EPA 560/5-78-002
A STUDY OF INDUSTRIAL DATA ON
CANDIDATE CHEMICALS FOR TESTING
June 1978
Research Request No. 3
FINAL REPORT
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, D.C. 20460
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EPA 560/5-78-002
June 1978
A STUDY OF INDUSTRIAL DATA ON
CANDIDATE CHEMICALS FOR TESTING
Contract No. 68-01-4109
Research Request No. 3
Project Officer: James Darr
Prepared for
Office of Toxic Substances
U. S. Environmental Protection Agency
Washington, D.C. 20460
333 Ravenswood Ave. • Menlo Park, California 94025
(415) 326-6200 • Cable: STANRES, Menlo Park • TWX: 910-373-1246
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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 necessarily 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.
iii
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PREFACE
This report was prepared by an interdisciplinary team under the
general guidance of the EPA project officer, James Darr. The SRI team
consisted of C. Tucker Helmes, Barbara Lewin, Kirtland McCaleb (Project
Leader), Howard Peters, Margaret Power, Caroline Sigman, Patricia
Sullivan, Susanne Urso, Janet Walker, and Rose Wright.
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CONTENTS
LIST OP TABLES x
I. INTRODUCTION 1~1
II. SUMMARY, CONCLUSIONS, AND RECOMMENDATIONS 2-1
III. STUDIES OF SELECTED CHEMICALS 3"*1
AlkyI Phthalates 3-1
A. Summary of Physical and Chemical Data 3-1
1. Identification and Properties of Compounds . . . '-1
a. Structure and Nomenclature 3-1
b. Chemical and Physical Properties 5-13
2. Known or Likely Contaminants 3-13
3. Composition of Mixtures 3-13
B. Summary of Data on Occupational and Environmental
Exposure 3-14
1. Names and Locations of Producers 3-14
2. Production and Trade Statistics 3-14
3. Use Patterns 3-22
4. Occupational Standards and Workers Exposed . . . 3-25
5. Mode of Entry into the Environment 3-25
6. Quantities Released into the Environment .... 3-27
7. Environmental Transport 3-30
8. Environmental Degradation 3-36
C. Biological Effect* 3-44
1. Ecological Hazards 3-44
a. Toxicity to Wildlife 3-44
(1) Acute Toxicity 3-44
(2) Reproductive System Effects 3-44
b. Toxicity to Plants 3-45
c. Toxicity to Microorganisms 3-46
2. Effects Related to Human Health Hazards .... 3-46
a. Carcinogenicity 3-46
b. Mutagenicity 3-48
vii
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Contents (Continued)
c. Te ra tog eni city 3-49
d. Systemic Toxicity 3-50
e. Dermatological and Sensitization Studies . . 3-56
f. Neurotoxicity 3-57
g. Behavioral Toxicity 3-58
h. Metabolism 3-58
(1) Pharmacokinetics and Distribution . . . 3-58
(2) Metabolic Modification 3-60
Cresols and Cresylic Acids 3-63
A. Summary of Physical and Chemical Data 3-63
1. Identification and Properties of Compounds . . . 3-63
a. Structure and Nomenclature 3-63
b. Chemical and Physical Properties 3-63
(1) Chemical Properties 3-63
(2) Physical Properties 3-66
2. Known or Likely Contaminants 3-66
3. Composition of Mixture 3-66
B. Summary of Data on Occupational and Environmental
Exposure 3-69
1. Names and Locations of Producers 3-69
2. Production and Trade Statistics 3-69
3. Use Patterns 3-75
4. Occupational Standards and Workers Exposed . . . 3-78
5&6. Mode of Entry and Quantities Released into
the Environment 3-78
7. Environmental Transport 3-80
8. Environmental Degradation 3-81
C. Biological Effects 3-89
1. Ecological Hazards 3-89
a. Toxicity to Wildlife 3-89
(1) Acute Toxicity 3-89
(2) Reproductive System Effects 3-91
% b. Toxicity to Plants . 3-92
c. Toxicity to Microorganisms 3-92
Vlll
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Contents - Continued
2. Effects Related to Human Health Hazards .... 3-93
a. Carcinogenicity 3-93
(1) Animal Data 3-93
(2) Human Data 3-94
b. Mutagenicity 3-95
c. Teratogenicity 3-95
d. Systemic Toxicity 3-95
(1) Human Data 3-95
(2) Animal Data 3-100
e. Dermatological and Sensitization Studies . . 3-102
(1) Human Data 3-102
(2) Animal Data 3-103
f. Neurotoxicity 3-103
g. Behavioral Toxicity 3-104
h. Metabolism 3-104
(1) Pharmacokinetics and Distribution . . . 3-104
(2) Metabolic Modification 3-105
IV. References for Alkyl Phthalates 3-109
V. References for Cresols and Cresylic Acids ... 3-119
Appendix
A. Aquatic Toxicity Rating A-l
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LIST OF TABLES
Alkyl Phthalates
I Physical and Chemical Properties of Some Alkyl
Phthalates 3-4
II Producers of Some Alkyl Phthalates 3-15
III Alkyl Phthalate Producers and Locations 3-17
IV U.S. Production of Alkyl Phthalates 3-19
V U.S. Imports of Alkyl Phthalates 3-20
VI U.S. Exports of Alkyl Phthalates 3-21
VII Plasticizer Uses of Phthalate Esters 3-23
VIII Estimated Number of Workers Exposed to Some Alkyl
Phthalates In Selected Industries 3-26
IX Accumulation of ^^C-di-2-ethylhexyl Phthalate
by Aquatic Organisms 3-32
X Accumulation of ^ C-di-n-butyl Phthalate by Aquatic
Invertebrates 3-33
XI "Biologic Magnification" of 14C-Labelled Di-Ethylhexyl
Phthalate From Water by Five Species of Aquatic
Invertebrates 3-34
XII "Biologic Magnification" of 14OLabelled Di-n-Butyl
Phthalate From Water by Six Species of Aquatic
Invertebrates at 21°C 3-34
XIII 96-Hour LC50 Values in Fish and Crustaceans 3-44
XIV LD50 Values of Some Alkyl Phthalates 3-51
Cresols and Cresylic Acids
I Structure and Nomenclature of Cresols and
Cresylic Acid 3-64
II Physical Properties of Cresols and Cresylic Acid t . . . 3-67
*
%
III U.S. Producers of Cresols and Gresylic Acid 3-70
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Tables (Continued)
IV Location of U.S. Producers of Cresols and Cresylic
Acid 3-71
V Capacity and Raw Materials of Cresylic Acid Producers . 3-72
VI U.S. Production of Cresols and Refined Cresylic Acid . . 3-73
VII U.S. Imports of Cresols and Cresylic Acid 3-74
VIII Volatilization Rate Constants For p_-Cresol 3-80
IX Rate Constants For Photolysis of 1.0 yg ml~l
p_-Cresol 3-87
X Transformation and Transport of pj-Cresol Predicted
by the One-Compartment Model 3-87
XI Distribution of pj-Cresol in Various Aquatic Systems
at Steady State 3-88
XII Acute Toxicity of Cresols in Experimental Animals . . . 3-98
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I. INTRODUCTION
A. Background
The Office of Toxic Substances of the Environmental Protection
Agency needs to produce information packages as a basis for decisions
about testing chemicals for unreasonable risk to human health or the
environment. Contract No. 68-01-4109 with SRI International (formerly
Stanford Research Institute) was established as a first step in producing
these packages. It calls for SRI to provide, in answer to Research
Requests provided by the Project Officer, selected economic, chemical,
and biological information on selected commercial chemicals.
B. Objectives
The objectives of this study were to provide selected information
as designated by the Project Officer concerning physical and chemical
properties, occupational and environmental exposure, and biological
effects on two classes of chemicals of interest: alkyl phthalates and
cresols. The data are presented in tabular summary and text form for
each class of chemicals.
1-1
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II. SUMMARY, CONCLUSIONS, AND RECOMMENDATIONS
A. Summary
This report describes the work carried out on Research Request
No. 3.
Data were collected on physical and chemical properties, production
and trade statistics, past and current uses, occupational exposure and
standards, entry, transport, and degradation in the environment,
ecological effects and human health hazards for the commercially
significant members of the two classes of chemicals.
B. Conclusions and Recommendations
Because Research Request No. 3 was designed to provide certain
specified information on selected chemicals, no conclusions were drawn
from the studies performed, nor are any recommendations appropriate.
2-1
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III. STUDIES OF SELECTED CHEMICALS
ALKYL PHTHALATES
A. Summary of Physical and Chemical Data
1. Identification and Properties of Compounds
a. Structure and Nomenclature
This class of chemicals includes diesters of ortho-phthalic acid
in which at least one ester group is linked to a nonaromatic carbon.
Excluded from this study are the esters of isophthalic acid, tere-
phthalic acid, and tetrahydrophthalic acid, and polymeric phthalates
derived from glycols and phthalic acid or anhydride.
The alkyl phthalates included in this study are those believed
to be commercially significant at the present time based largely on two
publications:
1) The 1976 and 1975 editions of Synthetic Organic Chemicals,
U.S. Production and Sales, published by the U.S. Inter-
national Trade Commission;
2) The 1977 edition of the Directory of Chemical Producers,
published by SRI International.
The TSCA Inventory list and the Plasticizers chart in the 1976-
1977 edition of the Modern Plastics Encyclopedia were also consulted.
However, if the alkyl phthalate was not listed in either Synthetic
Organic Chemicals or the Directory of Chemical Producers, it was not
considered to be commercially produced at present. The alkyl phthalates
meeting the above requirements are listed in Table I together with their
molecular structures and physical properties. Molecular structures of
the alkyl groups are not specifically drawn in Table I in cases where
no systematic name exists for the compound. The alkyl group is repre-
sented by its molecular formula (e.g., isodecyl as -C. H ) with no
indication of location and extent of branches.
The terminology commonly used for the C--C. alkyl groups of alkyl
phthalates does not follow the strict nomenclature for alkyl groups and,
3-1
-------
in some cases, indefinite names appear to be used to allow the manufac-
turer some latitude in the composition of the products sold for their
functional properties. In general, the term "iso" is used to denote
the mixture of primary alkyl groups formed when olefins are converted
to alcohols by reaction with carbon monoxide and hydrogen in the oxo
process. For example, diisodecyl phthalate is produced by the reaction
of phthalic anhydride with isodecyl alcohol derived from nonene (pro-
pylene trimer) by the oxo reaction. To further complicate proper
identification, the "iso" part of the name is sometimes dropped (e.g.,
isotridecyl is more frequently referred to as merely tridecyl).
The names used for the C0 alkyl groups of alkyl phthalates are
o
particularly confusing since the general term 'octyl1 is often used
without any differentiation between n-octyl, 2-ethylhexyl, and iso-
octyl. It appears that 2-ethylhexyl is most frequently the alkyl group
intended when the general term octyl is used, however.
Because a number of these alkyl phthalates are specifically
mentioned many times in the text of this report, particularly in the
environmental and biological sections, we have adopted the following
abbreviations.
3-2
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Key to Abbreviations
BBP Butyl benzyl phthalate
BPBG Butyl phthalyl butyl glycolate
DAP Diallyl phthalate
DBF Dibutyl phthalate
DCHP Dicyclohexyl phthalate
DEHP Di(2-ethylhexyl) phthalate
DEP Diethyl phthalate
DIBP Diisobutyl phthalate
DIDP Diisodecyl phthalate
DIOP Diisooctyl phthalate
DMEP Di(2-methoxyethyl) phthalate
BMP Dimethyl phthalate
DNP Dinonyl phthalate
OOP Dioctyl phthalate
DPP Dipropyl phthalate
DUP Diundecyl phthalate
EPEG Ethyl phthalyl ethyl glycolate
MBP Monobutyl- phthalate
3-3
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Table I
Physical and Chemical Properties of Some Alkyl Phthaiatea
CAS Number
84-61-7
84-64-0
84-66-2
84-69-5
Name (Chera. Abstr. Name)
Dicyclohexyl phthalate
(1,2-Benzenedicarboxylic acid,
dicyclohexyl ester)
Butyl cyclohexyl phthalate
(1,2-Benzenedicarboxylic acid.
butyl cyclohexyl ester)
Diethyl phthalate
(1,2-Benzenedicarboxylic acid,
diethyl ester)
Diisobutyl phthalate
(1,2-Benzenedicarboxylic acid,
bis (2-methylpropyl)ester)
Structure & Molecular Formula3
O
fP^*- & - °-{5)
C20H26°4
0
It
X\_ C-0-CH2-CH2-CH2-CH3
^0
C18H24°4
O
ii
l^-^l- C-O-CH CH,
^*s^ ,, i. 3
0
C12H14°4
O CH,
^^"^ C-O-CH_-CH-CH3
0 CH3
C16H22°4
Melting
Point
58-65
-4
-50
Boiling
Point
°C
212-218
at 5mm
231-248
at 10mm
189-222
at 5mm
296
327
Specific
Gravity
25°C
1.29
1.076
1.115-
1.119
1.040
(20°C)
Solubilityb
Insoluble
in water,
soluble in
alcohol and
ether
O.lt at
18°C.
miscible
with alcohol
and ether,
soluble in
acetone and
benzene
<0.025%
Vapor
Pressure
nn Hg
<0.1 at 150°C
55 at 200°C
Partition
Coefficient
Log P c
6.94
6.26
3.42
3.22e
5.32
-------
Table I (Continued)
CAS Number
84-72-0
84-74-2
84-75-3 g
84-76-4
84-78-6
Name (Chera. Abstr. Name)
Ethyl phthalyl ethyl glycolate
( 1 , 2-Benzenedicarboxyl ic acid ,
2-ethoxy-2-oxoethyl ethyl
ester)
Dibutyl phthalate
( 1 , 2-Benzenedicarboxylic acid ,
dibutyl ester)
Di-n-hexyl phthalate
( 1 , 2-Benzenedicarboxy 1 ic acid ,
dihexyl ester)
Dinonyl phthalate3
(1, 2-Benzenedicarboxylic acid,
dinonyl ester)
n-Butyl n-octyl phthalate
(1, 2-Benzenedicarboxylic acid,
butyl octyl ester)
Structure & Molecular Formula8
O O
ii •
x£N- C-O-CH--C-O-CH--CH.
1 1) I
l^J- C-0-CH2-CH3
0
C14H16°6
O
•
^v-X^ C— O— CH_— Wl_ — CH_— CH_
f 2223
O PRO
C16H22°4
ff
[Qlc^ra2-!ra2!^
° C20H30°4
0
(OJc-O-cY9
° C26H42°4
0
II
XX" C-O-CH,- (CH,) -CH,
^^ „ 2 263
o
C H O
U20 30 4
Melting
Point
°C
<-35
-40
<50
(pour
point)
<-50
Boiling
Point
190 at
5mm
335
210 at
5mm
413
225 at
5mm
Specific
Gravity
25°C
1.177
1.042-
1.049
0.900-
1.007
0.965-
0.972
0.993
Solubilityb
0.050
0.013%,
miscible with
alcohol ,
ether, and
benzene
<0.025%
Insoluble
in water
Vapor
Pressure
mm Hg
<0.01 at 20°C
1.1 at 150°C
14 at 200°C
5 at 2100C
1 at 205°C
Partition
Coefficient
Log F c
2cn
. 59
5.58
3.70e
7.74
10.98d.f
7 1A
1 . /I
Ul
-------
Table I (Continued)
CAS Number
85-68-7
85-69-8
85-70-1
85-71-2
89-13-49
Name (Chen. Abstr. Name)
Butyl benzyl phthalate
(1,2-Benzenedicarboxylic acid,
butyl phenylmethyl ester)
Butyl 2-ethylhexyl phthalate
(1,2-Benzenedicarboxylic acid,
butyl 2-ethylhexyl ester)
Butyl phthalyl butyl glycolate
(1,2-Benzenedicarboxylic acid,
2-butoxy-2-oxoethyl butyl
ester)
Methyl phthalyl ethyl
glycolate
(1,2-Benzendicarboxylic acid, -
2-ethoxy-2-oxoethyl methyl
ester)
2-Ethylhexyl isodecyl
phthalate*
(Phthalic acid, 2-ethylhexyl
8-methylnonyl ester)
Structure & Molecular Formula^
0
_ il
fs-^T- C-O-CH -CH -CH -CH
l^j- C-O-CH2-@
- ° C19H20°4
O
II
l>-^i- C-0-CH,-CH-CH,-CH_-CH -CH
^~^ b 2 j, 2 2 2 3
6 CH2
C20H30°4
0 0
,1 .1
xOSy. OO-CH,-C-O-CH,-CH_-CH,-CH
1 1 1 1
V^J- C-O-CH2-CH2-CH2-CH3
° C18H24°6
O 0
j^^V C-O-CH -C-O-CH2-CH3
0 C13H14°6
0
x"\." C H
lyj- C-O-CH _-CH- (CH ) -CH
^^^ ;| * A» « 3
0 | 2
CH,
C26H42°4
Melting
Point
-37
(pour
point)
...
-48
(pour
point)
Boiling
Point
°C
370
224 at
5mm
219 at
5mm
189 at
5mm
245 at
5mm
Specific
Gravity
25°C
1.111-
1.123
0.9941
1.097
1.220
0.973
Solubilityb
Insoluble
in water
0.018%
0.053%
Vapor
Pressure
mm Hg
0.16 at 150°C
1.9 at 200°C
1.8 at 200°C
0.54 at 200°C
Partition
Coefficient
log Pc
5.63
7.61
4.75
2.05
10.72<>.f
-------
Table I (Continued)
CAS Number
89-18-9 g
89-19-0
117-81-7
117-82-8
117-83-9
117-84-0
Name (Chen. Abstr. Name)
Butyl isodecyl phthalate8
(1,2-Benzenedicarboxylic acid,
butyl 8-nethylnonyl ester)
n-Butyl n-decyl phthalate
(Phthalic acid, butyl decyl
ester)
Bis(2-ethylhexyl) phthalate
(1,2-Benzenedicarboxylic acid,
bis (2-ethylhexyl) ester)
Bis ( 2-methoxyethy 1 ) phthalate
(1,2-Benzenedicarboxylic acid,
bis (2-methoxyethyl) eater)
Bis ( 2-butoxyethyl ) phthalate
(1,2-Benzenedicarboxylic acid,
bis (2-butoxyethyl) ester)
Di-n-octyl phthalate
(1,2-Benzenedicarboxylic acid,
dioctyl ester)
Structure & Molecular Formula8
°
ff-\r C-C-CH2-CH2-CH2-CH3
o 10 21
C22H34°4
(§rbE3£?
° C22H34°4
CH
^° **
/^-N-C-0-CH2-CH-CH2-CH2-CH2-CH3
S^J-C-0-CH2-CH-CH2-CH2-CH2-CH3
* C24H38°4
O
v^^>- C-O-CHj-CHj-C—CH.,
C14H18°6
O
I»S^LC-C~CH,-CH,-O-CH_-CH,-CH,-CH,
^^ II 22 2223
° C20H30°6
l^J-C-0-CH2- (CH2) -CH3
° C24H38°4
Melting
Point
°C
-50
-50
-46
(pour
point)
-40
-25
Boiling
Point
°C
229 at
5mm
220 at
5mm
231 at
5mm
236 at
10mm
190-210
at 340mm
210-233
at 4mm
220-248
at 4mm
Specific
Gravity
25«C
0.991-
0.998
0.991
0.980-
0.9861
1.171
(20°C)
1.063
0.978
(20°C)
Solubility13
<0.01% at
20°
0.838%
<0.1% at
25°C
Insoluble
in water
Vapor
Pressure
mm Hg
1.20-1.32
at 200°C
<0.01 at 20°C
0.25 at 150°C
<0.01 at 20°C
0.06 at 150°C
<0.20 at 150°C
Partition
Coefficient
Log Pc
8.69f
8.82
9.64
1.10
4.34
9.90
-------
Table I (Continued)
CAS Number
119-05-19
119-06-2 „
fc
119-07-39
- 131-11-3
Name (Chem. Abstr. Name)
Isooctyl isodecyl
phthalate"
(Phthalic acid, 6-methylheptyl
8-methylnonyl ester)
Bis (tridecyl) phthalate3
(1,2-Benzenedicarboxylic acid,
ditridecyl ester)
n-Decyl n-octyl phthalate
(1,2-Benzenedicarboxylic acid.
decyl octyl ester)
Dimethyl phthalate
(1,2-Benzenedicarboxylic acid,
dimethyl ester)
Structure & Molecular Formula
>^<5
[C\T^~°~ 8 17
XXLC-°'CioH21
O
C26H42°4
0
i^^VC-O-C H
IOL_ 13 27
\^-°-C13H27
0 C34H58°4
O
^^ f
\(~} T ^ 263
kSoJ-C-O-CH - (CH_) 0-CH,
^s<^ a 2 « o J
O C H O
C26 42°4
0
^~. It
jgj-C-0-CH3
^"^^ II ^ C H O
0 <"10"10U4
Melting
Point
°C
-48
-37
(pour
point)
-28
0
Boilinq
Point
°C
235-248
at 4mm
240 at
2mm
250 at
5mm
283
Specific
Gravity
25°C
0.967
0.9512
0.970
1.194
(20°C)
Solubility15
0.4%,
miscible
with
alcohol and
ether, solu-
ble in
benzene
Vapor
Pressure
mm Hcf
<0.01
Partition
Coefficient
Log P c
„.,*..
15.30d'f
10.98d
2.34
2.22e
V
oo
-------
Table I (Continued)
CAS Number
131-15-7
131-17-9
146-50-9
3648-20-2
Name (Chem. Abstr. Name)
Di-sec-octyl phthalate
(1, 2-Benzenedicarboxylic acid.
bis (1-methylheptyl) ester)
(also known as dicapryl
phthalate)
Diallyl phthalate
(1, 2-Benzenedicarboxylic acid,
di-2-propenyl ester)
Diisohexyl phthalate a
(Phthalic acid, diisohexyl
ester)
Diundecyl phthalate*
(1 , 2-Benzenedicarboxylic acid ,
diundecyl ester
Structure & Molecular Formula8
0 CH
S~^t 1 3
XX^-O-CH- (CH2) 5~°H3
CH
O 3
C H O
U24 38°4
O
IWJ-C-o-CH -CH-CH
t _ . _
0 C14H14°4
O
.^^ ll
jOOv-C-0-CgHj3
Vov^C-0-C H
ll
0
C H O
C20H30°4
0
H
[Olc-o-c1^23
O
C H 0
30 50 4
Melting
Point
°C
<-60
65
-20
Boiling
Point
°C
215-240
at 4mm
290
Specific
Gravity
25°C
0.965-
0.978
1.120
(20°C)
0.95
Solubilityb
<0.03%
0.01%
Vapor
Pressure
mm Hg
Partition
Coefficient
Log Pc
9.46
2.72
7.48f
13. 14**
-------
Table I (Continued)
CAS Number
25724-58-79
26761-40-0
•
27215-22-1
27554-26-3
28553-12-0
Name (Chem. Abstr. Name)
n-Decyl n-hexyl phthalate
(Phthalic acid, decyl hexyl
ester)
Diisodecyl phthalate*
(1 , 2-Benzenedicarboxylic
acid, diisodecyl ester)
Isooctyl benzyl phthalate*
(Phthalic acid, benzyl iso-
octyl ester)
Oiisooctyl phthalate*
(1 , 2-Benzenedicarboxylic
acid, diisooctyl esterj
Diisononyl phthalate*
(1, 2-Benzenedicarboxylic acid,
diisononyl ester
Structure & Molecular Formula8
O
S^-C-0-CH - (CH.) --CH,
— - || z 283
C24H38°4
0
O
C28H46°4
0
O
C23H28°4
0
0
C24H38°4
O
U-C-C-C9H19
C26H42°4
Melting
Point
°C
-37
' -46
(pour
point)
<-50.0
Boiling
Point
°C
356
—
228-
229 at
5mm
222-230
at 5mm
Specific
Gravity
25°C
0.961-
0.967
. 1.069
0.986
(20°C)
0.982
Solubilityb
Insoluble
in water
Vapor
Pressure
mm Hg
0.3 at
200°C
0.5 at
200°C
1.0 at
200°C
<0.01
Partition
Coefficient
log Pc
9.90
11.80d'f
7.67«
9.64£
10.50a'f
f
H*
O
-------
Table I (Continued)
CAS Number
61702-81-6
61886-60-0
-
Name
-------
Table I (Concluded)
Source: Compiled from several sources, including Autian (.19731, Buttrey (J.960), Modern Plastics
Encyclopedia (1976), and Weast (1977).
a. See discussion in text concerning structure of groups with non-systematic names.
b. Solubilities are for water unless otherwise noted. r . . . . ,-i
_.... «*. * ^ . ^ , « ji *. " ji x.1. -, [concentration in octanol
c. Partition coefficient is expressed as log P. defined as the log|-« . .. : —'—I
. .,..-. , , . , ,.. . ., m . * I concentration in water
at equilibrium calculated according to the method suggested "- J
by Leo, A., Jow, P.Y.C., Silipo, C., & Hansch, C,.(1975), J% Med% Chemt/ 18(9), 865-868.
d. Calculated values for log P's greater than 10 may be artifactual and may hot reflect values
which would be obtained experimentally.
e. Measured using toluene as the organic phase; cited in Tomita, A., Ebina, N., & Tamai, Y.
