U.S. DEPARTMENT OF COMMERCE
National Technical Information Service
PB-273 206
Investigation of Selected Potential
Environmental Contaminants
Halogenated Benzenes
Ebon Research Systems, Washington, D C
Prepared for
Environmental Protection Agency, Washington, D C Office of Toxic
Substances
Jul 77
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EPA 560/2-77-004
INVESTIGATION OF SELECTED POTENTIAL
ENVIRONMENTAL CONTAMINANTS:
HALOGENATED BENZENES
July 1977
FINAL REPORT
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, D.C. 20460
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TECHNICAL REPORT DATA
(Please read Irutrucrions on the reverse before completing)
1. REPORT NO.
RPA
2.
3. RECIPIENT'S ACCESSION>NO.
4. TITLE AND SUBTITLE
Investigation of Selected Potential Environmental
Contaminants: Halogenated Benzenes
5. REPORT DATE
July, 1977
8. PERFORMING ORGANIZATION CODE
7. AUTHORIS)
!. PERFORMING ORGANIZATION REPORT NO.
Sylvia A. Ware, William L. West, Ph.D.
9. PERFORMING ORGANIZATION NAME ANO ADDRESS
Ebon Research Systems
1542 9th Street, N.W.
Washington, D.C. 20001
10. PROGRAM ELEMENT NO.
11. CONTHACT/GRANTNO.
68-01-4183
12. SPONSORING AGENCY NAME ANO ADDRESS
Office of Toxic Substances
U.S.Environmental Protection Agency
Washington, D.C. 20460
13. TYPE OF REPORT ANO PERIOD COVERED
Final Technical Report
14. SPONSORING AGENCY CODE
IS. SUPPLEMENTARY NOTES
ie. ABSTRACT ' = ; !
Bus report reviews the potential environmental hazard from use of the halogen-
ated benzenes. Major focus is in the commercially important chlorinated benzenes,
though fluorinated, brcminated and iodinated benzenes are also discussed as well
as mixed halogen compounds. Hexachlordbenzene is not included in this study except
where information relates to trends within the group of chlorinated benzenes.
Chlorinated benzenes are used as solvents, chemical intermediates, for moth
repellency and as space odorizers. Several chlorinated benzenes have been detected
in drinking and raw water sources throughout the U.S. p-Dichlorcbenzene has been
found in human blood samples from New Orleans, and with 1,2,4,5-tetrachlorobenzene
and hexachlorobenzene in human .adipose tissue samples collected in Tokyo, Japan.
While of comparatively low acute toxicity, chronic or 'subacute1 efffects are
seen at fairly low concentrations. These effects include: porphyria, necrosis of
liver, kidneys and lungs, and possible blood abnormalities. Several of .the chlor-
inated benzenes are known mutagens in plants. Carcinogenic studies completed were
of a short duration and must be considered inconclusive until studies are repeated
using, current methodologies.
The extent of metabolism of these compounds depends on the degree of substitution,
the position(s) of substitution and the type .of halogen.
17.
KEY WORDS ANO DOCUMENT ANALYSIS
DESCRIPTORS
b.lOENTIFIERS/OPEN ENDED TERMS C. COSATI Field/Group
Halogenated benzenes
Chlorinated benzenes
Fluorinated benzenes
Broninated benzenes
Chemical marketing information
Toxicology
Iodinated benzene!
Pollution
Pollution
Environmental effects
Necrosis
Mutagens
Chemical intermediates
13. DISTRIBUTION STATEMENT
Document is available to public through
The National Technical Information
Service, Springfield, Virginia 22151
19. SECURITY CLASS (This Report)
Unclassified
21.
20. SECURITY CLASS (Thispage)
Unclassified
22. PRICE
AI
EPA Form 2220-1 (9-73)
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EPA 560/2-77-004
INVESTIGATION OF SELECTED POTENTIAL
ENVIRONMENTAL CONTAMINANTS:
HALOQ2NATED BENZENES
Sylvia A. Ware
William L. West, Ph.D.
Contract No: 68-01-4183
July 1977
Project Officer: Frank J. Letkiewic2
Prepared for:
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, D.C. 20460
Document is available to the public through the National
Technical Information Service, Springfield, Virginia 22151
/ CU
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NOTICE
This report has been reviewed by the Office of Toxic Substances, EPA, and
approved for publication. Approval does not signify that the contents neces-
sarily reflect the views and policies of the Environmental Protection Agency,
nor does mention of trade names or commercial products constitute endorsement
or recommendation for use.
11
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TABLE OF CONTENTS
EXECUTIVE SUMMARY 1
I PHYSICAL AND CHEMICAL DATA 4
1. Chemical Structure 4
2. Nomenclature 4
3. Physical Properties of the Pure Material 7
4. Physical Properties and Contaminants
of the Commercial Material 15
5. Chemical Properties 18
(a) General Discussion 18
(b) Chemical Reactions Involved in Use 19
II ENVIRONMENTAL EXPOSURE FACTORS 24
A. Production and Consumption 24
(a) Chlorinated Benzenes 24
1. Quantity Produced, Market Trends and Prices 24
2. Producers, Processors, Production Sites 31
3. Production Methods and Processes 34
Production of Monochlorobenzene 38
Dichlorobenzenes 41
Trichlorobenzenes 43
Tetrachlorobenzenes 43
Pentachlorobenzene 44
(b) Fluorinated Benzenes 44
1. Quantity Produced, Market Trends 44
2. Producers, Processors and Production Sites 46
3. Production Methods and Processes 49
4. Market Prices 53
(c) Brominated Benzenes 54
1. Quantity Produced, Market Trends 54
2. Producers, Processors, Production Sites 54
3. Production Methods and Processes 55
4. Market Prices 58
(d) lodinated Benzenes 58
1. Production and Market Trends 58
2. Producers, Processors and Production Sites 58
3. Production Methods and Processes 58
111
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B. Uses 60
(a) Chlorinated Benzenes 60
1. Major and Minor Uses 60
Monochlorobenzene 60
o-Dichlorobenzene 64
£-Dichlorobenzene 66
Trichlorobenzenes 67
Tetrachlorobenzenes . 69
Pentachlorobenzene 70
2. Discontinued Uses 70
3. Projected or Proposed Uses . 71
4. Alternatives to Use 72
(a) As Dielectric Fluids 72
(b) As Heat Transfer Fluids 73
(c) As Solvents 73
(b) Fluorinated Benzenes 74
1. Major and Minor Uses, Potential Uses 74
(c) Brominated Benzenes 77
1. Major and Minor Uses, Chemistry Involved in Use .77
(d) lodinated Benzenes .. 79
1. Major and Minor Uses, Potential Uses, Chemistry of Use 79
C. Environmental Contamination Potential 81
1. General Discussion 81
2. Production 81
3. Transport and Storage .. 83
4. Usage 85
5. Disposal Methods Used 88
6. Potential Inadvertent Production in
Other Industrial Processes 91
7. Potential Inadvertent Production in the Environment 93
D. Current Handling Practices and Control Technology 95
1. Special Handling 95
2. Storage and Transport ... 95
3. Emergency Procedures 96
(a) Spill or Leak 96
(b) Fire 97
(c) First Aid 98
E. Analytical Methods 98
1. Standard Methods Used 98
Chlorinated Benzenes 99
(a) Preparation of Samples 99
(b) Purification Techniques 101
(c) Gas Chromatography 101
Fluorinated Benzenes 110
IV
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Brominated Benzenes 113
Separation of Monohalogens 113
F. Monitoring Efforts 117
III. HEALTH AND ENVIRONMENTAL EFFECTS 135
A. Environmental Effects 135
1. Persistence 135
(a) Biological Degradation 135
(b) Chemical and Photolytic Degradation 142
2. Bioaccumulation and Biomagnification 143
3. Environmental Transport 145
B. Biological Effects i.. 149
1. Toxicity and Clinical Studies in Man 149
(a) Poisoning Incidents and Case Histories 149
Monochlorobenzene .. 149
Dichlorobenzenes 149
Other Chlorinated Benzenes 151
2. Effects of Nonhuman Mammals 151
(a) Absorption and Excretion 151
Monohalogenated Benzenes 155
Dichlorobenzenes 157
Higher Chlorinated Benzenes 158
Monobromobenzene 162
Dibromobenzenes 165
Higher Brominated Benzenes 167
(b) Pharmacology and Metabolism 168
Background Discussion 168
. Pharmacology and Metabolism of Halogenated Benzenes .. 170
(c) Relationship Between Metabolism and Toxicity 175
(d) Acute Toxicity 186
(e) Subacute Toxicity 193
Monochlorobenzene 197
Dichlorobenzenes 198
Trichlorobenzenes and Tetrachlorobenzenes 199
Hexahalogenated Benzenes 205
(f) Effects on the Eye 205
(g) Dermatological Pathology 207
(h) Teratogenicity 207
(i) Mutagenicity/ Carcinogenicity 210
(j) Behavioral Effects 212
(k) Possible Synergisms 216
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3. Effects on Other Vertebrates 217
(a) Fish 217
(i) Metabolism and Toxicity 217
(b) Amphibians - the Frog 219
4. Effects on Invertebrates ; 220
(a) Insects 220
(b) Marine Organisms and Fresh Water Species 225
5. Effects on Plants 229
(a) Mutagenicity .. 229
(b) Effect on Germination 229
6. Effects on Microorganisms 232
(a) Fungicidal Effectiveness 232
(b) Bactericidal and Sporicidal Efficiency 232
(c) Effect on Phytoplankton 234
(d) Mutagenicity Studies 234
IV. REGULATIONS AND STANDARDS 237
A. Current Regulations 237
1. Food, Drug and Cosmetic Act 237
2. Federal Environmental Pesticide Control Act;
Food, Drug and Cosmetic Act 237
3. Air and Water Acts 238
4. Other Environmental Protection Agency Authority 240
5. Occupational Safety and Health Administration (OSHA) 241
6. Department of Transportaton (DOT) 241
7. State Regulations 242
B. Consensus and Similar Standards 246
1. Threshold Limit Values 246
2. Public Exposure Limits 247
3. Foreign Standards 248
4. Other 249
SUMMARY AND RECOMMENDATIONS 251
1. Summary 251
2. Recommendations 257
LIST OF REFERENCES 260
VI
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LIST OF TABLES
Number
1. Synonyms and Trade Names for Chlorinated Benzenes 6
2. Physical Properties of Halogenated Benzenes 8.
3. Properties of Mixed Halogenated Benzene Derivatives 10
4. Solubilities of Halogenated Benzenes 7
5. Solubilities of Mixed Halogenated Benzenes 11
6. Vapor Pressures of Halogenated Benzenes 12
7. Azeotropic Mixtures of Chlorobenzene 14
8. Fire and Explosion Hazard Data for Some Halogenated Benzenes 14
9. Additional Properties of Chlorinated Benzenes 16
10. Representative Analyses of Commercially Important Chlorinated
Benzenes 17
11. U.S. Production of Monochlorobenzene, 1966-1975 25
12. U.S. Production of £-Dichlorobenzene, 1966-1975 26
13. U.S. Production of pj-Dichlorobenzene, 1966-1975 26
14. U.S. Production of 1,2,4-Trichlorobenzene, 1968-1973 28.
15. U.S. Imports of Chlorinated Benzenes, 1971-1974 30
16. Chlorinated Benzenes, Capacities in Millions of Pounds/Year 32
17. U.S. Producers of Chlorinated Benzenes 33
18. Locations of Production Sites 35
19. Imports of Fluorinated Benzenes 46
20. U.S. Manufacture of Fluorinated Benzenes 47
21. Fluorinated Benzenes Available Through Aldrich Chemicals 48
22. Market Prices of Fluorinated Benzenes 53
23. U.S. Manufacturers of Brominated Benzenes 56
24. U.S. Manufacture of lodinated Benzenes 59
25. 1973 Consumption of Monochlorobenzene 60
26. Pesticidal Use by Category and Geographical Region 66
27. Uses of 1,2,4-Trichlorobenzene 68
28. Estimated Loss of Materials During Batch Manufacture of
Chlorobenzene 82
29. Concentration of jHDichlorobenzene in
Human Adipose Tissue and Blood 87
30. Relative Retention Times of Hexachlorobenzene (HCB) and
Hexachlorocyclohexane (HCH) Isomers on a Given
Chromatography Column 103
31. Rf Values of Chlorinated Insecticides and Chlorobenzenes
in a Given System 103
32. Relative Retention Times of Halogenated Aromatics
on a Given Chromatography Column 105
33. Retention and Weight Factor Data for Compounds Chromatographed ... 108
34. Physical Properties of Selected Polyfluorobenzenes Ill
35. Experimental Parameters for Plasmagrams Run for Compounds
Studied 114
36. Drift Time and Structure Assignments of Charged Species
Observed in Plasmagrams of Halogenated Benzenes 115
37. Methods for the Separation and Detection of Halogenated
Benzenes 116
38. Monitoring for Chlorinated Benzenes in Water Systems 119
VII
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TABLES (continued) Page
39. Halogenated Benzenes Found in Drinking Water in the U.S 122
40. Chlorinated Benzenes Identified in the Environment in
Region IV 123
41. Municipal Wastewater Chlorobenzene Concentrations Determined
by Electron-Capture Gas Chromatography and Mass Spectrometry .. 126
42. Estimated Chlorobenzene Concentrations in Major Municipal
Wastewaters 127
43. Surface Runoff of Chlorinated Hydrocarbons, Los Angeles
River, Feb. 1976 128
44. Aerial Fallout of Chlorinated Hydrocarbons off Southern
California, Spring 1976 129
45. Chlorinated Hydrocarbons Measured in High-Volume Air Samples
Collected Off Los Angeles Basin, 1976 130
46. Effects of 1,2,4-Trichlorobenzene on BOD 139
47. Rates of Degradation of Pentachlorobenzene and
Hexachlorobenzene in Soil 141
48. Ecological Magnification of Monochlorobenzene and
Hexachlorobenzene in Various Aquatic Species 144
49. Molecular Properties and Biological Response of Several
Chlorinated Benzenes 146
50. Human Exposure to Chlorinated Benzenes — Case Reports 152
51. A Comparison of Major Metabolites of Benzene and
Monohalogenated Benzenes in Rabbits 156
52. The Quantitative Aspects of the Metabolism of
Halogenated Benzenes in Rabbits 159
53. Metabolism of 1,3,5-Tri-, Penta- and Hexachlorobenzene
in Rabbits 161
54. Summary of Metabolism of Higher Chlorinated Benzene
Isomers in Rabbits 161
55. Effects of Pretreatment of Rats with Phenobarbital and SKF-525A
Bile Excretion of Bromobenzene Metabolites and on Bile Flow ... 163
56. Tissue Distribution of Bromobenzene in Rats After
Oral Administration 165
57. Bromobenzene Metabolites in Rat Urine 166
58. Summary of Rabbit Urinary Metabolites of Some Isomeric
Brominated Benzenes 167
59. Species Variation in the Distribution of Cyt. P-450, P-450
Reductase, NADPH Cyt-c Reductase and Hydroxy benzpyrene
Formed ••••<• 171
60. Metabolism of C-Chlorobenzene in Different Species 171
61. Effect of Phenobarbital and SKF-525A Administration on Covalent
Binding of Halogenated Benzene Derivatives on Rat Liver
Protein in Vivo, Six Hours After Administration 173
62. Covalent Binding, Hepatotoxicity, and Mercapturic Acid
Excretion of Halogenated Benzene Derivatives 178
63. Species Differences in Bromobenzene's Hepatotoxicity
and Metabolism 14 180
64. Distribution of Covalently Bound C
Bromobenzene in the Mouse 181
Vlll
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TABLES (continued) Page
65. Binding of Aromatic Hydrocarbons in Rat Lung: Effects
of Phenobarbital 181
66. Mean Peak Values of Urinary Porphyrins and Urinary Precursors
Following Treatment of Male Rats with the. Maximum
Doses Tried of Each Chlorinated Benzene 183
67. Porphyrins, Porphobilinogen and Catalase Activity in
Livers of Rats Treated with Chlorinated Benzenes,
Allylisopropylacetamide or Sedormid 183
68. Effect of Chlorinated Benzenes on Aminolevulinic Acid
Synthetase and Cytochrome P-450 Content of Rat Liver 185
69. Effect of Chlorinated Benzenes Administered p.o. for
14 Days on Various Parameters of Xenobiotic Metabolism 185
70. Acute Toxicity Data <- 187
71. Acute Toxicity Data (Additional) .* 188
72. A Comparative Study of the Toxicity of Benzene and
Monochlorobenzene 190
73. The Acute Toxicity of Fluorinated Benzenes - Test Animal Mice .... 191
74. An Evaluation of Tetrafluorobenzenes in Anesthesia 194
75. Hexafluorobenzene in Anesthesia 195
76. Chronic Toxicity Data , 200
77. A Comparison of the Subacute Inhalation Toxicity of
Hexasubstituted Benzene for Rats 206
78. Effects of Halogenated Benzenes on the Eye 208
79. Topical Application/Dermatological 209
80. The Effects of Halogenated Benzenes on the Course of
Gestation in Mice and Rats 211
81. Carcinogenic and Related Studies 213
82. Summaries of Carcinogenic Testing of o-Dichlorobenzene 214
83. Summaries of Carcinogenic Testing of pj-Dichlorobenzene 214
84. Hepatic Levels of Cytochrome P-450 and NADPH-Cytochrome c
Reductase Activity in Trout Compared with Values for
Man and Rat 218
85. Spectrophotometrie Estimation of Chloromonophenols Present
in Hydrolysed Urine of Animals Dosed with Chlorobenzene 221
86. Acute Effects of Chlorobenzenes in Insects 223
87. Effect of Various Halogenated Benzenes on Invertebrate
Marine Life and Fresh Water Species 226
88. Effects of p_-Dichlorobenzene on Mitotic Division 230
89. Effects of ODCB on Growth of Marine Phytoplankton 235
90. Adopted Threshold Limit Values 246
91. Recommended Maximal Allowable Concentrations in Other Countries .. 248
92. Chemicals Selected for Phase II Study by the NSF
Workshop Panel (Shortened List) 250
IX
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LIST OF FIGURES
Number . Page
1. Configurations of the Halogenated Benzenes 5
2. Reactions Involved in Use of Chlorbbenzene 20
3. Reactions Involved in Use of 1,2-Dichlorobenzene 21
4. Reactions Involved in Use of 1,4-Dichlorobenzene 22
5. Reactions Involved in Use of 1,2,4-Trichlorobenzene 23
6. Production of Monochlorobenzene, 1966-1975 27
7. U.S. Production of Dichlorobenzenes 27
8. U.S. Production Si-tes for the Chlorinated Benzenes 36
9. N.E. Reg-ion Production Sites for Chlorinated Benzenes 37
10. Plant Diagram — Chlorination of Benzene 40
11. Production Schematic for Pentachlorobenzene by
Chlorination of Benzene, Chlorobenzene 45
12. Consumption Pattern for Chlorinated Benzenes 63
13. Uses and Potential Uses of Fluorinated Benzenes 75
14. Chromatogram Obtained from 8 wt.% Bentone^34/10 wt.% DC-200
Silicone Oil Column at 160°C and 30 mls/min. He 106
15. Computer Plot of Parent Mass Numbers of Chlorinated Benzenes 106
16. Analysis of Human Fat by Gas Chromatography/Mass Spectrometry .... 107
17. Chromatogram of an Authentic Mixture of Fluorobenzenes 112
18. Composite Positive Plasmagrams of Monohalogenated Benzenes 112
19. Chlorinated Benzenes as Found in Lake Superior Trout
Near Coppermine Point 132
20. Chlorinated Benzenes as Found in Lake Huron Burbot
Near Mackinac 132
21. Accumulation of Halogenated Catechols in a
Culture with P. putida 136
22. Pathways of Bromobenzene Metabolism 174
23. Dose Responses of Fungi to Vapors of Chlorobenzenes
in the Soil 233
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ACKNOWLEDGMENTS
We wish to thank Dr. Shiv K. Soni for the contributions made as Principal
Investigator during the initial four months of the contract. Also, we are
grateful to the persons who spent many long hours searching various libraries
and other facilities for the numerous articles that form the basis of this
report. The consultant reviewers provided a most valuable service in assur-
ing the overall comprehensiveness of the information included in the document.
We would like to thank Guy Hudgins for assistance in editing and typing the
final manuscript.
We especially would like to express our sincere appreciation to Frank
Letkiewicz, the Project Officer, who provided technical support in a most
effective manner during the development of this presentation.
XI
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EXECUTIVE SUMMARY
>
Halogenated benzenes are substituted benzene compounds containing fluo-
rine, chlorine, bromine and/or iodine. Substitution may involve replacement
of one to six hydrogen atoms of the benzene by a halogen. This report exam-
ines all fluoro-, chloro-, bromo- and iodobenzenes from the mono- to the hexa-
substituted. Hexachlorobenzene, which has been the subject of several rel-
ated studies, is discussed only when data for this compound illustrate a
trend within the group of chemicals, or help clarify the significance of giv- -
en information.
Halogenated benzenes are a group of chemically stable compounds. The
chlorinated benzenes are of particular industrial importance. Production
of monochlorobenzene exceeds 300 million pounds per year, while production of
o- and £-dichlorobenzene, 1,2,4-trichlorobenzene and 1,2,4,5-tetrachloroben-
zene is in excess of tens of millions of pounds each per annum.
Chlorinated benzenes are used as solvents, as heat transfer and dielec-
tric fluids, as chemical intermediates, and as deodorizers and insect repel-
lents. These latter two uses have both industrial and household applications.
As intermediates, chlorinated benzenes are precursors of phenolic compounds,
diazonium salts and various herbicides.
Environmental contamination occurs as a result of manufacture, use, dis-
posal and possibly transportation of chlorinated benzenes. pj-Dichlorobenzene
has been detected in human blood samples taken in the New Orleans area. A
recent Japanese study has shown the presence of £-dichlorobenzene, 1,2,4,5-
tetrachloro- and hexachlorobenzene in human fatty tissue, with the para-
compound also detected in human blood. Chlorinated benzenes have been de-
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tected in fish, in raw water sources and even in drinking water. They have
also been found in the air and soil. Brominated benzenes have been located
in raw water sources and in drinking water.
Lower halogenated compounds are absorbed by mammals through the intact
skin, the lungs and the gastrointestinal system. Higher halogenated com-
pounds tend to be poorly absorbed, though once in the system, they will
accumulate in fatty tissue. All halogenated benzenes appear to be lipid
soluble. Higher chlorinated benzenes resist biodegradation, though some
decomposition occurs for lower chlorinated compounds.
Acute effects of exposure to halogenated benzenes include either stimu-
lation or depression of the central nervous system (CNS). Acute depression
may result in respiratory failure and death. There are animal species dif-
ferences in the ability of halogenated benzenes to produce CNS effects. The
extent of metabolism of these compounds tends to decrease with greater number
of halogen substitutions. Again there are species differences in ability to
metabolize halogenobenzenes.
- Chronic effects due to exposure include porphyria, necrosis of liver,
lung and kidney and possible blood abnormalities. Pentachlorobenzene was
shown to be carcinogenic in mice in one test system, but there is little ev-
idence that the other compounds are carcinogenic. However, chronic studies
completed in the past were either of a short duration or inconclusive. Hence,
carcinogenic testing of those chlorinated benzenes found in the environment
should be performed according to current methodologies.
Several chlorinated benzenes are known to interfere with cell division in
higher plants and in some microorganisms. There are no reports of mutagene-
sis in mammals. There are indications that both pentachlorobenzene
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and hexachlorobenzene are teratogenic. No teratogenicity studies have been
performed for the lower halogenated compounds.
Considering the extent to which chlorinated benzenes are entering the en-
vironment, and the evidence suggesting bioaccumulation, there is a need to
know more about possible chronic effects of exposure to these compounds.
There is an accompanying need to establish the behavior of the halogenated
benzenes once in the environment.
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I. PHYSICAL AND CHEMICAL DATA
1. Chemical Structure
The halogenated benzenes to be discussed in this report include all
fluoro-, chloro-, bromo- and iodobenzenes from the mono- to the hexa-substi-
tuted. Hexachlorobenzene is not included except when data for this compound
illustrate a trend within the group of chemicals, or help clarify the sig-
nificance of given information. Mixed halogenated benzenes are discussed
wherever information was found. No halogenated compounds with other sub-
stituents in the ring are part of this study.
Figure 1 lists all possible configurations for the halogenated benzenes.
2. Nomenclature
There are a number of ways to name each of the compounds discussed in
this study. Synonyms and trade names for the commercially important chlorin-
ated benzenes are found in Table 1. Chemical names for the other halogenated
compounds follow the same pattern/ e.g. monobromobenzene: phenyl bromide,
benzene bromide, etc.
Abbreviations used for chlorinated compounds are those listed in the same
table. Please note that where found PCB stands for polychlorinated biphenyl
as is the usual practice, and not for pj-dichlorobenzene which has sometimes
been used.
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FIGURE 1
CONFIGURATIONS OF THE HALOGENATED BENZENES
X
X = F, Cl, Br, I
o-
X
mono-substituted
m-
X
©
di-substituted
X
tri-substituted
X 1,2,4- 1,.3,5-
penta-substituted
tetra-substituted
hexa-substituted
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TABLE 1
SYNONYMS AND TRADE NAMES FOR CHLORINATED BENZENES
Monochlo robenzene:
chlorobenzene; chlorobenzol; benzene
chloride; phenyl chloride; MCB
o-Dichlorobenzene:
orthodichlorobenzene; ortho-dichlorobenzene;
ortho-dichlorobenzol ; 1,2-dichlorobenzene;
ODB; ODCB; Dizene®; Chloroben (S) ;
Dowtherm(§) E
j>-Dichlorobenzene:
paradichlorobenzene; para-dichlorobenzene;
para-dlchlorobenzol; 1,4-dichlorobenzene;
PDB; PDCB; Di-chloricide (§); Paracide(§) ;
Paradi(g>; Paradow(|D; Paramoth® ;
Santochlor (5.1
m-Dichlorobenzene:
metadichlorobenzene; meta-dichlorobenzol;
meta-dichlorobenzene; 1,3-dichlorobenzene
1,2,3-Trichlorobenzene: 1,2,3-trichlorobenzol; 1,2,3-TCB
1,2,4-Trichlorobenzene:
1,2,4-trichlorobenzol; 1,2,4-TCB;
uns-trichlorobenzene
1,3,5-Trichlorobenzene: 1,3,5-trichlorobenzol; 1,3,5-TCB;
sym-trichlorobenzene
1,2,3,4-Tetrachlorobenzene: 1,2,3,4-tetrachlorobenzol
1,2,3,5-Tetrachlorobenzene: 1,2,3,5-tetrachlorobenzol
1,2,4,5-Tetrachlorobenzene: 1,2,4,5-tetrachlorobenzol
Pentachlorobenzene:
quintochlorobenzene; QCB
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3. Physical Properties of the Pure Material .
Ihe monohalogenated benzenes are all colorless, neutral, relatively vola-
tile liquids with a pungent aromatic odor. The boiling points are sufficient-
ly different (see Table 2) that they may be separated by fractional distilla-*
tion. Ihey are all denser than water, as are all of the halogenated benzenes
and most of the mixed halogenated benzenes (see Table 3).
Monohalobenzenes are almost insoluble in water (see Table 4). If mono-
halobenzenes accumulate in raw water systems, they tend to sink. Because of
their comparatively high volatility, there may be a greater tendency to ao
cumulate in still lake waters rather than fast moving streams and rivers (see
Section III).
TABLE 4
SOLUBILITIES OF MONOHALOGENATED BENZENES
(Seidell, 1952)
Compound Solubility
Monochlorobenzene ' 0.0488 g/lOOg @ 30°C
Monofluorobenzene 0.154 g/lOOg @ 30°C
Monobromobenzene 0.0446 g/lOOg @ 30°C
Monoiodobenzene 0.034 g/lOOg @ 30°C
Monohalogenated benzenes have a high solubility in nonpolar solvents (see
Table 5). They are all highly soluble in lipids. Partition coefficient data
for several chlorinated benzenes is found in Table 49. For the limited data
presented, there was an increase in partition coefficient from mono- to hexa-
chlorobenzene. Lu and Metcalf (1975) reported a positive correlation between
partition coefficient and degree of bioaccumulation.
Monochlorobenzene forms azeotropic mixtures with a number of solvents
(see Table 7). .
The monoderivatives are classified as flammable liquids. Flash point
data and explosive limits are presented in Table 8. Because of the possibil-
ity of combustion with oxidizing agents, special care must be taken in hand- .
ling during manufacture, use and transportation (see Section IID).
7
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TABLE 2
PHYSICAL PROPERTIES OF HALCGENATED BENZENES
(Feast and Musgrave, 1971; Weast, 1976)
Compound
Monofluorobenzene
o-Oifluorobenzene
n-Di fluorobenzene
£-Difluorobenzene
1,2, 3-Tr ifluorobenzene
1,2, 4-Tr ifluorobenzene
1 , 3 , 5-Tr ifluorobenzene
1,2,3,4-Tetrafluorobenzene
1 , 2 , 3 , 5-Tetr afluorobenzene
1,2,4, 5-Tetr afluorobenzene
Pentaf luorobenzene
Hexafluorobenzene
Manochlorobenzene
£-Dichlorobenzene
m-Dichlorobenzene
£-Oichlorobanzene
1 , 2 , 3-Tr ichlorobenzene
Melting
Point
-41.9
-34
-59.3
-13.0
-13.5
-35
- 5.5
-42
-48
4
-48
5
-45.2
-17.2
-26.3
53.0
52.4
Boiling Density
Point ,
(°C) (go/ear }
85 dj5 1.0309
91 dj5 1.1496
83 d*° 1.1572
89 d*° 1.1716
95
88
75.5 d*° 1.277
95 df 1.422
83 d*5 1.410
90 d*5 1.424
85 d*° 1.531
80 d20 1.6182
132.0 dj5 1.117
179.2 df 1.2973
172 d25 1.2799
174.5 d|5 1.2495
218
Refractive
Index
nj*° 1.4667
n£° 1.4452
n^0 1.4410
n^° 1.4421
n£° 1.4230
n^° 1.4140
nj° 1.4069
n^5 1.4011
n^° 1.4045
n^5 1.3881
n^5 1.3761
n^1 1.5275
n^°'41.5485
n2°-91.5457
n^9>91.5267
1,2,4-Trichlorobenzene 16.6 213 d|5 1.4634 n£ 1.5524
1,3,5-Trichlorobenzene 63 208
1,2,3,4-Tetrachlorobenzene 47.5 254
-------
TABLE 2 (continued)
Compound
1,2,3, 5-Tetrachlorobenzene
1,2, 4, 5-Tetrachlorobenzene
Pentachlorobenzene
Hexachlorobenzene
Monobromo benzene
o-Dibromo benzene
m-Dibronc benzene
£-Dibromo benzene
1, 2, 3-Tribcorao benzene
1,2, 4-Tr ibromo benzene
1,3, 5-Tr ibronc benzene
1 , 2 ,3 , 4-Tetr abromobenzene
1,2,3, 5-Tetr abromobenzene
1,2,4, 5-Tetr abrcraobenzene
Pentabromo benzene
Hexabromo benzene
Mono iodobenzene
o-Di iodobenzene
m-Di iodobenzene
£-Di iodobenzene
1 , 2 , 3-Tr i iodobenzene
1,2, 4-Tr i iodobenzene
1,3, 5-Tr iiodobenzene
1,2,3, 4-Tetraiodobenzene
1,2,3, 5-Tetr aiodobenzene
1,2,4, 5-Tetr aiodobenzene
Pentaiodobenzene
Hexaiodobenzene
Melting
Point
51
138
87
229
-30.6
+• 6.7
- 7
+87.3
88
44
119
47.5
98
173
159
326
-31
26.7
35
129
116
91.5
134
136
148
254
172
340-350
Boiling
Point
246
244
276
326
156.2
225
220
220
275
271
254
329
sub.
188.5
286
235
235
sub.
sub.
sub.
sub.
sub.
sub.
sub.
Density Refractive
3 Index
(gm/cm )
d|2 1.858
dU'Sl.8342
df '6 1.5691
df 1.4946 n^° 1.5597
df 1.956 n^° 1.6155
df 1.952 n£7 1.6083
df°1.8322 nQ 1.5742
2.658
df 3.072
df 3.072
df 1.823 n£7*81.6213
df 2.54 n2,0 1.7179
df 2.47
-------
TABLE 3
PROPERTIES OF MIXED HALOGENATED BENZENE DERIVATIVES
(Feast and Musgrave, 1971; Weast, 1976)
Name
l-Bromo-2-chlorobenzene
l-Bromo-3-chlorobenzene
l-Bromo-4-chlorobenzene
l-Bromo-2 , 3-dichlorobenzene
l-Bromo-3 , 5-dichlorobenzene
2-Bromo-l , 3-dichlorobenzene
2-Bromo-l , 4-dichlorobenzene
4-Bromo-l ,2-dichlorobenzene
l-Bromo-3- f 1 uo r obenzene
l-Bromo-2-fluorobenzene
l-Bromo-4-fluorobenzene
l-Bromo-2-iodobenzene
l-Bromo-3-iodobenzene
l-Bromo-4-iodobenzene
l-Chloro-2-fluorobenzene
l-Chloro-4-fluorobenzene
l-Chloro-2-iodobenzene
l-Chloro-3-iodobenzene
l-Chloro-4-iodobenzene
l-Fluoro-4-iodobenzene
l-Fluoro-2-iodobenzene
Molecular
Weight
191.46
191.46
191.46
225.91
225.91
225.91
225.91
225.91
175.01
175.01
175.01
282.92
282.92
282/92
130.56
130.56
238.47
238.47
238.45
222.00
222.00
Melting
Point
-12
-21
67
60
74
65
35
25
-17
2-5
- 9
92
-43
-28
v
-
56-57
-20
-41.5
Boiling Density
Point (gm/OTH)
204
196
196
243
232
242
235
237
151
57/22mm
152
257
252
251-252
138-140
130
234-235
230
226-7
182
188
1.6382
1.6302
1.576
_
-
-
-
-
-
1.4946
2.2571
—
—
1.2233
1.226
1.9515
-
1.886
1.9523
—
Refractive
Index
1.5809
1.5771
1.5531
_
- •>
- .
-
-
-
1.5604
1.6618
—
—
1.4968
1.4990
1.6331
-
-
1.5270
—
1,4-Dichloro-2-iodobenzene
272.90
21
250-1
-------
TABLE 5
SOLUBILITIES OF HALOGENATED BENZENES
(Vfeast, 1976)
Compound Water
Mono fluo robe nzene
Monochlorobenzene
1 , 2-Oichlorobenzene
1 , 3-DichIorobenzene
1 , 4-Oichlocobenzene
1,2, 3-Tr ichlorobenzene
1,2, 4-Tr ichlorobenzene
1 , 3 / 5-Tr ichlorobenzene
1,2,3,4-Tetrachlorobenzene
1 , 2 , 3 , S^Tetracnlorobenzene
1,2,4,5-Tetrachlorobenzene
Pentachlorobenzene
Hexachlorobenzene
Monobromobenzene
1 , 2-Dibronobenzene
1 , 3-Dibrooobenzene
1 , 4-Oibrcnobenzene
1,2, 3-Tr ibrcmobenzene
1 , 2 , 4-Tr ibroraobenzene
1,3, 5-Tr ibromobenzene
1,2,3, 4-Tetr abromobenzene
1,2,3, 5-Tetr abroroobenzene
1,2,4, 5-Tetrabromobenzene
Pentabroro benzene
Hexabronc benzene
Monoiodobenzene
1 , 2-Diiodobenzene
1 , 3-Diiodobenzene
1 , 4-Diiodobenzene
1,2, 3-Tr iiodobenzene
1,2, 4-Tr i iodobenzene
1 , 3 , 5-Tr iiodobenzene
1,2, 3, 4-Tetr aiodobenzene
1,2,3, 5-Tetr aiodobenzene
1,2,4, 5-Tetr aiodobenzene
Pentaiodobenzene
Hexaiodobenzene
l-Bromo-2-chlorobenzene
l-Brono-3-chlorobenzene
l-BroraD-4-chlorobenzene
l-Brcmo-2 , 3-dichlorobenzene
l-Brono-3 , 5-dichlorobenzene
2-Bront>-l , 3-dichlorobenzene
2-Brorao-l , 4-dichlorobenzene
4-Brono-l ,2-d ichlorobenzene
l-Bromo-4-fluorobenzene
l-Bron»-2-iodobenzene
l-Brorao-3-iodobenzene
l-Brorao-4-iodobenzene
l-Chloro-2-fluorobenzene
l-Chloro-4-fluorobenzene
l-Chloro-2-iodobenzene
l-Chloro-3-iodobenzene
l-Chloro-4-iodobenzene
l-Fluoro-4-iodobenzene
1 ,4-Dichloro-2-iodobenzene
i
i
i
i
i
i
i
i
i
a (hot)
i
i
i
i
i
i
i
i
i
i
—
i
i
—
i
i
S3
i
i
i
i
i
—
i
i
i
i
i
i
i
i
i
i
i
i
i
i
i
i
i
i
i
i
i
i
i
Alcohol
00
oo
s
a
oa
S3
S3
S3
aa
as
ea
a
aa
vs
s
s
s
ss
s
ss
—
s
ss
ss
ss
s
ss
3
s'
s
s
ss
vs
S3
33
S3
i
—
vs
ss
ss
s
—
s
ss
s
ss
ss
S3
—
s
—
—
s
s
s
Ether
00
00
s
s
3
vs
VS
VS
vs
s
s
S3
S
vs
0*
00
VS
vs
vs
s
—
s
vs
S3
S3
00
VS
S
vs
s
3
33
VS
SS
SS
S3
i
—
VS
3
—
S
vs
vs
vs
s
—
—
s
—
s
s
s
Benzene
OD
VS
09
s
s
vs
—
vs
—
a
a
aa
vs
vs
OD
—
VS
—
S3
S
s
—
s
s
00
—
——
—
—
— —
ss
—
—
—
s
—
vs
—
s
vs
vs
vs
vs
vs
—
—
—
—
s
s
—
—
• —
—
•WM
Chloroform
vs
—
— —
s
-—
——
__
— —
—
s
ss
3
—
•—
—
—
—
S
—
—
—
S
s
s
—
s
—r
S
s
S3
VS
—
—
S
—
— -
— —
s
_
s
vs
vs
vs
—
• — -
—
—
—
—
.—
—
s
oo - infinitely soluble
vs - very soluble
s - soluble
ss - slightly soluble
i - insoluble
11
-------
TABLE 6
VAPOR PRESSURES OF HALOGENATED BENZENES
(Bardie, 1964; Richardson, 1968; Olin Chemicals, 1974)
Fluorinated Benzenes
Vapor Pressure (psig)
Monofluorobenzene
1,2-Difluorobenzene
1,3-Difluorobenzene
1,4-Difluorobenzene
1,2,3-Tr ifluorobenzene
1,2,4-Trifluorobenzene
1,3,5-Trifluorobenzene
1,2,3,4-Tetrafluorobenzene
1,2,3,5-Tetrafluorobenzene
Pentafluo robenzene
Hexafluorobenzene
16.9 (Reid)
16.7 (100°C)
17.15 (Reid)
log10P(torr) = 6.9183 -
[at 6-50°C]
logP(torr) = 7.19386 -
10
[at 6-50°C]
log10P(torr) = 7.07758 -
[at 6-50°C]
1218
log10P(nun) = 6.94904 - toc f
[at 19-85°C]
log10P(torr) = 6.86088 -
Chlorinated Benzenes
Vapor Pressure (ram/Hg at 25°C
unless otherwise indicated)
Monochlorobenzene
1,2-Dichlorobenzene
1,3-Dichlorobenzene
1,4-Dichlorobenzene
1,2,3-Trichlorobenzene
1,2,4-Trichlorobenzene
1,3,5-Tr ichlorobenzene
1,2,3,4-Tetrachlorobenzene
1,2,3,5-Tetrachlorobenzene
1,2,4,5-Tetrachlorobenzene
Pentachlo robenzene
Hexachlorobenzene
3(0°C), 9(20°C), 26(40°C), 65(60°C)
144(80°C), 292(100°C), 543{120°C)
1.28
1.89
0.4(25°C), 6.6(50°C), 11.5(60°C),
67(100°C), 545(160°C)
0.07
0.29
0.15
0.05
-5
1.09 x 10 (at 20°C)
12
-------
The three difluorobenzene isomers are colorless, neutral liquids at room
temperature. Like monofluorobenzene, they are highly flammable and have low
flash points. Very little solubility data was found for fluorinated ben-
zenes. The tendency is towards insolubility in water and solubility in
nonpolar solvents.
Ortho- and meta-dichlorobenzene are neutral, mobile, colorless liquids
i
with similar and characteristic odors. jpj-Dichlorobenzene is a pleasant \
smelling white crystalline solid. The crystals readily sublime at room |
temperature. Solubilities of the dichlorobenzenes are similar to MCB, and
like the monocompound, they form a number of azeotropic mixtures (Bardie,
1964). All three are combustible. Additional data on physical properties
are found in Tables 2 and 5.
Like the dichlorobenzene compounds, o- and m-dibromobenzene are colorless
liquids at room temperature. p-Dibromobenzene is a white crystalline solid.
All dibromobenzenes are insoluble in water, soluble in alcohol and infinitely
soluble in ether. The diiodobenzenes are all crystalline solids. o-Diiodo-
benzene is slightly soluble in water and all diiodobenzenes are soluble in
non-polar solvents.
The trihalogenated benzenes are white crystalline solids except for the
trifluorobenzenes and the 1,2,4-trichlorobenzene isomer. Solubilities are
similar, with insolubility in water, generally good solubility in alcohol,
ether, benzene and chloroform, and relatively high lipid solubility.
All the polyfluorinated compounds are colorless liquids. Tetra-, penta-
and hexachlorobenzene are white crystalline solids at room temperature. The
polybromo- and polyiodobenzene compounds are white crystalline solids which
tend to sublime.
13
-------
TABLE 7
AZEOTROPIC MIXTURES OF CHLORQBENZENE
(Hardie, 1964}
Other Components
Boiling Point
of Azeotrope, (°C)
Chlorobenzene
% by wt.
Water
% by wt.
Hydrogen
chloride
% by wt.
Binary:
water
l-amino-2-propanol
3-methyl-l-butanol
(isoamyl alcohol)
2-methyl-l-butanol
(d-amyl alcohol)
_n-propanol
Ternary:
hydrogen chloride
and water
90.2
128.3
124.4
96.5
96.9
71.6
87.0
57
20.0
74.5
28.4
20.2
5.3
Reprinted with permission of Interscience Publishers, John Wiley and Sons,
Inc., New York
TABLE 8
FIRE AND EXPLOSION HAZARD DATA FOR SOME HALOGENATED BENZENES
(Montrose Chemical Corp., 1972; Olin Chemicals, 1974;
Great Lakes Chemical Corp., 1975; Merck, 1976; Dow Chemical, 1977b)
Compound
Flash point Method Used
Flammable Limits
(STP in air)
Lower Upper
Fluorobenzene
1 , 2-Dif luorobenzene
1 , 3-Dif luorobenzene
1 , 4-Dif luorobenzene
Monochlorobenzene
1 , 2-Dichlorobenzene
1 , 4-Dichlorobenzene
1,2, 3-Trichlorobenzene
1,2, 4-Tr ichlorobenzene
1,3, 5-Tr ichlorobenzene
1,2,4,5-Tetra-
chlorobenzene
Hexachlorobenzene
9°
45°
12°
11°
82°
160°
152°
235°
210°
225°
311°
468°
-12.8°
7.2°
-11.1°
-11.7°
27.8°
71.1°
66.7°
112.8°
98.9°
107.2°
155.0°
242.2°
Open cup
Open cup
Open cup
Open cup
Closed cup
Closed cup
Closed cup
Closed cup
Closed cup
Closed cup
Closed cup
Closed cup
m m
-
- .
-
1.3%
2.2%
r-
-
(none
-
-
-
^
-
-
-
7.1%
9.2%
-
-
at 25°C)
-
• -
-
14
-------
Solubility tends to be lower in all solvents, for the hexahalobenzene com-
pounds. Hexaiodobenzene is insoluble in water, alcohol, and ether, while
hexabromobenzene is insoluble in water, and only slightly soluble in chloro-
form. Hexachlorobenzene is insoluble in water and only slightly soluble in
i
alcohol and ether. There is a tendency for tetra- and pentahalogenated
benzenes to be slightly less soluble in alcohol than the lower homologues.
Polyiodinated benzenes as a group are less soluble in alcohol, ether, benzene
and chloroform than are the corresponding chloro- and bromo- compounds. All
halogenated benzenes have high lipid solubility.
While fluorinated benzenes and the lower chlorinated and brominated
compounds tend to be flammable or combustible liquids, higher brominated
benzenes have been used as fire-retardant materials, and some higher chlori-
nated benzenes have been suggested for this use.
Several chlorinated benzenes are used for heat transfer or as dielectric
fluids in transformers and capacitors. Properties important for such uses
include: chemical stability, value of the dielectric constant, viscosity,
surface tension and thermal conductivity. Values are listed in Table 9.
4. Physical Properties and Contaminants of the Commercial Material
No specific data is recorded in this section. It might be noted that
contaminants of the commercially available materials are either other isomers
or homologues (see Table 10).
As solvent properties of the mixtures tend to be close to those of the
pure products, for solvent uses, it often does not matter if the compound is
pure or not.
15
-------
TABLE 9
ADDITIONAL PROPERTIES OF CHLORINATED BENZENES
(Dow Chemical, 1970, 1972)
CTl
Compound Dielectric
Constant (25°C)
Monochlor obenzene 5 . 621
1 , 2-Dichlorobenzene 9.93
1,4-Dichlorobenzene 2.41 [50°]
1,2,4-Trichlorobenzene 2.24 [20°]
Surface Tension
(dynes/cm. 25°C)
32.65
36.61
31.4 [ 60°]
27.2 [100°]
38.54
Thermal Conductivity*
(25°C)
3.038
2.878
3.08
2.58
2.582
-4
-4
-4
-4 [60°]
-4 [28°]
Viscosity
(cp) (25°C)
0.756
1.3018
-
1.8848
in
cal
sec on (°C/cm)
-------
TABLE 10
REPRESENTATIVE ANALYSES OF COMMERCIALLY IMPORTANT CHLORINATED BENZENES
(Dow Chemical, 1970; Montrose Chemical Corp., 1972; Allied Chemical, 1973;
Manufacturing Chemists Association, 1974; Great Lakes Chemical Corp., 1975)
Chemical %
Monochloro- 99.9
benzene 90
1,2-Dichloro- 99
benzene 75-85
82.7
80
60-75
1,4-Dichloro- 99.95
benzene 99.5
96
65
1,2,4-Tri- 100
chlorobenzene 99
1,2,4,5-Tetra- 97
chlorobenzene •
Pentachloro-
benzene
Hexachloro- 90-99
benzene
(T|
C
QJ
N
if
J2
O
X
0.07
X
X
X
X
X
-------
5. Chemical Properties
(a) General Discussion
Phenyl halides are much less reactive than the corresponding alkyl com-
pounds, and are similar in reactivity to the vinyl halides. They are very
stable to nucleophilic attack — a fact attributed to resonance in the
molecule resulting in shortening of the carbon-halogen bond distance, and
hence an increase in bond strength (Fieser and Fieser, 1960).
At room temperature and pressure, halogenated benzenes are not attacked
by air, moisture or light. They are not affected by steam, prolonged boiling
with aqueous or alcoholic ammonia, other alkalis, hydrochloric acid or dilute
sulfuric acid. Hydrolysis takes place at elevated temperatures in the pres-
ence of a catalyst to form phenols.
Halogenated benzenes are subject to attack by hot concentrated sulfuric
acid to form a halobenzene-p-sulfonic acid. Nitric acid will substitute m-,
p- in the ring to form halonitrobenzenes at -30° to 0°C. At higher tempera-
tures, the nitration will either proceed further to form a dinitrohalo com-
pound, a halonitrophenol or a nitrophenol.
The stability of halogenated benzenes to nucleophilic attack decreases in
the order F > Cl > Br >I. Additional substitution in the ring activates the
nucleus to nucleophilic attack. Hence, polyhalogenated benzenes are more sus-
ceptible to nucleophiles because of the electron attractive•(Iff ') effect of
the substituents. Nucleophilic attack is also possible in the presence of a
catalyst (often a cuprous salt) and at elevated temperatures and pres-
sures.
Halogenated benzenes are attacked by electrophilic agents. Here the
order of reactivity is greatest for the fluorine compounds decreasing toward
the iodobenzenes. Substitution for mono compounds is predominantly para,
18
-------
with some ortho substitution. The higher halogenated benzenes tend to resist
electrophilic substitution but can be substituted using extreme conditions.
For example, Friedel-Crafts alkylation of pentafluorobenzene occurs under
autogenous pressure at 150°C (Feast and Musgrave, 1971).
Halogenated benzenes also undergo some free radical reactions. Formation
of organometallic compounds (Grignards, aryl-lithium compounds) provides a
useful route to many organic intermediates (see Section IIB).
Photochemical transformations occur on irradiation of halogenated ben-
zenes which are much less stable to radiation than benzene. On ultraviolet
irradiation or pulse hydrolysis in solution, halogenated benzenes may poly-
merize to biphenyls, halonapthalenes, or other more complex products (Matsu-
ura and Qnura, 1966; MacKenzie ^t al., 1965; MacLachlan and McCarthy, 1962).
Photochemical interchange of halogens is also possible:
ArX + X1 »• ArX' + X
Here, bromine replaces iodine in iodobenzenes, chlorine replaces bromine or
iodine, etc. Echols et al. (1967) have shown that the rate of the photo-
chemical reaction 2PhBr + Cl —> 2PhCl + Br in carbon tetrachloride sol-
ution is proportional to the square root of the light intensity, halogen con-
centration and to the bromobenzene concentration over a limited range.
(b) Chemical Reactions Involved in Use
Chemical reactions involved in use are discussed in detail in Section IIB.
Figures 2, 3, 4 and 5 summarize possible reactions for the commercially im-
portant chlorinated benzenes, and serve as an introduction to the following
section. The nitration reaction is the single most important industrial
reaction. The reactions diagrammed in Figures 2-5 are not necessarily
industrially significant, but are examples of possible reactions.
19
-------
FIGURE 2 REACTIONS INVOLVED IN USE OF CHLOROBENZENE
(Dow Chemical, 1975b)
(a)
(e)
I 0
Cl
1
CCHoCl
6' 2
(a) Catalytic addition of ammonia to form aniline, high temperature and
pressure
(b) Friedel-Crafts arylating agent in presence of a Lewis acid
(c) Acid catalyzed addition of an olefinic grouping
(d) Oxidative iodination to p-chloroiodobenzene
(e) Ring substitution, here to o- and p-chloronitrobenzene
20
-------
FIGURE 3 REACTIONS INVOLVED IN USE OF 1,2-DICHLOROBENZENE (ODCB)
(Dow Chemical, 1975b)
(c)
or
Cl
(a) Friedel-Crafts alkylation in fifth position
(b) Reaction of o-aminophenol with a base results in formation of phenoxazine
(c) Ready aromatic substitution- nitric acid to nitro- and dinitro- compounds
(d) Acid catalyzed substitution in fifth position
21
-------
FIGURE 4 REACTIONS INVOLVED IN USE OF 1,4-DICHLOROBENZENE
(Dow Chemical, 1975b)
Oh3-
(a)
(e)
(b)
(d)
NHR
(c)
(a) Linear polymers such as polyphenylene sulfide can be formed,
Wurtz-Fittig reaction also used
(b) For example, aqueous ammonia and cupric oxide catalyst produce
p-phenylene diamine
(c) Acid catalyzed substitution
(d) Readily nitrated in 1-position
(e) Friedel-Crafts addition of an acid chloride, also with alkenes and alkyl
halides.
22
-------
FIGURE 5 REACTIONS INVOLVED IN USE OF 1,2,4-TRICHLOROBENZENE
(Dow Chemical, 1975b)
NHR
Cl
ClCH-jCCCl cl
A1C13
(b)
OH
(a) Mild Friedel-Crafts conditions: alkylation and acylation in fifth
position
(b) Catalyzed reaction with primary amine to form a dichlorinated secondary
amine
(c) Nitration of ring in fifth position
(d) Alkaline.hydrolysis to 2,5-dichlorophenol
Also note, 2,5-dichlorobenzoic acid is formed by cyanation followed by
hydrolysis of 1,2,4-trichlorobenzene.
Figures 2-5 reprinted with permission
23
-------
II. ENVIRONMENTAL EXPOSURE FACTORS
A. PRODUCTION AND CONSUMPTION
(a) CHLORINATED BENZENES
1. Quantity Produced/ Market Trends/ Market Prices
Chlorobenzene was first produced in the United States by the Dow Chemical
Company in 1915 (Bardie, 1964). It was one of the first organic chemicals
produced in large quantities. U.S. production figures are available through
the U.S. International Trade Commission reports published since 1922. The
U.S. International Trade Commission (USTIC) was formerly the U.S. Trade
Commission (USTC). Table 11 documents production and sales figures for the
ten year period 1966 to 1975. As can be clearly seen in Figure 6, monochloro-
benzene production has been on the decrease since 1969, dropping to around
300 million pounds production in 1975. The low figure for 1974 is attributed
to long strikes at Dow Chemical and PPG Industries, and to a shortage of
benzene early in the year (Chemical Marketing Reporter, 1974a). Preliminary
figures for 1976 are also down — the nine month accumulative figures from
January to September show production of 252,078 x 10 pounds.
Tables 12 and 13, and Figure 7 illustrate market trends for a- and £-
dichlorobenzene over the last ten years. Preliminary figures for 1975 show a
decreased production of o-dichlorobenzene to about 54 to 55 million pounds.
Nevertheless, future markets for ODCB look promising, and the industry ex-
pects the demand for this isomer to increase (Chemical Marketing .Reporter,
1975). The versatility of ODCB as a solvent accounts for its expanding
markets. Preliminary figures for 1975 indicate a decrease in production of
jD-dichlorobenzene to 40 million pounds. The market for the para isomer is
limited by the possible uses of the chemical, and is considered saturated.
24
-------
TABLE 11
U.S. PRODUCTION OF MONOCHLORQBENZENE, 1966-1975
(USITC, 1966a-1975a)
Year
1966
1967
1968
1969
1970
1971
1972
1973
1974
1975*
1955
1956
Production
(103 Ibs.)
576,749
483,294
575,751
601,959
484,914
408,908
403,505
397,481
379,181
306,030
435,593
452,434
Quantity
(103 Ibs.)
130,570
67,857
142,654
93,164
66,755
71,475
85,244
125,735
71,683
77,363
55,195
68,444
Sales
Total value
($103)
7,795
4,145
8,501
5,231
3,699
3,779
4,817
8,237
15,312
20,410
4,412
5,127
Unit Value
($/lb.)
0.06
0.06 ;
0.06
0.06
0.06
0.05
0.06
0.07
0.214
0.25
0.08
0.07
* Preliminary figures
Please note that weights are expressed in pounds (avdp.) as is customary
in this country. 10 pounds = 0.454 metric ton, 1 pound = 0.454 kg.
25
-------
TABLE 12
U.S. PRODUCTION OF 2-DICHLOROBENZENE, 1966-1975
(USITC, 1966a-1975a)
Year
1966
1967
1968
1969
1970
1971
1972
1973
1974
1975*
Production
(103 Ibs.)
51,386
50,366
60,603
70,372
66,219
53,640
62,386
66,035
n.a.
54,679
Quantity
(103 Ibs.)
50,726
45,970
46,290
53,027
35,074
55,935
62,389
67,055
n.a.
50,456
Sales
Total Value
($103)
5,065
4,721
4,977
5,532
3,503
5,829
7,233
8,659
n.a.
13,960
Unit Value
($/lb.)
0.10
0.10
0.11
0.10
0.10
0.10
0.12
0.13
n.a.
0.28
Preliminary figures
TABLE 13
U.S. PRODUCTION OF P-DICHLOROBENZENE, 1966-1975
(USITC, 1966a-1975a)
Year
1966
1967
1968
1969
1970
1971
1972
1973
1974
1975*
Production
(103 Ibs.)
66,307
66,482
70,338
52,060
69,606
70,418
77,317
62,743
n.a.
45,755
Quantity
(103 Ibs.)
65,659
64,719 .
69,117
53,934
69,669
69,187
70,704
69,398
n.a.
34,099
Sales
Total Value
($103)
5,893
5,782
6,646
4,991
6,165
5,805
6,285
6,436
n.a.
8,371
Unit Value
($/lb.)
0.09
0.09
0.10
0.09
0.09
0.08
0.09
0.09
n.a.
0.25
Preliminary figures
26
-------
FIGUEE 6
U S PBOCUCnON OF JtMOOOOHOBENZElE, 1966-1975
. ( OSITC 1966a-1975a )
106 iba.
600
500
400
Preliminary
figure
T5721973 '1974 1975 \
1966 1967
FIGUSE 7 U.S. PRODUCTION OF DICHLOICBHJZESES
( USITC, 1966«-1975a )
10s Ibs.
75'
70.
63J
60
PDC3
ODQ3
* Preliminary figure
ODCT 1,2-Dichlorcbenzene
PDCB 1,4-Oi dvlorcbenzene
50
45'-
1966 1967 1968 1969 1970 1971 1972 1973 1974 1975
27
-------
In 1973, production of 1,2,4-trichlorobenzene was 28,268 x 10pounds.
Table 14 gives production and sales data for trichlorobenzene from 1968 to
1973. In 1973, production of 1,2,4,5-tetrachlorobenzene was estimated at 18
million pounds (Lewis, 1975). Pentachlorobenzene production for commercial
sales was estimated at less than 1 ton in 1972 (Mumma and Lawless, 1975).
Figures for captive production were not available. The estimated total pro-
duction of hexachlorobenzene was 350 tons in 1973 (Mumma and Lawless, 1975).
TABLE 14
U.S. PRODUCTION OF 1,2,4-TRICHLOROBENZENE, 1968-1973
(USITC, 1968a-1973a)
Year
1968
1969
1970
1971
1972
1973
Production
3
(10-3 Ibs.)
10,867
15,217
9,344
11,034
15,522
28,268
Sales
Quantity Total Value
T
(10J Ibs.)
11,069
13,329
9,531
12,130
15,667
26,198
•t
($10J)
1,295
1,564
1,185
1,361
2,020
3,607
Unit Value
($/lb.)
0.12
0.12
0.12
0.11
0.13
0.14
As explained below, higher chlorinated benzenes are coproduced with the
monosubstituted compound in varying proportions, depending on reaction con-
ditions. The Dow Chemical Company is replacing and expanding its chlorinated
benzene production machinery in Midland, Michigan. The plant is capable of
manufacturing approximately 300 to 350 million pounds of chlorobenzene per
year, much of which is converted to phenol. Some of the MCB goes to produce
a- and £-dichlorobenzene, trichlorobenzene and tetrachlorobenzene. It has
28
-------
been estimated (Chemical Marketing Reporter, 1975) that about 22 million
pounds of the monochlorobenzene goes to o-dichlorobenzene production and 16
i
million pounds to production of the para isomer. Dow technology is being
altered to produce higher chlorobenzenes and to permit greater flexibility in
production. Over the long term, Dow intends to phase out phenol production
via monochlorobenzene in favor of phenol production at its cumene-based plant
in Oyster Creek, Texas.
Please note, USITC does not have figures for production of 1,2,4-tri-
chlorobenzene for 1974 or 1975. This is presumably because the chemical is
produced by only a few manufacturers and publication of data would reveal
proprietary information.
USITC reports do not give any figures for production of other chlorinated
(or other halogenated) benzenes. This is also presumably either because of
monopolies or near-monopolies of manufacture and/or because the chemicals are
not produced in great enough quantities to warrant entry in the Federal
government reports. The criteria for inclusion require that the chemical be
produced in excess of 1,000 pounds/annum or have a value of at least $1,000.
Some indication of importance of specific chemicals can be deduced from
Section IIB below. Lewis (1975) reported 1973 production of 1,2,4,5-tetra-
chlorobenzene of 18 million pounds.
Import data for several of the chlorinated benzenes are found in Table
15. Principal chlorobenzene-producing countries include West Germany, the
United Kingdom, France and Japan (Hardie, 1964). In 1974, imports of
1,2,4-trichlorobenzene in to the U.S. exceeded 2 million pounds (USITC
1974b). The chief exporting nations were Belgium, France and West Germany.
With reference to the completeness of Table 15, it should be noted that
29
-------
for benzenoid intermediates, the data collected by the U.S. International
Trade Commission are reported to be 99% complete (USITC 1974b). Carry-over
of year end entries to the following year tends to be reasonably constant
from year to year. Hence, though year-to-year comparisons are possible for
chemicals imported on a regular basis, for chemicals imported irregularly,
there is some statistical distortion.
TABLE 15
U.S. IMPORTS OF CHLORINATED BENZENES, 1971-1974
(USITC, 1971b-1974b)
Product 1971
(Ibs.)
Monochlorobenzene *
o-Dichlorobenzene *
m-Dichlorobenzene *
Pj-Dichlorobenzene *
Tr ichlorobenzene *
(mixed isomers)
1,2, 4-Tr ichlorobenzene *
1,3, 5-Tr ichlorobenzene *
1,2, 4, 5-Te trachlor obenzene *
1972 1973
(Ibs.) (Ibs.)
* *
13,800 *
* 2,191
* 3,527
* *
* *
2,870 45,492
* 167,551
1974
(Ibs.)
