FINAL DRAFT
ECAO-CIN-041
Unued States April, 1984
Environmental Protection r
Agency
&EPA Research and
Development
HEALTH AND ENVIRONMENTAL
EFFECTS PROFILE FOR
SELECTED TOLUENEDIAMINE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
Prepared by
Environmental Criteria and
Assessment Office
Cincinnati OH 45268
DRAFT DO NOT CITE OR QUOTE
NOTICE
This document 1s a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
on Us technical accuracy and policy Implications.
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DISCLAIMER
This report 1s an external draft for review purposes only and does not
constitute Agency policy. Mention of trade names or commercial products
does not constitute endorsement or recommendation for use.
11
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TABLE OF CONTENTS
LIST OF TABLES . . . 1v
LIST OF ABBREVIATIONS v
1. INTRODUCTION 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 1
2. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES 6
3. EXPOSURE 7
4. PHARMACOKINETICS B
4.1. ABSORPTION 8
4.2. DISTRIBUTION 9
4.3. METABOLISM 9
4.4. EXCRETION 9
5. EFFECTS 12
5.1. CARCINOGENICITY 12
5.2. MUTAGENICITY 13
5.3. TERATOGENICITY 17
5.4. OTHER REPRODUCTIVE EFFECTS 18
5.5. CHRONIC TOXICITY 18
5.6. OTHER RELEVANT INFORMATION 20
6. AQUATIC TOXICITY 21
6.1. ACUTE TOXICITY 21
6.2. CHRONIC EFFECTS 21
6.3. PLANT EFFECTS 21
6.4. RESIDUE 21
6.5. OTHER RELEVANT INFORMATION 21
7. EXISTING GUIDELINES AND STANDARDS 22
7.1. HUMAN 22
7.2. AQUATIC 22
8. RISK ASSESSMENT 23
9. REFERENCES 27
APPENDIX 32
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LIST OF TABLES
Table Page
1-1 Structure, CAS Numbers and Common Synonyms for 2.5-TDA,
3,4-TDA and 2,3-TOA 2
1-2 Physical Properties of Toluened1am1ne (Commercial Mixture)
and the Four Isomers 3
1-3 Producers of Toluenedlamlne and Four of the Isomers 5
5-1 Mutagen1c1ty Testing for Toluene-2,5-D1am1ne 14
5-2 MutagenUHy Testing for Toluene-2,6-D1am1ne 15
5-3 Mutagenldty Testing for Toluene-3,4-D1am1ne 16
1v
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
BCF Bloconcentratlon factor
DNA DeoxyHbonuclelc acid
LD Lowest dose lethal to recipients
Lo
LD5Q Dose lethal to 50% of recipients
NOAEL No-observed-effect level
ppb Parts per billion
ppm Parts per million
TWA Time-weighted average
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUNBER
Toluenedlamlne 1s the commercial mixture composed of six Isomers,
r
2,4-toluened1am1ne, 2,6-toluened1am1ne. 2,3-toluened1am1ne, 3,4-toluened1a-
mlne, 2,5-toluened1am1ne and 3,5-toluened1am1ne (Mllllgan and Gilbert,
1978). This hazard profile will address only the commercial mixture and the
four Isomers: 2,5-toluened1am1ne, 3,4-toluened1am1ne, 2.6-toluenedlamlne
and 2.3-toluened1am1ne.
The molecular formula for toluenedlamlne and Us Isomers 1s
C H N and the molecular weight of these compounds 1s 122.2. Tol-
uenedlamlne (commercial mixture) 1s also known as dlamlnotoluene and methyl-
phenylene dlamlne (NIOSH, 1978). The Chemical Abstract Service (CAS)
Registry Number 1s 25376-45-8. The structure, CAS numbers and common
synonyms for the 4 Isomers addressed 1n this profile are Included 1n Table
1-1.
Toluene-2,5-d1am1ne sulfate (CAS No. 6369-59-1) 1s a salt of toluene-
2,5-d1am1ne and sulfuMc add and 1s used In place of toluene-2.5-d1am1ne 1n
many of the studies cited 1n this profile. Both compounds are used 1n
hair-dye formulations (IARC. 1978).
1.2. PHYSICAL AND CHEMICAL PROPERTIES
Some of the physical properties of toluenedlamlne and the 4 Isomers are
listed 1n Table 1-2.
1.3. PRODUCTION DATA
The toluenedlamlnes are prepared by the dlnltratlon of toluene, which
occurs 1n two stages. Mononltratlon occurs In a mixed acid of 30% HN03
and 55% H^SO. at 30-70°C. The mononltrotoluenes formed are then
2 4
nitrated with SOX HN03 and 63% H2S04 to yield 78% 2,4-. 19.5% 2,6-,
0502p -1- 04/27/84
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o
o
rvj
TABLE 1-1
Structure, CAS Numbers and Common Synonyms for 2,5-TDA, 3,4-TDA. 2.6-TOA and 2.3-TDA
Compound
Structure
CAS Number
Common Synonyms
Toluene-2,5-d1am1ne
CH.
NH.
95-70-5
2-methyl-l,4-benzene-d1am1ne;
4-am1no-2-methyl aniline;
2-methyl-para-phenylene dlamlne;
para-toluenedlamlne and para,
metatolylene dlamlne (IARC, 1978)
r\j
i
ro
-j
co
Toluene-3,4-d1am1ne
Toluene-2,6-d1am1ne
Toluene-2,3-d1am1ne
CH
NH,
NH,
496-72-0 4-methyl-l,2-benzened1am1ne;
3,4-d1am1notoluene and 3,4-
toluylenedlamlne (NIOSH, 1978)
823-40-5 2-methyl-l,3-benzene-d1am1ne;
2,6-d1am1notoluene and 2,6-
toluylene dlamlne (NIOSH, 1978)
2687-25-4 3-methyl-l,2-benzene-dlamlne;
1,2-d1am1no-3-methylbenzene
and 2,3-toluylened1am1ne -
(U.S. EPA/NIH, 1983)
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TABLE 1-2
Physical Properties of Toluenedlamlne
(Commercial Mixture) and the Four Isomers
Isomer
Melting point °C:a
Boiling point °C:a
Vapor pressure (mm Hg)a
at 150°C:
at 160°C:
at 180'C:
Solubility:3
Log octanol/water partition
coeff1dents:b
2,3-
63-64
255
0.009
0.014
0.02
NR
0.65
2.5-
99
292
NR
NR
NR
soluble
In water
0.25
2,6-
105
NR
0.016
0.025
0.057
NR
0.5
3.4-
88.5
265
NR
NR
NR
NR
0.65
Commercial
Mixture
90
283
NR
NR
NR
NR
1.96C
aSource: M1ll1gan and Gilbert, 1978
bSource: Federal Register, 1982
C1.96 1s the log bloconcentratlon factor determined experimentally by
Mackay, 1982
NR = Not reported
0502p
-3-
04/27/84
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0.7X 2,5-, 1.5X 2,3- and 2.5X 3,4-dimtrotoluene (MllUgan and Gilbert,
1978). These d1n1trotoluenes are subsequently catalytlcally hydrogenated to
the corresponding toluenedlamlnes.
