FINAL DRAFT
United States
Environmental Protection
_ AM^X^ A X"N/^IKI^^ AAO
500ECAOCING002
vEPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS DOCUMENT
FOR SELECTED CHLORINATED TOLUENES
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection /Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTrc^0
' """-'- 6060J'
NOTICE
This document 1s a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
on Its technical accuracy and policy Implications.
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DISCLAIMER
This report Is an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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PREFACE
Health and Environmental Effects Documents (HEEOs) are prepared for the
Office of Solid Waste and Emergency Response (OSVIER). This document series
Is Intended to support listings under the Resource Conservation and Recovery
Act (RCRA) as well as to provide health-related limits and goals for emer-
gency and remedial actions under the Comprehensive Environmental Response,
Compensation and liability Act (CERCU). Both published literature and
Information obtained from Agency Program Office files are evaluated as they
pertain to potential human health, aquatic life and environmental effects of
hazardous waste constituents. The literature searched for In this document
and the dates searched are Included In "Appendix: Literature Searched."
Literature search material Is current up to 8 months previous to the final
draft date listed on the front cover. Final draft document dates (front
cover) reflect the date the document Is sent to the Program Officer (OSW£R).
Several quantitative estimates are presented provided sufficient data
are available. For systemic toxicants, these Include Reference doses (RfOs)
for chronic and subchronlc exposures for both the Inhalation and oral
exposures. The subchronlc or partial lifetime RfD, Is an estimate of an
exposure level that would not be expected to cause adverse effects when
exposure occurs during a limited time Interval, for example, one that does
not constitute a significant portion of the Hfespan. This type of exposure
estimate has not been extensively used, or rigorously defined as previous
risk assessment efforts have focused primarily on lifetime exposure
scenarios. Animal data used for subchronlc estimates generally reflect
exposure durations of 30-90 days. The general methodology for estimating
subchronlc RfOs Is the same as traditionally employed for chronic estimates,
except that subchronlc data are utilized when available.
In the case of suspected carcinogens, RfDs are not estimated. A
carcinogenic potency factor, or q-\* (U.S. EPA, 1980), Is provided Instead.
These potency estimates are derived for both oral and Inhalation exposures
where possible. In addition, unit risk estimates for air and drinking water
are presented based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxlclty and cardno-
genlclty are derived. The RQ 1s used to determine the quantity of a hazar-
dous substance for which notification 1s required 1n the event of a release
as specified under the CERCLA. These two RQs (chronic toxlclty and cardno-
genlclty) represent two of six scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxlclty, and acute mammalian toxlclty).
Chemical-specific RQs reflect the lowest of these six primary criteria. The
methodology for chronic toxlclty and cancer-based RQs are defined In U.S.
EPA, 1984 and 1986a, respectively.
111
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EXECUTIVE SUMMARY
The M selected thlurtrtoluenes can te classified 1n two general cate-
gories: 1) ring-chlorinated and 2) ring- plus a-chlor1nated toluenes.
The ring-chlorinated chlarotoluene? are colorless^ stable compounds
(Gelfand, 1979a). The chlorotoluenes are either sparingly soluble or
Insoluble 1n water. Three U.S. manufacturers have been cited for recent or
current production of two of the selected chlorotoluenes (USITC, 1386; SRI,
19flt>); other chlorotoluenes are produced as an on-site Intermediate for
further chemical synthesis (such as p,a,
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partially transport from the troposphere to stratosphere. In the aquatic
environment, the ring-chlorinated toluenes may not be susceptible to
hydrolysis Uaber el al.. 1984; Lyman et al.. 1984), oxidation (Jaber et
a!., 1984) or direct photolysis. The a-subst1tuted chlorotoluenes,
however, are susceptible to hydrolysis. Based on measured hydrolysis rate
data {Hyne et a"L, 1962-, Tomulla, 19tfc; fuchs and Carlton, 19&3K the
hydrolytlc half-lives of a,p-d1ch1orotoluene, a,m-d1chlorotoluene and
a,3,4-tr1chlorotoluene at 25°C range from -57-250 hours. The volatiliza-
tion half-life of all the selected chlorotoluenes from a river 1 M deep,
flowing at a speed of 1 m/sec with a wind velocity of 3 m/sec has been
estimated to be ~5 hours; however, adsorption to sediment may significantly
reduce the relative Importance of volatilization as an environmental trans-
port process. Adsorption to sediment 1s expected to be significant based on
estimated K values and sediment monitoring data from the Niagara River
and Lake Ontario (Jaffe and H1tes, 1984). Experimental (Oliver and N11m1,
1984, 1985) and estimated BCF values for the ring-chlorinated toluenes
Indicate that bloaccumulatlon In aquatic organisms will be significant.
Limited blodegradatlon data (Wellens, 1984; Vandenbergh et al., 1981; OmoH
and Alexander, 1978) suggest that the chlorotoluenes may be susceptible to
blodegradatlon, but the data are Insufficient to predict their blodegrada-
tlon fate. The detection of dlchlorotoluenes, tMchlorotoluenes and tetra-
chlorotoluene 1n the two bottom sediment cores (22.5 and 30.5 cm) of the
Niagara River (Jaffe and H1tes, 1984) suggests that blodegradatlon under
anaerobic conditions Is very slow. In soil, estimated K values
(890-35,000) Indicate that little or no leaching will occur In most soil
types; however, chlorotoluenes have been observed to leach from hazardous
waste disposal sites In Niagara Falls, NY (Elder et al., 1981). In this
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case, leaching probably occurred because of the effects of other solvents 1n
enhancing the Teachability of cnlorotoluenes and the saturation of soil
attetJTptltm *1tes by ottwr pollutants. Tht a-sutsfltuted tnlwtjtoluenes
are expected to be susceptible to hydrolysis 1n moist soils. B1odegradat1on
way tee t*» only degradatVre process tn soil for the ring-chlorinated
toluenes. Therefore, the ring-chlorinated toluenes are expected to be
persistent 1n all three environmental media.
Various specified and unspecified Isoroers of the chlorotolaenes have
been detected 1n the surface water, fish and sediments of the Niagara River
and Lake Ontario (Elder et al., 1981; Oliver and Nlcol, 1984; Oliver, 1984;
Great Lakes Water Quality Board, 1983; Jaffe and H1tes, 1984; Kamlnsky et
al., 1983; Yuravecz, 1979). The presence of chlorinated organic compounds
(Including the chlorotoluenes) 1n the Niagara River/Lake Ontario region has
been attributed to effluents and leachates from Industrial chemical waste
dump sites (Elder et al., 1981; Oliver and Nlcol, 1984). Chlorotoluenes
have also been detected 1n the ambient air of the Niagara Falls region
(Pelllzzan, 1982; Pelllzzarl et al., 1979; Mauser and Bromberg, 1982) and
In the air of source-dominated areas In Deepwater, NJ (Brodzlnsky and Singh,
1982). Adequate monitoring data are not available for estimating the dally
human exposure to chlorotoluenes, because drinking water and foods are
Ingested or Inhaled.
The data concerning toxlclty of chlorotoluenes to aquatic organisms were
limited. The lowest reported toxic concentration was 0.148 mg/j, 3,4-dl-
chlorotoluene, which reduced growth and survival of fathead minnows In an
early life stage test (Call et al., 1985). These authors also calculated a
MATC of 0.107 mg/l.
v1
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The 1 sower for which the most complete pharmacoklnetlc profile was
available was p,a,a,o-t«traehlorotoluene. This compound was readily
absorbed by the gastrointestinal tract of rats {Qulstad et al., 1985).
p.a.a.a-Tetrachlorotoluene 1s not selectively distributed to any
particular tissue, but after an artificially high dose was given, the parent
compound and the metabolite, «.«1,4,4'-tetrachlorost1lbene accumulated
1n the abdominal fat of rats {Qulstad et al., 1985). This result agrees
with the findings of Le Bel and Williams (1986). who Identified 2,4,5-trl-
chlorotoluene 1n human adipose tissue. The metabolites of p,a,a,a-
tetraclilorotalaetie were excreted primarily in the urine (87%), but fetal
excretion occurred as well. Qulstad et al. (1985) found that the major
urinary metabolite of p,a,o,a-tetrachlorotoluene was 4-chloroh1ppur1c
add, which accounted for 78% of the dose. Many fecal metabolites were
unextractable, but 4-chlorobenzo1c add and a,a' ,4,4'-tetrachloro-
stllbene were Identified 1n the extractable portion. Little p,a,a,a-
tetrachlorotoluene was excreted unchanged In the rat.
Few data were available upon which to base an adequate toxlcologlcal
profile. A Russian study reported that rats chronically exposed to 0.0013
mg/l dlchlorotoluene (not otherwise specified) by Inhalation exhibited
only slight deviations from controls (Stankevlch and Osetrov, 1963). Rats
given dietary 2,3,6- or
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2,3,6-trlchlorotoluene In mice (NIOSH, 1986); 700 and 1350 mg/kg
p»a,a.«-tetracftlorotoluene In rats and mice, respectively (Khalepo et
al., 1964]; awl 820 fl»g/*g p,«,«,«-tetr3chl«rotoltiene 1ti rats (Hooker
Chemical Co., 1980). Signs and symptoms of acute toxldty Included motor
activity, tremors, diarrhea, plloerectlon and chromodacryorrhea and gastric
Irritation (Hooker Chemical Co., 1980). An Inhalation threshold and JLCg-
of 22.4 and 123 «g/«*, respectively., for unspecified durations for both
rats awl mice was reported by Khalepo et al. (1984). Hooker Chemical Co.
O380) reported a dermal U)«j >2 g/kg for p,.*^«-i,eiTatfc"Joro-
toluene. a,o-D1chlorotoluene was positive In skin sens1t1zat1on tests
(Cohen et al., 1967).
No data were available to assess the carcinogenic potential of the
chlorinated toluenes from Inhalation. Fukuda et al. (1979) gave mice 0,
0.05, 0.13, 0.32, 0.8 and 2 yl of p,a,a,a-tetrachlorotoluene by
gavage for 17.5 weeks. Tumors 1n the. stomach, lung, skin and lymphatic
organs were observed 18 months later. Tumors 1n the digestive system were
also noted after dermal application of p,a,a,a-tetrachlorotoluene to
mice (Fukuda et al., 1979). No data concerning the mutagenlc effect of the
chlorinated toluenes were located.
The only study available concerning the teratogenlclty of the chlori-
nated toluenes was by Ruddlck et al. (1982), who gave pregnant rats 0-400
mg/kg/day 2,3,6- or o,2,6-tr1chlorotoluene by the oral route. Hlstopatho-
loglc lesions In the thyroid, bone marrow, kidney and liver occurred In dams
at unspecified doses. Reduced fetal body weight and liver damage of pups
occurred at all doses of 2,3,6- and a,2,6-tr1chlorotoluene, but were most
severe at 400 mg/kg/day 2,3,6-trlchlorotoluene. No data were available
concerning the other reproductive effects of the chlorinated toluenes.