1,485,106
1,631,404
31,006
*
940,715
2,770,245
21,525
1,467,819
* Note: no information given for these chemicals
30
-------
2. Producers, Processors and production Sites
Dow Chemical Company, the Monsanto Company, PPG Industries, the Montrose
Chemical Corporation of California and the Standard Chlorine Chemical Company
are the largest producers of monochlorobenzene in the U.S. ICC Solvent Com-
pany, inc. and Allied Chemical Corporation also manufacture monochloroben-
zene. Annual manufacturing capacity of the individual companies is indicated
in Table 16. Dow Chemical has an annual capacity of 300 to 350 million
pounds at its Midland, Michigan, plant. As previously indicated, Dow Chemic-
al is adapting its plant to produce higher chlorinated benzenes in greater
quantities. The Monsanto Company has an annual capacity of about 125 million
pounds at its Sauget, Illinois, facility. Both PPG Industries and Standard
Chlorine completed expansions of their plants in 1974 and are planning fur-
ther new units for the near future (Chemical Marketing Reporter, 1975).
The same companies produce the bulk of &- and p-dichlorobenzene (see
Table 16). A complete tabulation of all companies listed by USITC as
manufacturers is given in Table 17. All manufacturers listed in the 1975
Stanford Research Institute (SRI) directory for 1976 were contacted for
verification of their status as producers or major processors. One firm,
Transvaal, Inc., indicated that it no longer produces tetrachlorobenzene, but
finds it cheaper to import the chemical (Transvaal Inc., 1976). The first
shipment is now on order from West Germany.
In general, producers manufacture a range of chlorinated benzenes. Each
plant therefore has the flexibility to produce more or less of a particular
chemical depending on market demand. Processors buy mixtures of chloroben-
zenes to separate and upgrade the mixture by fractional distillation (e.g.,
Specialty Organics).
31
-------
TABLE 16
CHLORINATED BENZENES, CAPACITIES* IN MILLIONS OF POUNDS/YEAR
(Lewis, 1975)
Producer
Mono-Dichloro-
chlorobenzene benzene (o- and £-)
TricnToro-
benzene (1,2,4-)
u>
Allied Chemical Corp.,
Industrial Chemicals
Div.
Dow Chemical, USA.
Monsanto Company,
Industrial Chem. Div.
Montrose Chemical Corp.
of California
Occidental Petroleum Corp.
Hooker Chems. and t
Plastics Corp.
PPG Inc.
Industrial Chems. Div.
ICC Industries, Inc.
Solvent Chemical Company
(a) Maiden, Mass. $
(b) Niagara Falls, N.Y.
Standard Chlorine Chem. Co.
Total
20
350
125
70
30
75
670
22
40
12
40
(10)
75
204
10
not recovered
n.a.
n.a.
18
35
* Many capacities believed understated. List partially outdated by expansions of PPG Industries to
135 million pounds by end of 1975. Further expansion of PPG Industries Natrium facility is
increasing production to 300 million pounds (Chemical Marketing Reporter, 1974b).
t Hooker Chemical Corp. no longer produces any chlorinated benzenes.
t Maiden plant phasing out. Production now centered at Niagara Falls.
-------
TABl£ 17
U)
U.S. PRODUCERS Of
ailJORlNA-Jia} BENZENES
Allied Chun. Corp.
Dow Chan. Co.
ICC-Solvent Chan. Co.
fimsanto Co.
Montrose Chan. Corp. of Calif.
(looker Chan. & Plastics Co. 3
PPG Indust. Inc.
Standard Chlorine
Dover Chemical Corp.
Chemical Products Corp. i 3
Specialty Organ ics
Eastman Kodak
Guardian Chan. Co.
Transvaal, Inc. 2
Aceto Chemical Co.
Chan. Procurement Labs. Inc.
Stauffer Chen. Co.
0
tonochloi
A 0
A 0
o
A 0
A 0
o
A C
o
0
O V
"i
A 0
A 0
C
A 0
A 0
A 0
O
0
O
0
j-DichlOJ
'benzene
o
0
o
0
j-Dichloi
"benzene
A 0
A 0
A 0
A 0
A 0
O
A
0
,i
H o
( H
<*> o
*3
A
A
A
I
|_^ Q
vs
*3
MJ
o
o
0
1
in o
•i3
14 flj
4J N
fc
*• Ul
ro O
«3
0
M V
4J N
fl) C
in O
rT O
•il
kj 01
•^ N
di c
in o
":1
~3
A 0
O
0
«
"entachlc
benzene
4
4
4
4
*
*
i
texachlo:
benzene
A 0
*
Key,
1 Processor
2 Transvaal, Inc. no
longer runs unit,
cheaper to iirport
(Transvaal, Inc., 1976)
3 No longer produce or
process
4 Captive by-product
(Munma and lawless,
1975)
A U.S. International
Trade Camu.ssion,1975a
o Stanford Research Inst-
itute, 1975a, 1976
* Munma and Lawless, 1975
-------
Table 18 and Figure 8 give the manufacturing sites for chlorinated ben-
zene production. Tb clarify the map, seven of the sites pinpointed make
three or more chlorinated benzenes, i.e. usually monochlorobenzene, £- and
pj-dichlorobenzene and trichlorobenzenes. Those sites where production is
greatest are indicated by the dark circle.
Three other facilities are identified on the map by a solid triangle.
These plants are smaller, and are indicated in Table 17 as manufacturing two
or less of the chemicals.
3. Production Methods and Processes
Chlorobenzene and higher chlorinated benzenes are produced when benzene
reacts with chlorine at slightly elevated temperatures in the presence of
various catalysts. The reaction is exothermic.
CCH, + Cl_ >* C..H_C1 + HC1 -I- 40 k.cal
O O f. O D
CCH_C1 + Cl. > C.H.C1- + HC1
DO z o 4 2.
After one chlorine has substituted onto the benzene ring, further substi-
tution takes place principally in the ortho and para positions. All three
V
dichlorobenzenes yield a preponderant amount of 1,2,4-trichlorobenzene on
further chlorination. The rate of substitution decreases with degree of
chlorination (Bardie, 1964). Because of the slowness of reaction and the
strong directing effect of previous substitution, some isomers must be
prepared by other routes (see below).
34
-------
TABLE 18
LOCATIONS OP PRODUCTION SITES
(USITC, 1974a; Lewis, 1975)
Company
Division
Location
OJ
(Jl
Allied Chemical Corp.
Dow Chemical, U.S.A.
Monsanto Company
Montrose Chemical Corp.
of California
PPG Industries, Inc.
Standard Chlorine Chemical
Co., Inc.
ICC Industries, Inc.
Industrial Chemicals Division
Industrial Chemicals Division
Industrial Chemicals Division
Solvent Chemical Company
Syracuse, N.Y.
Midland, Michigan
Sauget, Illinois
Henderson, Nevada
Natrium, W. Virginia
Delaware City, Delaware
Maiden, Mass*
Niagara Falls, New York
*Phasing out production
-------
FIGURE 8 U.S. PRQCUCHON SITES FOR THE CHLORINATED BENZENES
U>
NORTH
CENTRAL
WEST
Q At least 3 ootpounds
A 2 or less coipounds
-------
FIGUTCE 9 N.K.REGION PRODUCTION SITES FOR dHORINKTED BENZENES
u>
0 At least 3
A 2 or less caifxaunds
Iden (phasing out)
-------
The most common catalyst used is sublimed ferric chloride (Bardie, 1964).
Other catalysts employed include anhydrous aluminum chloride, stannic chlor-
ide, iron or aluminum. Addition of fuller's earth decreases production of
dichlorobenzenes, while the aluminum chloride catalyst increases disubsti-
tution (Bardie, 1964). The temperature of reaction is also a very important
parameter. By manipulation of catalyst and reaction conditions, it is pos-
sible to maximize production of specific chlorobenzenes. Bowever, it is not
possible to avoid coproduction of higher substituted chlorobenzenes entirely.
Production of Monochlorobenzene
Prior to reaction, the benzene is dried by either azeotropic distillation
or with silica gel, caustic soda or alumina (Bardie, 1964). Thiophene im-
purities do not affect the course of the reaction. Chlorine is scrubbed with
concentrated sulfuric acid to dry and remove impurities. The reaction vessel
is usually made from cast iron or mild steel. Cooling coils are made from
steel and chlorine feed pipes are glass lined (Booker Chemicals and Plastics
Corp., 1977).
A continuous process, with immediate distillation of monochlorobenzene as
it forms, decreases yield of dichlorobenzenes and may result in a product
containing up to 95% MCB. The plant consists of a series of small externally
cooled steel vessels containing the catalyst. Chlorine is piped into each
vessel; at all times the chlorine concentration is kept to a minimum. At
20° to 40°C, monochlorobenzene forms and is removed from the excess benzene
by fractional distillation. The benzene is recycled to the chlorinator. The
by-product, hydrogen chloride, can be removed by washing with a refrigerated
solvent. Holding the temperature below 40°C slows the rate of formation of
chlorinated benzenes to one tenth that for monosubsititution (Bardie, 1964).
38
-------
For batch production, the catalyst is usually ferric chloride. Again the
temperature is kept below 45°C to minimize production of dichlorobenzenes
(Hardie, 1964). Faith, Keyes and Clark (1965) described a higher temperature.
batch process for manufacture of chlorobenzene (see Figure 10). Chlorine is
bubbled into a cast-iron or steel tank containing dry benzene with 1% its own
weight of iron filings. Tfemperature is maintained at 40° to 60°C until den^
sity studies indicate that all the benzene is chlorinated. The temperature.
is raised to 55° to 60°C for six hours, when the density rises to 1.280 g/on .
Chlorinated benzene is removed to an insulated steel tank with a reflux
condenser. The mixture is agitated for several hours with a 10% caustic soda
solution to remove HCl. Further agitation with 50% caustic soda at 60°C
removes added chlorine. This neutralizing tank is heated by a steam jacket.
The material then enters a separator where the alkaline sludge containing
mainly dichlorobenzenes is removed for distillation. The lighter material is
fractionally distilled to produce four fractions. Fractions one and two
contain benzene, water, and chlorobenzene and are recycled for further pro-
cessing. The third fraction contains chlorobenzene which is collected. The
fourth fraction containing mainly dichloro- and trichlorobenzene is collected
and fractionally distilled to separate the o- and j>-dichlorobenzene isomers
from 1,2,4-trichlorobenzene.
Hydrogen chloride formed in the chlorinator is led to a scrubber to re-
move benzene and chlorobenzene using a low vapor-pressure oil. The gas is
then absorbed in water to give high quality hydrochloric acid.
At 100% chlorine consumption, the yield is approximately 80% MCB, 15%
p-dichlorobenzene and.5% o-dichlorobenzene (Faith, Keyes and Clark, 1965).
39
-------
FIGURE 10
PIANT DIAGRAM - CHLORINATION OF BENZENE
(Faith, Reyes and Clark, 1965)
benzene or
chlorobenzenej
1
i
W
hydrochloric
^
• T
acid — '
benzene
CHIDRUMMOR *•
—V-T
cnj.orine — • • • •
^
H- -i- n ~ ~* r/-w^ri 4- HPT
wa1
sodiv
:er
1 t
1
\
>v«
HCl^
m hydroxide
i
NEUTRALE
TAM
ZING
K
-ifcenzene and water
-^benzene and chloro-
benzene
"fchlorobenzene
->dichloro- and polychloro-
benzenes to distillation
(70-75% yield, monochlorobenzene)
dichlorobenzene
sludge to recovery
CgH5Cl + C12
C6H4C12 + HC1
(10-20% yield, dichlorobenzene)
Reprinted with permission from the senior
author, Dr. W.L.Faith
-------
Vapor phase chlorination of benzene takes place at 220° to 260°C in the
Raschig process (Hardie, 1964). Hydrogen chloride is catalytically oxidized
in a preheated mixture of benzene vapour, air and steam to form chlorine. The
chlorine reacts with the benzene to form MCB. A mixed catalyst of copper
oxide and transition metal oxides is contained on silica gel. "temperature
control is accomplished by packing the catalyst in small diameter tubes. Only
10% of the benzene reacts at a time.
Dichlorobenzenes
Ortho- and para-dichlorobenzene can be produced by chlorinating benzene
or chlorobenzene at 150° to 190°C with a ferric chloride catalyst (Hardie,
1964). The isomers may be separated by fractional distillation (b.p. ODCB -
179°C, b.p. PDCB - 173°C). Alternatively, PDCB can be crystallized out.
Crystalline £-dichlorobenzene is washed with methanol and dried under vacuum
at 100°C. PDCB can also be separated from the ortho isomer by treating the
mixed isomers with chlorosulfonic acid at 15°C. p-Dichlorobenzene is separa-
ted from o-dichlorobenzene sulfonic acid by distillation.
An orienting catalyst such as benzene sulfonic acid or j>-methyl benzene
sulfonic acid will increase yields of £-dichlorobenzene to a high of 86%
(Hardie, 1964).
1,2,4-Trichlorobenzene forms more rapidly by chlorination of o-dichlorp-
benzene than p-dichlorobenzene. Trichlorobenzene is easily separated from
PDCB by fractional distillation (b.p. 210°C & 179.5°C, respectively). Thus,
allowing the ODCB to form 1,2,4-trichlorobenzene is yet another way of iso-
lating pure p-dichlorobenzene.
m-Dichlorobenzene may be prepared by isomerizatidn of the o- and p-
isomers by heating to 120°C under 650 psi pressure in the presence of a
41
-------
catalyst (Hardie, 1964). Catalysts used include aluminum chloride and hydro-
gen chloride. Alternatively, higher chlorinated benzenes can be catalytical-
ly reduced to m-dichlorobenzene. Tr ichlorobenzene mixtures have been reduced
using molybdenum oxide, nickel chloride or chromium oxide as a catalyst.
Hexachlorobenzene and hydrogen react at 350° to 500°C in the presence of a
cuprous halide or alumina to form m-dichlorobenzene (Hardie, 1964).
Rucker (1960) described a method for selective hydrogenation of chiorc—
benzenes involving effective control of the degree of dehalohydrogenation by
continuously fractionating the reaction products. The reaction takes place
in the liquid phase from 100°C to the reflux temperature. Palladium (0.5% of
5% Pd) is deposited on activated charcoal as the catalyst. Hydrogen is led
into the reaction vessel and as dehalogenation takes place, the products are
continuously distilled off. As the lower chlorobenzenes are more volatile
than the higher-substituted chlorobenzenes, any lighter product can be ob-
«
tained from the starting material by controlling the distillation temper-
ature. The chlorobenzenes are reduced at a rate almost directly proportional
to their concentration in the reaction vessel.
According to Rucker, 100% m-dichlorobenzene can be formed by catalytical-
ly reducing 1,3,5-trichlorobenzene for 7 hours at 205°C. Excess hydrogen and
by-product hydrogen chloride are removed through a reflux condenser.
Crowder and Gilbert (1958) patented a vapor-phase dehalogenation of
1,3,5-trichlorobenzene using platinum on activated charcoal as a catalyst at
i
a temperature of 375°C and 1 ps.ig pressure. Distillation of products was
said to yield 65% m-dichlorobenzene. Other catalysts mentioned in the liter-
ature are cuprous chloride and titanium dioxide mixtures, nickel, nickel
chromite, copper chromite, molybdenum oxide and chromium oxide.
42
-------
Trichlorobenzenes
As indicated previously, 1,2,4-trichlorobenzene together with 1,2,3-tri-
chlorobenzene are formed by catalytic chlorination of o-dichlorobenzene
(Hardie, 1964). All three trichlorobenzenes may be obtained by reacting
a -, 0-, or ^benzene hexachloride with alcoholic caustic potash. The
1,2,4-trichlorobenzene is formed by reacting a—benzene hexachloride with
calcium hydroxide at 100°C (Hardie, 1964). All three isomers are produced
when a-benzene hexachloride is dehydrohalogenated by pyridine. Further
manufacturing details are not available.
Tetrachlorobenzenes
Tetrachlorobenzenes may be prepared from trichlorobenzenes as indicated
below. Kissling (1957) patented a method to separate pure 1,2,4,5-tetra-
chlorobenzene from a mixture of trichloro-, pentachloro- and other tetra-
chlorobenzene isomers by fractional crystallization in acid solution. Hydro-
gen chloride concentration should be 0.2 moles HCl/mole tetrachlorobenzene and
the concentration of a Friedel-Crafts catalyst should be from 0.01 to 5% by
weight. Optimum temperatures for crystallization are in the range 0° to 30°C.
Routes to Tetrachlorobenzenes (Hardie, 1964)
Cl
1,2,3-trichlorobenzene • > 1,2,3,4-tetrachlorobenzene
catalyst
1,3,5-trichlorobenzene >1,2,3,5-tetrachlorobenzene
aluminum amalgam
1,2,4-trichlorobenzene - > 1,2,4,5-tetrachlorobenzene
aluminum amalgam
Sandmeyer reaction
1,2,4-trichlorobenzene > 1,2,4,5-tetrachlorobenzene
(nitration, reduction,
diazotization)
43
-------
2,3,5-trichloroaniline > 1,2,3,5-tetrachlorobenzene
Sandmeyer reaction
Note: Yields not indicated
The hydrogen chloride produced as a by-product of the chlprination of
benzene or chlorobenzenes remains in the reaction vessel to facilitate the
crystallization. Crystals of 1,2,4,5-tetrachlorobenzene are filtered,
centrifuged or decanted, and washed with either methanol, ethanol, acetone
and/or liquid chlorobenzenes. The supernatant liquid still contains up to
50% of the 1,2,4,5-tetrachlorobenzene formed. Further cooling will precip-
itate a second crop of 1,2,4,5-tetrachlorobenzene.
Pentachlorobenzene
Pentachlorobenzene may be formed by chlorination of benzene in the
presence of ferric chloride at 150° to 200°C, or by chlorination of any of
the lower chlorobenzenes (Mumma and Lawless, 1975). A production schematic
for pentachlorobenzene (or quintochlorobenzene, QCB) is shown in Figure 11.
Chlorination of 1,3,4,5-tetrachlorobenzene is faster than chlorination of
1,2,4,5-tetrachlorobenzene (Bardie, 1964).
(b) FLUORINATED BENZENES
1. Quantity Produced, Market Trends
Little numerical data exists to document the quantities of fluorobenzenes
produced or processed in this country. Limited imports of monofluorobenzene
and hexafluorobenzene are reported by USITC (1971b-74b)(see Table 19).
No conclusions regarding market trends can be gathered from such scanty
information. Some new uses of the compounds which would expand the market
are still under evaluation (see Section IIB below).
44
-------
FIGURE 11 PRODUCTION SCHEMATIC FOR PENTACHLOROBENZENE BY CHLORINATION OF BENZENE, CHIOROBENZENE
(Muntna and Lawless, 1975)
CL,
C6H* >
t-n
PRIMARY
REACTOR
SCRU
^~
BBER
pV
Ul
Partially chlorinated
benzenes
PACKAGING
Shipment of HCl
>! CENTRIFUGE
i
PURIFIC.
& DRYING
"
PACKAGING
SEPARATION
OF LOWER
CHIDROBENZS.
PURIFICATION
AND DRYING
PACKAGING
i
Shipment of
Hexachlorobenzene
Shipment of
Pentachlorobenzene
-------
TABLE 19
IMPORTS OF FLUORINATED BENZENES (in pounds)
(USITC, 1971b-74b)
1971 1972 1973 1974
Monofluorobenzene 11,059 42,037 58,071 29,089
Hexafluorobenzene 55 220 35
£-Brcmofluorobenzene - 222
2. Producers, Processors and Production Sites
According to the Stanford Research Institute (1976), fluorobenzenes are
manufactured by the 01in Corporation, the Aldrich Chemical Company, PCR In-
dustries and Whittaker Chemicals. The Olin Handbook of Aromatic Fluorine
Compounds (Olin Chemicals, 1974) lists 145 fluorobenzenes containing only
fluorine or fluorine with chlorine, bromine and/or iodine to form mixed halo-
genated benzenes. The Olin Corporation (1976) reported that the company does
not manufacture any simple fluorobenzenes as defined in this report. The
firm purchases monofluorobenzene to manufacture fluorinated benzenes with
additional non-halogen groupings in the molecule.
The Whittaker Corporation is listed both by Stanford Research Institute
(1975a, 1976) and USITC (1975a) as producing hexafluorobenzene. On contact,
Whittaker indicated that the Corporation does not now, nor has ever, manu-
factured this or any other halogenated benzene compound (Whittaker, 1976).
The company operated a high technology research and development activity in
the San Diego area under contract with the U.S. Government. It was suggested
that the above reports of hexafluorobenzene manufacture "perhaps" refer to
this work related to the space and missile fields.
46
-------
TABLE 20
U.S. MANUFACTURE OF FLUORINATED BENZENES
Fluorobenzene
o-Di f 1 uo r obenzene
m-Di f luo robenzene
p-Di f luo robenzene
Hexafluorobenzene
6
6
.5
'6*
0
o
o
o
•
6.
•6
•H
<
O
•
4J
%
1
S
°L
III
4J
s
°AJ
A. USITC 1975a
o Stanford Research
Institute, 1975a
1 Processor not manufacturer
(PCR Industries, 1976b)
2 Does not manufacture hexa-
fluorobenzene though "may
have done so" for U.S.
Government contracts in the
space and missile field
(Whittaker, 1976).
o-Bromofluorobenzene
nh-Bromo fl uo robenzene
j>-Bromo f 1 uo robenzene
o-Chlorofluorobenzene
2 , 4-Dibromof luo robenzene
m-Chlorofluorobenzene
pj-dlorofluorobenzene
•
6
.5
0
o
0
0
o
o
o
o
•
6
•6
<
0
locations
The Olin Corporation is
located at Rochester, New
York and the Aldrich Chemical
Company is operational at
Milwaukee, Wisconsin.
Note: The Olin Corporation
indicates that it does not
currently manufacture any
simple fluorinated benzenes,
but purchases monofluoroben-
zene for use as an aromatic
intermediate.
47
-------
PCR Industries does not manufacture hexafluorobenzene either (PCR
Industries, 1976b) though the firm offers several fluorobenzenes for sale
including monofluorobenzene, hexafluorobenzene, iodopentafluorobenzene,
1,2,3,5-tetrafluorobenzene, 1,2,4,5-tetrafluorobenzene, 1,2,4- and
1,3,5-trifluorobenzene and o-, m- and p_-dif luorobenzene (PCR Industries,
1976a). PCR Industries (1976b) indicated that fluorobenzenes are imported
from England and Germany.
The Aldrich Chemical Company offers a variety of fluorobenzenes through
Aldrich Chemicals and through the Alfred Bader Chemical Division.
TABLE 21
FLUORINATED BENZENES AVAILABLE THROUGI ALDRICH CHEMICALS
(Aldrich Chemical Co., 1976}
Available through Aldrich Chemicals Available through Alfred Bader Chemicals
o-Di fluorobenzene
2,4-Dibromo-l-fluorobenzene
l-Chloro-3-fluorobenzene (99%)
l-Chloro-2-fluorobenzene (99%)
2-Bromofluorobenzene (99%)
3-Bromofluorobenzene (99%)
4-Bromofluorobenzene (97%)
Brcmopentafluorobenzene
Monofluorobenzene (99%)
m-Difluorobenzene (97%)
p-Difluorobenzene (98%)
Hexafluorobenzene (99%)
Pentafluorobenzene (98%)
1,2,3,4-TetrafLuorobenzene (98%)
1,2,3,5-Tetrafluorobenzene (99%)
1,2,4,5-Tetrafluorobenzene (98%)
1,2-Dichloro-4-fluorobenzene
*1,2-Diiodotetrafluorobenzene
*1,4-Dibromotetrafluorobenzene
1,2-Dibromotetrafluorobenzene
*1,3-Dibromotetrafluorobenzene
2-Fluoroiodobenzene
1,3-Dichloro-4-fluorobenzene
3-Chloroiodobenzene
4-Fluoroiodobenzene
* Retail at $10/5g
48
-------
The Alfred Bader Chemical Division sells chemicals gathered from labor-
atories in universities and other institutions in this country and throughout
the world. It was not possible to pinpoint the sources of this very diverse
and specialized collection. Aldrich Chemicals manufactures some of these
fluorinated benzenes, while purchasing others from different companies. More
complete information was not available.
3. Production Methods and Processes
*
Monofluorobenzene cannot be prepared by direct fluorination of benzene,
but is generally manufactured through the Sandmeyer reaction. According to
Barbour et al. (1966), in Germany quantities of as high as 1000 kg have been
batch-prepared at yields of 81%. Aniline is diazotized in anhydrous hydrogen
fluoride.
G
NaN02
HF
+ -i
O
,- A
81%
Barbour et ai^. did not mention a catalyst, but presumably the thermal
decomposition of the diazonium compound can be controlled by use of a cuprous
salt. Dower yields of monofluorobenzene result from the reaction of a solu-
tion of benzene diazonium chloride with fluoroboric acid at 10°C (50 to 60%)
(Fieser and Fieser, 1960). Fluoroboric acid is made by dissolving solid
boric acid in 60% hydrofluoric acid. Barbour et al. (1966) gave the fol-
lowing yields for preparation of small quantities of monofluorobenzene:
49
-------
benzene diazonium fluoroborate 51%
benzene diazonium fluorosilicate 30%
benzene diazonium hexafluorophosphate 60-75%
Engineering details were not available for preparation of fluorobenzenes,
in fact many of these compounds are only prepared in small quantities on the
bench scale. The o_-, m- and £-difluorobenzenes are usually prepared through
Balz-Schiemann procedures (Barbour et al., 1966). The meta isomer is
prepared through diazotization of m-phenylenediamine. The diazonium salt
(usually the chloride) is treated with 45% fluoroboric acid at 0°C to form
bisdiazonium fluoroborate. Decomposition of the bisdiazonium salt gives a
73% yield of 1,3-difluorobenzene.
£-Difluorobenzene is similarly prepared from pj-phenylenediamine. Yields are
lower (60%), but may be improved by decomposing 1,4-bisdiazonium fluoroborate
in aqueous acetone with cuprous chloride. Separation of difluorobenzene from
the reaction mixture may be accomplished by steam distillation.
o-Difluorobenzene is prepared from o-nitroaniline by first substituting
one fluorine through the Balz-Schiemann reaction described above. The nitro
group is reduced and the second fluorine atom is introduced into the molecule
through a second Balz-Schiemann reaction.
Diazotization of 2,5-difluoroaniline (Balz-Schiemann) yields only 30% of
1,2,4-trifluorobenzene (Barbour et al., 1966). Yields of this isomer are
higher by boiling 2,3,5,6-tetrafluorophenylhydrazene with _3N caustic soda (up
to 61%).
The 1,3,5-trifluoro compound can also be prepared through a Balz-Schiemann
diazotization of 3,5-difluoroaniline. Yields of 60% have been reported.
50
-------
N-methyl pyrrolidone, tetramethylene sulfone (sulfolane) and dimethyl forma-
mide have all been successfully used as solvents.
Yields are higher and the product mixture less complicated using sul-
folane as the solvent. At temperatures below 200° and reaction times less
than 12 hours, the reaction is cleaner and yields are higher. However, the
degree of fluorination is less (Holbrook et al. , 1966). Although hexabrbmo-
benzene can be produced in a polar solvent, hexachlorobenzene can be hexa-
fluoro substituted using potassium fluoride without a solvent. The reaction
takes place under pressure at 400° to 500°C. Again, a mixture of chloro-
fluorobenzenes is formed (Barbour et al . , 1966), e.g.:
C.Cl-F
.-,. - — - - , - C, .-. ,-,-,
66 66 624 633
21%
Commercially, 1,2,3,4-tetrafluorobenzene is prepared by fluorinating benzene
with cobalt trifluoride. The polyfluorinated cydohexenes formed are de-
hydrofluorinated to mixed products including 1,2,3,4-tetrafluorobenzene.j The
1,2,3,5- and the 1,2,4,5-tetrafluorobenzene may be similarly prepared through
the fluorocyclohexene. The fluorination of hexachlorobenzene with potassium
fluoride (see above) gives varying yields of 1,2-dichlorotetrafluorobenzene
which is dechlorinated to form 1,2,3,5-tetrafluorobenzene. 1,2,4,5-tetra-
fluorobenzene is produced in 90% yield through heating pentafluorophenyl-
hydrazine with caustic soda (2N) (Barbour et al. , 1966) .
Pentafluorobenzene may also be prepared starting from benzene and fluor-
inating with cobalt trifluoride to produce isomers of octafluorocyclohexane
which are dehydrofluorinated with concentrated potassium hydroxide. Deflupr-
51
-------
ination of 1,3- and 1,4-heptafluorocyclohexadienes also produces pentafluoro-
benzene. The dienes are formed by dehydrofluorination of nonafluorocyclo-
hexanes (Harbour et al., 1966).
Hexafluorobenzene is also prepared commercially through the diene route
starting with benzene and cobalt trifluoride. the initial reaction takes
place at 150°C. Treatment with aqueous sodium or potassium hydroxide con-
verts the mixture of fluorocyclohexanes to polyfluorocyclohexenes and hexa-
dienesV Passage of these cyclic aliphatic fluorocarbons in the vapor phase
over a heated metal (iron or nickel gauze) results in defluorination (Coe et
al., I960). The reaction takes place in a nitrogen atmosphere. Hexa-
fluorobenzene (9%) can be separated from the coproducts, pentafluoro- and
tetrafluorobenzene, by fractional distillation.
Falk (1963) described the pyrolysis of dichlor of luor one thane as a route
to hexafluorobenzene, chloropentafluorobenzene, and dichlorotetrafluoro-
benzene. At 650° to 720°C, dichlorofluoromethane decomposes on passage
through a nickel tube to furnish 4 to 4.5% (by wt.) hexafluorobenzene. The
compound is separated from other products by fractional distillation and
purified by freeze-filtering the distillate. The filtrate is evacuated at
low temperatures to give hexafluorobenzene of 99% purity.
Chloropentafluorobenzene is separated from the product mixture by fract-
ional distillation (b.p. range 108° to 124°C). Freeze filtering produces a
compound of 65% purity. Dichlorotetrafluorobenzene distills as a higher
boiling fraction between 156° to 162°C. Both compounds are purified by
column chromatography. Yields of Chloropentafluorobenzene are less than 5%,
and yields of dichlorotetrafluorobenzene are below 2%.
Copyrolysis of dichlorofluoromethane (CHC1?F) and chlorofluoromethane
52
-------
(CH GIF)) at 650° to 730°C is reported to give 6 to 10% pentafluorobenzene,
5 to 8% hexafluorobenzene, 5 to 8% chloropentafluorobenzene, and 2 to 4%
dichlorotetrafluorobenzene (Falk, 1963).
4. Market Prices
The catalogue prices for fluorinated benzenes are as follows (see Tables
21 and 22): (a) All Alfred Bader Division chemicals listed retail for $10/5g
unless indicated by an asterisk*; all items marked * are available at $10/250
mg; (b) all PCR Chemicals have the following market prices (list correct as
of March 1, 1976) in dollars:
TABLE 22
MARKET PRICES OF FLUORINATED BENZENES($'s)
(PCR Industries, 1976a)
Ig 5g IQg 25g 50g IQOg 250g Ik
Monof 1 uor obenzene
o-Difluorobenzene
m-Dif luorobenzene
p-Dif luorobenzene
1 , 2 ,3-Tr if luorobenzene
1 , 2 ,4-Tr if luorobenzene
1,3, 5-Tr if luorobenzene
1,2,3 ,4-Tetrafluorobenzene
1 , 2 , 3 , 5-Tetr af luorobenzene
1 , 2 , 4 , 5-Tetraf luorobenzene
Pentaf luorobenzene
Hexa f 1 uor obenzene
lodopentaf luorobenzene
------ 15.25 53.50
- - - 28.50 100
- 39 136
18 - 63 -
________
9.90 40.00 - - - - -
16.10 57 - -
_________
-25 - - - ---
25 - - - -
- 12 40 - - -
30 - 90
12 - 36
53
-------
As is clear from the above table/ the fluorinated benzenes are expensive
chemicals sold only in small quantities.
(c) BRCMINATED BENZENES
1. Quantity Produced, Market Trends
It was not possible to document the quantities of bromobenzene produced
or processed in this country. USITC reports did not contain any reference to
imports of brominated benzene compounds/ except for a listing of p_-bromo-
fluorobenzene (222 pounds) imported in 1974 and imports of hexabromobenzene
in 1972 (7,165 pounds) and 1973 (9,909 pounds). Manufacturers considered
such data to be confidential and were unable to give estimates. While it
appears that brominated compounds could be used instead of the corresponding
chlorinated compounds where properties are equivalent, the higher costs of
the brominated compounds make this substitution unlikely. Also, there does
not appear to be any substitution likely on the grounds of improved
ecotoxicological properties (vide infra).
2. Producers, Processors and Production Sites
USITC (1974a) listed Dow Chemical, Midland, Michigan, as a manufacturer
of monobromobenzene, £-dibromobenzene, and £-bromochlorobenzene. Stanford Re-
search Institute (1976) also listed Dow Chemical for the three bromobenzenes
and additionally cited the Northrop Carolina Company as a producer of tri-
brcmobenzene (isomer not specified). Dow Chemical reported that it no longer
manufactures any brominated benzenes though retaining the capacity to do so
(Dow Chemical, 1977a). Three companies listed as manufacturers of hexabromo-
benzene have all ceased production in the last few years (see Table 23). They
indicated that the Cyanamid Company was the principal purchaser of hexabromo-
54
-------
benzene/ and that without its business, they were unable to manufacture the
compound profitably. Great Lakes Chemical Corp. (1976) stated that Cyanamid no
longer purchased hexabromobenzene, but had replaced the fire-retardant material
with decabromodiphenyloxide.
A number of brominated compounds as well as mixed halogens are available
through the Aldrich Chemical Company. It is not clear if Aldrich Chemical
produces or processes these chemicals. The following chemicals are available
through the Alfred Bader Chemical Division: l-bromo-*2,5-dichlorobenzene;
l-bromo-2,4-dichlorobenzene; l-iodo-2,4,6-tribromobenzene. Aldrich Chemicals
sells bromobenzene, o- and £-dibromobenzene, 1,3,5-tribromo-, hexabromobenzene
and the following mixed halogenated benzenes: 2-bromochloro- and 4-bromo-
chlorobenzene.
3. Production Methods and Processes
Heating molar equivalents of bromine and benzene in the presence of a
bromine carrier (usually iron filings) results in formation of monobromoben-
zene. Varying amounts of o- and £-dibromobenzene are coproduced with the
monocompound. Dibromination results in production of approximately 70%
Pj-dichlorobenzene and 30% o-dichlorobenzene. Further bromination results in
formation of 1,2,4-tribromobenzene and 1,2,4,5-tetrabromobenzene (cf. chloro-
benzene). Hydrogen bromide is formed as a by-product of each bromo-substitu-
tion reaction.
C.H,. + 3r- > CcHj-Br + HBr, 2 CcH,-Br0 + Br~—> 2 CcH/1Br0+ 2 HBr
bo / D j b _> ^ e. o4^
The products are separated by fractional distillation. Preparation of the
highly brominated benzenes can be readily accomplished by reaction of benzene
with dibromoisocyanuric acid in concentrated sulfuric acid, oleum or
55
-------
TABLE 23
U.S. MANUFACTURERS OF BRQMINATED BENZENES
Bromobenzene
I>-Dibromobenzene
2
Tr ibromobenzene
Hexabromobenzene
£-Bromochlorobenzene
1
O1
O
O
o
Michigan
Chem. Corp.
o1
I
8
A
Northrop
Carolina Co.
O
1
0) •
ij C
0!
8 Q
\/i JT
"in o
M O
-p •
A
Oi
Key
A USITC 1975a
O Stanford Research Institute, 1976
* Personal Communication
1 no longer produces this compound
2 isomer not specified
Note
The White Chemical Corporation,.Great Lakes Chemical Corporation
and the Michigan Chemical Corp. have all ceased production of
hexabromobenzene within the past few years. The chemical was
purchased largely by Cyanamid as a fire-retardant for monacrylic
carpet fibers (Great Lakes Chemical Corp., 1976). As hexabromo-
benzene sublimes, it is hardly the ideal fire-retardant, and has
been replaced by decabromodiphenyloxide.
56
-------
fluorosulfonic acid (Feast and Musgrave, 1971).
As in the preparation of chlorobenzenes, the use of a different catalyst
alters the yield of products. pj-Dibromobenzene can be manufactured from
benzene in yields as high as 85% with ferric bromide as the carrier (Fieser
and Fieser, 1967). Yields of 61 to 71% are reported for aluminum bromide as
catalyst (Fieser and Fieser, 1960). The temperature of reaction is usually
around 40°C. At elevated temperatures, meta substitution increases, so that
at 5UO°C, bromination of monobromobenzene results in 57% yield of m-dibromo-
benzene (Sykes, 1963).
Shell Chemicals reported that bromination between 75°C and 120°C in the
presence of an aluminum halide increases yield of m-dibromobenzene. The firm
indicated that for good yields of the meta compound, the catalyst should be
present in low amounts (2 to 6% of total) and gradually added to the reaction
mixture as the bromination proceeds. This technique results in yields of the
%
meta isomer exceeding 50% starting from either benzene or monobromobenzene,
and with either aluminum chloride or bromide as the carrier. It is difficult
to separate the m- and o-dibromobenzenes by fractional distillation because
of the closeness of their boiling points (220°C and 225°C, respectively).
Hexabromobenzene is manufactured by treating hexachlorobenzene with
excess bromine trifluoride. The mixture is heated with antimony penta-
fluoride, and the intermediates washed and refluxed in alcohol with zinc
dust. Engineering details were not available for this and the other
processes described above.
57
-------
4. Market Prices
Great Lakes Chemical Corp. (1975) provided the following market prices
for monobromobenzene (F.O.B. El Dorado, Arkansas):
Standard Truckload 39,000 Ibs (65 drums) $0.92/lb
24,000 - 38,400 Ibs (40-64 drums) 0.93/lb
2,400 - 23,400 Ibs ( 4-39 drums) 0.95/lb
600 - 1,800 Ibs ( 1- 3 drums) 0.99/lb
As can be seen above, monobromobenzene is appreciably more expensive than
monochlorobenzene (q.v.). Catalogue price of hexabromobenzene as quoted by
PCR Industries (1976a) is $5 for 5g.
(d) IODINATED BENZENES
1. Production and Market Trends
USITC reports from 1971 to 1974 contain no reference to imports of any of
the iodinated benzenes. Very little information was found relating to pro-
duction of iodobenzene, thus it is not possible to make any comment on future
markets.
2. Producers, Processors, and Production Sites
Eastman Kodak Organic Chemicals Division is a manufacturer of iodobenzene
(Eastman Kodak, 1976) and according to USITC (1974a) and Stanford Research
Institute (1974, 1975a, 1976) they have also produced m-ipdobenzene (see
Table 24). The company also manufactures small quantities of jg-iodobenzene-
sulfonyl chloride for laboratory use. No additional information was found
relating to major production of iodobenzene.
3. Prodution Methods and Processes
Iodobenzene cannot be prepared by direct iodination of benzene unless an
oxidizing agent such as concentrated nitric acid is present. Then the re-
58
-------
action yield is 86 to 87% with traces of nitrobenzene contaminating the
product (Fieser and Fieser, 1960). Alternatively, iodobenzene can be
prepared in yields in excess of 80% through diazotization of aniline followed
by reaction with potassium iodide (Feast and Musgrave, 1971). The compound
can also be synthesized by addition of iodine to benzene with peracetic acid
as the oxidizing agent (Fieser and Fieser, 1967).
o-Bromoiodobenzene is prepared from o-bromoaniline through the Sandmeyer
reaction as described previously. Note: Mixed halogenobenzenes are most
easily obtained through the diazonium compound prepared from the correspond-
ing halogen-substituted aniline. Also, halogen exchange is possible in polar
solvents such as sulfolane (q.v. fluorobenzenes) through reaction with the
sodium or potassium halide. Fluorine cannot be replaced by this method.
Polyiodobenzenes are formed when iodine reacts with benzene in the
presence of sulfuric acid. Control of temperature and concentration of acid
4h
varies the degree of iodination. Hexaiodobenzene has been prepared in 80%
yield using 60% oleum at 170° to 180°C (Feast and Musgrave, 1971).
TABLE 24
U.S. MANUFACTURE OF IQDINATED BENZENES
Mono iodobenzene
m-Di iodobenzene
p_-Di iodobenzene
I*
r-l
-------
B. USES
(a) CHLORINATED BENZENES
1. Major and Minor Uses
Monochlorobenzene
The bulk of monochlorobenzene manufactured in the mid 1960's was used to
produce phenol (60%), DDT (25%) and aniline (Hardie, 1964). The 1973 con-
sumption pattern is shown in Table 25.
TABLE 25
1973 CONSUMPTION OF MONOCHLOROBENZENE
(Lewis, 1975)
Chemical Consumption
Phenol 123 million pounds
o- and pj-Nitrochlorobenzene 140
Solvent uses 75
DDT 30
Other ^0
Total 398
The market for monochlorobenzene is in considerable flux, so it is possible
that the 1973 consumption pattern given is now out-of-date. The decrease in
DDT production from 1964 to 1973 is indicative of regulatory action limiting
usage of DDT in this country, and world poverty restricting purchases of DDT
for the World Health Organization malaria control program (Chemical Marketing.
Reporter, 1974a).
Hydrolysis of monochlorobenzene by dilute caustic soda at 300°C and 2000
to 3,000 psig pressure forms sodium phenylate which reacts with hydrochloric
acid to yield phenol (Fieser and Fieser, 1960). In a continuous modification
of this process, the reactants pass along a mile long tube for twenty minutes
60
-------
C6H5a "-Tii9 C&™a -"-HC1 -" C6H5OH
Diphenyl oxide is formed in a side reaction of the phenylate and the
phenol. As this reaction is reversible, accumulation of the oxide is mini-
mized by recycling the equilibrium mixture. Tarry wastes remaining after
distillation of the phenol contain 20 to 25% o- and £-hydroxydiphenyl.
The diphenyl ethers are formed through condensation of chlorobenzene with
phenol, and by condensation of two molecules of chlorobenzene to chlorodir
phenyls which hydrolyze to the hydroxydiphenyl compounds. In the U.S., this
reaction is now used only by Dow Chemical, the firm which initially developed
the process in 1928. Dow Chemical is phasing out manufacture of phenol from
chlorobenzene, preferring the more convenient route from cumene (Chemical
Marketing Reporter, 1975).
Phenol can also be prepared from chlorobenzene by the Raschig process.
As described previously, hydrogen chloride is catalytically oxidized at 230°C
to form chlorine which chlorinates the benzene. At 425°C and with a cata-
lyst, the chlorobenzene hydrolyzes to phenol (Fieser and Fieser, 1960).
DDT is prepared by condensation of chlorobenzene with chloral hydrate in
the presence of sulfuric acid (Fieser and Fieser, 1960).
Cl-< (~V/ + CHODH), + / (~) \—Cl > Cl ' (~*\ \ CH —
\ W / | 2 \\^> / _ ^v W / Y"
I " \v-x/ \^ / '
cci3 >—' \—/ ecu
DDT (dichlorodiphenyltrichloro-
etnane)
Other isomers of DDT are also formed, with the £,£* compound the most
biologically active. Production has dropped from nearly 180 million pounds
in 1963 to 59 million pounds in 1970 (Lewis, 1975). The DDT contains MCB as
an impurity (Lewis, 1975).
61
-------
High yields of o- and p-chloronitrobenzene are produced from MCB by E.I.
duPont de Nemours and Co., Inc. at Deepwater, New Jersey, and by Monsanto
Industrial Chemicals Co. at Sauget, Illinois, These chloronitrobenzenes are
converted to intermediates such as j>-nitroaniline and p-nitrophenol. The
phenol is mainly used to manufacture the pesticides, parathion and methyl
parathion (Lewis, 1975). Phenylenediamine, an important dye intermediate, is
produced from o-chloronitrobenzene by American Color and Chemical Corp..
(Lockhaven, Pennsylvania) and by E.I. duPont de Nemours and Co., Inc., at
Deepwater, New Jersey. The latter firm indicated a moderate growth in use of
chloronitrobenzene (Lewis, 1975).
Monochlorobenzene reacts with ammonia at 340°C and 340 atmospheres to
form aniline though MCB is rarely used as a precursor to aniline. Aniline
is an important intermediate in the dye industry and is more commonly manu-
factured by reduction of nitrobenzene.
As indicated in Figure 12, a quantity of chlorobenzene can be further
chlorinated to form 1,2,4,5-tetrachlorobenzene. The 1973 estimated produc-
tion of 1,2,4,5-tetrachlorobenzene was 18 million pounds (Lewis, 1975).
Allied Chemical Corporation (1973) cited usage of monochlorobenzene as a
solvent in the manufacture of adhesives, paints, polishes and waxes. The
firm also cited use of monochlorobenzene as an inert process solvent for the
manufacture of diisocyanates, Pharmaceuticals and natural rubber, and as a
dye carrier in textile dying. Chlorobenzene is a valuable solvent, partly
because of its non-corrosive nature and its ability to dissolve many com-
pounds. The Mobay Chemical Company (New Martinsville, West Virginia, and
Cedar Bayou, Texas) and the Upjohn Company (La Porte, Texas) are two
producers of isocyanates who use MCB as a solvent (Lewis, 1975).
62
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FIGURE 12
CONSUMPTION PATTERN FOR CHLORINATED BENZENES
OJ
^^-^chlor i ne
benzene ^~**~~-^^
\ _^J
i — chlorobenzene
I p-dichloro-
1 Benzene
— ITi
benzene
— o-dichloro-
Eenzene
H benzene
hexachloride
i 25%
s
in 2°*
m 1
LJz-J
s
^1
i J
_£.
1.2,4,5-tetra-
chlorobenzene
COT
phenol
3,4-dichloro-
1-nitrobenzene
hexachloro-
benzene
i]
h
P
i
d
i
f
12,4,5-tri-
1 chlorophenol
ciijorpf^enol
2,4-dl-
chlorophenol
3,4-dichloro-
aniline
i
i
d
r
J
i
,4,5-T
2,4-D
Diuron
tinuron
P
'I
p
P
Adapted from Munma and 1-awless, 1975
Key to Uses
a air freshener
d dye intermediate
f fungicide
h heat transfer liq.
i insecticide
m moth repellent
p pesticide
s solvent
-------
o-Dichlorobenzene
Lewis (1075) estimated the following distribution for o-dichlorobenzene:
61% to organic synthesis; 20% to toluene diisocyanate production; 12%
miscellaneous solvents; and 7% to other uses.
Brown et al. (1975) indicated that approximately 29% of annual production
of_o-dichlorobenzene is used as an inert process solvent for toluene diiso-
cyanate (TDI) production. This figure represents 50% of the quantity of ODCB
manufactured annually which goes to nonintermediate dispersive use. Lewis
(1975) stated that ODCB use is expected to grow at a 9% annual rate through
1977, with solvent use for TDI production representing the bulk of the growth.
In synthesis of TDI, phosgene is treated with toluene diamine in ODCB solu-
tion. MCB is also used as a solvent for TDI manufacture.
MANUFACTURERS OF TOLUENE DIISOCYANATE
(Lewis, 1975)
Company location 1973 Capacity
(millions of pounds)
Allied Chemical Corp. Moundsville, W.Va. 70
BASF Wyandotte Corp. Geisman, La. 40
E.I. duPont de Nemours Deepwater, N.J. 170
and Co., Inc.
Mobay Chemical Co. New Martinsville, W. Va. 200
Mobay Chemical Co. Cedar Bayou, Tex. 150
Olin Corp. Ashtabula, Oh. 40
Olin Corp. Lake Charles, La. 90
Rubicon Chemicals, Inc. Geisman, La. 110
Union Carbide Corp. Institute, W. Va. 55
Total 925
64
-------
ODCB is non-corrosive and stable, and so finds use as a solvent for soft
carbon deposits, and tars and wool oils in the textile industry (Dow Chemi-
cal, 1975b). Allied Chemical Corporation (1973) indicated that ODCB is used
to degrease leather and metals, and together with emulsified muriatic acid is
found as a grease solvent in formulated toilet bowl cleaners. Solvent uses
of ODCB account for some 20% of production (i.e. approximately 42% of dis-
persive use - Brown et al_., 1975). ODCB is also used to remove lead, gum and
resins from automobile and aircraft engine parts (Allied Chemical Corp.,
1973; Hardie, 1964). Lewis (1975) reported that because of environmental
concern, use of ODCB as an aircraft engine degreaser has slumped. Barsbl(§),
cresylic solvents and aqueous alkalis are being substituted for ODCB. Though
only small amounts of ODCB are used to clean automobile engines, the use is
fairly widely spread (Lewis, 1975).
According to Allied Chemical Corp. (1973), ODCB is used to strip neoprene
tank linings, and will form a rustproofing mixture with high boiling alco-
hols. The use of ODCB as an odorant is reportedly limited (Midwest Research
Institute, 1974) but appears to be increasing, as ODCB has been found in
industrial wastewater effluents throughout the country (Kopp, 1977).
ODCB is a very important intermediate for manufacture of the herbicides,
diuron and linuron. Dupont manufactures diuron, monuron and neburon at La
Porte, Texas. The ODCB is readily nitrated to 3,4-dichloro-l-nitrobenzene
which is reduced to 3,4-dichloroaniline. The 3,4-dichloroaniline is used to
manufacture the herbicides and also as a dye intermediate. Dow Chemical
(1975b) also cited usage of 3,4-dichloroaniline as an intermediate for poly-
ethers and as a cross-linkage agent in epoxy tar products.
Dowtherm (R) E is a heat transfer fluid (Lewis, 1975).
65
-------
While ODCB is registered for use as a pesticide against termites,
beetles, bacteria, slime and fungi, little is used for pesticide control at
present (Lewis, 1975).
p-Dichlorobenzene
Brown et al. (1975) indicated that of a total U.S. production and con-
sumption of 77.3 million pounds of p_-dichlorobenzene per year (year not spec-
ified), 69.6 million pounds went to nonintermediate dispersive use. This fig -
gure is about 90% of production. They cited 39.0 million pounds/year [36%]
used as a space odorant, and 30.6 million pounds/year [44%] used in moth
control.
The consumption of p-dichlorobenzene as a pesticide is greatest in the
Northeast and Northcentral regions, followed by the Southeast and South-
central (see Table 26).
TABLE 26
PESTICIDAL* USE BY CATEGORY AND GEOGRAPHICAL REGION
(Midwest Research Institute, 1974)
Region Agricult. Indust/Commercial Govt. Domestic Uses
N.E.
S.E.
N.C.
S.C. negl.
N.W.
S.W.
Total negl.
4t
2
4
2
0.5
1.5
14.0
0.7 t
0.3
0.4
0.3
0.1
0.2
2.0
lot
7
10
7
1.4
3.6
39.0
Total
14.7 t
9.3
14.4
9.3
2.0
5.3
55.0
*As defined by Midwest Research Institute, this includes use for moth control
and toilet-space deodorizing only.
tQuantities in million pounds.
66
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As the above table shows, domestic uses of PDCB are by far the most im-
portant. Use of p_-dichlorobenzene as a moth control agent for wool is de-
clining as more synthetic fabrics are produced. It acts as either a repel-
lent or a larvicide (Midwest Research Institute, 1974).
As a fungistat and insecticide, PDCB is effective in the control of
mildew, tobacco blue mold, bark beetles, moths and peach tree borers (Allied
Chemical Corp., 1973). £-Dichlorobenzene has also been used as a fumigant to
control lice, mites and cockroaches (Dow Chemical, 1975b).
The volatility, density and pleasant odor of p-dichlorobenzene explain
its use as a deodorant for toilets, garbage and diaper pails, etc. pj-Di-
chlorobenzene is used in molding grinding wheels, as the compound readily
volatilizes to leave voids in the molds (Allied Chemical Corp., 1973). PDCB
is also used as a disintegrating paste for molding concrete and stoneware
(Dow Chemical, 1975b).
Small amounts of £-dichlorobenzene are used to manufacture polyphenylene-
sulfide resins by reaction with sodium sulfide (Dow Chemical, 1975b). As an
intermediate, PDCB is diazotized to yield the dye intermediate 4-chloro-2-
nitroaniline (Dow Chemical, 1975b). Bardie (1964) mentioned minor use of
p-dichlorobenzene as an extreme pressure lubricant.
Trichlorobenzenes
1,2,4-Trichlorobenzene (1,2,4-TCB) is the most important of the tri-
chlorobenzene isomers. The consumption of this isomer is shown in Table 27
for 1973.
When used as a dye carrier, 1,2,4-TCB is mixed with a disperse dye and a
leveling agent, and then applied to mainly polyester materials for several
hours at 100°C. The excess carrier is removed by either: (a) alkaline scour
67
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TABLE 27
USES OF 1,2,4-TRICHLOROBENZENE, 1973
(Lewis, 1975)
Use Millions of Pounds
Dye carrier 13
Herbicide intermediate 8
Functional fluids 5
Miscellaneous __2
Total 28
at 70° to 80°C with a sulfated fatty alcohol; or (b) after rinsing the mater
ial, it may be heated to 190°C for one minute (Lewis, 1975)..
1,2,4-TCB reacts with cuprous cyanide to form 2,4-dichlorophenyl nitrile
which hydrolyses to the herbicide 2,5-dichlorobenzoic acid (Dow Chemical,
1975b). It is also used to make Banrel (§)(3,6-dichloro-o-anisic acid) and
Phosvel ® .
1,2,4-Trichlorobenzene is a flame-retardant, stable and non-corrosive
compound with "potential" as a dielectric fluid for transformers (Dow Chem-
ical, 1975b). 1,2,4-Trichlorobenzene has degreasing properties similar to
the lower chlorinated benzenes (Bardie, 1964).
This isomer has a comparatively high boiling point (210°C) and melts at
17°C. It is used as a solvent for the fractional crystallization of high
melting point compounds. 1,2,4-Trichlorobenzene has insecticidal activity
68
-------
against termites (Hardie, 1964), but according to Lewis (1975) little of the
isomer is used in termite control at present. Dow Chemical (1975b) reported
use of 1,2,4-trichlorobenzene as a heat transfer medium.
A mixture of the three isomers is used for solvent purposes (Hardie,
1964). This mixture contains predominantly 1,2,4-TCB (85%) and 1,2,3-TCB
(7.3%) with trace amounts of dichloro- and terachlorobenzenes. The mixture
is also used as a lubricant and as a dielectric fluid (Hardie, 1964).
The 1,2,3- and 1,3,5-trichlorobenzene isomers have minor importance as
intermediates in chemical syntheses.
Tetrachlorobenzenes
As shown in Figure 12, 1,2,4,5-tetrachlorobenzene is used to manufacture
2,4,5-trichlorophenoxyacetic acid (2,4,5-T). Lewis (1975) estimated that
1973 production of 2,4,5-trichlorophenol (TCP) consumed 6 million pounds of
1,2,4,5-tetrachlorobenzene, while an additional 10 million pounds went to
2,4,5-T production.
TCP can be used for the same purposes as pentachlorophenol — as a fungi-
cide, a disinfectant, a preservative for leather, wood and textiles (Dow
Chemical, 1975b; Lewis, 1975). It is an intermediate for the preparation of
both Silvex (§) and Ronnel (§). Silvex (g) is a herbicide and Ronnel (R) is
a systemic insecticide (Lewis, 1975). The sodium salt of 2,4,5-trichloro-
phenol reacts with monochloroacetic acid to yield 2,4,5-T, the herbicide.
Since the end of the Vietnamese War, the use of this and similar herbicides
has decreased.
Both 2,4,5-trichlorophenol and 2,4,6-trichlorophenol form methylene-
bridged dimers with germicidal properties. Hexachlorophene, the most well-
known of these dimers, is now restricted for usage in this country.
69
-------
Like 1,2,4-trichlorobenzene, 1,2,4,5-tetrachlorobenzene has been used as
a dielectric fluid. The isomer is also used to impregnate materials for
moisture resistance and as a temporary fire-retardant protection in packaging.
Pentachlorobenzene
Pentachlorobenzene has very limited use as an intermediate. Lewis (1975)
reported that the 01in Corporation purchases higher chlorinated benzenes to
nitrate to the fungicide, pentachloronitrobenzene.
2. Discontinued Uses
As discussed above, certain current uses of chlorinated benzenes as in-
termediates are being phased-out in favor of more convenient routes to the
desired end-product. The most obvious example is the gradual phasing-out of
phenol production from chlorobenzene.
As previously mentioned ODCB has been replaced as a degreasing agent for
aircraft engines, because of environmental concern relating to its use.
Several uses of chlorinated benzenes as chemical intermediates are in
decline not because of environmental concern surrounding the chlorinated
benzenes themselves, but because of the toxicity of the final product or its
impurities. Production of the defoliant 2,4,5-T from 1,2,4,5-tetrachloro-
benzene is in decline partly because of the a hazardous nature of the im-
purity, dioxan, but also because the Vietnamese war is now over.
1,2,4,5-Tetrachlorobenzene is the starting material for manufacture of
2,4,5-trichlorophenol which dimerizes to produce hexachlorophene. The use of
this once widely used germicide is now restricted because of its toxicity.
ftonsanto Chemical Intermediates Co. (1977) pointed out that because of
its physical characteristics, TCB has limited applications as a replacement
for PCBs in dielectric fluids. Hence, as replacements are found for askarel
70
-------
mixtures, use of chlorinated benzenes in dielectric fluids will decline.
3. Projected or Proposed Uses
As discussed previously, expansion of certain current uses is likely to
continue, while other uses are phased out. For example, use of ODCB as a
solvent for toluene diisocyanate production is expected to grow.
There are several potential uses of chlorinated benzenes which might de-
velop within the next few years. A number of halogenated benzenes have been
found to Q switch the carbon dioxide laser. Izatt j|t al. (1974) looked at a
range of compounds including monochlorobenzene, o-dichlorobenzene, nj-di-
chlorobenzene, bromobenzene, rn-difluoro-, penta- and hexafluorobenzene. Other
halogenated benzenes chosen because of their absorption spectra are expected
to Q switch similarly. The above listed compounds operated on a large number
of lines in both the 9.6 and 10.6 bands and are all liquids at room tempera-
ture. Mode locking occurred for all vapors tested except hexafluorobenzene
(Izatt et al., 1974).
Penta- and hexachlorobenzene have been mentioned as possible chloro-
aromatic precursors of aryl ether amines used to produce tractable polyamide-
imides and polyimides, and thermosetting polyimides (Kwiatkowski et al.,
1976). The chlorinated benzene (or polychlorinated biphenyl) undergoes nuc-
leophilic condensation with p-aminophenol. For example, p-aminophenol and
hexachlorobenzene react together in a ratio of 2:1 to form tetrachlorophenyl
bisether diamine (see below).
o.
-ONa +
H2N-\O
71
-------
Of all the diamines evaluated by Kwiatkowski, only the above compound is
considered suitable as a thermoplastic intermediate. The aryl amines are
stable to heat and oxygen, fire-retarding, soluble in common solvents and
have reduced amine activity compared to aniline.
As research and development is still continuing for both of the above
uses, it is not possible to state whether or not they are likely to develop
as either major or minor uses for these chemicals.
4. Alternatives to Use
(a) As Dielectric Fluids
Some chlorinated benzenes (especially trichlorobenzene isomers) are used
as dielectric fluids in capacitors and transformers in standardized mixtures
with polychlorinated biphenyls (PCBs). These mixtures are called askarels
and are of slightly different composition depending on whether they are used
in capacitors or transformers (Interdepartmental Task Force, 1972). The mix-
tures are non-flammable, chemically stable, have a low vapor pressure and a
high dielectric constant. The askarel mixtures for use in capacitors have a
dielectric constant similar to the capacitor paper, creating a homogeneous
electric field of durability and strength. Addition of TCB to the PCB
mixtures lowers the viscosity of the mixture. Replacements for askarels in
capacitors have received a great deal of attention specifically with regard
to their PCB content. (Though capacitors are sealed, they are discarded if
leaks occur.) Various replacements suggested (gas capacitors, silicones,
mineral oils, etc.) have numerous disadvantages.
Gas dielectric fluids have inferior electrical properties, fluorocarbons
may have toxic decomposition products, while silicones have too low a dielec-
tric constant. No substitute for askarels with equivalent properties meeting
72
-------
the stringent standards of the Underwriters Laboratory has yet been found for
either capacitor or transformer use. Oil transformer fluids are cheaper than
askarels but cannot be used indoors because of flammability. Dry transformers
may be used indoors but cost 1 1/2 times as much as askarels and are usually
bulkier.
There are several disadvantages to use of askarels: (a) hydrogen chloride
which is extremely corrosive is formed as a decomposition product; (b) prob-
able toxicity of the components (both PCBs and chlorobenzenes); (c) for
transformer use, askarels are expensive compared to oil ($1.80/gallon as
opposed to $0.25/gallon for oil).
(b) As Heat Transfer Fluids
Chlorinated benzenes are used as heat transfer fluids because of their
high heat capacity and conductivity. They are chemically and physically
stable, and have a low viscosity (for free flow through the system). There
are a number of other heat transfer fluids for possible use including: (a)
water (disadvantages: corrosion problem, temperature limit 374°C, need for
high pressure at temperatures above 100°C); (b) molten salts and metals
(advantages: resistant to radiation damage/ therefore useful for reactor
coolants; disadvantages: corrosion, chemical or radiochemical hazards; (c)
fluorocarbons (advantages: low toxicity, high thermal stability;
disadvantage: cost).
(c) As Solvents
The chlorinated benzenes are used as solvents in a wide variety of pro-
cesses. They are chemically stable, relatively inexpensive and will often
dissolve compounds which are insoluble in other common solvents. Replacement
of chlorinated benzenes when used as solvents must be considered on a process-
73
-------
by-process basis. It has not been possible to make this detailed evaluation
in the context of the scope of this report.
However, it should be mentioned in particular that ODCB is an extremely
versatile solvent which will be difficult to replace. Nevertheless, CDCB
has already been replaced to some extent as a degreasing agent by Barsol (§)
cresylic solvents and aqueous alkalis.
