-------
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
TMchloropropanes are colorless liquids at room temperature and have an
odor typical of chlorinated hydrocarbons (Williams, 1949). They are
sparingly soluble 1n water (see Table 1-2). When heated to decomposition,
trlchloropropanes emit toxic chlorine fumes (Sax, 1984). The U.S EPA TSCA
Production File (U.S. EPA, 1977) reported that one manufacturer produced
1,1,2- and 1,2,2-tMchloropropane and four manufacturers produced l,2,3-tr1-
chloropropane during 1977; however, this source contained no production
Information on 1,1 ,l-tr1chloropropane or a tMchloropropane mixture. SRI
(1986) cites Dow Chemical U.S.A. In Freeport, TX, and Shell 011 Co. In Deer
Park, TX, as the only current manufacturers of 1,2,3-tr1chloropropane 1n the
United States. Production data on 1,1,1-, 1,1,2- and 1,2,2-tMchloropropane
and tMchloropropane mixture were not located In current sources of chemical
production and sales Information, suggesting that these compounds have
IHtle, 1f any, commercial Importance In the United States. 1,2,3-Trl-
chloropropane 1s used as a crossHnklng agent, chemical Intermediate for
agricultural and pharmaceutical products (Kuney, 1985), solvent, degreaslng
agent, and paint and varnish remover (Hawley, 1981).
In water, volatilization 1s expected to be a p/lmary removal mechanism
for trlchloropropanes. The volatilization half-life of 1,2,3-tr1chloropro-
pane from water 1 m deep, flowing at a speed of 1 m/sec with a wind speed of
3 m/sec has been estimated to be -9 hours. Trlchloropropanes are not
expected to undergo significant chemical hydrolysis, oxidation, photolysis
(Jaber et al., 1984), bloaccumulatlon In aquatic organisms or adsorption to
suspended solids or sediments. Insufficient data are available to determine
the significance of mlcroblal degradation as a removal mechanism. In air.
1v
-------
tMchloropropanes are expected to exist entirely 1n the vapor phase. These
compounds are expected to react with photochemlcally generated hydroxyl
radicals. Estimated reaction half-lives for 1,1,1-, 1,1,2-, 1,2,2- and
1,2,3-trlchloropropane at 25°C have been estimated to be 15, 6, 30 and 7
days, respectively (U.S. EPA, 1987b). Potential exists for removal from the
atmosphere by dissolution Into clouds and washout; however, trlchloropro-
panes removed by dissolution or washout are.likely to reenter the atmosphere
by volatilization. These compounds may be persistent In the atmosphere. In
soil, leaching and volatilization are expected to be Important transport
processes for the tMchloropropanes. These compounds are not expected to
hydrolyze or oxidize and H Is not known whether m1crob1al degradation would
be significant because soil blodegradatlon studies on these compounds are
not available.
TMchloropropane Isomers have been detected In drinking water from New
Orleans, LA {Keith et a!., 1976), Ames, IA (U.S. EPA, 1983b) and Cincinnati,
OH (Lucas, 1984) and surface water samples from Narragansett Bay, RI
(Wakeham et al., 1983), the Delaware River basin (DeWalle and Chlan, 1978)
and the Rhine River (U.S. EPA, 1983b). Since trlchloropropanes are volatile
compounds, 1t 1s likely that workers using these compounds would be exposed
by Inhalation. Based on the National Occupational Exposure Survey, NIOSH
(1984) estimated that 490 workers are likely to be occupatlonally exposed to
1,2,3-tr1chloropropane. Pertinent monitoring data for estimating the dally
human exposure to trlchloropropanes by Inhalation, Ingestlon of food and
drinking water or dermal contact could not be located 1n the available
literature as dted 1n Appendix A.
-------
Little Information was available concerning effects of trlchloropropanes
on aquatic biota. The only data were those of Hutchlnson et al. (1980) who
reported 3-hour EC5Qs for Inhibition of photosynthesis of 112 mg/i
1,2,3-trlchloropropane for Chlamydomonas angulosa and 170 mg/a, for
Chlorella vulgaMs.
Patterns of excretion of radioactivity following oral administration of
14C-1,2,3-tr1chloropropane to rats (Slpes et al., n.d.) are similar to
those observed following Intravenous treatment (Volp et al., 1984), which
suggests that gastrointestinal absorption was fairly rapid and nearly com-
plete. Data were not located regarding absorption by the respiratory tract.
Following Intravenous treatment 1n rats, 1,2,3-tr1chloropropane was
distributed rapidly (half-life 0.29 hours) from the blood, primarily to
adipose tissue, muscle and skin (Volp et al., 1984). After 4 hours, concen-
trations of radlolabel, associated primarily with metabolites, were highest
In the kidneys and liver. No organ or tissue showed a tendency to retain
i
radlolabel following a single Intravenous (Volp et al., 1984) or oral (Slpes
et al., n.d.) dose, although no prediction can be made for a chronic dosing
schedule.
Metabolism of 1,2,3-tMchloropropane appears to be rapid; and carbon
dioxide, at 25X of the dose, Is the major metabolite. Urinary metabolites
(several, but unidentified) accounted for 40% of the dose by 24 hours.
Conjugation with glutathlone results 1n metabolites that are excreted 1n the
bile. The metabolism of other trlchloropropanes 1s likely to occur by
1somer-spec1f1c Intermediate pathways, with the probability of the formation
of Isomer-speclf1c.toxic Intermediates. The liver appears to be the princi-
pal site of metabolism. Excretion of Intravenously administered 1,2,3-trl-
chloropropane and Its metabolites was virtually complete (99% of dose) by 6
v1
-------
days (Volp et al., 1984). Excretion occurred primarily by the urinary and
respiratory routes (40 and 30% of dose by 24 hours) and less (18% of dose)
by the fecal route. Biliary excretion 1s substantial (30% of dose within 6
hours), but appears to be followed by Intestinal absorption. Excretion
patterns following oral administration (S1pes et al., n.d.) are similar to
those following Intravenous dosing^
Few data were located regarding the Inhalation toxldty of the tr1-
chloropropanes. Several Russian studies reported the effect of l,2,3-tr1-
chloropropanes 1n rats exposed continuously for 7 days to 3 months. The
liver and lungs appeared to be the target organs 1n these studies, which
reported hlstopathologlcal lesions after 3 months exposure to 2 mg/m3
(Sldorenko et al., 1979; Tsulaya et al., 1977, 1979; Bonashevskaya, 1977).
Lesions were not reported at 0.4 or 0.45 mg/m3. Chronic Inhalation
toxldty data were not located.
Oral toxldty data were limited to subchronlc studies. In a 13-week
drinking water study using rats. 1,1,2- or 1,2,3-tr1chloropropane was
administered to both sexes; and 1000 mg/i was a LOAEL associated with mild
but significant lesions In the liver, lungs and thyroid. The 100 mg/l
level was a NOAEL for both compounds. Subchronlc gavage studies were
performed with 1,2,3-tr1chloropropane using rats (NTP, 1983a) and mice (NTP,
1983b). Rats were more sensitive than mice, as Indicated by greater
mortality at 250 mg/kg, the highest dosage tested. The dosage of 8 mg/kg, 5
days/week (5.7 mg/kg/day) 1n rats was a NOAEL associated with transient
clinical signs and blood chemistry alterations, and elevated relative liver
weight. The next higher dosage, 16 mg/kg, 5 days/week (11.4 mg/kg/day), was
a LOAEL asso- dated with c!1n1copatholog1cal evidence of liver damage. The
NOAEL and LOAEL for mice were 32 and 63 mg/kg (22.9 and 45.0 mg/kg/day),
respectively.
-------
Completed cardnogenldty studies were not located for any of the tr1-
ch.loropropanes by either oral or Inhalation exposure. The NTP Is evaluating
the cardnogenlcHy . of 1,2,3-tr1chloropropane by gavage In rats and mice
(NTP, 1986). Data were not located regarding the cardnogenlclty of the
tMchloropropanes by other routes of exposure. Mutagenldty data were
located only for the 1,2,3-1somer. Positive results were obtained In the
reverse mutation test In S. typhlmuMum. Results In various mammalian test
systems were mixed. The mammalian data are difficult to evaluate as they
are primarily presented In only abstract form.
1,2,3-Trlchloropropane was not associated with fetotoxldty or terato-
genldty In an Intraperltoneal study using rats (Hardln et al., 1981} and
had no effect on mating performance, fertility or hlstomorphology of the
testes In a dominant lethal study using rats (Salto-Suzukl et al., 1982).
Data regarding the . developmental or reproductive toxlclty of the other
trlchloropropanes could not be located 1n the available literature as cited
1n Appendix A.
Because no data were available regarding the cardnogenlclty of trl-
chloropropanes, these chemicals were placed 1n EPA Group D, not classifiable
as to human cardnogenlclty. A subchronlc oral RfD, of 0.2 rag/kg/day or 14
mg/day for a 70 kg man and a chronic oral RfD of 0.02 mg/kg/day or 1 mg/day
for a 70 kg man were derived for 1,1,2-trlchloropropane based on a sub-
chronic NOAEL of 100 mg/l (20.3 mg/kg/day) 1n drinking water of rats for
13 weeks. At the LOAEL of 1000 mg/l, the rats had hlstopathologlcal
lesions In the liver, kidney and thyroid (Vllleneuve et al., 1985).
Uncertainty factors of 100 for the subchronlc RfD and 1000 for the chronic
RfD were used. The uncertainty factors reflect factors of 10 each for
1nterspec1es and Intraspecles variability for the subchronlc and chronic
RfDs and an additional factor of 10 for the use of subchronlc data to derive
-------
a chronic RfD. An RQ of 1000 was derived for 1,1,2-tr1chloropropane based
on the hlstopathologlcal lesions In rats treated at a drinking water level
of 1000 mg/a, for 13 weeks 1n the study by Vllleneuve et al. (1985).
A subchronlc oral RfD of 0.06 mg/kg/day or 4 mg/day for a 70 kg man and
a chronic oral RfD of 6 wg/kg/day or 0.4 mg/day for a 70 kg man were
derived for 1,2,3-trlchloropropane based on a subchronlc oral NOAEL of 8
mg/kg/day, 5 days/week (5.7 mg/kg/day) administered to rats for 120 days
(NTP, 1983a). At the LOAEL of 16 mg/kg/day, 5 days/week (11.4 mg/kg/day)
rats had biochemical evidence of Impaired liver function. Uncertainty
factors of 100 for the subchronlc RfD and 1000 for the chronic RfD were
used. The uncertainty factors reflect factors of 10 each for 1nterspec1es
and Intraspedes variability for the subchronlc and chronic RfDs and an
additional factor of 10 for the use of subchronlc data to derive a chronic
RfD. An RQ of 100 was derived for 1,2,3-trlchloropropane based on the NOAEL
of 5.7 mg/kg/day for slight biochemical evidence of Impaired liver function
of rats treated for 120 days In the study by NTP (1983a). .
1x
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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 1
1.4. USE DATA 5
1.5. SUMMARY 5
2. ENVIRONMENTAL FATE AND TRANSPORT 7
2.1. AIR 7
2.1.1. Reaction with Hydroxyl Radicals 7
2.1.2. Reaction with Ozone 7
2.1.3. Physical Removal Processes 7
2.2. WATER 7
2.2.1. Hydrolysis 7
2.2.2. Oxidation 8
2.2.3. Photolysis 8
2.2.4. M1crob1al Degradation 8
2.2.5. Adsorption 8
2.2.6. B1oaccumulat1on .• 8
2.2.7. Volatilization.' 8
2.3. SOIL 9
2.3.1. Chemical Degradation 9
2.3.2. Leaching 9
2.3.3. Volatilization 9
2.4. SUMMARY. . . 10
3. EXPOSURE ' 11
3.1. WATER 11
3.2. FOOD 11
3.3. INHALATION 11
3.4. DERMAL 12
3.5. SUMMARY 12
4. AQUATIC TOXICITY 13
4.1. PLANT EFFECTS 13
4.2. SUMMARY 13
5. PHARMACOKINETCS 14
5.1. ABSORPTION 14
5.2. DISTRIBUTION 16
-------
TABLE OF CONTENTS (cont.)