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Based QO the positive carcinogenicUy studies by fukuda et al. (1979),
1ti which p,a,a,*-tetrachlorotoluene was administered orally and
dermally to mice, and on the structural similarity of p,a,a,a-tetra-
chlorotoluene to benzotMchloMde, an EPA 82 chemical carcinogen, there Is
sufficient evidence that p,*.*,a-tetrachlorotoluene (benzotrlchlorlde)
is carcinogenic to animals. In the absence of data for humans. 1t was
classified as an EPA B2 chemical, that Is, a probable human carcinogen. A
q,* of 20 {mg/kg/day)~a for oral exposure was derived based on the dose-
response data for luag adenocardnoraas In the oral study in female nice by
f\rtctwft et al. t"W9). "The concentrations 1n water associated with an
Increased lifetime risk of cancer at risk levels of 10~5, 10~* and
NT7 are 2xlO~5, 2x10"* and 2xlO~7 mg/l, respectively. An F
factor of 136 (mg/kg/day)""1 was also calculated based on the Fukuda et al.
(1979) oral data. Thus p.a.a.a-tetrachlorotoluene Is a Potency
Group 1 and EPA B2 chemical with a HIGH hazard ranking under CERCLA and an
RQ of 1 based on cardnogenldty.
Subchronlc oral RfOs of 0.00005 mg/kg/day for both 2,3,6- and
a,2,6-tr1chlorotoluene were derived based on LOAELs of 0.05 mg/kg/day for
both Isomers In the 28-day study by Chu et al. (1984), using an uncertainty
factor of 1000. Effects at the LOAEL Included mild lesions of the liver,
kidney and thyroid. Low confidence was placed 1n the subchronlc oral RfD,
which was considered Inadequate for extrapolation to a chronic oral RfO.
RQs of 100 based on chronic toxldty were also derived for both
2,3,6- and 0,2,6-trlchlorotoluene based on the Chu et al. (1984) study.
Data were Insufficient to derive q,*s, RfDs or RQs for any of the other
chlorinated toluenes.
1x
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TABLE OF CONTENTS
1. IHTSOOUCTION
1.1. STRUCTURE AND CAS REGISTRY NUMBER ............. 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES ............. 1
1,3, PRODUCTION DATA. , . . . ................. 1
1.4. USE DATA ......................... 12
1.5. SUMMARY .......................... 12
2. ENVIRONMENTAL fATf AiU) TRANSPORT ........... . ...... 14
2.1. AIR ............................ 14
2.1.1. Reaction with Hydrosyl Radicals ......... 14
2.1,2, Direct Photolysis ....... , ........ 14
2.2. WATER ........................... 14
2.2.1. Hydrolysis .................... 14
2.2.2. Oxidation .................... 16
2.2.3. Photolysis .................... 17
2.2.4. Mlcroblal Degradation .............. 17
2.2.5. Volatilization .................. 18
2.2.6. Adsorption .................... 18
2.2.7. B1oconcentrat1on .................. 19
2.3. SOIL .... ....................... 19
2.3.1. Mlcroblal and Chemical Degradation ....... 19
2.3.2. Adsorption/Leaching ............... 19
2.4. SUMMARY .......................... 22
3. EXPOSURE ............................. 24
3.1. WATER ........................... 24
3.2. FOOD ........................... 25
3.3. INHALATION ........................ 25
3.4. DERMAL .......................... 26
3.5. SUMMARY .......................... 26
4. AQUATIC TOXICITY ......................... 28
4.1. ACUTE TOXICITY ...................... 28
4.2. CHRONIC EFFECTS ...................... 28
4.3. PLANT EFFECTS ....................... 28
4.4. SUMMARY .......................... 30
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TABLE OF CONTENTS (cont.)
Page
5. WAWWCOKlttTCS 31
5.1. ABSORPTION 31
5.2. DISTRIBUTION 31
5.3. METABOLISM 32
5.4. mania*!, 32
5.5. SUHMARY 33
6. EFFECTS 34
6.1. SYSTEMIC TOXICITY 34
6.1.1. Inhalation Exposures 34
6.1.2. Oral Exposures. 34
6.1.3. Other Relevant Information 35
6.2. CARCINOGENICITY 36
6.2.1. Inhalation 36
6.2.2. Oral 36
6.2.3. Other Relevant Information 36
6.3. MUTAGENICITY 39
6.4. TERATOGENICITY 39
6.5. OTHER REPRODUCTIVE EFFECTS 39
6.6. SUMMARY 41
7. EXISTING GUIDELINES AND STANDARDS 43
7.1. HUMAN 43
7.2. AQUATIC 43
8. RISK ASSESSMENT 44
8.1. CARCINOGENICITY 44
8.1.1. Inhalation 44
8.1.2. Oral 44
8.1.3. Other Routes 44
8.1.4. Weight of Evidence 44
8.1.5. Quantitative Risk Estimates 45
8.2. SYSTEMIC TOXICITY 46
8.2.1. Inhalation Exposure 46
8.2.2. Oral Exposure 47
x1
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TABLE OF CONTENTS (cont.)
«€PflSTA8L€ SUAJfTITIfS ...................... 48
9.1. BASED ON SYSTEMIC TOXICITY ....... . ..... ... 48
9.2. BASED ON CARCINOGENICITY ................. 53
10. RETIRENCES ................... , ........ 55
APPENDIX A: LITERATURE SEARCHED .................... 66
APPENDIX 8: CAWCER DATA SWEET FOR OERIVATNW OF q-|* .......... 69
APPENDIX C: SUHMASY TABL£ ....................... 70
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LIST OF TABUS
No. Title Page
1-1 Synonyms, CAS numbers, Empirical Formulas and Structures
of Selected Chlorotoluenes 2
1-2 Physical Properties of Selected Chlorotoluenes 7
1-3 1«77 Protection 0ata for the Ciilorotolwnes 9
2-1 Vapor-Phase Reaction Half-lives for Selected Chlorotoluenes . 15
2-2 Estimated BCF Values for Selected Chlorotoluenes 20
2-3 Estimated Koc Values for Selected Chlorotoluenes 21
4-1 Acute ToxIcUy of Chlorinated Toluenes to Aquatic
Organisms ..... 29
6-1 Tumor Incidence 1n Female ICR-SLC Mice Given p,a,a,a,-
Tetrachlorotoluene of Unspecified Purity 1n Sesame 011
Twice Weekly by Gavage for 17.5 Weeks, Followed by a
54.5-Week Observation 37
6-2 Incidence of Tumors In Mice Treated Dermally with 5 pi
p,a,a,a-Tetrachlorotoluene Twice Weekly for 30 Weeks
Followed by a 7-Week Observation Period 40
9-1 Oral Tox1c1ty Summary for 2,3,6- and
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LIST OF ABBREVIATIONS
VCf Bloconcentratlon
CAS Chemical Atrstratrt "Services
CS Composite score
EC5Q Concentration effective to 50% of recipients
Soil sorptlon coefficient
Octant)l-«ater partition coefficient
Concentration lethal to SOX of recipients
1050 Dose lethal to 50% of recipients
JJDAEL Lowest-observed-adverse-effect level
LOEC Lowest-observed-effect concentration
MATC Maximum acceptable threshold concentration
MED Minimum effective dose
MTD Maximum tolerated dose
NOAEL No-observed-a"dverse-effect level
NOEC No-observed-effect concentration
ppb Parts per billion
ppm Parts per million
ppt Parts per trillion
RQ Reportable quantity
RV,j Dose-rating value
RVe Effect-rating value
UV Ultraviolet
x1v
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1. INTRODUCTION
1.1. STRUCTURE AND'CAS REGISTRY MUMB£fi
The synonyms, CAS Registry numbers, empirical Formulas and structures of
the selected chlorotoluenes are listed 1n Table 1-1. The selection of
cblorloaied toluenes MAS oade on the basis of coomerlcal Importance and
excluded some compounds for which a Health and Environmental Effects Profile
exists.
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Available physical properties of the en1orotoluenes are listed In Table
1-2. The selected chlorotoluenes can be classified In two general cate-
gories: 1) ring-chlorinated and 2) ring- plus a-chlorlnated toluenes.
The ring-chlorinated chlorotoluenes are colorless, stable compounds
(Gelfand, 1979a). The a-substHuted chlorotoluenes are susceptible to
hydrolysis at the a-chlorlne group (Section 2.2.1.).
1.3. PRODUCTION DATA
The most recent chlorotoluene production data available are from the
public portion of the U.S. EPA TSCA Production File (Table 1-3). World
production of polychlorotoluenes (ring-chlorinated) has been estimated to be
0.2-2.0 million pounds annually (Gelfand. 1979a).
Tenneco Chemical produced a number of chlorotoluenes 1n 1977 (see Table
1-3); however, Tenneco ceased production of chlorotoluenes In 1978 and sold
Its product line to American Hoechst Corp., which now produces those
chemicals overseas (U.S. EPA, 1983). USITC (1986) reported that Stauffer
Agricultural Chemical produced a,2 (or 3), 4-trlchlorotoluene and
Occidental Chemical a,p-d1chlorotoluene In the United States In 1985.
Occidental Chemical acquired Hooker Chemical (Niagara Falls, NY), which was
listed as a major manufacturer of chlorotoluenes In 1977 (see Table 1-3).
0030d -1- 08/26/87
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-------
TABLE 1-3
1977 Production Data for the Chiorotoluenes2
Chlorotoluene
2,3-D1chloro-
toluene
2,4-01chloro-
toluene
2,5-D1chloro-
toluene
2,6-D1chloro-
toluene
3,4-Qlchloro-
toluene
a,m-D1chloro-
toluene
a,o-D1chloro-
toluene
a,p-D1chloro-
toluene
Tetrachloro-
toluene
Company/Location
American Hoechst
Coventry, RI
Tenneco Chera.
Fords, NJ
Montco Research
Hoi lister, FL
Hooker Chem.
Niagara Falls, NY
Hooker Chem.
Niagara Falls. NY
American Hoechst
Coventry, RI
DuPont
Deepwater, NJ
Tenneco Chera.
Fords, NJ
Hooker Chem.
Niagara Falls, NY
none
Columbia Organlcs
Columbia, SC
Tenneco Chem.
Fords, NJ
confidential
Stauffer Chem.
Edison. NJ
Tenneco Chem.
Fords, NJ
American Hoechst
BMdgewater, NJ
none
Manufacturer/
Importer
manufacturer
manufacturer
manufacturer
manufacturer
manufacturer
Importer
manufacturer
manufacturer
manufacturer
none
manufacturer
manufacturer
manufacturer
manufacturer
manufacturer
Importer
none
Yearly Volume
(pounds)
noneb
none
1-10 thousand
0.1-1 million
0.1-1 million
confidential
10-100 thousand
' «
none
0.1-1 million
none
<1000
none
10-100 thousand
confidential
10-100 thousand
confidential
none
0030d
-9-
05/19/87
-------
TABLE 1-3 (cont.)