(1977), J. Amer. Chem. Soc., 99, 5725.
"f. Calculation of log P requires that the structure be known. For any alkyl group in this table
w not having a systematic name, the following assumptions regarding its structure were made
,1, (for log P calculations only):
to
1) Linearity was assumed in the absence of any qualifier such as iso;
2) When the prefix iso was present, it was taken in its strict sense: one methyl
group on the next-to-last carbon atom and no other branches;
3) Ethylhexyl was assumed to be 2-ethylhexyl
g~. To reflect common usage, the name listed here for this compound is slightly different
(more specific in some cases, less specific in others) than the Chemical Abstracts Services
index name, which is shown in parenthesis.
-------
b. Chemical and Physical Properties
(1) Chemical Properties
Alkyl phthalates undergo the typical reactions of carboxylic esters,
e.g., saponification by strong bases, hydrolysis in the presence of
strong aqueous acids, reduction to alcohols by the action of hydrogen,
ester interchange, and conversion to amides by reaction with ammonia
(Morrison & Boyd, 1973).
Phthalate plasticizers can undergo oxidation during plastics pro-
cessing, forming peroxides which later decompose with development of
colored and odorous compounds. Antioxidants such as bisphenol A are
added to the resin to inhibit this reaction (Fishbein & Albro, 1972).
(2) Physical Properties
Selected physical properties of the alkyl phthalates, where
available, are listed in Table I.
2. Known or Likely Contaminants
Since alkyl phthalates are used almost exclusively as plasticizers
and the purity requirements for this use are very high, most products
are offered in purities of 99% or greater, with a residual maximum
acidity of 0.01% (presumably monoalkyl phthalates containing one car-
boxylic acid group). Phthalic anhydride, from which the alkyl phthalates
are prepared, is usually 99.5% pure. The remaining 0.5% could be iso- -
phthalic acid, terephthalic acid, and maleic anhydride; these compounds
would be converted to the corresponding diesters in the esterification
process.
3. Composition of Mixtures
As indicated in Section III A.I.a. above, many of these products are
really isomeric mixtures because they are prepared by esterifying phthalic
anhydride with an isomeric mixture of alcohols derived from the oxo
reaction on olefins - a reaction which results in alcohols with varying
amounts of branching. Hence, the resulting products, although identified
by a single name are not pure compounds. In addition, some producers
offer an ester made from a mixture of two or more alcohols. Thus, di-
(heptyl, nonyl) phthalate may consist of diheptyl phthalate, dinonyl
3-13
-------
phthalate and heptyl nonyl phthalate. An even more complicated mixture
may be present in a product designated as di(heptyl, nonyl, undecyl)
phthalate.
B. Summary of Data on Occupational and Environmental Exposure
1- Names and Locations of Producers
The thirty-seven alkyl phthalates believed to be commercially pro-
duced at the present time are listed in Table II along with the twenty"
seven companies that produce them. These companies and locations of
their producing plants are listed in Table III. The numbers in the
columns in Table II refer to the sources used to determine the commer-
ciality of the chemicals (see footnote to Table II). The 1976 edition
of Synthetic Organic Chemicals was given first priority since the
minimum quantity which the International Trade Commission requires for
inclusion therein is 5,000 pounds (or $5,000 worth) per producer. The
requirements for the 1975 Synthetic Organic Chemicals and the 1977
Directory of Chemical Producers are 1,000 pounds (or $1,000 worth) per
producer.
2. Production and Trade Statistics
U.S. production of alkyl phthalates was reported to the Interna-
tional Trade Commission as early as 1921. Table IV summarizes U.S.
production of some alkyl phthalates since 1970. Tables V and VI summarizc
data for U.S. imports and exports since 1970. For those alkyl phthalates
not found in Table IV, the minimum production level can be estimated by
consulting Table II. For those chemicals in the 1976 Synthetic Organic
Chemicals (denoted by a 6), each producer made at least 5,000 pounds
(or $5,000 worth). For those chemicals not in the 1976 Synthetic Organic
Chemicals, but in the 1975 edition (denoted by a 5) or in the 1977
Directory of Chemical Producers (denoted by a 7), each producer made at
least 1,000 pounds (or $1,000 worth). For example, at least 10,000
pounds of dicyclohexyl phthalate (two producers) were produced in 1976,
at least 2,000 pounds of dinonyl phthalate (two producers) were produced
in 1975, and at least 1,000 pounds of hexyl isodecyl phthalate (one
producer) were produced in 1977. In the case of di-n-hexyl phthalate,
at least 10,000 pounds (two producers) were produced in 1976. Since the
3-14
-------
Tlbl* II
Producer* of son* Alkyl PhthclctM
01
Phth«l«t«
•utyl Iwniyl
•utyl cyclotWKyl
n-lutyl n-dicyl
Butyl J-»thylh«xyl
•utyl liodteyl
n-Butyl n-ootyl
•utyl phthalyi butyl olycoUt**
cyolohvxyl liobutyl
n-Moyl n>h*xyl*
n-Moyl n-ootyl
Diallyl
01 (2-butoxy«thyl)
Dlbutyl*
Dloyolohcxyl
Dlcthyl*
Dl(a-*thylh*xyl)*
Dl-n-h»nyl
Dlliobutyl
Dllceteoyl
Dlliohixyl
Dlliononyl
5
6
6
6
6
6
6
6
6
•
7
6
6
6
5
6
6
S
6
r
6
6
7
i
7
7
6
6
6
7
6
6
7
r -
7
5
7
/ •
6
6
(N.J.)
S
6 (Ho.)
(Mlil.)
«
(M«Si.)
< (MO.)
6 (Tx.)
7 (Mo.)
6
r -
6
/
7
6
6
7
6
7
/ -
7
e
«
6
6
6
7
6
ft
6
6
7
6
/
6
6
6
r ~
6
r -
6
S
/ —
6
6
6
6
6
6
-------
Table II (Concluded)
Diisooctyl
Di(2-methoxyethyl)
Dimethyl*
Dlnonyl
Di-n-octyl
Di-aec-octyl
Ditridecyl*
Diundecyl
2-Bthylhexyl isodecyl
Ethyl phthalyl ethyl glycolate*
Meryl isodecyl
Hexyl Isooctyl
Isodecyl tridecyl
Isooctyl benzyl
Isooctyl Isodecyl
Methyl phthalyl ethyl glycolate*
5 (Ito.)
5 (Tx.)
5 (Ho.)
7 (NJ)
7 (No.)
7d
* Current production volumes given in Table IV.
a. Numbers in columns refer to the following sources:
6- 1976 Synthetic Organic Chemicals, O.S. Production and Sales
5- 1975 Synthetic Organic Chemicals, D.S. Production and Sales
7« 1977 Directory of Chemical Producers
See discussion in text for priority of these sources.
b. See Table III for locations of producers.
c. State in parentheses refers to specific Monsanto location. Where known.
d. This conpany also sakes "diisooctyl and mixed dioctyl phthalatea."
e. This coapany is listed in the 1976 Synthetic Organic Chemicals as producing "dicyclohexyl
2-ethylhexyl phthalate," which appears to be a typographical error.
f. Hercules Inc. is listed in the 1976 Synthetic Organic Chemicals as a producer of
"all other glycol phthalate esters."
g. This company is listed in the 1976 Synthetic Organic Chemicals as a producer of "all
other phthalic anhydride esters."
-------
Table III
U)
I
Company
Akzona Inc.
BASF Wyandotte Corp.
Chemical & Pollution Sciences, Inc.
Continental Oil Co.
Eastman Kodak Co.a
Exxon Corp.
FMC Corn.
B. F. Goodrich Co.
w. R. Grace & Co.
C. P. Hall Co.
Hardwicke Chemical Co.
International Minerals & Chemical Corp.
Interatab Chemicals Inc.
Kay-Fries Chemicals Inc.
Monsanto Co.
Occidental Petroleum Corp.
Alkyl Phthalate Producers and Locations
Division "
Armak Co., subsidiary
Armak Industrial Chemicals Division
Colors & Intermediates Group
GPS Chemical Company Division
Conoco Chemicals Division
Eastman Chemical Products, Inc., subsidiary
Tennessee Eastman Co,
Exxon Chemical Co., division
Exxon Chemical Company, U.S.A.
Chemical Group
Industrial Chemical Division
B. F. Goodrich Chemical Co., division
Hatco Group
Hatco Chemical Division
IMC Chemical Group, Inc., subsidiary
Monsanto Chemical Intermediates Co.
Monsanto Industrial Chemicals Co.
Hooker Chemical Corp., subsidiary
RUCO, subsidiary
Location
Philadelphia, Pa. 19135
Kearny, N.J. 07032
Old Bridge, N.J. 08857
Aberdeen, Miss. 39730
Klngsport, Tenn, 37662
Baton Rouge, La. 70821
Baltimore, Md. 21226
Avon Lake, Ohio 44012
Fords, N.J. 08863
Chicago, 111. 60638
Elgin, S.C. 29045
Terre Haute, Ind. 47808
New Brunswick, N.J. 08903
Stony Point, N.Y, 10980
St. Louis, Mo. 63177
Bridgeport, N.J. 08014
Everett, Mass, 02149
Texas City, Tex. 77590
Hlcksville, N.Y. 11802
-------
00
Pfizer Inc.
Reichhold Chemicals, Inc.
Richardson-Merrell Inc.
Sherwin-Williams Co.
Stauffer Chemical Co.
Sybron Corp.
Teknor Apex Co.
Tenneco Inc.
Union Camp Corp.
Onion Carbide Corp.•
United States Steel Corp.
Table XII (Continued)
Chemicals Division
J. T. Baker Chemical Co., subsidiary
Chemicals Group
Chemicals Division
Specialty Chemical Division
The Tanatex Chemical Company, division
Tenneco Chemicals, Inc.
Chemical Products Division
DSS Chemicals, division
Greensboro, N.C. 27403
Carteret, N.J. 07008
Phillipsburg, N.J. 08865
Chicago, 111. 60628
Gallipolis Ferry, W.Va, 25515
Lyndhurst, N.J. 07071
Hebronville, Mass. 02703
Cheatertown, Md. 21620
Dover, Ohio 44622
New York, N.Y. 10017
(Plant location unknown)
Neville Island, Pa. 15225
The location at which this company produces di-n-octyl phthalate is not known.
-------
10
Table IV
U.S. Production of Alkyl Phthalates
(millions of pounds).
Phthalic Acid Ester
Butyl octyla Dibutyl
1970
1971
1972
1973
1974
1975
1976
1970
1971
1972
1973
1974
1975
1976
11.9
16.0
11.4
7.4
Dimethyl
8.1
10.6
9.7
11.3
10.0
6.8
8.8
22.9
23.0
29.1
37.9
35.5
12.3
13.7
Other dioctyl
8.2
5.5
10.0
17.2
Dicyclohexyl Diethyl Di(2*-ethylhexyll Diisodecyl Diisooc
4.5 20.6
16.9
19.0
19.5
19.7
11.7
16.1
Phthalic Acid Ester
Ditridecyl n-Hexyl n-.decyl
15.1 9.3
20.3
16.0
19.7
27.2 10.2
15.7 14.5
10.5 19.8
350.4
386.3
435.0
378.1
389.7
302.5
296.7
n-Octyl n-decyl
58.9
134.3
123.4
135.7
153.3
170.8
146.7
105.7
143.1
Other
144.7
172.4
439.9
507.1
563.1
424.8
516.9
85.1
51.0
32.3
43.2
Totalb
855.1
978.2
1145.7
1203.1
1207.3
903.8
1042.9
Source: Synthetic Organic Chemicals, U.S. Production and Sales, published by the U.S. International
Trade Commission.
a Includes butyl 2-ethylhexyl phthalate, isobutyl 2-ethylhexyl phthalate, and butyl n-octyl phthalate,
b
Totals may not add up due to rounding
-------
Table V
U.S. Imports of Alkyl Phthalatesa
(thousands of pounds)
Phthalic Acid Ester
1970
1971
1972
1973
1974
1975
w
L 1976
1970
1971
1972
1973
1974
1975
1976
Source :
Butyl benzyl Diallyl Dibutyl Dicyclohexyl Diethyl Di(2-ethylhexyl) Dihex<
220.3
250.6
252.0
33.1 36.0 78.5
»
1,455.9 444.6 252.0 4,179.7 25.9
173.1 179.7 172.5 38.4
991.7 204.6 240.6 161.0
Phthalic Acid Ester
Diisodecyl Diisononyl Diisooctyl Dimethyl Di-n-octyl Ditridecyl Diundecyl
72.3 639.2 45.6 34.4 377.3 1.9
179.9 2.2 220.5
3,303.9
Imports of Benzenoid Chemicals and Products, published by U.S. International Trade Commissi
Through principal U.S. customs districts*
-------
Table VI
U.S. Exports of Alkyl Phthalates
(millions of pounds)
a b
Dioctyl phthalate Other phthalic acid esters
1970 36.0 36.4
1971 14.6 47.6
1972 16.8 105.8
1973 14.6 78.4
1974 24.7 81.9
1975 20.4 50.9
1976 29.9 75.5
Source: U.S. Exports, FT410, published by the U.S. Department of
Commerce, Bureau of the Census.
Dioctyl esters include di (2-ethylhexyl), di(n-octyl), dicapryl, and
diisooctyl phthalates, Flexol Plasticizer OOP, and Good-Rite
Plasticizer GP-261 (dioctyl phthalate).
Other phthalates include butyl benzyl, di(2-ethylbutyl), di(2-methoxy-
ethyl), diisobutyl, dibutyl, dicyclohexyl, diethyl, diisoamyl, diisodecyl,
dimethyl, diphenyl, isoamyl, methyl, and n-octyl n-decyl phthalates,
dimethyl glycol phthalate, dimethyl isophthalate, ethyl phthalyl ethyl
glycolate, glycol phthalate, di(2-ethylhexyl) hexahydrophthalate
and Santicizer 602.
3-21
-------
1977 edition of the Synthetic Organic Chemicals is not yet available,
it can be assumed that at least 2,000 pounds of di-n-hexyl phthalate
(two producers), were produced in 1977.
3. Use Patterns
The alkyl phthalates have largely been used as plasticizers for
plastic materials, mostly in polyvinyl chloride resins. Of the estimated
1,078 million pounds of phthalates consumed in the U.S. in 1974, 965
million pounds (89.5%) were used in polyvinyl chloride resins, 35 million
pounds (3.2%) in other vinyl resins (e.g., polyvinyl acetate), 30 million
pounds (2.8%) in cellulose ester plastics (eig., cellulose acetate),
22 million pounds (2%) in synthetic elastomers (e.g., chlorinated rubber),
6 million pounds (0.6%) in other polymers (e.g., acrylics), and 20
million pounds (1.9%) in nonplasticizer uses. Nonplasticizer applica-
tions include use as carriers or dispersing media for catalysts, pesti-
cides, cosmetics, and colorants, as defoaming agents in paper manufacture,
in lubricating oils and munitions, and as a crosslinking agent in un-
saturated polyester resins.
Current data on amounts of phthalates used in specific products are
not available. However, an estimate has been published of the consump-
tion pattern by application areas for the 822 million pounds of phthalate
esters consumed in the U.S. in 1970. This consumption pattern is repro-
duced in Table VII.
Plasticizers are used at high levels in polyvinyl chloride resins
primarily to impart flexibility or a soft feel to the finished product.
The proportion of phthalate plasticizer used in polyvinyl chloride resin
is usually 55 parts by weight plasticizer to 100 parts by weight resin.
The choice of plasticizers depends on a number of factors: (1) the
compatibility of the plasticizer with the resin; (2) the vapor pressure
of the plasticizer (it must be low enough to assure retention in the
resin during processing); (3) the odor and color of the plasticizer (low
odor and color level are needed for consumer products); (4) the relative
toxicity of the plasticizer; (5) the resistance of the plasticizer to
extraction by solvents, oils, and soapy water; (6) the amount of surface
3-22
-------
Table VII
Plasticizer Uses of Phthalate Esters
Millions of Pounds
Building and Construction
Wire and cable 185
Flooring 150
Swimming pool liners 20
Weatherstripping 13
Window splines 10
Other 9
Total 387
Home Furnishings
Furniture upholstery 90
Wall coverings 38
Housewares 30
Garden hose 15
Appliances 10
Other 20
Total 203
Transportation
Upholstery and seatcovers 80
Auto mats 15
Auto tops 12
Other 10
Total 114
Apparel
Footwear 45
Outerwear 20
Baby pants 7
Total 72
Food Surfaces and Medical Products
Food wrap film 18
Closures 7
Medical tubing 15
Intravenous bags 6
Total 46
TOTAL 322
Source: Graham (1973)
3-23
-------
migration of the plasticizer to adjoining resins; (7) the electrical
properties and flammability resistance of the plasticized products (the
importance depends on the product's end use); and (8) the cost per pound
of the plasticizer (Anon., 1977).
Pi(2-ethylhexyl) phthalate (DEHP) is the phthalate ester produced
in the largest quantity. It is used as a plasticizer for polyvinyl
chloride resins and synthetic rubbers for use in wire insulation, cloth
coatings, elastomeric molded materials, and extruded or calendered
compositions. Polyvinyl chloride films plasticized with DEHP are used
in food packaging* such as wrap for meat and produce packaging, and wheat
sealing applications, and in biomedical applications such as blood bags.
Phthalates based on linear CR-C;Q alcohols are used heavily as
plasticizers in polyvinyl chloride resins for automotive applications,
and to a lesser extent, in plastisols and dispersion coatings, and in
other film, sheeting, coated fabric, and extrusion applications.
Diisodecyl phthalate is used as a plasticizer in automotive upholstery,
polyvinyl chloride and urethane foams, and in wire and cable insulation
in combination with diisononyl, ditridecyl, diisooctyl, and di(2~ethyl-
hexyl) phthalates.
Butyl_benzyl phthalate (BBP)is primarily used as a plasticizer in
polyvinyl chloride flooring but also finds use in polyvinyl chloride
foams, coatings, polyvinyl acetate adhesives, and acrylic caulking com-
pounds .
Dibutyl phthalate (DBP) is used mostly as a plasticizer in
polyvinyl acetate emulsions for surface coatings, adhesives, paper
treating, and textile treating.
Dihexyl phthalate, and to a lesser extent, DBP are used as
plasticizers in plastisols for carpet backcoating.
Diethy1 and dimethyl phthalate are used almost entirely as plasti-
cizers for cellulose ester plastic film and sheet (photographic, blister
packaging, and tape applications) and molded and extruded articles
(consumer articles such as toothbrushes, automotive components, tool
handles, and toys).
Dicyclohexyl phthalate is a specialty plasticizer used in nitro-
cellulose lacquers and adhesives.
3-24
-------
Diallyl phthalate is used chiefly as a cross-linking agent in un-
saturated polyester resins. It is also used to make molded articles
(particularly for the electronics industry) and to make insulating
varnishes.
4. Occupational Standards and Workers Exposed
Only three of the alkyl phthalates have OSHA regulations governing
worker exposure to them: (1) DBF; (2) DEHP; and (3) DMP. These regula-
tions require that an employee's exposure to any one of these phthalates
shall not exceed an 8-hour time-weighted average of 5 mg/m3 in any
8-hour workshift of a 40-hour work week. Although OSHA has not as yet
adopted it, the American Conference of Governmental Industrial Hygienists
(ACGIH) has recommended a TLV (threshold limit value) of 5 mg/m3 for PEP.
Based on the 1974 National Occupational Hazard Survey (NOHS) of
plants in selected industries, NIOSH has estimated the total number of
workers exposed to certain chemicals in these industries. The estimates
of the number exposed to some alkyl phthalates are summarized in
Table VIII.
5. Mode of Entry into the Environment
The means by which alkyl phthalates enter the environment are not
well defined or understood. One author (Peakall, 1975) has reviewed the
available information and has discussed various possibilities:
a. Biosynthesis— There is some evidence that phthalic acid
and alkyl phthalates occur naturally in plants and animals, including
microorganisms. Some of the phthalates may have been present as a result
of contamination but phthalates were found in some samples even after
extreme care was taken to avoid contamination.
b. Loss during manufacturing and processing— Phthalates could
be present in air emissions, aqueous effluents, or solid waste products
from phthalate ester manufacturing plants or plastics processing plants.
c. Escape during use of phthalate-containing products— The uses
of phthalates, both as plasticizers (as shown in Table VII) and in non-
plasticizer applications can be divided into four broad categories:
3-25
-------
Table VIII
Estimated Number of Workers Exposed to Some Alkyl Phthalates
In Selected Industries (Based on NOHS)
Phthalate ester Estimated number of workers
Bis(diethylene glycol monoethyl ether) 7,740
Bis(2-ethylhexyl) 602,250
Bis(tridecyl) 11,250
Butyl benzyl 31,800
Butyl octyl 59,160
Decyl octyl 23,580
Diallyl 19,440
Dibutyl 869,130
Dicapryl (di-sec-octyl) 8,130
Dicyclohexyl 24,600
Didecyl 7,350
Diethyl l,240,071a
Diheptyl 7,620
Dihexyl 9,450
Diisobutyl 8,220
Diisodecyl 80,250
Diisononyl 8,190
Diisooctyl 9,750
Dimethyl 36,480
Dinonyl 7,350
Diundecyl 11,490
a" This estimate is considered highly suspect since the quantity of
diethyl phthalate produced in 1974 was only 19.7 million pounds — 1974
production of bis(2-ethylhexyl) phthalate was 389.7 million pounds.
3-26
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(1) High likelihood of escape. This includes those uses*
such as a pesticide carrier, in cosmetics, munitions, and lubricating
oils, where the phthalate is not encased in a plastic matrix.
(2) Directly in contact with liquids. This includes uses
such as swimming pool liners, garden hoses, and medical products such as
blood bags, transfusion and infusion assemblies, artificial kidney
connecting tubing, catheters, and many others.
(3) Films or sheets in contact with air. These uses are
flooring, weather stripping and window splines, furniture upholstery,
auto upholstery and seat covers, wall coverings, auto mats and tops,
clothing, and food wrap film.
(4) Materials with low surface contact. This includes cable
and wire, housewares, appliances, and miscellaneous uses in building and
construction, home furnishings, and transportation.
d. Loss from phthalate-containing plastics in disposal sites—
Although the useful life of plastics varies considerably, most will be
discarded within a few years. These materials end up as solid waste
and are either incinerated or landfilled. Although most discarded
plastics end up in dumps, a small proportion is also distributed
throughout the environment, i.e., the plastic cup in the ditch, and the
plastic items found floating in the open ocean.
6. Quantities Released into the Environment
The amounts of alkyl phthalates that may enter the environment are
not known. However, the author mentioned above (Peakall, 1975) has made
some estimates which are summarized here:
a. Biosynthesis— No attempt was made to estimate this possible
source.
b. Loss during manufacturing and processing— These losses were
not estimated, but the comment was made that with a production volume
of a billion pounds a year, even a loss factor of 0.1% results in a
potential one million pounds of phthalates lost.