5.3. METABOLISM 19
5.4. EXCRETION 21
5.5. SUMMARY 22
6. EFFECTS . 24
6.1. SYSTEMIC TOXICITY 24
6.1.1. Inhalation Exposures 24
6.1.2. Oral Exposures 25
6.1.3. Other Relevant Information 32
6,2. CARCINOGENICITY 34
6.2.1. Inhalation 34
6.2.2. Oral 34
6.2.3. Other Relevant Information 34
6.3. MUTAGENICITY 34
6.4. TERATOGENICITY . 36
6.5. OTHER REPRODUCTIVE EFFECTS 36
6.6. SUMMARY. 36
7. EXISTING GUIDELINES AND STANDARDS . 39
7.1. HUMAN. 39
7.2. AQUATIC. . 39
8. RISK ASSESSMENT 40
8.1. CARCINOGENICITY 40
8.1.1. Weight of Evidence 40
8.1.2. Quantitative Risk Estimates 40
8.2. SYSTEMIC TOXICITY '. 40
8.2.1. Inhalation Exposure 40
8.2.2. Oral Exposure 41
9. REPORTABLE QUANTITIES 45
9.1. BASED ON SYSTEMIC TOXICITY 45
9.2. BASED ON CARCINOGENICITY 55
10. REFERENCES 56
APPENDIX A: LITERATURE SEARCHED 67
APPENDIX B: SUMMARY TABLE FOR 1,1,2-TRICHLOROPROPANE 70
APPENDIX C: SUMMARY TABLE FOR 1,2,3-TRICHLOROPROPANE . . 71
x1
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LIST OF TABLES
No. Title
1-1 Synonyms, Structure and CAS Registry Number of Selected
TMchloropropane Isomers
1-2 Some Physical Properties of Selected TMchloropropane
Isomers ........................... 3
1-3 Production Data for the TMchloropropane Isomers ....... 4
5-1 Cumulative Excretion of Radioactivity In Male Fischer 344
Rats 8 Days Following Single Oral Doses of Radlolabeled
1 ,2,3-TMchloropropane .................... 15
5-2 Tissue/Blood Radlolabel Concentration Ratios at
Representative Times After Administration of 1,2,3-TM-
chloropropane ........................ 18
6-1 Mutagen1c1ty Testing of 1 ,2,3-TMchloropropane. ....... 35
9-1 Toxldty Summary for 1 ,1 ,2-Tr1chloropropane 1n a 13-Week
Drinking Water Experiment 1n Rats .............. 46
9-2 Oral Toxldty Summary for 1 ,2,3-TMchloropane ......... 47
9-3 Oral Composite .Scores for 1 ,1,2-Trlchloropropane
Using Rats ........... . . . . ...... ..... 50
9-4 Oral Composite Scores for 1,2,3-Trlchloropropane ....... 52
9-5 1,1,2-TMchloropropane: Minimum Effective Dose (MED)
and Reportable Quantity (RQ) ................. 53
9-6 1,2,3-Trlchloropropane: Minimum Effective Dose (MED)
and Reportable Quantity (RQ) ....... ......... . 54
-------
LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
BCF B1oconcentrat1on factor
BUN Blood urea nitrogen
CAS Chemical Abstract Service
CHO Chinese hamster ovary
CNS Central nervous system
CS Composite score
DMSO Dimethyl sulfoxlde
ONA Deoxyrlbonuclelc acid
EC5Q Concentration effective In 50% of recipients
HPLC High performance liquid chromatography
K Soil sorptlon coefficient
oc
K Octanol/water partition coefficient
LDrQ Dose lethal to 50% of recipients
LOAEL Lowest-observed-adverse-effect level
MED Minimum effective dose
MTD Maximum tolerated dose
NAOPH N1cot1nam1de adenlne dlnucleotlde phosphate, reduced form
NOAEL No-observed-adverse-effect level
OCT Orn1th1ne carbamyl transferase
PEL Permlssable exposure level
ppm Parts per million
RfD Reference dose
RQ Reportable quantity
RV. Dose-rating value
RV Effect-rating value
SDH Sucdnlc dehydrogenase
SGOT Serum glutamlc oxaloacetlc transamlnase
SGPT Serum glutamlc pyruvlc transamlnase
STEL Short-term exposure level
TLV Threshold-limit value
TOC Total organic carbon
TWA Time-weighted average
-------
1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
The synonyms, structures and CAS Registry numbers for selected tr1-
chloropropanes are provided In Table 1-1. All of the trlchloropropane
Isomers have a molecular weight of 147.43 and an empirical formula of
C3H5C13.
1.2. PHYSICAL AND CHEMICAL PROPERTIES
TMchloropropanes are colorless liquids at room temperature and have an
odor typical of chlorinated hydrocarbons (Williams, 1949). 1,2,3-Tr1chloro-
propane 1s mlsclble with acetone, ethyl alcohol and higher alcohols, benzene
and other aliphatic hydrocarbons, and with other chlorinated hydrocarbons.
'It Is moderately to highly soluble 1n cellulose derivatives, chlorinated
rubbers, fats, oils and waxes (Williams, 1949). When heated to decomposi-
tion, trlchloropropanes emit toxic chlorine fumes (Sax, 1984). Selected
physical properties are listed 1n Table 1-2. The conversion factor at 20°C
for the selected Isomers Is 1 mg/m3 = 0.16 ppm.
1.3. PRODUCTION DATA
Table 1-3 lists production data for the tMchloropropane Isomers; no
production data were available for 1,1 ,l-tr1chloropropane or a commercial
trlchloropropane mixture.
SRI (1986) dtes Dow Chemical U.S.A. In Freeport, TX, and Shell 011 Co.
In Deer Park, TX, as the only current domestic manufacturers of l,2,3-tr1-
chloropropane; however, recent production volume data could not be located
In the available literature as cited 1n Appendix A. Production data for the
other trlchloropropane Isomers could not be located 1n the available
literature as dted In Appendix A, which suggests that these compounds
have Uttle, 1f any, commercial Importance 1n the United States.
OOlld -1- 04/10/87
-------
o
o
TABLE 1-1
Synonyms. Structures and CAS Registry Numbers of Selected TrIchloropropane Isomers
TrIchloropropane
Synonym
Structure
CAS Registry Number
1,1.1-TrIchloropropane
1,1,2-TrIchloropropane
1.2.2-TrIchloropropane
1,2,3-TrIchloropropane
Trlchloropropane mixture
ethylchloroforra
NR
NR
allyl trichloride.
glycerol trlchlorohydrtn
trtchlorohydrln
trIchloropropane
Cl H H
I I I
Cl-C—C—C—H
I I I
Cl H H
Cl H H
I I I
H-C—C—C—H
I I I
Cl Cl H
Cl Cl H
I I I
H-C—C—C—H
I I I
H Cl H
Cl Cl Cl
I I I
H-C—C—C—H
I I I
H H H
NR
7789-89-1
598-77-6
3175-23-3
96-18-4
25735-29-9
NR = Not reported
o
•»v
CD
-------
TABLE 1-2
o
Q.
Trlchloropropane
Isoroer
1.1.1-
1.1.2-
1.2,2-
1.2.3-
i
CJ
boroe i
Melting
Point
-77.64a
-68. 7a
-66.183
-14. 7b
'nysicai m
Boiling
Point
107. Oa
130. 9a
121. 3a
156.85b
iperues or beie
Vapor
Pressure
(mm Hg)
30 (25°C)d
12 (25°C)d
19 (25°C)h
2 (20*C)b
3.1 (25*C)C
ctea iricnioropi
Water
Solubility
(rag/l)
210 (25°C)g
710 (25°C)g
710 (25*C)9
1900 (20°C)C
ropane isomers
Specific
Log Kow Gravity
3.01e 1.287j3f
2.58e 1.37215f
2.58e 1.31825f
1.98e 1.38892^^
Refractive
Index. NJJ0
1.4490a
1.46843
1.46163
1.4852a
aU1111aros. 1949
bDow Chemical Co.. 1985
cNacKay and Shul. 1981
dPerry and Green. 1984
eU.S. EPA. 1987a
fUeast. 1985
QEsttmated using the equation, log 1/S = 1.221 log Kow - 0.832 (Lyroan et al., 1982)
o "Estimated by the method of Neely and Blau (1985)
o
•^
GO
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TABLE 1-3
Production Data for the TMchloropropane Isomers*
Isomer
Company/Location
Freeport, TX
Dow Chemical Co.
Midland, HI
Columbia Organic Chemicals Co.
Columbia, SC
Shell Oil Co.
Deer Park, TX
1977 Production Volume
(million pounds)
1,1,2-
1,2,2-
1,2,3-
Columbia Organic Chemicals Co.
Columbia, SC
Columbia Organic Chemicals Co.
Columbia, SC
Dow Chemical Co.
<0.001
<0.001
10.00-50.00
(site limited use)
10.00-50.00
(site limited use)
<0.001
1.00-10.00
*Source: U.S. EPA, 1977
001 Id
04/10/87
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1,1,1-TMchloropropane 1s manufactured by the reaction of 1 ,l-d1chloropro-
pane with HC1 1n the presence of A1CK. 1,1,2-Tr1chloropropane 1s manu-
factured by the chlorlnatlon of either 1-chloropropane or 1,2-d1ch1oropro-
pane, and 1,2,2-tr1chloropropane 1s made by the chlorlnatlon of either
1,2-d1chloropropane or 2-chloropropane (Williams, 1949). 1,2,3-Tr1chloro-
propane Is derived from the chlorlnatlon of propylene (Hawley, 1981).
1.4. USE DATA
1,2,3-TMchloropropane 1s used as a crossllnking agent, chemical Inter-
mediate for agricultural and pharmaceutical products (Kuney, 1985), solvent,
degreaslng agent, and paint and varnish remover (Hawley, 1981). Uses for
the other Isomers could not be located 1n the available literature as dted
1n Appendix A.
1.5. SUMMARY
TMchloropropanes are colorless liquids at room temperature and have an
•
odor typical of chlorinated hydrocarbons (Williams, 1949). They are
sparingly soluble 1n water (see Table 1-2). When heated to decomposition,
trlchloropropanes emit toxic chlorine fumes (Sax, 1984). The U.S EPA TSCA
Production File (U.S. EPA, 1977) reported that one manufacturer produced
1,1,2- and 1,2,2-tMchloropropane and four manufacturers produced 1,2,3-trl-
chloropropane during 1977; however, this source contained no production
Information on 1,1 ,l-tr1chloropropane or a tMchloropropane mixture. SRI
(1986) cites Dow Chemical U.S.A. 1n Freeport, TX, and Shell 011 Co. 1n Deer
Park, TX, as the only current manufacturers of 1,2,3-tMchloropropane 1n the
United States. Production data on 1,1,1-, 1,1,2- and 1,2,2-tr1chloropropane
and trlchloropropane mixture were not located 1n current sources of chemical
production and sales Information, suggesting that these compounds have
OOlld -5- 05/12/87
-------
little, 1f any, commercial Importance 1n the United States. 1,2,3-TM-
chloropropane 1s used as a crossHnklng agent, chemical Intermediate for
agricultural and pharmaceutical products (Kuney, 1985), solvent, degreaslng
agent, and paint and varnish remover (Hawley, 1981).
001 Id -6- 04/10/87
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2. ENVIRONMENTAL FATE AND TRANSPORT
Limited data pertaining to the environmental- fate and transport of
tMchloropropanes were located 1n the available literature as dted In
Appendix A. Information concerning fate and transport of these compounds
was derived from physical property data or molecular structures.
2.1. AIR
2.1.1. Reaction with Hydroxyl Radicals. Based on the relatively high
vapor pressures of the trlchloropropane Isomers (see Table 1-2), these
compounds are expected to exist almost entirely In the vapor phase In the
atmosphere (E1senre1ch et al., 1981). The half-lives for 1,1,1-, 1,1,2-,
1,2,2- and 1,2,3-tMchloropropane vapor reacting with photochemically
generated hydroxyl radicals have been estimated to be 15, 6, 30 and 7 days,
respectively, using an ambient hydroxyl radical concentration of S.OxlO9
molecules/cm3 and estimated reaction rate constants of 6.7xlO~13,
1.6xlO~12, 3.3xlO~ia and l.SxlO"12 cm'-sec/molecule, respectively,
at 25°C (U.S. EPA, 1987b).
2.1.2. Reaction with Ozone. TMchloropropanes are not susceptible to
oxidation by ozone (U.S. EPA, 1987b).
2.1.3. Physical Removal Processes. Based on the water solubilities
listed In Table 1-2, potential exists for removal of small amounts of
trlchloropropanes from the atmosphere by dissolution Into clouds or wet
deposition; however, any trlchloropropane removed from the atmosphere by
dissolution or washout 1s likely to reenter the atmosphere by volatilization.
2.2. WATER
2.2.1. Hydrolysis. Based on estimated neutral hydrolysis reaction rate
constants of 2xlO"«, 8x10"*, 8xlO"» and 8xlO"5 hour"1 for 1,1,1-,
OOlld -7- 04/10/87
-------
1,1,2-, 1,2,2- and 1,2,3-tMchloropropane, respectively, hydrolysis of
trlchloropropanes 1s not expected to be environmentally relevant (Jaber et
al., 1984).
2.2.2. Oxidation. Trlchloropropanes are not expected to be susceptible
to oxidation (Jaber et al., 1984).
2.2.3. Photolysis. Photolysis of trlchloropropanes Is not expected to be
environmentally relevant (Jaber et al., 1984).
2.2.4. M1crob1al Degradation. An aerobic blodegradatlon screening study
using 55 mg/i of 1,2,3-tMchloropropane Inoculated with activated sludge
at 25°C resulted 1n 40, 51 and 76% TOC removal after 2, 4 and 6 hours,
respectively (Matsul et al., 1975).
2.2.5. Adsorption. Given the water solubilities of the trlchloropropane
Isomers listed 1n Table 1-2 and KQC values of 69-231 (Section 2.3.2.),
physical adsorption of these compounds to suspended solids and sediments Is
not expected to be significant.
2.2.6. B1oaccumulat1on. Based on the estimated log K values listed
ow
1n Table 1-2, BCFs of 114, 54, 54 and 19 were estimated for 1,1,1-, 1,1,2-,
1,2,2- and 1,2,3-trVchloropropane, respectively, using the following
equation (Lyman et al., 1982): log BCF = 0.76 log KQW - 0.23. These BCF
values suggest that bloaccumulatlon of trlchloropropanes 1n aquatic organ-
Isms would be of limited environmental significance.
2.2.7. Volatilization. The half-life for evaporation of 1,2,3-trlchloro-
propane from a 1 ppm aqueous solution at 25°C with a depth of 6.5 cm, under
200 rpm stirring In still air (<0.2 mph air currents) was measured to be
56.1 minutes (Dining, 1977). Henry's Law constant for 1,2,3-tMchloro-
propane has been estimated to be 2xlO~* atm-mVmol based on a vapor
pressure of 2 mm Hg at 20°C and a water solubility of 1900 mg/i at 20°C.
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Using this value of Henry's Law constant and the method of Lyman et al.
(1982), the volatilization half-life of this compound from water 1 m deep,
flowing at a speed of 1 m/sec with a wind speed of 3 m/sec has been
estimated to be 8.8 hours. These data suggest that volatilization may be a
primary method for removal of 1,2,3-tMchloropropane from water. Because of
the similarities 1n the physical properties among the trlchloropropanes,
volatilization Is also expected to be a primary removal mechanism for the
other trlchloropropane Isomers.