The commercial mixture of toluenedlamlnes and the four Isomers are
produced by a number of manufacturers (Table 1-3). The principal areas of
production for all the compounds are Louisiana, West Virginia, New Jersey,
Texas, Kentucky and New York (U.S. EPA, 1983).
Practically all the toluenedlamlne produced 1s captlvely consumed In the
production of toluene dllsocyanate (SRI, 1976). In 1982, 695 million pounds
of toluene dllsocyanate were produced (SRI, 1983). Some toluenedlamlne
(unknown amount) Is used 1n manufacturing polymers and dyes for hair,
fabrics and fur (Thlrtle, 1968).
0502p -4- 04/27/84
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TABLE 1-3
Producers of Toluened1am1ne and Four of the Isomers*
Isomer
Manufacturer
Location
Production
Volume (Ibs)
Toluenedlamlne
(commercial mixture)
Toluene-2,5-d1am1ne
Toluene-3,4-d1am1ne
i
in
i
Toluene-2,6-d1am1ne
Toluene-2,3-d1am1ne
a
«i
ro
-«j
"X.
CO
Mobay Chemical Co.
Union Carbide Corp.
BASF Uyandotte Corp.
Allied Chemical Co.
Rubicon Chemicals, Inc.
Air Products and Chemicals, Inc.
Kodak Park Division
OUn Corp.
BASF Uyandotte Corp.
Allied Chemical Co.
Air Products and Chemicals, Inc.
DuPont and Co.
Olln Corp.
Union Carbide Corp.
BASF Wyandotte Corp.
Allied Chemical Corp.
OUn Corp.
BASF Uyandotte Corp.
Allied Chemical Co.
Air Products and Chemicals, Inc.
DuPont and Co.
Marshall. UV
Chambers. TX
Kanawha. UV
Gelsmar, LA
Moundsvllle. UV
Gelsmar, LA
Pasadena, TX
Rochester. NY
Brandenburg, KY
Gelsmar, LA
Moundsvllle. UV
Pasadena, TX
Deepwater, NJ
Lake Charles, LA
Brandenburg, KY
Kanawha, WV
Gelsmar, LA
Moundsvllle, UV
Brandenburg, KY
Gelsmar. LA
Moundsvllle. UV
Pasadena, TX
Deepwater, NJ
NR
NR
NR
50,000,000-
100.000.000
50,000,000-
100.000.000
NR
100.000-1.000.000
10,000-100.000
100.000-1,000.000
100.000-1.000.000
NR
100.000-1.000,000
100,000-1,000.000
10,000,000-
50,000,000
1,000.000-
10,000,000
NR
10.000.000-
50.000.000
NR
100.000-1.000,000
1.000.000-
10.000.000
NR
1,000,000-
10,000.000
100,000-1.000.000
*Source: U.S. EPA, 1983
NR = Not reported
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2. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES
Data regarding the fate and transport of the toluenedlamlnes 1n the
environment are sparse. Although no data were available on the persistence
of these compounds, 1t 1s expected that they may undergo rapid transforma-
tion 1n the environment since the aromatic amines are relatively reactive
compounds.
The log octanol-water partition coefficient for each of the 4 1soners 1s
<0.65 (see Table 1-2) and the log BCF for the commercial mixture Is 1.96
(Mackay, 1982). These data suggest that there 1s little potential for bio-
accumulation 1n aquatic organisms. Because the alkaline nature of these
compounds, 1t 1s likely that they will react with adds 1n the aqueous or
soil media to form salts. Although no specific data were available, the
fate and transport of the compounds 1n these environments may then depend on
their ability to dissolve 1n water or leach through soil columns. Addi-
tional data regarding the fate and transport of the toluenedlamlnes In the
soil, water or atmospheric environments were not located 1n the available
literature.
0502p -6- 04/27/84
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3. EXPOSURE
Toluened1am1nes are used either directly 1n hair dyes as color-yielding
compounds or as chemical Intermediates 1n the synthesis of dllspcyanates or
dyes; therefore, exposure to these compounds will be greatest in the manu-
facturing facilities or from consumer use of products containing these dyes.
According to the Federal Register (1982) the U.S. EPA reported that -15
million people are potentially exposed to the toluenedlamlnes and other
phenyldlamlnes as a result of personal use or 1n the application of hair
dyes to other people (47 PR 979). Exposure may also result from the manu-
facture or use of products containing these chemicals. Toluenedlamlne
concentrations of 0.008-0.39 mg/m3 were measured 1n the work air of an
Ol1n Chemical Company manufacturing facility (Ahrenholz, 1980). Toluene-
2,6-d1am1ne (an Intermediate 1n the production of toluened11socyanate) was
detected 1n aqueous extracts from food-packaging products (boll-ln-bags and
retortable pouches) at levels ranging from <0.1-2.2 ppb (Snyder et al..
1982).
0502p -7- 04/27/84
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4. PHARMACOKINETICS
4.1. ABSORPTION
A 1.6X aqueous solution of [methyl-14C]-labeled toluene-2,5-d1am1ne
hydrochlorlde (10 mg toluene-2,5-d1am1ne) was administered by gavage to male
and female rats. HHhln 24 hours, >70X of the administered radioactivity
was excreted 1n the urine and <5X was excreted 1n the feces (Hruby, 1977).
These data suggest that toluene-2,5-d1am1ne 1s efficiently absorbed from the
gastrointestinal tract of rats following oral administration.
Hruby (1977) applied dermally 7.5 mg i«C-toluene-2,5-d1am1ne (pH 10.1)
to rats and 1.4 g l4C-toluene-2.5-d1am1ne (pH 10.1) to dogs. The position
of the label was as noted above for the oral experiments. Approximately
0.2X of the administered radioactivity was absorbed through the skin of rats
and 0.127% was cutaneously absorbed In the dog as Indicated by the amount
excreted 1n the urine and feces plus the amount 1n the total-body homogenate
(Hruby, 1977).
