United Ststes
Environmental Protection ECAO-CIN-P223
Agency June, 19Q7
EPA Research and
Development
HEALTH AND ENVIRONMENTAL EFFECTS PROFILE
FOR 3,3'-DIMETHYLBENZIDINE
Prepared for
OFFICE OF SOLID WASTE AND
EMERGENCY RESPONSE
D . .
Prepared by 230 south 0** street
Chicago, |/iino;s 60604
Environmental Criteria and Assessment Office
Office of Health and Environmental Assessment
U.S. Environmental Protection Agency
Cincinnati, OH 45268
DRAFT: DO NOT CITE OR QUOTE
NOTICE
This document Is a preliminary draft. It has not been formally released
by the U.S. Environmental Protection Agency and should not at this stage be
construed to represent Agency policy. It Is being circulated for comments
on Its technical accuracy and policy Implications.
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DISCLAIMER
This report 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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PREFACE
Health and Environmental Effects Profiles (HEEPs) are prepared for the
Office of Solid Waste and Emergency Response by the Office of Health and
Environmental Assessment. The HEEPs are Intended to support listings of
hazardous constituents of a wide range of waste streams under Section 3001
of the Resource Conservation and Recovery Act (RCRA), as well as to provide
health-related limits for emergency actions under Section 101 of the Compre-
hensive Environmental Response, Compensation and Liability Act (CERCLA).
Both published literature and Information obtained from Agency program
office files are evaluated as they pertain to potential human health,
aquatic life and environmental effects of hazardous waste constituents. The
literature searched and the dates of the searches are Included 1n the
section titled "Appendix: Literature Searched." The literature search
material Is current through November, 1985.
Quantitative estimates are presented provided sufficient data are
available. For systemic toxicants, these Include Reference doses (RfDs) for
chronic exposures. An RfD 1s defined as the amount of a chemical to which
humans can be exposed on a dally basis over an extended period of time
(usually a lifetime) without suffering a deleterious effect. In the case of
suspected carcinogens, RfDs are not estimated In this document series.
Instead, a carcinogenic potency factor of q-j* 1s provided. These potency
estimates are derived for both oral and Inhalation exposures where possible.-
In addition, unit risk estimates for air and drinking water are presented
based on Inhalation and oral data, respectively.
Reportable quantities (RQs) based on both chronic toxldty and cardno-
genlclty are derived. The RQ Is used to determine the quantity'of a hazard-
ous substance for which notification 1s required 1n the event of a release
as specified under CERCLA. These two RQs (chronic toxldty and carclnogen-
1c1ty) represent two of six scores developed (the remaining four reflect
1gn1tab1l1ty, reactivity, aquatic toxldty and acute mammalian toxldty).
The first draft of this document was prepared by Syracuse Research
Corporation under EPA Contract Mo. 68-03-3228. The document was subse-
quently revised after reviews by staff within the Office of Health and
Environmental Assessment: Carcinogen Assessment Group, Reproductive Effects
Assessment Group, Exposure Assessment Group, and the Environmental Criteria
and Assessment Office 1n Cincinnati.
The HEEPs will become part of the EPA RCRA and CERCLA dockets.
111
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EXECUTIVE SUMMARY
3,3'-D1methylbenz1d1ne 1s a white to reddish crystalline compound at
ambient temperature. It Is sparingly soluble In water and 1s soluble 1n
ether, alcohol and dilute adds (Wlndholz, 1983). It 1s a weak base and
undergoes reactions similar to those of benzldlne (IARC, 1972; Ferber,
1978). 3,3'-01methylbenz1d1ne 1s made by the reaction of o-n1trotoluene
with zinc dust and caustic soda to form hydrazotoluene, which 1s subsequent-
ly rearranged by boiling with sulfurlc or hydrochloric acid (Lurle, 1964;
Powell et al., 1979). No current commercial manufacturers of 3,3'-d1methyl-
benzldlne 1n the United States were reported 1n SRI (1986) or USITC (1985).
In 1983, 75,307 pounds of this compound was Imported Into the United States
through principal customs districts (USITC, 1984). It Is estimated that
>75X of the 3,3'-d1methylbenz1d1ne consumed Is used as an Intermediate 1n
the production of azo dyes and pigments used for coloring paper, textiles
and leathers and for diverse applications 1n the petroleum, rubber,
plastics, wood, soap, fur and hair dye Industries (Powell et al., 1979;
NIOSH, 1980). Approximately 20% of the 3,3'-d1methylbenz1d1ne consumed
domestically 1s used 1n the production of polyurethane-based high strength
elastomers, coatings and rigid plastics and <5X 1s used for chlorine detec-
tion and other laboratory procedures (Powell et al., 1979).
3,3'-D1methylbenz1d1ne 1s a weak base and as such, may be protonated and
form salts that are more soluble than the parent compound. Variations In
the behavior of 3,3'-d1methylbenz1d1ne 1n the environment may result from
protonatlon. If released to water, 3,3'-d1methylbenz1d1ne Is expected to be
oxidized by Fe{*3) and other cations fairly rapidly (U.S. EPA, 1979). The
half-life of this oxidation may be <4 hours. It 1s likely to be resistant
1v
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to hydrolysis (Schmltz and Rooze, 1981; Lyman et al., 1982). Potential
exists for significant photolysis of 3,3'-d1methylbenz1d1ne. Adsorption to
mlcrocrystalUne clay and covalent binding to suspended solids and sediments
may be significant (U.S. EPA, 1979; ParMs, 1980). In fact, adsorption by
mlcrocrystalUne clays may be the most Important process 1n water. Bloaccu-
mulatlon 1n aquatic organisms and volatilization from water should not be
significant removal processes. If released to air, vapor phase 3,3'-d1-
methylbenzldlne 1s predicted to react with hydroxyl radicals and has an
estimated half-life of 4.0 hours at 25°C (U.S. EPA, 1986b). Direct photoly-
sis In the troposphere Is also likely to be a significant removal mechanism.
Reaction with ozone Is unlikely (U.S. EPA, 1986b). If released to soil,
3,3'-d1methylbenz1d1ne Is likely to be resistant to hydrolysis (Lyman et
al., 1982). 3,3'-01methylbenz1d1ne may be Immobilized 1n soil by physical
adsorption and covalent binding. Some mobilization may occur In acidic
*
soils because of the protonatlon process. Volatilization from wet and dry
soil surfaces should not be significant. Soil-catalyzed oxidation of
3,3'-d1methylbenz1d1ne may be the most significant reaction of this chemical
and the half-life of this reaction may be <1 day (U.S. EPA, 1980; Lapp et
al., 1981).
Monitoring data regarding 3,3'-d1methylbenz1d1ne could not be located In
the available literature as cited In the Appendix. This compound 1s not
known to occur naturally 1n the environment (U.S. EPA, 1980). Potential
sources of major -release are In air-borne partlculate matter and wastewater
from manufacturing and processing plants for dyes and pigments derived frpm
3,3'-d1methylbenz1d1ne (U.S. EPA, 1980; Lapp et al., 1981).
Minor sources of release may originate from clothing, colored paper,
textiles, leather and other dyed materials that are commonly disposed of In
solid waste disposal sites (U.S. EPA, 1980).
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The workers who manufacture and handle 3,3'-d1methylbenz1d1ne-based dyes
and pigments are likely to be the most exposed segment of the population
(U.S. EPA, 1980)i." Urine samples from some workers exposed to azo dyes
during manufacture (two sites) and use (four sites) contained ppb levels of
3,3'-d1methylbenz1d1ne (Lowry et al., 1980). Workers In biochemical and
clinical laboratories where 3,3'-d1methylbenz1d1ne 1s used may also be
exposed (U.S. EPA, 1980). Exposure can occur by Inhalation, Ingestlon and
skin contact (OSHA/NIOSH, 1980). Dermal exposure to the general population
could result from consumer use of dyes packaged for home use, products
derived from 3,3'-d1methylbenz1d1ne, as well as products treated with these
compounds (U.S. EPA, 1980).
Pertinent data regarding effects of 3,3'-d1methylbenz1d1ne on aquatic
biota could not be located In the available literature as dted 1n the
Appendix.
3,3'-01methylbenz1d1ne 1s' absorbed after oral or dermal exposure. Rats
treated orally with l4C-3,3'-d1methylbenz1d1ne excreted -40% of the dose
of radioactivity 1n the urine and -59X 1n the feces 1n 8 days (Bowman et
al., 1982). Bowman et al. (1982) suggested that biliary excretion was
substantial, since ~89X of the fecal radioactivity was present as possible
biliary metabolites. Thus, gastrointestinal absorption may be as great as
93%. The appearance of 3,3'-d1methylbenz1d1ne 1n the urine of occupation-
ally exposed humans Indicates that dermal absorption occurs (Melgs et al.,
. 1954). Following absorption, 3,3'-d1methylbenz1d1ne 1s widely distributed
1n rats (Bowman et al., 1982). Metabolites Identified 1n the urine of
exposed rats were 1,l-d1acetyl-3,3'-d1methylbenz1d1ne, alkaline hydrolyzable
conjugates and monoacetyl-3,3'-d1methylbenz1d1ne as well as parent compound.
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Metabolites Identified 1n the urine of exposed workers were mono- and d1-
acetyl-3,3'-d1methylbenz1d1ne, 5-hydroxy-3,3'-d1methylbenz1d1ne and possibly
3,3'-benz1d1ned1carboxyl1c add.
Grlswold et al. (19"68) observed an Increased Incidence of mammary tumors
In rats treated by gavage with a total of 500 mg/rat over 30 days and
observed for 9 months compared with controls. No tumors were observed 1n
hamsters treated with 3,3'-d1methylbenz1d1ne In the diet at 0.1 or 0.3% for
the Hfespan (Safflotl et al., 1967; Sellakumar et al., 1969). Ferber
(1977) reported a study 1n which one case of bladder cancer was observed 1n
1/4 dogs 8 years after being fed 3,3'-d1methylbenz1d1ne at 200 mg/day for
8-9 months. 3,3'-01methylbenz1d1ne 1s being tested by the National Toxicol-
ogy Program (NTP, 1986). Preliminary pathological results Indicate that
3,3'-d1methylbenz1d1ne administered 1n drinking water Induces a carcinogenic
effect In F344 rats (Mennear, 1987).
There are numerous positive cardnogenlcHy studies for 3,3'-d1methyl-
benzldlne as well as some that are negative. Overall the animal evidence 1s
considered sufficient using EPA's we1ght-of-evidence criteria (Group B2).
Several positive cardnogenlcHy studies by Injection and subcutaneous
administration were available as well. In rats given subcutaneous doses of
3,3'-d1methylbenz1d1ne, tumors were observed In the Zymbal gland, preputlal
gland, forestomach, skin,'lung (PUss and Zabezhlnsky, 1970), heart (rhabdo-
myosarcoma) (Pllss and VoVfson, 1973) and external auditory canal (Spitz et
al., 1950). In- rats subcutaneously Implanted with pellets containing
3,3'-d1methylbenz1d1ne, Zymbal gland, mammary gland, skin, liver and hemato-
poletlc system tumors were observed (PUss and Zabezhlnsky, 1970). Increased
Incidences of mammary and lung tumors were observed 1n the offspring of mice
Injected subcutaneously during gestation (Golub et al., 1974).
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The possible carcinogenic effects of 3,3'-d1methylbenz1d1ne In humans
are not assessed adequately to determine the direct effect of 3,3'-d1methyl-
benzldlne alone. Urinary system cancer In workers exposed to mixtures of
benzldlne, 3,3'-d1methylbenz1d1ne and 3,3'-d1methoxybenz1d1ne has been
reported (MacAlplne, 1947; Kuratsune and Takemura, 1969); however, adequate
1nterpret1on of these results are confounded by the presence of benzldlne, a
known human bladder carcinogen.