3-27
-------
c. Escape during use of phthalate-containing products— Using
the above estimates and some arbitrary loss factors, the author made
estimates of losses from the use categories described above:
(1) High likelihood of escape. Essentially all of the
phthalates in these nonplasticizer uses are believed to enter the
environment. The total was estimated at 50 million pounds in 1972.
(2) Directly in contact with liquids. Using an arbitrary
loss factor of 1% per year, the loss to the environment from these uses
was estimated to have been 570,000 pounds in 1970.
(3) Films or sheets in contact with air. Using an arbitrary
loss factor of 0.1% per year, the loss to the environment from these
uses was estimated to have been 490,000 pounds in 1970.
(4) Materials with low surface contact. Using an arbitrary
loss factor of 0.01% per year, the loss to the environment from these
uses was estimated to have been 30 thousand pounds in 1970.
(Note that the total estimated losses of approximately 1 million
pounds for these last three (plasticizer) uses is small compared to the
estimated 50 million pounds from nonplasticizer uses.)
d. Loss from phthalate-containing plastics in disposal sites— Of
the plastics containing phthalates that end up as solid waste, an
estimated 10 to 20 percent are destroyed by high-temperature incineration,
and two percent are subjected to open burning or low-temperature
incineration. The author assumed that one-third (0.67 percent of total
usage) of the phthalates contained in these plastics subjected to open
burning or low-temperature incineration would escape destruction and
be vaporized.
3-28
-------
Because the useful life of most plastics is relatively short (a few
years) , the rate of discard was considered equal to the rate of consump-
tion. Based on the 1970 consumption estimate of 822 million pounds of
phthalate plasticizers and applying the percentage figures estimated by
this author, an estimated 82-164 million pounds of phthalates would have
been destroyed by high-temperature incineration, 11 million pounds of
phthalates would have been destroyed by open burning or low-temperature
incineration, and 6 million pounds of phthalates would have been vaporized
by open burning or low-temperature incineration. The remaining phthalates
would have been contained in landfilled plastic products. An estimate
of the amount of phthalates that escape through leaching or vaporization
from landfilled plastics was not found in the literature. Excluding this
unknown, the author (Peakall, 1975) estimated the environmental input
resulting from the manufacture and use of phthalates in plastics at
about 8 million pounds per year based on 1970 use estimates.
3-29
-------
7. Environmental Transport
Alkyl phthalates occur ubiquitously in the environment/ having been
identified in a myriad of materials such as water, soil, sediment, air,
human and animal tissues and blood, fish, food, solvents and non-
phthalate-plasticized plastic products (Marx, 1972; Mathur, 1974a).
They have also been reported as possible natural products in animals,
plants, microorganisms, and geochemical materials, although the possibility
of phthalic acid ester contamination of these materials before or during
sampling cannot be excluded (Mathur, 1974a).
Phthalates are believed to be transported in aquatic systems,
volatilized at high temperatures and transported through the atmosphere,
and to accumulate in aquatic organisms, on sediments and in plants.
Although the phthalate esters are almost insoluble in water and
have high boiling points, they appear to migrate readily from plastics
and related material into ambient air and liquid or solid media (Mathur,
1974a). Incineration has been reported to be an incomplete method of
disposal, as DBF, DEHP, and BPBG were detected in air samples near a
municipal incineration plant (Thomas, 1973; Mathur, 1974a).
Several studies have indicated that increased surface area and high
temperatures cause volatilization of the normally poorly volatile
phthalates from products such as polyvinyl chloride car upholstery and
other polyvinyl chloride products (Marx, 1972; Graham, 1973; Mathur, 1974a).
Other indications of the atmospheric transport of phthalates have also
been reported (Morita, 1974; Giam, et^ al., 1976). Leaching of phthalates
from polymer tubing by water passing through the tubing has been reported,
and the amount of phthalates leached has been found to increase with the
flow rate (Junk, et al., 1974).
In his review of the literature, Autian (1973) reported that
phthalate esters are readily sequestered or absorbed by organic residues
and solid surfaces in aquatic systems. Ogner and Schnitzer (1970) and
Matsuda and Schnitzer (1971) have investigated the "complexation" of
phthalates with fulvic acid, a water-soluble humic material which occurs
widely in soils and waters. They suggested that the fulvic acid can
3-30
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form stable complexes with the phthalate esters/ thus solubilizing them
and possibly mediating their transport in an aquatic environment. Under
laboratory conditions, Matsuda and Schnitzer (1971) found that the amount
of phthalate solubilized by the fulvic acid was dependent on the structure
of the specific ester, with DEHP complexed the most and DBF the least.
Increasing the pH from 2.5 to 7 decreased the complexation of the
phthalates by 25%. As no evidence of a chemical reaction was obtained,
the investigators concluded that the phthalates are adsorbed onto the
surface of the fulvic acid by an unknown mechanism.
Giam, et al^. (1976) reported a high affinity of DEHP for surfaces,
and phthalates have been reported to accumulate on sediment samples
(Jungclaus, et al., 1978). Morita, et al. (1974) reported that
phthalates dissolved or suspended in water may be absorbed onto
the sediment or may settle with other suspended material, resulting
in phthalate-free water. They further suggested that the processes of
sedimentation, uptake by aquatic animals and plants, and biodegradation
probably determined the fate of phthalates in river water and that the
actual river concentration of phthalates is dependent on an equilibrium
between entry and removal from the water.
A number of investigators have reported the ability of phthalates
to accumulate in food chains and in lipid-rich tissues of both plants
and animals (Pishbein and Albro, 1972; Marx, 1972; Metcalf, ejt a^., 1973;
Mathur, 1974a). Numerous laboratory and ecosystem studies have documented
the bioaccumulation and magnification of a number of phthalate esters in
such aquatic organisms as the waterflea, scud, shrimp, guppy, snail and
other fish (flayer, e_t al^, 1972; Metcalf, est al., 1973; Mayer and
Sanders, 1973; Sanders, et al., 1973; Sanborn, et^ al^, 1975; Booth, et
al., 1977; Mayer, 1976). In his review, Peakall (1975) concluded that
because of the fairly rapid metabolism of phthalates in fish and mammals,
the largest concentrations of these esters are expected at intermediate
points on the food chain, rather than at the end. Giam, et al., (1976)
also suggested that phthalates may be readily metabolized in biota from
the open ocean.
Continuous exposure of aquatic organisms to radiolabelled phthalates
such as -^C-DEHPy DOT, and DBP results in an initial rapid uptake and
accumulation of radioactive residues (Mayer and Sanders, 1973; Sanders,
3-31
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et al., 1973). Sanborn, £t al., (1975) investigated the fate of 14C-
labelled POP in two model ecosystems utilizing a variety of organisms.
At the end of a 33-day study in a terrestrial-aquatic ecosystem which
contained POP, algae contained the largest residues of POP and the water-
flea , the least, with intermediate values for mosquito fish, snails and
mosquito larvae. The biomagnification values were reported as 28,500 for
algae, 13,600 for snails, 9,400 for fish and mosquitoes, and 2,600 for
waterfleas. In a three-day aquatic ecosystem, higher POP, residues were
detected in all the tested organisms except for fish. In this system,
waterfleas had the highest residue levels, and snails, fish and algae,
the least. Magnification factors were 9,426 for waterfleas, 5,300 for
mosquitoes, 660 for algae, 438 for snails and 1.16 for fish. The
investigators suggested that the higher accumulation factors resulting
from longer exposure indicated the persistence and accumulation of POP.
Using the same 33-day model ecosystem with ^4C-PEHP_, Metcalf,
et al. (1973) and Booth, et_ al. (1977) reported magnification factors
of 107,670 for mosquito larvae, 53,890 for algae, 21,480 for snails, and
130 for fish. Uptake studies conducted in this same experiment similarly
demonstrated that the mosquito larvae accumulated the most PEHP and the
aquatic plant Elodea canadensis , the least. Mayer and Sanders (1973)
reported accumulation of PEHP residues in scuds at levels 3,600
times greater than in water during 14 days of continuous exposure (see
Table IX), while in an earlier study Mayer, et al. (1972) reported an
accumulation factor in scuds of 13,400 after the same length of exposure.
Table IX
Accumulation of ^4C-»-di-2-ethylhexyl phthalate by aquatic organisms
Organism
Waterflea
(Daphnia magna)
Scud
(Gammarus pseudolimnaeus)
Midge
(Chironomus plumotus)
Mayfly
(Hexagenia bilineata)
Fathead minnow
(Pimephalet promeltu)
Water
concentration,
JUg/l.
0.3
0.1
0.3
0.1
1.9
1 day
93
720
270
210
135
Accumulation
3 days
250
1,380
330
250
245
factor after
7 days
420
3,900
350
575
369
14 days
—
3,600
-^
-
458
Source: Mayer and Sanders, 1973
3-32
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The dynamics of DBF accumulation in scud were also investigated in
these same two studies. Mayer, et al. (1972) reported residue accumu-
lations of DBF at 6,700 times the water concentration within 14 days,
while the 1973 study by Mayer and Sanders yielded a value of 1,400 times
the water concentration within the same time period (see Table X) .
Table X
Accumulation of -^C-di-n-butyl phthalate by aquatic invertebrates
Organism
Waterflea
(Daphnia magna)
Scud
(Gammarui pseudolimnaeus)
Midge
(Chironomut plumoius)
Mayfly
(Hexagenia bilincata)
Water
concentration,
Mg/1.
0.08
0.10
0.18
0.08
Accumulation factor after
Iday
170
360
380
130
3 days
280
780
420
230
7 days
400
1,350
720
430
14 days
400
1,400
Source: Mayer and Sanders, 1973
Sanders, et al. (1973) studied the ability of aquatic organisms to
accumulate DEHP and DBF. The values these investigators
obtained for magnification factors (see Tables XI and XII) for DBF and
DEHP are considerably higher than those obtained in other studies.
Sanborn, et al. (1975) questioned these high values on the basis of their
own work with POP indicating that determination of accumulation factors
using analyses of total radioactivity could lead to misleadingly high
results. These authors believed that the DEHP magnification factors were
probably considerably lower than those Sanders, et al. had reported.
For example, Marx (1972) reported that Stalling, et al. have found accu-
mulation factors of 350 to 3,900 times the water concentration for DBF
and DEHP in organisms after seven days.
3-33
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Table XI
"Biologic Magnification" of 14C-Labelled Di-Ethylhexyl Phthalate From
Water by Five Species of Aquatic Invertebrates
Organism
Si-mi Gammarua
p*ni(lolimnaeu8
Miil^e larvae Chironotmis
pliiinosai
tt'aterflea Daphnia magna
Mayfly Hcxagenia bilineata
Sett-hug Atelhu brevicaudiu
"Nkf> Der
-*"• >JCI
sample
IS
IS
IS
ISO
9
4
4
Water
fog/1 ± SE-)
0.1 ± 0.01
62. S ± 3.31'
0.3 ± 0.04
0.3 ± 0.04
0.1 ± 0.01
1.9 ±0.12«
62.3 ± 3.31'
Magnification factor* after (days)
1
2SOO
30
2400
1200
S50
—
—
3
5300
100
2600
2500
1000
—
—
7
13600
116
3100
5200
2300
SO
20
14
13400
270
_
_
__
71
230
21
_
260
_
,-,—
_
70
250
- Samples taken in triplicate sad. expressed as mean ± SE
-------
their accumulation studies that the magnification of DEHP residues in
scud was much lower when they were exposed to a higher phthalate concen-
tration and increased water temperature. This suggested to these in-
vestigators that phthalate accumulation was favored in scud at low con-
centrations. Higher phthalate concentrations and increased water
temperatures may stimulate metabolism and elimination and result in
decreased magnification. They also suggested that the balance between
accumulation and elimination is largely what determines the extent of
magnification in an organism.
Mayer (1976) conducted a study in which fathead minnows were exposed
to labelled BBHP for 56 days at concentrations ranging from 1.9 to 62 yg/1.
Accumulation factors of 34 to 137 times the level in water were
observed in 24 hours. These factors are in agreement with results
reported by Metcalf, et aJL. (1973) in a study using guppies. Equilibria
of I^C-DEHP in the minnows were reached more slowly as the concentration
of DEHP increased. Accumulation factors which ranged from 91 to 569
for DEHP and from 155 to 886 for total ^C decreased as exposure concen-
tration increased. This possibly indicated the induction of detoxifying
enzymes in the liver with the ultimate effect of lower accumulation
factors through increased degradation and elimination. As exposure con-
centrations were increased, the proportion of DEHP decreased and degra-
dation products increased.
In earlier studies, Mayer and Sanders (1973) continuously exposed
fathead minnows to -^C-DEHP for 56 days. The accumulation factor of
458 measured after 14 days had increased to 1,380 by the time equilibrium
was reached after 28 days of exposure. Once equilibrium was achieved no
further residue accumulation was observed in the fish upon additional
exposure. Similar results were obtained for DBP in the water flea by
Sanders, et al. (1973). After equilibrium was achieved in waterfleas
on seven days of exposure, no further residue magnification was
observed following an additional seven days' exposure. In other work,
Mayer, et al. (1972) reported residue levels of DEHP in fathead minnows
to be only 28 times that found in water after a 28-day exposure.
3-35
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The data from these studies demonstrate that phthalates are accumu-
lated in the environment and undergo biomagnification in aquatic organisms.
There are also indications that these compounds are biodegradable. In-
deed, Morita, et al. (1974) have observed that aquatic animals and plants
may play a significant role in the removal of phthalates from river
water as will be discussed in the following section.
8. Environmental Degradation
In his review, Peakall (1975) commented that the usually slow leach-
ing of phthalates from plastics in "terrestrial situations" can be
accelerated by various environmental factors. For example, Decoste (1968)
found ants feeding on plasticized wire insulation and Pazinski (1973)
reported Streptomyces rubrireticuli growing on polyvinyl chloride
material. The biodegradation of phthalates has been reported in labora-
tory cultures of pure or mixed microbial populations (Mathur, 1974b;
Mathur and Rouatt, 1975; Engelhardt, et al., 1975; Keyser, et al., 1976;
Perez, c_t al_. , 1977), in fresh water hydrosoil (Johnson and Lulves, 1975),
and in river water and activated sludge (Saeger and Tucker, 1973 and 1976)
Phthalate degradation has also been observed in organisms such as fish
and snails (Mayer, et al_. , 1972; Mayer and Sanders, 1973; Sanders, et al.,
1973; Metcalf, et al,, 1973; Sanborn, et al., 1975; Booth, et ad., 1977;
Mayer, 1976). These studies and some general considerations on the de-
gradation of phthalates in the environment are described briefly in the
following paragraphs.
The available data on degradation and elimination indicate that
phthalate esters with partially oxidized or short alkyl chains such as
DBP are more easily biodegraded than long chain alkyl esters such as
DEHP (Keyser, et ail., 1976). In contrast, a laboratory study by Morita,
et al. (1974) showed that DBP (because of its greater polarity and
solubility) is more difficult to remove from water by complexing with
chemicals such as alum than is DEHP. In model ecosystem studies,
Sanborn, et al. (1975) also found that DEHP, possibly because of its
greater hydrolytic stability arising from its branching, accumulated
more than did POP. Keyser and his colleagues (1976) commented that
photochemical transformations of the phthalates may occur, but they found
no detailed reports in the literature. They also stated that it is not
certain how stable the phthalates are to hydrolysis, such as that
3-36
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catalyzed by clay minerals or other agents. It has been estimated
(Mabey, personal communication) that, although phthalates in the environ-
ment can undergo uncatalyzed hydrolysis, the hydrolysis half-lives at pH
3-7 are greater than one year. If phthalates remain in solution (i.e.,
are not absorbed on particulates in aquatic systems) the hydrolysis
half-lives at pH >8 may be less than one year. The hydrolysis half-
lives at pH 1-3 will also be greater than one year.
In their reviews of the literature, Peakall (1975) and Mathur (1974a)
reported that in early experiments undertaken to study the biodeteriora-
tion of plastics, phthalates were not utilized by 24 species of fungi,
and DEHP and POP were utilized only to a negligible degree by strains
of Aspergillus and the bacteria Pseudompnas commonly found on degraded
plastic films. Strains of the yeasts Saccharomyces and Zygosaccharomyces
were similarly unable to utilize POP and PEHP (Mathur, 1974a). In a
multi-laboratory study it was determined that PIOP was also not utilized
by any of 23 fungal isolates tested (Mathur, 1974a). Klausmeier and
Jones (1960) found that POP and PAP did not support the growth of micro-
organisms, and growth was scanty with PMP. Moderate growth was observed
with PEP, PPP, PBP, and with butyl isodecyl, n-octyl n-decyl, and iso-
octyl isodecyl phthalates. Other reports providing evidence of the
inability of microorganisms to utilize phthalates have been reviewed
by Mathur (1974a).
There is evidence from more recent studies that the microbial de-
gradation of phthalates does occur. Pata from various studies indicate
that mixed microbial populations appear to be the most effective in
degrading the phthalates (Engelhardt, et ail^., 1975; Saeger and Tucker,
1976). Regardless of the particular organism(s) involved, the biodegra-
dation of phthalates appears to proceed via common intermediates.
Evidence for at least part of the scheme of microbial degradation pro>-
posed by Keyser, et al. (1976) (see Figure 1) has been obtained from
virtually every recent study. The most common route of degradation of
the diesters is via hydrolysis to the monoester (Engelhardt, et al., 1975)
The most difficult step appears to be hydrolysis of the second ester
moiety (Engelhardt, et al., 1975) , and much less is known about the
3-37
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COOR
COOR
COO
COOR
Diester
Monotester
COO
COO~
o-Phthalate
4,5-Dihydroxyphthalate
COO
HO
Protocatecbuate
coo" *^*
ooc
OBC-
a-Hydroxy-y-carboxymuconic
semialdehyde
ooc
2 Pyruvate + 2 CO
2,6-Cyclohexadiene-4,5-diol-
1,2-dicarboxylate
OOC
"ooc
•COO
ooc
"ooc
B-Ketoadipate
Succinate
Figure 1: Proposed Scheme of Microbial Degradation
Source: Keyser, et al^., 1976
3-38
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degradation of this moiety (Keyser, et al., 1976). Bacterial degradation
usually results in complete oxidation of the aromatic ring (Keyser,
et al., 1976).
Perez, et al. (1977) isolated the bacterial strain Enterobacter
aerogenes from old plastic tubing and found it capable of utilizing DMP
as the sole carbon source. These bacteria, which are found in sewage,
soil, water, dairy products and the human intestinal tract, utilized
67.4% of the chemical during a 41-day incubation. Engelhardt, et al.
(1975) found that isolates of several soil bacteria and of the fungus Peni-
cillium lilacinum grown with DBP as the carbon source formed the monoesfeer
within one to four weeks almost quantitatively as the only metabolite.
They also found that the bacterial cells grown on DBP were able to utilize
the monoester degradation product, phthalic acid and protocatechuic acid
as carbon sources (see the proposed scheme in Figure 1). Because both
phthalic acid and protocatechuic acid were utilized by these bacteria,
it was suggested that the organisms degrade phthalic acid via 4,5-
dihydroxy phthalic acid, protocatechuic acid, and cis,cis-&-carboxy
muconic acid, (see Ribbons and Evans, 1960 for evidence of a similar
pathway in soil Pseudomonads). DIBP, POP, DEHP, and MBP were also able
to support bacterial growth while DMP was utilized by only two of the
bacteria. With each of the diesters, the corresponding monoester was
detected as a degradation product. A somewhat different but unspecified
mechanism of degradation was believed to occur in the Penicillium fungus,
since several unidentified metabolites with an intact phthalic acid
moiety were isolated from cultures growing on DBP, POP and DEHP.
Mathur (1974b) reported that Eggins, et al. (1971) found four of
18 thermophilic fungi able to grow in a POP-containing medium. In his
own studies, Mathur (1974b) found POP and DEHP to be utilized by soil
microorganisms at 22° and 32°C, but not at 4° or 10°C. DIBP was degrad-
ed at all temperatures, but at a slower rate at the lower temperatures.
A later study by Mathur and Rouatt (1975) demonstrated that Serratia
marcescens Bizio (found in soil, water, and food), was capable of
growth on DEHP and POP at substrate concentrations of up to 2.5% and on
phthalic acid at levels below 1.25%. No growth was detected using 2-
3-39
-------
ethylhexanol as the substrate, but 0.8% DEHP was utilized to the extent of
about 95% in three weeks. Phthalic acid was believed to be a primary
product of the metabolism of DEHP and POP.
Using cell extracts of Micrococcus grown on PMP_, Keyser, et al. (1976)
found that hydrolysis of DMP, PBP, and PEP readily occurred, with PEP
hydrolyzed the most rapidly. Using Pseudomonas fluorescens PHK, they
also determined that the dihydrodiol, 4,5-dihydro-4,5-dihydroxyphthalate,
is a probable intermediary metabolite between o-phthalate and 4,5-
dihydroxyphthalate. Nakazawa and Hayashi (1977) studied the degradation of
phthalates in Pseudomonas testosteroni and found that it too was eapable of
degrading the phthalate anion via 4,5-dihydroxyphthalate and proto-
catechuate.
Limited work by Graham (1973) indicating the degradation of PEHP
and BBP by a semi-continuous activated sludge system was expanded upon
by Saeger and Tucker (1973 and 1976) who examined the degradation of
phthalates in acclimated activated sludge and unacclimated river water.
Using the Semi-Continuous Activated Sludge Biodegradation Test to
examine sludge from a domestic sewage treatment plant, they found that
phthalic acid, MBP, BPBG, and BBP were completely degraded to phthalic
acid-related intermediates, while PEHP was degraded to the extent of 70 to
78%. BPBG and BBP also underwent complete degradation to water-soluble
aromatic intermediates, which then underwent enzymatic ring cleavage to
smaller nonaromatic molecules. In the River Pie Away Test, which more
closely simulates "real life" conditions, BPBG and BBP underwent degra-
dation faster than the sulfonate control compound. PEHP and the mixed
di (heptyl, nonyl, undecyl)phthalate also underwent degradation but at
a slower rate (Saeger and Tucker, 1973). Saeger and Tucker (1976) also
found that PUP was degraded to the extent of 45% when added to the
activated sludge system at a rate of 5 mg/cycle while an additional rate
of 20 mg/cycle decreased the degradation rate to 29%. In a separate test
to measure the evolution of carbon dioxide, it was found that BBP, PEHP,
and the mixed di(heptyl, nonyl, undecyl)phthalate were essentially
completely degraded under the mild test conditions (Saeger and Tucker,
1976). The investigators concluded that the data on BBP and BPBG, indi-
cating the conversion of phthalates to the monoesters and phthalic acid
3-40
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and ultimately to carbon dioxide and water, were in agreement with the
bacterial data of Engelhardt, et al. (1975).
The data of Saeger and Tucker (1976) were also in basic agreement
with the experiment of Johnson and Lulves (1975) who examined the degra-
dation of DBF and DEHP in freshwater hydrosoil. Under aerobic conditions,
46% of labelled DBF was degraded to the monoester within 24 hours and
almost 98% of all the activity had disappeared after five days. Under
similar conditions, 14 days were required for 53% of labelled DEHP
to disappear. Under anaerobic conditions, degradation of both esters
was retarded. Almost 70% of the activity of DBF remained after five
days of incubation; however, almost 98% of the labelled compound had
disappeared from the soil after 30 days of incubation (hydrolysis of
DBF, therefore, required twice as much time under anaerobic conditions
and decarboxylation took six times longer). No significant degradation
of 14QDEHP was observed even after 30 days. Following a one-day
incubation, the major degradation product of DBF under either condition
was identified as the monoester (46%) together with smaller amounts of
phthalic acid and some unidentified compounds. Under anaerobic conditions,
an increase in the monoester was observed after long incubation, but
none of the more polar degradation products accumulated. The monoester
of DEHF was also identified under aerobic conditions, but no other
degradation products were found. Respirometry data indicated rapid
decarboxylation of phthalic acid in hydrosoil. The authors proposed that
under either aerobic or anaerobic conditions, diesters in hydrosoil are
intially hydrolyzed at the ester linkage to form the monoester and the
corresponding alcohol. The monoester is subsequently degraded primarily
to phthalic acid, which may be decarboxylated to catechol or benzene.