Manufacturer/
Importer
Yearly Volume
(pounds)
cii lor o toluene
2.3,4-Trl-
cnlorotoluene
2.3,5~Tr1-
tfclorotoluene
2,3,6-Tr1-
cnlorotoluene
2,4,5-TM-
chlorotoluene
2,4,6-TM-
chlorotoluene
3,4,5-Trl-
chlorotoluene
Trlchloro-
toluene
(mixture)
-------
SRI (1986) lists Montco Research Products (Hamster, FL) as a current
roantifattwer of tt.2.4-tMth1oTott>1ueive. Other selected chlorotoluenes may
currently be manufactured 1n the United States but are net Isolated or sold
as end-products. For example, p,a,a,a-tetrachlorotoluene 1s manufac-
tured for captive use as an on-slte Intermediate for the production of
p-chlorobenzotrlFluoride at the Hooker Chemical facility {U.S. EPA, 1983).
According to CMR (1986), the following selected chlorotoluenes are
available for commercial sale: 2,4,6-trlchlorotoluene; 2,3,6-tMchlorotolu-
ene; a,m-d1ch]orotoluene; a,o-d1chlorotoluene; a,p-d1chlorotoluene;
2,4-dlchlorotoluene; 2,5-
-------
1.4. USE DATA
2,4-Qlchltjrotoluene and 2,6-dlchlorotoluene are used as Intermediates
for the production of herbicides, dyestuffs and dlchlorobenzoyl chloride
(Gelfand, 1979a). 2,3,6-TMchlorotoluene 1s used 1n small quantities as a
herbicide Intermediate, while the other polyrlntj-chloMnated toluenes have
United Industrial use (Gelfand, 1979a). Ring-chlorinated toluene Isoroer
mixtures and mixtures high In o-monochlorotoluene content have been used In
solvent applications such as reaction solvents, dye carrier formulations,
sludge solvent, and paint and rubber stripping formulations (Gelfand,
1979a). 2,W)1ch"loroto1uene 1s also used as a solvent (Chemical Week, 1976).
The a,o- and
-------
be formed as by-products during toluene chlorlnatlon processes. Twelve of
tne selected chlorotoluenes have been listed as currently available for
cofflmerclal sale (CNR, 1986). 2,W)1chlorotoluen«, 2,6-dlchlorotoluene and
2,3,6-tMchlorotoluene can be used as Intermediates for the production of
n*rtlt1d*s, dy«stuffs awl trtfcer ctrewltals (Selfand* 1S7Sa). «lt»q-cnlort«at«d
toluene Isoraer mixtures and 2,4-d1chlorotoluene can be used 1n a variety of
solvent applications (Selfand, 1979a; Chemical Week, 1976). The ^substi-
tuted chlorotoluenes are used as Intermediates for the production of herbi-
cides, Pharmaceuticals, dyes and organic chemicals (Gelfand, 1979b; Hawley,
1981; U.S. EPA, 1983).
0030d -13- 08/26/87
-------
2. ENVIRONMENTAL FATE AND TRANSPORT
2.1, AIR
2.1.1. Jteacilou *3iJ> Hydraxyl Badl«l$. Th* calcalatsa1 half-Uv*5 for
the vapor phase reaction of the selected chlorotoluenes with photochemically
produced hydroxyl radicals In a typical ambient atmosphere are given In
Table 2-1 t\).S. EPA, 1987). It 1s apparent that the r1ng-chlw1nated
toluenes are more 3ia£l« toward this reaction than the «-chlorotoluenes.
2.1.2. Direct Photolysis. Utf spectra of the ring-chlorinated toluenes
(2,4-d1ct)lorotolu«ne, 2,5«~dUhlorotolu«ne. 2,6-dlchlorotoluene, 3,4-d1-
chlorotoluene, 2,3,6-trlchlorotoluene, 2,4,5-trlchlorotoluene) show very
little, 1f any, absorption In the environmentally Important regions of the
spectrum (Sadtler, 1961, 1966a,b, 1975, 1976, 1977). Therefore, direct
photolysis of these compounds 1s not expected to occur In the troposphere.
With sufficiently long atmospheric residence times, some diffusion Into the
stratosphere may occur.
UV spectra of the «-subst1tuted chlorotoluenes (290 nm) (Sadtler, 1960, 1966c,d,
1974, 1980). This Indicates that some direct photolysis may be possible;
however, kinetic data were not available to predict the relative signifi-
cance of direct photolysis.
2.2. WATER
2.2.1. Hydrolysis. Ring-chlorinated aromatic compounds are generally
resistant to environmental hydrolysis (Lyman et al., 1982). Jaber et al.
(1984) listed 2,4-d1chlorotoluene and 2,4,6-dlchlorotoluene as Inert to
neutral and alkaline hydrolysis. Therefore, the selected ring-chlorinated
toluenes are not expected to hydrolyze significantly In the environment.
0030d -14- 05/19/87
-------
TABLE 2-1
Vapor-Phase Reaction Half-Lives for Selected Chlorotoluenes3
Chlwotoltiene
Ring-chlorinated d1 Chlorotoluenes
Ring-chlorinated trlchlorotoluenes
Ring-chlorinated tetrachlorotoluene
o,.m-, a,o- and a,p-01chlorotoluene
a, 2, 4- and a,3,4-Tr1chlorotoluene
p,a,a,a,p-Tetraciilorotoluene
Half-L1feb
18.36 days
1 .45 months
2.48 months
5.77 days
14.64 days
6.68 days
Rate Constant
(cm3 'molecule-sec)
5.46 xlO~13
2.3013x10'"
1.3501x10-"
1.737. X.10'"
6.848 x!0~"
1.401 x!0~"
aSource: U.S. EPA, 1987
^Estimated using respective rate constants and assuming an average atmo-
spheric hydroxyl radical concentration of 8xlOs molecules/cm3.
OOSOd -15- 05/19/87
-------
The ^-substituted chlorotoluenes are susceptible to hydrolysis at the
*-ch1or1ne; the kinetics of the reaction has been studied by various
Investigators. Hyne et al. 09*12) measured the rate constant for the
hydrolysis of a,p-d1chlorotoluene 1n 100% water at 42.86°C to be
5.69xlQ~s sec"1, which corresponds to a half-life of 3.4 hours. Con-
parlson with hydrolysis rate data for a-roonochlorotoluene over a tempera-
ture range of 25-60'C {Uyi* et al., 1962} indicates that a.p-dichloro-
toluene win have a half-life of -155 hours at 25*C. In a dilute aqueous
solution of dimethyl sulfoxlde (700 rai/l of water; 22.4 wt % dimethyl
sulfoxlde) at 25°C, Tommlla (1966) measured an a,p-d1chlorotoluene
first-order hydrolysis rate constant of 3.4xlO~6 sec"1; this corresponds
to a half-life of 57 hours, which 1s reasonably close to the previous
estimate. Similarly, Tommlla (1966) measured a first-order rate constant of
0.913x10"' sec"1 for a,m-d1chlorotoluene at 25°C (in 500 mg/l water;
53.6 wt % dimethyl sulfoxlde), which corresponds to a half-life of 211 hours.
Fuchs and Carlton (1963) measured hydrolysis rates of a,p-d1chloro-
toluene, a,m-d1chlorotoluene, and a,3,4-trichlorotoluene 1n a 50%
aqueous ethanol solution at 60°C. The rate constant for a,3,4-trichloro-
toluene (0.427xlO~5 sec"1) was -25% slower than for a.m-dichloro-
toluene and -4 times slower than for
-------
2.2*3. Photolysis. The ring-chlorinated toluenes (2,4-d1chlorotoluene,
2.5-d1ch1ort>toluene, 3«4-d1chlorotoluene, 2,3,&-tr1ch1ort>toluene, 2.4,5-tr1-
ctrtorotoluene) show very little or no absorption In the environmentally
Important region of the UV spectrum 1n a methanol solvent (Sadtler, 1966a,b,
1975. 197$. 1977). This suggests tnat direct photolysis 1n the aquatic
environment will not be significant.
The a-substltuted chlorotoluenes (a,o-d1chlorotoluene, ct,m-d1-
chlorotoluene, a,2,4-tr1ch"lorotoluene, a,3,4-tr1chlorotoluene), 1n a
methanol solvent, show some minor absorption in the UV region >290 nro
{Sadtler, 1966c,d, 1974, 1980); therefore, some direct photolysis Is
possible. Kinetic photolysis data are not available to predict the relative
significance of direct photolysis. It 1s not expected, however, to be
Important 1n relation to hydrolysis or volatilization.
2.2.4. M1crob1al Degradation. Only limited blodegradatlon data are
available for the selected chlorotoluenes. Wellens (1984) used a static
blodegradabHUy test (OECD) and determined that an unspecified Isomer of
the a-substltuted dlchlorotoluenes required a 5- to 10-day acclimation
period before Initiation of blodegradatlon. Vandenbergh et al. (1981)
Isolated bacteria from a soil at a landfill site used for the disposal of
chlorinated organic wastes and found that the bacteria were able to use
2,6-d1chlorotoluene and 3,4-d1chlorotoluene as sole carbon and energy
sources for growth. Omorl and Alexander (1978) also used bacteria obtained
by soil enrichment cultures to demonstrate metabolism of the a-subst1tuted
dlchlorotoluenes; the products of metabolism were found to Include chloro-
benzyl alcohol and chlorobenzolc add.
The relatively constant concentrations of dlchlorotoluenes, trlchloro-
toluenes and tetrachlorotoluene 1n the two bottom sediment cores (22.5 and
0030d -17- 06/04/87
-------
30,5 cm) of the Niagara River (Jaffe and Hltes, 1984) suggest that these
compounds are not readily biodegradable under anaerobic conditions.
2.2-5. Volatilization. OHyer (1385) measured a Henry's Law constant of
1.5xlO~3 atm-m3/mo1 for 2,4,5-tMchlorotoluene and 2,3,6-tMchloro-
toluene at 20°C, which Indicates that volatilization from environmental
waters may be rapid (Lyman et al., 1982). Using the method outlined 1n
iyman -et al. (1982). tJ» volatilization half-life from a river 1 H deep.
flowing at a speed of 1 m/sec, with a wind velocity of 3 m/sec 1s estimated
to be -5 hours.
fjilaatloa of Henry's law constant using the method of Mine and
Mookerjee (1975) for the ring-chlorinated toluenes (dlchlorotoluenes,
trlchlorotoluenes, tetrachlorotoluene) and for the a-subst1tuted chloro-
toluenes (dlchlorotoluenes, trlchlorotoluenes) yields values reasonably
similar to the experimental value for 2,4,5-trlchlorotoluene and 2,3,6-trl-
chlorotoluene cited above. Therefore, volatilization from the water column
may be rapid for all of the selected chlorotoluenes; however, adsorption to
sediment and suspended matter 1n natural water may significantly decrease
the relative Importance of volatilization as an environmental transport
process.
2.2.6. Adsorption. The K values estimated 1n Section 2.3.2. suggest
that adsorption to sediment may be an Important transport process for the
selected chlorotoluenes. The detection of dlchlorotoluenes, trlchloro-
toluenes and tetrachlorotoluene 1n sediment and sediment cores from the
Niagara River and Lake Ontario (Section 3.1.) support this suggestion.
Since the a-subst1tuted chlorotoluenes will undergo hydrolysis, however,
adsorption may not be a significant process for these compounds.