The mutagenlclty of 3,3'-d1methylbenz1d1ne has been tested In various
prokaryotlc and eukaryotlc systems. 3,3'-01methylbenz1d1ne gave predomi-
nantly positive results 1n frameshlft sensitive tester strains of Salmonella
typhlmurlum after liver S-9 metabolic activation (Reid et al., 1984a;
Waalkens et al., 1981; Anderson and Styles, 1978; Kenelly et al., 1984;
Lazear and Louie, 1977; Prlval et al., 1984; Ferettl et al., 1977).
Positive results were obtained 1n DNA repair tests In the Escher1ch1a coll
*
growth' differential test (N1sh1oka and Ogasawara, 1978), hepatocytes
Isolated from rats and hamsters, and 1n HeLa cells with rat liver metabolic
activation (Martin et al., 1978). Positive results were obtained 1n the
\
sex-Hnked recessive lethal test using Drosophlla melanoqaster after feeding
adult males 3,3'-d1methylbenz1d1ne (Valencia et al., 1985). Negative
results, however, were found In DrosophUa for the Induction of reciprocal
translocatlons-. Positive results were obtained In a mlcronucleus test 1n
rats (C1hak, 1979), In a testlcular DNA synthesis test 1n mice (Seller,
1977) and 1n a ce.ll transformation test 1n rat embryo cells (Freeman et al.,
1973).
The teratogenldty of 3,3'-d1methylbenz1d1ne has not been adequately
assessed by a relevant route of administration. WHson (1955) observed no
malformations 1n progeny of pregnant rats subcutaneously Injected with
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3,3'-d1methylbenz1d1ne, but did observe a -7% Increase of resorptlons. Ema
et al. (1984) did not observe fetotoxlc effects In progeny of rat dams sub-
cutaneously Injected with 3,3'-d1methylbenz1d1ne. Pertinent data regarding
the reproductive effects of 3,3'-d1methylbenz1d1ne could not be located 1n
the available literature as cited 1n the Appendix.
The chronic and subchronlc toxldty of 3,3'-d1methylbenz1d1ne has not
been studied.
The lack of subchronlc and chronic toxldty data on 3,3'-d1methylbenz1-
dlne precludes the derivation of an RfD or RQ. 3,3'-01methylbenz1d1ne 1s
considered to be an animal carcinogen based on the results of subcutaneous.
Injection and oral studies. The U.S. EPA (1986a) listed an F factor of 34
(mg/kg/day)""1. This F factor would place 3,3'-d1methylbenz1d1ne In
Potency Group 2. U.S. EPA (1986a) assigned an EPA we1ght-of-evidence
classification of C; however, this assessment amends that classlflctlon to
Group 82 and a medium hazard ranking under CERCLA. A preliminary q * of
9.2 mg/kg/day'1 was derived from the Grlswold et al. (1968) study. When
the current NTP study becomes available, the carcinogenic potency of
3,3'-d1methylbenz1d1ne will be reevaluated.
1x
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TABLE OF CONTENTS
Page
1. INTRODUCTION. 1
1.1. STRUCTURE AND CAS NUMBER 1
1.2. PHYSICAL AND CHEMICAL PROPERTIES 1
1.3. PRODUCTION DATA 2
1.4. USE DATA 2
1.5. SUMMARY 4
2. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES 5
2.1. WATER 5
2.1.1. Hydrolysis 5
2.1.2. Oxidation 5
2.1.3. Photolysis 5
2.1.4. Other Chemical Reactions 6
2.1.5. B1odegradat1on 6
2.1.6. Adsorption 6
2.1.7. Volatilization 6
2.1.8. Bloaccumulatlon 7
2.2. AIR 7
2.2.1. Reaction with Hydroxyl Radicals 7
2.2.2. Reaction with Ozone 7
2.2.3. Photolysis " 7
2.3. SOIL 7
2.3.1. Chemical and H1crob1al Degradation 7
2.3.2. Adsorption 8
2.3.3. Volatilization 8
2.4. SUMMARY 9
3. EXPOSURE 10
4. PHARMACOKINETCS . 11
4.1. ABSORPTION 11
4.2. DISTRIBUTION 11
4.3. METABOLISM 12
4.4. EXCRETION 12
4.5. SUMMARY 13
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TABLE OF CONTENTS (cont.)
Page
5. EFFECTS . . ; 14
5.1. CARCINOGENICITY 14
5.1.1. Animal Studies 14
5.1.2. Human Studies 17
5.2. MUTAGENICITY 18
5.3. TERATOGENICITY 22
5.4. OTHER REPRODUCTIVE EFFECTS 22
5.5. CHRONIC AND SUBCHRONIC TOXICITY 22
5.6. OTHER RELEVANT INFORMATION 22
5.7. SUMMARY 23
6. AQUATIC TOXICITY 26
7. EXISTING GUIDELINES AND STANDARDS 27
7.1. HUMAN 27
7.2. AQUATIC 27
8. RISK ASSESSMENT 28
9. REPORTABLE QUANTITIES 34
9.1. REPORTABLE QUANTITY (RQ) RANKING BASED ON CHRONIC
TOXICITY 34
9.2. HEIGHT OF EVIDENCE AND POTENCY FACTOR (F=1/ED10)
FOR CARCINOGENICITY 34
10. REFERENCES 37
APPENDIX: LITERATURE SEARCHED 48
x1
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LIST OF TABLES
No. Title Page
1-1 Manufacturers or Importers of 3,3'-D1methylbenz1d1ne
In 1977 3
5-1 Mammary Tumor Incidence 1n 45-Day-Old Female Sprague-
Dawley Rats Given 50 mg 3,3'-01methylbenz1d1ne of
Unspecified Purity 1n Sesame 011 at 3-Day Intervals for
30 Days, Followed by a 9-Month Observation Period 15
5-2 MutagenlcHy Testing of 3,3'-D1methylbenz1d1ne 19
8-1 Derivation of Potency Factor (F factor) for
3,3'-D1methylbenz1d1ne 32
9-1 3,3'-D1methylbenz1d1ne: Minimum Effective Dose (MED) and
Reportable Quantity (RQ) 35
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LIST OF ABBREVIATIONS
ADI Acceptable dally Intake
BCF B1oconcentrat1on factor
CAS Chemical Abstract Service
DNA Deoxyr1bonucle1c acid
FMN Flavin mononucleotlde
Koc Soil sorptlon coefficient standardized
with respect to organic carbon
Kow Octanol/water partition coefficient
HTO Maximum tolerated dose
ppb Parts per billion
RfD Reference dose
RQ Reportable quantity
TLV Threshold limit value
TRNA Transfer rlbonuclelc add
TWA Time .-weigh ted average
UDS Unscheduled ONA synthesis
UV Ultraviolet
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1. INTRODUCTION
1.1. STRUCTURE AND CAS NUMBER
3,3'-D1methylbenz1d1ne 1s also known as o-to!1d1ne, 3,3'-d1methy1-l ,V-
b1phenyl-4,4'-d1am1ne, d1am1nod1tolyl and C.I. Azoic 01azo Component 113
(C.I. 37230). The structure, molecular weight, empirical formula and CAS
Registry number for 3,3'-d1methylbenz1d1ne are as follows:
H,C CH,
Molecular weight: 212.28
Empirical formula: CT4HigN2
CAS Registry number: 119-93-7
1.2. PHYSICAL AND CHEMICAL PROPERTIES
3,3'-D1methylbenz1d1ne 1s a white to reddish crystalline compound at
ambient temperature (Wlndholz, 1983). It 1s a weak base (IARC, 1972) and
Us reactions are s1m1!1ar to those of benzldlne, which undergoes chemical
reactions characteristic of primary arylamlnes as well as those reactions
related to Us dlfunctlonal character such as oxidation to qulnonold struc-
tures and copolymerlzatlon (Ferber, 1978). 3,3'-D1methylbenz1d1ne forms
Intense blue compounds with chlorine and bromine vapors (Lurle, 1964).
3,3'-D1methylbenz1d1ne Is soluble In alcohol, ether and dilute adds
(Wlndholz, 1983). Selected physical properties are as follows:
Melting point:
Boiling point:
Vapor pressure at 20*C:
129-13TC
416-419°C
(estimated)
2.7xlO"7 mm Hg
(estimated)
Wlndholz, 1983
Neely and Blau, 1985
Neely and Blau, 1985
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Water solubility at 25°C: 2400 rng/l Lyman et al., 1982
(estimated) (equation 2-2)
Log Kow: 2.34 Hansch and Leo, 1985
1.3. PRODUCTION DATA
3,3'-D1methylbenz1d1ne 1s made by the reduction of o-n1trotoluene with
zinc dust and caustic soda to hydrazotoluene, which Is subsequently
rearranged by boiling with sulfurlc or hydrochloric acid (Lurle, 1964;
Powell et al., 1979). Organic diluents such as solvent naphtha and alcohol
are used to moderate this vigorous reaction (Lurle, 1964). No current
commercial manufacturers of 3,3'-d1methylbenz1d1ne 1n the United States were
reported (SRI, 1986; USITC, 1985). Table 1-1 lists the U.S. manufacturers
or Importers of this compound 1n 1977 and their production volumes.
In 1978, Upjohn discontinued manufacturing this compound and began
Importing H (Powell et al., 1979). In 1983, 75,307 pounds of 3,3'-d1-
methylbenzldlne was Imported Into the United States through principal
customs districts (USITC, 1984).
1.4. USE DATA
It 1s estimated that >75% of the 3,3'-d1methylbenz1d1ne consumed Is used
as an Intermediate 1n the production of dyes and pigments (Powell et al.,
1979). Twenty-two azo dyes are produced domestically from 3,3'-d1methyl-
benzldlne (U.S. EPA, 1980), the most Important of which are Direct Red 2,
Direct Red 39 and Direct Blue 25 (Ferber, 1978). The use pattern for
benz1d1ne-based dyes 1s as follows: paper coloring, 40%; textile coloring,
25%; leather coloring, 15%; diverse applications 1n the petroleum, rubber
plastics, wood, soap, fur and hair dye Industries, 20% (NIOSH, 1980).
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TABLE 1-1
Hanufacturers or Importers of 3,3'-D1methylbenz1d1ne 1n 1977*
Company/Location
The Upjohn Co.
North Haven, CT
Aceto Chem Co., Inc.
Flushing, N.Y.
American Hoechst Corp.
Brldgewater, NJ
Nagase America Corp.
New York, NY
GAP Corp.
New York, NY
Manufacturer
or Importer
manufacturer
Importer
Importer
Importer
Importer
Production/Import Volume
(million pounds)
confidential
0.010-0.100
confidential
0.010-0.100
0.001-0.010
*Source: U.S. EPA, 1977
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Approximately 20% of 3,3'-d1methylbenz1d1ne consumed domestically 1s used 1n
the production of polyurethane-based high strength elastomers, coatings and
rigid plastics. 3;3'-D1methylbenz1d1ne Is also used for chlorine detection
and other laboratory procedures; however, this accounts for <5% of the
3,3'-d1methylbenz1d1ne used domestically (Powell et al., 1979).