Because of the position of the radioactive label (on the carbonyl carbon),
they were unable to obtain evidence suggestive of ring cleavage after
ester hydrolysis.
In evaluating the work of Johnson and Lulves (1975) , Keyser, e_t al.
(1976) commented on the observation that the monoester and phthalate
anion were completely degraded within 7 days in hydrosoil; whereas, only
50% of the 14C was recovered from the diester during this same period.
3-41
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Since about 50% of the diester was hydrolyzed to the monoester in one
day, Keyser and his associates suggested that the phthalate diesters
may partially inhibit their own biodegradation under some conditions.
Studies in aquatic organisms provide further evidence for the bio-
degradation of phthalates. In the model ecosystem studies of Sanborn,
et al. (1975), analysis of water samples taken from both aquatic and
terrestrial-aquatic systems (containing such organisms as algae,
mosquito fish, snails, waterfleas and mosquito larvae) at three-day
intervals demonstrated that POP was rapidly degraded by the organisms in
the study and was not detectable in water samples after 15 days. An
approximate half-life of five days was estimated for POP in water.
Coupled with the decline in POP in water was a rapid rise in the concen-
tration of phthalic acid, which comprised 55-65% of the ether-extractable
material after ten days. Also identified was the monoester which reached
a maximum concentration on the sixth day. Transformation of the ester
to polar metabolites was also indicated. After 12 days, the unextract-
able activity reached a maximum of 60% and remained constant for the
duration of the experiment.
In the studies of Metcalf, et al. (1973) and Booth, et al. (1977)
using ^C-DEHP in the 33-day ecosystem, the coneentration of radioactivity
in the aquatic phase reached a peak of 0.031 ppm by the fifth day of the
experiment, declining to 0.0077 ppm by the end of the study, indicating
accumulation by the organisms. Only DEHP was found in algae and mosquito
larvae, indicating little degradative ability by these organisms. The
snail produced substantial quantities of the monoester, phthalic acid,
and phthalic anhydride. Fish were the most active in metabolizing DEHP,
with half the activity in the form of phthalic anhydride, presumably from
phthalic acid. Studies of the uptake of DEHP by guppies revealed that a
steady decline in activity was observed in the guppy, with total activity
declining from 88.5% after one day to 37.1% after two days and to 16.8%
after seven days. Polar metabolites increased from 11.5% after one day
to 34.2% after two days and to 80.6% after seven days. Phthalic acid,
which comprised 23.8% of the activity after two days, declined to 4.8%
after seven days. Small amounts of phthalic anhydride also were identified.
3-42
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A similar degradation pattern was observed in uncontaminated guppies,
which had been fed water fleas exposed to C-DEHP for one day. The
snail/ clam, waterflea, and aquatic plant Elodea exhibited low degrada-
tive capacity. The snail still contained 86.6% of the initial concen-
tration of DEHP after seven days, together with small amounts of the
anhydride and an unknown metabolite. Metcalf, et_ al^ (1973) proposed
that the major degradative pathways appeared to be through hydrolysis
of the ester group to produce the monoester, then phthalic acid, and
then the anhydride.
Studies by Mayer and Sanders (1973) revealed that elimination of
50% of DEHP and its degradation products from minnows exposed to
DEHP in their environmental water for 56 days occurred within seven days
after they were placed in fresh water. In addition to the di- and mono-
esters, residues comprising 5 to 26% of the total activity were identified
as free and conjugated phthalic acid and monoester. Mayer (1976) re-
ported the half-life of DEHP in fathead minnows to be 12.2 days. Scuds
exposed to DEHP for seven days and then transferred to fresh water re-
tained only 20% of the radioactivity after four days in fresh, water and
only 6% after ten days. Water fleas similarly exposed to DBP lost 50%
of the radioactivity after three days in fresh water, and 75% after seven
days. Stallings, et al. (1973) exposed channel catfish to 1 vg/1 14C-
DEHP for 24 hours and identified metabolites similar to those found in
other organisms. They stated that the presence of appreciable amounts
of the monoester in fish suggested that this metabolite was refractive
to further degradation. Studies in vitro by these investigators using
hepatic microsomes from channel catfish indicated that DBP was metabolized
16 times faster than DEHP. In vitro, formation of monoesters as well as
of unidentified metabolites was observed. In experiments with microsomal
enzyme inhibitors and cofactors, these investigators determined that, in
this system, the monoester is not further degraded, and the unidentified
metabolites are derived directly from the parent ester.
All the evidence summarized above indicates that the phthalate
esters are biodegraded by a variety of organisms under laboratory and
simulated environmental conditions, but Johnson and Lulves (1975) have
commented that the fate of phthalate esters in the natural aquatic
environment is still largely unknown.
3-43
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C. Biological Effects
1. Ecological Hazards
a. Toxicity to Wildlife
(1) Acute Toxicity
Few toxic effects have been observed in birds, fish, and other aquatic
organisms following exposure to alkyl phthalates. Driaze, et al_. (1948)
reported an oral LD value of 8.5 ml/g for DMP in chickens. The 96-hour LC
values of DBF and DEHP in fish and crustaceans reported by Mayer and Sanders
(1973) and Sanders, et al. (1973) are listed in Table XIII, and range
from 0.73 mg/1 for DBF in bluegills to more than 32 mg/1 for DEHP in
scud. The LCso values for these compounds are approximately three orders
of magnitude greater than the LC^Q values of DDT in the same organisms,
indicating a much lower level of toxicity for the alkyl phthalates.
Table XIII
96-Hour LCso Values in Fish and Crustaceans
(Milligrams per Liter)
Organism DBF DEHP
Fathead minnow 1.30 >10
Bluegill 0.73 >10
Channel catfish 2.91 >10
Rainbow trout 6.47 >10
Scud 2.10 >32
Crayfish >10.00 >10
Source: Mayer and Sanders, 1973 plus Sanders, et al^., for data on
scud
•
An exception to the low toxicity has been reported for DBP, which
has been observed to exert a toxic effect on shrimp larvae at a concen-
tration of 3.7 x 10"5M, as evidenced by an increased mortality rate
compared to controls (Sugawara, 1974).
(2) Reproductive System Effects
Alkyl phthalates have been reported to induce significant adverse
reproductive effects in chickens and aquatic organisms. Bower, et al.
(1970) injected eight phthalates into the yolk sacs of groups of developing
3-44
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chick embryos in volumes ranging from 0.025 to 0.10 ml, and determined
the toxicity of the compounds to the embryos as evidenced by the number
of embryos not surviving. DMEP at a dose of 0.1 ml exhibited the highest
embryotoxicity, since 46/50 (92%) of the embryos died before hatching,
compared to 45 and 53% mortality with sesame oil- and Crisco oil-
treated controls, respectively.
Mayer, et al. (1972) exposed zebra fish to a diet containing 50 or
100 yg/g DEHP. As many as 88% of the offspring died before they began
foraging, compared to 50% among controls. In addition, the progeny of
the phthalate-treated fish all died in tetany, while tetany was not
observed among progeny of controls.
Sanders, et al. (1973) exposed waterfleas to DEHP at concentrations
of 3, 10, and 30 yg/1 for a complete life cycle of 21 days. The chemical
reduced reproduction by 60, 70, and 83% at the three doses, respectively.
The concentrations found to induce these decreases in reproduction were
1/700 to 1/11000 the LC,-O concentrations. In another study, DBP at
three concentrations (1,8, and 19 x 10~^M) and DEHP at the highest con-
centration tested (28 x 10~5n) significantly reduced the number of brine
shrimp larvae hatched/mg eggs (Sugawara, 1974).
Although acute toxicity studies indicate a very low order of
toxicity for these esters to birds and aquatic organisms, it has been
hypothesized that the adverse reproductive effects of the chemicals
at very low dose levels could cause a serious imbalance in the food
chain (Sanders, e_t al., 1973).
b. Toxicity to Plants
DBP and DIBP have been reported to induce toxic effects such as
symptoms of chlorosis in egg plant, cucumber, tomato, pepper, and
strawberry plants following exposure of the plants to vapors of the
esters (Inden and Tachibana, 1975). DBP and POP have been reported to
inhibit the elongation of wheat coleoptile, as well as to delay the
aging process in Rumex obtusifolius leaves (Gudin and Harada, 1974).
3-45
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c. Toxicity to Microorganisms
The toxicity of the alkyl phthalates to various microorganisms
appears to be very low. Recent studies indicate the ability of micro-
organisms to grow in the presence of the chemicals, and in some cases,
to utilize the esters as their sole carbon source (see Section III B.8).
2. Effects Related to Human Health Hazards
a. Carcinogenicity*
In the several animal carcinogenicity tests of alkyl phthalates
reported in the literature, no carcinogenic effects related to the treat-
ments have been observed. In one study, EPEG was administered orally
in the diet to 150 rats for two years at dose levels ranging from 0.05
to 5.0%. Six rats were reported to have tumors but the investigators
did not attribute them to the treatment. At the highest dose level,
100% mortality by 55 weeks was reported (Hodge, et ail., 1953; Shubik
and Hartwell, 1957).
Carpenter, et al. (1953; Shubik and Hartwell, 1957) investigated
DEHP by oral administration of 0.04 to 0.4% of the chemical in the diet
for two years to 192 Sherman rats. Nine treated rats were reported to
have neoplasms (which were not characterized pathologically) ; this
tumor incidence was not considered by the investigators to be significant.
In a different study, Harris, et al. (1956; Shubik and Hartwell, 1969)
administered the chemical in the diet to 172 weanling Albino^Wistar rats
for two years at dose levels of 0.1 and 0.5%. A total of three fibro-
liposarcomas were observed, that were considered by the investigators
to be unrelated to the treatment. Pew treated or control animals were
reported to have survived the total two-year testing period.
In their study of six phthalates applied to mouse skin as 5 and 10%
acetone solutions, Wynder and Hoffmann (1964) observed that only DAP
induced some hyperplastic reaction on mouse skin. No tumor-promoting
activity was observed after five months with DBP or POP applied to mouse
skin that had been initiated with 300 yg of the carcinogen 7,12-di-
methylbenz(a)anthracene•
* The alkyl phthalates BBP, DAP and DEHP are currently on test in the
NCI Carcinogenesis Bioassay Program.
3-46
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In a recent short-term study using the test for induction of
pulmonary lung adenomas developed by Shimkin (Shimkin and Stoner, 1975),
BBP* was injected intraperitoneally into strain A/St male mice at doses
of 160, 400, and 800 mg/kg, three times weekly for eight weeks. No
statistically significant increase in the incidence of lung tumors over
controls was observed (Theiss, 1977).
In several other experiments, no carcinogenic effects of alkyl
phthalates were observed. These tests were the following:
1) DBF (Smith, 1953; Shubik and Hartwell, 1957; Lefaux, 1968),
dibutoxyethyl phthalate (Mallette and von Haam, 1952;
Shubik and Hartwell, 1957), dicapryl phthalate (Mallette
and von Haam, 1952; Shubik and Hartwell, 1957) or DCHP
(Lefaux, 1968) in rats;
2) DMP in rats (White and Edwards, 1942; Draize, et al.,
1948; Hartwell, 1951; Shubik and Hartwell, 1957),
chickens, mice, guinea pigs (Draize, ejt al_., 1948;
Shubik and Hartwell, 1957), and rabbits (Draize, et al.,
1948; Haag, et al., 1948 and 1950; Shubik and Hartwell,
1957);
3) DEHP in dogs (Carpenter, e_t al^., 1953; Harris, et al.,
1956; Shubik and Hartwell, 1957 and 1969) , rats
(Shubik and Hartwell, 1969), and guinea pigs
(Carpenter, et al^., 1953; Shubik and Hartwell, 1957); or
4) EPEG in rats and dogs (Hodge, e_t al^., 1953; Shubik and
Hartwell, 1957).
All these experiments, however, were of a shorter duration and
were carried out with fewer test animals than are usually considered
adequate for a carcinogenicity test.
* The identity of the chemical tested in this study is not certain, as
the structure given for BBP is actually that of butyl benzyl tere-
phthaiate in which the ester moieties are para- to each other.
3-47
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b. Mutagenicity
Although various alkyl phthalates have been tested for mutagenicity
and induction of gene damage (EMIC, 1978), the only demonstrated activities
were the induction of dominant lethal mutations in male mice by DEHP and by
DMEP. In these experiments, groups of male mice were given single intra-
peritoneal injections of one of the two chemicals at three dose levels
(12.78, 19.17, and 25.56 ml/kg DEHP, and 1.19, 1.79, and 2.38 ml/kg
DMEP) f and were subsequently mated with two females each week for twelve
weeks. Mutagenic effects were evidenced by decreased implants/pregnancy
and increased early fetal deaths, both at the highest dose levels during
the first three weeks after exposure of the males to the chemicals
(Dillingham and Autian, 1973; Singh, 1974). It should be noted that
the adequacy of these tests is limited by the small numbers of animals
treated (10 per group) and the lack of dose-response. Also, the intra-
peritoneal route of administration may not be relevant to determination
of human health hazards from phthalates.
DMP was reported by Yurchenko (1977) to induce chromosome aberra-
tions in regenerating hepatocytes of rats receiving repeated skin
applications of the chemical, but no data or experimental details were
available.
Alkyl phthalates were also tested in the following mutagenicity
and chromosome-damaging tests, but no significant adverse effects were
reported. Stenchever, et al. (1976) reported that DEHP induced no
significant increase in chromosome aberrations in vitro in human
leukocytes from four subjects at four dose levels, or in lung cells of
a single human fetus at one dose level in vitro. PEP, DBP_, DEHP, and
BPBG were also reported to not induce significant chromosome aberrations
in Chinese hamster cells in vitro at several dose levels (Ishidate and
Odashima, 1977; Omori, 1976; Abe and Sasaki, 1977), although the inci-
dence of sister chromatid exchanges in these cells was slightly elevated
in the presence of DEHP and DBP (Abe and Sasaki, 1977).
PEP, DBP, POP, BBP, DCHP, EPEG, BPBG, dihexyl, diheptyl, di(iso-
heptyl, isononyl), di(octyl, decyl), and diisodecyl phthalates were tested
3-48
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in microbial assays such as induction of point mutations in Escherichia
coli and Salmonella typhimurium, and tests of the potential of a chemical
for inducing DMA damage in strains of Bacilus subtilis and E_. coli. The
chemicals were reported to be inactive in these assays, but no experi-
mental data were given (Kurata, 1975; Szybalski, 1958; Yagi, et al^, 1976).
c. Teratogeni ci ty
Alkyl phthalates have been reported to exert teratogenic effects
in rats, mice, and chickens. Singh, et al. (1972) tested DMP, DMEP, PEP,
DBF, DIBP, BPBG, POP, and PEHP in female rats, administering intraperitoneal
injections of the chemicals on days 5, 10, and 15 of gestation. The
first six chemicals were given in doses of 1/10, 1/5, and 1/3 the LP
levels, and the latter two were administered at dose levels of 5 and 10
ml/kg. The females were then killed before the end of pregnancy, and
the fetuses were examined. All of the esters exhibited teratogenic
effects, such as resorptions, decreased fetal size, fetal death, gross
abnormalities, and skeletal malformations, although the degree of potency
varied among compounds. The more water-soluble chemicals exerted
stronger effects. DMEP and PMP were the most potent teratogens, in-
ducing high rates of resorption, as well as absence of eyes, absence of
tail, twisted hind legs, elongated and fused ribs, and incomplete bone
development in skull and legs. PEP, DBF, PIBP, and BPBG treatment re-
sulted in the skeletal abnormalities, and the middle dose of PIBP also
resulted in the absence of eyes in two dead fetuses. Grossly malformed
fetuses, especially twisted hind legs, were seen in groups treated with
POP. Effects of PEHP were seen only at the higher dose level, and
consisted of one fetus with twisted hind legs, and 9/41 with heman-
giomas of the legs. Yagi, et al^ (1976) reported a significant incidence
of external and skeletal malformations in the fetuses of mice treated
with PEHP. Onda, et al. (1974) reported that the formation of renal
cysts was increased in the offspring of mice fed PBP and PEHP.
Bower, et al. (1970) tested the teratogenicity of BBP, PBP, PEP,
POP, PMEP, dibutoxyethyl. octyl isodecyl, and octyl decyl phthalates in
chick embryos. Pibutoxyethyl phthalate induced the most potent tera-
togenic effect. Chicks exposed to the chemical as embryos had defects
3-49
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such as neuromuscular abnormalities in which the chicks could not stand
and demonstrated odd positioning of the legs, crania bifida, absence of
eyes, malformation of the upper beak, grossly enlarged eye due to the
absence of a normal orbit in the skull, and absence of the cornea.
Exposure of embryos to DMEP and octyl isodecyl phthalate resulted in the
neuromuscular abnormalities which included lack of normal coordination,
and one chick exposed to PEP had a severe malrotation of the left leg.
Guess, ejt al. (1967) reported deformed legs and neurological abnormalities
in chicks exposed to butyl octyl or butyl decyl phthalates as embryos,
and Haberman, et al. (1968) reported neurological defects in chicks
following exposure to POP, butyl octyl, and octyl isodecyl phthalates.
d. Systemic Toxicity
Alkyl phthalates evidence very low acute toxicity in mammals, ranging
from 2.4 g/kg (rat, oral) for DMP to >100 gAg (rat, oral) for DNP.
The LDgQ values for a number of the esters in several mammalian and one
avian species by various routes of administration are listed in Table XIV.
In general, the toxicity of these compounds decreases with increasing
chain length of the ester.
In numerous studies, administration of single oral doses of various
phthalate esters to humans and animals has produced very few toxic effects.
For example, the only toxic effect reported by Shaffer, et al. (1945) in
two humans ingesting 5 or 10 g DEHP was diarrhea. Lefaux (1968) reported
nausea, vertigo, hepatitis, and toxic nephritis in a human ingesting 10 g
DBF, but no after-effects were observed within two weeks. The only toxic
effect reported in rats receiving 110 g/kg DEHP and in rats and mice in-
gesting 20 g/kg di(heptyl, nonyl) phthalate was diarrhea (Hodge, 1943;
Gaunt, et al., 1968), and in rats receiving 5-10 g/kg diisononyl phthalate
was oily fur (Livingston, 1976). Dermal application of various phthalates
to rabbits and guinea pigs has been found to produce very low lethal toxic-
ity from absorption (3-20 g/kg).
3-50
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TABLE XIV
LD- Values of Some Alkyl Phthalates
PHTHALATE ESTER
SPECIES
ROUTE
LD50(gAg)
REFERENCES
Dimethyl
Diethyl
Di (Kethoxyethyl)
Di-n-propyl
Diallyl
Diisopropyl
Dibutyl
Diisobutyl
Rat
Mouse
Guinea pig
Rabbit
Rat
Mouse
Rabbit
Rat
Mouse
Guinea pig
Mouse
Rat
Mouse
Rabbit
Mouse
Rat
Mouse
Rabbit
Rat
Mouse
Guinea pig
Oral
IP
Oral
IP
Oral
Oral
Dermal
Oral
IP
IP
Oral
Oral
IP
Oral
IP
Oral
Dermal
IP
Oral
IP
Oral
Dermal
IP
Oral
IP
IM
SC
Inn
Oral
IP
Dermal
Oral
IP
Oral
IP
Dermal
2.4-6.9
3.38*
7.2
3.98
2.4
4.4
10.0
8.2*
5.06*
3.22
1.0
4.4
3.7
3.2-6.4
2.5
1.6-3.2
10.0
<1.25
1.7
0.7
1.7
3.4*
<1.25
8-12
3.1*
8.0
<6.2
0.7-0.9**
8
3.57
20.0*
20-25
3.75
12.8
3.99
10.0*
Patty, 196 7a, Lehman, 1955
Singh, et al^. , 1972
Lehman, 1955
Lawrence , et al. , 1975
Lehman, 1955
Lehman , 1955
Patty, 1967a
Tyson, unpublished,
1972
Singh, et al . , 1972
Lawrence, et al_. , 1975
Patty, 1967a
Patty, 1967a
Galley, et al^. , 1966
Patty, 1967a
Galley, et al., 1966
Patty, 1967a
Patty, 1967a
Galley, et al. , 1966
Patty, 1967a
Patty, 1967a
Patty, 1967a
Patty, 1967a
Galley, et al. , 1966
Smith, 1953; W.R. Grace,
& Co., 1948
Singh, £t al^. , 1972
Patty, 1967a
Kowalski & Bassendowsa,
1965
Spasovski , 1964
Smith, 1953
Lawrence , et al. , 1975
Patty, 1967a
Patty, 1967a
Singh, et al. , 1972
Patty, 1967a
Lawrence, et al_. , 1975
Patty, et a,!. , 1967a
3-51
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TABLE xiV (Continued)
PHTHALATE ESTER
SPECIES
ROUTE
REFERENCES
Butyl phthalyl butyl
glycolate
Dihexyl
Dicyclohexyl
Dioctyl
Diisooctyl
Di(2-ethylhexyl)
Butyl benzyl
Dicapryl
Oinonyl
Diisononyl
Diisodecyl
Ditridecyl
Butyl octyl
Butyl decyl
Hexyl decyl
n-HexyJ n-octyl n»*decyl
Rat
House
Rat
Rabbit
Rat
Rat
Mouse
Guinea pig
Rat
Rat
Mouse
Rabbit
Guinea pig
Rat
Mouse
Mouse
Rat
Mouse
Rat
Rat
Mouse
Rat
Rat
Rat
Rat
Rat
Oral
IP
IP
Oral
Dermal
Oral
Oral
IP
Oral
IP
Dermal
Oral
Oral
IP
Oral
IP
Oral
Oral
Dermal
Oral
IP
IP
IP
Oral
IP
Oral
Oral
IP
Oral
Oral
Oral
Oral
Oral
14.6*
6.89
6.88
30.0
20.0*
30.0*
30.0
50.0*
13.0
65.7
5.0*
22.6*
26-34
50.0*
34.0*
38.4*
33.9
26.3
10.0
4.0
1.8
3.2
14.2
2.0
>100
>10
>64
MOO
>64
>63*
20.8*
49.4*
45.2*
Patty, 1967a
Singh, et al. , 1972
Lawrence, et al . , 1975
Patty, 1967a
Patty, 1967a
Lefaux, 1968
Radeva & Dinoeva, 1966
Singh, et a^. , 1972
Patty, 1967a
Lawrence, et al. , 1975
Patty, 1967a
W.R. Grace & Co., 1948
Patty, 1967a; Hodge, 1943
Singh, e£ al. , 1972
Union Carbide Corp. ,
unpublished
Lawrence, et al^. , 1975
Patty, 1967a
Union Carbide Corp . ,
unpublished
Patty, 1967a
Mallette & Von Haam, 1952
Mallette & Von Haam, 1952
Galley, et al. , 1966
Galley, et al . , 1966
Patty, 1967a
Lawrence , et al. , 1975
Livingston, unpublished
Smyth, e_t al., 1962
Lawrence , et, al. , 1975
Smyth, e_t al^. , 1962
W.R. Grace & Co., 1948
Smyth, et al. , 1969
Smyth, et al. , 1969
W.R. Grace & Co. , 1948
3-52
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PHTHAIATE ESTER
TABLE XIV (Continued)
SPECIES ROUTE LD_ (gAg)
REFERENCES
Heptyl nonyl
Rat
Mouse
Oral
Oral
>19.3
>19.3
Brown, e* al_. , 1970
Brown, et al., 1970
Heptyl nonyl undecyl
Rat
Mouse
Oral
Oral
>20
>20
Brown, et al., 1970
Brown, et al., 1970
Octyl decyl
Rat
Oral
45.2*
Smyth, et al., 1969
2-Ethylhexyl benzyl
Rat
Oral
60.3
Younger , unpublished
Nonyl undecyl
Rat
Mouse
Oral
Oral
>19.7
>19.7
Brown, e£ al^, 1970
Brown, et al., 1970
*« ml/kg
**= mg/1
3-53
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Experiments involving inhalational exposure of the phthalate esters to
animals have also indicated few toxic effects (Autian, 1973) .
