlc effects of 1-chlorobutane In rats Included hyperactlvlty,
tremors and convulsions at 60 and 120 mg/kg and decreased weight gain,
cytoplasmlc vacuollzatlon of the adrenal cortex, nephropathy, alveolar and
brain hemorrhage, hemos1deros1s and reduced survival at 120 mg/kg.
The carcinogenic potential of 1-chlorobutane was also studied 1n mice
given gavage doses of 1-chlorobutane at 0, 25, 500 or 1000 mg/kg for 103
weeks (NTP, 1986). Although some tumors occurred, they were not considered
to be compound-related. The authors concluded that under the conditions of
this study, there Is no evidence of carclnogenldty for 1-chlorobutane.
Nonneoplastlc effects that occurred 1n mice at 1000 mg/kg Include the
following: hyperactlvlty, convulsions and tremors In female mice; brain and
lung hemorrhages 1n female mice; and decreased survival In male and female
mice.
In a study reported by Rudnev et al. (1979) and by Tomashevskaya and
Zholdakova (1979), 1-chlorobutane was given to rats 1n oral doses of 0,
0120d -30- 07/20/88
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0.02, 0.2 or 2 mg/kg for 6 months. The activities of blood alkaline phos-
phatase, chollnesterase and sucdnate dehydrogenase were altered and blood
- •"" " v
levels of Inorganic phosphate were Increased 1n rats given 2 mg/kg 1-chloro-
butane.
In a study reported by Vlnogradov (1979) and Rudnev et al. (1979), rats
were dosed orally with 1-chlorobutane at 0, 0.00022, 0.0022, 0.022 or 110
mg/kg for 309 days. Antibodies against hepatic tissues were present In rats
given doses >0.0022 mg/kg. After 30 days, an autoimmune response In the
blood and an Increase of basophll degranulatlon of the peripheral blood
occurred 1n the 0.0022-110 mg/kg groups.
Wright and Schaffer (1932) observed liver and kidney lesions 1n dogs
given single oral doses of 0.1-10.0 cc/kg (87.5-8750 mg/kg) of 1-chloro-
butane and 0.1-0.5 cc/kg (87-435 mg/kg) of 2-chlorobutane. Gastrointestinal
Irritation was also observed 1n dogs given 2-chlorobutane; the effects
associated with 2-chlorobutane administration were more severe than those
associated with 1-chlorobutane. These compounds were given to parasite-
Infested dogs to assess their effectiveness as vermifuge agents. The
effects noted 1n dogs treated with 1-chlorobutane may not have been due to
the compound, because similar effects were also seen 1n controls.
Oral LD,Qs of 2670 mg/kg 1n female rats and Inhalation LC,Qs of 8000
ppm for 4 hours In rats have been reported for 1-chlorobutane (Smyth et al.,
1954). Tomashevskaya and Zholdakova (1979) determined LD5Q values
(unspecified route of administration) for 1-chlorobutane 1n mice, rats and
guinea pigs of 5600, 2200 and 8000 mg/kg, respectively; Rudnev et al. (1979)
reported Identical results for oral administration to rats and mice. A
dermal LD5Q of >20 ml/kg (>17,500 mg/kg) In rabbits was reported by
Smyth et al. (1954). Smyth et al. (1969) reported an oral LD5Q for
2-chlorobutane of 20 ml/kg (17,400 mg/kg) 1n rats, a dermal LD5Q of 20
0120d -31- 07/22/88
-------
ml/kg (17,400 mg/kg) 1n. rabbits and a LC5Q of 8000 ppm for 4 hours 1n
rats. Smyth et al. (1969) also reported necrosis of eyes and skin of
• -" "»
rabbits after contact with 2-chlorobutane. Eye and skin necrosis 1n rabbits
and dermal Inflammation leading to ulcers and necrosis (species not
reported) have also been reported after skin and eye contact with 1-chloro-
butane (Rudnev et al., 1979; Smyth et al., 1954).