0030d -18- 05/19/87
-------
2.2.7. B1oconcentrat1on. Oliver and N11fl»1 {1984, 1985) measured the BCF
of 2.4,5-trlchlorotoluene 1n rainbow trout using a steady-state approach and
determined BC? values of 4800-8500. These values Indicate that bloconcen-
tratlon Is significant.
The 8CF of an vrganlc chemical can b« estimated by t!w
equation (Lyman et al., 1982): log BCF . 0.76 log K - 0.23. Estimated
ow
BCF values using the log K values from Table 1-2 are given 5n Table 2-2.
With the exception of the <*-subst1tuted dlchlorotoluenes and trlchloro-
toluenes. bloconcentratlon of the selected chlorotoluenes 1s expected to be
significant.
2.3. SOIL
2.3.1. M1crob1al and Chemical Degradation. Based on the discussion In
Section 2.2.4., the chlorotoluenes may be susceptible to blodegradatlon In
soil; however, 1n the absence of sufficient experimental data, the relative
•
significance or the kinetics of such blodegradatlon processes cannot be
predicted. In the case of the ring-chlorinated toluenes, chemical degrada-
tion processes such as hydrolysis are not expected to be significant 1n
soil; therefore, blodegradatlon Is probably the only degradatlve process
that 1s relevant with such chemicals.
As presented In Section 2.2.1., the «-subst1tuted chlorotoluenes are
susceptible to significant hydrolysis. Therefore, they are expected to
hydrolyze 1n moist soil.
2.3.2. Adsorption/Leaching. Relevant experimental studies pertaining to
the adsorption of the chlorotoluenes were not located. The K can be
estimated from the following regression equation (KaMckhoff, 1985): log
KQC = 0.72 log KQW + 0.49. Estimated KQC values using the log KQW
values from Table 1-2 are given In Table 2-3. Log K values between 500
0030d -19- 06/04/87
-------
TABLE 2-2
Estimated BCF Values for Selected Diloroioluaws
ttolorotoluene
8tf Value
Ring-chlorinated dlchlorotoluenes
Ring-chlorinated trlchlorotoluenes
Ring-chlorinated tetrachlorotoluenes
a,2,4-Tr1chlorotoluene
a-D1chlorotoluenes
p,a,a,a-Tetrachlorotoluene
1,000
3,300
11,300
470
230
2,800
0030d
-20-
05/19/87
-------
TABU 2-3
Estimated Koc Values for Selected Chlorotoluenes
Chlorotoluene K Values
RIng-sufastHuted dlchlorotoluenes 3,500
Ring-substituted trlchlorotoluenes 11.000
Ring-substituted Tetrachlorotoluene 35,000
-------
and 2000 Indicate low soil mobility, while K values >2000 Indicate
slight or no mobility (Swann et al., T983). Therefore, results Indicate
thai the chlorotoluenes, In general, are -not expected ia leach slgnlfJcantly
In roost soils; however, chlorotoluenes have been observed to leach from
hazardous waste disposal sites 1n Niagara Falls, KY (Elder et al., 1961),
In this case, leaching can be attributed to effects of other solvents In
enhancing the leachatoHlty and the saturation of soil sorptlon sites by
other pollutants.
2,4. SUHMARY
The ring-chlorinated toluenes are more stable than the a-subst1tuted
chlorotoluenes and are therefore more persistent In the environment. In the
atmosphere, the chlorotoluenes will react with photochemlcally produced
hydroxyl radicals. The calculated half-life for this reaction 1s 18.36 days
to 2.48 months for the ring-chlorinated toluenes and 5.77-14.64 days for the
a-substHuted chlorotoluenes (U.S. EPA, 1987). In the absence of any
other known environmental reactions, the ring-chlorinated toluenes may
partially transport from the troposphere to stratosphere. In the aquatic
environment, the ring-chlorinated toluenes may not be susceptible to
hydrolysis (Jaber et al., 1984; Lyman et al., 1984), oxidation (Jaber et
al., 1984) or direct photolysis. The
-------
reduce the relative Importance of volatilization as an environmental trans-
port process. Adsorption to sediment 1s expected to be significant based on
estimated K values and sediment monitoring data from the Niagara IMver
and Lake Ontario (Jaffe and H1tes, 1984). Experimental (Oliver and N11m1,
1984, 1385) and estimated BCF values for the rlngchlorlnated toluenes
Indicate that bloaccumulatlon 1n aquatic organisms will be significant.
Halted blodegradatlon data (Weilens, 1984; Vandenbergh et a!.. 1981; OmoM
and Alexander, 1978) suggest that the chlorotoluenes may be susceptible to
blodegradatlon, but the data are Insufficient to predict their blodegrada-
tlon fate. The detection of dlchlorotoluenes, tMchlorotoluenes and tetra-
chlorotoluene 1n the two bottom sediment cores (22.5 and 30.5 cm) of the
Niagara River (Jaffe and HHes, 1984) suggests that blodegradatlon under
anaerobic conditions 1s very slow. In soil, estimated K values
(890-35,000) Indicate that Uttle or no leaching will occur 1n most soil
types; however, chlorotoluenes have been observed to leach from hazardous
waste disposal sites 1n Niagara Falls, NY (Elder et a!.. 1981). In this
case, leaching was attributed to the effects of other solvents 1n enhancing
the Teachability of chlorotoluenes and the saturation of soil adsorption
sites by other pollutants. The «-subst1tuted chlorotoluenes are expected
to be susceptible to hydrolysis 1n moist soils. Blodegradatlon may be the
only degradatlve process In soil for the ring-chlorinated toluenes. There-
fore, the ring-chlorinated toluenes are expected to be persistent 1n all
three environmental media.
0030d -23- 06/04/87
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3. EXPOSURE
3.1. WAT!*
«,2,4-TTlcn1«rott>laene and «,3,4-tr1cfl1orotola«n* have b««n tenta-
tively Identified 1n drinking water concentrates taken from Cincinnati, OH,
In October* 1976, and ojB-dlchlorotoluene was tentatively Identified 1n
•drinking water concentrates taken from New Orleans, LA, 1n January, 197*
{Ujcas, 1984}. 2,4-01chl«rotoluene, 2* 6-d1-chloro toluene, 2.3,6-trVchlofo-
toluene, 2,4,6-tMthlorotoluene, 2,3,5,6-tetratrhlorotolwne, and unspecified
Homers of dlchlorotoluenes, trldilorotoluenes and tetrathlorotoluenes tiave
been qualitatively detected In the western basin of Lake Ontario and the
Niagara River (Great Lakes Water Quality Board, 1983).
Elder et al. (1981) collected water and sediment samples from areas near
hazardous waste disposal sites 1n Niagara Falls, NY, and found levels of
20-90 ppm unspecified dlchlorotoluenes, 50-100 ppm unspecified trlchloro-
toluenes and 10-40 ppm unspecified tetrachlorotoluenes; the authors
suggested that leachates from these hazardous waste disposal sites were
contaminating the Niagara River. Oliver and Nlcol (1984) monitored the
Niagara River (at N1agara-on-the-Lake) over a 2-year period (September, 1981
to September, 1983) and found mean concentrations of 1.3 ppt 2,4,5-trl-
chlorotoluene and 0.84 ppt 2,3,6-tMchlorotoluene. Oliver and Nlcol (1984)
estimated that 20-200 kg/year of 2,4,5-tMchlorotoluene and 2,3,6-trlchloro-
toluene are transported by the Niagara River to Lake Ontario. Jaffe and
Hltes (1984) detected unspecified Isomers of dlchlorotoluenes, tMchloro-
toluenes and tetrachlorotoluenes 1n sediment core samples taken from the
Niagara River at Niagara Falls, NY, at depths ranging from 1.0-30.5 cm;
concentrations ranged from 0.003-220 ppm. Kamlnsky et al. (1983) found
unspecified tHchlorotoluenes at levels of a trace to 1.5 ppb 1n sediment
0030d -24- 05/19/87
-------
samples from the western portion of Lake Ontario. Oliver (1984) detected
2,4,5-trlchlorotoluene and 2«3,6-tr1cn1oroto1uene at levels of 1.8-46 ng/g
1fl 5«d1nieivt samples frt>m tlw western, central awl eastern t>as1t« vf tafc«
Ontario. Hauser and Bromberg (1982) reported the qualitative detection of
2,4-dlchlorotoluene In sedlnent/soH/water samples froa tt« Love Canal near
Niagara Fall*, NY.
Kauss and Hamdy (1985) used blomonltors (clams) to confirm the presence
of 2,3,6-trlchlorotoluene In waters of the St. Clalr-DetroU River corridor
between Lake Erie and Lake Huron during 1382 and 1383. Concentrations of
0.37 ppb dlchlorotoluene and 0.02-0.03 ppb trlchlorotoluene have been
detected 1n the Rhine River In Germany (Sonthelmer, 1980; StleglHz and
Roth, 1976).
The presence of chlorinated organic compounds (Including the chloro-
toluenes) 1n the Niagara River/Lake Ontario region has been attributed to
effluents from chemical manufacturtng plants and leachates from chemical
waste dump sites (Elder et al.t 1981; Oliver and Nlcol, 1984).
3.2. FOOD
Yurawecz (1979) detected 2,6-d1chlorotoluene and 2,4,5-trlchlorotoluene
In the edible portion of fish (bass) taken from the Niagara River In
January, 1976; the level of 2,4,5-trlchlorotoluene found 1n the bass was
0.31 ppm.
3.3. INHALATION
PelUzzar! (1982) detected an unspecified dlchlorotoluene at 0.04-0.45
(0.006-0.07 ppb) and an unspecified trlchlorotoluene at 0.57
(0.09 ppb) In the ambient air of Niagara Falls, NY, downwind from
the Industrial area; the substances were not detected In upwind samples.
0030d -25- 05/19/87
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Levels of dlchlorotoluenes, trlchlorotoluenes and tetrachlorotoluenes fouad
1n the air of basements 1n houses 1n the Love Canal area varied from
0.13-370, 0.11-120 and 0.06-0.17 vg/m3 {0.02-5*1, 0.02-18.2, 0.009-0.03
ppb), respectively (PelUzzarl, 1982). PelUzzarl et al. (1979) also
reported dlchlorotoluene Isower concentrations of a trace to 648 ng/m* and
trlchlorotoluene Isomer concentrations of a trace to 568 ng/m3 In the
ambient air of Niagara falls, ttaaser and Sromberg (1982) found 2,4-d1-
chlorotoluene In the ambient air of Love Canal.
Brodzlnsky and Singh (1982) reported a mean dlchlorotoluene ambient air
concentration of 9.7 ppt from four source-dominated areas In Oeepwater, NJ.
The presence of chlorotoluenes In the ambient air Is most likely the result
of emissions from chemical manufacturing and waste disposal sites.
3.4. DERMAL
Pertinent data regarding dermal monitoring for the chlorotoluenes could
not be located 1n the available literature as cited 1n Appendix A.