In an epidemiological study of 147 workers exposed to phthalate
plasticizers in factory air for 1/2 to 19 years, hypertensive reactions
were observed in 28.3% of the subjects, and hypertensive disease in 6%
of the workers. Slightly decreased levels of platelets and leukocytes,
hemoglobin, and the blood color index, as well as slight reticulocytosis ,
enhanced rate of erythrocyte sedimentation among females, and moderate
hyperbilirubinemia were also observed (Milkov, et al. , 1973) . It
should be noted that the workers were also exposed to very low levels of
other chemicals such as vinyl chloride, carbon monoxide, and hydrogen
chloride, but the major contaminants of air samples within the factory
were the phthalates.
A number of oral and inhalational subacute and chronic toxicity
studies of phthalate esters have been conducted in rats, mice, rabbits,
guinea pigs, and dogs. These studies have indicated a very low order of
toxicity of these chemiaals to animals. Decreased rates of weight gain
and increased liver and kidney weights at high oral dose levels (>200
mg/kg/day DEHP , for example) are the only effects commonly noted by
investigators (Carpenter, et al. , 1953) . In one dog and in rats given
repeated oral doses of C-j to C;Q alkyl phthalates, Carpenter, et al.
(1953) and Brown, et al. (1970) have detected vacuolization in liver
cells from fatty deposits in the liver. Fatty vacuolization in the
kidney of the dog was also observed.
There is some evidence to suggest that alkyl phthalates have a
cumulative toxic effect. Lawrence, et al. (1975) found that following
five intraperitoneal injections per week of several phthalates in mice,
the LDso values decreased over time. For example, the acute LD5Q of
DEHP was found to be 38.35 ml/kg, the calculated LDso after one week was
6.40 mlAg, and after 10 weeks was 1,37
Seth, et al. (1976) and Cater, et al. (1976, 1977) have reported
testicular atrophy in rats following three intraperitoneal injections
of 5 mlAg DEHP or daily oral doses of 2 g/kg DBP. A significant de-
crease in testes weights was noted, and histopathological examination
3-54
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revealed a decrease in spermatocytes and spermatogonia, as well as
degenerated tubules and vacuolization in the cytoplasm of spennatogonial
cells.
The phthalate esters also appear to exert adverse effects on repro-
duction in female rats. Singh, et al. (1972) administered DMP, PMEP,
PEP, DBF, DIBP, BPBG, POP, and DEHP to pregnant rats on days 5, 10, and
15 of gestation. The first six compounds were given at dose levels of
1/10, 1/5, and 1/3 of the LD5Q values, and the last two were given at
dose levels of 5 and 10 ml/kg. The compounds varied in the number of
resorptions and fetal deaths induced, with DMEP, the most embryotoxic
compound, inducing 89.7 and 96.5% resorptions at the two higher doses,
compared to 6-11% among water, saline, or cottonseed oil controls.
Fetal deaths appeared to be induced only by DMP, DMEP, and DIBP. In
another study, DEHP has also been reported to induce fetal deaths in
mice (Yagi, ejt al., 1976).
It has been suggested that chronic inhalational exposure of animals
to high concentrations of PEP may cause an irritant response (Patty,
1967b). In more recent studies by Lawrence, et al. (1975) in which
groups of mice were exposed to air which was virtually saturated with
DEHP and POP vapors for two hours/day, three days/week, for 4-16 weeks,
no adverse toxicological or histological effects were found.
DMP may cause central nervous system depression in animals exposed
by inhalation over long periods of time (Autian, 1973).
Various effects of phthalates on the blood chemistry and enzyme
levels in exposed animals have been reported. DEHP fed in the diet at
levels of 0.5, 2, or 4% to groups of rats and mice for 1 or 4 weeks
significantly reduced the serum cholesterol and triglyceride levels, and
the authors associated this effect with observed increases in hepatic
catalase and carnitive acetyltransferase activities (Reddy, et aJU , 1976)
Lake, et al. (1975) associated liver weight gain in rats induced by DEHP
with decreased activities of microsomal glucose-6-phosphatase, aniline
4-hydroxylase, and mitochondrial succinate dehydrogenase, and Inouye,
et al. (1978) have reported results which suggest that DBP uncouples
3-55
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oxidative phosphorylation in vitro. Piekacz (1971) reported a statisti-
cally significant increase in serum alanine aminotransferase in rats fed
POP at 1 and 5% of the diet for three months, and a significant increase
in both alanine and asparagine amino trans f erases in rats fed the chemical
as 1% of the diet for one year. Pvoskin, e_t al. (1969) detected a
transient increase in gamma globulin and alterations in phagocytic
activity of neutrophils in rats exposed by inhalation to 0.2 or 0.4 mg/nr3
DBF for 2.5 months.
Several phthalate esters have been tested for their effect on hexo-
barbital- or pentobarbitone-induced sleeping time in mice and rats.
DEHP has been reported to prolong barbituate-induced sleeping time in rats
and mice (Rubin and Jaeger, 1973; Lawrence, et. al., 1975; Swinyard, et
al. , 1976; Seth, et al., 1977), although Hidaka, et al. (1977) reported
a decrease in hexobarbital-induced sleeping time in immature female
mice. Lawrence, et al. (1975) also reported that DMP, DBF, POP, DMEP,
and EPEG prolonged pentobarbital-induced sleeping time in rats. The
effect of PEP was equivocal, and DIBP decreased the drug-induced sleeping
time. BPBG also was reported to prolong the barbituate effect (Rubin
and Jaeger, 1973).
e. Permatological and Sensitization Studies
Alkyl phthalates have been reported to be essentially non- irritating
j
following dermal application to humans and most animals, and the
compounds do not appear to exhibit sensitizing potential (Autian, 1973),
but intradermal injections of the esters in rabbits have been reported
to produce significant irritant responses. Some of the relevant studies
reported in the literature are summarized in the following paragraphs.
Following 20 daily applications of 100 mg DBP, BBP, POP, and higher
ester phthalates to the skin of guinea pigs, Pueva and Aldyreva (1966)
reported minor irritation to the reticuloendothelial cells of the skin
only with the higher molecular weight compounds. Lawrence, et al. (1975)
tested PMP, PEP, DBF, DIBP, POP, PEHP, PNP, PIPP, PUP, PMEP, EPEG, and
BPBG as irritants by applying them to the eyes of rabbits. No obvious
irritation was observed for up to 48 hours after application.
3-56
-------
In contrast, the investigators tested the same group of compounds
for primary irritation by intradermal injection of the undiluted chemical
into rabbits followed by injection of a dye which will concentrate in an
inflamed region, and found DMP, PEP, and PMEP to induce a significant
degree of irritation. In a similar study in which phthalate esters were
injected as a suspension in 3% saline acacia solution, Galley, et al.
(1966) reported marked irritant responses to DMP, PEP, and PEHP, moderate
responses to PBP, PIBP, PMEP, and BBP, and mild response to dicapryl
phthalate.
f. Neurotoxicity
Neurotoxic effects of alkyl phthalates were observed in an epidemic-
logical study of 147 workers exposed to phthalate plasticizers used in
the manufacture of artificial leather and films that were based on
polyvinylchloride resins. Although the workers were exposed to very low
levels of other chemicals such as vinyl chloride, carbon monoxide, and
hydrogen chloride, the major contaminants of air samples within the factory
were the phthalates; in many cases the other chemicals were not even
detected. The duration of exposure of -workers to the phthalates ranged
from 1/2 to 19 years, with 93 workers exposed for more than six years.
Forty-seven workers (32%) were found to have polyneuritis, and the in-
cidence was higher among workers exposed for longer periods of time.
The main symptoms of the inflammatory disease were pain and numbness
in the extremities, depression of tendon reflexes, as well as some cases
of slight paralysis, degeneration, and fasciculation. In addition,
22 workers (15%) were reported to have functional disturbances of the
nervous system.
Workers exposed to the plasticizers also evidenced decreased sensi-
tivity to pain (66.7%), decreased sensitivity to vibrations (33.8%). and
depression of both vestibulosomatic and olfactory excitability (78, and
50 to 82%, respectively) (Milkov, et al., 1973).
3-57
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g. Behavioral Toxicity
In one study, DEHP appeared to depress two different activities in
rats. One group of animals had surgically implanted electrodes in the
hypothalmic pleasure center in the brain, so that the animals could
receive a pleasurable stimulus by pressing a bar. Two hours after an
intraperitoneal injection of 500 mg DEHP in saline acacia solution, the
rate of bar pressing was reduced to 30% of the untreated control rate,
while the rate among vehicle-treated animals was slightly lower than
controls (90% of the untreated control rate). The second group of rats
were metered for spontaneous running activity on a wheel during a 24-
hour period. Rats were given a single injection of 500 mg DEHP in saline
acacia solution, and the investigators observed that the activity of
vehicle-treated animals was only 60% of the activity of untreated controls,
while the activity of phthalate-treated animals was essentially completely
inhibited (5% of untreated control rate). The investigators noted that
although activity of the rats was decreased in these two studies by DEHP.
the animals did not seem to be anesthesized, but were reasonably alert
in response to outside stimuli (Rubin and Jaeger, 1973).
h. Metabolism
(1) Pharmacokinetics and Distribution
Alkyl phthalates are absorbed from the gastrointestinal tract, intra-
peritoneal cavity, and skin, as evidenced by their detection in tissues
such as liver and lungs following oral, intraperitoneal, or dermal
administration to animals (Autian, 1973). Daniel and Bratt (1974) found
that approximately half of an oral dose of DEHP was absorbed in rats,
the other half being recovered in the feces. Dermal absorption of the
phthalate esters appears to increase with decreasing molecular weight
(Autian, 1973).
The phthalates are removed from the blood rapidly, and the rate of
disappearance follows a biphasic pattern with a short initial half-
time of disappearance and a slower second phase. For example, Schulz
and Rubin (1973) measured the initial half-time (T^a) of disappearance
3-58
-------
of DEHP in rats given an intravenous injection of 0.1 mg/kg to be 4.5
minutes, followed by a second half-time (TjjP) of 22 minutes. The rate
of disappearance appears to increase as the dose level increases;
the initial half-time after a dose of 200 mgAg DEHP was 9 minutes.
These esters are widely distributed throughout the body. For
example, Schulz and Rubin (1973) reported that one hour after rats were
given an intravenous dose of 200 mg/kg of radioactively-labelled DEHP,
5% or more of the dose was detected in the liver, carcass, and spleen,
with lower levels present in the lungs, stomach and small intestines,
kidney, heart, and fat deposits, as well as trace amounts in the thymus,
brain, and testes. Several studies have indicated that the esters are
distributed mainly to the liver; Daniel and Bratt (1974) measured 38%
of a 600 mg/kg intravenous dose of DEHP in the liver of rats after two
hours, with 11% of the initial dose remaining after 48 hours. Distribu-
tion of phthalate esters to the lungs is highly variable, and appears
to depend on the particle size of the chemical preparation. Schulz and
Rubin (1973), for example, used DEHP in bovine serum albumin solution
which was sonicated to give a true solution, and they detected only low
levels of the labelled chemical in the lungs of rats. In contrast,
Daniel and Bratt (1974) used an emulsion of the compound in oleic acid,
and detected 26% of the dose (600 mg/kg, IV) in the lungs of rats after
two hours, with 8.5% of the dose remaining after 48 hours.
Daniel and Bratt (1974) reported that DEHP accumulated in the body
tissues of animals fed a diet containing the chemical over a number of
weeks, but the chemical reached a dose-dependent equilibrium tissue
concentration within 1-2 weeks. When the ester was removed from the diet,
its tissue concentration declined to a negligible level in 3-5 weeks.
For example, following administration of a diet containing 1000 ppm
labelled DEHP to rats, steady-state concentrations of the compound in
different tissues were: 40-50 ppm, liver; 7-9 ppm, fat? 1-6 ppm, heart;
and <1 ppm, brain. At a level of 5000 ppm in the diet, the concentrations
were: 120 ppm, liver; 80 ppm, fat; 15-20 ppm, heart; and 2-3 ppm, brain.
When the animals were returned to a normal diet, the half-time of dis-
appearance of the labelled compound from the liver was 1-2 days, and
from the fat, 3-5 days.
3—59
-------
14
Virtually all of the radioactivity from a single oral dose of C-
DEHP given to rats was recovered within seven days, distributed nearly
equally between the urine and feces (Daniel and Bratt, 1974) . When
Schulz and Rubin (1973) injected the labelled ester intravenously in
rats, approximately 17% of the dose was detected in the feces 24 hours
after injection, indicating that the chemical is excreted in the bile.
(2) Metabolic Modification
The initial stage of metabolism of phthalate esters by humans and
animals involving hydrolysis to the monoester appears to be the same as
that by fish and microorganisms (see Section B.8) . The studies
summarized below support the currently postulated mechanism of subsequent
w- and (o>-l) oxidation of the remaining alkyl chain.
Albro, e_t al. (1973) have studied the metabolites of DEHP in the
urine of rats receiving one or two oral doses of 0.2 ml of the radio-
actively-labelled compound. Four main metabolites were detected, all
of which were derivatives of monoethylhexyl phthalate, and these four
compounds with the percentages detected are shown in the metabolic
scheme below (Figure 2). The compounds result from o>- or (w-l)-oxidation
of the remaining monoethylhexyl ester. These reactions are presumed to
occur in the hepatic smooth endoplasmic reticulum, catalyzed by NADPH-
dependent enzymes (Gillete, 1966). Following w-oxidation, compound III
may then undergo 3-oxidation to yield compound IV. Hydrolysis of the
parent compound to the monoester may be catalyzed by pancreatic lipase,
since Daniel and Bratt (1974) found that when DEHP was incubated with
rat pancreatic lipase in vitro, 67% of the dose was hydrolyzed to mono-
ethylhexyl phthalate in one hour, and 77% had been hydrolyzed in five
hours. Hydrolysis by a rat-liver homogenate was also detected, but to
a lesser extent (8% hydrolysis after one hour). Albro and co-workers (1973)
detected no DEHP in the urine, and only 2.8% of the dose was recovered
as phthalic acid. The investigators also detected no glycine or glucuronic
acid conjugates of the parent compound or any of its metabolites.
In a similar study, Albro and Moore (1974) investigated the meta-
bolites of DMP, DBP, and POP in the urine of rats given the chemicals
3-60
-------
VB
O
II
C-OH
C-OCH_CHCH_CH
II
O
(I)
27%
(III)
39%
O
ll
C-OH
C-OCH
M
0
0
(I
,CH2CCH3
(ID
22%
C-OCHgCHCH-C-OH
(IV)
9%
Figure 2: Metabolism of DEHP in the Rat
Source: Based on Albro, et al.(19V3)
3-61
-------
by gavage. The major urinary metabolites of DMP were monomethyl
phthalate (77.5%) and phthalic acid (14.4%), as well as 8.1% unchanged
DMP. The major metabolite of DBF was monobutyl phthalate (89.8%).
Derivatives of this metabolite produced by u- and (u>-l)-oxidation (as
with DEHP) were also present in the urine at low levels (0.1-3.5%) , and
phthalic acid was detected at a low level (2.7%). POP appeared to
be metabolized in a manner very similar to DEHP. Although monooctyl
phthalate was virtually absent from the urine (0.1%), the metabolites
were all derivatives of the monoester which would be formed by u- or
(w-1)-oxidation of the remaining octyl chain, followed by successive a-
and B-oxidations.
Lake, et al. (1977) reported in vitro hydrolysis of DMP, PEP, DBP,
PCHP, POP, and PEHP to the monoesters by human intestinal preparations.
In a similar study with the same compounds, Rowland, et al. (1977)
reported that the rate of in vitro hydrolysis of the compounds to the
monoesters in the presence of rat small intestinal contents was greater
for the lower molecular weight compounds (PMP to PBP).
3-62
-------
CRESOLS AND CRESYLIC ACID
A. Summary of Physical and Chemical Data
1. Identification and Properties of Compounds
a. Structure and Nomenclature
This class of chemicals includes the following commercially signi-
ficant products: ortho-, meta-. and para-cresol, cresols (mixed), and
cresylic acid. The Chemical Abstracts Registry Serial Numbers the
molecular structures, the molecular formulas, and synonyms of these
compounds are shown in Table I.
The exact compositions of the mixed cresols and of cresylic acid
are not known. As defined by the U.S. International Trade Commission,
phenolic mixtures in which 50% boils below 204 C are called cresols, and
mixtures in which 50% boils above 204°C are called cresylic acids. These
products are not merely mixtures of the three cresols but are much wider
fractions of phenolic compounds derived from coal tar or petroleum,
which also contain phenol, xylenols , and other higher-boiling phenols.
b. Chemical and Physical Properties
(1) Chemical Properties
The cresols and cresylic acid react similarly to phenol. They are
mildly acidic, forming alkali-metal salts at about pH 10 which are
soluble in water and can be regenerated to the cresols by treatment with
mineral acids or carbon dioxide.
The cresols are readily substituted by both electrophilic and
nucleophilic reagents. The substituent groups add, where possible,
in the ortho- and para-posttions relative to the hydroxyl groups.
Although acidic, the cresols will form esters such as tricresyl phos-
plates with weak acids or acid chlorides.
Oxidation of the cresols yields different and generally complex
products depending on the oxidizing agent used. Catalytic reduction
with noble metals convert the cresols to methylcyclohexanols and/or
3-63
-------
Table I
Structure and Nomenclature of Cresols and Cresylic Acid
CAS Number
Name
(Chem. Abstr. Name)
Structure & Molecular Formula
Synonyms
95-48-8
ortho- Gresol
u>
a\
o-Cresol; 2-cresol; o-cresole;
o-cresylic acid;
l-hydroxy-2-methylbenzene ;
o-hydroxy toluene; 2-hydroxy-
toluene; o-methyl-hydroxybenzene ;
o-methylphenol ;
2-methylphenol ;
o-flnethyl-phenylol ;
o-oxy toluene; o-toluol;
o-tolyl alcohol
106-44-5
para-Cresol
p-Cresol; 4-cresol; p-cresole;
p-cresylic acid;
l-hydroxy-4-methylbenzene ;
p-hydroxy toluene ;
4-hydroxytoluene; p-methyl-
hydroxybenzene ;
p-methylphenol; 4-methy Iphenol ;
p-methyl-pheny lol ; p-oxytoluene;
p-toluol; p-tolyl alcohol
108-39-4
meta-Gresol
C7H8°
m-Cresolf 3-cresol; m-cresole;
m-cresylic acid;
l-hydroxy-3-methylbenzene ;
m-hydroxy toluene ;
3-hydroxytoluene ; m-methyl-
hydroxybenzene ; m-methy Iphenol ;
3-methy Iphenol ; m-methyl-phenylol ;
m-oxy toluene; m-toluol
m-tolyl alcohol
-------
Table I (Concluded)
CAS Number
(Chem. Abstr. Name)
Structure & Molecular Formula
Synonyms
1319-77-3
Cresols mixed
Mixture of the three isomers
Bacillol; cresoles;
hydroxy-methylbenzenes;
hydroxytoluenes; methyl-hydroxy-
benzenes;
methylphenols; methyl-phenylols;
oxytoluenes; ar-toluenols;
toluols; tolyl alcohols;
tricresols
u>
at
en
8006-62-0
Cresylic acid
Mixture of three isomers plus
phenol, other substituted
phenols, and xylenols
-------
methylcyclohexanones depending upon the catalyst and conditions used.
Treatment of cresols with hydrogen in the vapor phase over mixed oxide
catalysts generally results in conversion to toluene or benzene.
The three cresol isomers do not all possess the same degree of
activity when condensed with formaldehyde to produce cresol-formaldehyde
resins. The o- and p-isomers react more slowly than m-cresol , and give
less highly crosslinked products (McNeil, 1965).
(2) Physical Properties
Selected physical properties of the cresols and cresylic acid, where
available, are listed in Table II.
2. Known or Likely Contaminants
o-Cresol has been reported to contain the following contaminants:
phenol, m-cresol, p-cresol, and 2-xylenol. m-Cresol and p-cresol
probably contain the other isomers of cresol as contaminants. Mixed
cresols are likely to contain other phenols and cresylic acid is re-
ported to contain phenol, cresols, xylenols, and other higher boiling
phenols. Cresols and cresylic acid derived from coal tar and petroleum
may contain traces of pyridine bases and neutral oils (McNeil, 1965;
Hawley, 1978).
3. Composition of Mixtures
Cresols and cresylic acid are obtained primarily as isomeric mixtures
from the refining of coal tar acids and the thermal or catalytic crack-
ing of petroleum. The initial separation of the crude acids, in both
methods, yields a phenolic mixture which contains mainly cresols, phenols,
and xylenols. These may be separated further to meet a wide variety of
specifications and grades of either mixtures of cresols or or indivi-
dual isomers. Each manufacturer produces grades of cresols according to
mutually agreed upon customer specifications (McNeil, 1964).
As mentioned earlier, phenolic mixtures in which 50% of the material
boils above 204°C are called cresylic acids and mixtures in which 50%
3-66
-------
Table II
Physical Properties of Cresols and Cresylic Acid
o-Cresol m-Cresol p^Cresol
Description
Melting Point (°C)
Boiling Point (°C)
Density, d|°
Solubility
Water, g/100 g (°C)
Other
Colorless
crystals
30.8
191.003
1.0465
1.3 (0)
4.5 (104.5)
Soluble in
mineral oil
(2.5%), readily
soluble in
organic solvents,
vegetable oils,
diethyl ether,
and ethyl alcohol
Liquid at room White crystals
temperature
10.9 35.5
202.251 201.94
1.0341 1.0341
Mixed Cresols Cresylic Acid
solid or liquid solid or liquid
2.7 (50.8)
4.5 (92.2)
Readily soluble
in organic sol-
vents, vege-
table oils, and
ethyl alcohol
17.0 (35)
5.4 (105)
Miscible with
organic solvents,
vegetable oils,
diethyl ether, and
ethyl alcohol
11-35
50% <204
a
a
a
50% >204
a
0.2453
0.63 x 10-10
1.95
0.1528
0.98 x 10-10
1.95
0.1080
0.67 x 10-1°
1.95
Vapor Pressure
mm Hg (25°C)
Disassociation
Constant (Ka)
Lipid/Water
Partition Coefficient
(log P)b
Source:Compiled from several sources, including McNeil (1965); Hawley (1977); Hatch & Matar (1977); Windholz
(1976); and Sax (1975).
a. Similar to properties of a mixture of cresol isomers
b. In octanol (Machleid, et al., 1972; Dum & Hansch, unpublished data)
-------
boils below 204°C are called mixed cresols. The mixed cresols and
cresylic acids used for the manufacture of phenolic resins are available
in grades based on distillation range, minimum content of the meta- and
para-isomers, and maximum content of neutral oils and pyridine bases.
One commercial grade of refined cresylic acid has been reported to
have the following composition (by weight): o-cresol, 12-15%; m-cresol,
13-17%; p-cresol, 5-6%; phenol 8-9%; xylenols, 27-32%; and other phenols
27-32%.
Commercial mixed cresols contain about 20% o-cresol, 40% m-cresol,
30% p-cresol and small amounts of phenol and xylenols.
Although o-cresol can be separated from the others by fractionation
of crude tar acids, the meta- and para-isomers boil at nearly the same
temperature and consequently are frequently sold as mixtures. These
mixtures are commercially available from coal tar and petroleum refining
sources in a variety of grades. The grades are usually specified by
the minimum m-cresol content (e.g., 50 to 70%), distillation range,
neutral oil content (e.g., 0.25% maximum) and pyridine^base content.
The ortho-cresol appears to be the only isomer available in a
relatively pure state when produced from petroleum or coal tar.
Although there are no industry-wide specifications, this o-cresol is
generally available in four grades: 98.5-99.5% (minimum freezing point,
30.5°C); 97.5-98.5% (freezing point, 30.0-30.49OC); 95-97.5% (freezing
point, 29.0-29.99°C) and 85-95% (freezing point, 25-28.99°C). The
contents of neutral and basic impurities are restricted to 0.25% and
0.1%, respectively.
The US Pharmacopeia describes a mixture of cresols for use as a
reagent. The specification for this Reagent Grade cresol require that
90% distills between 195 and 205°C and that the specific gravity is
1.030-1.038.
3-68
-------
The National Formulary (Twelfth Edition, 1965) describes a mixture
of cresols, with the same specifications as the USP Reagent Grade, for use
as a disinfectant. This entry was included in N.F. XIII (1970) but was
not included in N.F. XIV (1975).