The difference between the oral L05_s of 2- and 1-chlorobutane suggest
that 2-chlorobutane Is more toxic than 1-chlorobutane; however, Inhalation
L0,.s suggest that the two compounds have comparable toxic potency. Also,
PolMer et al. (1975) reported the MTDs of 1- and 2-chlorobutane to be 65
and 35 mm/kg, respectively, 1n mice treated 1ntraper1toneally.
*
Mutagenlc effects of 1- and 2-chlorobutane and t-butylchlor1de have been
studied 1n Salmonella and E_. coll assays, and 1n bone marrow cells of rats
(Eder et al., 1980, 1982a,b; Barber et al., 1981; Barber and Donlsh, 1982;
Zelger, 1987; Zelger et al., 1987; Fluck et al., 1976; Simmon, 1981; Rudnev
et al., 1979). All of the data, except that from the reverse mutation
Salmonella studies by Simmon (1981), Indicate that 1-chlorobutane Is
nonmutagenlc. Simmon (1981) also provided evidence 1n this assay suggesting
that 2-chlorobutane and t-butylchlorlde are mutagenlc.
Developmental effects have been reported In rats given oral doses of 733
mg/kg 1-chlorobutane on gestation days 1-19 (Rudnev et al., 1979; Leonskaya,
1980). Effects Included Internal hemorrhaglng 1n fetuses, Increased
embryonic mortality among the fetuses of treated dams and Increased
embryonic mortality among the fetuses of untreated dams from the second
generation of treated dams.
0120d -32- 07/20/88
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
• •"" "»
Pertinent guidelines and standards, Including EPA ambient water and air
quality criteria, drinking water standards, FAO/WHO ADIs, EPA or FDA
tolerances for raw agricultural commodities or foods, and ACGIH, NIOSH or
OSHA occupational exposure limits were not be located In the available
literature cited 1n Appendix A.
7.2. AQUATIC
Pertinent guidelines and standards for the protection of aquatic life
from the effects of the monochlorobutanes were not located In the available
literature cited In Appendix A.
0120d -33- ' 05/27/88
-------
8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Inhalation. Pertinent data regarding the carc1nogen1c1ty of
Inhaled 1- or 2-chlorobutane or t-butylchlorlde were not located In the
available literature cited In Appendix A.
8.1.2. Oral. An NTP (1986) carclnogenlclty bloassay was conducted using
groups of 50 male and 50 female F344/N rats and B6C3F1 mice. Rats and mice
were treated by gavage with 1-chlorobutane In corn oil at doses of 0, 60 and
120 or 0, 250, 500 and 1000 mg/kg/day, respectively, for 103 weeks.
Although a few tumor types occurred at a marginally significant Incidence In
rats and mice, -dose-related responses were not observed, and NTP (1986)
•
concluded that there was no evidence for a carcinogenic response In either
species 1n these studies.
8.1.3. Other Routes. Po1r1er et al. (1975) performed a strain A/Heston
mouse pulmonary tumor response assay on 1- and 2-chlorobutane and t-butyl-
chlorlde. Mice were given 13-24 Intraperltoneal Injections of 100, 50 or
20% of the MID 3 times/week and were sacrificed 24 weeks after the first
Injection. Statistically significant Increases In lung tumors/mouse
occurred In both the 2-chlorobutane and t-butylch1or1de groups.
8.1.4. Height of Evidence. No evidence of carclnogenlclty was found with
orally administered 1-chlorobutane 1n 2-year studies using rats and mice
(NTP. 1986). Fifty male and 50 female mice and rats were used In each study
and comprehensive hlstologlcal examinations were performed. Another study
by Po1r1er et al. (1975) showed no significant development of lung tumors 1n
the strain A/Heston mouse pulmonary tumor assay where mice were Injected
with 1-chlorobutane. No other human or animal data are available regarding
the carclnogenlclty of this compound. Po1r1er et al. (1975) also studied
0120d -34- 07/20/88
-------
the carcinogenic potential of 2-chlorobutane and t-butylchlor1de In the
strain A/Heston mouse lung tumor assay. Both of these compounds produced
• ~ ' ^
slight but significant Increases In the number of lung tumors/mouse. No
other data were available regarding the cardnogen1c1ty of 2-chlorobutane
and t-butylchlor1de. According to the U.S. EPA (1986b) guidelines for
carcinogen risk assessment, 2-chlorobutane and t-butylchloMde are most
appropriately classified as Group D compounds — not classifiable as to
human carclnogenlclty, and 1-chlorobutane 1s appropriately classified as a
Group E compound -- evidence of noncarclnogenldty for humans.