3.5. SUMMARY
Various specified and unspecified Isomers of the chlorotoluenes have
been detected 1n the surface water, fish and sediments of the Niagara River
and Lake Ontario (Elder et al., 1981; Oliver and N1col, 1984; Oliver, 1984;
Great Lakes Water Quality Board, 1983; Jaffe and HHes, 1984; Kamlnsky et
al., 1983; Yurawecz, 1979). The presence of chlorinated organic compounds
(Including the chlorotoluenes) 1n the Niagara River/Lake Ontario region has
been attributed to effluents and leachates from Industrial chemical waste
dump sites (Elder et al., 1981; Oliver and N1col, 1984). Chlorotoluenes
have also been detected 1n the ambient air of the Niagara Falls region
(PelUzzaM, 1982; PelUzzarl et al., 1979; Hauser and Bromberg, 1982) and
0030d -26- 06/04/87
-------
1n the air of source-dominated areas 1n Oeepwater, NJ (Brodzlnsky and Singh,
1932). Adequate monitoring data are not available for estimating the dally
human exposure to cnlorotoluenes because drinking water and foods are
Ingested or Inhaled.
0030d -27- 06/04/87
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4. AQUATIC TOXICITY
4.1. ACUTE TOXICTTT
Data concerning the aurte toxlclty of chlorl'natetl toluenes to aquatic
organisms are presented 1n Table 4-1. ToxIcHy to a particular species
appears to Increase with Increasing chlor1«at1on. The lowest reported
acutely toxic concentration was 0.24 mg/i a,2,4-tr1ch1orotoluene. a
14-4ay ICcQ for gupples. Poecllja retlculata (Konaeraann, 1981).
4.2. CHRONIC EFFECTS
Only two studies concerning chronlc/sjubchronlc studies with chlorinated
toluenes In aquatic organisms were found. Call et al. (1985) conducted
early life stage tests with fathead minnows, Plmephales promelas. exposed to
3,4-d1chlorotoluene. Embryos, larvae and juveniles were continuously
exposed under flow-through conditions for a total of 31-33 days. The
authors determined a LOEC of 0.148 mg/i, which caused significant reduc-
tions 1n standard length and percent survival at 28 days post-hatch. The
highest NOEC was 0.078 mg/l. Using these data, the authors calculated a
HATC (geometric mean of LOEC and NOEC) of 0.107 mg/J,.
Hermens et al. (1984) conducted static-renewal bloassays with Daphnla
magna exposed to 4-chlorotoluene for 16 days. They calculated a 16-day
LC5Q of 1.59 mg/8, and a 16-day EC5Q (reproduction) of 0.58 mg/l.
4.3. PLANT EFFECTS
LlHtle Information was available concerning toxldty of chlorinated
toluenes to aquatic plants. Frank et al. (1961) reported that 5 mg/l of
unspecified trlchlorotoluene damaged or killed three species of aquatic
macrophytes (Elodea canadensls. Potamoqeton nodosus. Potamogeton pectlnatus)
exposed for 4 weeks. Kamlet et al. (1986) found that the EC5Q for Inhibi-
tion of luminescence 1n the bacterium, Photobacterlum phosphoreum. was 1.4
mg/l In a Mlcrotox test.
0030d -28- 06/04/87
-------
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0030d
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-------
4.4. SUMMARY
The data concerning toxlclty of chlorotoluenes to aquatic organisms were
Halted. The lowest reported toxic caacefliraiton *a$ O.T4B ng/1 3,4-d1-
chlorotoluene, which reduced growth and survival of fathead minnows In an
early life stage test (Call et al.. ISflS). These authors also calculated a
MATC of 0.107 mg/i.
0030d -30- 05/19/87
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5. PHARMACOKJNETICS
5.1. ABSORPTION
Hats were given a single oral dose of 1.3 rag/kg 1*C-p ,*,«,«-
tetrachlorotoluene (uniformly ring-labeled) In corn oil by gavage. Within
4-S days, 87 and 9% of the radioactivity was recovered 1n tne urine and
feces, respectively, which Indicates substantial absorption from the gastro-
intestinal tract (Qulstad et al., 1985). Le Bel and Williams (1986) Identi-
fied 2,4,5-tMchlorotoluene 1n samples of human adipose tissue, which
Indicates absorption of the compound; however, the route of absorption Is
not known. The observed systemic toxldty of 2,3,6-tMchlorotoluene follow-
ing oral exposure (Chapter 6) Indicates that the compound Is absorbed from
the gastrointestinal tract. Barkley et al. (1980) Identified unspecified
Isomers of the dlchlorotoluenes In the breath of one resident of the Love
Canal area 1n New York but not In samples of the blood and urine. Exposure
was primarily from Inhalation. These findings suggest that either the com-
pound was not readily absorbed by respiratory surfaces, that H was absorbed
and excreted rapidly or that the analytical method was not sensitive enough.
Pertinent data regarding the absorption of the other chlorinated toluenes
could not be located 1n the available literature as dted 1n Appendix A.
5.2. DISTRIBUTION
Qulstad et al. (1985) sacrificed experimental rats 4-6 days after the
oral dose of p,a,o,a-tetrachlorotoluene was given (see Section 5.1.)
and ~4% of this dose had been retained 1n the carcass. Except for one rat
given an artificially high dose of p,a,a,
-------
1n the abdominal fat. As Indicated In Section 5.1., 2,4,5-trlchlorotoluene
was Identified 1n samples of human adipose tissue (LeBel and Williams,
1986). Pertlwnt
-------
5.5. SUMMARY
The Isomer For which the most complete pharmacofclnetlc profile was
available was p,«,a,«-tetrachlorotoluene. This compound was readily
absorbed by the gastrointestinal tract of rats (Qulstad et al., 1985).
p,«,«,t*~Tetrachlorotolttef»« does not appear to selectively distributed
to any particular tissue, but after an artificially high dose was given, the
parent compound and the metabolite, <*,<*' ,4,4'-tetrachlorost1lbene accu-
mulated 1n the abdominal fat of rats {Qulstad et al-, 1985). This result
agrees with the findings of le Bel and Williams (1386), who Identified
2,4,5-tMchlorotoluene 1n human adipose tissue. Qulstad et al. (1985) found
that the major urinary metabolite of p.a.a.a-tetrachlorotoluene was
4-chloroh1ppur1c acid, which accounted for 78% of the dose. Many fecal
metabolites were unextractable, but 4-chlorobenzo1c add and a,a',4,4'-
tetrachlorostllbene were Identified In the extractable portion. Little
p.a.a.a-tetrachlorotoluene was excreted unchanged In the rat. The
metabolites of p.a.a.a-tetrachlorotoluene were excreted primarily In
the urine (87%), but fecal excretion occurred as well.
OOSOd -33- 08/26/87
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6. EFFECTS
6.1, SYSTEMS TOXKITY
6.1.1.1. SUBCHRONIC — Pertinent data regarding the subchronlc
inhalation toxiclty of tit* chlurlnatsd toluenes could not be located In the
available literature as cited 1n Appendix A.
6.1.1.2. CHROMIC — In a chronic study, Stankevlch and Osetrov {1963}
•exposed rats to 0.0013 mg/i of dlchloroioluene (not otherwise specified)
by Inhalation, Only "slight deviations from control rats" were reported.
Few details were provided 1n this brief abstract, and data concerning the
chronic Inhalation toxldty of the other chlorinated toluenes were not
located.
6.1.2. Oral Exposures.
6.1.2.1. SUBCHRONIC — Chu et al . (1984) gave groups of 10 female and
10 male Sprague-Dawley rats 2,3,6- or a,2,6-tr1chlorotoluene 1n the diet
at concentrations of 0, 0.5, 5, 50 or 500 ppm for 28 days. Endpolnts of
toxldty examined were general appearance, body weight, food consumption,
biochemical parameters and hematology; gross and histopathologlcal examina-
tions were also performed. Growth, food consumption and mortality were
unaffected by treatment.
Absolute liver weights were significantly Increased In male rats given 5
and 500 ppm 2,3,6-trlchlorotoluene. Increased sorbltol dehydrogenase activ-
ities were found 1n the 5 ppm 2,3,6-trlchlorotoluene males. Dose-related
Increased Incidences and severity of mild histopathologlcal lesions 1n the
liver, kidney and thyroid were observed 1n treated rats, presumably at all
doses.
0030d -34- 05/19/87
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Male rats fed 500 ppm «,2,6-tr1chlorotoluene had Increased activities
of ttepatlc mlcrosonal amlno-pyrlne-N-deirethylase. As with 3,'4,&-tr1ch1oro-
ioluene, 2 g/kg
for p,a,a,a-tetrachlorotoluene. Stankevlch and Osetrov (1963) report-
ed that skin application of dlchlorotoluene (Isomer not specified) resulted
In hyperemla, erosion (2 days), fissures and hyperkeratosls (3-5 days).
0030d -35- 05/19/87
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>-D1cJi lor o toluene was positive In skin sensU1zatIon tests (Cohen et
al., 1967). Intraperltiwieal and Intramuscular injection of hepaMn and
warfarin, respectively, decreased the Intensity of this reaction. This
Inhibition was attributed to the anticoagulant effect of these compounds.
Other relevant Information for the other trhlorlnated toluenes was not found.
6.2. CARCIJWGfNICITY
6.2.1. Inhalation, Pertinent data regarding the Inhalation cardno-
genlclty of the chlorinated toluenes could not be located In the available
literature as cited 1n Appendix A.
6.2.2. Oral. In an oral carclnogenlcHy study by Fukuda et al. (1979),
groups of 30 female ICR-SLC mice were given 0, 0.05, 0.13, 0.32, 0.8 and 2.0
lit of p,a,a,a-tetrachlorotoluene In sesame oil by gavage twice
weekly for 17.5 weeks. Mice were necropsled 54.5 weeks later.
p.a.a.a-Tetrachlorotoluene produced tumors 1n the stomach, lungs, skin
and lymphatic organs (Table 6-1). Other tumors observed Included mammary
adenocarclnoma, ear canal squamous cell carcinoma, salivary gland adeno
carcinoma and ovary granulosa cell tumor. Tumor development and death
occurred earlier In the high-dose group. The Incidence of adenocardnomas
of the lungs In female mice was highly significant In the third and fourth
dose groups; also, a dose-effect relationship was observed In total tumor
Incidence. Data concerning the carclnogenlcHy of the other chlorinated
toluenes following oral dosing could not be located 1n the available litera-
ture as cited 1n Appendix A.
6.2.3. Other Relevant Information. Hooker Chemical Co. (1980) also
reported a dermal carclnogenlclty study summarized briefly by Fukuda et al.
(1979) In which 5 yl of p,a,o,a-tetrachlorotoluene was applied to
the skin of two groups of 21 or 22 mice twice weekly for 30 weeks, followed
0030d -36- 08/26/87
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TABLE 6-1
Timor Incidence In female ICR-SLC Mice Given p,a,a,a-Tetracnloroto1uene
of Unspecified Purity 1n Sesame 011 Twice Weekly by Savage for
17.5 Weeks, followed by a 54.5-Week Observation Period*
Dose
Target Organ
or System
Tumor Type
Timor Incidence
0
0.05
0.13
0.32
lung
lung
stomach
stomach
stomach
tnymus
lymphatic
skin
lung
lung
stomach
stomach
stomach
thymus
lymphatic
skin
lung
lung
stomach
stomach
stomach
thymus
lymphatic
skin
lung
lung
stomach
stomach
stomach
thymus
lymphatic
skin
adenocarclnoma
multiple adenoma
squamous cell carcinoma
carcinoma in. sUu
multiple papllloma
thywona
malignant lymphoma
NSC
adenocarclnoma
multiple adenoma
squamous cell carcinoma
carcinoma in situ
..multiple paplHoma
thymoma
malignant lymphoma
NSC
adenocarclnoma
multiple adenoma
squamous cell carcinoma
carcinoma In situ
multiple papllloma
thymoma
malignant lymphoma
NSC
adenocarclnoma
multiple adenoma
squamous cell carcinoma
carcinoma in situ
multiple papllloma
thymoma
malignant lymphoma
spindle cell sarcoma
0/26 (0)
(p«0. 00001 5 )b
1/26 (4)
0/26 (0)
0/26 (0)
0/26
-------
TABLE 6-1 (cont.)