B. Summary of Data on Occupational and Environmental Exposure
1. Names and Locations of Producers
The cresol and cresylic acid products believed to be commercially
produced at the present time are listed in Table III along with the comp-
nies that produce them. These companies and the locations of their
producing plants are listed in Table IV. Additional data on the pro-
ducers of cresylic acid, including annual capacity and information on raw
materials is given in Table V.
The numbers in the columns in Table III refer to the sources used to
determine the commerciality of the chemicals (see footnote in Table III).
The 1976 edition of Synthetic Organic Chemicals was given first priority
since the minimum quantity which the International Trade Commission
requires for inclusion therein is 5000 pounds (or $5000 worth) per pro-
ducer. The requirements for the 1975 Synthetic Organic Chemicals and the
1977 Directory of Chemical Producres are 1000 pounds (or $1000 worth) per
producers.
2. Production and Trade Statistics
The reported total U.S. production of cresols and refined cresylic
acid in recent years are shown in Table VI and the reported U.S. imports
are given in Table VII.
In 1964, the last year for which separate exports data were reported,
U.S. exports of cresols and cresylic acid (natural and synthetic; code
512.80240) were reported to have been 10.5 million pounds. Since 1965,
cresols and cresylic acid have been aggregated in the code 512.0219 (Coal
tar and other cyclic intermediate acids, except phenol and isophthalic acid)
with more than 100 chemicals. Industry sources estimate that about 15 million
pounds of cresols and cresylic acid were exported in 1975. On January 1; 1978,
3-69
-------
U)
Chemical
Table III
U.S. Producers of Cresols and Cresylic Acid a'
1
o-Cresol*
m-Cresol
p-Cresol
m, p-Cresol Mixture
Mixed Cresols
Cresylic Acid*
7
7
6e
7
7
6Cfd
6C,d
7
6c,d
6C
6
6°
6C
6C
6*
6*
7
6d
7
6*
6
6«
5<
* Current production volumes given in Table V
a. Numbers in columns refer to the following sources;
6= 1976 Synthetic Organic Chemicals, U.S. Production and Sales
5= 1975 Synthetic Organic Chemicals, U.S. Production and Sales
7= 1977 Directory of Chemical Producers
See discussion in text for priority of these sources.
b. See Table IV for locations of producers
c. From coal tar
d. From petroleum
e. From sources other than coal tar
-------
Table IV
Location of U.S. Producers of Cresols and Cresylic Acid
Company
Continental Oil Co.
Fallek Chemical Co.
Ferro Corp.
Koppers Company, Inc.
«*» The Merichem Co.
^j
H
Mobil Corp.
The Sherwin-Williams Co.
Stimson Lumber Co.
Division
Conoco Chemicals Division
Pitt - Consol Chemicals
Alabama Western Chemical
Corporation, Subsidiary
Productol Chemical Division
Organic Materials Division
Mobil Oil Corporation
United States Division
Chemicals Group
Chemicals Division
Northwest Petrochemicals
Corporation, division
Location
Newark, N.J. 07105
Tuscaloosa, Ala. 35400
Santa Fe Springs, Ca. 90670
Follansbee, W. Va. 26037
Houston, Tex. 77015
Beaumont, Tex. 77704
Chicago, 111. 60628
Anacortes, Wash. 98221
United States Steel Corp.
USS Chemicals, division
Clairton, Pa. 15025
-------
I
-J
N>
Table V
Capacity and Raw Materials of Cresylic Acid Producers
Annual Capacity
(Millions of Founds)
Continental Oil Co.
Conoco Chems. Div.
Pitt-Consol Chems.
Fallek Chem. Co.
Alabama Western Chem. Corp.
subsid.
Ferro Corp.
Productol Chem. Div.
Koppers Co., Inc.
Organic Materials Div.
The Merichein Co.
Mobil Corp.
Mobil Oil Corp.
United States Div.
Newark, N.J.
Tuscaloosa, Ala.
Santa Fe Springs, Calif.
Follansbee, W.Va.
Houston, Tex.
Beaumont, Tex.
Stimson Lumber Co.
Northwest Petrochem. Corp. div. Anacortes, Wash.
United States Stel Corp.
USS Chems. div.
Clairton, Pa.
TOTAL
50
20
30
5
30
100
30
20
288
' Raw Material
Phenols and methanol
Petroleum
Petroleum
Phenols and methanol
Coal tar
Petroleum; recycles
cresylate spent
caustics and sulfide
spent caustics
Petroleum
Petroleum
Coal tar
Note: Capacity figures are for tar acids, including cresols and natural phenol, and represent ability
to produce tar acids provided feedstocks are available.
Source: Directory of Chemical Producers (1977), published by SRI International
-------
Year
1970
1971
1972
1973
1974
1975
1976
w
1
-J 1970
1971
1972
1973
1974
1975
1976
ortho-Cresol
23,110
22,736
49,668
24,741
23,354
20,481
22,187
10,492
10,322
22,549
11,232
10,603
9,298
10,073
meta-Cresol
> 2
> 2
> 2
> 1
> 1
> 1
> 5
(thousanc
>0-9
>0.9
>0.9
>0.45
>0.45
>0.45
>2.3
Table VI
U.S. Production of Cresols and Refined Cresylic Acid
(thousands of pounds)
Cresol
para-Cresol (meta-, para-mixture)
>
>
>
>
>
>
>
2
2
2
1
1
1
5
>0.9
>0.9
>0.9
>0.45
>0.45
>0.45
>2.3
41,007
39,182
28,292
31,377
> 4
> 4
>25
18,617
17,789
12,845
14,245
> 1.8
> 1.8
Refined
Total Cresylic
eeesol-a^»b Acid a
91,414
87,674
106,273
115,436
114,015
93,220
100,221
41,502
39,804
48,248
52,408
51,763
42,322
45,500
98,334
69,475
54,981
57,524
77,271
44,852
57,107
44,644
31,542
24,961
26,116
35,081
20,363
25,927
Source: Synthetic Organic Chemicals, US Production and Sales, Published by the US International Trade
Commission
a. Includes orth-cresol, meta-cresol, para-cresol, meta-, para-cresol mixtures, and ortho, meta-,
para-cresol mixtures from coal tar and petroleum sources.
b. Data for 1970-1974 include data for coke ovens and gas-retort ovens, reported to the Division of
Fuels Data, U.S. Bureau of Mines. Data for 1975 and 1976 exclude production from these sources.
The Bureau of Mines only reports that the combined value of "other tar derivatives" (including
cresoate oil, cresols, cresylic acid, naphthalene, phenol, refined tar, and tar paint) amounted to
$13.3 million in 1975 (1975 Bureau of Mines, Minerals Yearbook, Coke and Coal Chemicals Preprint, p.40)
-------
Table VII
I
-J
*•
U.S. Imports of Cresols and Cresylic Acid
(thousands of pounds)
Imports Through Principal U.S. Customs Districts
Total Imports
Year
1970
1971
1972
1973
1974
1975
1976
1970
1971
1972
1973
1974
1975
1976
meta-Cresol
2 _
2
82
223
311
60
101
(thousands
.9
.9
37
101
141
27.2
45.9
Source: Imports of Benzonoid Chemicals and
and US Imports
a. Described as o-
b. Described as ha
for Consumption and
i ID.— i p—» and m—,p— ,
ving 5% maximum boil
para-Cresol
2,059
5,671
4,970
5,209
7,505
4,741
4,248
of kilograms)
935
2,575
2,256
2,356
3,407
2,152
Cresol
(meta-, para-mixture)
5,341
14,743
9,083
5,886
9,917
7,079
2,425
6,693
4,124
2,672
4,502
3,214
Crude Cresylic
Cresols3 Acid b
7,707
20,416
17,702
11,188
19,720
10,574
4,610
3,499
9,269
8,037
5,079
8,953
4,801
1,929 2,083
Products, published by the US International Trade
General Imports
, published by the US
all having a purity of 75% minimum
.ing below 190°C and 75% boiling below
Department
215°C
7,900
5,000
4,200
800
300
600
300
3591
2273
1909
364
136
273
136
Commission;
of Commerce.
-------
the U.S. International Trade Commission established an industry code
(401.09) for the reporting of exports of cresylic acid (having a boiling
point of 204°C or above) . Thus, data on exports should be available in
the future.
3. Use Patterns
The 1976 consumption pattern for the cresols and cresylic acid has
been reported to be as follows:
Use Percentage
Phosphate esters 20
Magnet wire 15
Antioxidants 15
Resins 15
Export 10
Cleaning compounds 6
Ore flotation 6
Miscellaneous uses 13
TOTAL 100
*
Anonymous, 1976
Commercially produced phosphate esters based on cresols and cresylic
acids include tricresyl phosphate and cresyl diphenyl phosphate. Separate
production data for tricresyl phosphate (which is believed to be pro-
duced from the meta-/ para-cresol mixture and from cresylic acids) have
not been reported since 1973 but U.S. production in 1974 is estimated to
have been 56 million pounds (consuming an estimated 55 million pounds of
cresols or cresylic acids). Production of cresyl diphenyl phosphate in
1976 was reported as 4.5 million pounds (consuming an estimated 1.6
million pounds of cresols). These phosphate esters are used as flame
retardants with a secondary plasticizing function in polyvinyl chloride
and a number of other resins (McNeil, 1965; US International Trade
Commission, 1970-1976).
Cresylic acids are believed to be used as solvents for nylon and
other polymers in the production of magnet wire coatings.
3-75
-------
Antioxidants produced from cresols include 4-methyl-2,6-di-tert-
butylphenol (also known as 2,6-di-tert-butyl-p-cresol, butylated
hydroxytoluene, and BHT), 2,2-methylenebis(6-tert-butyl-p-cresol), and
2,2'-methylenebis-6-(l-methylcyclohexyl)-p-cresol derived from p-cresol
plus 4,4'-butylidenebis(6-tert-butyl-m-cresol), 4,4'-thiobis(6-tert-
butyl-m-cresol) and 1,1,3-tri(2-methyl-4-hydroxy-5-tert-butylphenyl)-
butane derived from m-cresol. The first of these antioxidants, BHT,
is believed to be the most important. In 1976, U.S. production of food
grade BHT amounted to 8.9 million pounds and 10.9 million pounds of
technical grade BHT were produced.(McNeil, 1965; US International Trade
Commission, 1976).
Consumption of cresols in phenol-formaldehyde type resins appears
to be limited to m-cresol (for resins used in molding compositions and
adhesives) and p-cresol (for oil-soluble resins) (McNeil, 1965).
Cleaning compounds are believed to include products marketed as
disinfectants for home and industrial uses. Although so-called generic
lysol (which is available in the United Kingdom and other countries)
contains cresol and soap, the tradename Lysol(R) products sold in the
U.S. do not contain cresols. No evidence was found that cresols them-
selves are components of commonly used cleaning formulations with the
possible exception of some stock and poultry cleaners, paint removers, and
products termed phenol disinfectants (Gosselin, ejt al., 1976).
Ore flotation agents made from cresols, or, more lifcely, cresylic
acids include dicresylphosphorodithioic acid and its ammonium and sodium
salts. These products are believed to be used as collectors for sulfide
ores of metals such as copper, lead, zinc, and antimony (Anonymous, 1976b),
Cresols and cresylic acid also find use in ore flotation as frothers
(Fuerstenau, 1962).
Miscellaneous uses of cresols and cresylic acids include their usage
as chemical intermediates for other chemicals as well as a variety of
applications for the chemicals themselves.
3-76
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A derivative of o-cresol, 2-chloro-4-nitro-o-cresol, is reportedly
used as an intermediate in the manufacture of sulfur dyes. Another
derivative, o-cresolinic acid has been reported to be used to produce
some cotton and azo dyestuffs (McNeil, 1965).
Cresylic acid has been reported to be used as a metal degreasing
agent but this could not be verified (McNeil, 1965).
The sulfonated derivatives of cresol formaldehyde condensates are
used as synthetic tanning agents (McNeil, 1965).
A major use of o-cresol is in the manufacture of the herbicides, 2,4-
dinitro-o-cresol (DNOC), and 2-methyl-4-chlorophenoxyacetic acid (MCPA).
U.S. consumption of MCPA is estimated to have been 3.9 million pounds in
1975. Very small quantities of p-cresol are used as a flavoring agent in
foods and in perfumes and some of its derivatives find use in this field
(McNeil, 1965).
3-77
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4. Occupational Standards and Workers Exposed
The U.S. Occupational Safety and Health Administration health
standards for exposure to air contaminants require that an employee's
exposure to cresol (all isomers) does not exceed an eight-hour time-
weighted average of 5 ppm (approximately 22 mg/m^) in the working
atmosphere in any eight-hour work shift for a forty-hour work week.
Based on the 1974 National Occupational Hazard Survey (NOHS) of plants
in selected industries, NIOSH has estimated the total number of workers
exposed to certain chemicals in these industries. The NIOSH estimate of
the number exposed to cresols is 1,913,823 people. Based on the avail-
able data, it is estimated that 32,000 people were exposed to ortho-
cresol, 9,000 to meta-cresol, and 14,000 to para-cresol.
5&6. Mode of Entry and Quantities Released into the Environment
Little quantitative data was located which estimated the amounts of
cresols and cresylic acid that are released into the environment.
In a recent review article, Gordon (1976) reported that no data on
ambient concentrations of cresols in air were found. He concluded that
the principal sources of cresol emissions to the atmosphere are the pro-
duction of cresols and coke and estimated that annual U.S. emissions of
cresol to the air amounted to 443 thousand pounds during cresol produc-
tion (231 thousand pounds from coal tar and petroleum-derived products
and 212 thousand pounds from synthesis of p-cresol) and 2,950 thousand
pounds during coke production. Based on a model for a hypothetical
plant producing 80 million pounds-per-year cresol, Gordon concluded
that the population living in the vicinity of cresol production plants
is at low risk of exposure to cresols.
This author also estimated that total annual emissions to waste
water from cresol production amounted to 244 thousand pounds (127 thou-
3-78
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sand pounds from coal tar and petroleum derived products and 117 thousand
pounds from synthesis of p-cresol).
No estimate was made by this author of the amount of cresols and
cresylic acid released into the environment as a result of the disposal
of these chemicals or products containing them.
Gordon (1976) pointed out that cresols occur in various substances
to which workers and the general population are exposed. He specifically
mentioned tea, fragrances/ (including ylang ylang and oil of jasmine),
tobacco leaves and smoke, marijuana smoke, and household disinfectants.
He does not estimate the quantities released from these sources.
3-79
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7. Environmental Transport
Little is known about the environmental transport of cresols, but
the most recent and relevant information available from a critical litera-
ture review and laboratory studies indicates that volatilization of
p-cresol is not important to its environmental fate. Smith et al. (1977)
calculated (by the methods of Mackay & Wolkoff, 1973) the volatilization
half-life for p-cresol from a lake to be 167 days, and estimated the
Henry's law constant to be 36 torr. Using the method of Hill et al.
(1976), these researchers measured the volatilization half-life of
p-cresol in aqueous solution to be about 160 hours at a moderate stirring
rate. The volatilization rate constants listed in the following table
indicate p-cresol is not very volatile.
TABLE VTII Volatilization Rate Constants for p-Cresol
Oxygen p-Cresol
reaeration volatilization
rate, k°r rate, k£ Ratio
Experiment 1 3.55 ± 0.24 (3.38 - 0.67) x 10~3 (0.95 i 0.25) x 10~3
Experiment 2 2.97 ± 0.21 (4.50 - 0.39) x 10~3 (1.5 - 0.24) x 10"3
Average (1.2 ± .3) x 1Q-3
Source: Smith, et al., 1977
These experiments noted that it was difficult to measure the volatiliza-
tion because biodegradation was so rapid (see Section B.8.).
No information was found on the volatilization of the other cresol
isomers or mixtures but it is probable that because their physical and
chemical properties are similar to those of para-cresol, their fates are
also similar to those of the para-isomer. (See Physical/Chemical
properties, Table I.)
Smith, et al. (1977) have also examined the distribution of the
para-isomer in water and concluded that both sorption and volatility are
unimportant in the transport of the chemical. The high solubility of
3-80
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cresols suggested that they will remain in solution and transport will
be governed by the hydrological factors in the water body (i.e.,
dilution, flow rates, et.).
Little is known about the sorption or transport of cresols in
naturally-occurring soils. Smith, et al. (1977) examined the sorption
of p-cresol on the clay, and sediments and measured a partition
coefficient (sediment/water) of 9.1 - 6.5 on sediment from a creek in
California. From their experiments, the authors concluded that p-cresol
will not be significantly sorbed onto sediments. The lack of sorption
and the rapid biodegradation indicate desorption from sediments will not
be a source of pollution over the long term. By extrapolation on the
basis on similarities in physical and chemical properties this may also
be true for the other cresol isomers.
No information was found in the literature on the bioaccumulation
of cresols.
8. Environmental Degradation
The major environmental degradation pathway for cresols is biodegra-
dation by soil and water bacteria (primarily Pseudomonas sp.), although
biodegradation by yeast, algae, higher plants, and mammals is also known
to occur. There are a multiplicity of degradative pathways, depending
on the species and particular isomer involved.
The common genus of bacteria, Pseudomonas, frequently occur in soil
and water, and degrade cresols either by oxidation of the methyl group
followed by ring cleavage, or by ring hydroxylation followed by ring
cleavage.
Dagly and Patel (1957) have shown that degradation of p-cresol by a
non-fluorescent Pseudomonas putida strain N.C.1.B.8893 is initiated by
oxidation of the methyl group; p-hydroxybenzaldehyde and p-hydroxybenzoic
acid are successive metabolites in the formation of the protocatechuic
acid that undergoes benzene ring fission. When cresols are metabolized
by certain fluorescent species of Pseudomonas, the ring-fission substrate
is a catechol with an unoxidized cresylic methyl group (Dagley, et al.,
1964; Ribbons, 1964). That is, p-cresol is oxidized by Pseudomonas U
3-81
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to 4-methyl catechol which is cleaved to form 2-hydroxy-5-methyl muconic
semialdehyde (Bayly, et al. , 1966; Dagley, et. a^. , 1964). Cell extracts
of Pseudomonas putida U have been reported to oxidize the semialdehyde
to 4-hydroxy-2-ketovalerate (Nishizuka, et aJU , 1962). In a similar
manner, o-cresol is oxidized to 3-methyl catechol and 2-hydroxy-6-keto-
hepta-2,4-dienoic acid by Pseudomonas aeruginosa strain Tl (Ribbons,
1964; Catelani, jet al. , 1968). Continued metabolism of the keto acid
by this strain results in 4-hydroxy-2-keto valeric acid and acetic acid
(Ribbons, 1966).
Pseudomonas putida metabolizes m-cresol to a meta-substituted
catechol (presumably 4-methyl catechol) and a ring-fission product by
opening of the ring between two carbons, only one of which is hydroxy-
lated (Hopper, et al., 1975). The fission product is probably 2-hydroxy-
5-methyl muconic semialdehyde.
Beyond the above studies with laboratory cultures of Pseudomonas,
several experiments have shown that the naturally occurring bacteria
degrade cresols in the same manner. A culture of mixed Pseudomonas sp.
isolated from soil, compost, or mud from a catalytic cracking plant
waste lagoon have been shown to degrade all cresol isomers (Chambers,
e_t al., 1963) . It has been estimated that there are 19 species of
naturally occurring fluorescent Pseudomonas capable of degrading cresols
(Cobb, et al., 1975; Olive, et al., 1976). The degradation is fairly
rapid, although somewhat slower than the degradation of phenol.
Kaplin et al. (1968), in a study carried out on samples of 5 liters
of river water containing 50 ml of effluent from a coking plant,
observed that phenol decomposed immediately but that the cresol isomers
required two days of "adaptation.11 Using cultures of Pseudomonas iso-
lated from a paint-stripping room, Olive, et al. (1976) determined that
optimum growth and cresol metabolism occurred at 35°C and pH 8.3; the
removal rate of cresol ranged from 0.72 to 2.96 g/hour on a glass column
filled with porcelain berl saddles and inoculated with a cell suspension
containing 1.8 g of the isolated culture of Pseudomonas.
In addition to species of Pseudomonas, other bacteria are known to
degrade cresols. Landa, et al. (1953) observed that an Escherichia coli
3-82
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strain cultivated from Moldavian water degraded p-cresol, although at a
rate two to five times slower than it degraded phenol. An obligate
thermophilic strain of Bacillus stearothermophilus (strain PH24), isolated
from industrial sediments, was reported to grow readily at 55°C using
the cresol isomers as the major carbon source (Buswell, 1976). Cell
extracts prepared from these cultures catalyzed the oxidation of o-
cresol to 3-methyl catechol and m-cresol and p-cresol to 4-methyl catechol.
Decomposition of o-cresol by a species of Achromobacter (generally this
genus occurs in soil or in fresh or salt water) has also been reported
(Glaus, 1964). Fourteen species belonging to the genera Achromobacter,
Micrococcus, and Vibrio are known to use cresols as carbon sources
(Kramer & Doetsch, 1950). But no information is available on the rate of
environmental degradation of cresols by these bacteria.
Certain fungi can also degrade the cresols. Landa, et al. (1953)
observed that an Oospora culture (a genus of imperfect fungi which is
associated with disease of citrus trees and potatoes) degraded cresols,
but more slowly than did Escherichia coli. The yeast Candida tropicalis
(commonly part of the normal flora of the skin, mouth, intestinal tract,
and vagina) has been found to degrade cresols only if sensitized by treat-
ment with phenol (Nei, et al., 1973; Hashimoto, K., 1973). The
metabolite from p- or m-cresol degradation by C_. tropicalis phenol-
adapted cells was isolated and identified as 5-formyl-2-hydroxy-4-methyl-
2,4~pentadienoic acid. The same compound was obtained when 4-methyl
catechol was used as a substrate. It was suggested by the authors that
p- and m-cresol are hydroxylated to form 4-methyl catechol, followed by
ring cleavage (Hashimoto, 1973). The oxidation of o-cresol at a slower
rate was also demonstrated. The yeast Trichosporon cutaneum can also
use the cresols as a carbon source (Neujahr and Varga, 1970).
Algae (.Nitella, Chara fragilis and Dodegonium) and higher aquatic
plants (Elodea canadenls and Myriophyllum) degrade p-cresol (Timofeeva,
1975). Under test conditions, p-cresol, at an initial concentration of
10"3M, disappeared entirely from the solution within 15-20 days, p-
Cresol was degraded faster than phenol in this test system, but more
slowly than pyrocatechol or hydroquinone.
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The importance of the rapid biodegradation of cresols in the environ-
ment has been demonstrated by the experiments of Smith, et al. (1977)
with p-cresol and mixed microbial cultures obtained from environmental
samples. Enrichment biodegrading systems were obtained with water
samples from several Northern California locations (including Coyote
Creek, a pond near Searsville Lake, aeration effluents from the Palo Alto
and South San Francisco sewage plants, aeration effluent from a Shell
Oil refinery wastewater treatment plant, and Lake Tahoe). There were
inductive (or lag) periods before p-cresol biodegradation began. For
example, in eutrophic pond water no significant biodegradation occurred
until 5.5 and 6 hours for concentrations of 3 or 10 yg/ml, respectively;
degradation was complete at 7 and 8.5 hours, respectively. For the
effluent from the Palo Alto sewage plant, total degradation at the 3
and 10 yg/ml p-cresol levels occurred at <4 and 6 hours, respectively.
In one experiment with pond water and extreme levels of 100, 300, and
1000 yg/ml p-cresol, the respective degradations and times were 100% at
<24 hours, 100% at approximately 32 hours, and 30% at 72 hours.
Apparently, the highest concentration inhibited or killed many micro-
organisms. The cultures from Lake Tahoe water, and Lake Tahoe water
mixed with sediment and allowed to settle, showed total decomposition
of 10 yg/ml p-cresol in <144 and <96 hours, respectively. On microscopic
examination and in a plating-out study of the Lake Tahoe cultures it was
obvious that many types of microorganisms were present. It is not known
how many of these were primary utilizers of p-cresol, or secondary
utilizers that grew on metabolites, or how many grew on excretion pro-
ducts associated with living or dying p-cresol metabolizers. These
mixed cultures are, however, more representative of conditions in nature
and probably include many of the microorganisms previously discussed.