(b) FLUORINATED BENZENES
1. Major and Minor Uses, Potential Uses
The fluorinated benzenes have not been widely used as commercial chemi-
cals in the past. New routes to the highly fluorinated benzenes have devel-
oped over the last 10 to 15 years, resulting in higher yields of previously
synthesized f],uorobenzenes, and first time formation of some compounds. Fig-
ure 13 summarizes the uses and potential uses of some of the fluorobenzenes.
Literature references to this opening market appeared over ten years ago
(Falk, 1963). From contact with current manufacturers of fluorinated aromat-
ics, it does not appear that these uses have developed to the extent predic-
ted in the past. The reasons for this are not clear, but are probably re-
lated to the high cost of the fluorinated benzenes, low yields in production,
and/or manufacture of other chemicals with similarly desirable properties.
In any event, the following discussion of the usefulness of fluorinated
benzenes and their derivatives is based on literature speculation. The
potential market appears to be for the higher fluorinated compounds. While
1,2,4,5-tetrafluorobenzene, penta- and hexafluorobenzene show promise as vet-
erinary anesthetics, their flammability in oxygen has limited development for
this purpose. The hexafluorobenzene appears to be the most likely of these
three to be exploited as a veterinary anesthetic (see Section IIIB).
74
-------
FIGURE 13
USES AND POrawriAL USKS OF FIDOIUNATQ} BENZENES
benzene
1,2,4,5-tetra-
fluorobenzene i
1,4-torono-
tetrafluoro-
27375,6-
tatrafluoro-
Dhenvl cmods
1,2,3,5-tetra-
hexachlcaro-
bcnzene
r
fluorcbenzene
1,3-dichloro-
tetrafluoco-
benzene
1
i
2,3,4,6-
tetrafluoro-
chenvl onnda
_ linked per-
fluorophenyl-
polvmers
liexafluoro- a
benzene i
pentafluoro-
thiophenol i
polymers
benzene
penta f luoro-
benzene i
brcncpenta- i
fluorcbenzene
broiDtetra- f
fluorophenol
pentafluoro-
benzene sulf- i
cnyl chloride
pentafluoro-
benzene i
SEU 1 f onanticle
AC 1
AC 2
Key to Uses
a veterinary anesthesia
c coolant
f fungicide
i intermediate
P plasticizer
AC
1
2
anti-ccnvulsant
4-piperidino-2,3,5,6-tetrafluorobenzeneaulf^onamide
4-cyclohexylamino-2,3,5,6-tetrafluorobenzenesuifcnamide
-------
The tetra- and pentafluorophenyl compounds have a variety of uses. The
bromotetrafluorobenzene forms low p-1inked polymers when heated with activa-
ted copper powder (Barbour et al., 1966). Similarly, 1,3-dichlorotetra-
fluorobenzene forms stable m~Iinked polymers on heating with copper in di-
methyl formamide for 24 hours at 154°C. Both liquid and solid polymers of
great thermal stability are formed. The polymer ClCCgFJ.gCl may be heated
for 20 hours at 250°C with a weight loss of only 0.9% (Barbour et al., 1966).
The perfluoropolyphenyls are extremely stable to both heat and radiation and
have been suggested as heat-transfer fluids for nuclear power plants (Falk,
1963). The use of perfluoropolyphenyls as high-temperature fluids for mili-
tary purposes has also been mentioned (Falk, 1963). Compounds of general
formula: CCF-(CCF.) C..F,. or C-F^-X-C-FJ- X-C..F,.
b b o 4 b b b b b 4 n b b
[where X = CF2/ CF2CF2, CF^CF, OO, 0)
may also find use as plastics, lubricants, hydraulic and gyroscope fluids.
Where n is greater than 4, boiling points are in excess of 1,000°F. The
fluidity is greatest for the m-1inked polymers.
Fluorinated phenols which contain other substituted halogens in addition
to fluorine are fungicidal and could be incorporated into anti-fungal oint-
ments (Barbour et al., 1966). Sulfonamides derived from pentafluorothio-
phenol have anti-convulsant activity. The 4-piperidino-2,3,5,6-tetrafluoro-
benzenesulfonamide is prepared by the reaction of pentafluorobenzenesulfon-
amide (I) with piper id ine. Reaction of cyclohexylamine with (I) produces
4-cyclohexylamino-2,3,5,6-tetraf luorobenzenesulfonamide.
Hexafluorobenzene has been used as a solvent in scintillation counters
and has potential as a solvent for proton nuclear magnetic resonance spec-
troscopy. Hexafluorobenzene is a very stable solvent.
76 .
-------
Monofluorobenzene is also a solvent and an intermediate used in the
preparation of insecticides and larvicides, as well as a reagent for plastic
or resin polymers (Hawley, 1971).
BROMINATED BENZENES
1. Major and Minor Uses, Chemistry Involved in Use
Monobromobenzene is used as a solvent for oils, motor fuels and top-
cylinder compounds (Great Lakes Chemical Corp., 1975; Hawley, 1971). Mono-
bromobenzene is also used as a crystallizing solvent, and as an important
intermediate for organic syntheses. Unlike chlorobenzene, monobromobenzene
forms a Grignard reagent without difficulty and in good yields (Fieser and
Fieser, 1960). Monoiodobenzene also forms a Grignard. Itie ability of the
bromo- and iodobenzenes to form Grignards is of value in organic syntheses,
as aromatic compounds generally cannot be prepared by means of a Claisen con-
densation (ethyl acetoacetate) or through reaction with ethyl malonate (Mann
and Saunders, 1961). Grignard formation takes place through reaction of the
aryl halide with dry magnesium granules in dry ether or in tetrahydrofuran
(Fieser and Fieser, 1960). Addition of iodine may help start formation of
the Grignard, which continues spontaneously as the solvent boils.
Although iodobenzene also easily forms the Grignard reagent, diphenyl is
formed in a side reaction in appreciable quantities. Hence, bromobenzene is
the preferred aryl halide (Mann and Saunders, 1961). Phenyl magnesium
2 Phi + Mg > Ph-Ph + Mgl_
77
-------
bromide is seldom isolated, but reacts with additional reagents in situ to
form the desired compounds.
Example
(1) Addition to a carbonyl group
(a) Phenyl magnesium bromide reacts with cyclohexanone to form the tert-
iary carbinol which is oxidized with chromic anyhydride and anhydrous acetic
acid to form C-phenyl-n-caproic acid, an extremely useful agent for organic
syntheses (Fieser and Fieser, 1960).
PhMgBr
cyclchexanone - HOAc HOOC
£"- phenyl-n-caproic
acid
(b) Phenyl magnesium bromide also reacts with ethyl benzoate to form the
stable acidic triphenylcarbinol. The intermediate ketone is unstable, and
immediately reacts with a second mole of the Grignard to form the carbinol.
H~0
C6H5OOOC2H5 + 2C6H5MgBr - > (C6H5) 3CCMgBr — ±_> (CgH5) 3OOH
91%
ethyl benzoate phenyl magnesium triphenylcarbinol
bromide
Triphenylcarbinol reacts with formic acid to form triphenylmethane.
(2) Preparation of S-containing aromatics
Phenyl magnesium bromide reacts with sulfur dioxide to yield phenyl sul-
fenic acid (PhSO H) on hydrolysis. The phenyl sulfuryl chloride reduces
with zinc dust and an acid (hydrochloric or sulfuric) to thiophenol.
(3) Addition across -C=C-
Phenyl magnesium bromide will add 1,4- across the conjugated diene system
78
-------
of napthacene quinone, to form a compound which goes through three additional
reactions to form the polynuclear hydrocarbon, rubrene (Fieser and Fieser,
1960).
The o- and JD- bromochlorobenzenes will also form mono-Grignard reagents,
and are therefore important organic intermediates.
Like chlorobenzene, bromobenzene forms aryl-lithium compounds as well as
reacting with sodium in the Wurtz-Fittig reaction. The Grignard reagent
prepared from a bromobenzene is usually preferred to the aryl-lithium
compound (though both will attack a polyfunctional carbonyl group) because
the Grignard generally produces higher yields of final product.
While brominated benzenes have been used as organic intermediates as de-
-scribed above, the current extent of their use is not clear.
o-Dibromobenzene is used as a solvent similar to monobromobenzene, and
also finds application in ore flotation techniques (Hawley, 1971). p-Di-
bromobenzene is useful for synthesis of dyestuffs and drugs (Hawley, 1971).
Formerly, hexabromobenzene was used as a fire-retardant material for mona-
crylic fibres; however, it has been largely replaced by retardants which do
not sublime.
.(d) IODINATED BENZENES
1. Major and Minor Uses, Potential Uses, Chemistry of Use
The principal use of iodobenzene is to prepare the positive iodine com-
pounds, the iodsyl, iodyl and iodonium salts (Hart ^t al^., 1966). Chlorine
reacts with iodobenzene in cold chloroform solution to form the moderately
stable iodobenzene dichloride (C^H_IC1_) (87 to 94% yield — Fieser and
652
Fieser, 1960). The dichloride reacts with caustic soda after grinding with
79
-------
sodium carbonate and ice to form iodosobenzene:
r H TTI NaOH
C6H5IC12 -- 61F52S - > C6H5Z
iodosobenzene
Iodosobenzene has been suggested as a reagent for oxidation of sulf ides
to sulfanes (Fieser and Fieser, 1967) but whether it is manufactured for this
purpose is unclear .
On heating or on exposure to light, iodobenzene dichloride decomposes to
p-chloro iodobenzene. Iodobenzene dichloride is apparently used to convert
cholesterol to the 5,6-dichloride (used in the further synthesis of steroids)
(Fieser and Fieser, 1967).
Reaction of iodobenzene with 30% peroxyacetic acid produces iodosobenzene
diacetate ( [PhlOCOCH ] CH-COO" ) used as a coupling agent in the prepar-
ation of diaryliodonium salts.
The iodyl (formerly iodoxy-RIO ) compounds can be prepared from the
iodosyl compounds by steam distillation (Feast and Musgrave, 1971).
2PhIO - > Phi + PhI02
These compounds are of theoretical interest, but are not of industrial
importance. Diphenyliodonium compounds have been prepared by reaction of
iodosobenzene with phenyl magnesium bromide. Diphenyl iodonium hydroxide
( [Ph I] OH ) is a strong base and forms stable salts on neutralization.
Though of academic interest, iodonium salts are of no commercial importance
(Hart et al. , 1966).
p-Di iodobenzene is a photosensitizer and has been shown to increase the
speed of cross-linking of photosensitive polyacetylenes (Hawley, 1974). It
is not known if p-di iodobenzene is commercially used for this purpose.
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C. ENVIKDNMENTAL CONTAMINATION POTENTIAL
1. General Discussion
At present, the only halogenated benzenes of great concern as environ-
mental contaminants are the chlorinated benzenes. This is because:
(a) only the chlorinated benzenes are currently manufactured in large
quantities;
(b) the use of chlorinated benzenes is widespread in this country and
throughout the industrial nations;
(c) the uses of the chloro compounds are varied, and result in exposure
at home and in the garden, as well as in the working environment;
(d) chlorinated benzenes have been detected in wastewaters, drink-
ing waters, rivers and lakes as well as in the soil;
(e) at least two chlorinated benzenes have already been detected in
human fatty tissues and blood. They are p-dichlorobenzene and
hexachlorobenzene.
Therefore, this section will deal with chlorinated benzenes only, unless
there is specific data relating to other halogenated benzenes. It should be
pointed out that a number of brominated benzenes including monobromobenzene,
bromochlorobenzene, and dibromobenzene have been identified in drinking water
in the U.S. (EPA, 1975b)
2. Production
There are a number of reports of contamination in the industrial environ-
ment resulting in worker exposure to several of the chlorinated benzenes.
Table 50 documents the effects of human exposure to mono-, o- and p-dichloro-
benzene. Contact with the vapors of chlorinated benzenes may occur during
their manufacture, or when used as chemical intermediates.
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A recent EPA report (EPA, 1976a) gives the following breakdown for loss
of chemicals to the environment during batch production of monochlbrobenzene
(see Table 28). These figures are based on a plant similar to that dia-
grammed in Figure 10. The composition of the sludge is not indicated.
TABLE 28
ESTIMATED LOSS OF MATERIALS DURING BATCH MANUFACTURE OF CHLOROBENZENE
(EPA, 1976a)
Chemical
Source
Quantity Produced
Destination
(kg/kg MCB)
Hydrogen chloride
Monochlorobenzene
Hot scrubber vent
Dichlorobenzene
0.0014.
0.00088
Air
Water stream
column
Dichlorobenzenes "
(isomers not
specified)
Monochlorobenzene Fractionating towers
Dichlorobenzenes
Polychlor inated
sludge*
Distillation residues
0.0037
0.004
0.0001
0.044
Land
disposal
* Designated as hazardous
Pagnotto and Walkley (1965) studied industrial exposure to o- and p_-di-
chlorobenzene (PDCB) during manufacture using the urinary metabolite, £-di-
chlorophenol as a measure of exposure to PDCB. During washing of PDCB cry-
stals, Pagnotto and Walkley measured air concentrations averaging 34.0 ppm
(range: 7 to 48 ppm). During shoveling and centrifuging, the average air
concentration was 33 ppm (10 to 49 ppm) while urinary concentration averaged
103 mg/1 (range: 54 to 233 mg/1).
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During packaging, pulverizing of the crystals resulted in an average 70
mg/1 (53 to 87 mg/1) in urine, and 25 ppm in air (18 to 34 ppm). At-no time
during PDCB manufacture, household product packaging or abrasive manufacture
did urinary levels fall below 10 mg/1. Air concentrations were never less
than 8 ppm.
Brown et^ al. (1975) reported a 0.9 million pounds/annum loss of o-di-
chlorobenzene during manufacture. Use of ODCB as a solvent for TDI produc-
tion may be a major source of disappearance at the workplace (Lewis, 1975).
Losses occur through venting and scrubber washings. During manufacture, loss
of £-dichlorobenzene per year was estimated at 1.2 million pounds by Brown et
al.
Additional quantified data on loss of chlorinated benzenes to the envir-
onment during production are not available. As all of the lower chlorinated
benzenes are highly volatile, contamination of the working environment is
very probable due to leaks in piping and inadequate venting.
3. Transport and Storage
Monochlorobenzene is classified by the U.S. Department of Transportation
(DOT) as a flammable liquid (DOT, 1976). Ortho- and para-dichlorobenzene are
classified as combustible liquids. Hence, special precautions must be ob-
served during transport and storage of chlorinated benzenes. Dow Chemical
has issued a transportation equipment data sheet for monochlorobenzene (MCB),
o_-dichlorobenzene, and 1,2,4-trichlorobenzene. Details of the company's
transportation control technology are found in section II D below.
Monochlorobenzene is shipped in uninsulated carbon steel tank trucks or
cars (Dow Chemical, 1975c) which must be clean, dry and free of odor or
scale. Allied Chemical Corporation (1973) ships MCB by tank trucks, tank
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cars or in steel drums (500 pounds). Montrose Chemical Corp. (1972) either
ships in bulk or in returnable drums. All firms ship MOB full strength.
Prior to 1974, Dow Chemical transported p_-dichlorobenzene as a solid or a
liquid. The solid was carried either in railroad cars or in drums (200
pounds). Now, all PDCB is shipped by Dow Chemical as a liquid in heated in-
sulated cars (at 99.5% purity). A 96% product is also transported is the
same manner. The Allied Chemical Corporation (1973) ships PDCB as a liquid by
tank truck or car, as a solid in fiber drums (200, 300 pounds) or in cartons
(1250 pounds). £-Dichlorobenzene is shipped by the Monsanto Company in non-
returnable combustible fiber-pack drums (200 pounds), or in tank trucks
equipped with heating coils (Midwest Research Institute, 1974).
o-Dichlorobenzene is also transported full-strength in carbon steel tank
trucks or tank cars, with no insulation or heating required. Alternatively,
it may be packaged in returnable steel drums. The Manufacturing Chemists
Association (1974) has issued a Chemical Safety Data Sheet for ODCB. The
Manufacturing Chemists Association and Dow Chemical stress the importance of
grounding equipment (piping, pumps, storage tanks, etc.) when handling or
storing because of the danger of explosion. It is also necessary to ground
equipment when handling monochlorobenzene, which is even more likely to
explode than ODCB or mixtures of the two dichlorobenzene isomers (Montrose
Chemical Corp., 1972).
The importance of adequate venting when handling or storing all of the
chlorinated benzenes is emphasized by the manufacturers. Montrose Chemical
Corp- recommends that mono-, o-, and pj-dichlorobenzene be stored outside in
grounded steel tanks within a diked enclosure. The enclosure should either
be covered to avoid contamination of rainwater, or provision made to treat
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rainwater run-off to remove dissolved organics. Many local authorities re-
quire that the lower chlorinated benzenes be stored with an automatic sprink-
ler system.
1,2,4-Trichlorobenzene is loaded at 90° to 100°F (32° to 38°C) into
stainless steel or carbon steel tank trucks or tank cars. Insulation and
heating coils are required. Dow Chemical consumes all the 1,2,4,5-tetra-
chlorobenzene which it manufactures internally, and therefore does not pub-
lish shipping regulations for this chemical (Dow Chemical, 1977a). Mono-
bromobenzene is shipped by Great Lakes Chemical Corp. in non-returnable lined
steel drums (55 gallons).
It would appear that environmental contamination is more likely during
loading and unloading of transportation and storage tanks rather than actual
transport. However, there is always the possibility of faulty or damaged
equipment, and because of high volatility, losses of chlorinated benzenes may
occur during both transportation and storage. Elaborate safety precautions
are described by all manufacturers. No quantified data are available, how-
ever, to document the extent of any loss during transportation and storage.
4. Usage
MCB and ODCB are lost to the environment through inadequate venting,
scrubbers and leaking equipment, when used as solvents for TDI production
(Lewis, 1975). Figures for this loss are not available. Hydrogen chloride
and the, polymeric low grade sludge remaining after manufacturing TDI appar-
ently contain less than a few hundred ppm of ODCB (Lewis, 1975).
There are several reports of monochlorobenzene contamination of the work-
ing environment from Russian and Romanian sources. Rozenbaum et a^. (1947)
reported worker exposure to monochlorobenzene used as a solvent in the manu-
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facture of perchlorovinyl lacquer in a plant in the Soviet Union. The equip-
ment used was described as "outfitted by chance and which exhibited a number
of substantial defects, involving a large number of manual operations per-
formed with open equipment." Concentrations of 0.034 to 1.44 mg/1 were re-
corded during production. The high of 1.44 mg/1 was detected near the
chlorinator at the end of unloading of the concentrate. Concentrations of MCB
varied from 0.06 to 0.6 mg/1 in the workshop where the perchlorinated con-
centrate was mixed with solvents and dyes.
Gabor and Paucher (1960) found an average concentration of 0.02 mg/1 of
monochlorobenzene in the atmosphere of a DDT manufacturing plant. The high-
est value detected was 0.3 mg/1. The plant investigated was new and "met
present-day requirements" (Romania). Levina et al_. (1966), noted that mono-
chlorobenzene was present in the atmosphere of a monuron production plant in
concentrations of 1 to 10 mg/m (258 analyses).
ODCB used as a heat transfer fluid could presumably leak into the envi-
ronment from faulty or damaged equipment. No description of this possibility
was found in the literature.
There is apparently wide spread use of ODCB as an odor-controller for
industrial wastewater treatment plants. Consequently, ODCB is entering water
systems throughout the country, and is being detected in average con-
centrations of 2 ppm (Kopp, 1977).
As previously mentioned, 69.6 million pounds of PDCB are used annually
for moth control or as a space odor ant (Brown et al., 1975). Presumably each
year, a similar quantity of p_-dichlorobenzene sublimes into the atmosphere.
Because the compound readily sublimes, it is thought unlikely to enter foods
via the environment. However, as Lewis has indicated, there remains the pos-
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sibil ity of absorption of the highly lipophilic PDCB by fatty foods, espe-
cially if they are prepared near stores of p-dichlorobenzene.
a and nhi (,1P7^) established that there is a relatively high concen-
tration of p-dichlorobenzene in the atmosphere of the Tokyo Metropolitan Area
(2.1 to 4.2 pg/m ). They reported indoor concentrations from use as a moth
repellent or space odorizer of 1700 pg/m (inside wardrobe); 315 pg/m
(closet); and 105 pg/m (bedroom). They believe that inhalation of PDCB is
probably a major path of entry into the human body. Human blood samples
collected contained three times as much p-dichlorobenzene as PCBs (Morita
and Ohi, 1975). However, £-dichlorobenzene and polychlor inated biphenyls
were present in human adipose tissue in approximately equal concentrations.
Table 29 summarizes their data.
TABLE 29
CONCENTRATION OF P-DICHLOROBENZENE IN HUMAN ADIPOSE TISSUE AND BLOOD
No. of Sex
Samples
17 M,F
1 M
1 F
6 - M,F
1 F
1 M
(Morita and Ohi,
Age Sample
(years)
25-80 Adipose tissue
43
71
21-35 Blood
22
24
1975)
Concentration (pg/g)
0.2 - 11.7
11.7
0.2
2.3 (Average value)
4-16 mg/ml
16
4
9.5 (Average value)
Reprinted with permission from Environ. Poll., 8:272, 1975. Copyright
1975 by Applied Science Publishers, Barking, Essex, England.
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In the past, jpj-dichlorobenzene was used in comparatively large quantities
to control the peach tree borer. The chemical was spread around the base of
the tree and could have been absorbed into the tissues of the fruit or sub-
limed into the environment (Hooker Chemicals and Plastics Corp., 1977).
The use of p-dichlorobenzene in toilet blocks must result in additional
environmental contamination as PDCB is flushed into sewer systems throughout
the country. Some p-dichlorobenzene enters the atmosphere through this usage,
but considering the placing of the toilet blocks and the density of the
p-dichlorobenzene vapor, most enters the wastewater stream. The appearance
of chlorinated benzenes (including PDCB) in wastewater from sewage treatment
plants indicates that complete biodegradation does not always take place. It
is believed that trichlorobenzenes enter the environment with PCBs, when used
in askarels as dielectric fluids (Veith, 1976).
5. Disposal Methods used
The quantities and nature of waste products generated during monochloro-
benzene manufacture were previously given in Table 28. In 1972, EPA esti-
mated that 6.97 thousand short tons of solid waste were generated through
production of monochlorobenzene. The estimated cost of incinerating this
waste with hydrogen chloride scrubbing was given as $ 104,000. Hooker
Chemicals and Plastics Corp. (1977) feels that this estimate is about 30% too
low based on their own experience. Because of an anticipated decrease in
monochlorobenzene production, the 1982 solid waste projection was 6.58
thousand short tons (Saxton and Narkus-Kramer, 1975).
At Dow Chemical, the polychlorinated sludge or "tetra tar" is reduced in
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quantity through a proprietary process to reclaim dichlorobenzenes (Midwest
Research Institute, 1974). Hydrochloric acid is recycled to chlorine pro-
duction. In the event of a spill of MCB, Dow Chemical recommends recovery if
possible, otherwise disposal in a secure landfill (Dow Chemical, 1977b).
In the past, the Monsanto Company disposed of the polychlorinated sludge
in a secure landfill on their own property. Wells surrounding the fill were
periodically tested (Midwest Research Institute, 1974). The firm currently
incinerates its chlorobenzene wastes. Hydrogen chloride is recovered, though
small amounts escape through venting or in wash-waters.
The Montrose Chemical Corp. of California (1972) has indicated the desir-
ability of resource recovery from mono- and dichlorobenzene wastes rather
than disposal, because of the value of the product and potential pollution
through waste disposal. Company officials have recommended that monochloro-
benzene be covered with water and contained in dikes or sumps until recover-
ed. Leaking or non-returnable drums should be decontaminated by steam
cleaning before disposal.
Both the Manufacturing Chemists Association (1974) and Dow Chemical
(1974) have recommended the incineration of ODCB wastes, and have emphasized
that this must be accomplished according to local emission standards. An
off-gas scrubber should be used to prevent discharge of hydrogen chloride to.
the atmosphere. oHDichlorobenzene burns to form carbon oxides, hydrogen
chloride, chlorine and water. No data were found describing the extent to
which controlled incineration of ODCB was practiced.
The Manufacturing Chemists Association (1974) stated that ODCB should not
be allowed to enter standard sewage treatment plants or chemical landfills,
except under special supervision. However, chemical/physical plants using
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carbon adsorption can handle ODCB satisfactorily according to Hooker
Chemicals and Plastics Corp. (1977). ODCB should never be deliberately
discharged into the aquatic environment.
As previously mentioned, ODCB is being added to industrial wastewater
treatment plants as a deodorizer and is now found in aquatic systems through-
out this country (see Section P). It would appear that recommended methods
of waste control technology are not being followed by some users of the
product.
The appearance of lower chlorinated benzenes in textile waste effluents
has received attention for some years. Murray State College, Kentucky, is
conducting an on-going study to identify chemicals present in textile wastes.
They have reported the presence of chlorobenzene, jj>-di-, and 1,2,4-tri-
chlorobenzene in textile finishing plant effluents (Erisman and Gordon,
1975). The compounds have not yet been quantified.
The American Dye Manufacturers Institute under contract from EPA is in-
vestigating methods for treatment of textile wastes (Lewis, 1975). No ad-
ditional information was obtained.
The Southeast Water Laboratory, EPA, has identified 1,2,4-trichloro-
benzene in effluents from sewage plants handling textile wastes. A level of
0.46 mg/1 of 1,2,3-trichlorobenzene was detected in effluents from the Long
Creek, Gastonia, sewage plant. They have also detected lower chlorinated
benzenes in streams near textile mills in Wallace, N.C., Dalton and Augusta,
Georgia. As Lewis has pointed out, these effluents may eventually drain to
coastal areas in which commercial shell fishing is important. Shellfish are
soon contaminated by chlorobenzenes, thus any such drainage should be
critically controlled.
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Dow Chemical recommends land disposal for ]D-di-, 1,2,4-tri- and 1,2,4,5-
tetrachlorobenzene. More specifically, ^-dichlorobenzene should be contained
in an "approved landfill"; 1,2,4-TCB buried "away from water supplies"; and
1,2,4,5-tetrachlorobenzene buried in a "non-crop area."
In 1972, damage approximating $380,000 worth was accrued as a result of
hexachlorobenzene (HCB) contamination of cattle in Louisiana. This cost did
not include losses due to delayed marketing of about 30,000 head of cattle.
Air, soil and vegetation over a 100 sg. mile area were contaminated by HCB.
Cows grazing in the contaminated area accumulated HCB to values as high as
1.52 ppm. The USDA action guideline for HCB in beef fat is 0.3 ppra. Levels
of hexachlorobenzene up to 5,000 ppm were found in the soil. The source of
this contamination was primarily volatilization of HCB from a local landfill
(EPA, 1976c).
This report suggests that other chlorinated benzenes could volatize from
landfills, resulting in additional environmental contamination. Such a pos-
sibility deserves further study. In the past, it was common to bury drums of
contaminated or decomposed chlorinated benzenes. A considerable quantity was
disposed of in this fashion and could enter ground water or the atmosphere as
a result (Hooker Chemicals and Plastics Corp., 1977).
It would appear that controlled incineration of chlorinated benzenes is
the most environmentally acceptable waste-management technology if resource
recovery is not possible. Incineration, however, must follow state and
Federal emissions guidelines.
6. Potential Inadvertent Production in Other Industrial Processes
As is made clear in Sections I and IIA, halogenated benzenes of varying
degrees of substitution are found contaminating each other as inadvertent
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by-products (see Table 10). Therefore, whenever a specific chlorinated ben-
zene is utilized, lower or higher chlorinated benzenes are present in varying
proportions, depending on the quality of product. Any environmental contam-
ination resulting from this use will lead to a variety of chlorinated ben-
zenes entering the environment.
For example, pentachlorobenzene is a contaminant of hexachlorobenzene in
proportions as high as 9.6% (Courtney et al., 1976). HCB now appears to be
widely distributed throughout the abiotic environment, in water, in soil and
probably in the atmosphere. Hexachlorobenzene has been detected in wild life
(DeVos et al., 1975), in edible animal tissue and in food and feed grains
(EPA, 1973; Booth and McDowell, 1975). It has also been detected in human
blood (Siyali, 1972) and human body fat (Brady and Siyali, 1972). Recently,
there have been European reports of pentachlorobenzene contamination
coexisting with hexachlorobenzene pollution (Stijve, 1971; Greve, 1973).
This may be either because pentachlorobenzene (QCB) is a contaminant of HCB,
or because it is formed by the decomposition of hexachlorobenzene perhaps
through photolysis. The former possibility has received the most attention.
Pentachlorobenzene is also a contaminant of pentachloronitrobenzene
(PCNB) which is used as a soil fungicide. Olin Chemicals indicates that
there is less than 0.2% QCB in their pentachloronitrobenzene. Pentachloro-
benzene has been detected with pentachloronitrobenzene (and other impurities
and metabolites) in soil and in potatoes and carrots grown in soil treated
with pentachloronitrobenzene (Greve, 1973; Beck and Hansen, 1974).
It would appear that the use of pentachloronitrobenzene results in
additional environmental contamination from the higher chlorinated benzenes
either: (a) through presence as a contaminant in the technical PCNB, or
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(b) through degradation (whether biological, chemical or photolytic).
7. Potential Inadvertent Production in the Environment
Chlorinated benzenes have been identified as degradation products of
lindane metabolism by various species. In a study to determine the inter-
action between lindane and soil microorganisms, Tu (1975) separated and
identified a number of degradation products including pentachlorobenzene.
However, in field experiments with a number of crops treated with lindane, no
chlorobenzenes were detected (Tu, 1975).
14
Rohli et al. (1976b) investigated the conversion of [ C]lindane (hexa-
chlorocyclohexane) by lettuces grown in a hydroponic culture. Uiey reported
the following chlorinated benzenes among the metabolic products of lindane:
1,2,3-tr ichlorobenzene, 1,2,4-tr ichlorobenzene, 1,2,3,4-tetrachlorobenzene,
pentachlorobenzene and hexachlorobenzene.
All of the above chlorobenzenes were present in the nutrient medium but
only the trichloro- and pentachlorobenzene were detected in the lettuce
plants. Hexachlorocyclohexene, found in both plants and medium, was thought
to be an intermediate in the formation of the chlorinated benzenes. Further
degradation of chlorobenzenes resulted in formation of phenols and/or their
conjugates (also present in both plants and medium).
Reed and Forgash (1969, 1970) studied the metabolism of lindane in sus-
ceptible, moderately resistant and highly resistant houseflies. Metabolites
were identified by mass spectrometry and gas liquid chromatography. After
topical application or injection of lindane (4pg/fly), greater amounts of
1,2,4- and 1,2,3-trichlorobenzene, 1,2,3,4- and 1,2,4,5-tetrachlorobenzene,
pentachlorobenzene and iso-pentachlorocyclohexene (iso-PCCH) were formed by
the highly resistant flies than the other two groups. The resistant flies
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also produced more 1,2,4-tri- and 1,2,4,5-tetrachlorobenzene on topical
application or injection of Y-PCCH (4ug/fly) and more pentachlorobenzenes
from iso-PCCH. Reed and Porgash also demonstrated that 1,2,4-trichloro-
benzene, 1,2,4,5- and 1,2,3,4-tetrachlorobenzene did not appear to be metabo-
lized further by injecting flies with each of these compounds and analyzing
for metabolites.
Six chlorobenzenes have also been "tentatively" detected as products of
lindane metabolism in the rabbit (Karapally et al., 1971). They are £-di-
chlorobenzene, 1,2,4-trichlorobenzene, tetra- and pentachlorobenzene.
Considering the world-wide use of lindane as a pesticide and with our
present knowledge of lindane metabolism in various species, some chloroben-
zenes must be entering the environment as lindane degradation products. The
quantities are probably very small if past research is any guide (Kohli et
al., 1976b). There is not enough data available to estimate quantities.
The photodecomposition of pentachloronitrobenzene may result in inad-
vertent production of chlorinated benzenes in the environment. In labora-
o
tory studies, irradiation of pentachloronitrobenzene at 2537 A resulted in
formation of the three tetrachlorobenzene isomers and pentachlorobenzene
(Crosby and Hamadmad, 1971).
Tetrachlorobenzene was identified as a constitutent (1.2%) of the essen-
tial oils of Mississippi salt marsh grass (Juncus roemerianus) by Miles et
al. (1973). It was speculated that chlorination of naturally occuring ben-
zene compounds within the plant resulted in formation of tetrachlorobenzene.
It might thus be anticipated that other salt-water plant species could con-
tain tetrachlorobenzene or other chlorinated benzenes.
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D. CURRENT HANDLING PRACTICES AND CONTROL TECHNOLOGY
1. Special Handling
Ventilation must be sufficient to control mono- and dichlorobenzenes to
below their threshold limit values. When handling 1,2,4-TCB and 1,2,4,5-
tetrachlorobenzene, Dow Chemical stated that "good room ventilation" is
adequate for "most operations" (Dow Chemical, 1977b). Fume systems must be
designed to control the accumulation of dense femes at floor level.
If monochlorobenzene is to be handled at 75 ppn to 2% for one hour or
less, a full face mask with organic vapor canister must be worn. For greater
exposures, a self-contained breathing apparatus or its equivalent is used
(Dow Chemical, 1977b). Handling ODCB at 50 ppm to 2% for 30 minutes or less
requires a full face mask and canister. At greater concentrations or for
longer periods of time, a contained breathing apparatus should be worn. No
respiratory protection is normally necessary when handling p_-dichlorobenzene
below 75 ppm. At greater concentrations, a full face mask fitted with an
organic vapor canister is used. No respiratory protection is considered
necessary when using 1,2,4-TCB as long as ventilation is adequate. If
respiratory protection is required when handling 1,2,4,5-tetrachlorobenzene,
an approved dust respirator is used (Dow Chemical, 1977b).
Clean and protective body clothing should be worn when handling chloro-
benzenes. If contact with ODCB is likely, impervious gloves must be worn.
Safety glasses with sideshields should always be used; for 1,2,4,5-tetra-
chlorobenzene, washing facilities near the work area must be provided.
2. Storage and Transport
Monochlorobenzene is classified by the Department of Transportation (DOT)
as a flammable liquid. Because of the flammability of MCB, special care
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must be taken to prevent ignition. All equipment used in handling during stor-
age and transport should be grounded. Special care must be taken to prevent
contact with aluminum and its alloys, rubber and plastics (Dow 1975c, 1977b).
Centrifugal or positive displacement pumps of stainless or carbon steel
are used to move the liquid. Hoses may be made of seamless stainless steel,
Teflon, seamless bronze, seamless steel, or neoprene. Approved gaskets are
made from asbestos, Teflon, Viton or neoprene. At a minimum, chemical gog-
gles and rubber gloves should be worn (Dow Chemical, 1975c).
Both o- and £-dichlorobenzene are classified by DOT as combustible liq-
uids. (Note: While PDCB is a solid at room temperature, it is often trans-
ported as a liquid as described previously.) Like MCB, both dichlorobenzenes
and 1,2,4-trichlorobenzene (TCB) will react with aluminum and its alloys.
o-Dichlorobenzene will also react with magnesium alloys, rubber and plastics.
Therefore, essentially the same materials (as listed above) may be used to
construct pumps and gaskets, and similar safety should be precautions taken.
All equipment involved in the loading or unloading of ODCB should be elect-
rically grounded (Dow Chemical, 1973).
Monochlorobenzene and o-dichlorobenzene are loaded at ambient tempera-
ture, while 1,2,4-TCB is loaded at 90° to 100° F (32° to 38° C) (Dow, 1975b).
Liquid pj-dichlorobenzene is also loaded at elevated temperatures. During
cold weather, TCB may freeze, causing special problems in handling.
3. Emergency Procedures
(a) Spill or Leak .
An explosion may occur on spillage of even small quantities of mono-, o-
and £-dichlorobenzene. In case of a spill or leak, the area is immediately
evacuated and roped off, as efforts are made to contain the spill while
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working upwind (Dow Chemical, 1974, 1975a). For a small spill, every effort
is made to prevent entry of the chemicals into wastewater outlets. The
compounds are covered with a non-combustible material such as sand, and swept
or scooped into waste bins. In the case of a larger spill or leak, the
material is initially diked and the harmful vapors are contained with water
fog/spray (Dow Chemical 1975a). Full protective clothing including gloves
and breathing apparatus are worn while decontaminating. Local authorities
must be contacted with regard to disposal of spilled chlorobenzenes.
1,2,4-Trichlorobenzene will crystallize, if spilled at temperatures below
its freezing point (16.7°C). Then, it may be shovelled into waste contain-
ers. Above 16.7°C, a TCB spill is handled in the same fashion as the lower
chlorinated benzenes: the liquid is contained to prevent entry into waste-
water, covered with sand, and vapors contained with water fog/spray (Dow
Chemical, 1975a). Again, the authorities must be contacted. Vhile decon-
taminating a spill in an enclosed area, respiratory protection and a life-
line and safety harness should be worn. An attendant should be present.
(b) Fire
Before attempting to put out a fire caused by leaking chlorinated ben-
zenes, the leak must first be shut off. Chlorinated benzenes may decompose
to form products of greater flammability or toxicity (e.g. carbon monoxide,
hydrogen chloride, chlorine). Snail fires are extinguished using dry chem-
icals or carbon dioxide. In the event of large fires, water spray or foam is
preferred. An advanced fire must be fought from a protected position using
monitor nozzles and hose streams to cool containers exposed to the fire in
order to prevent bursting. The water runoff must be diked to prevent entry
into sewers, drains and water courses.
97
-------
Bromobenzene has a relatively low flashpoint and is handled similarly to
the chlorinated benzenes.
(c) First Aid
In the event of eye contact with halogenated benzenes, the eye is flushe d
thoroughly with low pressure water for at least fifteen minutes (Dow Chemi-
cal, 1974, 1975a). A physician should be called if the exposure is severe.
Skin contact is treated by thoroughly flushing with water followed by
washing with soap and water (Manufacturing Chemists Association, 1974; Dow
Chemical, 1974, 1975a). Contaminated clothing and shoes are immediately re-
moved. Clothing must be well washed before being worn again. All contamin-
ated leather goods should be destroyed.
After excess inhalation of chlorinated benzene vapors, the exposed person
should initially be removed from the contaminated area. If unconscious,
suitable artificial respiration should be immediately commenced. The con-
scious patient is administered oxygen by a person authorized to do so by a
physician. While waiting for the physician, the patient should be kept quiet
and comfortably warm (Dow Chemical, 1974, 1975a).
In case of accidental ingest ion of chlorinated benzenes, vomiting is
induced using a common emetic such as soapy water.
E. ANALYTICAL METHODS
1. Standard Methods Used
An analytical procedure adequate for determination of a given halogenated
benzene in supervised laboratory studies may not be effective for samples of
an unknown history. Procedures for determination in foods or living organ-
isms such as insects or marine life may be quite different from determination
of levels in substrates such as air, water or the soil.
98
-------
It has been difficult to develop a generally accepted procedure for de-
termination of halogenated benzenes in any substrate. This is because of
interference from natural and synthetic chemicals sampled with the halogen-
ated benzenes, metabolite interference, the presence of other pesticides and
variation in apparatus and chemical reagents. Additionally, the residue pro-
blem surrounding the halogenated benzenes has been somewhat neglected. In
designing a prodedure for determining halogenated benzenes, the reason for
the analysis, the nature of the sample, and the type and extent of interfer-
ence likely to be met, must all be considered. Also desirable would be a
positive identification of the compound.
Confirmation of identity may be accomplished by gas chromatography/mass
spectrometry techniques. However, the electron impact induced fragmentation
limits the use of the mass spectrometer for structural studies, though it
does give information on the number of halogen atoms. In characterizing com-
ponents, other combinations of techniques have also been employed including:
gas liquid chromatography (GDC) retention times on different columns; infra-
red spectra; and nuclear magnetic resonance spectroscopy. Thin layer and
paper chromatography are also used.
Chlorinated Benzenes
Hexachlorobenzene was the first of the halogenated benzenes to cause
concern as an environmental contaminant. Hence, many procedures for detect-
ion of this compound are well documented. The following methods were first
used to detect HCB in cereals, animal fat and dairy products, and are also
now applied to other halogenated benzenes.
(a) Preparation of Samples
There are a number of ways to prepare samples of halogenated benzenes for
99
-------
analysis. Pour such methods are described below.
(i) Direct Steam Distillation (Stijve, 1971)
Between 10 to 20 grains of a finely ground sample are weighed and placed
in a one liter round bottom flask. Distilled water (750 ml) plus pure ben-
zene (3 ml) are added, and the flask connected to a Dean and Stark apparatus.
On condensation, the distillate flows into the receiver, and the benzene
fraction separates from water as a 3 cm upper layer. A system of communic-
ating vessels returns the water to the boil flask at the same rate at which
the distillate condenses. In a determination of wheat or cereals, the dis-
tillation requires four hours. Animal fats (3 to 5 g) take six hours.
or (ii) Extraction with Pentane or Hexane (Stijve, 1971)
A soxhlet apparatus is used for a four hour extraction of 10 to 25 g
samples. The extract obtained is analyzed by GLC or thin layer chromato-
graphy.
or (iii) Melting and Filtration (Smyth, 1972)
Finely chopped meat fat or grated cheese (30g) is heated at 100°C to
melt. Samples of the liquid fat or cheese (Ig) are then analyzed. Butter
(30g) is also melted at 100° C, and the clear fat is filtered through glass
wool. A Ig sample is analyzed. Whole mixed egg (2g) is first extracted with
hexane and anhydrous sodium sulfate. The hexane layer is filtered through
glass wool and the extraction is repeated. The two filtrates are combined
for analysis.
or (iv) Partitioning with acetonitrile/pertoleum ether (Yurawecz et al., 1976)
Another effective method of preparing whole eggs, milk, fish and spinach
was summarized by Yurawecz et al. (1976). Either acetonitrile extracts of
nonfatty foods, or the combined acetonitrile extracts obtained in acetc—
100
-------
nitrile-petroleum ether partitioning of isolated fats, are diluted with
water. The material is then extracted with petroleum ether.
(b) Purification Techniques
Deactivated florisil (4") is added to anhydrous sodium sulfate in a
chromatography tube. The column is prewetted with hexane. The sample is
mixed with deactivated florisil and poured into the column. Fractions are
eluted with dichloromethane: hexane (20:80) and concentrated in a Kuderna-
Danish evaporator to 1 ml (Snyth, 1972).
An alternative florisil purification procedure was described by YUrawecz
et ad. (1976). The column is prewetted with 40 to 50 ml of petroleum ether
and the concentrated sample extract (maximum volume, 10 ml) is transferred
onto the column, rinsing with 5 ml petroleum ether. Fractions up to 100 ml
are eluted with petroleum ether. In order to avoid loss of volatile halogen-
ated benzenes, the eluate is concentrated to 5 to 10 ml in Kuderna-Danish
concentrators equipped with Snyder distilling columns. The volume is adjust-
ed by addition of petroleum ether so that a 3 to 8 jul aliquot is equivalent
to 20 mg for a nonfatty sample, or 3 mg for a fatty sample. For volatile
compounds like the chlorinated benzenes, the solvent should never be evapo-
rated under a jet of air or nitrogen, or loss of material will occur.
(c) Gas Chromatography
The separation of hexachlorobenzene from hexachlorocyclohexane isomers
was achieved by gas chromatography on a mixed liquid phase loading of 1.5%
OV-17 and 1.95% QF-1 columns (Stijve, 1971). OV-17 is a phenyl substituted
polysiloxane column. The "Burke column", a mixture of DC-200 silicone and
QF-1 fluorinated silicone, is also used to separate chlorinated pesticides.
Identity was confirmed by reverse phase thin layer chromatography on liquid
101
-------
paraffin impregnated alumina columns. Acetonitrile-roethanol-water-acetone
(4:3:2:1) was used as the mobile phase. Hexachlorobenzene was separated not
only from other chlorinated pesticides, but from several chlorobenzenes as
well (see Tables 30 and 31).
Of the cereals, oils, and animal fat samples analyzed by this technique
by Stijve, 28% contained hexachlorobenzene in concentrations from 0.01 to 0.1
ppm. HCB was found in greatest amounts in chicken fat, which also contained
pentachlorobenzene.
Smyth (1972) found HCB residues in dairy products, meat fat and eggs
using gas chromatographic columns similar to thse used by Stijve. The limit
of detectability in these procedures is about 0.002 ppm.
The Food and Drug Administration (FDA) has modified the procedures of
Yurawecz et al. (1976) to identify early eluting industrial chemicals includ-
ing halogenated benzenes found in fish tissue (Yurawecz, 1976).
The separation of a number of chlorinated and brominated benzenes and
derivatives can be achieved under the following GLC parameters:
(a) Column - glass, 6' x 4 mm i.d., packed with 10% DC-200 or 10%
OV-101, or 6% OV-101 on 80-100 mest Chromosorb W(HP).
(b) Temperature (°C) - column, 130°C; injector, 150°C; detector, 200°C.
(c) Carrier gas - nitrogen, flow rate adjusted to elute QCB in 8-10
min. (ca. 120 ml/min).
(d) Detector - titanium source, concentric type, operated in electron
capture mode, DC voltage set to give 1/2 full scale
deflection (FSD) for 0.5 ng hexachlorobutadiene.
—9
(e) Electrometer - 3 x 10 ampere for full scale deflection with
sensitivity 5 millivolt recorder.
102
-------
TABLE 30
RELATIVE RETENTION TIMES OF HEXACHLOROBENZENE (HCB) AND HEXACHUOROCYCLOHEXANE
(HCH) ISOMERS ON A 1.5% OV-17 + 1.95% QF-1 COLUMN AT A TEMPERATURE Of 200° C
AND A N CARRIER GAS FLOW OF 60 ML/MINUTE '
2 (Stijve, 1971)
Aldrin
HCB
a -HCH
Y -HCH
B -HCH
S -HCH
e -HCH
1.00
0.47
0.53
0.67
0.67
0.80
0.98
(reference compound)
Various stereoisomers of hexachlorocyclohexane (HCH)
TABLE 31
R,-VALUES OF CHLORINATED INSECTICIDES AND CHLOROBENZENES IN THE SYSTEM:
r Al O-, + 5% PARAFFIN/CH-CN-CH,OH-ACETONE (4:3:2:1 V/V)
* * J(Stijve, 1971)
DDE
Heptachlor
DDT
Heptachlorepoxide
TDE*
Dieldrin
Lindane
a -HCH
g -HCH
0.27
0.37
0.42
0.55
0.62
0.68
0.72
0.76
0.84
HCB
Pentachlorobenzene
1 , 2 , 3 / 4-Tetrachlorobenzene
1 , 2 , 4 , 5-Tetrachlorobenzene
1,3, 5-Tr ichlorobenzene
1,2, 4-Tr ichlorobenzene
1,2, 3-Tr ichlorobenzene
0.16
0.23
0.41
0.34
0.38
0.50
0.57
2,2-Bis (£-chlorophenyl)-1,1-dichloroethane
Tables 30 and 31 reprinted with permission of the author and the publishers
of Mitt. Gebiete Lebensm. Hyg.
103
-------
Operation of the pin-cup electron capture detector as described above
gives a linear response range for the early eluting chloro- and bromoben-
zenes, usually not above 10 to 90% FSD at the given electrometer sensitivity and
higher voltage. To ensure validity of data, the quantity of residue injected
must be within the linear range for that compound within the system. Quanti-
ties of sample and relative retention times are found in Table 32.
Karasek and Vassilakopulos (1971) described a rapid method for gas
chrcmatographic separation and quantitative analyses of mixtures of benzene,
chlorobenzene and the three bromochlorobenzene isomers. They used a 10 ft.
stainless steel column packed with 8 wt. % Bentone-34 modified with 10 wt. %
DC-200 silicone oil on 80 to 100 mesh Chromosorb W. Their method is described
as taking only 14 minutes, and giving component resolutions greater than five.
Methylene chloride was used as a solvent. The Carle 8000 gas chromatograph was
operated isothermally in the 30° to 200°C range, so that the helium carrier flow
rate and the column temperature were optimum for quick separation and quantit-
ative analysis. Column temperature was 60°C, detector and inlet temperatures
were 170°C. The size of the sample was 0.5 microliter; helium flow rate was 30
ml/min, and detector output was 1 mV. Figure 14 shows the chromatogram obtained
under these conditions. Table 33 gives the retention and weight factor data for
the compounds chromatographed.
Morita and Chi (1975) identified three chlorinated benzenes in human fatty
tissue by mass fragmentography and mass spectroscopy. p-Dichlorobenzene,
1,2,4,5-tetrachlorobenzene and hexachlorobenzene were all detected in levels
above 0.010 /jg/g fat (see Figure 16).
104
-------
. TABLE 32
RELATIVE RETENTION TIMES OF HALOGENATED AROMATICS
WITH 10% DC-200 ON 80-100 MESH CHROMOSORB W (HP)
(Yurawecz, 1976)
FDA
Standard
No.
1295
244
101
190
1293
196
195
1301
194
-
-
-
-
-
-
1273
1272
1204
1271
-
-
-
1300
-
1250
-
1203
-
-
255
80
280
1305
77
Compound
Monobromobenzene
1 , 3-Dichlorobenzene*
1 , 4-Dichlorobenzene*
1 , 2-Dichlorobenzene*
l-Brono-4-chlorobenzene
1,3, 5-Tr ichlorobenzene*
1,2, 4-Tr ichlorobenzene*
1 , 4-Dibromobenzene
1,2, 3-Trichlorobenzene*
3 , 5-Dichloroanisole
2 , 5-Dichloroanisole
2 , 4-Dichloroanisole
3 , 4-Dichloroanisole
2 , 3-Dichloroanisole
2 , 4 , 6 -/Tr ichloroanisole
1,2,4, 5-Tetrachlorobenzene*
1,2,3, 5-Tetrachlorobenzene*
Dibromophenpl
1,2,3, 4-Tetrachlorobenzene*
2,4, 5-Tr ichloroanisole
2 , 3 , 5-Tr ichloroanisole
3,4, 5-Tr ichloroanisole
Tr ibromobenzene
2 , 3 , 4-Tr ichloroanisole
Pentachlorobenzene*
2 , 3 , 5 , 6-Te t r achloroani sole
2,4, 6-Tr ibromophenol
2,3,4, 5-Tet rachloroanisole
2 , 3 , 4 , 6-Tetrachloroanisole
BHC (Beta)*
Hexachlorobenzene*
Pentachloroani so le*
1,2,4, 5-Tet rabromobenzene
BHC (gamma)*
Amount Needed
for 1/2 PSD
(ng)
300
60
110
65
8
15
25
3.6
9
100
100
100
100
100
100
7
7
3.5
7
10
10
10
6.5
10
1.5
5.5
25
5.5
5.5
10
4
4
5
5
Retention time
relative to penta-
chlorobenzene
0.05
0.08
0.08
0.09
0.14
0.15
0.18
0.20
0.22
0.25
0.29
0.31
0.31
0.35
0.39
0.40
0.40
0.44
0.50
0.68
0.70
0.72
0.74,0.20,2.54t
0.90
1.0
1.00
1.89
1.89
1.04
2.28
2.40
2.54
2.55
2.76
Indicates compound is recovered in the 6% florisil eluate when it is ana-
lyzed by the Assocciation of Official Analytical Chemists (AOAC) method
for organochlorine pesticides in non-fatty foods.
Major peak is listed first in multicomponent mixture.
105
-------
FIGURE 14 CHROMftTOGRAM OBTAINED FROM 8 WT % BENTONE-34/10 WT % DC-200
SILICONS OIL COUMJ AT 160°C AND 30 ML/MIN He.
CM
i,
CO
I
Reprinted with permission
from Karasek, F.W. and P.
Vassilakcpulos. Analysis
of Bronochlorobenzenes by
Gas Chramatography. Chrom-
atographia. 4(9):389, 1971.
Copyright © 1971, Perganon
Press Ltd.
e ' io '
12
FIGURE 15 OOJ«>UTER PLOT OF PARENT MASS NUMBERS OF CHLORINATED BENZENES
(Arrows indicate the retention times of actual samples,
GLC conditions described in text} (Kforita et al.,1975)
H««o
Pcntg
Tetra
Reprinted with permission fron Applied Science Publishers Ltd.,
Barking, Essex, England
106
-------
FIGURE 16
ANALYSIS OF HUMAN FAT BY GAS CHRMRTOGFAPHY/TyjASS SPECTBOMETKY
(Sample was purified by steam distillation and H2S04 treatment)
(Jtorita and Ohi, 1975)
Moss frogmentgrom
Psflk 1
146
Moss spectrum of peok 1
75
r
100
ISO
Reprinted with permission from Applied Science Publishers Ltd., Barking,
Ehgland
107
-------
TABLE 33
RETENTION AND WEIGHT FACTOR DATA FOR COMPOUNDS CHROMATOGRAPHED ON 8 WT. %
BENTCNE-34/10 WT. % DC-200 SILICONS OIL COLUMN AT 160°C AND 30 ML/MIN,
CARRIER FLOW
(Karasek and vassilakopulos, 1971)
Confound Boiling
Point °C
Air
Benzene 80.1
Monochloro- 132.0
benzene
l-Br-4-ClBz 196.0
l-Br-3-ClBz 196.0
1-BT-2-C1BZ 204.0
Weight
Factors
1.00
1.06
1.46
1.44
1.62
Retention
Time (Sec)
28.6
57.2
131.4
254.5
419.0
793.7
Capacity
Ratio*
1.0
3.6
7.9
13.7
26.7
Reso-
lutiont
7.78
7.15
5.48
703
Retention
Index
837
1077
1227
1326
1451
*k. = (t. - ta)/ta
t R = [2(t.. - tjH/Cw.. + wt)
Reprinted with permission from Chromatographia, 4(9) :389f 1971. ©1971,
Pergamon Press Ltd.
Materials for analysis were prepared by a combination of steam distilla-
tion and treatment with sulfuric acid. This step was emitted for analysis of
penta- and hexachlorobenzene as it did not give good recovery. Column pack-
ings were Bentone 34(5%) + DC-200 (5%) on Chromosorb W, AW-DCMS (60 to 80
mesh) and Dexsil 300 G(3%) on Chromosorb W, AW-DCMS (60 to 80 mesh). The de-
tector was BCD (Ni ). The carrier gas was nitrogen flowing at 60 ml/minute.
The temperature of the detector was 200°C, as was the injection temperature.
For analysis of lower chlorinated benzenes, the column temperature was lower.
A computer plotting of results is shown in Figure 15.
108
-------
Morita and Chi (1975) also detected p-dichlorobenzene in blood using sim-
ilar procedures. Blood samples were prepared as for the fatty tissues (i.e.
steam distillation, hexane extraction, sulfuric acid) except that before in-
jection the n-hexane layer was condensed with a Kunderna-Danish evaporator.
The National Institute of Occupational Safety and Health (NIOSH) has
published analytical methods for detection of chlorobenzene and o-dichlorc—
benzene in air (Stanford Research Institute, 1975b, 1975c). A known volume
of air is drawn through a charcoal trap and the adsorbed organic vapors are
eluted with carbon disulfide. An aliquot of the desorbed sample is injected
into a gas chromatograph equipped with a flame ionization detector.
For chlorobenzene detection, the column (10 ft. x 1/8 in. stainless
steel) is packed with 10% FFAP on 80 to 100 mesh, acid washed DMCS Chromosorb
W. Nitrogen gas flow is typically 50 ml/minute (60 psig) and hydrogen gas
flow to the detector is 65 ml/minute (50 psig). Air flow to the detector is
500 ml/minute (50 psig). Injector temperature is 190°C, manifold temperature
is 250°C and volume temperature is 105°C.
This method was validated over the range of 183 to 736 mg/mm at 25°C and
761 mm Hg for a 10 liter sample. It is probably useful for detection of
35 to 1035 mg/m , though it may be capable of measuring smaller amounts if
the desorption efficiency is adequate. At high humidity, or when several
other compounds are also present, especially those with the same or close
retention time, there is interference with the determination. The Coeffic-
ient of variation (CV) for the complete sampling and analytical method in the
range of 183 to 736 mg/m , was 0.056. This corresponds to a standard
deviation of 19 mg/m .
109
-------
For o-dichlorobenzene analysis, the sample is injected onto a column
packed with 10% OV-101 on 100 to 120 mesh Supelcoport. Nitrogen flow is
typically 30 ml/minute (60 psig) and hydrogen gas flow is 35 ml/minute (25
psig). Injector temperature is 225°C, teitperature of manifold is 250°C and
of the column 140°C.
This method was validated over the range 150 to 629 mg/mm. The precision
of the determination (CV.) = 0.067. This corresponds to a standard devia-
tion of 20 mg/m3.
Fluorinated Benzenes
Seiler and Sams (1972) studied the separation of selected polyfluorinated
benzenes by gas liquid chromatography. p-Difluorobenzene, 1,2,4- and 1,3,5-
trifluoro-, 1,2,4,5- and 1,2,3,5-tetrafluoro-, pentafluoro- and hexafluoro-
benzene were separated using a 15% Carbowax 20M Chromosorb W column. Other
columns tried were not effective in separating monofluorobenzene, though some
were effective in separating other halogenated benzenes. The retention be-
havior on Carbowax columns is shown in Figure 17, and certain physical prop-
erties are found in Table 34.
MacBeath et al. (1969) examined the photochemistry of the vapor phase of
o
monofluorobenzene between 2350 and 2710 A. The sensitized emission of bi-
acetyl was used to detect both the singlet and the triplet state yields for
o
exciting wave lengths of 2470, 2550, 2590 and 2670 A. The effect of cyclo-
hexane on yield was also studied. Addition of cyclohexane to monofluoro-
benzene increased the fluorescent yield for an excitation wavelength of 2470
o
A, but did not alter the yield for the other wavelengths examined. The
results were:
110
-------
CompoundExcitationSum of the $ Singlet and $ Triplet
A State Yields
o
Monofluoro- 2470 A 0.67
benzene 2550 0.75
2590 0.93
2670 0.82
Durban (1969) examined j>- and £-d ifluorobenzene by similar spectrofluoro-
metic techniques. He obtained the following values:
Compound Excitation X Sum of the * Singlet and $ Triplet State
Yields
o-oifluorobenzene
p-Difluorobenzene
o
2500 A
2580
2660
2770
2660
2740
2760
0.34
0.52
0.75
0.97
0.50
0.50
0.70
TABLE 34
PHYSICAL PROPERTIES Of SELECTED POLYFLUORDBENZENES
(Seiler and Sams, 1972)
Material Boiling Point Electric Dipole moments (Debye) by
(°C/760 Torr) the Law of Cosines of Ferguson
Benzene
1 ,4-Difluorobenzene
1,2 , 4-Tr ifluorobenzene
1,3, 5-Tr ifluorobenzene
1,2,4 ,5-Tetrafluorobenzene
1,2,3, 5-Te tr af luorobenzene
Pentafluorobenzene
Hexafluorobenzene
80.6
88.5
88.5
75.5
88
83
80.5
80.5
0
0
1.5
0
0
2.55
1.5
0
Some data extrapolated from Branch, G.E.K. and M. Calvin. The Theory of
Organic Chemistry, p. 135, as cited by Ferguson, L.N., The Modern Structural
Theory of Organic Chemistry. Prentice-Hall, Englewood Cliffs, N.J., 1964, p.
204.
Ill
-------
FIGURE 17 CHROMATOGRAM OF AN AUTHENTIC MIXTURE OF FLUOROBENZENES ON A
10 Ft 15% CARBOWAX 20M ON 60-80 MESH CHROMDSORB W AT 70^, He 33CM3/MTN.
[Seller and Seats, 1972)
10
s
M
_-
15
Reprinted with permission from
the Elsevier Scientific Publish-
ing Company, Amsterdam, The
Netherlands.
Time (min.)
FIGURE 18
COMPOSITE POSITIVE PLASMAGRAMS OF MONOHALOGENATED BENZENES
(Karasek and Tatone, 1972)
lOeeHMIINt
>IOMOMMIINI
cmoietiHiiMi
nuoioiiNiixt
Drift time
(ntLllisecs.)
10
Reprinted with permiss-
ion from Karasek, F.W.
and O.S.Tatone. Plasma
Chrcnatcgraphy of the
Monohalogenated Benzenes.
Anal. Chem.,44(ll):1762,
1972. Ccpyri^it by the
American Chemical Society.
112
-------
The difluorobenzenes were shown to undergo photoisomerization, and an
oxygen effect was also present.
Brominated Benzenes
Kolbasina and Lulova (1976) developed a method for the separation of
bromobenzenes using gas chromatography. The 3 cm long columns were run at
180°C filled with Bentone-245 on Spherochrorae 1 (0.3 to 0.4 irni particle size)
with a helium flow rate of 33 ml/minute. o-Dibromobenzene had a longer re-
tention time than the para isoraer.
Nakada et: al. (1970) used the following columns: silicone-SE-30 (4 mm x
2 m) isothermal at 120° and 160°; and Bentone-34 (4 mm x 2m) isothermal at
100° and 160°C. Each temperature increase was programmed. The chromatc—
graphic patterns of bromine and chlorine derivatives were similar. Ofce fol-
lowing chlorinated and brominated benzenes were measured: monohalogenated
benzenes; 1,4-, 1,3-, and 1,2-dihalobenzenes; 1,3,5-, 1,2,4-, 1,2,3-trihalo-
benzenes; 1,2,4,5-tetrahalo-; 1,2,3,5- and 1,2,3,4-tetrabromobenzene; penta-
bromobenzene; and hexahalobenzenes.
Separation of Monohalogens
Karasek and Tatone (1972) studied detection of the monohalobenzenes by a
technique called plasma chromatography. Ihis technique gives data for analy-
sis of fundamental ion-molecule reactions. Also, it provides mechanisms for
the gas chromatographic electron capture detector and stable ion species ob-
served in mass spectra. Experimental conditions are shown in Table 35.