About 40 mg of toluene-2,5-d1am1ne was absorbed through the skin of dogs
during application of toluene-2,5-d1am1ne sulfate (1.4 g toluene-2,5-d1a-
mlne) 1n 50 ml of a lauryl sulfate-based gel (pH 9.5) to the hair and skin
for 3 hours. The amount of toluene-2,5-d1am1ne absorbed decreased to <3 mg
when 3% hydrogen peroxide was present 1n the gel, simulating hair-dyeing
conditions (K1ese et al., 1968). Urinary excretion data were used to esti-
mate absorption.
Klese and Rauscher (1968) found that application of a hair dyeing pre-
paration containing 2.5 g of toluene-2,5-d1am1ne sulfate and 2.5 g resor-
dnol with 3X hydrogen peroxide (pH 9.5) to the hair and scalp of human
subjects for 40 minutes resulted In the absorption of -4.6 mg toluene-2,5-
dlamlne. This value was calculated from urinary excretion data.
0502p -8- 04/27/84
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4.2. DISTRIBUTION
Hruby (1977) administered by gavage a 1.6X aqueous solution of
[methyl-14C]-labeled toluene-2,5-d1am1ne hydrochlorlde containing 10 mg of
r
toluene-2,5-d1am1ne to rats and found 1.4 + 0.02X of the radioactivity 1n
the gastrointestinal tract and 1.2 + 0.08X 1n the total-body homogenate
after 5 days. Following cutaneous application of 7.5 rag "C-toluene-2,5-
dlamlne (pH 10.1) to rats, -0.1X of the radioactivity was found In the
total-body homogenate and -1.2% remained at the site of application (Hruby,
1977).
4.3. METABOLISM
Following dermal application of 2.5 g of toluene-2,5-d1am1ne sulfate and
2.5 g resordnol with hydrogen peroxide (pH 9.5) to humans, -3.7 mg N,N'-
d1acetyl-p-toluened1am1ne appeared In the urine. Following subcutaneous
Injection of 5.5 mg toluene-2,5-d1am1ne, 47.6X of the dose was excreted as
N,N'-d1acetyl-p-toluened1am1ne (-4.5 mg) 1n the urine of humans (K1ese and
Rauscher, 1968).
4.4. EXCRETION
Excretion of toluene-2,5-d1am1ne (or metabolites) 1n the urine of dogs
and rats appears to occur more rapidly and extensively following oral,
subcutaneous or Intravenous administration than following cutaneous applica-
tion of the compound. Excretion of the metabolite N,N'-d1acetyl-p-toluene-
dlamlne 1n humans occurs slowly whether toluene-2,5-d1am1ne Is applied
dermally or Injected subcutaneously.
Following administration by gavage of a 1.6X aqueous solution of
»«C-toluene-2,5-d1am1ne hydrochlorlde (10 mg toluene-2.5-d1am1ne) to rats,
>70X of the radioactivity was excreted 1n the urine and <5X was excreted 1n
the feces within 24 hours. Excretion of the radioactivity 1n the urine and
feces was essentially complete within 5 days (Hruby. 1977).
0502p -9- 04/27/84
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Cutaneous application of 7.5 mg l4C-toluene-2,5-d1am1ne (pH 10.1) to
rats resulted 1n 0.08-0.14X of the radioactivity being excreted 1n the urine
and 0.004X excreted In the feces within 24 hours (Hruby, 1977). Following
dermal application of 1.4 g l4C-toluene-2,5-d1am1ne (pH 10.1) "to dogs, the
amount of radioactivity excreted In the urine and feces over 4 days totalled
0.092i0.009X and 0.840+0.10X, respectively, of the administered dose (Hruby,
1977).
Approximately 0.41 mg of toluene-2,5-d1am1ne was excreted 1n the urine
within 24 hours after application of 1.4 g toluene-2,5-d1am1ne (as the
sulfate; pH 9.5) to the skin of dogs. The urine collected on the second day
contained nearly 0.1 mg and traces of toluene-2,5-d1am1ne were detected 1n
the urine on the third day (K1ese et al., 1968).
Following application of hair-dye preparations containing 2.5 g toluene-
2,5-d1am1ne sulfate and 2.5 g resordnol with 3X hydrogen peroxide (pH 9.5)
to humans, 3661 vg of N,N'-d1acetyl-p-toluened1am1ne was excreted In the
urine within 48 hours (K1ese and Rauscher, 1968).
Following Intravenous administration of 0.14 g [methyl-14C]-labeled
toluene-2,5-d1am1ne to dogs, total amounts of radioactivity excreted 1n the
urine and feces were 60+8.OX and 19+4.0% of the administered dose, respec-
tively. The majority of the 4-day excretion occurred within the first 24
hours (Hruby, 1977).
Subcutaneous Injection of a 0.4X aqueous solution of 14C-toluene-2,5-
dlamlne (containing 3-5 mg of toluene-2,5-d1am1ne and labeled 1n the
position described above) resulted 1n -67X of the radioactivity being
excreted 1n the urine and <5X being excreted 1n the feces of rats within 24
hours (Hruby. 1977).
0502p -10- 04/27/84
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Following the subcutaneous Injection of 5.54 mg toluene-2,5-d1am1ne (as
the sulfate) 1n aqueous solution to humans, 4455 yg of N,N'-d1acetyl-p-
toluene-dlamlne (47.6X) was excreted 1n the urine within 48 hours (K1ese and
r
Rauscher, 1968). :.
0502p -11- 04/27/84
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5. EFFECTS
5.1. CARCIMOGEN1CITY
A dietary cardnogenlclty bloassay of toluene-2,5-d1am1ne rsulfate was
conducted by the National Cancer Institute (NCI, 1978) using'Fischer 344
rats and B6C3F1 mice. Fifty animals of each sex and species were maintained
on diets containing TWA concentrations of 0. 0.06 or 0.2% for rats and 0,
0.06 or 0.10% toluene-2,5-d1am1ne sulfate for mice for 78 weeks. No
statistically significant change 1n the Incidences of tumors were observed
1n either male or female mice or rats under the conditions of this bloassay
(NCI, 1978).
Sufficient evidence was not obtained to demonstrate the cardnogenldty
of toluene-2,6-d1am1ne dihydrochlorlde 1n rats and mice (NCI, 1980). Groups
of 50 rats of each sex were fed diets containing 0, 50. 250 or 500 ppm
toluene-2,6-d1am1ne dihydrochlorlde for 103 weeks and observed for an addi-
tional week. Similarly, 50 mice of each sex were fed 0. 50 or 100 ppm
toluene-2,6-d1am1ne dihydrochlorlde for 103 weeks (NCI, 1978). A statisti-
cally significant Increase In Interstitial-cell neoplasms of the testes was
observed 1n rats, but this was not considered treatment-related since these
neoplasms are common 1n rats and have a highly variable Incidence. Conclu-
sive evidence of a carcinogenic effect of toluene-2,6-d1am1ne hydrochloMde
for mice or rats was not provided under the conditions of this bloassay.