Dose
Target Organ
or System
lung
lung
stomach
stomach
stomach
thymus
lymphatic
skin
Tunwr Type
Tumor Incidence
(X)
0.8 lung
lung
stomach
stomach
stomach
thymus
lymphatic
skin
adenocardnoma
multiple adenoma
squamous cell carcinoma
carcinoma l£ situ
multiple papHloma
thymoma
malignant lymphoma
spindle cell sarcoma and
sebaceous gland carcinoma
15/29 (52)
(p=0. 0000065)
10/29 (34)
6/29 (21)
4/29 {14)
2/29 (7)
4/29 (14)
0/29 (0)
2/29 (7)
adenocardnoma
multiple adenoma
squamous cell carcinoma
carcinoma J[n_ situ
multiple papllloma
thymoma
malignant lymphoma
squamous cell carcinoma
2/29 (7)
(p.0.3)
17/29 (59)
7/29 (24)
3/29 (10)
1/29 (3)
8/29 (28)
5/29 (17)
6/29 (21)
Strengths of Study:
Weakness of Study:
QUALITY OF EVIDENCE
Several dosage levels were administered by a relevant
route to sufficient numbers of animals with a suffi-
cient observation period for tumor development.
One sex of one species was tested twice weekly for a
limited period of time. The MTD was not estimated by
pre-testlng. The nature and extent of hlstopatho-
loglcal examination were not reported. Although the
mice were observed for a sufficient period for tumor
development, they were treated for only 17 weeks.
Dosing schedule was 2 days/week.
Overall Adequacy: Adequate
aSource: Fukuda et a!., 1979
bCochran-Arm1tage test performed excluding data from high-dose group
cF1sher Exact test performed at SRC
NS = Not specified
0030d
-38-
05/19/87
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by a 7-week observation period. Tumors developed primarily In the digestive
system and skin (Table 6-2), Indicating either systemic uptake by skin or
Ingestlon, which was due to grooming. Relevant Information regarding the
carc1nogen1c1ty of other chlorinated toluenes were not located.
6.3. HUTAfiEMICmf
Pertinent data regarding the mutagenlclty of the chlorinated toluenes
could not be located In the available literature as cited 1n Appendix A.
6.4. TERATOG£NICmr
As reported in abstract form, Ruddlck et al. (1982) administered 2,3.6-
and a,"2,6-tr1ctrtorotoluene by gavag* to pregnant rats on days 6-15 of
gestation at doses of 0, 100, 200 or 400 mg/kg/day. Maternal toxlclty was
measured by weight gain changes, organ weight changes, hematology, micro-
scopic examination and 15 biochemical parameters. LHter size, fetal
weight, dedduoma, skeletal and visceral examination, and microscopic exami-
nations were used to evaluate fetotoxldty and teratogen1c1ty. 2,3,6-TM-
chlorotoluene treatment resulted 1n reduced fetal weight at 400 mg/kg/day.
Treatment with a,2,6-tr1chlorotoluene resulted In significantly (p<0.05)
reduced maternal weight gain at 200 and 400 mg/kg/day. H1stolog1cal changes
were observed In the thyroid, bone marrow, kidney and liver of dams
presumably at all doses of both Isomers. Pups had liver damage and the
liver damage was most severe at 400 mg/kg/day 2,3,6-trlchlorotoluene. It
was Inferred that liver damage of pups occurred at all doses of 2,3,6- or
a,2,6-tr1chlorotoluene.
6.5. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding the other reproductive effects of the chlori-
nated toluenes could not be located 1n the available literature as cited In
Appendix A.
0030d -39- 08/26/87
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TABLE 6-2
Incidence of Tumors In Mice Treated Dermally with 5 p
P,a,a*a-Tetrachloroto1uene Twice Weekly for 30 Weeks
followed .by a 7-Week Observation Period*
Incidence
Target Organ
Skin
Lung
Esophagus
Forestomach
Glandular stomach
Hematopo1et1c system
Thymus
Tumor Type
squamous cell carcinoma
sarcoma
papllloma
carcinoma
carcinoma
carcinoma
carcinoma
leukemia
thymoma
Group A
(n-22)
12/22
2/22
2/22
1/22
5/22
2/22
1/22
1/22
1/22
Group B
(n-21)
9/21
1/21
4/21
3/21 .
2/21
0/21
0/21
0/21
2/21
*Source: Fukuda et a!., 1979
0030d
-40-
05/19/87
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6,6. SUMMARY
Few data were available upon which to base an adequate toxlcologlcal
pmfH«. A Russian study reported that rats chronically exposed to 0,0013
mg/a, dlchlorotoluene (not otherwise specified) by Inhalation exhibited
only slight deviations from controls (Stankevlch and Osetrov, 1963). flats
given dietary 2,3,6- or a,2,6-tr1ch"lorotoluene at concentrations of 0,
0.5. 5, 50 or 500 ppm for 28 days exhibited Increased liver weight (5 and
500 ppra 2,3,6-trlchlorotoluene males), Increased sorbltol dehydrogenase
activity (5 ppm 2,3,6-trlchlorotoluene males), Increased activities of
hepatic mlcrosomal enzymes (500 ppm o,2,6-tr1chloroto"luene males} and
dose-related lesions of the liver, kidney and thyroid (all treated rats)
(Chu et al., 1984). The following oral LD50s were reported: 2000 mg/kg
2,3,6-trlchlorotoluene 1n mice (NIOSH, 1986); 700 and 1350 mg/kg
p,a,a,a-tetrachlorotoluene 1n rats and mice, respectively (Khalepo et
al., -7984); and 820 mg/kg p,a,a,a-tetrachlorotoluene 1n rats (Hooker
Chemical Co., 1980). Signs and symptoms of acute tox1c1ty Included motor
activity, tremors, diarrhea, plloerectlon and chromodacryorrhea and gastric
Irritation (Hooker Chemical Co., 1980). An Inhalation threshold and LC5Q
of 22.4 and 123 mg/ma, respectively, for unspecified durations for both
rats and mice was reported by Khalepo et al. (1984). Hooker Chemical Co.
(1980) reported a dermal LD5Q >2 g/kg for p,o,a,a-tetrachlorotolu-
ene. a,o-D1chlorotoluene was positive In skin sensltlzatlon tests (Cohen
et al., 1967).
No data were available to assess the carcinogenic potential of the
chlorinated toluenes from Inhalation. Fukuda et al. (1979) gave mice 0,
0.05, 0.13, 0.32, 0.8 and 2 yi of p,a,a,a-tetrachlorotoluene by
gavage for 17.5 weeks. Tumors 1n the stomach, lung, skin and lymphatic
0030d -41- 05/19/87
-------
organs were observed 18 months later. Tumors 1n the digestive system were
also noted after denaal application of p,a,a.«-tetrachlOToto1u«n« to
nice Ifakute si al., 1979). No data concerning the muUgenlc effect of the
chlorinated toluenes were located.
The only study available concerning the teratogenlclty of the chlori-
nated toluenes was by Ruddlck et al. (1982), who gave pregnant rats 0-400
mg/kg/day 2,3,6- or «,2t6-tr1chlorotoluen€ by th« oral route. Hlstopatho-
loglc lesions In the thyroid, bone marrow, kidney and liver occurred In dams
at unspecified doses. Reduced fetal body weight and liver damage of pups
occurred at all doses of 2,3,6- and a.2v6-tr1th1or»to"ltrene, but were most
severe at 400 mg/kg/day 2,3,6-tMchlorotoluene. No data were available
concerning the other reproductive effects of the chlorinated toluenes.
0030d -42- 05/19/87
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7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
Pertinent guidelines and standards. Including IPA ambient water and air
quality criteria, drinking water standards, FAO/HHO ADIs, EPA or FDA toler-
ances for raw agricultural commodities or foods, and ACGJH, NI0SH or OSHA
occupational exposure limits could not be located 1n the available litera-
ture as cited In Appendix A.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the effects of chlorinated toluenes could not be located In the available
literature as cited 1n Appendix A.
0030d -43- 05/19/87
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8. RISK ASSESSMENT
B.I, CARciNOGmcmr
fl.1,1. Inflation, 1to data were available to assess tlw carcinogenic
potential of the chlorinated toluenes from Inhalation.
8.1.2. Oral, One study by ttw oral route was available for
p,a,a,a-tetrachloroto1uene. Fukuda et al. (1979) gave mice D, 0.05.
0.13, 0.32, 0.8 and 2 v* of p,a,a,*-tetracJilorotoluene for 17.5
weeks; 18 months later cancer of the stomach, lung, skin and lymphatic
organs was observed (see Table 6-1).
8.1.3. Other Routes. Cancer of the digestive system was also noted after
dermal application of p,a,a,a-tetrachlorotoluene to mice (Fukuda et
al., 1979) (see Table 6-2).
8.1.4. Weight of Evidence. Pertinent data regarding the carcinogenic
effect of the chlorinated toluenes 1n humans could not be located 1n the
available literature as cited 1n Appendix A. An Increased Incidence of
malignant and benign tumors was observed at multiple sites after oral
administration of p,a,o,a-tetrachlorotoluene and early onset of tumors
was noted In the high-dose group (Fukuda et al., 1979). This study had
several limitations: the MTD was not estimated by adequate pre-testlng;
only one sex of one species was tested; dosing was only twice a week; and
testing was for less than lifetime. Strengths of the study Included testing
of adequate numbers of mice by a relevant route at several dose levels, and
the observation period was sufficient for tumor development. The Increased
incidence of adenocardnomas was dose-related and significant. The positive
dermal carclnogenlclty study 1n mice by Fukuda et al. (1979) supports the
oral study. Furthermore,
-------
animal evidence was considered sufficient, and 1n the absence of human data,
assignment to EPA Group B2, a probable human carcinogen, Is Indicated.
8.1.5. Quantitative Risk Estimates.
8.1.5.1. INHALATION — Inhalation data were not available to calcu-
late a q,* for Inhalation exposure.