Figure 18 shows separation of the monohalogens.
Using thermal electrons and positive reactant ions from nitrogen gas,
both positive and negative chromatograms of the monohalogenated benzenes were
obtained. In general, positive chromatograms showed protonated molecular
113
-------
TABLE 35
EXPERIMENTAL PARAMETERS FOR PLASMAGRAMS RUN FOR COMPOUNDS STUDIED
Sample temperature:
React ant gas flow:
Drift gas flow:
Ion-molecule reaction space:
Ion-drift space:
Electric field:
Injection pulse:
Gating pulse:
Recorded scan:
Electrometer sensitivity:
Compounds:
Gas:
127° C
100 cc of dry
450 cc of dry N/minute
6.0 cm
6.0 cm
250 V/cm
0.1 millisecond
0.1 millisecond
2 minutes
10~12 A full scale
CP reagent grade with greater than
99% purity
Nitrogen-Linde high purity grade
(99.996%), dried by metal trap of
2.25-liter capacity, packed with
Linde Molecular Sieve 13X
Reprinted with permission from Karasek, F;W. and O.S. Tatone. Plasma
Chromatography of the Monohalogenated Benzenes. Analytical Chem., 44(11)
1759, 1972. Copyright by American Chemical Society.
ions containing one or two molecular species. Negative chromatograms had a
strong halogen peak, except for monofluorobenzene.
114
-------
TABLE 36
DRIFT TIME AND STRUCTURE ASSIGNMENTS OF CHARGED
SPECIES OBSERVED IN PIASMAGRAMS OF HALOGENATED BENZENES
Compound
Nitrogen
(reactant gas)
Monobromobenzene
Monoiodobenzene
Ions
(H20)2H
Carbon tetrachloride
n-Butyl chloride
Electrons
Monofluorobenzene (CJ*
6 .
Monochlorobenzene
Br
I
Cl"
Drift time
(milliseconds)
5.75
6.47
7.11
Continuum
7.39
8.44
7.81
8.60
5.47
8.12
9.00
6.13
8.59
9.94
6.40
5.42
5.42
6.10
Reprinted from Karasek, F.W. and O.S. Tatone. Plasma Chromatography of the
Monohialogenated Benzenes. Analytical Chem., 44(11):1758-1763, 1972. Copyright
by American Chemical Society.
115
-------
TABLE 37
tRHOOS FOR THE SEPARATION AND DETECTION Of HALOGBiAXED BENZENES
Qonpound
Nonochlorobenzena
Hanochlorobenzene
Nonochlorobenzene
Manochlorobenzene
Monochlorobenzene
All dlchlorobenzenea
All dibromooenzenea
All trichloro- and
tribromobenzenes
All tetrachloro- and
l«ti ill >nn limneiuM
Pent*- and hexachloro-
benzene •
D^Oichlorobenzene
1,2,4,5-^fetrachloro-
benzene
Dichlorobenzenes
Dichlorobenzenes
Dlchlorobenzenea "1
Tr ichlorobenzenes
letrachlorobenzenesj
Pentachloroberaene
Hexachlorobenzene
Hexachlorobenzene
Hexachlorobenzene
Hexachlorobenzene
Hexachlorobenzene
Hexachlorobc.^
o-oichlorobenzene
p-Oichlorobenzene
1, 2 , 4-Tr ichlorobenzene
Tetrachlorobenzene
1 , 2 , 4 , 5-Tetrabrcno-
benzene
2-lodoehlorobenzene
1 , 4-Di£luorpbenzene
1 , 2 , 4-Tr ifluorobenzene
wchod ol
detection
u.v. absorption
spectra
OC flane
ionization
GLC equilibration
method
Plasma
chf onatogr aphy
6LC, i.r. spect.
QC/MS
Mas fragment-
ography
OC/MS
OCC/tbermal
conductivity
ionization,
TIC
GIC/MS
OC/EC
OC/BC,
reverse phase
TIC
GtC/BC
High pressure
liquid chromat-
ography, reverse
phase TLC
(ZC/EC, IXC
OC/BC
Ponnation of
polyne thine
dyes
Plaona
emission
detector
GLC-thernai
conductivity
Sanpie
Air
Air
(sensitive
to 2 ag/tt?)
Air
Lab. mixture
Lab. mixture
Hunan adipose
tissue
Hunan blood,
air
aoaan blood,
water
Lab. mixture
Lab. mixture
Eted, animal
fat, poul-
try products
ttteat
Cereals,
dairy pro-
ducts, fat
Patty foods
Monkey feces
Hunan body
fat
Hunan body
fat
Air
Pesticide
residues-
Lab. mixture
Reference
Kisarov et al.,
1962
Suibayev and
Rakhybenko, 1975
Selucky et al . ,
Karasek et al.,
1971 —
Kakada et al.,
310-
Horita and Chi,
1975
Marita et al.,
Oowty et
1975
Babboush
TBmeeah,
al..
and
1970
Yasuda, 1973
CSreve, 1973
Levi et al.,
Stij\e, 1971
Smyth, 1972
Yang et al., 1975
Brady and Slyali,
1972
Curley et al.,
1973
Balyafcov et al.,
1972
Bache et al., 1968
Seller and Sams,
1972
1,3,5-TTifluorobanzene
1,2,4,5-Tetrafluoro-
benzene
1,2,3,3-tetrafluoro-
benzsne
Pentafluorobenzene
Hexafluorobenzene
116
-------
F. MONITORING EFFORTS
A number of chlorinated and brominated benzenes have been detected in raw
water and drinking water throughout the U.S. The National Organic Reconnais-^
sance Survey (EPA, 1975b) analyzed raw water sources of five basic types to
determine their organic chemical content. A summary of their findings with
location and type of water source is included in Table 38.
.Two analytical techniques are indicated in this same table. Volatile
organic analysis (VDA) involves aeration of the water sample with an inert
gas to purge organic contaminants. In the carbon/chloroform technique,
organic contaminants are adsorbed onto activated carbon and eluted with
chloroform. The TOA figures have been corrected for recovery efficiencies,
but the carbon-chloroform data have not, and are therefore possibly low (EPA,
1975b).
Monochlorobenzene was detected in nine of the ten cities surveyed for
this study: in ground water, in "uncontaminated" upland water, and in waters
contaminated by either industrial, municipal or agricultural wastes.
The work by Erisman and Gordon (1975) is still in progress. The data
made available for this report are included in Table 38 but are not yet
quantified. Mono-, pj-di- and 1,2 4-trichlorobenzene were all detected in
textile waste effluents.
Dichlorobenzene (isomer not specified) was detected in wastewaters from
Lakeway Chemical, Inc., in Muskegon, Michigan (Christensen and Long, 1976).
Monitoring of wastewaters took place during one 24-hour period starting July
12, 1976. Lakeway Chemical produces a lauryl alcohol base detergent, dye
intermediates, pesticides and herbicides. During the monitoring period, only
the detergent plant was operational.
117
-------
Process cooling and domestic water used within the plant were discharged
without treatment to the sewage system. (Process water from the pesticide
and herbicide plants was not discharged, but hauled away by licensed haul-
ers.) Cooling water from the different plants was recycled through cooling
towers or a spray pond, it was treated with Dearborn 726 and/or calcium
hypochlorite. Overflow from either towers or ponds was retained in a seepage
lagoon behind the plant. Other seepage lagoons for retaining process water
are no longer in use, but have drained to a residual sludge. Because the
soil is sandy, wastewaters quickly seep through to discharge into a swampy
area draining into Big Black Creek.
Grab samples were taken from the east and west seepage areas, from cool-
ing water, and up and downstream along Big Black Creek. Continuous samples
were collected from the Creek, up and downstream, by displacement of air from
a submerged container. The quantity of each contaminant discharged daily was
calculated from:
Ib/day = flow (mg/d) x cone, (mg/1) x unit weight of the water
(8.34 Ib/gal)
Flow rate was determined during continuous monitoring of the Creek. Hie
report did not give the analytical techniques used to determine the various
wastewater constituents. Quantities of dichlorobenzene of just under 10 jug/1
were detected in both seepage and cooling waters.
The plant produces dichlorobenzidine-dihydrochloride from o-nitrochloro-
benzene. This process might be responsible for the appearance of dichloro-
benzene in wastewaters of the plant.
118
-------
TABLE 38
MONITORING FOR CHLORINATED BENZENES IN WATER SYSTEMS
Concentration Location
Source
Analytical Methods
Reference
(a) Monochlorobenzene;
d Miami, Florida
d "
1.0 "
Ground water
Volatile organic analysis EPA, 1975b
(VGA)
Carbon/chloroform extract
0.5
Seattle, Washington "Uncontaminated"
upland water
VGA
d
d
0.1
d
Ottumwa, Iowa
Philadelphia,
Pennsylvania
Raw water contaminated with
agricultural run-off
Raw water contaminated with
municipal waste
H
n
VGA
VGA
VGA
VGA
d Cincinnati, Ohio Raw water contaminated Carbon/chloroform extract
with industrial discharges
0.1 " VGA
VGA
4.7 New York, New York "Uncontaminated"
upland water
0.12 Lawrence, Mass.
Raw water contaminated with
industrial discharges
d - detected by 500 ml TOA but not quantified. Limits of sensitivity not indicated.
-------
TABLE 38 (Continued)
to
o
Concentration Location
(Aig/1)
d
5.
d
Grand Falls,
North Dakota
6 Terrebone Parish,
Louisiana
not indicated
(b) o-Dichlorobenzene:
1.0 Miami, Florida
d
d
d
Philadelphia, Pa.
Cincinnati, Ohio
Source Analytical Methods
Raw water contaminated with VQA
agricultural runoff
Raw water contaminated with VQA
municipal waste
Textile plant effluents Not indicated
Ground water Carbon/chloroform
extract
VQA
Raw water contaminated VQA
with municipal waste
Raw water contaminated ... ... VQA
with industrial discharge
Reference
EPA, 1975b
n
Erisman and
Gordon,
1975
EPA, 1975b
d - detected by 500 ml VQA but not quantified. Limits of sensitivity not indicated.
-------
TABLE 38 (Continued)
Concentration Location
(pg/D
(c) m-Dichlorobenzene :
0.5 Miami, Florida
d
d
d
d
Philadelphia, Pa.
Cincinnati, Ohio
Lawrence, Mass.
(d) p-Dichlorobenzene
0.5 Miami, Florida
d
d
d
Philadelphia, Pa.
Cincinnati, Ohio
Source
Ground water
Raw water contaminated
with municipal waste
Raw water contaminated
with municipal waste
Raw water contaminated
with industrial discharge
Ground water
Raw water contaminated
with municipal waste
Raw water containing
industrial discharge
Analytical Methods
Carbon /chloroform
extract
VGA
VGA
VQA
VGA
Carbon/chloroform
extract
TOA
VGA
VGA
Reference
EPA, 1975b
EPA, 1975b
d - detected by 500 ml VQA but not quantified. Limits of sensitivity not indicated.
-------
Table 39 lists the halogenated benzenes detected in drinking water in the
U.S. The list was compiled from Environmental Protection Agency reports and
through examination of the literature. It should not be considered a com-
plete listing. Table 40 gives details of monitoring efforts in Region IV EPA.
TABLE 39
HALOGENATED BENZENES POUND IN DRINKING WATER IN THE U.S. (EPA, 1975b)
Chemical Highest Reported Concentration (jug/1)*
Monobromobenzene
Bromochlorobenzene
Monochlorobenzene 5.0
Dibromobenzene
o-Dichlorobenzene 1.0
m-Dichlorobenzene 3.0
p-Dichlorobenzene 1.0
Hexachlorobenzene
Trichlorobenzene 1.0
*Sample site and concentration range were not indicated.
Young et al. (1976) are conducting a major monitoring effort to detect
and quantify chlorinated benzenes in major municipal wastewaters of southern
California. Hexachlorobenzene was first detected by electron capture gas
chromatbgraphy while investigating levels of PCBs and other chlorinated
pesticides. During two seasonal surveys in 1975, Young et al. detected other
chlorinated benzenes in the wastewaters. Their concentrations were compar-
able to PCB levels and in excess of HCB values by at least an order-of -
magnitude.
The samples were collected from submarine outfalls of effluents from the
Joint Water Pollution Control plant (JWPCP), the Hyperion Sewage Treatment
Works, L.A. (5 mile and 7 mile effluents); the Orange County Sewage Depart-
ment (OCSD); and Port Loma and Oxnard Sewage Treatment Plants.
122
-------
TABLE 40
UIUQRINATED BENZENES IDENTIFIED IN THE ENVIRONMENT IN REGION IV (EPA, 1977a)
Compound State
HCB KY
KY
KY
TCB GA
NC
I-1 NC
NJ .
LL)
OOCB NC
TO
KY
KY
Receiving Water Sample Type
Ohio River Industrial
discharge
It W
• •
Coosa River Municipal
discharge
Catawba Creek "
Catawba Creek "
Catawba River Industrial
discharge.
Big Bigby Creek " -
none Ground water
unknown Industrial
waste holding
pond
Concentration
(rog/1)*
0.011
unknown
o.ost
0.005+
0.041
0.019
0.69
0.04t
0.071
0.015
Method of
Detection
Hall electrolytic conduc-
tivity detector
-
Mass spectrometer
Mass spectrometer
Flame ionization detector
N
Plane ionization detector
N
Hall electrolytic conduc-
tivity detector
•
Date
74/7
7V7
75/8
76/2/25
7V7
7V7
74/9/18
76/5/19
76/6/3
'Qualified value — same as the true value but no recovery studies were performed. True value compares response of
compound in sample to standard compound. Recovery data for the compound spiked in distilled water is 70% or greater.
Values not corrected for recovery.
tEstimated concentration based on relative response of standard compound vs. organic compounds similar to standard.
Also, no sample preparation recovery data are available.
-------
TABLE 40 (continued)
Compound
ODCB
1,2,3-TCB
1,2,4-TCB
1,3,5-TCB
PDCB
State
KY
NC
NC
NC
TO
TO
TO
TO
Receiving Water
none
Catawba Creek
N
Catawba River
Chattanooga Cr.
Chattanooga River
Holsbon River
Big Bigby Creek
Sample Type
Ground water
Municipal
discharge
"
Industrial
discharge
•
Municipal
discharge
Industrial
discharge
Industrial
discharge
Concentration
(HKj/1)*
0.0012
0.021
0.046
0.012
0.5t
unknown
0.026
0.058
Method of
Detection
Hall electrolytic conduc-
tivity detector
Flame ionization
detector
"
Flame ionization
detector
"
Hall electrolytic con-
ductivity detector
Flame ionization
detector
Date
76/6/3
73/7
73/7
73/7
73/3
73/3
74/9/26
74/9/18
'Qualified value — sane as the true value but no recovery studies were performed. True value compares response of
compound in sample to standard compound. Recovery data for the compound spiked in distilled water is 70% or greater.
Values not corrected for recovery.
tEstimated concentration based on relative response of standard compound vs. organic compounds similar to standard.
Also, no sample preparation recovery data are available.
-------
to
01
TABLE! 40 (continued)
Compound State
MCB SC
SC
GA
Dichloro- SC
benzene
TN
SC
NC
KY
KY
KY
Receiving Water
Lawsons Fork Creek
N
Coosa River
Lawsons Fork Creek
Big Bigby Creek
Lawsons Fork Creek
Catawba River
unknown
none
none
Sample Type
Industrial
Discharge
"
Municipal
Industrial
Discharge
*
"
H
Industrial
waste holding
Ground water
Ground water
Concentration
(ns/1)*
0.008
0.017
0.027 t
0.032
unknown
0.012
0.033
0.0009 t
0.012 t
0.0012 t
Method of
Detection
Flame ionization
detection
N
Mass spectrometer
Flame ionization
detection
"
"
H
Hall electrolytic
conductivity detector
N
M
Date
76/5/27
76/5/23
76/2/25
76/5/27
75/V26
76/5/23
73/7
76/6/03
76/5/19
76/6/3
*Qualifled value — same as the true value but no recovery studies were performed. True value compares response of
compound in sample to standard compound. Recovery data for the compound spiked in distilled water is 70% or greater.
Values not corrected for recovery.
tEstimated concentration based on relative response of standard compound vs. organic conpounds similar to standard.
Also, no sample preparation recovery data are available.
-------
Table 41 gives the estimated chlorinated benzene content of wastewaters
analyzed during these two surveys.
In 1976, large grab samples were collected from JWPCP, OCSD and Hyperion
5 and 7 mile sludge effluents. Replicate sets (volumes 1,10 and 10 1) were
extracted and processed. Each sample was independently analyzed by: (1) the
Southern California Coastal Water Research Project Authority; (2) California
Analytical Laboratories (CAL) in Sacremento; and (3) EPA Environmental
Research Laboratory in Athens, Georgia.
The CAL samples were analyzed by mass fragmentography. Confirmation of
identity of the compounds was made on the basis of retention time and detect-
ion of molecular ions. 1,3,5-TCB was not confirmed. The Athens laboratory
also determined the presence of chlorinated benzenes in the samples. Table
42 gives the data as analyzed by CAL. It agrees well with data contained in
the previous table.
TABLE 41
MUNICIPAL WASTEWATER CHLOROBENZENE CCNCENTRATICNS (pg/1) DETERMINED BY
ELECTRON-CAPTURE GAS CHRCMATOGRAPHY (gc/ec) AND MASS SPECTRDMETRY (gc/ms)
(Young et al., 1976)
Chlorp-
benzene
PDCB
ODCB
1,2,4-TCB
l,3,5^rCB
HCB
Total
chlorinated
benzenes
gc/ec
7.6
5.1
0.58
< 0.01
0.10
13
JWPCP
gc/ms
7.4
3.3
0.54
• • -
0.05
11
Hyp.
gc/ec
90
183
86
0.3
0.45
360
7-mi.
gc/ms
7.8
14
34
-
0.41
56
OCSD
gc/ec
2.8
1.3
0.08
0.001
0.010
4.2
gc/ms
. -
-
-
0.007
-
. 126
-------
TABLE 42
ESTIMATED CHLORQBENZENE CONCENTRATIONS (pg/1) IN MAJOR MUNICIPAL WASTEWATERS
(Young et al., 1976)
Chlorobenzene JWPCP *
PDCB
OPCB
1,2,4-TCB
1,3,5-TCB
HCB
Total
Chlorinated
Benzenes
Sum.
7.4
7.3
6.0
0.2
0.4
21
Fall
12
12
1.8
0.8
0.2
27
Hyp-5 mi t
Sum.
3.4
1.9
5.7
<0.01
0.07
11
Fall
5.1
4.0
3.1
< 0.01
0.01
12
Hyp-7 mi f
Sum.
34
30
275
0.9
1.9
340
Fall
230
440
130
<0.2
6.8
800
OCSD §
Sum. Fall
4.9
2.4
0.3
0.02
0.04
7.7
Pt
Sum.
-
2.2
0.23
0.02
0.01
2.5
. Lama
Fall
0.42
< 0.01
< 0.01
< 0.01
< 0.01
0.4
Oxnard
Sum.
9.3
4.7
0.9
0.4
0.4
16
Fall
3.1
2.3
0.25
<0.01
0.04
5.8
* Joint Water Pollution Control Plant
t Hyperion Sewage Treatment Works - 5 mile effluents
Hyperion Sewage Treatment Works - 7 mile effluents
Orange County Sewage Department
-------
young et al. found that surface runoff of chlorinated benzenes into the
Los Angeles River is of much less significance as a source of marine pollu-
tion than are wastewater effluents. Table 43 gives data from a sampling of
the river following a major storm in February 1976. Samples ware collected
over a four day period using an all metal depth-integrating sampler. While
input of chlorinated benzenes into the Bight via the Los Angeles River run-
off was comparatively low/ this River is the single most important route
for entry of other chlorinated hydrocarbons into coastal waters of the area
(young et al., 1976).
TABLE 43
SURFACE RUNOFF OF CHLORINATED HYDROCARBONS, LOS ANGELES RIVER, FEB. 1976
(Young et al., 1976)
Chlorinated
Hydrocarbon
PDCB
ODCB
1,2,4-TCB
1,3,5-TCB
HCB
Total DDT
Aroclor 1254
Aroclor 1242
Net. Cone.
Oug/D
0.05
0.01
0.007
0.006
0.001
0.33
0.47
<0.18
Mi. Blank
(JXJ/1)
0.03
0.01
0.003
0.001
< 0.001
< 0.004
0.004
0.005
In order to determine the importance of aerial fallout of chlorinated
benzenes, high volume air samples were collected from five stations in the
Los Angeles Basin. Results are summarized in Table 44.
128
-------
TABLE 44
AERIAL FALLOUT OF CHLORINATED HYDROCARBONS OFF SOUTHERN CALIFORNIA —
SPRING 1976 (ng/m2-<3ay)
(Young et al., 1976)
Chlorinated
Benzene
PDCB
ODCB
1,2,4-TCB
1,3,5-TCB
HCB
Total DDT
Aroclor 1254
Aroclor 1242
El
Segundo*
_
—
<20
-
0.9
640 t
860
<260
Catalina
Island
w
< 8
-
< 1
1.7
73
230
< 70
San
Clemente
Island
—
27
< 3
< 3
0.1
280
98
<150
La
Jolla
.
—
< 2
< 10
3.4
30
98
<180
Santa
Barbara
fm
< 53
< 19
< 8
0.9
820
78
<250
Median
^
< 27
< 11
< 6
1
280
170
< 180
* Medians of six collections made during Fall 1975
t The median value measured for dieldrin was 10 ng/m2-day
Two types of samplers were used: an unoiled iced fallout sampler, and a
high volume air sampler made of a glass fiber filter and five layers of poly-
urethane foam padding. The sampling interval was 24 hours at El Segundo, and
48 hours for the other stations.
Table 45 gives the concentrations of chlorinated hydrocarbons detected in
the high volume air samples for three of the stations. The DDT and PCB val-
ues are considered indicative of good sampling efficiency as most of these
compounds was detected on the front layers of the foam pad. The p-dichloro-
benzene values are questionable because of high and variable values of
pj-dichlorobenzene in the process blanks. The other chlorinated benzene con-
centrations are also suspect because of high values in the blanks, and very
low levels detected in the samples.
129
-------
TABLE 45
CHLORINATED HYDROCARBONS (ng) MEASURED IN HICK-VOLUME AIR SAMPLES COLLECTED
OFF LOS ANGELES BASIN, 1976*
(young et al., 1976)
El Segundo (2/26-27):
Filter
(net)
PDCB < 62 t
ODCB
1,2,4-TCB
1,3,5-TCB
HCB
Total DDT
Aroclor 1254
Catalina Is. (4/6-8) :
PDCB
ODCB
1,2,4-TCB
1,3,5-TCB
HCB
Total DDT
Aroclor 1254
San Clemente (3/15-17)
PDCB
ODCB
1,2,4-TCB
1,3,5-TCB
HCB
Total DDT
Aroclor 1254
<14 t
< 6 t
<3 t
<1 t
610
390
103
-
<2 t
< 3
0.2t
4
14
•
•
38
< 2.6t
< 1.0
< 0.4
< 0.2
18
15 t
1st
l,600t
500
37
21
225
2,630
4,220
loot
56
14
44
35
260
1,420
250
< 2
5
<1
55
620
1,560
Foam Pads
3rd
200t
<15
51
12
248
< 8
73
150t
68
18
6
27
10
48
850
.< 6
15
< 1
60
2
13
(net)
5th
240t
48
30
22
68
<17
6
loot
30
12
< 0.3
22
18
260
70
<1
1
<1
54
13
120
Process
Filter
145
28
< 6
< 3
< 1
<13
< 22
428
945
< 1.5
11
0.2
4
16
80
< 2.6
<1.0
<0.4
<0.2
<1.8
28
Blanks
Foam
2,090
22
30
7
< 0.2
< 12
22
660
5
9
< 0.2
0.8
8
25
350
< 2.6
18
1.3
4.4
7
24
* Approximately 2000 m"
tGross value
sampled per 24 hour day
130
-------
Consideration of this data leads Young to conclude that aerial fallout of
chlorinated benzenes is much less likely than fallout of DDT and PCBs, be-
cause of the higher volatility of the former compounds.
The Environmental Research Laboratory at Duluth, Minnesota, has been
monitoring chlorinated benzene content of fish taken from Lake Superior and
Lake Huron. While detecting HCB for a number of years, they have recently
observed trichlorobenzene as a result of improvements in analytical tech-
niques (Veith, 1976). Figure 19 gives the GLC/MS spectrum for chlorinated
benzenes found in trout taken from Lake Superior. Figure 20 presents data
for burbot caught in Lake Huron. The mass number ranges were used to ident-
ify the following chlorobenzene isomers: tricnlorobenzenes, 180 to 184;
tetrachlorobenzenes, 214 to 218; pentachlorobenzene, 248 to 252; and hexa-
chlorobenzene, 282 to 286.
Levels of HCB in trout were 70 ppb and levels in burbot were 10 ppb. The
results are similar to data applicable to fish extracts taken from Lakes
Ontario and Michigan, and the Detroit, Ohio and Hudson Rivers. Veith
believes that the large amount of trichlorobenzene detected is due to its
heavy use in askarels to reduce viscosity of the mixture.
Pentachlorobenzene has been detected in the living and non-living
environments. In a two month survey of 212 samples of animal feed, fat and
poultry products, Greve (1973) identified pentachlorobenzene as a limited
contaminant of animal fat, eggs and meat products. Five samples of pork fat
originating from the same farm contained pentachlorobenzene in excess of 0.02
ppm, and as high as 0.09 ppm (by electron capture/gas liquid chromatography).
Fodder samples from the same farm contained 3.7 ppm pentachlorobenzene (QCB)
and 45 ppm hexachlorobenzene. It was not established whether or not
131
-------
FIGURE 19
CHLORQJATED BENZINES AS FOUND IN LAKE SUPERIOR TJCUT
NEAR COPPERMINE POINT
(Veith, 1976)
Hexachlorobenzene
Gone. - 70 ng/g
30000 -
20000 -
10000 _
282-286
248-252
214-218
180-184
FIGURE 20
CHLOKDWTED BENZENES AS FOUND IN LAKE HURON BURBOT NEAR tftOONAC
(%ith, 1976)
30000
20000
10000
Trichlorobenzene
Tetrachlorbbenzene
Hexachlorcbenzene
Cone. - 10 ng/g
Pentarfilorobenzene
r\
7
.A
282-286
248-252
214-218
180-184
10
20
30 40
Spectrum nurrber
50
60
70
80
132
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this same fodder had been fed to the pigs. The fodder contained spinach seed
which had been treated with HCB.
Fifteen samples of the wheat and pollard pellets were analyzed. They
contained in excess of 0.01 ppm of pentachlorobenzene with a high value of
0.15 ppm (electron capture GLC). Pentachlorobenzene content correlated with
HCB content of the feed, supporting the belief that the pentachlorobenzene
was a contaminant of the fungicide, HCB.
Both HCB and QCB have been detected in chicken fat (Stijve, 1971) where
pentachlorobenzene was present in amounts between 7 to 15% of the HCB content
Beck and Hansen (1974) analyzed 22 soil samples from fields spread with
technical grade pentachloronitrobenzene (PNCB) for a period of 11 years.
Analysis of the samples by electron capture gas chromatography showed that
for soils treated with PCNB up to 1970, there was an average accumulation of
0.37 mg of pentachlorobenzene per kilogram of soil. For samples treated for
an additional two years, average accumulation of QCB was 0.32 mg/kg soil.
Ten samples of greenhouse soil analyzed for PCNB and HCB content were
also found to contain pentachlorobenzene (DeVos et al., 1974). Data were de-
veloped by mass spectrometry after initial screening by electron capture/
liquid chromatography . Pentachlorobenzene and hexachlorobenzene were both
detected in small amounts in the feces of beagle dogs fed PCNB for up to two
years. The primary metabolite was pentachloroaniline (Kuchar et al., 1969).
All three dichlorobenzenes were detected in human blood samples collected
in the New Orleans area (Dowty et al., 1975). None of the chlorinated ben-
zenes were detected in a 400 liter sample of air nor in New Orleans drinking
water, though many other organic compounds were confirmed. It was not clear
133
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how the dichlorobenzenes entered the human body, nor their point of origin.
As previously mentioned, MDrita and Chi (1975) detected p-dichlorobenzene
in human adipose tissue and blood samples taken in the Tokyo Metropolitan
Area. Average concentration in blood was 9.5 jug/ml, and in adipose tissue
was 2.3 AJg/ml. They also detected 1,2,4,5-tetrachlorobenzene and hexachlorc—
benzene in human adipose tissue at levels above 0.010 pg/g fat.
To summarize, many of the chlorinated benzenes appear to be widespread in
the abiotic environment having been detected in rivers, lakes, municipal and
industrial discharges, ground water, drinking water, air and soil. Mono-
bromobenzene, dibromobenzene (isomer not specified) and bromochlorobenzene
have also been detected in drinking water.
Several chlorinated benzenes have been detected in living organisms in-
cluding fish, chickens, pigs, cattle and humans. Fish in Lakes Huron and
Superior contained higher concentrations of hexachlorobenzene and trichloro-
benzene isomers with smaller amounts of tetrachlorobenzene and pentachloro-
benzene. Dichlorobenzenes have been detected in human blood samples taken in
New Orleans and Tokyo, Japan, and £-dichlorobenzene, 1,2,4,5-tetrachloro-
benzene and hexachlorobenzene have been found in human adipose tissue.
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III. HEALTH AND ENVIRONMENTAL EFFECTS
A. ENVIRONMENTAL EFFECTS
1. Persistence
It is clear that there is now a greater awareness of the extent of envi-
ronmental contamination by chlorinated benzenes. Certain chlorinated ben-
zenes are extremely resistant to chemical, biological or photolytic degrada-
tion, and have been detected in wildlife and aquatic ecosystems. The persis-
tence and distribution of hexachlorobenzene in the environment has received
much attention. Improved analytical techniques and increased monitoring
efforts are producing evidence of persistence of lower chlorinated benzenes,
including penta-, tetra-, tri- and dichlorobenzenes. In this context, it is
|
imperative to establish the extent of degradation of all of the chlorinated
benzenes which are now being detected in the biosphere.
(a) Biological Degradation . -.!
In general, halogenated benzenes may be broken down in the environment.
The extent to which they do break down varies greatly, and depends on a I
number of factors including type of halogen, and number and position of ,
halogens in the ring. The higher halogenated compounds are more resistant to
biodegradation.
The oxidative degradation of the monohalogenated benzenes by Pseudomonas
putida has been investigated by Gibson et al. (1968). Monochloro-, mono-
bromo-, and monoiodobenzene were oxidized to the 3-halocatechol at approxi-
mately the same rate. The rate of oxidation of monofluorobenzene was half
that of monochlorobenzene. Figure 21 shows the accumulation of halogenated
catechols in cultures of P. putida initially grown on toluene for 15 hours
and then grown on a halogenated benzene for up to 20 hours. P. putida
135
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FIGURE 21
ACCUMULATION OF HALOGENATED CATECHOLS
IN A CULTURE WITH P. PUTIDA
(Gibson et al.,1968)
, •• I
8 IT
Time (hours)
Key
3-Iodocatechol
3-Bronocatechol
3-Chlorocatechol
3-Fluorocatechol
Reprinted with permission from Gibson, D.T., et al.
Oxidative Degradation of Aromatic Hydrocarbons by
Microorganisms. II. Metabolism of Halogenated Aro-
matic Hydrocarbons. Biochem., 7(11):3796, 1968.
Copyright by American Chemical Society.
136
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grows rapidly on toluene. The concentration of each halogenated benzene was
corrected for the vapor pressure of the compound. Toluene served as the sole
source of carbon and the halogenated benzenes were always added as an addi-
tional substrate for each of the oxidative systems. None of the halobenzenes
served as a growth substrate when introduced into the medium by blowing air
first through the incubation flask containing the monohalobenzene and then
into the medium. It appears from this study that P. putida can only oxidize
halogenated benzenes when they are already growing on an aromatic carbon
source.
Lu and Metcalf (1975) reported values for the biodegradability index of
monochlorobenzene ranging from 0.014 to 0.063 in organisms found in the model
aquatic ecosystem described in Section 2 below. The biodegradability index
(BI) is defined as the ratio of polar products of degradation to the nonpolar
products. A low value of BI indicates that a compound resists biodegrada-
tion. For comparison, Lu and Metcalf reported a biodegradability index for
DDT of 0.012 in mosquito fish compared to 0.014 for monochlorobenzene, and
0.015 for aldrin.
There is a report that Bacillus polymyxa utilizes monobromobenzene as the
sole source of carbon (Shelat and Patel, 1973). B. polymyxa was isolated
from sewage sludge and identified by the poured plate method using a mineral
solution containing 0.5% w/v of monobromobenzene as the sole source of car-
bon. Ammonium nitrate was the nitrogen cource. After 72 hours incubation at
28°C, lobate translucent and fimbriate colonies were formed. These colonies
were identical to B. polymyxa colonies grown on nutrient agar. The method of
utilization was still to be determined.
The effects of biological action on the lower chlorinated benzenes in
137
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aqueous systems has been studied by Garrison and Hill (1972). Mono-, o-di-
and p-dichlorobenzene volatilized completely from aerated mixed cultures of
aerobic microorganisms in less than a day. 1,2,4-Trichlorobenzene persisted
for nine days. No additional data were given.
There are other reports of the biological degradation of lower chlori-
nated benzenes. Midwest Research Institute (1974) reported that p_-dichloro-
benzene is degradable by biological organisms to 2,5-dichlorophenol, di-
chloroquinol and conjugates. No additional information was given, nor were
references supplied. Gubser (1969) reported that o-dichlorobenzene is
degraded by sewage sludge organisms. The degradation products were not given.
Using sewage microflora, Heukelekian and Rand (1955) showed a relation-
ship between the biochemical oxygen demand (BOD) of a chemical and its
structure. They found that introduction of certain chemical groupings into
the molecule resulted in a lowered BOD. For example, introduction of chlor-
ine atoms into an organic molecule was shown to decrease BOD. This decrease
in BOD indicates a resistance to microbial attack. The BOD of benzene was
reported as 1.20 g/g while that of monochlorobenzene was 0.03 g/g. Alexander
and Lustigman (1966) also found that the presence of a chlorine atom on the
benzene ring retarded the rate of biodegradation.
Levels of approximately 0.46 mg/1 of 1,2,3-trichlorobenzene were detected
in effluents from a sewage plant treating textile wastes in Gastonia, N.C.
(Lewis, 1975). 1,2,3-Trichlorobenzene was present in the effluents prior to
treatment. The wastes were aerated in a lagoon, clarified and then chlori-
nated. There was no evidence that the 1,2,3-TCB was formed as a result of
chlorination. This report suggests that 1,2,3-trichlorobenzene may not be
biodegradable.
138
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TABLE 46
EFFECTS OF 1,2,4-TRICHLORCBENZENE ON BOD
Source of Organisms ^^on Reference
(% of theoretical value)
Microorganisms from industrial Hintz, 1962
waste treatment plant 78
100 Alexander, 1972
Mixture of microorganisms from Porter and Snider, 1974
4 different textile treatment
plants 50
Microorganisms from "typical" Haas et al., 1974
treatment plant 0
(2 days)
Table 46 summarizes twenty day biochemical oxygen demand data (BOD_0) for
1,2,4-trichlorobenzene. The BOD_0 values are given as a % of the theoretical
value. Determination of BOD which measures oxygen uptake of the chemical is
at best only an indirect indication of degradation. Results are difficult to
interpret unless either no oxygen uptake or 100% uptake are found. The test
does not give an indication of degradation products.
Haas et al. (1974) subjected 1,2,4-trichlorobenzene (50 ppm) to precon-
ditioned treatment plant cultures. After 50 hours, there was only a slight
decrease in concentration (cells + waters) of 1,2,4-trichlorobenzene, proba-
bly due to atmospheric loss. Approximately 40% of 1,2,4-TCB was absorbed by
the organisms, though not biodegraded.
Other studies have reported various values for the BOD depending on
the conditions and microorganisms used. Simmons et al. (1976) undertook a .
quantitative study of the biodegradation of 1,2,4-trichlorobenzene in order
139
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to clarify the extent and rate of degradation and the role of acclimatiza-
tion. They used unacclimatized industrial wastewater microorganisms in their
i
study. After 10 days, nearly all (99%) of the 1,2,4-trichlorobenzene (init-
ial concentration 1.7 mg/1) as measured by gas chromatography/electron cap-
ture had disappeared from the experimental mixture. However, the BOD value
after ten days indicated that 55% of theoretical value was removed. The 45%
theoretical oxygen demand remaining was assumed to be due to incompletely
oxidized metabolites of 1,2,4-TCB probably incorporated in the cell wall.
Like Haas et al. (1974), Simmons et al. (1976) found no apparent degradation
as measured by BOD in the first few days of monitoring. However, gas chroma-
tography/electron capture analysis indicated a 14% reduction in 1,2,4-TCB
s,
concentration after only 24 hours, a 36% reduction at 72 hours and a 43%
reduction at seven days.
At a higher concentration of 1,2,4-TCB (2.6 mg/1), the rate of degrada-
tion was apparently lower for the first few days. After seven days, the con-
centration of 1,2,4-TCB had decreased 28% by gas chromatography/electron cap-
ture analysis. However, after ten days all the trichlorobenzene had disap-
peared from the BOD bottles.
14
The formation rate of (XL through biodegradation of 1,2,4-TCB by
activated sludge was also examined by Simmons eit al. After 5 days, 13% TCB
remained. There was 56% conversion to carbon dioxide, 23% conversion to pol-
ar metabolites and 7% volatization as TCB. The maximum rate of overall con-
version of 1,2,4-TCB to C0_ was 40 mg/g MLVS*/day. Approximately 80% of the
trichlorobenzene was adsorbed on solids, accounting for the low volatility
*MLVS - mixed liquor volatile solids
140
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from the system. It seems clear that biodegradability of 1,2,4-trichloro-
benzene depends on a number of factors including: (a) prior exposure of the
TCB; (b) aeration rate; (c) residence time; and (d) volatility.
In a series of laboratory experiments/ Beck and Hansen (1974) investi-
gated the half-life of penta- and hexachlorobenzene in the soil. Table 47
summarizes their data.
TABLE 47
RATES OF DEGRAPATION OF PEMI&CHLOROBENZENE and HEXACHLOROBENZENE IN SOIL
(Beck and Hansen, 1974)
Compound Concentration Slope
(kg/ha) (xl(f4)
Pentachlorobenzene
Pentachlorobenzene
Hexachlorobenzene
Hexachlorobenzene
10
10
10
10
15.4913
8.735
3.1056
1.4412
S.D.* of Slope
(xlO~4)
3.7817
1.6819
1.1586
0.4813
Half-life
(days)
194
345
969
2089
*S.D. - standard deviation
Reprinted with permission of the senior author.
The slope was determined from the regression lines for the relationship
between time and concentration of compound. Half -lives (RL ) were cal-
culated from the equation RL5Q = - -gj§pf. These results are not statis-
tically significant. In order to show significant degradation of the two
compounds, it is necessary to either alter the research protocol or extend
the experiment. It does appear from this data, however, that QCB and HCB are
very persistent in the soil.
An additional discussion of the biodegradability of chlorinated benzenes
is found in Section 2 below.
141
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(b) Chemical and Photolytic Degradation
Information relating to chemical and photolytic degradation is limited
and concerns chlorinated benzenes only.
Billing et al. (1976) studied the photodecomposition rates of a number of
chlorinated hydrocarbons in a simulated atmosphere. Monochlorobenzene de-
composed relatively slowly. In the presence of nitric oxide, MCB (10 ppm)
underwent 43% reaction in 7.5 hours. This gives a half-life of 8.7 hours.
The reactor, was a water-jacketed Pyrex cylinder maintained at 27± 1°C and 35%
relative humidity. Gas samples were analyzed by gas chromatography. Dilling
e_t al. also studied the decomposition rates in combination with other organic
compunds, but did not include chlorobenzene or any other halogenated benzene
in this second phase of their study.
Both o- and j>- dichlorobenzene are resistant to autoxidation by the per-
oxy radical (PD ) in water, and by ozone (0 ) in air (Brown et al., 1975).
£. 3
The dichlorobenzenes are reactive to hydroxyl radicals (HO) in air with a
half-life of approximately three days. Products of these reactions were not
indicated. Hexachlorobenzene is also unreactive towards ozone and RD , but
is moderately reactive toward HO in air, with a half-life of approximately
two days. Pentachlorophenol is formed.
1,2,4-Trichlorobenzene is also susceptible to attack by the hydroxyl
radical in air. The rate of degradation is not known, but is estimated to be
of the order of one to several days (Simmons et al., 1976).
There is little information available relating to environmental hydroly-
sis of chlorinated benzenes which is of course limited by the insolubility of
the compounds in water. There is a possibility that mono- and polyhydric
phenols could be produced through hydrolysis. As previously mentioned, the
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halogenated benzenes are relatively stable to nucleophiles. The polyhalo-
genobenzenes are more easily attacked by nucleophiles such as OH~ because
the electron attractive effect of the added halogens activates the ring. If
environmental hydrolysis does occur, because of the insolubility of the com-
pounds it must take place very slowly to form phenols or conjugates. It
should be pointed out that higher chlorinated phenols are themselves highly
toxic materials.
2. Bioaccumulation and Biomagnification
Lu and Metcalf (1975) studied the environmental fate and biodegradabil-
ity of relatively volatile benzene derivatives in a model aquatic ecosystem.
A three-liter flask containing daphnia, mosquito larvae, snails, green fila-
mentous algae and mosquito fish was maintained at 80°F with 12 hour daylight
exposure. Air and minerals were provided. Radiolabelled derivatives were
added to the flask in concentrations of 0.01 to 0.1 ppm. After 24 hours,
larvae, daphnia and fish were removed for radioassay, and after 48 hours, the
experiment was terminated. The quantities of parent compound, metabolites
and degradation products were radioassayed, and where possible identified.
Monochlorobenzene and hexachlorobenzene were found to be highly persis-
tent compounds. Table 48 illustrates the extent to which the various species
retained the halobenzenes. The mosquitos degraded approximately 65% of mono-
chlorobenzene to form mainly the hydroxylated compounds, o- and p-chlorophe-
nol and 4-chlorocatechol. These three compounds were also found in the
water. o-Chlorophenol was identified in algae, and both chlorophenols in all
other species. A number of degradation products were not identified.
143
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TABLE 48
ECOLOGICAL MAGNIFICATION (EM)* OF M3NOCHLOROBENZENE
AND HEXACHLOROBENZENE IN VARIOUS AQUATIC SPECIES
(Lu and Metcalf, 1975)
SPECIES
Common Name
Mosquito fish
Mosquito larvae
Snails
Daphnia
Algae
Generic Name
Gambusia affinis
Culex quinquifasciatus
Physa
Daphnia magna
Oedogonium cardiacum
(cf . Ecological magnification of aldrin
in mosquito fish is 16,960.
MCB
645
1292
1313
2789
4185
in mosquito
CHEMICAL
HCB
1166
2622
2672
1129
3969
fish « 1,312;
PCP
296
16
121
165
1.58
EM of DDT
* The ecological magnification (or bioconcentration) is the ratio of the
concentration of the chemical in an organism to the concentration in water.
Hexachlorobenzene was largely unchanged in the snail (84% of radioactiv-
ity) , in daphnia (67%), in mosquito larvae (65%) and in fish (64%). The only
identified degradation product was pentachlorophenol which was found in
algae, mosquito larvae and water extracts. [Note: pentachlorophenol (PCP)
was also studied in this investigation, see table above for EM values.]
Pentachlorophenol is degraded by microorganisms to lower chlorinated phenols
(Menzies, 1974).
144
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This study also established a significant correlation between water solu-
bility, partition coefficient and Hammett a constant. Water solubility and
partition coefficient apparently control the degree of bioaccumulation, while
a constant limits metabolism. The partition coefficient is defined as the
ratio of the equilibrium concentration of the chemical between a non-polar
and a polar solvent. In all the examples in Table 49, the solvents are
n-octanol and water.
Laska et al. (1976) investigated the biomagnification of hexachloroben-
zene in mosquito fish. Concentrations of hexachlorobenzene in mosquito fish
ranged from 71.8 ppb at Garyville, to 379.8 ppb above Baton Rouge. The lat-
ter concentration represents a biomagnification of 172. Concentrations of
HCB in crayfish were from 22.2 ppb at Romeville to 194.3 ppb at Darrow.
It is clear from an examination of Tables 48 and 49 and the literature
references, that the chlorinated benzenes investigated are persistant chemi-
cals which may be accumulating in the environment. Additional data are re-
quired to quantify the extent of any possible accumulation. No data were
available relating to the brominated, fluorinated, or iodinated compounds.
3. Environmental Transport
The comparatively high volatility of the chlorinated benzenes suggests
that they must rapidly vaporize and distribute through the atmosphere. Gar-
rison and Hill (1972) showed that mono-, o-di-, p-di- and 1,2,4-trichloro-
benzene volatilized from aerated distilled water in less than four hours.
Concentrations were 300 mg/1, 100 mg/1, 300 g/1 and 100 g/1 respectively.
The same concentrations of the four chlorinated benzenes volatilized from un-
aerated distilled water in less than:three days. 1,2,4-Trichlorobenzene dis-
appeared from unaerated water in less than two days. Cnce in the air, the
145
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49
MOLECULAR PROPERTIES AND BIOLOGICAL RESPONSE OF SEVERAL CHLORINATED BENZENES
Compound
Monochlorobenzene
o-Dichlorobenzene
£-Dichlorobenzene
p-Dichlorobenzene
Hexachlorobenzene
Hexachlor obenzene
Water Log Partition EM
Solubility Partition Coefficient mosquito
ppm Coeffic. fish
100 2.176 150 650
0.145g/l 3.38 2,399
0.008g/100g 3.39 2,455
insol. 3.38 2,399
0.006 4.132 13,560* 1,166
0.006 6.18 1,514,000*
BI References
mosquito
fish
0.014 Lu and Metcalf,
1975
Brown et al., 1975
Brown et al., 1975
Neely et al., 1974
0.377 Lu and Metcalf,
1975
Neely et al. , 1974
*Note - the discrepancy between the two values of partition coefficient for hexachlorobenzene. The
first value is experimentally derived, while the second value is calculated from the partition co-
efficient for p-dichlorobenzene by adding a substituent constant (0.7/C1 atom) for each chlorine atom
substituted in the ring. In view of this discrepancy, it was decided not to calculate partition
coefficients for other chlorinated benzenes using the substituent constant.
-------
chlorinated benzenes are subject to OH attack. NO degradation products were
detected in the water.
Simmons et al. (1976) calculated that the rate constant for evaporation
of 1,2,4-trichlorobenzene from water is 9.3 cc/hr. This corresponds to a
half-life of 45 minutes in water 10 cm deep measured at standard temperature
and pressure.
Young et al. (1976) indicated that since chlorinated benzenes have a
higher volatility than either DDT or PCBs, they are less likely to be carried
from the atmosphere to land or water as dry particulate fallout. Additional
data relating to aerial fallout of chlorinated benzenes off southern Califor-
nia is found in Section IIP.
There is also a possibility that 1,2,4-trichlorobenzene will be trans-
ported through water. Simmons et al. (1976) indicated that 75% of 1,2,4-TCB
which remains in water (i.e. which is neither biodegraded nor volatilized) is
associated with solids in the waste sludge. Haas et al. (1974) reported that
approximately 40% of 1,2,4-TCB is absorbed into the cell wall of sludge
microorganisms. The extent to which 1,2,4-TCB is transported through flowing
water attached to particulate matter has not yet been investigated.
There has been at least one study of the distribution of hexachloroben-
zene and hexachlorobutadiene in water, soil and microorganisms along the
lower Mississippi River in Louisiana (Laska et al., 1976). Samples were
taken at five mile intervals between Baton Rouge and New Orleans and south to
Port Sulphur, a distance greater than 100 miles. Water samples (1 liter)
were collected near the river's edge at depths of approximately 15 cm. Soil
samples from beneath the water surface were taken from the levee at the same
location. Mud samples were obtained from the adjacent drainage ditch running
147
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parallel to the levee. Fish and aquatic invertebrates were sampled where
located.
Hexachlorobenzene and/or hexachlorobutadiene were found in every water
collection between Baton Rouge and New Orleans. A concentration of HCB (2.2
ppb) was recorded above Baton Rouge, downstream from a heavily industrialized
area. HCB is formed as a by-product by chemical plants in the vicinity of
Plaquemine and Darrow, where a water sample contained 90.3 ppb HOB (electron
capture GLC). Hexachlorobenzene carried in suspension by the river accumula-
ted in soil from the levee and the drainage ditch in concentrations to a high
of 874.4 ppb at Darrow. Runoff from the slopes of the levee accounted for
accumulation of HCB in drainage ditches. HCB was also detected in soil sam-
ples at three sites well removed from the transect along the Mississippi
River.
More information is clearly required to determine the factors involved in
environmental transport of chlorinated benzenes. The persistence and accumu-
lation of chlorinated benzenes in the atmosphere must also be further studied.
148
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B. BIOLOGICAL EFFECTS
1. Toxicity and Clinical Studies in Man
(a) poisoning Incidents and Case Histories
Most of the poisoning incidents reported in the literature resulted from
inhalation of chlorinated benzenes. Accidental inhalation can occur either
in the home or at work. There are several cases, however, when a chlorinated
benzene was either accidentally or deliberately ingested (see Table 50).
Monochlorobenzene (MCB)
Atmospheric exposure to monochlorobenzene causes headaches, irritation of
eyes and upper respiratory tract, numbness, inhibition and eventual loss of
consciousness (Girard et al., 1969; Smirnova and Granik, 1970). A two year
old male survived ingest ion of 5 to 10 ccs of MCB. When hospitalized, he was
unconscious, cyanotic and twitching in the head and neck regions (Reich,
1934). There was no long term follow-up of this patient.
Chlorobenzene causes a burning sensation or irritation in contact with
skin (Dow Chemical, 1977b). In contrast to benzene and hexachlorocyclohexane,
the irritation appears to last for a long time, indicating an absence of ap-
preciable analgesic or local anesthetic effects. Severe irritation is char-
acterized by erythema, hyperemia and wheal formation (Von Oettingen, 1955).
Dichlorobenzenes
One case of sensitization to o-dichlorobenzene was reported for a man who
regularly handled window sashes dipped in the compound (Downing, 1939). Vftien
applied to the skin, there was a burning sensation after 15 minutes and for
the duration of exposure. The site of application showed a reddish hue which
increased up to 24 hours later, when blisters formed. A brown pigmentation
formed later and persisted for three months. The man was forced to seek
14S
-------
alternative employment.
Girard et al. (1969) reported three cases of leukemia resulting from
chronic exposure to o-dichlorobenzene (QDCB). One man hospitalized for
chronic lymphoid leukemia worked with a solvent containing 80% ODCB and 15%
p-dichlorobenzene (PDCB) for 10 years. A girl hospitalized with acute mye-
loblastic leukemia died 10 months later of peripheral leukoblastosis. She
reportedly had a neurotic compulsion to remove dirt and grease stains from
her clothes, which she did repeatedly with a product containing 37% ODCB (no
benzene or toluene). Another man exposed to a glue containing 2% o-dichloro-
benzene, methyl ethyl ketone and cyclohexane for a period of 29 years died of
chronic lymphoid leukemia. No further details of these incidents were given.
In cases where moderate exposure to p-dichlorobenzene were documented,
patients complained of severe headaches, profuse rhinitis and periorbital
swelling for approximately 24 hours after exposure (Cotter, 1953; Campbell
and Davidson, 1970). Anorexia, nausea, vomiting, weight loss and yellow
atrophy of the liver were reported for high exposure concentrations (Petit
and Champeix, 1948; Cotter, 1953; Hallowell, 1959).
Wallgren (1953) reported loss of weight, exhaustion, decrease of appetite
and blood dyscrasias in 27 men who manufactured p-dichlorobenzene for 1 to 7
months. Cotter (1953) described the case of a woman who demonstrated pro-
ducts containing PDCB and who complained of tiredness, nausea, headache and
• • *
vomiting. Clinical studies showed that she had subacute yellow atrophy and
cirrhosis of the liver.
Heavy use of p-dichlorobenzene as either a moth-repellent or a deodorizer
has apparently resulted in weakness, nausea, blood vomiting and jaundice
(Perrin, 1941; Cotter, 1953; Weller and Crellin, 1953). One man and his wife
150
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died within months of each other of acute yellow atrophy of the liver (con-
firmed by autopsy). Their house was apparently saturated with PDCB moth ball
vapor for a period of at least three to four months (Cotter, 1953).
There are at least two reports of deliberate ingestion of p-dichloro-
benzene. One woman who developed a pica for PDCB during the first trimester
of her pregnancy complained of general tiredness, mild anorexia, dizziness
and edema of the ankles. She was hospitalized with hemolytic anemia and
delivered a health child several months later (Campbell and Davidson, 1970).
Another woman who ingested 4 to 5 PDCB pellets (size not indicated) daily for
2 1/2 years complained about increased patchy pigmentation. Unsteadiness and
tremors occurred when she stopped taking the pellets, but these symptoms were
thought to be due to psychological rather than physiological withdrawal
(Frank and Cohen, 1961).
Other Chlorinated Benzenes
There is a report of severe aplastic anemia in a man who regularly soaked
his clothes in trichlorobenzene to remove grease (Girard et al., 1969).
in 1955, there was an outbreak of cutaneous porphyria in southeastern
Turkey which was traced to consumption of wheat treated with hexachloroben-
zene. Over 5000 cases were reported, mostly in children. Intake of HCB was
as high as 200 mg/day for several months before the epidemic was recognized.
Symptoms disappeared when contaminated wheat was no longer eaten (Cckner and
Schmid, 1961).
2. Effects on Nonhuman Mammals
(a) Absorption and Excretion
The absorption and excretion of halogenated benzene compounds takes place
by the method of simple diffusion. Halogenated benzenes may be absorbed from
151
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TABLE SO
Subject
70 year old
female
2 year old
male
3 adults
Sewage
workers
47 year
old male
40 year
old male
IS year
old female
53 year
old male
15 year
old female
36 year
old female
21 year old
pregnant
female
34 year old
female
HJMAN EXPOSURE TO CHLORINATED BENZENES - CASE REPORTS
Exposure
1958-1964 to a
glue containing
07% MCB (no ben-
zene or higher
homologues)
Swallowed MCB,
5-10 cc
Occupational
exposure to
MCB
OCXS effluents
from dry-cleaning
establishment
above sewer
ODCB in dipping
solution for
window sashes,
occupational
1940-1950
occupational
exposure to
solvent - 80%
CDCB, 15%-PDCB
Dry-cleaning
and dyeing shop
0X3
1932-1961, glue
containing 2%
COCB, methyl
ethyl ketone &
cyclohexane, (no
benzene or homo-
logues)
Cleaned clothes
with products con-
taining 37% COCB,
(no benzene or
toluene)
PDCB moth killer
in house
Pica for PDCB
toilet blocks,
first trimester
Demonstrating
PDCB containing
products
Symptoms
Headaches, irrit-
ation of eyes and
upper respiratory
tract
Otconscioua, no
reaction to skin
stimuli, muscle
spasms, cyanotic
Numbness, inhibit-
ion, loss of consc-
iousness, hyperemia
of conjunctivae,
sealer a, pharynx
Eye and upper res-
piratory tract
irritation, vomit-
ing
water blisters on
face, hands, arms
Weakness, fatigue
Pallor, tired-
ness, headaches,
vomiting, violent
gastric pains
Weakness, fatigue
Initially hos-
pitalized with
retroclavicular
adenopathy
Periorbital
swelling, intense
headaches, profuse
rhinitis
General tiredness,.
mild anorexia,
dizziness, edema
of ankles
Tiredness, nausea,
headache, vomiting
Clinical Report
Msdullar aplasia
MCB intoxication
MCB intoxication
COCB intoxication
Eczema to id derma-
titis due to ODCB •
Chronic lymphoid
leukemia
Severe hemolytic
anemia 1.5 x 10*
erythrocytes
Chronic lymphoid
leukemia, periph-
eral and abdominal
adenopathy, spleno-
megalia
Acute myeloblastic
leukemia
Exposure to PDCB
Hemolytic anemia
Subacute yellow
atrophy and
cirrhosis of the
liver
Follow-up Studies
1966- "satisfactory"
1967- "mediocre"
Odor of MCB present in
urine and air exhaled
5-6 days later. General
health appeared un-
disturbed
follow-up studies were
performed, data not clear
on results
ttot indicated
dot indicated
Treatment on-going
10 months later, eryth-
rocytes "excellent" but
leucocyte equilibrium
showed tendency to
neutropenia .
Died 1968
Died 10 months later of
100% peripheral leuko-
blastosis
Symptoms subsided within
24 hours
Healthy child delivered
several months later
Not indicated
Rsferenct
Girard «£ al. t
1969
«»l«h, IM4
Smirnova and
Granik, 1970
Dupont, 1938
Downing, 1939
Girard et al.,
1969
Gadrat et al.,
1962
Girard et al.,
1969
Girard et al.,
1969 '
Cotter, 1953
Campbell and
Davidson, 1970
Cotter, 1953
152
-------
TABLE 50 (continued)
Subject
19 year old
female
20 year old
male ( + 7
workmates)
19 year old
female
(black)
Exposure
Preparation of
PDCB for 18
months
PDCB manufacture
1 to 7 months
exposure
4 to S PDCB pellets
ingested daily foe
2 1/2 years
Symptoms
Asthenia, dizziness.
weight loss
Loss of weight,
exhaustion, de-
crease of appetite
Increased patchy
pigmentation
Clinical Report
Slight anemia,
react ional
hyper leucocytes ia
MBtbenoglobinenia
and other blood
pathologies
Due to PDCB ingea-
tion. Unsteadiness
and tremors on
ceasing constnption
Follow-up Studies
Not indicated
All workers transferred
to other working «nvi-
ronoent
Pigment returned to
normal
Reference
Petit an]
Coampeix, 1948
wallgren, 1953
Frank and
Cohen, 1961
thought psychological
60 year old
male
Wife of male
above
52 year old
male
62 year old
male
53 year old
female
3 year old
male
68 year old
male
60 year old
male
Male worker
Epidemic
Heavy PDCB moth
ball vapor in
house for 3 to
4 months
As above
PDCB exposure
in fur storage
plant
PDCB in bathroom
12 to 15 year
exposure to PDCB
moth balls in
house
Played with PDCB
crystals
Cleaned with basins
of trichlorobenzene
(isomer not spec.)
1930 to 1960
shipping mono.
o-di- and tri-
cnlorobsnzene
exposure to MCB,
leaking punp
sprayed into
atmosphere
Exposure to agri-
cultural chemical
KB. Seeds were
eaten by a popu-
lation
Height loss, loose
bowels, tarry
stools, numbness.
clumsiness
might and strength
loss, ^»v**^«i
swelling, jaundice.
Weakness, nausea,
blood vomiting.
jaundice.
Asthenia, dizziness
Cough, progressive
dyspnea, fatigue.
mucoid sputun
Cough, listless-
ness, black urine
Weakness, tiredness
Neakness, tiredness
General discomfort.
massive hemoptysis
several hours later
Porphyria cutanea
tardia, hepatomegaly,
hydroa aestivale
not physiological
Acute yellow
atrophy of the
liver (confirmed
by autopsy)
Acute yellow
atrophy of the
liver (confirmed
by autopsy).
splenomegaly
Subacute yellow
atrophy of the
liver
Light hyper chronic
anemia, after 1
month increase in
anemia, hypogran-
ulocytosis
Pulmonary granuloma-
tosis? focal
necrosis of liver
Acute heaolytic
anemia
Acute hemolytic
anemia
t
Anemia, 3 x 10
erythrocytes
Poisoning due to
MCB
Porphyria
Developed ascites and
died
Died 1 year after
initial exposure
4 years later reported
•in good health *
General hematological
inprovement but in-
crease in hypogranulo-
cytosis at 6 months
Wt indicated
Complete recovery
Complete recovery
Not indicated
not indicated
__
Cotter, 1953
Cotter, 1953
Cotter, 1953
Perrin, 1941
Heller and
Crellin. 1953
Hallowell, 1959
Girard et al.,
1969
Girard et al..
1969
Ehrlicher, 1968
Cckner and
Schraid, 1961
153
-------
the gastrointestinal tract, the lungs, and through the skin. Higher halogen-
ated benzenes, in general, are more poorly absorbed from the gastrointestinal
tract than the lower homologues. Most of the halobenzenes are relatively
insoluble in water, and possess varying degrees of high lipid solubility.
These lipid soluble compounds cross most of the barrier membranes in the
animal including the gastrointestinal epithelium, the hepatic parenchyma,
placenta! membranes, renal tubules and the skin.
When halogenated benzenes enter the body, mono-, ^- and m-dihalogenated,
1,2,3- and 1,2,4-trihalogenated, and the 1,2,3,4-tetrahalogenated benzenes
are metabolized to a greater extent than the ]>di- and 1,3,5-tri-, 1,2,4,5-
and 1,2,3,5-tetrahalogenated, penta- and hexahalogenated benzenes. Those
compounds which escape biotransformation may be excreted in part unchanged in
the urine, feces or expired air. Alternatively, they may change spontaneous-
ly after an initial oxidative reaction. This 'spontaneous reaction1, for the
most part with glutathione (later shown to be enzymatic), gives rise to mer-
capturic acids in the urine (Williams 1959; Boyland and Chasseaud, 1969).