Fifty male and 50 female Swiss Webster mice received weekly or fort-
nightly dermal applications for 18 months of 0.05 ml hair-dye preparations
(1 volume of 3% toluene-2.5-d1am1ne sulfate and 1.5% p-phenyld1am1ne with
either 0.2% toluene-2.4-d1am1ne. 0.38% 2,4-d1am1noan1sole sulfate or 0.17%
M-phenylene-dlamlne mixed with an equal volume of 6% hydrogen peroxide)
(Burnett et al., 1975). No statistically significant Increase In the
0502p -12- 04/27/84
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Incidences of lung tumors was observed 1n the test animals when compared
with the controls. Limited data were available from a similar study 1n
which 28 male and 28 female Swiss Webster mice were dermally .treated once
r
weekly for an unspecified period of time with 0.05 ma of a hair-dye
formulation (1 volume of 3X toluene-2.5-d1am1ne sulfate, 1.5X p-phenylene-
dlamlne and either 0.2 or 0.6X toluene-2,4-d1am1ne mixed with an equal
volume of 6% hydrogen peroxide) (Giles et al., 1976). Data from this study
were deemed Inadequate for the evaluation of the cardnogenlclty of toluene-
2t5-d1am1ne sulfate (IARC. 1978).
Klnkel and Holzman (1973) tested three hair-dye preparations (1 volume
of 0, 3 or 4% toluene-2,5-d1am1ne mixed with an equal volume of 6% hydrogen
peroxide). Fifty male and 50 female Sprague-Oawley rats were dermally
treated twice weekly with 0.5 ml for 2 years. No statistically signif-
icant differences were observed 1n tumor Incidences between the experimental
and control group.
5.2. HUTAGENICITY
Many mutagenldty bloassays of toluene-2,5-d1am1ne, toluene-2,6-d1am1ne
and toluene-3,4-d1am1ne have been conducted using a variety of test systems.
These studies are summarized In Tables 5-1, 5-2 and 5-3.
Toluene-2,5-d1am1ne gave positive results 1n the Salmonella typhlmurlum
(strain TA1538) reverse mutation assay, but only when assayed with a mamma-
lian metabolic activation system (rat liver S-9) (Ames et al., 1975). This
compound was also positive In the transformation assay with primary and
secondary hamster embryo cells (NEC), before and after the addition of
Simian Adenovlrus (SA7) (Greene and Friedman, 1980). Toluene-2,5-d1am1ne
sulfate was Inactive In the in vivo mlcronucleus test with rats (Hossack and
Richardson, 1977), but exhibited a positive, dose-related response 1n the In
vivo testlcular DNA synthesis bloassay with mice (Greene et al., 1981).
0502p -13- 04/27/84
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f\»
•o
TABLE 5-1
Mutagenlclty Testing for Toluene-2.5-Dlam1ne
Assay
Reverse nutation
Transformation
assay
Transformation
assay
Transformation
assay
^ Hlcronucleus
i test
Testlcular DNA
synthesis
Indicator
Organism
Salmonella
tvphlmurlum
TA1538
Syrian Golden
primary HEC
Syrian Golden
primary HEC
Syrian Golden
secondary HEC
CFV rats (5 males/
5 females)
C57B1/6 x C3H mice
Application
spot test
plate
Incorporation
plate
Incorporation
plate
Incorporation
by gavage
Intraperl-
toneally
Concentration Activation
or Dose System
0.25 mg/mt or ±S9
10 mg/mt
3.13-50.0 vg/mt NR
1.0-5.0 tig/ml NR
1.0-50.0 pg/ml NR
total dose: 120 mg/kg NA
In 0.5X gum traga-
canth with 0.5X sodium
sulflte
40.0-55.0 mg/kg NA
Response Comment
* Addition of
HjOp resulted
In a 40-fold
Increase 1n rever-
tants when S9 was
present.
f Before addition
of SAT
» After addition
of SA7
« Chemical transfor-
mation of HEC
NC
* Dose related at
>40 mg/kg; signifi-
cantly Inhibited
the incorporation
of ['«i]iodo-
deoxyurldlne Into
murlne testlcular
DNA
Reference
Ames et al.. 1975
Greene and Friedman.
1980
Greene and Friedman,
1980
Greene and Friedman.
1980
Hossack and
Richardson. 1977
Greene et al.. 1981
NR . Not reported
NC - No comment
NA . Not applicable
GO
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TABLE 5-2
Hutagenlclty Testing for Toluene-2,6-D1am1ne
Assay
Reverse mutation
Transformation
assay
Transformation
assay
Transformation
assay
DNA repair assay
Testlcular DNA
synthesis
Indicator
Organism
Salmonella
tvohlmurlum
TA98
TA100
TA1535
TA1537
Syrian Golden
primary HEC
Syrian Golden
primary HEC
Syrian Golden
secondary HEC
Fischer 344 male
rats
C57B1/6 x C3H mice
Application
plate
Incorporation
plate
Incorporation
plate
Incorporation
plate
Incorporation
by gavage In
corn oil
Intraperl-
toneally
Concentration
or Dose
0.03-30 vmoles/plate
313.0-5000.0 vg/ml
150.0-750.0 pg/mt
0.5-200.0 vg/mt
5.0 and 20.0 rag/kg
30.0-100.0 rag/kg
Activation
System Response
»S9 »
TS9 *
*S9
»S9
NR »
NR »
NR »
NA
NA
Comment
Dose-related
>0.03 timoles/plate
for TA98 and TA100
Marginally active
before addition
of SA7
After addition
of SA7
Chemical trans-
formation
NC
NC
Reference
Florin et al., 1980
Greene and Friedman,
1980
Greene and Friedman,
1980
Greene and Friedman,
1980
Nlrsalls et al.,
1982
Greene et al.. 1981
NR - Not reported
NC . No comment
NA - Not applicable
-------
in
O
TABLE 5-3
Mutagenlclty Testing for Toluene-3.4-D1am1ne
Assay
Reverse mutation
Transformation
assay
Transformation
assay
Transformation
assay
Nlcronucleus
test
Testlcular DMA
synthesis
Indicator
Organism
Salmonella
tvphlmurluip
TA98
TA100
TA1535
TA1537
Syrian Golden
primary HEC
Syrian Golden
primary HEC
Syrian Golden
secondary HEC
NHRI mice
2 males and
2 females per dose
C57B1/6 x C3H mice
Application
spot test
plate
Incorporation
plate
Incorporation
plate
Incorporation
Intraperl-
toneally
Intraperl-
toneally
Concentration
or DOSP
3 pinoles/plate
12.5-200 wg/mt
10.0-100.0 pg/mt
2.5-20.0 pg/mt
2 x 122. 244 or
366 mg/kg
100-300 mg/kg
Activation
System
»S9
»S9
»S9
»S9
NR
NR
NR
NA
NA
Response Comment
NC
•
•
•
•
* Before addition
of SA7
* After addition of
of SA7
+ Chemical trans-
formation
+ * at 224 and
366 mg/kg
+ Significantly
Inhibited the
Incorporation of
[125i]iododeoxy
urldlne Into
murlne testlcular
ONA
Reference
Florin et al.. 1980
Greene and Friedman.