2.3. SOIL
2.3.1. Chemical Degradation. Based on Information available on the
chemical degradation of trlchloropropanes In water, these compounds are not
expected to hydrolyze or oxidize 1n soil (see Sections 2.2.1. and 2.2.2.).
2.3.2. Leaching. The KQC values, of 1,1,1-, 1,1,2-, 1,2,2- and
1,2,3-tMchloropropanes were estimated to be 231, 118, 118 and 69, respec-
tively, using the water solubility data given 1n Table 1-2, and the equation
log KQ = -0.55 log S * 3.64 (Lyman et al., 1982). KQC values of 72,
79, 72 and 99 were estimated for 1,1,1-, 1,1,2-, 1,2,2- and 1,2,3-tMchloro-
propane using the quantitative structure-activity analysis method of SablJIc
(1984). Based on these K values trlchloropropanes are expected to be
highly mobile 1n soil (Swann et al., 1983).
2.3.3. Volatilization. The relatively high vapor pressure of the
trlchloropropane Isomers (ranging from 3-30 mm Hg at 25°C) suggest that
volatilization from dry soil surfaces 1s likely to be significant. Evapora-
tion from moist soils may also be significant since these compounds do not
tend to adsorb to soil and apparently evaporate rapidly from water (see
Sections 2.2.7. and 2.3.2.).
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2.4. SUMMARY
In water, volatilization 1s expected to be a primary removal mechanism
for trlchloropropanes. The volatilization half-life of 1,2,3-tMchloropro-
pane from water 1 m deep, flowing at a speed of 1 m/sec with a wind speed of
3 m/sec has been estimated to be ~9 hours. Trlchloropropanes are not
expected to undergo significant chemical hydrolysis, oxidation, photolysis
(Jaber et al., 1984), bloaccumulatlon 1n aquatic organisms or adsorption to
suspended solids or sediments. Insufficient data are available to determine
the significance of mlcroblal degradation as a removal mechanism. In air,
trlchloropropanes are expected to exist entirely In the vapor phase. These
compounds are expected to react with photochemlcally generated hydroxyl
radicals. Estimated reaction half-lives for 1,1,1-, 1,1,2-, 1,2,2- and
1,2,3-trlchloropropane at 25°C have been estimated to be 15, 6, 30 and 7
days, respectively (U.S. EPA, 1987b). Potential exists for removal from the
atmosphere by dissolution Into clouds and washout; however, trlchloroprd-
panes removed by dissolution or washout are likely to reenter the atmosphere
by volatilization. These compounds may be persistent In the atmosphere. In
soil, leaching and volatilization are expected to be Important transport
processes for the trlchloropropanes. These compounds are not expected to
hydrolyze or oxidize and H 1s not known whether mlcroblal degradation would
be significant because soil blodegradatlon studies on these compounds are
not available.
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3. EXPOSURE
3.1. WATER
1,1,1-Trlchloropropane and 1,2,3-tMchloropropane have been detected at
concentrations of <0.1 and 0.2 yg/l, respectively, In drinking water
taken from the Carrollton Water Plant 1n New Orleans, LA, during August 1974
(Keith et al., 1976). 1,2,3-TMchloropropane was also detected 1n the
drinking water of Ames, IA (U.S. EPA, 1983b) and trlchloropropane (Isomer
not specified) was qualitatively Identified 1n drinking water taken from
Cincinnati, OH during 1978 (Lucas, 1984). 1,2,3-TMchloropropane was
qualitatively Identified 1n water samples taken from Narragansett Bay, RI
during 1979-1981 (Wakeham et al., 1983) and trlchloropropane (Isomer not
specified) was detected In 1/30 water samples taken from the Delaware River
1n February, 1976 (DeWalle and Chlan, 1978). 1,2,3-TMchloropropane has
also been found In the Rhine River 1n Germany at maximum and mean concentra-
tions of 0.1 and 1.3 yg/i, respectively (U.S. EPA, 1983b)l Trlchloro-
propane (Isomer not specified) was Identified 1n water taken from an
advanced waste treatment plant 1n Lake Tahoe, CA, during 1974 (Lucas, 1984).
3.2. FOOD
Pertinent monitoring data regarding the presence of tMchloropropanes 1n
food could not be located 1n the available literature as dted 1n Appendix A.
3.3. INHALATION
Limited monitoring data were available concerning the detection of
tMchloropropanes 1n the atmosphere. Since tMchloropropanes are volatile.
It 1s likely that workers using these compounds would be exposed by Inhala-
tion. Based on the National Occupational Exposure Survey, NIOSH (1984)
estimated that 490 workers are likely to be occupatlonally exposed to
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1,2,3-trlchloropropane.- 1,2,3-TMchloropropane was detected In the
atmosphere of Bochum, Germany at a concentration of 0.4 yg/m3 (U.S. EPA,
1983b).
3.4. DERMAL
Pertinent data regarding dermal exposure to trlchloropropanes could not
be located 1n the available literature as cited 1n Appendix A.
3.5. SUMMARY
TMchloropropane Isomers have been detected 1n drinking water from New
Orleans, LA (Keith et al., 1976), Ames, IA (U.S. EPA, 1983b) and Cincinnati,
OH (Lucas, 1984), and surface water samples from Narragansett Bay, RI
(Wakeham et al., 1983). the Delaware River basin (DeWalle and Chlan, 1978)
and the Rhine River (U.S. EPA, 1983b). Since trlchloropropanes are volatile
1t 1s likely that workers using these compounds would be exposed by Inhala-
tion. Based on the National Occupational Exposure Survey, NIOSH (1984)
estimated that 490 workers are -likely to be occupatlonally exposed to
1,2,3-trlchloropropane. Pertinent monitoring data for estimating the dally
human exposure to trlchloropropanes by Inhalation, 1ngest1on of food and
drinking water or dermal contact could not be located In the available
literature as cited 1n Appendix A.
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4. AQUATIC TOXICITY
Pertinent data regarding acute or chronic toxlclty of tMchloropropanes
to aquatic organisms could not be located In the available literature as
cited 1n Appendix A.
4.1. PLANT EFFECTS
Hutchlnson et al. (1980) reported 3-hour EC5Qs for Inhibition of
photosynthesis of 112 mg/a 1,2,3-tr1chloropropane for Chlamydomonas
anqulosa and 170 mg/l for Chlorella vulgarls.
4.2. SUMMARY
Little Information was available concerning effects of tMchloropropanes
on aquatic biota. The only data were those of Hutchlnson et al. (1980) who
reported 3-hour EC,Qs for Inhibition of photosynthesis of 112 mg/l
1,2,3-tMchloropropane for Chlamydomonas anqulosa and 170 mg/l for
Chlorella vulqarls.
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5. PHARMACOKINETICS
5.1. ABSORPTION
•
S1pes et al. (n.d.) reported the results of oral administration of
single doses of 14C-1,2,3-tMchloropropane In ethanol/Emulphor EL-60/water
to groups of three male Fischer 344 rats at 0.35, 3.0 or 32 mg/kg.. Cumula-
tive excretion of radioactivity 1n urine and feces during an 8-day collec-
tion period are presented 1n Table 5-1. Because total recovery was particu-
larly low 1n the 3.0 mg/kg group, expired air was collected from one rat 1n
this group for 24 hours and was found to contain "30% of the administered
dose of radioactivity. Upon sacrifice at 8 days, the body was found to
contain -1-3% of the dose of radioactivity.
Assuming exhalation of -30% of the dose, urinary excretion of 37.6-56.3%
and body retention of -2%, a minimal gastrointestinal absorption of -70-80%
can be estimated. Alternatively, minimum gastrointestinal absorption can be
estimated by subtracting the percentage of the dose recovered 1n the feces
from 100%. Using this method, minimum gastrointestinal absorption of
-75-83% can be estimated. In this study, however, total recovery was only
54.3-81.6%.
Biliary excretion may be substantial as demonstrated by Volp et al.
(1984), who administered an Intravenous 3.6 mg/kg dose of 14C-1,2,3-tr1-
chloropropane to male Fischer 344 rats with bile duct cannulae and recovered
30% of the dose of radioactivity 1n the bile within 6 hours (Section 5.4.).
In Intact rats at 24 hours after treatment, 18% of the dose was recovered 1n
the feces, 50% In the urine and 30% 1n the expired air. The similarities In
the disposition of radioactivity following Intravenous administration of 3.6
mg/kg and oral administration of 0.35-32 mg/kg suggest that both previous
*
estimates of minimum extent of gastrointestinal absorption are low and that
absorption may be virtually complete.
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TABLE 5-1
Cumulative Excretion of Radioactivity In Male Fischer 344 Rats
8 Days Following Single Oral Doses of Radlolabeled
1,2,3-Tr1chloropropanea
Dose
(mg/kg)
0.35b
3.0b
3.2C
Percent of
Urine
42.5
37.6
56.3
Dose Recovered
Feces
19.5
16.8
25.3
1n
Total
62.0
54.3
81.6
aSource: Slpes et al., n.d.
cn=3
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The excretion data reported by Slpes et al. (n.d.) suggest that the rate
of absorption from the gastrointestinal tract Is fairly rapid following oral
administration. Urinary excretion at all three dose levels was >91%
complete within the first 24 hours, accounting for 34-51% of the dose. An
additional 30% was recovered from the expired air of one 3.0 mg/kg rat
within 24 hours, which also suggests that the rate of gastrointestinal
absorption Is fairly rapid.
5.2. DISTRIBUTION
Volp et al. (1984) Investigated the fate of [1,3-14C]-l,2,3-trlchloro-
propane In young adult male Fischer 344 rats given single Intravenous 3.6
mg/kg doses. Following administration, the disappearance of unchanged
parent compound from the blood was observed to be rapid and blexponentlal,
with a phase I (distribution phase) half-life of 0.29 hours. These observa-
tions suggest rapid uptake by the tissues of the body. Maximum levels of
radioactivity In adipose tissue, skin and muscle were reached by 15 minutes,
with 37, 16 and 18% of the dose located In these tissues, respectively.
These tissues contained most of the radioactivity that remained 1n the body
through 4 hours posttreatment. After 4 hours, the liver contained a greater
portion of the administered dose than did other tissues. Maximum levels of
radioactivity 1n the liver (7.3% of dose) and small Intestinal tissue (9.3%
of dose) were measured at 1 hour, 1n the kidney (2.8% of dose) at 2 hours
and In large Intestinal tissue (2.0% of dose) at 8 hours.
The concentration of unaltered parent compound as well as total radio-
activity was measured 1n several tissues, and for all tissues the rate of
decline of unchanged parent compound was found to be greater than the
decline of total radioactivity. At 1 hour, parent compound consisted of
0
<10% of the radioactivity present In liver and kidney and 45 and 34% of the
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radioactivity In muscle and skin, respectively. By 24 hours, parent com-
pound had declined to <12% of the radioactivity In these tissues as well.
In fat, however, unaltered parent compound was 69% of the radioactivity
present at 4 hours and 37% at 24 hours.
The concentrations of radlolabel 1n tissue/blood for several tissues at
three time points are presented 1n Table 5-2. With the exception of the
data for adipose tissue, levels of radioactivity represent predominantly
metabolites. Coupled with the data presented above, these data suggest that
adipose tissue may serve as a primary but temporary depot for the distribu-
tion of 1,2,3-tMchloropropane. No tissue studied exhibited a propensity to
bloaccumulate the parent compound following a single dose. The levels of
radioactivity 1n the liver and kidneys appear to be relatively persistent.
Slpes et al. (n.d.) reported the tissue concentrations of radioactivity
In several tissues of rats at 8 days after single oral doses of
l4C-l,2,3-tr1chloropropane to be 0.35, 3.0 or 32 mg/kg. Concentrations
were expressed as percent of the dose In each tissue and as the ratio of the
concentration In tissue to blood. Because total recovery of radioactivity
1n this experiment was low, IHtle confidence can be placed 1n the absolute
values reported. Generally, however, these data confirm the observations
reported by Volp et al. (1984) following Intravenous administration. At all
dose levels, the greatest percentages of the dose of radioactivity were
located In the muscle, blood, skin and adipose tissue. Ratios of tissue
radioactivity to blood radioactivity at 8 days were >1 only In liver and
kidneys, and this occurred only at the low and high doses. No tissue
appeared to retain radioactivity to a great extent following oral adminis-
tration.
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TABLE 5-2
Tissue/Blood Radlolabel Concentration Ratios at
Representative Times After Administration of
1,2,3-TMchloropropane (x±SO, n=3)a«b
Tissue
Liver
Kidneys
Adipose tissue
Skin
Muscle
Testes
Ep1d1dym1des
Blood concentration
(nmol-equ1v/g)
1 Hour
2.9*0.2
5.4*1.1
6.5*2.4
0.9*0.3
0.4*0.1
0.5*0.1
1.8*0.1
11.0*0.0
Time
8 Hours
5.5*0.4
10.8*0.3
2.7*0.4
1.3*0.3
0.4*0.1
0.7*0.1
ND
4.8*0.2
2 Days
4.1*0.7
6.7*1.7
0.6*0.5
0.6*0.2
0.3*0.1
0.2*0.1
0.6*0.0
2.0*0.3
aSource: Volp et al., 1984
b3.6 mg/kg Intravenous
NO > Not determined
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5.3. METABOLISM
In the rat study by Volp et al. (1984) (see Section 5.2.), 25X of the
administered dose of radioactivity was recovered from the expired air as
carbon dioxide within 24 hours. Urinary excretion of metabolites within 24
hours accounted for 40X of the dose. In rats with biliary cannulae, 28.5X
of the administered dose was recovered from the bile as metabolites within 6
hours. Although these urinary and biliary metabolites have not been defini-
tively Identified, the Investigators noted that a large number of metabo-
lites were present and that no one metabolite constituted >10% of the
administered dose. The large number of urinary metabolites observed and the
rapid recovery of 25X of the dose as expired carbon dioxide suggest that
'one- and two-carbon fragments may have been Incorporated Into endogenous
molecules.