1.5. SUMMARY
3,3'-D1methylbenz1d1ne 1s a white to reddish crystalline compound at
ambient temperature. It Is sparingly soluble 1n water and 1s soluble In
ether, alcohol and dilute acids (VMndholz, 1983). It 1s a weak base and
undergoes reactions similar to those of benzldlne (IARC, 1972; Ferber,
1978). 3,3'-01methylbenz1d1ne Is made by the reaction of o-n1trotoluene
with zinc dust and caustic soda to form hydrazotoluene,. which 1s subse-
quently rearranged by boiling with sulfurlc or hydrochloric add {Lurle,
1964; Powell et al., 1979). No current commercial manufacturers of
3,3'-d1methylbenz1d1ne 1n the United States were reported (SRI, 1986; USITC,
1985). In 1983, 75,307 pounds of this compound was Imported Into the United
States through principal customs districts (USITC, 1984). It 1s estimated
that >75X of the 3,3'-d1methylbenz1d1ne consumed 1s used as an Intermediate
1n the production of azo dyes and pigments used for coloring paper, textiles
and leathers and for diverse applications In the petroleum, rubber,
plastics, wood, soap, fur and hair dye Industries (Powell et al., 1979;
NIOSH, 1980). Approximately 20% of the 3,3'-d1methylbenz1d1ne consumed
domestically Is used In the production of polyurethane-based high strength
elastomers, coatings and rigid plastics and <5% 1s used for chlorine
detection and other laboratory procedures (Powell et al., 1979).
0857p -4- 04/10/87
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2. ENVIRONMENTAL FATE AND TRANSPORT PROCESSES
3,3'-01methylbenz1d1ne 1s a weak base that may be protonated under
acidic conditions to form salts that are more water soluble than the parent
compound. Protonatlon can alter the behavior of a compound 1n water and
soil, for example, by decreasing volatilization as well as Increasing or
decreasing adsorption to soil, sediments and suspended solids In water.
2.1. WATER
2.1.1. Hydrolysis. Based on the structure of 3,3'-d1methylbenz1d1ne,
this compound 1s likely to be resistant to hydrolysis (Lyman et a!., 1982).
2.1.2. Oxidation. Pertinent data regarding the oxidation of this
compound could not be located In the available literature as cited 1n the
Appendix; however, unsubstHuted benzldlne Is very rapidly oxidized by
Fe(*3) and other naturally occurring cations found 1n natural waters (U.S.
EPA, 1979). Because of the two methyl substltuents on the aromatic ring,
3,3'-d1methylbenz1d1ne may have a higher tendency to undergo this oxidation
by metal cations. Based on the fate of benzldlne 1n water (U.S. EPA, 1979),
oxidation by other oxldants Including molecular 0_ and H02 radicals will
also take place, although oxidation by metal cations 1n natural water may be
more rapid. On the basis of the estimated oxidation half-life of benzldlne
In natural water (U.S. EPA, 1979), the half-life of 3,3'-d1methylbenz1d1nes
1s estimated to be <4 hours.
2.1.3. Photolysis. D1methylbenz1d1ne 1n methanol strongly absorbs UV
light 1n the environmentally significant wavelength range of >290 nm
(Sadtler, n.d.). These data Indicate that direct photolytlc reactions may
be significant 1n removing 3,3'-d1methylbenz1d1ne from water. Experimental
>
data on the photolysis of this compound could not be located In the avail-
able literature as cited In the Appendix.
0857p -5- 04/10/87
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2.1.4. Other Chemical Reactions. Schmltz and Rooze (1981) reported that
3,3'-d1methy1benz1d1ne reacts rapidly with chlorine and with chlorine diox-
ide 1n aqueous solution, suggesting that these reactions could contribute
significantly to the removal of 3,3'-d1methy1benz1d1ne from water, particu-
larly during the disinfection of drinking water.
2.1.5. Blodegradatlon. Pertinent data regarding the blodegradatlon of
3,3'-d1methylbenz1d1ne were limited. An aerobic blodegradatlon screening
study using 20 mg/i 3,3'-d1methylbenz1d1ne Inoculated with activated
sludge at 25°C resulted 1n 99-100% depletion of the parent compound 1n 6
hours (Balrd et al., 1977). The metabolic Intermediates, however, were
speculated to be toxic to microorganisms and the oxygen consumption 1n
experiments with 3,3'-d1methylbenz1d1ne was less than the endogenous process.
2.1.6. Adsorption. Based on observed covalent binding of primary amines
to humates (Parrls, 1980) and the estimated K of 60-271 (Section
2.3.2.), physical adsorption and covalent bonding to suspended solids and
sediments 1n water may be significant. In fact, based on the studies with
benzldlne and 3,3'-d1chlorobenz1d1ne (U.S. EPA, 1979) 1t 1s likely that
adsorption by suspended mlcrocrystalUne clays may be the most Important
process and the half-life of that process may be <1 hour.
2.1.7. Volatilization. 3,3'-01methylbenz1d1ne should not volatilize
significantly from water because of possible protonatlon In water at pH<7.
The adsorption to mlcrocrystalllne clays and covalent binding with humates
1n water will also reduce volatility. The volatility may be higher at pH>7
than at pH<7.
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2.1.8. B1oaccurou1at1on. The BCF for 3,3'-d1methylbenz1d1ne has been
estimated using the following recommended linear regression equations (Lyman
et a!., 1982):
log BCF = 0.76 log KQW - 0.23 (2-1)
log BCF = 2.791 - 0.564 log S(rag/1J (2-2)
Based on the estimated log K of 2.34 and solubility of 2400 mg/i at
25°C, the BCF for 3,3'-d1methylbenz1d1ne has been calculated to be 35 and 8
from Equations 2-1 and 2-2, respectively. These BCF values Indicate that
3,3'-d1methylbenz1d1ne should not bloaccumulate significantly In aquatic
organisms.
2.2. AIR
2.2.1. Reaction with Hydroxyl Radicals. 3,3'-01methylbenz1d1ne 1n the
vapor phase will react 1n the atmosphere with photochemlcally generated
hydroxyl radicals. The hydroxyl reaction rate constant has been estimated
to be 6.02X10"11 cmVmolecule-sec at 25°C. Assuming an ambient hydroxyl
radical concentration of 8.0x10= molecules/cm3, the reaction half-life
has been estimated to be 4.0 hours (U.S. EPA, 1986b).
2.2.2. Reaction with Ozone. 3,3'-01methylbenz1d1ne 1s not susceptible to
oxidation by ozone (U.S. EPA, 1986b).
2.2.3. Photolysis. Since 3,3'-d1methylbenz1d1ne In methanol strongly
absorbs UV light of wavelengths >290 nm (Sadtler, n.d.), direct photolysis
may be significant In the troposphere.
2.3. SOIL
2.3.1. Chemical and M1crob1al Degradation. Pertinent data regarding the
chemical or mlcroblal degradation of 3,3'-d1methylbenz1d1ne In soil could
not be located 1n the available literature. Based on the molecular struc-
ture of 3,3'-d1methylbenz1d1ne, this compound Is likely to be resistant to
0857p -7- 06/10/87
-------
hydrolysis (Lyman et al., 1982). Benzldlne, a cogener of 3,3'-d1methyl-
benzldlne Is reported to undergo rapid oxidation In clay soils with a
half-life of <1 day (U.S. EPA, 1980; Lapp et al., 1981). Therefore, H Is
expected that 3,3'-d1methylbenz1d1ne will also undergo this soil-catalyzed
oxidation and the half-life of this reaction may be <1 day.
2.3.2. Adsorption. ParMs (1980) experimentally determined that primary
amines covalently bind to humates (soil organic matter) Initially by a
rapid, reversible reaction followed by a slower Irreversible binding
process. The K for 3,3'-d1methylbenz1d1ne has been calculated using the
following linear regression equations (Lyman et al., 1982):
log KQC = -0.55 log S(mg/l) + 3.64 (2-3)
log KQC = -0.54 log S(mol fraction) + 0.44 (2-4>-
Based on a water solubility of 2400 mg/l at 25°C, KQ(. values of 60 and
271 were calculated from Equations 2-3 and 2-4, respectively. These K
values suggest that 3,3'-d1methylbenz1d1ne may be moderately mobile 1n soil
(Swann et al., 1983); however, since benzldlne and substituted benzldlne are
known to adsorb strongly and rapidly to mlcrocrystalUne clays (U.S. EPA,
1979), 3,3'-d1methylbenz1d1ne may be significantly Immobilized 1n certain
soil types by physical adsorption and covalent binding. In addle soils
some mobilization of the compound Is expected because of protonatlon.
2.3.3. Volatilization. Pertinent experimental data regarding volatiliza-
tion of 3,3'-d1methylbenz1d1ne 1n soil could not be located In the available
literature as cited 1n the Appendix. Based on the water solubility (2400
mg/l at 25°C), possible protonatlon 1n acidic soils and adsorption and
covalent binding to soils (see Section 2.3.2.), volatilization from wet and
dry soil surfaces 1s not expected to be significant.
Q857p -8- 06/10/87
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2.4. SUMMARY
3,3'-D1methy1benz1d1ne Is a weak base and as such, may be protonated and
form salts that are more soluble than the parent compound. Variations In
the behavior of 3,3'-d1methylbenz1d1ne In the environment may result from
protonatlon. If released to water, 3,3'-d1methylbenz1d1ne 1s expected to be
oxidized by Fe{+3) and other cations fairly rapidly (U.S. EPA, 1979). The
half-life of this oxidation may be <4 hours. It Is likely to be resistant
to hydrolysis (Schmltz and Rooze, 1981; Lyman et al.. 1982). Potential
exists for significant photolysis of 3,3'-d1methylbenz1d1ne. Adsorption to
mlcrqcrystalUne clay and covalent binding to suspended solids and sediments
may be significant (U.S. EPA, 1979; ParMs, 1980). In fact, adsorption by
mlcrocrystalUne clays may be the most Important process In water. Bloaccu-.
mulatlon In aquatic organisms and volatilization from water should not be
significant removal processes. If released to air, vapor phase 3,3'-d1-
methylbenzldlne 1s predicted to react with hydroxyl radicals and has an
estimated half-life of 4.0 hours at 25°C (U.S. EPA, 1986b). Direct photoly-
sis In the troposphere 1s also Hkely to be a significant removal mechanism.
Reaction with ozone Is unlikely (U.S. EPA, 1986b). If released to soil,
3,3'-d1methylbenz1d1ne Is likely to be resistant to hydrolysis (Lyman et
al., 1982). 3,3'-D1methylbenz1d1ne may be Immobilized 1n soil by physical
adsorption and covalent binding. Some mobilization may occur In acidic
soils because of protonatlon. Volatilization from wet and dry soil surfaces
should not be significant. Soil-catalyzed oxidation of 3,3'-d1methylbenz1-
dlne may be the most significant reaction of this chemical and the half-life
of this reaction may be <1 day (U.S. EPA, 1980; Lapp et al., 1981).
0857p -9- 06/10/87
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3. EXPOSURE
Monitoring data regarding 3,3'-d1methylbenz1d1ne could not be located In
the available literature as cited 1n the Appendix. This compound 1s not
known to occur naturally In the environment (U.S. EPA, 1980). Potential
sources of major release are 1n airborne partlculate matter and wastewater
from manufacturing and processing plants for dyes and pigments derived from
3,3'-d1methylbenz1d1ne (U.S. EPA, 1980; Lapp et al., 1981).
Minor sources of release may originate from clothing, colored paper,
textiles, leather and other dyed materials that are commonly disposed of 1n
solid waste disposal sites (U.S. EPA, 1980).
The workers who manufacture and handle 3,3'-d1methylbenz1d1ne-based dyes
and pigments are likely to be the most exposed segment of the population
(U.S. EPA, 1980). Urine samples from some workers exposed to azo dyes
during manufacture (two sites) and use (four sites) contained ppb levels of
3,3'-d1methylbenz1d1ne (Lowry et al., 1980). Workers 1n biochemical and
clinical laboratories where 3,3'-d1methylbenz1d1ne 1s used may also be
exposed (U.S. EPA, 1980). Exposure can occur by Inhalation, Ingestlon and
skin contact (OSHA/NIOSH, 1980). Dermal exposure to the general population
could result from consumer use of dyes packaged for home use, products
derived from 3,3'-d1methylbenz1d1ne, as well as products treated with these
compounds (U.S. EPA, 1980).