1980
Greene and Friedman,
1980
Greene and Friedman.
1980
Wild et al.. 1980
Greene et al.. 1981
NR . Not reported
NC - No comment
NA . Not applicable
IN)
~J
CO
-------
Toluene-2,6-d1am1ne was positive 1n the Salmonella typhlmurlum reverse
mutation assay with strains TA98 and TA100, but only 1n the presence of S-9
(Florin et al., 1980). This compound produced negative responses In the ONA
r
repair assay with rats (M1rsal1s et al., 1982), and 1n the testlcular DNA
synthesis assay with mice (Greene et al., 1981). Positive results were
obtained 1n the transformation assay of primary and secondary HEC both
before and after the addition of SA7 (Greene and Friedman, 1980).
Toluene-3,4-d1am1ne produced negative responses In the reverse mutation
assay using four strains of Salmonella typhlmurlum. both with and without
S-9 (Florin et al., 1980). Positive responses were obtained with this
compound 1n the transformation assay of primary and secondary HEC (Greene
and Friedman, 1980) and 1n the 1rt vivo testlcular DNA synthesis assay with
mice (Greene et al., 1981).
5.3. TERATOGENICITY
In experiments with JCLrddn mice, Inouye and Murakami (1977) found
skeletal malformations 1n 20/109 (18X) fetuses from dams treated with a
single subcutaneous Injection of 50 mg/kg toluene-2,5-d1am1ne dlhydrochlo-
rlde on the 8th day of pregnancy. Skeletal malformations were also observed
1n 7/20 (35X) fetuses from dams treated with a single subcutaneous Injection
of 75 mg/kg and 1n 17/38 (45X) fetuses from dams treated with 50 mg/kg
toluene-2,5-d1am1ne dlhydrochlorlde Intraperltoneally on the 8th day of
pregnancy. Similar abnormalities were found 1n four fetuses from dams
treated with a 50 mg/kg subcutaneous Injection on days 7 and 9 of pregnancy.
Statistical analyses of these data were not provided; however, no skeletal
malformations were observed 1n the 132 fetuses examined 1n the control
group. Other effects observed Included an Increased Incidence of dead and
resorbed fetuses and maternal deaths 1n dams treated with subcutaneous or
0502p -17- 04/27/84
-------
IntraperUoneal doses of 75 and 50 mg/kg toluene-2.5-d1am1ne dlhydrochlorlde
on day 8 of pregnancy (Inouye and Murakami, 1977).
Marks et al. (1981) found no teratogenU effects 1n CD-I mice treated
dally with IntraperHoneal Injections of 16, 32, 48 or 64 mg/kg-toluene-2,5-
dlamlne sulfate on days 6-15 of gestation. At doses of 64 and 48 mg/kg/day,
Increased Incidences (4/31 and 9/11) of maternal deaths were observed
compared with 0/31 for the control group. Average fetal weight decreased as
the dose Increased, and at dosages of 32, 48 and 64 mg/kg/day, a significant
(P<0.05) decline 1n fetal weights was observed (Harks et al., 1981).
A hair-dye preparation containing 3X toluene-2,5-d1am1ne sulfate, 4X
2,4-d1am1noan1sole sulfate and 2X p-phenylened1am1ne mixed with an equal
volume of 6X hydrogen peroxide was tested for teratogenldty 1n 20 pregnant
Charles River CO rats (Burnett et al., 1976). The formulation was applied
to the skin at a dose of 2 ml/kg on days 1, 4, 7, 10, 13, 16 and 19 of
gestation. Skeletal abnormalities were observed 1n 6/169 fetuses; this
Incidence was statistically significantly different from Incidences In three
control groups. When a group of 20 female rats was treated as above with a
hair dye preparation containing 6X toluene-2,5-d1am1ne sulfate, no signif-
icant Increase 1n skeletal abnormalities was found 1n fetuses when compared
with controls (Burnett et al.. 1976).
5.4. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding reproductive effects of the specified
toluene-dlamlnes were not located 1n the available literature.
5.5. CHRONIC TOXICITY
No overt signs of toxldty or h1stopatholog1c changes attributable to
treatment were observed 1n Fischer 344 rats and B6C3F1 mice fed diets
containing 0.06 or 0.2% (600 or 2000 ppm) and 0.06 or 1% (1000 or 600 ppm)
0502p -18- 04/27/84
-------
toluene-2,5-d1am1ne sulfate, respectively, for 78 weeks (NCI, 1978). Exper-
imental details were described 1n Section 5.1. Survival was not affected by
treatment. High-dose females of both species had slightly lower body
weights than did controls during the study.
No toxic effects were observed from the chronic feeding of diets con-
taining 250 or 500 ppm, and 50 or 100 ppm toluene-2,6-d1am1ne dlhydrochlor-
Ide to F344 rats and B6C3F1 mice, respectively, for 103 weeks' (NCI. 1980) as
described 1n Section 5.1. Slight, dose-related depression of mean body
weights occurred 1n the treated female rats during the study. Survival was
unaffected In both species.
In the subchronlc feeding study on toluene-2,6-d1am1ne (NCI, 1980),
groups of 10 male and 10 female F344 rats of each sex were fed 0. 100. 300,
1000, 3000 or 10,000 ppm of the compound In the diet for 91 days. Body
weight gain was depressed 1n males at all doses and 1n females at >1000 ppm.
At 10.000 ppm. 2 of 10 males and 7 of 10 females died; no deaths occurred 1n
any other group. At 3000 ppm, diffuse bilateral adenomatous hyperplasla of
the thyroid occurred 1n the males, and at 10,000 ppm, nephrosls, bone marrow
hyperplasla and thyroid hyperplasla occurred 1n both sexes. Groups of 10
male and 10 female B6C3F1 mice fed the same dietary levels of toluene-2,6-
dlamlne as 1n the experiment with rats had weight gain depression at >300
ppm and renal hyperplgmentatlon 1n a few animals at 1000 ppm (NCI. 1980).
No deaths occurred at any dose level and no other effects were noted.