Carbon tetrachloride, chloroform and trichloroethylene once considered
relatively inert, have been reinvestigated (Daniel, 1963; Paul and Rubin-
stein, 1963). With the use of modern techniques, it has been shown that they
are metabolized to a minor extent. This minor extent of metabolism is a very
important aspect of both acute and chronic toxicity (National Cancer Instit-
ute, 1976a, 1976b). Similarly, halogenated benzenes which are not extensive-
ly metabolized could be hazardous (if they form an arene oxide intermediate)
since an overall effect of metabolism is to make compounds more polar and
less lipid soluble and/or more water soluble so that they can be readily
excreted (Williams, 1959). Lipid soluble halogenated benzenes, which undergo.
154
-------
biotransformation to a minor extent, not only tend to accumulate in the body
and reach toxic levels, but may recirculate for long periods of time. Toxic
intermediates produced through metabolism may cause repeated insults on a
tissue, increasing the chance for cellular damage. The tendency toward cum-
ulative effects is greater as the number of halogens per benzene ring in-
creases. However, the number of halogens is not the only variable. The
presence or absence of vicinal positions, the vapor pressure of the compound,
its lip id solubility, the halogen substituent and the extent of metabolism are
all variables.
Monohalogenated Benzenes
Halogenated benzenes are eliminated partly in urine, bile, feces, and
expired air. The biliary route of elimination depends upon the species and
the molecular weight of the compound. Air expired from the lungs is an im-
portant route of excretion of the more volatile halogenated benzenes such as
monofluoro- and monochlorobenzene.
Parke and Williams (1950) and Azouz et al. (1952) noted in studies on
rabbits that monofluorobenzene (b.p. 85°, v.p. 96.6 mm at 30°C) behaves more
like benzene than the other monohalogenated compounds. As can be seen in
Table 51, 44% of fluorobenzene (0.5 mg/kg body weight) is excreted via the
lungs. If the dose were doubled, 64% of fluorobenzene would be eliminated
unchanged by this route. Monochlorobenzene has a higher boiling point (132°C)
and a lower vapor pressure (v.p. 15.5 mm at 30°C) than fluorobenzene. Hence,
only 27% of the total dose of MOB (0.5 mg/kg body weight) is excreted via the
lungs. Oily a small amount of the higher boiling nonobromo- and iodobenzene
are exhaled unchanged. About 6% of an oral dose of bromobenzene (v.p. 5.7 mm
at 30°C) is respired unchanged (see Table 51). The overall elimination of
155
-------
TABLE 51
A COMPARISON OF MAJOR METABOLITES OF BENZENE AND MONOHALOGENATED BENZENES
IN RABBITS AFTER AN ORAL DOSE (0.5 mg/kg body weight)
(Azouz et al., 1952)
Ul
Compound
Benzene
Fluorobenzene
Chlorobenzene
Bromobenzene
lodobenzene
Glucuronides
(% of
original
dose)
11
10
25
40
31
Ethereal
Sulfate
(% of
original
dose)
. 25
21
27
37
40
Mercapturic
Acid
{% of
original
dose)
1
1.6
20.0
21.0
23.0
Unchanged*
(% of
original
dose)
39
44
27
6
3
Vapor Total
Pressuret (% of
(iron Hg) original
dose)
117.5 (78) 76
96.6 (96) 77
15.5 (112.5) 99
5.7 (157) 104
1.5 (204) 87
* Pulmonary excretion.
t Vapor pressure at 30°C from Young, 1910.
Numbers in parentheses represent molecular weight.
Reprinted with permission from Biochem. J., 50:706, 1952.
-------
unchanged monohalogenated benzenes usually takes 30 to 40 hours in the rabbit
(Parke and Williams, 1950; Azouz et al., 1952; Williams, 1959).
Some 30% or more of the monohalogenated benzenes are oxidized in vivo and
may be excreted via kidneys as ethereal sulfates, mercapturic acids and glu-
curonides. Ihe oxidized forms include monohalogenated phenols and catechols.
The ethereal sulfate and glucuronic acid conjugates show considerable varia-
tion quantitatively in the rabbit. Relative amounts produced depend on the
halogen substituent. Mercapturic acids (conjugates of glutathione) are also
excreted via the kidney. For rabbits, about 25% of a dose (0.5 mg/kg body
weight) of chloro-, bromo- and iodobenzene is excreted as mercapturic acids
(Parke and Williams, 1950: Azouz et al., 1952).
In the rabbit, monofluorobenzene is excreted as conjugates of glucuronic
acid (10% of original dose), ethereal sulfate (21%) and glutathione (1.6%)
(Parke and Williams, 1950; Azouz et al., 1952). The glutathione conjugates,
which appear in the urine mainly as mercapturic acids, are small when com-
pared to equimolar doses of other monohalogenated benzenes. They resemble
those derived from equimolar doses of benzene. Glutathione conjugates of
chloro-, bromo- and iodobenzene are 20%, 21% and 23% of the total dose re-
spectively. For MCB, glucuronic acid conjugates are 25% and ethereal sul-
fates are 27%. Conjugated glucuronic acid excretion is 40% of original dose
for monobromobenzene, and 31% for monoiodobenzene, while sulfate excretion is
37% for monobromobenzene and 40% for iodobenzene (see Table 51).
Dichlorobenzenes
The dichlorobenzenes may be absorbed through the gastrointestinal tract,
intact skin and lungs. After oral administration (0.5 mg/kg body weight) to
rabbits, all dichlorobenzenes are slowly metabolized by oxidation, mainly to
157
-------
dichlorophenols. The phenols and their conjugation products are excreted in
five to six days. The peak excretion occurs on the first day for <>- and m-
isomers, and on the second day for p-dichlorobenzene. The major phenolic
metabolites of the dichlorobenzenes are shown below:
Isomer Major phenolic Product % of total dose
o-Dichlorobenzene 3,4-Dichlorophenol 30%
m-Dichlorobenzene 2,4-Dichlorophenol 24%
p-Dichlprobenzene 2,5-Dichlorophenol 35%
About 3 to 11% of the c>- and m- isomers are excreted as dichlorocatechols,
though p-dichlorobenzene does not seem to form this metabolite. The o- and
m- isomers form mercapturic acids (5 to 10% of total), but p-dichlorobenzene
does not (Williams, 1959). The orientation of mercapturic acid is the same
as for the major phenolic product for each isomer. in the case of j>-di-
chlorobenzene, there are two none-phenolic metabolites: 3,4- and 2,3-di-
chlorophenol. These metabolites do not reach their peak excretion at the
same time; the 3,4-isomer peaks on the first day, and the 2,5-isomer on the
second day. The phenolic metabolites are excreted conjugated with glucuronic
and sulfuric acids (Azouz etal., 1952; Azouz et al., 1955; Parke and Wil-
liams, 1955).
Higher Chlorinated Benzenes
As the number of halogens on the benzene ring increases, mercapturic acid
and catechol formation decreases. The tri-, tetra- and pentahalogenated ben-
zenes are metabolized mainly to monohydric phenols, as is shown for polychlor
inated benzene in Table 52 (Williams, 1959). The polyhalogenated compounds
are slowly absorbed from the gastrointestinal tract, a fact which has made
158
-------
TABLE 52
THE QUANTITATIVE ASPECTS OF THE METABOLISM OF
HALOGENATED BENZENES IN RABBITS*
(oral doses of 0.5 gAg body weight)
(Williams, 1959)
Compound
Benzene
Monofluorobenzene
Monochlorobenzene
Monobrono benzene
Monoiodobenzene
1 , 2-Dichlorobenzene
1 , 3-Dichlorobenzene
1 , 4-Dichlorobenzene
1,2, 3-Tr ichlor o-
benzene
1,2, 4-Tr ichloro -
benzene
1,3,5-Trichloro-
benzene
1,2,3, 4-Tetrachloro-
benzene
1,2,3, 5-Tet r achloro-
benzene
1,2,4, 5-Tetrachlorc—
benzene
Pentachlorobenzene
Hexachlorobenzene
Time of
excre-
tion
Days §
1-2
1-2
1-2
1-2
1-2
5
5
5
5
5
8
6
6
6
6
6
% of dose excreted as
Mercap-
turic
Acid
1
1-2
25
25
25
5
11
0
0.3
0.4
0
0
0
0
0
0
Mono-
phenols t
25
+
2-3
2-3
2-3
40
25
35
78
42
9
43
5
2
1
0
Cate-
cholst
2.5(5)
12
27 '
28
21
4
3
0 (6)*
tr.
tr.
0
tr.
0
0
0
0
Total
0-
conju-
gates t
36
31
47
58
53
69
27
63
62
38
23
34
8
5
9
0
Eliminated
unchanged
in expired
air or
feces
39 in air
44 in air
27 in air
6 in air
3 in air
-
— •
-
0 in feces
0
10(51)#"
5(10) #"'
14(23)1"
16(48) #"
5(50)#"
6(77) t
* The figures in this table were obtained in the author's laboratory and are
intended to give a rough indication of the various routes of metabolism
of the halogenated benzenes.
t In some cases these figures give the amounts isolated.
± Conjugated glucuronic acid + ethereal sulfate.
s The excretion of metabolites had not ceased after this time, but were
being produced at a low rate.
f These figures are for quinol.
# The figures in brackets are the percentages of the dose of hexa-, penta-
and tetrachlorobenzenes which were found unchanged in the tissues six
days after the dose.
Reprinted with permission of original publisher, Chapman and Hall, Ltd.,
London, England. -
159
-------
accounting for the total metabolites difficult. 1,4-Dihalogenated, 1,3,5-
tr ihalogenated, tetra- and pentahalogenated benzenes probably do not undergo
mercapturic acid formation in rabbits (Azouz et al., 1952; Azouz et al.,
1955; Parke and Williams, 1955).
The three isomers of trichlorobenzene are absorbed from the gastrointest-
inal tract, intact skin and lungs. In rabbits, these compounds are metab-
olized in varying degrees to phenols (see Table 52). The 1,2,3- isomer is
metabolized to a greater extent (78% of original dose) than either the 1,2,4-
isomer (42%) or the 1,3,5- isomer (9%). All are excreted in about five days.
Very small amounts of mercapturic acids are formed, and their spatial orien-
tation is the same as the phenolic metabolites (Azouz etal., 1952; Azouz et
al., 1955; Parke and Williams, 1955). The 2,4,5-trichlorophenol was shown to
be partially dechlor inated to the extent of about 1%, yielding p-chlorophenol
(Kohli et al., 1976a).
Tetrachlorobenzene is absorbed through the gastrointestinal tract at a
rate considerably lower than the mono- or dihalogenated benzenes (see Tables
52 to 54). The three isomers differ in their ability to undergo metabolism
in rabbits. The 1,2,3,4- isomer is mainly converted to 2,3,4,5-tetrachloro-
phenol. The 1,2,3,5- and 1,2,4,5- isomers are highly resistant to oxidation.
Some of the tetrachlorobenzenes are also partially dechlorinated (Kohli et
al., 1976a). The trichlorobenzenes and other dehalogenated benzenes which
result from dechlorination may have formed in the gastrointestinal tract by
the action of bacterial enzymes (Kohli et al., 1976a).
In the rabbit, some pentachlorobenzene is converted to pentachlorophenol
which has been shown to be highly toxic in a number of studies (Kohli et al.,
1976a). It usually takes about six days to eliminate the tetra- and penta-
160
-------
TftBLE S3
METABOLISM OF 1,3,5-TRI-, PENT*- AND HDCACHLOTOBQJZEKE IN RABBITS
(Parke and Williams, 1960)
Doses
ware given orally mless otherwise indicated
% of Original Dose
urine
Oaapound
TCichlorobenxene
Penta-
Hexa-
chlorobenaene
Dose
(gAg)
O.S
0.5
O.S
0.5
o.st
0.4
0.4
0.1
Time
after
dosing
(days)
8
9
3
4
10
5
5
5
Tri- or
penta-
chloro-
phenol
3
10
0.2
0.2
0.7
0
0
0
Other
phenols
1
4
1
1
1
0
0
0
Efecea
13
1.5
5
5
1.5
6
C
0.3
out
contents
23*
18
45
31
0.5
78
73
0.2
Pelt
5
S
1
3
47*
1
1
75
Depot
fat
3
4.5
15
9
22*
1
1
1
Beat of
body
22
20
6
5.5
10
1
2
1
Total
accounted
for 5
(%)
85
74
82
78
83
84
83
76
• 4% as monochlorobenzem
t injected subcutaneously
t Located mainly at site of action
s Snail aaounta were detected in the expired air
Reprinted with permission from Biochem. J., 74(51:8, 1960 and the senior author.
TABLE 54
SUMMARY OF teZABOUSM OP HIGHER OLQBIMAZED EOCENE ISOERS IN RABBITS
(KDhli at al., 1976a)
Administered*
N>tabolit«
% Yield
1,2,4-Tticfalorobenzene
1,2,3-Tt ichlorobenzene
1,3,5-Trichlorobenzene
1,2,3,4-Tetrachlorobenzene
1,2,3,5-Tetrachlorobenzene
1,2,4,5-Tetr achlorobanzene
Pentadilorobenzene
Bexachlorobenzene
2,4,5-Ttichlorophenol
2,3,5-Ttichlorophenol
3,4,5-Trichlorophenyl acetate
2,3,4-Ttichlorophenol
2,3,6-Ttichlorophenol
2,3,5-TCichlorophenol
2,4,6-Tt ichlorophenol
2,3,4,5-TMr achloroohenol
2,3,4,6-T*trachlorophenol
2,3,4,5-T»trachloropnenol
2,3,5,6-Tetracnlorophenol
2,3,4,6-Ofetrachlorophenol
2,3,5,6-Tctrachlorophenol
2,3,4,5-retrachloropncnol
5
6
2
11
1
1.5
3.0
20
2
3
2
1.5
* Dose was 300 tug in vegetable oil given to 4 to 5 leg rabbits by
intraperitoneal injection.
Reprinted with permission of the National Research council of Canada from the
Canadian Journal of Biochemistry, 54: 203-208, 1976.
161
-------
chlorobenzenes (see Table 52). The reasons for this delay may be enterc—
hepatic circulation and/or high lipid solublity as is suggested from the re-
sults of Sipes et al. (1974).
The hexahalogenated benzenes in general are slowly absorbed from the
gastrointestinal tract or intact skin. Hexachlorobenzene has been studied in
greatest detail, while there are only a few scattered reports on other hexa-
halogen compounds. Hexachlorobenzene when administered orally to rabbits was
not readily absorbed. After five days, about 85% of a dose (0.4 g/kg body
weight) was recovered unchanged in the gastrointestinal tract and the feces
(see Table 53)(Parke and Williams, 1960). Once absorbed, hexachlorobenzene
is metabolized in trace amounts to pentachlorophenol (Lui and Sweeney, 1975).
1,2,4,5-Tetrachlorobenzene was also detected in the intestinal contents.
Bacterial flora in the gastrointestinal tract may have contributed to these
dehalogenations (Kohli et al., 1976a). Traces of dehalogenated compound were
also found in the expired air for tests on monkeys (Yang et al., 1975).
Monobromobenzene
It has been shown in studies on rats that drug conjugates having a molec-
ular weight greater than 300 are often excreted in the bile. Sipes et al.
(1974) found conjugates of glutathione in the bile of rats and studied the
effects of stimulation and inhibition of drug metabolism. They reported that
after bromobenzene administation an increase in bile flow occurs following
prior stimulation with phenobarbital, and a decrease following prior inhib-
ition with 2-<3iethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF—525A)
(see Table 55). It is apparent that in the rat, the biliary route represents
a major means of excretion of metabolites of bromobenzene, and possibly of
other halogenated benzenes. In the rat, 56% of the total dose was excreted
162
-------
TABLE 55
EFFECTS OF PRETREATMENT OP RATS WITH PHENOBARBITAL (80 mgAg, intraperitoneally fi.p.J foe 3 days)
AND SKF-52SA (75 mgAg, i.p. 2 hr before) ON THE BILE EXCRETION OP BROfCBENZENB
METABOLITES AND ON BILE FLOW
(Sipea et al., 1974)
U)
Pretreatment
Time After
Bromobenzene
(min)
0-30
30-60
60-90
90-120
120-150
150-180
None
Bromobenzene
metabolites
Guides)
2.9 ±0.38
4.6 ±0.51
2.9 ±0.43
2.1 ±0.14
1.3 ±0.12
0.8 ±0.05
Phenobarbital
Volume of
bile
(ml)
0.59 ±0.04
0.55 ±0.07
0.55 ±0.06
0.47 ±0.03
0.42 ±0.04
0.45 ±0.03
Broubenzene
metabolites
(iroles)
9.1 ± l.l.t
4.7 ± 0.56
2.1 i 0.19
1.4 ± 0.08 t
0.67± 0.23t
0.76± 0.08
Volume of
bile
(ml)
1.00 ±0.06 t
0.80 ±0.04 i
0.70 ±0.05
0.60 ±0.04
0.58 ±0.04
0.58 ±0.06
SKP-525A
Bromobenzene
metabol itea
(Ambles)
0.8 tO. lOt
3.4 tO. 30 t
2.8 ±0.42
2.1 *0.37
1.6 ±0.28
1.0 to. 15
volume of
bile
(ml)
0.39 ±0.02$
0.42 ±0.03
0.45 ±0.04
0.42 ±0.03
0.40 ±0.04
0.46 ±0.07
14
C-bromobenzene was administered intravenously at a dose of 20 mg/kg (130 jssolea/kg body
weight, sp. act., 2 pCi/umole).
Each value is the mean of five to six rats ± S.E.
t p < 0.01 compared to control rats.
±
< 0.05 compared to control rats.
SKF-525A is 2-diethylaminnethyl-2>2-diphenylvalerate hydrochloride.
Reprinted with permission from Biochem. phannacol., 23(2) ;453, 1974. Oopyright
Pergamon Press, Ltd.
1974,
-------
in the bile. These biliary metabolites appear to be conjugates derived from
the alkylation of glutathione by the highly reactive arene oxides or epoxides
(Sipes et al., 1974). A correlation exists between the ability to form such
arene oxide intermediates and hepatic cytotoxicity (Mitchell et al., 1971).
Reid et al. (1971b) and Zampaglione et al. (1973) indicated that 80% of a
dose of monobromobenzene (oral administration 750 mg/kg body weight) may be
recovered after 24 hours in the urine of rats as monophenois, catechols,
conjugates of glucuronic acid, sulfate and glutathione. Sipes et al. (1974)
found 56% of an intravenously injected dose of monobromobenzene (20 mg/kg
body waight) in the bile after three hours. Hence, they suggested that the
majority of the dose excreted in the bile must be reabsorbed from the
intestine and later excreted via the kidney.
Table 56 shows the concentration of bromobenzene in the tissues of the
rat after an oral dose of 750 mg/kg body weight. These tissue distribution
studies revealed high concentrations in tissue when compared to plasma.
Especially noteworthy was the higher concentration in adipose tissue. After
reducing the dose to 250 mg/kg, the decline in most tissue concentrations was
shown approximately to parallel that in the plasma. Also in these studies,
adipose tissue had a somewhat longer half-life (Reid et al., 1971b).
Stimulators and inhibitors of drug metabolism may determine the extent of
metabolism, which in turn determines the toxicity and distribution of the
bromobenzene (Reid et al., 1971b; Zampaglione et al., 1973). Table 57 shows
the effects of prior administration of phenobarbital (stimulator) and
3-methylcholanthrene (inhibitor) on the metabolism of bromobenzene in a study
on rats. These findings are discussed below. Most striking in reference to
absorption, distribution, recirculation and excretion is the potential for
164
-------
TABLE 56
TISSUE DISTRIBUTION OF BROMQBENZENE
IN RATS AFTER ORAL ADMINISTRATION OF 750 rag/kg BODY WEK3TT
(Reid et al., 1971b)
1
Tissue
i
Plasma
Liver
Kidney
Brain
Heart
Lung
Stomach
Fat
4 hr
>ug/g±S.E.
34 ± 5
282 ± 32
235 ± 50
206 ± 27
146 ± 21
142 ± 41
132 ± 37
5,600 ± 900
Bromobenzene concentration
24 hr
jjg/g±S.E.
2.1 ±0.4
10.7 ±1.2
18. 9 ±4.6 .
7.0 ±1.4
5.0 ±1.2 ,
6. 2 ±1.0
16. 8 ±6.1
400 ±150
Reprinted with permission from Pharmacology, 6:49, 1971.
A.G., Basel, Switzerland.
Copyright S. Karger
bioaccumulation and cumulative effects if a halogenated compound is not
metabolized extensively. Since many of these halogenated benzenes are
volatile, they may be continuously lost into the surroundings.
Dibromobenzenes
1,2-Dibrcmobenzene is absorbed through the gastrointestinal tract. It is
also absorbed through intact skin (see reviews in Williams, 1959 and Parke,
1968). As can be seen in Table 58, two major phenolic metabolites have been
identified in rabbits, the 3,4- and 2,3-dibromophenols (Ruzo et al., 1976).
One other metabolite has not been identified. 1,3-Oibromobenzene is metabol-
ized to four phenolic products: two phenolic isomers were 2,4- and 2,6-di-
brcmophenol (no additional data was given by Ruzo et al. for this isomer).
165
-------
TABLE 57
BROMOBENZENE METABOLITES IN RAT URINE*
(Zampaglione et al., 1973)
CTi
Treatment and Dose Bromophenyl
of Monobromobenzene Mercapturic
Acid
4-Bromophenol
Bromocatechol
Bromophenyl
Dihydrodiol
2-Bromo-
phenol
% of total urinary metabolites
None
Nontoxic dose (0.05 mmol/kg) 70 ± 5
Toxic dose (10 mmoVkg) 48 * 5
Phenobarbital
Nontoxic dose (0.05 mmol/kg) 65* 5
Toxic dose (1.5 mmol/kg) 46*4
3-Methylcholanthrene
Nontoxic dose (0.05 ramol/kg) 72*4
Toxic dose (10 mmol/kg) 31*4
18 ±4
37 ±4
21 ±3
36 ±4
14 ±3
20 ±3
4±2
6±2
8±2
9±2
6±2
10 ±1
4±1
4 ±1
4 ±2
7±1
3±2
17 ±2
3 ±1
4 ±1
1 ±1
1 ±1
4±2
21 ±2
Nontoxic dose given i.v. as a solution in plasma (0.5 ml).
Toxic dose given i.p. as a solution in sesame oil (1 ml).
Urinary metabolites collected for 48 hours over dry ice.
Values are mean ±SD for eight rats. Recovery of administered monobromobenzenes was >90%.
Reprinted with permission from J. Exp. Ther., 187(1):224, 1973. Copyright
and Wilkins Co., Baltimore, Maryland.
1973, The Willians
-------
1,4-Dibronobenzene is metabolized to a greater extent than 1,2-dibromobenzene.
The metabolism of dibromobenzenes is similar to the metabolism of dichloro-
benzenes.
TABLE 58
SUMMARY OF RABBIT URINARY METABOLITES OF SOME ISGNERIC BROMINATED BENZENES
» " i
Substrate* Metabolite % Yield t
Bromobenzene 4-Bromophenol 1.2
3-Bromophenol 1.0
1,2-Dibrcmobenzene 2,3-Dibromophenol 0.9
3,4-Dibr onophenol 0.9
1,4-Dibronobenzene 2,4-Dibromophenol 1.5
2,5-Dibromophenol 1.0
1,3,5-Tribromobenzene 2,4,6-Tribromophenol 1.3
2,3,5-Tribromophenol^: 1.1
1,2,4-Tribromobenzene 2,4,5-Tribromophenol 1.0
2,4,6-Tribromophenol 0.4
* 300 mg was administered to each of two rabbits.
t The figure shown is the percent yield of metabolite obtained by
extraction and purification of the ether extracts of the hydrolyzed :
rabbit urine.
t Not conclusively identified due to the unavailability of an authentic
standard.
Reprinted with permission from Ruzo, L.O., S. Safe and O. Hutzinger.
Metabolism of Bromobenzenes in the Rabbit. J. Agric. Food Chem., 24(2):292,
1976. Copyright by American Chemical Society.
Higher Brominated Benzenes
l/SfS-Tribromobenzene is metabolized slightly to 2,4,6-tribronophenol and
anotheV tribromophenol. Since only one vicinal position is available for dir-
ect hydroxylation, the other tribromophenol must be formed via migration of
bromine (NIH shift) (Daly et al., 1972). The NIH shift is a molecular re-
167
-------
arrangement often accompanied by a 1,2-H or substituents (i.e. Cl, Br, CH_)
shift from site of hydroxylation to the adjacent carbon (Daly et al., 1972).
This suggestion is consistent with the concept of an arene oxide intermedi-
ate. Similar evidence has been presented for this intermediate in metabolism
of dibromobenzene isomers (Ruzo^t al., 1976).
1,2,4,5-Tetrabromobenzene yields only trace amounts of a dehalogenated
metabolite (Ruzo et al., 1976). These authors also reported that penta-
bromobenzene yields trace amounts of pentabromophenol and that no data were
available for hexabromobenzene.
In summary, lower brominated benzenes are metabolized partially to phe-
nols (see Table 58). Some hydroxylations are accompanied by the migration of
bromine, suggesting an arene oxide intermediate. In general, the higher
brominated compounds are more resistant to oxidations than the chlorinated
compounds, but are metabolically degradable in trace amounts, with products
appearing in the urine and feces.
(b) Pharmacology and Metabolism
Background Discussion
Most mammals contain a group of enzymes that specialize in the biotrans-
formation of foreign compounds. These enzymes are located in the endoplasmic
reticulum of the liver cells. The metabolic transformation of foreign com-
pounds usually leads to the conversion of lipophilic materials into more po-
lar compounds, which are readily eliminated from the hepatocyte and excreted
from the body. Thus, compounds which are of little nutritive value (anutri-
ents or xenobiotics) are prevented from accumulating in cells and tissues.
In this way, undesired effects may be avoided (see reviews in Williams, 1959;
Parke, 1968).
168
-------
The endoplasmic reticulum of the cell is the site for the location of
many enzymes such as glucose-G-phosphatase, glucuronyl transf erase, various
steroids, hydroxylases and protein synthetases (Parke, 1972). The enzymes
concerned with the metabolism of drugs and other xenobiotics are frequently
referred to as mixed function oxidases or monooxygenases. All the monooxy-
genase drug metabolizing enzymes require reduced nicotinamide adenine di-
nucleotide phosphate (NADPH-)* molecular oxygen and a cytochrone known as
P-450. This subcellular structure, endoplasmic reticulum (ER), is not only
associated with the oxidation of drugs, but also the biosynthesis of cholest-
erol, the catabolism of bile acids, the oxidation of fatty acids and the
oxidation of prostaglandins. In addition to mixed function oxygenase activi-
ties, the hepatic endoplasmic reticulum contains a number of reductases, some
of which utilize cytochrome P-450 and NADPH- (Williams, 1959; Parke, 1968).
I
The biotransformation of drugs and xenobiotics appears to occur in two
distinct phases. The first phase includes reactions classified as oxida-
tions, reductions and hydrolyses. in the second phase, the reactions are
referred to as syntheses or conjugations. These enzyme reactions, especially
oxidations which require cytochrome P-450, have been examined throughout the
animal kingdom. Contrary to the suggestion of an evolutionary trend for the
appearance of cytochrome P-450 in mammals, this cytochrome is apparently
ubiquitous (Ahokas et al., 1976).
j
However, quantitative differences in metabolism exist for example among
livers from various species, among various tissues from a single animal, and
between the neonate and adult within a species. It has also been well
documented that enzymes of biotransformation may be regulated (stimulated or
depressed) by xenobiotics or steroids (Parke, 1972). While there does appear
169
-------
to be a ubiquitous distribution of cytochrome P-450/ the concentration in
different animal species varies greatly, as can be seen in Table 59. Since
these species have differing amounts of cytochrome P-450, they must have
different abilities to manufacture toxic intermediates. They also have
varying abilities to metabolize benzpyrene and halogenated benzenes.
Species differences in metabolism of monochlorobenzene are shown in Table
60. However, this ability does not appear to be related directly to the con-
centration of cytochrome P-450 (see Table 59). The postulated rate limiting
step in the oxidation of xenobiotic compounds is formation of cytochrome
P-450 reductase (Gigon et al^, 1968). There is no apparent correlation be-
tween this step and the ability to form hydroxy metabolites. Comparing the
values for the rabbit in Tables 59 and 60, we observe relatively high levels
of cytochrome P-450, low levels of cytochrome P-450 reductase and high
ability to form 4-chlorophenol and 4-chlorocatechol. The rat with a high
level of cytochrome P-450 reductase has a different pattern of metabolites.
Two other factors may determine whether a compound is toxic or not: one is
the concentration of enzymes which catalyze conjugation with glutathione and
form mercapturic acids, and the other is the concentration of the enzyme
epoxide hydrase. The differences above are reflected in the metabolites of
chlorobenzene in various species as shown in Table 60.
Pharmacology and Metabolism of Halogenated Benzenes
The lipid soluble halogenated benzenes are distributed throughout mam-
malian tissues and appear to traverse most tissue barriers including the
brain and placenta. As was discussed previously, o- and m-dihalogenated,
1,2,3- and 1,2,5-trihalogenated and 1,2,3,4-tetrahalogenated benzenes are
extensively metabolized.
170
-------
TABLE 59
SPECIES VARIATION IN TOE DISTRIBUTION OF CVT. P-450,
P-450 REDUCTASe, NADPII CYT.-C REOUCTASE, AM) HYDRCKY BENZPYRENE FORMED.
(Kato, 1966| Gigonet al., i968| Davleset al., 1969; Flynnet al., 1972)
Animal Sex
House
Rat
Rabbit
H
F
Wild Rat H
P
Wild R. H
Monkey F
Wild S. H
Monkey F
Tupaia H
P
Pig
Man
Trout
Cyt. P-450
nmol/mg
1.23*
0.86*
0.82*
0.67*
1.10*
1.28*
1.05*
1.09*
0.97t
0.84t
1.16t
1.19t
0.44t
0.39t
0.53t
o.eot
o.aet
0.911
0.28*
0.63*
0.20
Cyt. P-450
Reductase
11.2
12.3
8.4
7.3
3.8
4.2
3.0
3.4
* n raol/nq P
t A -A 450-490 per 09 P x 10
f n BDl. product/miiVnrq P
§ n nol. per og liver per hr.
1 n mol. per ng P/min.
NADPH Cyt-c
Reductase
144
166
150
145
132
145
130
150
228
217
192
182
81
76
146
146
217
240
78
118
20
Hydroxy benz-
pyrene formed
1.B2S
2.92$
2.07 S
1.12S
0.14*
0.041
0.1H
0.101
0.151
0.191
0.2H
0.32(1
0.111
0.141
TABLE 60
METABOLISM OP "c-CHUTOBENZENE IN DIFFERENT SPECIES
(Millions et al., 1975)
Species
Man
Rhesus monkey
Squirrel nonkey
Capuchin nnkey
Dog
Ferret
Hedgehog
Rabbit
Mouse
Gerfoil
Hanster
Guinea pig
Rat
toC
4-Chlorophenol
33
19
14
19
14
33
20
29
20
13
15
27
23
24 hour excretion of
4-Chlorocatechol
31
37
37
36
45
31
12
38
31
26
23
35
22
"C as:
4-Chlorophenyl
ttercapturic acid
16
40
50
41
42
24
65
26
«
51
43
21
49
Reprinted with petal salon from Mclntyre, A.D. an) C.P. Kills (eds.),
Ecological Toxicologlcal Research. Plenum Press, Net* York, 1975.
-------
Sane 56% or more of an administered dose of the nonohalogenated benzenes
are oxidized in vivo. As stated in Section (a) above, the oxidized products
may be found in the urine as phenols, catechols, sulfates and glucuronides
(see Table 51). The main pathway of oxidative metabolisn of monohalogenated
benzene in the rabbit is an oxidation to phenols and subsequent conjugations.
Significant amounts of monofluorobenzene (44%) and monochlorobenzene (27%)
are excreted unchanged in the expired air.
There is strong evidence that some of the oxidations proceed through the
formation of arene oxides intermediates. Such evidence includes: a correla-
tion of overall toxicity and cellular toxicity with metabolism; a correlation
of toxicity with in vivo and in vitro covalent binding of metabolites with
all proteins; and the appearance of increased toxicity associated with a de-
pletion of tissue levels of glutathione (Reid est jal., 1973; Reid and Krishna,
1973) (see Table 61).
Monofluorobenzene formis both o- and p-fluorophenols. In the rabbit the
major hydroxy metabolite formed is 4-fluorocatechol (Azouz et al., 1952).
Following a nontoxic dose of monochlorobenzene (0.5g/kg body weight), the
urine of rabbits contained dihydrodihydroxybenzene, p-chlorophenol and
4-chlorocatechol. The ratio of p-chlorophenol to 4-chlorocatechol metabo-
lites was 1:20. Small amounts of c^- and p-chlorophenol were also found. The
ratio of glucuronides, ethereal sulfates, mercapturic acids, and unchanged
chlorobenzene was approximately 3:3:2:3. The major hydroxy metabolite of
chlorobenzene in rabbits was 4-chlorocatechol (Williams, 1959; Parke, 1968).
Monobromobenzene has received the greatest attention in metabolic studies.
A possible metabolic route for monobromobenzene is shown in Figure 22
(Gillette, 1975a). Following a nontoxic dose of monobromobenzene (210
172
-------
TABLE 61
EFFECT OF PHENOBARBITAL AND SKF-525A ADMINISTRATION CN COVALENT BINDING OF HALOGENATED
BENZENE DERIVATIVES TO RAT LIVER PROTEIN IN VIVO 6 HOURS AFTER ADMINISTRATION
(Reid et al., 1973.; Reid and Krishna, 1973)
Control
(nM/mg protein
± S.E.)
Phenobarbital
(nM/mg protein
± S.E.)
Phenobarbital*
SKF-525A
(nM/mg protein
± S.E.)
14
Monobromobenzene- C (1 mM.kg)
14
Monochlorobenzene- C (1 mM/kg)
14
Monoiodobenzene- C (1 raM/kg)
14
Monofluorobenzene- C (1 mM/kg)
o-Dichlorobenzene- C (0.5 mM/kg)
14
p-Dichlorobenzene- C (0.5 mM/kg)
0.267 ±0.034
0.364 ±0.053
0.090+0.015
0.085+ 0.015
0.234+ 0.015
0.021± 0.002
0.550 +0.0311
1.268±0.278t
0.545±0.129t
0.054 + 0.008
0.308 ±0.038
0.012+O.OOlf
0.036±0.024t
0.483 ±0.144 §
0.666 ±0.304
0.052 + 0.005
0.186 ±0.014 §
0.006 ±0.001
* 2-Diethylaminoethyl-2,2-diphenylvalerate hydrochloride (SKF-525A) (75 mg/kg i.p.) was given 1 hour
before the hepatotoxin.
Values are the mean of 6 rats ± S.E.
i" p<0.01 compared with controls.
f p<0.01 compared with phenobarbital alone.
§ p<0.02 compared with phenobarbital alone.
-------
FIGURE 22
PATHWAYS OF BPCMDBENZENE METABOLISM
(Gillette, 1975a)
i—
•^i
.to.
epoxide synthet-
ase Cmicarosomes)
.__ ».
NAEPH + d0
bronobenzene
rearrange-
Br ment
'non-
enzyrnatic
p-brcroophenol
jr bronobenzene epcocide
nonenzymatic
oovalently bound
to rnacaronolecule
3,4-dihydro-3,4-
diliydrcQcy-brcmdbenzene
OH
H
•H
3,4-dihydro-3-hydroxy-
4-S-glutathionyl brono-
benzene
acetyltrans ferase
•4-
AcCys
acetyl-3,4-dihydro-
3-hydroxy-4-S-
cysteinyl bromobenzene
3,4-dihydroxy-
bronobenzene
3,4-dihydro-3-hydroxy-4-S-
cysteinyl bromobenzene
Reprinted with permission, MTP Press, Ltd., St. Leonardgate, Bigland
-------
mg/kg body weight) in rabbits, nearly 80% was oxidized to phenols and 20% to
p-bromophenylmercapturic acid. The main oxidative product in rabbits was
4-bromocatechol and the minor products were o- and ^-bromophenols (see Table
58, Ruzo et al., 1976). The theoretical arguments for the scheme diagrammed
in Figure 22 are presented in detail by Gillette (1975a).
For monoiodobenzene, a dose response relationship in rats has been shown
for covalent binding, toxicity and extent of metabolism (Azouz et al., 1953).
Below 720 mg/kg body weight., there is an increase in mercapturic acid for-
mation with dose. At and above 720 mg/kg body weight, there is a dramatic
falloff with a corresponding rise in oxidative metabolites. For the same
dose, rabbits form much less mercapturic acid than rats (see Table 60). The
major product of oxidative metabolism of monoiodobenzene is 4-iodocatechol.
In the rat, j>-iodophenol appears to be the major metabolite. Dihydrodi-
hydroxyiodobenzene has also been reported, p-iodophenol is a minor metabol-
ite in the rabbit (Azouz et al., 1953).
Metabolic products for higher chlorinated benzenes were discussed in the
previous section.
(c) Relationship Between Metabolism and Toxicity
Many workers have studied the possibility that occasional cellular damage
caused by many drugs is mediated via chemically reactive metabolites. Most
of the metabolites formed by the cytochrome P-450 enzymes are chemically
inert, but certain of the metabolites such as -the arene oxides or epoxides
may interact with physiological or biochemical processes, causing either
pharmacological or toxicological effects. Investigators are usually able to
determine if a response is caused by the parent compound or by one of the
metabolites by one of the following procedures (Gillette, 1975a, 1975b):
175
-------
a) Identify the metabolites and then administer them to the animal.
b) Identify covalent binding of metabolites in tissues.
c) Use inhibitors and inducers of drug metabolism, for either may alter
the pattern of effects. Inducers may also increase the metabolism
of active metabolites more than they increase the metabolism of the
parent compound. This makes it difficult to interpret these
studies.
d) Administer drugs chronically to see if the effect on cytochrome
P-450 enzymes is biphasic. Almost all of the inducers studied have
shown initial inhibition of these enzymes, followed by an increase
12 to 24 hours later. Hence, one substrate seems not only to induce
the enzymatic activity for its own metabolism, but also for that of
other xenobiotics and steroids.
Inducers of endoplasmic reticulum (ER) drug metabolizing enzymes in-
creased hepatic ER enyzmes when administered to rats for several days. They
had little or no effect on other enzymes in the ER (Parke, 1972). On the
other hand, hepatotoxic compounds such as halogenated hydrocarbons had an
effect on drug metabolizing enzymes, cytochrome P-450 and NADH cytochrome c
reductase (Ariyoshi et al., 1975; Carlson and Tardiff, 1976). Glucose
6-phosphatase was shown to undergo a change associated with conformational
alteration of ER membranes, which masks an increase in activity of the latent
enzyme (Pandhi and Baum, 1970). Induction of hepatic microsomal enzymes by
certain carcinogenic hydrocarbons such as 3-methylcholanthrene produces a
cytochrome with an absorption maximum at 448 nyu with carbon monoxide as a
ligand, whereas the phenobarbital-type is at 450 nju. The 2- and 4-hydroxyla-
tion of biphenyl is stimulated by pretreatment of rats with carcinogenic
176
-------
hydrocarbons, whereas only the 4-hydroxylation is stimulated with phenobarbi-
>
tal-type inducers. Thus, stereospecific hydroxylations and conformational
changes in ER membranes may occur following induction (Parke, 1972).
Recent studies of halogenated benzenes, using bromobenzene as a prototype,
(Brodie et al., 1971; Reid et al., 1971b; Mitchell et al., 1971) demonstrated
that hepatic necrosis produced on exposure to these compounds results from
their conversion to reactive toxic intermediates. The stimulation of metabo-
lism of bromobenzene by pretreatment with phenobarbital, potentiates hepatic
damage in rats, as can be seen in Table 61. Conversely, blocking metabolism
of bromobenzene by SKF-525A (2-diethylaminoethyl-2,2-diphenylvalerate hydro-
chloride) or piperonyl butoxide (a pesticide synergist) prevents their
hepatotoxicity (Reid et al., 1973; Reid and Krishna, 1973). j
Several studies have shown that bromobenzene induced hepatic necrosis
results from the arene oxide reacting with cellular macromolecules. The
severity of liver necrosis correlates well with the extent of covalent bind-
ing of metabolites in vitro and in vivo after various pretreatments, as can
be seen in Table 62. Direct kinetic evidence has shown that the 3,4-bromo-
benzene arene oxide is the reactive hepatotoxic metabolite. These studies
have also demonstrated that the bromobenzene arene oxide formed is preferen-
tially conjugated with glutathione (Reid et al., 1973; Reid and Krishna,
1973). The glutathione content in the liver is drastically decreased in the
presence of large doses of bromobenzene (see Table 62). Conjugation with
glutathione is believed to be an important detoxication mechanism. Liver
necrosis occurs when glutathione is depleted. Thus, a threshold dose seems
to exist for bromobenzene induced necrosis.
phenobarbital enhanced both the metabolism and the hepatic necrosis
177
-------
00
TABLE 62
COVELEWT BINDING, HEPATOTOKICITY, AND MERCAPTURIC ACID EXCRETION OF
HALOGENATED BENZENE DERIVATIVES
(Reid et al., 1971b; Reid et al.f 1973; Reid and Krishna, 1973) '
Compound
Monobromobenzene
Monochlorobenzene
Monoiodobenzene
Monofluorobenzene
o-Dichlorobenzene
p-Dichlorobenzene
(1 mM.kg)
(1 mM/kg)
(1 mM/kg)
(1 mH/kg)
(0.5 mH/kg)
(0,5 mH/kg)
Covalent binding
(nH/mg protein
±S.E.)
0.534± O.OSOt
0.604± 0.044t
0.323+ 0.054
0.060± 0.004t
0.234± 0.0155
0.021+ 0.002§
Hepatic
necrosis
Yes
Yes
Yes
No
Yes
No
Mercapturic
acid excretion
3+
3 +
3+
+
2 +
±
Glutathione
concentration
(% of control)*
67
Not determined
66 ±
82
48 t
101
Values are the mean of 6 rats.
* Glutathione concentration determined 3 hours after administration of the hydrocarbon.
t Killed at 24 hours.
f p<0.01 compared with control.
§ Killed at 6 hours.
-------
caused by monobromobenzene. In contrast, 3-methylcholanthrene did not alter
the metabolism of bromobenzene, but reduced hepatic necrosis in vivo. "Hie
determination of the urinary metabolites of monobromobenzene showed 3-methyl-
cholanthrene caused an increased excretion of bromophenyldihydrodiols and
bromocatechols, whereas phenobarbital did not. Thus 3-methylcholanthrene
increased the metabolism of the reactive metabolite greater than it did the
parent compound (Reid et al., 1971a).
The finding of increased amounts of dihydrocatechols, catechols and
2-bromophenol after administration of toxic doses of bromobenzene to animals
pretreated with 3-methylcholanthrene suggests that this pretreatment induces
an alternate pathway of metabolism. Hydrases acting on arene oxides may
compete with the arene oxide glutathione route for detoxication (see Figure
22, Gillette, 1975a).
!
Species differences in bromobenzene*s hepatotoxicity and metabolism are
summarized in Table 63. As can be seen in this table, intraperitoneal admin-
istration of monobromobenzene (1 ml/kg body weight) resulted in extensive
centrolobular necrosis in mice and rats, while no specific lesions were
detected in neonatal rats, hens, toads and frogs. No definite conclusions
regarding the metabolism and toxicity of nonobromobenzene in humans can be
drawn from these data.
Just as there are species differences in metabolism, there are differ-
ences in the metabolism of a halogenated benzene in different organs, i.e.,
lung may differ from kidney which differs from liver, etc. (see Tables 64 and
65). As can be seen in Table 65, phenobarbital does not increase covalent
binding in the lung as shown for the liver (Reid et al., 1973; Reid and
Krishna, 1973).
179
-------
TABLE 63
SPECIES DIFFERENCES IN BRDMOBENZENE1S HEPATOTOKICIIY AND METABOLISM
(Mitchell et al., 1971)
Severity of
Centrolobular
Necrosis
24
hr Bromobenzene
Concentration
Plasma
(ug/ml)
Mouse
Rat
Rabbit
Hamster
Neonatal rat
Hen
Toad
Frog
Extensive
Extensive
1
2
.0
.8
±0
±0
.1
.3
(4)
(7)
Minimal to moderate
Minimal to moderate
No specific
No specific
No specific
No specific
lesions
lesions
lesions
lesions
3
3
6
.2
.8
.9
±0
± 0
±1
-
—
.5
.3
.1
(3)
(6)
(7)
Liver
(ug/ml)
18
26
35
42
89
214
151
1701
±
+
+
±
±
+
+
4
3
12
9
24
39
34
±106
(4)
(7)
(3)
(3)
(6)
(7)
(6)
(6)
Animals were given bromobenzene (1 ml/kg, intraperitoneal injection) and
killed after 24 hr. Livers were examined histologically and bromobenzene
concentrations in plasma and liver were assayed. Values are means ±S.E. with
number of experiments in parentheses.
Reprinted with permission from Res. Common. Chem. Pathol. Pharmacol., 2:882,
1971. Copyright PJD Publications, Westbury, New York, 1971.
Phenobarbital or 3-methylcholanthrene enhance the activity of A— amino-
levulinic acid (A-ALA) synthetase, the rate-limiting factor in the enzymatic
synthesis of porphyrins. Some porphyrins are intermediates in the synthesis
of cytodhromes. Porphyria, a disturbance in porphyrin metabolism, is char-
acterized by increased formation and excretion of porphyrin precursors, cu-
taneous photosensitiyity, frequent hemolytic anemia and splenomegaly. Acute
abdominal and nervous system manifestations may also occur. In 1959, an
outbreak of porphyria in humans was traced to the ingestion of wheat which
had been previously treated with hexachlorobenzene. Since that time, hepatic
180
-------
TABLE 64
DISTRIBUTION OF CCVALENTLY BOUND 14C-BRCMOBENZENE IN THE MOUSE *
(Reid et al., 1973)
Tissue
Govalent binding
(nmoles/mg protein)
Liver
Kidney
Lung
Plasma
Ileum
Spleen
Heart
Stomach
Brain
Test is
1.
1.
0.
.890
.338
.345
0.130
0.113
0.061
0.049
0.049
0.031
0.030
* Mice were killed 24 hrs. after administration of a nepatatoxic dose of
14.
C-bromobenzene (4.8 rranoles/kg).
TABLE 65
BINDING OF AROMATIC HYDROCARBONS IN RAT LUNG:
EFFECT OF PHENOBARBITAL*
(Reid et al., 1973)
Time of
Compound Killing
(hour)
Bromobenzene- C,
ImM/kg
14
Chlorobenzene- C ,
ImM/kg
14
o-Dichlorobenzene- C,
0.5mM/kg
14
Pj-Dichlorobenzene- C ,
0.5 mM/kg
6
24
6
24
6
24
6
24
Binding of Hydrocarbon
(npnole/mg protein)
Control
141
117
268
164
27
20
4
3
± 18
± 14
± 60
± 26
.3
.9
.6
.4
±
±
±
±
1
2
0
0
.4
.4
.2
.4
in
Lung
Phenobarbital
77
88
172
91
18
15
3
1
.9
.3
.4
.8
±
±
±
±
±
±
±
7
7
20
4
2
2
0
0
.6t
.4
,7§
.2
.5
.2
*Values are the means ± SE of 6 animals.
t p<0.01
f p<0.02
§ p<0.05
Tables 64 and 65 reprinted with permission from the author and the
publishers, American Review of Respiratory Disease.
181
-------
porphyria has been produced in rats and rabbits by feeding them hexachloro-
benzene.
After the addition of 0.25% hexachlorobenzene in the diet of rats, por-
phyria was produced in 6 to 12 weeks (Lui and Sweeney, 1975). Also occurring
were an increase in liver weight, an increase in smooth ER induction of
cytochrome P-450 and hepatocellular damage. Evidence was presented that
pentachlorophenol is formed during metabolism.
The pentachlorophenol metabolite was found also in the monkey after HCB
administration (Yang et al., 1975). Rimington and Ziegler (1963) showed that
in rats chronic administration of 500 to 800 rag/kg body weight of chlorinated
benzenes (except pentachlorobenzene) leads to a hepatic porphyria character-
ized by elevated levels of precursor porphyrins in liver and feces. The first
signs of intoxication were an increase in urinary coproporphyria and porpho-
bilinogen (PEG). Aminolevulinic acid excretion was a late effect. The most
active compounds were j>-dichlorobenzene, 1,2,4-trichlorobenzene and 1,2,3,4-
tetrachlorobenzene (see Tables 66 and 67). Histologic examination showed
liver necrosis and fatty changes over large areas. Mono-, 1,2-di- and
1,2,4-trichlorobenzene were the most toxic.
After administration of 1,2,4-trichlorobenzene, liver glutathione content
was found to have decreased in starved rats. Glutathione given to these
highly porphyric rats had a protective effect (Rimington and Ziegler, 1963).
In additional studies, all the chlorinated benzenes were shown to produce
distubances in porphyria. If the studies with chlorinated benzenes could
serve as a prototype for other halogenated benzenes, it might be said that
the severity of this biochemical lesion should vary with both dose and com-
pound. The mechanism for the unique biochemical lesion produced seems similar
182
-------
TABLE 66
MEAN PEAK VALUES OF URINARY PORPHXRINS AND PORPHXRIN PRECURSORS FOLLOWING TREATMENT OP MALE RATS
WITH THE MAXIMUM DOSES TRIED OF EACH CHLORINATED BENZENE; VALUES FOR ALLYUSOPROPYLACETAMIDE
AND SEDORMID ABE GIVEN FOR COMPARISON
(Rimington and Ziegler, 1963)
Ho. of Compound
rats
Sol-
vent
Max.
dose
(ma/kg)
Days
on
max.
dose
Copro-
porphyrin
tug/day)
Uropor-
phyrin
(ug/day)
PBG
(jjg/day
ALA
(Pi/day)
ALA PBG
Controls*
4.3-6.3
0.1-0.3 2.5-6.5 38.7-51.6
3 Monoehlorobensene P 1140
3 1,2-Dichlorooenzene P 455
3 1,4-Oidilorobenzene P 770
3 1,2,3-Ttichlorobenzene C 785
3 1,2,4-TridilorabenzefM C 730
3 1,2,3,4-TetracnlorabeMene P 660
6 1,2,4,5-Tetrachlorobenzene C 905
3 AIA Pr.g 250
2 AIA Pt.g 500
4 Seooraid Pr.g 250
P • liquid paraffin; C • 1% oellofas; Pr.g •
PBS • porphobilinogen; ALA «A-aminol«vulic
5
15
5
7
15
10
5
10
6
10
30.50
43.10
61.80
3C.59
58.31
28.96
4.10
17.35
43.07
8.32
• prbpylene glycol;
acid.
1.40
2.01
10.99
0.72
2.73
3.80
0.22
5.00
16.61
3.60
AIA «
26.70
26.65
1328.10
57.38
179.00
520.63
6.50
863.67
2339.61
851.56
ailylisopr
56.40
11.32
437.41
36.26
145.70
315.78
18.08
an. 45
2378.68
444.99
opylacetanid
2.98
2.11
0.36
1.01
1.06
0.61
6.69
0.71
0.96
0.52
e;
* Mean rax. and nin. of 5 rats during 41 days.
Reprinted with permission froa Biochen. Phana., 12:1390, 1963.
Copyright©1963 by Pergamon Press, Ltd.
TABLE 67
PQRPHYRINS, PORPHCBILINO3EN AND CAZALASE ACTIVITY IN LIVERS OP RATS TREATED WITH CHLORINATED BENZENES,
ALLXUSOFROPYLACETAMIDB OR SEDORMID
(Rimington and Ziegler, 1963)
Ho. of compound
rats
Max.
dose
(mg/kg)
Days
on
max.
dose
Copco-
porphyrin
(pg/100 g)
Protopoc-
pnyrin
(U9/100 g)
Oropor-
phyrin
(W/100 g
tnoorrected)
PBG Catalase
(m.eq. rag)
wet wt.
Controls*
4.5
9.7
1.3 —
0.85
2
2
2
2
5
3
2
3
1
2
Monochlorobenzene 1400
1,2-Oichlorobenaene 450
1 , 4-Dichlorobenzene 770
1,2, 3-Tt ichlorobenzene 780
1,2.4-Trichlorobenzene 500
1,2,3,4-Tetrachlorobanzene 660
1,2,4,5-Tetrachlorobenzene 850
AIA 250
AIA 500
Sedonnid 250
5
15
5
7
10
10
s
10
6
10
Ttace
10.05
5.07
2.65
42.56
35.04
6.30
17.35
73.60
9.29
13.00
34.80
60.50
3.55
55.60
56.57
9.90
19.10
114.50
12.91
6.35
14.40
60.35
20.00
52.70
41.32
2.15
13.08
18.49
17.07
0.502
0.364
0.880
0.857
•H- 0.747
+ 0.772
0.838
•H- 0.320
, -H- 0.140
•H- 0.220
AIA » allylispropylaoetanide; PBG - porphobilinogen.
* Mean of 2 rats.
Reprinted with permission from Biochem. Pharm., 12:1393, 1963. Copyright© 1963 by Perganon Press,
Ltd.
183
-------
to that seen following administration of other inducers of drug metabolism.
It'is also similar to that seen in man following exposure to ethanol, syn-
thetic estrogens and progesterins (Parke,1972).
Ariyoshi et al. (1975) have shown an initial increase in content of
cytochrome P-450 and an initial decrease in A-ALA synthetase activity fol-
lowing oral administration of chlorinated benzenes, they also reported a
dose-response relationship. In the time course after a single oral dose of
250 mg/kg body weight, the activity of A-ALA synthetase decreased at six
hours, was normal at 12 hours and increased at 24 hours. The opposite
changes were noted in the content of cytochrome P-450 (see Table 68). The
spectral change in cytochrome P-450 is of the phenobarbital type (Type I).
Carlson and Tardiff (1976) studied the effects of chlorobenzene; 1,4-di-
chlorobenzene, l-bromo-4-chlorobenzene, 1,2,4-trichlorobenzene and hexa-
chlorobenzene on adult male rats for 14 days at low doses from 10 to 40 mg/kg
body weight.
All halogenated benzenes except monochlorobenzene decreased hexabarbital
sleeping time immediately and/or 14 days following treatment. As can be seen
in Table 69, cytochrome c reductase, cytochrome P-450 content, O-ethyl
O-pj-nitrophenyl phenylphosphonothioate (EPN) detoxication, glucuronyl trans-
fer ase, benzpyrene hydroxylase and azoreductase were increased to varying
degrees (Carlson and Tardiff, 1976). Administration of 1,4-di- and 1,2,4-
trichlorobenzene for 90 days resulted in an increase in EPN detoxication,
benzyprene hydroxylation and azoreductase. The increases were still appar-
ent 30 days later. 1,2,4-Trichlorobenzene was the most potent inducer of
cytochrome c reductase and cytochrome P-450. Either no change or a decrease
was reported for glucose-6-phosphatase and isocitrate dehydrogenase
184
-------
TABLE 68
EFFECT OF CHLORINATED BENZENES ON AMINOLEVULINIC ACID
snnHETASE AND OTOCHRCHE p-4so CONTENT OP RAT LIVER *
(Rinington and Ziegler, 1963; Poland et al., 1971; Ariyoshi et al
Chlorinated
benzene
Control
Muiiijtihlorobenzens
1 , 2-Oichlorobenaene
1 , 3-Oichlorobenzene
1,4-Oichlorobenrene
l,2,3-Ttichloroben2ene
1,2,4-Trichlorobenzene
1 ,3 ,5-Trichlorobenzene
1,2,3, 4-Tetr achlorobenzene
1,2,3,5-Vetrachlorobcnzene
1,2, 4,5-Tetr achlorobenzene
Pontachlorobenzene
Bexachlorobenzene
Free Possibility
vicinal of epoxide
positions formation
2,3,4,5,6 +
3,4,5,6 *
4,5,6 +
2,3,5,6 +
4,5,6 +
5,6 f
NDIM . ••
5,6 +
(tone
Hone
None
tone
Extent of
metabolism
High
High
High
High
High
High
tow
High
tow
tow
Vtery low
Wry low
., 1975) Williams et al. , 1975)
P-450
n raolas/g
0.68
0.56
0.66
0.77
0.73
0.84
1.63
0.73
0.97
1.14
0.99
1.16
0.97
AIA
Synthetase
n ooles/g/hr
22.6
49.2
36.3t
29.8t
32.3
33.6
47.5t
34.8
33. 3t
35.4t
27.5
98. 7t
51.8
Forphyria£
yes
-
yes
yes
yes
yes
-
-
yes
(1140)
( 455)
( 770)
( 785)
( 730)
( 660)
( 400)
* Rats were pretraatcd orally with 250 mg/hg body wt. for three days and were sacrificed 24
hours after the last dose.
t Significantly increased over control.
f Nmbers in parenthesis indicate dose in ng/kg body wt. uMd to produce parphytia in 5 days.
[note: glutathione reduces porphyria produced by Halogenated benaenes.]
TABLE 69
EFFECT OP CHLORINATED BENZENES ADMINISTERED po FOR 14 DAYS ON VARIOUS PARAMETERS OF XEND3ICTIC tSTABOUSM
(Carlson and Tardiff, 1976)
expound
Monochlorobenzene
1 , 4-Oichlorobenzene
l-Brono-4-
chlorobcnzcns
1,2,4-Trichloro-
benzene
Hexachlorobenzene
Dose
(mg/kg/day)
0
200
400
800
0
10
20
40
0
10
20
40
0
10
20
40
0
10
20
40
Cytochrcot c
reductase
(rnol
cytocnrome c
reduced/rain
ng protein)*
100 * 25
110 * 8
109 * 9
78 * 5
156 * 9
151 * 6
165 * 8
176 * 10
149 * 22
126 * 6
123 * 4
141 * 5
103 ± 8
139 ± 15
192 * 12
183 * 9
85 * 7
106 ± 10
109 ± 7
100 * 7
CytochroDB
P-450 (AE/mg
protein x 10)
236 * 20
209 * 10
197 * 14
133 t 15
178 * 20
174 * 15
167 * 11
193 * 13
205 * 35 •
180 * 7
202 t 7
245 * 19
72 * 13
99 * 18
212 * 45
268 * 15
128 * 18
204 * 18
190 ± 16
150 1 27
ducuronyl-
transferase
(Rnol/fain/mg
protein)
5.8* 0.4
9.4* 0.6
12.2* 0.3
13.0* 0.5
5.9* 0.6
7.8* 0.6
11.3* 1.0
9.6* 0.6
5.8* 1.4
5.6* 0.8
9.0* 0.7
9.1* 0.5
5.0* 0.4
5.1* 0.4
8.6* 1.6
8.3* 0.7
6.3* 1.0
4.5* 0.5
6.8* 0.3
6.6* 0.3
EPNt
detoxication
(m
p-nitrophenol/
50 0*3/30 min)
6.7*0.6
7.1*0.5
8.4*0.9
7.4*0.7
6.7*0.6
7.2*0.6
9.5*1.1
9.0*0.5
9.5* 0.8
11.4*0.9
12.4* 1.1
14.4* 0.6
5.8* 0.3
10.3* 0.9
12.0* 0.8
15.4* 0.4
5.3* 0.9
15.0* 1.1
18.4* 0.8
18.9* 0.7
Benrpyrene
hydroxylase
(rpoVmin/mj
protein)
1.39* 0.43
0.89* 0.05
0.92*0.04
0.78*0.16
2.36 * 0.49
1.75*0.13
3.53*0.68
2.15 * 0.34
1.51 ± 0.20
1.37*0.17
2.06*0.26
2.35*0.23
2.82*0.53
3.82*0.65
5.37*1.01
5.22*1.14
2.79*0.54
4.76 ±0.58
4.08 ±0.37
4.24 ±0.82
Azoreduc-
tase
(ng/min/ng
protein)
63.9* 2.8
67.5* 2.5
71.4 * 4.3
79.2 * 6.6
59.1 * 2.5
60.9 * 2.6
69.7 ± 4.2
79.4 ± 2.7
72.4 ±11.1
102.0 ± 2.7
91.1 ± 4.6
130.7 ± 5.3
122.0 ±24.9
187.7 ± 7.4
210.0 ± 7.4
262.7 ±19.1
* value is mean * S.E. for group of six rats except for beiizpyrene hydroxylase group receiving 40 mg/kg of 1.2,4-trichloro-
benzene. In that group, there were five rats.
t EPN - a-ethyl fl-B-nitrophenylpnenylphosphonothioate
Reprinted with permission of the author and the publishers. Academic Press, Inc.
185
-------
activities.
These findings demonstrate the ability of halogenated aromatic compounds
at low doses to induce enzyme systems associated with the metabolism of
foreign compounds. This type of action may influence the metabolism of en-
dogenous steroids, other foreign compounds and drugs. Indirect evidence has
been presented which suggests that 1,2,4-trichlorobenzene persists in the
animal for some time, continually influencing drug metabolism (Carlson and
Tardiff, 1976).
(d) Acute Toxicity
The toxicity of the halogenated benzenes may be influenced by the route
of administration whether inhalation, skin absorption, or ingestion. Pos-
sibly more important are the solutions or forms in which a halogenated ben-
zene is suspended and/or applied. Most of the halogenated benzenes are less
toxic than benzene except possibly monochlorobenzene. All of the halogenated
benzenes, like benzene, produce an array of central nervous system effects
when administered orally. Among these CNS effects are either stimulation
and/or depression.
Most monohalogenated benzenes were shown to produce narcosis. Mono-
fluoro-, monochloro-, monobromo- and monoiodobenzene produced varying degrees
of sedation, analgesia and anesthesia after oral or parenteral administration.
Relatively large doses of monohalogenated benzenes are necessary to produce
acute poisoning as can be seen in Tables 70 and 71. However, chronic effects
may occur at relatively low doses. Acute poisoning is characterized by symp-
toms primarily originating in the nervous system. There may be hyperexcita-
bility, restlessness, muscle spasms or tremors followed by varying degrees of
CNS depression. The most frequent cause of death is respiratory failure.