0857p -10- 10/01/86
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4. PHARMACOKINETICS
4.1. ABSORPTION
Bowman et a1..(1982) .treated male rats with single oral doses that con-
tained 17 yg of l*C-3,3'-d1methylbenz1d1ne (uniformly ring-labeled) oral
765 yg of unlabeled 3,3-d1methylbenz1d1ne-2HCl. The vehicle was dilute
aqueous HC1. After 192 hours, -40 and 59% of the radioactive dose was
excreted 1n the urine and feces, respectively. As 89% of the fecal radio-
activity represented possible biliary metabolites, biliary excretion may
have accounted for the high degree of fecal excretion. Therefore, absorp-
tion by the gastrointestinal tract may have been at least 93%. Bowman et
al. (1982) did not Investigate biliary excretion 1n bile duct cannulated
rats, however. Melgs et al. (1954) detected 3,3'-d1methylbenz1d1ne In the
urine of occupatlonally exposed workers, Indicating that dermal exposure of
humans results 1n absorption by this route.
4.2. DISTRIBUTION
Bowman et al. (1982) gave rats single oral doses of l*C-3,3'-d1methyl-
benzldlne (see Section 4.1.) and assayed the tissues for distribution 72
hours later. Radioactivity was widely distributed to tissues. The highest
levels of 14C were observed In the liver (0.907 yg equ1v/g), lung (0.459
yg equ1v/g) and kidney (0.130 yg equ1v/g). Small amounts of radioactiv-
ity (0.004-0.048 yg equlv/g) were also found In brain, muscle, testes,
heart, spleen, blood and urinary bladder. Levels In adipose tissue were
below detection levels (<0.014 yg equ1v/g).
PUss and Zabezhlnsky (1970) subcutaneously Injected rats with 3,3'-d1-
methylbenz1d1ne 1n sunflower oil at a dose of 20 mg/rat once weekly for 8
months. At 3 days after the last dose, the rats were killed and the levels
Q857p -11- 04/10/87
-------
of amines were measured for several organs. The highest amlne levels (free
and bound added together) as mg/g tissue 1n descending order were observed
1n the Zymbal gland', kidney, omentum, spleen and liver.
4.3. METABOLISM
Dleteren (1966) Identified the urinary metabolites of workers occupa-
tlonally exposed to 3,3'-d1methylbenz1d1ne. The parent compound was found
as well as the metabolites d1acetyl-3,3'-d1methylbenz1d1ne, 5-hydroxy-3,3'-
d1methylbenz1d1ne or Us ester and possibly monoacetyl-3,3'-d1methylbenz1-
dlne. The authors emphasized that other metabolites were present as well
(e.g., 3,3'-benz1d1ned1carboxyl1c add, which can be obtained by oxidation
of the methyl groups).
Bowman et al. (1982) gave Fischer 344 rats single oral doses (see
Section 4.1.) of l*C-3,3'-d1methylbenz1d1ne and Identified the following
urinary metabolites: d1acetyl-3,3'-d1methylbenz1d1ne (2.IX of the dose);
alkaline hydrolyzable conjugates (0.4%); monoacetyl-3,3'-d1methylbenz1d1ne
(0.2%). Other unidentified metabolites were present as well. Unchanged
3,3'-d1methylbenz1d1ne constituted 0.4% of the dose. The Interval of peak
excretion of metabolites was between 8 and 16 hours.
4.4. EXCRETION
Bowman et al. (1982) gave Fischer 344 rats single oral doses of
l4C-3,3'-d1methylbenz1d1ne (see Section 4.1.) and found that -40 and 59%
of the dose of radioactivity was excreted In the urine and feces, respec-
tively, within 192 hours. About 1-6% of the dose was excreted as the parent
compound. Urinary and fecal excretion peaked at 16 hours.
0857p -12- 04/10/87
-------
4.5. SUMMARY
3,3'-01methylbenz1d1ne Is absorbed after oral or dermal exposure. Rats
treated orally with l*C-3,3'-d1methylbenz1d1ne excreted -40% of the dose
of radioactivity In the urine and -59% 1n the feces 1n 8 days (Bowman et
a!., 1982). Bowman et al. (1982) suggested that biliary excretion was
substantial, since -89X of the fecal radioactivity was present as possible
biliary metabolites. Thus, gastrointestinal absorption may be as great as
93%. The appearance of 3,3'-d1methylbenz1d1ne In the urine of occupation-
ally exposed humans Indicates that dermal adsorption occurs (Melgs et al.,
1954). Following absorption, 3,3'-d1methylbenz1d1ne 1s widely distributed
1n rats (Bowman et al., 1982). Metabolites Identified 1n the urine of
exposed rats were d1acetyl-3,3'-d1methylbenz1d1ne, alkaline hydrolyzable
conjugates and monoacetyl-3,3'-d1methylbenz1d1ne as well as parent compound.
Metabolites Identified 1n the urine of exposed workers were mono- and
d1acetyl-3,3'-d1methylbenz1d1ne, 5-hydroxy-3,3'-d1methylbenz1d1ne and
possibly 3,3'-benz1d1ned1carboxyl1c add.
Q857p -13- 10/01/86
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5. EFFECTS
5.1. CARCINOGENICITY
5.1.1. Animal Studies. Grlswold et al. (1968) treated a group of twenty
45-day-old female Sprague-Dawley rats by gavage with 10 doses of 50 mg/rat
(total 500 mg/rat) 3,3'-d1methy1benz1d1ne In sesame oil at 3-day Intervals
for 30 days, followed by a 9-month observation period (Table 5-1). Sixteen
rats survived the observation period. Rats that died or were killed at the
end of the study were necropsled. Hlstologlcal examination was performed on
grossly apparent lesions, mammary glands, Intestinal tract, pituitary,
liver, ovaries and adrenals. The mammary tumor Incidence In treated female
rats was 3/16; whereas an Incidence of 5/132 was observed 1n the control
data pooled from several experiments. IARC (1972) considered this experi-
ment to be of doubtful significance because of the small number of rats'
tested.
Saff1ott1 et- al. (1967) gave groups of 30 male and 30 female 9-week-old
Syrian golden hamsters 0.1% 3,3'-d1methylbenz1d1ne In the diet for their
Hfespan. The authors estimated 60 mg of the test substance was Ingested
per week based on food Intake data. Controls were given food that did not
contain 3,3'-d1methylbenz1d1ne. No tumors were observed 1n the treated
hamsters. In a similar experiment, Sellakumar et al. (1969) reported
negative results 1n 30 male and 30 female hamsters maintained on a diet
containing 0.3% 3,3'-d1methylbenz1d1ne for the llfespan.
Ferber (1977) reported a study 1n which four young mongrel female dogs
were given 200 mg 3t3'-d1methylbenz1d1ne 1n capsules dally for 8-9 months
for a total dose of 50 g/dog. Cystoscoplc examinations before and after
treatment were negative. One of the four treated dogs developed bladder
cancer (papillary tumor and cystitis) 8 years later. The remaining dogs
either died of natural causes or were killed, but no tumors were observed.
0857p -14- 04/10/87
-------
TABLE 5-1
Mammary Tumor Incidence 1n 45-Day-Old Female Sprague-Oawley Rats Given
50 mg of 3,3'-01methylbenz1d1ne of Unspecified Purity 1n Sesame 011 at
3-day Intervals for 30 Days, Followed by a 9-Month Observation Period*
Dose
Incidence
50 mg/rat
(500 mg total dose)
5/132 (-
3/16 (-19%)
(NS)
Strength of Study:
Weakness of Study:
Overall Adequacy:
QUALITY OF EVIDENCE
A relevant route of administration was 'used.
was established by pre-testlng.
The MTO
Only one sex of one species was tested. Only one dose
was tested and the duration of exposure was not for the
Hfespan of the organism. A limited number of organs
were examined hlstologlcally and the data were not
statistically analyzed.
Valid for we1ght-of-ev1dence,
analysis
limited for statistical
*Source: Grlswold et al., 1968
0857p
-15-
06/10/87
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3,3'-D1methylbenz1d1ne Is being tested for carclnogenlclty by the
National Toxicology Program {NTP, 1986). Preliminary results Indicate that
3,3'-d1methylbenz1d1ne Induces a carcinogenic effect 1n F344 rats when the
compound 1s administered 1n drinking water (Mennear, 1987).
Several studies that used less relevant routes of administration were
located In the available literature. PUss and Zabezhlnsky (1970) subcuta-
neously Injected 27 male and 26 female rats with 20 mg/rat 3,3'-d1methyl-
benzldlne 1n sunflower oil once weekly for 13 months and observed tumors 1n
60% of the treated rats. The first tumor appeared at 8 months, at which
time 25 rats/sex survived. Zymbal gland tumors (14/25 males, 6/25 females)
were the primary tumor type observed, but tumors also developed In the
preputlal gland (2/25 males, 1/25 females), forestomach (2/25 males, 0/25
females), skin (2/25 males, 1/25 females) and mammary gland (5/25 females).
No treatment-related tumors were observed 1n a group of 50 control rats
Injected subcutaneously with sunflower oil (Pllss, 1963). Pllss and
Zabezhlnsky (1970) also subcutaneously Implanted pellets containing 20 mg
3,3'-d1methylbenz1d1ne 1n 24 male and 24 female rats, once weekly for 14
months. The first tumor appeared at 12 months at which time 16 males and 20
females were alive. The treated rats developed primarily Zymbal gland
(6/16 males, 5/20 females) and mammary gland tumors (7/20 females, 0/16
males). Tumors of the skin, liver and hematopoletlc system were observed as
well. PUss and Vol'fson (1973) observed a rhabdomyosarcoma of the heart In
rats subcutaneously Injected, once weekly with 10 mg 3,3'-d1methylbenz1d1ne
for 33 weeks. Holland et al. (1974) reported that 18/21 rats given a
cumulative subcutaneous dose of 5.4 g/kg over 241 days developed tumors.
0857p -16- 06/10/87
-------
SpHz et al. (1950) observed no cirrhosis of the liver or hepatomas 1n 105
rats subcutaneously Injected with 60 mg 3,3'-d1methylbenz1d1ne once weekly
for a total dose of 5.5 g. Cancer of the external auditory canal was
observed 1n 4.3X of the treated rats.
Golub et al. (1974) subcutaneously Injected BALB/c mice with 2 mg/lnjec-
tlon of 3,3'-d1methylbenz1d1ne In sunflower oil 4 or 5 times during the last
week of pregnancy. The control group consisted of the progeny of untreated
dams. No effects of treatment were reported In the dams. Survival of the
progeny of treated dams was diminished; however, no additional data were
provided. The progeny of treated dams had a higher total tumor Incidence
(13/24, 50%) compared with controls (6/30, 20X). Major types of tumors
observed In treated mice were lung and mammary tumors.
5.1.2. Human. MacAlplne (1947) reported two cases of urinary tract
tumors, which eventually resulted 1n death of workers occupatlonally exposed
to benzldlne and 3,3'-d1methylbenz1d1ne. Kuratsune and Takemura (1969)
reported 23 cases of urinary system cancer 1n Japanese workers exposed to
*#
benzldlne, 3,3'-d1methylbenz1d1ne and 3,3'-d1methoxybenz1d1ne. Fourteen of
these workers were exposed for <6 years. The workers exposed 1n these cases
were also exposed to benzldlne, a known bladder carcinogen. A review of the
carcinogenic effects observed 1n workers of the dyestuff Industry can be
found 1n several publications (NIOSH, 1978, 1980; OSHA/NIOSH, 1980). The
available ep1dem1olog1c data clearly show that benzldlne base dyes are human
carcinogens. The data also show that benzldlne 1n combination with
3,3'-d1methyl- and d1methoxybenz1d1ne Is carcinogenic to humans. There Is,
however, no data available for dlmethylbenzldlne alone.