Volp et al. (1984) suggested that the biliary metabolites were products
of glutathlone conjugation, formed either by direct conjugation following
dechlortnatlon or after cytochrome P-450 catalyzed oxidation. Administra-
tion of glycldol to deplete hepatic glutathlone before treatment with
l4C-l,2,3-tr1chloropropane resulted 1n a 69-84X reduction In excreted
biliary radlolabel. Reacting bile from non-glyc1dol treated rats with
2,4-d1n1trofluorobenzene (to form 2,4-d1n1trophenyl derivatives of products
of glutathlone conjugation that are separable by HPLC) led to the separation
of five major fractions representing metabolites formed from conjugation
with glutathlone. Four of these fractions were present at very low concen-
trations and the fifth was decreased by 40X 1n the bile from glyddol-
treated rats. These data support the theory that glutathlone conjugation 1s
Important In the metabolism of 1,2,3-tr1chloropropane and suggest that the
liver 1s the major site of this blotransformatlon reaction.
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Several ]_n vitro studies have been performed with various chlorinated
alkanes to Investigate their Interactions with mlcrosomal hepatic drug
metabolizing enzymes, and the Impact of chemical structure on enzymatic
dechloMnatlon and the mechanisms by which 1t occurs (Ivanetlch et al.,
1978; Van Dyke and Wlneman, 1971; Salmon et al., 1981). 1,2,3-TMchloropro-
pane has been shown to undergo Type I binding to cytochrome P-450 derived
from the livers of phenobarbHol-lnduced male Wlstar rats and cause degrada-
tion of Us heme moiety (Ivanetlch et al., 1978). Van Dyke and Wlneman
(1971) Investigated the dechlorlnatlon of several chlorinated ethanes and
propanes 1n a system using mlcrosomes and cell supernatant from the livers
of male rats. Dechlorlnatlon was found to be NADPH-dependent. The presence
of a single hydrogen molecule on the dechlorlnated carbon atom appeared to
enhance dechlorlnatlon. After 30 minutes of Incubation In this system,
1,1,2-tr1chloropropane, the only trlchloropropane tested, was 40.8% dechlor-
lnated. By comparison, dechlorlnatlon of various mono- and dlchloHnated
propanes ranged from 2.5-24.6X.
Salmon et al. (1981) noted marked differences 1n the toxic potencies of
several haloalkanes that appeared to be roughly correlated with the extent
of dechlorlnatlon they undergo ^n vivo. It had been suggested that the
breaking of a C-C1 bond, presumably with the formation of a reactive Inter-
mediate, was responsible for the toxldty of these compounds. These authors
Investigated the enzymatic dechlorlnatlon of six chlorinated ethanes and
reviewed the data of Van Dyke and Wlneman (1971) for chlorinated ethanes and
propanes. and concluded that the extent of dechlorlnatlon was strongly
dependent on molecular structure. They also noted that the tendency toward
dechlorlnatlon was not linearly correlated with either the effective charge
a
on the most electron-deficient carbon atom or with hydrophobldty of the
001 Id -20- 05/12/87
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test chemical, which suggested to them that dechloMnatlon of different
chloroalkanes probably proceeds by different mechanisms.
According to the data of Van Dyke and Wlneman (1971) and Salmon et al.
(1981), marked differences may be expected 1n the metabolic reactions and
their rates In the b1otransformat1on of the various Isomers of trlchloropro-
pane. Since toxic potency and effects may depend at least partially on
these reactions, marked differences may also be expected 1n the toxldty of
these chemicals.
5.4. EXCRETION
Following the Intravenous administration of a single 3.6 mg/kg dose of
14C-l,2,3-tr1chloropropane to male rats, 99% of the dose of radioactivity
was excreted within 6 days through urine, feces and expired air (Volp et
al., 1984). Total excretion appeared to be blphaslc with half-times of 5.1
and 44 hours for phase I and phase II, respectively. Within the first 24
hours, expired air contained 30% of the dose of radioactivity, urine
contained 40% and feces 18%.
The expiration of unchanged parent compound, accounting for 5% of the
dose, was trlphaslc with half-times of 0.44, 1.2 and 4.0 hours, and was 85%
complete after 4 hours. Expiration of carbon dioxide was blphaslc with
half-times of 1.2'and 3.4 hours.
•r
Unchanged parent compound was not detected In urine. Intestinal
contents contained 1% of the dose as unchanged compound at 15 and 30 minutes
but <0.1% of the dose at >4 hours. Excretion by either route was blphaslc,
with half-times of 2.6 and 54 hours for urinary excretion and 5.1 and 44
hours for fecal excretion.
In rats with biliary cannulae, 30% of the dose of radioactivity (5% of
0
dose as unchanged compound) was recovered from the bile within 6 hours. At
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24 hours, only 18% of the dose was found 1n the feces, which suggests that
Intestinal absorption of biliary excretion products occurred, followed
possibly by further metabolism and excretion by alternate routes.
The excretion of radioactivity following oral treatment of rats with
14C-l,2,3-tr1chloropropane at doses of 0.35, 3.0 and 32 mg/kg (Slpes et
al., n.d.) was reported 1n Section 5.1. Although confidence In these data
1s low because total recovery of radioactivity was poor, the excretion
patterns following oral treatment are similar to those following Intravenous
treatment. Urinary excretion accounted for 37.6-56.3% and fecal excretion
for 16.8-25.3X of the dose by 8 days posttreatment. Expiration of ~30X of
the dose occurred within 24 hours.
5.5. SUMMARY
Patterns of excretion of radioactivity following oral administration of
l4C-l,2,3-tr1chloropropane to- rats (Slpes et al., n.d.) are similar to
those observed following Intravenous treatment (Volp et al., 1984), which
suggests that gastrointestinal absorption was fairly rapid and nearly
complete. Data were not located regarding absorption by the respiratory
tract.
Following Intravenous treatment 1n rats, 1,2,3-tr1chloropropane was
distributed rapidly (half-life 0.29 hours) from the blood, primarily to
adipose tissue, muscle and skin (Volp et al., 1984). After 4 hours, concen-
trations of radlolabel, associated primarily with metabolites, were highest
1n the kidneys and liver. No organ or tissue showed a tendency to retain
radlolabel following a single Intravenous (Volp et al., 1984) or oral (Slpes
et al., n.d.) dose, although no prediction can be made for a chronic dosing
schedule.
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Metabolism of 1,2,3-tMchloropropane appears to be rapid, and carbon
dioxide, at 25% of the dose, 1s the major metabolite. Urinary metabolites
(several, but unidentified) accounted for 40% of the dose by 24 hours.
Conjugation with glutathlone results 1n metabolites that are excreted 1n the
urine. The metabolism of other trlchloropFopanes 1s likely to occur by
1somer-spec1f1c Intermediate pathways, with the probability of the formation
of 1somer-spedf1c toxic Intermediates. The liver appears to be the
principal site of metabolism. Excretion of Intravenously administered
1,2,3-tr1chloropropane and Us metabolites was virtually complete (99% of
dose) by 6 days (Volp et a!., 1984). Excretion occurred primarily through
the urine and expired air (40 and 30% of dose by 24 hours) and less (18% of
dose) by the feces. Biliary excretion 1s substantial (30% of dose within 6
hours), but appears to be followed by Intestinal absorption. Excretion
patterns following oral administration (Slpes et al., n.d.) are similar to
those following Intravenous dosing.
001 Id -23- 05/12/87
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6. EFFECTS
6.1. SYSTEMIC TOXICITY
6.1.1. Inhalation Exposures.
6.1.1.1. SUBCHRONIC — Several Inhalation studies with 1.2,3-trl-
chloropropane In adult male white rats, all performed at the same labora-
tory, have been reported (Tsulaya et al., 1977, 1979; Bonashevskaya and
Belyaeva, 1975, Bonashevskaya, 1977; Bonashevskaya et al., 1978; Belyaeva et
al., 1977; Tarasova, 1975; Shalpak, 1976; Sldorenko et al., 1979). Although
H was not clearly stated 1n each report, 1t appears that continuous
exposure was used 1n all of these experiments and the duration of exposure
ranged from 7 days to 3 months.
The evaluated parameters of toxldty Included rate of body weight gain,
hematology, and hlstopathologlcal appearance of the liver and lungs.
Several h1stochem1cal, biochemical and CNS function parameters of unknown or
questionable biological significance were also reported. The nature and
severity of the effects observed at each concentration were not always
clearly presented.
In experiments lasting <3 months, which Investigated atmospheric concen-
trations of 0.2-800 mg/m3 1,2,3-tr1chloropropane, no effects on rate of
body weight gain or hematologlcal parameters occurred 1n rats at any concen-
tration tested (Sldorenko et al., 1979; Tsulaya et al., 1979; Bonashevskaya,
1977). At 2 mg/m3, mild hlstopathologlcal lesions 1n the Hver Included
mlcrodrculatory alterations, fatty Infiltration, hypochromlc and (rarely)
lysed nuclei (Tsulaya et al., 1977). Significant hlstopathologlcal altera-
tions 1n the liver were not observed at 0.45 mg/m3 (Bonashevskaya, 1977)
or 0.4 mg/m3 (Tsulaya et al., 1977).
001 Id -24- 05/12/87
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The lungs appeared to be another target organ In these studies. Degen-
erative lesions (desquamatlon and proliferation of bronchial and bronchlolar
epithelium, macrophage Infiltration and "reactive alterations In the pleural
mesothellum" were reported at 2 mg/m3 but not at 0.4 mg/m3 (Tsulaya et
al., 1977). Based on the effects reported 1n the liver and lungs, known
target organs for 1,2,3-tr1chloropropane (Section 6.1.2.1.), continuous
exposure to 2 mg/ra3 appears to be a subchronlc LOAEL and 0.4 mg/m3 a
NOAEL for rats In these Russian studies.
6.1.1.2. CHRONIC — Pertinent data regarding the chronic toxlclty of
Inhalation exposure to the trlchloropropanes could not be located In the
available literature as dted 1n Appendix A.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC ~ Vllleneuve et al. (1985) administered
1,1,2- or 1,2,3-tr1chloropropane to groups of 10 male and 10 female weanling
Sprague-Oawley rats at concentrations of 1, 10, 100 or 1000 mg/i In the
drinking water for 13 weeks. Emulphor (0.5X) was used as a solub1l1z1ng
agent: Controls consisted of a group given tap water alone and another
group given tap water containing Emulphor. Parameters evaluated Included
clinical appearance, body weight, water consumption and at termination,
comprehensive hematology and clinical serum chemistry determinations,
hepatic mixed-function oxldase activities, organ weights and hlstopatho-
loglcal examination of major (unspecified) organs and tissues.
The equivalent dosages of each test chemical for each treatment group
are estimated from starting body weight, weight gain and water Intake data
provided by the Investigators for vehicle control rats and groups that
differed significantly from vehicle controls. For 1,1,2-tr1chloropropane,
males Ingested -0, 0.15, 1.5, 15.0 or 150 mg/kg/day and females Ingested 0,
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0.20, 2.0, 20.3 or 203 mg/kg/day at 0, 1, 10, 100 and 1000 mg/i, respec-
tively. For 1,2,3-trlchloropropane, doses were estimated at 0, 0.15, 1.5,
15.0 and 113 mg/kg/day for males and 0, 0.20, 2.0, 17.6 and 149 mg/kg/day
for females, respectively.
One male given 1000 mg/l and one female given 100 mg/l I,l,2-tr1-
chloropropane died of undetermined causes. Water consumption and body
weight gain were unaffected by treatment at any level. Increased relative
liver weight was noted 1n 1000 mg/l males and Increased serum cholesterol
was measured 1n 1000 mg/l females. There were no effects on hematology or
mixed-function oxldase activity. H1ld but significant hlstopathologlcal
lesions were observed 1n the liver, kidney and thyroid of males and females
'at 1000 mg/l but not at <100 mg/l. Liver changes Included anlsokaryo-
s1s, accentuated zonatlon and occasional fatty vacuolatlon. Kidney effects
Included eos1noph1l1c Inclusions, pyknosls, nuclear displacement, fine
glomerular adhesions and occasionally Interstitial reactions and hlstologlc
protelnurla. Thyroid changes consisted of angular collapse of some
follicles, reduction In colloid density and Increased epithelial height.
Lesions appeared to be milder and less prevalent 1n females than males. In
this study, the level of 1000 mg/l, 150 mg/kg/day 1n the males and 203
mg/kg/day In the- females, was clearly a LOAEL, and 100 mg/l, 15.0
mg/kg/day In males and 20.3 mg/kg/day 1n females, was a NOAEL.
1,2,3-Trlchloropropane appeared to be slightly more toxic than
1,1,2-trlchloropropane 1n this study. Water Intake and body weight gain
were reduced 1n rats of both sexes at 1000 mg/l 1,2,3-tr1chloropropane,
and water consumption was reduced In females at 100 mg/l. One 100 mg/l
female died, but the cause of death could not be determined. Elevated
relative organ weights were observed 1n the livers and kidneys In males at
OOlld -26- 04/10/87
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1000 mg/l and 1n females at 100 and 1000 mg/l, and In the brains 1n both
sexes at 1000 mg/l. The Increased relative kidney and brain weights were
attributed to reduced body weights and were not considered toxic manifesta-
tions of 1,2,3-trlchloropropane. Significantly Increased serum cholesterol
levels were noted 1n females at 1000 mg/l. Mixed-function oxldase activi-
ties were Increased 1n both sexes at 100 mg/l. There were no statisti-
cally significant effects on hematology. Mild hlstopathologlcal lesions
similar to those observed with 1,1,2-trlchloropropane occurred In the
livers, kidneys and thyroids of both sexes at 1000 mg/l. Lesions were
more prevalent and more severe than those observed with 1,1,2-trlchloropro-
pane and were more marked and occurred more frequently 1n males than females.