8.1.5,2. ORAL — The data for lung adenocardnoma (see Table 6-1) In
the oral study 5n mice by Fukuda et al. (1979) were used to calculate the
q..* because the highest tumor Incidences were noted for this tumor type
and a dose-effect relationship was Indicated. Benign tumors were not pooled
with the malignancies and tumors at multiple sites were not pooled because
Individual pathology data were not available. Since the data for adeno-
cardnomas were not statistically analyzed In the original report, the
Fisher Exact and Cochran-ArmHage tests were performed. The Fisher Exact
test showed that, with the exception of the high-dose group, the observed
tumor Incidences 1n the treated groups significantly differed from the
controls. A high Incidence of multiple adenomas was observed 1n the high-
dose group, which Indicated a tumorlgenlc response, If not a carcinogenic
response. The lack of malignancies at the high dose Is difficult to
explain; however, mice 1n this group died earlier and had a high Incidence
of lung adenomas. When the high dose was Included 1n the Cochran-Armltage
test, a significant dose-related trend was not Indicated; however, when the
high dose data were excluded, a positive dose relationship resulted. To
calculate the q *. the doses given In vi In the original report were
converted to mg/kg/day by multiplying by the density of p,a,a,a-tetra-
chlorotoluene (1.485 mg/yl) and dividing by the assumed body weight of
mice (0.03 kg). The doses were expanded over 7 days because the mice were
treated by gavage only 2 days/week. The duration of treatment was less than
0030d -45- 08/26/87
-------
the duration of the study; therefore, the dose was multiplied bythe ratio
of the length of exposure to the length of the experiment to yield the
transformed doses tftppendlx 1)- T1» unadjusted q * of 5.12xlO~a
(mg/kg/day)"1 was calculated using the multistage model of Howe and Crump
(1992). The data for the highest dose group were excluded because when
Included the data did not fit the model. The human q * of 20 {mgAg/
day)"1 was obtained by multiplying the unadjusted q.* by the cube root
of tne ratio of the reference human body weight of 70 kg to the reference
mouse body weight of 0.03 kg and by multiplying by the cube of the ratio of
llfespan to the length of the experiment because the duration of the study
was less than the Hfespan of the animal.
The concentration of the chemical 1n drinking water associated with a
risk a level of 10~5 was calculated by dividing the risk level of 10~5
by the q,*, multiplying by 70 kg and dividing by 2 I to give a concen-
tration of 2xlO~5 mg/a. Concentrations associated with risk levels of
10"* and 10~7 • are 2xlO~« and 2xlO~7 mg/l, respectively. Data for
calculating a q,* for the other chlorinated toluenes could not be located
1n the available literature as cited In Appendix A.
8.2. SYSTEMIC TOXICITY
8.2.1. Inhalation Exposure.
8.2.1.1. LESS THAN LIFETIME EXPOSURES (SUBCHRONIC) -- No data were
available to calculate a subchronlc Inhalation RfD for any of the chlori-
nated toluenes.
8.2.1.2. CHRONIC EXPOSURES — A Russian study reported that rats
chronically exposed to 0.0013 mg/8, dlchlorotoluene by Inhalation exhibited
only slight deviations from controls (Stankevlch and Osetrov, 1963). The
abstract of this study did not provide sufficient detail to support a quan-
titative risk assessment.
0030d -46- 08/26/87
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£.2.2. Oral Exposure.
8.2.2.1. USS THAU LIFETIME EXPOSURES (SUBCHRONIC) ~ Rats given
dietary 2,3,6- and a,2,&-tr1chloroto1u«ne at concentrations of 0, 0.5, 5,
50 and 500 ppm for 28 days exhibited Increased liver weight (5 and 500 ppm
2,3,fc-trlthlorotoltietYe wales)« Increased sorfcUtfl tJehydrogenase activity {5
ppm 2,3,6-trlchlorotoluene males). Increased activities of a mlcrosomal
enzyme (500 ppm a,2,6-tr1chlorotoluene males) and dose-related lesions of
the liver, kidney and thyroid (all treated rats) (Chu et a!., 1984). This
study defined tOAELs of 0.5 ppm (0.05 mgAg/day average dose of both Isomers
estimated by the authors) for 2,3,6-trlchlorotoluene and a,2,6-tr1chloro-
toluene to the liver, kidney and thyroid gland. Dividing these LOAELs by an
uncertainty factor of 1000 (10 for species to species extrapolation, 10 for
a LOAEL and 10 to protect sensitive humans) yields subchronlc RfOs of
0.00005 mg/kg/day or 0.004 mg/day for a 70 kg human. These RfOs are much
lower than the levels (>100 mg/kg/day) of 2,3,6- and o,2,6-tr1chloro-
toluene associated with maternal and fetoxlc effects In the oral teratugen-
1c1ty study by Ruddlck et al. (1982). The confidence level 1n the RfO Is
low because of small sample size and the short duration of the Chu et al.
(1984) study. Additionally, a NOAEL could not be defined and supporting
data were lacking. Data for deriving subchronlc RfDs for the other chlori-
nated toluenes were not located.
8.2.2.2. CHRONIC EXPOSURES -- The oral subchronlc RfD (see Section
8.2.2.1.) based on the effects of liver, kidney and thyroid toxldty
reported by Chu et al. (1984) could not be used as a basis for a chronic RfD
because the 28-day exposure period, although adequate for a subchronlc RfD,
1s not adequately long for a chronic RfD, even 1f the dose 1s divided by an
uncertainty factor of 10 to approximate chronic exposure. A 90-day study Is
recommended before an RfD for chronic oral exposure can be calculated.
0030d -47- 08/26/87
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9. REPORTABU QUANTITI£S
9.1. 8AS£0 OH SYSTEHIC TOXJCITY
Th« toxldty and teratogcnlclt? tif 2,1,ft- and a,2,ft-tr1chlorotoluene
were discussed In Chapter 6, and the dose-response data are summarized 1n
TafcTe 9-1- Cha et al. (1984) observed ti1stopattu>1og1cal lesions of the
liver, kidney and thyroid 1n rats given oral doses >0,05 mg/kg/day for 2B
days. Although the duration of this study was only 28 days, 1t should be
considered for RQ determination because of the nature of the effects at low
doses and because longer-term studies are lacking. Ruddle* et al, {1982}
observed liver damage In the offspring of dams given oral doses of >10Q
mg/kg/day 2,3,6- or a,2,6-tr1chlorotoluene during organogenesls. The most
severe effect observed was fetotoxldty (liver damage), which was given an
RV of 8 (Table 9-2). The MED was calculated by multiplying the equiva-
lent human dose of 17 mg/kg/day by 70 kg. The MED of 1190 mg/day corre-
sponds to an RV. of 1. A CS of 8 was obtained for this endpolnt by
multiplying the RV, by the RV . Although fetoxldty was the most severe
effect, H occurred at a much higher dose than the toxlclty observed by Chu
et al. (1984). Dividing the equivalent human dose of 0.006 mg/kg/day by an
uncertainty factor of 10 and multiplying by 70 kg yields an MED of 0.042
mg/day, which corresponds to an RV of 7.6. The hlstopathologlcal lesions
of the liver, kidney and thyroid were assigned an RV of 3 because they
were described as mild. Thus, a CS of 23 was calculated for the liver,
kidney and thyroid toxIcHy observed by Chu et al. (1984), which corresponds
to an RQ of 100 pounds. The RQ 1s recommended for 2,3,6-trlchlorotoluene
and for a,2,6-tr1chlorotoluene (Tables 9-3 and 9-4). Data suitable for RQ
derivation for the other chlorinated toluenes were not located.
0030d -48- 08/26/87
-------
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TABLE 9-3
2,3,6-TMchlorotoluene
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 0.042 mg/day
Effect: mild liver, kidney and thyroid toxlclty
Reference: Chu et al., 1984
RVd: 7.6
RVe: 3
Composite Score: 23
RQ: TOO
'Equivalent human dose (MED)
0030d -51- 08/26/87
-------
TABLE 9-4
«,2,6-Tr1eft1orotoluene
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route: oral
Dose*: 0.042 nig/day
Effect: mild liver, kidney and thyroid lesions
Reference: Chu et al., 1984
RVd: 7.6 .
RVe: 3
*
Composite Score: 23
RQ: 100
*Equ1valent human dose (MED)
0030d -52- 08/26/87
-------
9.2. BASED OM CARCINOGENICIPr
One Japanese study by the oral route was available for
tetrachlorotoluene. Fukuda et al. (1379) gave mice 0, 0.05, 0.13, 0.32, 0.8
and 2 n* of p.o.o.o-tetrachlorotoluene for 17.5 weeks. Cancer of
the stomacn, lung, skin awl lyapnatlt organs was otiscrwi 54.5 weeks later
(see Table 6-1). Cancer of the digestive system was also noted after dermal
application of p,a,*,«-tetrachlorotoluene to mice (Fukuda et al.,
1979) (see Section 6.1., Table 6-1). The animal evidence was considered
sufficient, and In the absence of human data, assignment to EPA Group 82, a
probable human carcinogen, was Indicated. As discussed In Chapter B, a
q * was calculated for p,«,a,a-tetrachlorotoluene based on data for
adenocarclnomas In mice (Fukuda et al., 1979). The same data can be used to
calculate the F factor (Table 9-5). The transformed doses were calculated
as described. 1n Chapter 8. The unadjusted 1/ED10 was calculated using the
multistage model without the data from the high-dose group because the data
did not fH the model when this group was Included. The absence of tumors
1n the high-dose group may be attributable to early deaths of this group
since they had a high Incidence of adenomas, which may have progressed to
carcinomas had the rats lived longer. The unadjusted I/ED,- of 3.4 was
multiplied by the cube root of the ratio of the human body weight to the
l/T
mouse body weight [(70 kg/0.03 kg) ] and by the cube of the ratio of the
Hfespan of the mouse to the duration of the study [(104 weeks/72
weeks)3], yielding an adjusted 1/ED1Q of 136 (mg/kg/day)"1. Because
the F Factor Is >100, p,a,o,a-tetrachlorotoluene was placed In Potency
Group 1, which along with an EPA grouping of B2 gives p,a,a,a-tetra-
chlorotoluene a HIGH hazard ranking under CERCLA and an RQ of 1.
0030d -53- 08/26/87
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TABLE 9-5
Derivation of Potency Factor (F Factor) for p,a,«,a-Tetrachlorotoluene
Reference:
Exposure route:
Species:
Strain:
Sex:
Vehicle or physical state:
Body weight:
Duration of treatment:
Duration of study:
Ufespan of animal:
Target organ:
Tumor type:
Experimental doses/exposures:
Transformed doses (mg/kg/day);
Tumor Incidence:
Unadjusted 1/ED10:
Adjusted l/ED-|o (F Factor):
Ftikuda et a!., 1979
oral
mouse
1CR-SLC
female
sesame oil
0.03 kg
17.5 weeks
72 weeks
104 weeks
lung
adenocardnoma
0, 0.05, 0.13, 0.32, 0.8 and 2.0 V9.,
2 days/week
0, 0.17, 0.45, 1.10, 2.75 and 6.88*
0/26, 3/22, 7/28, 10/22, 15/29, 2/29*
3.409 (mg/kg/day)~1
136 (mg/kg/day)'1
"High dose data excluded from calculation (see text)
0030d
-54-
08/26/87
-------
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1984. Materials for determlng the maximum permissible concentration of
a,a,a-tr1chloro-4-chlorotoluene 1n workplace air. G1g. Tr. Prof.