No signs of toxIcUy were observed In 50 male and 50 female Swiss
Webster mice treated dermally once a week or once every other week for 18
months with 0.05 ml of a hair-dye formulation containing 1 volume of 3%
toluene-2.5-d1am1ne sulfate mixed with an equal volume of 6X hydrogen perox-
ide (Burnett et al.. 1975).
0502p -19- 04/27/84
-------
Doses of 0.5 ml of hair-dye formulations containing 1 volume of 4 or
3X toluene-2,5-d1am1ne sulfate mixed with an equal volume of 6X hydrogen
peroxide were applied to the skin of 50 male and 50 female Sprague-Dawley
rats twice weekly for 2 years (Klnkel and Holzmann, 1973). No differences
were observed 1n behavior, feeding, body-weight gain, hematological param-
eters, mean Hfespan, mortality or liver function (serum transamlnase and
bromosulfthaleln secretion). No pathologic changes were observed at
necrospy (Klnkel and Holzmann, 1973).
5.6. OTHER RELEVANT INFORMATION
The following LD s have been reported for toluene-2,5-d1am1ne (NIOSH,
1978):
oral - unspecified mammal: 3600 mg/kg
subcutaneous - rat: 50 mg/kg
- rabbit: 100 mg/kg
The oral LD_Q of toluene-2,5-d1am1ne sulfate 1n an o1l-1n-water
emulsion 1n rats was reported as 98 mg/kg; the 1ntraper1toneal LD,.. of the
compound 1n dimethylsulfoxide 1n rats was 49 mg/kg (Burnett et al.. 1977).
Female Sprague-Dawley rats receiving 33.3 or 50 mg/100 g body weight
toluene-3,4-d1am1ne by gavage twice dally for 5 days developed duodenal
ulcers (Selye, 1973; Selye and Mecs, 1974). Single subcutaneous Injections
of 62.5-500 mg/kg toluene-3,4-d1am1ne to male and female Sprague-Dawley rats
resulted 1n gastric and duodenal lesions (Perkins and Greene, 1975).
0502p -20- 04/27/84
-------
6. AQUATIC TOXICITY
6.1. ACUTE TOXICITY
The effects of toluene-2,3-d1am1ne were determined on gupples, PoeclHa
retlculata. and the water flea, Daphnla maqna (Crustacea) (Smlrnova et al.,
1967). Data available 1n the abstract of this Russian study Indicate that
exposure to 200 mg toluene-2,3-d1am1ne/i (time unspecified) caused no
observable effects on P. retlculata. Daphnla were more sensitive, with a
toxlclty threshold at 2 and 5 mg/a causing death after 510 days of
exposure.
6.2. CHRONIC EFFECTS
Pertinent data regarding the effects of chronic toluenedlamlne exposure
were not located 1n the available literature.
6.3. PLANT EFFECTS
An abstract from a Russian study (Smlrnova et al., 1967) Indicated that
no toxic effects were evident 1n the green alga, Scenedesmus obllquus. after
exposure to toluene-2,3-d1am1ne. Toxicant concentration and exposure
duration, however, were not specified.
6.4. RESIDUE
VeHh et al. (1979) reported that the BCF for toluenedlamlne was 91 (log
BCF = 1.96) 1n fathead minnows. Plmephales promelas. exposed at 0.001 mg/a
for 32 days.
6.5. OTHER RELEVANT INFORMATION
Additional data relevant to the toxlclty of toluenedlamlne to aquatic
organisms were not located In the available literature.
0502p -21- 04/27/84
-------
7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
Pertinent data regarding existing guidelines and standards for the
r
toluenedlamlnes were not located 1n the available literature.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic organisms from
the toxic effects of toluenedlamlne were not located 1n the available
literature.
0502p -22- 04/27/84
-------
6. RISK ASSESSMENT
Toluene-2,5-d1am1ne sulfate was tested for cardnogenldty by the NCI
(1978), Klnkel and Holzmann (1973), Burnett et al. (1975) and Giles et al.
(1976). No carcinogenic effects were seen In rats administered 0, 0.06 or
0.2% and 1n mice administered 0, 0.06 or 0.10X toluene-2.5-d1am1ne sulfate
1n the diets for 78 weeks (NCI, 1978). No carcinogenic effects were seen 1n
mice or rats receiving dermal applications of toluene-2,5-d1am1ne sulfate 1n
hair-dye preparations (Burnett et al., 1975; Giles et al., 1976; Klnkel and
Holzman, 1973). Sufficient evidence was not obtained to demonstrate the
cardnogenldty of toluene-2,6-d1am1ne dlhydrochlorlde In rats fed 50, 250
or 500 ppm or 1n mice fed 50 or 100 ppm of the compound 1n the diet for 103
weeks (NCI, 1980).
Toluene-2,5-d1am1ne produced positive results 1n a reverse mutation
assay with S. typh1mur1um TA1538 (Ames et al., 1975) and 1n the
transformation assay with hamster embryo cells (Greene and Friedman, 1980).
negative results 1n the in vivo mlcronucleus assay with rats, and positive
results 1n the l£ vivo testlcular ONA synthesis assay with mice (Greene et
al., 1981).
Toluene-2,6-d1am1ne gave positive results were obtained with toluene-
2,5-d1am1ne 1n a reverse mutation assay with two strains (TA98 and TA100) of
S. typhlmurlum (Florin et al., 1980) and 1n the transformation assay with
hamster embryo cells (Greene and Friedman. 1980). Negative results were
obtained 1n the In. vivo DNA repair assay (H1rsal1s et al.. 1982) and the
testlcular DNA synthesis assay (Greene et al.. 1981).
Toluene-2,5-d1am1ne sulfate and toluene-2,6-d1am1ne dlhydrochlorlde
failed to demonstrate oncogenlc activity 1n rats or mice fed these compounds
1n the diet; however, positive results were obtained from both of these
compounds In In vitro mutagenlclty assays with bacteria and hamster embryo
0502p -23- 04/27/84
-------
cells. Although these compounds exhibited positive mutagenlc activity 1n
two test systems, the lack of conclusive evidence for the tumoMgenlclty of
toluene-2,5-d1am1ne sulfate and toluene-2,6-d1am1ne dlhydrochlorlde preclude
the classification of these compounds as carcinogens.
Toluene-3,4-d1am1ne produced negative results In the reverse mutation
assay with four strains of S. typhlmurlum bacteria (Florin et al., 1980) and
positive results 1n the transformation assay with hamster embryo cells
(Greene and Friedman, 1980) and the in vivo testlcular DNA synthesis assay
(Greene et al., 1981).