'As with 1,1,2-tr1chloropropane, 1000 mg/l (113 mg/kg/day In males; 149
mg/kg/day In females) was a LOAEL and 100 mg/l (15.0 mg/kg/day 1n males;
17.6 mg/kg/day In females) was a NOAEL.
The NTP (1983a,b) performed preliminary subchronlc 120-day gavage
studies with 1,2,3-trlchloropropane In Fischer 344 rats and B6C3F1 mice; a
chronic cancer experiment Is still In progress (NTP, 1986). Treatment
groups contained 20 an1ma1s/sex/spec1es and the control groups contained 30
an1ma1s/sex/spedes. Controls received the corn oil vehicle on the same
5-day/week schedule that treated animals received the test chemical at 8,
16, 32, 63, 125 or 250 mg/kg. Parameters of toxkUy evaluated Included
food consumption and body weight gain, clinical observations, and at termi-
nation, gross necropsy, body and organ weights,, clinical blood chemistry,
hematology, limited urlnalysls, sperm count and morphology, and hlstopatho-
loglcal examination. In addition, an Interim sacrifice of 10 controls/sex/
species and one-half of the animals 1n each test group was performed after
60 days for evaluation of clinical chemistry, hematology, urlnalysls,
testlcular and ep1d1dymal weights and gross and microscopic pathology.
OOlld -27- 04/10/87
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Extensive hlstopathologlcal examinations were performed on animals that died
or were sacrificed 1n a moribund condition, and at both the 60-day and
terminal sacrifices on control animals of both species and on rats at 125
mg/kg, male mice, at 125 and 250 mg/kg and female mice at 250 mg/kg. In
other groups of rats, hlstopathologlcal examination was limited to selected
target organs at 63 mg/kg at the 60-day Interim sacrifice and at 32 and 63
mg/kg at termination. In other groups of mice, hlstopathologlcal examina-
tion at termination was restricted to selected target organs of males at 32
and 63 mg/kg and of females at 16, 32, 63 and 125 mg/kg.
In the NTP (1983a) study using rats, all rats at 250 mg/kg and one male
and five females at 125 mg/kg died from renal and hepatic toxldty. Food
consumption was markedly decreased at 250 mg/kg, slightly decreased In
females at 125 mg/kg, but comparable with controls In other test groups. A
decrease 1n rate of body weight gain, resulting 1n significantly reduced
terminal body weights, was marked 1n rats of both sexes at 125 mg/kg and
moderate 1n males at 63 mg/kg. Clinical signs Including a transient hunched
and thin appearance were observed 1n all test groups early 1n the study.
These signs disappeared In males after week 7 and 1n females after week 9.
Alopecia 1n 125 mg/kg males and 63 mg/kg females persisted throughout the
study.
The liver and kidney appeared to be the major target, organs for
1,2,3-tr1chloropropane. A dose-related statistically significant Increase
1n absolute and relative liver weights occurred 1n all treated groups of
males and 1n females at >16 mg/kg. Significantly elevated relative kidney
weights occurred 1n both sexes at >32 mg/kg. Relative testlcular weight was
elevated at both 60 and 120 days and epldldymal weight was decreased at 60
days at 125 mg/kg, but there were no effects on sperm count or morphology.
OOlld -28- 05/12/87
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Biologically and statistically significant clinical chemistry alterations
reflected hepatotoxldty and Indicated greater sensitivity 1n females com-
pared with males. In males, decreased BUN at 125 mg/kg and pseudochollnes-
terase activities at 63*and 125 mg/kg were observed at both 60 and 120 days.
In females, elevated S60T, SGPT and SDH were observed at 125 mg/kg,
decreased BUN was noted at >32 mg/kg, and decreased pseudochollnesterase
activity was noted In all treated groups at >8 mg/kg and at >16 mg/kg at
termination. There appeared to be few other differences between observa-
tions at 60 or 120 days. Decreased erythrocyte count, hematocrU, and blood
hemoglobin concentrations attributed to reduced erythropolesls was observed
1n rats of both sexes at >16 mg/kg at both time points. The changes at 16
and 32 mg/kg at termination, however, seemed to have little biological sig-
nificance. There were no treatment-related effects on urlnalysls parameters.
Altered gross appearance of organs at necropsy, limited to the stomach
and kidney, were observed only In rats that died or were sacrificed when
moribund. Several necrotlc and degenerative hlstopathologlcal lesions were
noted 1n the liver, kidney and nasal turblnates of rats of both sexes at 125
mg/kg at both time points. Milder lesions 1n the kidney and nasal
turblnates were observed In both sexes at 63 mg/kg at 60 and 120 days.
Minimal renal changes were observed 1n male rats 1n the 32 mg/kg group at
termination.
The dosage of 8 mg/kg (5.7 mg/kg/day) 1s designated a NOAEL, although 1t
1s associated with mild clinical signs 1n both sexes, reduced
pseudochollnesterase activity 1n females at 60 but not 120 days, and
Increased relative liver weight 1n males. At this dosage, the clinical
signs were transient, having disappeared by 7 weeks. The elevated relative
liver weight 1n male rats may be considered an adaptive response since there
OOlld -29- 05/12/87
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was no functional Impairment Indicated by c!1n1copatholog1cal tests and no
morphological alteration Indicated by h1stopatholog1cal examination. The 16
mg/kg (11.4 mg/kg/day) dose may be considered a LOAEL associated with
chronically depressed psuedochollnesterase values, which, according to NTP
(1983a), 1n the absence of known Inhibitors may represent reduced synthesis
that 1s due to hepatocellular damage.
The mice 1n the NTP (1983b) study exhibited fewer signs of toxldty than
did rats 1n the NTP (1983a) study. Treatment-related mortality (8 females
and 17 males) occurred only 1n the high-dose group, and appeared to be
related to hepatotoxldty and renal toxldty. Food consumption was
unaffected at <125 mg/kg and elevated 1n males at 250 mg/kg. Body weight
gains and terminal body weights were unaffected except for being reduced In
surviving 250 mg/kg males. Clinical signs Including a thin and hunched
appearance, rough fur and alopecia, and sores on the genital areas occurred
In control and treated groups; a dose- or treatment-related trend was not
apparent.
Reduced relative testlcular weight was observed at 125 mg/kg and reduced
relative epldldymal weight was observed at 32 and 125 mg/kg (not at 63
mg/kg) at the 60-day sacrifice but not at the 120-day sacrifice. Results of
the sperm studies were Inconclusive, but the lack of testlcular lesions at
either the 60- or 120-day sacrifice reduces concern that the decreased
testlcular and epldldymal weights observed at 60 days reflect a biologically
significant change. Although the absolute and relative weights of several
other organs differed significantly from controls, only elevated absolute
and relative liver weights at >125 mg/kg were accompanied by hlstopatho-
loglcal change, suggesting biological significance.
001 Id -30- 05/12/87
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Although there were sporadic significant changes 1n clinical chemistry
and hematologlcal parameters and no dose-related response was apparent,
these changes with one exception were not attributed to treatment.
Decreased BUN at >16 mg/kg In females was observed at 60 but not at 120
days. Clinical chemistry tests were hampered by small sample size. No
effects were reported on appearance or specific gravity of urine. There
were no apparent effects on gross appearance at necropsy. Hlstopathologlcal
examinations of surviving mice revealed the lung, spleen, forestomach and
esophagus to be target organs. At the 60-day sacrifice, necrotlc lesions
were noted 1n the liver at 125 mg/kg In males and 250 mg/kg 1n females.
Regenerative lesions were noted 1n the lungs of high-dose females.
Hyperkeratosls was observed 1n the forestomach of males at 125 and 250
mg/kg. At termination 1n females, liver lesions were noted at >125 mg/kg
and changes 1n the bronchlolar epithelium and hyperkeratosls of the
forestomach were observed at >63 mg/kg. Splenic lesions, consisting of
slightly Increased hematopolesis, occurred In most groups of both sexes at
>32 mg/kg.
In this study, 63 mg/kg (45 mg/kg/day) 1n mice 1s designated a LOAEL
associated with hlstopathologlcal lesions In the bronchlolar epithelium and
forestomach. The minor and transient depression 1n BUN at >16 mg/kg and the
slight extramedullary hematopolesis observed 1n the spleen at >32 mg/kg are
not considered adverse; therefore, 32 mg/kg (22.9 mg/kg/day) 1s considered a
NOAEL.
«
6.1.2.2. CHRONIC — Completed studies of the chronic oral toxldty of
the tMchloropropanes could not be located In the available literature as
cited 1n Appendix A. 1,2,3-TMchloropropane 1s undergoing cancer testing 1n
a NTP gavage study 1n rats and mice (NTP, 1986). When completed, this
experiment may provide useful chronic toxldty data.
001 Id -31- 05/12/87
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6.1.3. Other Relevant Information. In a series of range-finding experi-
ments using male Carworth-Hlstar rats, Smyth et al. (1954, 1962) reported
oral LD50 values for 1,1,1-, 1,1,2- and 1,2,3-tMchloropropane of 7.46
ml/kg, 1.23 g/kg and 0.32 ml/kg, respectively. LD5Q values for the
l,2,3-1somer for mice, guinea pigs, rabbits and rats of 369, 340, 380 and
505 mg/kg were reported 1n a Russian study (Shcherban and PHen'ko, 1975),
but the route of administration was not reported. Sax (1984) and NIOSH
(1986) reported an oral LD5Q of 1230 mg/kg for 1,2,2-tMchloropropane.
In a preliminary screening study of the anthelmlntlc efficacy of several
chemicals, Wright and Schaffer (1932) administered single 0.2-0.5 mi/kg
oral doses of 1,2,3-tMchloropropane to three dogs. Complete narcosis
occurred within 1.5 hours, followed by death within 2 days. Severe liver
necrosis was observed during h1stopatholog1cal examination of all three dogs.
The acute Inhalation toxlclty of the trlchloropropanes was Investigated
1n an experiment 1n which groups of six male rats were exposed for 4 hours
(Smyth et al., 1954, 1962). 1,1,1-TMchloropropane at 8000 ppm (48 g/m3)
killed four of six rats, 1,1,2-trlchloropropane at 2000 ppm (12 g/m3)
killed three of six rats and 1,2,3-tMchloropropane at 1000 ppm (6 g/m3)
killed five of six rats. In a similar experiment using mice, 20-m1nute
exposures to 1,2,3-tMchloropropane at 30 mg/i (30 g/m3) killed 8/15
mice within 48 hours and an additional 4 mice within 10 days (McOmle and
Barnes, 1949). Reducing both the exposure time and concentration by
one-half resulted In the death of 7/10 mice exposed for 10 days.
Smyth et al. (1954, 1962) reported dermal LDcgS 1n rabbits of >20,
14.1 and 1.77 ml/kg for the 1,1,1-, 1,1,2- and 1,2,3-1somers, respec-
tively. Following oral, Inhalation or dermal exposure, the l,2,3-1somer
appears to be most toxic and the l,l,l-1somer appears to be least toxic.
OOlld -32- 05/12/87
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These Investigators also scored the ability of the trlchloropropanes to act
as primary skin and eye Irritants In rabbits on a scale of 1 (least severe)
to 10 (most severe). For skin Irritation, 1,1,1-, 1,1,2- and 1.2,3-tM-
chloropropane scored 4, 4 and 1, respectively. For eye Irritation the
scores were 2, 5 and 4. McOmle and Barnes (1949) considered 1,2,3-trl-
chloropropane to be an Intense skin Irritant 1n rabbits.
Ruth (1986) reported that 1,2,3-tMchloropropane has a strong, acrid
odor, which 1s Irritating at 300 mg/m3. Based on a !5-m1nute exposure,
the majority of a group of 12 human subjects (both sexes) predicted that 50
ppm (-300 mg/m3) would be satisfactory for an 8-hour exposure. All
subjects found exposure to 100 ppm (-600 mg/m3) to be Irritating to the
eyes and throat.
The liver 1s the major target organ for 1,2,3-tMchloropropane by any
natural route of exposure. In order to measure the Interaction of known
hepatotoxlcants 1n producing liver toxIcHy, Drew et al. (1978) exposed
groups of 15 adult male CD-I rats to 1,2,3-trlchloropropane .at 500 ppm
(-3000 mg/m3) or 1,2-d1chloropropane at 1000 ppm (-4600 mg/m3) or to the
mixture at the same concentrations for 4 hours. Hepatotoxlclty was
evaluated by measuring SGOT, SGPT, serum glucose-6-phosphatase and serum OCT
periodically for 48 hours posttreatment. SGOT, SGPT and OCT were elevated
by exposure to each compound. The effects on SGOT and OCT were additive and
the effect on SGPT was synerglstlc at 24 hours. By 48 hours, the effect on
SGOT, SGPT and OCT was less than additive. Neither compound alone affected
glucose-6-phosphatase levels, but the combination caused a reduction In the
serum level of this enzyme at 4 and 24 hours after treatment. The Investi-
gators concluded that there was little evidence that 1,2,3-trlchloropropane
and 1,2-dlchloropropane, when combined, had an additive effect on producing
liver damage.
OOlld -33- 05/12/87
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6.2. CARCINOGENICITY
6.2.1. Inhalation. Pertinent data regarding the carclnogenlclty of the
tMchloropropanes by Inhalation could not be located 1n the available
literature as cited 1n Appendix A.
6.2.2. Oral. 1,2,3-Trlchloropropane Is undergoing chronic testing In an
NTP gavage study using rats and mice (NTP, 1986). The subchronlc studies
are discussed 1n Section 6.1.2.1.
6.2.3. Other Relevant Information. Other relevant carclnogenlclty
Information for the trlchloropropanes could not be located In the available
literature as dted In Appendix A.