Zabol. 6: 41-43. (CA 101:124312b)
0030d -59- 08/26/87
-------
Konnemann, H. 1981. Quantitative structure-activity relationships (QSARs)
In fish toxldty studies. Part 1: Relationship for Industrial pollutants.
Txalcalagy. T9<3)i 205^221.
Le flel. 6,1. and D.T. Williams, 19B6. Determination of halogenated contam-
inants 1n human adipose tissue. J. Assoc. Off. Anal. Chem, 69(3): 451-453.
Lucas, S.V. 1984. EC/US Analysis of Organic* 1n Drinking Water Concen-
trates and Advanced Waste Treatment Concentrates: Vol. 1. Analysis Results
for 17 Drinking Water, 16 Advanced Waste Treatment and 3 Process Blank
Concentrates. Health Eff. Res. Lab, Columbus Labs, Columbus, OH. p. 321.
EPA 600/1 -84-020A.
Lyman, W.J., W.F. Reehl and O.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. McGraw-Hill Book Co., New York. p. 15-16 to
15-29; 5-4; 7-4.
NIOSH (National Institute for Occupational Safety and Health). 1986. RTECS
(Registry of Toxic Effects of Chemical Substances). Online: November 1986.
Oliver, B.G. 1984. No title provided. Can. 3. Fish. Aquat. Sc1. 41(6):
878-883.
Oliver, B.G. 1985. Oesorptlon of chlorinated hydrocarbons from spiked and
anthropogenlcally contaminated sediments. Chemosphere. 14: 1087-1106.
OOSOd -60- 08/26/87
-------
Oliver, 8.6. and K.O. Nlcol. 1984. Chlorinated contaminants In the Niagara
River, 1981-1983. Sc1. Total Environ. 39: 57-70.
Oliver, B.G. and A.3. N11m1. 1984. Rainbow trout bloconcentratlon of some
halogeoated aromatics froa water at environmental concentrations. Environ.
Toxlcol, Chen, 3: 271-279.
Oliver, G.B. and A.3. N11m1. 1985. Bloconcentratlon factors of some halo-
genated organlcs for rainbow trout. Limitation In their use for predictions.
£ft»1ron. Scl. Technol, 19: 842-849.
Omorl, T. and H. Alexander. 1978. Bacterial and spontaneous dehalogenatlon
of organic compounds. Appl. Environ. Mlcrob. 35: 512-516.
PelUzzarl, E:0. 1982. Analysis for organic vapor emissions near Indus-
trial and chemical waste disposal sites. Environ. Sc1. Techno!. 16(11):
781-785.
PelUzzaM, E.G., M.O. EMckson and R.A. Swe1d1nger. 1979. Formulation of
preliminary assessment of halogenated organic compounds In man and environ-
mental media. U.S. EPA, Research Triangle Park, NC. EPA 560/13-79-006.
Quemeneur, F., B. BaMou and M. Kerfano. 1971. A critical study of the
hydrolysis of para-substituted a,a-d1chloro- and a,a,a-tr1chloro-
toluenes In 50% aqueous acetone. C.R. Acad. Sc1. Paris. Ser C. 272:
497-499. (Cited In U.S. EPA, 1983)
0030d -61- 08/26/87
-------
Qulstad, G.B., K.H. Mulholland, G. Skllles and G.C. Jaroleson. 1965.
ftetatooHsra of 4-cJilorot>enzotr1cn1or1de In rats. 3. Agrlc. Food there,
33(1 J: 95-98.
c, D.A., D.C, imiwwim, V. Secoras anti V.t. ValH. 1982. K trans-
placenta! and teratologlcal evaluation of three trltnlorotoluene congeners
1n the rat. Teratology. 25(2): 72A-73A,
Sadtler. 1960, 209 UV. Sadtler Research laboratories, ?nnade!ph1a, PA.
Sadtler. 1961. 5404 UV. Sadtler Research Laboratories, Philadelphia, PA.
Sadtler. 1966a. 211 UV. Sadtler Research Laboratories, Philadelphia, PA.
Sadtler. 1966b. 210 UV. Sadtler Research Laboratories, Philadelphia, PA.
Sadtler. 1966c. 206 UV. Sadtler Research Laboratories, Philadelphia, PA.
Sadtler. 1966d. 203 UV. Sadtler Research Laboratories, Philadelphia. PA.
Sadtler. 1974. 21,877 UV. Sadtler Research Laboratories, Philadelphia, PA.
Sadtler. 1975. 22,985 UV. Sadtler Research Laboratories, Philadelphia, PA.
Sadtler. 1976. 23,715 UV. Sadtler Research Laboratories, Philadelphia, PA.
Sadtler. 1977. 24,689 UV. Sadtler Research Laboratories, Philadelphia, PA.
0030d -62- 08/26/87
-------
Sadtler. 1980. 29,636 UV. Sadtler Research Laboratories, Philadelphia* PA.
Shell 051 DJ. 1962. 7SCA S(dJ Submission 878210113. B1
-------
Toswila, E. 1966. Solvolysls of benzyl chloride In dimethyl sulfoxlde
water mixtures. Arta. Chem. Scatid. 20(4): 923-936.
Ulanova, I.P., P.M. Dyachkov and A.I. Khalepo 1986. Electronic structure,
toxltsmetry paraweters atwl nyrjtenlc regulations of Halfltjen thwlvatlves of
toluene. Gig. Tr. Prof. Zabol. 3: 6-11. {CA 104(22):192160n)
U.S. EPA. 1971. Computer print-out of nonconfIdentlal prwJtrctlon data from
TSCA Inventory. OPTS, CID, U.S. EPA, Washington, DC.
U.S. EPA. 1980. Guidelines and Methodology Used In the Preparation of
Health Effect Assessment Chapters of the Consent Decree Water Quality
Criteria Documents. Federal Register. 45(231): 49347-49357.
U.S. EPA. 1983. Chemical Hazard Information Profile: p-Chlorobenzotr1-
chlo«-lde. Draft Report. Prepared by Oak Ridge National Laboratory. Office
of Toxic Substances, U.S. EPA, Washington, DC.
U.S. EPA. 1984. Methodology and Guidelines for Reportable Quantity Deter-
minations Based on Chronic Toxldty Data. Prepared by the Office of Health
and Environmental Assessment, Environmental Criteria and Assessment Office,
Cincinnati, OH for the Office of Solid Waste and Emergency Response,
Washington, DC.
U.S. EPA. 1986a. Methodology for Evaluating Carclnogenlclty 1n Support of
Reportable Quantity Adjustments Pursuant to CERCLA Section 102. Prepared by
the Office of Health and Environmental Assessment, Washington, DC for the
Office of Solid Waste and Emergency Response, Washington, DC.
0030d -64- 08/26/87
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U.S. EPA. 1986b. Health and Environmental Effects Profile for BenzotM-
chlorlde. Prepared by the Office of Health and Environmental Assessment,
fn*5r0nfflental Criteria and Assessment Office. Cincinnati. OH for the Office
of Solid Waste and Emergency Response, Washington, DC.
U.S. IWL 1987. Graphical Exposure Modeling System (GfWS). Octanol-Water
Partition Coefficient (CLOGP) and/or Fate of Atmospheric Pollutants (FAP)
computer data systems. U.S. EPA, Research Triangle Park. NC.
USITC {U.S. International Trade Commission). 1984. Imports of BenzeneId
Chemical and Products 1983. USITC Publ. 1548, Washington, DC. p. 16.
USITC (U.S. International Trade Commission). 1986. United States Produc-
tion and Sales, 1985. USITC Publ. 1892, Washington, DC. p. 38.
Vandenbergh, P.A., R.H. Olsen and J.F. Colaruotolo. 1981. Isolation and
genetic characterization of bacteria that degrade chloroaromatlc compounds.
Appl. Environ. H1crob1ol. 42: 737-739.
Weast, R.C., Ed. 1985. CRC Handbook of Chemistry and Physics, 66th ed.
CRC Press, Inc., Boca Raton, FL. p. C-143, 148, 149, 519, 521, 522.
Wellens, H. 1984. Determination and evaluation of biological degradabllUy.
Vom Wasser. 63: 191-198.
Yurawecz, M.P. 1979. Gas-I1qu1d chromatographlc and mass spectrometrlc
Identification of chlorinated trlfluorotoluene residues In Niagara River
fish. J. Assoc. Off. Anal. Chem. 62(1): 36-40.
0030d -65- 08/26/87
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APPENDIX A
LITERATUR£ SEAROO
This HEED Is based on data Identified by computerized literature
searches of the following:
TSCATS
CASR onllM {U.S. EPA Chemical Activities Status Report)
TOXLINE
TOXBACK 76
TOXBACK 65
OHM TADS
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted In December, 1986. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 5-9), and the following
secondary sources should be reviewed:
AC6IH (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. 28. John VlHey 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.
0030d -66- 08/26/87
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Grayson, M. and D. Eckroth, Ed. 1978-1984. K1rk-0thmer Encyclo-
pedia of Chemical Technology, 3rd ed. John Wiley awl Sons, NY, 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA, 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Hwaans. WHO, IARC, Lyons, frame.
Oaber, H.M., W.R. Mabey, A.T. Lieu, T.H. 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. MTIS
PB84-243906.
NTP {National Toxicology Program). 1986. Toxicology tesearth 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 1n the Special Review
Program, Registration Standards Program and the Data Call In
Programs. Registration Standards and the Data Call In 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.
0030d -67- 08/26/87
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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. OC.
Johnson, W.W. and M.T. Flnley. I960. Handbook of Acute Toxlclty
of Chemicals to F1sh and Aquatic Invertebrates. Summaries of
Toxlclty Tests Conducted at Columbia National Fisheries Research
Laboratory, 1965-1978. U.S. Dept. Interior, Fish and «Jldl1fe
Serv. Res. Publ. 137, Washington, OC.
McKee. J.f. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Control Board. Fubl. No. 3- A.
Plmental, D. 1971. Ecological tffects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS P8 80-196876.
U.S. Environmental Protection Agency
Region V, Library
230 South Dearborn Street
Chicago, Illinois 60604.
OOSOd -68- 08/26/87
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APPENDIX B
Cancer Data Sheet for Derivation of q-j*
Compound: p,a,a,a-tetrachloroto1uene
Reference: Tukuda et a*L, 19T9
Specles/straln/sex: mouse, ICR-SLC, female
Route/vehicle: oral, sesame oil
Length of exposure (le) - 17.5 weeks
Length of experiment (Le) * 72 weeks
Llfespan of animal (L) = 104 weeks
Body weight = 0.03 kg (assumed)
Tumor site and type: lung, adenocardnoma
Exposure
(vl, 2 days/week)
0
0.05
0.13
0.32
0.8
2
Transformed Dose
(mg/kg/day)
0
0.17
0.45
1.10
2.75
6.88
Incidence
No. Responding/No. Tested
0/26
3/22
7/28
10/22
15/29
2/29t
tData for the high-dose group were excluded from q-j* derivation because
their Inclusion led to a poor fit.
Unadjusted q-j* = 5.12098X10"1 mg/kg/day)~l
Human q-j* = 20.47 (mg/kg/day)'1
0030d
-69-
08/26/87
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