186
-------
TABLE 70 ACUTE TCKICIOY DATA
(U.S. Public Health Service, 1975)
Chemical
Monochlorobenzene
o-Dichlorobenzene
p_-Dichlorobenzene
1,2, 4-Tr ichloro-
benzene
1,2,4,5-Tetra-
chlorobenzene
Hexachlorobenzene
1, 3, 5-Tr ichloro,
2,4,6-trifluoro-
benzene
Monofluorobenzene
Difluorobenzene
Hexafluorobenzene
l-Fluoro-2-
brono benzene
l-Fluoro-3-
brono benzene
Animal
Rat
Rat
Rabbit
Rat
Mouse
Rabbit
Guinea pig
Guinea pig
Human
Rat
Rat
Mouse
Guinea pig
Rat
Mouse
Mouse
Rat
Mouse
Rat
Mouse
Cat
Rabbit
Rat
Mouse
Mouse
Mouse
Rat
Rat
Route
Oral
s.c.
Oral
Inhal.
i.v.
i.v.
Inhal.
Inhal.
Oral
Oral
i.p.
Oral
Oral
Oral
Oral
i.p.
Oral
Oral
oral
Oral
Oral
Oral
Inhal.
Inhal.
Inhal.
Inhal.
Oral
Oral
LD50
rag/kg
2,910
4,000
2,830
• -
500
2,500
2,950
756
766
1,500
1,035
3,500
4,000
1,700
2,600
—
- .
-.
-
1,850
670
LC50 LDLO
rag/kg mgAg
-
520
- • 330
2,000
. - TD 300
2,800
500
- -
- -
— —
45mg/m3/2H
55mg/m /-2H
95mg/m3/2H
- • -
— —
LCLO
mg/kg
-
707 ppVTH
800 ppV24H
-
- ' '
-
-
380
-
-
'- -
-
—
- Lowest published lethal dose
LCLO - Lowest published lethal concentration
TD - Toxic Dose
187
-------
Table 71
ACUTE TCKICm DMA
Chemical Animal
Monochlorobenzene ttiite mouse
ttiite cat
Rabbit
Guinea pig
Mouse
Monochlorobenzene Guinea pig
o-Dichlorobenzene Mouse
Bat
Rabbit
Guinea pig
p-Dichlorobenzene Mouse
Rat
Rabbit
Guinea pig
j>-Dichlorobenzene Mouse
1,2,4-rcichloco- Rat
benzene Mouse
Rat
1,2,4, 5-Tetra- Mouse
fluorobenzene
Pentafluorobenzene Mouse
Pentafluorobromo- Mouse
benzene
Pentaduoco- Mouse
chlorobenzene
Monobrcmobenzene Rat
Monoiodobenzene Rat
Bexabronobenzene Mouse
Monofluorobenzene Rat
Monofluorobenzene Mouse
Pentafluorobenzene Mouse
Bromopenta£Luoro- Mouse
benzene
ChloropentaCLuoco- Mouse
benzene
Route
Oral
Oral
Oral
Oral
inhal.
mhal.
Oral
Oral
Oral
Oral
Oral
Oral
Oral
Oral
s.c.
Oral
Oral
Per cut.
mhal.
Oral
Oral
Oral
Oral
Oral
P.O.
Oral
mhal.
Oral
Oral
Oral
LD50 LCSO
mg/1 og/1
1,445
2,390
2,250
5,060
20
0.05
2,000
2,138
1,875
3,375
3,220
2,512
2,812
7,593 -
5,145
756
766
6,139
4.5%
710
959
1,250
1,600
400-3200
14.28 g/kg -
4 g/kg
45 mg/1*
710
959
1,250
Reference
Varshavskaya, 1967
Rozenbaun et al. , 1947
lecca-Radu, 1959
Varshavskaya, 1967
Varshavskaya, 1967
ttieet al., 1973
Brown et al . , 1969
Neal and Robson, 1966
Lapik, 1965
Lapik, 1965
Lapik, 1965
Eastman Kodak, 1976
Kitagawa et al . , 1975
Olin Chemicals, 1974
01 in Chemicals, 1974
Olin Chemicals, 1974
Olin Chemicals, 1974
Olin Chemicals, 1974
* Median lethal cone.
188
-------
Halogenated benzenes like aliphatic halogenated hydrocarbons are thought to
sensitize the myocardium to catechol amines/ and thus set up conditions
favoring ventricular arrhthmyias (Von Oettingen, 1955).
Monochlorobenzene has been studied extensively by most routes of admin-
istration and in different species. Monochlorobenzene does not appear to
have a high acute toxicity, when administered orally or parenterally. In
rats, subcutaneous injection of 4 to 5 g/kg body weight caused no immediate
effect, but resulted in death within a few days. On autopsy, the rats were
found to have necrosis in liver and kidneys. Larger doses in rats produced
CNS depression and acute ataxia. Between 7 to 8 g/kg body weight were fatal
in a few hours (Von Oettingen, 1955). In rabbits, monochlorobenzene produced
potent CNS depression. The toxic dose of the vapor was 20 mg/1 while that
for benzene was 30 mg/1. Table 72 presents data from a comparative study of
the acute toxicity of benzene and MOB (Pozenbaum et al., 1947).
Descriptions of acute pharmacological effects from doses of bromobenzene
are scarce in the large volume of literature found on this compound. Bromo-
benzene may cause depression or "apparent" stimulation of the CNS depending
on the dose. Kbch-Weser et al. (1953) reported acute centrolobular necrosis
of liver in rats after intraperitoneal injection of 75 to 450 mg/100 g body
weight of monobromobenzene. In rabbits, subcutaneous injection of 2 cc of
monobromobenzene resulted in an increase in hemoglobin, erythrocytes and
leucocytes and an initial relative lymphocytosis followed by a relative
pseudoeosinophilia.
o-Dichlorobenzene is toxic in many species of mammal, the extent of
toxicity depending on the species and route of administration. Doses of
0.25 to 0.5 cc/kg body weight administered intravenously to rabbits were
189
-------
BVBLE 72
A COMPARATIVE STOCK Of THE TOdCm OP BOBBIE MO MCNOCHLCKBENZaJB
(Roaenbaui et al., 1947)
Oianical Animal
Dose
Duration Routa
Nbignt
Lass
OB
ft|ftOfjl
Dyscrasias histol.
Deaths Marks
Benzene
Babbits
0.9 ng/feg
body wt.
2-20
injections
over •
2 week
period
B.C.
(24-30%)
4/4
At 2,3,6 6 11 in-
jections, % of
hemoglobin t no. of
•rythrocytea notice-
ably reduced.
Mrrcv - almost
Benzene
Mica
(40)
5-30 rag/1 2 hrs. mhal.
42%
Death due to paral-
ysis of respiratory
center
•30 mg/1 Clonic t tonic
spaaaa preceding
death.
Manochloro-
benzene
Mica
(40)
5-30 mg/1 2 hrs. mhal.
63%
narcosis earlier
onset & stronger
than for benzene
•20 09/1 Death due to res-
piratory failure.
Clonic and tonic
Nmochloro-
benzene
Rabbits 0.9 mg/kg
2-20
inject.
over a
2 week
period
(5-16%)
1 died after 6
Injections; 2
died after 8
injections.
Blood - increase
in no. of
stabnuclear
form and
pseudoesinophils,
no regular reduc-
tion in no. of
leucocytes detec-
ted. Nb changes
in marrow detec-
ted. Kidneys -
welling of epi-
theliun of tubu-
les I glomerules.
liver - swelling,
fatty droplets.
• Absolutely lethal concentration
•H- Strongly abnormal effect
+ Abnormal effect
d Depression
190
-------
TABLE 73
THE ACUTE TOKICITT OF FLOORINATED BENZENES — TEST ANIMAL MICE (250 total)
(Lapik, 1965)
Chemical
Dose
Route
"V
mg/1 mM/1*
Benzene
Monofluorobenzene
o-Di fluorobenzene
vo
m-Di fluorobenzene
Pj-Di fluorobenzene
Hexafluorobenzene
10-65 mg/1 Inhal. for
2 hrs.
10- 65 mg/1
[10 -. 115 mgAl
35 - 40 mg/1
80 — 90 mg/1
95 - 110 ragA
37 0.47 Tremors of torso, CNS depres-
sion, spasms of extremities
45 0.46
55 0.48
55 0.48
55 0.48
95 0.51
See benzene above.
More severe inhibition of CNS
than benzene, monofluorobenzene
or the m- and £- isomers.
Breathing deep and slow.
Reflexes were weakened.
See benzene above
See benzene above
Sedation and sleep
Severe narcosis
Significant inhibition of res-
piration, heart continued to
work for several minutes.
Death due to paralysis of
repiratory center.
* millimoles/liter
-------
fatal within 24 hours, and doses of 1.00 cc/kg body weight were fatal within
20 seconds (Cameron et al., 1937). Dogs exposed to 2 cc/m (0.04%) showed
no adverse effects, whereas 0.08% produced somnolence (Riedel, 1941). Hist-
ological studies following administration of acute and 'subacute1 doses
showed damage to liver and kidneys. Exposing mice to similar concentrations
caused CNS stimulation for about twenty minutes followed by CNS depression,
muscular twitching, slow and irregular respiration, cyanosis near the end of
an hour, and death within 24 hours. Rats and guinea pigs appear more resist-
ant than mice (Riedel, 1941).
pj-Dichlorobenzene is much less toxic than o-dichlorobenzene. (LD 's for
both compounds are found in Tables 70 and 71). Rabbits exposed to 4.6 to 4.8
mg/1 (770 to 800 ppm) for eight hours per day showed muscular weakness, trem-
ors, nystagmus, edema of cornea and transitory edema of optic nerve. Some
died after a few exposures, while a few withstood 62 exposures (Pike, 1944).
Rats responded similarly to toxic doses, exhibiting a greater degree of CNS
depression and increased irritation of mucosa. Granulocytopenia was also
present (Von Oettingen, 1955).
Ihe symptoms of acute toxicity caused by inhalation of several fluori-
nated benzenes appear in Table 73. The description closely parallels the
effects of toxic exposure to chlorinated benzenes. ^-Difluorobenzene was
shown to be more acutely toxic than benzene, monofluorobenzene or p_-difluoro-
benzene.
Higher fluorinated benzenes have been investigated as potential veter-
inary anesthetics, and a great deal of data exists evaluating this potential
use (Neal and Robson, 1966; Garmer and Leigh, 1967; Hall and Jackson, 1973).
192
-------
Tetra-, penta- and hexafluorobenzene have received most attention. As can be
seen in Table 74, 1,2,3,5-tetrafluorobenzene is the roost toxic of the tetra-
fluorobenzene isomers.
Administration of 0.5% v/v 1,2,3,5-tetrafluorobenzene to mice for 60 min-
utes did not produce anesthesia, but killed 80% of the mice within 24 to 48
hours. Autopsy showed necrosis of the liver and kidney. 1,2,3,4-Tetra-
fluorobenzene administered at 0.5% v/v for 50 minutes did produce 12% anes-
thesia (Neal and Robson, 1966). On autopsy, mice were shown to have centri-
lobular coagulative necrosis of liver parenchyma! cells.
Table 75 summarizes additional testing mainly for hexafluorobenzene. For
all animals tested, administration of 4 to 6% v/v hexafluorobenzene resulted
in lowered blood pressure. Administration of 4 to 6% v/v hexafluorobenzene
resulted in respiratory stimulation in ponies, dogs and sheep and a decrease
in respiration in pigs. In cats and dogs, cardiac output decreased (Hall and
Jackson, 1973). Garner and Leigh (1967) and Hall etal. (1975) reported
hypotension and bradycardia in cats administered 1.5 to 3.5% v/v hexafluoro-
benzene. These effects were less marked than after administration of equiva-
lent concentrations of halothane. Recovery from hexafluorobenzene induced
anesthesia was similar to recovery from halothane anesthesia for all animals
except the cats. The recovery time for cats administered hexafluorobenzene
(1.5 to 2.5% v/v) was longer than for halothane anesthesia and was character-
ized by retching, salivation, ataxia and skin irritation (Garner and Leigh,
1967; Hall et al., 1975).
(e) Subacute Toxicity
Chronic effects from halogenated benzenes are enlarged livers and cellu-
lar degenerations (possible necrosis) in lung, liver and kidney. There may
193
-------
Table 74
AN EVALUATION OP TBTRAFUJOROBENZENES IN ANESTHESIA
(Neal and Jtobson 1965, 1966)
Chenical
Animal Premedi- Induc-
cation tion
Dose
Analgesia Anesthesia Toxic Effects
1,2,3,4-Tetrafluoro- Mice None None 0.5% v/v
benzene for 60 min.
1,2,3,5-ltetrafluoro- Mice None None 0.5% v/V
benzene for 60 min.
12% Centrilobular co-
agulation necrosis
of liver parenchy-
mal cells
0% Mast toxic of the
three isomers,
death of 80% of
mice within 24-48
nrs. Necrosis of
liver and kidney
vo
1,2,4,5-Tetrafluoro- Mice None None
benzene
Dogs None Thio-
psntone
(30-50
ing/kg
body wt.
by i.v.)
Morphine "
(2 rag/kg)
Morphine "
(1.7 mg/k9
body wt.)
and atropine
(0.05 rog/kg
body wt.)
20 minutes at:
0.5% v/v -H-
0.25% v/v +
2.0% v/v -H-
4-10% v/v +
8% v/v +
12% v/v +
-
-
•f
_
+
-H- Surgical anesthesia
for 60 min. (ven-
tricular fibril-
lation in one dog
after only 15 min.
inhalation)
++ Highly positive effect
+ Positive effect
+ Weakly positive effect
- No effect
-------
TABLE 75
fffiXAFUUOHCBQCEMB IN ANESTHESIA
VO
cn
Animal
Ponies
(4)
0093
(10)
Sheep
Pre-Medi-
cation
Acepronazine
(0.05 rag/kg body
wt) and atropine
(0.6 mg/kg)
Acepronazlne
(0.1 rag/kg body
wt) and atropine
(0.6 rag/kg)
none
Induction
Sodiua
thiopentone
<8-9mg/kg
body wt)
Sodium
thiopentone
(10 ng/kg
body wtj
none
Dose of
Hexafluoro-
benzene
4» v/v in O2
(19-45 min)
endotracheal
intubation
5% vA in
2:1 NO/Oj
(endotracheal
intubation)
5-6% vA In
N0*t>»(by mask,
Blood
Pressure
Depression
Depression
Depression
one animal, one
Pigs
(2)
none
Halothane
o»
by endotracheal
intubation
5% v/v in NOaA>t Inmediate
(endotracheal
intubation)
depres-
sion.
rapid re-
covery
and then
gradual
Call
Cardiac
Effects
Initial
increase,
slow return
to normal
No cardiac
irregular-
ities on
electro-
cardiogram.
Slight de-
crease in rate
followed by
increase
Increase in
heart rate
and in cardiac
output.
none
Respiration
Initial stim-
ulation of rate
and depth. At
high levels,
respiratory
arrest.
Increase in rate
and depth
Stimulation
Initial
stimulation
followed by
depression,
inhalation
discontinued
after 5 minutes
because of
depression
Recovery
Sweating
and sali-
vation,
free from
excitement
Sone
shivering, 1
excited,
generally
slow and
quiet, no
vomiting. 2
ate 30 nin.
after
recovery
Similar to
recovery
from
halothane
More rapidly
than halo-
thane
Reference
Hall and
Jackson,
1973
•
Hall and
Jackson,
1973.
Hall et
al. , "T975
m
-------
TABLE 75 (continued)
Animal Pre-Medi-
cation
Cat Atropine
(8)
Induction
4% v/v hexa-
fluorobenzene
(by mask)
Dose of
Hexafluoro-
benzene
1.5-2%
v/v
(by mask)
Blood
Pressure
Depression,
less than
halothane
Cardiac
Effects
None
indicated
Respiration Recovery Reference
Depression less banger time Hall et
than halothane than with al. , 1975
halothane.
4 cats had
conjunctiva!
congestion
though faces
were not below
the mask.
Cats
10
Thiopentone 1.5-2.5% Depression, No spon-
(20-30 ing/kg) v/v less than taneous
(by mask) halothane cardiac
arrhythmia
Depression
Long "hang-
over" reluc-
tance to move,
ataxia, skin
irritation.
1 cat - fac-
ial edema and
conjunctival
hyperemia.
Gartner and
Leigh,
1967
-------
be muscle tremors and hyperirritability. Changes in the metabolism of endog-
enous steroids may also occur, and if persistent may alter normal levels. The
halogenated benzenes are stored in fat; those least metabolized may accumu-
late or persist in the body. These compounds may alter reactions to stress
and bring about cyclic changes (e.g. estrus cycles) or induce changes in ges-
tation and/or reproduction. Halogenated benzenes and endogenous steroids
compete for cytochrome P-450 and metabolic degradation. These latter effects
have not been studied in detail.
On chronic administration, the halogenated benzenes which induce drug
metabolizing enzymes enhance the activity of A-aminolevulinic acid synthe-
tase as mentioned previously. This may result in porphyria.
The halogenated benzenes produce blood dyscrasias on chronic administra-
tion (see Table 76). Early death, if it occurs, may be due to toxic depres-
sion of bone marrow, the pancytopenia leading to hemorrhage and overwhelming
infection (Robinson et al., 1975).
Monochlorobenzene
The chronic effects of exposure to monochloro- and monobromobenzene in-
clude a decrease in growth rate, and liver, lung and kidney damage (possibly
necrosis) and blood dyscrasias. Monochlorobenzene has been shown to inter-
fere with the Schwartzman phenomenon. This is a severe hemorrhagic reaction
with necrosis, seen on the abdomen of the rabbit that is first injected with
0.25 cc subcutaneously of typhoid or other culture filtrates, and within 24
hours injected intravenously with 0.01 cc of the same filtrate. The lesion
is at the subcutaneous injection site on the abdomen. Whether monochloro-
benzene is an immunosuppressant or not needs to be clarified.
While monochlorobenzene reportedly caused leucopenia in rabbits in one
197
-------
study (Cameron et al., 1937), another investigation found an increase in red
and white corpuscles after repeated subcutaneous administration of mono-
chlorobenzene (0.9 wg/kg body weight) (Rozenbaum et al., 1947).
Lecca-Radu (1959) showed a change in the regulating influence of the CMS
for white rats inhaling 1 mg/m monochlorobenzene for 60 days. Gabor and
Raucher (1960) and Tarkhova (1965) also reported abnormalities in alimentary
and motor conditioned reflexes in rats after chronic inhalation of MCB (see
Table 76).
Dichlorobenzenes
o-Dichlorobenzene was shown to be absorbed and toxic after repeated
cutaneous application. The subcutaneous injection of o-dichlorobenzene
regularly produced a localized edema and necrosis of adjoining tissue
(Riedel, 1941). Repeated subcutaneous administration in rabbits produced
blood dyscrasias characterized by agranulocytosis, with little or no effect
on red blood cells.
Inhalation of o-dichlorobenzene by rats at 800 ppm for 11 to 50 hours was
irritating to eyes and nose, produced slight changes in the tubular epithel-
ium of the kidney, and resulted in confluent massive necrosis of the liver
(Cameron et al., 1937). Oral administration to white rats for five months at
doses of 0.001 mg/kg to 0.1 mg/kg had a predominant effect on the haematopoi-
etic system and increased prothrombin time (Varshavskaya, 1967). There were
also abnormalities in conditioned reflexes.
Rabbits exposed continuously to 100 mg/1 of £-dichlorobenzene snowed -ir-
ritation of eyes, nose, muscular twitching, tremors, CNS depression, nystag-
mus and rapid labored breathing, but recovered within 30 to 120 minutes.
Granulocytopenia was present and persisted for three weeks (Zupko and Ed-
198
-------
wards, 1949). In rats, CNS depression was greater than in rabbits, and
irritation of mucous membranes was observed. Of 18 rats administered 100
mg/1 for 5 to 9 days, granulocytopenia was confirmed in eight cases, while
there was a tendency to granulocytopenia in three additional rats (Zupko and
Edwards, 1949). The response of guinea pigs was similar to that of rats and
rabbits.
p-Oichlorobenzene reportedly produces histological changes in kidneys,
liver, spleen and heart in a number of mammalian species. These changes
include cloudy swelling, vacuolization and necrosis (Hollingsworth et al.,
1956; Frada and Call, 1958; Totaro, 1961; Zupko and Edwards, 1949).
Trichlorobenzenes and Tetrachlorobenzenes
Trichlorobenzene (isomer not specified) was fed to rats at a level of
0.01 mg/kg body weight daily for 5 1/2 months. There was an increase in
eosinophiles, reticulocytes and leucocytes in the blood, and reduced oxygen
consumption (Gurfein and Pavlova, 1962). A dose of 0.003 rag/kg body weight
fed daily for 7 to 8 months did not affect conditioned reflexes (Gurfein and
Pavlova, 1962).
Tetrachlorobenzene (isomer not specified) was fed to rats at levels of
0.005 and 0.05 mg/kg body weight daily for eight months (Fomenko, 1965). At
the lower dosage, there was a change in conditioned reflexes, an increase in
the weight coefficient of the liver, and a decrease in -SH groups in blood
serum. At the higher level, there was an increase in ascorbic acid content
of the organs.
In the same study, 0.05 mg/kg body weight of tetrachlorobenzene was fed
daily to rabbits for eight months. There was a tendency toward disorders of
glycogen function of the liver, and an initial increase in -SH in blood serum
199
-------
TABLE 76
CHRCNIC TOXiaiY DftIA
Chemical
Animal Dose
Duration
Route
Remarks
Reference
Monochloro-
benzene
ttiite
rats
1.0 ng/n3
0.1 wg/m3
24 hrs/day
70-82 days
Inhalation
Rabbits 0.9 mg/kg
(6) body wt.
6-20 shots
Sub-
cutaneous
Guinea
pigs
0.1 to 1.5
mg/1
White 1 mg/1
cats 0.1 mg/1
(150)
Every 2nd
day for 3
hrs., 62 wks.
60 days
60 days
Inhalation
Inhalation
d * •«• + m kidney caused foci Khanin, 1969
d - - - of large cell hyper-
plasia. TOxic
encephalopathy and
inflannation of
internal organs.
Protein dystrophy of
liver.
d + 4+ + Wight loss (18-20 Rozenbaun, et
shots) 5-16%, 3 deaths al., 1947
after 8 injections.
Blood showed increase
in number of stab-
nuclear fuimu and
pseudoesinophils, no
changes in marrow.
+ Blood-red cells, ac- Lecca-Radu,
tivlty of carbonic 1959
anhydrase and indophe-
nol-oxjdases lowered
at large dose only.
Change in regulating
Influence of CMS,
muscle reflexes
abnormal rise in
cholinesterase
activity, tto weight
change with either
dose.
Lecca-Radu,
1959
Monochloco-
benzene
ttiite 0.001 nq/kg
rats 0.01 mg/kg
(M) 0.1 mg/kg
5 months
Oral
£-Oichloro-
benzene
White 0.001 mg/kg
rats 0.01 mg/kg
0.1 mg/kg
Rats 800 pm
(10)
Rats
(10F)
18.8 mg/kg
188 rag/kg
376 rog/kg
5 months
11-50 hrs.
5 days/wk.
138 doses
in 192 days
Oral
d -t-
Inhalation • d
Intubation
4+
Change in conditioned Varshavskaya,
reflexes. Predominant 1967
effect on hematopoietic
system, shift in blood
to left, increase in
prothrorabin tine and
greater activity of
trsnsaoinases and
alkaline phosphatase.
Predominant effect on Varshavskaya,
benatopoietic system, 1967
change in conditioned
reflexes. Increase in
prothrombin time.
Confluent massive Cameron et al.,
necrosis of liver. 1937
Slight changes in
tubular epitheliua of
kidney. Irritating to
eyes and nose.
No adverse effects Bollingsuorth
detected at low dose. et al., 1958
Slight increase in av-
erage weight of liver •
and kidney. At high
dose, moderate increase
in weight of liver,
slight decrease in weight .
of spleen, cloudy swelling
of liver.
+• " abnormal effect '
- « no detected abnormality
6+ • slight abnormality
d - depressant
200
-------
TABLE 76 (continued)
Oienlcal Animal Dose
p-Oichloro- Rats 341 ppn
benzene (2CH) ( 2. 05 mg/1 )
(5) 173 pps
(1.04 ng/1)
(10) 158 ppn
(0.95 ma/1)
(10) 96 prn
(0.58 ma/1)
Guinea 125 09 in
pigs 50t sain.
(3)
(3) 250 mg
Guinea 125 mg/kg
pigs 50% w/w
(4) olive oil
(4) -125 rag/tog
p-Dichloro- Nice 158 pen
benzene (ION) (0.95 nj/1)
9«P5»>
(0.56 ,g/l)
Mice 150 ppn
Rats(2) 10 ng/kg
(2) 100 mgAg
(4) 500 ng/hg
in 10% sain.
Rats 18.8 rag/kg
(10P)
188 og/kg
376 rag/kg
1 1
Duration Route fc •no ' fr 3 Remarks Reference
0 o?S fi w &
8> OS, * 2 JT
a sff a 3 1
7 hrs/day Inhalation ««• - 4+ -
5day«/Vk.,
6 months
7 bra/day Inhalation 4+ 4+ j+ 6+
5 days/*., (P)
16 day*
• Inhalation + * -
(•)
Inhalation ....
10 days Intramuscular +f
injection
10 days • ++
11 days
+ +
20 days " «• +
7 hw/day Inhalation - - - -
5 days/wk.,
157-219 days
• Inhalation - - - -
8 hrs/day Inhalation 4+ 4+
16 days
5 days/Wk. Oral ....
for 20 doses
- + - -
5 days/wk. , Oral - -
138 doses
in 192 days
4+ 4+
* *
Slight increase in Hollingsuorth
average Height of at al., 1956
liv«r and kidney "
Slight interstitial
edenia and congestion of
lungs. Slight increase
in wight of liver and
kidney.
Cloudy sueUing or
granular degeneration
of livur
tb abnomalities
detected
Intense staatosis of Prada and Cali,
livwr. Height decrease, 1938
loner hepatic glycogen.
Height decrease,
intense staatosis of
liver, lower hepatic
glycogen
Height loss
Height loss, increase Tbtazo, 1961
in level of blood serua
transaninsse .
No abnomalities Bollingsuorth
detected «tSi" ^56
Ho abnocnaliti«s
detected
Histology of lungs Irie et al. , 1973
and liver normal.
Shrinkage of nucleus,
m^afhrnmivf i4 of
protoproan 2 deaths.
BollingsHorth
rt.al., 1956
Marked cloudy swelling
and necrosis in
central areas of liver
lobules.
Increase in weight of
liver and kidneys.
Increase in weight of
liver, kidney, spleen,
slight cirrhosis and
fiocal necrosis of
liver.
aonormal effect
- » no detected abnormality
4+ » slight abnormality
d » depressant
201
-------
TABLE 76 (continued)
Chemical Animal
pj-Dichloro- Guinea
benzene pigs
^
(5)
Guinea
pigs
Guinea
pigs
(8M)
(8F)
(5)
ttiite Peking
Ducks
Rats
(19M)
(ISP)
Guinea
pigs
(16M)
(7F)
p-Oichloro- Rabbits
benzene (3M, 8F)
Raboits
(1M, IP)
Rabbits
(1M, IP)
Rabbits
(18M)
Monkey
(18)
Guinea
pigs
(8)
(8)
Guinea
pigs
' . (9M)
Dose
125 g
(50%)
125 g
(50%)
314 ppn
(2.05 mg/1)
173 ppn
(1.04 mg/1)
0.5% of
diet
798 ppn
798 ppn
(4.8 og/1)
798 ppn
(4.8 mg/1)
173 ppn
(1.04 mg/1)
158 ppn
(0.95 mg/1)
100 mg/1
for 30
tains.
158 ppn
(0.95 mg/1)
153 ppn
(0.95 mg/1)
96 ppn
(0.58 mg/1)
100 mg/1
Duration Route tea 8 fr %
81 8 5-J ? fr
33 131
20 days Intramuscular d +
injection
21 days " +
7 hrs/day. Inhalation +
5 days/wk..
6 months
7 hrs/day, " 3* 4-f «* 5+
5 days/wk. , (P) (M)
16 days
35 days Oral
8 hrs/day. Inhalation d + +
5 days/wk. , (F)
doses
1-46 (M)
9-69 (P)
8 hrs/day, * d +
5 days/wk.,
1-23 (M)
11-20 (P)
8 hrs/day Inhalation d +• +
5 days/wk., (2)
1-62 exposures
7 hrs/day, • - - - « +
5 days/wk..
16 days
7 hrs/day, • - - -
5 days/wk.,
157-219 days
5-9 days Inhalation d + + • + +
7 hrs/day " - - - -
5 days/wk. ,
157-219 days
« « 5 + - - -
(P)
** ' * -» -• « •*
5-9 days " d + + + +
Remarks
Height loss 11.4%.
Increase of blood
strua transaminases
Increase in reaction
and clotting forma-
tion tine
Cloudy swelling.
fatty degeneration
focal necrosis, slight
cirrhosis of liver
Slight decrease in
weight of spleen.
slight edema and
congestion of lungs
3 deaths after 28
days, no cataracts
Tremors, weakness.
cloudy swelling of
liver. Death: 2M,2P
Deaths - 2 M
Reversible non-spe-
cific eye changes
Slight edema and
congestion of lungs
W> apparent problems
detected
Granulocytopenia
U/18, irritation of
mucosa, weight loss
14/18. Tremors, rapid
but labored breathing.
death 12/18.
«j3 apparent adverse
effects on organs
Increase in liver
weight of female. De-
crease in overall wt.
Ho adverse reactions
detected.
Granulocytopenia 5/9,
weight loss 6/9,
tendency to granulo-
cytopenia 2/9
Reference
Totaro and Licari,
1964
Coppola et al..
1963
aollingsworth
et al., 1956
Bollingsworth
et al., 1958
Zupko and Edwards,
1949
aollingsworth
et al. , 1956
Zupko and Edwards
1949
abnormal effect
- » no detected abnormality
S + » slight aonormality
d * depressant
202
-------
TABLE 76 (continued)
Qjenical
flnimal Dose Duration Route
a
•5
.. m!
«
M
fr 3 Remarks Reference
e en (i
e-oict
bera
iloro- Mistar rats 100 mg/1 5-9 days Inhalation d + + + > Granulccytopenia Zupxo and Edwards,
ane (9M, 9P) 20 min. 8/18, tendency to 1949
grsnulocytopania,
3/18
Rabbits 1000 tog/kg 92 doses in Oral + * + loss of weight, Hollinginnrt-h
(5) 219 days trenors, weakness, et al.T
cloudy swelling and
focal necrosis of liver
1956
1,2,4,5-
Tetrafluoro-
benzene
Bexabrcmo-
benzene
(7)
Mice
(10)
500 ing/kg 5 days/week
for 263
dosss
Oral
1%
1/2 hr/day. Inhalation
Sdaya
Hie* 0.075 g/kg Daily,
(M) 1.75 9/kg 30 days
Oral
Honoiodo-
benzene
Rabbits 2 cc
s.c.
Swelling and focal
necrosis
Ons oouae with Rial and tobson,
bronchitis with sever* 1966
and extcjaive acut*
nous* - nore cytD-
yv^liit ion»
No significant patho-
logical changes in
heart, lung, kidneys,
testia, stoBsch, anall
intesting, spleen,
lungs, adrenals, thy-
roid, thyous and oere-
brun. Slight lyqpho-
cytic infiltration in
peripheral area.
Kitagawa
1975
et al..
Increase of
globin, red and
white blood cells,
beginning of relative
granulocytosis.
Relative pseudo-
eosinophilia.
Miyamoto,
1938
Honochloro- Rats 0.1 ng/1 3 hrs every Inhalation +
benzene (38) other day
for 37 wka.
CNS disorders ap-
peared 7th and 14th
week; increase in
inhibitory process
and return to normal
state (chronaxy of
nuscular extensor
tibialis), alimentary
ootor conditioned re-
flexes abnormal.
Blood: abnormal enzy-
matic activity (perox-
idase of leukocytes
indophenol-oxidase,
carbonic anhydrase).
Gabor and Raucher,
1960
+ " abnormal effect
- » no detected abnormality
<5+ =» slight abnormality
d • depressant
203
-------
TABLE 76 (continued)
Chemical
Animal Dose
Duration
Route
Remarks
Reference
o-Dichloro- Rats 93 ppn 7 hrs/day Inhalation
"benzene (20) (0.56 mg/1) 5 days/wk.,
6-7 months
(20) 49 ppn
Guinea 93 ppn
pigs
(8)
(8) 49 ppn
Rabbits 93 ppn
(IN)
(18)
Monkeys 93 ppn
(28)
Nice 49 ppn
(108)
7 hrs/day
S days/wk.,
6 1/2 month*
7 hra/day
S days/wk.,
6-7 months
7 hrs/day
S days/wk.,
6 1/2 months
7 hrs/day
5 days/wk.,
6-7 months
7 hrs/day
5 days/wk.,
6-7 months
7 hrs/day
5 days/wk.,
6 1/2 months
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
Inhalation
It> adverse effects Sollingsworth
judged on gross et al., 1958
appearance, organ
weights, henatology,
urea, and gross and
nicroscopic examination*
Without adverse et- Bolllngsworth
fects as judged by et al., 1958
gtoss and microscopic
•lamination, henatology
and organ weights.
Monochloro- Rats 1 mg/m3 60 days
benzene (30M) 0.1 mg/m3
Inhalation + **+
Changes in ratio of
motor chronaxia of
flexor and extensor
muscles - reverse
ratio due to CHS
imbalance. Rise in
chollnesteraae activ-
ity at 1 mg/m3 only.
Total amount of blood
serum proteins did
not change, no
changes in leucocytes.
At 1 mg/m3, lowering
of alpha and increase
in beta globulins.
Tarkhova, 1965
+ • abnormal effect
- • no detected abnormality
5+ » slight abnormality
d - depressant
204
-------
followed by a decrease. There was also an increase in hemoglobin content of
*•
blood and in content of reticulocytes in the peripheral blood (Fomenko,
1965).
Hexahalogenated Benzenes
Chronic studies in rats have shown that hexachlorobenzene at a 0.25%
level in the diet produced porphyria in 6 to 12 weeks. Other changes were a
weight gain, an increase in smooth endoplasmic reticulura, and a reduction of
cytochroroe P-450 content. Histological changes showed evidence of centri-
lobular necrosis in liver. This relatively recent report suggests hexa-
chlorobenzene may not be as inert as once thought (Lui and Sweeney, 1975).
Hexabromo- and hexafluorobenzene appear to be less toxic than hexachloro-
benzene (Gage, 1970; Hall and Jackson, 1973; Hall et al., 1975; Kitagawa et
al., 1975). In mice fed hexabromobenzene at levels from 0.875 to 7 g/kg body
weight daily for 30 days, there was no evidence of necrosis or porphyria even
at the highest dosage (Kitagawa et al., 1975). Gage (1970) detected no ab-
normalities in rats exposed to 500 ppm of hexafluorobenzene for 15 six hour
exposures. At 1000 ppm for the same period of time he detected reactive
hyperplasia in the spleen of rats. Inhalation of mixed hexahalogenated ben-
zenes resulted in narcosis, eye irritations, porphyria in some cases, and
nose irritations. Gage (1970) showed a definite increase in subacute inhala-
tion toxicity as successive fluorine atoms in hexafluorobenzene are replaced
by chlorine (see Table 77).
(f) Effects on the Eye
As mentioned previously, halogenated benzenes are irritating to eyes and
mucosa in varying degrees depending on the compound and extent of exposure.
In 1939, there was a report of cataract formation in two women allegedly
205
-------
TABLE 77
A CEMPARISCN OF THE SUBfiCUTE INHALATION TOXIdTV OP HECASUBSTITUTEI)
(Gage, 1970)
BENZENE FOR RAXS
Dose No. ot Exposure
(ppn) Rats
Baxafluoro-
Oiloropenta-
fluorobenzene
1,3-Oichloro-
tetrafluoro-
benzene (5t 1,«
1,3,5-Trichloro- 1,2,4-Tri-
trifluorobenzene chloro-
benzene
3000
1 x 30 min
Eye Irritation,
nasal discharge,
respiratory dif-
ficulty, light
narcosis
1000 4M
6 x 6 hr.
4 x 6 hr.
4 x 6 hr.
500 4M 15 x 6 hr
4F
No wt. gain (F)
autopsy (histol.)
lungs- macro-
pbages, spleen-
reactive hyper-
plasia
No porphyrinuria
blood and urine
normal, autopsy-
organs normal
Lethargy.
incoordinatioh,
no porphyrinuria,
autopsy- organs
normal
Unresponsive,
no porphyrin—
uria, autopsy-
organs normal
380
2H 2 x 6 hr
2F
250 4M 15 x 6 hr
4F
200 2M 15 x 6 hr
2F
100 4H 15 x 6 hr
4F
83 4M 15 x 6 hr
4P
70 2M 15 x 6 hr
2P
NO toxic signs,
autopsy - organs
normal
Light narcosis,
recovery overnight,
increased urinary
coproporphyrin (M),
porphobilinogen (KSF)
histology- damage to
kidney tubules
Light narcosis
recovered overnight,
retarded wt. gain,
h|«yyf And urine
normal (histology),
slight kidney tubu-
lar lesions
NOse irritation
respiratory dif-
ficulty, narcosis,
males died. In-
crease in urinary .
protein and porpho-
bilinogen, high
blood urea. Liver-
focal necrosis,
CTntr^i0**^*r vacu—
olation with fatty
changes in kidney,
tubular necrosis.
Lethargy,
retarded
wt. gain,
autopsy -
organs
normal
No toxic signs,
autopsy -
organs normal
NO toxic signs
blood and urine
normal, livers
enlarged
50 4M 15 x 6 hr
4F
20 4H 20 x 6 hr
4F
No toxic signs,
autopsy - organs
normal
Initial
lachry-
nations,
lethargy,
retarded
wt. gain,
autopsy -
organs
normal
No toxic
signs,
autopsy -
organs
normal
Data reprinted with permission
206
-------
exposed to mothballs containing p_-dichlorobenzene (Berliner, 1939). While it
was neither confirmed that the cataracts were due to p_-dichlorobenzene, nor
clear the extent of exposure, several animal studies have concentrated on
documenting the effects of chlorinated benzenes on the eye.
Berliner found that no opacity of the lens (of rabbits) was produced on
inhalation of pj-dichlorobenzene (5 g every two days) daily for 5 to 47 days.
After feeding rabbits 5 g daily for three weeks, Berliner found slight to
moderate opacity of the lens. Impurities in the chemical (perhaps naphtha*
lene?) might explain this reaction. Other studies seem to indicate that eye
changes due to excessive exposure to p_-dichlorobenzene (or other chlorinated
benzenes) are reversible in nature (see Table 78).
I
(g) Dermatological Pathology j
Available studies are summarized in Table 79. Effects seen on topical
administration of 1,2,4-trichlorobenzene to rabbits and guinea pigs included
spongiosis, acanthosis, parakeratosis (Brown et al., 1969). No signs of skin
sensitization were noted for either species.
(h) Teratogenicity
There were very few studies on the effects of halogenated benzenes in the
pregnant mammal. Those found are summarized in Table 80. No teratogenicity
studies were found for the chlorinated benzenes in greatest commercial use.
Khera and Villeneuve (1975) reported both maternal and fetal accumulation of
pentachlorobenzene fed to pregnant rats at doses of 50 to 200 mg/kg body
weight/day for the 6th to 15th days of gestation. There was a decrease in
fetal weight, significant incidence of extra rib formation, and retarded
sternal development at the highest dose.
Courtney et al. (1976) showed a minimal incidence of teratogenic effects
207
-------
TABLE 78
EFFECTS OP HALOGENATBD BENZENES ON THE EYE
M
O
00
Chemical
£-Oichloro-
benzene
£-Dichloro-
benzene*
j>-Dichloro-
benzene
£-Dichloro-j.
benzene
o-Dichloro-
benzene
1,2,3-Tri-
chlorobsnzene
Animal Exposure
Rabbits 4.6 to 4.8 mg/1
(770-800 ppro) for
8 hours, inhalation
2 Women To moth ball fumes?
Rabbits Inhalation. 5 gm
vaporized/2 days
5-47 days
Rabbits Oral, 5 gas FOB daily
for 3 weeks
Rabbits 2 drops in each eye
Rabbits Drops?
Effects
Lateral nystagraiaa, transitory
edema of cornea. - edema of
optic nerve. Eye changes
reversible (17 days). No lens
changes or deposits in the
vitreous.
(1) both eyes - cataracts,
(2) left eye - anterior
cortical changes, esp.
periphery of lens. Separation
of lamellae and severe large
water slits.
No opacity of the lens (liver
necrosis & death)
Opacity of lens slight and
mod.
Pain slight. Conjunctival
irrit. cleared 7 days
Severe pain, conjunctivitis,
chemosis & discharge without
cornea! involvement, lids v.
swollen. Conjunctivae
inflamed at least 48 hrs.
Wash water helped relieve pain.
Reference
Pike, 1944
Berliner, 1939
Berliner, 1939
Berliner, 1939
Boiling sworth,
et al.. 19S8
Brown et al..
1969
* Purity not established, identity of PDCB not proven.
t Purity not established.
-------
TABLE 79
TOPICAL APPLICATIOH/bfiI»«IOaX3ICAL
to
O
VO
Chemical
o-Oichloro-
benzene
1,2,4-Tri-
chlorobenzene
1,2,4-Tri-
chlorobenzene
1,2,4-^Tri-
chlorobenzene
Animal
Man
Han
Rabbits
(«, 4P)
Rabbits
(1M, IF)
Guinea
pig
(5M, 5P)
Guinea
pig
Dose
r
—
1 ml, 6 he/
day for
3 daya
1 ml/day
(5days/wk)
3 weeks
0.5 ml/day
foe 5 daya/
wk, 3 wka.
0.1% wA
3days/wk
for 3 wks.
NQ treat-
ment for
10 days.
llth day
challenge
Exposure
•topical applic.
to skin
window sashes
treated with
COB
Covered skin
test
tttoovered skin
test
Uncovered skin
Intradermal or
topical
Remarks Reference
After 15 minutes - burning Riedel, 1941
sensation, turned red, more
marked after 24 hrs..
blisters, brown pigmentation
lasting over 3 months
Watery blisters on face, Downing, 1939
hands, arms. Disappeared and
reappeared w/application.
Patch test showed sensitivity
boOOCB
Spongiosis, acanthosis. Brown et al. ,
parakeratosis 1969
^nngiosis, acanthosis.
parakeratosis plus some
superficial dermis
Spongiosls, acanthosia. Brown et al..
parakeratosis. "Same' 1969
deaths. - necrotic foci in
liver - no zonal pattern of
necrosis
No signs of skin Brown et al.,
sensitization 1969
-------
in rats fed hexachlorobenzene (100 mg/kg body weight orally). There was ma-
ternal and fetal accumulation of hexachlorobenzene, especially in fatty tis-
sue. Abnormalities detected were an increased incidence of 14th rib formation
and sternal defects. It is obvious that more information is needed concern-
ing the effects of hexachlorobenzene on fetal development in mammals.
Khera and Villaneuve (1975) also examined the effects of hexabromobenzene
on fetal development in the rat. There was some maternal and fetal tissue
accumulation at 200 mg/kg body weight, indicating that hexabromobenzene did
pass the placenta! barrier. No statistically significant evidence of terato-
genicity was found.
(i) Mutagenicity/Carcinogenicity
There has been at least one in.vitro study of the inhibitory effect of
dichlorobenzene (isomer not specified) on the number of mitoses in rat lung
cell cultures (Guerin et al., 1971). The dose of 5 pg did not produce any
significantly different number of mitoses than the control, i.e. in this test
system, dichlorobenzene gave a negative result, it did not exert any inhib-
itory action on the cultures. No additional mutagenic data were found for
mammals, though several chlorinated benzenes are known mutagens for plants
and microorganisms (q.v.).
In an earlier study, Guerin and Cuzin (1961) found that dichlorobenzene
(isomer not specified) gave a slight response for carcinogenic activity in
mice, as measured by the sebaceous gland and the hyperplasia tests. In both
cases, dichlorobenzene (1 g/lOOcc solution in acetone) was applied to the
skin of Swiss mice three times (0.1 cc solution). The sebaceous gland test
was based on the disappearance of the glands after application of the test
compound. The hyperplasia test examined the thickening of the skin epithel-
210
-------
TABLE 80
THE EFFECTS OP HAUKBNA1HD BENZENES ON TOE COURSE OF GESTATION IN MICE MO RMS
Chemical
Animal
Dose
ng/kg/day
Maternal
Body Wt.
Maternal
Body Accura.
Fetal
Aocumul.
Uarato-
genic
Description
Reference
Pentachloro-
benzene
Rat
200
(6-15 day of
gestation)
100
SO
Decrease in fatal
wt., extra rib,
retarded sternal
development
Extra rib
Extra rib
Khera and
Villaneuve,
1975
Villaneuve and
Khera, 1975
Pentachloro-
benzene
Mouse
66+
None
detected
Courtney et
al., 1976~
Hexabrooo-
benzene
Rat
200
100
50
Hot
statist.
eig.
Khera and
Villaneuve,
1975
•H-stronger positive effect
•(•positive
6+mildly positive
-negative effect
* Please note, this study was to determine the teratogenic effects of
pentachloronitrobenzene (PQffi) and haxachlorobenaene (HCB). Pentachloro-
benzene (QCB) is a contaainant of both chemicals. Administration of a
single oral dose of PCHB (50 ng/kg body wt.) with < O.lft QCB or HCB
(50 ng/kg/day, 7 to 11 days of gestation) with tapurity 9.6% QCB in ma-
ternal fatty tissue. QCB did not appear in fetal tissue in either test.
-------
ium after application. On an arbitrary scale of 0 to 4 (negative to strongly
positive), dichlorobenzene scored 0.9 on the former test, and 0.7 on the
latter.
Carcinogenesis has mainly been studied for the lower halogenated benzenes
in what appars to be subacute or chronic type studies (Hollingsworth et al.,
1956, 1958). These studies were negative. The formation of an arene oxide
intermediate has been associated with mutagenesis and carcinogenesis. Since
halogenated benzenes form these reactive intermediates, one would have to
conclude that these tests are inadequate by today's standards for carcino-
genic as well as mutagenic testing. It appears that no carcinogenic tests
have been conducted lasting over a year in duration, a short time period
according to today's standards.
Murphy and Sturm (1943) studied the effects of pj-dichlorobenzene on
induced resistance to a transplanted leukemia in the rat. Forty rats .were
immunized by intraperitoneal injection of either defibrinated rat blood, or
chopped 15 day old rat embryo. They were exposed to saturated p-dichloroben-
zene vapors for two to three hours daily for 14 days, and then injected with
0.2 cc of leukemia cells.
There were 67.5% animals with tumors in the immunized group exposed to
pj-dichlorobenzene. An. immunized group not exposed recorded 20.5% tumors
while the control (no immunization) was 84.2% positive. It would appear that
pj-dichlorobenzene modified the induced resistance of the rats to the leukemia
However, there is not sufficient evidence to state that there are possible
immunosuppressant effects resulting from exposure to p-dichlorobenzene.
(j) Behavioral Effects
Gabor and Raucher (1960) and Tarkhova (1965) reported abnormalities in
212
-------
TABLE 81
CARCINOGENIC AND RELATED STUDIES
ISJ
I-"
OJ
Chemical
Pentachloro-
benzene
Bromobenzene
pj-Dichloro-
benzene
p-Dichloro-
benzene
i '
Test System
Mice
Rats
Dog
Rat
Liver
Leukemia
in rats
Irradiated
mice
Irradiated
mouse
Control mice
Exposure
-
—
2.5 rog/kg
body weight
Fumes
0.2% i.p. in
sesame oil with
silica
0.2% s.c. with
silica
0.2% s.c. in
sesame oil with
Result
Tumors
None
None
Neg.
Ascites,
sarcoma-
like
growth
_
Sarcoma
Remarks
-
Unlike CGU},
bromobenzene did
not alter poly-
somal pattern
Modified induced
resistance to
transplanted
leukemia cells.
Suggest immuno-
suppression
One animal tumor
when grafted gave
100% takes
_
1 animal
Reference
Preussman,
1975
Sanna
et al.,
1974
Murphy and
Sturm,
1943
Parsons,
1942
\ '
silica
-------
TABLE 82
SUMMARIES OP CARCINOGENIC TESTING OF ORTHODICHLOROBBCEME
(Hollingsworth et al., 1956)
Animal No.
Rats 17
Rats 18
Rats 40
Guinea 8
pig
Guinea 7
pigs
Guinea 16
pigs
Mice 10
Rats 10
Rats 10
Strain or Sex Preparation and Dose Site
Type
P 93 ppn (0.
7 hrs/d..
exposures
— M 93 ppa (0.
7 hrs/d..
exposures
— lOaa 49 ppn (0.
7 hrs/d..
— M 93 ppn (0.
7 hr a/day.
— P 93 ppa (0.
7 hrs/day.
— 8aa 49 ppa (0.
7 hcs/day.
— P 49 ppn (0.
7 hrs/day,
Miite F 376 mg/hg
5 d./wk.,
ttiite P 188 on/kg
or Tunors Survival Duration
Route
56 mg/1) of vapor Inhalation 0 — 190 days
5 d./wk.; 131
56 mg/1) of vapor
5 d./wk.; 125
29 mg/1) of vapor
5 d./wk.
56 mg/1) of vapor
5 d./wk.
56 mg/1) of vapor
5 d./wk.
29 mg/1) of vapor
5 d./wk.
29 mg/1) of vapor
5 d./wk.
0 182 days
0 6 V2
months
0 197 days
0 199 days
0 6 V2
months
0 61/2
months
in olive oil, p.o. 0 9 at 192 days
138 doses stomach tube 192 days
in olive oil, p.o. 0 5 at 192 days
5 d./Vk. 138 doses
Rats 10
TABLE 83
ttiite P 18.8 tog/kg
138 doses
192 days
in olive oil, p.o. 0 7 at 192 days
192 days
SUMMARIES OF CARCINOGENIC TESTING OP PARA-OICHLOROBENZENE
(Bollingswocth et.al.,~l956)
Animal* No.
Rats IS
Strain or Sex Preparation and Dose ^ Site or Tumors Survival Duration
Type
Route
— P 798 ppn of vapors 8 hrs/d.. Inhalation- 0 — 7 months
5 d/Vk., total of 9-69
Rats 20
Rats 10
Rats 10
Rabbits 16
Rabbits 2
Rabbits 2
Guinea 16
pig
Guinea 8
pig
Guinea 3
pig
exposures
— M 341 ppa of vapor 7 hrs/d. ,
S d./wk. for 6 months
— — 158 ppn of vapor 7 hrs/d.
5 d./wk. for 157-219 days
— — ' — 96 ppn of
vapor 7 hrs/d..
5 d./wk for 6-7 months
M,F 798 ppn of vapor 8 hrs/d..
5 d./wk total of 1-62
exposures
— M,P 158 ppn of vapor 7 hrs/d..
5 d./wk.
M,F 96 ppn of
5 d./wk.
vapor 7 hrs/d.,
— M 798 ppn of vapor 7 hrs/d..
5 d./wk.
— M 341 ppn of vapors 7 hrs/d.
5 d./wk.
— F 341 ppn of vapors 7 hrs/d.
5 d./wk.
i
0 — 6 months
0 — 219 days
0 — 7 months
0 4 died 14 weeks
0 219 days
0 7 months
0 2 died 4 1/2
weeks
0 6 months
T 0 6 months
214
-------
TABLE 83 (continued)
Animal *
Guinea
pigs
Monkey
Monkey
Mice
Mice
Rats
Rats
Rats
Rabbits
Rabbits
Ducks
Mice
Mouse
Mice
No.
8
1
1
10
10
10
10
10
5
7
10
6
' 1
10
Strain or Sex Preparation and Doset Site or Tumors Survival
Type Route
— — 158 pp» of vapor 7 hrs/d.. Inhalation 0* 100%
3 d./wk.
— P 158 ppn of vapor 7 hrs/d..
5 d./wk.
P 96 ppa of vapor 7 hrs/d.
5 d./wk.
— M 158 ppn of vapor 7 hrs/d.
5 dd./Wk.
P 96 ppn of vapor 7 hrs/d.,
5 d./wk.
o=f —
0 — '
°£ -"•
04 —
White P 376 ng/kg in olive oil, P.O. 09 —
5 d./wk for 138 doses stomach tube
White P 188 ng/kg in olive oil.
5 d./wk for 138 doses
White P 18.8 mg/hg in olive oil.
5 d./wk. for 138 doses
White - M,F 1000 ng/kg in olive oil
colored for 92 doses
— — 500 ng/kg fed 5 d./Vk. for
263 doses
White- — 0.5% in diet for 35 days
Peking
0 —
0
0 sona
deaths
0 —
0 ' 3 died
after
* 28 d.
Stock — 0.4 ng in sesame oil s.c. 0 3 died
in 10
days
Stock — 0.4 ng in sesana oil i.p. 1 3 died
in 10
days
Stock — 0.4 ng in seams oil, s.c. 1 4 died
9 tines in 30
days
Duration
219 days
219 days
7 months
219 days
7 months
219 days
192 days
192 days
219 days
219 days
35 days
10 days
10 days
77 days
* young adult
t rain purity, 99%
t histopathology negative
§ cirrhosis and hepatic necrosis
215
-------
conditioned reflexes in rats after chronic inhalation of o-dichlorobenzene.
Fomenko (1965) reported a change in conditioned reflexes of rats fed 0.005
rag/kg body weight of tetrachlorobenzene (isomer not specified) for eight
months, A similar study with trichlorobenzene did not find any evidence of
alteration in conditioned reflexes (Gurfein and Pavlova, 1962).
No other studies on behavioral effects were found. It is reasonable to
expect that because of the action of halogenated benzenes on the CNS, that
there may be additional behavioral effects not yet described.
(k) Possible Synergisms
Ihe halogenated benzenes as a group appear to interact with cytochrcme
P-450 in those animal species investigated. In mammals in particular, they
seem to stimulate and inhibit drug metabolism, and alter the levels of cyto-
chromes in the cell. Since many compounds, whether they are agricultural and
industrial chemicals or drugs, are similarly handled by the cytochrome P-450
system, there would appear to be many possibilities for synergistic as well
as antagonistic actions.
Experiments to determine this should be carefully designed. For example,
in man phenobarbital has been shown to stimulate the drug metabolism at three
to four days. If therapy continues, it appears that the marked stimulation
is lost. This has not been taken into consideration in many animal studies,
i.e., only the three to four day effect has been studied.
From recent studies in man using identical or fraternal twins, the role
of the environment as an explanation for differences in metabolism is being
deemphasized in favor of genetic differences. If this is the case, people
who have genetic susceptibility to inducible drug-metabolizing enzymes may be
more prone to adverse effects, if there is a toxic' intermediate or product
216
-------
formed in vivo (Goujon et al., 1972; Vesell et al., 1976). Goujon et al.
(1972) found that hexachlorobenzene differentially inhibits aryl hydrocarbon
hydroxylase in genetically responsive and non-responsive mice. Similarly,
Vesell et al. (1976) showed that the toxicity of chloroform to the kidney is
different in genetically susceptible and non-susceptible mice.
It should be emphasized that toxicity is not determined by a single locus
gene but may involve multiple loci. For example, epoxide hydrase or gluta-
thione conjugase may also be important in determining toxicity.
Goujon et al. (1972) and Vessell et al. (1976) demonstrated genetically
controlled variations in the susceptibility of mice to hexachlorobenzene and
chloroform. Hence/ exposure to a wide range of environmental contaminants
including the halogenated benzenes could affect the ability of these animals
to detoxify xenobiotic substances. Synergistic effects of the halogenated
benzenes in combination or with other environmental contaminants could be
especially damaging for the genetically susceptible individual.
There was one example of synergistic effects of halogenated benzenes on a
target organism found in the literature (Hinze et al., 1970). The antifungal
activity of halogenated benzenes was synergistic with organo-tin compounds.
The mechanism of the toxicity was not discussed. There were no studies found
on synergistic effects in mammals or other nonmammalian species.
3. Effects on Other Vertebrates
(a) Fish
(i) Metabolism and Toxicity
Trout have the necessary hepatic enzymes to metabolize halogenated ben-
zenes (see Table 84). The lower homologues can be biotransformed to a
greater extent than the polyhalogenated compounds. The concentration of
217
-------
TABLE 84
HEPATIC LEVELS OF CYTOCHROME P-450 AND NADPH-CYTOCHRCME C REDOCTASE ACTIVITY,
IN TROUT COMPARED WITH VALUES FOR MAN AND RAT
(Pelkonen et al., 1973; Ahokas et al., 1976)
Trout Man Rat
Cytochrome P-450 in 12,000 x g supernatant 7 13.6* 31*
(nmol/g liver)
NADPH-cyt. c reductase in homogenate 2000 3008 3508
(nmol cyt. c reduced/g liver/min.)
In the microsomal fraction:
Cytochrome P-450
(nmol/nig microsomal protein)
NADPH - cytochrome c reductase
(nmol cyt. c reduced/ing microsomal
protein/min.)
0.2t 0.53
0.17±0.03 §
20t 78
±14 ±3 §
1
0.72
96
* Determined from the homogenate.
t Livers pooled from 10 fish.
± Individual livers of 8 fish.
§ Mean ± S.D.
Reprinted with permission.
cytochrome P-450 in the trout is lower than in mammalian species. It would
appear that the content of the trout microsomal enzyme fraction is lower than
in man and rats (see Table 84). As mentioned earlier both the tissue level
of epoxide hydrase and glutathionase are important in determining toxicity.
Hence, the cytochrome P-450 content alone does not give the information
needed for evaluating the toxic potential in fish.
No studies on behavioral effects in fish were.found. Here again there is
a need for information, especially documenting the effects of long-term, low
level doses of specific chlorinated benzenes on the migratory and reproduc-
tive behavior of fish.
218
-------
Leach (1977) is currently investigating the persistence and metabolism of
chlorinated benzenes in fish tissue. Rainbow trout are exposed to di-, tri-,
tetra- and pentachlorobenzenes. After three weeks, the fish are transferred
to fresh water/ and monitored to determine how long it takes the fish to
excrete the chemicals. A metabolic study is being conducted parallel to the
persistence evaluation, and a chronic toxicity evaluation will be undertaken
some time in the future. A report is expected from the group by late Spring
1977.
Webber (1977) and his group at Oregon State have just started a structure
activity relationship study of the hepatotoxicity of chlorinated benzenes.
They will also examine several of the chlorinated nitrobenzenes and selected
brominated benzenes. They are using hundreds of inbred guppies for this
study. A second study of the impact of hexachlorobenzene on liver function
will be conducted with rainbow trout. ..
I
Peterson (1977) indicated that his group is interested in a future study
of the mechanism of elimination of chlorinated benzenes after administration
to fish. He is currently studying the effects of chlorinated benzenes on the
liver and the pancreas of rats. An abstract of his work will be available
some time this year. Monochlorobenzene, o-dichlorobenzene, the three tri-
chlorobenzene isomers and monobromobenzene altered the excretory functions of
both liver and pancreas. pj-Dichlorobenzene did not have this effect. Both
3-methylcholanthrene and cystine protected the rats from the toxicity of
monobromobenzene.
(b) Amphibians - the Frog
Safe et al. (1976) investigated the metabolism of chlorinated benzenes
and other chlorinated aromatic compounds in the frog (Rana pipiens). A
219
-------
solution of each of the chlorinated benzenes tested (80 mg in 4 to 5 ml of
vegetable oil) was administered in four equal aliquots by intraperitoneal
injection to each of four frogs. The frogs were provided with water (250 ml)
but no food. After four days, the water was changed, and after eight days
both samples of water were analyzed. Metabolites were extracted with chloro-
form, purified by preparative thin layer chromatography and analyzed by gas
liquid chromatography/mass spectrometry.
Mono-, di-, tri and tetrachlorobenzenes all yielded only small percent-
ages of phenolic metabolites. Monochlorobenzene and 1,2,3-trichlorobenzene
yielded approximately 1% of 4-chlorophenol and 2,3,4-trichlorophenol re-
spectively. 1,3,5-Trichlorobenzene underwent approximately 0.7% conversion
to 2,4,6-trichlorophenol; and 1,2,4-trichlorobenzene was metabolized to the
same extent to 2,4,5-trichlorophenol. pj-Dichlorobenzene yielded trace
amounts of 2,5-dichlorophenol. Dechlorinated and rearranged metabolites were
identified for 1,2,3,5-tetrachlorobenzene (<1.0% 2,3,5-trichlorophenol) and
1,2,4,5-tetrachlorobenzene (<1.0% 2,4,5-trichlorophenol). No metabolites of
penta- and hexachlorobenzene were detected for this eight day period.
The formation of 2,3,4,6-tetrachlorophenol from 1,2,3,4-tetrachloroben-
zene requires an NIH shift, and suggests that there was an arene oxide inter-
mediate (Daly et al., 1972). The metabolites of 1,2,4,5- and 1,2,3,5-tetra-
chlorobenzene are also typically formed from arene oxide intermediates. As
previously mentioned, arene oxide intermediates have been associated with
chemical carcinogenicity.