6.3. MUTAGENICITY
Hutagenldty testing of the trlchloropropanes has been limited to the
1,2,3-lsomer. Results of several tests In prokaryotes and mammalian test
systems are presented 1n Table 6-1. 1,2,3-Trlchloropropane was consistently
positive In the reverse mutation test In at least two strains of Salmonella
typh1mur1um. Generally, the presence of an activating system was required
for a positive result. Results 1n mammalian tests yielded mixed results.
Positive results were obtained In viral transformation (Hatch et al., 1983).
sister chromatld exchange and mlcronucleus tests (Douglas et al., 1985) in
vitro, but negative results were reported for the mlcronucleus test (Douglas
et al., 1985). unscheduled DNA synthesis test (Nlrsalls et al., 1983) and
dominant lethal test (Sa1to-Suzuk1 et al., 1982) in. vivo. It should be
noted that the structurally-similar compounds, 1,2,3-trlbromopropane and
1,2-d1bromo-3-chloropropane both yielded positive responses In the
dominant-lethal test (Salto-Suzukl et al., 1982). The Interpretation of
these mammalian studies Is limited 1n that all but the dominant lethal study
were reported only as abstracts with no data, and the dominant lethal study
was conducted using a single dose.
001 Id -34- 07/07/87
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TABLE 6-1
o
o
«j
0.
1
a
i
07/07/8
Assay
Reverse
mutation
Enhancement
of viral
transformation
of DNA
Sister
chromattd
exchange
Hlcronucleus
test
Unscheduled
DNA synthesis
Dominant
lethal
Indicator
Organism
Salmonella
typhlmurlum
TA9B. TA100.
1A1535. TA1537
S. typhlmurlum
TA100
S. typhlmurlum
TA98. TA100
TA1535. TA1537
S. typhlmurlum
TA9B. TA100.
TA1535. TA1537
Syrian hamster
embryo cells
CHO cells
CHO cells
mouse bone
marrow
male rat
hepatocytes
SO rats
nuiag
Purity Application
NR plate
Incorporation
99* plate
Incorporation
99. IX prelncubatlon
NR plate
Incorporation
NR cell culture
NR cell culture
NR cell culture
t
NR In vivo
NR In vivo
(gavage)
>99X 5 days by
gavage In
olive oil
(eniciiy icsung or i.^.j-iricnl
Concentration Activating
or Dose System
NR ±S 9
1 or O.T tS-9
i«ol/plate
0-333 »S-9
i«ol/plate
0.5-5000 iS-9
tMol/plate
NR none
NR none
NR none
NR NA
NR NA
80 mg/kg/dose NA
oropropane
Response Comments
i Applied In DNSO 1:50;
negative In TA98
| Response was dose-related and
greater In presence of S-9
» Negative In TA9B. TA1537
» Negative In TA9B. TA1537
t Treatment enhanced transfor-
mation with SA7 virus
t Abstract only
» Abstract only
Abstract only
Abstract only
Structurally-related 1.2.3-
trlbromopropane and 1.2-dl-
bromo-3-chloropropane were
used as positive controls
single dose <20X of ID^o
Reference
Blomedtcal Testing
Laboratories Inc.,
1979
Stolzenberg and
Hlne. 1980
Haworth et al.,
1983
Ratpan and
Maumann. 1985
Hatch et al.. 1983
Douglas et al. .
1985
Douglas et al..
1985
Douglas et al. ,
1985
Nlrsalls et al..
1983
Salto-Suzukl
et al.. 1982
NR - Not reported; NA - not applicable; NC • no comment
-------
6.4. TERATOGENICITY
The only Investigation of the developmental toxldty of the tMchloro-
propanes available was a preliminary study with 1,2,3-tMchloropropane
(purity not reported) In Sprague-Oawley rats. Groups of 10-15 mated rats
were given 0 or 37 mg/kg/day In corn oil by 1ntraper1toneal Injection on
days 1-15 of gestation (Hardln et al., 1981). This dosage was determined as
the MTD resulting 1n no mortality, no marked signs of toxldty and <10X
reduction In rate of body weight gain In nonpregnant females treated by
Intraperltoneal Injection for 15 consecutive days. Dams were sacrificed on
gestation day 21 and fetuses were examined for abnormalities and signs of
fetal toxldty. In treated rats, maternal toxldty was manifested as
statistically significantly altered absolute or relative weights of two or
more organs. There was no evidence of fetal toxldty or teratogenlclty.
6.5. OTHER REPRODUCTIVE EFFECTS
The only study available regarding the reproductive effects of the
tMchloropropanes was the dominant lethal study using SO rats by
Salto-Suzukl et al. (1982). No effects on mating, fertility or hlstologlcal
appearance of the testes were observed 1n a group of 15 rats treated by
gavage with 80 mg/kg 1,2,3-tMchloropropane In olive oil for 5 days. The
structurally-related chemical 1,2,3-tr1bromopropane was associated with
reduced fertility and hlstopathologlcal lesions In the testes 1n this
study. Similar lesions were also observed with 1,2-d1bromo-3-chloropropane,
which was used as a positive control In the dominant lethal test.
6.6. SUMMARY
Few data were located regarding the Inhalation toxldty of the tM-
chloropropanes. Several Russian studies reported the effect of l,2,3-tr1-
chloropropanes In rats exposed continuously for 7 days to 3 months. The
liver and lungs appeared to be the target organs In these studies, which
001 Id -36- 07/07/87
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reported hlstopathologlcal lesions after exposure to 2 mg/m3 for 3 months
(Sldorenko et al., 1979; Tsulaya et al., 1977, 1979; Bonashevskaya, 1977).
Lesions were not reported at 0.4 or 0.45 mg/m3. Chronic Inhalation
toxldty data were not located.
Oral toxldty data were limited to subchronlc studies. In a 13-week
drinking water study using rats, 1,1,2- and 1,2,3-tr1chloropropane were
administered to both sexes; and 1000 mg/8. was a LOAEL associated with mild
but significant lesions 1n the liver, lungs and thyroid. The 100 mg/l
level was a NOAEL for both compounds. Subchronlc gavage studies were
performed with 1,2,3-trlchloropropane using rats (NTP, 1983a) and mice (NTP,
1983b). Rats were more sensitive than mice, as Indicated by greater
mortality at 250 mg/kg, the highest dosage tested. The dosage of 8 mg/kg, 5
days/week (5.7 mg/kg/day) In rats was a NOAEL associated with transient
clinical signs and blood chemistry alterations, and elevated relative liver
weight. The next higher dosage, 16 mg/kg, 5 days/week (11.4 mg/kg/day), was
a LOAEL associated with cllnlcopathologlcal evidence of liver damage. The
NOAEL and LOAEL for mice were 32 and 63 mg/kg (22.9 and 45.0 mg/kg/day).
respectively.
Completed carclnogenlcHy studies were not located for any of the tr1-
chloropropanes by either oral or Inhalation exposure. The NTP Is evaluating
the carclnogenlcHy of 1,2,3-trlchloropropane by gavage In rats and mice
(NTP, 1986). Data were not located regarding the carclnogenlcHy of the
trlchloropropanes by other routes of exposure. Mutagen1c1ty data were
located only for the 1,2,3-lsomer. Positive results were obtained 1n the
reverse mutation test In S. typhlmuMum. Results In various mammalian test
systems were mixed.
OOlld -37- 07/07/87
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1,2,3-TMchloropropane was not associated with fetotoxldty or terato-
genlclty 1n an 1ntraper1toneal study 1n rats (Hardln et al., 1981} and had
no effect on mating, fertility or hlstomorphology of the testes In a
dominant lethal study using rats (Salto-Suzukl et al., 1982). Data
regarding the developmental or reproductive toxldty of the other
tMchloropropanes could not be located 1n the available literature as dted
In Appendix A.
OOlld -38- 07/07/87
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
ACGIH (1986a) adopted a TLV-TWA of 50 ppm (-300 mg/m3) for l,2,3-tr1-
chloropropane. A STEL of 75 ppm (450 mg/m3) was also recommended. ACGIH
(1986b) recommended that the STEL be dropped and the TLV-TWA be reduced to
10 ppm (-60 mg/m3), based primarily on the NTP (1983a,b) oral data on rats
and mice 1n which the dosage of 8 mg/kg for 5 days/week was a NOAEL 1n rats.
Assuming equivalent exposure among species, human Inhalation of 10
m'/workday, a human body weight of 70 kg and 100% absorption of Inhaled
chemical. ACGIH (1986b) estimated an equivalent human exposure concentration
level of -56 mg/m3 (9-10 ppm). The current OSHA (1985) standard PEL for
1,2,3-tMchloropropane Is 50 ppm (300 mg/m3).
U.S. EPA (1986b) verified an RfO of 6 yg/kg/day or 0.4 mg/day for a 70
kg human for 1,2,3-tr1chloropropane based on a NOAEL of 5.7 mg/kg/day In
rats 1n the NTP (1983a) study (Sections 8.2.2.1. and 8,2.2.2.).
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects of tMchloropropanes could not be located In the available
literature as cited 1n Appendix A.
OOlld -39- 05/12/87
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8. RISK ASSESSMENT
8.1. CARCINOGENICITY
8.1.1. Weight of Evidence. A gavage study with 1,2,3-tMchloropropane 1n
rats and mice 1s 1n progress (NTP, 1986). No studies by other routes of
exposure were located that contribute to the quantitative evaluation of the
cardnogenlcHy of the trlchloropropanes to animals. Results of mutagenlc-
Hy tests with 1,2,3-tMchloropropane, positive 1n S. typh1mur1u'm and mixed
In mammalian test systems, suggest that this chemical may be carcinogenic.
However, most of the mammalian mutagenldty data are available only In
abstract form. Neither human case reports nor epldemlologlcal studies were
located regarding the trlchloropropanes. According to the guidelines of
U.S. EPA (1986c), all trlchloropropane Isomers and all mixtures of
trlchloropropane Isomers are Included In EPA Group 0 - not classified.
8.1.2. Quantitative Risk Estimates. The lack of data regarding the
carclnogenldty of any • of the trlchloropropanes precludes estimation of
carcinogenic potency for Inhalation or oral exposure.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) — Data regarding
subchronlc Inhalation exposures are limited to several Russian reports
concerning 1,2,3-trlchloropropane (see Section 6.1.1.1.). Experiments
lasting up to 3 months (Sldorenko et al.t 1979; Tsulaya et al., 1977, 1979;
Bonashevskaya, 1977) Investigated continuous exposure of rats to atmospheric
concentrations of 0.2-800 mg/m3. Although 1t was reported that there were
no effects on rate of body weight gain or hematology at the highest concen-
tration tested, hlstopathologlcal lesions 1n the "liver and lungs were
reported at 2 mg/m3. ACGIH (1986b) dismissed these Russian reports as
•not entirely consistent* with the NTP (1983a,b) gavage studies using rats
OOlld -40- 07/07/87
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and mice. In which 8 mg/kg, 5 days/week was a NOAEL 1n rats, the more
sensitive species. Primarily because the Russian studies were Incompletely
reported and because It 1s not possible to critically evaluate either the
experimental method or the results, these studies are judged to be
Inadequate for quantitative risk assessment; and a subchronlc Inhalation RfO
1s not derived for any of the tMchloropropanes.
8.2.1.2. CHRONIC EXPOSURES ~ Chronic Inhalation studies of the
trlchloropropanes could not be located In the available literature as cited
1n Appendix A. ACGIH (1986a) recommends a TLV of 50 ppm (300 mg/m3) for
occupational exposure to the 1,2,3-1somer. In the most recent ACGIH (1986b)
documentation, based on the NTP (1983a) study using rats, a change In the
TLV-TWA to 10 ppm (-60 mg/m3) Is proposed to protect against damage to the
liver and kidneys, known target organs for this compounds. In the absence
of adequate chronic or subchronlc Inhalation data, the current and the
proposed TLV-TUAs are considered Inadequate to serve as the basis of a
chronic Inhalation RfD. Therefore, no chronic Inhalation RfOs are derived
for any of the trlchloropropanes.
8.2.2. Oral Exposure.
8.2.2.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) ~ Subchronlc oral
data were located for 1,1,2- and 1,2,3-tMchloropropane. Vllleneuve et al.
(1985) administered 0, 1, 10, 100 or 1000 mg of 1,1,2-tr1chloropropane In
drinking water to rats for 13 weeks. H1ld but significant hlstopathologlcal
lesions 1n the liver, kidneys and thyroid were observed at 1000 mg/i but
not at 100 mg/l. The NOAEL of 100 mg/l, equivalent to dally dosages of
15.0 mg/kg In males and 20.3 mg/kg In females, 1s an appropriate basis for a
subchronlc oral RfO. Choosing the higher NOAEL of 20.3 mg/kg/day In females
and applying an uncertainty factor of 100 (10 for Interspedes extrapolation
OOlld -41- 05/12/87
-------
and 10 to protect unusually sensitive Individuals) results In a subchronlc
oral RfD for 1,1,2-tr1chloropropane of 0.2 mg/kg/day or 14 mg/day for a 70
kg human. Confidence 1n this study Is high, the database low and this RfO
medium because the cardnogenlclty and developmental toxldty of this
chemical have not been tested.
VUleneuve et al. (1985) also administered 1,2,3-tr1chloropropane to
rats In drinking water at 0, 1, 10, 100 or 1000 mg/i for 13 weeks. At
1000 mg/l, lesions similar to but more severe than those observed with the
1,1,2-lsomer were observed 1n the liver, kidney and thyroid. Lesions were
not observed at 100 mg/l (15.0 mg/kg/day In males, 17.6 mg/kg/day In
females), which was considered a NOAEL. Effects observed at 100 mg/l
Included reduced water Intake and altered relative liver and kidney weights
In females.