0857p -17- 06/10/87
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5.2. MUTAGENICITY
The ability of 3,3'-d1methylbenz1d1ne to cause point mutations 1n the
Salmonella typhlmurlum hlstldlne reverse mutation test Is well established
(Table 5-2). In general, 3,3'-d1methylbenz1d1ne was mutagenlc In frame-
sh1ft-sens1t1ve tester strains (namely, TA98 and TA1538) 1n the presence of
rat, mouse or hamster Hver S9 metabolic activation (Reid et al., 1984a,b;
Waalkens et al., 1981; Kennelly et al., 1984; Lazear and Louie, 1977; PMval
et al., 1984; Anderson and Styles, 1978; Ferrettl et al., 1977). Negative
or weakly positive results were obtained In base-pair substitution tester
strains (I.e., TA1535, TA1537, TA100) of Salmonella.
N1sh1oka and Ogasawara (1978) obtained positive results In a growth
differential test of Escher1ch1a coll using DNA repair-deficient and
proficient strains. Kornbrust and Barfknecht (1984, 1985) observed positive
results 1n ONA repair tests using hepatocytes Isolated from both male
Sprague-Dawley rats or male Golden Syrian hamsters. 3,3'-01methylbenz1d1ne
Induced unscheduled DNA synthesis In Hela cells with rat Hver metabolic
activation (Martin et al., 1978). In the sex-1Inked recessfve lethal test
1n DrosophUa melanoqaster. positive results were obtained when 3,3'-d1-
methylbenz1d1ne was administered by feeding adult males and produced
equivocal results after adult Injection (Valencia et al., 1985). However,
3,3'-d1methylbenz1d1ne did not Induce reciprocal translocatlons In Droso-
phlla (Valencia et al., 1985). A statistically significant treatment-
related Increased frequency of mlcronucleated polychromatic erythrocytes was
observed In bone marrow smears from Wlstar rats given 3,3'-d1methylbenz1d1ne
1n olive oil by stomach tube (C1hak, 1979). Testlcular DNA synthesis was
Inhibited 1n mice given 3,3'-d1methylbenz1d1ne orally (Seller, 1977).
Freeman et al. (1973) obtained positive results In ^n vitro transformation
tests using Fischer rat embryo cell line F1706 P88.
0857p -18- 06/10/87
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5.3. TERATOGENICITY
Pertinent data regarding the teratogenlclty of 3,3'-d1methylbenz1d1ne
administered by the oral or Inhalation route could not be located In the
available literature as cited 1n the Appendix. Wilson (1955) observed no
malformations 1n progeny of rats subcutaneously Injected with 30 mg of
3,3'-d1methylbenz1d1ne on days 7, 8 and 9 of gestation. The Incidence of
resorptlons was -7%. No control data or maternal toxldty data were
reported. Ema et a "I. (1984) observed no fetotoxldty 1n progeny of Wlstar
rat dams subcutaneously Injected with 3,3'-d1methylbenz1d1ne on day 7 of
pregnancy.
5.4. OTHER REPRODUCTIVE EFFECTS
Pertinent data regarding other reproductive effects of 3,3'-dlmethyl-
benzldlne could not be located 1n the available literature as cited In the
Appendix.
5.5. CHRONIC TOXICITY
Pertinent data regarding the oral or Inhalation chronic or subchronlc
toxlclty of 3,3'-d1methylbenz1d1ne could not be located In the available
literature as cited In the Appendix.
5.6. OTHER RELEVANT INFORMATION
Sololmskaya (1970) subcutaneously Injected rats with 100 mg/kg 3,3'-d1-
methylbenzldlne and observed Increased monoamlne oxldase and hlstamlnase
activity. In rats subcutaneously Injected with 100 mg/kg once weekly for 2
months. Increased- activity of the enzymes catalyzing oxldatlve deamlnation
was observed.
Emmett et al. (1985) demonstrated by changes 1n crossed Immunoelectro-
phoresls patterns that 3,3'-d1methylbenz1d1ne binds to serum proteins. As
demonstrated by autoradlography, 3t3'-d1methylbenz1d1ne bound to a and 0
0857p -22- 06/10/87
-------
"Mpoprotelns. The authors suggested that bound 3,3'-d1methylbenz1d1ne may
be transported to tissues by serum proteins. Wise et al. (1984) reported
that dog bladder transitional epithelial prostaglandln H synthase activated
3,3'-d1methylbenz1d1ne binding to protein, tRNA and DNA. Tsurata et al.
(1985) reported that the peroxIdase/H.O- system catalyzed the binding of
3,3'-d1methylbenz1d1ne to DNA.
5.7. SUMMARY
The cardnogenldty of 3,3'-d1methylbenz1d1ne has not been adequately
assessed by oral and Inhalation routes of administration. However, there Is
a wealth of animal data showing that a high level and varied carcinogenic
responses do occur In tissues exposed to 3,3'-d1methylbenz1d1ne. Gr1swoId
et al. (1968) observed an Increased Incidence of mammary tumors In rats.
treated by gavage with a total of 500 mg/rat over 30 days and observed for 9
months compared with controls. IARC (1972), however, considered this
experiment to be of doubtful significance because of the small sample size
(20 rats).
No tumors were observed 1n hamsters treated with 3,3'-d1methylbenz1d1ne
1n the diet at 0.1 or 0.3% for the Hfespan (Safflotl et al., 1967;
Sellakumar et al., 1969). Ferber (1977) reported a study In which one case
of bladder cancer was observed In 1/4 dogs 8 years after being fed 3,3'-d1-
methylbenz1d1ne at 200 mg/day for 8-9 months. 3,3'-D1methylbenz1d1ne has
been tested by the National Toxicology Program (NTP, 1986). Preliminary
results of hlstopathology Indicate that 3,3'-d1methylbenz1d1ne Induces a
carcinogenic effect In F344 rats when the compound 1s administered In
drinking water (Mennear, 1987).
0857p -23- 06/10/87
-------
Numerous cardnogenlclty studies by a less relevant route of administra-
tion were available as well. In rats given subcutaneous doses of 3,3'-d1-
methylbenz1d1ne, tumors were observed In the Zymbal gland, preputlal gland,
forestomach, skin, lung (PUss and Zabezhlnsky, 1970), heart (rhabdomyo-
sarcoma) (PUss and Vol'fson 1973), and external auditory canal (Spitz et
al., 1950). In rats subcutaneously Implanted with pellets containing
3,3'-d1methylbenz1d1ne, Zymbal gland, mammary gland, skin, liver and
hematopoletlc system tumors were observed (PUss and Zabezhlnsky, 1970).
Increased Incidences of mammary and lung tumors were observed In the
offspring of mice Injected subcutaneously during gestation (Golub et al.,
1974). The possible carcinogenic effect of 3,3'-d1methylbenz1d1ne In humans
has not been assessed adequately. Urinary system cancer 1n workers exposed
to mixtures of benzldlne, 3,3'-d1methylbenz1d1ne and 3,3'-d1methoxybenz1d1ne"
has been reported (MacAlplne, 1947; Kuratsune and Takemura, 1969); however,
adequate 1nterpret1on of these results are confounded by the presence of
benzldlne, a known human bladder carcinogen.
The mutagenldty of 3,3'-d1methylbenz1d1ne has been tested 1n various
prokaryotlc and eukaryotlc systems. 3,3'-D1methylbenz1d1ne gave predomi-
nantly positive results In the S. typhlmuMum reverse mutation test with S-9
metabolic activation (Reid et al., 1984a; Waalkens et al., 1981; Anderson
and Styles, 1978; Kenelly et al., 1984; Lazear and Louie, 1977; PMval et
al., 1984; Ferettl et al., 1977). Positive results were obtained 1n ONA
repair tests In Escher1ch1a coll (N1sh1oka and Ogasawara, 1978) and In
hepatocytes Isolated from rats and hamsters. 3,3'-D1methylbenz1d1ne Induced
UDS 1n HeLa cells with metabolic activation (Martin et al., 1978). Positive
and negative results, respectively, were obtained 1n oral and Injection
studies 1n the sex-linked recessive lethal tests 1n Drosophlla melanoqaster
0857p -24- 04/10/87
-------
(Valencia et al., 1985). Positive results were obtained In a mlcronucleus
test In rats (Clhak, 1979), In a testlcular DNA synthesis test 1n mice
(Seller, 1977) and In a cell transformation test In rat embryo cells
(Freeman et al., 1973).
The teratogenldty of 3,3'-d1methylbenz1d1ne has not been adequately
assessed by a relevant route of administration. Wilson (1955) observed no
malformations 1n progeny of pregnant rats subcutaneously Injected with
3,3'-d1methylbenz1d1ne, but did observe an ~1% Increase of resorptlons. Ema
et al. (1984) did not observe fetotoxlc effects 1n progeny of rat dams sub-
cutaneously Injected with 3,3'-d1methylbenz1d1ne. Pertinent data regarding
the reproductive effects of 3,3'-d1methylbenz1d1ne could not be located 1n
the available literature as cited In the Appendix.
The chronic and subchronlc toxlclty of 3,3'-d1methylbenz1d1ne has not
been studied.
0857p -25- 10/01/86
-------
6. AQUATIC TOXICITY
Pertinent data ~regarding effects of 3,3'-d1methylbenz1d1ne on aquatic
biota could not be located 1n the available literature as cited 1n the
Appendix.
0857p -26- 10/01/86
-------
7. EXISTING GUIDELINES AND STANDARDS
7.1. HUMAN
ACGIH (1985-1986, 1986) did not recommend or adopt a TLV-THA for
3,3'-d1methylbenz1d1ne and considered this compound to be a suspected human
carcinogen. U.S. EPA (1981) decided not to require additional health and
environmental effects testing of benzldlne, o-to!1d1ne and o-d1an1s1d1ne
based dyes. NIOSH (1978) recommended that 3,3'-d1methylbenz1d1ne "be
handled as a suspect human carcinogen," and that "exposure to o-to!1d1ne be
kept as low as possible through strict adherence to a program of monitoring,
engineering controls and stringent work practices." Occupational exposure
should not exceed 20 yg/m3 1n air, "determined from an air sample
collected at 0.2 liters/minute for 60 minutes." Users of laboratory test
tapes and kits containing 3,3'-d1methylbenz1d1ne were excluded from monitor-
Ing and surveillance requirements of this recommended standard. OSHA/NIOSH
(1980) published a Health Hazard Alert for 3,3'-d1methylbenz1d1ne-based dyes.
7.2. AQUATIC
Guidelines and standards for the protection of aquatic biota from the
effects of 3,3'-d1methylbenz1d1ne could not be located 1n the available
literature as cited In the Appendix.
0857p -27- 10/01/86
-------
8. RISK ASSESSMENT
The cardnoger>1c1ty of 3,3'-d1methylbenz1d1ne has not been adequately
assessed by the oral .and Inhalation routes of administration. However,
there Is a wealth of animal data showing that a high level and varied car-
cinogenic responses do occur 1n tissues exposed to 3,3'-d1methylbenz1d1ne.
Grlswold et al. (1968) observed a 19% Incidence of mammary tumors 1n rats
treated by gavage with a total of 500 mg/rat over 30 days and observed for 9
months compared with 4% In control rats, which were pooled from several
experiments. IARC (1972), however, considered this experiment to be of
doubtful significance because of the small sample size (20 rats).
No tumors were observed In hamsters treated with 3,3'-d1methylbenz1d1ne
1n the diet at 0.1 or 0.3% for the Hfespan (Saff1ot1 et al., 1967;'
Sellakumar et al., 1969). Ferber (1977) reported a study In which one case
of bladder cancer was observed In 1/4 dogs 8 years after being fed 3,3'-d1-
methylbenzldlne at 200 mg/day for 8-9 months. 3,3'-D1methylbenz1d1ne has
been tested by the National Toxicology Program (NTP, 1986). Preliminary
hlstopathology data Indicate that 3,3'-d1methylbenz1d1ne Induces a carcino-
genic effect In F344 rats when the compound 1s administered In drinking
water (Hennear, 1987).