4. Effects on Invertebrates
(a) Insects
Insects can oxidize halogenated benzenes similarly to nonhuman marwnal-
220
-------
ians. Certain oxidations show characteristics which seem to be peculiar to
the endoplasmic reticulum (microsoraes) of mammalian cells (Hook et al.,
1968). The similarities between products of oxidation in both vertebrate and
invertebrate systems suggest that enzymes in invertebrate insects may be of
the same type as those found in mammals. Most significant is the hydroxyla-
*•
tion of the benzene ring with substituents which withdraw or attract elec-
trons. Monochlorobenzene is biotransformed in the locust to o- (1 to 6.9%),
m- (2 to 20%), and £-chlorophenols (4 to 33%) and 4-chlorocatechol (10 to
37%) (Hook et al., 1968). Ihe proportion of these isomers varies among the
species of insect studied (Hook et al., 1968). Table 85 illustrates the
difference in proportion of the chlorophenol isomers among locusts and
different mammals.
TABLE 85
SPECTROPHOTCMETRIC ESTIMATION OF OJLORQMONOPHENOLS
PRESENT IN HYDRQLYSED URINE OF ANIMALS DOSED WITH CHLOROBENZENE
(Gessner and Smith, 1960)
Expt.
Locusts
Rabbit
Rat
Ferret
Cat
no.
1
2*
1
2
1
2
3
1
2
1
2
% of Dose
ortho
2.6
—
1.1
1.2
1.8
2.5
2.8
1.2
0.4
1.4
1.6
as Chlorophenols
meta
2.0
4.4
2.8
2.8
2.9
1.8
3.6
0.8
0.3
3.1
3.1
para
4.2
9.4
4.6
6.1
4.9
3.7
6.0
5.9
2.7
14.9
19.8
Ratio
(ortho: meta: para)
1.3:1:2.1
- :1:2.1
0.4:1:1.6
0.4:1:2.2
0.6:1:1.7
1.4:1:2.1
0.8:1:1.7
1.5:1:7.4
1.3:1:9.0
0.5:1:4.8
0.5:1:6.4
* Estimated by isotopic dilution
Reprinted with permission from Biochem. J.-, 75(1):175, 1960.
221
-------
In vitro experiments using homogenates of insects have shown that chlor-
inated benzenes appear to be oxidized by enzymes similar to mammalian liver
endoplasmic enzymes. Homogenates of insects or their organs have yielded
products which were inhibitors of oxidations. The inhibitors were sometimes
concentrated in a single organ such as the head (Hook et al., 1968). Some
inhibitory compounds were removed by centrifugation, but others could not be
removed. Satisfactory homogenates for study have been prepared from abdomens
and fat bodies. Tissues must also be examined for inhibitors as well as
enzymes.
Insects differ widely in their ability to oxidize xenobiotic compounds.
House flies are more active than some vertebrate species on a weight basis
(Smith, 1967; Hook et al., 1968). In insects, the ability to oxidize the
methyl group of p-nitrotoluene decreases in the order: housefly> mustard
beetle >German cockroach >cabbage caterpillar > locust> American cockroach>
cricket>meal beetle > cotton stainer> grass grub.
The acute effects of insect exposure to chlorinated benzenes are summar-
ized in Table 86. Though both o- and p-dichlorobenzene have been used as
insecticides, the latter has found the widest application. However, there
are only a limited number of toxicity studies available even for p-dichloro-
benzene. Arnold (1957) found that while a low (2.3 to 3.2 mg/1) concentra-
tion of p-dichlorobenzene would repel black carpet beetle larvae, higher con-
centrations were needed to ensure 100% mortality of larvae after four days.
Punt (1950) described initial respiratory and central nervous system
stimulation followed by depression in insects exposed to p-dichlorobenzene
vapor. After four hours, there was an increase in carbon dioxide output
followed by a decrease. The activity of p-dichlorobenzene against insects
222
-------
TBBLE 86
ACUTE EFFECTS Cf CTLORCBENZENES IN INSECTS
Qjemical
Monochloro—
benzene
o-Dichloro-
benXBne
o-Oichloro-
Eenzene
p-Oichloro-
benzens
Organism
Locust
CJmex lectularis
pendroetonus
pseudotsaiae
XHopk.J
Calandra granaria
aphis ruBicis
Pertplaneta
ansricana
Exposure
In vitro
hoaegenatas
Ptndgant
1 part •«• 5 part
diesel oil
Funigant
•
Injection
Remarks
Gives rise to ccn-
parable anounts of
uh* and 9"piittnuA
HKVOUS ayatefi
effects (not
described)
100% aortality
Nervous systea
effects (not
described)
Sarooeis
Nervous eyatan
effects - increase
Haference
Gtssnir and
Saith, 1960
Booh et al.,
1968
Caaecuti et al.,
1937
Gibson, 1957
Csneron et al. ,
1937
Tattersrield
«t al., 1925.
Hunson and
Meager, 1945.
neacralis Vapor
in activity tol-
lowed by decrease
and spasDOdic
contr actions.
Respiratory and
nervous system
effects: stimula-
tion followed by
depression. Delayed
increase in CO.
output.
Punt, 1950
p-Oichloro- Calliphora
benzene erthnooapnala
Iriatcraa
rubrofaseiata
Vapor
Vapor
Punt, 1950
Caabarus vtrilis
Larvae:
Tlneola bisselliella
(Bunnl) (clothes~noth)
Attagenus megatoaa
(olack carpet beetle)
Applied to
nerve sheath
Facilitation followed
by depression of
nerve transmission
Vapor at varying: 100 % mortality
tenp., 4-9 days higher temperature
kills faster. Shown
effective against
larvae.
Batth, 1971
Tcichloro-
benzene
g-Oichloro-
benzene
flttagenua piceus (Oliv.) 2.3 - 3.2 og/1
(black carpet beetle)
Tfennitas:
Gly
dilatatus
Solid or liquid
fuoigant
Low concentration
repel larvae: very
high cone, needed
to kill
Effective in control.
Trichlorobenzana coo-
pounds phytotoxic to
tea plants
Trichloro- Dandroctonus pseudotsugae 1 part + 5 parts 100% mortality
benzene (Douglas Fir beetle)diesel oil
Arnold,
1957
Dantbarayana
and Fernando,
1970s, 1970b
Gibson,
1957
223
-------
has been described as similar in nature to DDT, though DDT is the more potent
insecticide (Winteringhan and Barnes, 1955). Awad (1971) found that a 25%
solution of p-dichlorobenzene resulted in 100% mortality of the wood borer,
Lyctus africanus, after eight days. A 5% solution of DDT resulted in 100%
mortality in only two days.
Honma (1967) conducted a comparative study of the toxicity of chloro-,
bromo- and iodobenzene to Tyrophagus dimidiatus (mites). Of the halogenated
benzenes tested, monobromobenzene gave the shortest kill time (3 minutes)
followed by o-dichlorobenzene (4 minutes). o-Dibromobenzene was less effect-
ive than o-dichlorobenzene with a 100% kill time of 20 minutes.
Both monochlorobenzene and monoiodobenzene took 10 minutes to produce
100% mortality. After 20 minutes exposure to 1,2,3-trichlorobenzene, all
mites were dead. All halogenated benzenes were dissolved in Tween 20 and
water (0.4:9.5); concentration of solutions was 0.5% v/v.
Qrosch and Hoffman (1973) investigated the effects of 1,2,3-trichloroben-
zene on reproduction of the wasp Bracon hebetor Say. A single concentrated
dose (0.5 pi) of 10 ppn solution in acetone of 1,3,5-trichlorobenzene was
injected between the 2nd and 3rd abdominal segments of Bracon hebetor Say
virgin females. Each female was placed in its own stender dish with two
prestung caterpillars. Eggs were collected daily, immersed in mineral oil,
and females and eggs incubated at 30°C. Hatchability was determined at 30
hours. There was a marked increase in mortality of embryos in eggs deposited
from the 7th to the 14th day after treatment with 1,2,3-trichlorobenzene.
Hatchability prior to the 6th day and after the .15th day did not differ
significantly from the controls. The greatest proportion of dead embryos
were found among those derived from progenitor cells engaged in mitoses to
224
-------
give oocyte-trophocyte nests (Stage 1 Death). Egg production decreased only
slightly.
(b) Marine Organisms and Fresh Water Species
Several chlorinated and fluorinated benzenes are known to be toxic to a
variety of marine organisms including molluscs and crustacean species. Be-
cause of this known toxicity/ there have even been suggestions that mixtures
of polychlorinated benzenes be spread around oyster beds to safeguard the
crop from predatory species (especially oyster drills). In one test of this
possibility, 1,650 Ibs. of 40% polychlorobenzene (tri-, tetra-, penta-) were
spread over a 1 acre oyster bed in Long Island Sound mixed with low volatile
matter (LVM) attapulgus clay to anchor the pesticide to the bottom of the sea
bed treated (Ashton and Weil, 1965). Divers inspected the bed six weeks
later, and reported that the oyster drills were immobile.
A later study found that a similar mixture called Polystream ® limited
the number of drills for at least two years (MacKenzie, 1971). The paper re-
ported that oyster growth was "normal" but made the statement that Polystream
(§) was toxic to "only small percentages of the fish, clams and crabs". Poly-
stream ® apparently accumulated in oysters and clams after treatment, but
the residues "gradually disappeared". No indication was given of the extent
of this accumulation, nor the time taken for the residues to disappear.
Davis and Hidu (1969) have reported that a concentration of 3.13 ppn TCB
caused an approximately 50% reduction in the number of oyster eggs developing
into normal straight-hinge larvae (48 hour TL ) (see Table 87).
m
1,3,5-TCB adversely affected the reproductive performance of Artemia
salina (the brine shrimp). Data are summarized in Table 87 for 1971 studies
(Grosch, 1973). In 1972, cultures from the previous year were reconstituted
225
-------
TABLE 87
EFFECT OF VARIOUS HALOGENATED BENZENES ON
INVERTEBRATE MARINE LIFE AND FRESH WATER SPECIES
(a) Marine Organisms
Chemical
Organism
Exposure
Remarks
Reference
o-Dichloro-
benzene
hard clams
(Mercenaria
mercenaria)
eggs (48 hrs)
larvae (14 day)
Trichloro-
benzene
to
American oyster
(Crassostrea
virginica)
eggs (48 hrs)
larvae (14 day)
hard clams
eggs (48 hrs)
larvae (14 day)
Davis and
Hidu, 1969
100 ppn
100 ppm
TL
3.13 ppm
10 ppm
10 ppn
TL
m
Davis and
Hidu, 1969
Polychloro-
benzenes
(tri-, tetra-
and penta-
chlorobenzene,
variable iso-
mers and %)
Oyster bed predators
esp. oyster drills
Immobilized oyster Ashton and
drills. Tested on 1 Weil, 1965
acre oyster bed in Long
Island Sound - 1,650 IDS
of 40% polychlorobenzenes,
granular 8-15 mesh using
LVM attapulgus clay. Divers
inspected over 5-6 weeks, and
oyster drills were found
immobile.
-------
TABLE 87 (continued)
Chemical
Organism
Exposure
Remarks
Reference
o-Dichloro- Oyster drills
benzene
Crabs
Drills would not cross a Loosanoff
barrier of ODCB and sand 8" et al.,
wide [Feb '59 - March '60] 1960
extreme swelling in gastro-
pods, immobility and death,
curling of tips of rays.
Lost equilibrium, went into
convulsions "ODCB alone does
not seriously affect crabs or
stop them".
tO
to
vj
Polystream (§}
(95% active
tri-, tetra-
and penta-
chlorobenzene
Oyster drills
Eupleura caudata
Urosalpinxcinerea cinereus
9.5 kiloliters/hectare MacKenzie,
killed 85%; low number of 1971
drills for at least 2
years; toxic to "only small
percentages" of the fish,
clams and crabs. After
treatment oysters, clams and
"other" organisms had small
amounts of Polystream Qy res-
idues gradually disappeared.
Oyster growth normal.
o-Dichloro
Benzene
Oysters
(C. Virginia)
1 ppm 1 ppm is the minimum
concentration which
inhibits the growth of
young oysters after 24
hours exposure; no accumu-
lation noted, pollutant
excreted by organism when
chemical removed from the
water.
Butler et
al.,
-------
TABLE 87 (continued)
Chemical
Organism
Exposure
Remarks
Reference
00
1,3,5-Tri- Artemia salina
chlorobenzene (shrimp)
10 ppm; 1. Trend toward decrease
24 hrs. of life span
2. Delay in appearance of
first brood
3. Decrease in average no.
of broods per pair
4. Decrease in average no.
of zygotes produced
Grosch,
1973
(b) Fresh Water
Tetra-
fluorobenzene
Hexafluoro-
benzene
Species
Biomphalaria
glabrata
(host for
Schistosoma
mansoni)
host for
Schistosoma
mansoni
10 ppm (pH - 5.5) LD5Q
10 ppm (pH 5.5-7.7, in artificial
hard water) ID
Duncan and
Pavlik,
1970
n
-------
by adding distilled water to their contents. All the adults which had sur-
vived died in less than a week without producing young.
(5) Effects on Plants
(a) Mutagenicity
p-Dichlorobenzene induces abnormal mitotic division in higher plants.
Effects seen include shortening and thickening of chromosomes, precocioqs
separation of chromatids, tetraploid cells, binucleate cells and chromosome
bridges (c-mitosis). Available studies are suimarized in Table 88.
Abnormal mitotic division of the onion, Allium cepa, on treatment with
several halogenated benzenes has been described by Ostergren and Levan
(1943). Monochloro-, monobromo and monoiodobenzene at concentrations of
1,000 x 10 mol caused full c-mitosis disturbances. Partial disturb-
ances (not described) occurred at 300 x 10 mol. o-Dichlorobenzene
—6
produced full c-
-------
TABLE 88
EFFECTS OF P-OICHDORCBENZENE ON MTTOTIC DIVISION
Organism
Treatment
Frag- Persistence
ments of
Fragments
Remarks
Reference
Fenugreek seedo
Fenugreek
seedlings
4-24 hours soak
In sat. soln.
4 hour "exposure"
not
indicated
No change in morphology or
cytology of seedlings
Root tip chromosomes con-
tracted and arrested at
mttaphase
Gupta, 1972
Greater than 4
hours (not
specified)
Six spades of 4 1/2 hour soak +
monocotyledon in sat. soln. :
angiospema-
root tips
Nine species of 1-4 hours +
dicotyledon depending on
angiosperms- plant
root tips
Three species 4-6 hours in sat. +
of Vicieae - soln.
root tips
After 'longer* treatment, •
mitosis appeared normal
+ Frequency of fragments at Shanna and
matapnaa* tended to Bhattacharyya,
decrease. Frequency 1956
high-24,48 hrs. and
decreased at 72, 96 hrs.
2 plants still highly
fragmented at 96 hrs. 1
couplet* recovery.
+ 2 plants recovered before "
96 hrs. 1 plant died
after 48 hrs. 3 plants
very highly fragmented
at 96 hrs.
not c-mttosis abnormalities. Srivastava,
indicated Breaks associated with 1966
heterochroaatic chromosome • •
regions
Nothosoordun
fragrana Kunth
Root tips
Root tips
Pollen
3 V2 hrs.
soak in sat.
aoln.
6 hrs. sat.
soln.
6 hours
not .
indicated
not
indicated
Grosion and
fragmentation of
chromosomes both at
metaphase and anaphase
Erosion and stickiness,
increase in fragments
from 3 1/2 hour soak.
No fragmentation,
diplochrcoosoniBS.
Shanna and
Sarkar, 1957
In-
dication of slight
disturbance in spindle
mechanise and failure in
cation.
Fenugreek seeds
Fenugreek
seedlings
H
[Flower buds]
4-24 hours soak
in sat. soln.
4 hours
above 4 hours
[3 V2 hrs.
sat. soln.]
- -
+ not
indicated
-.
[-1 t-1
No changes in morphology
or cytology of aeedi noted.
Root tips contracted and
arrested at metaphase.
Mitosis appeared normal
[ Heiotic division - only
stickiness of chromosomes
noted.]
Gupta, 1972
H
H
Shairoa and
Sarkar, 1957
(6 hrs. sat. sol.] [-] [-]
[ lagging, non-disjunction
and stickiness of chromo-
somes. No fragments.]
* c-mitosis as in colchicine-mitosis — shortening and thickening of chromosomes, precocious
separation of chromatids, tetraploid .cells, binucleate cells, chromosome bridges.
+ fragments present
" fragments absent , . -
230
-------
Seeds ware stored in Mesa, Arizona, in open and closed Mason jars (1 qt)
containing 25 g of PDCB for up to eight years. No attempt was made to con-
trol temperature or humidity. After four years, none of the California
Imperial flax seeds (Linum usitatissimum L.) germinated from either the open
or the closed test container. The open control registered 77% germination
I
after four years, while the closed control averaged 82%. Arivat barley seeds
(Hordeum vulgare. L.) stored in the closed test jar averaged 3% germination
t
after eight years, while germination of the barley seed in the open test jar
j
was 54%. The controls averaged 59% and 72% in the closed and open containers
respectively (Day and Thompson, 1965).
After three years, none of the seeds of Piroa S-l fuzzy cotton (Gossypium
barbadense L.) from the closed test container germinated (control 58%).
After 8 years in the open test container, 43% of the fuzzy cotton seeds
germinated (control 68%).
Arisen et al. (1960) studied the effects of 1,2,4,5-tetrachlorobenzene on
the germination and seedling vigor of barley, oats and wheat. Four types of
soil (sand, loam, clay loam, and clay) were pretreated with tetrachloroben-
zene prior to planting of the seeds. Seedling vigor and germination per-
centage decreased for all four soils. However, damage was most severe in the
sandy soil. No germination of barley or oats occurred when planted one day
after soil treatment. Planting 25 days after treatment produced 100% germin-
ation for barley and 95% for oats. The height of the seedlings increased
with time interval between treatment and planting. (This was presumably be-
cause tetrachlorobenzene volatilized from the soil.) Barley was more resist-
ant to the tetrachlorobenzene than oats or wheat in the sandy soil. The de-
crease in seedling vigor and germination percentage was less pronounced for
231
-------
crops grown in clay than in any of the light soils. The one exception was a
poor growth performance for seedlings in the clay loam. This was thought to
be due to high concentrations of soluble salts (7,700 ppm) present in that
soil.
6. Effects on Microorganisms
(a) Fungicidal Effectiveness
The antifungal vapor phase activity of chlorobenzenes in the soil was
investigated by Richardson (1968). A relationship was established between
chemical structure and vapor action.
The percentage retardation of radial growth of the three fungal species
tested, (Pythium ultimum, Rhizoctonia solani and Trichoderma viride) was
greatest for dichloro- and tricolorobenzene. Antifungal activity decreased
for tetrachlorobenzene and pentachlorobenzene. Neither benzene nor hexa-
chlorobenzene retarded growth of T. viride at 1,000 ppm. While the di- and
trichlorinated benzenes were effective against all three fungal species,
tetra- and pentachlorobenzene were more species selective. Thus, P. ultimum
was the most sensitive to 1,2,4,5- tetrachlorobenzene while T. viride growth
was inhibited to a greater extent by pentachlorobenzene (See Figure 23).
(b) Bactericidal and Sporicidal Efficiency
o-Dichlorobenzene is lethal to Mycobacterium smegmatis as both a liquid
or a vapor (Crowle, 1958). Torres et aL. (1970) showed that at a dilution of
1:800, ODCB was active against Staphylococcus aureus and Escherichia coli in
vitro. In the presence of organic matter (10% defibrinated sheep blood),
ODCB was effective against the spores of Bacillus anthracis after 15 minutes
contact. Under the same conditions, excellent bactericidal action was shown
against the cells of Salmonella typhimurium, B. anthracis, Staphylococcus
232
-------
23 COSE RESPONSES OF FtNSI TO VAFOBS OF CHEOKBESZENES IN THE SOIL
(RLdiaxdscn, 1968)
M
I :
%
to
o
t«./7
u£
ii> X9O S90 *M3 * '* Ji ** 11) «0 5^3 *MJ • •( J. il US 1
coHcrNTRArtoM or CHCMICAI IN SOIL - ».».».
Iteprinted with
of the Anerican Fhytopathological Society
233
-------
aureus, and E. coll., According to Brown et al. (1975), £-dichlorobenzene is
not toxic to Ustilago maydis.
(c) Effect on Phytoplankton
Ukeles (1962) conducted a laboratory study of the tolerance of five
species of marine phytoplankton to concentrations of various toxicants
including o-dichlorobenzene. Marine phytoplankton are important food for
clams and oysters, and are the base of many marine food chains.
o-Dichlorobenzene had no significant effect on growth of any of the
tested species at 8 ppm. At 13 ppm none of the organisms grew, but all were
viable. Lethal concentrations were reached at around 80 ppm, and at 130 ppm
all species were dead (see Table 89).
Ukeles pointed out that high concentrations of toxicants used for pred-
ator control might be "safe" when used in shellfish hatcheries, though haz-
ardous under natural conditions. This is because plankton food is grown
apart from the hatchery and periodically added to it. Hence, inhibition of
phytoplankton growth would not occur. In nature, phytoplankton blooms are
important as a source of food. Therefore, any alteration in growth of
phytoplankton resulting from use of halogenated benzenes for predator control
could have consequences along the food chain,
(d) Mutagenicity Studies
Anderson et al. (1972) evaluated 110 herbicides for their ability to pro-
duce point mutations in a number of different microbial systems (Ames proce-
dures) . When tested in a culture of histidine requiring mutants of Salmon-
ella typhimurium, both o-dichlorobenzene and trichlorobenzene (isomer not
specified) gave a negative response, i,e,f they were not mutagenic. The
culture was chosen because of a reported high probability of detecting point
234'
-------
10
TABLE 89
EFFECTS OF ODCB ON GROWTH OF MARINE PHYTOPIANKTON
Concentration
(ppn) of
ODCB
1.3
7.6
13
130
Lindane
concentration
7.5
9
Protococcus
sg.
0.71
0.80
0.00*
0.00
0.75
1.0
Chlorella
sp_.
0.82
0.95
0.00*
0.00
0.36
0.33
Dunarliella
euchlora
0.71
0.90
0.00*
0.00
0.73
0.60
Phaeodactylun
tricornutum
0.74
0.80
0.00*
0.00
0.00*
0.00*
Monochrysis
lutheri
1.00
0.65
0.00*
0.00
0.00
0.00
* no growth, but organisms viable
All numbers represent the ratio of optical density (o.d.) of growth in the presence of
toxicants to o.d. in the basal medium with no added toxicants. Hence 1 = approximately
normal growth.
Reprinted with permission from Ukeles, R. Growth of Pure Cultures of Marine Phytoplankton in
the Presence of Toxicants. Appl. Microbiol.r 10:534, 1962. Copyright (c) 1962 by American
Society for Microbiology.
-------
mutations to single genophores onto the Dt& molecule within this system.
Pentachlorophenol, a metabolite of pentachlorobenzene, was also negative in
this test system. The metabolites of other halogenated benzenes were not
evaluated. More specifically, the activated intermediates were not tested as
would be the case in a typical Ames assay (Ames et al., 1973). Under Ames
procedures, a homogenate of the tissues of the species is added to the chem-
ical in order to generate short-lived intermediates.
The spores of the vitamin B -deficient mutant Streptococcus antibiotic-
us 400 were treated with monochlorobenzene (0.05 and 0.1 ml). After 24
hours, all spores were dead. At six hours, the maximum yield of back muta-
tions observed exceeded the controls by a factor of 187 (low dose) and 1400
(high dose). The mutagenic activity was estimated from the frequency of
induced reverse mutations from auxotrophic to prototrophic phenotype
(Keskinova, 1968).
Prasad (1970) investigated the mutagenic effects of the herbicide
3l,4'-dichloropropionanilide and its degradation products including mono-
chlorobenzene and the three dichlorobenzene isomers. The chemicals were
evaluated for frequency of back mutation of the methione-requiring (meth_)
locus in the fungus, Aspergillus nidulans. The mutagenic activity of mono-
chlorobenzene did not differ significantly from the control. The mutagenic-
ity of the dichlorobenzenes increased in the order: o-dichlorobenzene -
5/10 spores; m-dichlorobenzene - 9/10 spores; j>-dichlorobenzene -
11/10 spores.
236
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IV. REGULATIONS AND STANDARDS
A. CURRENT REGUIATIONS
1. Food, Drug and Cosmetic Act
Monochlorobenzene (MCB) is a solvent in the manufacture of several resins
which are used to make articles intended for repeated food contact. It is
regulated as a Pood Additive under Section 409(c)(l), 72 Stat. 1786; 21 USC
348(c)(l) of the Act. Under special rules published in the Federal Register
in 1969, MCB must not exceed a concentration of 500 ppm as a residue in poly-
sulfone resins intended for food-contact use (HEW, 1969). Monochlorobenzene
must not exceed 500 ppm as a residue in polycarbonate resins destined for
food-contact use (HEW, 1967).
£-Dichlorobenzene reacts in equijnolar parts with sodium sulfide to form
polyphenylene sulfide resins. Under the same section of the Food and Drug
Act, pj-dichlorobenzene concentrations must not exceed 0.8 ppm in the finished
resin when used to coat articles intended for repeated contact with food
(HEW, 1972).
2. Federal Environmental Pesticide Control Act; Food, Drug and Cosmetic Act
All pesticides must be registered with the Environmental Protection Agen-
cy under the Federal Environmental Pesticide Control Act of 1972. Forty-
three uses of o-dichlorobenzene are registered under Section 3 of this Act.
£-Dichlorobenzene has 304 uses while 1,2,4,-trichlorobenzene has five regis-
tered with the Office of Pesticide Programs. There are 26 registered under
the Act for hexachlorobenzene. Currently one claim is pending for a product
237
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containing nonochlorobenzene to be used as a disinfectant (EPA, 1977b).
In 1971, monochlorobenzene (MCB) was exempted from the requirement of a
tolerance when used as an inert solvent or cosolvent in manufacture of
pesticides applied to growing crops before or after emergence from the soil
(EPA, 1971). This authority is designated under the Food, Drug and Cosmetic
Act, Section 408(d)(2), 68 Stat. 512, 21 USC 346 a(d)(2). MCB must be
present in concentrations no greater than 1%. Ihe pesticide should not be
used after the edible parts of the plant begin to form. Livestock are not
permitted to graze on the treated areas until 48 hours after application.
The chlorinated benzenes registered as pesticides are categorized as
Class III toxins i.e., their oral LD5Q's range from 500 to 5000 mg/kg and
LC _'s are from 0.2 through 20 mg/1 (EPA, 1975a). They must, therefore,
carry the following precautionary statement on the label:
Harmful if swallowed (inhaled or absorbed through the skin). Avoid
breathing vapors (dust or spray mist). Avoid contact with skin
(eyes or clothing), in case of contact immediately flush eyes or
skin with plenty of water. Get medical attention if irritation
persists.
Ihe human hazard signal word "caution" should be used on the front panel
(EPA, 1975a).
3. Air and Water Acts
Chlorobenzene has been designated a hazardous substance under the Federal
Water Pollution Control Act Amendments of 1972. Under proposed rules
published in the Federal Register on December 30, 1975, monochlorobenzene is
a Class B toxin, i.e. LC^ value is within the range 1 to 10 ppm for
aquatic organisms (EPA, 1975d). Category B substances are so classified
because they:
238
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(a) bioaccumulate with a short retention time of the order of 1 week or
less; or
(b) are liable to produce tainting of seafood; or
(c) are moderately toxic to aquatic life.
It is proposed that substances in this category should not be discharged into
navigable waters, adjoining shorelines or waters of the contiguous zone from
vessels or onshore and offshore facilities in quantities exceding 10 pounds
(4.54 kg). This value is defined as the harmful quantity (BQ).
In the event of discharges above this value, the authorities must be
immediately notified. It is proposed that penalties for exceeding the BQ be
based on the behavior of the chemical in water. Monochlorobenzene is defined
as an insoluble sinker (i.e. it is heavier than water and insoluble). The
proposed penalty for dumping quantities of MCB in excess of the Harmful Quan-
tity is $36 per excess pound dumped. It is also proposed that the dumping of
any quantity of designated hazardous substances (including monochlorobenzene)
into "special waters" be forbidden. "Special waters" are defined as:
(a) drinking water
(b) waters of the National Wildlife Refuge System
(c) waters of the National Forest Wilderness
(d) waters of the National Park System
(e) waters of the National Wilderness Preservation System
Under 40 CFR 141, Subpart E of the Safe Drinking Water Act, PL. 93-523, a
basic monitoring study for organic chemicals in drinking water was estab-
lished in December 1975. Included in this regulation was a listing of
chemicals which "may" be included in the monitoring effort. This list
included p-dichlorobenzene and 1,2,4- trichlorobenzene (EPA, 1975c).
239
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4. Other Environmental Protection Agency Authority
In June 1976, EPA issued a Proposed Revision of Regulations and Criteria
relating to Ocean Dumping (EPA, 1976b). Under these changes, organohalogen
compounds would be prohibited from ocean dumping operations unless present as
a trace contaminant, ihe total concentration of organohalogen constituents
within the waste should be less than the toxic concentrations toward marine
life, as determined by existing or developed scientific data. Ihis proposed
stricture is applicable to all halogenated benzenes.
The EPA Administrator now has authority under Section 608, the Toxic Sub-
stances Control Act of 1976, to prohibit manufacture, processing or distribu-
tion of hazardous chemicals. He may also limit quantities manufactured for
specific uses, require additional labeling and obligate manufacturers both to
make and maintain records of processes and to monitor or conduct tests to in-
sure compliance with the Law. Oh is broad authority has not been applied to
manufacture.and use of halogenated benzenes, though it would be applicable if
needed.
The Solid Waste Disposal Act (42 USC 3251) as amended by the Resource
Conservation and Recovery ACt of 1976 (PL 94-580) has broad authority over
the management of hazardous waste. Criteria for identifying and listing
hazardous waste will be developed and published in the Federal Register
within 18 months from enactment of the legislation. Once identified, the Act
mandates that such waste be accurately labeled, complete records kept of
disposal (both quantities and method of disposition), and that all hazardous
waste treatment, storage and disposal facilities be run in accordance with
Federal regulations. It might be anticipated that certain halogenated
benzenes will be included in the list of hazardous wastes.
240
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5. Occupational Safety and Health administration (OSHA)
Exposure to mono-, o~ and £-dichlorobenzene is regulated in the work en-
vironment by OSHA under 40 F.R. 23073, May 28, 1975 (OSHA, 1976). A worker
may not be exposed to average concentrations of monochlorobenzene exceeding
75 ppm over an eight hour tine period. The time weighted average for p_-
dichlorobenzene is also 75 ppm. o-Dichlorobenzene has a ceiling value of 50
ppm, i.e., worker exposure should at no tine exceed this value.
6. Department of Transportation (DOT)
The Department of Transportation (DOT) regulates interstate transport of
goods. Overseas transportation is regulated through the Coast Guard. Mono-
chlorobenzene is classified as a flammable liquid (DOT, 1975, 1976). As
such, it must be packaged according to DOT specifications. If transported in
tank trucks or cars, MCB is exempt from the specification packaging, marking
and labeling requirements of the Transport Regulations (173.118) except that
the tank cab or trucks must be labeled "flammable liquid". When transported
by air in a passenger carrying aircraft, the maximum net quantity permitted
is 10 gallons. When carried by water, packages must be identified by label-
ing according to the contents. In the event of an accident during transpor-
tation, the authorities must be immediately notified.
Monobromobenzene is classified as a combustible liquid. No labels are
required by DOT regulations. The flashpoint of monobroraobenzene is above
73°F. This should be indicated on the outside container. There is no limit
to the net quantity contained in one package which may be shipped by air.
Monofluorobenzene, o-, m- and pj-difluorobenzene have low flashpoints
(9°F, 45°F, 12°F, and 11°F) and require a DOT Fed Label.
241
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o-Dichlorobenzene and pj-dichlorobenzene are classified as ORM-A hazards.
This category is defined as an "Other Regulated Material" which:
...has an anesthetic, irritating, noxious, toxic or other similar
property and which can cause extreme annoyance or discomfort to
passengers and crew in the event of leakage during transportation.
ORM-A liquids with a flashpoint between 100° and 200°F when transported
with more than 11 gallons in one container are classified as combustible
liquids. Both ODCB and PDCB fall into this category (flashpoints, 160° and
152°F respectively). Hence, when transported in bulk, both dichlorobenzenes
must conform to specifications for handling combustible materials.
There is no limit to the quantities of either compound which may be
contained in one package transported by air. Additional details of regulated
handling procedures for halogenated benzenes in interstate transportation
were discussed in Section II D.
The Coast Guard has published warning data sheets for mono, o- and £-
dichlorobenzene. All are classified as combustible. In the event of a
spill, the local health and pollution control authorities and the local fire
department must be notified. Both monochlorobenzene and pj-dichlorobenzene
are stated to be hazardous to aquatic life in very low concentrations.
p_-Dichlorobenzene may foul the shoreline. It is also stated that the effects
of low concentrations of o- and £-dichlorobenzene on aquatic life are
unknown. (U.S. Coast Guard, 1970)
7. State Regulations
A number of states have passed or are considering special legislation
regulating the manufacture, use and/or disposal of toxic substances. Very
often state legislation mirrors Federal legislation, regulations and guide-
lines. For example, New Jersey has an Economic Poison Act under which any
242
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pesticide used in the State must be registered after submission of a product
data sheet to the regulatory department. Only those pesticides registered by
EPA under the Federal Environmental Pesticide Control Act are eligible for
registration under the State law. Other states have similar regulations
governing use of pesticides.
Die State of Virginia has implemented a Toxic Substances information Act
(Virginia, 1976) to gather data on hazardous chemicals used in any manufac-
turing process with the State. As currently amended, use of all substances
with a threshold limit value (TLV) should have been reported to the State
Board of Health by January 1, 1977. This stipulation applied to mono-, c—
and p-dichlorobenzene all of which have TLV's.
Other substances defined as toxic by the enactment must be inventoried by
July 1, 1977, when a report documenting the extent and distribution of their
usage will be published. A Toxic Substance List has been posted in at least
five locations around the state. A toxic substance is defined as any chemi-
cal which is:
(a) radiologically active and licensed under the Federal Atomic Energy
Act;
(b) listed in the Registry of Toxic Substances;
(c) listed in Water Quality Criteria, Appendices 2 and 3;
(d) registered as a pesticide with EPA.
This regulation is, therefore, applicable to all halogenated benzenes listed
in Table 70 (Registry of Toxic Effects).
Currently, the Virginia General Assembly is considering an amendment to
modify the Toxic Substances Information Act to apply to any chemical used in
a manufacturing process. The House (1454H) and Senate (631S) versions differ
243
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slightly, but there is apparently an excellent chance that the listing will
become obsolete (Wickline, 1977). On completion of the inventory, the State
i
Health Department will publish a Class I List containing regulations and
safeguards controlling usage of the greater risk chemicals. The Department
is also interested in determining the prevalence of these chemicals in the
watershed and in the environment generally.
Last year, the State of Maryland began a similar inventory of toxic
materials "handled" within the State. Materials to be reported were either
classified by NIOSH as accepted or suspected carcinogens or were generally
toxic materials. No halogenated benzenes were included in this listing. As
several firms chose not to reply to the survey, legislation is now pending
before the Maryland General Assembly to give the State authority to collect
the necessary data.
In 1972, the State of California passed a Hazardous Waste Law to estab-
lish regulations and to maintain a program providing for the safe handling
and disposal of hazardous wastes, under regulations effective July 2, 1974,
chlorobenzene is defined as a flammable hazardous waste (California Depart-
ment of Health, 1975). As such, chlorobenzene can only be disposed of at an
eligible disposal site by a licensed waste hauler after at least five days
notice to the Department of Health. DOT labels are required when hauling MCB
to the waste facility. The weight of the waste must be measured or estimated
prior to disposal at the site, and submitted to the State along with a State
hazardous waste fee. All operators of hazardous waste facilities must submit
a monthly report to the State Department of Health.
Colorado regulates controlled disposal of hazardous chemicals in desig-
nated landfills. The State has broad authority within these regulations to
244
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prohibit certain chemicals from state landfills. This prohibition is decided
on a case-by-case basis. It is not known if halogenated benzenes have ever
come under this prohibition (Stoddard, 1977).
The State of Oregon has registered o-, j>- and 1,2,4-trichlorobenzene as
pesticides for use in the State under ORS Chapter 634 regulated by the State
Department of Agriculture. Disposal of pesticides in Oregon is regulated by
the Department of Environmental Quality under ORS 459.410-459.690 and OAR
Chapter 340, Division 6(3). All pesticides must be disposed of at an En-
vironmentally Hazardous Waste (EHW) facility. While the other halogenated
benzenes are not yet formally classified as environmentally hazardous, in
practice they are not accepted by other landfills in the State (Oregon,
1977). The State Workmen's Compensation Board regulates handling of chem-
icals in the work environment as described under OSHA requirements. The
Public Utility Commission has adopted Federal DOT rules relating to transport
of hazardous chemicals.
Several states are considering new legislation to regulate the manufac-
ture, use, handling, transportation and/or disposal of hazardous wastes. The
Texas Water Control Board has jurisdiction over a recently passed State act
to control disposal of all types of hazardous waste (including halogenated
benzenes). Oklahoma has an Industrial Waste Disposal Act applicable general-
ly to all industrial wastes. Arkansas, Louisiana and New Mexico are all
developing inventories of hazardous waste management systems within these
states, and are planning to introduce legislation covering disposal of all
hazardous wastes (Dyer, 1977).
State water and air pollution authorities follow Federal guidelines in
regulating water and air quality standards within each state (see above).
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B. CONSENSUS AND SIMILAR STANDARDS
1. Threshold Limit Values (TLVs)
TLV's refer to the tine-weighted concentrations for a 7 or 8 hour work
day and a 40 hour week. Values above the TLV are permitted, providing that
there is an equivalent drop below the TLV that same day. Ihe "C" value
assigned to o-dichlorobenzene (ODCB) indicates that this is a ceiling value
above which ODCB concentration should not rise (see Table 90).
TABLE 90
ADOPTED THRESHOLD LIMIT VALUES
(American Conference of Governmental Industrial Hygienists, 1971)
Chemical Concentration
ppm rng/tn
Monochlorobenzene 75 350
o-Dichlorobenzene 50 300
Pj-Dichlorobenzene 75 450
The maximal concentration for MCB exposure is based on analogy with other
chemicals, and on limited industrial exposure data (American Industrial Hy-
giene Association, 1964a). The American Conference of Governmental Industrial
Hygienists (ACGIH) has indicated that this value is probably too high, and in
fact it is much higher than standards in other countries (see below). The
values for ODCB and PDCB are not low enough to prevent eye irritation based
on past human sensory response to the vapors (American Industrial Hygiene
246
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Association, 1964a). The American Conference of Governmental Industrial
Hygienists recently recommended a time-weighted average of 50 ppm for £-di-
chlorobenzene, based on animal data and human experience and response.
The American Conference of Governmental Industrial Hygienists has pub-
lished a Notice of Intended Change recommending a 5 ppm ceiling for 1,2,4-
trichlorobenzene. In the absence of any established government standard
regulating exposure to 1,2,4,5-tetrachlorobenzene, Dow Chemical has suggested
a time-weighted average of 0.4 ppm as a conservative guideline for inter-
mediate usage (Dow, 1977a). No TLVs have been established for the other
halogenated benzenes. In a list of provisional operational limits published
by ACGIH in 1966, the following limits were proposed: 1,2,4-trichlorobenzene,
25 ppm^hexafluorobenzene, 100 ppm; chloropentafluorobenzene, 100 ppm; and
1,3,5-trichlorotrifluorobenzene, 25 ppm.
2. Public Exposure Limits
The American Conference of Governmental Industrial Hygienists recommends
i
the following short-term atmospheric exposure limits based on animal data and
human experience (American Industrial Hygiene Association, 1964b):
Monochlorobenzene 2200 ppm for 0.2 hrs daily
4400 ppm for 0.1 hrs daily
8800 ppm for 0.03 hrs daily
o-Dicnlorobenzene 900-1000 ppm for 2 hrs daily
Pj-Dichlorobenzene*
*Humans will not voluntarily tolerate acute exposure likely to cause serious
health problems.
An atmospheric exposure of 6500 ppm of monochlorobenzene for 1/2 hour or 2000
ppm for one hour should not cause death (American Industrial Hygiene Associa-
tion, 1964b). A concentration of o-dichlorobenzene of 1700 ppm (saturated
atmosphere) is not likely to endanger life after a 30 minute exposure. The
247
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air concentration of p-dichlorobenzene immediately hazardous to human life is
not known, but the saturation concentration at room temperature is not con-
sidered imminently dangerous. The 1976 tentative short-terra exposure limits
(STEL) recommended by the AOGIH are 75 ppm and 50 ppm for raonochlorobenzene
and _pj-dichlorobenzene respectively. The tentative STEL for j>-dichlorobenzene
(PDCB) is 110 ppm (Oak Ridge National Laboratories, 1977).
Little (1968) in a report to the Manufacturing Chemists Association (MCA)
listed the odor threshold for MCB as 0.21 ppm for both 50 and 100% response.
The odor threshold for ODCB is 2 to 4 ppm (American Industrial Hygiene Assoc-
iation, 19645). At 10 to 15 ppm, the smell becomes very noticeable, and at
around 25 to 30 ppm it is considered unpleasant. Eye irritation becomes a
problem at the same concentration range, while at exposures of 60 to 100 ppm,
eye and mucous membrane irritation may be very painful. The odor threshold
for PDCB is from 15 to 30 ppm for unacclimated persons (American Industrial
Hygiene Association, 1964b). Eye irritation begins at around 50 to 80 ppm
and exposure becomes painful at 160 ppm.
3. Foreign Standards
As can be seen in Table 91 below, much lower exposure limits are opera-
tional in several foreign countries.
TABLE 91
RECOMMENDED MAXIMAL ALLOWABLE CONCENTRATIONS IN OTHER COUNTRIES
Country
Soviet Union
Czechoslovakia
Romania
Soviet Union
Soviet Union
Year
1966
1969
1960
1970
1970
Chemical
Monochlorobenzene
Monochlorobenzene
Monochlorobenzene
o-Dichlorobenzene
p-Dichlorobenzene
Concentration
10 ppm
43 ppn
0.05 mg/1
20 mg/m3
20 mg/m3
Reference
ACGIH, 1971
AGGIH, 1971
Gabor and Raucher,
1960
International Agency
for Research on
Cancer, 1974.
n
248
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4. Other
In 1975, the National Science Foundation sponsored a workshop to identify
v
manufactured organic chemicals of greatest environmental and/or health con-
cern. During Phase I of the study, lists of potentially hazardous materials
were drawn up, based on their release rate and known toxicity. Over 337
chemicals were examined individually and rated by panel members on the scale
of 0 (no interest) to 5 (highest interest - i.e., as an environmental pollut-
ant) . A short list of 80 compounds was selected for further study in Phase
II and a final "Hazard Priority Ranking of Manufactured Chemicals" was devel-
oped. Hexachlorobenzene, p-dichlorobenzene and o-dichlorobenzene were se-
lected for Phase II study. Table 92 summarizes this ranking and includes
other hazardous chemicals to give perspective to the degree of hazard im-
plicit in this listing.
In 1974, Midwest Research Institute produced a report for the Council on
Environmental Quality that included a ranking of selected pesticides accord-
ing to their negative environmental impact. Of 125 pesticides examined,
Pj-dichlorobenzene was ranked 14th in a table of pesticides requiring further
study, first in its group of five fumigants and twenty-first in total rank-
ing. For comparison, creosote was ranked first, pentachlorophenol was sec-
ond, chlordane was third, 2,4-D was twenty-second and aldrin was twenty-fifth
(Midwest Research Institute, 1974). These rankings were based on quantities
found in the environment and established toxicity data.
249
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TABLE 92
CHEMICALS SELECTED FOR PHASE II STUDY BY THE NSF WORKSHOP PANEL
(SHORTENED LIST)
(Brown et al., 1975)
Final Score
Chemical
No.
4
5
17
18
21
29
31
34
47
62
Release
Rate Rank
65
*
80
131
56
100
185
*
60
237
Environmental
Interest
2.60
3.90
4.00
3.00
3.75
2.75
2.63
4.63
4.00
1.86
Health
Interest
3.40
3.20
4.25
2.38
4.88
2.00
1.88
4.13
4.25
1.29
Chemical
Vinyl chloride
Hexachlorobenzene
Carbon tetrachloride
Chlorinated paraffins
(35-64% chlorine)
Benzene (chemical uses)
£-Dichlorobenzene
o-Dichlorobenzene
Polyhalogenated biphenyls
Chloroform
Napthalene
* Not ranked, but nominated as a "Chemical of Particular Concern" by a Panel
Member.
250
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SUMMARY AND RECOMMENDATIONS
(a) Summary
Generally, halogenated benzenes are chemically stable. All fluorinated
benzenes, nonochloro-, £- and ro-dichlorobenzene, monobromo-, p- and m-di-
bromobenzene and monoiodobenzene are colorless liquids at room temperature.
Other halogenated benzenes are white crystalline solids. Pentabromobenzene
and the tri-, tetra-, penta- and hexasubstituted iodobenzenes have a tendency
to sublime. pj-Dichlorobenzene (b.p. 174.5°C) also readily sublimes at room
temperature.
The halobenzenes are comparatively volatile compounds. They are poorly
soluble in water but readily soluble in non-polar solvents and lipids.
Several fluorinated, chlorinated and brominated compounds have low
flashpoints. Apart from a tendency of the lower halogenated compounds to
react with oxidizing agents, the chemical stability of the group is good.
Halogenated benzenes are neutral compounds that are generally unreactive to
acids, alkalis and other common laboratory reagents. lower substituted
halogenated compounds are especially resistant to nucleophilic attack, but
substitution by additional halides increases susceptibility to nucleophiles.
The reverse is true for electrophilic substitution, where lower halogenated
compounds are more easily attacked by electrophiles. Several halobenzenes
form organometallic compounds of great use- in organic synthesis.
Of the halogenated benzenes studied, only the chlorinated compounds are
produced in bulk. There has been a recent tendency to introduce mixed
halogen compounds (e.g. £-bromochlorobenzene and o-chlorofluorobenzene) that
have properties similar to the chlorinated compounds in order to obtain pro-
ducts with more desirable characteristics.
Presently, over 300 million pounds of monochlorobenzene are produced
251
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annually in this country alone; however, this figure is down almost 50% from
the 1969 high. Production of. pj-dichlorobenzene was nearly 55 million pounds
in 1975, while £-dichlorobenzene production in 1975 was about 46 million
pounds. Production of o- and £-dichlorobenzene has also dropped off some-
what from previous years. 1,2,4-Tricnlorobenzene is also a major industrial
chemical; in 1973, just over 28 million pounds were produced. Production of
1,2,4,5-tetrachlorobenzene was estimated at 18 million pounds for 1973. Sub-
stantial amounts (about two million pounds each) of monochlorobenzene, Oj-d4-
chlorobenzene, 1,2,4-trichlorobenzene and 1,2,4,5-tetrachlorobenzene, as we^l
as lesser amounts of other chlorinated benzenes, were reportedly imported
during 1971 to 1975.
Monobromobenzene and bromochlorobenzene appear to be the most commercial-
ly important of the brominated compounds. Fluorinated benzenes are expens-
ive, and a market for higher fluorinated derivatives has not developed.
Monoiodobenzene and diiodobenzenes have limited industrial application.
Chlorinated benzenes are basically used for five purposes: (i) as sol-
vents; (ii) as functional fluids (heat transfer and in dielectric mixtures);
(iii) as chemical intermediates, especially for the manufacture of phenolic
compounds, herbicides and dyes; (iv) as insect repellents or pesticides, (v)
for deodorizing. Other halogenated benzenes are either chemical intermit"
iates or solvents.
Environmental contamination occurs during manufacture of chlorobenzenes.
During production, an estimated 0.00488 kg of monochlorobenzene enters the
waste stream for every kilogram of monochlorobenzene produced. Estimated
losses of dichlorobenzenes during manufacture are 0.0038 kgAg monochloro-
benzene produced. A "polychlorinated sludge" is also produced. Annual loss
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to the environment during manufacture of o-dichlorobenzene has been estim-
ated at 0.9 million pounds/year, and for pj-dichlorobenzene at 1.2 million
pounds per annum.
Apart from losses during manufacture, there is also environmental con-
tamination resulting from use of chlorinated benzenes. Monochlorobenzene
and o-dichlorobenzene enter the environment when used as solvents, especially
for toluene diisocyanate production. Lower chlorinated benzenes also enter
the environment when used as dye-carrier solvents. o-Dichlorobenzene is
apparently being deliberately added to treated industrial wastewater to mask
odor. It has been estimated that nearly 70 million pounds of £-dichloroben-
zene are used annually for moth control or as a space odor ant. Presumably
each year a similar quantity sublimes into the atmosphere. Chlorinated ben-
zenes may also be entering the environment as break-down products of the
pesticides, lindane, pentachloronitrobenzene and hexachlorobenzene, or may be
present in these chemicals as impurities.
Chlorinated benzenes have been found in drinking water and raw water
sources in the United States and in Europe. Trichlorobenzene has been det-
ected in fish caught in Lake Superior and Lake Huron. There are several
European reports of pentachlorobenzene accumulation in soil and in vegetables
treated with hexachlorobenzene. £-Oichlorobenzene has been detected in human
blood samples in this country, and with 1,2,4,5-tetrachlorobenzene and hexa-
chlorobenzene, has been identified in human blood and adipose tissue in Japan.
As previously mentioned, chemical characteristics of the halogenated ben-
zenes vary with degree of substitution and type of halogen substituted. Bio-
logical properties are remarkably similar for all halogenated benzenes in a
given series, e.g. all the monosubstituted compounds or all disubstituted
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halobenzenes. Slight differences in biological effects appear to be re}.a.t-
ed to isosteric characteristics.
In general, halogenated benzenes appear to produce central nervous. SyS"*
tern effects. These effects may be either stimulation or depressiont ftoq£ qf
the acute effects are reversible if the chemicals are withdrawn. Depression
of the CNS may proceed to anesthesia. Accompanying the depression may be
some analgesic effects. The fluorinated conpounds appear to have the
analgesic properties, and the least potential for producing toxicity?
is a species difference in the ability of halogenated benzenes to prgd,upjjf
effects, for example, in dogs the polyfluorinated benzenes appear to be quite
analgesic, whereas in mice they are not.
Several studies described alterations in conditioned reflexes of rats
fed monochlorobenzene, o-dichlorobenzene or tetrachlorobenzene. As the halo-
genated benzenes produce central nervous system effects, it is reasonable to
expect that there may be other behavioral effects not yet described.
There is at least one study suggesting that perhaps £-dichlorobenzene mod-
ified the induced resistance of rats to leukemia. Monochlorobenzene has been
shown to interfere with the Schwartzman phenomenon. No other evidence,
found that halogenated benzenes are iramunosuppressants, though as
benzenes affect the central nervous system which has some control over
responses, this remains an unexplored possibility.
In terms of acute toxicity, the halogenated benzenes are not highly toxic
compounds. But in all the subacute or chronic toxicity studies, biological
effects are evident at comparatively low concentrations. For the halogenated
benzenes there is no relationship between acute toxicity and the ability of
the compound to produce damage.
254
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In general, halobenzenes are metabolized by hydroxylation with possible
formation of an arene oxide intermediate. The arene oxide intermediate ap-
pears to be responsible for chronic effects, such as necrosis in liver, lung
and kidney. The effects of the arene oxide metabolite can, however, be miti-
gated by other metabolic and, perhaps, genetic factors. Only those halogen-
ated benzenes with a free vicinal position are capable of forming such toxic
intermediates, but do not necessarily do so. Resistance to the formation of
the arene oxide intermediate by fluorinated benzenes and the pj-disubstituted
halogenated benzenes is well documented.
All halogenated benzenes appear to be highly lipid soluble. Although
there are very few data on partition coefficients, for the chlorinated series
there appears to be an increase in value of partition coefficient as degree
of ohlorination increases. A high value of partition coeffecient is assoc-
iated with accumulation in the lipids of organisms. Also, as the number of
/' ...
halogens increases, the compounds are apparently more resistant to biodegrad-
ation. These factors suggest that the higher-substituted chlorinated ben-
zenes are more likely to bioaccumulate than the lower-substituted compounds.
However, also a factor in bioaccumulation is the rate of absorption into the
system, which appears to decrease as chlorination increases. Thus, it be-
comes obvious that opposite forces are at work, perhaps in favor of the ac-
cumulation of the lower or the higher chlorinated benzenes.
If all forces are taken into consideration and remembering that signif-
icant amounts of the monohalogenated benzenes are excreted unchanged in ex-
pired air, it would appear that all chlorinated benzenes tend to accumulate
in the environment. Alternatively, the quantities of chlorinated and brom-
inated benzenes detected in the environment may reflect an increased monit-
255
-------
oring effort or an improvement in methods of detection.
Every halogenated benzene investigated appears to induce porphyria though
not to the same degree. This ability to induce porphyria may be closely
related to an induction effect on cytochrome P- drug metabolizing enzymes
located in the endoplasmic reticulum. In the late 1950's, there was, an
outbreak of several cases of porphyria in man after ingestion of wheat con-
taminated by hexachlorobenzene. Symptoms subsided when the wheat was re-
placed by uncontaminated grain.
Since it is generally known from laboratory experiments that certain pes-
ticides likewise induce porphyria and that these pesticides are also environ-
mental contaminants, it seems highly possible that these substances may be
either additive or synergistic in terms of their porphyria-producing charac-
teristics. The combined effects of chemicals as they might occur in the en-
vironment have not been studied.
Halogenated benzenes are metabolized by those enzymes associated with
the biosynthesis of cholesterol, the catabolism of bile acids and the oxid-
ation of prostaglandins. However, no studies were found which described the
effects of halogenated benzenes on the metabolism of endogenous substances.
The mutagenicity and carcinogenicity of the halogenated benzenes have not
been well documented in mammals. In some plants exposed to p_-dichlorphe^zene
there appears to be reasonable evidence for mutagenic effects. Inhibition
of mitosis has also been reported, though in one study the germination of
spores was unaffected. In the only study of its kind identified, o-dichloro-
benzene and trichlorobenzene did not produce point mutations in microorgan-
isms. One of the metabolites of pentachlorobenzene, pentachlorophenol, was
also negative in this test system. The metabolites of other halogenated
256
-------
benzenes were not evaluated. More specifically, the activated intermediates
have not been tested, as would be the case in a typical Ames assay.
There were scattered reports of carcinogenicity in roan and animals. Ihe
chronic toxicity studies of Hollingsworth are inconclusive as to the carcino-
genicity of o- and p-dichlorobenzene. While there was no evidence of hyper-
plasia, these studies were of too short a duration to rule out definitely the
possibility of carcinogenic activity in these two compounds. Other chronic
studies (seven to eight months) with tri- and tetrachlorobenzenes in rats gave
no evidence of hyperplasia, though one 82-day study of monochlorobenzene in
rats did show hyperplasia.
In man, there are several reports of blood dyscrasias apparently caused
by chlorinated benzenes. Ib a certain extent these results are confirmed in
experimental animals. In general, other effects which appear to be confirmed
in laboratory animals are the eye and skin effects which reportedly have ap-
peared in man on exposure to several of the chlorinated benzenes.
For the most part, halobenzenes have not been tested for reproductive
effects or teratogenicity in mammals; therefore, it is not possible to make
generalized conclusions regarding effects on reproduction. There were two
carefully controlled studies investigating the reproductive effects of 1,3,5-
trichlorobenzene on (i) the brine shrimp and (ii) a species of wasp. For both
arthropods, results were positive for a slight decrease in life span of adult,
delayed appearance of first brood, decrease in average number of offspring,
and also a decrease in number of zygotes produced. In addition, in the study
on the wasp, evidence was presented that 1,2,3-trichlorobenzene interferes
with the mitotic apparatus of the ovariole sequence.
Tsratogenic studies are also lacking for any species. The few studies
257
-------
which have evaluated the effects of penta- and hexacnlorobenzene in the preg-
nant rat have shown teratogenic effects for'these two compounds.
(b) Recommendations
1. There is a need for long-terra, low-dose studies to establish the carcin-
ogenic risk of exposure to chlorinated benzenes. The higher chlorinated
benzenes must be studied because of their persistence. Pentachloroben-
zene in particular resists biodegradation and is apparently accumulating
in the environment with hexachlorobenzene. Human exposure to the lower
chlorinated benzenes is great, and hence, although it appears that the
anticipated tests may be negative, there is also a high priority for test-
ing these compounds by current carcinogenic methodologies.
2. There is very little information on behavioral effects as a result of
exposure to chlorinated benzenes. All of those compounds which have been
detected in the environment should be studied for behavioral effects in
animals.
3. Possible synergistic effects with other environmental contaminants need
further study since the halogenated benzenes interact with cytochrome P-
450 as do many other environmental contaminants and endogenous steroids.
4. As compounds which interact with cytochrome P-450 and other drug meta-
bolizing enzymes, there is also a need to evaluate the effects of chlor-
inated benzenes on the metabolism of endogenous substances including all
steroids (adrenal, cortical, reproductive and progesterones) and Vitamin
D. The ability of the halobenzenes to induce hypovitaminosis (D) should
also be investigated.
5. There should be studies designed to evaluate the effects of chlorinated
benzenes on reproductive capacity. The compounds which should be evalu-
258
-------
ated are those found in the environment to the greatest extent, namely,
mono-, o-di-, £-di, 1,2,4-tri-, 1,2,4,5-tetra-, penta-, and hexachloro-
benzene as well as monobrcroobenzene and £-bromochlorobenzene.
6. The scattered reports of immunosuppression found in the literature do
not in themselves justify the testing of halogenated benzenes for immuno-
suppression. However, since the halogenated benzenes appear to affect
the nervous system, which in turn is known to have some control over im-
mune responses, it is felt that immunosuppressive effects should be ex-
amined for the halogenated benzenes.
7. There is a definite need to establish the behavior of chlorinated ben-
zenes in the environment. For the lower chlorinated compounds especial-
ly, there are few data describing environmental fate and transportation.
While the lower compounds appear to be biodegradable, the products of
degradation must be identified. The rate of disappearance of chlorinat-
ed benzenes from the environment also needs to be investigated. More
studies are required to establish the extent of transport from water to
air, and aerial fallout.
8. The extent of any possible bioaccumulation of chlorinated benzenes
should be quantified and should include monitoring of aquatic species
(microorganisms, animals and plants).
9. It would also be valuable to establish the extent of environmental con-
tamination resulting from home use of pj-dichlorobenzene including use in
toilet-blocks. Similarly, the extent of use of o-dichlorobenzene as a
sewage deodorant requires immediate documentation.
259
-------
It should be pointed out that environmental contamination by chlorinate^
benzenes especially is widespread and likely to continue. No constraint h«q
been placed upon production and use of chlorinated benzenes to date. Jt is
clear that there is insufficient ecotoxicological evidence to assess the
of hazard presented to human health and the environment by exposure to
inated benzenes. However, there is sufficient information available tP
gest that chlorinated benzenes may pose some risk. The extent of this risk
should be determined.
260
-------
LIST OF REFERENCES
Ahokas, J.T., O. Pelkonen and N.T. Karki. Cytochrone P-450 and Drug-Induced
Spectral Interactions in the Hepatic Microsomes of Trout, Salmo trutta
lacustris. Acta Pharmacol. Toxive, 38(5):440-449, 1976.
Aldrich Chemical Company, inc. D. Griffiths, Technical Information Services,
Personal Communication. Milwaukee, Wisconsin, November 1976.
Alexander, M. pollution Characteristics of 1,2,4-Trichlorobenzene.
Unpublished DOW Report, Midland, Michigan, 1972. Cited in Simmons, P.,
D. Branson and R. Bailey. 1,2,4-Trichlorobenzene: Biodegradable or
Not? Canadian Assoc. of Textile Colourists and Chemists, 1976. Inter-
national Technical Conference, Quebec, Canada, October 13-15, 1976.
Alexander, M. and B.K. Lustigroan. Effect of Chemical Structure on Microbial
Degradation of Substituted Benzenes. J. Agric. Food Chem., 14:410,
1966.
Allied Chemical Corporation. Product Data Sheets - Monochlorobenzene,
o-Dichlorobenzene, p-Dichlorobenzene. Morristown, New Jersey, 1973.
Ameen, O.A., A.D. Day and K.C. Hamilton. Effect of 1,2,4,5- Tetrachloroben-
zene on the Germination and Seedling Vigor of Barley, Oats and Wheat.
Agron. J., 52(2):87-89, 1960.
American Conference of Governmental' industrial Hygienists (ACGIH).
Documentation of the Threshold Limit Values for Substances in workroom
Air, 3rd Ed. American Conference of Government industrial Hygienists,
1971.
American Industrial Hygiene Association. Chlorobenzene. Amer. Indust. Hyg.
Ass. J., 25:97-9, 1964a.
American Industrial Hygiene Association. £-Dichlorobenzene and £-Dichloro-
benzene. Amer. Indust. Hyg. Assoc. J., 25:330-325, 1964b.
Ames, B.N., W.E. Durston, E. Yamasaki and F.D. Lee. Carcinogens are
Mutagens: A Simple Test System Combining Liver Homogenates for
Activation and Bacteria for Detection. Proc. Nat. Acad. Sci. U.S.A.,
70:2281-2286, 1973.
Anderson, K.J., E.G. Leighty and M.T. Takahashi. Evaluation of Herbicides
for Possible Mutagenic properties. J. Agr. Food Chem., 20:649-656,
1972.
Ariyoshi, T., K. Ideguchi, K. Iwasaki and M. Arakaki. Relationship between
Chemical Structure and Activity. II. Influences of Isomers in pichloro-
benzene, Trichlorobenzene and Tetrachlorobenzene on the Activities of
Drug-Metabolizing Enzymes. Chem. Pharm. Bull., 23(4):824-830, 1975.
261
-------
Arnold, J.W. Toxicity and Repellency of Paradichlorobenzene to Larvae of the
Black Carpet Settle. J. Econ. Entom., 50(4):469-471, 1957.