The NTP performed 120-day gavage studies with 1,2,3-tr1ch1oropropane 1n
.rats (NTP, 1983a) and mice (NTP, 1983b). Animals were treated 5 days/week
at 0, 8, 16, 32, 63, 125 or 250 mg/kg. Mice appeared to be less sensitive
than rats, since mortality occurred only In the high-dose group. In mice,
biologically significant alterations 1n relative organ weights were observed
at >125 mg/kg, along with hlstopathologlcal lesions 1n the liver, kidney and
stomach. Lesions In the bronchlolar epithelium and forestomach were
observed 1n females at >63 mg/kg. The 32 mg/kg dosage (22.9 mg/kg/day) Is
designated a NOAEL associated with a transient depression 1n BUN at 60 days
but not at termination and a slight Increase 1n splenic (extramedullary)
hematopolesis In the absence of significant hematologlcal effects.
In rats, mortality occurred at 125 and 250 mg/kg (NTP, 1983a). Lesions
were observed 1n the liver and kidneys at 125 mg/kg and 1n the kidneys of
OOlld -42- 05/12/87
-------
males at >32 mg/kg. Cl1n1copatholog1cal data (reduced BUN and pseudcholln-
esterase activity) suggest Impaired liver function at >16 mg/kg, particu-
larly In females. The 8 mg/kg dosage (5.7 mg/kg/day) was designated a NOAEL
associated with transient clinical signs 1n both sexes and Increased
relative liver weight In males. The 16 mg/kg (11.4 mg/kg/day) dosage 1s
regarded a LOAEL.
The NOAEL of 5.7 mg/kg/day from the NTP (1983a) study using rats 1s the
only NOAEL below which adverse effects have not been observed and 1s chosen
as the basis of a subchronlc oral RfD for 1,2,3-tr1chloropropane. Applying
an uncertainty factor of 100 (10 for Interspedes extrapolation and 10 to
protect unusually sensitive Individuals) results In an RfD of 0.06 mg/kg/day
of 4 mg/day for a 70 kg human. The confidence In the study 1s considered
high and 1n the database low. The cardnogenlcHy and developmental
toxlclty of this compound have not yet been tested adequately. Confidence 1n
the RfD. Is rated medium.
Data regarding the subchronlc oral toxlclty of other trlchloropropanes
or mixtures of trlchloropropanes were not located; 1t Is Inappropriate to
derive RfDs by analogy to 1,1,2- or 1,2,3-tr1chloropropane.
8.2.2.2. CHRONIC EXPOSURES — Chronic oral data were not located for
any of the trlchloropropanes. An NTP chronic gavage study In rats and mice
1s 1n progress, but results are not yet available (NTP, 1986). Chronic oral
RfDs can be estimated for 1,1,2- and 1,2,3-trlchloropropane by applying an
additional uncertainty factor of 10 to the subchronlc oral RfDs estimated
from the subchronlc studies (see Section 8.2.2.1.). The subchronlc oral RfD
for 1,1,2-tr1chloropropane was 0.2 mg/kg/day, based on a NOAEL of 20.3
mg/kg/day (Vllleneuve et al., 1985). The chronic oral RfD for 1,1,2-trl-
chloropropane, therefore, Is 0.02 mg/kg/day or 1 mg/day for a 70 kg human.
OOlld -43- 05/12/87
-------
Confidence In this RfD Is rated medium for the reasons discussed 1n Section
8.2.2.1. For 1,2,3-tr1chloropropane, the subchronlc oral RfD was 0.06
mg/kg/day based on application of an uncertainty factor of 100 to a NOAEL of
5.7 mg/kg/day. The chronic oral RfD for 1,2,3-tr1chloropropane, therefore,
1s 6 yg/kg/day or 0.4 mg/day for a 70 kg human. A confidence level of
medium Is assigned to this RfD as discussed 1n Section 8.2.2.1. This
analysis reflects the U.S. EPA (1986b) analysis for 1,2,3-tMchloropropane.
For reasons discussed previously, this RfO 1s not applied to the other
Isomers or mixtures of Isomers of trlchloropropane.
OOlld -44- 05/12/87
-------
9. REPORTABLE QUANTITIES
9.1. BASED ON SYSTEMIC TOXICITY
Tox1c1ty studies with the tMchloropropanes Include the Russian Inhala-
tion studies (Tsulaya et al., 1977, 1979; Bonashevskaya and Belyaeva, 1975;
Bonashevskaya, 1977; Bonashevskaya et al., 1978; Belyaeva et al., 1977;
Tarasova, 1975; Shalpak, 1976; Sldorenko et al., 1979) briefly summarized In
Section 6.1.1.1. In these studies, rats were exposed continuously to
1,2,3-tr1chloropropane for 1 week to 3 months at concentrations ranging from
0.2-800 mg/m3. These reports associated hlstopathologlc lesions 1n the
liver with exposure to 2 mg/m3. The ACGIH (1986b) noted that these
reports were Inconsistent with the results of the NTP (1983a,b) studies
using rats and mice, and dismissed the Russian studies from further
consideration In derivation of a TLV. As noted 1n Chapter 8, the Russian
studies were Insufficiently reported for critical evaluation and were not
considered In the derivation of Inhalation R'fDs. Because of the lack of
confidence 1n these reports, they are not considered In the derivation of
toxiclty-based RQs.
Subchronlc oral tox1c1ty data for the 1,1,2- and 1,2,3-lsomers are
summarized In Tables 9-1 and 9-2, respectively. For the 1,1,2-1somer, mild
histologic, biochemical and organ weight changes were observed at 1000
mg/i 1n rats 1n a 13-week drinking water study. CSs for 1,1,2-tr1chloro-
propane are presented 1n Table 9-3. For both males and females, the mild
lesions observed 1n liver, kidney and spleen were assigned an RV of 5.
The higher RV. calculated for the males reflects the substantially lower
dosage consumed by the males In this experiment. The CS of 11. which was
associated with hlstopathologlcal lesions In male rats, Is chosen to repre-
sent the chronic toxldty of 1,1,2-tr1chloropropane since 1t 1s slightly
higher than the CS of 10.5 for females.
OOlld -45- 05/12/87
-------
TABLE 9-1
Toxlclty Summary for 1,1,2-Trlchloropropane (99X Pure) In a 13-Heek Drinking Mater Experiment In Ratsa-b
o
CL
Average
Sex Body Weight
Male 0.301
0.301
0.301
0.301
0.301
i
Female 0.177
0.177
0.177
0.177
0.177
Exposure
0 •
1
10
100
1000
0
1
10
100'
1000
Transformed
Animal Dose
(mg/kg/day)c
0
0.15
1.5
15.0
150
0
0.20
2.0
20.3
203
Equivalent
Human/Dose
(rag/kg/day)d
0
0.02
0.24
2.4
24.4
0
0.03
0.27
2.77
27.7
Response
no effects
no effects
no effects
no effects
biochemical and mild
change, organ weight
no effects
no effects
no effects
no effects
biochemical and mild
change, organ weight
hlstologlcal
changes
hlstologlcal
changes
aSource: Vllleneuve et al.. 1985
2 D10 weanling Sprague-Dawley rats/sex/group
0 Estimated from data provided by Investigators
GO
dCalculated by multiplying transformed animal dose by the cube root of the ratio of the animal to human
(70 kg) body weight.
-------
Oral loxlclty Summary for 1,2.3-TrIchloropropane
•^
Q. Species/
Strain
Rat/Sprague-
Oawley
i Rat/Sprague-
5 Dawley
i
Rat/f Ischer
r-344
O
•t*
•v.
O.
•^
CO
Sex
H
H
N
N
N
f
f
f
r
f
H
N
N
No. at
Start
10
10
10
10
10
10
10
10
10
10
30
20
20
Average
Height
(kg)
0.301
0.301
0.301
0.301
0.241
0.177
0.177
0.177
0.170
0.151
0.33
0.33
0.33
Vehicle/
Physical
State
drinking
water
drinking
water
drinking
water
drinking
water
drinking
water
drinking
water
drinking
water
drinking
water
drinking
water ,
drinking
water
corn oil
corn oil
corn oil
Purity
NA
99X
99X
99X
99X
NA
99X
99X
99X
99X
NA
>99X
>99X
Exposure
0 mg/l for 13 weeks
1 mg/l for 13 weeks
10 *g/t for 13 weeks
100 mg/l for 13 weeks
1000 mg/t for 13 weeks
0 «g/l for 13 weeks
1 mg/t for 13 weeks
10 mg/» for 13 weeks
100 mg/t for 13 weeks
1000 mg/» for 13 weeks
0 mg/kg. S days/week.
for 120 days
6 mg/kg. S days/week
for 120 days
16 mg/kg. 5 days/week
for 120 days
,
Transformed
Anlnal Dose
(•g/kg/day)
0
0.15a
1.5a
15. Oa
113a
0
0.20^
2.0a
17. 6a
149a
0
5-'
11.4
Transformed .
Hunan Oosed
(•g/kg/day)
0
0.02
0.24
2.44
17.1
0
0.03
0.27
2.37
19.3
0
1.0
1.9
Response
NA
No adverse treatment -
related effects
No adverse treatment-
related effects
No adverse treatment -
related effects
Biochemical and hlsto-
logtc changes, organ
weight changes
NA
No adverse treatment-
related effects
No adverse treatment -
related effects
No adverse treatment-
related effects
Biochemical and hlsto-
loglc changes, organ
weight changes
NA
Elevated relative
liver weight
Elevated relative
liver weight
Reference
VIDeneuve
et al.. 1985
Vllleneuve
et al.. 1985
Vllleneuve
el al.. 1985
Vllleneuve
et al.. 1985
Vllleneuve
et al.. 1965
Vllleneuve
et al.. 1985
Vllleneuve
et al.. 1985
Vllleneuve
et al.. 1985
Vllleneuve
et al.. 1985
Vllleneuve
et al.. 1985
NTP. 1983a
NTP. 1983a
NTP. 1983a
-------
TABLE 9-2 (conl.)
§ Species/
^ Strain
0.
Rat/flscher
f-344
Rat/flscher
f-344
i
00
Mouse/B6C3M
o
•^
o
CO
Sex
M
M
M
M
f
f
f
f
f
f
r
N
M
M
M
No. at
Start
20
20
20
20
30
20
20
20
20
20
20
30
20
20
20
Average
Weight
(kg)
0.33
0.32
0.275
NAb
0.20
0.20
0.20
0.20
0.20
0.15
NA°
0.029
0.029
0.029
0.029
Vehicle/
Physical
State
corn oil
corn oil
corn oil
corn oil
corn oil
corn oil
corn oil
corn oil
corn oil
corn oil
*
corn oil
corn oil
corn- oil
corn oil
corn oil
Purity
>99X
>99X
>99X
>99X
NA
>99X
>99X
>99X
>99X
>99X
>99X
NA
>99Xe
>99XC
>99XC
Exposure
32 ag/kg, 5 days/week
for 120 days
63 ag/kg. 5 days/week
for 120 days
125 ag/kg. 5 days/week
for 120 days
250 ag/kg. 5 days/week11
0 ag/kg. 5 days/week.
for 120 days
8 ag/kg. 5 days/week
for 120 days
16 ag/kg. 5 days/week
for 120 days
32 ag/kg. 5 days/week
for 120 days
63 ag/kg. 5 days/week
for 120 days
125 ag/kg. 5 days/week
for 120 days
250 ag/kg. 5 days/week0
0 ag/kg. 5 days/week.
for 120 days
8 ag/kg. 5 days/week
for 120 days
16 ag/kg. 5 days/week
for 120 days
32 ag/kg. 5 days/week
for 120 days
Transforaed
Anlaal Dose
(ag/kg/day)
22.9
45.0
89.3
179
0
5.7
11.4
22.9
45.0
89.3
179
0
5.7
11.4
22.9
Transforaed
Human Oosea
(mg/kg/day)
3.8
7.5
14.1
NAD
0
0.8
1.6
3.2
6.4
11.5
NAD
0
0.42
0.85
1.71
Response
Elevated relative
liver weight
Liver damage, at Id
lesions
Mortality, severe
lesions
Mortality
NA
Mild biochemical
changes
Altered biochemistry
Altered biochemistry
Liver damage, mild
hlstopathologlc lesions
Mortality, severe
hlstopathologlc lesions
Mortality
NA
No definite treatment-
related adverse effects
No definite treatment-
related adverse effects
Mild splenic lesions
Reference
NTP.
NTP.
NTP.
NTP.
NTP.
NTP.
NTP.
NTP.
NTP.
NTP.
NTP.
NTP.
NTP.
NTP.
NTP.
1983a
1983a
1983a
1983a
1983a
1983a
1983a
1983a
1983a
1983a
1983a
19B3b
1983b
19B3b
1983b
-------
1ABII 9-2"[conl.)
g Species/ No. at Average Vehicle/ Transformed
— • Strain Sex Start Height Physical Purity Exposure Animal Dose
^ (kg) State (mg/kg/day)
Mouse/B6C3fl N 20 0.029 corn oil >99XC 63 mg/kg. 5 days/week 45.0
for 120 days
M 20 0.029 corn oil >99XC 125 mg/kg. 5 days/week 89.3
for 120 days
N 20 0.029 corn oil >99XC 250 mg/kg. 5 days/week 179
for 120 days i
Nouse/B6C3Fl F 30 0.023 corn oil NA 0 mg/kg. 5 days/week. 0
for 120 days
F 20 0.023 corn oil >99XC B mg/kg. 5 days/week 5.7
for 120 days
F 20 0.023 corn oil >99XC 16 .mg/kg. 5 days/week 11.4
for 120 days
, F 20 0.023 corn oil >99XC 32 mg/kg. 5 days/week 22.9
4* for 120 days
^O
F 20 0.023 corn oil >99XC 63 mg/kg. 5 days/week 45.0
for 120 days
F 20 0.023 corn oil >99XC 125 mg/kg. 5 days/week 89.3
for 120 days
F 20 0.023 corn oil >99XC 250 mg/kg. 5 days/week 179
> for 120 days
^Estimated from data provided by Investigators.