Numerous carc1nogen1c1ty studies by subcutaneous and Injection adminis-
tration are available as well. In rats given subcutaneous doses of 3,3'-d1-
methylbenzldlne, tumors were observed 1n the Zymbal gland, preputlal gland,
forestomach, skin, lung (PUss and Zabezhlnsky, 1970), heart (rhabdomyo-
sarcoma) (PUss and Vol'fson 1973), and external auditory canal (SpHz et
al., 1950). In rats subcutaneously Implanted with pellets containing
3,3'-d1methylbenz1d1ne, Zymbal gland, mammary gland, skin, liver and hema-
topoletlc system tumo-s were observed (PUss and Zabezhlnsky, 1970).
0857p -28- 06/10/87
-------
Increased Incidences of mammary and lung tumors were observed In the off-
spring of mice Injected subcutaneously during gestation (GoTub et al.,
1974). The possible carcinogenic effect of 3,3'-d1methylbenz1d1ne In humans
has not been assessed adequately. Urinary system cancer 1n workers exposed
to mixtures of benzldlne, 3,3'-d1methylbenz1d1ne and 3,3'-d1methoxybenz1d1ne
has been reported (MacAlplne, 1947; Kuratsune and Takemura, 1969); however,
adequate Interpretlon of these results are confounded by the presence of
benzldlne, a known human bladder carcinogen. Given the available positive
response data showing that 3,3'-d1methylbenz1d1ne causes a carcinogenic
response 1n various animal tissues following tissue exposure, and knowledge
that 3,3'-d1methylbenz1d1ne has been Identified 1n humans exposed to benzl-
dlne based dyes, 3,3'-d1methylbenz1d1ne 1s given an EPA Group 82 welght-
of-ev1dence ranking. Preliminary NTP results of a new bloassay of 3,3'-d1-
methylbenzldlne In drinking water are supportive of this as well as a
recognition that, while Information for 3,3'-d1methylbenz1d1ne alone Is
nonexistent, the Information for 3,3'-d1methylbenz1d1ne and benzldlne and
3,3'-d1methoxybenz1d1ne are clearly positive for humans.
The mutagenldty of 3,3'-d1methylbenz1d1ne has been tested In various
prokaryotlc and eukaryotlc systems. 3,3'-01methylbenz1d1ne has been shown
to produce gene mutations 1n Salmonella typhlmurlum after liver S-9
metabolic activation (Reid et al., 1984a; Waalkens et al., 1981; Anderson
and Styles, 1978; Kenelly et al., 1984; Lazear and Lowle, 1977; Ferettl et
al., 1977) and 1n DrosophUa melanogaster after feeding adult males
(Valencia et al., 1985). Positive results were obtained 1n ONA repair tests
1n Escherlchla coll (Nlshloka and Ogasawara, 1978), 1n hepatocytes Isolated
from rats and hamsters, and 1n HeLa cells with rat liver metabolic activa-
tion (Martin et al., 1978). Positive results were obtained In a micro-
nucleus test In rats (C1hak, 1979), but negative results were reported for
0857p -29- 06/10/87
-------
reciprocal translocatlons 1n DrosophUa (Valencia et al., 1985). In a
testlcular DNA synthesis test 1n mice positive results were found (Seller,
1977). 3,3'-D1methylbenz1d1ne was reported to be positive 1n a cell trans-
formation test In rat embryo cells (Freeman et al., 1973).
Therefore, the welght-of-evldence Indicates that 3,3'-d1methylbenz1d1ne
Is mutagenlc and may pose a risk to somatic cells. Mutations In somatic
cells may lead to the onset of cancer, developmental abnormalities, and
possibly other diseases. Further, 3,3'-d1methylbenz1d1ne Induces heritable
mutations 1n DrosophUa and affects testlcular DNA synthesis In mice. These
findings suggest that 3,3'-d1methylbenz1d1ne (or an active form) may reach
the mammalian gonad and produce mutations In germ cells. Germ cell muta-
tions may be passed on to future generations and Increase the Incidence of
genetic disease In the population. The above conclusions are consistent
with the welght-of-evldence approach described 1n the U.S. EPA guidelines
for mutagenlcHy risk assessment (U.S. EPA, 1986c).
The teratogenlclty of 3,3'-d1methylbenz1d1ne has not been adequately
assessed by a relevant route of administration. Wilson (1955) observed no
malformations 1n progeny of pregnant rats subcutaneously Injected with
3,3'-d1methylbenz1d1ne, but did observe an ~7X Increase of resorptlons. Ema
et al. (1984) did not observe fetotoxlc effects 1n progeny of rat dams sub-
cutaneously Injected with 3,3'-d1methylbenz1d1ne. Pertinent data regarding
the reproductive effects of 3,3'-d1methylbenz1d1ne could not be located In
the available literature as cited In the Appendix.
The chronic toxlclty of 3,3'-d1methylbenz1d1ne has not been studied.
3,3'-01methylbenz1d1ne Is considered to be an animal carcinogen and 1s
suspected of being carcinogenic to humans (IARC, 1972, 1979; NIOSH, 1978;
OSHA/NIOSH, 1980; ACGIH, 1986) and by EPA (with this assessment). An EPA
1986 (reportable quantity) carc1nogen1c1ty evaluation, which assigned a
0857p -30- 06/10/87
-------
weight of evidence of limited animal data (Group C), Is superceded by this
Group B2 ranking 1n this risk assessment. NIOSH (1978) recommended that
3,3'-d1methylbenz1d1ne be handled as a suspect human carcinogen based upon
positive results 1n mutagenldty studies and development of tumors In
rodents. OSHA/NIOSH (1980) published a Health Hazard Alert for 3,3'-d1-
methylbenzldlne based dyes. ACGIH (1985-1986, 1986) considered 3,3'-d1-
methylbenzldlne a suspected human carcinogen and noted Its structural
similarity to the known human bladder carcinogen, benzldlne.
Given the above cardnogenldty classifications, 1t 1s Inappropriate to
derive an RfO (formerly called ADI). For cardnogenldty, however, consid-
eration of deriving a cancer potency Is appropriate. All of the studies
that used a relevant route of administration (oral) are flawed to varying
degrees and thus the quantitative risk assessment will necessarily have some'
additional uncertainty.
Grlswold et al. (1968) observed an Increased Incidence of mammary tumors
(3/16, 19%) 1n 20 female rats given 10 doses of 50 mg of 3,3'-d1methylbenz1-
dlne by gastric Intubation over 30 days, followed by a 9-month observation
period compared with pooled controls (5/132, 4%). The purity of the com-
pound administered was not reported, only one sex was tested for a period of
time (30 days), which was substantially less than the Hfespan of the animal
(2 years), size of the group tested was small (20) and was compared with
pooled controls, and limited hlstopathologlcal examination was performed.
The data were also not statistically analyzed by the author. IARC (1972)
considered this study to be of doubtful significance because of the small
sample size tested. While the noted deficiencies exist, this study has been
selected for derivation of cancer potency. The q * was determined from
this data to be 9.2 (mg/kg/day)'1 as shown 1n Table 8-1.
0857p -31- 06/11/87
-------
TABLE 8-1
Derivation of Potency Factor (F factor) for 3,3'-D1methylbenz1d1ne
Reference:
Exposure route:
Species:
Strain:
Sex:
Body weight:
Duration of treatment:
Duration of study:
Ufespan of animal:
Tumor site, type:
Nominal dose:
Average dally dose:
Equivalent human dose:
Tumor Incidence:
Potency (q-j*):
Potency (1/ED10): -
GHswold et al., 1968
gastric Intubation with sesame oil
rat
Sprague-Dawley
female
0.35 kg (assumed)
1 month (10 doses 3 days apart)
9 months
24 months (assumed)
mammary carcinomas and hyperplasla
Control
0.00
0.00
0.00
5/132
9.2 mg/kg/day
34.1
Animal
500.00 mg (total lifetime dose)
5.29 mg/kg/day
0.90 mg/kg/day (surface-area adj)
3/16
Q857p
-32-
06/11/87
-------
Safflotl et al. (1967) and Sellakumar et al. (1969) gave hamsters 0.1
and 0.3% dietary 3,3'-d1methylbenz1d1ne for their Hfespan and observed no
tumors. Ferber (1977) observed bladder cancer 1/4 dogs 8 years after being
fed a total of 50 g 3,3'-d1methylbenz1d1ne for 8-9 months. This study was
not reported 1n sufficient detail to support a risk assessment. Numerous
studies 1n which 3,3-d1methylbenz1d1ne was administered subcutaneously were
available; however, a conventional risk assessment cannot be based on these
studies because of the routes of administration and the related difficulty
of estimating an effective dose comensurate with oral or Inhalation expo-
sure. Urinary system cancer 1n workers exposed to mixtures of benzldlne,
3,3'-d1methylbenz1d1ne and 3,3'-d1methoxybenz1d1ne has been reported
(MaCalplne, 1947; Kuratsune and Takemura, 1969); however, adequate Interpre-
tation of these results for 3,3'-d1methylbenz1d1ne are confounded by the
presence of benzldlne, a known human bladder carcinogen. NTP (1986) Is
testing 3,3'-d1methylbenz1d1ne for cardnogenlcHy. Preliminary results of
hlstopathology Indicate that 3,3'-d1methylbenz1d1ne Induces a carcinogenic
effect In F344 rats when the compound 1s administered In drinking water
(Mennear, 1987).
0857p -33- 06/10/87
-------
9. REPORTABLE QUANTITIES
9.1. REPORTABLE QUANTITY (RQ) RANKING BASED ON CHRONIC TOXICITY
No chronic or- subchronlc oral or Inhalation studies of 3,3'-d1methyl-
benzldlne were available; therefore, data are Insufficient to derive an RQ
based on chronic toxldty (Table 9-1).
9.2. WEIGHT OF EVIDENCE AND POTENCY FACTOR (F*1/ED1Q) FOR CARCINOGENICITY
3,3'-01methylbenz1d1ne 1s considered to be an animal and/or suspected
human carcinogen (NIOSH, 1978; OSHA/NIOSH, 1980; ACGIH, 1985-1986, 1986;
IARC, 1972, 1979) and EPA (In this assessment); however, most oral studies
were sufficiently flawed and precluded their use In quantitative risk
assessment. In female rats given 10 doses of 50 mg 3,3'-d1methylbenz1d1ne
by gastric Intubation over 30 days followed by a 9-month observation period,
Grlswold et al. (1968) observed an Increased Incidence of mammary tumors
(3/16, 19X) compared with pooled controls (5/132, 4%). The purity of the
compound administered was not reported, only one sex was tested for a period
of time (30 days), which was substantially less than the Hfespan of the
animal (2 years), size of the group tested was small (20) and was compared
with pooled controls, and limited hlstopathologlcal examination was per-
formed. The data were also not statistically analyzed. IARC (1972) consid-
ered this study to be of doubtful significance because of the small sample
tested. Saff1ot1 et al. (1967) and Sellakumar et al. (1969) gave hamsters
0.1 a'nd 0.3X dietary 3,3'-d1methylbenz1d1ne for their Hfespan and observed
no tumors. Ferber (1977) observed bladder cancer 1n one of four dogs 8
years fafter being fed a total of 50 g 3,3'-d1methylbenz1d1ne for 8-9
months. This study was not reported In sufficient detail to support a risk
assessment. Numerous studies In which 3,3'-d1methylbenz1d1ne was adminis-
tered subcutaneously were available (see Section 5.1.); however, they cannot
support a risk assessment because of the Irrelevant route of administration.