Ashton, W.E. and E.D. Weil, immobilization of Oyster Drills in Oyster Beds.
U.S. Patent No. 3,433,877, 1965.
Awad, L.A. The Effect of Certain Insecticides on the Wood Borer, c
Lyctus africanus, Lesne. Agr. Res. Rev., 49(l):81-85, 1971.
Azouz, W.M., D.V. Parke and R.T. Williams. Studies in Detoxication, 42:
Fluorobenzene. Spectrophotometric Determination of the Elimination of
Unchanged Halogenobenzenes by Rabbits. A Comparison of the Oxidation _in
vivo of Fluorobenzene and Benzene. Biochem. J., 50:702-706, 1952.
Azouz, W.M., D.V. Parke and R.T. Williams. Studies in Detoxication, 51: The
Determination of Catechols in Urine, and the Formation of Catechols in
Rabbits Receiving Halogenobenzenes and Other Compounds, Dihydroxylation
in vivo. Biochem. J., 55(1):146-151, 1953.
Azouz,; W.M., D.V. Parke and R.T. Williams. Studies in Detoxication, 62: The
Metabolism of Halogenobenzenes. Ortho- and Paradichlorobenzenes.
Biochem. J., 59(3):410-415, 1955.
Bache, C.A. and D.J. Lisk. Microwave-Powered Emission Determination of
Residues of Organic Bromine, Chlorine, Iodine, Phosphorus, and Sulfur
Pesticides in Helium Plasma. Biomed. Appl. Gas Chromatog., 2:165-178,
1968.
Balba, M.H. and J.G. Saha. Metabolism of Lindane-14C by Wheat Plants Grown
from Treated Seed. Environ. Lett., 7(3):181-194, 1974.
Barbour, A.K., M.W. Buxton and G. Fuller. Fluorinated Aromatic Compounds.
In: Kirk-Othmer Encyclopedia of Chemical Technology, 2nd Ed. John <
Wiley and Sons, New York, 9:775-802, 1966.
Batth, S.S. Influence of Temperature on the Effectiveness of Paradichloro-
benzene Fumigation of Webbing Clothes Moth Larvae. J. Econ. Entorool.,
64(4):989-90, 1971.
Beck, J. and K.E. Hansen. The Degradation of Quintozene, Pentachlorobenzene,
Hexachlorobenzene, and Pentachloroaniline in Soil. Pestic. Sci., 5(1):
41-48, 1974.
Belyakov, A.A., L.V. Mel'Nikova and A.Y. Tubina. Determination of Some
Halogen Derivatives of Benzene in Air Based on the Formation of
Polymethine Dyes. Gig. Sanit., 37(12):74-75, 1972.
Berliner, M.C. Cataract Following the Inhalation of Paradichlorobenzene
Vapor. Arch. Ophthalmol. (Chicago), 22:1023-1034, 1939.
262
-------
Booth, N.H. and J.R. McDowell. Ibxicity of Hexachlorobenzene and Associated
Residues in Edible Animal Tissues. J. Am. Vet. Med. Assoc.,
166(6):591-595, March 15, 1975.
Boyland, E. and L.F. Chasseaud. The Role of Glutathione and Gluthathione
S-Transferases in Mercapturic Acid Biosynthesis. Adv. Enzymol.,
32:173-219,1969.
Brady, M.N. and D.S. Siyali. Hexachlorobenzene in Human Body Fat. Med.
J. Austr., 1(4):158-161, 1972.
Brauer, R.W. Mechanism of Bile Secretion. JAMA., 169:1462-1466, 1959.
Brodie, B.B., W.D. Reid, A.K. Cho, G. Sipes, G. Krishna, J.R. Gillette.
Possible Mechanism of Liver Necrosis Caused by Aromatic Organic
Compounds. Proc. Nat'l. Acad. Sci. (U.S.), 68(1):160-164, January 1971.
Brown, J., K. Hyde, C. Muir, E. Thorpe. Acute Ibxicity and Skin Irritant
Properties of 1,2,4-Trichlorobenzene. Eng. Ann. Occup. Hyg.,
12(4):209-212, 1969.
Brown, S.L., F.Y. Chan, J.L. Jones, D.M. Liu, K.E. McCaleb, T. Mill,
K.N. Supios and D.E. Schendel. Research Program on Hazard Priority
Ranking of Manufactured Chemicals: Phase II, Final Report; Chemicals
1-19, Chemicals 21-40. Stanford Research Institute, Menlo Park,
California, 1975.
Butler, P.A., A.J. Wilson, Jr. and A.J. Rick. Effect of Pesticides on
Oysters. Proc. Natl. Shell Fish. Assoc., 51:23-32, 1960.
California Department of Health. Hazardous Waste Management: Law,
Regulations and Guidelines for the Handling of Hazardous Waste. State
of California, Sacremento, California, February 1975.
Cameron, G.R., J.C. Thomas, S.A. Ashmore, J.L. Buchan, E.H. Warren and
A.W. McKenny Hughes. The Tbxicity of Certain Chlorine Derivatives of
Benzene with Special Reference to o-Dichlorobenzene. J. Path. Bact.,
44:281-296, 1937.
Campbell, D.M. and R.J.L. Davidson. Toxic Haemolytic Anaemia in Pregnancy
Due to A Pica for Paradichlorobenzene. J. Obstet. Gynaec. Brit.
Cmnwlth., 77:657-659, 1970.
Carlson, G.P. and R.G. Tardiff. Effect of Chlorinated Benzenes on the
Metabolism of Foreign Organic Compounds. Tbxicol. Appl. Pharmacol.,
36:383-394, 1976.
Chemical Marketing Reporter. Chemical Profile Supply: Monochlorobenzene.
Chemical Marketing Reporter, 206(20):3, November 11, 1974a.
263
-------
Chemical Marketing Reporter. PPG Plans Triple Chlorobenzene Capacity by
Building a New Plant. Chemical Marketing Reporter, 206(21):3, 6,
November 18, 1974b.
Chemical Marketing Reporter. Chlorobenzene Expansion for Dow's Midland
Facilities. Chemical Marketing Reporter, 207(2) :3, 19, January 13, 1975.
Christensen, R. and W. Long. Report of an industrial Wastewater Survey
Conducted at Lakeway Chemical Inc. Michigan Dept. of Natural Resources,
July 12, 13, 1976.
Coe, P.L., C.R. Patrick and J.C. Tatlow. Aromatic Polyfluoro Compounds V.
The Preparation of Highly Fluor inated Benzenes by Defluorination of
Polyfluorocyclohex -anes, -enes and Dienes. Tetrahedron, 9:240-245,
I960.
Cotter, L.M. Paradichlorobenzene poisoning from Insecticides. N.Y. State J.
Med., 53:1690-1692, 1953.
Conney, A.H. Pharmacological Implications of Microsomal Enzyme Induction.
Pharmacol Rev., 19:317-366, 1967.
Coppola, A., S. DiBlasi, A. Scorsone and G. Licari. Thromboelastographic
Changes in Subacute Poisoning with Paradichlorobenzene. Folia Medica
(Naples), 4b:1104-ll09, 1963.
Courtney, K.D., M.F. Copeland and A. Robbins. The Effects of Pentachlorc—
nitrobenzene, Hexachlorobenzene, and Related Compounds on Fetal
Development. Toxicol. Appl. Pharmacol., 35(2):239-256, 1976.
Crosby, D.G. and N. Hamadmad. The Photoreduction of Pentachlorobenzenes.
J. Agric. Food Chem., 19(6) .-1171-1174, 1971.
Crowder, J.A. and E.E. Gilbert. Dihalobenzenes. Allied Chemical Corp.,
U.S. Patent No. 2,866,828, December 30, 1958.
Crowle, A.J. Filtration of Mycobacteria from Organic Solvents. Amer. Rev.
Tuber., 77(2) .-290-300, 1958.
Curley, A., V.W. Burse, R.W. Jennings and B.C. Villaneuva. Chlorinated
Hydrocarbon pesticides and Related Compounds in Adipose Tissue from
People of Japan. Nature, 242(5396):338-340, 1973.
Daly J., D. Jerina and W. Witkop. Arene Oxides and the NIH Shift: The
Metabolism, Toxicity and Carcinogenicity of Aromatic Compounds.
Experentia, 28(10):1129-1264, 1972.
Daniel, J.W. The Metabolism of el- Labelled Trichloroethylene and Tetra-
chloroethylene in the Rat. Biochem. Pharmacol., 12:795-802, 1963.
Danthanarayna, W. and S.N. Fernando. Biology and Control of the Livewood
Termites of Tea. Tea Quarterly 4l(I):34-52, 1970a.
264
-------
Dantharayana, W. and S.N. Fernando. Controlling Termite Colonies that Live
within Plants. Int. Pest. Contr., 12(1):10-14, 1970b.
Davies, D.S., p.L. Gigon and J.R. Gillette, Species and Sex Differences in
Electron Transport Systems in Liver Microsomes and their Relationship
to Ethylmorphine Demethylatron. Life Sci., 8(II):85-91, 1969.
Davis, D.O., M. Hashimoto and J.R. Gillette. Effects of Bromobenzene and
Carbon Tetrachloride on Synthesis and Release of Proteins by Perfused
Rat Liver. Biochera. Pharmacol., 22(16):1989-2001, 1973.
Davis, B.C. and H. Hidu. Effects of Pesticides on Embryonic Development of
Clams and Oysters and on Survival and Growth of the Larvae. U.S. Fish
and Wildlife Serv., Fish Bull., 67(2):393-408, 1969.
Day, A.D. and R.R. Thompson. Some Effects of p-Dichlorobenzene, Naphthalene,
DDT and Ceresan on the Germination of Field Crop Seeds. Agron J.,
57(4):321-2, 1965.
Devos, R.H., M.C. Ten Noever Brauw, and P. Olthof. Residues of Pentachloro-
nitrobenzene and Related Compounds in Greenhouse Soils. Bull. Environ.
Contam. Toxicol., 11(6):567-571, 1974.
Dilling, W.L., C.J. Bredeweg and W.B. Tefertiller. Organic Photochemistry—
Simulated Atmospheric photodecomposition Rates of Methylene Chloride:
1,1-Trichloroethane, Trichloroethylene, Tetrachloroethylene and Other
Compounds. Environ. Sci. Tech., 10:351-356, 1976.
DOT Code of Federal Regulations 49. Transportation Parts 100 to 199, as
Revised, October 1, 1975.
DOT Materials Transportation Bureau. Hazardous Materials Regulations:
Consolidation and Miscellaneous Amendments. Federal Register, 41(252):
57018-57072, December 30, 1976.
Dow Chemical, U.S.A. Transportation Equipment Data Sheet — 1,2,4-
Trichlorobenzene. Midland, Michigan, 1967.
Dow Chemical, U.S.A. Physical Property Sheets — Monochlorobenzene,
o-Dichlorobenzene, p-Dichlorobenzene. Midland, Michigan, 1970.
Dow Chemical, U.S.A. Physical Property Sheet — 1,2,4-Trichlorobenzene.
Midland, Michigan, 1972.
Dow Chemical, U.S.A. Transportation Equipment Data Sheet —
o-Dichlorobenzene. Midland, Michigan, 1973.
Dow Chemical, U.S.A. Emergency Response Information Sheets —
Monochlorobenzene, o-Dichlorobenzene. Midland, Michigan, 1974.
Dow Chemical, U.S.A. Emergency Response Information Sheets —
p-Dichlorobenzene, 1,2,4-Tr ichlorobenzene. Midland, Michigan, 1975a.
265
-------
Dow Chemical, U.S.A. Organic Chemicals from Dow — Chlorinated Aromatics.
Midland, Michigan, 1975b.
Dow Chemical, U.S.A. Transportation Equipment Data Sheet —
Monochlorobenzene. Midland, Michigan, 1975c.
Dow Chemical, U*S.A. J.W. Condor, Health and Environmental Research
Division, Personal Communication. Midland, Michigan, January 1977a.
Dow Chemical, U.S.A. Material Safety Data Sheets — Monochlorobenzene,
o-Dichlorobenzene, £-Dichlorobenzene; 1,2,4-Trichlorobenzene; 1,2,4,5-
Ttetrachlorobenzene. Midland, Michigan, 1977b.
Downing, John G. Dermatitis from Orthodichlorobenzene. JAMA, 112:1457,
1939.
Dowty, B., D. Carlisle, J. Laseter and J. Storer. Halogenated Hydrocarbons
in New Orleans Drinking Water and Blood Plasma. Science, 187:75-77,
1975.
Duncan, J. and J. Pavlik. Effects of Structural Rearrangement on the
Molluscicidal Activity of Certain Fluorinated Aromatic Compounds. Bull.
WHO., 42(5):820-825, 1970.
Dupont, R. Origin of a Discomfort Experienced by Workers During the Cleaning
of a Sewer. Arch. Malad. Profess., 1:312-14, 1938.
Durham, J.L. Photochemistry of o- and p-Difluorobenzene. Diss Abstr. Int.
B, 30(7):3318, 1970.
Dyer, N. Chief, Pesticides and Hazardous Materials Division, USEPA Region
VI, Private Communication. Dallas, Texas, January 1977.
Eastman Kodak Organic Chemicals Divison. Warren Jones, Supervisor, Occupa-
tional Health Services, Health, Safety and Human Factors Laboratory,
Personal Communication. Rochester, New York, December 1976.
Echols, J.T. V.T.-C. Chuang, C.S. Parrish, J.E. Pose and B. Milligan.
Photochemical Interchange of Halogens in Aromatic Compounds III. J. Am.
Chem. Soc., 89(16) .-4081-4088, 1967.
Ehrlicher, M. Observations and Experiences in Industry Concerning the
Tbxicity (Physiopathologic) Effect of Chlorinated Benzene Vapors.
(Mono- to Hexachlorobenzene). Zbl. Arbeitsmed., 18:204-205, 1968.
EPA. Tolerances and Exemptions from Tolerances for Pesticide Chemicals in or
on Raw Agricultural Commodities: Subpart D Exemptions from Tolerances:
Chlorobenzene. Federal Register, 36(175):18080, September 9, 1971.
EPA. Open Public Hearing of the Hazardous Materials Advisory Committee,
Meeting Chaired by E. Mrak. Washington, D.C., August 6-7, 1973.
266
-------
EPA. Regulations for the Enforcement of the Federal Insecticide, Fungicide
and Rodenticide Act, Subpart A. - Registration, Re-registration and
Classification Procedures. Federal Register, 40(129) .-28242-28281, July
3, 1975a.
EPA. Preliminary Assessment of Suspected Carcinogens in Drinking Water:
Report to Congress. USEPA Report PB-250 961. National Technical
Information Service, Springfield, Virginia, December 1975b.
EPA. water Programs — National Interim Primary Drinking Water Regulations.
Federal Register, 40(248): 59566-59588, December 1975c.
EPA. Hazardous Substances, Designations, Removability, Harmful Quantities,
Penalty Rates. Federal Register, 40(250), December 30, 1975d.
EPA. Assessment of Industrial Hazardous Waste Practices- Organic Chemicals,
Pesticides and Explosives Industry. USEPA Report SW-118C, 1976a.
EPA. Ocean Dumping, Proposed Revision of Regulations and Criteria. Federal
Register 41(125): 26644-26657, June 28, 1976b.
EPA. Hazardous Waste Disposal Damage Reports No. 3. EPA/530/SW-151.2,
Cincinnati, Ohio, June 1976c.
EPA. Computer Printout of Organic Chemicals Found in Waters in Region IV.
Athens, Georgia, February 1977a.
EPA. Office of Pesticide Programs, Sue Hummel, Private Communication.
Washington, D.C., 1977b.
Erisman, H. and M. Gordon. Identification of Organic Compounds in Textile
Plant Effluents, presented at the First Chemical Congress of the North
American Continent, Mexico City, Mexico, November 30-December 5. Murray
State College, Murray, Kentucky, 1975.
Faith, W.L., D.B. Keyes and R.L. Clark. Chlorobenzene-Dichlorobenzene. In:
Industrial Chemicals, 3rd Ed. John Wiley and Sons, New York,
pp. 261-266, 1965.
Falk, R.A. Hexafluorobenzene and Related Fluoroaromatic Compounds. Sperry
Engineering Review, Fall 1963.
Feast J. and w. Musgrave. Halogen Derivatives of Benzene and its Homologues.
In: Rodd's Chemistry of Carbon Compounds (S. Coffey, ed.), Volume III,
Aromatic Compounds, Part A. Elsevier Pub. Co., London, pp. 241-269, 1971.
Fieser, L.F. and M. Fieser. Chapter 27. Aryl Hal ides. In: Organic Chem-
istry, 3rd Ed. Reinhold Publishing Corporation, New York, pp. 644-655.
1960.
Fieser, L.F. and M. Fieser. Reagents for Organic Synthesis. Wiley and Sons,
New York, 1967.
267
-------
Flynn, E.J., M. Lynch, and v.G. Zannoni. Species Differences and Drug
Metabolism. Biochem Pharmacol., 21:2577-2590, 1972.
Fomenko, v.N. Detection of Maximum Permissable Concentration of Tetra-
chlorobenzene in Water Basins. Gig. Sanit., 30(1-3):8-15,1965.
Frada, G. and V. Cali. Toxicity of Paradichlorobenzene. Folia Med.
(Naples), 41:349-355, 1958.
Frank, S.B. and H.J. Cohen. Fixed Drug Eruption Due to Paradichlorobenzene.
New York J. Med. ,61:4079, 1961.
Gabor, S. and K. Paucher. Studies on the Determination of the Maximum
Permissible Concentrations of Benzene and Monochlorobenzene. J. Hyg.
Epidemiol. Microbiol. Bnmunol., 4(2):223-231, 1960.
Gadrat, J., J. Monnier, A. Ribet and R. Bourse. Acute Hemolytic Anemia in a
Female Worker of a Dyeing and Dry-Cleaning Shop Exposed to inhalation of
Chlorobenzenes. Arch. Mai. Profess. Med. Travail et Securite Sociale,
23(10/11):710-714, 1962.
Gage, J.C. Subacute Inhalation Toxicity of 109 Industrial Chemicals. Brit.
J. ind. Med., 27(1):1-18, 1970.
Garmer, N.L. and J.M. Leigh. Some Effects of Hexafluorobenzene in Cats.
Brit. J. Pharmacol. Chemother., 31(2):345-350, 1967.
Garrison, A.W. and S.W. Hill. Organic Pollutants from Mill Persist in
Downstream Waters. American Dyestuff Reporter, 21-25, February 1972.
Gessner, T. and j.W. Smith. Comparative Detoxication 7, The Metabolism of
Chlorobenzene in Locusts: Excretion of Unchanged Chlorobenzene and
Cysteine Conjugates. Biochem. J., 75(1):166-172, 1960.
Gibson, A.L. Tests of Bark-Penetrating Insecticides to Control the Douglas
Fir Beetle. Econ,. Entomol., 50:266-268, 1957.
Gibson, D.T., J.R. Koch; C.L. Schuld and R.E. Kallio. Oxidative Degradation
of Aromatic Hydrocarbons by Microorganisms. II. Metabolism of
Halogenated Aromatic Hydrocarbons. Biochem., 7(11):3795-3802, 1968.
Gigon, P.L. T.E. Gram and J.R. Gillette. Effect of Drug Substrates in the
Reduction of Hepatic Microsomal Cytochrome P-450 by NADPH. Biochem.
Biophys. Res. Comm., 31(4) :558-562, 1968.
Gillette, J.R. Mechanism of Hepatic Necrosis Induced by Halogenated Aromatic
Hydrocarbons. In: Pathogenesis and Mechanisms of Liver Cell Necrosis.
(D. Keppler, ed.). MTP Press, St. Leonardgate, England, 1975a.
Gillette, J.R. Reactive Metabolites of Organohalogen Compounds. In:
Ecological Toxicblogical Research, (A.D. Mclntyre and C.F. Mills, eds.).
Plenum Press, New York, pp. 107-122, 1975b.
268
-------
Girard, R., F. Iblot, P. Martin and J. Bourret. Serious Blood Disorders and
Exposure to Chlorine Derivatives of Benzene (A Report of 7 Cases). J.
Med. Lyon, 50(1164):771-73, 1969.
Goujon, P.M., D.W. Nebert and J.E. Gielen. Genetic Expression of Aryl
Hydrocarbon Hydroxylase Induction. IV. Interaction of Various
Compounds with Different Forms of Cytochrome P-450 and the Effect of
Benzo(a)pyrene Metabolism in Vitro. Molec. Pharraacol., 8:667-680,
1972.
Great Lakes Chemical Corporation. Product Information, Price Information-
Bromobenzene. West Lafayette, Indiana, 1975. I
Great Lakes Chemical Corporation. D. Williams, Private Communication. West
Lafayette, Indiana, 1976. J
Greve, P.A. Pentachlorobenzene as a Contaminant of Animal Feed. Med. Fac.
Lahdbouwwet Rijksoniv. Gent., 38(3):775-784, 1973.
Grosch, D.S. Reproduction Tests: The Toxicity for Artemia of Derivatives
from Non-Persistent Pesticides. Biol. Bull. (Woods Hole), 145:340>351,
1973. I
I
Grosch, D.S. and A.C. Hoffman. Vulnerability of Specific Cells in the
Cogentic Sequence of Bracon hebetor Say to Some Degradation Products of
Carbamate Pesticides.Environ. Entomol., 2:1029-1032, 1973.
Gubser, H. Purification of Chemical Wastewaters. Gas Wasser Abwasser, 49,
1969.
Guerin, M. and J. Cuzin. Skin Tests on Mice for Determining the Carcinogenic
Activity of Cigarette Tobacco Smoke Tar. Bulletin de 1'Association
Francaise pour I1Etude du Cancer, 48(1):112-121, 1961.
Guerin, M., P. Lazar and I. Chouroulinkov. Inhibitory Action of Chemical
Carcinogens on Mitosis of Rat Lung Cell Cultures. 2. Comparative Study
of Carcinogenic and Noncarcinogenic Substances. C.R. Seances. Soc.
Biol. Filiales, 165:2255-2258, 1971.
Gupta, K.C. Effects of Some Antimitotics on the Cytology of Fenugreek Roots
in Vivo and in Vitro. Cytobios., 5(19):179-87, 1972.
Gurfein, L.W. and Z.K. Pavlova. The Limit of Allowable Concentrations of
Chlorobenzenes in Water Basins. In: USSR Literature on Water Pollution,
(B.S. Levine, ed.). Department of Commerce, Washington, D.C., 3:58-65,
1962.
Haas, J.M., H.W. Earhart and A.S. Todd. Environmental Considerations
Concerning the Selection of Dye Carrier Solvents. Presented at the 1974
American Association of Textile Chemists and Colorists National
Technical Conference, October 9-11, 1974.
269
-------
Habboush, A.E. and A.H. Tameesh. GLC of Disubstituted Benzene Isomers. I.
Separation and Study of the Dichlorobenzenes. J. Chromat., 53:143-149,
1970.
Hall, L.W. and S.R.K. Jackson. Hexafluorobenzene as an Anaesthetic Agent.
Anaesthesia, 28(2):155-159, 1973.
Hall, L.W. S.R. Jackson and G.H. Massey. Hexafluorobenzene in Veterinary
Anaesthesia. In: Recent progress in Anaesthesiology and Resuscitation,
(A. Arias et al. eds.). Excerpta Medica, Amsterdam, pp. 201-204,
1975.
Hallowell, M. Acute Haemolytic Anemia Following the Ingestion of Para-
dichlorobenzene. Arch. Dis. Child, 34:74-75, 1959.
Bardie, D.W.F. Chlorinated Benzenes. In: Kirk-Othmer Encyclopedia of Chemi-
cal Technology, 2nd Ed. John Wiley and Sons, New York, 5:253-267, 1964.
Hart, A.W., M.G. Gergel and J. Clarke. Organic iodine Compounds. In:
Kirk-Othmer Encyclopedia of Chemical Technology, 2nd Ed. John Wiley and
Sons, New York, 11:861-870, 1966.
Hawley, G.G. (ed). The Condensed Chemical Dictionary, 8th Ed. Van Nostrand
Reinhold Co., New York, 1971.
Heukelekian, H. and M.C. Rand. Biochemical Oxygen Demand of Pure Organic
Compounds. Sewage Ind. Wastes, 27:1040, 1955.
HEW. Food Additives Resulting from Contact with Containers or Equipment and
Food Additives Otherwise Affecting Food - Polycarbonate Resins. Federal
Register 32:14324, October 17, 1967.
HEW. Food Additives Subpart F- Food Additives Resulting from Contact with
Containers or Equipment and Food Additives Otherwise Affecting Food:
Polysulfone Resins. Federal Register, 34(206):17332, October 25, 1969.
HEW. Additives Resulting from Contact with Containers or Equipment and Food
Additives Otherwise Affecting Food: Polyphenylene Sulfide Resins.
Federal Register, 37:22374, October 19, 1972.
Hintz, M. Pollution Characteristics of 1,2,4-Trichlorobenzene. unpublished
Dow report, Midland, Michigan, 1962. Cited in Simmons, P., D. Branson
and R. Bailey. 1,2,4-Trichlorobenzene: Biodegradable or Not? Canadian
Assoc. of Textile Cblourists and Chemists, 1976. International Technical
Conference, Quebec, Canada, October 13-15, 1976.
Hinze, Wolfgang, H. Kruger and D. Klotzer. Synergistic Agents for
Organostannic Fungicidal Compounds. British Patent NO: 1,177, 433,
January 1970.
Holbrook, G.W., L.A. Loree and O.R. Pierce. Fluorination of Perhalobenzenes
with Potassium Fluoride in Polar Solvents. J. Org. Chem., 31:1259-1261,
1966.
270
-------
Hollingsworth, R.L., V.K. Rowe, F. Oyen, H.R. Hoyle and H.C. Spencer.
Tbxicity of Paradichlorobenzene: Determinations on Experimental Animals
and Human Subjects. AHA Arch. Ind. Hlth., 14:138-147, 1956.
Hollingsworth, R.L., V.K. Rowe, F. Oyen, T.R. Tbrkelson, and E.M. Adams.
Toxicity of o^Dichlorobenzene: Studies on Animals and Industrial
Experience. AMA Arch. Ind. Hlth., 17(l):180-87, 1958.
Honma, S. Effect of Various Chemicals on Mites. Yakuzaigaku, 27(3):192-6,
1967.
Hook, G., T.W. Jordan and J.N. Smith. Factors Affecting Insect Microsonal
Oxidations. Proc. Conf. Enzy. Oxid. Toxic., 27-46, 1968.
Hooker Chemicals and Plastics Corp. J. Wilkenfeld, Director, Corporate
Health, Personal Communication. Niagara Falls, New York, 1977.
Interdepartmental Task Force on PCBs. Polychlorinated Biphenyls and the
Environment. National Technical Information Service, U.S. Department of
Commerce, COM-72-10419, Springfield, Virginia, pp. 42-67, May 1972.
International Agency for Research on Cancer (IARC). The Evaluation of
Carcinogenic Risk of Chemicals to Man. International Agency for
Research on Cancer, World Health Organization, 7:231-244, 1974.
Irie, D., T. Sasaki, and R. Ho. Acute Toxicity, Inhalation Toxicity and Skin
Irritation of Cyclododecane, Tricyclododecane, Naphthalene and
p-Dichlorobenzene. Toho. Igakkai. Zasshi., 20(5/6): 772-775, 1973.
Izatt, J.R., Caudle, G.F. and B.L. Bean. Q Switching and Mode locking of
CO. Laser with Aromatic Halogenated Hydrocarbons. Appl. Phys. Lett.,
25T8):446-448, October 15, 1974.
Karapally, J.C., J.G. Saha, and Y.M. Lee. Metabolism of Lindane- C in the
Rabbit: Ether-Soluble Urinary Metabolites. J. Agr. Food Chem., 21(5):
811-818; 1971.
Karasek, F.W. and P. vassilakopulos. Analysis of Bromochlorobenzenes by Gas
Chromatography. Chrcmatographia, 4(9):388-390, 1971.
Karasek, F.W., R.L. Laub and E. DeDecker. Computer Resolution of Plasma
Chrcroatographic Peaks. J. Chromat., 93(1):123-128, 1974.
Karasek, F.W. and O.S. Tatone. Plasma Chromatography of the Monohalogenated
Benzenes. Anal. Chem., 44(11);1758-1763, 1972.
Kato, R. Possible Role of Cytochrome P-450 in the Oxidation of Drugs in
Liver Microsomes. J. Biochem (Tokyo), 59:574-583, 1966.
Keskinova, D.V. The Effect of Dimethylcyclodiazomethane in Chlorobenzene
Solution on Mutagenesis in Actinomyces antibioticus 400. Genetika,
4(8):121-125, 1968.
271
-------
Khanin, A.G. Pathohistological Changes in the Central Nervous System and
Internal Organs of/Experimental Animals after Chronic, 24-hour
Inhalation of Toxic Substances. T. Tsent. Inst. Vsoversh. Vrachei.,
135:97-106, 1969.
Khera, K.S. and D.C. Villeneuve. Teratogenicity Studies on Halogenated
Benzenes (Pentachloro-, Pentachloronitro- and Hexabromo-) in Rats.
Toxicol., 5(1):117-122, 1975.
Kisarov, V.M., A.A. Balaznina and E.M. Kormovaya. Calculating Chlorobenzene
Levels in Air and Water. Gig. Sanit., 27(12):49-50, 1962.
Kissling, L.F. 1,2,4,5-Tetrachlorobenzene. U.S. Patent NO: 2,805,264,
September 3, 1957.
Kitagawa, H., T. Satoh and Y. Fukuda. Subacute Toxicities of Hexabromoben-
zene. Oyo Yakuri, 9(5):663-673, 1975.
Koch-Weser, D., J. de la Huerga, C. Yesinick and H. Popper. Metabolism,
2:248, 1953. Cited by Von Oettingen W.F. The Halogenated Aromatic
Hydrocarbons, In: The Halogenated Aliphatic, Olefinic, Cyclic, Aromatic
and Aliphatic Aromatic Hydrocarbons, Including the Halogenated insecti-
cides, their Toxicity and Potential Dangers. U.S. Department of Health
Education and Welfare, Public Health Service, Rockville, Maryland, No.
414:283-299, 1955.
Kohli, I., D. Jones and S. Safe. The Metabolism of Higher Chlorinated
Benzene Isomers. Can. J. Biochem., 54(3): 203-208, 1976a.
Kohli, J., I. Weisgerber and w. Klein. Balance of Conversion of
Carbon-14-labeled Lindane in Lettuce in Hydroponic Culture. Pestic.
Biochem. Physiol., 6(l):91-97, 1976b.
Kolbasina, E.V. and N.I. Lulova. Gas-chromatographic Analysis of Broraoben-
zenes. Usp. Gasov. Khromatogr., 2:154-159, 1970.
Kopp, Tom, Office of Toxic Substances, EPA, Private Communication.
Washington, D.C., 1977.
Kuchar, E.J.; P.O. Geenty, W.P. Griffith and R.J. Thomas. Analytical Studies
of Metabolism of Terraclor in Beagle Dogs, Rats and Plants. J. Agr.
Food Chem., 17(6):1237-40, 1969.
Kwiatkowski, G.T., G.L. Erode and A.W. Beduin. Chloroaromatic Ether Amines.
J.Poly. Sci., 14:2649-2657, 1976.
Lapik, A.S. Experimental Study of the Toxicity of Certain Fluorinated
Aromatic Compounds: I. Acute Toxicity of Monofluorobenzene, Ortho, Meta
and Para-Difluoro, Hexafluoro, etc. IZV. Sibiok. Otd. Akad. Nai. SSSR.
SER. BIOL-MED. NAUK., 3:91-94, 1965.
272
-------
Laska, A.L., C.K. Bartell, and J.L. Laseter. Distribution of Hexachloroben-
zene and Hexachlorobutadiene in Water, Soil and Selected Aquatic
Organisms Along the Lower Mississippi River, La. Bull. Environ. Contam.
Ibxicol., 15(5).:535-42, May 1976.
Leach, J. Private Communication. University of Wisconsin Medical School,
Madison, Wisconsin, February 1977.
Lecca-Radu, M. Modifications of Blood Carbonic Anhydrase and Leucocytic
Indophenol Oxidase in Chronic Benzene and Monochlorobenzene
Intoxication. Igiena, 8:231-239, 1959
Levi, I. P.O. Mazur and T. Nowicki. Rapid Screening Method for the
Determination of Organochlorine Pesticide Residues in Wheat by Electron
Capture Gas Chromatography. J. Ass. Off. Anal. Chera., 55(4):749, 1972.
Levina, M.M., T.B. Kurando, A.A. Belyakov, V.G. Smimova and S.L. Cdlyzhko.
Issues Concerning Sanitary Working Conditions and the State of Health of
those Workers in the Field of Monuron Production. Gig. Tr. Prog.
Zabol., U:54-56, 1966.
Lewis, P.F. Chlorinated Benzenes. Department of Health, Education and
Welfare, Public Health Service, Division of Chemical Technology,
Rockville, Maryland, January 1975.
Little, A.D. Research on Chemical Odors: Part I. Odor thresholds for 53
Commercial Chemicals. Manufacturing Chemists Association, Washington,
D.C., pp. 22-23, October 1968.
Loosanoff, C.L., C.L. MacKenzie Jr. and L.W. Shearer. Use of Chemicals to
Control Shellfish Predators. Science, 131:1522-3, 1960.
Lu, P.Y. and R.L. Metcalf. Environmental Fate and Biodegradability of
Benzene Derivatives as Studied in a Model Aquatic Ecosystem.
Envir. Hlth. Perspec., 10:269-284, 1975.
Lui, H. and G.D. Sweeney. Hepatic Metabolism of Hexachlorobenzene in Rats.
Fed. Bur. Biochem. Soc. Lett., 51(1):225-226; 1975.
MacBeath, M.E., G.P. Semeluk and I. Unger. Spectrofluorometric Studies IV.
Seme New Aspects of the Photochemistry of Monofluorobenzene. J. Phys.
Chem., 73(4):995-1000, 1969.
MacKenzie, C.L. Jr. Control of Oyster Drills, Eupleura caudata and
Urosalpinx cinereus, with the Chemical Polystream. Nat. Oceanic Atmos.
Admin. (U.S.), Fish., 68(2):285-97, 1971.
MacKenzie, D.R., F.W. Bloch and R.H. Wiswall, Jr. Radiation Chemistry of
Sane Cyclic Fluorocarbons. Phys. Chem., 69(8):2526-2530, 1965.
MacLachlan, A. and R.L. McCarthy. Pulse Radiolysis of Aromatic Compounds. J.
Am. Chem. Soc., 84:2519-24, 1962.
273
-------
Mann, F.G. and B.C. Saunders. Practical Organic Chemistry, 4th Ed.
Longmans, London, pp. 278-284, 1961.
Manufacturing Chemists Association. Chemical Safety Data Sheet-SD-54:
Ortho-Dichlorobenzene. Manufacturing Chemists Association, Washington,
D.C., 1974.
Matsuura, T. and K. Qnura. Kioto-Induced Reactions III: The Synthesis of
Biphenyls from Aromatic Bromo-compounds. Bull. Chem. Soc. Japan,
39(5):944-7, 1966.
Menzies, C.M. Metabolism of Pesticides — An Update. U.S. Dept. Interior
No. 184, Washington,. D.C., pp 54-56, 285-289, 1974.
Merck and Co., Inc. The Merck Index. Rahway, New Jersey, 1972.
Midwest Research Institute. Production, Distribution, Use and Environmental
Impact Potential of Selected Pesticides. Council on Environmental
Quality, PB-238 795, Washington, D.C., pp. 318-324, March 1974.
Miles, D.M., N.V. Mody, and J.P. Mingard. Constituents of Marsh Grass: Survey
of the Essential Oils in Juncus roemerianus. Phytochemistry,
12:1399-1404, 1973.
Mitchell, J.R., W.D. Reid, B. Christie, J. Moskowitz, G. Krishna and B.B.
Brodie. Bromobenzene-Induced Hepatic Necrosis: Species Differences and
Protection by SKF 525-A. Res. Commun. Chem. Path. Pharmacol.,
2:877-888, 1971.
Miyamoto, Y. Zentralbl. Gew. Hyg. Unfallverttt, 25:70, 1938. Cited by Von
Oettingen, W.F. The Halogenated Aromatic Hydrocarbons, In: The
Halogenated Aliphatic, Olefinic, Cyclic, Aromatic and Aliphatic Aromatic
Hydrocarbons Including the Halogenated Insecticides, their Toxicity and
Potential Dangers. U.S. Department of Health Education and Welfare,
Public Health Service, Rockville, Maryland, No. 414:283-299, 1955.
Monsanto Chemical Intermediates Chemicals Co. George Papageorge, Manager,
Product Acceptance, Personal Communication. St. Louis, Missouri,
1977.
Montrose Chemical Corporation of California. Product Safety Information,
Monochlorobenzene, Dichlorobenzene. Henderson, Nevada, 1972.
Morita, M. and G. Ohi. Paradichlorobenzene in Human Tissue and Atmosphere in
Tokyo Metropolitan Area. Environ. Pollut., 8:267-274, 1975.
Morita, M., S. Mimura, G. Ohi, H. Yagyu and T. Nishizawa. A Systematic
Determination of Chlorinated Benzenes in Human Adipose Tissue. Environ.
Pollut., 9:175-179, 1975.
274
-------
Mumma, C.E. and E.W. Lawless. Survey of Industrial Processing Data: Task I
— Hexachlorobenzene and Hexachlorobutadiene 'Pollution from Chlorocarbon
Processes. Midwest Research Institute for EPA, Office of Toxic
Substances, Washington, D.C., June 1975.
Munson, S.C. and J.F. Yeager. J. Econ. Entomol., 38:618, 1945. Cited in
Winteringhan, F.P.W. and J.M. Barnes. Comparative Responses of Insects
and Mammals to Certain Halogenated Hydrocarbons used as Insecticides.
Physiol. Revs. (Agr)., 35:701-739, 1955.
Murphy, J.B. and Ernest Sturm. The Effect of Sodium Pentobarbital, Paradi-
chlorobenzene, Amyl Acetate, and Sovasol on Induced Resistance to a
Transplanted Leukemia of the Rat. Cane. Res., 3: 173-175, 1943.
Nakada, M., S. Fukushi, H. Tomita and Y. Mashiko. Gas Chromatographic
Analysis of Bromobenzenes and Influence of Thermal Decomposition of
Stationary Liquid on Retention Time. Kogyo Kaguku Zasshi, 73(5):
929-932, 1970.
National Cancer Institute. Report on Carcinogenesis Bioassay of Chloroform.
National Cancer Institute, Bethesda, Maryland, June 10, 1976a.
National Cancer institute. Carcinogenesis Technical Report Series, NO. 2:
Carcinogenesis Bioassay of Trichloroethylene. National Cancer
Institute, Bethesda, Maryland, June 14, 1976b.
Neal, M.J. and J.M. Robson. Analgesic Properties of Subanaesthetic Doses of
Fluorinated Anaesthetics in the Mouse. Brit. J. Pharmacol. Chemother.,
24(2): 519-525, 1965.
Neal, M.J. and J.M. Robson. The Analgesic and Anaesthetic Actions of
Tetrafluorobenzene. Brit. J. Pharmacol. Chemother., 26(2): 482-493,
1966.
Neely, W.B., D.R. Branson, and G.E. Blau. Partition Coefficient to Measure
Bioconcentration Potential of Organic Chemicals in Fish. Environ. Sci.
Technol., 8(13): 1113-1115, 1974.
Oakridge National Laboratories. Personal Communication. Oakridge,
Tennessee, 1977.
Cckner, R.K. and R. Schmid. Acute Porphyria in Man and Rat due to Hexa-
chlorobenzene Intoxication. Nature, 4763:499, February 11, 1961.
01 in Chemicals. Handbook of Aromatic Fluorine Compounds. Olin Corporation,
Stamford, Connecticut, 1974.
Olin Corporation. Personal Communication, Stamford, Connecticut, 1976.
Oregon, State of. Mr. Bromfield, Department of Environmental Quality,
Personal Communication. Eugene, Oregon, January 1977.
275
-------
Qrrenius, S., A. Ellin, S.V. Jakobsson. The Cytochrome P-450 Containing
Mono-oxygenase System of Rat Kidney Cortex Microsomes. Drug Metab.
Disposit., l(l):350-357, 1973.
OSHA. General industry, OSHA Safety and Health Standards (29 CFR 1910).
OSHA 2206. U.S. Department of Labor, Occupational Safety and Health
Administration, Washington, D.C., Revised January 1976.
Ostergren, G. and A. Levan. The Connection Between C-Mitotic Activity and
Water Solubility in Some Monocyclic Compounds. Hereditas, 29:496-498,
1943.
Pagnotto, L.D. and J.E. Walkley. Urinary Dichlorophenol as an index of
Paradichlorobenzene Exposure. Amer. Indust. Hyg. Assoc. J., 26:137-142,
1965.
Pandhi, P.N. and M. Baum. Effect of Pasting and of Phenobarbital on the
Distribution and Latency of Glucose-6-phosphatase in Microsomal
Subfractions of Rat Liver. Life Science, 9:87, 1970.
Parke, D.V. The Biochemistry of Foreign Compounds. Pergamon Press, Oxford,
pp. 43, 92-96, 196-197, 217, 1968.
Parke, D.V. The Effects of Drugs and Steroid Hormones on the Enzymes of the
Endoplasmic Reticulum. In: Effects of Drugs on Cellular Control Mecha-
nisms, (B.R. Rabin and R.B. Preedman, eds.). university Park Press,
Baltimore, pp. 69-104, 1972.
Parke, D.V. and R.T. Williams. Studies in Detoxication, 30: The Metabolism
of Benzene, (a) The Determination of Benzene, (b) The Elimination of
Unchanged Benzene by Rabbits. Biochem. J., 46:236-238, 1950.
Parke, D.V. and R.T. Williams. Studies in Detoxication: The Metabolism of
Halogenobenzenes. (a) Metadichlorobenzene; (b) Further Observations on
the Metabolism of Chlorobenzene. Biochem. J. 59:415-422, 1955.
Parke, D.V. and R.T. Williams. Studies in Detoxication, 81: The Metabolism
of Halogenobenzenes, (a) Penta- and Hexachlorobenzenes, (b) Further
Observations on 1,3,5-Trichlorobenzene. Biochem. J. 74:5-9, 1960.
Parsons, L.D. On Early Tumour Formation in Pure-Line Mice Treated with
Carcinogenic Compounds and the Associated Blood and Tissue Changes. J.
Path. Bact., 54:321-330, 1942.
Paul, B.B. and D. Rubinstein. Metabolism of Carbon Tetrachloride and
Chloroform by the Rat. J. Pharmac. Exp. Therap., 141:141-148, 1963.
PCR Industries. Chemicals for Research Scientists, G-9. PCR Incorporated,
Gainesville, Florida, March 1, 1976a.
PCR Industries. Eugene Stump, Vice President, Private Communication.
Gainesville, Florida, 1976b.
276
-------
Pelkonen, 0., E.H. Kaltiala, T.K. Larmi, and N.T. Karki. Comparison of
Activities of Drug-metabolizing Enzymes in Human Fetal and Adult Livers.
Clin. Pharmacol. Therap., 14:840-846, 1973.
Perrin, Maurice. Possible Harmfulness of Paradichlorobenzene Used as a Moth
Killer. Bull. Acad. Med., 125:302-304, 1941.
Peterson, Richard, Private Communication. College of Pharmacology,
university of Wisconsin, February 1977.
Petit, G. and J. Champeix. Does an Intoxication Caused by Paradichloro-
benzene Exist? Arch. Mai. Prof. Med., 9:311-312, 1948.
Pike, M.H. Ocular Pathology Due to Organic Compounds. J. Mich. State Med.
Soc., 43:581-584, 1944.
Poland, A., J. Goldstein, P. Hickman, V.W. Burse. A Reciprocal Relationship
between the Induction of A-Aminolevulinic Acid Synthetase and Drug
Metabolism Produced by m-Dichlorobenzene. Biochem. Pharmacol.,
20(6):1281-1290, 1971.
Porter, E.M. and J.J. Slider. Thirty Day Biodegradability of Textile
Chemicals and Dyes. Presented at the 1974 American Association of
Textile Chemists and Colorists National Technical Conference. October
9-11, 1974.
Powers, M.B., W.B. Coate and T.R. Lewis. Repeated Topical Applications of
1,2,4-Trichlorobenzene. Arch. Environ. Health, 30(4):165-167, 1975.
Prasad, I. Mutagenic Effects of the Herbicide 3'4l-Dichloroproprionanilide
and its Degradation Products. Can. J. Microbiol., 16:369-372, 1970.
Preussman, R. Chemical Carcinogens in the Human Environment. Hand. Allg.
Pathol., 6:421-594, 1975.
Punt, A. The Influence of Insecticides on Respiration in insects. Acta
Physiol. Pharmacol. Neerl., 1:82-89, 1950.
Reed, W.T. and A. Forgash. Metabolism of Lindane to Tetrachlorobenzene. J.
Agr. Food Chem., 17(4):893-897, 1969.
Reed, W.T. and A.J. Forgash. Metabolism of Lindane to Organic Soluble
Products by Houseflies. J. Agric. Food Chem., 18:475-481, 1970.
Reich, H. Puran (Monochlorobenzene) Poisoning in a 2-Year-Old Child.
Samml. von Vergiftungsfalien, 5: 193-194, 1934.
Reid, W.D. Mechanism of Renal Necrosis Induced by Bromobenzene or
Chlorobenzene. Exp. Molec. Pathol., 19:197-211, 1973.
277
-------
Reid, W.D. Relationship Between Tissue Necrosis and Covalent Binding of
Toxic Metabolites of Halogenated Aromatic Hydrocarbons. Pharmacology
and the Future of Man: Proc. 5th Int. Congr. Pharmacology, San
Francisco, 2:62-74, 1974.
Reid, W.D., A.K. Cho, G. Krishna and B.B. Brodie. On the Mechanism by which
Organic Compounds Produce Tissue Lesions. I. Hepatotoxicity of Aromatic
Hydrocarbons and Enhancement by Phenobarbital. Pharmacologist, 12:208,
1970.
Reid, W.D., B. Christie, M. Eichelbaum and G. Krishna. 3-Methylcholanthrene
Blocks Hepatic Necrosis Induced by Administration of Bromobenzene or
Carbon Tetrachloride. Exp. Molec. Pathol., 15: 363-372, 1971a.
Reid, W.D., B. Christie, G. Krishna, J.R. Mitchell, J. Moskowitz and B.B.
Brodie. Bromobenzene Metabolism and Hepatic Necrosis. Pharmacology,
6:41-55, 1971b.
Reid, W.D., K.F. Ilett, J.M. Click and G. Krishna. Metabolism and Binding of
Aromatic Hydrocarbons in the Lung; Relationship to Experimental Bronchi-
olar Necrosis. Am. Rev. Resp. Dis., 107:539-551, 1973.
Reid, W.D. and G. Krishna. Centrolobular Hepatic Necrosis Related to
Covalent Binding of Metabolites of Halogenated Aromatic Hydrocarbons.
Exp. Molec. Pathol., 18:80-99, 1973.
Resource Conservation and Recovery Act of 1976, P.L. 94-580, Washington,
D.C., October 21, 1976.
Richardson, L.T. Selective Vapor Phase Activity of Chloronitro- and
Chlorobenzene in Soil. Phytopathology, 58(3):316-322, 1968.
Riedel, H. Arch. Gew. Path. Gew. Hyg. 10:546, 1941. Cited by Von Oettingen,
W.F. The Halogenated Aromatic Hydrocarbons, in: The Halogenated Ali-
: phatic, Olefinic, Cyclic, Aromatic and Aliphatic Aromatic Hydrocarbons,
Including the Halogenated Insecticides, their Toxicity and Potential
Dangers. U.S. Department of Health Education and Welfare, Public Health
Service, Rockville, Maryland, No. 414:283-299, May 1955.
Rimington, C. and G. Ziegler. Experimental Porphyria in Rats induced by
Chlorinated Benzenes. Biochem. Pharmacol., 12:1387-1397, 1963.
Robinson, G.E. and J.M. Vernon. Photochemical Reactions of Chlorobenzene
Derivatives in Benzene. J. Chem. Soc., 20:3363-3367, 1971.
Robinson, J.B., J.S. Felton, R.C. Levitt, S.S. Thorgeirsson and D.W. Nebert.
Relationship Between "Aromatic Hydrocarbon Responsiveness" and the
Survival Times in Mice Treated with Various Drugs and Environmental
Compounds. Mol. Pharmacol., 11(6):850-865, 1975.
278
-------
Rozenbaum, N.D./ R.S. Block, S.N. Kremneva, S.L. Ginzburg and I.V.
,Pozhariskii. Use of Chlorobenzene as a Solvent from the Standpoint of
Industrial Hygiene. Gig. Sanit., 12(l):21-24, 1947.
RSA Chemicals, Personal Communication. Ardsley, New York, October 1976.
Rucker, J.T. Selective Hydrogenation of Chlorobenzenes. U.S*. Patent No.
2,949,491, August 16, 1960.
Ruzo, L.O., S. Safe and 0. Hutzinger. Metabolism of Bromobenzenes in the
Rabbit. J. Agric. Pood Chenu, 24(2):291-3, 1976.
Safe, S., 0. Jones, J. Konli and L.O. Ruzo. The Metabolism of Chlorinated
Aromatic Pollutants by the Frog. Can. J. Zool., 54:1818-1823, 1976.
Sandier, F. Inaug. Dissert. Kiel, 1933. Cited by Von Oettingen W.F. The
Halogenated Aromatic Hydrocarbons, In: The Halogenated Aliphatic,
Olefinic, Cyclic, Aromatic and Aliphatic Aromatic Hydrocarbons,
Including the Halogenated Insecticides, their Toxicity and Potential
Dangers. U.S. Department of Health Education and Welfare, Public Health
Service, Rodcville, Maryland, No. 414:283^299, 1955.
Sanna, A., S. Dessi, F.P. Corongiu and L. Congiu. Polysomal Patterns of Rat
Liver During Bromobenzene Intoxication. Riv. Farmacol. Ter.,
5{2):93-95, 1974.
Saxton, J.C. and M. Narkus-Kramer. EPA Findings on Solid Wastes from
Industrial Chemicals. Chem. Eng., pp. 107-112, April 28, 1975.
Seidell, A. The Solubility of Inorganic and Organic Compounds, 3rd Ed.
supplement, D. Van Nostrand Co., New York, 1952.
Seiler, K.E. and L.C. Sams. Separation of Selected Polyfluorinated Benzenes
by Gas-Liquid Chromatography. J. Chromatog., 69(2):363-365, 1972.
Selucky, M., J. Novak and J. Janak. The Use of Chromatographic Equilibration
Procedure for Air Pollution Studies. J. Chromatog., 28:285-292, 1967.
Sharma, A.K. and N.K. Bhattacharyya. Chromosome Breakage Through Paradi-
chlorobenzene Treatment. Cytologia, .21:353-360, 1956.
Sharma, A.K. and S.K. Sarkar. A Study on the Comparative Effect of Chemicals
on Chromosomes of Roots, Pollen Mother Cells and Pollen Grains.
Proc. Ind. Acad. Sci. B., XLV(xxx):288-293, 1957.
Shelat, V.A. and K.S. Patel. Utilization of Brcmobenzene as a Sole Source of
Carbon by Bacillus polymyxa. Curr. Sci., 42(10):368, 1973.
Simmons, P., D. Branson and R. Bailey. 1,2,4-Trichlorobenzene: Biodegradable
or Not? Canadian Assoc. of Textile Colourists and Chemists, 1976.
International Technical Conference, Quebec, Canada, October 13-15,
1976.
279
-------
Sipes, I.G.f L. Gigon and G. Krishna. Biliary Excretion of Metabolites of
Bromobenzene. Biochem. Pharmacol., 23(2):451-455, 1974.
Siyali, D.S. Hexachlorobenzene and other Organochloride Pesticides in Human
Blood. Med. J. of Aust., 2:1063-1066, 1972.
Smirnova, N.A. and N.P. Granik. Remote Consequences of Acute Occupational
Poisoning by Some Hydrocarbons and Their Derivatives. Gig. Truda i
Prof. Zabol., 5:50-51, 1970.
Smith, J.N. The Comparative Metabolism of Xenobiotics. Adv. Comp. Physiol
Biochem., 3:173-232, 1967.
Smyth, R.j. Detection of Hexachlorobenzene Residues in Dairy Products, Meat,
Fat and Eggs. J. Ass. Off. Anal. Chem., 55(4) :806-808, 1972.
Snider, E.M. and J.J. Porter. Thirty Day Biodegradability of Textile Chemi-
cals and Dyes. Paper presented at the 1974 American Assoc. of Textile
Chemists and Colorists Natural Technical Conference, October 9-11, 1974.
Srivastava, L.M. Induction of Mitotic Abnormalities in Certain Genera of
Tribe Vicieae by Paradichlorobenzene. Cytologia, 31:166-171, 1966.
Stanford Research Institute. 1974 Directory of Chemical Producers. Stanford
Research Institute, Menlo Park, California, 1974.
Stanford Research Institute. 1975 Directory of Chemical Producers. Stanford
Research institute, Menlo Park, California, 1975a.
Stanford Research Institute. NIOSH Analytical Methods for Set I. U.S. Dept.
of Commerce, Washington, D.C., PB-246 152:1331-1338, October 1975b.
Stanford Research Institute. NIOSH Analytical Methods for Set II. U.S.
Department of Commerce, Washington, D.C., PB 246 153:1351-1359, October
1975c.
Stanford Research Institute. 1976 Directory of Chemical Producers. Stanford
Research Institute, Menlo Park, California, 1976.
Stijve, T. Determination and Occurrence of Hexachlorobenzene Residues. Mitt.
Geb. Lebensmittelunters. Hyg., 62(4):406-414, 1971.
Stoddard, O., State of Colorado, Solid and Hazardous Waste Management
Programs, Private Communication. Denver, Colorado, February 1977.
Sumbayev, E.G. and Rakhybenko, V.P. Determination of Permissable Concen-
trations of Benzene and Chlorobenzene in the Air of Industrial Locations
By the Chromatographic Method. Gig. Sanit., 2:112-113, 1975.
Sykes, P. A Guidebook to Mechanism in Organic Chemistry. Longmans, London,
1963.
280
-------
Tarkhova, L.P. Materials for Determining the Maximum Permissible Concentra-
tion of Chlorobenzol in Atmospheric Air. Gig. Sanit., 30(3):327-333,
1965.
Tattersfield, P., C.T. Giminghan and H.M. Morris. Ana. Appl. Biol., 12:218,
1925. Cited in Winteringhan, F.P.W. and J.W. Barnes. Comparative
Response of Insects and Mammals to Certain Halogenated Hydrocarbons Used
as Insecticides. Physiol. Rev. (Agr)., 35:701-739, 1955.
Torres. W.L., J.A. Bottino, J.C. Panetta and M. Nakago. Tests on the
Bactericidal and Sporicidal Efficiency of o-Dichlorobenzene. Biologico,
36(6)-.152-156, 1970.
Totaro, S. Serum Transaninase and Aldolase Activity in Subacute Experimental
Intoxication with pj-Dichlorobenzene. Folia Med., 44:586-594, 1961.
Totaro, S. and G. Licari. Serum Transaminases in Subacute Poisoning with
p-Dichlorobenzene: Influence of Some Lipotropic Factors. Folia Med.,
"5:507-511, 1964.
The Toxic Substances Control Act. P.L. 94-469, 94th Congress, Washington,
D.C., October 11, 1976.
Transvaal Inc., Personal Communication. Jacksonville, Arkansas, November
1976.
Tu, C.M. Interaction Between Lindane and Microbes in Soils. Arch.
Microbiol., 105(2):131-134, 1975.
Ukeles, R. Growth of Pure Cultures of Marine Phytoplankton in the Presence
of Toxicants. Appl. Microbiol., 10:532-537, 1962.
U.S. Coast Guard. CHRIS: A Condensed Guide to Chemical Hazards. National
Technical Information Service, Springfield, Virginia, 1975.
U.S. International Trade Commission. Synthetic Organic Chemicals: U.S.
Production and Sales. G.P.O., Washington, D.C., 1966a-1975a.
U.S. international Trade Commission. Imports of Benzenoid Chemicals and
Products. G.P.O., Washington, D.C., 1971-1974b.
U.S. Public Health Service. Registry of Toxic Effects of Chemical
Substances. Department of Health, Education and Welfare, Rockville,
Maryland, June 1975.
Varshavskaya, S.P. Comparative Toxicological Characteristics of Chloroben-
zene and Dichlorobenzene (Ortho- and para- Isomers) in Relation to the
Sanitary Protection of Water Bodies. Gig. Sanit., 33(10):17-23, 1967.
Veith, G.D. Monitoring of Trichlorobenzene, Interagency Communication. U.S.
Environmental Protection Agency, Environmental Research Laboratory,
Duluth, Minnesota, June 29, 1976.
281
-------
Vesell, E.S., C.M. Lang, W.J. White, G.T. Passananti, R.N. Hill, T.C.
Clemens, D.K. Liu and W.D. Johnson. Environmental and Genetic Factors
Affecting the Response of Laboratory Animals to Drugs. Fed. Proc.,
35(5):1125-1132, 1976.
Villeneuve, D.C. and Khera,K.S. Placental Transfer of Halogenated Benzenes
(Pentachloro-, Pentachloronitro-, and Hexabromo-) in Rats. Environ.
Physiol Biochem., 5(5):328-331, 1975.
Virginia, Commonwealth of. Toxic Substances Information Act. Title 32,
Chapter 28 of the Code of Virginia, Richmond, Virginia, 1976.
Von Oettingen. The Halogenated Aromatic Hydrocarbons. In: The Halogenated
Aliphatic, Olefinic, Cyclic, Aromatic and Aliphatic Aromatic
Hydrocarbons, Including the Halogenated Insecticides, their Toxicity and
Potential Dangers. U.S. Department of Health Education and Welfare,
Public Health Service, Rockville, Maryland, No. 414:283-299, 1955.
Wallgren, K. Chronic Intoxications in the Manufacture of Mothproofing Agents
Consisting Mainly of Paradichlorobenzene. Zentralbl. Arbeitsmed.
Arbeitschutz, (Darmstadt), 3:14-15, 1953.
Weast, Robert C. (ed.). Handbook of Chemistry and Physics. Chemical Rubber
Company, New York, 1976.
Webb, J.M., M. Fonda, E.A. Brouwer. Metabolism and Excretion Patterns of
Fluorescein and Certain Halogenated Fluorescein Dyes in Rats. J.
Pharmacol. Exp. Therap., 137:141-147, 1962.
Webber, L., Private Communication. Oregon State University, February 1977.
Waller, R.W. and A.J. Crellin. Pulmonary Granulomatosis Following Extensive
Use of Paradichlorobenzene. Arch. Intern. Med., 91:408-413, 1953.
Welsh, J.H. and H.T. Gordon. The Mode of Action of Certain Insecticides on
the Arthropod Nerve Axon. J. Cell Comp. Physiol., 30:147-171, 1947.
Whittaker Corporation. Arthur Burns, Vice President, Personal Communication.
San Diego, California, 1976.
Wickline, Robert, Director of Toxic Substance Information, Commonwealth of
Virginia, Personal Communication. Richmond, Virginia, February 1977.
Williams, R.T. The Metabolism of Halogenated Aromatic Hydrocarbons. In:
Detoxication Mechanisms, 2nd Ed. John Wiley and Sons., New York,
pp. 237-258, 1959.
Williams, R.T., P.C. Hirom and A.G. Renwick. Species Variation in the
Metabolism of Some Organic Halogen Compounds, in: Ecological
. Toxicological Research, (A.D. Mclntyre and C.F. Mills, eds.),
Plenum Press, New York, pp. 91-105, 1975.
282
-------
Winteringham, F.P.W. and J.M. Barnes. Comparative Response of Insects and
Mammals to Certain Halogenated Hydrocarbons Used as Insecticides.
Physiol. Rev. (Agr)., 35:701-739, 1955.
Yang, R.S.H., F. Coulston and L. Golberg. Chromatographic Methods for the
Analysis of Hexachlorobenzene and Possible Metabolites in Monkey Fecal
Samples. J. Assoc. Off. Anal. Chera., 58(6):1197-1201, 1975.
Yasuda, S.K. Determination of Impurities in 1,3,5-Trichlorobenzene. J.
Chrccnatog., 75(l):39-44, 1973.
Young, D.R., T.C. Heesen and D.J. McDermott-Erlich. Synoptic Survey of
Chlorinated Hydrocarbon Inputs to the Southern California Bight. Draft
Report to National Environmental Research Center, Environmental Protec-
tion Agency, Corvallis, Oregon, June 1976.
Yurawecz, M.P. Analytical Behavior of Early Eluting Industrial Chemicals,
GDC, Data File and Retrieval System — Laboratory Information Bulletin.
U.S. Food and Drug Administration, Industrial Chemical Contaminants
Branch, Bureau of Foods, Rockville, Maryland, March 1976.
Yurawecz, M.P., R.A. Dreifuss and L.R. Kamps. Determination of Hexachloro-
1,3-butadiene in Spinach, Eggs, Fish and Milk by Electron Capture
Gas-Liquid Chromatography. J. Ass. Off. Anal. Chem., 59(3):552-558,
1976.
Zampaglione, N., D.J. Jollow, J.R. Mitchell, B. Stripp, J.R. Gillette and M.
Hamrick. Role of Detoxifying Enzymes in Bronobenzene-Induced Liver
Necrosis. J. Pharmacol. Exp. Ther., 187(1):218-227, 1973.
Zupko, A. and L.D. Edwards. A lexicological Study of £-Dichlorobenzene.
J. Amer. Pharm. Assoc. Sci. Ed., 38(3):124-131, 1949.
283
------- |