DA11 animals died within first 5 weeks of experiment.
cBased on analysis of test chemical of same lot number reported by NTP (1983a).
NA = Not applicable
o
4^
^^
^k»
O
^^
0°
Transformed
Human Oosea Response
(mg/kg/day)
3.35 Nlld splenic lesions
6.66 lesions In liver.
stomach
13.3 Mortality
0 NA
0.39 No definite treatment-
related adverse effects
0.79 No definite treatment-
related adverse effects
1.58 Nlld splenic lesions
3.11 Lesions In stomach
and lungs
6.16 Lesions tn liver
12.4 Mortality
Reference
NTP. 19836
NTP. 19836
NTP. 19836
NTP. 19836
NTP. 19836
NTP. 19836
NTP. 19836
NTP. 19836
NTP. 19836
NTP. 19836
-------
TABLE 9-3
Oral Composite Scores for 1.1.2-Trlchloropropane Using Rats3
' ft
Sex Animal Dose
(rog/kg/day)
i
o Hale 150
Female 203
Chronic
Human NED
(rag/day)b
171
194
RVd
2.2
2.1
Effect RVe CS
mild hlstopatho- 5 11
logic lesions
mild hlstopatho- 5 10.5
logic lesions
RQ
1000
1000
aSource: Vlllcneuve et al.. 1985 ,
bAn uncertainty factor of 10 was applied to expand from subchronlc to chronic exposure.
o
•—
CO
-------
Subchronlc oral toxIcHy studies with 1,2,3-tMchloropropane Include the
drinking water study 1n rats (VUleneuve et al., 1985) and the gavage
studies 1n rats and mice (NTP, 1983a,b) (see Table 9-2). Data were not
available from oral or Inhalation developmental toxlclty or reproductive
toxldty studies. Generally, the effects observed 1n the oral studies and
their associated RV s were mortality (RV =10), severe degenerative or
hyperplastlc hlstopathologlc lesions (RV =8), mild cellular changes
(RV =5), organ weight changes (RV =4) and biochemical evidence of
Impaired organ function (RV =6). Table 9-4 presents CSs for each of these
effects. When a given effect was observed at more than one dosage or 1n
more than one species or sex, the CS for that effect was calculated only for
the data point for which the lowest human equivalent dose was calculated. A
CS was not calculated for severe hlstopathologlc effects because they were
observed only at dosages associated with mortality. CSs ranged from
17.2-26.4, which correspond to RQs of '100 or 1000. It 1s apparent that rats
exposed by gavage develop more serious effects at lower dosages than do rats
exposed by drinking water. Rats appear to be more sensitive than mice to
the oral effects of 1,2,3-tMchloropropane. The highest CS, 26.4, was
associated with biochemical evidence of Impaired liver function 1n female
rats (NTP, 1983a)-. This value 1s chosen to represent the chronic toxldty
of 1,2,3-tMchloropropane.
The CSs chosen for the 1,1,2- and 1,2,3-1somers are presented In Table
9-5 and 9-6, respectively. Data were not sufficient for calculation of CSs
for the other tMchloropropane Isomers or mixtures of the Isomers. It 1s
Inappropriate to adopt the CS for either 1,1,2- or 1,2,3-tr1chloropropane as
the CS for the other Isomers or for mixtures of Isomers.
OOlld -51- 05/12/87
-------
o
o
TABLE 9-4
Oral Composite Scores for 1,2.3-Trlchloropropane
Species/Sex
Rat/female
i
7* Mouse/female
Rat/male
Rat/female
*An uncertainty
o
•**
o
CO
Chronic
Animal Dose Human NED
(mg/kg/day) (rog/day)*
89.3 80.6
22.9 11.1
5.7 6.7
5.7 5.7
factor of 10 was applied
RVd Effect RVe CS RQ
2.6 Mortality 10 26 100
3.9 Mild hlstopathologlc 5 19.5 1000
lesions
4.3 Organ weight changes 4 17.2 1000
4.4 Biochemical evidence 6 26.4 100
of Impaired liver
function
to expand from subchronlc to chronic exposure.
•
Reference
NTP. 1983a
NTP. 1983b
NIP. 1983a
NTP. 1983a
-------
TABLE 9-5
1,1,2-TMchloropropane
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 171 mg/day
Effect: mild hlstopathologlc lesions
Reference: Vllleneuve et al., 1985
RVd: 2.2
RVe: 5
Composite Score: 11
RQ: 1000
'Equivalent human dose
OOlld -53- 04/10/87
-------
TABLE 9-6
1,2,3-TMchloropropane
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 5.7 mg/day
Effect: biochemical evidence of Impaired liver function
Reference: NTPt 1983a
RVd: 4.4
RVe: 6 •
Composite Score: 26.4
RQ: 100
'Equivalent human, dose
0011d -54- 04/10/87
-------
9.2. BASED ON CARCINOGENICITY
As noted In Section 6.1., there were no studies of the carcinogenic
potency of any of the tMchloropropanes by any route of administration.
Because of the lack of animal data and because ep1dem1olog1c data were not
located, these compounds were assigned an EPA classification of D: not
classifiable as to human carcinogenic potency. Data were Insufficient for
estimation of an F factor. Since these compounds are classified In EPA
Group D, no hazard ranking can be performed and no RQ for cardnogenldty
can be assigned.
OOlld -55- 07/07/87
-------
10. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986a.
TLVs: Threshold L1mH Values and Biological Exposure Indices for 1986-1987.
Adopted by ACGIH with Intended changes for 1986-1987. Cincinnati, OH.
p. 32.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986b.
Documentation of the Threshold Limit Values, 5th ed. Cincinnati, OH.
p. 601-602.
Belyaeva, N.N., V.R. Tsulaya, T.L. Marshak and V.Y. Brodsk11. 1974. Effect
of 1,2,3-tr1chloropropane on the ploldy of rat hepatocytes. Byull. Eksp.
B1ol. Med. 78(12): 74-77. (CA 082:133673H)
Belyaeva, N.N., T.I. Bonashevskaya, T.L. Marshak and V.Y. Brodskll. 1977.
Study of the effect of some chlorinated hydrocarbons on the composition of
rat liver hepatocyte populations. Byull. Eksp. B1ol. Med. 83(3): 345-348.
(Russian with English translation)
B1omed1cal Testing Laboratories, Inc. 1979. Mutagenlclty Testing, Monthly
Report, Submitted to NIOSH under Contract No. 210-76-0153. August 15, 1979
(unpaglnated). (CUed 1n Franklin Research Center, 1981)
Bonashevskaya, T.I. 1977. Morphological characteristics of the adaptation
of the liver to the effect of some chemical substances. Gig. Sanlt. 4:
45-50. (Russian with English translation)
001 Id -56- 05/12/87
-------
Bonashevskaya, T.I. and N.N. Belyaeva. 1975. Structural and hlstochemlcal
changes 1n the liver 1n exposure to a series of aromatic and halogenated
hydrocarbons. Gig. Sanlt. 6: 111-112. (Russian with English translation)
Bonashevskaya, T.I., V.R. Tsulaya, V.V. Zykova, N.B. Kumpan and V.V. Shalpak.
1978. Effect of chlorine derivatives of propane and ethylene on white rat
lungs. Subacute experiment. Deposited Doc. ISS VINITI 1733-78: 11 p. (CA
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Dewalle, F.B. and E.S.K. Chlan. 1978. Presence of trace organlcs In the
Delaware River and their discharge by municipal and Industrial sources.
Proc. Ind. Waste Conf. 32: 908-919.
D1ll1ng, H.L. 1977. Interphase transfer processes. II. Evaporation rates
of chloroetha'nes, ethanes; ethylenes, propanes, and propylenes from dilute
aqueous solutions. Comparisons with theoretical predictions. Environ. Scl.
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Douglas, G.R., E.R. Nestmann, E. Lee, R. Marshall and J.A. Heddle. 1985.
How well do jji vitro tests predict in vivo genotoxlclty. Environ. Mutagen.
7(3): 31. (Abstract)
Dow Chemical Company. 1985. Allyllcs the allyl chloride family of Inter-
mediates. Dow Chemical Co., Midland, MI.
Drew, R.T., J.M. Patel and F.N. Lin. 1978. Changes 1n serum enzymes 1n
rats after Inhalation of organic solvents singly and 1n combination.
Toxlcol. Appl. Pharmacol. 45(3): 809-819.
OOlld -57- 04/10/87
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Elsenrelch, S.J., B.8. Looney and J.D. Thornton. 1981. Airborne organic
contaminants In the Great Lake Ecosystem. Environ. Sc1. Technol. 15(1):
30-38.
Franklin Research Center. 1981. TMchloropropanes. ISS NIOSH-210-79-0091;
Order No. PB83-112870. 91 p.
Hardln, B.O., G.P. Bond, M.R. S1kov, P.O. Andrew. R.P. Bellies and R.W.
N1eme1er. 1981. Testing of selected workplace chemicals for teratogenlc
potential. Scand. J. Work Environ. Health. 7(4): 66-75.
.Hatch, G., T. Anderson, E. Elmore and S. Nesnow. 1983. Status of enhance-
ment of DNA viral transformation for determination of mutagenlc and carcino-
genic potential of gaseous and volatile compounds. Environ. Mutagen. 5:
422. (Abstract)
Hawley, G.G. 1981. The Condensed Chemical Dictionary, 10th ed. Van
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001 Id -58- 04/10/87
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001 Id -59- 04/10/87
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Mackay, 0. and H.Y. Shlu. 1981. A critical review of Henry's Law constants
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Activated sludge degradabllHy of organic substances 1n the waste water of
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OOlld -60- 04/10/87
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OOlld -61- 04/10/87
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OOlld -62- 04/10/87
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OOlld -64- 05/12/87
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OOlld -6S- 05/12/87
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APPENDIX A
LITERATURE SEARCHED
This HEED Is based on data Identified by computerized literature
searches of the following:
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted. 1n December, 1986. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 5-9), and the following
secondary sources should be 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).
1986-1987. TLVs: Threshold Limit Values for Chemical Substances In
the Work Environment adopted by ACGIH with Intended Changes for
1986-1987. Cincinnati, OH. Ill 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.
OOlld -67- 05/12/87
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Grayson, M. and 0. Eckroth, Ed. 1978-1984. K1rk-0thmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley and Sons, NY. 23
Volumes.
Hamilton, A. and H.I. 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. WHO, IARC, Lyons, France.
Jaber, H.M., W.R. Mabey, A.T. Lieu, T.W. Chou and H.L. Johnson.
1984. Data acquisition for environmental transport and fate
screening for compounds of Interest to the Office of Solid Waste.
SRI International, Menlo Park, CA. EPA 600/6-84-010. NTIS
PB84-243906.
NTP (National Toxicology Program). 1986. 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). 1986. Directory of Chemical
Producers. Menlo Park, CA. . .
U.S. EPA. 1986. Report on Status Report In the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call 1n Programs.
Office of Pesticide Programs. Washington, DC.
U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington, DC.
USITC (U.S. International Trade Commission).. 1985. Synthetic
Organic Chemicals. U.S. Production and Sales, 1984, USITC Publ.
1422, Washington. DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals, 2nd ed. Van Nostrand Relnhold Co., NY.
Wlndholz. M.. Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
OOlld -68- 05/12/87
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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 Fish 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, 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.
001 Id -69- 05/12/87
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APPfNOIX B
ry Table for 1,1,2-TrJchloropropane
Species/
Sex
Inhalation Exposure
Subchrontc ID
Chronic ID
Carclnogenlclty ID
Oral Exposure
Subchrontc rat/
female
Chronic rat/
female
Carctnogenlclty ID
BJ PORTABLE QUANTITIES
Based on Chronic Toxtclty:
Based on Carclnogenlclty:
Exposure
ID
ID
ID
100 mg/t In drinking
water for 13 weeks
(20.3 mg/kg/day)
100 mg/t In drinking
water for 13 weeks
(20.3 mg/kg/day)
ID
t
1000
ID
Effect
10
ID
ID
htstopathologlcal lesions
In liver, kidney, thyroid
at 1000 mg/l
hlstopathologlcal lesions
In liver, kidney, thyroid
at 1000 mg/l
10
RfD or q)* Reference
ID NA
ID NA
ID NA
0.2 mg/kg/day Vllleiieuve
or 14 mg/day et al., 198S
for 70 kg human
0.02 *g/kg/day Vllleneuve
or 1 ng/day for et al.. 1985
70 kg human
NA
Vllleneuve
et al.. 198S
NA
ID » Insufficient data; NA * not applicable
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APPENDIX C
Suonary Table for 1.2,3-Trlchloropropane
Species Exposure
Inhalation Exposure
Subchronlc 10 10
Chronic ID 10
Carclnogentclty ID ID
Oral Exposure
Subchronlc rat 8 mg/kg. 5 days/week
J5.7 Mg/kg/day)
Chronic rat 8 Mg/kg. 5 days/week
(5.7 Mg/kg/day)
Carclnogenlclty ID ID
RE PORT ABL E QUANTJT 1 E S
Based on Chronic Toxlclty: 100
Based on Carclnogenlclty: ID
Effect
ID
ID
ID
transient clinical signs;
elevated relative liver
weight In Mies
transient clinical signs;
elevated relative liver
weight In Males
ID
RfD or qj»
ID
10
10
0.06 mg/kg/day or
4 Mg/day for 70 kg
human
6 »jg/kg/day or 0.4
mg/day for 70 kg
human
NA
Reference
NA
NA
NA
NIP. 1983a
NTP. 1983d
NTP. 1983a
NA
ID . Insufficient data; NA « not applicable
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