In addition to biodegradation, photolytic degradation of cresols
may occur in the environment. Direct photolysis of p-cresol in water
at 254 nm gave 2,2'-dihydroxy-4,4'-dimethyIbipheny1 (I), 2-hydroxy-3,4'-
dimethyldiphenylether (II), and 4-methylcatechol (III) (Miller, et al.,
1977) .
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OH
OH
CH3
a
OH
CHa
CH.
III
Dye-senitized (methylene blue) photooxidation of mixed cresols in organic
wastes has also been reported, although the oxidation products have not
been identified (Sargent and Sanks, 1974); this is probably not
environmentally relevant because of the reaction conditions.
Based on their calculations and laboratory studies, Smith, et al.
(1977) suggested that photolysis is an important environmental degrada-
tion pathway for p-cresol, and probably for the other cresol isomers.
The half-life for direct photolysis of p-cresol in sunlight as a function
of the time of year was calculated by the procedure of Zepp and Cline
(1977) using the quantum yield of 0.079 and the measured UV absorption
spectrum of p-cresol; these data are plotted in Figure 1. It should be
noted that the experimentally measured half-life for the solar photolysis
of p-cresol is about 35 days (see Table IX, footnote e).
Smith, e_t al. (1977) have also shown that the presence of humic
acid in solution accelerates the photolysis of p-cresol by factors of
2-12 compared to photolysis in pure water. It was postulated that this
acceleration may arise from a sensitized photolysis in which humic acid
serves to transfer excitation energy to p-cresol; humic acid could act as a
photoinitiator (a triplet diradical, for example) that initiates a
radical oxidation process. Reaction products from photooxidation of
p-cresol in the presence of 4,4'-azo bis(4-cyanovaleric acid) were Pummerer's
ketone (IV) and 2,2'-dihydroxy-4,4'-dimethylbiphenyl (I); these were
identified by comparing retention time with those samples prepared by
literature procedures (Haynes, etal., 1956).
IV i
These two products accounted for only about 25% of the reacted p-cresol,
and after an initial photoperiod, the biphenyl began to decrease with
longer irradiation.
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00
3200
2800
2400
in
•8 20CX)
ul 1800
1200
800
400
0
1I1I\\III~T
I i I I
JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC
MONTH OF YEAR
FIGURE 1 ANNUAL VARIATION OF PHOTOLYSIS HALF-LIFE FOR £-CRESOL
Source: Smith, et al., 1977
-------
TABLE IX Rate Constants for Photolysis of 1.0 yg ml~l p-Cresola
Irradiation
source Solution
Extent of
reaction (%)
Rate constant
kpx 10~6 sec"1
Ratio of kp
with humic acid
to that in
pure water
Solar, in Pure water
April
Pure water with
9.5 yg ml~l humic
acid
32
93
0.68 ± 0.12b'c'd'e
8.0 ± 0.2d'f
12
a 1.0 ug ml"1 p_-cresol in water= 9.2 10~6 M.
k Standard deviation.
c Quantum yield for g-cresol disappearance was 0.079.
^ Calculated assuming 12 hours of sunlight per day; weather was mostly overcast
during the two-week reaction period. To obtain average ratio constant for
full calendar day (24 hours), divide rate constant by three.
e Half-life of 35 days.
f Half-life of 3.0 days.
Source: Smith, et al., 1977
Although no model ecosystem studies were found for o- or m-cresol,
Smith, et al. (1977) assessed the environmental fate of p-cresol using
computer calculations for a one-compartment model (water), following an
acute discharge (see Table X) , and for nine compartments during chronic
discharge to each of four types of water bodies (see Table XI).
TABLE X Transformation and Transport of j»-Cresol Predicted
by the Compartment Model
Process
Eutrophic Eutrophic Oligotrophic
River pond lake lake
Photolysis, half-life (hr)a
Biotrans formation, half-life (hr)
Half- life for all processes
except dilution (hr)
Half-life for all processes
including dilution
4,800
12
12
0.55
> 10,000
12
12
12
> 10,000
12
12
12
2,400
> 10,000
2,400
2,400
a Estimates are the average photolysis rates on a summer day at 40° latitude.
Photolysis rates in midwinter are at least three times slower.
Source: Smith, et al., 1977
3-87
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TABLE XI
DISTRIBUTION OK g-CKESUl IN VARIOUS AQUATIC SYSTEMS AT STEADY STATE
(input ioiu:unC rat luns nt i UK ml~' p-cresol)
I'oiiipartiiiunl I
(surl'ai-e w.ilurj
So lull tin
Suspended solids
'Uoiup.u IniviiL 2
(SUll.Kr Walcf)
So lut Inn
Suspended sol ids
r<>m|>, ii lim-iil i
(r.tii lui-e Water 1
,. Snl nil. in
| buspeudu>l solids
CD
CD
(.iniipai tniuiii t>
(l.ulCi)in water)
Solution
Suspended Solids
Comp.irUuMits 7-9
i if 21
S.ilutl.'ii
S.ili.l.,
" The amounts vlviin
lot su^iiendud sul
Pond River
Mass Cone . Mass Cone .
(kg) (tits B") (kg) (IIB K~l)
J.40 x 10" 1.70 \ 10"* 2.94 x 102 9.80 x 10"' 9
9.55 x 10~J 1.70 x 10"1 2.94 x 10"' 9.80 4
2.89 \ II)-1 9.66 x 10"' 6
J.89 x 10" ' 9.66 J
2.85 :v 10" 0.50 x 10"' 2
^.85 K 10"' -J.50 I
7
3
4.25 x 10"2 1.70 x I0~2 2.A1 9.65 x 10" 8
l.U x 10"' 1.70 x 10-' 1.95 x 102 9.65 1
tor solCd aiul solucion pliasus Lu Che sedioiuiir >:ooi|>ai (.incurs uro
ids anU niay hu overosl iui;il ud beu.iusu il was assumed Chat, blodegr
Eucropliic
Mass
(kn)
.44 3
.72 x 10"J 3
.02 2
.01 x 10"J 2
.49 :< 10"' 9
.24 x. 10" 9
.22 x JO"' 2
.61 x 15-' 2
.75 x 10" 9
. 30 9
estimated trom
lake
Cone .
(UK e")
.77 x 10"a
.77 x 10"
.40 x 10"
.40 x 10--1
.99 x 10"-
.99 x 10"J
.89 x I0's
.89 x 10—
.58 x 10"J
.58 x Itr2
die sorpc ion
Ollgolrophic lake
Mass COIH .
(k«) (,,K K"')
5. 32 x 10 2.20 x 10"'
2.66 x 10"2 2.20
1.55 x 10a 1.28 \ 10"'
1.60 x 10"' 1.28
1. 00 .-.i(\ ! .-".) \ 10" '
1 .50 x lo"1 I. JO
5.25 x 10 2.10 :t lO"2
2.62 x 10"' 2.10 x 10"'
8.29 x 10"' 9.48 x 10"2
1.29 < 10 9.48 s 10"
part il Inn c»'«t t Ii- ienl
aila l ton ol oorbed mateiial dou& n.ii nci-ur.
Source: Smith, et al., 1977
-------
From these results, the authors concluded that biodegradation is the
dominant transformation pathway in eutrophic waters, but it is four times
slower than photolysis in oligotrophic waters. Dilution was considered
important only in relation to biotransformation in rivers, and sorption
and volatilization were considered unimportant in all waters.
The nine-compartment environmental exposure model predicted (using
the half-lives predicted from the one-compartment model) the following
steady-state concentrations of p-cresol in solution, suspended solids,
and sediments near point sources in the presence of a discharge of 1
ml (1 ppm) p-cresol:
Half-life
(hr)
0.55
12
12
Solution
(ug ml-1)
0.980
0.017
0.037
Suspended
solids
(ug g"1)
9.80
0.17
0.37
Sediments
(ug g-1)
9.65
0.17
0.10
River
Pond
Eutrophic
lake
Oligotrophic 2400 0.0221 2.20 0.94
lake
Source: Smith, e_t al^., 1977
The half-life for p-cresol in the river is small in comparison to the
half-lives in other water bodies due to the higher flow rate used in the
river. The higher concentrations for the river are due to the larger amount
of p-cresol needed to achieve the initial concentration in the river simula-
tion, with the rapid flow removing p-cresol from the river segment before
biodegradation occurs. The half-lives of p-cresol predicted in these studies
suggested to the authors that p-cresol is not persistent, "as the term is
usually applied with respect to pesticides."
C. Biological Effects
1. Ecological Hazards
a. Toxicity to Wildlife
(1) Acute Toxicity
The cresol isomers are known to be directly toxic to fish, amphibians,
and aquatic invertebrates; they also have a high demand which results in oxygen
depletion of water and produces undesirable flavors in edible
3-89
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fish. Of the three isomers, the least toxic is m-cresoL, Reports for
the relative toxicity of o- and p-cresol are inconsistent (Mitrovic, et.
al., 1973). Data on the acute toxicity of the cresol isomers and phenol
were given by Albersmayer and Erichsen (1959) for several species over a
range of temperatures of 13-19QC, as follows:
Approximate 24-hour LCso (mg/1)
Phenols
Phenol
0-crcsol
m-cresol
p-crcsol
Crucian carp
25
30
25
21
Roach
15
16
23
17
Tench
17
15
21
16
"Trout" embryos
5
2
7
4
Source: Albersmayer & Erichsen (.1959)
Pickering and Henderson (1966) reported the 96-hour LCso of o-cresol
for goldfish as 17-31 mg/1 at 25°C. The 96-hour LC50 of o-cresol channel
catfish was reported as 66.8 mg/1 (Clemens and Snad, 1959). For rainbow
trout, the 96-hour LCso at 10°C was reported to be 3.2 to 5.6 mg/1 for
cresylic acid (Webb, et al., 1976). Cresylic acid has also been reported
to be acutely toxic to Pacific salmon (chinook, silver, and pink species)
over a concentration range of 3.12 to 6.98 mg/1 during a three-day expo-
sure in both fresh and salt water (Hawley, 1972).
The isomers of cresol incapacitate fish and fish may tend to avoid
localized concentrations of the chemicals. p-Cresol is the most active
of the three isomers in inducing total incapacitation of trout (Rowland,
1969). Bucksteeg, et al. (1955) found that the threshold concentration
for loss of coordinated movement in perch was 10 mg/1. Minnows have
been reported to avoid 400 mg/1 of p- and o-cresol but not lower concen-
trations (Jones, 1951).
The cresol isomers are also toxic to .amphibians. Both
m-cresol and p-cresol were lethal to frogs bu subcutaneous injection with
dosages of 250 mg/kg and 150 mg/kg, respectively (Specter, 1955). The
3-90
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lowest lethal subcutaneous doses in the frog for the para- ortho-, and
meta-isomers have been reported to be 150, 200, and 250 mg/kg respectively
(Anonymous,, 1935).
The cresols are also toxic in laboratory studies to non-target
invertebrates. In the fresh water crustacean Daphnia sp., 100% mortality
occurs within 72 hours at a cresylic acid concentration of 0.1 mg/1
(Hawley, 1972). Ellis (1937) has reported a lethal concentration to
13. magna of a mixture of cresols to be 0.01 mg/1.
Studies reviewed by Mitrovic et al. (1976) indicate that, as in
fish, m-cresol is the least toxic of the isomers to Daphinia sp. and
p-cresol, the most toxic isomer (Bringmann and Kuhn, 1959a,b;
Albersmayer & Erichsen, 1959). The minute aquatic crustacean Cyclops^
strenuus and the ostracod Pionocyprus vidua are also sensitive to cresols
but no data on these studies are available (Albersmayer & Erichsen, 1959) .
Emery (1970) determined that for Gamtnarus fasciatus and Asellus
militaris (species of benthic crustaceans) concentrations below
0.525-0.70 mg cresols/1 water were not acutely toxic. Exposure periods of
48 hours revealed that adult asellids were about twice as tolerant to cresols
(mean TL^S 65.1 mg/1) as adult gammarids (mean TL^S 31.1 mg/1) , and
immature asellids were about four times as tolerant (mean TL^8 33.3 mg/1)
as immature gammarids (mean TL^S 3.6 mg/1) . Cresols are also known to
be effective nematocides for soil incorporation (Establissements, 1972,
1974)..
An overall aquatic toxicity rating of 10-1 ppm has been assigned
to cresol (Christensen, 1977). This figure is derived from a bioassay
conducted under static or continuous flow conditions with a variety of
organisms (.e.g., finfish, shrimp). Using a system of ranking outlined
in Appendix A Can excerpt from Christensen, 1977) . the above value can be
described as highly toxic.
(.2) Reproductive System Effects
No information was found on the reproductive effects of cresols.
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b. Toxicity to .Plants
There is some evidence that cresols can be toxic to
plants. Mixed cresols have been reported to be toxic to green algae
(Scenedesmus quadricauda) in a cell multiplication inhibition test, but
the data were not available (Bringmann and Kuehn, 1977).
o-Cresol has been reported to be toxic to the algae Nitella sp.
.(Stom and Beim, 1976)- At 1/32 saturation, o-cresol stopped the move-
ment of protoplasm within 15 minutes.
Chlorosis in Lemna minor (common duckweed)is also known to be pro-
duced by o-cresol (Blackman, e_t al., 1955).
One study suggested o-cresol affects the reproductive process of
germination by effectively breaking dormancy for barnyard grass (Echino-
chloa crusgalli var oryzicola). The meta- and para-isomers were in-
effective (Shimizu, et aJ., 1972).
c. Toxicity to Microorganisms
The cresol isomers are known germicides (Berry, 1951; Khoroshavin,
et al^., 1971; Kaye & Proudfoot, 1971; Bean & Dempsey, 1971) capable of
damaging non-pathogenic microorganisms in the environment, although, as
noted in Environmental Degradation (Section B.8.) they can also serve as
the carbon source for a variety of organisms. The meta-isomer is the
most active against most common bacteria, especially the acid-fast
bacteria (Gurney, 1972). The antibacterial activity of all the isomers
is considerably decreased in the presence of soaps (as in generic lysol
which is 50% solution of mixed cresols in soap) (Gosselin, et al., 1976) .
m-Cresol at a concentration of 1,000 yg/ml inhibited the growth of
Escherichia coli about 50% with no effect on cell size (Loveless, et al.,
1954). Mixed cresols have been reported to be toxic to Pseudomonas putida
in a cell multiplication inhibition test, but no data are available
(Bringmann and Kuehn, 1977).
All the cresol isomers are also toxic to the ciliates Paramecium
caudatum {Halsband and Halsband, 1954) and Microregma heterostoma
(Bringmann and Kuehn, 1959).
3-92
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Ortho-Cresol has been reported to reduce the rate of radial spread
of the mycelium of the fungi Trichoderma viride (Blackman, et al., 1955 ) .
Cresols have been reported to be used as fungicides (Chakravarty and
Baruah, 1970; Takahashi, 1972).
Cresols can also be toxic to viruses. Fixed rabies virus was com-
pletely inactivated in vitro by a 0.6% solution of p-cresol (Spicher and
Timm, 1973). Cresols have also bee reported to kill AHC entrovirus but
not Poliovirus, Coxsackie virus B-5, or Echo virus-7 (Watanabe, et al.,
1975).
2. Effects Related to Human Health Hazards
a. Carcinogenicity
(1) Animal Data
No adequate tests have been reported demonstrating that any of the
cresols or cresylic acid are carcinogens. Each of the three isomers,
o-cresol, m-cresol, and p-cresol, have been found active as mouse skin
tumor promoters (Boutwell, 1967). In these experiments, twice weekly
applications of a 10% solution of the cresol in benzene were delivered
to the skin of mice, beginning one week after initiation by a single
topical application of 75 yg of 7,12-dimethylbenz(a)anthracene (DMBA).
By 24 weeks after initiation, the incidence of skin papillomas approached
100% for each of the three isomers of cresol. For mice receiving either
a single application of DMBA alone, twice weekly applications of only
a 10% solution of the cresol in benzene without prior DMBA treatment,
or DMBA followed by twice weekly applications of benzene only, the
incidence of skin tumors was insignificant.
As part of a study of the tumor-promoting activity of subtractions
of cigarette smoke condensate, an acetone solution of a synthetic dis-
tillate of known composition containing 0.204% phenol, 0.037% o-cresol,
0.035% m-cresol, 0.070% p-cresol, 0.017% 2,4-xylenol, 0.028% 3,5-xylenol,
and 0.027% guaiacol was tested on mouse skin and compared to the
3-93
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activity of the cigarette smoke condensate (Bock, et al., 1971). The
mice were initiated with a single topical application of 125 yg DMBA
and, beginning three weeks later, were painted five times a week with
0.25 ml of the synthetic distillate solution. After 56 weeks of testing,
skin tumors were observed in 7 of 35 survivors. No skin tumors were
observed in 25 surviving controls that received DMBA followed by acetone
only. In a second experiment as part of the same study, an acetone
solution containing 0.231% phenol, 0.055% o-cresol, 0.045% m-cresol,
0.090% p-cresol, 0.026% 2,4-xylenol, 0.052% 3,5-xylenol, and 0.042%
guaiacol was tested similarly. The incidence of skin tumors in this
experiment was not signficantly different from pooled negative controls
painted with DMBA and acetone only.
(2) Human Data
There have been no reports of a direct association between human
cancer and chronic exposure to cresols. Cresylic acid is obtained from
coal tar which is a recognized cancer hazard in humans (Hueper and
Conway, 1964). Similarly, creosote (including both wood creosote and
coal creosote), a mixture containing phenols and cresols, including
2-methoxy-p-cresol, and aromatic hydrocarbons, is a recognized carcino-
gen in humans (Hueper and Conway, 1964).
A clinical observation has been made of two patients with multi-
focal transitional cell carcinoma of the bladder (Garrett, 1975). Both
patients had chronic exposure to cresol and creosote but details of their
exposure to other chemicals or smoking habits were not revealed.
One study has been reported of the health hazards associated with
coal hydrogenation processes in which the potential exists for the
environmental discharge of considerable quantities of hazardous materials
including cresols (Wadden, 1976). In this study of a group of workers
at a coal liquefaction plant, skin cancer was found in 10 out of 359
3-94
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workers examined over a five-year period. This incidence was considered
16 to 37 times the incidence of skin cancer expected in the chemical
industry. Analysis of the liquids produced in this plant revealed a
number of materials found to be carcinogenic in laboratory animals.
High levels of benzo(a)pyrene (as much as 18,000 yg/1000 m3), a recog-
nized carcinogen, were also identified by air measurements in working
areas. The specific presence of cresylic acid or any of the three
isomeric cresols was not noted.
b. Mutagenicity
There were no mutagenicity data for cresols reported in the litera-
ture (EMIC, 1978) but there are two reports indicating that they may be
capable of producing genetic damage. Chromosome fragments were seen in
onion roots (Allium cepa) treated with the various cresol isomers (con-
centrations 0.1 to 0.00001 moles/liter for 4-24 hours (Levan and Tjio, 1948;
c. Teratogenicity
No information was found on the teratogenicity of cresols.
d. Systemic Toxicity
(1) Human Data
The toxicity of the cresols to humans is very similar to that of
phenol (Gosselin, et aJL, 1976; Hamilton and Hardy, 1949; Deichmann and
Keplinger, 1963). In the older literature it was common to group cases
of phenol, cresol, and cresylic acid poisoning together (Bruce, et al.,
Isaacs, 1922; Roster, 1943). It is now believed that the toxicity of
mixed cresols and the met a isomer are somewhat less than that of phenol,
while OT-cresol is more toxic than m-cresol and p-cresol is the most
toxic of the isomers (Fairhall, 1957).
Cresols are potent primary corrosive irritants (Gafafer, 1964,-
Deichmann and Keplinger, 1963), and there have been several reports of
severe systemic damage produced by cresol-containing substances follow-
ing acute exposures by inhalation, skin absorption, or ingestion.
3-95
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In general, the systemic damage produced by the cresols in humans
arises primarily from effects on the central nervous system; this damage
can include muscular weakness, gastrointestinal distress, severe depre-
ssion, convulsions, respiratory distress, collapse, and death. Also
it is not uncommon to see kidney, liver, pancreas, heart, and spleen
damage, with albuminuria and hematuria (Deichmann and Keplinger, 1963;
Plunkett, 1976).
There have been reports of systemic damage resulting from acute dermal
or inhalational exposure to cresols. Cason (1959) reported the case of a
47-year old man who fell into a vat of "ardox" (a cresylic acid derivative).
Although he was quickly removed and washed thoroughly under a shower, six
hours later he was found to have apparently superficial burns over 15%-of his
lower body. Thirty-six hours after the accident anuria developed indi-
cating toxic amounts of cresylic acid had been absorbed. Apart from
renal insufficiency, he remained satisfactory until the seventh day when
he developed respiratory distress. On the tenth day he became unconscious
and developed congestive heart failure and died within 18 hours of becoming
comatose. Green (1975) reported a similar case of fatal cresol poison-
ing from skin absorption of the cresols in Wright's Coal Tar Vaporizer
(90% cresols in water). In the report, a 12-month old boy was exposed
five minutes to about 20 ml of this fluid poured in his head. The boy's
mother washed the fluid off with soap and water and took the boy to the
hospital. within ten minutes because he was "blue in the face.:" On
admission, the boy was deeply unconscious, shocked, and cyanosed. He
died in a coma four hours later. The autopsy report revealed burns on
7% of the body, but not on the lips or tongue, and there was no evidence
of inhalation. Histology showed early acute kidney necrosis, extensive
centrolobular and midzonal liver necrosis, and edema in the brain. In
another report, a six-year-old child died after being contaminated
(45% of his body surface) with undiluted generic lysol (Ferry, 1965).
Histologic examination of the kidney suggested a direct nephrotoxic
action in the proximal tubule. Absorption of cresols through the
mucous membranes of the vagina resulted in the death of a woman within
six days following use of lysol as a douche. The death was the result of
pulmonary edema and renal tubular necrosis (Finzer, 1961).
3-96
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There have been a number of reports on acute poisoning from inges-
tion of products containing the cresol isomers. Bruce, et^ al_. (1976)
have reported two cases of fatal poisoning from the ingestion of unknown
amounts of the popular disinfectant lysol (a mixture of cresols and
soap). In both cases there was brown discoloration of the face and
mouth and there was extensive necrosis of the esophageal mucosa. The
most striking pathological changes were in the liver and renal cortex
where there were large accumulations of lipofuscin. Fisher (1955)
reported on an adult male who had ingested one half pint of generic
lysol. The initial signs of poisoning were a deep coma punctuated by
periods of restlessness. There was pharyngeal edema, jaundice with
elevated serum bilirubin, and a low platelet count, but the man eventually
recovered. Two Chinese females who ingested 100 ml and 250 ml of lysol
(containing 50% cresols) suffered coma, methemoglobinemia, Heinz bodies
and evidence of massive intravascular hemolysis as reported by Chan,
et al. (1971). The patient ingesting the larger dose died. Simpson
(1932) reported the case of a male who ingested about 75 ml of a 50%
mixed cresol ("trieresol") solution. About five to eight hours follow-
ing ingestion, the patient died. The post mortem examination revealed
acute necrosis of the pancreas, and gastric mucosa.
Limited reports from industrial situations suggest that systemic
damage may also occur after chronic exposure to-:cresols. Workers
engaged in the manufacture of enamel-coated wire and exposed to cresol
vapor and heat were reported to have increased heart rates but no ''severe
ill effects11 (Yamaguchi, 1970) . Workers engaged in the production of
triaryl phosphates and exposed to cresols as well as to phenol, and to
tricresyl, triphenyl, and trixylyl phosphates, showed some systemic
toxicity. The first stage of toxicity (which in some cases, developed
after 2-3 years) was characterized by a perivascular form of polyneuritis.
Often this was accompanied by decreasing activity of plasma cholinesterase
and chronic gastritis. The second stage showed toxic encephalopathy,
hypophthalamic syndrome, and polyneuritis (Aizenshadt, 1975).