At dose levels of 50 and 75 mg/kg administered subcutaneously and 50
mg/kg administered 1ntraper1toneally to mice on day 8 of gestation, toluene-
2,5-d1am1ne dlhydrochlorlde Induced skeletal malformations 1n fetuses
(Inouye and Murakami, 1977). At dose levels of 16. 32. 48 or 64 mg/kg of
toluene-2,5-d1am1ne sulfate administered 1ntraper1toneally to mice on days
6-15 of gestation, no teratogenlc effects were observed. Maternal toxldty
was observed at the 64 and 48 mg/kg doses; fetal weight decreased at doses
of 32, 48 and 64 mg/kg/day (Marks et al.. 1981). Skeletal abnormalities
were observed 1n the offspring of pregnant rats dermally treated with
hair-dye preparations containing a 1:1 mixture of 3X toluene-2,5-d1am1ne
sulfate and 6X hydrogen peroxide on days 1. 4, 7. 10. 13. 16 and 19 of
gestation (Burnett et al.. 1976). No significant Increases 1n skeletal
abnormalities were observed 1n fetuses whose mothers had been treated In a
similar manner with a hair-dye preparation containing 6X toluene-2,5-d1am1ne
sulfate (Burnett et al.. 1976).
There 1s little Information regarding the effects of chronic exposure to
toluenedlamlne or the four specified Isomers. The chronic dietary studies
of the NCI (1978, 1980) appear to Identify NOAELs In rats of 2000 ppm for
0502p -24- 04/27/84
-------
toluene-2,5-d1am1ne sulfate and 500 ppm for toluene 2,6-d1am1ne hydrochlor-
1de, as weight gain depression was observed In females at these dose levels,
but no overt signs of toxlclty or hlstopathologlc changes attributable to
treatment were found.
Using the NOAEL of 500 ppm toluene-2,6-d1am1ne dlhydrochlorlde In rats,
derived from the NCI (1980) study, an ADI value can be derived. In lieu of
food consumption data, the assumption must be made that a rat consumes a
dally amount of food equivalent to 5X of Us body weight. Using this
assumption, an equivalent dose of 25.0 mg/kg/day can be calculated. Since
these data are for the dlhydrochlorlde salt of toluene-2,6-d1am1ne
{HH=195.10), an equivalent dose of 15.7 mg/kg/day for toluene-2,6-d1am1ne
(MVM22.2) must be used to calculate an ADI. An ADI value of 11.0 mg/day
for a 70 kg human can be calculated by multiplying the animal dose by an
assumed human body weight of 70 kg and applying an uncertainty factor of
100, to convert from experimental animal data to human data, and to protect
the more sensitive Individuals of a population.
The subchronlc feeding study by the NCI (1980) provides additional data
that can contribute to the Identification of a threshold for toxlclty of
this chemical to rats. This study appears to define a NOAEL In rats for
toluene-2,6-d1am1ne at 1000 ppm. Although body weight gain was depressed,
no significant adverse effects were observed at this dietary level. Thyroid
hyperplasla was observed at 3000 ppm and frank toxic effects, Including high
mortality, occurred at 10,000 ppm. The NOAEL of 1000 ppm supports the NOAEL
of 500 ppm previously Identified In the chronic study (NCI, 1980). The
NOAEL of 500 ppm was deemed more appropriate for derivation of an ADI
because of the greater number of animals and extended exposure 1n the
chronic study.
0502p -25- 04/27/84
-------
The ADI values for toluene-2,5-d1am1ne sulfate can be calculated 1n the
same manner, using the NOAEL of 2000 ppm Identified 1n the dietary study 1n
rats (NCI, 1978). Assuming that a rat consumes a dally amount of food
equivalent to 5X of Us body weight, an equivalent dose of 100 mg/kg/day can
be calculated. The corresponding dose for toluene-2,5-d1am1ne (the data are
for the sulfate salt of the compound, molecular weight of 220) Is 55.5
mg/kg/day. An ADI value of 38.9 mg/day can be calculated by multiplying the
animal dose by an assumed human body weight of 70 kg and applying an uncer-
tainty factor of 100.
0502p -26- 04/27/84
-------
9. REFERENCES
Ahrenholz, S.H. 1980. Health Hazard Evaluation Determination Report No. HE
79-113-728, Ol1n Chemical Company. Brandenburg. KY. NIOSH-HE-79-113, Order
No. PB 81-167819. p. 24.
Ames, B.N., H.O. Kammen and E. Yamasakl. 1975. Hair dyes are mutagenU:
Identification of a variety of mutagenlc Ingredients. Proc. Natl. Acad.
Sc1. 72: 2423-2427.
Burnett, C., B. Lanman, R. G1ovacch1n1, 6. Uolcott, R. Scala and H.
Kepllnger. 1975. Long-term toxlclty studies on oxidation hair dyes. Food
Cosmet. Toxlcol. 13: 353-357.
Burnett, C., E.I. Goldenthal, S.B. Harris, et al. 1976. Teratology and
percutaneous toxlclty studies on hair dyes. J. Toxlcol. Environ. Health.
1: 1027-1040. (CHed In IARC, 1978)
Burnett, C., R. Loehr and T. Corbett. 1977. Dominant lethal mutagenlclty
study on hair dyes. J. Toxlcol. Environ. Health. 2: 657-662. (Cited 1n
IARC. 1978)
Federal Register. 1982. Phenylenedlamlnes: Response to Interagency Testing
Committee. 47(5): 979.
Florin, I.. L. Rutberg. H. Curvall and C.R. Enzell. 1980. Screening of
tobacco smoke constituents for mutagenlclty using the Ames1 test. Toxico-
logy. 15(3): 219-232.
0502p -27- 04/27/84
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Giles, A.L., Jr., C.W. Chung and C. Kommlnenl. 1976. Dermal cardnogenU-
Uy study by mouse-skin painting with 2,4-toluened1am1ne alone or In repre-
sentative hair dye formulations. J. Toxlcol. Environ. Health. 1: 433-440.
(Cited 1n IARC. 1978)
Greene, E.J. and M.A. Friedman. 1980. In_ vitro cell transformation screen-
Ing of 4 toluenedlamlne Isomers. Mutat. Res. 79(4): 363-376.
Greene, E.J., A.J. Salerno and H.A. Friedman. 1981. Effect of 4 toluene
dlamlne Isomers on murlne testlcular DNA synthesis. Mutat. Res. 91(1):
75-79.
Hossack, D.J.N. and T.C. Richardson. 1977. Examination of the potential
mutagenlclty of hair dye constituents using the mlcronucleus test. Exper-
1ent1a. 33: 377-378.
Hruby, R. 1977. Absorption of para-toluened1am1ne by skin of rats and
dogs. Food Cosmet. Toxlcol. 15(6): 595-599.