8.1.5. Quantitative Risk Estimates. The lack of adequate positive data
precludes estimation of carcinogenic potencies for 1- or 2-chlorobutane or
t-butylchlorVde for either Inhalation or oral exposure.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure. Pertinent data regarding the Inhalation
toxldty of 1- or 2-chlorobutane or t-butylchlor1de were not located In the
available literature; therefore, subchronlc and chronic RfDs for Inhalation
exposure cannot be derived.
8.2.2. Oral Exposure. Chronic and suibchronlc toxldty data were avail-
able only for 1-chlorobutane. Single dose data (Wright and Schaffer, 1932)
1n dogs suggest that 2-chlorobutane may be more toxic than 1-chlorobutane.
Therefore, risk assessment values cannot be derived for 2-chlorobutane or
t-butylchlor1de by analogy to 1-chlorobutane.
8.2.2.1. LESS THAN LIFETIME (SUBCHRONIC) — Soviet studies have
reported altered enzyme activities, Increased blood Inorganic phosphate
levels, positive Immune responses and basophll degranulatlon 1n rats given
1-chlorobutane (Rudnev et al., 1979; Tomashevskaya and Zholdakova, 1979;
Vlnogradov, 1979); however, the exper1m1ntal protocol was Inadequately
0120d -35- 07/20/88
-------
reported and the toxlcologlcal significance of the effects reported Is
unclear. Therefore, - these studies will not be used 1n derivation of a
subchronlc oral RfO for 1-chlorobutane. In a dose range-finding study
conducted by the NTP (1986), groups of 10 male and 10 female B6C3F1 mice
were given gavage doses of 0, 30, 60, 120, 250, 500 or 1000 mg/kg 1-chloro-
butane and 10 male and 10 female F244/N rats were given gavage doses of 0,
30, 60, 120, 250 or 500 mg/kg 1-chlorobutane In corn oil, 5 days/week for 13
weeks. Animals were weighed weekly, and extensive hlstologlcal examinations
were performed. Rats were clearly the more sensitive species In these
studies and In an acute ID,, study by Tomashevskaya and Zholdakova (1979).
Statistically significant mortality occurred In males and females and
. •
splenic medullary hematopolesis occurred 1n males at 500 mg/kg. Reduced
rate of body weight gain exceeding 10% of that of controls was observed In
males at 250 and 500 mg/kg and 1n females at 500 mg/kg. Convulsions and
hyperactlvlty occurred 1n both sexes at >250 mg/kg.
In mice, convulsions, hyperactlvlty and statistically significant
mortality occurred 1n females 1n the* 1000 mg/kg group. No effects were
observed 1n males at any dosage or 1n females at <500 mg/kg.
The NOAELs for mice and rats are 500 and 120 mg/kg, respectively. In
deriving an RfO, the lower value from the more sensitive species will be
used. Therefore, 120 mg/kg will represent the subchronlc NOAEL level, based
on the rat data; however, since the dose was administered for only 5
days/week, this subchronlc NOAEL must be multiplied by 5/7 days to yield an
adjusted subchronlc dally NOAEL of 86 mg/kg/day. . This adjusted subchronlc
NOAEL 1s divided by an uncertainty factor of 100 (10 to allow for Inter-
species extrapolation and 10 to allow for sensitive Individuals within the
human population). The corresponding subchronlc RfD 1s 0.86 mg/kg/day,
0120d -36- 05/27/88
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which may be rounded off to 0.9 mg/kg/day, equivalent to 60 mg/day for a 70
kg human. Given that a developmental toxldty study by Leonskaya (1980)
reported no adverse effects 1n the fetuses of pregnant rats given oral doses
of 110 mg/kg/day 1-chlorobutane for days 1-19 of gestation and comprehensive
hlstologlcal examinations were performed 1n the NTP (1986) study, a high
degree of confidence can be placed 1n the critical study, the data base and
the subchronlc RfD.