0857p -34- 06/10/87
-------
TABLE 9-1
3,3'-D1methylbenz1d1ne
Minimum Effective Dose (MED) and Reportable Quantity (RQ)
Route:
Dose:
Effect:
Reference:
RVd:
RVe:
Composite Score:
RQ: Data are not sufficient for deriving an RQ
0857p -35- 06/10/87
-------
Urinary system cancer In workers exposed to mixtures of benzldlne, 3,3'-di-
methyl benzldlne and 3,3'-d1methoxybenz1d1ne has been reported (MacAlplne,
1947; Kuratsune and Takemura, 1969); however, adequate Interpretation of
these results are confounded by the presence of benzldlne, a known human
bladder carcinogen. NTP (1986) has tested 3,3'-d1methylbenz1d1ne for
carc1nogen1dty. Preliminary hlstopathology results Indicate that 3,3'-d1-
methylbenzldlne Induces a carcinogenic effect 1n F344 rats when the compound
1s administered In drinking water (Hennear, 1987). From Grlswold et al.
(1968) and this data a potency factor (F) of 34, a potency group of 2 and an
EPA Grouping of B2 were determined, which gives 3,3'-d1methylbenz1d1ne a
MEDIUM hazard ranking. The documentation supporting this ranking was dis-
cussed 1n Chapter 8. Nevertheless, since IARC (1979) and U.S. EPA (1986a)
consider the animal data to be sufficient and the human data to be Inade-
quate, 3,3'-d1methylbenz1d1ne 1s most appropriately classified as an EPA
Group 82 chemical, that 1s, a possible human carcinogen. When the NTP
current study on 3,3'-d1methylbenz1d1ne becomes available, this cancer
evidence w1l* be reevaluated and 1t will be reclasslfled based on the level
of carcinogenic evidence.
0857p -36- 06/11/87
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10. REFERENCES
ACGIH (American Conference of Governmental Industrial Hyg1en1sts). 1985-
1986. TLVs: Threshold. Limit Values for Chemical Substances and Physical
Agents 1n the Workroom Environment with Intended Changes for 1985-1986.
Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts). 1986.
Documentation of the Threshold Limit Values, 5th ed. Cincinnati, OH.
p. 577.
Anderson, D. and J.A. Styles. 1978. An evaluation of 6 short-term tests
for detecting organic chemical carcinogens. Appendix 2. The bacterial
mutation test. Br. 0. Cancer. 37: 924-930.
Balrd, R., L. Carmona and R.L. Jenkins. 1977. Behavior of benzldlne and
other aromatic amines In aerobic waste water treatment. J. Water Pollut.
Control Fed. 49: 1609-1015.
Bowman, M.C., W.L. Oiler, C.R. Nony, K.L. Rowland and S.M. BUledean. 1982.
Metabolism and distribution of two l4C-benz1d1ne-congener-based dyes 1n
rats as determined by GC, HPLC and radloassays. J. Anal. Toxlcol. 6:
164-174.
C1hak, R. 1979. Evaluation of benzldlne by the mlcronucleus test. Hutat.
Res. 67: 383-384.
0857p -37- 06/10/87
-------
Oleteren, H.M. 1966. The blotransformatlon of o-to!1d1ne. A qualitative
Investigation. Arch. Environ. Health. 12(1): 30-32.
Ema, M., H. Kawasaki, Y. Ogawa, T. Sta1m1 and S. Kanoh. 1984. Studies on
the pharmacological bases of fetal toxlclty of drugs. VI. Teratogenlc
effect of trypan blue and Its related compounds 1n rats. Toxicology. 101:
161.
Emraett, M., C.E. Cern1gl1a and A.J. Crowle. 1985. Differential serum
protein binding of benz1d1ne-based dyes and benzldlne congener based dyes
and their derivatives. Arch. Toxlcol. 57(2): 130-135.
Ferber, K.H. 1977. Carc1nogen1c1ty of orthotoUdlne 1n the urinary bladder
of the dog. Unpublished report submitted to NIOSH by Ferber KH, Allied
Chemical Division, Buffalo Dye Plant, Specialty Chemicals Division, Buffalo.
p. 11. (Cited In NIOSH, 1978)
Ferber, K.H. 1978. Benzldlne and related b1phenyld1am1nes. In.: K1rk-
Othmer Encyclopedia of Chemical Technology, Vol. 3, 3rd ed., M. Grayson and
D. Eckroth, Ed. John Wiley and Sons, Inc., New York. p. 775.
Ferrettl, J.J., W. Lu and M. Liu. 1977. Mutagenldty of benzldlne and
related compounds employed In the detection of hemoglobin. Am. J. CUn.
Pathol. 67(6): 526-527.
0857p -38- 06/10/87
-------
Freeman, A.E., E.K. Helsburger, J.H. Welsburger, R.G. Wolford, J.M. Maryak
and R.J. Huebner. 1973. Transformation of cell cultures as an Indication
of the carcinogenic potential of chemicals. J. Natl. Cancer Inst. 51(3):
799-808.
Golub, N.I., T.S. Kolesnlchenko and L.M. Shabad. 1974. Oncogenlc action of
some nitrogen compounds on the progeny of experimental mice. Bull. Exp.
B1ol. Med. (USSR). 78: 1402-1404.
GMswold, D.P., Jr., A.E. Casey, E.K. Welsburger and J.H. Welsburger. 1968.
The carclnogenlcHy of multiple IntragastMc doses of aromatic and hetero-
cycllc nltro or amlno derivatives 1n^ young female Sprague-Oawley rats.
Cancer Res. 28(5): 924-933.
Hansch, C. and A.J. Leo. 1985. Medchem Project Issue No. 26. Pomona
College, Claremont, CA.
Holland, V.R., B.C. Saunders, F.L. Rose and A.L. Walpole. 1974. A safer
substitute for benzldlne In the detection of blood. Tetrahedron. 30:
3299-3302.
IARC (International Agency for Research on Cancer). 1972. IARC Monographs
on the Evaluation of the Carcinogenic Risk of Chemicals to Man. 3,3-01-
methylbenzldlne (o-to!1d1ne). WHO, IARC, Lyons, France. Vol. 1, p. 87-91.
IARC (International Agency for Research on Cancer). 1979. IARC Monograph
on the Evaluation of the Carcinogenic Risk of Chemicals to Man. WHO, IARC,
Lyons, France. IARC Suppl. 1.
0857p -39- 06/10/87
-------
Karstadt, M., R. Bobal and I.J. Sellkoff. 1981. A survey of availability
of epldemlologlc data on humans exposed to animal carcinogens. Banbury
Report. 9: 223-246.
Kennelly, J.C., C.A. Stanton and C.N. Martin. 1984. The effect of acetylco
a supplementation on the mutagenldty of benzldlnes In the ames assay.
Mutat. Res. 137: 39-45.
Kornbrust, D.O. and T.R. Barfknecht. 1984. Comparison of 7 azo dyes and
their azo reduction products 1n the rat and hamster hepatocyte primary
culture/DNA repair assays. Mutat. Res. 136(3): 255-266.
Kornbrust, D.J. and T.R. Barfknecht. 1985. Comparison of azo dyes and
their reduction products genotoxldty 1n rat and hamster hepatocyte DNA
repair assay. Environ. Mutagen. 7(suppl. 3): 70.
Kuratsune, M. and N. Takemura. 1969. Occupational cancer. .In,: Occupa-
tional Health In Japan, H. K1ta, Ed. Tokyo, Organizing Committee of the
Sixteenth International Congress on Occupational Health, p. 62-68. (Cited
1n NIOSH, 1978)
Lapp, T.W., T.L. Ferguson, H. Gadberry, F. Haffmelster and F. Hopkins.
1981. Materials balance for dyes and pigments from benzldlne and three
benzldlne derivatives. Office of Toxic Substances, U.S. EPA, Washington,
DC. EPA 560/2-81-001. NTIS PB81 224289.
0857p -40- 06/10/87
-------
Lazear, E.J. and S.C. Louie. 1977. Mutagenlclty of some congeners of
benzldlne 1n the Salmonella typhlmuMum assay system. Cancer Lett. 4(1):
21-26.
Lowry, L.K., W.P. Tolos, M.F. Boenlger, C.R. Nony and M.C. Bowman. 1980.
Chemical monitoring of urine from workers potentially exposed to benzldlne
Drives azo dyes. Toxlcol. Lett. 7(1): 29-36.
Lurle, A.P. 1964. Tol1d1nes. In.: K1rk-0thmer Encyclopedia of Chemical
Technology, Vol. 3, 2nd ed., A. Standen, Ed. John Wiley and Sons, Inc., New
York. p. 414.
Lyman, W.3., W.F. Reehl and O.H. Rosenblatt. 1982. Handbook of Chemical
Property Estimation Methods. McGraw-Hill Book Co., New York. p. 2-14, 4-9,
5-5, 7-4.
MacAlplne, J.B. 1947. Papllloma of the renal pelvis 1n dye workers Two
cases, one of which shows bilateral growths. Br. J. Surg. 35: 137-140.
Martin, C.N., A.C. McOermld and R. Garner. 1978. Testing of known carcino-
gens and noncarclnogens for their ability to Induce unscheduled DNA synthe-
sis In hela cells. Cancer Res. 38: 2621-2627.
Melgs, 3.W., L.3. Sclarlnl and W.A. Van Sandt. 1954. Skin penetration by
dlamlnes of the benzldlne group. Arch. Industr. Hyg. 9: 122.
0857p -41- 06/10/87
-------
Mennear, Or. 1987. National Toxicology Program, Washington, DC. Personal
communication with Dr. C. Hlremath, Carcinogen Assessment Group, Washington,
DC. May.
Neely, W.B. and G.E. Blau. 1985. .In.: Environmental Exposure from Chemi-
cals. Vol. 1. CRC Press Inc., Boca Raton, FL. p. 30-31.
NIOSH (National Institute for Occupational Safety and Health). 1978.
Criteria for a Recommended Standard...Occupational Exposure to o-Tol1d1ne.
U.S. DHEW, PHS, CDC, Rockvllle, HD. Publ. No. 78-79. NTIS PB81-227084.
88 p.
NIOSH (National Institute for Occupational Safety and Health). 1980.
Special Occupational Hazard Review for Benzldlne Based Dyes. U.S. DHEW,
PHS, CDC, Rockvllle, MD. Publ. No. 80-109.
N1sh1oka, H. and H. Ogasauara. 1978. Mutagenlclty testing for dlphenyl
derivatives 1n bacterial systems. Mutat. Res. 54: 248-249.
NTP (National Toxicology Program). 1986. Management Status Report.
OSHA/NIOSH (Occupational Safety and Health Administration/National Institute
for Occupational Safety and Health). 1980. Health Hazard Alert: Benzldlne,
o-To!1d1ne and o-D1an1s1d1ne-Based Dyes. DHHS (NIOSH) Publ. No. 81-106.
Parrls, G.E. 1980. Covalent binding of aromatic amines to humates. 1.
Reactions with carbonyls and qulnones. Environ. Sc1. Technol. 14(9):
1099-1106.
0857p -42- 06/10/87
-------
PUss, G.B. 1963. On some regular relationships between cardnogenldty of
ara1nod1phenyl derivatives and the structure of substance. Acta Un. Int.
Cancer. 19: 499.
PUss, G.B. 1965. Concerning carclnogenous properties of ortho-toUdlne
and d1an1s1d1ne. Gig. Tr. Prof. Zabol. 9: 18. (Cited In IARC, 1972)
PUss, G.B. and N.I. VoVfson. 1973. Cardla rhabdomyosarcoma Inducted 1n a
rat under the action of o-to11d1ne. Vop. Onkol. 19(3): 98-99. (CA
79:1170y)
PUss, G.B. and M.A. Zabezhlnsky. 1970. Properties of orthotolldlne
(3,3'-d1methylbenz1d1ne). J. Natl. Cancer Inst. 45: 283.