IARC (International Agency for Research on Cancer). 1978. In: Some Aro-
matic Amines and Related NHro Compounds - Hair Dyes, Colouring Agents and
Miscellaneous Industrial Chemicals. IARC Monographs on the Evaluation of
the Carcinogenic Risk of Chemicals to Man. WHO. IARC. Lyon, France.
16: 97.
Inouye, M. and U. Murakami. 1977. TeratogenlcUy of 2,5-d1am1notoluene. a
hair dye constituent, 1n mice. Food Cosmet. Toxlcol. 15: 447-451.
0502p -28- 04/27/84
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K1ese, M. and E. Rauscher. 1968. The absorption of p-toluened1am1ne
through human skin 1n hair dyeing. Toxic. Appl. Pharmacol. 13: 325.
r
K1ese. M., M. Rachor and E. Rauscher. 1968. The absorption of some phen-
ylenedlamines through the skin of dogs. Toxlcol. Appl. Pharmacol. 12: 495.
Klnkel, H.J. and S. Holzmann. 1973. Study of long-term percutaneous toxlc-
1ty and cardnogenlcHy of hair dyes (oxidizing dyes) 1n rats. Food Cosmet.
Toxlcol. 11: 641648.
Mackay, D. 1982. Correlation of bloconcentratlon factors. Environ. Sc1.
Toxlcol. 16: 274-278.
Marks, T.A., B.N. Gupta, T.A. Ledoux and R.E. Staples. 1981. Teratogenk
evaluation of 2-n1tro-p-phenylened1am1ne, 4-n1tro-o-phenylened1am1ne and
2,5-toluened1am1ne sulfate In the mouse. Teratology. 24(3): 253-265.
Mllllgan. B. and K.E. Gilbert. 1978. Amines, Aromatic (Dlarylamlnes).
In: K1rk-0thmer Encyclopedia of Chemical Technology, H. Grayson, Ed., 3rd
ed., Vol. 2. John Wiley and Sons, Inc., NY. p. 321-329.
Mlrsalls, J.C., C. Tyson and B.E. Butterworth. 1982. Detection of geno-
toxlc carcinogens 1n the in v1vo-1n vitro hepatocyte DMA repair assay.
Environ. Mutagen. 4(5): 553-562.
NCI (National Cancer Institute). 1978. Bloassay of Toluene-2,5-d1am1ne
Sulfate for Possible CardnogenlcHy. NCI Carclnogenesls Tech. Rep. Ser.
No. 126. p. 50. [Also publ. as DHHS (NIH) 78-1381.]
0502p -29- 04/27/84
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NCI (National Cancer Institute). 1980. Bloassay of 2.6-Toluened1am1ne
DlhydrochloHde for Possible Carclnogenldty. NCI Carclnogenesls Tech. Rep.
Ser. No. 200. p. 109. [Also publ. as DHHS (NIH) 90-1756.]
NIOSH (National Institute of Occupational Safety and Health). 1978. RTECS
(Registry of Toxic Effects of Chemical Substances). May, 1983: Online.
Perkins, W.E. and T.J. Green. 1975. Effect of 3,4-toluenedlamlne on output
from l£ situ rat Brunner's glands pouches. Proc. Soc. Exp. Blol. Med.
149(4): 991-994.
Selye, H. 1973. Production of perforating duodenal ulcers by 3,4-toluene-
dlamlne 1n the rat. Proc. Soc. Exp. B1ol. Med. 142(4): 1192-1194.
Selye, H. and I. Mecs. 1974. Effect upon drug toxldty of surgical Inter-
ference with hepatic or renal function. Acta Hepato-Gastroenterol. 21(3):
191-202.
SmUnova, A.N., L.A. Toropova and V. Dobrovol'skaya. 1967. Effect of
2,3-toluened1am1ne and o-tolu1d1ne on aqueous organisms. Vodosnabzh.,
Kanallz., Gldrotehk. Sooruzhenlya. 5: 17-23. CA 70:94404e.
Snyder, R.C., U.C. Brumley, C.U. Breder and T. Fazio. 1982. Gas chromato-
graphlc and gas chromatographlc-mass spectrometrlc confirmation of 2,4- and
2,6-toluene-d1am1ne determined by liquid chromatography 1n aqueous extracts.
J. Assoc. Off. Anal. Chem. 65(6): 1388.
0502p -30- 04/27/84
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SRI (Stanford Research Institute). 1983. SRI Directory of Chemical Pro-
ducers. Menlo Park, CA.
SRI (Stanford Research Institute). 1976. Chemical Economics Handbook.
Organic Chemicals R-Z, 691.7040-699.9999. Stanford Research Institute,
Menlo Park, CA, Chem. Info. Services.
Thlrtle, J.R. 1968. Phenylened1am1nes. In: Klrk-Othmer, Encyclopedia of
Chemical Technology. E.P. Dukes, Ed., 2nd ed. John Wiley and Sons, Inc.,
NY. 15: 216-224.
U.S. EPA/NIH. 1983. SANSS - Structure and Nomenclature Search System.
Searched through CIS. Online, May. 1983.
U.S. EPA. 1983. TSCA Production File. 1977.
Velth, 6.D., D.L. Defoe and B.V. Bergstedt. 1979. Measuring and estimating
the bloconcentratlon factor of chemicals 1n fish. J. F1sh Res. Board Can.
36(9): 1040-1048.
Wild, 0.. M.-T. King and K. Eckhardt. 1980. Cytogenetlc effect of o-pheny-
lenedlamlne. Arch. Toxlcol. 43(4): 249-256.
0502p -31- 04/27/84
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APPENDIX: LITERATURE SEARCHED
This profile 1s based on data Identified by computerized literature
searches of:
CA SEARCH (Files 308, 309, 310, 311, 320)
TOXLINE
MEDLINE
RTECS
SCI SEARCH
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
EPCASR
Chemical Industry Notes
These searches were conducted 1n Hay, 1983. In addition, hand searches were
made of Chemical Abstracts (Collective Indices 7 and 8th), and the following
secondary sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1980. TLVs: Documentation of the Threshold Limit Values, 4th ed.
(Includes Supplemental Documentation, 1981). Cincinnati, OH.
p. 486.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1982. Documentation of the Threshold Limit Values for Chemical
Substances 1n Work A1r. Cincinnati, OH. p. 94.
Bruin, P., G.J. Bergen and J.J. Desta, Ed. 1980. Handling Chem-
icals Safely, 2nd ed. Dutch Assoc. of Safety Experts, Dutch
Chemical Industry Assoc. and Dutch Safety Institute, The Nether-
lands, p. 1013.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. p. 2878.
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