8.2.2.2. CHRONIC EXPOSURES -- An NTP (1986) carc1nogen1c1ty/tox1dty
bloassay was conducted using groups of 50 male and 50 female F344/N rats and
50 male and 50 female B6C3F1 mice. Rats and mice received gavage adminis-
tered 1-chlorobutane 1n corn oil at doses of 0, 60 and 120 or 0, 250, 500
•
and 1000 mg/kg/day, respectively, for 103 weeks. Sentinel animals were
found to have antibodies to the Sendal and RC viruses, but the Impact of the
presence of these viruses on the reliability of the study results 1s not
known. Nephropathy also occurred 1n female rats but did not occur In a
dose-related manner and was not accompanied by other evidence Indicating
that It was a compound-related adverse effect. The slight reduction 1n body
weight throughout the study 1n high-dose male rats was not considered to be
compound-related. Cytoplasmlc vacuollzatlon of the adrenal also occurred 1n
a dose-related manner In male rats. Although this effect Indicates a
build-up of fatty deposits, the biological significance of this effect 1s
not clear.
Lung alveolar and brain hemorrhage, lymphold depletion, hemoslderosis
and organ congestion occurred In a dose-related manner 1n male and female
rats. Generally, these effects were restricted to rats that died during the
study. The .Incidence of each of these effects was significant when compared
with control groups at a dose level of 120 mg/kg. Also, compound-related
0120d -37- 07/20/88
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mortality often preceded by hyperactWHy, tremors and convulsons occurred
1n a dose-related manner, being significant (p<0.001) 1n the 120 mg/kg group.
HyperactWHy, tremors and convulsions occurred 1n female mice after
gavage administration of the test compound. Also, a significant rate of
mortality (p<0.001) occurred In male and female mice In the 1000 mg/kg/day
group.
All of the compound-related effects 1n both rats and mice occurred at
120 and 1000 mg/kg, respectively. The chronic NOAELs for rats and mice are
60 and 500 mg/kg, repectlvely. The NOAEL of 60 mg/kg based on the rat study
will be used as the basis for the RfO because rats are the more sensitive
species. The rats received 1-chlorobutane once per day, 5 days/week.
Therefore, the dose must be multiplied by 5/7 days to yield a dally NOAEL of
43 mg/kg/day, which reflects a 7-day week. To calculate an RfD for
1-chlorobutane the NOAEL Is divided by an uncertainty factor of 100 (10 for
specles-to-spedes extrapolation and 10 for Individual variation 1n the
human population). The resulting RfO for 1-chlorobutane Is 0.43 mg/kg/day,
rounded • to 0.4 mg/kg/day, which 1s equivalent to 30 mg/day for a 70 kg
human. The confidence 1n the critical study, data base and RfD can be
considered high.
0120d -38- 05/27/88
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9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
An NTP (1986) cardnogenldty bloassay was conducted using groups of 50
male and 50 female F344/N rats and B6C3F1 mice. Rats and mice received
1-chlorobutane In corn oil by gavage at doses of 0, 60 and 120 or 0, 250,
500 and 1000 mg/kg/day, respectively, for 103 weeks. As summarized In Table
9-1, nonneoplastlc chronic effects In rats Included adrenal cytoplasmlc
vacuollzatlon In male rats and alveolar and brain hemorrhages, lymphold
depletion, hemos1deros1s, organ congestion and decreased survival 1n male
and female rats, all occurring at the 120 mg/kg dose. The primary
nonneoplastlc effect 1n mice was reduced survival; all but 10 females died
by week 44 and survival Tn males was also greatly reduced. Brain and lung
hemorrhages were found 1n female mice that died prematurely.
The effect considered for RQ derivation for 1-chlorobutane Is reduced
survival. The lowest equivalent human doses at which this effect occurred
are 52.0 and 13.1 mg/kg/day 1n mice and rats, respectively (see Table 9-1).