Powell, R., M. Murray, C. Chen and A. Lee. 1979. Survey of the manufac-
ture, Import and uses for benzldlne related substances and related sub-
stances and related dyes and pigments. Office of Toxic Substances, U.S.
EPA, Washington, DC. EPA-560/13-79-005.
Prlval, N.J., S.J. Bell, V.D. Mitchell, M.D. Pelperl and V.L. Vaughan.
1984. Mutagen1c1ty of benzldlne and benzldlne-congener dyes and selected
monoazo dyes In a modified Salmonella assay. Mutat. Res. 136(1): 33-47.
Reid, T.M., C.Y. Wang, C.M. King and K.C. Morton. 1984a. MutagenlcHy of
some benzldlne congeners and their N-acetylated and N,N'-d1acetylated
derivatives 1n different strains of Salmonella typhlmurlum. Environ.
Mutagen. 6(2): 145-151.
0857p -43- 06/10/87
-------
Reid, T.M., K.C. Morton, C.Y. Wang and C.M. King. 19845. Mutagenlclty of
azo dyes following metabolism by different reductlve/oxldatlve systems.
Environ. Mutagen. "6: 705-717.
Sadtler. n.d. Sadtler Standard Spectra. Sadtler Research Laboratory,
Philadelphia, PA.
Saff1ott1, U., F. Cefls, R. Montesano and A.R. Sellakumar. 1967. Induction
of bladder cancer 1n hamsters fed aromatic amines. ITK Bladder Cancer. A
Symposium, W. Delchmann and K.F. Lampe, Ed. Aesculapius, Birmingham, AL.
p. 129.
Schmltz, G. and H. Rooze. 1981. Reaction mechanisms for chlorite and
chlorine dioxide. 1. Sto1ch1ometry of chlorite reaction and kinetics 1n the
presence of ortho-toluldlne. Can. J. Chem. 59(8): 1177-1187.
Seller, O.P. 1977. Inhibition of testlcular DNA synthesis by chemical
mutagens and carcinogens. Preliminary results 1n the validation of a novel
short term test. Mutat. Res. 46: 305-310.
Sellakumar, A.R., R. Montesano and U. Saff1ott1. 1969. Aromatic amines
cardnogenldty In hamsters. Proc. Am. Assoc. Cancer Res. 10: 78.
Sololmskaya, E.A. 1970. Activity of some enzymes during the poisoning of
animals with carcinogenic aminodlphenyl-compounds. Vopr. Onkol. 16(4):
94-98. (CA 12:2255h)
0857p -44- 06/10/87
-------
Spitz, S., W.H. Magulgan and K.DobMner. 1950. The carcinogenic action of
benzldlne. Cancer. 3: 789-804.
SRI (Stanford Research Institute). 1986. 1986 Directory of Chemical
Producers: United States of America. SRI International, Menlo Park, CA.
Swann, R.L., O.A. Laskowskl, P.J. McCall, K. Vander Kuy and H.J. Olshburger.
1983. A rapid method for the estimation of the environmental parameters
octanol/water partition coefficient, soil sorptlon constant, water to air
ratio and water solubility. Residue Rev. 85: 17-28.
Tsuruta, Y., P.O. Josephy, A.D. Rahlmtula and P.J. O'Brien. 1985.
Peroxldase-catalyzed benzldlne binding to DNA and other macromolecules.
Chem.-81ol. Interact. 54(2): 143-158.
U.S. EPA. 1977. Computer print-out of non-confidential production data
from TSCA Inventory. OPTS, CID, U.S. EPA, Washington, DC.
U.S. EPA. 1979. Water-Related Environmental Fate of 129 Priority
Pollutants. Vol. II. Office of Water Planning and Standards, Office of
Water and Waste Management, U.S. EPA, Washington, DC. EPA 440/4-79-029b.
U.S. EPA. 1980.. Preliminary Risk Assessment: Phase I. Benzldlne, Us
congeners and their derivative dyes and pigments. Office of Pesticides and
Toxic Substances, Washington, DC. EPA 560/11-80-019.
0857p -45- 06/10/87
-------
U.S. EPA. 1981. Notice: EPA 1n Response to ITC Recommendations, decides
not to require additional testing of benzldlne, o-to11d1ne and o-d1an1s1-
dlne-based dye for health and environmental effects. Federal Register. 46:
55004.
U.S. EPA. 1986a. Technical Support Document and Summary Table for the
Ranking of Hazardous Chemicals Based on Cardnogenldty. Prepared by the
Office of Health and Environmental Assessment, Carcinogen Assessment Group,
Washington, DC for the Office of Solid Haste, Washington, DC.
U.S. EPA. 1986b. Graphical Exposure Modeling System (GEMS). Fate of
Atmospheric Pollutants (FAP). Office of Toxic Substances, U.S. EPA,
Washington, DC.
U.S. EPA. 1986c. Guidelines for MutagenlcHy Risk Assessment. Federal
Register. 51(185): 34006-34012.
USITC (U.S. International Trade Commission). 1984. Imports of Benzenold
Chemical and Products, 1983. USITC Publ. 1548, Washington, DC.
USITC (U.S. International Trade Commission). 1985. Synthetic Organic
Chemicals United States Production and Sales, 1984. USITC Publ. 1745,
Washington, DC.
Valencia, R., J.M. Mason, R.C. Woodruff and S. Z1mmer1ng. 1985. Chemical
mutagenesls testing In Drosophlla. III. Results of 48 coded compounds test-
ed for the National Toxicology Program. Environ. Mutagen. 7(3): 325-348.
0857p -46- 06/22/87
-------
Waalkens, D.H., H.F.P. Joosten, T.O. Via and A. Hoekstra. 1981. Mutagenlc-
1ty studies with o-to!1d1ne and 4,4'-tetramethyld1am1nod1phenylmethane.
Mutat. Res. 89(3): 197-202.
Wilson, J.G. 1955. Teratogenlc activity of several azo dyes chemically
related to trypan blue. Anat. Rec. 123: 313-334.
Wlndolz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co., Inc.,
Rahway, N3. p. 1362.
Wise, R.W., T.V. Zenger, F.F. Kadlubar and B.B. Davis. 1984. Metabolic
activation of carcinogenic aromatic amines by dog bladder and kidney prosta-
glandln H synthase. Cancer Res. 44(5): 1893-1897.
0857p -47- 06/10/87
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APPENDIX
LITERATURE SEARCHED
This profile 1s based on data Identified by computerized literature
searches of the following:
GLOBAL
TSCATS
CASR online (U.S. EPA Chemical Activities Status Report)
CAS online STN International
TOXLINE
TOXBACK 76
TOXBACK 65
RTECS
OHM TADS
STORET
SRC Environmental Fate Data Bases
SANSS
AQUIRE
TSCAPP
NTIS
Federal Register
These searches were conducted 1n April, 1986. In addition, hand searches
were made of Chemical Abstracts (Collective Indices 6 and 7), and the
following secondary sources were reviewed:
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1986. Documentation of the Threshold Limit Values and Biological
Exposure Indices, 5th ed. Cincinnati, OH.
ACGIH (American Conference of Governmental Industrial Hyglenlsts).
1985-1986. TLVs: Threshold L1mU Values for Chemical Substances
and Physical Agents 1n the Workroom Environment with Intended
Changes for 1985-1986. Cincinnati, OH. 114 p.
Clayton, G.D." and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2A. John Wiley and
Sons, NY. 2878 p.
Clayton, G.D. and F.E. Clayton, Ed. 1981. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2B. John WHey and
Sons, NY. p. 2879-3816.
0857p -48- 06/10/87
-------
Clayton, G.O. and F.E. Clayton, Ed. 1982. Patty's Industrial
Hygiene and Toxicology, 3rd rev. ed., Vol. 2C. John WHey and
Sons, NY. p. 3817-5112.
Grayson, H. and D. Eckroth, Ed. 1978-1983. Klrk-Othmer Encyclo-
pedia of Chemical Technology, 3rd ed. John WHey and Sons, NY. 23
Volumes.
Hamilton, A. and H.L. Hardy. 1974. Industrial Toxicology, 3rd ed.
Publishing Sciences Group, Inc., Littleton, MA. 575 p.
IARC (International Agency for Research on Cancer). IARC Mono-
graphs on the Evaluation of Carcinogenic Risk of Chemicals to
Humans. WHO, IARC, Lyons, France.
ITII (International Technical Information Institute). 1982. Toxic
and Hazardous Industrial Chemicals Safety Manual for Handling and
Disposal with Toxldty and Hazard Data. ITII, Tokyo, Japan. 700 p.
Jaber, H.M., W.R. Mabey, S.T. Liu, T.W. Chow and H.L. Johnson.
1984. Data aqulsltlon for environmental transport and fate screen-
Ing for compounds of Interest In the Office of Solid Waste. EPA
600/6-84-010. NTIS PB84-243906. SRI International, Menlo Park, CA.
NTP (National Toxicology Program). 1986. Toxicology Research and
Testing Program. Chemicals on Standard Protocol. Management
Status.
Ouellette, R.P. and J.A. King. 1977. Chemical Week Pesticide
Register. McGraw-Hill Book Co., NY.
Sax, N.I. 1979. Dangerous Properties of Industrial Materials, 5th
ed. Van Nostrand Relnhold Co., NY.
SRI (Stanford Research Institute). 1984. Directory of Chemical
Producers. Menlo Park, CA.
U.S. EPA. 1985. Status Report on Rebuttable Presumption Against
Registration (RPAR) or Special Review Process. Registration Stan-
dards and the Data Call 1n Programs. Office of Pesticide Programs,
Washington, DC.
U.S. EPA. 1985. CSB Existing Chemical Assessment Tracking System.
Name and CAS Number Ordered Indexes. Office of Toxic Substances,
Washington, DC.
USITC (U.S. International Trade Commission). 1983. Synthetic
Organic Chemicals. U.S. Production and Sales, 1982, USITC Publ.
1422, Washington, DC.
Verschueren, K. 1983. Handbook of Environmental Data on Organic
Chemicals. 2nd ed. Van Nostrand Relnhold Co., NY.
0857p -49- 06/10/87
-------
U.S. Environmental Protection Agency.
Region V, Library -
230 South Dearborn Street ^
Chicago, Illinois 60604
-------
Wlndholz, M., Ed. 1983. The Merck Index, 10th ed. Merck and Co.,
Inc., Rahway, NJ.
Worthing, C.R. and S.B. Walker, Ed. 1983. The Pesticide Manual.
British Crop Protection Council. 695 p.
In addition, approximately 30 compendia of aquatic toxldty data were
reviewed, Including the following:
Battelle's Columbus Laboratories. 1971. Water Quality Criteria
Data Book. Volume 3. Effects of Chemicals on Aquatic Life.
Selected Data from the Literature through 1968. Prepared for the
U.S. EPA under Contract No. 68-01-0007. Washington, DC.
Johnson, W.W. and M.T. Mnley. 1980. Handbook of Acute Toxldty
of Chemicals to Fish and Aquatic Invertebrates. Summaries of
Toxldty Tests Conducted at Columbia National Fisheries Research
Laboratory. 1965-1978. U.S. Dept. Interior, Fish and Wildlife
Serv. Res. Publ. 137, Washington, DC.
McKee, J.E. and H.W. Wolf. 1963. Water Quality Criteria, 2nd ed.
Prepared for the Resources Agency of California, State Water
Quality Control Board. Publ. No. 3-A.
Plmental, D. 1971. Ecological Effects of Pesticides on Non-Target
Species. Prepared for the U.S. EPA, Washington, DC. PB-269605.
Schneider, B.A. 1979. Toxicology Handbook. Mammalian and Aquatic
Data. Book 1: Toxicology Data. Office of Pesticide Programs, U.S.
EPA, Washington, DC. EPA 540/9-79-003. NTIS PB 80-196876.
0857p -50- 06/10/87
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