Very early reports of industrial cresol poisoning cited liver and
kidney damage, and secondary lesions of the heart and brain as the most
3-97
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TABLE XII
Acute Toxicity of Cresols in Experimental Animals
CHEMICAL ROUTE LETHAL DOSE
p-Cresol Oral LD50: 207 mgAg
LD50: 1800 mgAg
LD50: 1460 mgAg
LD50: 344 mgAg
LD10: 620 mgAg
Dermal LD50: 750 mgAg
LD50: 301 mgAg
LD50: 3600 mgAg
Subcutaneous LDio: I50 mgAg
LD10; 80 mgAg
LD1Q: 300 mgAg
Intraperitoneal i&io'- 100 mgAg
Intravenous u>lo: 18° "g/^g
o-Cresol Oral LD50: 121 mgAg
LD50: 1350 mgAg
LD50: 1470 mgAg
LD50: 344 mgAg
LD10: 940 mgAg
Dermal LD50: 620 mgAg
LD50: 1380 mgAg
Subcutaneous ^10 : 41° m9/^9
LD10: 55 mg/kg
LD1Q: 450 mgAg
Intraperitoneal L^io* 36° mgAg
Intravenous LD-m: 180 mgAg
±\J
m-Cresol Oral LD50: 242 mgAg
LD50: 2020 mgAg
LD50: 2010 mgAg
LD50: 828 mgAg
LD : 1400 mgAg
SPECIES
Rat
Rat
Rat
Mouse
Rabbit
Rat
Rabbit
Rabbit
Mouse
Cat
Rabbit
Guinea pig
Rabbit
Rat
Rat
Rat
Mouse
Rabbit
Rat
Rabbit
Mouse
Cat
Rabbit
Guinea pig
Rabbit
Rat
Rat
Rat
Mouse
Rabbit
REFERENCE
Industrial Bio Test
Laboratories
Deichmann S Witherup, 1944
Uzhdavini, et al . , 1974
Uzhdavini, et al., 1974
Deichmann & Witherup, 1944
Uzhdavini, et al. , 1976
Industrial Bio Test
Laboratories
Denirie, 1973
Anon. , 1935
Deichmann fi Witherup, 1944
Anon. , 1935
Anon. , 1895
Deichmann & Witherup, 1944
Industrial Bio Test
Laboratories
Deichman & Witherup, 1944
Uzhdavini, et al^. , 1974
Uzhdavini , et al . , 1974
Deichmann & Witherup, 1944
Uzhdavini , et al. , 1976
Industrial Bio Test
Laboratories
Anon. , 1909
Deichmann & Witherup, 1944
Anon . , 1935
Anon., 1935
Deichmann & Witherup, 1944
Industrial Bio Test
Laboratories
Deichmann & Witherup, 1944
Uzhdavini, et al . , 1974
Uzhdavini, et al., 1974
Deichmann & Witherup, 1944
3-98
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Table XII (Cont'd)
Acute Toxicity of Cresols in Experimental Animals
ROUTE LETHAL DOSE SPECIES REFERENCES
Dermal LD50: 1100 mgAg Rat Dzhdavini, et_ al., 1976
LD50: 2050 mgAg Rabbit Industrial Bio Test
Laboratories
Subcutaneous ^lO* 450 mgAg Mouse Anon., 1935
LD10: 180 mgAg Cat Deichmann & Witherup, 1944
LD1Q: 500 mgAg Rabbit Anon., 1935
Intraperitoneal I^io8 100 mgAg Guinea pig Anon., 1935
Intravenous LD10: 28° "gAg Rabbit Deichmann & Witherup, 1944
Mixed
Cresols Oral LD50: 1454 mgAg Rat NTIS PB225-283
LD50: 861 mgAg Mouse NTIS PB225-283
3-99
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common manifestations of toxicity (International Labor Office, 1930;
Duvoir, et aJU , 1938), but detailed analyses of these cases are not
available.
(2) Animal Data
The toxicity of cresols is very similar to that of phenol in experi-
mental animals on both acute and chronic exposure (Deichmann and
Keplinger, 1963). As in humans, acute exposures by all routes of
absorption may cause central nervous system depression, muscular weak-
ness, gastroenteric disturbances, convulsions, and death. The acute
toxicity of the cresols is summarized in Table XII.
The pathological changes induced by exposure to cresols include
irritation, hemorrhages, destruction of the gastrointestinal lining
(following oral administration) , kidney tubule damage, nodular pneumonia,
and liver damage (Deichmann and Keplinger, 1963 ; Plunkett, 1976).
Deichmann and Witherup (1944) have reported the acute oral toxicity
of the cresols in rabbits and rats. When administered orally to rats in
the 10% solutions in olive oil, o-cresol was the most toxic, and was
followed by p-cresol, and m-cresol (Table XII). When given orally
to rabbits in the form of 20% aqueous emulsions, the most toxic were p-
and o-cresol; m-cresol was the least toxic. Signs and symptons of
poisoning in these animals included weakness and collapse, convulsions,
and coma. On the whole, the convulsions were less severe than those
produced by phenol, but the cresols resulted in deeper coma. Campbell
(1941) reported that "the higher-boiling petroleum cresylic materials
were less toxic when ingested by white mice than the low-boiling cresylic
materials."
The cresols are very corrosive and their immediate effect on skin
is frequently severe burning; however, toxic amounts have been shown to
be absorbed through the skin of rats (Uzhdavini and Gilev, 1976), mice
(Uzhdavini, _et al., 1974), and rabbits (Industrial Bio-Test Laboratories)
(Table XII). Rats poisoned by dermal exposure showed hemorrhagic,
dystrophic changes in the liver, kidneys, and myocardium (Uzhdavini and
Gilev, 1976).
3-100
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Several studies have shown that acute exposures to cresols by in-
halation can result in severe systemic damage. Uzhdavini, e_t a^. (1972)
observed irritation of the mucous membranes, convulsions, and hematuria
in mice given a single exposure (for an unspecified time) to a mixture
of o-cresol vapor and aerosol (amounts not given). Histological examina-
tion showed lung, liver (including centrolobular necrosis), and kidney
damage in mice that survived the acute poisoning. Similarly,
Uzhdavini, et al. (1974) observed that all the cresol isomers produced
convulsions in mice acutely exposed to vapors and aerosol (unspecified
amounts). It should be noted, according to the authors, that the
airborne cresol also precipitates on the skin of the animals and is
absorbed through the skin. Pereima (1977) reported that p-cresol was
the most toxic isomer when inhaled by rats and that m-cresol was the least
toxic (no data were available).
Experiments in which animals were exposed by parenteral routes have
shown that o-cresol is the most toxic isomer following acute exposures
and m-cresol is the least toxic (Table XII). Deichmann and Witherup
(1944) injected cats with a single subcutaneous dose of the cresols as
10% solutions in olive oil with the following results (one animal was
used at each dose):
PME
(»./»(•
0.024
0.030
0.035
0.080
0.12
0.1S
0.28
0.42
0.02
0.04
••ClUOt
M-TICML I fciaoi
' lunnlHltntk • .
survived
survived '
60
GO
2!?
S.5
3
7
4
mirvivcd
survived
27
4
12
7
5.5
.
survived
survived
120
34
21
4.5
10
S
7
Sourcei Deichmann & Witherup, 1944
When single intravenous dose.(10.5% aqueous solutions) were given to
rabbits by these same investigators, a similar relative toxicity was
observed:
OOSK
!-./*».
o.os
0.12
0.18
0.2S
0.42
••CBCIOL
•-CBttOl
FOUOt
trart Hit talk
survived
survived
8
10
survived
survived
15
7
survived
survived
15
10
Source: Deichmann & Witherup, 1944
3-101
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There is only limited information on the chronic toxicity of cresols
in experimental animals (also see Carcinogenicity Section C.2.a). In a
Subchroriic study, Uzhdavini, et al. (1972) exposed mice two hours per day,
six days per week, for one month to o-cresol vapor and aerosol concentrations
fluctuating from 26 to 76 mg/m3, and averaging 50 mg/m3- After 18-20 days,
the ends of the tails of some of the mice had mummified and fallen off.
At the end of this experiment, microscopic examination of the central
nervous system showed plethora and dystrophic changes of the nerve cells
and glial elements. Other pathological changes included: respiratory
tract edema, lung hemorrhages, catarrhal bronchitis, dystrophic changes
in the myocardium, and "protein dystrophy" in the liver and kidneys.
Rats and guinea pigs were exposed to o-cresol vapor (two months, six
hours per day, five days per week, and two months, four hours per day,
five days per week) with a mean concentration of 9- 0.9 mg/m3. Signs
of toxicity in rats included: an increased number of leukocytes in
males; some irritation of the hematopoietic tissue (namely the red
portion of the bone marrow); disruption of liver function; and a slight
decrease in the activity of the pituitary-adrenal system. In guinea
pigs there was an increase in the number of eosinophils. Morphological
studies showed symptions of irritation in the upper respiratory tract,
and inflammation, edema, and perivascular sclerosis in the lungs in
both species. Kurlyandskii, et al. (1975) reported that chronic expo-
sure (time not reported) of rats to 0.5 mg/m3 mixed cresols decreased
the level of gamma-globulin in the serum, increased excitability of
the central nervous system, and caused functional changes in the lungs
and liver, but no supporting data are available.
e. Dermatological and Sensitization Studies
(1) Human Data
As previously noted,-the cresols are strong corrosives. Cutaneous
application causes local tissue corrosion, burns, and dermatitis.
Certain individuals are hypersensitive to cresols (Deichmann and
Keplinger, 1963). There have been numerous cases of burns and skin
corrosion from acute contact with cresols in the industrial environment
(Anon., 1940; Goodman, 1933; Zalecki, 1965). Berwick and Treweek (1933)
3-102
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reported a case of burning and/or sensitization from dermal contact with
cresols-in which a patient was exposed for two hours to an anesthesia
mask which had been sterilized a week previously in a solution con-
taining approximately 10% of a "compound solution of cresol." When the
mask was removed, there was marked erythema of the face. This became
worse, with blistering of the skin. Scarring from the burns was still
present one year following the accident. The authors determined that
the mask could have contained from 21.1 to 64.2 mg of cresols. In
another study, p-cresol tested at a 4% concentration in petrolatum pro-
duced no sensitization or irritation reactions in 25 volunteers (Kligman,
1966; Kligman, 1972) after a either a "maximization test or a 24-hour
closed patch test."
(2) Animal Data
Cresols also have dermatological effects in experimental animals.
When p-cresol was applied full strength to intact or abraded rabbit skin
irritation was produced (Denine, 1973). When applied to the skin of
rats (at the LD5Q concentrations), the various cresols produced skin
necrosis (Uzhdavini and Gilev, 1976). p-Cresol has been identified as •-.
the active chemical in a laundry ink which caused depigmentation of hair
in mice (Shelley, 1974). The mice in the experiment were treated
topically three times a week for six weeks with a 0.5% p-cresol solution
in acetone following plucking or clipping of the hair. It has been
suggested that the structure of p-cresol may mimic the structure of
tyrosine, the amino acid building block for melanin, and, thereby,
inhibit the production of melanin. The authors believe it is more
likely that tyrosinase acts on p-cresol to form free radical derivatives
that may initiate lipid peroxidation with consequent permanent damage
to or destruction of melanocytes.
f. Neurotoxicity
Most of the toxic effects produced by the cresols involve central
nervous system (.see Section C.2.d., Systemic Toxicity) . Because of
this, these chemicals can be considered neurotoxins.
3-103
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g. Behavioral Toxicity
No information was found in the literature specifically on the
behavioral toxicity of the cresols.
h. Metabolism
(1) Pharmacokinetics and Distribution
The cresol isomers are absorbed through the skin, open wounds,
and mucous membranes of the gastrointestinal and respiratory tracts of
mammals (Deichmann and Keplinger, 1963). There is only limited data on
the rate of absorption, however, in one study, the rate of absorption
for p-cresol orally administered to fasting rats, was 3 mg per 100 g
body weight per hour during the first 15 minutes. The rate of phenol
absorption at the same point was 14 mg per 100 g body weight per hour
(Mareque and Marenzi, 1937). Other reports reviewed by Deichmann and
Keplinger (1963) indicate that the rate of absorption of cresols is
similar to that of phenol, but the data are not available (Embody, et.
al., 1940; Hunaki, 1940; Klinger and Norton, 1945).
There is little information available on the tissue distribution of
the cresols, but post mortem examination of humans accidentally poisoned
with generic lysol have been reported. Bruce, et al. (1976)detected
mixed cresols by gas chromatography in two humans poisoned by lysol
ingestion as follows:
Material Caso 1 Case 2
Blood (nig per 100 mlj
Urine (mp per 100 ml)
Brain (mg per 100 g)
Liver (mg per 100 g)
Kidney (mg per 100 g)
Stomach contents (g)
19-0
304
NA
480
NA
32
7-1
NA
028
90-0
396
0-4
Source: Bruce, et al., 1976
The major route of excretion for the cresols is in the urine, but
some has been reported to be excreted in the bile (Wandel, 1907). The
rate of excretion in rabbits has been described by Bray, et al. (1950).
3-104
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The 24-hour urinary excretion products were reported as follows:
Compound administered
o-Cresol (000 nig.)
m-Crcsol (500 ing.)
-j-Cresol (250-WK) mg.)
Tyj«-
Kthcmil wilplmU-
Kthrr glururuiiidit
l-'rcc crosol
Tntnl Mvnnl
KHiiTcnl ml, Imtc
KHicr
Totiil m-w.l
Klhorcnl SHlj-liate
Kthrr Rluwiroiiide
I Yrrrntngc of 3-'°
ft -«
s| Sli
12-21
3i ».r,
«» I-
AvcrnSl>
J.
80
Total crc»«l
01
-
0!5
Sources Bray, et al., 1950
(2) Metabolic Modification
Evidence from experimental animals indicates that the cresols are
oxidized and/or conjugated with either sulfuric or glucuronic acid in
vivo. in early experiments Bauman and Herter (1877; 1878) observed
that commercial cresols Cprobably a mixture) administered orally,
resulted in the formation of urinary sulfate in the horse and dog.
Neuberg and Kretschmer C1911) demonstrated conjugation of the hydroxyl
group in p~cresol with glucuronic acid by isolation of the metabolite
from the urine of dogs treated with p-cresol. Jonescu (1906) showed
that sulfuric and glucuronic acid conjugates of cresols were excreted
in the urine of dogs; in an unspecified amount of time, 30-50% of the
administered o-cresol, 46.5-50% of the m-cresol, and 23-27% of the
administered p-cresol were excreted as conjugates. As early as 1881,
Preusse found that the dog oxidized p-cresol to p-hydroxybenzoic acid
and o-cresol to 2,5-dihydroxytoluene.
Babbits metabolize the cresols in the same manner as dogs.
Deichmann and Thomas (1943) noted that orally administered o-f m-, or
p-cresol caused a marked rise in urinary glucuronic and sulfuric acids
3-105
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in rabbits one to four days after treatment. Williams (1938) found that
the percentages of doses of the various isomers excreted in the rabbit
urine as the sulfate conjugate were 22% (for o-cresol and m-cresol) and
16% (for p-cresol). The experiments of Bray, et al. (1950) elucidated
the metabolism of the cresols in rabbits. Using paper chromatography,
they determined the urinary metabolites following single oral doses of
500-600 mg o- or m-cresol, or 200-300 mg p-cresol. The following table
summarizes their findings from 24-hour rabbit urine:
KfelaboliJr* of crenola in fat. rabbit detected by paper chromatoffrriphif
( + j-, about 7 % of dose; +, about 3 % of dose, or less; Tr., trace; -, absent.)
Metabolites
_^_ _ _ <^. _ ^ _ ^—___. „_ „_ _.
Position of
Tlydroxybpii/nic acid hylroxy!s iti Diliydroxytoliu-ne Uihydroxyhcnzotc. acid
administered Frri- Conjugated compnnniis Frpp ('niijti^nlcd Kreo (Conjugated
o-Cresol - - 2:5
2:3
m-Crc,iol - - ti;.r. - i
2:3
3:4 - Tr.
7>-Cr«iol i i + 3:4 Tr.
Source: Bray, et al^., 1950
Studies in vitro with rat liver suggest similar metabolic trans-
formation for p- and o^cresol (Sato, elt al^., 1956). p-Cresol was con-
verted sequentially to p-hydroxybenzyl alcohol, p-hydroxybenzaldehyde,
p-hydroxybenzoic acid, and 3,4~d±hydroxybenzoic acid, o«Cresol was
converted to 2, 5*-dihydroxy toluene and a trace of o-hydroxy benzyl
alcohol; m-cresol was converted to 2,5-dihydroxy toluene and- m-hydroxy
benzyl alcohol.
From these studies in vivo and in vitro, the following metabolic
modification sequence can be constructed.
3-106
-------
m-hydroxy
benzl alcohol
HCO
fT
£-hydroxy-benzyl
alcohol
OH
j>-hydroxy
benzaldehyde
HO L
2,5-dihydroxy toluene
glucuronide or
sulfate
conjugates
C02H
/
OH
3,4-dlhydroxy
toluene
glucuronide
or sulfate
conjugates
£-hydroxy benzole
/ acid
002H
3,4-dihydroxy benzoic
acid
glucuronide
or sulfate
conjugate
3-107
-------
No information was found on the metabolism of cresols in humans,
but it should be noted that free cresols, particularly p-cresol, are
normally present in human urine. It has been reported that the normal
human excretes from 16 to 39 mg of p-cresol in the urine per day
(Deichmann and Keplinger, 1963). From studies with germ free rats, it
is apparent that this p-cresol is the result of metabolic action of the
normal gastrointestinal microflora (Bakke and Midtvedt, 1970). Studies
in vitro have shown that it is the metabolism of tyrosine by these
bacteria in the human gastrointestinal tract that produces the p-cresol
which is subsequently absorbed and excreted in the urine (Bone and Tamm,
1976; Bone, et al., 1976).
3-108
-------
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Spector, W,S. (ed.l, Handbook of Toxicology, NAS-NRC Wright Air Develop-
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Ecological Effects of Pesticides on Non-Target Species. Executive
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Stom, D.I., and Beim, A.M. (1976), Effects of Phenols on Some Species of
Algae. Gidrobiol. Zh., 12.(6), 53-57 (Chemical Abstracts 86: 184067g)
Takahashi, H. (1972), Effects of Topical Anti-fungal Agents. Nippon
Hifuka Gakkai Zasshi, 82, 421-437; cited in Gordon, J. (1976), Air
Pollution Assessment of Cresols. U.S. EPA contract 68-02-1495,
NTIS, PB-256 737
Timofeeva, S.S., Belykh, L.I., Butorov, V.V., & Stom, D.I. (1975), Role
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US International Trade Commission (1970-1976) Synthetic Organic Chemicals,
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US Occupational Safety and Health Administration (1976) Air Contaminants
US Code of Federal Regulations, Title 29, 1910.1000, p.60
3-127
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APPENDIX A
Aquatic Toxicity Rating
Chemicals are rated on the basis of their toxicity to aquatic life.
Finfish were selected as one of the most sensitive groups for which
toxicological data are available with information on shrimp and other
aquatic organisms being used to fill in the gaps. The 96 hour TL^ test*
was used to provide the basis for making five rankings of the toxic
potential. It was considered that if the substance would not be lethal
according to this test at greater than 1,000 mg/1 then it posed no major
toxic hazard to aquatic life.
The system rankings are outlined below.
Grade Description TLm Concentration
0 Insignificant hazard >1,000 mg/1
1 Practically non-toxic 100-1,000 mg/1
2 Slightly toxic 10-100 mg/1
3 Moderately toxic 1-10 mg/1
4 Highly toxic <1 mg/1
Most of the 96 hour TI^ test data available were derived from tests
with adult or juvenile aquatic organisms, usually from upper levels of
the food chain. It was recognized, however, that other stages, e.g.,
larvae or eggs, or organisms lower but critically important in the food
web, might be much more susceptible than the organisms or the stages of
organisms that were tested.
Although it was believed that at the present time acute toxicity
TLft, data are more complete and, therefore, present the best method of
ranking substances according to hazard, it was recognized that chronic or
sub- lethal effects may ultimately be more important ecological consider-
ations. Fish are known to be able to detect concentrations as low as
10"" 3 to 10~8 mg/1 of a range of substances. Behavior and chemo-recep-
tion (as involved in food finding, mating, migration) might be adversely
affected by concentrations considerably lower than the 96 hour
n— The concentration of a substance which will, within a specified
period of time (generally 96 hours) kill 50% of the exposed test organi^-
sms. The concentration is usually expressed in parts per million (mg/1).
The bioassay may be conducted under static or continuous flow conditions.
A-l
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For many of the chemicals no published aquatic toxicity data are
available. In these cases, the ratings were estimated from physical pro-
perties and by extrapolation of data from chemically similar compounds.
Some of the estimates used those of the previous rating list, adjusted
for the revised toxicity scales. Ratings for substances for which no
toxicity data have been located are given in parenthesis. Where infor-
mation was available for more than one of the preferred aquatic organ-
isms, the figure for the most susceptible species was generally used.
Rating Reductions
Consistent with the rating of other pollution hazards, these ratings
were modified in some cases for chemicals having low water solubility
or high volatility, which accordingly, will not normally pollute waters.
A Tlfln concentration value was taken as prima facie evidence that a lethal
concentration in water can be reached. Adjustments to aquatic toxicity
ratings based on low water solubility are made only where it can be shown
that reported TI^ concentrations were acheived in the laboratory by
techniques that would not be available in normal situations.
Similarly, highly volatile substances which are insoluble and tend
to float on the surface are reduced in ratings. Where any doubt existed,
the ratings were not reduced. The rationale for a reduction is given
in the discussion section of the ratings.
A-2
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TECHNICAL REPORT DATA
(Please read Instructions on the reverse before completing)
1. REPORT NO.
EPA 560/5-78-002
4. TITLE AND SUBTITLE
3. RECIPIENT'S ACCESSION NO.
A Study of Industrial Data on Candidate
Chemicals for Testing
5. REPORT DATE
June 1978
6. PERFORMING ORGANIZATION CODE
7. AUTHOR(S)
8. PERFORMING ORGANIZATION REPORT NO.
9. PERFORMING ORGANIZATION NAME AND ADDRESS
SRI International
333 Ravenswood Avenue
Menlo Park, CA 94025
10. PROGRAM ELEMENT NO.
MEU-5722
11. CONTRACT/GRANT NO.
68-01-4109
Research Request No.
12. SPONSORING AGENCY NAME AND ADDRESS
Office of Toxic Substances
U.S. Environmental Protection Agency
Washington, D.C. 20460
13. TYPE OF REPORT AND PERIOD COVERED
Final Report
14. SPONSORING AGENCY CODE
15. SUPPLEMENTARY NOTES
16. ABSTRACT
This report describes the work done on Research Request No. 3 as specified by the
Project Officer.
Data were collected for the chemicals in two classes, alkyl phthalates and cresols. The
phthalates class included thirty-seven alkyl phthalates believed to be commercially
significant at the present time. The cresol class included ortho-cresol, meta-cresol,
para-cresol, mixed cresols, and cresylic acid. The following information is provided
on the two' classes: physical and chemical properties, contaminants; composition of
mixtures; production and trade statistics, current (and in some cases, past) uses;
names and locations of .producers; worker exposure and occupational standards; environ-
mental emissions, mode of entry, transport, and degradation in the environment; and
biological effects (including ecological hazards and human health hazards).
17.
KEY WORDS AND DOCUMENT ANALYSIS
a.
DESCRIPTORS
b.IDENTIFIERS/OPEN ENDED TERMS
c. COSATi Field/Group
Cresols
Monohydric Phenols
Phthalates
Chemical Industry
Organic Compounds
Production
Consumption
Occurrence
Teratogens
Carcinogens
Mutagens
Toxicity
Metabolism
Chemical Properties
Hazardous
Environmental Release
Industrial Chemicals
Chemical Economics
Cresols/Phthalates
Care inogens/Mutagens
Toxicology
Ecology
06/05
07/03
07/03 05/03
07/03
06/05
06/20
06/06
18. DISTRIBUTION STATEMENT
Release unlimited
19. SECURITY CLASS (This Report)
21. NO. OF PAGES
148
20. SECURITY CLASS (This page)
22. PRICE
EPA Form 2220-1 (Rev. 4-77) PREVIOUS EDITION is OBSOLETE
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