A CS 1s calculated only for reduced survival 1n rats because the lowest
equivalent human dose was calculated for rats. Multiplying 13.1 mg/kg/day
by 70 kg yields an MED of 917 mg/day, equivalent to an RVd of 1. Reduced
survival 1s assigned an RV of 10. Multiplication of the RV. and the
RVe yields a CS of 10. which corresponds to an RQ of 1000 (Table 9-2).
RQs for 2-chlorobutane and t-butylchlor1de cannot be calculated because
of a lack of pertinent toxldty data.
9.2. BASED ON CARCINOGENICITY
CardnogenUUy data for 1-chlorobutane consist of negative 2-year
studies using rats and mice (NTP, 1986) and negative results from a
pulmonary tumor response mouse assay In mice (Polrler et al., 1975).
0120d -39- 10/19/88
-------
ro
o
Q.
I
4^
O
O
en
TABLE 9-1
Oral ToxicHy Summary for l-Chlorobutanea
Species/
Stra1n/Sexb
No. at
Start
Average
Body Weight0
(kg)
Exposure1'
Transformed
Animal Dose
(mg/kg/day)
Transformed
Human Dose6 Response
(mg/kg/day) ':
i
Rats/F344/N
50
0.252
M1ce/B6C3Fl
50
0.027
120 mg/kg/day.
5 days/week
for 103 weeks
1000 mg/kg/day.
5 days/week
for 103 weeks
85.7
13.1
714
52.0
Reduced survival
and several agonal
and stress-related
hlstopathologlcal
changes
Reduced survival
^Source: NTP. 1986
°0nly data from the females of each species were considered because their lower body weight compared
with males result In lower transformed human dosages.
cEst1mated from data provided by Investigators.
dAll animals were treated by gavage with 99.5% pure 1-chlorobutane In corn oil.
Calculated by multiplying the transformed animal dose by the cube root of the ratio of animal to
reference human body weight.
CD
00
-------
TABLE 9-2
1-CHLOROBUTANE
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 917 mg/kg/day
Effect: decreased survival
Reference: NTP, 1986
RVd: 1
RVe: 10
Composite Score: 10
RQ: 1000
•Equivalent human dose
0120d -41- 07/20/88
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Despite the negative results obtained from both studies, the data base for
cardnogenlclty of 1-chlorobutane 1s considered 'Inadequate* due to
deficiencies of the 2-year NTP study, such as the varied residual tumor
Incidences In vehicle control animals and the adverse effects observed 1n
female rats at the high dose level. Therefore, 1-chlorobutane 1s assigned
as a Group 0 compound; I.e., not classifiable as to human cardnogenldty,
according to the guidelines outlined by U.S. EPA (1986b). The only data
regarding the carclnogenldty of 2-chlorobutane and t-butylchlor1de are
positive results from a pulmonary tumor response mouse assay (Po1r1er et
al.. 1975). According to the guidelines outlined by the U.S. EPA (19865),
2-chlorobutane and t-butylchlorlde are not classifiable as to human cardno-
genldty and are, therefore, assigned as Group D compounds. Hazard ranking
for cardnogenldty 1s not possible for U.S. EPA Group D chemicals;
therefore, RQs based on cardnogenldty cannot be derived for
monochlorobutanes.
0120d -42- 10/20/88
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0120d -51- 07/20/88
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APPENDIX A
LITERATURE SEARCHED
This HEED Is 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 In February 1988, and the following secondary
sources vere reviewed:
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyg1en1sts).
1987. TLVs: Threshold Limit Values for Chemical Substances 1n the
Work Environment adopted by ACGIH with Intended Changes for
1987-1988. Cincinnati, OH. 114 p.
Clayton, G.D. and F.E. Clayton; Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
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.
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Grayson, M. and 0. Eckroth, Ed. 1978-1984. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John WHey and Sons, NY. 23
Volumes.
Hamilton,"A", and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. IARC, WHO, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. L1eu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Haste.
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. Chemltal 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. - _
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In addition, approximately 30 compendia of aquatic toxldty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Flnley. 1980. Handbook of Acute Toxldty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, F1sh and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control. Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Spedes. Prepared for the U.S. EPA, Washlogton, 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.
0120d -54- 05/27/88
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